[go: up one dir, main page]

WO2002017912A1 - Endothelin antagonists - Google Patents

Endothelin antagonists Download PDF

Info

Publication number
WO2002017912A1
WO2002017912A1 PCT/US2001/027220 US0127220W WO0217912A1 WO 2002017912 A1 WO2002017912 A1 WO 2002017912A1 US 0127220 W US0127220 W US 0127220W WO 0217912 A1 WO0217912 A1 WO 0217912A1
Authority
WO
WIPO (PCT)
Prior art keywords
trans
benzodioxol
carboxylic acid
ethyl
pyrrohdine
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/US2001/027220
Other languages
French (fr)
Inventor
Martin Winn
Steven A. Boyd
Charles W. Hutchins
Jae Hwan-Soo
Andrew S. Tasker
Tomas W. Von Geldern
Jeffrey Kester
Bryan K. Sorensen
Bruce G. Szczepankiewicz
Kenneth Henry
Gang Liu
Steven J. Wittenberger
Steven A. King
Todd J. Janus
Robert J. Padley
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Abbott Laboratories
Original Assignee
Abbott Laboratories
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from US09/653,563 external-priority patent/US7208517B1/en
Application filed by Abbott Laboratories filed Critical Abbott Laboratories
Publication of WO2002017912A1 publication Critical patent/WO2002017912A1/en
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives

Definitions

  • the present invention relates to compounds which are endothelin antagonists, processes for making such compounds, synthetic intermediates employed in these processes and methods and compositions for antagonizing endothelin.
  • ET Endothelin
  • Big ET precursor peptide big endothelin
  • ECE endothelin converting enzyme
  • Endothelin has been shown to constrict arteries and veins, increase mean arterial blood pressure, decrease cardiac output, increase cardiac contractility in vitro, stimulate mitogenesis in vascular smooth muscle cells in vitro, contract non-vascular smooth muscle including guinea pig trachea, human urinary bladder strips and rat uterus in vitro, increase airway resistance in vivo, induce formation of gastric ulcers, stimulate release of atrial natriuretic factor in vitro and in vivo, increase plasma levels of vasopressin, aldosterone and catecholamines, inhibit release of renin in vitro and stimulate release of gonadotropins in vitro.
  • vasoconstriction is caused by binding of endothelin to its receptors on vascular smooth muscle (Nature 332 411 (1988), FEBS Letters 23! 440 (1988) and Biochem. Biophys. Res. Commun. 154 868 (1988)).
  • An agent which suppresses endothelin production or an agent which binds to endothelin or which inhibits the binding of endothelin to an endothelin receptor will produce beneficial effects in a variety of therapeutic areas.
  • an anti-endothelin antibody has been shown, upon intrarenal infusion, to ameliorate the adverse effects of renal ischemia on renal vascular resistance and glomerular filtration rate (Kon, et al., J. Clin.
  • an anti-endothelin antibody attenuated the nephrotoxic effects of intravenously administered cyclosporin (Kon, et al., Kidney Int. 37 1487 (1990)) and attenuated infarct size in a coronary artery ligation- induced myocardial infarction model (Watanabe, et al., Nature 344 114 (1990)).
  • Z is -C(Ri 8 )(Ri9)- or -C(O)- wherein Ris and R19 are independently selected from hydrogen and loweralkyl; n is 0 or 1;
  • R is -(CH2) m -W wherein m is an integer from 0 to 6 and W is (a) -C(O)2-G wherein G is hydrogen or a carboxy protecting group,
  • Ri and R2 are independently selected from hydrogen, loweralkyl, alkenyl, alkynyl, alkoxyalkyl, alkoxycarbonylalkyl, hydroxyalkyl, haloalkyl, haloalkoxyalkyl, alkoxyalkoxyalkyl, thioalkoxyalkoxyalkyl, cycloalkyl, cycloalkylalkyl, aminocarbonylalkyl, alkylaminocarbonylalkyl, dialkylaminocarbonylalkyl, aminocarbonylalkenyl, alkylaminocarbonylalkenyl, dialkylaminocarbonylalkenyl, hydroxyalkenyl, aryl, arylalkyl, aryloxyalkyl, arylalkoxyalkyl, (N-alkanoyl-N-alkyl)aminoalkyl, alkylsulfonylamidoalkyl, heterocyclic, (hetero
  • R 3 is (a) R4-C(O)-R 5 - , R4- sa- , R4- O)- R 5 -N(R 6 )- , R 6 -S(O) 2 -R 7 - or R 26 -S(O)-R 2 7- wherein R5 is (i) a covalent bond, (ii) 'alkylene, (iii) alkenylene, (iv) -N(R 2 o)-Rs- or -R 8a -N(R 20 )-R 8 - wherein Rs and R 8a are independently selected from the group consisting of alkylene and alkenylene and R20 is hydrogen, loweralkyl, alkenyl, haloalkyl, alkoxyalkyl, haloalkoxyalkyl, cylcoalkyl or cycloalkylalkyl or (v) -O-R9- or -R 9a ⁇ O-R 9 -
  • R5a is (i) alkylene or (ii) alkenylene;
  • R7 is (i) a covalent bond, (ii) alkylene, (iii) alkenylene or (iv) -N(R2i)-R ⁇ o- or -R 10a -N(R2i)-R ⁇ o- wherein Rio and R 10a are independently selected from the group consisting of alkylene and alkenylene and R 2 1 is hydrogen, loweralkyl, alkenyl, haloalkyl, alkoxyalkyl, haloalkoxyalkyl, aryl or arylalkyl; R4 and R are independently selected from the group consisting of
  • Ri ⁇ a and R ⁇ 2a are independently selected from alkyl and the other is aryl;
  • R26 is (i) loweralkyl, (ii) haloalkyl, (iii) alkenyl, (iv) alkynyl, (v) cycloalkyl,
  • R22-O-C(O)-R 23 - wherein R22 is a carboxy protecting group or heterocycHc and R23 is (i) a covalent bond, (ii) alkylene, (iii) alkenylene or
  • a preferred embodiment of the invention is a compound of formula (II)
  • substituents -R2, -R and -Ri exist in a trans, trans relationship and Z, n, R, Ri, R2, and R 3 are as defined above.
  • Another preferred embodiment of the invention is a compound of formula (I) or (II) wherein n is 0 and Z is -CH2-.
  • Another preferred embodiment of the invention is a compound of formula (I) or (II) wherein n is 1 and Z is -CH2-.
  • Another preferred embodiment of the invention is a compound of formula (I) or (II) wherein n is 0, Z is -CH2-, and R3 is R4-C(O)-Rs- , R ⁇ -S(O)2-R7- or R 6-S(O)-R27- wherein R , R 5 , R 6 , R 7 , R 26 and R 7 are as defined above.
  • Another preferred embodiment of the invention is a compound of formula (I) or (II) wherein n is 0, Z is -CH2-, and R3 is alkoxyalkyl or alkoxyalkoxyalkyl.
  • n is zero;
  • Z is -C(Ri 8 )(Ri 9 )- wherein Rig and R 19 are hydrogen;
  • R is -C(O) 2 -G wherein G is hydrogen
  • Ri is aryl substituted with one substituent selected from alkoxy and alkoxyalkoxy;
  • R 2 is heterocycle which is 1,3-benzodioxyl
  • R 3 is R 4 -C(O)-R 5 wherein R 5 is methylene and R 4 is selected from (Rn)(Ri 2 )N- and
  • Rn and R 12 is hydrogen and the other is selected from arylalkyl and diarylalkyl, wherein each aryl group of the diarylalkyl is substituted with one or two alkyl substituents; and
  • Rna or Ri 2a is alkyl and the other is aryl;
  • Another preferred embodiment of the invention is a compound of formula (I) or formula (II) wherein n is zero; Z is -C(R ⁇ g)(Ri 9 )- wherein Rig and R 19 are hydrogen; R is - C(O) 2 -G wherein G is hydrogen; Ri is aryl substituted with one substituent selected from methoxy, methoxyethoxy, and isopropoxyethoxy; R 2 is l,3-benzodiox-5-yl; R 3 is R 4 -C(O)- R 5 wherein R 5 is methylene and R 4 is selected from (Ru)(Ri 2 )N- and (Rn a )(Ri 2a )N-N(H)- wherein one of Rn and R 12 is hydrogen and the other is selected from arylalkyl and diarylalkyl wherein each aryl group of the diarylalkyl is substituted with methyl or ethyl, and one of Rn a or R ⁇ 2a
  • Another preferred embodiment of the invention is a compound of formula (I) or formula (II) wherein n is zero; Z is -C(Ri 8 )(Ri 9 )- wherein Rig and R 19 are hydrogen; R is - C(O) 2 -G wherein G is hydrogen; Ri is phenyl substituted with one substituent selected from methoxy, methoxyethoxy, and isopropylethoxy; R 2 is l,3-benzodiox-5-yl; R 3 is R 4 -C(O)-Rs wherein R5 is methylene and R4 is selected from (R ⁇ )(R ⁇ 2 )N- and (R ⁇ a )(Ri 2a )N-N(H)- wherein one of Rn and R 12 is hydrogen and the other is selected from phenylalkyl and diphenylalkyl wherein each phenyl group of the diphenylalkyl is substituted with methyl or ethyl, and one of
  • a more preferred embodiment of the invention is a compound of formula (I) or (II) wherein n is 0, Z is -CH 2 -, and R3 is R 4 -C(O)-R 5 - wherein R 4 is (Rn)(R l2 )N- as defined above and R5 is alkylene or R3 is R6-S(O) 2 -R 7 - or R 2 6- (O)-R 27 - wherein R7 is alkylene, R 27 is alkylene and R ⁇ and R 2 6 are defined as above.
  • Another more preferred embodiment of the invention is a compound of formula (I) or (II) wherein n is 0, Z is -CH 2 - and R 3 is R4-C(O)-N(R 2 o)-R8- or R 6 -S(O)2-N(R 2 ⁇ )-R ⁇ o- wherein Rs and Rio are alkylene and R 4 , R ⁇ , R 20 and R 2 1 are defined as above.
  • An even more preferred embodiment of the invention is a compound of formula (I) or (II) wherein n is 0, R is tetrazolyl or -C(O) 2 -G wherein G is hydrogen or a carboxy protecting group or R is tetrazolyl or R is -C(O)-NHS(O) 2 R 16 wherein R 16 is loweralkyl, haloalkyl or aryl, Z is -CH 2 -, Ri and R 2 are independently selected from (i) loweralkyl, (ii) cycloalkyl, (iii) substituted aryl wherein aryl is phenyl substituted with one, two or tliree substituents independently selected from loweralkyl, alkoxy, halo, alkoxyalkoxy and carboxyalkoxy, (iv) substituted or unsubstituted heterocyclic, (v) alkenyl, (vi) heterocyclic (alkyl), (vii) arylalkyl
  • R3 is R 4 -C(O)-Rs- wherein R 4 is (Rn)(Ri 2 )N- wherein R n and R 12 are independently selected from loweralkyl, haloalkyl, alkoxyalkyl, haloalkoxyalkyl, aryl, arylalkyl, heterocyclic, hydroxyalkyl, alkoxy, aminoalkyl, and trialkylaminoalkyl, and R 5 is alkylene; or R3 is R4-C(O)-N(R2o)-R8- or R6-S(O) 2 -N(R2i)-R ⁇ o- wherein R4 is loweralkyl, aryl, alkoxy, alkylamino, aryloxy or arylalkoxy and
  • a yet more preferred embodiment of the invention is a compound of formula (I) or (II) wherein n is 0, R is -C(O) 2 -G wherein G is hydrogen or a carboxy protecting group, tetrazolyl or -C(O)-NHS(O) 2 R 16 wherein R 16 is loweralkyl, haloalkyl or aryl, Z is -CH 2 -, Ri is (i) loweralkyl, (ii) alkenyl, (iii) alkoxyalkyl, (iv) cycloalkyl, (v) phenyl, (vi) pyridyl, (vii) furanyl,(viii) substituted or unsubstituted 4-methoxyphenyl, 4-fluorophenyl, 3 -fluorophenyl, 4-ethoxyphenyl, 4-ethylphenyl, 4-methylphenyl, 4-trifluoromethylphenyl, 4-pentafluoroeth
  • Another yet more preferred embodiment of the invention is a compound of formula (I) or (II) wherein n is 0, R is -C(O) 2 -G wherein G is hydrogen or a carboxy protecting group, tetrazolyl or -C(O)-NHS(O) 2 R 16 wherein R 16 is loweralkyl, haloalkyl or aryl, Z is -CH 2 -, Ri is (i) loweralkyl, (ii) alkenyl, (i ⁇ ) alkoxyalkyl, (iv) cycloalkyl, (v) phenyl, (vi) pyridyl, (vii) furanyl,(v ⁇ i) substituted or unsubstituted 4-methoxyphenyl, 4-fluorophenyl, 3-fluorophenyl, 4-ethoxyphenyl, 4-ethylphenyl, 4-methylphenyl, 4-trifluoromethylphenyl, 4-pentafluoroethyl
  • 1,3-benzodioxolyl 7-methoxy-l,3-benzodioxolyl, 1,4-benzodioxanyl, 8-methoxy- 1,4-benzodioxanyl, dihydrobenzofuranyl, benzofurnayl,
  • R 3 is R 4 -C(O)-R 5 - wherein R 5 is alkylene and R 4 is (R ⁇ )(R- l2.
  • N- wherein R- ⁇ and R 12 are independently selected from loweralkyl, haloalkyl, alkoxyalkyl, haloalkoxyalkyl, aryl, arylalkyl, heterocyclic, hydroxyalkyl, alkoxy, aminoalkyl, and tiialkylaminoalkyl.
  • Another yet more preferred embodiment of the invention is a compound of formula (I) or (II) wherein n is 0, R is -C(O) 2 -G wherein G is hydrogen or a carboxy protecting group, tetrazolyl or -C(O)-NHS(O) 2 R 16 wherein R 16 is loweralkyl, haloalkyl or aryl, Z is -CH 2 -, Ri is (i) loweralkyl, ( ⁇ ) alkenyl, (iii) heterocyclic (alkyl), (iv) aryloxyalkyl, (v) arylalkyl, (vi) aryl, (vii) (N-alkanoyl-N-alkyl)aminoalkyl, or (viii) alkylsulfonylamidoalkyl, R 2 is substituted or unsubstituted 1,3-benzodioxolyl, 7-methoxy-l,3-benzodioxoly
  • Another yet more preferred embodiment of the invention is a compound of formula (I) or (II) wherein n is 0, R is -C(O)2-G wherein G is hydrogen or a carboxy protecting group, tetrazolyl or -C(O)-NHS(O) 2 R 16 wherein R 16 is loweralkyl, haloalkyl or aryl, Z is -CH2-, Ri is (i) loweralkyl, (ii) alkenyl, (iii) heterocyclic (alkyl), (iv) aryloxyalkyl, (v) arylalkyl, (vi)
  • N-alkanoyl-N-alkyl)aminoalkyl or (vii) alkylsulfonylamidoalkyl,(vii) phenyl, or (ix) substituted or unsubstituted 4-methoxyphenyl, 3-fluoro-4-methoxyphenyl, 3 -fluorophenyl,
  • Another yet more preferred embodiment of the invention is a compound of formula (I) or (II) wherein n is 0, R is -C(O)2-G wherein G is hydrogen or a carboxy protecting group, tetrazolyl or -C(O)-NHS(O) 2 R 16 wherein R 16 is loweralkyl, haloalkyl or aryl, Z is -CH 2 -, Ri is (i) substituted or unsubstituted 4-methoxyphenyl, 3-fluoro-4 ⁇ methoxyphenyl, 3- fluorophenyl, 3-fluoro-4-ethoxyphenyl, 4-methoxymethoxyphenyl, 1,3-benzodioxolyl or
  • 1,4-benzodioxanyl wherein the substituent is selected from loweralkyl, haloalkyl, alkoxy and alkoxyalkoxy, (ii) loweralkyl, (iii) alkenyl, (iv) heterocyclic (alkyl), (v) aryloxyalkyl, (vi) arylalkyl, (vii) (N-alkanoyl-N-alkyl)aminoalkyl, (viii) alkylsulfonylamidoalkyl,or (ix) phenyl, R 2 is substituted or unsubstituted 1,3-benzodioxolyl, 7-methoxy-l,3-benzodioxolyl,
  • 1,4-benzodioxanyl 8-methoxy- 1,4-benzodioxanyl, dihydrobenzofuranyl, 4-methoxyphenyl, dimethoxyphenyl, fluorophenyl or difluorophenyl wherein the substituent is selected from loweralkyl, alkoxy and halogen and R3 is alkoxycarbonyl or R6-S(O) 2 -N(R2i)-R ⁇ o- wherein Rio is alkylene, R is loweralkyl, haloalkyl, alkoxyalkyl or haloalkoxyalkyl and R21 is loweralkyl, haloalkyl, alkoxyalkyl or haloalkoxyalkyl.
  • Another yet more preferred embodiment of the invention is a is a compound of formula (I) or (II) wherein n is 0, R is -C(O)2-G wherein G is hydrogen or a carboxy protecting group, tetrazolyl or -C(O)-NHS(O) 2 R 16 wherein R 16 is loweralkyl or haloalkyl, Z is -CH2-, Ri is loweralkyl,alkenyl, heterocyclic (allkyl), aryloxyalkyl, aryalkyl, aryl, (N- alkanoyl-N-alkyl) aminoalkyl,, or alkylsulfonylamidoalkyl, and R3 is R4-C(O)-R5- wherein R5 is alkylene and R4 is (Rn)(Ri2)N- wherein R ⁇ and R 12 are independently selected from alkyl, aryl, hydroxyalkyl, alkoxy, aminoalkyl, trialkylaminoalky
  • a still more preferred embodiment of the invention is a compound of formula (I) or
  • R is -C(O)2-G wherein G is hydrogen or a carboxy protecting group, tetrazolyl or -C(O)-NHS(O) 2 R 16 wherein R 16 is loweralkyl or haloalkyl, Z is -CH2-, Ri is substituted or unsubstituted 4-methoxyphenyl, 4-fluorophenyl, 2-fluorophenyl, 4- methylphenyl, 4-trifluoromethylphenyl, 4-pentafluoroethylphenyl, 4-methoxymethoxyphenyl, 4-hydroxyphenyl, 4-ethylpl ⁇ enyl, 1,3-benzodioxolyl, 1,4- benzodioxanyl or dihydrobenzofuranyl wherein the substituent is selected from alkoxy, alkoxyalkoxy and carboxyalkoxy, (ii) loweralkyl, (iii) alkenyl, (i
  • R is -C(O)2-G wherein G is hydrogen or a carboxy protecting group, tetrazolyl or -C(O)-NHS(O) 2 R 16 wherein R 16 is loweralkyl or haloalkyl, Z is -CH2-, Ri is loweralkyl, alkenyl, heterocyclic (alkyl), aryloxyalkyl, arylalkyl, (N-alkanoyl-N- alkyl)aminoalkyl, alkylsulfonylamidoalkyl, phenyl, or alkoxyalkyl, R 2 is 1,3-benzodioxolyl, 1,4-benzodioxanyl, dihydrobenzofuranyl, benzofuranyl, 4-methoxyphenyl, dimethoxyphenyl, fluorophenyl or difluorophenyl and R 3 is R4-C(O)-R
  • a most highly preferred embodiment of the invention is a compound of formula (I) or
  • R is -C(O) 2 -G wherein G is hydrogen or a carboxy protecting group, Z is -CH2-, Ri is substituted or unsubstituted 4-methoxyphenyl, 4-fluorophenyl, 2-fluorophenyl, 4-methylphenyl, 4-trifluoromethylphenyl, 4-pentafluoroethylphenyl, 4-methoxymethoxyphenyl, 4-hydroxyphenyl, 4-ethylphenyl, 1,3-benzodioxolyl, 1,4- benzodioxanyl or dihydrobenzofuranyl wherein the substituent is selected from alkoxy, alkoxyalkoxy and carboxyalkoxy, R 2 is 1,3-benzodioxolyl, 1,4-benzodioxanyl, dihydrobenzofuranyl, benzofuranyl, 4-methoxyphenyl, dimethoxyphenyl, fluorophen
  • Another most highly preferred embodiment of the invention is a compound of formula (I) or (II) wherein n is 0, R is -C(O)2-G wherein G is hydrogen or a carboxy protecting group, Z is -CH2-, Ri is substituted or unsubstituted 4-methoxyphenyl, 4- fluorophenyl, 2-fluorophenyl, 4-methylphenyl, 4-trifluoromethylphenyl, 4- pentafluoroethylphenyl, 4-methoxymethoxyphenyl, 4-hydroxyphenyl, 4-ethylphenyl, 1,3-benzodioxolyl, 1,4- benzodioxanyl or dihydrobenzofuranyl wherein the substituent is selected from alkoxy, alkoxyalkoxy and carboxyalkoxy, R 2 is 1,3-benzodioxolyl, 1,4-benzodioxanyl, dihydrobenzofuranyl, benzofuranyl, 4-meth
  • Another most highly preferred embodiment of the invention is a compound of formula (I) or (II) wherein n is 0, R is -C(O)2-G wherein G is hydrogen or a carboxy protecting group, Z is -CH2-, Ri is substituted or unsubstituted 4-methoxyphenyl, 3-fluoro- 4-methoxyphenyl, 3 -fluorophenyl, 2-fluorophenyl, 3-fluoro-4-ethoxyphenyl, 4- methoxymethoxyphenyl,
  • Another most highly preferred embodiment of the invention is a compound of formula (I) or (II) wherein n is 0, R is -C(O)2-G wherein G is hydrogen or a carboxy protecting group, Z is -CH2-, Ri is substituted or unsubstituted 4-methoxyphenyl, 3-fluoro-4- methoxyphenyl, 3 -fluorophenyl, 2-fluorophenyl, 3-fluoro-4-ethoxyphenyl, 4-methoxymethoxyphenyl, 1,3- benzodioxolyl, 1,4-benzodioxanyl or dihydrobenzofuranyl wherein the substituent is selected from loweralkyl, haloalkyl, alkoxy, alkoxyalkoxy and carboxyalkoxy, R 2 is substituted or unsubstituted 1,3-benzodioxolyl, 7-methoxy-l,3-benzodioxolyl, 1,4-benzodi
  • R is -C(O)2-G wherein G is hydrogen or a carboxy protecting group, Z is -CH2-, Ri is loweralkyl,alkenyl, heterocyclic (alkyl), aryloxyalkyl, aryalkyl, aryl, (N-alkanoyl-N-alkyl)aminoalkyl, or alkylsulfonylamidoalkyl, and R 3 is R4-C(O)-R5- wherein R5 is alkylene and R4 is (Rn)(Ri2)N- wherein R and R 12 are independently selected from alkyl, aryl, hydroxyalkyl, alkoxy, aminoalkyl, trialkylaminoalkyl, and heterocyclic, with the proviso that one or R and R 12 is alkyl.
  • Another most highly preferred embodiment of the invention is a compound of formula (I) or (II) wherein n is 0, Z is -CH2-, and R3 is R_j.-C(O)-R5- wherein R4 is (Rll)(Rl2)N- as defined therein and R5 is alkylene.
  • Another most highly preferred embodiment of the invention is a compound of formula (I) or (II) wherein n is 0, Z is -CH2-, Rl is loweralkyl, and R3 is R4-C(O)-Rs- wherein R4 is (Ri ⁇ )(Ri2)N- as defined therein and R5 is alkylene.
  • Another most highly preferred embodiment of the invention is a compound of formula (I) or (II) wherein n is 0, Z is -CH2-, Rl is alkenyl, and R3 is R4-C(O)-Rs- wherein R4 is (Rn)(Ri2)N- as defined therein and R5 is alkylene.
  • Another most highly preferred embodiment of the invention is a compound of formula (I) or (II) wherein n is 0, Z is -CH2-, Rl is heterocyclic (alkyl), and R 3 is R4-C(O)-R5- wherein R4 is (Ri ⁇ )(Ri2)N- as defined therein and R5 is alkylene.
  • Another most highly preferred embodiment of the invention is a compound of formula (I) or (II) wherein n is 0, Z is -CH2-, Rl is aryloxyalkyl, and R 3 is R4-C(O)-R5- wherein R4 is (Rn)(Ri 2 )N- as defined therein and R 5 is alkylene.
  • Another most highly preferred embodiment of the invention is a compound of formula (I) or (II) wherein n is 0, Z is -CH2-, Rl is arylalkyl, and R 3 is R_j.-C(O)-R5- wherein R4 is (Rn)(Ri2)N- as defined therein and R 5 is alkylene.
  • Another most highly preferred embodiment of the invention is a compound of formula (I) or (II) wherein n is 0, Z is -CH2-, Rl is aryl, and R 3 is R4-C(O)-Rs- wherein R4 is (Rll)(Rl2)N- as defined therein and R5 is alkylene.
  • Another most highly preferred embodiment of the invention is a compound of formula (I) or (II) wherein n is 0, Z is -CH2-, Rl is (N-alkanoyl-N-alkyl)aminoalkyl, and R 3 is R4-C(O)-R5- wherein R4 is (Rn)(Ri2)N- as defined therein and R5 is alkylene.
  • Another most highly preferred embodiment of the invention is a compound of formula (I) or (II) wherein n is 0, Z is -CH2-, Rl is alkylsulfonylamidoalkyl, and R 3 is R4-C(O)-R5- wherein R4 is (Rn)(Rl2)N- as defined therein and R5 is alkylene.
  • the present invention also relates to processes for preparing the compounds of formula (I) and (II) and to the synthetic intermediates employed in these processes.
  • the present invention also relates to a method of antagonizing endothelin in a mammal (preferably, a human) in need of such treatment, comprising administering to the mammal ' a therapeutically effective amount of a compound of formula (I) or (II).
  • the invention further relates to endothelin antagonizing compositions comprising a pharmaceutical carrier and a therapeutically effective amount of a compound of formula (I) or (II).
  • the compounds of the invention comprise two or more asymmetrically substituted carbon atoms.
  • racemic mixtures, mixtures of diastereomers, as well as single diastereomers of the compounds of the invention are included in the present invention.
  • the terms "S" and "R” configuration are as defined by the IUPAC 1974 Recommendations for Section E, Fundamental Stereochemistry, Pure Appl. Chem. (1976) 45, 13 - 30.
  • carboxy protecting group refers to a carboxylic acid protecting ester group employed to block or protect the carboxylic acid functionality while the reactions involving other functional sites of the compound are carried out.
  • Carboxy protecting groups are disclosed in Greene, "Protective Groups in Organic Synthesis” pp. 152- 186 (1981), which is hereby incorporated herein by reference.
  • a carboxy protecting group can be used as a prodrug whereby the carboxy protecting group can be readily cleaved in vivo , for example by enzymatic hydrolysis, to release the biologically active parent.
  • carboxy protecting groups are Ci to Cs alkyl (e.g., methyl, ethyl or tertiary butyl and the like); haloalkyl; alkenyl; cycloalkyl and substituted derivatives thereof such as cyclohexyl, cylcopentyl and the like; cycloalkylalkyl and substituted derivatives thereof such as cyclohexylmethyl, cylcopentylmethyl and the like; arylalkyl, for example, phenethyl or benzyl and substituted derivatives thereof such as alkoxybenzyl or nitrobenzyl groups and the like; arylalkenyl, for example, phenylethenyl and the like; aryl and substituted derivatives thereof, for example, 5- indanyl and the like; dialkylaminoalkyl (e.g., dimethylaminoalkyl (e.g., dimethylaminoalkyl (e.g
  • N-protecting group or “N-protected” as used herein refers to those groups intended to protect the N-terminus of an amino acid or peptide or to protect an amino group against undersirable reactions during synthetic procedures. Commonly used N-protecting groups are disclosed in Greene, “Protective Groups In Organic Synthesis,” (John Wiley & Sons, New York (1981)), which is hereby incorporated by reference.
  • N-protecting groups comprise acyl groups such as formyl, acetyl, propionyl, pivaloyl, t-butylacetyl, 2-chloroacetyl, 2-bromoacetyl, trifluoroacetyl, trichloroacetyl, phthalyl, o- nitrophenoxyacetyl, chlorobutyryl, benzoyl, 4-chlorobenzoyl,
  • N-protecting groups are formyl, acetyl, benzoyl, pivaloyl, t-butylacetyl, phenylsulfonyl, benzyl, t-butyloxycarbonyl (Boc) and benzyloxycarbonyl (Cbz).
  • alkanoyl refers to an alkyl group as previously defined appended to the parent molecular moiety through a carbonyl (-C(O)-) group. Examples of alkanoyl include acetyl, propionyl and the Hke.
  • alkanoylamino refers to an alkanoyl group as previously defined appended to an amino group.
  • alkanoylamino include acetamido, propionylamido and the Hke.
  • alkanoylaminoalkyl refers to R43-NH-R44- wherein R43 is an alkanoyl group and R44 is an alkylene group.
  • alkanoyloxy alkyl refers to R 30 -O-R 3 1- wherein R30 is an alkanoyl group and R 3 1 is an alkylene group.
  • alkanoyloxyalkyl include acetoxymethyl, acetoxyethyl and the Hke.
  • alkenyl refers to a straight or branched chain hydrocarbon radical containing from 2 to 15 carbon atoms and also containing at least one carbon-carbon double bond.
  • Alkenyl groups include, for example, vinyl (ethenyl), allyl (propenyl), butenyl, 1 -methyl-2-buten- 1 -yl and the Hke.
  • alkenyloxy refers to an alkenyl group, as previously defined, connected to the parent molecular moiety through an oxygen (-O-) linkage. Examples of alkenyloxy include allyloxy, butenyloxy and the Hke.
  • alkoxy refers to R41O- wherein R41 is a loweralkyl group, as defined herein.
  • alkoxy include, but are not limited to, ethoxy, tert-butoxy, and the Hke.
  • alkoxyalkoxy refers to RgoO-RsiO- wherein Rso is loweralkyl as defined above and Rsi is alkylene.
  • Representative examples of alkoxyalkoxy groups include methoxymethoxy, ethoxymethoxy, t-butoxymethoxy and the like.
  • alkoxyalkoxy alkyl refers to an alkoxyalkoxy group as previously defined appended to an alkyl radical.
  • Representative examples of alkoxyalkoxyalkyl groups include methoxyethoxyethyl, methoxymethoxymethyl, and the like.
  • alkoxyalkyl refers to an alkoxy group as previously defined appended to an alkyl radical as previously defined. Examples of alkoxyalkyl include, but are not limited to, methoxymethyl, methoxyethyl, isopropoxymethyl and the like.
  • alkoxycarbonyl refers to an alkoxyl group as previously defined appended to the parent molecular moiety through a carbonyl group. Examples of alkoxycarbonyl include methoxycarbonyl, ethoxycarbonyl, isopropoxycarbonyl and the Hke.
  • alkoxycarbonylalkenyl refers to an alkoxycarbonyl group as previously defined appended to an alkenyl radical.
  • alkoxycarbonylalkenyl include methoxycarbonylethenyl, ethoxycarbonylethenyl and the like.
  • alkoxycarbonylalkyl refers to R34-C(O)-R35- wherein R 3 4 is an alkoxy group and R35 is an alkylene group.
  • alkoxycarbonylalkyl include methoxycarbonylmethyl, methoxcarbonylethyl, ethoxycarbonylmethyl and the like.
  • alkoxycarbonylaminoalkyl refers to R 38 ⁇ C(O)- H-R 3 9- wherein R 38 is an alkoxy group and R 3 9 is an alkylene group.
  • alkoxycarbonyloxyalkyl refers to R36-C(O)-O-R37- wherein R 3 6 is an alkoxy group and R37 is an alkylene group.
  • (alkoxycarbonyl)thioalkoxy refers to an alkoxycarbonyl group as previously defined appended to a thioalkoxy radical.
  • Examples of (alkoxycarbonyl)thioalkoxy include methoxycarbonylthiomethoxy, ethoxycarbonylthiomethoxy and the Hke.
  • alkoxyhaloalkyl refers to a haloalkyl radical to which is appended an alkoxy group.
  • alkyl and loweralkyl refer to straight or branched chain alkyl radicals containing from 1 to 15 carbon atoms including, but not Hmited to, methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, t-butyl, n-pentyl, 1-methylbutyl, 2,2- dimethylbutyl, 2-methylpentyl, 2,2-dimethylpropyl, n-hexyl and the Hke.
  • (N-alkanoyl-N-alky aminoalkyl) refers to R85C(O)N(R86)R87- wherein R85 is an alkanoyl as previously defined, R86 is loweralkyl, and R87 is alkylene.
  • alkylamino refers to R51NH- wherein R51 is a loweralkyl group, for example, ethylamino, butylamino, and the like.
  • alkylaminoalkyl refers to a loweralkyl radical to which is appended an alkylamino group.
  • alkylaminocarbonyl refers to an alkylamino group, as previously defined, appended to the parent molecular moiety through a carbonyl (-C(O)-) linkage.
  • alkylaminocarbonyl include methylaminocarbonyl, ethylaminocarbonyl, isopropylaminocarbonyl and the Hke.
  • alkylaminocarbonylalkenyl refers to an alkenyl radical to which is appended an alkylaminocarbonyl group.
  • alkylaminocarbonylalkyl refers to a loweralkyl radical to which is appended an alkylaminocarbonyl group.
  • alkylaminocarbonylaminoalkyl refers to R40-C(O)-NH-R4i- wherein R4 0 is an alkylamino group and R41 is an alkylene group.
  • alkylene denotes a divalent group derived from a straight or branched chain saturated hydrocarbon having from 1 to 15 carbon atoms by the removal of two hydrogen atoms, for example -CH 2 -, -CH 2 CH 2 -, -CH(CH 3 )-, -CH 2 CH 2 CH 2 -, -
  • alkylsulfonylamidoalkyl refers R88S(O)2NHR89- wherein R88 is loweralkyl and R89 is alkylene.
  • alkylsulfonylamino refers to an alkyl group as previously defined appended to the parent molecular moiety through a sulfonylamino (-S(O)2-NH-) group.
  • alkylsulfonylamino include methylsulfonylamino, ethylsulfonylamino, isopropylsulfonylamino and the Hke.
  • alkynylene refers to a divalent group derived by the removal of two hydrogen atoms from a straight or branched chain acycHc hydrocarbon group containing from 2 to 15 carbon atoms and also containing a carbon-carbon triple bond.
  • alkynylene include -C ⁇ C-, -C ⁇ C-C 2 -, -C ⁇ C-CH(CH 3 )- and the Hke.
  • aminoalkyl refers to a -NH2, alkylamino, or dialkylamino group appended to the parent molecular moiety through an alkylene.
  • aminocarbonyl refers to H2N-C(O)- .
  • aminocarbonylalkenyl refers to an alkenyl radical to which is appended an aminocarbonyl (NH 2 C(O)-) group.
  • aminocarbonylalkoxy refers to H2N-C(O)- appended to an alkoxy group as previously defined.
  • aminocarbonylalkoxy include aminocarbonylmethoxy, aminocarbonylethoxy and the like.
  • aminocarbonylalkyl refers to a loweralkyl radical to which is appended an aminocarbonyl (NH 2 C(O)-) group.
  • trialkylaminoalkyl refers to (R90)(R91)(R92)N(R93)- wherein R90, R91, and R92 are independently selected from loweralkyl and R93 is alkylene.
  • aroyloxy alkyl refers to R 32 -C(O)-O-R 33 - wherein R 3 2 is an aryl group and R 33 is an alkylene group. Examples of aroyloxyalkyl include benzoyloxymethyl, benzoyloxyethyl and the like.
  • aryl refers to a mono- or bicyclic carbocycHc ring system having one or two aromatic rings including, but not limited to, phenyl, naphthyl, tetrahydronaphthyl, indanyl, indenyl and the Hke.
  • Aryl groups can be unsubstituted or substituted with one, two or three substituents independently selected from loweralkyl, halo, haloalkyl, haloalkoxy, hydroxyalkyl, alkenyloxy, alkoxy, alkoxyalkoxy, alkoxycarbonyl, alkoxycarbonylalkenyl, (alkoxycarbonyl)thioalkoxy, thioalkoxy, amino, alkylamino, dialkylamino, aminoalkyl, trialkylaminoalkyl, aminocarbonyl, aminocarbonylalkoxy, alkanoylamino, arylalkoxy, aryloxy, mercapto, cyano, nitro, carboxaldehyde, carboxy, carboxyalkenyl, carboxyalkoxy, alkylsulfonylamino, cyanoalkoxy, (heterocyclic)alkoxy, hydroxy, hydroxalkoxy, phenyl and t
  • substituted aryl groups include tetrafluorophenyl and pentafluorophenyl.
  • arylalkenyl refers to an alkenyl radical to which is appended an aryl group, for example, phenylethenyl and the like.
  • arylalkoxy refers to R42O- wherein R42 is an arylalkyl group, for example, benzyloxy, and the Hke.
  • arylalkoxyalkyl refers to a loweralkyl radical to which is appended an arylalkoxy group, for example, benzyloxymethyl and the Hke.
  • arylalkyl refers to an aryl group as previously defined, appended to a loweralkyl radical, for example, benzyl and the Hke.
  • aryloxy refers to R45O- wherein R45 is an aryl group, for example, phenoxy, and the Hke.
  • arylalkylcarbonyloxyalkyl refers to a loweralkyl radical to which is appended an arylalkylcarbonyloxy group (i.e., R 62 C(O)O- wherein R 62 is an arylalkyl group).
  • aryloxyalkyl refers to an aryloxy group as previously defined appended to an alkyl radical. Examples of aryloxyalkyl include phenoxymethyl, 2-phenoxyethyl and the like.
  • carboxydehyde refers to a formaldehyde radical, -C(O)H.
  • carboxy refers to a carboxylic acid radical, -C(O)OH.
  • carboxyalkenyl refers to a carboxy group as previously defined appended to an alkenyl radical as previously defined. Examples of carboxyalkenyl include 2-carboxyethenyl, 3 -carboxy- 1 -ethenyl and the like.
  • carboxyalkoxy refers to a carboxy group as previously defined appended to an alkoxy radical as previously defined. Examples of carboxyalkoxy include carboxymethoxy, carboxyethoxy and the Hke.
  • cyanoalkoxy refers to an alkoxy radical as previously defined to which is appended a cyano (-CN) group.
  • cyanoalkoxy examples include 3- cyanopropoxy, 4-cyanobutoxy and the like.
  • cycloalkanoyloxyalkyl refers to a loweralkyl radical to which is appended a cycloalkanoyloxy group (i.e., R 60 -C(O)-O- wherein R 60 is a cycloalkyl group).
  • cycloalkyl refers to an aliphatic ring system having 3 to 10 carbon atoms and 1 to 3 rings including, but not Hmited to, cyclopropyl, cyclopentyl, cyclohexyl, norbornyl, adamantyl, and the like.
  • Cycloalkyl groups can be unsubstituted or substituted with one, two or three substituents independently selected from loweralkyl, haloalkyl, alkoxy, thioalkoxy, amino, alkylamino, dialkylamino, hydroxy, halo, mercapto, nitro, carboxaldehyde, carboxy, alkoxycarbonyl and carboxamide.
  • cycloalkylalkyl refers to a cycloalkyl group appended to a loweralkyl radical, including but not Hmited to cyclohexylmethyl.
  • dialkylamino refers to R 56 R 57 N- wherein Rs ⁇ and R 57 are independently selected from loweralkyl, for example diethylamino, methyl propylamino, and the Hke.
  • dialkylaminoalkyl refers to a loweralkyl radical to which is appended a dialkylamino group.
  • dialkylaminocarbonyl refers to a dialkylamino group, as previously defined, appended to the parent molecular moiety through a carbonyl (-C(O)-) linkage.
  • dialkylaminocarbonyl include dimethylamino carbonyl, diethylaminocarbonyl and the like.
  • dialkylaminocarbonylalkenyl refers to an alkenyl radical to which is appended a dialkylaminocarbonyl group.
  • dialkylaminocarbonylalkyl refers to R 5 o-C(O)-R 5 i- wherein R 50 is a dialkylamino group and R 51 is an alkylene group.
  • diarylalkyl refers to two aryl groups, as defined herein, attached to the parent molecular moiety through an alkyl group. Tha aryl groups of the diarylalkyl can be optionaUy substituted with 1-5 alkyl substituents. Examples of “diarylalkyl” include diphenylmethyl (benzhydryl), 2,2-diphenylethyl, 1,2-diphenylethyl, bis(2-methylphenyl)methyl, and the Hke.
  • halo or halogen as used herein refers to I, Br, Cl or F.
  • haloalkenyl refers to an alkenyl radical to which is appended at least one halogen substituent.
  • haloalkoxy refers to an alkoxy radical as defined above, bearing at least one halogen substituent, for example, 2-fluoroethoxy, 2,2,2-trifluoroethoxy, trifluoromethoxy, 2,2,3,3,3-pentafluoropropoxy and the Hke.
  • haloalkoxyalkyl refers to a loweralkyl radical to which is appended a haloalkoxy group.
  • haloalkyl refers to a lower alkyl radical, as defined above, to which is appended at least one halogen substituent, for example, chloromethyl, fluoroethyl, trifluoromethyl or pentafluoroethyl and the Hke.
  • heterocyclic ring or “heterocyclic” or “heterocycle” as used herein refers to any 3- or 4-membered ring containing a heteroatom selected from oxygen, nitrogen and sulfur; or a 5-, 6- or 7-membered ring containing one, two or three nitrogen atoms; one oxygen atom; one sulfur atom; one nitrogen and one sulfur atom; one nitrogen and one oxygen atom; two oxygen atoms in non-adjacent positions; one oxygen and one sulfur atom in non-adjacent positions; or two sulfur atoms in non-adjacent positions.
  • the 5-membered ring has 0-2 double bonds and the 6- and 7-membered rings have 0-3 double bonds.
  • heterocyclicHc also includes bicyclic groups in which any of the above heterocyclic rings is fused to a benzene ring or a cyclohexane ring or another heterocyclic ring (for example, indolyl, dihydroindolyl, quinolyl, isoquinolyl, tetrahydroquinolyl, tetrahydroisoquinolyl, decahydroquinolyl, decahydroisoquinolyl, benzofuryl, dihydrobenzofuryl or benzothienyl and the Hke).
  • Heterocyclics include: aziridinyl, azetidinyl, pyrrolyl, pyrrolinyl, pyrroHdinyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, imidazolyl, imidazolinyl, imidazoHdinyl, pyridyl, piperidinyl, homopiperidinyl, pyrazinyl, piperazinyl, pyrimidinyl, pyridazinyl, oxazolyl, oxazoHdinyl, isoxazolyl, isoxazolidinyl, morphoHnyl, thiomorpholinyl, thiazolyl, thiazolidinyl, isothiazolyl, isothiazoHdinyl, indolyl, quinolinyl, isoquinolinyl, benzimidazolyl, benzothiazolyl, benzox
  • Heterocyclics also include compounds of the formula where X* is -CH 2 - or -O- and Y* is -C(O)- or [-C(R") 2 -] V where R" is hydrogen or C 1 -C 4 - alkyl and v is 1, 2 or 3 such as 1,3-benzodioxolyl, 1,4-benzodioxanyl and the Hke.
  • Heterocyclics also include bicyclic rings such as quinuclidinyl and the Hke.
  • nitrogen containing heterocycles can be N-protected.
  • (heterocycHc)alkoxy refers to a heterocyclic group as defined above appended to an alkoxy radical as defined above.
  • Examples of (heterocyclic)alkoxy include 4-pyridylmethoxy, 2-pyridylmethoxy and the like.
  • (heterocychc)alkyl refers to a heterocyclic group as defined above appended to a loweralkyl radical as defined above.
  • heterocycliccarbonyloxyalkyl refers to R46-C(O)-O-R47- wherein R46 is a heterocyclic group and R47 is an alkylene group.
  • hydroxy refers to -OH.
  • hydroxyalkenyl refers to an alkenyl radical to which is appended a hydroxy group.
  • hydroxyalkoxy refers to an alkoxy radical as previously defined to which is appended a hydroxy (-OH) group.
  • hydroxyalkoxy include 3-hydroxypropoxy, 4-hydroxybutoxy and the Hke.
  • hydroxyalkyl refers to a loweralkyl radical to which is appended a hydroxy group.
  • leaving group refers to a halide (for example, Cl, Br or I) or a sulfonate (for example, mesylate, tosylate, triflate and the Hke).
  • mercapto refers to -SH.
  • methylenedioxy and "ethylenedioxy” refer to one or two carbon chains attached to the parent molecular moiety through two oxygen atoms. In the case of methylenedioxy, a fused 5 membered ring is formed. In the case of ethylenedioxy, a fused 6 membered ring is formed. Methylenedixoy substituted on a phenyl ring results in the formation of a benzodioxolyl radical. . Ethylenedioxy substituted on a phenyl
  • tetrazolylalkoxy refers to a tetrazolyl radical as defined above appended to an alkoxy group as defined above. Examples of tetrazolylalkoxy include tetrazolylmethoxy, tetrazolylethoxy and the Hke.
  • thioalkoxy refers to R70S- wherein R70 is loweralkyl.
  • thioalkoxy examples include, but are not Hmited to, methylthio, ethylthio and the like.
  • thioalkoxyalkoxy refers to RsoS-RsiO- wherein Rso is loweralkyl as defined above and Rsi is alkylene.
  • alkoxyalkoxy groups include CH 3 SCH 2 O-, EtSCH 2 O-, t-BuSCH 2 O- and the Hke.
  • thioalkoxyalkoxyalkyl refers to a thioalkoxyalkoxy group appended to an alkyl radical.
  • alkoxyalkoxyalkyl groups include CH 3 SCH 2 CH 2 OCH 2 CH 2 -, CH 3 SCH 2 OCH 2 -, and the Hke.
  • R2 relative to the central substituent R as shown R 1 or .
  • This definition encompasses both the case where R and R2 are cis and R and Ri are trans and the case where R2 and R are trans and R and Ri are cis.
  • cis, cis refers to the orientation of substituents (Ri and R2) relative to the central substituent R as shown
  • Preferred compounds of the invention are selected from the group consisting of: tr_. «j-tr_.«i'-2-(4-Methoxyphenyl)-4-(l,3-benzodioxol-5-yl)-l-[3-(N-propyl-N- ⁇ - pentanesulfonylamino)propyl] - ⁇ yrrolidine-3 -carboxylic acid; tr_./w,tr_.n.;-2-(4-Methoxymethoxyphenyl)-4-(l,3-benzodioxol-5-yl) ⁇ (2-(N-propyl-N-n- pent_Hiesulfonylamino)ethyl]pyrroHdine-3-carboxylic acid; trans, trans-2-(3 ,4-Dimethoxyphenyl)-4-( 1 ,3 -benzodioxol -5-yl)- 1 -[
  • trans trans-2-(2-( 1 -pyrazolyl) ethyl)-4-( 1 ,3-benzodioxol-5-yl)- 1 -[(N-4-heptyl-N-(4-fluoro-3- methylphenyl)amino)carbonylmethyl]-pyrroHdine-3-carboxy lie acid; trans, trans-2-(2-( 1 -pyrazolyl) ethyl)-4-( 1 ,3-benzodioxol-5-yl)- 1 -[(N-butyl-N-(3- hydroxypropyl)amino)carbonylmethyl]-pyrrolidine-3-carboxylic acid; trans, trans-2-(2-( 1 -pyrazolyl) ethyl)-4-( 1 ,3-benzodio
  • trans trans-2-(2-( 1 -pyrazolyl) ethyl)-4-( 1 ,3-benzodioxol-5-yl)- 1 -[(N-butyl-N-(4- dimethylaminobutyl)amino)carbonylmethyl]-pyrrolidine-3-carboxylic acid; trans, trans-2-(2-( 1 -pyrazolyl) ethyl)-4-(7-methoxy- 1 ,3-benzodioxol-5-yl)- 1 -(N,N- dibutylaminocarbonylmethyl)-pyrroHdine-3-carboxylic acid; trans, trans-2-(2-( 1 -pyrazolyl) ethyl)-4-(7-methoxy- 1 ,3-benzodioxol-5-yl)- 1 -[(N-pyrazolyl) ethyl)-4-(7-methoxy- 1 ,3
  • trans trans-2-(2-( 1 ,3-Dioxol-2-yl)ethyl)-4-( 1 ,3-benzodioxol-5-yl)- 1 -(N,N-di(n- butyl) amino carbonylmethyl)-pyrroHdine-3 -carboxylic acid; tr ⁇ s,tr ⁇ r ⁇ -2-(2,2,-Dimethyl-2-(l,3-dioxolan-2-yl)ethyl)-4-(l,3-benzodioxol-5-yl)-l-(N,N- di(n-butyl)aminocarbonylmethyl)-pyrrolidine-3-carboxyHc acid; trans, trans-2-(2-( 1 ,3-Dioxol-2-yl)ethyl)-4-(l ,3-benzodioxol-5-yl)-
  • Scheme I illustrates the general procedure for preparing the compounds of the invention when n and m are 0, Z is -CH2- and W is -CO2H.
  • a ⁇ -ketoester 1 where E is loweralkyl or a carboxy protecting group is reacted with a nitro vinyl compound 2, in the presence of abase (for example, l,8-diazabicyclo[5.4.0]undec-7-ene (DBU) or sodium ethoxide or sodium hydride and the Hke) in an inert solvent such as toluene, benzene, tetrahydrofuran or ethanol and the Hke.
  • DBU l,8-diazabicyclo[5.4.0]undec-7-ene
  • the condensation product 3 is reduced (for example, hydrogenation using a Raney nickel or platinum catalyst).
  • the resulting amine cyclizes to give the dihydro pyrrole 4.
  • Reduction of 4 for example, sodium cyanoborohydride or catalytic hydrogenation and the Hke
  • a protic solvent such as ethanol or methanol and the like
  • Chromatographic separation removes the cis-cis isomer leaving a mixture of the trans, trans and cis, trans isomers which is further elaborated.
  • the cis-cis isomer can be epimerized (for example, using sodium ethoxide in ethanol) to give the trans, trans isomer and then carried on as described below.
  • the pyrrolidine nitrogen is (1) acylated or sulfonylated with R3-X (R3 is R4-C(O)- or R6-S(O)2- and X is a leaving group such as a halide (Cl is preferred) or X taken together with R4-C(O)- or R6-S(O)2- forms an activated ester including esters or anhydrides derived from formic acid, acetic acid and the Hke, alkoxycarbonyl haHdes, N-hydroxysuccinimide, N-hydroxyphthalimide, N- hydroxybenzotriazole, N-hydroxy-5-norbornene-2,3-dicarboxamide, 2,4,5-trichlorophenol and the like) or (2) alkylated with R 3 -X where X is a leaving group (for example, X is a halide (for example, Br or I) or X is a leaving group such as a sulfonate (for example, mesylate
  • the anion of compound 1_1 is formed using a base such as n- butyllithium and then reacted with Ri-QH ⁇ -X' wherein X' is a leaving group such as a halide or sulfonate to give compound 12.
  • the dithiane protecting group is cleaved (for example, using a mercuric salt in water) to give the keto compound 13.
  • Reaction of ketone 13 with benzyl amine and formaldehyde gives the keto piperidine compound 14.
  • Treatment of compound 14 with an activated nitrile such as trimethylsilyl cyanide foUowed by a dehydrating agent such as phosphorous oxychloride provides the isomeric ene nitriles 15.
  • alpha-Keto ester 20 (wherein E is loweralkyl or a carboxy protecting group) is reacted with an alpha-haloester 21 (where J is lower alkyl or a carboxy protecting group and the halogen is bromine, iodine or chlorine) in the presence of a base such as NaH or potassium tert-butoxide or Hthium dnsopropylamide in an inert solvent such as THF or dimethoxyethane to give diester 22.
  • a base such as NaH or potassium tert-butoxide or Hthium dnsopropylamide
  • an inert solvent such as THF or dimethoxyethane
  • Compound 52 is treated with diazomethane to give the diazo ketone 53.
  • Rearrangement of compound 53 (for example, using water or an alcohol and silver oxide or silver benzoate and triethylamine, or heating or photolysis in the presence of water or an alcohol) affords the acetic acid compound 54 or an ester which may be hydrolyzed.
  • Compounds where m is from 2 to 6 can be obtained by repetition of the above described process. A preferred embodiment is shown in Schemes V and VI.
  • a benzoyl acetate 26 is reacted with a nitro vinyl benzodioxolyl compound 27 using l,8-diazabicyclo[5.4.0]undec-7- ene (DBU) as the base in toluene to give compound 28.
  • DBU l,8-diazabicyclo[5.4.0]undec-7- ene
  • Catalytic hydrogenation using Raney nickel leads to reduction of the nitro group to an amine and subsequent cyclization to give the dihydropyrrole 29.
  • the double bond is reduced with sodium cyanoborohydride to give the pyrroHdine compound 30 as a mixture of cis-cis, trans, trans and cisjrans isomers. Chromatography separates out the cis-cis isomer, leaving a mixture of the trans Jrans and cisjrans isomers (31).
  • Scheme VI illustrates the further elaboration of the trans,trans isomer.
  • the mixture (31) of trans, trans and cis, trans pyrroHdines described in Scheme IV is reacted with N- propyl bromoacetamide in acetonitrile in the presence of ethyldiisopropylamine to give the alkylated pyrrolidine compound 32, still as a mixture of trans, trans and cis, trans isomers.
  • Scheme VII iUustrates the preparation of a specific piperidinyl compound.
  • Benzodioxolyl methyl chloride 35 is reacted with Hthio dithiane 36 to give the alkylated compound 37.
  • Treatment of compound 37 with 4-methoxybenzyl chloride in the presence of lithium diisopropylamide gives compound 38- Cleavage of the dithiane protecting group using a mercuric salt in aqueous solution gives ketone 39.
  • Treatment of 39 with benzylamine and formaldehyde gives the keto piperidine 40.
  • Treatment of compound 40 with trimethylsilyl cyanide foUowed by phosphorous oxychloride gives the ene nitrile as a mixture of isomers 41.
  • Scheme IX illustrates the preparation of compounds where n is 0, Z is -CH2-, and W is other than carboxylic acid.
  • Compound 55 which can be prepared by the procedures described in Scheme IV, is converted (for example, using peptide couphng condition, e.g. N- methylmorpholine, EDCI and HOBt, in the presence of ammonia or other amide forming reactions) to give carboxamide 56.
  • the carboxamide is dehydrated (for example, using phosphorus oxychloride in pyridine) to give nitrile 57.
  • Nitrile 57 under standard tetrazole forming conditions sodium azide and triethylamine hydroehloride or trimethylsilylazide and tin oxide
  • tetrazole 58 is reacted to give tetrazole 58.
  • nitrile 57 is reacted with hydroxylamine hydroehloride in the presence of a base (for example, potassium carbonate, sodium carbonate, sodium hydroxide, triethylamine, sodium methoxide or NaH) in a solvent such as DMF, DMSO, or dimethylacetamide to give amidoxime 59.
  • a base for example, potassium carbonate, sodium carbonate, sodium hydroxide, triethylamine, sodium methoxide or NaH
  • solvent such as DMF, DMSO, or dimethylacetamide
  • the amidoxime 59 is allowed to react with a methyl or ethyl chloroformate in a conventional organic solvent (such as, chloroform, methylene chloride, dioxane, THF, acetonitrile or pyridine) in the presence of a base (for example, triethylamine, pyridine, potassium carbonate and sodium carbonate) to give an O-acyl compound.
  • a base for example, triethylamine, pyridine, potassium carbonate and sodium carbonate
  • Heating of the O-acyl amidoxime in an inert solvent such as benzene, toluene, xylene, dioxane, THF, dichloroethane, or chloroform and the Hke
  • an inert solvent such as benzene, toluene, xylene, dioxane, THF, dichloroethane, or chloroform and the Hke
  • an inert solvent for example, chloroform, dich
  • Scheme X illustrates the preparation of compounds in which R3 is an acylmethylene group.
  • a carboxylic acid 62 (where R4 is as previously defined herein) is treated with oxalyl chloride in a solution of methylene chloride containing a catalytic amount of N,N- dimethylformamide to give the acid chloride.
  • Treatment of the acid chloride with excess ethereal diazomethane affords a diazoketone, and then treatment with anhydrous HCl in dioxane gives the ⁇ -chloroketone 63.
  • the carboxy protected pyrroHdine 5, prepared in Scheme I, is reacted with a difunctionaHzed compound X-Rs-X where Rs is alkylene and X is a leaving group (for example a haHde where Br is preferred) to give N-alkylated compound 66.
  • Treatment of 66 with an amine (R2 0 NH2) affords secondary amine 67.
  • This amine (67) can be reacted with an activated acyl compound (for example, R4-C(O)-Cl) and then carboxy deproteeted (for example, hydrolysis of an ester or hydrogenation of a benzyl moiety) to afford amide 68.
  • amine 67 can be reacted with an activated sulfonyl compound (for example, R6-S(O)2-Cl) and then carboxy deproteeted (for example, hydrolysis of an ester or hydrogenation of a benzyl moiety) to afford sulfonamide 69.
  • Scheme XII illustrates a method for synthesizing pyrrolidines by ah azomethine ylide type [3+2]-cycloaddition to an acrylate.
  • General structures such as compound 70 are known to add to unsaturated esters such as 71 to provide pyrrolidines such as compound 72 (O. Tsuge, S. Kanemasa, K. Matsuda, Chem. Lett.
  • This method can be modified to provide the N-acetamido derivatives directly by reacting 73 and 74 with the appropriate bromoacetamide (for example, dibutyl bromoacetamide) in the presence of tetrabutylammonium iodide and cesium fluoride to give compound 76.
  • the appropriate bromoacetamide for example, dibutyl bromoacetamide
  • tetrabutylammonium iodide and cesium fluoride to give compound 76.
  • Scheme XIII illustrates a method for producing an enantiomerically pure pyrroHdine 80, which can be further elaborated on the pyrroHdine nitrogen.
  • Intermediate racemic pyrroHdine ester 77 (for example, prepared by the procedure described in Scheme V) is Boc- nitrogen protected (for example, by treatment with B0C2O) and then the ester is hydrolyzed
  • t-butyl carbamoyl pyrrolidine carboxylic acid 78 (for example, using sodium or Hthium hydroxide in ethanol and water) to give t-butyl carbamoyl pyrrolidine carboxylic acid 78.
  • the carboxylic acid is converted to its (+)- cinchonine salt, which can be recrystalHzed (for example from ethyl acetate and hexane or chloroform and hexane) to afford the diastereomerically pure salt.
  • This diastereomerically pure salt can be neutrahzed (for example, with sodium carbonate or citric acid) to afford enantiomerically pure carboxylic acid 79.
  • the pyrroHdine nitrogen can be deproteeted (for example, using trifluoroacetic acid) and the ester reformed by the use of ethanolic hydrochloric acid to give salt 80.
  • ethanolic hydrochloric acid to give salt 80.
  • ethanol HCl to cleave the protecting group and form the ester in one step.
  • the pyrrolidine nitrogen can be further elaborated (for example, by treatment with the dibutyl amide of bromoacetamide in acetonitrile in the presence of diisopropylethylamine) to give optically active compound 81.
  • the use of (-)-cinchonine will give the opposite enantiomer.
  • Scheme XTV describes another procedure for preparation of pyrroHdines.
  • PyrroHdines may be synthesized by the use of an azomethine ylide cycloaddition to an acrylate derivative as described by CottreU, I. F., etal., J. Chem. Soc, Perkin Trans. 1, 5:
  • the azomethine ylide precursor 82 (where R 5 5 is hydrogen or methyl) is condensed with a substituted acrylate 83 (wherein R2 is as described herein and R$ ⁇ is loweralkyl) under acidic conditions to afford the substituted pyrrolidine 84-
  • the N- protecting group can be removed (for example, by hydrogenolysis of an N-benzyl group) to give 85, which can be alkylated under the conditions described above to provide the N- substituted pyrroHdine 86- Standard ester hydrolysis of 86 produces the desired pyrrolidine carboxylic acid 87.
  • Nitro vinyl compound (88) is reacted with beta-keto ester 89 in the presence of a base such as sodium ethoxide and the Hke or a trialkylamine such as triethylamine or diisopropylethylamine and the like or an amidine such as DBU and the like in an inert solvent such as THF, toluene, DMF, acetonitrile, ethyl acetate, isopropyl acetate or methylene chloride and the Hke at a temperature of from about 0° C to about 100° C for a period of time from about 15 minutes to overnight to give compound 90.
  • a base such as sodium ethoxide and the Hke
  • a trialkylamine such as triethylamine or diisopropylethylamine and the like or an amidine such as DBU and the like
  • an inert solvent such as THF, toluene, DMF, acetonitrile, eth
  • Reduction of the nitro group foUowed by cyclization was effected for example by catalytic hydrogenation with a hydrogen pressure of from about atmospheric pressure to 300 p.s.i. over from about 1 hour to about 1 day of compound 90 in an inert solvent such as THF, ethyl acetate, toluene, ethanol, isopropanol, DMF or acetonitrile and the like, using a hydrogenation catalyst such as Raney nickel, palladium on carbon, a platinum catalyst, such as platinum oxide, platinum on carbon or platinum on alumina and the like, or a rhodium catalyst, such as rhodium on carbon or rhodium on alumina and the Hke, and the like affords intermediate nitrone 91a or a mixture of nitrone 91a and imine £lb.
  • a hydrogenation catalyst such as Raney nickel, palladium on carbon
  • a platinum catalyst such as platinum oxide, platinum on carbon or platinum on alumina and the like
  • reaction mixture comprising the nitrone or nitrone/imine mixture is treated with an acid such as trifluoroacetic acid or acetic acid or sulfuric acid or phosphoric acid or methanesulfonic acid and the Hke, and the hydrogenation is continued to give pyrroHdine compound 92 as the cz ⁇ cz ' s-isomer.
  • an acid such as trifluoroacetic acid or acetic acid or sulfuric acid or phosphoric acid or methanesulfonic acid and the Hke
  • Epimerization at C-3 is effected by treatment of compound 92 with a base such as sodium ethoxide, potassium t-butoxide, lithium t-butoxide or potassium t-amyloxide and the like or a trialkylamine such as triethylamine or diisopropylethylamine and the Hke or an amidine such as DBU and the like in an inert solvent such as ethanol, ethyl acetate, isopropyl acetate, THF, toluene or DMF and the Hke at a temperature of from about -20° C to about 120° C to give the transjrans compound 93.
  • Compound 93 itself can optionally be resolved into enantiomers prior to reacting with X-R 3 .
  • the substantially pure i.e., at least
  • the substantially pure (i.e., at least 95%o of the desired isomer) optically active (-)-isomer of compound 93 can be selectively crystaUized by reaction of a mixture of the (+)-isomer and the (-)-isomer of 93 with L-tartaric acid, L-dibenzoyl tartaric acid or L-pyroglutamic acid and the Hke, leaving the desired (+)-isomer of compound 93 in solution.
  • Compound 93 (racemic or optically active) is reacted with X-R3 (where X is a leaving group (for example, a halide or a sulfonate) and R 3 is as previously defined) using a base such as dusopropylethylamine, triethylamine, sodium bicarbonate or potassium carbonate and the like in an inert solvent such as acetonitrile, THF, toluene, DMF or ethanol and the like at a temperature of from about 0° C to about 100° C to give the intermediate ester 94.
  • a base such as dusopropylethylamine, triethylamine, sodium bicarbonate or potassium carbonate and the like
  • an inert solvent such as acetonitrile, THF, toluene, DMF or ethanol and the like at a temperature of from about 0° C to about 100° C to give the intermediate ester 94.
  • the ester can be isolated or converted in situ to the carboxyHc acid (95) using hydrolysis conditions such as a base such as sodium hydroxide or Hthium hydroxide or potassium hydroxide and the Hke in a solvent such as ethanol-water or THF-ethanol and the Hke.
  • hydrolysis conditions such as a base such as sodium hydroxide or Hthium hydroxide or potassium hydroxide and the Hke in a solvent such as ethanol-water or THF-ethanol and the Hke.
  • AHphatic ⁇ -ketoesters may be prepared by copper- catalyzed addition of a Grignard reagent (for example, propylmagnesium bromide) to an unsaturated ester, for example, ethyl 3,3-dimethylacrylate.
  • a Grignard reagent for example, propylmagnesium bromide
  • the resultant ester is hydrolyzed, for example with sodium hydroxide in aqueous alcohol, and is homologated in stepwise fashion to the corresponding ⁇ -ketoester, for example by activation using carbonyldiimidazole and condensation with magnesio-ethoxymalonate.
  • olefinic alpha-ketoesters may be prepared by Claisen rearangement of the corresponding aUylic alcohols; hydrolysis and homologation as described above produce the desired alpha - ketoester.
  • N-alkyl,O-alkyl bromohydroxamates are prepared according to Scheme XVII.
  • N- Boc-O-aUyl hydroxylamine is alkylated with and alkyl halide, for example using sodium hydride as base; the double bond is selectively reduced, for example using hydrogen and a paUadium catalyst.
  • the resultant amine is acylated, for example using bromoacetyl bromide.
  • ⁇ -ketoesters described in Scheme XVI may be converted to pyrrolidine derivatives as described in Scheme XVIII.
  • Michael addition onto a nitrostyrene derivative can be catalyzed with base, for example DBU or potassium t-butoxide; the resultant adduct is hydrogenated, for example using Raney Nickel as catalyst, to give an imine, which is reduced further, for example using sodium cyanoborohydride under controUed pH.
  • base for example DBU or potassium t-butoxide
  • the resultant adduct is hydrogenated, for example using Raney Nickel as catalyst, to give an imine, which is reduced further, for example using sodium cyanoborohydride under controUed pH.
  • a mixture of isomers are generated, in which the trans-trans is generally preferred.
  • Scheme XIX describes several strategies for resolving the racemic pyrroHdines described above.
  • Treatment with a chiral acid may provide a crystaUine derivative, which can be further enriched through recrystaUization.
  • the salt may be washed with base to extract the resolving agent and return the optically active pyrroHdine product.
  • the amino ester can be N-protected (for example with Boc-anhydride) and hydrolyzed (for example with sodium hydroxide) to give the corresponding N-protected amino acid.
  • Activation of the acid for example as the pentafluorophenyl ester, foUowed by coupling with a chiral nonracemic oxazolidinone anion, provides the corresponding acyloxazolidinone diastereomers, which may be separated chromatographically.
  • a similar transformation may be accomphshed through coupling of the protected amino acid with a chiral nonracemic amino alcohol. After chromatographic separation of the resultant diastereomers, the amide is cleaved and the protecting group is removed to provide optically enriched product.
  • Optically active amino esters prepared as described above may be alkylated (Scheme XX) with a variety of electrophUes, for example dibutyl bromoacetamide, N-butyl,N-alkoxy bromoacetamide, N-(4-heptyl)-N-(3-methyl-4-fluorophenyl) bromoacetamide, orN-( ⁇ - hydroxyalkyl)-N-alkyl haloacetamide.
  • Hydrolysis of the resultant ester for example using sodium hydroxide in aqueous alcohol, provides the product.
  • Halo Cl, Br, or I 22
  • amines may be prepared according to Scheme XXII.
  • An aryl aldehyde or ketone (aldehyde shown), which may be acquired commercially or prepared, for example, tlirough a Friedel-Crafts acylation of a benzene derivative with an acyl halide, is reacted with an amine, for example ammonia, hydroxylamine or the like.
  • the resultant imine is reduced, for example using sodium borohydride or sodium cyanoborohydride or a metal Hke zinc or tin or the like, to give the corresponding optionally substituted carbinylamine, which is converted to the target compound according to the procedures described above.
  • StiU other amines may be prepared according to Scheme XXII.
  • An optionally substituted aryl hahde (Rn a is the optionally substituted aryl and X is bromo or iodo) is reacted with a metallated amine (for example, lithium tert-butylamide, or sodium benzylamide, or the Hke) to provide an optionally substituted anUine.
  • a metallated amine for example, lithium tert-butylamide, or sodium benzylamide, or the Hke
  • This compound is reacted with an oxidized nitrogen compound, for example nitrous acid or the like to provide an N,N-disubstituted hydrazine, which is converted to the target compound according to the procedures described above.
  • Rl and R2 are independently selected from hydrogen, loweralkyl, alkenyl, alkynyl, alkoxyalkyl, alkoxycarbonylalkyl, hydroxyalkyl, haloalkyl, haloalkoxyalkyl, alkoxyalkoxyalkyl, thioalkoxyalkoxyalkyl, cycloalkyl, cycloalkylalkyl, aminocarbonylalkyl, alkylaminocarbonylalkyl, dialkylaminocarbonylalkyl, aminocarbonylalkenyl, alkylaminocarbonylalkenyl, dialkylaminocarbonylalkenyl, hydroxyalkenyl, aryl, arylalkyl, aryloxyalkyl, arylalkoxyalkyl, (N-alkanoyl-N-alkyl)aminoalkyl, alkylsulfonylamidoalkyl, heterocyclic, (heter
  • R aa is aryl or arylalkyl
  • R bb is hydrogen or alkanoyl
  • R cc is alkylene, with the proviso that one or both of R j and R 2 is other than hydrogen; or a salt thereof; or a compound of the formula:
  • W is (a) -C(O)2-G where G is hydrogen or a carboxy protecting group, (b) -PO 3 H2, (c) -P(O)(OH)E where E is hydrogen, loweralkyl or arylalkyl, (d) -CN, (e) -C(O)NHRi7 where R17 is loweralkyl, (f) alkylaminocarbonyl,
  • Rl and 2 are independently selected from hydrogen, loweralkyl, alkenyl, alkynyl, alkoxyalkyl, alkoxycarbonylalkyl, hydroxyalkyl, haloalkyl, haloalkoxyalkyl, alkoxyalkoxyalkyl, thioalkoxyalkoxyalkyl, cycloalkyl, cycloalkylalkyl, aminocarbonylalkyl, alkylaminocarbonylalkyl, dialkylaminocarbonylalkyl, aminocarbonylalkenyl, alkylaminocarbonylalkenyl, dialkylaminocarbonylalkenyl, hydroxyalkenyl, aryl, arylalkyl, aryloxyalkyl, arylalkoxyalkyl, (N-alkanoyl-N-alkyl)aminoalkyl, alkylsulfonylamidoalkyl, heterocyclic, (hetero
  • R aa is aryl or arylalkyl, R ⁇ . is hydrogen or alkanoyl and R cc is alkylene, with the proviso that one or both of R 1 and R 2 is other than hydrogen; or a salt thereof.
  • Preferred intermediates include compounds of formula (III), (IV) and (V) wherein m is zero or 1;
  • W is -CO 2 -G wherein G is hydrogen or a carboxy protecting group, and Ri and R2 are as defined above; or the substantially pure (+)- or (-)-isomer thereof.
  • Particularly preferred intermediates are compounds of formula (III), (IV) and (V) wherein n and m are both 0; is -CO2-G wherein G is hydrogen or a carboxy protecting group; and Ri is (i) loweralkyl, (n) alkenyl, (Hi) alkoxyalkyl, (iv) cycloalkyl, (v) phenyl,
  • Q is a leaving group; is (a) -C(O)2-G where G is hydrogen or a carboxy protecting group, (b) -PO 3 H2,
  • Rl and R2 are independently selected from hydrogen, loweralkyl, alkenyl, alkynyl, alkoxyalkyl, alkoxycarbonylalkyl, hydroxyalkyl, haloalkyl, haloalkoxyalkyl, alkoxyalkoxyalkyl, thioalkoxyalkoxyalkyl, cycloalkyl, cycloalkylalkyl, aminocarbonylalkyl, alkylaminocarbonylalkyl, dialkylaminocarbonylalkyl, aminocarbonylalkenyl, alkylaminocarbonylalkenyl, dialkylaminocarbonylalkenyl, hydroxyalkenyl, aryl, arylalkyl, aryloxyalkyl, arylalkoxyalkyl, (N-alkanoyl-N-alkyl)aminoalkyl, alkylsulfonylamidoalkyl, heterocyclic, (heter
  • R aa is aryl or arylalkyl, R ⁇ . is hydrogen or alkanoyl and R cc is alkylene, with the proviso that one or both of R j and R 2 is other than hydrogen; or a salt thereof; or a compound of the formula:
  • R 5t is alkylene
  • Q is a leaving group
  • W is (a) -C(O)2-G where G is hydrogen or a carboxy protecting group, (b) -PO3H 2 ,
  • Rl and R are independently selected from hydrogen, loweralkyl, alkenyl, alkynyl, alkoxyalkyl, alkoxycarbonylalkyl, hydroxyalkyl, haloalkyl, haloalkoxyalkyl, alkoxyalkoxyalkyl, thioalkoxyalkoxyalkyl, cycloalkyl, cycloalkylalkyl, aminocarbonylalkyl, alkylaminocarbonylalkyl, dialkylaminocarbonylalkyl, aminocarbonylalkenyl, alkylaminocarbonylalkenyl, dialkylaminocarbonylalkenyl, hydroxyalkenyl, aryl, arylalkyl, aryloxyalkyl, arylalkoxyalkyl, (N-alkanoyl-N-alkyl)aminoalkyl, alkylsulfonylamidoalkyl, heterocyclic, (hetero
  • R aa is aryl or arylalkyl
  • R ⁇ . is hydrogen or alkanoyl
  • R cc is alkylene, with the proviso that one or both of R j and R 2 is other than hydrogen; or a salt thereof.
  • Preferred intermediates include compounds of formula (VI), (VII) and (VIII) wherein mis zero or 1; R 5 - is alkylene; Q is a leaving group;
  • W is -CO2-G wherein G is hydrogen or a carboxy protecting group, and Ri and R2 are as defined above; or the substantially pure (+)- or (-)-isomer thereof.
  • Particularly preferred intermediates are compounds of formula (VI), (VII) and (VIII) wherein n and m are both 0; R 5b is alkylene;
  • Q is a leaving group
  • W is -CO2-G wherein G is hydrogen or a carboxy protecting group; and Ri is (i) loweralkyl, (ii) alkenyl, (iii) alkoxyalkyl, (iv) cycloalkyl, (v) phenyl, (vi) pyridyl, (vii) furanyl or (vni) substituted or unsubstituted 4-methoxyphenyl, 4-fluorophenyl, 3 -fluorophenyl, 4-ethoxyphenyl, 4-ethylphenyl, 4-methylphenyl, 4-trifluoromethylphenyl, 4-pentafluoroethylphenyl, 3-fluoro-4-methoxyphenyl, 3-fluoro-4-ethoxyphenyl, 2-fluorophenyl, 4-methoxymethoxyphenyl, 4-hydroxyphenyl, 4-t-butylphenyl, 1,3-benzodioxolyl, 1,4-benz
  • R 20a is hydrogen, loweralkyl, alkenyl, haloalkyl, alkoxyalkyl, haloalkoxyalkyl, cycloalkyl, cycloalkylalkyl, aryl or arylalkyl; is (a) -C(O)2-G where G is hydrogen or a carboxy protecting group, (b) -PO 3 H2,
  • Rl and R 2 are independently selected from hydrogen, loweralkyl, alkenyl, alkynyl, alkoxyalkyl, alkoxycarbonylalkyl, hydroxyalkyl, haloalkyl, haloalkoxyalkyl, alkoxyalkoxyalkyl, thioalkoxyalkoxyalkyl, cycloalkyl, cycloalkylalkyl, aminocarbonylalkyl, alkylaminocarbonylalkyl, dialkylaminocarbonylalkyl, aminocarbonylalkenyl, alkylaminocarbonylalkenyl, dialkylaminocarbonylalkenyl, hydroxyalkenyl, aryl, arylalkyl, aryloxyalkyl, arylalkoxyalkyl, (N-alkanoyl-N-alkyl)aminoalkyl, alkylsulfonylamidoalkyl, heterocyclic, (heter
  • R aa is aryl or arylalkyl
  • R ⁇ is hydrogen or alkanoyl
  • R cc is alkylene, with the proviso that one or both of R j and R 2 is other than hydrogen; or a salt thereof; or a compound of the formula:
  • R 20a is hydrogen, loweralkyl, alkenyl, haloalkyl, alkoxyalkyl, haloalkoxyalkyl, cycloalkyl, cycloalkylalkyl, aryl or arylalkyl;
  • W is (a) -C(O)2-G where G is hydrogen or a carboxy protecting group, (b) -PO3H2, (c) -P(O)(OH)E where E is hydrogen, loweralkyl or arylalkyl,
  • Rl and R 2 are independently selected from hydrogen, loweralkyl, alkenyl, alkynyl, alkoxyalkyl, alkoxycarbonylalkyl, hydroxyalkyl, haloalkyl, haloalkoxyalkyl, alkoxyalkoxyalkyl, thioalkoxyalkoxyalkyl, cycloalkyl, cycloalkylalkyl, aminocarbonylalkyl, alkylaminocarbonylalkyl, dialkylaminocarbonylalkyl, aminocarbonylalkenyl, alkylaminocarbonylalkenyl, dialkylaminocarbonylalkenyl, hydroxyalkenyl, aryl, arylalkyl, aryloxyalkyl, arylalkoxyalkyl, (N-alkanoyl-N-alkyl)aminoalkyl, alkylsulfonylamidoalkyl, heterocyclic, (heter
  • R aa is aryl or arylalkyl
  • R bt is hydrogen or alkanoyl
  • R cc is alkylene, with the proviso that one or both of R j and R 2 is other than hydrogen; or a salt thereof.
  • Preferred intermediates include compounds of formula (IX), (X) and (XI) wherein m is zero or 1; R 5b is alkylene;
  • R 20a is hydrogen, loweralkyl, alkenyl, haloalkyl, alkoxyalkyl, haloalkoxyalkyl, cycloalkyl, cycloalkylalkyl, aryl or arylalkyl;
  • W is -CO 2 -G wherein G is hydrogen or a carboxy protecting group, and Ri and R 2 are as defined above; or the substantiaUy pure (+)- or (-)-isomer thereof.
  • Particularly preferred intermediates are compounds of formula (IX), (X) and (XI) wherein n and m are both 0; R 5b is alkylene; R 20a is hydrogen, loweralkyl, alkenyl, haloalkyl, alkoxyalkyl, haloalkoxyalkyl, cycloalkyl, cycloalkylalkyl, aryl or arylalkyl;
  • W is -CO 2 -G wherein G is hydrogen or a carboxy protecting group; and Ri is (i) loweralkyl, (ii) alkenyl, (Hi) alkoxyalkyl, (iv) cycloalkyl, (v) phenyl, (vi) pyridyl, (vii) furanyl or (vni) substituted or unsubstituted 4-methoxyphenyl, 4-fluorophenyl, 3 -fluorophenyl, 4-ethoxyphenyl, 4-ethylphenyl, 4-methylphenyl, 4-trifluoromethylphenyl, 4- pentafluoroethylphenyl, 3-fluoro-4-methoxyphenyl, 3-fluoro-4-ethoxyphenyl, 2- fluorophenyl, 4-methoxymethoxyphenyl, 4-hydroxyphenyl, 4-t-butylphenyl, 1,3- benzodioxolyl, 1,4-benz
  • the foUowing abbreviations are used: Boc for tert-butyloxycarbonyl, Cbz for benzyloxycarbonyl, DBU for l,8-diazabicyclo[5.4.0]undec-7-ene, EDCI for l-(3- dimethylaminopropyl-3-ethylcarbodiimide hydroehloride, EtOAc for ethyl acetate, EtOH for ethanol, HOBt for 1-hydroxybenzotriazole, Et 3 for triethylamine, TFA for trifluoroacetic acid and THF for tetrahydrofuran.
  • Example IA Ethyl 2-(4-methoxybenzoyl)-4-nitromethyl-3-( 3-benzodioxole-5-yl)butyrate
  • ethyl (4-methoxybenzoyl)acetate 23.0 g, 0.104 mol
  • 5-(2-nitrovinyl)-l,3-benzodioxole (17.0 g, 0.088 mol) dissolved in 180 mL of toluene and heated to 80 °C was added 1,8- diazabicyclo[5,4,0] undec-7-ene (DBU, 0.65 g) with stirring.
  • DBU 1,8- diazabicyclo[5,4,0] undec-7-ene
  • Example IA The compound resulting from Example IA (21 g) in 500 mL of ethanol was hydrogenated under 4 atmospheres of hydrogen pressure using a Raney nickel 2800 catalyst (51 g). (The Raney nickel was washed with ethanol three times before use.) The catalyst was removed by filtration, and the solution was concentrated under reduced pressure. The residue obtained was chromatographed on silica gel eluting with 8.5% ethyl acetate in methylene chloride to give 12.34 g of the desired product.
  • Example IC Ethyl 2-(4-methoxyphenyl-4-(l,3-benzodioxol-5-yl)-pyrroHdine-3-carboxylate) as a mixture of cis-cis; transjrans; and cisjrans -isomers
  • the compound resulting from Example IB (11.89 g, 0.324 mol) was dissolved in 27 mL of tetrahydrofuran and 54 mL of ethanol.
  • Sodium cyanoborohydride (2.35 g, 0.374 mol) and 5 mg bromocresol green were added.
  • Example ID tr-.nsJr_.ns-2-(4-Methoxyphenyl)-4-(1 -benzodioxol-5-yl)-l-(propylaminocarbonylmethyl)- pyrroHdine-3 -carboxylic acid The mixture of 64% transjrans- and 34% czs,trans-pyrroHdines (the mixture resulting from Example IC) (5.72 g, 15.50 mmol), ethyldiisopropylamine (4.20 g, 32.56 mmol), and N-propyl bromoacetamide (3.42 g, 19.0 mmol), prepared by the method of Weaver, W.E.
  • Example 2 trans. tr ⁇ ns-2-(4-Methoxyphenyl)-4-( 1 ,3-benzodioxol-5-yl)- 1 -(aminocarbonylmethyl)- pyrrolidine-3 -carboxylic acid
  • Example 3 trans.tr-.ns-2-(4-Methoxyphenyl)-4-( 3-benzodioxol-5-ylVl-(4-fluorobenzyl)-pyrroHdine-3- carboxylic acid
  • 300 mg of the mixture of 64% transjrans- and 34% cisjrans- pyrrolidines (the mixture resulting from Example IC)
  • 220 mg of diisopropylethylamine and 185 mg of 4-fluorobenzyl bromide were reacted at room temperature for 3 hours in 1 mL of acetonitrile to give 387 mg of a mixture of trans Jrans- and c-s,trans-N-alkylated esters.
  • Example 4 trans, tr_.ns-2-(4-MethoxyphenvD-4-( 1 ,3-benzodioxol-5-yD- 1 -(2-ethoxyethyl , -pyrrohdine-3- carboxylic acid Using the method described in Example ID, 300 mg.
  • Example 6A Ethyl trgns,trans-2-(4-methoxyphenyl)-4-(l,3-benzodioxol-5-yl) pyrroUdine-3-carboxylate To the pure cis, cts-compound resulting from Example IC (3.02 g) dissolved in 10 mL of ethanol was added 20 drops of a solution of 21% sodium ethoxide in ethanol. The reaction mixture was refluxed overnight, at which time thin layer chromatography in ethyl acetate indicated the absence of starting material. The NaOEt was neutraHzed with HCl in ethanol, and the solution was concentrated in vacuo.
  • Example 6B trans.tr ⁇ ns-2-(4-Methoxyphenyl -4-(l,3-benzodioxol-5-yl)-l-[2-(2-methoxyethoxy)ethyl]- pyrroHdine-3 -carboxylic acid Using the method described in Example ID, 250 mg of the compound resulting from
  • Example 6A 150 mg of 2-(2-methoxyethoxy) ethyl bromide and 175 mg dnsopropyl- ethylamine in 1 mL acetonitrile were heated at 100 °C for 3 hours to give 229 mg of the trans, trans-ester. A portion (200 mg) was hydrolyzed with 125 mg NaOH in 1 mL of water and 2 mL of ethanol to give 151 mg of the title compound as an amorphous powder.
  • Example 7 tr-.ns,trans-2-(4-Methoxyphenyl)-4-(l,3-benzodioxol-5-yl)-l-[2-(2-pyridyl)ethyl]- pyrroHdine-3 -carboxylic acid
  • 2-vinyl pyridine 355 mg
  • acetic acid 2-methoxyethanol
  • Example 8 trans, trans-2-(4-Methoxyphenyl)-4-( 1 ,3-benzodioxol-5-vD- 1 -(morphoHn-4-ylcarbonyl)- pyrrolidine-3 -carboxylic acid
  • a compound resulting from Example 6 A 300 mg
  • 164 mg triethylamine dissolved in 2 mL of methylene chloride and cooled in an ice bath was added 146 mg 1- morpholinocarbonyl chloride. The mixture was stirred 3 hours at room temperature.
  • Example 9 trans.trans-2-(4-Methoxyphenyl -4-(L3-benzodioxole-5-yl)-l-(butylaminocarbonylV pyrroHdine-3 -carboxylic acid
  • Example 10 trans. trans-2-(4-Methoxyphenyl)-4-( 1 ,3-benzodioxol-5-yl)- 1 -(4- methoxyphenylaminocarbonylV3-pyrroHdine-3-carboxyHc acid
  • the compound resulting from Example 6 A (300 mg) was treated with 133 mg of 4- methoxyphenyl isocyanate by the procedure described in Example 9.
  • the resulting ester was hydrolyzed with NaOH using the method described in Example ID to give 279 mg of the title compound. m.p. 185-187 °C.
  • Example 11 tr-.ns.trans-2-(4-Methoxyphenyl)-4-(l,3-benzodioxol-5-yl)-l-acetylpyrrolidine-3-carboxylic acid
  • the compound resulting from Example 6A 250 mg in 0.5 mL of toluene was treated with 200 mg of acetic anhydride. After stirring 2 hours at room temperature, water was added and the acetic acid neutralized with potassium bicarbonate. The mixture was extracted with toluene to give 273 mg of the intermediate ester. A portion of the ester (200 mg) was hydrolyzed using the method of Example ID to give 211 mg of the title compound, mp. 248-250 °C.
  • Example 12 trans.tr ⁇ ns-2-(4-Metho ⁇ yphenyl)-4-(1 -benzodioxol-5-yl)-l-(2-fuiOyl)-pyrrolidine-3- carboxylic acid
  • Example 13 transJrans-2-(4-Methoxyphenyl)-4-(l,3-benzodioxol-5-yl)-l-(phenylaminocarbonyl)- pyrroHdine-3-carboxylic acid
  • phenyl isocyanate Starting with the compound resulting from Example 6A, phenyl isocyanate and the procedures described in Example 9, the title compound was prepared. m.p. 209-211 °C.
  • Example 14 trans. tr_.ns-2-(4-Methoxyphenyl)-4-( 1 ,3-benzodioxol-5-yl)- 1 -(allylaminocarbonylmethyl)- pyrroHdine-3-carboxylic acid Using the procedures described in Example 1 the title compound was prepared. m.p. 138-140 °C. 1HNMR (CDC1 3 , 300 MHz) ⁇ 2.84 (d, IH), 2.90-3.10 (dt, 2H), 3.28 (d, IH),
  • Example 15 tr ⁇ ns,tr ns-2-(4-MethoxyphenylV4-(1 -benzodioxol-5-yl)-l-(n-butylaminocarbonylmethyl)- pyrrolidine-3 -carboxylic acid Using the procedures described in Example 1 the title compound was prepared. m.p. 105-107 °C.
  • Example 16 trans.trans-2-(4-Methoxyphenyl)-4-(1 -benzodioxol-5-yl)-l-(N-(n-propyl -N- methylaminocarbonylmethyl)-pyrroHdine-3 -carboxylic acid Using the procedures described in Example 1 the title compound was prepared as an amorphous sohd. Rotational isomers are seen in the NMR. 1H NMR (CDC_ 3 , 300 MHz) ⁇
  • Example 17 trans, trans-2-(4-Methoxyphenyl)-4-( 1 ,3-benzodioxol-5-yl)- 1 -(pyrrolidin- 1 - ylcarbonylmethyl)-pyrroHdine-3-carboxy lie acid Using the procedures described in Example 1 the title compound was prepared as an amorphous sohd.
  • Example 18 trans, trans-2-(4-Methoxyphenyl)-4-( 1 ,3-benzodioxol-5-ylV 1 - (isobutylaminocarbonylmethyl)-pyrroHdine-3-carboxylic acid
  • Example 2 Using the procedures described in Example 1 the title compound was prepared. m.p. 175-177 °C. 1HNMR (CD3OD, 300 MHz) ⁇ 0.87 (dd, 6H), 1.75 (septet, IH), 2.85 (d, IH), 2.90-3.10 (m, 4H), 3.23 (d, IH), 3.40 (m, IH), 3.58-3.67 (m, IH), 3.78 (s, 3H), 3.89 (d, IH), 5.92 (s, 2H), 6.76 (d, IH), 6.86 (dd, IH), 6.91 (d, 2H), 7.02 (d, IH), 7.40 (d, 2H).
  • Example 19 trans, tr_.ns-2-(4-Methoxyphenyl)-4-( 1 ,3-benzodioxol-5-yl)- 1 - (cyclopentylaminocarbonylmethyl)-pyrrolidine-3-carboxylic acid Using the procedures described in Example 1 the title compound was prepared, mp. 137-139 °C.
  • Example 20 trans.trans-2-(4-Methoxyphenyl)-4-( 3-benzodioxol-5-yl)-l-(morphoHn-4- ylaminocarbonylmethyl)-pyrroHdine-3-carboxylic acid Using the procedures described in Example 1 the title compound was prepared as an amorphous sohd.
  • Example 22 trans, trans-2-(4-Methoxyphenyl)-4-( 1 ,3-benzodioxol-5-yl)- 1 -(2- methoxyethylaminocarbonylmethyl)-pyrroHdine-3 -carboxyHc acid Using the procedures described in Example 1 the title compound was prepared, mp.
  • Example 23 tr ⁇ ns.trans-2-(4-Methoxyphenyl)-4-(l,3-benzodioxol-5-yl)-l-(2-butoxyethyl)-pyrroHdine-3- carboxylic acid Using the procedures described in Example 4 the title compound was prepared, mp. 53-55 °C.
  • Example 25 trans, trans-2-( 1 ,3-Benzodioxol-5-yl)-4-(4-methoxyphenylV 1 -(2-propoxyethyl)-pyrroHdine-
  • Example 26 trans, trans-2- 1 ,3-Benzodioxol-5-ylV4-(4-methoxyphenyl)- 1 -[2-(2-methoxyethoxy)ethyl)]- pyrrolidine-3 -carboxylic acid
  • Example 4 substituting the starting materials described in Example 25 and using 2-(2-methoxy ethoxy) ethylbromide to alkylate the pyrrolidine nitrogen afforded the title compound, p. 85-86 °C.
  • Example 27 trans. trans-2-( 1 -Benzodioxol-5-yl)-4-f 4-methoxyphenyl)- 1 -(butoxyethyl)-pyrroHdine-3- carboxylic acid Using the procedures described in Example 4, substituting the starting materials described in Example 25 and using 2-ethoxyethylbromide to alkylate the pyrroHdine nitrogen afforded the title compound, mp. 54-56 °C. !
  • Example 28 trans.trans-2-(4-Methoxyphenyl)-4-(1.4-benzodioxan-6-yl)-l-(propylaminocarbonylmethyl.- pyrroHdine-3-carboxylic acid Using the procedures described in Example 1 and substituting 6-(2-nitrovinyl)-l,4- benzodioxane for 5-(2-nitrovinyl)-l,3-benzodioxole afforded the title compound, mp. 80- 81 °C.
  • Example 29 trans. tr_.ns-2-(4-Methoxyphenyl , -4-( 1 ,4-benzodioxan-6-vD- 1 -(N-methyl-N- propylaminocarbonylmethylVpyrroUdine-3 -carboxylic acid
  • 6-(2-nitrovinyl)-l,4- benzodioxane for 5-(2-nitrovinyl)-l,3-benzodioxole and alkylating the pyrrolidine nitrogen with N-methyl-N-propyl bromoacetamide afforded the title compound, mp. 74-76 °C. Rotational isomers are seen in the NMR.
  • Example 30 trans. tr_.ns-2-(4-Methoxyphenyl)-4-( 1 ,3-benzodioxol-5-yl)- 1 -(N-methyl-N- butylaminocarbonylmethyl)-pyrrolidine-3-carboxy lie acid Using the procedures described in Example 1, the title compound was prepared. Rotational isomers are seen in the NMR.
  • Example 31 A Ethyl 2-(4-methoxy-2-methoxymethoxyphenyl-4-(l,3-benzodioxol-5-yl)-pyrroHdine-3- carboxylate) Using the procedures described in Examples IA and IB and substituting ethyl (4- methoxy-2-methoxymethoxybenzoyl)acetate for ethyl (4-methoxybenzoyl)acetate afforded ethyl 2-(4-methoxy-2-methoxymethoxyphenyl)-4-(l ,3-benzodioxol ⁇ 5-yl)-4,5-dihydro-3H- pyrrole-3-carboxylate.
  • Example 31 A N-butylaminocarbonylmethyl)-pyrroHdine-3-carboxylic acid
  • the compound resulting from Example 31 A was epimerized by the procedure described in Example 6A.
  • the resulting transjrans compound (100 mg, 0.23 mmol) was then reacted by the procedures described in Example ID substituting N-methyl-N-butyl bromoacetamide for N-propyl bromoacetamide to give the title compound (75 mg, 62%).
  • Example 32A Ethyl 2-(4-methoxybenzoyl)-3-carbomethoxy-l,3-benzodioxole-5-propionate
  • ethyl (4-methoxybenzoyl) acetate (4.44 g, 0.02 mmol) dissolved in 20 mL of anhydrous THF was added in portions 480 mg of NaH. The mixture was stirred for 30 minutes under nitrogen at ambient temperature.
  • Methyl (l,3-benzodioxol-5-yl) bromoacetate (5.46 g, 0.02 mol) in 5 mL of THF was added.
  • Example 32B Ethyl l-(3-ethoxypropyl)-2-(4-methoxyphenyl)-4-(l,3-benzodioxol-5-yl)-4.5-dihydro-5-oxo-
  • Example 32C Ethyl 1 -(3-ethoxypropyl)-2-(4-methoxyphenyl, -4-( 1 ,3-benzodioxol-5-yl)-pyrroUdin-5-one-3- carboxylate
  • the compound resulting from Example 32B (300 mg, 0.64 mmol) in 15 mL of methanol was reduced with 100 mg of 10% Pd/C under hydrogen for 3 hours at ambient temperature.
  • the catalyst was removed by filtration and the filtrate was concentrated under reduced pressure to give the title compound.
  • Example 32D tr-.ns.trans-2-(4-Methoxyphenyl)-4-( 3-benzodioxol-5-yl)-l-(3-ethoxypropyl -pyrrolidin-5- one-3 -carboxylic acid
  • To the compound resulting from Example 32C (100 mg, 0.21 mmol) dissolved in 1 mL of ethanol was added 3 drops of a solution of 21% sodium ethoxide in ethanol. The mixture was heated to 70-80 °C for 3 hours, and then a solution of sodium hydroxide (100 mg) in 1 mL of water was added and heating was continued for 1 additional hour.
  • Example 34 tr-.ns,trans-2-(4-Methoxyphenyl)-4-(l,3-benzodioxol-5-yl -l-(N,N- dnsoamylaminocarbonylmethyl)-pyrroHdine-3 carboxylic acid
  • the title compound was prepared as an amorphous soHd using the procedures described in Example 1.
  • Example 35 trans.tra7.s-2-(4-Methoxyphenyl)-4-( 3-benzodioxol-5-yl)-l-(N,N- dipentylaminocarbonylmethyl)-pyrrolidine-3 -carboxylic acid
  • the title compound was prepared as an amorphous sohd using the procedures described in Example 1.
  • Example 36 trans.trans-2-(4-Methoxyphenyl)-4-(1.3-benzodioxol-5-yl)-l-(N,N-di(2- methoxyethyl)aminocarbonylmethyl)-pyrrolidine-3-carboxy lie acid
  • Example 37 transJra»s-2-(4-Methoxyphenyl)-4-(l,3-benzodioxol-5-ylVl-(2-hexynyl)-pyrroHdine-3- carboxylic acid
  • the compound resulting from Example 6A was reacted with 109 mg of l-bromo-2-hexyne, prepared by the method described in Perkin I, , 2004 (1987), for 1 hour at 55 °C, to give 226 mg of the intermediate ester.
  • the ester was hydrolyzed using NaOH in ethanol-water for 3 hours at room temperature to give 175 mg of the title compound.
  • Example 38 trans.trans-2-(4-Methoxyphenyl)-4-(1 -benzodioxol-5-yl -l-(N-cyclopropylmethyl-N- propylaminocai"bonylmethyl)-pyrroHdine-3-carboxylic acid
  • the title compound was prepared using the procedures described in Example 1. m.p.
  • Example 39 t/' ⁇ ns,tr-.ns-2-(4-Methoxyphenyl)-4-(1.3-benzodioxol-5-yl)-l-(N-methyl-N- pentylaminocarbonylmethyl)-pyrrolidine-3-carboxylic acid
  • the title compound was prepared as an amorphous solid using the procedures described in Example 1. Rotational isomers were seen in the NMR. H NMR (CDCI3, 300
  • Example 40 transJrans-2-(4-Methoxyphenyl)-4-( 3-benzodioxol-5-ylVl-(N,N- dnsobutylaminocarbonylmethyl)-pyrroHdine-3-carboxylic acid
  • the title compound was prepared using the procedures described in Example 1. m.p.
  • Example 41 trans. trans-2-(4-Methoxyphenyl)-4-( 1.3-benzodioxol-5-yl)- 1 -(N-methyl-N-(2- propynyl)aminocarbonylmethyl)-pyrroHdine-3-carboxylic acid
  • Example 42 trans. trans-2-(4-Methoxyphenyl)-4-( 1 ,3-benzodioxol-5-yl)- 1 -(N-methyl-N-(n- hexyl aminocarbonylmethyl)-pyrrolidine-3-carboxy lie acid
  • the title compound was prepared as an amorphous solid using the procedures described in Example 1.
  • 1H NMR (CDC1 3 , 300 MHz) ⁇ 0.85 (2 triplets, I 7Hz, 3H), 1.00-
  • Example 44 tr-.nsJrans-2-(4-Methoxyphenyl)-4-(l,3-benzodioxol-5-yl)-l-(N,N- diethylaminocarbonylmethylVpyrroUdine-3-carboxylic acid
  • the title compound was prepared using the procedures described in Example 1. p. 132-134 °C.
  • Example 46 trans.tra?zs-2-(4-Methoxyphenyl)-4-(l,3-benzodioxol-5-yl)-l-(N-methyl-N- cyclohexylaminocarbonylmethyl -pyrroHdine-3-carboxylic acid
  • the title compound was prepared as an amorphous solid using the procedures described in Example 1. Rotational isomers were seen in the NMR.
  • Example 47 trans.tr-.ns-2-(4-Methoxyphenyl)-4-(l,3-benzodioxol-5-yl)-l-(N,N-di(n- propyl)aminocarbonyHnethyl)-pyrroUdine-3-carboxylic acid
  • the title compound was prepared using the procedures described in Example 1. mp. 170-172 °C.
  • Example 48 trans.trans-2-(4-Methoxyphenyl)-4-(l,3-benzodioxol-5-yl)-l-(N-methyl-N- isobutylaminocarbonylmethyl -pyrroUdine-3-carboxylic acid
  • the title compound was prepared as an amorphous sohd using the procedures described in Example 1. Rotational isomers were seen in the NMR.
  • Example 49A E-2-(3.4-MethylenedioxyphenyD- 1 -nitroethene
  • piperonal 75g, 500 mmol
  • methanol 120 mL
  • sodium hydroxide 21 g, 525 mmol, 1.05 eq
  • the reaction mixture became cloudy, turning to a thick paste.
  • Example 49B Ethyl 2-(4-methoxyphenyl)oxo-4-nitro-3-(3,4-methylenedioxyphenyl butyrate To a stirred solution of the nitrostyrene resulting from Example 49A (14.17 g, 73.34 mmol, 1.2 eq) in a mixture of propan-2-ol (75 mL) and tetrahydrofuran (175 mL) at room temperature was added successively a solution of ethyl (4-methoxybenzoyl) acetate (11.5 g, 51.7 mmol) in THF (50 mL) foUowed by l,8-diazabicyclo[5,4,0]undec-7-ene (DBU) (0.45 mL, 3.0 mmol, 0.05 eq).
  • DBU l,8-diazabicyclo[5,4,0]undec-7-ene
  • Example 50 trans. trans-2-(4-Methoxyphenyl)-4-( 1 ,3-benzodioxol-5-yl)- 1 -( t-butyloxycarbonylmethyl)- pyrroHdine-3 -carboxylic acid
  • acetonitrUe 2. mL was added successively diisopropylethylamine. (70 ⁇ L, 0.40 mmol, 1.5 eq) and t-butyl bromoacetate (48 ⁇ L, 0.29 mmol, 1.1 eq).
  • Example 51 trans. trans-2-(4-MethoxyphenylV4-( 1 -naphthyl)- 1 -(N-methyl-N- propyl)aminocarbonylmethyl)-pyrrolidine-3-carboxy lie acid
  • the title compound was prepared by the procedures described in Examples 1 and 49 substituting naphthalene- 1 -carboxaldehyde for piperonyl in Example 49 A. Rotational isomers are seen in the NMR.
  • Example 52B tr ⁇ ns.tr_-ns-2-(4-Methoxyphenyl)-4-(2,3-dihydrobenzofuran-5-ylVl-(N-methyl-N- propyl)aminocarbonylmethyl)-pyrroUdine-3-carboxylic acid
  • the title compound was prepared by the procedures described in Examples 1 and 49 substituting the compound resulting from Example 52A for piperonal in Example 49A. Rotational isomers are seen in the NMR.
  • l H NMR 300 MHz, CDCI 3
  • Example 53 trans.tr-.ns-2.4-Bis(4-methoxyphenyl)-l-( -methyl-N-propyl)aminocarbonylmethyl)- pyrrolidine-3 -carboxylic acid
  • Example 54 trans. trans-2-(4-Methoxyphenyl)-4-(3 ,4-dimethoxyphenyl)- 1 -(N-methyl-N- propyl)aminocarbonylmethyl)-pyrroHdine-3-carboxylic acid
  • Example 55 trans,trans-2-(4-Methoxyphenyl -4-(3-metho ⁇ yphenyl)-l-(N-methyl-N- propyl)aminocarbonylmethyl -pyrrolidine-3-carboxylic acid
  • the title compound was prepared by the procedures described in Examples 1 and 49 substituting 3-methoxybenzaldehyde for piperonal in Example 49A. Rotational isomers are seen in the NMR.
  • Example 56 trans. tr-.ns-2-(4-MethoxyphenyB-4-(2-naphthyl)- 1 -(N-methyl-N- propyl)aminocarbonylmethyl)-pyrroHdine-3-carboxy lie acid
  • the title compound was prepared by the procedures described in Examples 1 and 49 substituting naphthylene-2-carboxaldehyde for piperonal in Example 49 A. Rotational isomers are seen in the NMR.
  • Example 57 trans.trans-2-(4-Methoxyphenyl)-4-(l,3-benzodioxol-5-yl)-l-(2-(ethylsulfinyl)ethyl)- pyrroHdine-3-carboxylic acid
  • 2-chloroethyl ethyl sulfide 67.5 mg, 0.5 mmol, 2 equivalents
  • KI 0.5 mL
  • diisopropylethylamine diisopropylethylamine
  • Example 58 trans, trans-2-(4-Methoxyphenyl)-4-( 1 ,3-benzodioxol-5-yl)- 1 -(2-
  • Example 59 tr-.ns.tr-.ns-2-(4-Methoxyphenyl)-4-(l,3-benzodioxol-5-yl)-l-(2-(isobutoxy)ethyl)- pyrroHdine-3 -carboxylic acid
  • the title compound was prepared by the procedures described in Example ID from the compound resulting from Example IC and 2-(isobutoxy) ethyl bromide. m.p. 68-70 °C.
  • Example 60 trans. trans-2-(4-Methoxyphenyl)-4-(l .3-benzodioxol-5-yl)- 1 -(butylsulfonyl)-pyrroHdine-3- carboxylic acid To 100 mg (0.271 mmol) of the compound resulting from Example IC dissolved in
  • the ester 120 mg, 0.244 mmol was dissolved in 1 mL of EtOH, and a solution of 100 mg of NaOH in 1 mL of water was added. The mixture was stirred for 3 hours at room temperature and then concentrated under reduced pressure. Water (5 mL) was added and the solution was washed with ether to remove any unhydrolyzed trans-cis isomer. The aqueous solution was acidified to pH ⁇ 6 with acetic acid and then extracted with EtOAc (2 x 50 mL). The combined organic extracts were washed with brine, dried over sodium sulfate and concentrated under reduced pressure to afford the pure title compound (60 mg, 53%) as a white sohd. mp. 67-69 °C.
  • Example 61 trans. tr__ns-2-(4-Methoxyphenyl)-4-( 1.3-benzodioxol-5-yl)- 1 -(2-(N-methyl-N- isopropylcarbonylamino.ethyl pyrroHdine-3-carboxylic acid
  • Example 61 A trans.tr ⁇ ns-2-(4-Methoxyphenyl)-4-(1 -benzodioxol-5-yl)-l-(2-bromoethyl)-pyrroHdine-3- carboxylic acid ethyl ester
  • Example IC trans. tr__ns-2-(4-Methoxyphenyl)-4-( 1.3-benzodioxol-5-yl)- 1 -(2-(N-methyl-N- isopropylcarbonylamino.ethyl pyrroHdine-3-carboxylic acid
  • Example 61
  • Example 61 A To the compound resulting from Example 61 A (450 mg) dissolved in 10 mL of EtOH was added 0.5 mL of 40% aqueous methylamine and 50 mg of sodium iodide. The mixture was heated at 80 °C for 1 hour, and then the solvents were removed in vacuo. The residue was taken up in EtOAc and washed sequentially with water and brine, dried and concentrated in vacuo. The resultant product was carried on without further purification.
  • Example 61C trans. trans-2-(4-Methoxyphenyl)-4-( 1 ,3-benzodioxol-5-yD- 1 -(2-(N-methyl-N- isobutyrylamino)ethylVpyrroUdine-3-carboxylic acid
  • Example 62 trans. trans-2-(4-Methoxyphenyl)-4-( 1 ,3-benzodioxol-5-yl)- 1 -(2-(N-methyl-N- propionylamino)ethyl)-pyrroHdine-3-carboxyHc acid
  • the title compound was prepared by the procedures described in Example 61 substituting propionyl chloride for isobutyryl chloride in Example 61C.
  • Example 63 trans, trgns-2-(4-Methoxyphenyl)-4-( 1 ,3-benzodioxol-5-yl)- 1 -(N-methyl-N- benzylaminocarbonylmethylVpyrroHdine-3-carboxylic acid Using the procedures described in Example 1 the title compound was prepared.
  • Example 65 tr ⁇ ns.trans-2-(4-Methoxyphenyl)-4-(1 -benzodioxol-5-ylVl-(N-methyl-N-(2,2- dimethylpropyl)aminocarbonylmethylVpyrroUdine-3-carboxylic acid Using the procedures described in Example 1 the title compound was prepared.
  • Example 66 trans.tr-,ns-2-(4-Methoxyphenyl)-4-(1.3-benzodioxol-5-yl)-l-(2-(N-methyl-N- butylsulfonylamino.ethyl)-pyrroHdine-3-carboxy lie acid
  • Example 69A tr_.ns-5-Methylhex-2-enoic acid ethyl ester OU dispersion sodium hydride (0.85 g) was washed with hexanes and suspended in THF (20 mL), and the mixture was cooled in an ice bath to 0 °C.
  • Diisopropyl(ethoxycarbonylmethyl) phosphonate (5.0 mL) was added slowly and the mixture stirred for 20 minutes at 0 °C.
  • Isovaleraldehyde (2.0 mL) in THF (5 mL) was added dropwise over five minutes. The ice bath was removed and the mixture stirred for 18 hours at ambient temperature.
  • Example 69B trans-5-Methylhex-2-en- 1 -ol
  • the compound resulting from Example 69 A (2.0 g) was dissolved in toluene and cooled to 0 °C in an ice bath.
  • Diisobutylaluminum hydride (1.5 N in toluene, 20 mL) was added dropwise and the solution stirred at 0 °C for two hours.
  • Citric acid solution 25 mL was added very slowly to the cooled solution. The resulting mixture was stirred for 18 hours at ambient temperature. Diethyl ether (50 mL) was added, the sohds removed by filtration and washed with additional ether (2 x 25 mL).
  • Example 69B The compound resulting from Example 69B (1.0 g) was dissolved in diethyl ether and cooled to 0 °C in an ice bath. Phosphorus tribromide (2.5 g, 0.87 mL) was added dropwise and the solution stirred at 0 °C for two hours. The solution was poured onto ice, the layers separated, and the aqueous layer extracted with additional ether (3 x 25 mL). The ether layers were combined, dried, and evaporated to give a colorless oU which was used without further purification (0.95 g).
  • Example 70 trans. trans-2-(4-Methoxyphenyl , -4-( 1 ,3-benzodioxol-5-yl)- 1 -N-(trans-3 , 5-dimethylhex-2- enyl)-pyrroUdine-3-carboxylic acid
  • the title compound was prepared by the procedures described in Example 69 but substituting 4-methyl-2-pentanone for isovaleraldehyde in Example 69A, which gave ⁇ 7: 1 mixture of trans/cis olefins.
  • the crude product was purified by preparative HPLC (Vydac ⁇ C18) eluting with a 10-70% gradient of CH3CN in 0.1% TFA.
  • Example 71 A 1 -Chloro-3 - ⁇ ropyl-2-hexanone To 2-propylpentanoic acid (156.6 ⁇ l, 1.00 mmol) dissolved in anhydrous dichloromethane (2 mL) was added DMF (3 ⁇ L, 4 mole %), and the solution was cooled to 0 °C under a nitrogen atmosphere. To the solution was added oxalyl chloride (94.3 ⁇ L, 1.08 mmol) dropwise over a few minutes. The reaction was stirred 18 hours while warming to ambient temperature. The mixture was cooled to 0 °C and excess -0.3 M ethereal diazomethane solution was added. The reaction mixture was stirred 18 hours whUe warming to ambient temperature.
  • reaction mixture was washed with 1 M aqueous sodium carbonate solution (30 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure.
  • the residue was dissolved in ether (2 mL) and cooled to 0 °C under a nitrogen atmosphere.
  • Hydrogen chloride as a 4 N solution in dioxane (275 ⁇ L, 1.10 mmol) was added dropwise over a few minutes.
  • the reaction was stirred 18 hours while warming to ambient temperature.
  • the reaction mixture was concentrated under reduced pressure and the residual oU was used in the next step without further purification.
  • Example 7 IB tr-.ns.trans-Ethyl 2-(4-methoxyphenyl)-4-(l,3-benzodioxol-5-yl)-l-(4- heptylcarbonylmethyl)-pyrroUdine-3-carboxylate
  • a solution of the transjrans ethyl carboxylate from Example IC (295 mg, 0.80 mmol as a 50 % solution in toluene), diisopropylethylamine (700 ⁇ L, 4.00 mmol) and acetonitrile (4 mL).
  • Example 71 C transJrans-2-(4-Methoxyphenyl)-4-(l,3-benzodioxol-5-yl)-l-(4-heptylcarbonylmethyl)- pyrrolidine-3-carboxylic acid
  • a solution of lithium hydroxide 38 mg, 0.9065 mmol
  • water 2.5 mL
  • additional lithium hydroxide (19 mg, 0.4532 mmol) in water (0.5 mL) was added, and stirring was continued 24 hours.
  • Example 72 trans, trans-2-(4-Methoxyphenyl)-4-( 1 ,3-benzodioxol-5-yl)- 1 -(valerylmethyl -pyrroHdine-3 - carboxylic acid
  • Example 72A 1 -Chloro-2-hexanone Using the procedure described in Example 71 A and substituting pentanoic acid for 2- propylpentanoic acid afforded the title compound as an oU which was used in the next step without further purification.
  • Example 72B trans.tra7.s-Ethyl 2-(4-methoxyphenyl)-4-(l,3-benzodioxole-5-yl)-l-(valerylmethyl)- pyrroHdine-3 -carboxylate Substituting the compound resulting from Example 72A for l-chloro-3-propyl-2- hexanone and using the procedure described in Example 7 IB, except deleting the first addition of sodium iodide, stirring 18 hours at ambient temperature and purifying by silica gel chromatography eluting with 3:17 ethyl acetate-hexane, the title compound 305 mg (65%) was obtained as a yellow oU.
  • Example 72C trans. tr_.ns-2-(4-Methoxyphenyl)-4-( 1 ,3 -benzodioxol-5-yl)- 1 -(valerylmethylVpyrrolidine-3- carboxylic acid
  • trans-Ethyl 2-(4- methoxyphenyl)-4-(l,3-benzodioxol-5-yl)-l-(4-heptylcarbonylmethyl)-pyrroHdine-3- carboxylate and using the procedure described in Example 71C, except only one solution of lithium hydroxide (81.5 mg, 1.942 mmol) in water (3.5 mL) was added followed by stirring for 18 hours, the title compound 130 mg (46%) was obtained as an off white powder.
  • Example 73B trans, trans- and cis.
  • the resultant product from Example 73A (220 mg, 0.404 mmol) was dissolved in 2 mL dry THF and added dropwise to a stirred, cooled (0 °C) suspension of sodium hydride (23 mg of a 60% by weight mineral oU suspension, 16.5 mg, 0.69 mmol) in 0.2 mL THF, under an argon atmosphere.
  • Example 73 C trans. trans-2-(4-Methoxyphenyl)-4-( 1 ,3-benzodioxol-5-yl)- 1 -(N-(3.4-dimethoxybenzyl)-N- methylaminocarbonylmethyl)pyrrolidine-3-carboxylic acid
  • a solution of lithium hydroxide monohydroxide 17.0 mg, 0.41 mmol
  • the solution was concentrated in vacuo, and the residue was partitioned between 15 mL H 2 O and 15 mL Et 2 ⁇ .
  • the aqueous phase was extracted with 5 mL Et 2 O, then the aqueous phase was acidified with 10% aqueous citric acid.
  • the acidic aqueous phase was saturated with NaCl and extracted with 3 x 15 mL EtOAc.
  • the EtOAc extracts were combined, dried (Na 2 SO4), then filtered and concentrated in vacuo to give 40 mg (42%) of the title compound as a white foam.
  • Example 73C The procedure of Example 73C was used, with the substitution of the resultant compound from Example 73A for the resultant compound from Example 73B, to provide the title compound.
  • Example 75A trans. trans-2-(4-Methoxyphenyl . -4-( 1 ,3-benzodioxol-5-yl)- 1 -(( 1 R)- 1 - (benzy loxycarbonyl)butyl)pyrroHdine-3 -carboxylic acid ethyl ester
  • the procedure of Fung, et. al., I. Med. Chem., 35(10): 1722-34 (1992) was adapted.
  • the resultant compound from Example 6A (103 mg, 0.279 mmol) was dissolved in 0.7 mL of nitromethane and 0.7 mL of H 2 O, and ammonium carbonate (34 mg, 0.35 mmol) and
  • Example 75B trans. trans-2-(4-Methoxyphenyl , -4-( 1 ,3-benzodioxol-5-yl)- 1 -(( 1 R) - 1 -(N,N- dipropylaminocarbonyl)-l-butyl)pyrroUdine-3-carboxylic acid ethyl ester
  • the resultant compound from Example 75A (101 mg, 0.180 mmol) and 30 mg of 10% palladium on charcoal were stirred in 2 mL EtOAc under 1 atmosphere of H2 for 4 hours.
  • the reaction mixture was filtered through a plug of Celite, using 15 mL MeOH to wash the catalyst.
  • the combined filtrate and wash were concentrated in vacuo to give 81.4 mg (96%) of the crude acid as a white solid.
  • Example 76 (2S.3S,4S)-2-(4-Methoxyphenyn-4-(L3-benzodioxol-5-yl)-l-((lRVl-(N,N- dipropylaminocarbonyl)-l-butyl)pyrroHdine-3-carboxylic acid
  • the procedure of Example 73C was foUowed, with the substitution of the more polar isomer from Example 75B for the resultant product from Example 73B, to provide the title compound in 88% yield.
  • Example 77A trans. tr_.ns-2-(4-Methoxyphenyl -4-( 1 ,3-benzodioxol-5-vD- 1 -(( 1 S - 1 -(N,N- dipropylaminocarbonylVl-butyl)pyrrolidine-3-carboxylic acid ethyl ester (2R)-N,N-dipropyl 2-hydroxypentanamide (106 mg, 0.528 mmol, made by standard procedure) was dissolved in 2 mL THF under an argon atmosphere, dnsopropylethylamine (75 mg, 0.58 mmol) was added, then the solution was cooled to -20 °C.
  • Trifluoromethanesulfonic anhydride (95 ⁇ L, 159 mg, 0.565 mmol) was added to the cooled solution over 1 minute, and the reaction mixture was stirred at -20 °C for 1 hour, and at room temperature for an additional 1 hour. The resulting slurry was recooled to 0 °C, and a solution of the resultant compound from Example 6A (195 mg, 0.528 mmol) and dnsopropylethylamine (101 ⁇ L, 75 mg, 0.58 mmol) in 3 mL of CH 2 C1 2 was added. The reaction was stirred at 0 °C for 3 hours and for an additional 2 days at room temperature.
  • Example 77B (2S.3S,4S)-2-(4-MethoxyphenylV4-(1.3-benzodioxol-5-ylVl-((lSVl-(N.N- dipropylaminocarbonyl)-l-butyl)pyrroHdine-3-carboxylic acid
  • the procedure of Example 73 C was foUowed, with the substitution of the less polar isomer from Example 77A for the resultant product from Example 73B, to provide the title compound in 100% yield.
  • Example 78 (2R.3R.4RV2-(4-Methoxyphenyl -4-( 1.3-benzodioxol-5-yl , - 1 -(( 1 S 1 -(N.N- dipropylaminocarbonylVl-butyl)pyrrolidine-3-carboxylic acid
  • the procedure of Example 73 C was foUowed, with the substitution of the more polar isomer from Example 77A for the resultant product from Example 73B, to provide the title compound in 88% yield.
  • Example 79 trans.tr ⁇ ns-2-(4-Methoxyphenyl -4-(l,3-benzodioxol-5-yl)-l- N.N-_ t( - butyl)aminocarbonylmethyl)-3-(5-tetrazolyl)Oyn:o]idm.e
  • Carbonyldiirnida ⁇ ole (510 mg, 3.148 mmol) was added to 1.020 g (2.00 mmol) of the compound resulting from Example 43 in 2.7 mL THF, and the mixture was heated for 40 minutes at 50 °C. The reaction mixture was cooled in an ice bath, and 25% solution of ammonia in methanol was added.
  • Example 81 trans. trans-2-(4-Methoxyphenyl)-4-( 1 ,3 -benzodioxol-5-yl)- 1 -( ⁇ , ⁇ -di(n- butyl . amino carbonylmethy l)pyrroHdine-3 -carboxylic acid N,N-Dibutyl glycine (150 mg, 0.813 mmol), prepared by the method of Bowman, R.E., J. Chem. Soc. 1346 (1950), in 0.7 mL of THF was treated with 138 mg (0.852 mmol) carbonyldiimidazole and heated for 30 minutes at 50 °C.
  • Example 82 trans.trans-2-(4-Methoxyphenyl)-4-(l,3-benzodioxol-5-yl)-l-(N-n-butyl)-N-(n- propyl)aminocarbonylmethyl)pyrroHdine-3-carboxylic acid
  • the title compound was prepared using the procedures described in Example 1. m.p. 160-162 °C.
  • Example 83 trans.tra7.s-2-(4-Methoxyphenyl)-4-(l,3-benzodioxol-5-yl)-l-[2-(N,N-di(n- propyl)aminocarbonyl)ethyl]pyrrolidine-3-carboxylic acid
  • the compound resulting from Example 6A 250 mg, 0.677 mmol
  • 10 mg acetic acid were heated at 85 °C in 0.75 mL of methoxyethanol for one hour.
  • Toluene was added, and the solution was washed with bicarbonate solution, dried, and concentrated. Chromatography on sUica gel eluting with 3: 1 hexane-ethyl acetate gave 283 mg (80%) of the diallyl compound.
  • the diallyl compound was hydrogenated using 10% Pd/C catalyst (27 mg) in ethyl acetate (25 mL) under a hydrogen atmosphere.
  • the catalyst was removed by filtration, and the filtrate was concentrated to afford the dipropyl amide ethyl ester in 100% yield.
  • the ester was hydrolyzed to the title compound by the method of Example ID in 83% yield.
  • ⁇ NMR (CDC1 3 , 300 MHz) ⁇ 0.82 and 0.83 (two triplets, I 7Hz, 6H), 1.39-1.54 (m,
  • Example 84 trans.trans-2-(4-Methoxyphenyl)-4-(L3-benzodioxol-5-yl)-l-(N,N-di(n- butyl) amino carbonyl)pyrroHdine-3 -carboxylic acid
  • Example 85 trans.trans-2-(4-Methoxyphenyl)-4-(l,3-benzodioxol-5-yl)-l-tN.N-_/tt - bt.tv/)-.mtnoc_.rbonv/7?.et v/)pyrroHdine-3-carboxylic acid sodium salt
  • Sodium hydroxide 48.2 mg of 98.3% pure, 1.184 mmol
  • MeOH 610 mg, 1.196 mmol.
  • the solution was concentrated to dryness, and the resulting powder was stirred with heptane.
  • the heptane was removed in vacuo to give a powder which was dried in the vacuum oven for 2 hours at 60 °C to yield 627.5 mg of the title compound.
  • Example 86 trans.tr ⁇ ns-2-(4-Methoxyphenyl -4-(l,3-benzodio'xol-5-yl ' )-l-[2-( ⁇ , ⁇ -di(n- butyl)amino)ethyllpyrrolidine-3-carboxylic acid
  • Example 87 tra7?s,trans-2-(4-Methoxyphenyl)-4-(l,3-benzodioxol-5-yl)-l- ⁇ 2-[N-(N,N-di(n- butyl)aminocarbonyl)-N-methylamino]ethyl ⁇ pyrrolidine-3-carboxy lie acid
  • Dibutyl carbamoyl chloride (135 mg) was added to the compound resulting from Example 6 IB (250 mg) and 150 mg triethylamine in 1 mL dichloromethane. After stirring 1 hour at room temperature, toluene was added, and the solution was washed with potassium bicarbonate solution, dried over Na 2 SO4 and concentrated.
  • Example 88 trans,trans-2-(4-Methoxyphenyl)-4-(l,3-benzodioxol-5-yl)-l-(N,N-di(n- butyl) amino carbonylmethy l)pyrroUdine-3 -(N-methanesulfonyl)carboxamide
  • Carbonyldiimidazole (75 mg, 0.463 mmol) was added to 150 mg (0.294 mmol) of the compound resulting from Example 43 in 0.4 mL of tetrahydrofuran, and the solution was stirred at 60 °C for 2 hours.
  • Example 89 tr-.ns.tr-.ns-2-(4-Methoxyphenyl)-4-(l,3-benzodioxol-5-yl)-l-(N.N-di(n- butyl) amino carbonylmethy l)pyrroHdine-3 -(N-benzenesulfonyl) carboxamide
  • the compound resulting from Example 43 was converted to the title compound by the method of Example 88 substituting benzenesulfonamide for methanesulfonamide. m.p. 169- 171 °C for a sample recrystaUized from acetonitrile.
  • Example 90 tr-.ns.trans-2-(4-MethoxyphenylV4-(1.3-benzodioxol-5-ylVl-[TSl,N-di(n-butyl) aminosulfonylmethyl]-pyrroHdine-3-carbo ⁇ ylic acid
  • Chloromethyl sulfenyl chloride prepared by the method of Brintzinger et. al., Chem. Ber. 85: 455-457 (1952), is reacted with dibutylamine by the method of E. Vilsmaier described in Liebigs Ann. Chem. 1055-1063 (1980) to give N,N-dibutyl chloromethyl sulfenyl chloride.
  • dimethyl(methylthio)sulfonium tetraflouroborate is reacted with dibutylamine to give N,N-dibutyl methylsulfenyl chloride which is chlorinated with N- cMorosuccinimide to give chloromethyl sulfenyl chloride by the method of E. VUsmaier, described in the above reference.
  • N,N-dibutyl chloromethyl sulfenyl chloride is reacted with the compound resulting from Example 6A to give ethyl trans,tra7zs-2-(4-Methoxyphenyl)-4-(l,3- benzodioxol-5-yl)-l-psf,N-di(n-butyl)aminosulfenylmethyl]-pyrroHdine-3-carboxylate.
  • This is oxidized with osmium tetroxide and N-methyl morphoHne N-oxide by the method of S. Kaldor and M. Hammond, Tet. Lett. 32: 5043-5045 (1991) to give the title compound after hydrolysis of the ethyl ester.
  • Example 91 A ( ⁇ .-Dibutyl 2-bromopropanamide 2-Bromopropanoic acid (510 mg, 3.33 mmol) and 4-methylmorphoHne (0.74 mL, 6.73 mmol) were dissolved in 10 mL of CH 2 Cl2, the solution was cooled to 0 °C under a N2 atmosphere, and then treated dropwise with isobutyl chloroformate (0.45 mL , 3.5 mmol). After 10 minutes at 0 °C, dibutylamine (0.57 mL, 3.4 mmol) was added. The reaction was stirred at 0 °C for 1 hour and for an additional 16 hours at room temperature.
  • Example 9 IB trans, trans- and cis, trans-2-(4-Methoxyphenyl)-4-( 1 ,3-benzodioxol-5-yl)- 1 -((N.N-di(n- butyl)amino)carbonyl-l-(RS)-ethyl)pyrroUdine-3-carboxylic acid ethyl ester
  • a solution of the resultant mixture of trans Jrans and cisjrans compounds from Example IC (232 mg, 0.628 mmol) and the resultant compound from Example 91 A (183 mg, 0.693 mmol) in 2 mL of CH3CN was treated with dnsopropylethylamine (0.22 mL, 1.3 mmol).
  • Example 91 C trans.tr-.ns-2-(4-MethoxyphenylV4-(l,3-benzodioxol-5-yl)-l-((N,N-dibutylamino)carbonyl- l-(RS)-ethyl)pyrrolidine-3-carboxylic acid
  • the procedure of Example 73C was used, substituting the resultant compound from Example 9 IB for the resultant compound from Example 73 B to give the title compound in 61% yield.
  • a solution of the crude compound (660 mg, 2.07 mmol) in 3 mL methanol was treated with a solution of sodium methoxide (made by the addition of sodium metal (14 mg, 0.61 mmol) to 1 mL of methanol).
  • the resultant solution was heated at reflux for 18 hours.
  • the reaction was concentrated under reduced pressure, and the residue was partitioned between 25 mL saturated NaHCO3 diluted with 10 mL water and 30 mL of CH 2 C1 2 -
  • the aqueous phase was extracted (2 x 30 mL CH 2 C1 2 ), then the combined organic phases were washed with 20 mL brine, dried over Na 2 SO4, filtered and the filtrate concentrated under reduced pressure to afford the crude product.
  • Example 92C trans. trans-2-(Pentyl)-4-( 1 ,3-benzodioxol-5-yl)- 1 -(N,N-di(n- butyl) amino carbonylmethyl)pyrroHdine-3 -carboxylic acid
  • the procedures of Example IB-ID were used, with the substitution of the resultant compound from Example 92 A for the resultant compound from Example IB, to provide the title compound as a white foam.
  • Example 93 trans, trans-2-(PentylV4-( 1 ,3-benzodioxol-5-yl)- 1 - [2-(N-propyl-N- propylsulfonylamino)ethyl]pyrroHdine-3-carboxylic acid
  • Example 93A Methyl trans,trans-2-(pentylV4-fl,3-benzodioxol-5-yl -l-(2-bromoethyl pyrroHdine-3- carboxylate
  • the procedure of Example 61 A was used, with the substitution of the resultant compound from Example 92B for the resultant compound from Example IC, to provide the title compound as a yellow oU.
  • *H NMR (CDCI 3 , 300 MHz) ⁇ 0.89 (br t, J 7Hz, 3H), 1.24-
  • Example 93B Methyl trans.trans-2-(PentylV4-(l,3-benzodioxol-5-ylVl-[2-(N-propyl-N- propylsulfonylamino) ethyl]pyrroHdine-3 -carboxylate
  • the reaction was concentrated under reduced pressure, then the residue was dissolved in 35 mL ethyl acetate and extracted with 2 x 15 mL of 1 M aqueous Na2CO3. The organic phase was washed with 15 mL brine, then dried over Na2SO4, filtered and concentrated under reduced pressure to provide the crude secondary amine as a yellow oU (94.2 mg).
  • the crude amine was dissolved in 1 mL of CH2CI2, diiosopropylethylamine (65 ⁇ L, 0.373 mmol) was added, followed by propylsulfonyl chloride (29 ⁇ L, 0.26 mmol). The solution was stirred at room temperature for 4 hours.
  • Example 93 C trans.trans-2-(Pentyl)-4-(l,3-benzodioxol-5-yl)-l-[2-(N-propyl-N- propylsulfonylamino)ethyl]pyrroHdine-3-carboxy lie acid
  • Example 94 trans. trans-2-(Propyl)-4-( 1 ,3-benzodioxol-5-yl)- 1 -(N,N-di(n- butyl)aminocarbonylmethyl pyrrolidine-3-carboxylic acid
  • Example 94B Ethyl trans. trans-2-(propyl)-4-(l ,3-benzodioxol-5-yl)pyrroHdine-3-carboxylate
  • the procedure of Example 92B was foUowed, with the substitution of the resultant compound from Example 94A for the resultant compound from Example 92A, to afford the title compound.
  • Example 94C tr-.ns.trans-2-(Propyl)-4-(l,3-benzodioxol-5-yl)-l-((N,N-di(n-butyl)aminocarbonylmethyl)- pyrrolidine-3 -carboxylic acid
  • the procedure of Example 92C was foUowed, with the substitution of the resultant product from Example 94B for the resultant product from Example 92B, to give the title compound.
  • Example 95A trans, trans-2-(4-Methoxyphenyl)-4-( 1 ,3-benzodioxol-5-yl)- 1 -([tert- butyloxycarbonylaminocarbonylmethyl]pyrroHdine-3 -carboxylic acid
  • the resulting mixture of 64% transjrans- and cisjrans- pyrrolidines resulting from Example IC (3.01 g, 8.15 mmol) was dissolved in 50 mL of methylene chloride.
  • Example 95C (2R.3R.4SV(+ -Ethyl 2-(4-metho ⁇ yphenylV4-(1.3-benzodioxol-5-ylVpyrroHdine-3- carboxylate
  • the compound resulting from Example 95B (251 mg, 0.568 mmol) was dissolved in 20 mL of a saturated solution of anhydrous HCl(g) in anhydrous ethanol.
  • the resulting solution was heated at 50 C. with stirring for 18 hours at which point aU of the precipitated solid had dissolved.
  • the reaction mixture was concentrated to a solid which was partitioned between O.8 M aqueous sodium carbonate (50 mL) and methylene chloride (50 mL).
  • Example 95D (2R.3R.4S -(+)-2-(4-Methoxyphenyl.-4-( 3-benzodioxol-5-yl -l-(tert-butyloxycarbonyl- aminocarbonylmethy -pyrroHdine-3-carboxy lie acid
  • dHsopropylethylamine 137 mg, 185 ⁇ L, 1.06 mmol
  • acetonitrile (2 mL)
  • N,N-di-(n- butyl)bromoacetamide 133 mg, 0.531 mmol
  • Example 95A The product of Example 95A (2.858 g) was suspended in 10 mL of EtOAc. 0.7833 g of R (+) alpha methyl benzy lamine in 3 mL ethyl acetate was added. On swirling aU of the soHds were dissolved. The ethyl acetate was removed in vacuum. Ether (13 ml) was added to the residue. When aU of the residue had dissolved, 5 mg of seed crystals were added and these crystals were crushed with a metal spatula while cooling in ice. The product crystaUized very slowly. After 1 hour the sohd was filtered and washed with ether giving 1.4213 g, p. 163-167°.
  • the filtrate was concentrated, cooled and scratched with a spatula to give a second crop 0.1313 g, mp. 164-168°.
  • the filtrate was concentrated again and put in the refrigerator and let stand overnight giving 1.6906 g, mp. 102-110°. (HPLC of this showed 20%of the desired enantiomer and 80% of the unwanted enantiomer.)
  • Example 95B Treatment of the crystalline product with 10% citric acid and ether according the method described in Example 95B provided the title compound.
  • Example 96 tr_.ns.trans-2-(4-Methoxyphenyl)-4-(l,3-benzodioxol-5-yl)-l-[2-(N-propyl-N- butyrylamino) ethyl]py ⁇ OHdine-3 -carboxylic acid
  • the title compound was prepared by the methods described in Example 61, but substituting propylamine for methylamine in Example 61B and butyryl chloride for isobutyryl chloride in Example 61 C.
  • the product was purified by preparative HPLC (Vydac ⁇ C18) eluting with a 10-70% gradient of CH 3 CN in 0.1% TFA.
  • Example 97 trans.tr-.7.s-2-(4-Methoxyphenyl)-4-(1.3-benzodioxol-5-yl)-l-[2-(N-propyl-N- (ethylaminocarbonyl.amino ⁇ ethyl]pyrrolidine-3-carboxylic acid
  • the title compound was prepared by the methods described in Example 61 , but substituting propylamine for methylamine in Example 61B and ethyl isocyanate for isobutyryl chloride in Example 61C.
  • the crude product was purified by trituration with 1: 1 diethyl ether-hexane.
  • Example 98 tr-.ns.tr-.ns-2-(4-Methoxyphenyl)-4-(l,3-benzodioxol-5-yl)-l-[2-(N-butyl-N- butyrylamino . ethylJpyrrolidine-3 -carboxylic acid
  • the title compound was prepared by the methods described in Example 61, but substituting butylamine for methylamine in Example 61B and butyryl chloride for isobutyryl chloride in Example 61C.
  • the crude product was purified by trituration with 1: 1 diethyl ether-hexane.
  • Example 99 tra7zs.trans-2-(4-Methoxyphenyl)-4-(l,3-benzodioxol-5-yl)-l-[2-(N- ⁇ ropyl-N- ethoxycarbonylamino)ethyllpyrroHdine-3-carboxy lie acid
  • the title compound was prepared by the methods described in Example 61, but substituting propylamine for methylamine in Example 6 IB and ethyl chloroformate for isobutyryl chloride in Example 61C.
  • the crude product was purified by trituration with 1 : 1 diethyl ether-hexane.
  • Example 100 tra7.s.trans-2-(4-Methoxyphenyl)-4-(l,3-benzodioxol-5-yl)-l-[2-(N-methyl-N-(2- ethylbutyryl)amino)ethyl]pyrrolidine-3-carboxyHc acid
  • HOBt 60 mg
  • EDCI 85 mg
  • N-methylmoipholine 50 ⁇ L
  • DMF 2 mL
  • 2-Ethylbutyric acid was added and the solution stirred overnight at ambient temperature. Water (10 mL) was added, and the mixture was extracted with EtOAc (2 x 25 mL).
  • Example 101 tra7.s,trans-2-(4-Methoxypheny -4-(l,3-benzodioxol-5-ylVl-[2-(N-methyl-N-(2- propylvaleryl amino ethyl1pyrrolidine-3-carboxyHc acid
  • the title compound was prepared by the procedure described in Example 100, but substituting 2-propylpentanoic acid for 2-ethylbutyric acid.
  • the crude product was purified by preparative HPLC (Vydac ⁇ C18) eluting with a 10-70% gradient of CH3CN in 0.1%
  • Example 102 transJr_.ns-2-(4-Methoxyphenyl)-4-(l,3-benzodioxol-5-yl l-[2-(N-propyl-N-(tert- butyloxycarbonylmethyl) amino . ethyl]pyrroHdine-3 -carboxylic acid
  • the title compound was prepared by the methods described in Example 61, but substituting propylamine for methylamine in Example 61B and t-butyl bromoacetate for isobutyryl chloride in Example 61 C.
  • the crude product was purified by trituration with 1 : 1 diethyl ether-hexane.
  • Example 103 trans.trans-2-(4-Methoxyphenyl)-4-(1.3-benzodioxol-5-yl)-l-[2-(N-propyl-N-(n- propylaminocarbonylmethyl)amino)ethyl]pyrroHdine-3-carboxylic acid
  • the title compound was prepared by the methods described in Example 61, but substituting propylamine for methylamine in Example 6 IB and N-propyl bromoacetamide for isobutyryl chloride in Example 61C.
  • the crude product was purified by preparative HPLC (Vydac Cl 8) eluting with a 10-70% gradient of CH 3 CN in 0.1 % TFA.
  • Example 104 trans,tra72s-2-(4-Methoxyphenyl)-4-(l,3-benzodioxol-5-yl)-l-[2-(N-propyl-N-(4- methoxyphenoxycarbony 1) amino) ethyl]pyrrolidine-3 -carboxylic acid
  • the title compound was prepared by the methods described in Example 61, but substituting propylamine for methylamine in Example 6 IB and 4- methoxyphenylchloroformate for isobutyryl chloride in Example 61C.
  • the crude product was purified by trituration with 1 : 1 diethyl ether-hexane.
  • Example 105 trans. trans-2-( 4-Methoxyphenyl)-4-( 1 ,3-benzodioxol-5-yl)- 1 -[2-(N-propyl-N-(4- methoxybenzoyl)amino)ethyl]pyrrolidine-3-carboxy lie acid
  • the title compound was prepared by the methods described in Example 61, but substituting propylamine for methylamine in Example 61B and anisoyl chloride for isobutyryl chloride in Example 61 C.
  • the crude product was purified by trituration with 1 : 1 diethyl ether-hexane.
  • Example 106 trans,tr-.ns-2-(4-Methoxyphenyl -4-(l,3-benzodioxol-5-yl -l-[2-(N-propyl-N- benzoylamino) ethyl]pyrroHdine-3 -carboxylic acid
  • the title compound was prepared by the methods described in Example 61, but substituting propylamine for methylamine in Example 6 IB and benzoyl chloride for isobutyryl chloride in Example 61C.
  • the crude product was purified by trituration with 1 : 1 diethyl ether-hexane.
  • Example 107 trans.trans-2-(4-Methoxyphenyl)-4-(l,3-benzodioxol-5-yl)-l-[2-(N-propyl-N- benzyloxycarbonylamino) ethyl]py ⁇ oHdine-3 -carboxylic acid
  • the title compound was prepared by the methods described in Example 61, but substituting propylamine for methylamine in Example 6 IB and benzyl chloroformate for isobutyryl chloride in Example 61C.
  • the crude product was purified by preparative HPLC (Vydac ⁇ C18) eluting with a 10-70% gradient of CH3CN in 0.1% TFA.
  • Example 108 trans. trans-2-(4-Methoxyphenyl)-4-( 1.3-benzodioxol-5-yl)- 1 -[2-(N-propyl-N-(4- methoxybenzyloxycarbonyl)amino)ethyl]pyrroUdine-3-carboxy lie acid
  • the title compound is prepared by the methods described in Example 61, substituting propylamine for methylamine in Example 6 IB and 4-methoxybenzyl chloroformate for isobutyryl chloride in Example 61 C.
  • Example 109 transJr-.ns-2-(4-Methoxyphenyl)-4-(l,3-benzodioxol-5-yl)-l-[2-(N-butyl-N- ethoxycarbonylamino)ethyl]pyrroHdine-3-carboxy lie acid
  • the title compound was prepared by the methods described in Example 61, but substituting butylamine for methylamine in Example 6 IB and ethyl chloroformate for isobutyryl chloride in Example 61C.
  • the crude product was purified by preparative HPLC (Vydac ⁇ C18) eluting with a 10-70% gradient of CH3CN in 0.1% TFA.
  • Example 110 trans.tr ns-2-(4-Methoxyphenyl)-4-(1.3-benzodioxol-5-ylVl-[2-(N-butyl-N- propoxycartaonylamino)ethyl]pyrroUdine-3-carboxy lie acid
  • the title compound was prepared by the methods described in Example 61, but substituting butylamine for methylamine in Example 6 IB and propyl chloroformate for isobutyryl chloride in Example 61C.
  • the crude product was purified by trituration with 1 : 1 diethyl ether-hexane.
  • Example 111 tr_.ns,tr-.ns-2-(4-Methoxyphenyl)-4-(l,3-benzodioxol-5-yl)-l-[2-(N-propyl-N- propoxycarbonylamino) ethyl]pyrroUdine-3 -carboxylic acid
  • the title compound was prepared by the methods described in Example 61, but substituting propylamine for methylamine in Example 6 IB and propyl chloroformate for isobutyryl chloride in Example 61 C.
  • the crude product was purified by trituration with 1 : 1 diethyl ether-hexane.
  • Example 112 tra7.s,trans-l-(K,N-Di(n-butyl)aminocarbonylmethyl)-2,4-di(l,3-benzodioxol-5- yl)pyrrolidine-3 -carboxylic acid Ethyl (3 ,4-methylenedioxybenzoyl) acetate, prepared by the method of Krapcho et al,
  • Example 113 trans.trans-l-(2-(N-(n-Butyl)-N-propylsulfonylamino)ethyl)-2-(4-methoxyphenyl)-4-(l,3- benzodioxol-5-yl)pyrrolidine-3-carboxylic acid
  • Example 114 trans, trans- 1 -(N.N-Di(n-butyl.aminocarbonylmethyl)-2-(4-methoxyphenyl -4-( 1.3- benzodioxol-5-yl)pyrrolidine-3-carboxy lie acid
  • Example 116 trans, trans- 1 -(2-(N-Butyl-N-butylsulfonylamino)ethyl)-2-(4-methoxyphenyl)-4-( 1.3- benzodioxol-5-yl)pyrroHdine-3-cartaoxylic acid
  • Example 118 trans, trans- 1 -(2-(N,N-Di(n-butyl aminocarbonylmethyl)-2-(4-hvdroxyphenyl -4-( 1,3- benzodioxol-5-yl) ⁇ yrroHdine-3-carboxylic acid hydroehloride salt
  • the compound resulting from Example 116 was treated with concentrated HCl in 1 : 1
  • Example 120 tr ⁇ nsJr_-7zs-l-(2-(N-Be ⁇ zenesulfonyl-N-propylamino)ethyl -2-(4-methoxyphenyl -4-(1.3- benzodioxol-5-y pyrroHdine-3-carboxylic acid Using the procedures described in Example 66, the title compound was prepared as a white soHd. mp. 89-91 °C.
  • Example 121 trans, trans- 1 -(2-(N-(4-Methoxybenzenesulfonyl)-N-propylamino)ethyl)-2-(4- methoxyphenyl)-4-(l .3-benzodioxol-5-yl)pyrroHdine-3-carboxylic acid Using the procedures described in Example 66, the title compound was prepared as a white solid, p. 96-97 °C.
  • Example 122 trans, trans- 1 -(N,N-Di(n-butyl)aminocarbonylmethyl)-2-(2-methoxyethoxy-4- methoxyphenyl)-4-( 1.3-benzodioxol-5-yl)pyrrolidine-3-carboxylic acid
  • 2-Hydroxy-5-methoxyacetophenone was treated with sodium hydride and bromoethyl methyl ether in THF at 70 °C to provide ethyl 2-methoxyethoxy-4-methoxybenzoylacetate which was treated by the procedures described in Example 1 to provide the title compound as a white sohd. m.p. 63-65 °C.
  • Example 124 trans.trans-l-(2-(N-Propyl-N-(3-cMoropropylsulfonyl)amino)ethyl)-2-(4-methoxyphenyl)-4- (1.3-benzodioxol-5-yl)pyrroUdine-3-carboxylic acid Using the procedures described in Example 66, the title compound was prepared as a white sohd. mp. 75-76 °C.
  • trans, trans- l-(2-(N-Propyl-N- (vinylsulfonyl)amino)ethyl)-2-(4-methoxyphenyl)-4-(l,3-benzodioxol-5-yl)pyrroHdine-3- carboxylic acid was prepared. Ester hydrolysis using aqueous sodium hydroxide in methanol afforded the title compound as a white solid, mp. 62-64 °C.
  • Example 126 trans, trans- 1 -(2-(N-Propyl-N-(2-ethoxyethylsulfonyl)amino)ethyl)-2-(4-methoxyphenyl)-4- (1 ,3-benzodioxol-5-yl)pyrrolidine-3-carboxylic acid Using the procedures described in Example 66, the title compound was prepared as a white solid, mp. 58-60 °C.
  • Example 127 trans.tr_-ns-l-(2-(N-Propyl-N-(5-dimethylamino-l-naphthylsulfonyl)amino)ethyl)-2-(4- methoxyphenyl)-4-( 1.3-benzodioxol-5-yl)pyrroHdine-3-carboxylic acid
  • Example 128 trans, trans- 1 -(2-(N-Propyl-N-(ethylsulfonyl . amino)ethylV2-(4-methoxyphenyl)-4-( 1,3- benzodioxol-5-yl)pyrroHdine-3-carboxylic acid Using the procedures described in Example 66, the title compound was prepared as a white sohd. mp. 70-72 °C.
  • Example 129 trans.trans-l-(2-(N-Propyl-N-(4-methylbenzenesulfonyl)amino)ethyl)-2-(4-methoxyphenyl)- 4-(l .3-benzodioxol-5-yl)pyrroHdine-3-carboxylic acid Using the procedures described in Example 66, the title compound was prepared as a white solid, mp. 78-79 °C.
  • Example 130 trans.tr_-ns-l-(N.N-Di(n-butyl)aminocarbonylmethyl)-2-(3-pyridyl)-4-(l,3-benzodioxol-5- yl)pyrroUdine-3-carboxylic acid
  • Methyl nicotinoyl acetate was prepared by the method of Wenkert, et al., I. Org.
  • Example 132 trans.tr-.ns-l-(2-( -Propyl-N-(4-chlorober-zenesulfonyl amino)ethyl)-2-(4-methoxyphenyl)-
  • Example 133 trans.trans-l-(2-(N-Propyl-N-(benzylsulfonyl)amino)ethyl)-2-(4-methoxyphenyl)-4-(1.3- benzodioxol-5-yDpyrroHdine-3-carboxylic acid Using the procedures described in Example 66, the title compound was prepared as a white soHd. p. 88-89 °C.
  • Example 134 transJrans-l-(2-( -Propyl-N-(4-fluorobenzenesulfonyl)amino)ethyl)-2-(4-methoxyphenyl)- 4-(l ,3-benzodioxol-5-yl)pyrroHdine-3-carboxylic acid
  • Example 135 trans, trans- 1 -(N-Methyl-N-propylaminocarbonylmethyl)-2-(4-methoxyphenyl)-4-(4- benzofuranyl)pyrroUdine-3-carboxy lie acid
  • Example 135A Benzofuran-4-carboxaldehyde To a suspension of 60% sodium hydride in mineral oil (4.00 g, 100 mmol, 1.25 eq) in DMF (60 mL) at 0 °C was added a solution of 3-bromophenol (13.8 g, 80 mmol) in DMF (5 mL). After 10 minutes, bromoacetaldehyde diethyl acetal (14.9 mL, 96.6 mmol, 1.24 eq) was added, and the resultant mixture then heated at 120 °C for 2.5 hours. The mixture was cooled to room temperature and was poured into water, and extracted once with ether.
  • Example 135B trans, trans- 1 -(N-Methyl-N-propylaminocarbonylmethyl)-2-(4-methoxyphenyl . -4-(4- benzo fur anyl. pyrroHdine-3 -carboxy lie acid

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Cardiology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

A compound of the formula (I) or a pharmaceutically acceptable salt thereof is disclosed, as well as processes for and intermediates in the preparation thereof, and a method of antagonizing endothelin.

Description

ENDOTHELIN ANTAGONISTS
Technical Field
The present invention relates to compounds which are endothelin antagonists, processes for making such compounds, synthetic intermediates employed in these processes and methods and compositions for antagonizing endothelin.
Background of the Invention
Endothelin (ET) is a 21 amino acid peptide that is produced by endothelial cells. ET is produced by enzymatic cleavage of a Trp-Val bond in the precursor peptide big endothelin (Big ET). This cleavage is caused by an endothelin converting enzyme (ECE). Endothelin has been shown to constrict arteries and veins, increase mean arterial blood pressure, decrease cardiac output, increase cardiac contractility in vitro, stimulate mitogenesis in vascular smooth muscle cells in vitro, contract non-vascular smooth muscle including guinea pig trachea, human urinary bladder strips and rat uterus in vitro, increase airway resistance in vivo, induce formation of gastric ulcers, stimulate release of atrial natriuretic factor in vitro and in vivo, increase plasma levels of vasopressin, aldosterone and catecholamines, inhibit release of renin in vitro and stimulate release of gonadotropins in vitro.
It has been shown that vasoconstriction is caused by binding of endothelin to its receptors on vascular smooth muscle (Nature 332 411 (1988), FEBS Letters 23! 440 (1988) and Biochem. Biophys. Res. Commun. 154 868 (1988)). An agent which suppresses endothelin production or an agent which binds to endothelin or which inhibits the binding of endothelin to an endothelin receptor will produce beneficial effects in a variety of therapeutic areas. In fact, an anti-endothelin antibody has been shown, upon intrarenal infusion, to ameliorate the adverse effects of renal ischemia on renal vascular resistance and glomerular filtration rate (Kon, et al., J. Clin. Invest. 83 1762 (1989)). In addition, an anti-endothelin antibody attenuated the nephrotoxic effects of intravenously administered cyclosporin (Kon, et al., Kidney Int. 37 1487 (1990)) and attenuated infarct size in a coronary artery ligation- induced myocardial infarction model (Watanabe, et al., Nature 344 114 (1990)).
Clozel et al. (Nature 365: 759-761 (1993)) report that Ro 46-2005, a nonpeptide ET- A/B antagonist, prevents post-ischaemic renal vasoconstriction in rats, prevents the decrease in cerebral blood flow due to subarachnoid hemorrhage (SAH) in rats, and decreases MAP in sodium-depleted squirrel monkeys when dosed orally. A similar effect of a linear tripeptide- like ET-A antagonist, BQ-485, on arterial caliber after SAH has also been recently reported (S.Itoh, T. Sasaki, K. Ide, K. Ishikawa, M. Nishikibe, and M. Yano, Biochem. Biophys. Res. Comm. , 195: 969-75 (1993). These results indicate that agents which antagonize ET ET receptor binding will provide therapeutic benefit in the indicated disease states.
Agents with the ability to antagonize ET/ET receptor binding have been shown to be active in a number of animal models of human disease. For example, Hogaboam et al (EUR. J. Pharmacol. 1996, 309, 261-269), have shown that an endothelin receptor antagonist reduced injury in a rat model of colitis. Aktan et al (Transplant, Int 1996, 9, 201-207) have demonstrated that a similar agent prevents ischemia-reperfusion injury in kidney transplantation. Similar studies have suggested the use of endothelin antagonists in the treatment of angina, pulmonary hypertension, Raynaud's disease, and migraine. (Ferro and Webb, Drugs 1996, 51,12-27).
Abnormal levels of endothelin or endothelin receptors have also been associated with a number of disease states, including prostate cancer (Nelson et al, Nature Medicine 1995, 1, 944-949), suggesting a role of endothelin in the pathophysiology of these diseases.
Wu-Wong et al (Lfe Sciences 1996, 58, 1839-1847) have shown that both endothelin and endothelin antagonists bind tightly to plasma proteins, e.g., serum albumin. This plasma protein binding can decrease the effectiveness with which the antagonists inhibit endothelin' s action. Thus, endothelin antagonists with reduced plasma protein binding may be more effective than highly bound congeners.
Disclosure of the Invention
In accordance with the present invention there are compounds of the formula (I):
Figure imgf000003_0001
wherein Z is -C(Ri8)(Ri9)- or -C(O)- wherein Ris and R19 are independently selected from hydrogen and loweralkyl; n is 0 or 1;
R is -(CH2)m-W wherein m is an integer from 0 to 6 and W is (a) -C(O)2-G wherein G is hydrogen or a carboxy protecting group,
(b) -PO3H2,
(c) -P(O)(OH)E wherein E is hydrogen, loweralkyl or arylalkyl,
(d) -CN,
(e) -C(O)NHRi7 wherein R17 is loweralkyl, (f) alkylaminocarbonyl,
(g) dialkylaminocarbonyl,
(h) tetrazolyl,
(i) hydroxy,
(j) alkoxy, (k) sulfonamido,
(1) -C(O)NHS(O)2Ri6 wherein
Figure imgf000004_0001
is loweralkyl, haloalkyl, aryl or dialkylamino,
(m) -S(O)2NHC(O)Ri6 wherein R16 is defined as above,
Figure imgf000004_0002
H 0
(r)
Figure imgf000005_0001
JL CF3
- !
(t) , or
Figure imgf000005_0002
Ri and R2 are independently selected from hydrogen, loweralkyl, alkenyl, alkynyl, alkoxyalkyl, alkoxycarbonylalkyl, hydroxyalkyl, haloalkyl, haloalkoxyalkyl, alkoxyalkoxyalkyl, thioalkoxyalkoxyalkyl, cycloalkyl, cycloalkylalkyl, aminocarbonylalkyl, alkylaminocarbonylalkyl, dialkylaminocarbonylalkyl, aminocarbonylalkenyl, alkylaminocarbonylalkenyl, dialkylaminocarbonylalkenyl, hydroxyalkenyl, aryl, arylalkyl, aryloxyalkyl, arylalkoxyalkyl, (N-alkanoyl-N-alkyl)aminoalkyl, alkylsulfonylamidoalkyl, heterocyclic, (heterocyclic)alkyl and (Raa)(Rj..)N-Rcc- wherein Raa is aryl or arylalkyl, R^ is hydrogen or alkanoyl and Rcc is alkylene, with the proviso that one or both of Rj and R2 is other than hydrogen;
R3 is (a) R4-C(O)-R5- , R4- sa- , R4- O)- R5-N(R6)- , R6-S(O)2-R7- or R26-S(O)-R27- wherein R5 is (i) a covalent bond, (ii) 'alkylene, (iii) alkenylene, (iv) -N(R2o)-Rs- or -R8a-N(R20)-R8- wherein Rs and R8a are independently selected from the group consisting of alkylene and alkenylene and R20 is hydrogen, loweralkyl, alkenyl, haloalkyl, alkoxyalkyl, haloalkoxyalkyl, cylcoalkyl or cycloalkylalkyl or (v) -O-R9- or -R9a~O-R9- wherein R9 and R9a are independently selected from alkylene;
R5a is (i) alkylene or (ii) alkenylene; R7 is (i) a covalent bond, (ii) alkylene, (iii) alkenylene or (iv) -N(R2i)-Rιo- or -R10a-N(R2i)-Rιo- wherein Rio and R10a are independently selected from the group consisting of alkylene and alkenylene and R21 is hydrogen, loweralkyl, alkenyl, haloalkyl, alkoxyalkyl, haloalkoxyalkyl, aryl or arylalkyl; R4 and R are independently selected from the group consisting of
(i) (Rll)(Rl2)N- wherein Rn and R12 are independently selected from
(1) hydrogen,
(2) loweralkyl,
(3) haloalkyl,
(4) alkoxyalkyl,
(5) haloalkoxyalkyl,
(6) alkenyl,
(7) alkynyl,
(8) cycloalkyl,
(9) cycloalkylalkyl,
(10) aryl,
(11) heterocyclic,
(12) arylalkyl,
(13) (heterocyclic)alkyl,
(14) hydroxyalkyl,
(15) alkoxy,
(16) aminoalkyl,
(17) trialkylaminoalkyl,
(18) alkylaminoalkyl,
(19) dialkylaminoalkyl,
(20) carboxyalkyl, and
(21) diarylalkyl
(ϋ) loweralkyl,
(iii) alkenyl,
(iv) alkynyl,
(v) cycloalkyl,
(vi) cycloalkylalkyl,
( ϋ) aryl,
(viii) arylalkyl,
(ix) heterocyclic
(x) (heterocyclic)alkyl,
(xi) alkoxyalkyl,
(xii) hydroxyalkyl, (xiii) haloalkyl,
(xiv) haloalkenyl,
(XV) haloalkoxyalkyl,
(xvi) haloalkoxy,
(xvii) alkoxyhaloalkyl,
(xviii) alkylaminoalkyl,
(xix) dialkylaminoalkyl,
(xx) alkoxy,
Figure imgf000007_0001
wherein z is 0-5 and R7a is alkylene; and
(xxii) (Ri ia)(Ri2a)N-N(H)- wherein Ri ιa and Rι2a are independently selected from alkyl and the other is aryl; R26 is (i) loweralkyl, (ii) haloalkyl, (iii) alkenyl, (iv) alkynyl, (v) cycloalkyl,
(vi) cycloalkylalkyl, (vii) aryl, (viii) arylalkyl, (ix) heterocyclic, (x) (heterocyclic)alkyl, (xi) alkoxyalkyl or (xii) alkoxy-substituted haloalkyl; and R27 is alkylene or alkenylene;
(b) R22-O-C(O)-R23- wherein R22 is a carboxy protecting group or heterocycHc and R23 is (i) a covalent bond, (ii) alkylene, (iii) alkenylene or
(iv) -N(R24)- 25- wherein R25 is alkylene and R24 is hydrogen or loweralkyl,
(c) loweralkyl,
(d) alkenyl,
(e) alkynyl, ( ) cycloalkyl,
(g) cycloalkylalkyl,
(h) aryl,
(i) arylalkyl,
(j) aryloxyalkyl, (k) heterocyclic,
(1) (heterocyclic)alkyl,
(m) alkoxyalkyl,
(n) alkoxyalkoxyalkyl. or
(o) Ri3-C(O)-CH(R14)- wherein R13 is amino, alkylamino or dialkylamino and R14 is aryl or Rl5-C(O)- wherem R15 is amino, alkylamino or dialkylamino; or a pharmaceutically acceptable salt thereof.
A preferred embodiment of the invention is a compound of formula (II)
Figure imgf000008_0001
(II)
wherein the substituents -R2, -R and -Ri exist in a trans, trans relationship and Z, n, R, Ri, R2, and R3 are as defined above.
Another preferred embodiment of the invention is a compound of formula (I) or (II) wherein n is 0 and Z is -CH2-.
Another preferred embodiment of the invention is a compound of formula (I) or (II) wherein n is 1 and Z is -CH2-.
Another preferred embodiment of the invention is a compound of formula (I) or (II) wherein n is 0, Z is -CH2-, and R3 is R4-C(O)-Rs- , Rδ-S(O)2-R7- or R 6-S(O)-R27- wherein R , R5, R6, R7, R26 and R 7 are as defined above.
Another preferred embodiment of the invention is a compound of formula (I) or (II) wherein n is 0, Z is -CH2-, and R3 is alkoxyalkyl or alkoxyalkoxyalkyl.
In another preferred embo f the formula (I)
Figure imgf000008_0002
wherein n is zero; Z is -C(Ri8)(Ri9)- wherein Rig and R19 are hydrogen;
R is -C(O)2-G wherein G is hydrogen;
Ri is aryl substituted with one substituent selected from alkoxy and alkoxyalkoxy;
R2 is heterocycle which is 1,3-benzodioxyl; and
R3 is R4-C(O)-R5 wherein R5 is methylene and R4 is selected from (Rn)(Ri2)N- and
Figure imgf000009_0001
one of Rn and R12 is hydrogen and the other is selected from arylalkyl and diarylalkyl, wherein each aryl group of the diarylalkyl is substituted with one or two alkyl substituents; and
one of Rna or Ri2a is alkyl and the other is aryl;
or a pharmaceutically acceptable salt thereof.
Another preferred embodiment of the invention is a compound of formula (I) or formula (II) wherein n is zero; Z is -C(Rιg)(Ri9)- wherein Rig and R19 are hydrogen; R is - C(O)2-G wherein G is hydrogen; Ri is aryl substituted with one substituent selected from methoxy, methoxyethoxy, and isopropoxyethoxy; R2 is l,3-benzodiox-5-yl; R3 is R4-C(O)- R5 wherein R5 is methylene and R4 is selected from (Ru)(Ri2)N- and (Rna)(Ri2a)N-N(H)- wherein one of Rn and R12 is hydrogen and the other is selected from arylalkyl and diarylalkyl wherein each aryl group of the diarylalkyl is substituted with methyl or ethyl, and one of Rna or Rι2a is alkyl and the other is aryl.
Another preferred embodiment of the invention is a compound of formula (I) or formula (II) wherein n is zero; Z is -C(Ri8)(Ri9)- wherein Rig and R19 are hydrogen; R is - C(O)2-G wherein G is hydrogen; Ri is phenyl substituted with one substituent selected from methoxy, methoxyethoxy, and isopropylethoxy; R2 is l,3-benzodiox-5-yl; R3 is R4-C(O)-Rs wherein R5 is methylene and R4 is selected from (Rιι)(Rι2)N- and (Rπa)(Ri2a)N-N(H)- wherein one of Rn and R12 is hydrogen and the other is selected from phenylalkyl and diphenylalkyl wherein each phenyl group of the diphenylalkyl is substituted with methyl or ethyl, and one of Rna or Rι2a s alkyl and the other is phenyl. A more preferred embodiment of the invention is a compound of formula (I) or (II) wherein n is 0, Z is -CH2-, and R3 is R4-C(O)-R5- wherein R4 is (Rn)(Rl2)N- as defined above and R5 is alkylene or R3 is R6-S(O)2-R7- or R26- (O)-R27- wherein R7 is alkylene, R27 is alkylene and Rβ and R26 are defined as above.
Another more preferred embodiment of the invention is a compound of formula (I) or (II) wherein n is 0, Z is -CH2- and R3 is R4-C(O)-N(R2o)-R8- or R6-S(O)2-N(R2ι)-Rιo- wherein Rs and Rio are alkylene and R4, Rβ, R20 and R21 are defined as above.
An even more preferred embodiment of the invention is a compound of formula (I) or (II) wherein n is 0, R is tetrazolyl or -C(O)2-G wherein G is hydrogen or a carboxy protecting group or R is tetrazolyl or R is -C(O)-NHS(O)2R16 wherein R16 is loweralkyl, haloalkyl or aryl, Z is -CH2-, Ri and R2 are independently selected from (i) loweralkyl, (ii) cycloalkyl, (iii) substituted aryl wherein aryl is phenyl substituted with one, two or tliree substituents independently selected from loweralkyl, alkoxy, halo, alkoxyalkoxy and carboxyalkoxy, (iv) substituted or unsubstituted heterocyclic, (v) alkenyl, (vi) heterocyclic (alkyl), (vii) arylalkyl,
(viii) aryloxyalkyl, (ix) (N-alkanoyl-N-alkyl) aminoalkyl and (x) alkylsulfonylamidoalkyl, and R3 is R4-C(O)-Rs- wherein R4 is (Rn)(Ri2)N- wherein Rn and R12 are independently selected from loweralkyl, haloalkyl, alkoxyalkyl, haloalkoxyalkyl, aryl, arylalkyl, heterocyclic, hydroxyalkyl, alkoxy, aminoalkyl, and trialkylaminoalkyl, and R5 is alkylene; or R3 is R4-C(O)-N(R2o)-R8- or R6-S(O)2-N(R2i)-Rιo- wherein R4 is loweralkyl, aryl, alkoxy, alkylamino, aryloxy or arylalkoxy and Rβ is loweralkyl, haloalkyl, alkoxyalkyl, haloalkoxyalkyl, aryl or arylalkyl, R% and Rio are alkylene and R20 and R21 are loweralkyl; or R3 is R6-S(O)2-R7- or R26-S(O)-R27- wherein Rβ is loweralkyl or haloalkyl, R7 is alkylene, R26 is loweralkyl and R27 is alkylene.
A yet more preferred embodiment of the invention is a compound of formula (I) or (II) wherein n is 0, R is -C(O)2-G wherein G is hydrogen or a carboxy protecting group, tetrazolyl or -C(O)-NHS(O)2R16 wherein R16 is loweralkyl, haloalkyl or aryl, Z is -CH2-, Ri is (i) loweralkyl, (ii) alkenyl, (iii) alkoxyalkyl, (iv) cycloalkyl, (v) phenyl, (vi) pyridyl, (vii) furanyl,(viii) substituted or unsubstituted 4-methoxyphenyl, 4-fluorophenyl, 3 -fluorophenyl, 4-ethoxyphenyl, 4-ethylphenyl, 4-methylphenyl, 4-trifluoromethylphenyl, 4-pentafluoroethylphenyl, 3-fluoro-4-methoxyphenyl, 3-fluoro-4-ethoxyphenyl, 2-fluorophenyl, 4-methoxymethoxyphenyl, 4-hydroxyphenyl, 4-t-butylphenyl, 1,3-benzodioxolyl, 1,4-benzodioxanyl or dihydrobenzofuranyl wherein the substituent is selected from alkoxy, alkoxyalkoxy and carboxyalkoxy, (ix) heterocyclic (alkyl), (x) arylalkyl, (xi) aryloxyalkyl, (xii) (N-alkanoyl-N- alkyl)aminoalkyl, or (xiii) alkylsulfonylamidoalkyl, R2 is substituted or unsubstituted 1,3-benzodioxolyl, 7-methoxy-l,3-benzodioxolyl, 1,4-benzodioxanyl, 8-methoxy- 1,4-benzodioxanyl, dihydrobenzofuranyl, benzofurnayl, 4-methoxyphenyl, dimethoxyphenyl, fluorophenyl or difluorophenyl and R3 is R4-C(O)-N(R2θ)-Rδ- or R6-S(O)2-N(R2i)-Rιo- wherein R8 and Rio are alkylene, R2o and R21 are loweralkyl, R4 is loweralkyl, aryl, alkoxy, alkylamino, aryloxy or arylalkoxy and Rβ is loweralkyl, haloalkyl, alkoxyalkyl, aryl or arylalkyl.
Another yet more preferred embodiment of the invention is a compound of formula (I) or (II) wherein n is 0, R is -C(O)2-G wherein G is hydrogen or a carboxy protecting group, tetrazolyl or -C(O)-NHS(O)2R16 wherein R16 is loweralkyl, haloalkyl or aryl, Z is -CH2-, Ri is (i) loweralkyl, (ii) alkenyl, (iϋ) alkoxyalkyl, (iv) cycloalkyl, (v) phenyl, (vi) pyridyl, (vii) furanyl,(vϋi) substituted or unsubstituted 4-methoxyphenyl, 4-fluorophenyl, 3-fluorophenyl, 4-ethoxyphenyl, 4-ethylphenyl, 4-methylphenyl, 4-trifluoromethylphenyl, 4-pentafluoroethylphenyl, 3-fluoro-4-methoxyphenyl, 3-f_uoro-4-ethoxyphenyl, 2-fluorophenyl, 4-methoxymethoxypl enyl, 4-hydroxyphenyl, 4-t-butylphenyl, 1,3-benzodioxolyl, 1,4-benzodioxanyl or dihydrobenzofuranyl wherein the substituent is selected from alkoxy, alkoxyalkoxy and carboxyalkoxy, (ix) heterocyclic (alkyl), (x) arylalkyl, (xi) aryloxyalkyl, (xii) (N-alkanoyl-N- alkyl)aminoalkyl, or (xiii) alkylsulfonylamidoalkyl, R2 is substituted or unsubstituted
1,3-benzodioxolyl, 7-methoxy-l,3-benzodioxolyl, 1,4-benzodioxanyl, 8-methoxy- 1,4-benzodioxanyl, dihydrobenzofuranyl, benzofurnayl,
4-methoxyphenyl, dimethoxyphenyl, fluorophenyl or difluorophenyl and R3 is R4-C(O)-R5- wherein R5 is alkylene and R4 is (Rιι)(R-l2.N- wherein R-^ and R12 are independently selected from loweralkyl, haloalkyl, alkoxyalkyl, haloalkoxyalkyl, aryl, arylalkyl, heterocyclic, hydroxyalkyl, alkoxy, aminoalkyl, and tiialkylaminoalkyl.
Another yet more preferred embodiment of the invention is a compound of formula (I) or (II) wherein n is 0, R is -C(O)2-G wherein G is hydrogen or a carboxy protecting group, tetrazolyl or -C(O)-NHS(O)2R16 wherein R16 is loweralkyl, haloalkyl or aryl, Z is -CH2-, Ri is (i) loweralkyl, (ϋ) alkenyl, (iii) heterocyclic (alkyl), (iv) aryloxyalkyl, (v) arylalkyl, (vi) aryl, (vii) (N-alkanoyl-N-alkyl)aminoalkyl, or (viii) alkylsulfonylamidoalkyl, R2 is substituted or unsubstituted 1,3-benzodioxolyl, 7-methoxy-l,3-benzodioxolyl, 1,4- benzodioxanyl, 8-methoxy- 1,4-benzodioxanyl, dihydrobenzofuranyl, benzofurnayl, 4- methoxyphenyl, dimethoxyphenyl, fluorophenyl or difluorophenyl wherein the substituent is selected from loweralkyl, alkoxy and halogen and R3 is R4-C(O)-R5- wherein R5 is alkylene and R4 is (Rn)(Ri2)N- wherein R is loweralkyl and R12 is aryl, arylalkyl, hydroxyalkyl, alkoxy, aminoalkyl, trialkylamino alkyl, or heterocyclic.
Another yet more preferred embodiment of the invention is a compound of formula (I) or (II) wherein n is 0, R is -C(O)2-G wherein G is hydrogen or a carboxy protecting group, tetrazolyl or -C(O)-NHS(O)2R16 wherein R16 is loweralkyl, haloalkyl or aryl, Z is -CH2-, Ri is (i) loweralkyl, (ii) alkenyl, (iii) heterocyclic (alkyl), (iv) aryloxyalkyl, (v) arylalkyl, (vi)
(N-alkanoyl-N-alkyl)aminoalkyl, or (vii) alkylsulfonylamidoalkyl,(vii) phenyl, or (ix) substituted or unsubstituted 4-methoxyphenyl, 3-fluoro-4-methoxyphenyl, 3 -fluorophenyl,
3-fluoro-4-ethoxyphenyl, 2-fluorophenyl, 4-methoxymethoxyphenyl,
1,3-benzodioxolyl, 1,4-benzodioxanyl or dihydrobenzofuranyl wherein the substituent is selected from loweralkyl, haloalkyl, alkoxy, alkoxyalkoxy and carboxyalkoxy, R2 is substituted or unsubstituted 1,3-benzodioxolyl, 7-methoxy- 1,3-benzodioxolyl, 1,4- benzodioxanyl, 8-methoxy- 1,4-benzodioxanyl, dihydrobenzofuranyl, 4-methoxyphenyl, dimethoxyphenyl, fluorophenyl or difluorophenyl wherein the substituent is selected from loweralkyl, alkoxy and halogen and R3 is R6-S(O)2-N(R2i)-Rιo- wherein Rio is alkylene, Rβ is loweralkyl, haloalkyl, alkoxyalkyl, haloalkoxyalkyl, aryl or arylalkyl and R21 is loweralkyl, haloalkyl, alkoxyalkyl, haloalkoxyalkyl, aryl or arylalkyl.
Another yet more preferred embodiment of the invention is a compound of formula (I) or (II) wherein n is 0, R is -C(O)2-G wherein G is hydrogen or a carboxy protecting group, tetrazolyl or -C(O)-NHS(O)2R16 wherein R16 is loweralkyl, haloalkyl or aryl, Z is -CH2-, Ri is (i) substituted or unsubstituted 4-methoxyphenyl, 3-fluoro-4~methoxyphenyl, 3- fluorophenyl, 3-fluoro-4-ethoxyphenyl, 4-methoxymethoxyphenyl, 1,3-benzodioxolyl or
1,4-benzodioxanyl wherein the substituent is selected from loweralkyl, haloalkyl, alkoxy and alkoxyalkoxy, (ii) loweralkyl, (iii) alkenyl, (iv) heterocyclic (alkyl), (v) aryloxyalkyl, (vi) arylalkyl, (vii) (N-alkanoyl-N-alkyl)aminoalkyl, (viii) alkylsulfonylamidoalkyl,or (ix) phenyl, R2 is substituted or unsubstituted 1,3-benzodioxolyl, 7-methoxy-l,3-benzodioxolyl,
1,4-benzodioxanyl, 8-methoxy- 1,4-benzodioxanyl, dihydrobenzofuranyl, 4-methoxyphenyl, dimethoxyphenyl, fluorophenyl or difluorophenyl wherein the substituent is selected from loweralkyl, alkoxy and halogen and R3 is alkoxycarbonyl or R6-S(O)2-N(R2i)-Rιo- wherein Rio is alkylene, R is loweralkyl, haloalkyl, alkoxyalkyl or haloalkoxyalkyl and R21 is loweralkyl, haloalkyl, alkoxyalkyl or haloalkoxyalkyl. Another yet more preferred embodiment of the invention is a is a compound of formula (I) or (II) wherein n is 0, R is -C(O)2-G wherein G is hydrogen or a carboxy protecting group, tetrazolyl or -C(O)-NHS(O)2R16 wherein R16 is loweralkyl or haloalkyl, Z is -CH2-, Ri is loweralkyl,alkenyl, heterocyclic (allkyl), aryloxyalkyl, aryalkyl, aryl, (N- alkanoyl-N-alkyl) aminoalkyl,, or alkylsulfonylamidoalkyl, and R3 is R4-C(O)-R5- wherein R5 is alkylene and R4 is (Rn)(Ri2)N- wherein R^ and R12 are independently selected from alkyl, aryl, hydroxyalkyl, alkoxy, aminoalkyl, trialkylaminoalkyl, and heterocyclic.
A still more preferred embodiment of the invention is a compound of formula (I) or
(II) wherein n is 0, R is -C(O)2-G wherein G is hydrogen or a carboxy protecting group, tetrazolyl or -C(O)-NHS(O)2R16 wherein R16 is loweralkyl or haloalkyl, Z is -CH2-, Ri is substituted or unsubstituted 4-methoxyphenyl, 4-fluorophenyl, 2-fluorophenyl, 4- methylphenyl, 4-trifluoromethylphenyl, 4-pentafluoroethylphenyl, 4-methoxymethoxyphenyl, 4-hydroxyphenyl, 4-ethylplιenyl, 1,3-benzodioxolyl, 1,4- benzodioxanyl or dihydrobenzofuranyl wherein the substituent is selected from alkoxy, alkoxyalkoxy and carboxyalkoxy, (ii) loweralkyl, (iii) alkenyl, (iv) heterocyclic (alkyl), (v) aryloxyalkyl, (vi) arylalkyl, (vii) (N-alkanoyl-N-alkyl)amino alkyl, (viii) alkylsulfonylamidoalkyLor (ix) phenyl, R2 is 1,3-benzodioxolyl, 1,4-benzodioxanyl, dihydrobenzofuranyl, benzofuranyl, 4-methoxyphenyl, dimethoxyphenyl, fluorophenyl or difluorophenyl and R3 is R4-C(O)-R5- wherein R5 is alkylene and R4 is (Rll)(Rl2)N- wherein R and R12 are independently selected from loweralkyl, aryl, arylalkyl, hydroxyalkyl, alkoxy, aminoalkyl, trialkylaminoalkyl, or heterocyclic.
Another still more preferred embodiment of the invention is a compound of formula
(I) or (II) wherein n is 0, R is -C(O)2-G wherein G is hydrogen or a carboxy protecting group, tetrazolyl or -C(O)-NHS(O)2R16 wherein R16 is loweralkyl or haloalkyl, Z is -CH2-, Ri is loweralkyl, alkenyl, heterocyclic (alkyl), aryloxyalkyl, arylalkyl, (N-alkanoyl-N- alkyl)aminoalkyl, alkylsulfonylamidoalkyl, phenyl, or alkoxyalkyl, R2 is 1,3-benzodioxolyl, 1,4-benzodioxanyl, dihydrobenzofuranyl, benzofuranyl, 4-methoxyphenyl, dimethoxyphenyl, fluorophenyl or difluorophenyl and R3 is R4-C(O)-R5- wherein R5 is alkylene and R4 is (Rll)(Rl2)N- wherein R^ and R12 are independently selected from loweralkyl, aryl, arylalkyl, hydroxyalkyl, alkoxy, aminoalkyl, trialkylaminoalkyl, or heterocyclic.
A most highly preferred embodiment of the invention is a compound of formula (I) or
(II) wherein n is 0, R is -C(O)2-G wherein G is hydrogen or a carboxy protecting group, Z is -CH2-, Ri is substituted or unsubstituted 4-methoxyphenyl, 4-fluorophenyl, 2-fluorophenyl, 4-methylphenyl, 4-trifluoromethylphenyl, 4-pentafluoroethylphenyl, 4-methoxymethoxyphenyl, 4-hydroxyphenyl, 4-ethylphenyl, 1,3-benzodioxolyl, 1,4- benzodioxanyl or dihydrobenzofuranyl wherein the substituent is selected from alkoxy, alkoxyalkoxy and carboxyalkoxy, R2 is 1,3-benzodioxolyl, 1,4-benzodioxanyl, dihydrobenzofuranyl, benzofuranyl, 4-methoxyphenyl, dimethoxyphenyl, fluorophenyl or difluorophenyl and R3 is R4-C(O)-R5- wherein R5 is alkylene and R4 is (Rn)(Ri2)N- wherein R^ and R12 are independently selected from loweralkyl.
Another most highly preferred embodiment of the invention is a compound of formula (I) or (II) wherein n is 0, R is -C(O)2-G wherein G is hydrogen or a carboxy protecting group, Z is -CH2-, Ri is substituted or unsubstituted 4-methoxyphenyl, 4- fluorophenyl, 2-fluorophenyl, 4-methylphenyl, 4-trifluoromethylphenyl, 4- pentafluoroethylphenyl, 4-methoxymethoxyphenyl, 4-hydroxyphenyl, 4-ethylphenyl, 1,3-benzodioxolyl, 1,4- benzodioxanyl or dihydrobenzofuranyl wherein the substituent is selected from alkoxy, alkoxyalkoxy and carboxyalkoxy, R2 is 1,3-benzodioxolyl, 1,4-benzodioxanyl, dihydrobenzofuranyl, benzofuranyl, 4-methoxyphenyl, dimethoxyphenyl, fluorophenyl or difluorophenyl and R3 is R4-C(O)-R5- wherein R5 is alkylene and R4 is (Rn)(Ri2)N- wherein Rl t is loweralkyl and R12 is aryl.
Another most highly preferred embodiment of the invention is a compound of formula (I) or (II) wherein n is 0, R is -C(O)2-G wherein G is hydrogen or a carboxy protecting group, Z is -CH2-, Ri is substituted or unsubstituted 4-methoxyphenyl, 3-fluoro- 4-methoxyphenyl, 3 -fluorophenyl, 2-fluorophenyl, 3-fluoro-4-ethoxyphenyl, 4- methoxymethoxyphenyl,
1,3-benzodioxolyl, 1,4-benzodioxanyl or dihydrobenzofuranyl wherein the substituent is selected from loweralkyl, haloalkyl, alkoxy, alkoxyalkoxy and carboxyalkoxy, R2 is substituted or unsubstituted 1,3-benzodioxolyl, 7-methoxy-l,3-benzodioxolyl, 1,4- benzodioxanyl, 8-methoxy- 1,4-benzodioxanyl, dihydrobenzofuranyl, 4-methoxyphenyl, dimethoxyphenyl, fluorophenyl or difluorophenyl wherein the substituent is selected from loweralkyl, alkoxy and halogen and R3 is R6~S(O)2-N(R2i)-Rιo- wherein Rio is alkylene, Rβ is loweralkyl, haloalkyl, alkoxyalkyl or haloalkoxyalkyl and R21 is loweralkyl, haloalkyl or alkoxyalkyl. Another most highly preferred embodiment of the invention is a compound of formula (I) or (II) wherein n is 0, R is -C(O)2-G wherein G is hydrogen or a carboxy protecting group, Z is -CH2-, Ri is substituted or unsubstituted 4-methoxyphenyl, 3-fluoro-4- methoxyphenyl, 3 -fluorophenyl, 2-fluorophenyl, 3-fluoro-4-ethoxyphenyl, 4-methoxymethoxyphenyl, 1,3- benzodioxolyl, 1,4-benzodioxanyl or dihydrobenzofuranyl wherein the substituent is selected from loweralkyl, haloalkyl, alkoxy, alkoxyalkoxy and carboxyalkoxy, R2 is substituted or unsubstituted 1,3-benzodioxolyl, 7-methoxy-l,3-benzodioxolyl, 1,4-benzodioxanyl, 8- methoxy- 1,4-benzodioxanyl, dihydrobenzofuranyl, 4-methoxyphenyl, dimethoxyphenyl, fluorophenyl or difluorophenyl wherein the substituent is selected from loweralkyl, alkoxy and halogen and R3 is R4-C(O)-Rs- wherein R5 is alkylene and R4 is (Rn)(Ri2)N- wherein R is alkyl and R12 is selected from aryl, aminoalkyl, trialkylaminoalkyl, and heterocyclic.
Another most highly preferred embodiment of the invention is a compound of formula (I) or (II) wherein n is 0, R is -C(O)2-G wherein G is hydrogen or a carboxy protecting group, Z is -CH2-, Ri is loweralkyl,alkenyl, heterocyclic (alkyl), aryloxyalkyl, aryalkyl, aryl, (N-alkanoyl-N-alkyl)aminoalkyl, or alkylsulfonylamidoalkyl, and R3 is R4-C(O)-R5- wherein R5 is alkylene and R4 is (Rn)(Ri2)N- wherein R and R12 are independently selected from alkyl, aryl, hydroxyalkyl, alkoxy, aminoalkyl, trialkylaminoalkyl, and heterocyclic, with the proviso that one or R and R12 is alkyl.
Another most highly preferred embodiment of the invention is a compound of formula (I) or (II) wherein n is 0, Z is -CH2-, and R3 is R_j.-C(O)-R5- wherein R4 is (Rll)(Rl2)N- as defined therein and R5 is alkylene.
Another most highly preferred embodiment of the invention is a compound of formula (I) or (II) wherein n is 0, Z is -CH2-, Rl is loweralkyl, and R3 is R4-C(O)-Rs- wherein R4 is (Ri ι)(Ri2)N- as defined therein and R5 is alkylene.
Another most highly preferred embodiment of the invention is a compound of formula (I) or (II) wherein n is 0, Z is -CH2-, Rl is alkenyl, and R3 is R4-C(O)-Rs- wherein R4 is (Rn)(Ri2)N- as defined therein and R5 is alkylene.
Another most highly preferred embodiment of the invention is a compound of formula (I) or (II) wherein n is 0, Z is -CH2-, Rl is heterocyclic (alkyl), and R3 is R4-C(O)-R5- wherein R4 is (Ri ι)(Ri2)N- as defined therein and R5 is alkylene. Another most highly preferred embodiment of the invention is a compound of formula (I) or (II) wherein n is 0, Z is -CH2-, Rl is aryloxyalkyl, and R3 is R4-C(O)-R5- wherein R4 is (Rn)(Ri2)N- as defined therein and R5 is alkylene.
Another most highly preferred embodiment of the invention is a compound of formula (I) or (II) wherein n is 0, Z is -CH2-, Rl is arylalkyl, and R3 is R_j.-C(O)-R5- wherein R4 is (Rn)(Ri2)N- as defined therein and R5 is alkylene.
Another most highly preferred embodiment of the invention is a compound of formula (I) or (II) wherein n is 0, Z is -CH2-, Rl is aryl, and R3 is R4-C(O)-Rs- wherein R4 is (Rll)(Rl2)N- as defined therein and R5 is alkylene.
Another most highly preferred embodiment of the invention is a compound of formula (I) or (II) wherein n is 0, Z is -CH2-, Rl is (N-alkanoyl-N-alkyl)aminoalkyl, and R3 is R4-C(O)-R5- wherein R4 is (Rn)(Ri2)N- as defined therein and R5 is alkylene.
Another most highly preferred embodiment of the invention is a compound of formula (I) or (II) wherein n is 0, Z is -CH2-, Rl is alkylsulfonylamidoalkyl, and R3 is R4-C(O)-R5- wherein R4 is (Rn)(Rl2)N- as defined therein and R5 is alkylene.
The present invention also relates to processes for preparing the compounds of formula (I) and (II) and to the synthetic intermediates employed in these processes.
The present invention also relates to a method of antagonizing endothelin in a mammal (preferably, a human) in need of such treatment, comprising administering to the mammal'a therapeutically effective amount of a compound of formula (I) or (II).
The invention further relates to endothelin antagonizing compositions comprising a pharmaceutical carrier and a therapeutically effective amount of a compound of formula (I) or (II).
The compounds of the invention comprise two or more asymmetrically substituted carbon atoms. As a result, racemic mixtures, mixtures of diastereomers, as well as single diastereomers of the compounds of the invention are included in the present invention. The terms "S" and "R" configuration are as defined by the IUPAC 1974 Recommendations for Section E, Fundamental Stereochemistry, Pure Appl. Chem. (1976) 45, 13 - 30.
The term "carboxy protecting group" as used herein refers to a carboxylic acid protecting ester group employed to block or protect the carboxylic acid functionality while the reactions involving other functional sites of the compound are carried out. Carboxy protecting groups are disclosed in Greene, "Protective Groups in Organic Synthesis" pp. 152- 186 (1981), which is hereby incorporated herein by reference. In addition, a carboxy protecting group can be used as a prodrug whereby the carboxy protecting group can be readily cleaved in vivo , for example by enzymatic hydrolysis, to release the biologically active parent. T. Higuchi and V. Stella provide a thorough discussion of the prodrug concept in "Pro-drugs as Novel Delivery Systems", Vol 14 of the A.C.S. Symposium Series, American Chemical Society (1975), which is hereby incorporated herein by reference. Such carboxy protecting groups are well known to those skilled in the art, having been extensively used in the protection of carboxyl groups in the penicillin and cephalosporin fields, as described in U.S. Pat. No. 3,840,556 and 3,719,667, the disclosures of which are hereby incorporated herein by reference. Examples of esters useful as prodrugs for compounds containing carboxyl groups can be found on pages 14-21 of "Bioreversible Carriers in Drug Design: Theory and Application", edited by E.B. Roche, Pergamon Press, New York (1987), which is hereby incorporated herein by reference. Representative carboxy protecting groups are Ci to Cs alkyl (e.g., methyl, ethyl or tertiary butyl and the like); haloalkyl; alkenyl; cycloalkyl and substituted derivatives thereof such as cyclohexyl, cylcopentyl and the like; cycloalkylalkyl and substituted derivatives thereof such as cyclohexylmethyl, cylcopentylmethyl and the like; arylalkyl, for example, phenethyl or benzyl and substituted derivatives thereof such as alkoxybenzyl or nitrobenzyl groups and the like; arylalkenyl, for example, phenylethenyl and the like; aryl and substituted derivatives thereof, for example, 5- indanyl and the like; dialkylaminoalkyl (e.g., dimethylaminoethyl and the like); alkanoyloxyalkyl groups such as acetoxymethyl, butyryloxymethyl, valeryloxymethyl, isobutyryloxymethyl, isovaleryloxymethyl, l-(propionyloxy)-l -ethyl, l-(pivaloyloxyl)-l- ethyl, 1 -methyl- l-(propionyloxy)-l -ethyl, pivaloyloxymethyl, propionyloxymethyl and the like; cycloalkanoyloxy alkyl groups such as cyclopropylcarbonyloxymethyl, cyclobutylcarbonyloxymethyl, cyclopentylcarbonyloxymethyl, cyclohexylcarbonyloxymethyl and the like; aroyloxyalkyl, such as benzoyloxymethyl, benzoyloxyethyl and the like; arylalkylcarbonyloxyalkyl, such as benzylcarbonyloxymethyl, 2-benzylcarbonyloxyethyl and the like; alkoxycarbonylalkyl, such as methoxycarbonylmethyl, cyclohexyloxycarbonylmethyl, 1 -methoxycarbonyl- 1 -ethyl, and the like; alkoxycarbonyloxyalkyl, such as methoxycarbonyloxymethyl, t- butyloxycarbonyloxymethyl, 1 -ethoxycarbonyloxy- 1 -ethyl, 1 -cyclohexyloxycarbonyloxy- 1 - ethyl and the like; alkoxycarbonylaminoalkyl, such as t-butyloxycarbonylaminomethyl and the like; alkylaminocarbonylaminoalkyl, such as methylaminocarbonylaminomethyl and the like; alkanoylaminoalkyl, such as acetylaminomethyl and the like; heterocycliccarbonyloxyalkyl, such as 4-methylpiperazmylcarbonyloxymethyl and the hke; dialkylaminocarbonylalkyl, such as dimethylaminocarbonylmethyl, diethylaminocarbonylmethyl and the like; (5-(loweralkyl)-2-oxo-l,3-dioxolen-4-yl)alkyl, such as (5-t-butyl-2-oxo-l,3-dioxolen-4-yl)methyl and the like; and (5-phenyl-2-oxo-l,3- dioxolen-4-yl)alkyl, such as (5-phenyl-2-oxo-l,3-dioxolen-4-yl)methyl and the like. The term "N-protecting group" or "N-protected" as used herein refers to those groups intended to protect the N-terminus of an amino acid or peptide or to protect an amino group against undersirable reactions during synthetic procedures. Commonly used N-protecting groups are disclosed in Greene, "Protective Groups In Organic Synthesis," (John Wiley & Sons, New York (1981)), which is hereby incorporated by reference. N-protecting groups comprise acyl groups such as formyl, acetyl, propionyl, pivaloyl, t-butylacetyl, 2-chloroacetyl, 2-bromoacetyl, trifluoroacetyl, trichloroacetyl, phthalyl, o- nitrophenoxyacetyl, chlorobutyryl, benzoyl, 4-chlorobenzoyl,
4-bromobenzoyl, 4-nitrobenzoyl, and the like; sulfonyl groups such as benzenesulfonyl, p- toluenesulfonyl and the hke; carbamate forming groups such as benzyloxycarbonyl, p- chlorobenzyloxycarbonyl, p-methoxybenzyloxycarbonyl, p-nitrobenzyloxycarbonyl, 2-nitrobenzyloxycarbonyl, p-bromobenzyloxycarbonyl, 3 ,4-dimethoxybenzyloxycarbonyl, 3 ,5-dimethoxybenzyloxycarbonyl, 2,4-dimethoxybenzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, 2-nitro-4,5-dimethoxybenzyloxycarbonyl, 3,4,5-trimethoxybenzyloxycarbonyl, 1 -(p-biphenylyl)- 1 -methylethoxycarbonyl, δ -dimethyl-3,5-dimethoxyben__yloxycarbonyl, benzhy dry loxy carbonyl, t-butyloxycarbonyl, diisopropylmethoxycarbonyl, isopropyloxycarbonyl, ethoxycarbonyl, methoxycarbonyl, allyloxycarbonyl, 2,2,2,-trichloroethoxycarbonyl, phenoxycarbonyl,
4-nitrophenoxycarbonyl, fluorenyl-9-methoxycarbonyl, cyclopentyloxycarbonyl, adamantyloxycarbonyl, cyclohexyloxycarbonyl, phenylthiocarbonyl and the hke; alkyl groups such as benzyl, triphenylmethyl, benzyloxymethyl and the hke; and silyl groups such as trimethylsilyl and the Hke. Preferred N-protecting groups are formyl, acetyl, benzoyl, pivaloyl, t-butylacetyl, phenylsulfonyl, benzyl, t-butyloxycarbonyl (Boc) and benzyloxycarbonyl (Cbz). The term "alkanoyl" as used herein refers to an alkyl group as previously defined appended to the parent molecular moiety through a carbonyl (-C(O)-) group. Examples of alkanoyl include acetyl, propionyl and the Hke.
The term "alkanoylamino" as used herein refers to an alkanoyl group as previously defined appended to an amino group. Examples alkanoylamino include acetamido, propionylamido and the Hke.
The term "alkanoylaminoalkyl" as used herein refers to R43-NH-R44- wherein R43 is an alkanoyl group and R44 is an alkylene group.
The term "alkanoyloxy alkyl" as used herein refers to R30-O-R31- wherein R30 is an alkanoyl group and R31 is an alkylene group. Examples of alkanoyloxyalkyl include acetoxymethyl, acetoxyethyl and the Hke.
The term "alkenyl" as used herein refers to a straight or branched chain hydrocarbon radical containing from 2 to 15 carbon atoms and also containing at least one carbon-carbon double bond. Alkenyl groups include, for example, vinyl (ethenyl), allyl (propenyl), butenyl, 1 -methyl-2-buten- 1 -yl and the Hke.
The term "alkenylene" denotes a divalent group derived from a straight or branched chain hydrocarbon containing from 2 to 15 carbon atoms and also containing at least one carbon-carbon double bond. Examples of alkenylene include -CH=CH-, -CH2CH=CH-, -
C(CH3)=CH-, -CH2CH=CHCH2-, and the Hke. The term "alkenyloxy" as used herein refers to an alkenyl group, as previously defined, connected to the parent molecular moiety through an oxygen (-O-) linkage. Examples of alkenyloxy include allyloxy, butenyloxy and the Hke.
The term "alkoxy" as used herein refers to R41O- wherein R41 is a loweralkyl group, as defined herein. Examples of alkoxy include, but are not limited to, ethoxy, tert-butoxy, and the Hke.
The term "alkoxyalkoxy" as used herein refers to RgoO-RsiO- wherein Rso is loweralkyl as defined above and Rsi is alkylene. Representative examples of alkoxyalkoxy groups include methoxymethoxy, ethoxymethoxy, t-butoxymethoxy and the like.
The term "alkoxyalkoxy alkyl" as used herein refers to an alkoxyalkoxy group as previously defined appended to an alkyl radical. Representative examples of alkoxyalkoxyalkyl groups include methoxyethoxyethyl, methoxymethoxymethyl, and the like.
The term "alkoxyalkyl" as used herein refers to an alkoxy group as previously defined appended to an alkyl radical as previously defined. Examples of alkoxyalkyl include, but are not limited to, methoxymethyl, methoxyethyl, isopropoxymethyl and the like. The term "alkoxycarbonyl" as used herein refers to an alkoxyl group as previously defined appended to the parent molecular moiety through a carbonyl group. Examples of alkoxycarbonyl include methoxycarbonyl, ethoxycarbonyl, isopropoxycarbonyl and the Hke.
The term "alkoxycarbonylalkenyl" as used herein refers to an alkoxycarbonyl group as previously defined appended to an alkenyl radical. Examples of alkoxycarbonylalkenyl include methoxycarbonylethenyl, ethoxycarbonylethenyl and the like.
The term "alkoxycarbonylalkyl" as used herein refers to R34-C(O)-R35- wherein R34 is an alkoxy group and R35 is an alkylene group. Examples of alkoxycarbonylalkyl include methoxycarbonylmethyl, methoxcarbonylethyl, ethoxycarbonylmethyl and the like. The term "alkoxycarbonylaminoalkyl" as used herein refers to R38~C(O)- H-R39- wherein R38 is an alkoxy group and R39 is an alkylene group.
The term "alkoxycarbonyloxyalkyl" as used herein refers to R36-C(O)-O-R37- wherein R36 is an alkoxy group and R37 is an alkylene group.
The term "(alkoxycarbonyl)thioalkoxy" as used herein refers to an alkoxycarbonyl group as previously defined appended to a thioalkoxy radical. Examples of (alkoxycarbonyl)thioalkoxy include methoxycarbonylthiomethoxy, ethoxycarbonylthiomethoxy and the Hke.
The term "alkoxyhaloalkyl" as used herein refers to a haloalkyl radical to which is appended an alkoxy group. The terms "alkyl" and "loweralkyl" as used herein refer to straight or branched chain alkyl radicals containing from 1 to 15 carbon atoms including, but not Hmited to, methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, t-butyl, n-pentyl, 1-methylbutyl, 2,2- dimethylbutyl, 2-methylpentyl, 2,2-dimethylpropyl, n-hexyl and the Hke.
The term "(N-alkanoyl-N-alky aminoalkyl" as used herein refers to R85C(O)N(R86)R87- wherein R85 is an alkanoyl as previously defined, R86 is loweralkyl, and R87 is alkylene.
The term "alkylamino" as used herein refers to R51NH- wherein R51 is a loweralkyl group, for example, ethylamino, butylamino, and the like.
The term "alkylaminoalkyl" as used herein refers to a loweralkyl radical to which is appended an alkylamino group.
The term "alkylaminocarbonyl" as used herein refers to an alkylamino group, as previously defined, appended to the parent molecular moiety through a carbonyl (-C(O)-) linkage. Examples of alkylaminocarbonyl include methylaminocarbonyl, ethylaminocarbonyl, isopropylaminocarbonyl and the Hke. The term "alkylaminocarbonylalkenyl" as used herein refers to an alkenyl radical to which is appended an alkylaminocarbonyl group. The term "alkylaminocarbonylalkyl" as used herein refers to a loweralkyl radical to which is appended an alkylaminocarbonyl group.
The term "alkylaminocarbonylaminoalkyl" as used herein refers to R40-C(O)-NH-R4i- wherein R40 is an alkylamino group and R41 is an alkylene group. The term "alkylene" denotes a divalent group derived from a straight or branched chain saturated hydrocarbon having from 1 to 15 carbon atoms by the removal of two hydrogen atoms, for example -CH2-, -CH2CH2-, -CH(CH3)-, -CH2CH2CH2-, -
CH2C(CH3)2CH2- and the like.
The term "alkylsulfonylamidoalkyl" as used herein refers R88S(O)2NHR89- wherein R88 is loweralkyl and R89 is alkylene.
The term "alkylsulfonylamino" as used herein refers to an alkyl group as previously defined appended to the parent molecular moiety through a sulfonylamino (-S(O)2-NH-) group. Examples of alkylsulfonylamino include methylsulfonylamino, ethylsulfonylamino, isopropylsulfonylamino and the Hke. The term "alkynyl" as used herein refers to a straight or branched chain hydrocarbon radical containing from 2 to 15 carbon atoms and also containing at least one carbon-carbon triple bond. Examples of alkynyl include -C ≡ C-H, H-C = C-CH2-, H-C ≡ C-CH(CH3)- and the Hke.
The term "alkynylene" refers to a divalent group derived by the removal of two hydrogen atoms from a straight or branched chain acycHc hydrocarbon group containing from 2 to 15 carbon atoms and also containing a carbon-carbon triple bond. Examples of alkynylene include -C ≡ C-, -C≡C-C 2-, -C≡C-CH(CH3)- and the Hke.
The term "aminoalkyl" as used herein refers to a -NH2, alkylamino, or dialkylamino group appended to the parent molecular moiety through an alkylene. The term "aminocarbonyl" as used herein refers to H2N-C(O)- .
The term "aminocarbonylalkenyl" as used herein refers to an alkenyl radical to which is appended an aminocarbonyl (NH2C(O)-) group.
The term "aminocarbonylalkoxy" as used herein refers to H2N-C(O)- appended to an alkoxy group as previously defined. Examples of aminocarbonylalkoxy include aminocarbonylmethoxy, aminocarbonylethoxy and the like.
The term "aminocarbonylalkyl" as used herein refers to a loweralkyl radical to which is appended an aminocarbonyl (NH2C(O)-) group.
The term "trialkylaminoalkyl" as used herein refers to (R90)(R91)(R92)N(R93)- wherein R90, R91, and R92 are independently selected from loweralkyl and R93 is alkylene. The term "aroyloxy alkyl" as used herein refers to R32-C(O)-O-R33- wherein R32 is an aryl group and R33 is an alkylene group. Examples of aroyloxyalkyl include benzoyloxymethyl, benzoyloxyethyl and the like.
The term "aryl" as used herein refers to a mono- or bicyclic carbocycHc ring system having one or two aromatic rings including, but not limited to, phenyl, naphthyl, tetrahydronaphthyl, indanyl, indenyl and the Hke. Aryl groups can be unsubstituted or substituted with one, two or three substituents independently selected from loweralkyl, halo, haloalkyl, haloalkoxy, hydroxyalkyl, alkenyloxy, alkoxy, alkoxyalkoxy, alkoxycarbonyl, alkoxycarbonylalkenyl, (alkoxycarbonyl)thioalkoxy, thioalkoxy, amino, alkylamino, dialkylamino, aminoalkyl, trialkylaminoalkyl, aminocarbonyl, aminocarbonylalkoxy, alkanoylamino, arylalkoxy, aryloxy, mercapto, cyano, nitro, carboxaldehyde, carboxy, carboxyalkenyl, carboxyalkoxy, alkylsulfonylamino, cyanoalkoxy, (heterocyclic)alkoxy, hydroxy, hydroxalkoxy, phenyl and tetrazolylalkoxy. In addition, substituted aryl groups include tetrafluorophenyl and pentafluorophenyl. The term "arylalkenyl" as used herein refers to an alkenyl radical to which is appended an aryl group, for example, phenylethenyl and the like.
The term "arylalkoxy" as used herein refers to R42O- wherein R42 is an arylalkyl group, for example, benzyloxy, and the Hke.
The term "arylalkoxyalkyl" as used herein refers to a loweralkyl radical to which is appended an arylalkoxy group, for example, benzyloxymethyl and the Hke.
The term "arylalkyl" as used herein refers to an aryl group as previously defined, appended to a loweralkyl radical, for example, benzyl and the Hke.
The term "aryloxy" as used herein refers to R45O- wherein R45 is an aryl group, for example, phenoxy, and the Hke. The term "arylalkylcarbonyloxyalkyl" as used herein refers to a loweralkyl radical to which is appended an arylalkylcarbonyloxy group (i.e., R62C(O)O- wherein R62 is an arylalkyl group).
The term "aryloxyalkyl" refers to an aryloxy group as previously defined appended to an alkyl radical. Examples of aryloxyalkyl include phenoxymethyl, 2-phenoxyethyl and the like.
The term "carboxaldehyde" as used herein refers to a formaldehyde radical, -C(O)H. The term "carboxy" as used herein refers to a carboxylic acid radical, -C(O)OH. The term "carboxyalkenyl" as used herein refers to a carboxy group as previously defined appended to an alkenyl radical as previously defined. Examples of carboxyalkenyl include 2-carboxyethenyl, 3 -carboxy- 1 -ethenyl and the like. The term "carboxyalkoxy" as used herein refers to a carboxy group as previously defined appended to an alkoxy radical as previously defined. Examples of carboxyalkoxy include carboxymethoxy, carboxyethoxy and the Hke.
The term "cyanoalkoxy" as used herein refers to an alkoxy radical as previously defined to which is appended a cyano (-CN) group. Examples of cyanoalkoxy include 3- cyanopropoxy, 4-cyanobutoxy and the like.
The term "cycloalkanoyloxyalkyl" as used herein refers to a loweralkyl radical to which is appended a cycloalkanoyloxy group (i.e., R60-C(O)-O- wherein R60 is a cycloalkyl group). The term "cycloalkyl" as used herein refers to an aliphatic ring system having 3 to 10 carbon atoms and 1 to 3 rings including, but not Hmited to, cyclopropyl, cyclopentyl, cyclohexyl, norbornyl, adamantyl, and the like. Cycloalkyl groups can be unsubstituted or substituted with one, two or three substituents independently selected from loweralkyl, haloalkyl, alkoxy, thioalkoxy, amino, alkylamino, dialkylamino, hydroxy, halo, mercapto, nitro, carboxaldehyde, carboxy, alkoxycarbonyl and carboxamide.
The term "cycloalkylalkyl" as used herein refers to a cycloalkyl group appended to a loweralkyl radical, including but not Hmited to cyclohexylmethyl.
The term "dialkylamino" as used herein refers to R56R57N- wherein Rsβ and R57 are independently selected from loweralkyl, for example diethylamino, methyl propylamino, and the Hke.
The term "dialkylaminoalkyl" as used herein refers to a loweralkyl radical to which is appended a dialkylamino group.
The term "dialkylaminocarbonyl" as used herein refers to a dialkylamino group, as previously defined, appended to the parent molecular moiety through a carbonyl (-C(O)-) linkage. Examples of dialkylaminocarbonyl include dimethylamino carbonyl, diethylaminocarbonyl and the like.
The term "dialkylaminocarbonylalkenyl" as used herein refers to an alkenyl radical to which is appended a dialkylaminocarbonyl group.
The term "dialkylaminocarbonylalkyl" as used herein refers to R5o-C(O)-R5i- wherein R50 is a dialkylamino group and R51 is an alkylene group.
The term "diarylalkyl," as used herein, refers to two aryl groups, as defined herein, attached to the parent molecular moiety through an alkyl group. Tha aryl groups of the diarylalkyl can be optionaUy substituted with 1-5 alkyl substituents. Examples of "diarylalkyl" include diphenylmethyl (benzhydryl), 2,2-diphenylethyl, 1,2-diphenylethyl, bis(2-methylphenyl)methyl, and the Hke.
The term "halo" or "halogen" as used herein refers to I, Br, Cl or F. The term "haloalkenyl" as used herein refers to an alkenyl radical to which is appended at least one halogen substituent.
The term "haloalkoxy" as used herein refers to an alkoxy radical as defined above, bearing at least one halogen substituent, for example, 2-fluoroethoxy, 2,2,2-trifluoroethoxy, trifluoromethoxy, 2,2,3,3,3-pentafluoropropoxy and the Hke.
The term "haloalkoxyalkyl" as used herein refers to a loweralkyl radical to which is appended a haloalkoxy group.
The term "haloalkyl" as used herein refers to a lower alkyl radical, as defined above, to which is appended at least one halogen substituent, for example, chloromethyl, fluoroethyl, trifluoromethyl or pentafluoroethyl and the Hke.
The term "heterocyclic ring" or "heterocyclic" or "heterocycle" as used herein refers to any 3- or 4-membered ring containing a heteroatom selected from oxygen, nitrogen and sulfur; or a 5-, 6- or 7-membered ring containing one, two or three nitrogen atoms; one oxygen atom; one sulfur atom; one nitrogen and one sulfur atom; one nitrogen and one oxygen atom; two oxygen atoms in non-adjacent positions; one oxygen and one sulfur atom in non-adjacent positions; or two sulfur atoms in non-adjacent positions. The 5-membered ring has 0-2 double bonds and the 6- and 7-membered rings have 0-3 double bonds. The nitrogen heteroatoms can be optionally quaternized. The term "heterocycHc" also includes bicyclic groups in which any of the above heterocyclic rings is fused to a benzene ring or a cyclohexane ring or another heterocyclic ring (for example, indolyl, dihydroindolyl, quinolyl, isoquinolyl, tetrahydroquinolyl, tetrahydroisoquinolyl, decahydroquinolyl, decahydroisoquinolyl, benzofuryl, dihydrobenzofuryl or benzothienyl and the Hke). Heterocyclics include: aziridinyl, azetidinyl, pyrrolyl, pyrrolinyl, pyrroHdinyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, imidazolyl, imidazolinyl, imidazoHdinyl, pyridyl, piperidinyl, homopiperidinyl, pyrazinyl, piperazinyl, pyrimidinyl, pyridazinyl, oxazolyl, oxazoHdinyl, isoxazolyl, isoxazolidinyl, morphoHnyl, thiomorpholinyl, thiazolyl, thiazolidinyl, isothiazolyl, isothiazoHdinyl, indolyl, quinolinyl, isoquinolinyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, oxetanyl, furyl, tetrahydrofuranyl, thienyl, thiazoHdinyl, isothiazolyl, triazolyl, tetrazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, pyrrolyl, pyrimidyl
Figure imgf000024_0001
and benzothienyl. Heterocyclics also include compounds of the formula where X* is -CH2- or -O- and Y* is -C(O)- or [-C(R")2-]V where R" is hydrogen or C1-C4- alkyl and v is 1, 2 or 3 such as 1,3-benzodioxolyl, 1,4-benzodioxanyl and the Hke. Heterocyclics also include bicyclic rings such as quinuclidinyl and the Hke.
Heterocyclics can be unsubstituted or monosubstituted or disubstituted with substituents independently selected from hydroxy, halo, oxo (=0), alkylimino (R*N= wherein R* is a loweralkyl group), amino, alkylamino, dialkylamino, alkoxy, alkoxyalkoxy, aminoalkyl, trialkylaminoalkyl, haloalkyl, cycloalkyl, aryl, arylalkyl, -COOH, -SO3H, alkoxycarbonyl, nitro, cyano and loweralkyl. In addition, nitrogen containing heterocycles can be N-protected.
The term "(heterocycHc)alkoxy" as used herein refers to a heterocyclic group as defined above appended to an alkoxy radical as defined above. Examples of (heterocyclic)alkoxy include 4-pyridylmethoxy, 2-pyridylmethoxy and the like.
The term "(heterocychc)alkyl" as used herein refers to a heterocyclic group as defined above appended to a loweralkyl radical as defined above.
The term "heterocycliccarbonyloxyalkyl" as used herein refers to R46-C(O)-O-R47- wherein R46 is a heterocyclic group and R47 is an alkylene group. The term "hydroxy" as used herein refers to -OH.
The term "hydroxyalkenyl" as used herein refers to an alkenyl radical to which is appended a hydroxy group.
The term "hydroxyalkoxy" as used herein refers to an alkoxy radical as previously defined to which is appended a hydroxy (-OH) group. Examples of hydroxyalkoxy include 3-hydroxypropoxy, 4-hydroxybutoxy and the Hke.
The term "hydroxyalkyl" as used herein refers to a loweralkyl radical to which is appended a hydroxy group.
The term "leaving group" as used herein refers to a halide (for example, Cl, Br or I) or a sulfonate (for example, mesylate, tosylate, triflate and the Hke). The term "mercapto" as used herein refers to -SH.
The terms "methylenedioxy" and "ethylenedioxy" refer to one or two carbon chains attached to the parent molecular moiety through two oxygen atoms. In the case of methylenedioxy, a fused 5 membered ring is formed. In the case of ethylenedioxy, a fused 6 membered ring is formed. Methylenedixoy substituted on a phenyl ring results in the
Figure imgf000026_0001
formation of a benzodioxolyl radical. . Ethylenedioxy substituted on a phenyl
ring results in the formation of a benzodioxanyl radical
Figure imgf000026_0002
The term "substantiaUy pure" as used herein means 95% or more of the specified compound. The term "tetrazolyl" as used herein refers to a radical of the formula
N— N
or a tautomer thereof. The term "tetrazolylalkoxy" as used herein refers to a tetrazolyl radical as defined above appended to an alkoxy group as defined above. Examples of tetrazolylalkoxy include tetrazolylmethoxy, tetrazolylethoxy and the Hke. The term "thioalkoxy" as used herein refers to R70S- wherein R70 is loweralkyl.
Examples of thioalkoxy include, but are not Hmited to, methylthio, ethylthio and the like. The term "thioalkoxyalkoxy" as used herein refers to RsoS-RsiO- wherein Rso is loweralkyl as defined above and Rsi is alkylene. Representative examples of alkoxyalkoxy groups include CH3SCH2O-, EtSCH2O-, t-BuSCH2O- and the Hke. The term "thioalkoxyalkoxyalkyl" as used herein refers to a thioalkoxyalkoxy group appended to an alkyl radical. Representative examples of alkoxyalkoxyalkyl groups include CH3SCH2CH2OCH2CH2-, CH3SCH2OCH2-, and the Hke.
The term "trans, trans" as used herein refers to the orientation of substituents (Ri and
Figure imgf000026_0003
R2) relative to the central substituent R as shown 1
The term "trans, cis" as used herein refers to the orientation of substituents (Ri and
Figure imgf000026_0004
R2) relative to the central substituent R as shown R1 or
Figure imgf000027_0001
. This definition encompasses both the case where R and R2 are cis and R and Ri are trans and the case where R2 and R are trans and R and Ri are cis.
The term "cis, cis " as used herein refers to the orientation of substituents (Ri and R2) relative to the central substituent R as shown
Figure imgf000027_0002
i
Preferred compounds of the invention are selected from the group consisting of: tr_.«j-tr_.«i'-2-(4-Methoxyphenyl)-4-(l,3-benzodioxol-5-yl)-l-[3-(N-propyl-N-π- pentanesulfonylamino)propyl] -ρyrrolidine-3 -carboxylic acid; tr_./w,tr_.n.;-2-(4-Methoxymethoxyphenyl)-4-(l,3-benzodioxol-5-yl)~(2-(N-propyl-N-n- pent_Hiesulfonylamino)ethyl]pyrroHdine-3-carboxylic acid; trans, trans-2-(3 ,4-Dimethoxyphenyl)-4-( 1 ,3 -benzodioxol -5-yl)- 1 -[2-(N-propyl-N-n- pentanesulfonylamino)ethyl]pyrrolidine-3-carboxy lie acid; tr »_?-trα«_?-2-(3,4-Dimethoxyphenyl)-4-(l,3-benzodioxol-5-yl)-l-[2-(N-propyl-N-n- hexanesulfonylamino)ethyl]pyrroHdine-3-carboxyHc acid; trαns,tr ns-2-(4-Propoxyphenyl)-4-(l,3-benzodioxol-5-yl)-l-[2-(N-propyl-N-«- pentanesulfonylamino)ethyl]pyrroHdine-3-carboxylic acid; tr_.«-?,tr_.«j-2-(3,4-Difluorophenyl)-4-(l,3-benzodioxol-5-yl)-l-(N,N-di(n- butyl)aminocarbonylmethyl)-pyrrolidine-3-carboxylic acid; trans, trans-2-( ,4-Difluorophenyl)-4-( 1 ,3-benzodioxol-5-yl)- 1 -[2-(N-propyl-N-n- pentanesulfonylamino)ethyl]pyrrolidine-3-carboxylic acid; tr_.«5',tr_zni'-2-(3-Fluoro-4-methoxyphenyl)-4-(l,3-benzodioxol-5-yl)-l-[2-(N-propyl-N-n- hexanesulfonylamino)ethyl]pyrroHdine-3-carboxylic acid; tr_.?._.,tr-.ns-2-(3-Fluoro-4-methoxyphenyl)-4-(l,3-benzodioxol-5-yl)-l-(2-(N-propyl-N-(3- chloropropanesulfonyl)amino)ethyl)-pyπOhdine-3-carboxyHc acid; trans, trα«s-2-(3-Fluoro-4-methoxyphenyl)-4-( 1 ,3-benzodioxol-5-yl)-l -(2-(N-isobutyl-N-(3- chloropropanesulfonyl) amino) ethyl)pyrrolidine-3 -carboxylic acid; tr-.7j_τ,tr n_;-2-(3-Fluoro-4-methoxyphenyl)-4-(l,3-benzodioxol-5-yl)-l-[2-(N-propyl-N-(4- methylbutanesulfonyl) amino) ethyl]pyrroHdine-3 -carboxylic acid; trans, trα..s-2-(4-Methoxy-3-fluorophenyl)-4-(7-methoxy- 1 ,3-benzodioxol-5-yl)-l -[2-(N- propyl-N-(n-pentanesulfonyl)amino)ethyl]pyrrolidine-3-carboxylic acid; tr_zn_f,trατ.5-2-(3-Fluoro-4-methoxyphenyl)-4-(l,3-benzodioxol-5-yl)-l-[2-(N-propyl-N-
(2,2,3,3,3-pentafluoropropoxyethanesulfonyl)-amino)ethyl]pyrroHdine-3-carboxylic acid; trans, trans-2-( 1 ,4-Benzodioxan-6-yl)-4-(7-methoxy- 1 ,3-benzodioxol-5-yl)- 1 -[2-(N-propyl-
N-(» -pentanesulfony 1) amino) ethyl]pyrrolidine-3 -carboxylic acid; trans, trans-2-(3 -Fluoro-4-methoxyphenyl)-4-( 1 ,3-benzodioxol-5-yl)- 1 -(2-(N-isobutyl-N-
(pentanesulfonylamino)ethyl)pyrroHdine-3-carboxylic acid; trans, tr««_?-2-(3-Fluoro-4-methoxyphenyl)-4-(l ,3-benzodioxol-5-yl)- 1 -(2-(N-(2- methoxyethyl)-N-(3-cMoropropanesulfonyl)amino)-ethyl)pyrroHdine-3-cai'boxylic acid; tr__«5,tr n_.-2-(3-Fluoro-4-methoxyphenyl)-4-(l,3-benzodioxol-5-yl)-l-(2-(N-(2- methoxyethyl)-N-(pentanesulfonyl)amino)ethyl)pyrroHdine-3-carboxylic acid; trα7j^trαn_:-2-(3-Fluoro-4-methoxyphenyl)-4-(l,3-benzodioxol-5-yl)-l-[2-(N-propyl-N-
((2,2,2-trifluoroethoxyethane)sulfonyl)amino)-ethyl]pyrroHdine-3-carboxylic acid; trans, trans-2-(3 -Fluoro-4-methoxyphenyl)-4-( 1 ,3-benzodioxol-5-yl)- 1 -(2-(N-(2- methoxyethyl)-N-(butanesulfonylamino)ethyl)- pyrroHdine-3 -carboxylic acid; tr-.rø,tr «5,-2-(3-Fluoro-4-methoxyphenyl)-4-(l,3-benzodioxol-5- yl)-l-[2-(N-propyl-N-(2- methylpropanesulfonyl)amino)ethyl]pyrroHdine-3-carboxylic acid; tr_trø,trα7w-2-(3-Fluoro-4-methoxyphenyl)-4-(l,3-benzodioxol-5-yl)-l-(2-(N-isobutyl-N-
(butanesulfonylamino))ethyl)pyrrolidine-3-carboxylic acid; trans , trαws-2-(2-Methylpentyl)-4-( 1 ,3-benzodioxol-5-yl)- 1 -(N,N-di(n- butyl) amino carbonylmethy l)-pyrroHdine-3 -carboxylic acid; trans, trans -2-(2,2-Dimethylpentyl)-4-( 1 ,3-benzodioxol-5-yl)- 1 -(N,N-di(n- butyl)aminocarbonylmethyl)-pyrrolidine-3-carboxylic acid; trans, trans-2-(2-( 1 ,3-Dioxo-2-yl)e.hy_)-4-( 1 ,3-benzodioxol-5-yl)- 1 -(N,N-di(n- butyl)aminocarbonylmethyl)-pyrroHdine-3-carboxylic acid; trα«_,trα^-2-(2-(2-Tefrahydro-2H-pyran)ethyl)-4-(l,3-benzodioxol-5-yl)-l-(N,N-di(n- butyl)aminocarbonylmethyl)-pyrrolidine-3-carboxylic acid; tra«_:,trα?j_-2-(2,2,4-Trimethyl-3-pentenyl)-4-(l,3-benzodioxol-5-yl)-l-(N,N-di(n- butyl)aminocarbonylmethyl)-pyrrolidine-3-carboxy lie acid; tr_.n_,tr-_?.5-2-(2,2,-Dimethyl-2-(l,3-cHoxol_m-2-yl)ethyl)-4-(l,3-benzodioxol-5-yl)-l-(N,N- di(n-butyl)aminocarbonylmethyl)-pyrroHdine-3-carboxyHc acid; trans, trans-2-(2-( 1 ,3-Dioxo-2-yl)ethyl)-4-( 1 ,3-benzodioxol-5-yl)- l-[[N-4-heptyl-N(2 methyl-
3-fluorophenyl)] amino carbonylmethyl]-pyrrolidine-3 -carboxylic acid; trarø,trαπ5-2-(2-(l,3-Dioxol-2-yl)ethyl)-4-(7-methoxy-l,3-benzodioxol-5-yl)-l-(Ν,Ν-di(n- butyl) amino carbonylmethyl)-pyrroHdine-3 -carboxylic acid; trα«_.,trα?._.-2-((2-Methoxyphenoxy)-methyl)-4-(l,3-benzodioxol-5-yl)-l-(N,N-di(n- butyl) amino carbonylmethy l)-pyrrolidine-3 -carboxylic acid; (2S,3R,4S 2-(2,2-Dimethylpentyl)-4-(l,3-benzodioxol-5-yl)-l-(N-4-heptyl-N-(4-fluoro-3- methylphenyl))aminocarbonyHnethyl)-pyrrolidine-3-carboxylic acid; trans, trαn_.-2-(2-(2-Oxopyrrolidin- 1 -yl)ethyl)-4-( 1 ,3-benzodioxol-5-yl)-l -(N,N-di(n- butyl)aminocarbonylmethyl)-pyrroHdine-3-carboxylic acid; tr_.n..,tr-.rø-2-(2-(l,3-Dioxol-2-yl)ethyl)-4-(7-methoxy-l,3-benzodioxol-5-yl)-l-(N-4-heptyl-
N-(4-fluoro-3-methylphenyl))aminocarbonylmethyl)-pyrroHdine-3-carboxyHc acid; tr_.n_;,tr_.n-?-2-(2,2-Dimethylpentyl)-4-(7-methoxy-l,3-benzodioxol-5-yl)-l-(N,N-di(n- butyl)aminocarbonylmethyl)-pyrrolidine-3-carboxylic acid; trans, trαπ-.-2-(2,2-dimethylpentyl)-4-(2,3-dihydro-benzofuran-5-yl)- 1 -(N,N-di(n- butyl)aminocarbonylmethyl)-pyrroHdine-3-carboxylic acid; trαn5,trαn5-2-(2,2,-Dimethyl-2-(l,3-dioxolan-2-yl)ethyl)-4-(7-methoxy-l,3-benzodioxol-5- yl)-l-(N,N-di(n-butyl)aminocarbonylmethyl)-pyιτoHdine-3-carboxylic acid; trans, trans -2-(2-(2-Methoxyphenyl)-ethyl)-4-( 1 ,3-benzodioxol-5-yl)- 1 -(N,N-di(n- butyl)aminocarbonylmethyl)-pyriOHdine-3-carboxylic acid; trans, tr_.n_.-2-(2,2-Dimethyl-3-(E -pentenyl)-4-(7-methoxy-l ,3-benzodioxol-5-yl)- 1 -(N,N- di(n-butyl)aminocarbonylmethyl)-pyrrolidine-3-carboxyHc acid; trαn-?,tr_.n-?-2-(2-(2-pyridyl)ethyl)-4-(l,3-ber_zodioxol-5-yl)-l-(N,N-di(n- butyl)aminocarbonylmethyl)-pyrroHdine-3-carboxylic acid; (2S, 3R, S 2-(2-(2-oxopyrrolidin-l-yl)ethyl)-4-(l,3-benzodioxol-5-yl)-l-(N,N-di(n- butyl) amino carbonylmethy l)-pyrroHdine-3 -carboxylic acid; (2S, 3R, S)-2-(2-(2-oxopyrrohdin-l-yl)ethyl)-4-(l,3-benzodioxol-5-yl)-l-(N-4-heptyl-N-(4- fluoro-3-methylphenyl))aminocarbonylmethyl)-pyrroHdine-3-carboxylic acid; trans, trans-2-(2-( 1 -pyrazolyl)ethyl)-4-( 1 ,3-benzodioxol-5-yl)-l -(N,N-di(n- butyl)arr_inocarbonylmethyl)-pyrroHdine-3-carboxylic acid; trα«_?,tr_.n,s'-2-(4-Methoxyphenyl)-4-(l,3-benzodioxol-5-yl)-l-[(N-butyl-N-(4- dimethylaminobutyl)amino)carbonylmethyl]-pyrrolidine-3-carboxy lie acid; (2i?,3R,^-2-(3-Fluoro-4-methoxyphenyl)-4-(l,3-benzodioxol-5-yl)l-(2-(N-propyl-N- pentanesulfonylamino) ethyl) -pyrrolidine-3 -carboxylic acid; trans, trans -2-(2,2-Dimethylpentyl)-4-( 1 ,3-benzodioxol-5-yl)- 1 -((N-butyl-N-(4- dimethylamino)butyl)aminocarbonylmethyl)-pyrrolidine-3-carboxy lie acid; trαrø,trαn5,-2-(2,2-Dimethylpentyl)-4-(7-methoxy-l,3-benzodioxol-5-yl)-l-(N-4-heptyl-N-(4- fluoro-3-methylphenyl))aminocarbonylmethyl)-pyrroHdine-3-carboxy lie acid; trαrø,trαn5,-2-(2,2-Dimethylpentyl)-4-(7-methoxy-l,3-benzodioxol-5-yl)-l-((N-butyl-N-(4- dimethylamino)butyl)ammocarbonylmethyl)-pyπOlidine-3-carboxy lie acid; trans, trαns-2-(2,2-Dimethylpent~3~enyl)-4-( 1 ,3-benzodioxol-5-yl)- 1 -(N-4-heptyl-N-(4- fluoro-3-methylphenyl))aminocarbonylmethyl)-pyrrolidine-3-carboxylic acid; trans, trα«s-2-(2,2-Dimethylpent-3-enyl)-4-( 1 ,3-benzodioxol-5-yl)- 1 -((N-butyl-N-(4- dimethylamino)butyl)aminocarbonylmethyl)-pyrrolidine-3-carboxy lie acid; trα7.s,trαn ,-2-(2,2-Dimethylpent-3-enyl)-4-(7-methoxy-l,3-benzodioxol-5-yl)-l-(N,N-di(n- butyl)aminocarbonylmethyl)-pyrroHdine-3-carboxylic acid; trαn_.,trαns-2-(2,2-Dimethylpent-3-enyl)-4-(7-methoxy-l,3-benzodioxol-5-yl)-l-(N-4-heptyl-
N-(4-fluoro-3-methylphenyl))aminocarbonylmethyl)-pyrrolidine-3-carboxylic acid; trαn_.,trα«s-2-(2,2-Dimethylpent-3-enyl)-4-(7-methoxy-l,3-benzodioxol-5-yl)-l-((N-butyl-N-
(4-dimethylamino)butyl)aminocarbonylmethyl)-pyrrolidine-3-carboxy lie acid; trαrø,trα?.s-2-(2,2,4-Trimethylpent-3-enyl)-4-(l,3-benzodioxol-5-yl)-l-(N-4-heptyl-N-(4- fluoro-3-methylphenyl))aminocarbonylmethyl)-pyrroHdine-3-carboxylic acid; trαrø,trαns-2-(2,2,4-Trimethylpent-3-enyl)-4-(l,3-benzodioxol-5-yl)-l-((N-butyl-N-(4- dimethylamino)butyl)aminocarbonylmethyl)-pyrrolidine-3-carboxylic acid; trαrø,trαrø-2-(2,2,4-Trimethylpent-3-enyl)-4-(7-methoxy-l,3-benzodioxol-5-yl)-l-(N,N- di(n-butyl)aminocarbonylmethyl)-pyιiOHdine-3-carboxylic acid; trαn-.,trαns-2-(2,2,4-Trimethylpent-3-enyl)-4-(7-methoxy- 1 ,3-benzodioxol-5-yl)- 1 -(N-4- heptyl-N-(4-fluoro-3-methylphenyl))aιmnocarbonylmethyl)-pyrroHdine-3-cai'boxylic acid; trans, trα«s-2-(2,2,4-Trimethylpent-3-enyl)-4-(7-methoxy- 1 ,3-benzodioxol-5-yl)- 1 -((N-butyl- N-(4-dimethylamino)butyl)aminocarbonylmethyl)-pyrrolidine-3-carboxylic acid; trα«s,trαrø-2-(2-(l,3-Dioxol-2-yl)ethyl)-4-(l,3-benzodioxol-5-yl)-l-[(N-butyl-N-(4- dimethylaminobutyl)amino)carbonylmethyl]-pyrrolidine-3-carboxy lie acid; trans, trans-2-(2-( 1 ,3-Dioxol-2-yl)ethyl)-4-(7-methoxy- 1 ,3-benzodioxol-5-yl)-l -[(N-butyl-N-
(4-dimethylaminobutyl)an_ino)carbonylmethyl]-pyrrolidine-3-carboxylic acid; trαrø,trαns-2-(2,2,-Dimethyl-2-(l,3-Dioxol-2-yl)ethyl)-4-(l,3-benzodioxol-5-yl)-l-(N-4- heptyl-N-(4-fluoro-3-methylphenyl))aminocarbonylmethyl)-pyrroHdine-3-carboxylic acid; trα?.s,trα«s-2-(2,2-Dimethyl-2-(l,3-dioxolan-2-yl)ethyl)-4-(l,3-benzodioxol-5-yl)-l-[(N- butyl-N-(4-dimethylaminobutyl)amino)carbonylmethyl]-pyrroHdine-3-carboxyHc acid; trans, trα«s-2-(2,2,-Dimethyl-2-( 1 ,3-Dioxol-2-yl)ethyl)-4-(7-methoxy- 1 ,3-benzodioxol-5-yl)-
1 -(N-4-heptyl-N-(4-fluoro-3 -methylphenyl)) amino carbonylmethy l)-pyrroHdine-3 - carboxylic acid; trα«-.,trατ._.-2-(2,2-Dimethyl-2-(l,3-dioxolan-2-yl)ethyl)-4-(7-methoxy-l,3-benzodioxol-5- yl)-l-[(N-butyl-N-(4-dimethylaminobutyl)amino)carbonylmethyl]-pyrroHdine-3- carboxylic acid; trans, trans-2-(2-(2-Methoxyphenyl)-ethyl)-4-( 1 ,3-benzodioxol-5-yl)- 1 -(N-4-heptyl-N-(4- fluoro-3-methylphenyl))amino)carbonylmethyl]-pyrroHdine-3-carboxylic acid; trans, trα .s-2-(2-(2-Methoxyphenyl)-ethyl)-4-( 1 ,3-benzodioxol-5-yl)- 1 -[(N-butyl-N-(4- dimethylaminobutyl)amino)carbonylmethyl]-pyrrolidine-3-carboxylic acid; trα«j,trα«_?-2-(2-(2-Methoxyphenyl)-ethyl)-4-(7-methoxy-l,3-benzodioxol-5-yl)-l- (N,N- di(n-butyl)aminocarbonyknethyl)-pyιτoHdine-3 -carboxyHc acid; trans, trα«s-2-(2-(2-Methoxyphenyl)-ethyl)-4-(7-methoxy- 1 ,3-benzodioxol-5-yl)- 1 -(N-4- heptyl-N-(4-fluoro-3-methylphenyl))amino)carbonylmethyl]-pyrroHdine-3-carboxylic acid; trans, trα«_7-2-(2-(2-Methoxyphenyl)-ethyl)-4-(7-methcxy- 1 ,3-benzodioxol-5-yl)- 1 -[(N-butyl-
N-(4-dimethylaminobutyl)amino)carbonylmethyl]-pyrroHdine-3-carboxylic acid; trαn5,,trαn_?-2-((2-Methoxyphenoxy)-methyl)-4-(l,3-benzodioxol-5-yl)-l-(N-4-heptyl-N-(4- fluoro-3-methylphenyl))amino)carbonylmethyl]-pyrroHdine-3-carboxylic acid; trans, trαns-2-((2-Methoxyphenoxy)-methyl)-4-( 1 ,3-benzodioxol-5-yl)- 1 -[(N-butyl-N-(4- dimethylaminobutyl)amino)carbonylmethyl]-pyrrolidine-3-carboxy lie acid; trα«_?,trαn.-2-((2-Methoxyphenoxy)-methyl)-4-(7-methoxy-l,3-benzodioxol-5-yl)-l- (N,N- di(n-butyl)aminocarbonylmethyl)-pyrroHdine-3-carboxyHc acid; trans, trαns-2-((2-Methoxyphenoxy)-methyl)-4-(7-methoxy- 1 ,3-benzodioxol-5-yl)- 1 -(N-4- heptyl-N-(4-fluoro-3-methylphenyl))amino)carbonylmethyl]-pyrroHdine-3-carboxylic acid; trα«5,trαns-2-(2-(2-Methoxyphenoxy)-methyl)-4-(7-methoxy-l,3-benzodioxol-5-yl)-l-[(N- butyl-N-(4-dimethylaminobutyl)amino)caι-bonylmethyl]-pyπOlidine-3-carboxylic acid; trans,trans-2-(2-(2-Oxo 1,2-dihydro pyridin-l-yl)-ethyl)-4-(l,3-benzodioxol-5-yl)-l-(N,N- di(n-butyl)aminocarbonylmethyl)-pyrroHdine-3-carboxyHc acid; trans, trans -2-(2-(2-Oxoρyridin- 1 -yl)-ethyl)-4-( 1 ,3-benzodioxol-5-yl)- 1 -[(N-4-heptyl-N-(4- fluoro-3-methylphenyl)amino)carbonylmethyl]-pyrrolidine-3-carboxylic acid; trans, trα7._?-2-(2-(2-Oxopyridin- 1 -yl)-ethyl)-4-( 1 ,3-benzodioxol-5-yl)- 1 -[(N-butyl-N-(4- dimethylaminobutyl)amino)carbonylmethyl]-pyrrolidine-3-carboxylic acid; trans, trαπs-2-(2-(2-Oxopyridin- 1 -yl)-ethyl)-4-(7-methoxy- 1 ,3-benzodioxol-5-yl)- 1 -(N,N- di(N-butyl)aminocarbonylmethyl)-pyrroHdine-3-carboxylic acid; trα7._.,trαπ_.-2-(2-(2-Oxopyridin-l-yl)-ethyl)-4-(7-methoxy-l,3-benzodioxol-5-yl)-l-[(N-4- heptyl-N-(4-fluoro-3-methylphenyl)amino)carbonylmethyl]-pyrrolidine-3-carboxylic acid; trans, trans -2-(2-(2-Oxopyridin- 1 -yl)-ethyl)-4-(7-methoxy- 1 ,3-benzodioxol-5-yl)- 1 -[(N- butyl-N-(4-dimethylaminobutyl)amino)carbonylmethyl]-pyrroHdine-3-carboxylic acid; trans, trα«s-2-(2(-2-Oxopiperidin- 1 -yl)-ethyl)-4-( 1 ,3-benzodioxol-5-yl)- 1 -(N,N-di(N- butyl)aminocarbonylmethyl)-pyrroHdine-3-carboxylic acid; tr-.rø,trα«5,-2-(2-(2-Oxopiperidin-l-yl)-ethyl)-4-(l,3-benzodioxol-5-yl)-l-[(N-4-heptyl-N-(4- fluoro-3-methylphenyl)amino)carbonylmethyl]-pyrroHdine-3-carboxylic acid; trans, trans -2-(2-(2-Oxopiperidin- 1 -yl)-ethyl)-4-(7-methoxy- 1 ,3-benzodioxol-5-yl)- 1 -(N,N- di(N-butyl)aminocarbonylmethyl)-pyrroHdine-3-carboxylic acid; trans, trαns-2-(2-(2-Oxopiperidin- 1 -yl)-ethyl)-4-(7-methoxy- 1 ,3-benzodioxol-5-yl)- 1 -(N,N- di(N-butyl)aminocarbonylmethyl)-pyrrolidine-3-carboxylic acid; trα.w,trαns-2-(2-(2-Oxopiperidin-l-yl)-ethyl)-4-(7-methoxy-l,3-benzodioxol-5-yl)-l-[(N-4- heptyl-N-(4-fluoro-3 -methylphenyl) amino) carbonyhnethyl] -pyrroHdine-3 -carboxylic acid; trαn_.,trαn_.-2-(2-(2-Oxopiperidin-l-yl)-ethyl)-4-(7-methoxy-l,3-benzodioxol-5-yl)-l-[(N- butyl-N-(4-dimethyl-iminobutyl)amino)carbonylmethyl]-pvrroHdine-3-carboxylic acid; trαns,trα«5-2-(2-(2-OxopyrroHdin-l-yl)ethyl)-4-(l,3-benzodioxol-5-yl)-l-[(N-butyl-N-(3- hydroxypropyl) amino) carbonylmethy 1] -pyrrolidine-3 -carboxylic acid; trαn5,,trα«λ-2-(2-(2-Oxopyrrolidin-l-yl)ethyl)-4-(l,3-benzodioxol-5-yl)-l-[(N-butyl-N-
(propoxy) amino) carbonyhnethyl] -pyrroHdine-3 -carboxylic acid; trαns,trαn5,-2-(2-(2-Oxopyrrolidin-l-yl)ethyl)-4-(l,3-benzodioxol-5-yl)-l-[(N-butyl-N-(4 dimethylaminobutyl)amino)carbonylmethyl]-pyrrolidine-3-carboxy lie acid; trans, traτιs-2-(2-(2-Oxop τvoliάm.- 1 -yl)ethyl)-4-( 1 ,3-benzodioxol-5-yl)- 1 -[(N-butyl-N-(4- trimethylammoniobutyl)amino)carbonylmethyl]-pyrroHdine-3-carboxylic acid; trans, tra.w-2-(2-(2-OxopyrroHd_n- 1 -yl)ethyl)-4-(7-methoxy- 1 ,3-benzodioxol-5-yl)- 1 -(N,N- di(N-butyl)aminocarbonylmethyl)-pyrrolidine-3-carboxylic acid; trans, trans -2-(2-(2-Oxopyrrolidin- 1 -yl)ethyl)-4-(7-methoxy- 1 ,3-benzodioxol-5-yl)- 1 -[(N- butyl-N-(3-hydroxypropyl)amino)carbonylmethyl]-pyrroHdine-3-carboxylic acid; trαn_?,trαn-.-2-(2-(2-OxopyrroHdin-l-yl)ethyl)-4-(7-methoxy-l,3-benzodioxol-5-yl)-l-[(N-4- heptyl-N-(4-fluoro-3 -methylphenyl) amino) carbonylmethy 1] -pyrrolidine-3 -carboxylic acid; trαn_.,trαrø-2-(2-(2-OxopyrroHdin- 1 -yl)ethyl)-4-(7-methoxy- 1 ,3-benzodioxol-5-yl)- 1 -[(N- butyl-N-(propoxy)amino)carbonylmethyl]-pyrroHdine-3-carboxylic acid; trans, trαn_?-2-(2-(2-Oxopyrrolidin- 1 -yl)ethyl)-4-(7-methoxy- 1 ,3-benzodioxol-5-yl)- 1 -[(N- butyl-N-(4-dimethylaminobutyl)amino)carbonylmethyl]-pyπOHdine-3-cai'boxyHc acid; trans, trα..s-2-(2-(2-OxopyrroHdin- 1 -yl)ethyl)-4-(7-methoxy-l ,3-benzodioxol-5-yl)- 1 -[(N- butyl-N-(4-trimethylammomobutyl)amino)carbonyHnethyl]-pyrroHdine-3-carboxylic acid; trans, trαns-2-(2-(2-OxopyrroHdin- 1 -yl)ethyl)-4-(2,3-dihydro-benzofuran-5-yl)- 1 -(N,N-di(N- butyl)aminocarbonylmethyl)-pyrroHdine-3-carboxylic acid; trαns,trαns-2-(2-(2-OxopyrroHdin-l-yl)ethyl)-4-(2,3-dihydro-benzofuran-5-yl)-l-[(N-4- heptyl-N-(4-fluoro-3-methylphenyl)amino)carbonylmethyl]-pyrrolidine-3-carboxylic acid; trans, trαns-2-(2-(2-OxopyrroHdin- 1 -yl)ethyl)-4-(2,3-dihydro-benzo_uran-5-yl)- 1 -[(N-butyl-
N-(4-dimethylaminobutyl)amino)carbonylmethyl]-pyrroHdine-3-carboxy lie acid; trαrø,trαn5,-2-(2-(3,3-Dimethyl-2-oxopyrrolidin-l-yl)ethyl)-4-(l,3-benzodioxol-5-yl)-l-(N,N- di(N-butyl)aminocarbonylmethyl)-yrrolidine-3-carboxylic acid; trαns,trαn_.-2-(2-(3,3-Dimethyl-2-oxopyrroHdin-l-yl)ethyl)-4-(l,3-benzodioxol-5-yl)-l-[(N-
4-heptyl-N-(4-fluoro-3-methylphenyl)amino)carbonylmethyl]-pyrroHdine-3- carboxylic acid; trans, trans -2-(2-(3 ,3-Dimethyl-2-oxopyrrolidin- 1 -yl)ethyl)-4-( 1 ,3-benzodioxol-5-yl)- 1 -[(N- butyl-N-(4-dimethylaminobutyl)amino)carbonylmethyl]-pyrroHdine-3-carboxylic acid; trα»s,trαn5,-2-(2-(4,4-Dimethyl-2-oxopyrrolidin-l-yl)ethyl)-4-(l,3-benzodioxol-5-yl)-l-(N,N- di(N-butyl)aminocarbonylmethyl)-pyrrolidine-3-carboxy lie acid; trans, trαn>y-2-(2-(4,4-Dimethyl-2-oxopy_τoHdin- 1 -yl)ethyl)-4-( 1 ,3-benzodioxol-5-yl)- 1 -[(N- 4-heptyl-N-(4-fluoro-3 -methylphenyl) amino) carbonylmethyl]-pyrroHdine-3 - carboxylic acid; trαrø,trαn_f-2-(2-(4,4-Dimethyl-2-oxopyrrolidin-l-yl)ethyl)-4-(l,3-benzodioxol-5-yl)-l-[(N- butyl-N-(4-dimethylaminobutyl)amino)carbonylmethyl]-pyrroHdine-3-carboxyHc acid; trans, trans-2-(2-( 1 -propanesultamyl)ethyl)-4-( 1 ,3-benzodioxol-5-yl)- 1 -(N,N- dibutylaminocarbonylmethyl)-pyrroHdine-3-carboxylic acid; trαn_.,trαn5-2-(2-(l-propanesultamyl)ethyl)-4-(l,3-benzodioxol-5-yl)-l-[(N-4-heptyl-N-(4- fluoro-3-methylphenyl)amino)carbonylmethyl]-pyrrolidine-3-carboxylic acid; trαrø,trαns-2-(2-(l-propanesultamyl)ethyl)-4-(l,3-benzodioxol-5-yl)-l-[(N-butyl-N-(3- hydroxypropyl)amino)carbonylmethyl]-pyrrolidine-3-carboxylic acid; trans, trans-2-(2-( 1 -propanesultamyl)ethyl)-4-( 1 ,3-benzodioxol-5-yl)-l -[(N-butyl-N-
(propoxy) amino)carbonylmethyl] -pyrroHdine-3 -carboxyHc acid; trα7.s,trα«_.-2-(2-(l-propanesultamyl)ethyl)-4-(l,3-benzodioxol-5-yl)-l-[(N-butyl-N-(4 dimethylaminobutyl) amino) carbonylmethyl] -pyrrolidine-3 -carboxylic acid; trans, trans-2-(2-( 1 -propanesultamyl)ethyl)-4-(7-methoxy- 1 ,3-benzodioxol-5-yl)- 1 -(N,N- di(n-butyl)aminocarbonylmethyl)-pyrrolidine-3-carboxyHc acid; trans, trans-2-(2-( 1 -propanesultamyl)ethyl)-4-(7-methoxy- 1 ,3-benzodioxol-5-yl)- 1 -[(N-4- heptyl-N-(4-fluoro-3 -methylphenyl) amino) carbonylmethyl] -pyrroHdine-3 -carboxylic acid; trans, trans-2-(2-( 1 -propanesultamyl)ethyl)-4-(7-methoxy- 1 ,3-benzodioxol-5-yl)- 1 -[(N-butyl- N-(4-dimethylaminobutyl)amino)carbonylmethyl]-pyrroHdine-3-carboxylic acid; trans, trans-2-(2-( 1 -propanesultamyl)ethyl)-4-(2,3-dihydro-benzofuran-5-yl)- 1 -(N,N-di(n- butyl) amino carbonylmethy l)-pyrroHdine-3 -carboxylic acid; trans, trans-2-(2-( 1 -propanesultamyl)ethyl)-4-(2,3 -dihydro-benzofuran-5-yl)- 1 -[(N-4-heptyl-
N-(4-fluoro-3 -methylphenyl) amino) carbonylmethyl] -pyrroHdine-3 -carboxyHc acid; trαns,trαn_f-2-(2-(l-propanesultamyl)ethyl)-4-(2,3-dihyώO-benzofuran-5-yl)-l-[(N-butyl-N-
(4-dimethylaminobutyl)amino)carbonylmethyl]-pyrroHdine-3-carboxy lie acid; trans, trans-2-(2-( 1 -pyrazolyl) ethyl)-4-( 1 ,3-benzodioxol-5-yl)- 1 -[(N-4-heptyl-N-(4-fluoro-3- methylphenyl)amino)carbonylmethyl]-pyrroHdine-3-carboxy lie acid; trans, trans-2-(2-( 1 -pyrazolyl) ethyl)-4-( 1 ,3-benzodioxol-5-yl)- 1 -[(N-butyl-N-(3- hydroxypropyl)amino)carbonylmethyl]-pyrrolidine-3-carboxylic acid; trans, trans-2-(2-( 1 -pyrazolyl) ethyl)-4-( 1 ,3-benzodioxol-5-yl)- 1 -(N-butyl-N-
(propoxy)amino)carbonylmethyl]-pyrrolidine-3-carboxylic acid; trans, trans-2-(2-( 1 -pyrazolyl) ethyl)-4-( 1 ,3-benzodioxol-5-yl)- 1 -[(N-butyl-N-(4- dimethylaminobutyl)amino)carbonylmethyl]-pyrrolidine-3-carboxylic acid; trans, trans-2-(2-( 1 -pyrazolyl) ethyl)-4-(7-methoxy- 1 ,3-benzodioxol-5-yl)- 1 -(N,N- dibutylaminocarbonylmethyl)-pyrroHdine-3-carboxylic acid; trans, trans-2-(2-( 1 -pyrazolyl) ethyl)-4-(7-methoxy- 1 ,3-benzodioxol-5-yl)- 1 -[(N-4-heptyl-N-
(4-fluoro-3 -methylphenyl) amino) carbonylmethyl] -pyrrolidine-3 -carboxylic acid; trans, trans-2-(2-( 1 -pyrazolyl) ethyl)-4-(7-methoxy- 1 ,3-benzodioxol-5-yl)- 1 -[(N-butyl-N-(4- dimethylaminobutyl)amino)carbonylmethyl]-pyrrolidine-3-carboxylic acid; trαns,trαns-2-(2-(l-pyrazolyl)ethyl)-4-(2,3-dihydro-benzofuran-5-yl)-l-(N,N- dibutylaminocarbonylmethyl)-pyrroHdine-3-carboxylic acid; trαrø,trαns-2-(2-(l-pyrazolyl)ethyl)-4-(2,3-dihy(_ro-benzofuran-5-yl)-l-[(N-4-heptyl-N-(4- fluoro-3-methylphenyl)amino)carbonylmethyl]-pyrrolidine-3-carboxy lie acid; trα«_?,trαrø-2-(2-(l-pyrazolyl)ethyl)-4-(2,3-dihydro-benzofuran-5-yl)-l-[(N-butyl-N-(4- dimethylaminobutyl)amino)carbonylmethyl]-pyrrolidine-3-carboxy lie acid; trans, trαns-2-(2-(2-oxazolyl)ethyl)-4-( 1 ,3-benzodioxol-5-yl)- 1 -(N,N-di(n- butyl)aminocarbonylmethyl)-pyrroHdine-3-carboxylic acid; trαn_.,trα«_.-2-(2-(Oxazol-2-yl)ethyl)-4-(l,3-benzodioxol-5-yl)-l-[(N-4-heptyl-N-(4-fluoro-3- methylphenyl)amino)carbonylmethyl]-pyrrolidine-3 -carboxyHc acid; trαπs,trαns-2-(2-(Oxazol-2-yl)ethyl)-4-(l,3-benzodioxol-5-yl)-l-[(N-butyl-N-(3- hydroxypropyl)amino)carbonylmethyl]-pyrroHdine-3-carboxylic acid; trαns,trαns-2-(2-(Oxazol-2-yl)ethyl)-4-(l,3-benzodioxol-5-yl)-l-[(N-butyl-N-
(propoxy) amino) carbonylmethy l]-pyrroHdine-3 -carboxyHc acid; trans, trαns-2-(2-(Oxazol-2-yl) ethyl)-4-( 1 ,3-benzodioxol-5-yl)- 1 -[(N-butyl-N-(4- dimethylaminobutyl)amino)carbonylmethyl]-pyrrolidine-3-carboxy lie acid; trans, trα«5-2-(2-(Oxazol-2-yl) ethyl)-4-(7-methoxy- 1 ,3-benzodioxol-5-yl)- 1 -(N,N-di(n- butyl)aminocarbonylmethyl)-pyrroHdine-3-carboxylic acid; trans, trans-2-(2-(Oxazol-2-yV) ethyl)-4-(7-methoxy- 1 ,3-benzodioxol-5-yl)- 1 -[(N-4-heptyl-N- (4-fluoro-3 -methylphenyl) amino) carbonylmethy l]-pyrrolidine-3 -carboxylic acid; trαπs,trαn_;-2-(2-(Oxazol-2-yl)ethyl)-4-(7-methoxy-l,3-benzodioxol-5-yl)-l-[(N-butyl-N-(4- dimethylaminobutyl)amino)carbonylmethyl]-pyrrolidine-3-carboxylic acid; trατ...,trαns-2-(2-(5-Methyloxazol-2-yl)ethyl)-4-(l,3-benzodioxol-5-yl)-l-(N,N-di(n- butyl) amino carbonylmethy l)-pyrroHdine-3 -carboxylic acid; trans, trans -2-(2-(5-Methyloxazol-2-yl) ethyl)-4-( 1 ,3-benzodioxol-5-yl)- 1 -[(N-4-heptyl-N-(4- fluoro-3-methylphenyl)amino)carbonylmethyl]-pyrroHdine-3-carboxylic acid; trα»s,trαns-2-(2-(5-Methyloxazol-2-yl)ethyl)-4-(l,3-benzodioxol-5-yl)-l-[(N-butyl-N-(4- dimethy laminobutyl) amino) carbonylmethyl] -pyrrolidine-3 -carboxylic acid; trαn_?,trαn.;-2-(2-(2,5-DioxopyrroHdin-l-yl)ethyl)-4-(l,3-benzodioxol-5-yl)-l-(N,N-di(n- . butyl)aminocarbonylmethyl)-pyrroHdine-3-carboxylic acid; trαn5',trα7.5'-2-(2-(2,5-DioxopyrroHdin-l-yι)ethyl)-4-(l,3-benzodioxol-5-yl)-l-[(N-4-heptyl-
N-(4-fluoro-3 -methylphenyl) amino) carbonylmethyl] -pyrroHdine-3 -carboxyHc acid; trα«s,trαrø-2-(2-(2,5-DioxopyrroHdin-l-yl)ethyl)-4-(l,3-benzodioxol-5-yl)-l-[(N-butyl-N-(3- hydroxypropyl) amino) carbonylmethyl] -pyrroHdine-3 -carboxylic acid; trans, trans -2-(2-(2, 5-DioxopyrroHdin- 1 -yl)ethyl)-4-( 1 ,3-benzodioxol-5-yl)- 1 -[(N-butyl-N-
(propoxy) amino) carbonylmethyl] -pyrroHdine-3 -carboxyHc acid; trαn_.,trαπs-2-(2-(2,5-DioxopyrroHdin-l-yl)ethyl)-4-(l,3-benzodioxol-5-yl)-l-[(N-butyl-N-(4- dimethylaminobutyl) amino) carbonylmethyl] -pyrroHdine-3 -carboxylic acid; trατιs,trαn_-2-(2-(2,5-Dioxopyrrolidin-l-yl)ethyl)-4-(7-methoxy-l,3-benzodioxol-5-yl)-l-
(N,N-di(n-butyl)aminocarbonylmethyl)-pyrrolidine-3-carboxylic acid; trα«5,,trαπ-.-2-(2-(2,5-DioxopyrroHdin-l-yl)ethyl)-4-(7-methoxy-l,3-benzodioxol-5-yl)-l-
[(N-4-heptyl-N-(4-fluoro-3-methylphenyl)amino)carbonylmethyl]-pyrroHdine-3- carboxylic acid; trαns,trαns-2-(2-(Pyridin-2-yl)ethyl)-4-(l,3-benzodioxol-5-yl)-l-[(N-4-heptyl-N-(4-fluoro-3- methylphenyl)amino)carbonylmethyl]-pyrrolidine-3-caι-boxylic acid; trαns,trαns-2-(2-(Pyridin-2-yl)ethyl)-4-(l,3-benzodioxol-5-yl)-l-[(N-butyl-N-(3- hydroxypropyl)amino)carbonylmethyl]-pyrroHdine-3-carboxylic acid; trans, trans -2-(2-(Pyridin-2-yl) ethyl)-4-( 1 ,3-benzodioxol-5-yl)- 1 -[(N-butyl-N-
(propoxy)amino)carbonylmethyl]-pyrrolidine-3-carboxy lie acid; trans, trαnJs-2-(2-(Pyridin-2-yl) ethyl)-4-( 1 ,3-benzodioxol-5-yl)- 1 -[(N-butyl-N-(4- dimethylaminobutyl)amino)carbonylmethyl]-pyrrolidine-3-carboxylic acid; trans, trαns-2-(2-(Pyridin-2-yl) ethyl)-4-(7-methoxy- 1 ,3-benzodioxol-5-yl)- 1 -(N,N-di(n- butyl)aminocarbonylmethyl)-pyrroHdine-3-carboxy lie acid; trans, trαns-2-(2-(Pyridin-2-yl) ethyl)-4-(7-methoxy- 1 ,3-benzodioxol-5-yl)- 1 -[(N-4-heptyl-N-
(4-fluoro-3 -methylphenyl) amino) carbonylmethyl] -pyrroHdine-3 -carboxylic acid; trans, trαn_?-2-(2-(Pyridin-2-yl) ethyl)-4-(7-methoxy- 1 ,3-benzodioxol-5-yl)- 1 -[(N-butyl-N-(4- dimethylaminobutyl)amino)carbonylmethyl]-pyrrolidine-3-carboxylic acid; trΩMS,trαns-2-(2-(Pyrimidin-2-yl)ethyl)-4-(l,3-benzodioxol-5-yl)-l-(N,N-di(n- butyl) amino carbonylmethy l)-pyrroHdine-3 -carboxylic acid; trατ.s,trαns-2-(2-(Pyrirnidin-2-yl)ethyl)-4-(l,3-benzodioxol-5-yl)-l-[(N-4-heptyl-N-(4-fluoro- 3-methylphenyl)amino)carbonylmethyl]-pyrroHdine-3-carboxylic acid; trαns,trαrø-2-(2-(Pyrimidin-2-yl)ethyl)-4-(l,3-benzodioxol-5-yl)-l-[(N-butyl-N-(4- dimethylaminobutyl)amino)carbonylmethyl]-pyrrolidine-3-carboxylic acid; trαni_,,trαns-2-(2-(l,3-benzodioxol-4-yl)ethyl)-4-(l,3-benzodioxol-5-yl)-l-(N,N-di(n- butyl)aminocarbonylmethyl)-pyrroHdine-3-carboxy lie acid; trαns,trαRS-2-(2-(l,3-benzodioxol-4-yl)ethyl)-4-(l,3-benzodioxol- 5-yl)-l-[(N-4-heptyl-N-(4- fluoro-3-methylphenyl)amino)carbonylmethyl]-pyrroHdine-3-carboxylic acid; and trα7.5,,trαπ_v-2-(2-(l,3-benzodioxol-4-yl)ethyl)-4-(l,3-benzodioxol-5-yl)-l-[(N-butyl-N-(4 dimethylaminobutyl) amino) carbonylmethyl] -pyrrolidine-3 -carboxylic acid; (2S,3R,4S)-2-(2,2-Dimethylpentyl)-4-(l,3-benzodioxol-5-yl)-l-(N,N-di(n- butyl)aminocarbonylmethyl)-pyrroHdine-3-carboxylic acid; (2S,3R,4S)-2-(2,2-Dimethylpent-(E)-3-enyl)-4-(l,3-benzodioxol-5-yl)-l-(N,N-di(n- butyl) amino carbonylmethyl) -pyrroHdine-3 -carboxylic acid; (2S,3R,4S)-2-(2,2-Dimethylpent-(E)-3-enyl)-4-(7-methoxy-l,3-benzodioxol-5-yl)-l-(N,N- di(n-butyl)aminocarbonylmethyl)-pyrrolidine-3-carboxyHc acid; (2S,3R,4S)-2-((2-Methoxyphenoxy)-methyl)-4-( 1 ,3-benzodioxol-5-yl)- 1 -(N,N-di(n- butyl)arninocarbonylmethyl)-pyrrolidine-3-carboxy lie acid; (2S,3R,4S)-2-(2-(2-Methoxyphenyl)ethyl)-4-(l,3-benzodioxol-5-yl)-l-(N,N-di(n- butyl) amino carbonylmethy l)-pyrroHdine-3 -carboxylic acid; or a pharmaceutically acceptable salt.
Most preferred compounds of the invention are selected from the group consisting of:
trans, trans-2-(2-( 1 ,3-Dioxol-2-yl)ethyl)-4-( 1 ,3-benzodioxol-5-yl)- 1 -(N,N-di(n- butyl) amino carbonylmethyl)-pyrroHdine-3 -carboxylic acid; trαπs,trαrø-2-(2,2,-Dimethyl-2-(l,3-dioxolan-2-yl)ethyl)-4-(l,3-benzodioxol-5-yl)-l-(N,N- di(n-butyl)aminocarbonylmethyl)-pyrrolidine-3-carboxyHc acid; trans, trans-2-(2-( 1 ,3-Dioxol-2-yl)ethyl)-4-(l ,3-benzodioxol-5-yl)-
-l-[[N-4-heptyl-N-(2-methyl-3-fluorophenyl)] aminocarbonylmethyl]-pyrrolidine-3- carboxylic acid; trα«s,trαns-2-(2-(l,3-Dioxol-2-yl)ethyl)-4-(7-methoxy-l,3-benzodioxol-5-yl)-l-(N,N-di(n- butyl) amino carbonylmethyl) -pyrroHdine-3 -carboxylic acid; trans, trα«s-2-((2-Methoxyphenoxy)-methyl)-4-( 1 ,3-benzodioxol-5-yl)- 1 -(N,N-di(n- butyl) amino carbonylmethy l)-pyrroHdine-3 -carboxylic acid; trαRS,trαns-2-(2-(2-OxopyrroHdin-l-yl)ethyl)-4-(l,3-benzodioxol-5-yl)-l-(N,N-di(n- butyl)aminocarbonylmethyl)-pyrrolidine-3-carboxylic acid; trαrø,trαn_?-2-(2-(l,3-Dioxol-2-yl)ethyl)-4-(7-methoxy-l,3-benzodioxol-5-yl)-l-(N-4-heptyl-
N-(4-fluoro-3-methylphenyl))aminocarbonylmethyl)-pyrroHdine-3-carboxylic acid; trans, trαns-2-(2,2-Dimethylpentyl)-4-(7-methoxy- 1 ,3-benzodioxol-5-yl)- l-(N,N-di(n- butyl) amino carbonylmethy l)-pyrroHdine-3 -carboxylic acid; trα«-.,trα«5'-2-(2,2,-Dimethyl-2-(l,3-dioxolan-2-yl)ethyl)-4-(7-methoxy-l,3-benzodioxol-5- yl)-l-(N,N-di(n-butyl)aminocarbonylmethyl)-pyrroHdine-3-carboxylic acid; trans, trα?.s-2-(2-(2-Methoxyphenyl)-ethyl)-4-( 1 ,3 -benzodioxol-5-yl)- 1 -(N,N-di(n- butyl)aminocarbonylmethyl)-pyrroHdine-3-carboxylic acid; trans, trαns-2-(2,2-Dimethyl-3-(E)-pentenyl)-4-(7-methoxy- 1 ,3 -benzodioxol-5-yl)- 1 -(N,N- di(n-butyl)aminocarbonylmethyl)-pyrroHdine-3-carboxyHc acid; trαns,trα..s-2-(2-(2-pyridyl)ethyl)-4-(l,3-benzodioxol-5-yl)-l-(N,N-di(n- butyl) amino carbonylmethy l)-pyrrolidine-3 -carboxylic acid; (2S, 3R, 4S)-2-(2-(2-oxopyrroHdin-l-yl)ethyl)-4-(l,3-benzodioxol-5-yl)-l-(N,N-di(n- butyl) amino carbonylmethy l)-pyrrolidine-3 -carboxylic acid; (2S, 3R, 4S)-2-(2,2 Dimethylpentyl)-4-(7-methoxy-l,3-benzodioxol-5-yl)-l-(N,N-di(n- butyl)aminocarbonylmethyl)-pyrrolidine-3-carboxylic acid; (2S, 3R, 4S)-2-(2-(2-oxopyrroHdin-l-yl)ethyl)-4-(l,3-benzodioxol-5-yl)-l-(N-4-heptyl-N-(4- fluoro-3-methylphenyl))aminocarbonylmethyl)-pyrroHdine-3-carboxy lie acid; trans, trans-2-(2-( 1 -pyrazolyl) ethyl)-4-( 1 ,3-benzodioxol-5-yl)- 1 -(N,N-di(n- butyl)aminocarbonylmethyl)-pyrrolidine-3-carboxylic acid;
(2R, 3R, 4S)-2-(3-Fluoro-4-methoxyphenyl)-4-(l,3-benzodioxol-5-yl)-l-[((N-propyl-N- pentanesulfonyl)amino)ethyl]-pyrroHdine-3-carboxylic acid; (2S,3R,4S)-2-(2,2-Dimethylpentyl)-4-(l,3-benzodioxol-5-yl)-l-(N,N-di(n- butyl)aminocarbonylmethyl)-pyrroHdine-3-carboxylic acid; (2S,3R,4S)-2-(2,2-Dimethylpent-(E)-3-enyl)-4-(l,3-benzodioxol-5-yl)-l-(N,N-di(n- butyl) amino carbonylmethyl)-pyrroHdine-3 -carboxylic acid; (2S,3R,4S)-2-(2,2-Dimethylpent-(E)-3-enyl)-4-(7-methoxy-l,3-benzodioxol-5-yl)-l-(N,N- di(n-butyl)aminocarbonylmethyl)-pyrroHdine-3-carboxylic acid; (2S,3R,4S)-2-((2-Methoxyphenoxy)-methyl)-4-(l,3-benzodioxol-5-yl)-l-(N,N-di(n- butyl)aminocarbonylmethyl)-pyrroHdine-3-carboxylic acid;
(2S,3R,4S)-2-(2-(2-Methoxyphenyl)ethyl)-4-(l,3-benzodioxol-5-yl)-l-(N,N-di(n- butyl)_uι_inocarbonylmethyl)-pyrroHdine-3-carboxylic acid; trαrø,trαns-2-(4-methoxyphenyl)-4-(l,3-benzodioxol-5-yl)-l-(N-((bis-(o- tolyl)methyl)amino)carbonylmethyl)pyrrolidine-3-carboxylic acid; trαns,trαn_.-2-[4-(2-methoxyethoxy)phenyl]-4-(l,3-benzodioxol-5-yl)-l-(N-(2,2- dimethyl- 1 -phenylpropyl)- 1 -amino) carbonylmethy l)pyrrolidine-3 -carboxylic acid; trατ.s,trαRS-2-[4-(2-methoxyethoxy)phenyl]-4-(l,3-benzodioxol-5-yl)-l-(N-((bis-(o- tolyl)methyl)amino)carbonylmethyl)pyrroHdine-3-carboxylic acid; trα«s,trαns-2-[4-(2-isopropoxyethoxy)phenyl]-4-(l,3-benzodioxol-5-yl)-l-(N-(2,2- dimethyl-l-phenylpropyl)-l-amino)carbonylmethyl)pyrrolidine-3-carboxylic acid; trα7._.,trαn5,-2-(4-methoxyphenyl]-4-(l,3-benzodioxol-5-yl)-l-(N-(3,3-dimethyl-l- phenylbutyl)-l-amino)carbonylmethyl)pyιτoHdine-3-carboxylic acid; trα«s,trα?.-.-2-[4-(2-isopropoxyethoxy)phenyl]-4-(l,3-benzodioxol-5-yl)-l-(N-((l-(o- tolyl)-l-(o-ethylphenyl)methyl)amino)carbonylmethyl)pyrroHdine-3-carboxylic acid; trαn_.,trαn_-2-(4-(2-(2-propoxy)ethoxy)phenyl)-4-(l,3-benzodioxol-5-yl)-l-(N- phenyl-N-t-butylhydrazinocarbonylmethyl)pyιτoHdine-3-carboxylic acid; trαrø,trαns-2-(4-(2-methoxyethoxy)phenyl)-4-(l,3-benzodioxol-5-yl)-l-(N-phenyl-N- t-butylhydrazinocarbonylmethyl)pyrrolidine-3 -carboxylic acid; or a pharmaceutically acceptable salt thereof.
Methods for preparing the compounds of the invention are shown in Schemes I- XXIII.
Scheme I illustrates the general procedure for preparing the compounds of the invention when n and m are 0, Z is -CH2- and W is -CO2H. A α-ketoester 1, where E is loweralkyl or a carboxy protecting group is reacted with a nitro vinyl compound 2, in the presence of abase (for example, l,8-diazabicyclo[5.4.0]undec-7-ene (DBU) or sodium ethoxide or sodium hydride and the Hke) in an inert solvent such as toluene, benzene, tetrahydrofuran or ethanol and the Hke. The condensation product 3 is reduced (for example, hydrogenation using a Raney nickel or platinum catalyst). The resulting amine cyclizes to give the dihydro pyrrole 4. Reduction of 4 (for example, sodium cyanoborohydride or catalytic hydrogenation and the Hke) in a protic solvent such as ethanol or methanol and the like gives the pyrrolidine compound 5 as a mixture of cis-cis, trans, trans and cis, trans products. Chromatographic separation removes the cis-cis isomer leaving a mixture of the trans, trans and cis, trans isomers which is further elaborated. The cis-cis isomer can be epimerized (for example, using sodium ethoxide in ethanol) to give the trans, trans isomer and then carried on as described below. The pyrrolidine nitrogen is (1) acylated or sulfonylated with R3-X (R3 is R4-C(O)- or R6-S(O)2- and X is a leaving group such as a halide (Cl is preferred) or X taken together with R4-C(O)- or R6-S(O)2- forms an activated ester including esters or anhydrides derived from formic acid, acetic acid and the Hke, alkoxycarbonyl haHdes, N-hydroxysuccinimide, N-hydroxyphthalimide, N- hydroxybenzotriazole, N-hydroxy-5-norbornene-2,3-dicarboxamide, 2,4,5-trichlorophenol and the like) or (2) alkylated with R3-X where X is a leaving group (for example, X is a halide (for example, Cl, Br or I) or X is a leaving group such as a sulfonate (for example, mesylate, tosylate, triflate and the like)) in the presence of a base such as dnsopropyl ethylamine or triethylamine and the like to give the N-derivatized pyrroHdine 6 which is still a mixture of trans, trans and cis.trans isomers. Hydrolysis of the ester 6 (for example, using a base such a sodium hydroxide in EtOH H2θ) selectively hydrolyzes the trans, trans ester to give a mixture of 7 and 8, which are readily separated. Scheme II illustrates a general procedure for preparing the compounds of the invention when n is 1, m is 0, Z is -CH2- and W is -CO2H. A substituted benzyl chloride 9 is reacted with a Hthio dithiane 10 in an inert solvent such as THF or dimethoxyethane to give the alkylated adduct JJ.. The anion of compound 1_1 is formed using a base such as n- butyllithium and then reacted with Ri-QH^-X' wherein X' is a leaving group such as a halide or sulfonate to give compound 12. The dithiane protecting group is cleaved (for example, using a mercuric salt in water) to give the keto compound 13. Reaction of ketone 13 with benzyl amine and formaldehyde gives the keto piperidine compound 14. Treatment of compound 14 with an activated nitrile such as trimethylsilyl cyanide foUowed by a dehydrating agent such as phosphorous oxychloride provides the isomeric ene nitriles 15. Reduction of the double bond (for example, using sodium borohydride) affords the piperidinyl nitrile 16. Hydrolysis of the nitrile using hydrochloric acid in the presence of a carboxy protecting reagent (for example, an alkyl alcohol) affords ester 17 (where E is a carboxy protecting group). Debenzylation by catalytic hydrogenation under acidic conditions affords the free piperidine compound 18. Compound 18 is further elaborated by the procedures described in Scheme I for compound 5 to give the final product compound 19. Scheme III illustrates a general procedure for preparing the compounds of the invention when m and n are 0, Z is -C(O)- and W is -CO2H. alpha-Keto ester 20 (wherein E is loweralkyl or a carboxy protecting group) is reacted with an alpha-haloester 21 (where J is lower alkyl or a carboxy protecting group and the halogen is bromine, iodine or chlorine) in the presence of a base such as NaH or potassium tert-butoxide or Hthium dnsopropylamide in an inert solvent such as THF or dimethoxyethane to give diester 22. Treating compound 22 with R3-NH2 and heating in acetic acid gives the cyclic compound 23. The double bond is reduced (for example, by catalytic hydrogenation using a paUadium on carbon catalyst or sodium cyanoborohydride reduction) to give pyrrolidone 24. Epimerization with sodium ethoxide in ethanol to give the desired trans, trans configuration, followed by sodium hydroxide hydrolysis of the ester, affords the desired trans, trans carboxylic acid 25. Scheme IV illustrates a general procedure for preparing the compounds of the invention when n is 0, m is 1, Z is -CH2- and W is -CO2H. The trans, trans compound 7, prepared in Scheme I, is homologated by the Arndt-Eistert synthesis. The carboxy terminus is activated (for example, by making the acid chloride using thionyl chloride) to give compound 52, where L is a leaving group (in the case of an acid chloride, L is Cl).
Compound 52 is treated with diazomethane to give the diazo ketone 53. Rearrangement of compound 53 (for example, using water or an alcohol and silver oxide or silver benzoate and triethylamine, or heating or photolysis in the presence of water or an alcohol) affords the acetic acid compound 54 or an ester which may be hydrolyzed. Compounds where m is from 2 to 6 can be obtained by repetition of the above described process. A preferred embodiment is shown in Schemes V and VI. A benzoyl acetate 26 is reacted with a nitro vinyl benzodioxolyl compound 27 using l,8-diazabicyclo[5.4.0]undec-7- ene (DBU) as the base in toluene to give compound 28. Catalytic hydrogenation using Raney nickel leads to reduction of the nitro group to an amine and subsequent cyclization to give the dihydropyrrole 29. The double bond is reduced with sodium cyanoborohydride to give the pyrroHdine compound 30 as a mixture of cis-cis, trans, trans and cisjrans isomers. Chromatography separates out the cis-cis isomer, leaving a mixture of the trans Jrans and cisjrans isomers (31).
Scheme VI illustrates the further elaboration of the trans,trans isomer. The mixture (31) of trans, trans and cis, trans pyrroHdines described in Scheme IV is reacted with N- propyl bromoacetamide in acetonitrile in the presence of ethyldiisopropylamine to give the alkylated pyrrolidine compound 32, still as a mixture of trans, trans and cis, trans isomers. Sodium hydroxide in ethanol-water hydrolyzes the ethyl ester of the transjrans compound but leaves the ethyl ester of the cis,trans compound untouched, thus aHowing separation of the trans, trans carboxylic acid 33 from the cis, trans ester 34.
Scheme VII iUustrates the preparation of a specific piperidinyl compound. Benzodioxolyl methyl chloride 35 is reacted with Hthio dithiane 36 to give the alkylated compound 37. Treatment of compound 37 with 4-methoxybenzyl chloride in the presence of lithium diisopropylamide gives compound 38- Cleavage of the dithiane protecting group using a mercuric salt in aqueous solution gives ketone 39. Treatment of 39 with benzylamine and formaldehyde gives the keto piperidine 40. Treatment of compound 40 with trimethylsilyl cyanide foUowed by phosphorous oxychloride gives the ene nitrile as a mixture of isomers 41. Sodium borohydride reduction of the double bond gives the piperidinyl nitrile 42. Hydrochloric acid hydrolysis in the presence of ethanol gives ethyl ester 43. The N-benzyl protecting group is removed by catalytic hydrogenation to give the free piperidine compound 44. Compound 44 is further elaborated by the procedures described in Scheme V for compound 31 resulting in the formation of the N-derivatized carboxylic acid 45.
A preferred embodiment of the process shown in Scheme III is shown in Scheme VIII. 4-Methoxybenzoylacetate 46 (wherein E is loweralkyl or a carboxy protecting group) is reacted with an benzodioxolyl δ -bromoacetate 47 (wherein E is lower alkyl or a carboxy protecting group) in the presence of NaH in THF to give diester 48. Treating compound 48 with ethoxypropylamine and heating in acetic acid gives the cyclic compound 49. The double bond is reduced by catalytic hydrogenation using a paUadium on carbon catalyst to give pyrroHdone 50. Epimerization with sodium ethoxide in ethanol to give the desired trans Jrans configuration is followed by sodium hydroxide hydrolysis of the ester to afford the desired transjrans carboxylic acid 51.
Scheme IX illustrates the preparation of compounds where n is 0, Z is -CH2-, and W is other than carboxylic acid. Compound 55, which can be prepared by the procedures described in Scheme IV, is converted (for example, using peptide couphng condition, e.g. N- methylmorpholine, EDCI and HOBt, in the presence of ammonia or other amide forming reactions) to give carboxamide 56. The carboxamide is dehydrated (for example, using phosphorus oxychloride in pyridine) to give nitrile 57. Nitrile 57 under standard tetrazole forming conditions (sodium azide and triethylamine hydroehloride or trimethylsilylazide and tin oxide) is reacted to give tetrazole 58. Alternatively nitrile 57 is reacted with hydroxylamine hydroehloride in the presence of a base (for example, potassium carbonate, sodium carbonate, sodium hydroxide, triethylamine, sodium methoxide or NaH) in a solvent such as DMF, DMSO, or dimethylacetamide to give amidoxime 59. The amidoxime 59 is allowed to react with a methyl or ethyl chloroformate in a conventional organic solvent (such as, chloroform, methylene chloride, dioxane, THF, acetonitrile or pyridine) in the presence of a base (for example, triethylamine, pyridine, potassium carbonate and sodium carbonate) to give an O-acyl compound. Heating of the O-acyl amidoxime in an inert solvent (such as benzene, toluene, xylene, dioxane, THF, dichloroethane, or chloroform and the Hke) results in cyclization to compound 60. Alternatively reacting the amidoxime 59 with thionyl chloride in an inert solvent (for example, chloroform, dichloromethane, dixoane and THF and the Hke) affords the oxathiadiazole 61.
Scheme X illustrates the preparation of compounds in which R3 is an acylmethylene group. A carboxylic acid 62 (where R4 is as previously defined herein) is treated with oxalyl chloride in a solution of methylene chloride containing a catalytic amount of N,N- dimethylformamide to give the acid chloride. Treatment of the acid chloride with excess ethereal diazomethane affords a diazoketone, and then treatment with anhydrous HCl in dioxane gives the δ -chloroketone 63. Pyrrolidine ester 5 where E is lower alkyl or a carboxy protecting group, prepared in Scheme I, is alkylated with the -chloroketone 63 to provide alkylated pyrrohdine 64- Carboxy deprotection (for example, hydrolysis of an alkyl ester using lithium or sodium hydroxide in ethanol-water) gives the alkylated pyrroHdine acid 65. Scheme XI illustrates the preparation of "reverse amides and sulfonamides". The carboxy protected pyrroHdine 5, prepared in Scheme I, is reacted with a difunctionaHzed compound X-Rs-X where Rs is alkylene and X is a leaving group (for example a haHde where Br is preferred) to give N-alkylated compound 66. Treatment of 66 with an amine (R20NH2) affords secondary amine 67. This amine (67) can be reacted with an activated acyl compound (for example, R4-C(O)-Cl) and then carboxy deproteeted (for example, hydrolysis of an ester or hydrogenation of a benzyl moiety) to afford amide 68. Alternatively amine 67 can be reacted with an activated sulfonyl compound (for example, R6-S(O)2-Cl) and then carboxy deproteeted (for example, hydrolysis of an ester or hydrogenation of a benzyl moiety) to afford sulfonamide 69. Scheme XII illustrates a method for synthesizing pyrrolidines by ah azomethine ylide type [3+2]-cycloaddition to an acrylate. General structures such as compound 70 are known to add to unsaturated esters such as 71 to provide pyrrolidines such as compound 72 (O. Tsuge, S. Kanemasa, K. Matsuda, Chem. Lett. 1131-4 (1983), O. Tsuge, S. Kanemasa, T. Yamada, K. Matsuda, J. Org. Chem. 52 2523-30 (1987), and S. Kanemasa, K. Skamoto, O. Tsuge, BuH. Chem. Soc. Jpn. 62 1960-68 (1989)). A specific example is also shown in Scheme XII. Silylimine 73 is reacted with acrylate 74 in the presence of trimethylsilyl triflate and tetrabutylammonium fluoride to give the desired pyrroHdine 75 as a mixture of isomers. This method can be modified to provide the N-acetamido derivatives directly by reacting 73 and 74 with the appropriate bromoacetamide (for example, dibutyl bromoacetamide) in the presence of tetrabutylammonium iodide and cesium fluoride to give compound 76.
Scheme XIII illustrates a method for producing an enantiomerically pure pyrroHdine 80, which can be further elaborated on the pyrroHdine nitrogen. Intermediate racemic pyrroHdine ester 77 (for example, prepared by the procedure described in Scheme V) is Boc- nitrogen protected (for example, by treatment with B0C2O) and then the ester is hydrolyzed
(for example, using sodium or Hthium hydroxide in ethanol and water) to give t-butyl carbamoyl pyrrolidine carboxylic acid 78. The carboxylic acid is converted to its (+)- cinchonine salt, which can be recrystalHzed (for example from ethyl acetate and hexane or chloroform and hexane) to afford the diastereomerically pure salt. This diastereomerically pure salt can be neutrahzed (for example, with sodium carbonate or citric acid) to afford enantiomerically pure carboxylic acid 79. The pyrroHdine nitrogen can be deproteeted (for example, using trifluoroacetic acid) and the ester reformed by the use of ethanolic hydrochloric acid to give salt 80. Alternatively one can use ethanol HCl to cleave the protecting group and form the ester in one step. The pyrrolidine nitrogen can be further elaborated (for example, by treatment with the dibutyl amide of bromoacetamide in acetonitrile in the presence of diisopropylethylamine) to give optically active compound 81. The use of (-)-cinchonine will give the opposite enantiomer.
Scheme XTV describes another procedure for preparation of pyrroHdines. PyrroHdines may be synthesized by the use of an azomethine ylide cycloaddition to an acrylate derivative as described by CottreU, I. F., etal., J. Chem. Soc, Perkin Trans. 1, 5:
1091-97 (1991). Thus, the azomethine ylide precursor 82 (where R55 is hydrogen or methyl) is condensed with a substituted acrylate 83 (wherein R2 is as described herein and R$β is loweralkyl) under acidic conditions to afford the substituted pyrrolidine 84- The N- protecting group can be removed (for example, by hydrogenolysis of an N-benzyl group) to give 85, which can be alkylated under the conditions described above to provide the N- substituted pyrroHdine 86- Standard ester hydrolysis of 86 produces the desired pyrrolidine carboxylic acid 87.
A preferred process is shown in Scheme XV. Nitro vinyl compound (88) is reacted with beta-keto ester 89 in the presence of a base such as sodium ethoxide and the Hke or a trialkylamine such as triethylamine or diisopropylethylamine and the like or an amidine such as DBU and the like in an inert solvent such as THF, toluene, DMF, acetonitrile, ethyl acetate, isopropyl acetate or methylene chloride and the Hke at a temperature of from about 0° C to about 100° C for a period of time from about 15 minutes to overnight to give compound 90. Reduction of the nitro group foUowed by cyclization was effected for example by catalytic hydrogenation with a hydrogen pressure of from about atmospheric pressure to 300 p.s.i. over from about 1 hour to about 1 day of compound 90 in an inert solvent such as THF, ethyl acetate, toluene, ethanol, isopropanol, DMF or acetonitrile and the like, using a hydrogenation catalyst such as Raney nickel, palladium on carbon, a platinum catalyst, such as platinum oxide, platinum on carbon or platinum on alumina and the like, or a rhodium catalyst, such as rhodium on carbon or rhodium on alumina and the Hke, and the like affords intermediate nitrone 91a or a mixture of nitrone 91a and imine £lb. The reaction mixture comprising the nitrone or nitrone/imine mixture is treated with an acid such as trifluoroacetic acid or acetic acid or sulfuric acid or phosphoric acid or methanesulfonic acid and the Hke, and the hydrogenation is continued to give pyrroHdine compound 92 as the cz^cz's-isomer. Epimerization at C-3 is effected by treatment of compound 92 with a base such as sodium ethoxide, potassium t-butoxide, lithium t-butoxide or potassium t-amyloxide and the like or a trialkylamine such as triethylamine or diisopropylethylamine and the Hke or an amidine such as DBU and the like in an inert solvent such as ethanol, ethyl acetate, isopropyl acetate, THF, toluene or DMF and the Hke at a temperature of from about -20° C to about 120° C to give the transjrans compound 93. Compound 93 itself can optionally be resolved into enantiomers prior to reacting with X-R3. The substantially pure (i.e., at least
95% of the desired isomer) optically active (+)-isomer of compound 93 is obtained by treatment of a mixture of the (+)-isomer and the (-)-isomer of 93 with S-(+)-mandelic acid, D-tartaric acid or
D-dibenzoyl tartaric acid and the like in a solvent such as acetonitrile, ethyl acetate, isopropyl acetate, ethanol or isopropanol and the Hke. The (+)-isomer of 93 selectively crystaUizes as the salt, leaving the (-)-isomer of 93 in solution. Alternatively, the substantially pure (i.e., at least 95%o of the desired isomer) optically active (-)-isomer of compound 93 can be selectively crystaUized by reaction of a mixture of the (+)-isomer and the (-)-isomer of 93 with L-tartaric acid, L-dibenzoyl tartaric acid or L-pyroglutamic acid and the Hke, leaving the desired (+)-isomer of compound 93 in solution.
Compound 93 (racemic or optically active) is reacted with X-R3 (where X is a leaving group (for example, a halide or a sulfonate) and R3 is as previously defined) using a base such as dusopropylethylamine, triethylamine, sodium bicarbonate or potassium carbonate and the like in an inert solvent such as acetonitrile, THF, toluene, DMF or ethanol and the like at a temperature of from about 0° C to about 100° C to give the intermediate ester 94. The ester can be isolated or converted in situ to the carboxyHc acid (95) using hydrolysis conditions such as a base such as sodium hydroxide or Hthium hydroxide or potassium hydroxide and the Hke in a solvent such as ethanol-water or THF-ethanol and the Hke.
A more detaUed description of the preparation of some specific analogs is provided in Schemes XVI-XXI. AHphatic δ -ketoesters (Scheme XVI) may be prepared by copper- catalyzed addition of a Grignard reagent (for example, propylmagnesium bromide) to an unsaturated ester, for example, ethyl 3,3-dimethylacrylate. The resultant ester is hydrolyzed, for example with sodium hydroxide in aqueous alcohol, and is homologated in stepwise fashion to the corresponding δ -ketoester, for example by activation using carbonyldiimidazole and condensation with magnesio-ethoxymalonate. Alternatively, olefinic alpha-ketoesters may be prepared by Claisen rearangement of the corresponding aUylic alcohols; hydrolysis and homologation as described above produce the desired alpha - ketoester.
N-alkyl,O-alkyl bromohydroxamates are prepared according to Scheme XVII. N- Boc-O-aUyl hydroxylamine is alkylated with and alkyl halide, for example using sodium hydride as base; the double bond is selectively reduced, for example using hydrogen and a paUadium catalyst. After removal of the Boc protecting group, for example with TFA, the resultant amine is acylated, for example using bromoacetyl bromide.
The δ -ketoesters described in Scheme XVI may be converted to pyrrolidine derivatives as described in Scheme XVIII. Michael addition onto a nitrostyrene derivative can be catalyzed with base, for example DBU or potassium t-butoxide; the resultant adduct is hydrogenated, for example using Raney Nickel as catalyst, to give an imine, which is reduced further, for example using sodium cyanoborohydride under controUed pH. A mixture of isomers are generated, in which the trans-trans is generally preferred. Scheme XIX describes several strategies for resolving the racemic pyrroHdines described above. Treatment with a chiral acid, for example (S)-(+)-mandelic acid, may provide a crystaUine derivative, which can be further enriched through recrystaUization. The salt may be washed with base to extract the resolving agent and return the optically active pyrroHdine product. Alternatively, the amino ester can be N-protected (for example with Boc-anhydride) and hydrolyzed (for example with sodium hydroxide) to give the corresponding N-protected amino acid. Activation of the acid, for example as the pentafluorophenyl ester, foUowed by coupling with a chiral nonracemic oxazolidinone anion, provides the corresponding acyloxazolidinone diastereomers, which may be separated chromatographically. Alcoholysis of one acyloxazoHdinone diastereomer, foUowed by cleavage of the N-protecting group, returns an opticaUy enriched amino ester. A similar transformation may be accomphshed through coupling of the protected amino acid with a chiral nonracemic amino alcohol. After chromatographic separation of the resultant diastereomers, the amide is cleaved and the protecting group is removed to provide optically enriched product.
Optically active amino esters prepared as described above may be alkylated (Scheme XX) with a variety of electrophUes, for example dibutyl bromoacetamide, N-butyl,N-alkoxy bromoacetamide, N-(4-heptyl)-N-(3-methyl-4-fluorophenyl) bromoacetamide, orN-(Ω- hydroxyalkyl)-N-alkyl haloacetamide. Hydrolysis of the resultant ester, for example using sodium hydroxide in aqueous alcohol, provides the product.
For one particular class of electrophile, N-(Ω-hydroxyalkyl)-N-alkyl haloacetamides, further transformations of the alkylation product are possible (Scheme XXI). Activation (for example using methanesulfonyl chloride) of the alcohol, foUowed by displacement with halogen (for example, using Hthium bromide) provides the corresponding halide. Displacement of haHde with an amine, for example dimethylamine, provides the corresponding amino ester, which may be hydrolyzed as previously described to provide product.
Scheme I
Figure imgf000047_0001
Mixture of Cis-Cis
Trans-Trans Cis-Trans
Figure imgf000047_0002
Mixture of Trans-Trans R2""
Cis-Trans
Figure imgf000047_0003
Cis-Trans Scheme
Figure imgf000048_0001
11
10
Figure imgf000048_0002
MER
Figure imgf000048_0003
16
2H
Figure imgf000048_0004
Scheme III
Figure imgf000049_0001
Halo = Cl, Br, or I 22
Figure imgf000049_0002
24
23
Figure imgf000049_0003
C02H Trans-Trans
Scheme IV
Figure imgf000050_0001
52
CH2N2
Figure imgf000050_0002
^
~C02H O CHN2
54 53
Scheme V
Figure imgf000051_0001
Trans-Trans Chromatographic separation Cis-Trans
Figure imgf000051_0002
Cis-Cis + Mixture of Trans-Trans and Cis-Trans
31
Scheme VI
Figure imgf000052_0001
Cis-Trans
Figure imgf000052_0002
-
Figure imgf000052_0003
Trans-Trans Cis-Trans
33 34
Scheme VII
Figure imgf000053_0001
36 37
Figure imgf000053_0002
41
Scheme VII cont.
Figure imgf000054_0001
Y
Figure imgf000054_0002
Scheme VIII
3
Figure imgf000055_0001
C02H
51
Trans-Trans Scheme IX
Figure imgf000056_0001
(CH2)m (CH2)m
I C02H CONH 2
55 56
Figure imgf000056_0002
Figure imgf000056_0003
60 61 Scheme X
Figure imgf000057_0001
64
Scheme XI
Figure imgf000058_0001
5 66
2o
Figure imgf000058_0002
68 67
Figure imgf000058_0003
69 Scheme XII
Figure imgf000059_0001
70 71
72
Figure imgf000059_0002
73
74
Figure imgf000059_0003
Scheme XIII
Figure imgf000060_0001
1. (+)-cinchonine
2. recrystallize from EtOAc/hexane
3. Na2CQ3
Figure imgf000060_0002
Bu2NC(0)CH2Br EtNiPr2, CH3CN
Figure imgf000060_0003
Scheme XIV
Figure imgf000061_0001
82
Figure imgf000061_0002
Figure imgf000061_0003
86 87
Scheme XV
Figure imgf000062_0001
88 89
Figure imgf000062_0002
9 2 93
Figure imgf000062_0003
co2H C02E
95 94 SCHEME XVI
Figure imgf000063_0001
SCHEME XVII
BocHN
Figure imgf000063_0002
SCHEME XVIII
Figure imgf000063_0003
SCHEME XIX
recrystallization neutralization
Figure imgf000064_0002
Figure imgf000064_0001
(racemic)
Figure imgf000064_0003
(single enantiomer)
Figure imgf000064_0004
(single enantiomer)
Figure imgf000064_0005
(racemic)
Figure imgf000064_0006
SCHEME XX
Figure imgf000065_0001
SCHEME XXI
Figure imgf000065_0002
Other amines may be prepared according to Scheme XXII. An aryl aldehyde or ketone (aldehyde shown), which may be acquired commercially or prepared, for example, tlirough a Friedel-Crafts acylation of a benzene derivative with an acyl halide, is reacted with an amine, for example ammonia, hydroxylamine or the like. The resultant imine is reduced, for example using sodium borohydride or sodium cyanoborohydride or a metal Hke zinc or tin or the like, to give the corresponding optionally substituted carbinylamine, which is converted to the target compound according to the procedures described above.
Scheme XXII
Figure imgf000066_0001
StiU other amines may be prepared according to Scheme XXII. An optionally substituted aryl hahde (Rna is the optionally substituted aryl and X is bromo or iodo) is reacted with a metallated amine (for example, lithium tert-butylamide, or sodium benzylamide, or the Hke) to provide an optionally substituted anUine. This compound is reacted with an oxidized nitrogen compound, for example nitrous acid or the like to provide an N,N-disubstituted hydrazine, which is converted to the target compound according to the procedures described above.
Scheme XXIII
Figure imgf000066_0002
Compounds which are useful as intermediates for the preparation of compounds of the invention are:
Figure imgf000067_0001
wherein n is 0 or 1; m is 0 to 6; W is (a) -C(O)2-G where G is hydrogen or a carboxy protecting group, (b) -PO3H2,
(c) -P(O)(OH)E where E is hydrogen, loweralkyl or arylalkyl,
(d) -CN,
(e) -C(O)NHRi7 where Rπ is loweralkyl,
(f) alkylaminocarbonyl, (g) dialkylaminocarbonyl,
(h) tetrazolyl, (i) hydroxy, 0") alkoxy, (k) sulfonamido, (1) -C(O)NHS(O)2Ri6 where Rι6 is loweralkyl, haloalkyl, phenyl or dialkylamino,
(m) -S(O)2NHC(O)Ri6,
Figure imgf000067_0002
Figure imgf000068_0001
- °N s=o
00
Figure imgf000068_0002
Rl and R2 are independently selected from hydrogen, loweralkyl, alkenyl, alkynyl, alkoxyalkyl, alkoxycarbonylalkyl, hydroxyalkyl, haloalkyl, haloalkoxyalkyl, alkoxyalkoxyalkyl, thioalkoxyalkoxyalkyl, cycloalkyl, cycloalkylalkyl, aminocarbonylalkyl, alkylaminocarbonylalkyl, dialkylaminocarbonylalkyl, aminocarbonylalkenyl, alkylaminocarbonylalkenyl, dialkylaminocarbonylalkenyl, hydroxyalkenyl, aryl, arylalkyl, aryloxyalkyl, arylalkoxyalkyl, (N-alkanoyl-N-alkyl)aminoalkyl, alkylsulfonylamidoalkyl, heterocyclic, (heterocyclic)alkyl and
(Raa)(Rbl))N-Rcc- wherein Raa is aryl or arylalkyl, Rbb is hydrogen or alkanoyl and Rcc is alkylene, with the proviso that one or both of Rj and R2 is other than hydrogen; or a salt thereof; or a compound of the formula:
Figure imgf000069_0001
(IV) (V)
wherein n is 0 or 1; m is 0 to 6;
W is (a) -C(O)2-G where G is hydrogen or a carboxy protecting group, (b) -PO3H2, (c) -P(O)(OH)E where E is hydrogen, loweralkyl or arylalkyl, (d) -CN, (e) -C(O)NHRi7 where R17 is loweralkyl, (f) alkylaminocarbonyl,
(g) dialkylaminocarbonyl,
(h) tetrazolyl,
(i) hydroxy,
(j) alkoxy, (k) sulfonamido,
(1) -C(O)NHS(O)2Ri6 where Ri6 is loweralkyl, haloalkyl, phenyl or dialkylamino,
(m) -S(O)2NHC(O)Ri6,
Figure imgf000069_0002
Figure imgf000070_0001
Rl and 2 are independently selected from hydrogen, loweralkyl, alkenyl, alkynyl, alkoxyalkyl, alkoxycarbonylalkyl, hydroxyalkyl, haloalkyl, haloalkoxyalkyl, alkoxyalkoxyalkyl, thioalkoxyalkoxyalkyl, cycloalkyl, cycloalkylalkyl, aminocarbonylalkyl, alkylaminocarbonylalkyl, dialkylaminocarbonylalkyl, aminocarbonylalkenyl, alkylaminocarbonylalkenyl, dialkylaminocarbonylalkenyl, hydroxyalkenyl, aryl, arylalkyl, aryloxyalkyl, arylalkoxyalkyl, (N-alkanoyl-N-alkyl)aminoalkyl, alkylsulfonylamidoalkyl, heterocyclic, (heterocyclic)alkyl and
(Raa)(R,.b)N-Rcc- wherein Raa is aryl or arylalkyl, R^. is hydrogen or alkanoyl and Rcc is alkylene, with the proviso that one or both of R1 and R2 is other than hydrogen; or a salt thereof.
Preferred intermediates include compounds of formula (III), (IV) and (V) wherein m is zero or 1;
W is -CO2-G wherein G is hydrogen or a carboxy protecting group, and Ri and R2 are as defined above; or the substantially pure (+)- or (-)-isomer thereof.
Particularly preferred intermediates are compounds of formula (III), (IV) and (V) wherein n and m are both 0; is -CO2-G wherein G is hydrogen or a carboxy protecting group; and Ri is (i) loweralkyl, (n) alkenyl, (Hi) alkoxyalkyl, (iv) cycloalkyl, (v) phenyl,
(vi) pyridyl, (vii) furanyl or (vni) substituted or unsubstituted 4-methoxyphenyl,
4-fluorophenyl, 3 -fluorophenyl, 4-ethoxyphenyl, 4-ethylphenyl, 4-methylphenyl,
4-trifluoromethylphenyl, 4-pentafluoroethylphenyl, 3-fluoro-4-methoxyphenyl,
3-fluoro-4-ethoxyphenyl, 2-fluorophenyl, 4-methoxymethoxyphenyl,
4-hydroxyphenyl, 4-t-butylphenyl, 1,3-benzodioxolyl, 1,4-benzodioxanyl or dihydrobenzofuranyl wherein the substituent is selected from loweralkyl, haloalkyl, alkoxy, alkoxyalkoxy and carboxyalkoxy (ix) aryalkyl, (x) aryloxyalkyl, (xi) heterocycHc (alkyl), (xii) (N-alkanoyl-N-alkyl)aminoalkyl, and (xiii) alkylsulfonylamidoalkyl, and R2 is substituted or unsubstituted 1,3-benzodioxolyl, 7-methoxy- 1,3 -benzodioxolyl, 1,4-benzodioxanyl, 8-methoxy- 1,4-benzodioxanyl, dihydrobenzofuranyl, benzofurnayl, 4- methoxyphenyl, dimethoxyphenyl, fluorophenyl or difluorophenyl wherein the substituent is selected from loweralkyl, alkoxy and halogen; or the substantiaUy pure (+)- or (-)-isomer thereof.
Other compounds which are useful as intermediates for the preparation of compounds of the invention are:
Figure imgf000071_0001
wherein n is 0 or 1; m is 0 to 6; R5t) is alkylene;
Q is a leaving group; is (a) -C(O)2-G where G is hydrogen or a carboxy protecting group, (b) -PO3H2,
(c) -P(O)(OH)E where E is hydrogen, loweralkyl or arylalkyl,
(d) -CN,
(e) -C(O)NHRi7 where R17 is loweralkyl,
(f) alkylaminocarbonyl, (g) dialkylaminocarbonyl,
(h) tetrazolyl, (i) hydroxy, (j) alkoxy, (k) sulfonamido, (1) -C(O)NHS(O)2Ri6 where Ri6 is loweralkyl, haloalkyl, phenyl or dialkylamino,
(m) -S(O)2NHC(O)Ri6,
Figure imgf000072_0001
Figure imgf000073_0001
Rl and R2 are independently selected from hydrogen, loweralkyl, alkenyl, alkynyl, alkoxyalkyl, alkoxycarbonylalkyl, hydroxyalkyl, haloalkyl, haloalkoxyalkyl, alkoxyalkoxyalkyl, thioalkoxyalkoxyalkyl, cycloalkyl, cycloalkylalkyl, aminocarbonylalkyl, alkylaminocarbonylalkyl, dialkylaminocarbonylalkyl, aminocarbonylalkenyl, alkylaminocarbonylalkenyl, dialkylaminocarbonylalkenyl, hydroxyalkenyl, aryl, arylalkyl, aryloxyalkyl, arylalkoxyalkyl, (N-alkanoyl-N-alkyl)aminoalkyl, alkylsulfonylamidoalkyl, heterocyclic, (heterocyclic)alkyl and
(Raa)(Rbb)N-Rcc- wherein Raa is aryl or arylalkyl, R^. is hydrogen or alkanoyl and Rcc is alkylene, with the proviso that one or both of Rj and R2 is other than hydrogen; or a salt thereof; or a compound of the formula:
Figure imgf000073_0002
0 /II) (VIII)
wherein n is 0 or 1; m is 0 to 6;
R5t) is alkylene;
Q is a leaving group;
W is (a) -C(O)2-G where G is hydrogen or a carboxy protecting group, (b) -PO3H2,
(c) -P(O)(OH)E where E is hydrogen, loweralkyl or arylalkyl, (d) -CN,
(e) -C(O)NHRi7 where R17 is loweralkyl, (f) alkylaminocarbonyl,
(g) dialkylaminocarbonyl, (h) tetrazolyl,
(i) hydroxy,
(j) alkoxy,
(k) sulfonamido,
(1) -C(O)NHS(O)2Ri6 where Riβ is loweralkyl, haloalkyl, phenyl or dialkylamino,
(m) -S(O)2NHC(O)Ri6,
Figure imgf000074_0001
i-r -
N— « H ^
(r)
Figure imgf000074_0002
Figure imgf000075_0001
Rl and R are independently selected from hydrogen, loweralkyl, alkenyl, alkynyl, alkoxyalkyl, alkoxycarbonylalkyl, hydroxyalkyl, haloalkyl, haloalkoxyalkyl, alkoxyalkoxyalkyl, thioalkoxyalkoxyalkyl, cycloalkyl, cycloalkylalkyl, aminocarbonylalkyl, alkylaminocarbonylalkyl, dialkylaminocarbonylalkyl, aminocarbonylalkenyl, alkylaminocarbonylalkenyl, dialkylaminocarbonylalkenyl, hydroxyalkenyl, aryl, arylalkyl, aryloxyalkyl, arylalkoxyalkyl, (N-alkanoyl-N-alkyl)aminoalkyl, alkylsulfonylamidoalkyl, heterocyclic, (heterocyclic)alkyl and
(Raa)(Rb1.)N-Rcc- wherein Raa is aryl or arylalkyl, R^. is hydrogen or alkanoyl and Rcc is alkylene, with the proviso that one or both of Rj and R2 is other than hydrogen; or a salt thereof.
Preferred intermediates include compounds of formula (VI), (VII) and (VIII) wherein mis zero or 1; R5 - is alkylene; Q is a leaving group;
W is -CO2-G wherein G is hydrogen or a carboxy protecting group, and Ri and R2 are as defined above; or the substantially pure (+)- or (-)-isomer thereof.
Particularly preferred intermediates are compounds of formula (VI), (VII) and (VIII) wherein n and m are both 0; R5b is alkylene;
Q is a leaving group;
W is -CO2-G wherein G is hydrogen or a carboxy protecting group; and Ri is (i) loweralkyl, (ii) alkenyl, (iii) alkoxyalkyl, (iv) cycloalkyl, (v) phenyl, (vi) pyridyl, (vii) furanyl or (vni) substituted or unsubstituted 4-methoxyphenyl, 4-fluorophenyl, 3 -fluorophenyl, 4-ethoxyphenyl, 4-ethylphenyl, 4-methylphenyl, 4-trifluoromethylphenyl, 4-pentafluoroethylphenyl, 3-fluoro-4-methoxyphenyl, 3-fluoro-4-ethoxyphenyl, 2-fluorophenyl, 4-methoxymethoxyphenyl, 4-hydroxyphenyl, 4-t-butylphenyl, 1,3-benzodioxolyl, 1,4-benzodioxanyl or dihydrobenzofuranyl wherein the substituent is selected from loweralkyl, haloalkyl, alkoxy, alkoxyalkoxy and carboxyalkoxy, (ix) aryalkyl, (x) aryloxyalkyl, (xi) heterocyclic (alkyl), (xn) (N-alkanoyl-N-alkyl)aminoalkyl, and (xiii) alkylsulfonylamidoalkyl, and R2 is substituted or unsubstituted 1,3-benzodioxolyl, 7-methoxy-l,3-benzodioxolyl, 1,4-benzodioxanyl, 8-methoxy- 1,4-benzodioxanyl, dihydrobenzofuranyl, benzofurnayl, 4- methoxyphenyl, dimethoxyphenyl, fluorophenyl or difluorophenyl wherein the substituent is selected from loweralkyl, alkoxy and halogen; or the substantially pure (+)- or (-)-isomer thereof.
Other compounds which are useful as intermediates for the preparation of compounds of the invention are:
Figure imgf000076_0001
(IX)
wherein n is 0 or 1; m is 0 to 6; R5 - is alkylene;
R20a is hydrogen, loweralkyl, alkenyl, haloalkyl, alkoxyalkyl, haloalkoxyalkyl, cycloalkyl, cycloalkylalkyl, aryl or arylalkyl; is (a) -C(O)2-G where G is hydrogen or a carboxy protecting group, (b) -PO3H2,
(c) -P(O)(OH)E where E is hydrogen, loweralkyl or arylalkyl,
(d) -CN,
(e) -C(O)NHRi7 where R17 is loweralkyl,
(f) alkylaminocarbonyl,
(g) dialkylaminocarbonyl, (h) tetrazolyl,
(i) hydroxy, (j) alkoxy, (k) sulfonamido,
(1) -C(O)NHS(O)2Ri6 where Ri6 is loweralkyl, haloalkyl, phenyl or dialkylamino, (m) -S(O)2NHC(O)Ri6,
Figure imgf000076_0002
16 -
Figure imgf000077_0001
O
N'
:o
N
00 H
■ N
N'
^ CF,
N H
(t) . or
(u) ■K /> NHS02CF3 and
Rl and R2 are independently selected from hydrogen, loweralkyl, alkenyl, alkynyl, alkoxyalkyl, alkoxycarbonylalkyl, hydroxyalkyl, haloalkyl, haloalkoxyalkyl, alkoxyalkoxyalkyl, thioalkoxyalkoxyalkyl, cycloalkyl, cycloalkylalkyl, aminocarbonylalkyl, alkylaminocarbonylalkyl, dialkylaminocarbonylalkyl, aminocarbonylalkenyl, alkylaminocarbonylalkenyl, dialkylaminocarbonylalkenyl, hydroxyalkenyl, aryl, arylalkyl, aryloxyalkyl, arylalkoxyalkyl, (N-alkanoyl-N-alkyl)aminoalkyl, alkylsulfonylamidoalkyl, heterocyclic, (heterocyclic)alkyl and (Raa)(R|.b)N-Rcc- wherein Raa is aryl or arylalkyl, R^ is hydrogen or alkanoyl and Rcc is alkylene, with the proviso that one or both of Rj and R2 is other than hydrogen; or a salt thereof; or a compound of the formula:
Figure imgf000078_0001
(X) (XI)
wherein n is 0 or 1; m is 0 to 6; R5b is alkylene;
R20a is hydrogen, loweralkyl, alkenyl, haloalkyl, alkoxyalkyl, haloalkoxyalkyl, cycloalkyl, cycloalkylalkyl, aryl or arylalkyl;
W is (a) -C(O)2-G where G is hydrogen or a carboxy protecting group, (b) -PO3H2, (c) -P(O)(OH)E where E is hydrogen, loweralkyl or arylalkyl,
(d) -CN,
(e) -C(O)NHRi7 where R17 is loweralkyl,
(f) alkylaminocarbonyl,
(g) dialkylaminocarbonyl, (h) tetrazolyl,
(i) hydroxy,
(j) alkoxy,
(k) sulfonamido,
(1) -C(O)NHS(O)2Ri6 where R\β is loweralkyl, haloalkyl, phenyl or dialkylamino, (m) -S(O)2NHC(O)Ri6,
Figure imgf000078_0002
Figure imgf000079_0001
Rl and R2 are independently selected from hydrogen, loweralkyl, alkenyl, alkynyl, alkoxyalkyl, alkoxycarbonylalkyl, hydroxyalkyl, haloalkyl, haloalkoxyalkyl, alkoxyalkoxyalkyl, thioalkoxyalkoxyalkyl, cycloalkyl, cycloalkylalkyl, aminocarbonylalkyl, alkylaminocarbonylalkyl, dialkylaminocarbonylalkyl, aminocarbonylalkenyl, alkylaminocarbonylalkenyl, dialkylaminocarbonylalkenyl, hydroxyalkenyl, aryl, arylalkyl, aryloxyalkyl, arylalkoxyalkyl, (N-alkanoyl-N-alkyl)aminoalkyl, alkylsulfonylamidoalkyl, heterocyclic, (heterocyclic)alkyl and
(Raa)(Rbb)N-Rcc- wherein Raa is aryl or arylalkyl, Rbt) is hydrogen or alkanoyl and Rcc is alkylene, with the proviso that one or both of Rj and R2 is other than hydrogen; or a salt thereof.
Preferred intermediates include compounds of formula (IX), (X) and (XI) wherein m is zero or 1; R5b is alkylene;
R20a is hydrogen, loweralkyl, alkenyl, haloalkyl, alkoxyalkyl, haloalkoxyalkyl, cycloalkyl, cycloalkylalkyl, aryl or arylalkyl;
W is -CO2-G wherein G is hydrogen or a carboxy protecting group, and Ri and R2 are as defined above; or the substantiaUy pure (+)- or (-)-isomer thereof. Particularly preferred intermediates are compounds of formula (IX), (X) and (XI) wherein n and m are both 0; R5b is alkylene; R20a is hydrogen, loweralkyl, alkenyl, haloalkyl, alkoxyalkyl, haloalkoxyalkyl, cycloalkyl, cycloalkylalkyl, aryl or arylalkyl;
W is -CO2-G wherein G is hydrogen or a carboxy protecting group; and Ri is (i) loweralkyl, (ii) alkenyl, (Hi) alkoxyalkyl, (iv) cycloalkyl, (v) phenyl, (vi) pyridyl, (vii) furanyl or (vni) substituted or unsubstituted 4-methoxyphenyl, 4-fluorophenyl, 3 -fluorophenyl, 4-ethoxyphenyl, 4-ethylphenyl, 4-methylphenyl, 4-trifluoromethylphenyl, 4- pentafluoroethylphenyl, 3-fluoro-4-methoxyphenyl, 3-fluoro-4-ethoxyphenyl, 2- fluorophenyl, 4-methoxymethoxyphenyl, 4-hydroxyphenyl, 4-t-butylphenyl, 1,3- benzodioxolyl, 1,4-benzodioxanyl or dihydrobenzofuranyl wherein the substituent is selected from loweralkyl, haloalkyl, alkoxy, alkoxyalkoxy and carboxyalkoxy, (ix) aryalkyl, (x) aryloxyalkyl, (xi) heterocyclic (alkyl), (xii) (N-alkanoyl-N-alkyl)aminoalkyl, and (xiii) alkylsulfonylamidoalkyl, and R2 is substituted or unsubstituted 1,3-benzodioxolyl, 7- methoxy-l,3-benzodioxolyl, 1,4-benzodioxanyl, 8-methoxy- 1,4-benzodioxanyl, dihydrobenzofuranyl, benzofurnayl, 4-methoxyphenyl, dimethoxyphenyl, fluorophenyl or difluorophenyl wherein the substituent is selected from loweralkyl, alkoxy and halogen; or the substantiaUy pure (+)- or (-)-isomer thereof.
The foregoing may be better understood by reference to the foUowing examples which are provided for Ulustration and not intended to limit the scope of the inventive concept. The foUowing abbreviations are used: Boc for tert-butyloxycarbonyl, Cbz for benzyloxycarbonyl, DBU for l,8-diazabicyclo[5.4.0]undec-7-ene, EDCI for l-(3- dimethylaminopropyl-3-ethylcarbodiimide hydroehloride, EtOAc for ethyl acetate, EtOH for ethanol, HOBt for 1-hydroxybenzotriazole, Et3 for triethylamine, TFA for trifluoroacetic acid and THF for tetrahydrofuran.
Example 1 tr nir,tr-.π '- 2-(4-Methoxyphenyl)-4-(1 -benzodioxol-5-yl)-l-(propyl-iminocarbonylmethyl)- pyrroHdine-3 -carboxylic acid
Example IA Ethyl 2-(4-methoxybenzoyl)-4-nitromethyl-3-( 3-benzodioxole-5-yl)butyrate To ethyl (4-methoxybenzoyl)acetate (23.0 g, 0.104 mol), prepared by the method of Krapcho et al, Org. Syn. 47, 20 (1967), and 5-(2-nitrovinyl)-l,3-benzodioxole (17.0 g, 0.088 mol) dissolved in 180 mL of toluene and heated to 80 °C was added 1,8- diazabicyclo[5,4,0] undec-7-ene (DBU, 0.65 g) with stirring. The mixture was heated until all the nitro starting material dissolved. The solution was stirred without heating for 30 minutes (min) and then an additional 0.65 g of DBU was added. After stirring an additional 45 minutes, thin layer chromatography (5% ethyl acetate in methylene chloride) indicated the absence of nitro starting material. Toluene (200 mL) was added, and the organic phase was washed with dilute hydrochloric acid and NaCl solution. The organic phase was dried over sodium sulfate and then concentrated under reduced pressure. The residue obtained was chromatographed on sUica gel eluting with 3:1 hexane-ethyl acetate to give 21.22 g of the desired product as a mixture of isomers and 9.98 g. of recovered ethyl (4- methoxybenzoyl)acetate.
Example IB
Ethyl 2-(4-methoxyphenyl)-4-(1 -benzodioxol-5-yl)-4,5-dihydro-3H-pyrrole-3-carboxylate
The compound resulting from Example IA (21 g) in 500 mL of ethanol was hydrogenated under 4 atmospheres of hydrogen pressure using a Raney nickel 2800 catalyst (51 g). (The Raney nickel was washed with ethanol three times before use.) The catalyst was removed by filtration, and the solution was concentrated under reduced pressure. The residue obtained was chromatographed on silica gel eluting with 8.5% ethyl acetate in methylene chloride to give 12.34 g of the desired product.
Example IC Ethyl 2-(4-methoxyphenyl-4-(l,3-benzodioxol-5-yl)-pyrroHdine-3-carboxylate) as a mixture of cis-cis; transjrans; and cisjrans -isomers The compound resulting from Example IB (11.89 g, 0.324 mol) was dissolved in 27 mL of tetrahydrofuran and 54 mL of ethanol. Sodium cyanoborohydride (2.35 g, 0.374 mol) and 5 mg bromocresol green were added. To this blue solution was added dropwise a solution of 1 :2 concentrated HCl in ethanol at such a rate that the color was kept at light yellow-green. After the yellow color persisted without additional HCl, the solution was stirred an additional 20 minutes. The solution was concentrated in vacuo and then partitioned between chloroform and an aqueous potassium bicarbonate solution. The organic phase was separated, dried over sodium sulfate, and concentrated under reduced pressure. The residue was chromatographed on sUica gel eluting with 85: 15 ethyl acetate-hexane to give 5.96 g. of a mixture of 64% trans, trans-compound and 34% cis, trans-compound. Further elution with pure ethyl acetate gave 0.505 g of an unknown sohd foUowed by 3.044 g of pure c/s,c.s-compound.
Example ID tr-.nsJr_.ns-2-(4-Methoxyphenyl)-4-(1 -benzodioxol-5-yl)-l-(propylaminocarbonylmethyl)- pyrroHdine-3 -carboxylic acid The mixture of 64% transjrans- and 34% czs,trans-pyrroHdines (the mixture resulting from Example IC) (5.72 g, 15.50 mmol), ethyldiisopropylamine (4.20 g, 32.56 mmol), and N-propyl bromoacetamide (3.42 g, 19.0 mmol), prepared by the method of Weaver, W.E. and Whaley, W.M., J. Amer. Chem. Soc, 69: 515 (1947), in 30 mL of acetonitrile was heated at 50 °C for 1 hour. The solution was concentrated in vacuo. The residue was dissolved in toluene, shaken with potassium bicarbonate solution, dried over sodium sulfate and concentrated in vacuo to give 7.16 g of product as a mixture of transjrans- and cisjrans- ethyl esters. This mixture was dissolved in a solution of 50 mL of ethanol and 15 mL of water containing 5.00 g of sodium hydroxide and stirred for 3 hours at room temperature. The solution was concentrated in vacuo and 60 mL of water added. The mixture was extracted with ether to remove the unreacted cisjrans- ethyl ester. The aqueous phase was treated with hydrochloric acid until slightly cloudy. It was then further neutrahzed with acetic acid to give the crude acid product. The crude product was filtered and purified by dissolving it in tetrahydrofuran, drying over sodium sulfate, concentrating in vacuo, and crystalHzing from ether to give 3.230 g of the title compound, p. 151-153 °C. 1H NMR (CD3OD, 300 MHz)
0.87 (t, J = 7 Hz, 3H), 1.49 (sextet, J = 7 Hz, 2H), 2.84 ( d, I = 16 Hz, IH), 2.95-3.20 (m, 4H), 3.20 (d, = 16 Hz, IH), 3.34-3.42 (m, IH), 3.58-3.66 (m, IH), 3.78 (s, 3H), 3.88 (d, J = 10 Hz, IH), 5.92 (s, 2H), 6.75 (d, J = 8 Hz, IH), 6.86 (dd, J= 8 Hz, J = 1 Hz, IH), 6.90 (d, J = 9 Hz, 2H), 7.02 (d, I = 1 Hz, IH), 7.40 (d, I = 9 Hz, 2H).
Example 2 trans. trαns-2-(4-Methoxyphenyl)-4-( 1 ,3-benzodioxol-5-yl)- 1 -(aminocarbonylmethyl)- pyrrolidine-3 -carboxylic acid
Using the method described in Example ID, 300 mg of the mixture of 64% transjrans- and 34% c/s.trarø-pyrroHdines (the mixture resulting from Example IC), 220 mg of diisopropylethylamine and 184 mg iodoacetamide were reacted at 45 °C in 1 mL acetonitrUe to give 291 mg of a mixture of trans Jrans- and cisjrans- N-alkylated esters. A portion (270 mg.) was hydrolyzed with 200 mg NaOH in 1 mL of water and 3 mL of ethanol; a chloroform extraction was used to remove the unreacted cisjrans- ethyl ester. The isolation and purification procedures described in Example ID were used to give 134 mg of the title compound. m.p. 246-248 °C. 1H NMR (DMSO-d6, 300 MHz) δ 2.61 (d, I = 16 Hz,
IH), 2.71 (t, J = 9 Hz, IH), 2.90 (t, J = 9 Hz, IH), 2.98 (d, J = 16 Hz, lH),3.25-3.35 (m, IH), 3.45-3.55 (m, IH), 3.71 (s, 3H), 3.75 (d, I = 10 Hz, IH), 6.00 (s, 2H), 6.81 (s, 2H), 6.90 (d, J = 8 Hz, 2H), 7.10 (s, IH), 7.17 (s, IH), 7.34 (s, IH), 7.38 (d, J = 8 Hz, 2H).
Example 3 trans.tr-.ns-2-(4-Methoxyphenyl)-4-( 3-benzodioxol-5-ylVl-(4-fluorobenzyl)-pyrroHdine-3- carboxylic acid Using the method described in Example ID, 300 mg of the mixture of 64% transjrans- and 34% cisjrans- pyrrolidines (the mixture resulting from Example IC), 220 mg of diisopropylethylamine and 185 mg of 4-fluorobenzyl bromide were reacted at room temperature for 3 hours in 1 mL of acetonitrile to give 387 mg of a mixture of trans Jrans- and c-s,trans-N-alkylated esters. A portion (360 mg) was hydrolyzed with 250 mg NaOH in 1 mL of water and 4 mL of ethanol to give 160 mg of the title compound as an amorphous powder. 1H NMR (CDC13, 300 MHz) δ 2.74 (t, J = 9 Hz, IH), 2.95 (t, J = 7 Hz, IH), 2.98 (d, = 14, IH), 3.07 (dd, = 9 Hz, 1 Hz, IH), 3.42-3.53 (m, IH), 3.70 (d, J = 9 Hz, IH), 3.78 (d, J = 14, IH), 3.81 (s, 3H), 5.92 (s, 2H), 6.70 (d, J = 8 Hz, IH), 6.77 (dd, I = 8 Hz, 1 Hz, IH), 6.91 (d, I = 9 Hz, 2H), 6.94 -7.00 (m, 3H), 7.20 - 7.25 (M, IH), 7.44 (d, J = 9 Hz, 2H).
Example 4 trans, tr_.ns-2-(4-MethoxyphenvD-4-( 1 ,3-benzodioxol-5-yD- 1 -(2-ethoxyethyl , -pyrrohdine-3- carboxylic acid Using the method described in Example ID, 300 mg. of the mixture of 64% transjrans- and 34% c/s, trans-pyrroHdines (the mixture resulting from Example IC), 220 mg of diisopropylethylamine and 152 mg of 2-bromoethyl ethyl ether were refluxed in 1.5 mL acetonitrile for 3 hours (bath temperature at 95 °C) to give 346 mg of a mixture of transjrans- and cis, trans-esters. Hydrolysis with 250 mg NaOH in 1 mL of water and 3 mL of ethanol afforded 140 mg of the title compound, mp. 88 - 90 °C. 1H NMR (CDCI3, 300 MHz) δ 1.25 (t, I = 7 Hz, 3H), 2.21-2.32 (m, IH), 2.70-2.80 (m, IH), 2.85-2,94 (m, 2H),
3.38-3.55 (m, 6H), 3.67 (d, J = 10 Hz, IH), 3.79 (s, 3H), 5.94 (s, 2H), 6.72 (d, = 8 Hz, IH), 6.84 (m, IH), 6.84 (d, I = 9 Hz, 2H), 7.08 (d, J = 1 Hz, IH), 7.33 (d, J = 9 Hz, 2H).
Example 5 trans.trans-2-(4-Methoxyphenyl)-4-(1.3-benzodioxol-5-yl)-l-(2-propoxyethyl -pyrrolidine-
3 -carboxyHc acid Using the method described in Example ID, 520 mg of the mixture resulting from Example IC, 364 mg of diisopropylethylamine, 50 mg potassium iodide and 350 mg 2- chloroethyl propyl ether were reacted at 125 °C in 0.5 mL acetonitrUe for 4 hours to give 517 mg of a mixture of transjrans- and cis, trans-esters. A portion (500 mg) was hydrolyzed with 315 mg NaOH in 1 mL of water and 4 mL of ethanol to give 225 mg of the title compound as an amorphous powder. 1H NMR (CDC13, 300 MHz) δ 0.87 (t, J = 7 Hz, 3H),
1.53 (sextet, J = 7 Hz, 2H), 2.28-2.41 (m, IH), 2.71-2.83 (m, IH), 2.92-3.08 (m, 2H), 3.30 (t, J = 7 Hz, 2H), 3.40-3.60 (m, 4H), 3.72-3.83 (m, IH), 3.76 (s, 3H), 5.92 (s, 2H), 6.71 (d, J = 8 Hz, 2H), 6.74 (dd, J = 8 Hz, 1 Hz), 6.71 (d, J = 9 Hz, 2H), 7.07 (d, J = 9 Hz, 2H), 7.73 (d, J = 9 Hz, 2H).
Example 6 trans.tr-.ns-2-(4-Methoxyphenyl)-4-(l,3-benzodioxol-5-yl)-l-[2-(2-methoxyethoxy)ethyl]- pyrroHdine-3-carboxylic acid
Example 6A Ethyl trgns,trans-2-(4-methoxyphenyl)-4-(l,3-benzodioxol-5-yl) pyrroUdine-3-carboxylate To the pure cis, cts-compound resulting from Example IC (3.02 g) dissolved in 10 mL of ethanol was added 20 drops of a solution of 21% sodium ethoxide in ethanol. The reaction mixture was refluxed overnight, at which time thin layer chromatography in ethyl acetate indicated the absence of starting material. The NaOEt was neutraHzed with HCl in ethanol, and the solution was concentrated in vacuo. The residue was taken up in toluene and extracted with potassium bicarbonate in water. The toluene was dried over sodium sulfate and concentrated under reduced pressure to give 2.775 of the title compound which was pure by TLC (ethyl acetate).
Example 6B trans.trαns-2-(4-Methoxyphenyl -4-(l,3-benzodioxol-5-yl)-l-[2-(2-methoxyethoxy)ethyl]- pyrroHdine-3 -carboxylic acid Using the method described in Example ID, 250 mg of the compound resulting from
Example 6A, 150 mg of 2-(2-methoxyethoxy) ethyl bromide and 175 mg dnsopropyl- ethylamine in 1 mL acetonitrile were heated at 100 °C for 3 hours to give 229 mg of the trans, trans-ester. A portion (200 mg) was hydrolyzed with 125 mg NaOH in 1 mL of water and 2 mL of ethanol to give 151 mg of the title compound as an amorphous powder. H NMR (CD3OD, 300 MHz) δ 2.9-3.9 (m, 13H), 3.81 (s, 3H), 4.49 (d, I = 10 Hz, IH), 5.94 (s, 2H), 6.79 (d, I = 8 Hz, IH), 6.89 (dd, I = 8 Hz, 1 Hz, IH), 7.00 (d, I = 9 Hz, 2H), 7.05 (d, J = 1 Hz, IH), 7.49 (d, J = 9 Hz, 2H).
Example 7 tr-.ns,trans-2-(4-Methoxyphenyl)-4-(l,3-benzodioxol-5-yl)-l-[2-(2-pyridyl)ethyl]- pyrroHdine-3 -carboxylic acid The compound resulting from Example 6 A (250 mg), 2-vinyl pyridine (355 mg) and one drop of acetic acid were dissolved in 2-methoxyethanol, and stirred at 100 °C for 2.5 hours. Toluene was added, and the solution was washed with potassium bicarbonate solution. The solution was dried over potassium bicarbonate and concentrated in vacuo. Toluene was added and the solution re-concentrated. This was done until the odor of 2- vinylpyridine was gone. The residue was taken up in hot heptane, filtered to remove a smaU amount of insoluble impurity, and concentrated in vacuo to give 225 mg of intermediate ester. The ester was hydrolyzed by the method described in Example ID to give 202 mg of the title compound as the dihydrate. mp. 77-80 °C. 1H NMR (CD3OD, 300 MHz) δ 2.8 -
3.3 (m, 6H), 3.55-3.70 (m, 2H), 3.76 (s, 3H), 3.99 (d, J = 10 Hz, IH), 5.92 (d, I = 1 Hz, 2H), 6.72 (d, J = 8 Hz, IH), 6.80 (dd, I = 8 Hz, 1 Hz), 6.85 (d, J = 9 Hz, 2H), 6.92 (d, J = 1 Hz, IH), 7.20 (d, J = 9 Hz, 2H), 7.20-7.32 (m, 2H), 7.70-7.80 (m, 2H), 8.40 (d, J = 4 Hz, IH).
Example 8 trans, trans-2-(4-Methoxyphenyl)-4-( 1 ,3-benzodioxol-5-vD- 1 -(morphoHn-4-ylcarbonyl)- pyrrolidine-3 -carboxylic acid To the compound resulting from Example 6 A (300 mg) and 164 mg triethylamine dissolved in 2 mL of methylene chloride and cooled in an ice bath was added 146 mg 1- morpholinocarbonyl chloride. The mixture was stirred 3 hours at room temperature.
Toluene was added and the solution was washed with potassium bicarbonate solution, dried over sodium sulfate and concentrated in vacuo to give the intermediate ester. The ester was hydrolyzed by the method described in Example ID to give 288 mg of the title compound, mp. 244-246 °C. 1H NMR (DMSO-d6, 300 MHz) δ 2.96 (dd, I = 12,Hz, 13 Hz, IH), 3.03- 3.13 (m, 2H), 3.20-3.30 (m, 2H), 3.40-3.60 (m, 5H), 3.74 (s, 3H), 3.70-3.85 (m, 3H), 5.10 (d, J = 10 Hz, IH), 5.99 (d, I = 1 Hz, 2H), 6.80-6.90 (m, 2H), 6.87 (d, J = 9 Hz, 2H), 7.07 (s, lH), 7.25 (d, I = 9 Hz, 2H).
Example 9 trans.trans-2-(4-Methoxyphenyl -4-(L3-benzodioxole-5-yl)-l-(butylaminocarbonylV pyrroHdine-3 -carboxylic acid To the compound resulting from Example 6A (300 mg) dissolved in 2 mL tetrahydrofuran and cooled in an ice bath was added 88 mg of butyl isocyanate. After 40 minutes at room temperature, toluene was added, and the solution was concentrated in vacuo to give the intermediate ester. The ester was hydrolyzed by the method described in Example ID to give 232 mg of the title compound, mp. 220-221 °C. 1H NMR (DMSO-dό, 300
MHz) δ 0.78 (t, I = 7 Hz, 3H), 1.10 (sextet, J = 7 Hz, 2H), 1.22 (quintet, J = 7 Hz, 2H), 2.78- 3.05 (m, 3H), 3.40-3.56 (m, 2H), 3.74 (s, 3H), 3.95-4.05 (m, IH), 4.93 (d, = 9 Hz, IH), 5.80 (t, broad, I = 7 Hz, IH), 5.99 (s, 2H), 6.78-6.86 (m, 2H), 6.88 (d, I = 9 Hz, 2H), 7.00 (d, J = 1 Hz, IH), 7.12 (d, = 9 Hz, 2H).
Example 10 trans. trans-2-(4-Methoxyphenyl)-4-( 1 ,3-benzodioxol-5-yl)- 1 -(4- methoxyphenylaminocarbonylV3-pyrroHdine-3-carboxyHc acid The compound resulting from Example 6 A (300 mg) was treated with 133 mg of 4- methoxyphenyl isocyanate by the procedure described in Example 9. The resulting ester was hydrolyzed with NaOH using the method described in Example ID to give 279 mg of the title compound. m.p. 185-187 °C. 1H NMR (CDC13) 300 MHz) 3.23 (dd, I = 12 Hz, 13 Hz, IH), 3.55-3.68 (m, 2H), 3.72 (s, 3H), 3.83 (s, 3H), 4.50-4.65 (m, IH), 5.06 (d, = 10 Hz, IH), 5.90 (s, IH), 5.95 (s, IH), 6.72 (d, I = 9 Hz, 2H), 6.7-6.8 (m, 3H), 6.92 (d, J = 9 Hz, 2H), 6.97 (d, = 9 Hz, 2H), 7.37 (d, J = 9 Hz, 2H).
Example 11 tr-.ns.trans-2-(4-Methoxyphenyl)-4-(l,3-benzodioxol-5-yl)-l-acetylpyrrolidine-3-carboxylic acid The compound resulting from Example 6A (250 mg) in 0.5 mL of toluene was treated with 200 mg of acetic anhydride. After stirring 2 hours at room temperature, water was added and the acetic acid neutralized with potassium bicarbonate. The mixture was extracted with toluene to give 273 mg of the intermediate ester. A portion of the ester (200 mg) was hydrolyzed using the method of Example ID to give 211 mg of the title compound, mp. 248-250 °C. Rotational isomers are seen in the NMR. 1H NMR (DMSO-dβ, 300 MHz) 1.55 and 2.00 (s, 3H), 2.94 and 3.03 (dd, J = 12 Hz, 13 Hz, IH), 3.3-3.6 (m, 2H), 3.72 and 3.76 (s, 3H), 4.12 and 4.28 (dd, J = 12 Hz, 7 Hz, IH), 4.95 and 5.04 (d, = 10Hz, IH), 6.00 (s, 2H), 6.75-6.87 (m, 3H), 6.95 and 7.04 (d, I = 9 Hz, 2H), 7.18 and 7.32 (d, I = 9 Hz, 2H).
Example 12 trans.trøns-2-(4-Methoχyphenyl)-4-(1 -benzodioxol-5-yl)-l-(2-fuiOyl)-pyrrolidine-3- carboxylic acid To the compound resulting from Example 6 A (300 mg) and 164 mg triethylamine dissolved in 2 mL methylene chloride and cooled in an ice bath was added 138 mg of 2- furoyl chloride. The mixture was stirred 30 minutes at room temperature and then worked up by the procedures described in Example 8 to give the intermediare ester. The ester was hydrolyzed by the procedure described in Example ID to give 269 mg of the title compound as an amorphous powder. 1H MR (DMSO-d6, 300 MHz) δ 3.06 (dd, I = 12 Hz, 13 Hz, IH), 3.3-3.6 (m, 2H), 4.25 (m, IH), 5.19 ( d, J= 10 Hz, IH), 6.67.4 (m, 8H), 7.8-7.9 ( , IH).
Example 13 transJrans-2-(4-Methoxyphenyl)-4-(l,3-benzodioxol-5-yl)-l-(phenylaminocarbonyl)- pyrroHdine-3-carboxylic acid Starting with the compound resulting from Example 6A, phenyl isocyanate and the procedures described in Example 9, the title compound was prepared. m.p. 209-211 °C. H NMR (DMSO-d6, 300 MHz) δ 3.03 (dd, IH), 3.55 (m, IH), 3.70 (m, IH), 3.72 (s, 3H), 4.15 (m, IH), 5.13 (d, IH), 6.00 (s, 2H), 6.88 (m, 5H), 7.07-7.20 (m, 3H), 7.30 (d, 2H), 7.38 (d, 2H), 8.20 (bs, IH).
Example 14 trans. tr_.ns-2-(4-Methoxyphenyl)-4-( 1 ,3-benzodioxol-5-yl)- 1 -(allylaminocarbonylmethyl)- pyrroHdine-3-carboxylic acid Using the procedures described in Example 1 the title compound was prepared. m.p. 138-140 °C. 1HNMR (CDC13, 300 MHz) δ 2.84 (d, IH), 2.90-3.10 (dt, 2H), 3.28 (d, IH),
3.35 (dd, IH), 3.62 ( , IH), 3.72-3.97 (m, 3H), 3.80 (s, 3H), 5.13 (bd, 2H), 5.80 (m, IH), 5.97 (s, 2H), 6.74-6.97 (m, 5H), 7.38 (d, 2H).
Example 15 trαns,tr ns-2-(4-MethoxyphenylV4-(1 -benzodioxol-5-yl)-l-(n-butylaminocarbonylmethyl)- pyrrolidine-3 -carboxylic acid Using the procedures described in Example 1 the title compound was prepared. m.p. 105-107 °C. 1HNMR (CDCI3, 300 MHz) δ 0.90 (t, 3H), 1.30 (m, 2H), 1.45 (m, 2H), 2.80 (d, IH), 2.87-3.35 (m, 6H), 3.62 (m, IH), 3.80 (s, 3H), 5.97 (s, 2H), 6.75-6.92 (m, 5H), 7.28 (d, 2H). Example 16 trans.trans-2-(4-Methoxyphenyl)-4-(1 -benzodioxol-5-yl)-l-(N-(n-propyl -N- methylaminocarbonylmethyl)-pyrroHdine-3 -carboxylic acid Using the procedures described in Example 1 the title compound was prepared as an amorphous sohd. Rotational isomers are seen in the NMR. 1H NMR (CDC_3, 300 MHz) δ
0.73, 0.84 (2t, 3H), 1.49 (m, 2H), 2.80 (dd, IH), 2.85 (2s, 3H), 2.95-3.20 (m, 3H), 3.20-3.40 (m, IH), 3.40 (d, IH), 3.60 (m, IH), 3.79 (s, 3H), 5.93 (s, 2H), 6.73 (d, IH), 6.86 (m, 2H), 7.03 (m, IH), 7.32 (d, 2H).
Example 17 trans, trans-2-(4-Methoxyphenyl)-4-( 1 ,3-benzodioxol-5-yl)- 1 -(pyrrolidin- 1 - ylcarbonylmethyl)-pyrroHdine-3-carboxy lie acid Using the procedures described in Example 1 the title compound was prepared as an amorphous sohd. 1H NMR (CDC13, 300 MHz) δ 1.40-1.70 (m, 6H), 2.80 (d, IH), 3.00 (m, 2H), 3.24-3.43 (m, 5H), 3.60 (m, 2H), 3.73 (d, IH), 3.80 (s, 3H), 5.95 (s, 2H), 6.74 (d,. IH), 6.80-6.90 (m, 3H), 7.04 (d, IH), 7.30 (d, 2H).
Example 18 trans, trans-2-(4-Methoxyphenyl)-4-( 1 ,3-benzodioxol-5-ylV 1 - (isobutylaminocarbonylmethyl)-pyrroHdine-3-carboxylic acid
Using the procedures described in Example 1 the title compound was prepared. m.p. 175-177 °C. 1HNMR (CD3OD, 300 MHz) δ 0.87 (dd, 6H), 1.75 (septet, IH), 2.85 (d, IH), 2.90-3.10 (m, 4H), 3.23 (d, IH), 3.40 (m, IH), 3.58-3.67 (m, IH), 3.78 (s, 3H), 3.89 (d, IH), 5.92 (s, 2H), 6.76 (d, IH), 6.86 (dd, IH), 6.91 (d, 2H), 7.02 (d, IH), 7.40 (d, 2H).
Example 19 trans, tr_.ns-2-(4-Methoxyphenyl)-4-( 1 ,3-benzodioxol-5-yl)- 1 - (cyclopentylaminocarbonylmethyl)-pyrrolidine-3-carboxylic acid Using the procedures described in Example 1 the title compound was prepared, mp. 137-139 °C. 1HNMR (CDCI3, 300 MHz) δ 1.34 (m, 2H), 1.62 (m, 4H), 1.90 (m, 2H), 2.76 (d, IH), 2.90 (t, IH), 3.04 (dd, IH), 3.22 (d, IH), 3.28 (dd, IH), 3.40 ( , IH), 3.80 (s, 3H), 4.15 (m, IH), 5.97 (d, 2H), 6.75-6.95 (m, 5H), 7.27 (m, 2H). Example 20 trans.trans-2-(4-Methoxyphenyl)-4-( 3-benzodioxol-5-yl)-l-(morphoHn-4- ylaminocarbonylmethyl)-pyrroHdine-3-carboxylic acid Using the procedures described in Example 1 the title compound was prepared as an amorphous sohd. % NMR (CDCI3, 300 MHz) δ 2.82 (d, IH), 3.00 (m, 2H), 3.24 (m, IH), 3.30-3.52 (m, 4H), 3.52-3.75 (m, 8H), 3.80 (s, 3H), 5.95 (s, 2H), 6.75 (d, IH), 6.84 (d, 3H), 7.00 (s, IH), 7.28 (d, 2H).
Example 21 trans,trans-2-(4-Methoxyphenyl)-4-(l,3-benzodioxol-5-yπ-l-(2-phenoxyethyl)-pyrroHdine-
3-carboxylic acid Using the procedures described in Example 4 the title compound was prepared as an amorphous soHd. 1HNMR (CD3OD, 300 MHz) δ 2.82 (m, IH), 2.96 (dd, IH), 3.13 (m, IH), 3.32 (m, IH), 3.51-3.70 (m, 2H), 3.77 (s, 3H), 4.00 (d, IH), 4.07 (m, 2H), 5.91 (s, 2H), 6.72 (d, IH), 6.80-6.95 (m, 6H), 7.03 (d, IH), 7.22 (dd, 2H), 7.39 (d, 2H).
Example 22 trans, trans-2-(4-Methoxyphenyl)-4-( 1 ,3-benzodioxol-5-yl)- 1 -(2- methoxyethylaminocarbonylmethyl)-pyrroHdine-3 -carboxyHc acid Using the procedures described in Example 1 the title compound was prepared, mp.
107-109 °C. 1HNMR (CD3OD, 300 MHz) δ 2.82 (d, IH), 2.97 (q, 2H), 3.21 (d, IH), 3.38 (m, IH), 3.32 (s, 3H), 3.44 (m, 4H), 3.62 (m, IH), 3.79 (s, 3H), 3.86 (d, IH), 5.93 (s, 2H), 6.76 (d, IH), 6.85 (dd, IH), 6.91 (d, 2H), 7.01 (d, IH), 7.38 (d, 2H).
Example 23 trαns.trans-2-(4-Methoxyphenyl)-4-(l,3-benzodioxol-5-yl)-l-(2-butoxyethyl)-pyrroHdine-3- carboxylic acid Using the procedures described in Example 4 the title compound was prepared, mp. 53-55 °C. 1HNMR (CDCI3, 300 MHz) δ 0.88 (t, J=7Hz, 3H), 1.32 (sextet, J=7Hz, 2H), 1.50 (pentet, I=7Hz, 2H), 2.27 (tt, I=6Hz, 6Hz, IH), 2.92 (q, J=10Hz, 2H), 3.35 (t, J=7Hz, 2H), 3.42-3.56 (m, 4H), 3.68 (d, J=10Hz, IH), 3.78 (s, 3H), 5.94 (s, 2H), 6.73 (d, J=8Hz, IH), 6.83 (d, I=9Hz, 2H), 6.82-6.87 (m, IH), 7.06 (d, I=2Hz, IH), 7.32 (d, J=9Hz, 2H). MS m e 442 (M+H)+ Example 24 trans.trans-2-(l,3-Benzodioxol-5-yl)-4-(4-methoxyphenyl)-l-(propylaminocarbonylmethyl)- pyrroHdine-3 -carboxylic acid Using the procedures described in Example 1 and substituting ethyl (1,3-benzodioxol- 5-ylcarbonyl)acetate for ethyl (4-methoxybenzoyl) acetate and 4-(2-nitrovinyl)anisole for 5- (2-nitrovinyl)-l,3-benzodioxol-5yl afforded the title compound. m.p. 97-99 °C. H NMR (CDC13, 300 MHz) δ 0.78 (t, I=7Hz, 3H), 1.39 (sextet, J=7Hz, 2H), 2.72 (d, J=16Hz, IH),
2.74 (t, J=10Hz, IH), 2.80-3.10 (m, 4H), 3.26-3.38 (m, IH), 3.53 (m, IH), 3.73 (s, 3H), 3.80 (d, J=10Hz, 2H), 7.80 (t, I=6Hz, IH). MS (DCI/NH3) m/e 441 (M+H)+.
Example 25 trans, trans-2-( 1 ,3-Benzodioxol-5-yl)-4-(4-methoxyphenylV 1 -(2-propoxyethyl)-pyrroHdine-
3 -carboxyHc acid Using the procedures described in Example 5 and substituting ethyl (1,3-benzodioxol- 5-ylcarbonyl)acetate for ethyl (4-methoxybenzoyl) acetate and 4-(2-nitrovinyl)anisole for 5- (2-nitrovinyl)-l,3-benzodioxol-5yl afforded the title compound. m.p. 67-69 °C. H NMR (CDCI3, 300 MHz) δ 0.89 (t, J=7Hz, 3H), 1.56 (sextet, I=7Hz, 2H), 2.33 (m, IH), 2.78-3.00
(m, 3H), 3.32 (t, I=7Hz, 2H), 3.45-3.57 (m, 4H), 3.73 (m, IH), 3.79 (s, 3H), 5.93 (s, 2H), 6.22 (d, I=8Hz, IH), 6.85 (d, J=8Hz, 3H), 6.98 (s, IH), 7.37 (d, I=8Hz, 2H). MS (DCI/NH3) m/e 428 (M+H)+.
Example 26 trans, trans-2- 1 ,3-Benzodioxol-5-ylV4-(4-methoxyphenyl)- 1 -[2-(2-methoxyethoxy)ethyl)]- pyrrolidine-3 -carboxylic acid Using the procedures described in Example 4 and substituting the starting materials described in Example 25 and using 2-(2-methoxy ethoxy) ethylbromide to alkylate the pyrrolidine nitrogen afforded the title compound, p. 85-86 °C. 1H NMR (CD3OD, 300 MHz) δ 3.18-3.90 (m, 15H), 3.79 (s, 3H), 4.57 (d, J=10Hz, IH), 6.02 (s, 2H), 6.91 (d, J=8Hz, IH), 6.95 (d, J=9Hz, 2H), 7.06 (dd, J=8Hz, IH), 7.12 (dd, J=lHz, IH), 7.37 (d, J=9Hz, 2H). MS (DCI/NΗ3) m/e 444 (M+H)+.
Example 27 trans. trans-2-( 1 -Benzodioxol-5-yl)-4-f 4-methoxyphenyl)- 1 -(butoxyethyl)-pyrroHdine-3- carboxylic acid Using the procedures described in Example 4, substituting the starting materials described in Example 25 and using 2-ethoxyethylbromide to alkylate the pyrroHdine nitrogen afforded the title compound, mp. 54-56 °C. !H NMR (CDC13, 300 MHz) δ 0.89 (t, J-7Hz, 3H), 1.44 (sextet, I=7Hz, 2H), 1.52 (pentet, J=7Hz, 2H), 2.40 (m, IH), 2.74-2.98 (m, 3H), 3.46 (t, J=7Hz, 2H), 3.42-3.56 (m, 4H), 3.68 (d, J=10Hz, IH), 3.80 (s, 3H), 5.93 (dd, J=6Hz, 1Hz, 2H), 6.72 (d, J=8Hz, IH), 6.74 (dd, J=9Hz, 3H), 6.96 (s, IH), 7.36 (d, J=9Hz, 2H).
Example 28 trans.trans-2-(4-Methoxyphenyl)-4-(1.4-benzodioxan-6-yl)-l-(propylaminocarbonylmethyl.- pyrroHdine-3-carboxylic acid Using the procedures described in Example 1 and substituting 6-(2-nitrovinyl)-l,4- benzodioxane for 5-(2-nitrovinyl)-l,3-benzodioxole afforded the title compound, mp. 80- 81 °C. *H NMR (CDCI3, 300 MHz) δ 0.89 (t, I-7Hz, 3H), 1.49 (sextet, J=7Hz, 2H), 2.78 (d, J=16Hz, IH), 2.92 (t, J=10Hz, IH), 3.05-3.43 (m, 5H), 3.24 (d, J=16Hz, IH), 3.52-3.62 (m, IH), 3.80 (s, 3H), 3.80 (t, J=10Hz, IH), 4.27 (s, 4H), 6.74-6.93 (m, 5H), 7.29 (d, I=9Hz, 2H).
MS (DCI/NH3) m/e 455 (M+H)+.
Example 29 trans. tr_.ns-2-(4-Methoxyphenyl , -4-( 1 ,4-benzodioxan-6-vD- 1 -(N-methyl-N- propylaminocarbonylmethylVpyrroUdine-3 -carboxylic acid Using the procedures described in Example 1, substituting 6-(2-nitrovinyl)-l,4- benzodioxane for 5-(2-nitrovinyl)-l,3-benzodioxole and alkylating the pyrrolidine nitrogen with N-methyl-N-propyl bromoacetamide afforded the title compound, mp. 74-76 °C. Rotational isomers are seen in the NMR. 1H NMR (CDCI3, 300 MHz) δ 0.73, 0.83 (2t, J=7Hz, 3H), 1.48 (m, 2H), 2.78 (dd, IH), 2.85 (2s, 3H), 2.96-3.15 (m, 3H), 3.27-3.42 (m, 3H), 3.52-3.60 (m, IH), 3.75 (d, IH), 3.78 (s, 3H), 4.22 (s, 4H), 6.80-6.98 (m, 5H), 7.32 (d, 2H). MS (DCI/NH3) m/e 469 (M+H)+.
Example 30 trans. tr_.ns-2-(4-Methoxyphenyl)-4-( 1 ,3-benzodioxol-5-yl)- 1 -(N-methyl-N- butylaminocarbonylmethyl)-pyrrolidine-3-carboxy lie acid Using the procedures described in Example 1, the title compound was prepared. Rotational isomers are seen in the NMR. 1H NMR (CD3OD, 300 MHz) δ 0.86 (2t, 3H), 1.04-1.50 (m, 4H), 2.85 (2s, 3H), 2.93-3.20 (m, 4H), 3.40 (m, 2H), 3.52 (dd, IH), 3.60 ( , IH), 3.80 (s, 3H), 3.85 (m, IH), 5.91 (s, 2H), 6.74 (d, IH), 6.83-6.95 (m, 3H), 7.03 (dd, IH), 7.35 (dd, 2H).
Example 31 trans.trans-2-(4-Methoxy-2-methoxymethoxyphenyl)-4-(1.3-benzodioxol-5-yl)-l-(N-methyl- N-butylaminocarbonylmethyl)-pyrroHdine-3-carboxylic acid
Example 31 A Ethyl 2-(4-methoxy-2-methoxymethoxyphenyl-4-(l,3-benzodioxol-5-yl)-pyrroHdine-3- carboxylate) Using the procedures described in Examples IA and IB and substituting ethyl (4- methoxy-2-methoxymethoxybenzoyl)acetate for ethyl (4-methoxybenzoyl)acetate afforded ethyl 2-(4-methoxy-2-methoxymethoxyphenyl)-4-(l ,3-benzodioxol~5-yl)-4,5-dihydro-3H- pyrrole-3-carboxylate.
The above dihydro pyrrole carboxylate (3.0 g, 7.0 mmol) was dissolved in 20 mL of methanol, treated with 500 mg of 10% Pd/C and placed under hydrogen atmosphere for 32 hours. The catalyst was removed by filtration and the filtrate was concentrated under reduced pressure and chromatographed on siHca gel eluting with ethyl acetate to afford the title compound (1.9 g, 63%) as the cis-cis isomer.
Example 3 IB tr-.ns,tr-.ns-2-(4-Methoxy-2-methoxymethoxyphenyl)-4-(l,3-benzodioxol-5-yl)-l-(N-methyl-
N-butylaminocarbonylmethyl)-pyrroHdine-3-carboxylic acid The compound resulting from Example 31 A was epimerized by the procedure described in Example 6A. The resulting transjrans compound (100 mg, 0.23 mmol) was then reacted by the procedures described in Example ID substituting N-methyl-N-butyl bromoacetamide for N-propyl bromoacetamide to give the title compound (75 mg, 62%). p. 65-67 °C. Rotational isomers are seen in the NMR. 1H NMR (CDCI3, 300 MHz) δ 0.64, 0.68 (2t, I=7Hz, 3H), 1.14, 1.12 (2 sextet, J=7Hz, 2H), 1.40-1.48 (m, 2H), 2.86, 2.89 (2s, 3H), 2.95-3.42 (m, 6H), 3.50 (s, 3H), 3.43-3.65 (m, 2H), 3.78 (s, 3H), 4.30 (t, J=7Hz, IH), 5.09 (q, J=7Hz, 2H), 5.92 (s, 2H), 6.55 (dd, J=3Hz, IH), 6.68 (s, IH), 6.72 (s, IH), 6.85 (2t, I=lHz, IH), 7.04 (t, J=lHz, IH), 7.42 (dd, J=3Hz, IH).
Example 32 trαns.trαns-2-(4-Methoxyphenyl)-4-(1 -benzodioxol-5-yl)-l-(3-ethoxypropyl)-pyrroHdin-5- one-3-carboxylic acid
Example 32A Ethyl 2-(4-methoxybenzoyl)-3-carbomethoxy-l,3-benzodioxole-5-propionate To ethyl (4-methoxybenzoyl) acetate (4.44 g, 0.02 mmol) dissolved in 20 mL of anhydrous THF was added in portions 480 mg of NaH. The mixture was stirred for 30 minutes under nitrogen at ambient temperature. Methyl (l,3-benzodioxol-5-yl) bromoacetate (5.46 g, 0.02 mol) in 5 mL of THF was added. The mixture was stirred overnight at ambient temperature, diluted with 200 mL of EtOAc, and washed with water and brine. The organic phase was dried over sodium sulfate and concentrated in vacuo to afford the title compound (7.67 g, 92%) which was used without further purification.
Example 32B Ethyl l-(3-ethoxypropyl)-2-(4-methoxyphenyl)-4-(l,3-benzodioxol-5-yl)-4.5-dihydro-5-oxo-
1 H-pyrrole-3 -carboxylate A mixture of the compound resulting from Example 32A (700 mg, 1.69 mmol), 3- ethoxypropylamine (348 mg, 3.38 mmol) and 1 mL of acetic acid in a sealed tube was heated for 18 hours at 125 °C. After cooHng the contents of the tube to ambient temperature, 5 mL of water was added and the mixture extracted with ethyl acetate (2x100 mL). The combined organic extracts were washed with saturated sodium bicarbonate solution, water and brine, dried over sodium sulfate and concentrated under reduced pressure. The residue obtained was chromatographed on silica gel eluting with 3:2 hexane-ethyl acetate to give 330 mg (42%) of the title compound.
Example 32C Ethyl 1 -(3-ethoxypropyl)-2-(4-methoxyphenyl, -4-( 1 ,3-benzodioxol-5-yl)-pyrroUdin-5-one-3- carboxylate The compound resulting from Example 32B (300 mg, 0.64 mmol) in 15 mL of methanol was reduced with 100 mg of 10% Pd/C under hydrogen for 3 hours at ambient temperature. The catalyst was removed by filtration and the filtrate was concentrated under reduced pressure to give the title compound.
Example 32D tr-.ns.trans-2-(4-Methoxyphenyl)-4-( 3-benzodioxol-5-yl)-l-(3-ethoxypropyl -pyrrolidin-5- one-3 -carboxylic acid To the compound resulting from Example 32C (100 mg, 0.21 mmol) dissolved in 1 mL of ethanol was added 3 drops of a solution of 21% sodium ethoxide in ethanol. The mixture was heated to 70-80 °C for 3 hours, and then a solution of sodium hydroxide (100 mg) in 1 mL of water was added and heating was continued for 1 additional hour. The reaction mixture was cooled to ambient temperature, the ethanol was removed under reduced pressure, and water was added to the residue which was washed with ether. The aqueous layer was neutraHzed with 3 M HCl and allowed to stand overnight. The white crystalHne solid was coUectedby filtration to give the title compound (60 mg, 64%). mp. 134-140 °C. 1H MR (DMSO-d6, 300 MHz) δ 1.04 (t, J=7Hz, 3H), 1.55 (sextet, I=7Hz, 2H), 2.48-2.56 (m, IH), 2.93 (dd, I=9Hz, IH), 3.25 (t, J=7Hz, 2H), 3.28-3.40 (m, 2H), 3.48-3.57 (m, IH), 3.78 (s, 3H), 3.88 (d, J=10Hz, IH), 4.72 (d, J=10Hz, IH), 6.02 (s, 2H), 6.74 (dd, I=8Hz, 1Hz, IH), 6.87 (d, J=8Hz, 2H), 6.98 (d, I=8Hz, 2H), 7.38 (d, I=8Hz, 2H). MS (DCI/NH3) m/e
442 (M+H)+
Example 33 tr-.nsJrans-2-(4-Methoxyphenyl)-4-(l,3-benzodioxol-5-yl)-l-(3-methoxybenzyl)-pyrroHdin-
5-one-3 -carboxylic acid FoUowing the procedures described in Example 32 and substituting 3- methoxybenzylamine for 3-ethoxypropylamine afforded the title compound (123 mg, 65%). mp. 150-152 °C. 1H NMR (CD3OD, 300 MHz) δ 2.96 (dd, J-8Hz, lOHz, IH), 3.72 (s, 3H), 3.80 (s, 3H), 4.06 (d, I=10Hz, IH), 4.58 (d, J=8Hz, IH), 4.92 (q, I=16Hz, 2H), 5.92 (s, 2H), 6.55-6.63 (m, 2H), 6.82 (d, J=8Hz, 4H), 6.94 (d, I=8Hz, 2H), 7.15-7.22 (m, 3H). MS (DCI/NH3) m/e 475 (M+H)+.
Example 34 tr-.ns,trans-2-(4-Methoxyphenyl)-4-(l,3-benzodioxol-5-yl -l-(N,N- dnsoamylaminocarbonylmethyl)-pyrroHdine-3 carboxylic acid The title compound was prepared as an amorphous soHd using the procedures described in Example 1. 1H NMR (CDCI3, 300 MHz) δ 0.70 -0.90 (m, 12H), 1.10-1.60 (m, 10H), 2.75 (d, J=13Hz, IH), 2.90-3.10 (m, 4H), 3.15 - 3.30 (m, 2H), 3.40 (d, J=10Hz, IH), 3.40 - 3.52 (m, 2H), 3.55 - 3.62 (m, IH), 3.75 (d, J=12 Hz, IH), 3.79 (s, 3H), 5.93 (dd, =1 Hz, 3 Hz, 2H), 6.72 (d, I=8Hz, IH), 6.82-6.90 (m, 3H), 7.03 (d, J=2Hz, IH), 7.30 (d, J=9Hz, 2H).
Example 35 trans.tra7.s-2-(4-Methoxyphenyl)-4-( 3-benzodioxol-5-yl)-l-(N,N- dipentylaminocarbonylmethyl)-pyrrolidine-3 -carboxylic acid The title compound was prepared as an amorphous sohd using the procedures described in Example 1. % NMR (CDCI3, 300 MHz) δ 0.82 (t, J = 7Hz, 6H), 0.95-1.03 (m, 2H), 1.10-1.30 (m, 8H), 1.40-1.51 (m, 2H), 2.72 (d, I=13Hz, IH), 2.90-3.08 (m, 4H), 3.25- 3.50 (m, 3H), 3.37 (d, I=13Hz, IH), 3.52-3,60 (m, IH), 3.70 ( =10Hz, IH), 3.75 (s, 3H), 5.92 (dd, J=2Hz, 5Hz, 2H), 6.72 (d, I=8Hz, IH), 6.80-6.88 (m, 3H), 7.03 (d, J=2Hz, IH), 7.30 (d, J=9Hz, 2H).
Example 36 trans.trans-2-(4-Methoxyphenyl)-4-(1.3-benzodioxol-5-yl)-l-(N,N-di(2- methoxyethyl)aminocarbonylmethyl)-pyrrolidine-3-carboxy lie acid The title compound was prepared using the procedures described in Example 1. m.p. 120-122 °C. 1HNMR (CDC13, 300 MHz) δ 2.82 (d, J=13, IH), 2.94-3.08 (m, 2H), 3.12.(s,
3H), 3.23 (s, 3H), 3.20-3.70 (m, 11H), 3.73 (d, I=10Hz, IH), 3.79 (s, 3H), 5.92 (dd, J= 2Hz, 2Hz, 2H), 6.72 (d, J=8Hz, IH), 6.80-6.90 (m, 3H), 7.04 (d, J=2Hz, IH), 7.30 (d, I=9Hz, 2H).
Example 37 transJra»s-2-(4-Methoxyphenyl)-4-(l,3-benzodioxol-5-ylVl-(2-hexynyl)-pyrroHdine-3- carboxylic acid Using the procedures described in Example 4, 200 mg. of the pure transjrans isomer, the compound resulting from Example 6A was reacted with 109 mg of l-bromo-2-hexyne, prepared by the method described in Perkin I, , 2004 (1987), for 1 hour at 55 °C, to give 226 mg of the intermediate ester. The ester was hydrolyzed using NaOH in ethanol-water for 3 hours at room temperature to give 175 mg of the title compound. H NMR (CDCI3, 300 MHz) δ 1.00 (t, I=7Hz, 3H), 1.54 (m, 2H), 2.14-2.22 (m, 2H), 2.96 (dd, J=7Hz, 13Hz, IH), 3.07 (dd, J=18Hz, 2Hz, IH), 3.15 (dd, I=9Hz, 2Hz, IH), 3.26 (t, I=9Hz, IH), 3.36 (dd, J = 18 Hz, 2Hz, IH), 3.47-3.55 (m, IH), 3.79 (s, 3H), 3.88 (d, I=9Hz, IH), 5.95 (s, 2H), 6.72 (d, I=8Hz, IH), 6.80-6.88 (m, 3H), 7.03 (d, I=2Hz, IH), 7.22 (d, I=9Hz, 2H).
Example 38 trans.trans-2-(4-Methoxyphenyl)-4-(1 -benzodioxol-5-yl -l-(N-cyclopropylmethyl-N- propylaminocai"bonylmethyl)-pyrroHdine-3-carboxylic acid The title compound was prepared using the procedures described in Example 1. m.p.
167-169 °C. Rotational isomers were seen in the NMR. 1H NMR (CDCI3, 300 MHz) δ -0.1 (m), 0.05 (m), 0.12-0.25 (m), 0.32-0.51 (m), 0.67 and 0.74 (2 triplets, 3H), 0.90-1.00 (m), 1.20-1.55 (m), 2.72 (d, J=13Hz, IH), 2.85-3.29 (m, 4H), 3.30-3.50 (m, 3H), 3.52-3.62 (m, IH), 3.65-3.73 (2 doublets, J=10Hz, 2Hz, IH), 3.78 (s, 3H), 5.95 (2 singlets, 2H), 6.72 (2 doublets, 2H), 6.80-6.90 (m, 3H), 7.00 and 7.05 (2 doublets, J=9Hz, 2H). Example 39 t/'αns,tr-.ns-2-(4-Methoxyphenyl)-4-(1.3-benzodioxol-5-yl)-l-(N-methyl-N- pentylaminocarbonylmethyl)-pyrrolidine-3-carboxylic acid The title compound was prepared as an amorphous solid using the procedures described in Example 1. Rotational isomers were seen in the NMR. H NMR (CDCI3, 300
MHz) δ 0.85 (t, J=7Hz, 3H), 1.00-1.08 (m), 1.13-1.32 (m), 1.35-1,50 (m), 2.72-2.82 (2 doublets, I=13Hz, IH), 2.83 and 2.86 (2 singlets, 3H), 2.92-3.20 (m, 3H), 3.22-3.45 (m, 3H), 3.52-3.62 (m, IH), 3.72 (2 doublets, IH), 3.75 and 3.76 (2 singlets, 3H), 5.92 (2 singlets, 2H), 6.72 (d, J=8Hz, IH), 6.80-6.87 (m, 3H), 7.03 (2 doublets, I=2Hz, IH), 7.30 (d, J=9Hz, 2H).
Example 40 transJrans-2-(4-Methoxyphenyl)-4-( 3-benzodioxol-5-ylVl-(N,N- dnsobutylaminocarbonylmethyl)-pyrroHdine-3-carboxylic acid The title compound was prepared using the procedures described in Example 1. m.p.
141-143 °C. 1H MR (CDCI3, 300 MHz) δ 0.54 (d, J=7Hz, 3H), 0.70-0.90 (3 doublets, I=7Hz, 9H), 1.60-1.75 (m, IH), 1.90-2.02 (m, IH), 2.67 (d, I=13Hz, IH), 2.70 (d, J=13Hz, IH), 2.84 (dd, J=6Hz, 15Hz, IH), 2.96-3.06 (m, 2H), 3.20 (dd, I=9Hz, 15Hz, IH), 3.35 (dd, J=2Hz, 10Hz, IH), 3.44-3.60 (m, 4H), 3.70 (d, J=9Hz, IH), 3.79 (s, 3H), 5.94 (dd, J=2Hz, 2Hz, 2H), 6.72 (d, I=9Hz, IH), 6.82-6.90 (m, 3H), 7.03 (d, J=2Hz, IH), 7.31 (d, J=9Hz, 2H).
Example 41 trans. trans-2-(4-Methoxyphenyl)-4-( 1.3-benzodioxol-5-yl)- 1 -(N-methyl-N-(2- propynyl)aminocarbonylmethyl)-pyrroHdine-3-carboxylic acid
The title compound was prepared as an amorphous sohd using the procedures described in Example 1. Rotational isomers were seen in the NMR. H NMR (CDCI3, 300 MHz) δ 2.09 and 2.32 (2 triplets, I=2Hz, IH), 2.80-3.10 (m, 3H), 2.90 and 2.99 (2 singlets, 3H), 3.35-3.50 (m, 2H), 3.52-3.62 (m, IH), 3.78 (s, 3H), 4.03 (d, I=13Hz, IH), 4.00-4.30 (m, 3H), 5.93 (s, 2H), 6.72 (2 doublets, J=8Hz, IH), 6.80-6.90 (m, 3H), 7.02 and 7.11 (2 doublets, J = 2Hz, IH), 7.30 (2 doublets, I=9Hz, 2H).
Example 42 trans. trans-2-(4-Methoxyphenyl)-4-( 1 ,3-benzodioxol-5-yl)- 1 -(N-methyl-N-(n- hexyl aminocarbonylmethyl)-pyrrolidine-3-carboxy lie acid The title compound was prepared as an amorphous solid using the procedures described in Example 1. 1H NMR (CDC13, 300 MHz) δ 0.85 (2 triplets, I=7Hz, 3H), 1.00-
1.50 (m, 8H), 2.72-2.82 (2 doublets, I=13Hz, IH), 2.81 and 2.86 (2 singlets, 3H), 2.92-3.20 (m, 3H), 3.22-3.45 (m, 3H), 3.52-3.62 (m, IH), 3.72 (2 doublets, IH), 3.75 and 3.76 (2 singlets 3H), 5.94 (2 singlets, 2H), 6.72 (d, I=8Hz, IH), 6.80-6.87 (m, 3H), 7.03 (2 doublets, I=2Hz, IH), 7.30 (d, I=9Hz, IH).
Example 43 trans.tr-.ns-2-(4-Methoxyphenyl)-4-(1.3-benzodioxol-5-yl)-l-fN.N-- /t - butyl)aminocarbonylmethyl)-pyiΥo]idine-3-carboxylic acid
The title compound was prepared using the procedures described in Example 1. mp. 123-125 °C. 1H ΝMR (CDCI3, 300 MHz) δ 0.79 (t, I=7Hz, 3H), 0.85 (t, I=7Hz, 3H), 1.00- 1.50 (m, 8H), 2.74 (d, J=13Hz, IH), 2.90-3.09 (m, 4H), 3.23-3.50 (m, 3H), 3.38 (d, I=13Hz, IH), 3.52-3.62 (m, IH), 3.75 (d, =10 Hz, IH), 3.78 (s, 3H), 5.93 (dd, J=2Hz, 4Hz), 6.71 (d, I=8Hz, IH), 6.81-6.89 (m, 3H), 7.03 (d, J=2Hz, IH), 7.30 (d, J=9 Hz, 2H). MS
(DCI/NΗ3) m/e 511 (M+H)+. Anal calcd for C29H38N2O6: C, 68.21; H, 7.50; N, 5.49. Found: C, 68.07; H, 7.47; N, 5.40.
Example 44 tr-.nsJrans-2-(4-Methoxyphenyl)-4-(l,3-benzodioxol-5-yl)-l-(N,N- diethylaminocarbonylmethylVpyrroUdine-3-carboxylic acid The title compound was prepared using the procedures described in Example 1. p. 132-134 °C. ^NMR CDO , 300 MHz) δ 0.98 (t, J=7Hz, 3H), 1.06 (t, I=7Hz, 3H), 2.78 (d, =13 Hz, IH), 2.95-3.20 (m, 4H), 3.30-3.50 (m, 4H), 3.55-3.65 ( , IH), 3.76 (d, J=12 Hz, IH), 3.79 (s, 3H), 5.93 (s, 2H), 6.72 (d, J=8Hz, IH), 6.80-6.90 (m, 3H), 7.02 (d, I=2Hz, IH), 7.32 (d, J=9Hz, 2H).
Example 45 transJr-.ns-2-(4-Methoxyphenyl -4-(l,3-benzodioxol-5-yl)-l-(N-methyl-N- phenylaminocarbonylmethyl)-pyrroHdine-3-carboxylic acid
The title compound was prepared as an amorphous sohd using the procedures described in Example 1. 1H NMR (CD3OD, 300 MHz) . 2.75-2.85 (m, 2H), 3.05-3.13 (m, IH), 3.18 (s, 3H), 3.40-3.58 (m, 2H), 3.78 (s, 3H), 3.88 (d, I=12Hz, IH), 5.92 (s, 2H), 6.72 (d, J=8Hz, IH), 6.75-6.85 (m, 3H), 7.00-7.12 (m, 5H), 7.82-7.92 (m, 3H).
Example 46 trans.tra?zs-2-(4-Methoxyphenyl)-4-(l,3-benzodioxol-5-yl)-l-(N-methyl-N- cyclohexylaminocarbonylmethyl -pyrroHdine-3-carboxylic acid The title compound was prepared as an amorphous solid using the procedures described in Example 1. Rotational isomers were seen in the NMR. H NMR (CD3OD, 300 MHz) δ 1.00-1.85 (m, 10H), 2.72 and 2.78 (2 singlets, 3H), 2.75-2.82 (2 doublets, I=12Hz, IH), 2.96-3.22 (m, 3H), 3.40-3.65 (m, 3H), 3.68 and 3.82 (2 doublets, J=10Hz, IH), 3.77 and 3.78 (2 singlets, 3H), 5.92 (s, 2H), 6.72 (2 doublets, J=8Hz, IH), 6.82-6.88 (m, 3H), 7.02 (2 doublets, J=2Hz, IH), 7.30-7.40 (2 doublets, I=9Hz, 2H).
Example 47 trans.tr-.ns-2-(4-Methoxyphenyl)-4-(l,3-benzodioxol-5-yl)-l-(N,N-di(n- propyl)aminocarbonyHnethyl)-pyrroUdine-3-carboxylic acid The title compound was prepared using the procedures described in Example 1. mp. 170-172 °C. 1HNMR (CDCI3, 300 MHz) δ 0.69 (t, J=7Hz, 3H), 0.85 (t, I=7Hz, 3H), 1.20- 1.55 ( , 4H), 2.72 (d, I=13Hz, IH), 2.90-3.10 (m, 4H), 3.25-3.47 ( , 4H), 3.35-3.62 (m, IH), 3.72 (d, J=9Hz, IH), 3.79 (s, 3H), 5.94 (s, 2H), 6.72 (d, d, J=8Hz, IH), 6.80-6.90 (m, 3H), 7.02 (d, J=2Hz, IH), 7.30 (d, J=9Hz, 2H).
Example 48 trans.trans-2-(4-Methoxyphenyl)-4-(l,3-benzodioxol-5-yl)-l-(N-methyl-N- isobutylaminocarbonylmethyl -pyrroUdine-3-carboxylic acid The title compound was prepared as an amorphous sohd using the procedures described in Example 1. Rotational isomers were seen in the NMR. 1H NMR (CD3OD, 300 MHz) δ 0.65-0.85 (4 doublets, I=7Hz, 6H), 1.75-1.95 (m, IH), 2.80 and 2.90 (2 singlets, 3H), 2.90-3.10 (m, 4H), 3.10-3.65 (m, 4H), 3.74 9S, 3H), 3.81 and 3,88 (2 doublets, I=10Hz, IH), 5.93 (s, 2H), 6.72 (d, I=8Hz, IH), 6.80-6.90 (m, 3H), 7.02 (2 doublets, J=2Hz, IH), 7.80-7.90 (2 doublets, J=9Hz, 2H).
Example 49 Alternate Prepration of
Ethyl 2-(4-methoxybenzoyl)-4-nitromethyl-3-( 1 ,3-benzodioxole-5-yl)butyrate
Example 49A E-2-(3.4-MethylenedioxyphenyD- 1 -nitroethene To a stirred solution of piperonal (75g, 500 mmol) in methanol (120 mL) at 10 °C was added nitromethane (27.1 mL, 500 mmol, 1 eq) foUowed by the dropwise addition of sodium hydroxide (21 g, 525 mmol, 1.05 eq) in sufficient water to achieve a total volume of 50 mL whUe maintaining the temperature between 10-15 °C. The reaction mixture became cloudy, turning to a thick paste. The mixture was stirred for 30 minutes upon completion of the addition, and the mixture was then diluted with ice-water (-350 mL) maintaining the temperature below 5 °C, until solution was achieved. The resultant solution was poured in a narrow stream (such that it just failed to break into drops) into a rapidly stirred solution of 36% hydrochloric acid (100 mL) in water (150 mL). A yellow sohd precipitated (nitrostyrene), and this was collected by filtration, washed with water (1.5 L) until the filtrate was neutral. The filter cake was air dried and then recrystalHzed from hot ethanol (3 L) to yield E-2-(3,4-methylenedioxy)-nitrostyrene as yellow needles (53 g, 55%). XH NMR (300MHz, CDC13) 7.94 (IH, d, I=13.5Hz), 7.47 (IH, d, I=13.5Hz), 7.09 (IH, dd, I=7.5&2Hz), 7.01 (IH, d, J=2Hz), 6.87 (IH, d, J=7.5Hz), 6.06 (2H, s). MS (DCI/NH3) m/e 194 (M+H)+, 211 (M+H+NH3)+
Example 49B Ethyl 2-(4-methoxyphenyl)oxo-4-nitro-3-(3,4-methylenedioxyphenyl butyrate To a stirred solution of the nitrostyrene resulting from Example 49A (14.17 g, 73.34 mmol, 1.2 eq) in a mixture of propan-2-ol (75 mL) and tetrahydrofuran (175 mL) at room temperature was added successively a solution of ethyl (4-methoxybenzoyl) acetate (11.5 g, 51.7 mmol) in THF (50 mL) foUowed by l,8-diazabicyclo[5,4,0]undec-7-ene (DBU) (0.45 mL, 3.0 mmol, 0.05 eq). The resultant mixture was stirred at room temperature for 1 hour, then additional DBU (0.45 L, 3.0 mmol, 0.05 eq) was added. The mixture was stirred a further 1 hour, then the volatUes were removed in vacuo and the residue purified by flash chromatography on 500 g silica gel, eluting with 20% ethyl acetate-hexanes changing to 25% ethyl acetate-hexanes as the product eluted. The solvents, were removed in vacuo to yield the nitroketoester (19.36 g, 76%) as a viscous oU. Diastereomers were seen in the NMR. *H NMR (300 MHz, CDCI3,) δ 8.06 (2H, d, J=9Hz), 7.89 (2H, d, J=9Hz), 6.96 (2H, d, I=9Hz),
6.91 (2H, d, I=9Hz), 6.77 (IH, dd, J=9Hz,3Hz), 6.73 (IH, d, J=9Hz), 6.65 (IH, d, J=3Hz), 5.95 (2H, s), 5.89 (IH, d, J=4Hz), 5.88 (IH, d, I=4Hz), 4.90-4.60 (3H, m), 4.39 (IH, m), 4.18 (2H, q, J=7Hz), 3.94 (2H, ), 3.80 (3H, s), 3.78 (3H, s), 1.19 (3H, t, J=7Hz), 0.99 (3H, t, J=7Hz), MS (DCI/NH3) m/e 416 (M+H)+, 433 (M+H+NH3)+
Example 50 trans. trans-2-(4-Methoxyphenyl)-4-( 1 ,3-benzodioxol-5-yl)- 1 -( t-butyloxycarbonylmethyl)- pyrroHdine-3 -carboxylic acid To a stirred solution of the compound resulting from Example IC (100 mg, 0.27 mmol) in acetonitrUe (2. mL was added successively diisopropylethylamine. (70 δ L, 0.40 mmol, 1.5 eq) and t-butyl bromoacetate (48 δ L, 0.29 mmol, 1.1 eq). The mixture was stirred 2 hours, then the solvent was removed in vacuo to yield the crude diester. To a stirred solution of the diester in ethanol (1 mL) at room temperature was added 50% w/w sodium hydroxide (300 mg, 3.75mmol) in water. The mixture was stirred 2 hours, then the volatiles were removed in vacuo. The residue was dissolved in water (5 mL), and the solution was washed with ether. The aqueous phase was acidified with acetic acid (300 δ L), and then extracted with ethyl acetate (2x). The combined organic extracts were dried (Na2SO_ι), filtered, and concentrated to yield the title compound (74 mg, 60%) as a white sohd. *H
NMR (300 MHz, CDC13) δ 7.36 (2H, d, J=8Hz), 7.13 (IH, d, J=3Hz), 6.90 (IH, dt, J=3Hz,
8Hz), 6.88 (2H, d, I=8Hz), 6.76 (IH, d, I=8Hz), 5.96 (2H, s), 3.96 (IH, d, I=9Hz), 3.81 (3H, s), 3.58 (IH, ddd, J=12, 10Hz,3Hz), 3.52 (IH, dd, J=9Hz,3Hz), 3.32 (IH, d, J=17Hz), 3.08 (IH, t, I=10Hz), 2.92 (IH, dd, J=9Hz,7Hz), 2.83 (IH, d, J=17Hz). MS (DCI/NH3) m/e 456 (M+H)+.
Anal calc for C29H29NO7 • 0.3 H2O: C, 65.07; H, 6.48; N, 3.04. Found: C, 65.02; H, 6.42;
N, 2.93.
Example 51 trans. trans-2-(4-MethoxyphenylV4-( 1 -naphthyl)- 1 -(N-methyl-N- propyl)aminocarbonylmethyl)-pyrrolidine-3-carboxy lie acid The title compound was prepared by the procedures described in Examples 1 and 49 substituting naphthalene- 1 -carboxaldehyde for piperonyl in Example 49 A. Rotational isomers are seen in the NMR. *H NMR (300 MHz, CDCI3) 8.29 (IH, bd, J=8Hz), 7.86 (2H, d, I=8Hz),7.75 (IH, d, J=8Hz), 7.49 (3H, m), 7.34 (2H, dd, I=3Hz,9Hz), 6.83 (2H, dd, J=9Hz,2Hz), 4.50 (IH, m), 3.94 (IH, dd, I=9Hz,2Hz), 3.78 (3H, s), 3.65 (IH, m), 3.49 (IH, d, J=14Hz), 3.40-2.93 (5H, m), 2.91, 2.83 (3H, s), 1.48 (2H, sept, J=7Hz), 0.83, 0.77 (3H, t, J=7Hz). MS (DCI/NH3) m/e 461 (M+H)+. Anal calcd for C29H29NO7 • 0.5 HOAc: C, 71.00; H, 6.99; N, 5.71. Found: C, 70.95; H, 7.00; N, 5.46.
Example 52 trans,trans-2-(4-Methoxyphenyl)-4-(2,3-(Hhydrobenzofuran-5-yl)-l-(N-methyl-N- propyl)aminocarbonylm.ethyl)-pyrrolidine-3-carboxylic acid
Example 52A
2,3-Dihydrobenzofuran-5-carboxaldehyde To a stirred solution of α,α -dichloromethyl methyl ether (2.15 g, 19 mmol, 1.35 eq) in methylene chloride (30 mL) at -40 °C was added successively stannic chloride (1.65 g, 17 mmol, 1.2 eq) and 15 minutes later, a solution of 2,3-dihydrobenzofuran (1.68 g, 14 mmol) in CH2CI2 (5 mL) maintaining the temperature at or below -35 °C. The mixture was warmed to 0 °C, stirred 1 hour, then poured into ice-water, and stirred a further 30 minutes. The mixture was dUuted with ether, and the phases separated. The organic phase was concentrated in vacuo, and the residue purified by vacuum distillation to yield the title compound (1.25 g, 60%) as a colorless liquid, b.p. 119-121 °C at 0.3 mmHg.
Example 52B trαns.tr_-ns-2-(4-Methoxyphenyl)-4-(2,3-dihydrobenzofuran-5-ylVl-(N-methyl-N- propyl)aminocarbonylmethyl)-pyrroUdine-3-carboxylic acid The title compound was prepared by the procedures described in Examples 1 and 49 substituting the compound resulting from Example 52A for piperonal in Example 49A. Rotational isomers are seen in the NMR. lH NMR (300 MHz, CDCI3) δ 7.33 (IH, d,
I=8Hz), 7.28 (IH, m), 7.19 (IH, m), 6.87 (IH, d, J=8Hz), 6.73 (IH, d, I=8Hz), 4.56 (IH, t, J=8Hz), 3.83 (IH, d, I=10Hz), 3.80 (3H, s), 3.63 (IH, m), 3.4-3.0 (9H, m), 2.87, 2.84 (3H, s), 1.51 (2H, septet, I=7Hz), 0.88, 0.78 (3H, t, I=7Hz). MS (DCI/NH3) m/e 453 (M+H)+ Anal calc for C26H32N2O5 • 0.25 H2O: C, 68.33; H, 7.17; N, 6.13. Found: C, 68.60; H, 6.88; N, 5.80.
Example 53 trans.tr-.ns-2.4-Bis(4-methoxyphenyl)-l-( -methyl-N-propyl)aminocarbonylmethyl)- pyrrolidine-3 -carboxylic acid The title compound was prepared by the procedures described in Examples 1 and 49 substituting 4-methoxybenzaldehyde for piperonal in Example 49 A. Rotational isomers are seen in the NMR. lH NMR (300 MHz, CDCI3) δ 7.37 (2H, d, 1=7.5 Hz), 7.32 (2H, d, J=7.5
Hz), 6.86 (4H, m), 3.83 (IH, m), 3.81 (3H, s), 3.79 (3H, s), 3.64 (IH, m), 3.48-2.97 (6H, m), 2.87, 2.83 (3H, s), 2.85 (IH, m), 1.45 (2H, m), 0.84, 0.74 (3H, t, J=7.5 Hz). MS (DCI/NH3) m/e 441 (M+H)+. Anal calc for C25H32N2O5 • 0.5 H2O: C, 66.80; H, 7.40; N, 6.23. Found:
C, 67.15; H, 7.31; N, 6.00.
Example 54 trans. trans-2-(4-Methoxyphenyl)-4-(3 ,4-dimethoxyphenyl)- 1 -(N-methyl-N- propyl)aminocarbonylmethyl)-pyrroHdine-3-carboxylic acid The title compound was prepared by the procedures described in Examples 1 and 49 substituting 3,4-dimethoxybenzaldehyde for piperonal in Example 49A. Rotational isomers are seen in the NMR. *H NMR (300 MHz, CDC13) δ 7.33 (2H, d, J=7.5 Hz), 7.07 (IH, d,
J=2.0 Hz), 6.98 (IH, m), 6.85 (IH, d, 7.5 Hz), 6.82 (2H, d, 7.5 Hz), 3.91 (3H, s), 3.86 (3H, s), 3.83 (IH, m), 3.79 (3H, s), 3.64 (IH, m), 3.50-2.95 (6H, m), 2.87 (IH, m), 2.85, 2.83 (3H, s), 1.45 (2H, m), 0.84, 0.74 (3H, t, J=7.5 Hz). MS (DCI/NH3) m/e 471 (M+H)+ Anal calc for C26H34N2O6 • 0.5 H2O: C, 65.12; H, 7.36; N, 5.84. Found: C, 65.22; H, 7.27; N, 5.59.
Example 55 trans,trans-2-(4-Methoxyphenyl -4-(3-methoχyphenyl)-l-(N-methyl-N- propyl)aminocarbonylmethyl -pyrrolidine-3-carboxylic acid The title compound was prepared by the procedures described in Examples 1 and 49 substituting 3-methoxybenzaldehyde for piperonal in Example 49A. Rotational isomers are seen in the NMR. *H NMR (300 MHz, CDCI3) δ 7.33 (2H, d, =7.5 Hz), 7.24 (IH, t, =7.5 Hz), 7.05 (2H, m), 6.85 (2H, dd, I=7.5&2 Hz), 6.76 (IH, m), 3.83 (IH, m), 3.81 (3H, s), 3.79 (3H, s), 3.64 (IH, m), 3.48-2.97 (6H, m), 2.87, 2.83 (3H, s), 2.85 (IH, m), 1.45 (2H, m), 0.84, 0.74 (3H, t, J=7.5 Hz). MS (DCI NH3) m/e 441 (M+H)+. Anal calc for C25H32N2O5 • 0.5 H2O: C, 66.80; H, 7.40; N, 6.23. Found: C, 66.76; H, 7.36; N, 6.05.
Example 56 trans. tr-.ns-2-(4-MethoxyphenyB-4-(2-naphthyl)- 1 -(N-methyl-N- propyl)aminocarbonylmethyl)-pyrroHdine-3-carboxy lie acid The title compound was prepared by the procedures described in Examples 1 and 49 substituting naphthylene-2-carboxaldehyde for piperonal in Example 49 A. Rotational isomers are seen in the NMR. 2H NMR (300 MHz, CDCI3) δ 7.82 (4H, m), 7.69 (IH, m), 7.47 (2H, m), 7.37 (2H, dd, I=7.5&2 Hz), 6.85 (2H, dd, I=7.5&2 Hz), 3.90 (IH, d, J=8 Hz), 3.78 (3H, s), 3.57 (IH, m), 3.52-2.97 (6H, m), 2.93, 2.85 (3H, s), 2.90 (IH, m), 1.52 (2H, m), 0.86, 0.76 (3H, t, J=7.5 Hz). MS (DCI/NH3) m e 461 (M+H)+. Anal calc for C28H32 2O4 •
0.5 H2O: C, 71.62; H, 7.08; N, 5.97. Found: C, 71.58; H, 7.11; N, 6.01.
Example 57 trans.trans-2-(4-Methoxyphenyl)-4-(l,3-benzodioxol-5-yl)-l-(2-(ethylsulfinyl)ethyl)- pyrroHdine-3-carboxylic acid To the compound resulting from Example IC (100 mg, 0.27 mmol) and 2-chloroethyl ethyl sulfide (67.5 mg, 0.5 mmol, 2 equivalents) dissolved in 6 mL of acetonitrile was added 10 mg of KI and 0.5 mL of diisopropylethylamine. The mixture was refluxed for 4 hours and then concentrated in vacuo. The residue obtained was purified by flash chromatography on sUica gel eluting with 4: 1 hexane-ethyl acetate to afford 93 mg (75%) of the ethylthioethyl compound. To the sulfide (90 mg, 0.2 mmol) dissolved in 5 mL of CH2C12 in an ice bath was added 68 mg of 3-chloroperoxybenzoic acid. The mixture was stirred for 40 minutes in the ice bath and for 3 hours at room temperature. A 10% solution of sodium hydroxide (2 mL) was added, and the mixture was extracted with EtOAc (2 x 50 mL). The combined organic extracts were washed with water and brine, dried over sodium sulfate and concentrated in vacuo. The residue obtained was chromatographed on silica gel eluting with EtOAc and 10% MeOH in CH2C12 to afford the sulfoxide (62 mg, 65%).
The ethyl ester was hydrolyzed by the procedure described in Example ID to afford the title compound as a diastereomeric mixture, mp. 61-63 °C. MS (DCI/NH3) m/e 446
(M+H)+. 1HNMR (CDCI3, 300 MHz) 1.25, 1.32 (t, J=9Hz, 3H), 2.45-2.75 (m, 4H), 2.84- 2.96 (m, 3H), 3.02-3.08 (m, IH), 3.32, 3.36 (d, J=3Hz, IH), 3.47-3.58 (m, 2H), 3.65, 3.68 (d, I=7.5Hz, IH), 3.76, 3.80 (s, 3H), 5.94 (s, 2H), 6.72 (d, I=7.5Hz, IH), 3.84-3.89 (m, 3H), 7.02 (d, I=6Hz, IH), 7.30, 7.34 (d, I=7.5Hz, 2H).
Example 58 trans, trans-2-(4-Methoxyphenyl)-4-( 1 ,3-benzodioxol-5-yl)- 1 -(2-
(isopropylsulfonylamino ethyl)-pyrroHdine-3-carboxylic acid To 2-bromoethylamine hydrobromide (1 mmol) suspended in anhydrous CH3CN was added 1 equivalent of Et3N. The mixture was stirred for 30 minutes and then 1 equivalent of isopropyl sulfonyl chloride and 1 equivalent of Et3N were added. The resulting mixture was stirred for 2 hours at room temperature and then added to a solution of the compound resulting from Example IC (185 mg, 0.5 mmol) in 3 mL of CH3CN. The mixture was warmed at 50-60 °C for 2 hours, cooled to room temperature, treated with water and extracted with EtOAc. The combined organic extracts were washed with water and brine, dried and concentrated in vacuo. The residue obtained was chromatographed on sUica gel eluting with 3:2 hexane-EtOAc to give 195 mg (75%) of the ethyl ester. The ethyl ester (160 mg, 0.31 mmol) was hydrolyzed by the procedure described in Example ID to afford the title compound (133 mg, 88%). mp. 94-96 °C. 1HNMR (CD3OD, 300 MHz) δ 1.26 (d, I=6Hz, 6H), 1.97 (s, IH), 2.38 (m, IH), 2.77 (m, IH), 2.88 (t, I=9Hz, IH), 3.04 (m, IH), 3.14 (t, J=7.5Hz, 2H), 3.35 (m, 2H), 3.46 (m, IH), 3.58 (m, IH), 3.78 (s, 3H), 5.92 (s, 2H), 6.74 (d, J=9Hz, IH), 6.86 (dd, I=9Hz,3Hz, IH), 6.92 (d, J=9Hz, 2H), 7.00 (d, I=3Hz, IH), 7.36 (d, J=9Hz, 2H). MS (DCI/NH3) m/e (M+H)+. Example 59 tr-.ns.tr-.ns-2-(4-Methoxyphenyl)-4-(l,3-benzodioxol-5-yl)-l-(2-(isobutoxy)ethyl)- pyrroHdine-3 -carboxylic acid The title compound was prepared by the procedures described in Example ID from the compound resulting from Example IC and 2-(isobutoxy) ethyl bromide. m.p. 68-70 °C. 1HNMR (CDC13, 300 MHz) δ 0.88 (d, J=6Hz, 6H), 1.82 (quintet, I=6Hz, IH), 2.22 (m, 2H), 2.72-2.79 (m, IH), 2.86-2.95 (m, 2H), 3.13 (d, J=6Hz, 2H), 3.45-3.56 (m, 4H), 3.68 (d, I=9Hz, IH), 3.79 (s, 3H), 5.94 (s, 2H), 6.72 (d, J=7.5Hz, IH), 6.85 (dd, I=9Hz, 7.5 Hz, 3H), 7.08 (s, IH), 7.34 (d, J=9Hz, 2H). MS (DCI NH3) m/e 442 (M+H)+.
Example 60 trans. trans-2-(4-Methoxyphenyl)-4-(l .3-benzodioxol-5-yl)- 1 -(butylsulfonyl)-pyrroHdine-3- carboxylic acid To 100 mg (0.271 mmol) of the compound resulting from Example IC dissolved in
10 mL of THF was added 1-butanesulfonyl chloride (46.7 mg, 1.1 equivalents) and diisopropylethylamine (53 mg, 1.5 equivalents). The resulting mixture was stirred for 2.5 hours at room temperature and then the solvent evaporated. The crude product was purified by flash chromatography on sUica gel eluting with 3:2 hexane-EtOAc to afford 120 mg (90%) of the ethyl ester.
The ester (120 mg, 0.244 mmol) was dissolved in 1 mL of EtOH, and a solution of 100 mg of NaOH in 1 mL of water was added. The mixture was stirred for 3 hours at room temperature and then concentrated under reduced pressure. Water (5 mL) was added and the solution was washed with ether to remove any unhydrolyzed trans-cis isomer. The aqueous solution was acidified to pH~6 with acetic acid and then extracted with EtOAc (2 x 50 mL). The combined organic extracts were washed with brine, dried over sodium sulfate and concentrated under reduced pressure to afford the pure title compound (60 mg, 53%) as a white sohd. mp. 67-69 °C. 1H NMR (CDCI3, 300 MHz) δ 0.82 (t, I=7.5Hz, 3H), 1.20-1.33 (m, 2H), 1.58-1.68 (m, 2H), 2.48-2.69 (m, 2H), 3.28 (dd, I=9Hz, IH), 3.49 (t, J=12Hz, IH), 3.65 (dd, J=12Hz, IH), 3.82 (s, 3H), 4.32 (dd, I=12Hz, IH), 5.17 (d, I=9Hz, 2H), 5.95 (s, 2H), 6.70-6.78 (m, 3H), 6.92 (d, I=9Hz, 2H), 7.35 (d, J=9Hz, 2H). MS (DCI/NH3) m/e 462
(M+H)+.
Example 61 trans. tr__ns-2-(4-Methoxyphenyl)-4-( 1.3-benzodioxol-5-yl)- 1 -(2-(N-methyl-N- isopropylcarbonylamino.ethyl pyrroHdine-3-carboxylic acid Example 61 A trans.trαns-2-(4-Methoxyphenyl)-4-(1 -benzodioxol-5-yl)-l-(2-bromoethyl)-pyrroHdine-3- carboxylic acid ethyl ester To the mixture of cis,trans and transjrans pyrroHdines resulting from Example IC
(400 mg) dissolved in 9 mL of 1,2-dibromoethane was added 0.7 mL of dnsopropylethylamine and 30 mg of sodium iodide. The resultant mixture was heated at 100 °C for 1 hour, and then the solvents were removed in vacuo. The residue was taken up in EtOAc and washed sequentially with water and brine, dried and concentrated under reduced pressure. The crude product was purified by flash chromatography on silica gel eluting with 4: 1 hexane-EtOAc to give 470 mg of the title product.
Example 6 IB transJrans-2-(4-MethoxyphenylV4-(1.3-benzodioxol-5-yl)-l-(2-(methylamino)ethyl)- pyrroHdine-3 -carboxylic acid ethyl ester
To the compound resulting from Example 61 A (450 mg) dissolved in 10 mL of EtOH was added 0.5 mL of 40% aqueous methylamine and 50 mg of sodium iodide. The mixture was heated at 80 °C for 1 hour, and then the solvents were removed in vacuo. The residue was taken up in EtOAc and washed sequentially with water and brine, dried and concentrated in vacuo. The resultant product was carried on without further purification.
Example 61C trans. trans-2-(4-Methoxyphenyl)-4-( 1 ,3-benzodioxol-5-yD- 1 -(2-(N-methyl-N- isobutyrylamino)ethylVpyrroUdine-3-carboxylic acid To the compound resulting from Example 61B (~150 mg) dissolved in 5 mL of 1,2- dichloroethane was added 0.3 mL of dnsopropylethylamine. The solution was cooled to -40 °C, isobutyryl chloride (0.17 mL) was added, the bath was removed, and the solution was aUowed to warm to ambient temperature and stirred for 15 hours. The solvent was removed in vacuo; the residue was taken up in EtOAc and washed sequentially with 1 : 1 sodium bicarbonate solution/water and brine, dried and concentrated in vacuo. The product was purified by flash chromatography on silica gel eluting with a gradient 1 : 1 EtOAc-hexanes going to EtOAc and finally using 10% MeOH-EtOAc.
The ester was dissolved in 1.5 mL of EtOH; 0.75 mL of a 17% aqueous NaOH solution was added, and the resultant mixture was stirred at ambient temperature for 3 hours. The solvents were removed in vacuo; the residue was taken up in water and washed with ether. The aqueous phase was acidified with 1 N H3PO4 to pH 3 and extracted twice with ether. The combined organic extracts were washed with brine and dried over Na2SO4. The solvents were removed in vacuo to provide 82 mg of the title compound as a white foam. Rotamers were seen in the NMR. 1H NMR (CDCI3, 300 MHz) of the major rotamer 1.06
(d, 3H, J=10Hz), 1.12 (d, 3H, J=10Hz), 2.15 (m, IH), 2.5-3.0 (m, 3H), 2.91 (s, 3H), 3.32 (m, 2H), 3.50 (m, 2H), 3.65 (m, 2H), 3.77 (s, 3H), 5.92 (s, 2H), 6.73 (d, IH, I=8Hz), 6.75-6.9 (m, 4H), 6.96 (d, IH, I=2Hz), 7.29 (m, IH). MS (DCI NH3) m/z 469 (M+H)+. Analysis calcd for C26H32N2O6 • 0.3 TFA: C, 63.55; H, 6.48; N, 5.57. Found: C, 63.44; H, 6.71; N, 5.24.
Example 62 trans. trans-2-(4-Methoxyphenyl)-4-( 1 ,3-benzodioxol-5-yl)- 1 -(2-(N-methyl-N- propionylamino)ethyl)-pyrroHdine-3-carboxyHc acid The title compound was prepared by the procedures described in Example 61 substituting propionyl chloride for isobutyryl chloride in Example 61C. H NMR (CDCI3, 300 MHz) of the major rotamer 1.13 (t, 3H, I=8Hz), 2.19 (m, IH), 2.30 (m, 2H), 2.65-3.0 (m, 3H), 2.85 (s, 3H), 3.25-3.4 (m, 2H), 3.5-3.7 (m, 3H), 3.79 (s, 3H), 5.92 (s, 2H), 6.74 (d, IH, I=8Hz), 6.75-6.9 (m, 4H), 7.00 (bd s, IH), 7.29 (bd s, IH). MS (DCI NH3) m/z 455 (M+H)+. Analysis calcd for C25H3oN2O6 • 1.0 H2O: C, 63.55; H, 6.83; N, 5.93 . Found: C, 63.55; H, 6.52; N, 5.73.
Example 63 trans, trgns-2-(4-Methoxyphenyl)-4-( 1 ,3-benzodioxol-5-yl)- 1 -(N-methyl-N- benzylaminocarbonylmethylVpyrroHdine-3-carboxylic acid Using the procedures described in Example 1 the title compound was prepared. H NMR (CDCI3, 300 MHz) of the major rotamer δ 2.79 (s, 3H), 2.8-3.2 (m, 2H), 3.48 (m, 2H), 3.61 (m, 2H), 3.77 (s, 3H), 3.78 (m, IH), 4.3-4.5 (m, 2H), 5.95 (d, 2H, J=2Hz), 6.7-6.9 (m, 4H), 7.00 (m, IH), 7.15-7.35 (m, 7H). MS (FAB/NBA) m/z 503 (M+H)+. Anal calcd for C29H3oN2O6 • 0.5 H2O: C, 68.36; H,5.74; N, 5.50. Found: C.68.41; H, 5.74; N, 5.36 .
Example 64 trans.trans-2-(4-Methoxyphenyl -4-(L3-benzodioxol-5-yl)-l-(N-ethyl-N- butylaminocarbonylmethyl -pyrroHdine-3-carboxy lie acid Using the procedures described in Example 1 the title compound was prepared. 1H NMR (CDCI3, 300 MHz) of the major rotamer δ 0.88 (t, 3H, J=7Hz), 1.06 (t, 3H, J=7Hz),
1.27 (m, 2H), 1.45 (m, 2H), 2.8-3.6 (m, 11H), 3.79 (s,3H), 3.80 (m, IH), 5.92 (bd s, 2H), 6.75 (d, IH, I=8Hz), 6.85 (d, IH, J=8Hz), 6.92 (d, 2H, I=8Hz), 7.03 (s, IH), 7.33 (d, IH, I=8Hz). MS (DCI/NH3) m/z 483 (M+H)+ Anal calcd for C27H34N2O6 • 0.5 HOAc: C, 65.61; H,7.08; N, 5.46. Found: C,65.51; H, 6.70; N, 5.66.
Example 65 trαns.trans-2-(4-Methoxyphenyl)-4-(1 -benzodioxol-5-ylVl-(N-methyl-N-(2,2- dimethylpropyl)aminocarbonylmethylVpyrroUdine-3-carboxylic acid Using the procedures described in Example 1 the title compound was prepared. H NMR (CDC1 , 300 MHz) of the major rotamer δ 0.90 (s, 9H), 2.8-3.1 (m, 4H), 2.94 (s, 3H), 3.3-3.5 (m, 3H), 3.61 (m, IH), 3.80 (s, 3H), 3.82 (m, IH), 5.94 (bd s, 2H), 6.74 (d, IH, J=8Hz), 6.86 (d, 2H, J=8Hz), 6.87 (m, IH), 7.03 (d, IH, J=2Hz), 7.33 (d, 2H, J=8Hz). MS (DCI/NH3) m/z 483 (M+H)+.
Example 66 . trans.tr-,ns-2-(4-Methoxyphenyl)-4-(1.3-benzodioxol-5-yl)-l-(2-(N-methyl-N- butylsulfonylamino.ethyl)-pyrroHdine-3-carboxy lie acid
To the compound resulting from Example 61B (60 mg, 0.13 mmol) dissolved in 5 mL of CH3CN was added 0.2 mL of Et3N and 22 mg (0.143 mmol, 1.1 equivalents) of 1- butanesulfonyl chloride. The mixture was stirred for 1 hour at room temperature and then concentrated in vacuo. The crude product was purified by column chromatography on silica gel eluting with 1 : 1 EtOAc-hexane to yield 64 mg (90%) of the ester. Ester hydrolysis by the procedure described in Example ID afforded the title compound. m.p. 64-66 °C. H NMR (CDCI3, 300 MHz) δ 0.92 (t, J=7.5Hz, 3H), 1.39 (hexad, I=7.5Hz, 2H), 1.68-1.76 (m, 2H),
2.16-2.25 (m, IH), 2.72 (s, 3H), 2.75-2.92 (m, 5H), 3.12-3.20 (m, IH), 3.25-3.34 (m, IH), 3.46-3.55 (m, 2H), 3.65 (d, J=9Hz, IH), 3.78 (s, 3H), 5.53 (s, 2H), 6.72 (d, J=7.5Hz, IH), 6.82.(dd, I=7.5Hz,3Hz, IH), 6.86 (d, I=9Hz, 2H), 7.02 (d, I=3Hz, IH), 7.34 (d, I=9Hz, 2H). MS (DCI NH3) m/e 519 (M+H)+.
Example 67 trans.tr-.ns-2-(4-Methoxyphenyl -4-(l,3-benzodioxol-5-yl)-l-(2-(N-methyl-N- propylsulfonylamino.ethyl)-pyrroHdine-3-carboxylic acid
The title compound was prepared by the procedures described in Example 66 substituting 1-propanesulfonyl chloride for 1-butanesulfonyl chloride. m.p. 69-70 °C. 1H NMR (CDCI3, 300 MHz) δ 1.02 (t, J=7.5Hz, 3H), 1.78 (hexad, J=7.5Hz, 2H), 2.18-2.26 (m, IH), 2.72 (s, 3H), 2.75-2.95 (m, 6H), 3.13-3.22 (m, IH), 3.25-3.35 (m, IH), 3.47-3.58 (m, 2H), 3.66 (d, J=9Hz, IH), 3.80 (s, 3H), 5.96 (s, 2H), 6.74 (d, I=7.5Hz, IH), 6.84 (d,d, I=7.5Hz, 3Hz, IH), 6.87 (d, J=9Hz, 2H), 7.04 (d, J=3Hz, IH), 7.43 (d, J=9Hz, 2H). MS (DCI NH3) m/e 505 (M+H)+.
Example 68 tr_.ns.trans-2-(4-Methoxyphenyl)-4-( 3-benzodioxol-5-yl -l-(2-(propylsulfonyl)ethyl)- pyrroUdine-3-carboxylic acid To 1-propanethiol (3.5 g, 46.05 mmol) dissolved in 10 mL of anhydrous THF was added 632 mg (26.32 mmol) of NaH in portions under a nitrogen atmosphere. The mixture was heated at 60-70 °C for 1 hours. To this mixture was added the compound resulting from Example 61A (180 mg, 0.38 mmol) in 2 mL THF. Heating was continued at 60-70 °C for an additional 2 hours, and then the volatiles were removed under reduced pressure. The crude propylthioethyl adduct was purified by flash chromatography on sUica gel eluting with 3:2 hexane-EtOAc to give 170 mg (95%).
To a solution of 170 mg (0.36 mmol) of the sulfide and 93 mg (0.8 mmol) of N- methylmorpholine N-oxide (NMO) in a mixture of 20 mL of acetone and 5 mL of H2O was added a solution of osmium tetroxide (10 mg) in 0.3 mL of t-butanol. The resulting mixture was stirred overnight at room temperature and then concentrated under reduced pressure. The residue was partitioned between EtOAc and H O. The organic phase was washed with brine, dried over Na2SO4 and concentrated in vacuo. Flash chromatography afforded 177 mg (98%) of the ethyl ester which was hydrolyzed by the procedures described in Example ID to afford the title compound, mp. 73-75 °C. 1H NMR (CDCI3, 300 MHz) 1.04 (t, J=7.5Hz, 3H), 1.78 (hexad, I=7.5Hz, 2H), 2.59-2.66 (m, IH), 2.84-3.08 (m, 7H), 3.43 (dd, J=9Hz, 3Hz, IH), 3.53-3.60 (m, IH), 3.68 (d, J=9Hz, IH), 3.82 (s, 3H), 5.96 (s, 2H), 6.75 (d, I=7.5Hz, IH), 6.82 (dd, I=7.5Hz, 3Hz, IH), 6.88 (d, J=9Hz, 2H), 6.99 (d, I=3Hz, IH), 7.32 (d, J=9Hz, 2H). MS (DCI/NH3) m/e 476 (M+H)+
Example 69 tr-.ns.trans-2-(4-Methoxyphenyl)-4-(l,3-benzodioxol-5-yl)-l-N-(tr-.ns-5-methylhex-2-enyl)- pyrrolidine-3-carboxylic acid
Example 69A tr_.ns-5-Methylhex-2-enoic acid ethyl ester OU dispersion sodium hydride (0.85 g) was washed with hexanes and suspended in THF (20 mL), and the mixture was cooled in an ice bath to 0 °C. Diisopropyl(ethoxycarbonylmethyl) phosphonate (5.0 mL) was added slowly and the mixture stirred for 20 minutes at 0 °C. Isovaleraldehyde (2.0 mL) in THF (5 mL) was added dropwise over five minutes. The ice bath was removed and the mixture stirred for 18 hours at ambient temperature. Saturated ammonium chloride solution (50 mL) was added and the mixture extracted with diethyl ether (3 x 50 mL). The ether extracts were combined, dried with Na2SO4, and evaporated to give a colorless oU which was purified by flash chromatography on sUica gel eluting with hexanes. The title compound was isolated as a colorless oU (2.1 g).
Example 69B trans-5-Methylhex-2-en- 1 -ol The compound resulting from Example 69 A (2.0 g) was dissolved in toluene and cooled to 0 °C in an ice bath. Diisobutylaluminum hydride (1.5 N in toluene, 20 mL) was added dropwise and the solution stirred at 0 °C for two hours. Citric acid solution (25 mL) was added very slowly to the cooled solution. The resulting mixture was stirred for 18 hours at ambient temperature. Diethyl ether (50 mL) was added, the sohds removed by filtration and washed with additional ether (2 x 25 mL). The filtrate was extracted with ether (2 x 25 mL). The ether extractions and washings were combined, dried, and evaported to give a colorless oU which was purified by flash chromatography on silica gel eluting with 25% EtOAc-hexanes. The title compound was isolated as a colorless oil (1.25 g).
Example 69C trans- 1 -Bromo-5-methylhex-2-ene
The compound resulting from Example 69B (1.0 g) was dissolved in diethyl ether and cooled to 0 °C in an ice bath. Phosphorus tribromide (2.5 g, 0.87 mL) was added dropwise and the solution stirred at 0 °C for two hours. The solution was poured onto ice, the layers separated, and the aqueous layer extracted with additional ether (3 x 25 mL). The ether layers were combined, dried, and evaporated to give a colorless oU which was used without further purification (0.95 g).
Example 69D trans.trans-2-(4-Methoxyphenyl)-4-(1.3-benzodioxol-5-yl)-l-N-(trans-5-methylhex-2-enyl)- pyrroHdine-3 -carboxylic acid
The title compound was synthesized using the methods detailed in Example ID but substituting the compound resulting from Example 69C for N-propyl bromoacetamide. H NMR (CDC13, 300 MHz) δ 0.84 (d, 6H, J=8Hz), 1.57 (heptet, IH, J=8Hz), 1.87 (t, 2H, J=6Hz), 2.60 (dd, IH, J=8Hz,14Hz), 2.86 (t, IH, J=10Hz), 2.96 (dd, IH, I=8Hz,10Hz), 3.20 (dd, IH, = 5Hz,14Hz), 3.29 (dd, IH, J=3Hz,10Hz), 3.50 (m, IH), 3.70 (d, IH, J=10Hz), 3.78 (s, 3H), 5.47 (m, 2H), 5.93 (s, 2H), 6.71 (d, IH, J=8Hz), 6.83 (d, 3H, J=9Hz), 7.05 (s, IH), 7.32 (d, 2H, J=9Hz). MS (DCI/NH3) m/e 438 (M+H)+. Anal calcd for C26H3iNO5: C, 71.37; H, 7.14; N, 3.20. Found: C, 71.16; H, 7.24; N, 3.17.
Example 70 trans. trans-2-(4-Methoxyphenyl , -4-( 1 ,3-benzodioxol-5-yl)- 1 -N-(trans-3 , 5-dimethylhex-2- enyl)-pyrroUdine-3-carboxylic acid The title compound was prepared by the procedures described in Example 69 but substituting 4-methyl-2-pentanone for isovaleraldehyde in Example 69A, which gave ~7: 1 mixture of trans/cis olefins. The crude product was purified by preparative HPLC (Vydac μC18) eluting with a 10-70% gradient of CH3CN in 0.1% TFA. The desired fractions were lyophilized to give the product (and its diastereomer) as a white sohd. H NMR of the major (trans) isomer: (CDCI3, 300 MHz) δ 0.83 (d, 6H, I=8Hz), 1.56 (s,3H), 1.74 (m, IH), 1.92 (d,
2H, J=6Hz), 3.3-3.5 (m, 3H), 3.6-3.8 (m,4H), 3.78 (s, 3H), 3.9-4.0 (m, IH), 5.22 (m, IH), 5.90 (d, 2H, I=12Hz), 6.63 (m, IH), 6.78 (m, 3H), 6.95 (s, IH), 7.45 (d, 3H, I=8Hz). MS (DCI/NH3) m/e 438 (M+H)+. Anal calcd for C27H33NO5 • 1.0 TFA: C, 61.59; H, 6.06; N,
2.48. Found: C, 61.36; H, 6.10; N, 2.34.
Example 71 trans,trans-2-(4-Methoxyphenyl -4-(l,3-benzodioxol-5-yl)-l-(4-heptylcarbonylmethyl)- pyrroHdine-3 -carboxylic acid
Example 71 A 1 -Chloro-3 -ρropyl-2-hexanone To 2-propylpentanoic acid (156.6 μl, 1.00 mmol) dissolved in anhydrous dichloromethane (2 mL) was added DMF (3 μL, 4 mole %), and the solution was cooled to 0 °C under a nitrogen atmosphere. To the solution was added oxalyl chloride (94.3 μL, 1.08 mmol) dropwise over a few minutes. The reaction was stirred 18 hours while warming to ambient temperature. The mixture was cooled to 0 °C and excess -0.3 M ethereal diazomethane solution was added. The reaction mixture was stirred 18 hours whUe warming to ambient temperature. The reaction mixture was washed with 1 M aqueous sodium carbonate solution (30 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was dissolved in ether (2 mL) and cooled to 0 °C under a nitrogen atmosphere. Hydrogen chloride as a 4 N solution in dioxane (275 μL, 1.10 mmol) was added dropwise over a few minutes. The reaction was stirred 18 hours while warming to ambient temperature. The reaction mixture was concentrated under reduced pressure and the residual oU was used in the next step without further purification. Example 7 IB tr-.ns.trans-Ethyl 2-(4-methoxyphenyl)-4-(l,3-benzodioxol-5-yl)-l-(4- heptylcarbonylmethyl)-pyrroUdine-3-carboxylate To the compound resulting from Example 71A (1.00 mmol, maximum theoretical yield) was added a solution of the transjrans ethyl carboxylate from Example IC (295 mg, 0.80 mmol as a 50 % solution in toluene), diisopropylethylamine (700 μL, 4.00 mmol) and acetonitrile (4 mL). To the resulting solution was added sodium iodide (12 mg, 10 mole %), and the reaction mixture was stirred 18 hours under a nitrogen atmosphere at ambient temperature. Additional sodium iodide (24 mg, 20 mole %) and acetonitrUe (4 mL) were added, and the reaction mixture was heated at 45-50 °C with stirring for 18 hours. The reaction mixture was concentrated under reduced pressure, and the residue was chromatographed on sUica gel eluting with 1:9 ethyl acetate-hexane to give 237 mg (46%) of the title compound as a yellow oil.
Example 71 C transJrans-2-(4-Methoxyphenyl)-4-(l,3-benzodioxol-5-yl)-l-(4-heptylcarbonylmethyl)- pyrrolidine-3-carboxylic acid To the compound resulting from Example 71B (231 mg, 0.4532 mmol) dissolved in ethanol (10 mL) was added a solution of lithium hydroxide (38 mg, 0.9065 mmol) in water (2.5 mL). The solution was stirred for 18 hours under a nitrogen atmosphere, additional lithium hydroxide (19 mg, 0.4532 mmol) in water (0.5 mL) was added, and stirring was continued 24 hours. The reaction mixture was concentrated under reduced pressure to remove the ethanol, and the aqueous residue was diluted with water (45 mL) and washed with ether (50 mL). The aqueous layer was neutralized with 1 N hydrochloric acid to cloudiness and then 10% aqueous citric acid was added to adjust the pH to ~5. This solution was then extracted with 10% ethanol in chloroform (4 x 25 mL). The combined organic extracts were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by preparative TLC on silica gel eluted with 1 : 1 ethyl acetate-hexane to give 86 mg (39%) of the title compound as an off white powder. ^ MR (CDC13, 300 MHz) 0.73-0.97 ( , 6H), 1.03-1.33 (m, 6H), 1.36-1.58 (m, 2H), 2.46 (m,
IH), 2.80-2.98 (m, 3H), 3.38-3.64 (m, 3H), 3.75-3.90 (m, IH), 3.79 (s, 3H), 5.94 (s, 2H), 6.75 (d, IH), 6.86 (d, 2H), 6.92 (d, IH), 7.12 (s, IH), 7.32 (d, 2H). MS (FAB) m/e 482 (M+H)+ Anal calcd for C28H35NO6: C, 69.83; H, 7.32; N, 2.91. Found: C, 69.57; H, 7.41; N, 2.73. - I l l -
Example 72 trans, trans-2-(4-Methoxyphenyl)-4-( 1 ,3-benzodioxol-5-yl)- 1 -(valerylmethyl -pyrroHdine-3 - carboxylic acid
Example 72A 1 -Chloro-2-hexanone Using the procedure described in Example 71 A and substituting pentanoic acid for 2- propylpentanoic acid afforded the title compound as an oU which was used in the next step without further purification.
Example 72B trans.tra7.s-Ethyl 2-(4-methoxyphenyl)-4-(l,3-benzodioxole-5-yl)-l-(valerylmethyl)- pyrroHdine-3 -carboxylate Substituting the compound resulting from Example 72A for l-chloro-3-propyl-2- hexanone and using the procedure described in Example 7 IB, except deleting the first addition of sodium iodide, stirring 18 hours at ambient temperature and purifying by silica gel chromatography eluting with 3:17 ethyl acetate-hexane, the title compound 305 mg (65%) was obtained as a yellow oU.
Example 72C trans. tr_.ns-2-(4-Methoxyphenyl)-4-( 1 ,3 -benzodioxol-5-yl)- 1 -(valerylmethylVpyrrolidine-3- carboxylic acid By substituting the compound resulting from Example 72B for trans, trans-Ethyl 2-(4- methoxyphenyl)-4-(l,3-benzodioxol-5-yl)-l-(4-heptylcarbonylmethyl)-pyrroHdine-3- carboxylate and using the procedure described in Example 71C, except only one solution of lithium hydroxide (81.5 mg, 1.942 mmol) in water (3.5 mL) was added followed by stirring for 18 hours, the title compound 130 mg (46%) was obtained as an off white powder. *H NMR (CDC13, 300 MHz) δ 0.87 (t, 3H), 1.26 (m, 2H), 1.49 (m, 2H), 2.37 (m, 2H), 2.79-2.98
(m, 3H), 3.31-3.49 (m, 2H), 3.56 (m, IH), 3.77, 3.79 (d,s, 4H), 5.94 (s, 2H), 6.75 (d, IH), 6.81-6.93 (m, 3H), 7.09 (d, IH), 7.33 (d, 2H). MS (FAB) m/e 440 (M+H)+. Anal, calcd for C25H29 O6: C, 68.32; H, 6.65; N, 3.19. Found: C, 67.95; H, 6.64; N, 3.05.
Example 73 trans, tr_.ns-2-(4-Methoxyphenyl)-4-( 1 ,3-benzodioxol-5-yl)- 1 -(N-(3 ,4-dimethoxybenzyl)-N- methylamino carbonylmethyl)pyrroHdine-3 -carboxylic acid
Example 73A trans.trans- -.nt cts.trans-2-(4-Methoxyphenyl)-4-(l,3-benzodioxol-5-yl)-l-((3.4- dimethoxybenzyl)aminocarbonylmethyl)pyriOUdine-3-carboxylic acid ethyl ester
Using the procedure of Example ID, paragraph 1, substituting 3,4-dimethoxybenzyl bromoacetamide for dipropyl bromoacetamide, the desired product mixture was obtained as a white foam in 81% yield.
Example 73B trans, trans- and cis. trans-2-(4-Methoxyphenyl)-4-(l ,3-benzodioxol-5-yl)- 1 -(N-(3.4- dimethoxybenzyl)-N-methylaminocarbonylι_Qethyl)pyrroUdine-3-carboxylic acid ethyl ester The resultant product from Example 73A (220 mg, 0.404 mmol) was dissolved in 2 mL dry THF and added dropwise to a stirred, cooled (0 °C) suspension of sodium hydride (23 mg of a 60% by weight mineral oU suspension, 16.5 mg, 0.69 mmol) in 0.2 mL THF, under an argon atmosphere. The resulting mixture was stirred at 0 °C for 1 hour, then methyl iodide (28 μL, 64 mg, 0.45 mmol) was added. The reaction mixture was stirred at 0 °C for 45 minutes. TLC (Et2θ) indicated incomplete reaction. An additional portion of methyl iodide (28 μL, 64 mg, 0.45 mmol) and dry l,3-dimethyl-3,4,5,6-tetrahydro-
2(lH)pyrimidinone (50 μL, 0.41 mmol) were added. The reaction mixture was stirred at ambient temperature for 2 days. The reaction was poured into 25 mL of 0.5 M aqueous citric acid and extracted with 2 x 25 mL EtOAc. The combined organic extrracts were washed sequentially with 30 mL water and 30 mL brine, then dried (Na2SO4), filtered and concentrated under reduced pressure to produce 270 mg of crude material. Flash chromatography on silica gel eluting with Et2θ gave the title compounds as an inseparable mixture in 43% yield. *H NMR (CDC13, 300 MHz) 2.79 (s) and 2.81 (s), for the N-CH3 signals. MS m/z 591 (M+H)+.
Example 73 C trans. trans-2-(4-Methoxyphenyl)-4-( 1 ,3-benzodioxol-5-yl)- 1 -(N-(3.4-dimethoxybenzyl)-N- methylaminocarbonylmethyl)pyrrolidine-3-carboxylic acid To the resultant compound from Example 73B (98 mg, 0.17 mmol) dissolved in 1 mL EtOH and cooled to 0 °C was added a solution of lithium hydroxide monohydroxide (17 mg, 0.41 mmol) in 0.5 mL H2O. The resulting solution was stirred under a nitrogen atmosphere for 16 hours. The solution was concentrated in vacuo, and the residue was partitioned between 15 mL H2O and 15 mL Et2θ. The aqueous phase was extracted with 5 mL Et2O, then the aqueous phase was acidified with 10% aqueous citric acid. The acidic aqueous phase was saturated with NaCl and extracted with 3 x 15 mL EtOAc. The EtOAc extracts were combined, dried (Na2SO4), then filtered and concentrated in vacuo to give 40 mg (42%) of the title compound as a white foam. *H NMR (CD3OD, 300 MHz, two rotameric forms) 2.85 (s, 3H), 2.94-3.25 (br m, 3H), 3.35-3.70 (br m) and 3.64 (s, 4 H total), 3.70-3.97 (br m), 3.74 (s), 3.76 (s), 3.78 (s), 3.79 (s), 3.81 (s), and 4.03 (br d, =14 Hz, 8H total), 4.43 (AB, IH), 5.91 (s) and 5.93 (s, 2H total), 6.50-6.60 (m, IH), 6.67-7.02 (br m, 6H), 7.29 (br d) and 7.35 (br d, 2H total). HRMS calcd for C31H35N2O8 (M+H)+: 563.2393. Found: 563.2385.
Example 74 trans.tr_.ns-2-(4-Methoxyphenyl)-4-(L3-benzodioxol-5-yl)-l-(N-(3.4- dimethoxybenzyl)aminocarbonylmethyl)pyrroUdine-3-carboxylic acid
The procedure of Example 73C was used, with the substitution of the resultant compound from Example 73A for the resultant compound from Example 73B, to provide the title compound. *H NMR (CD3OD, 300 MHz) 285 (d, J=16Hz, IH), 2.92 (br t, I=9Hz,
IH), 2.98 (br t, J=10Hz, IH), 3.32-3.39 (br m, 2H), 3.54-3.65 (br m, IH), 3.67 (s, 3H), 3.78 (s, 3H), 3.80 (s, 3H), 3.85 (d, =10 Hz, IH), 4.21 (d, I=15Hz, IH), 4.41 (d, J = 15Hz, IH), 5.91 (s, 2H), 6.67 (d, J=8Hz, IH), 6.15-6.95 (m, 7H), 7.33-7.40 (m, 2H). HRMS calcd for C30H32N2O8 (M+H)+: 549.2237. Found: 549.2224.
Example 75
(2R.3R.4RV2-(4-MethoxyphenylV4-(1.3-benzodioxol-5-ylVl-((lRVl-(N.N- dipropylaminocarbonyl - 1 -butyl)pyrroHdine-3-carboxylic acid
Example 75A trans. trans-2-(4-Methoxyphenyl . -4-( 1 ,3-benzodioxol-5-yl)- 1 -(( 1 R)- 1 - (benzy loxycarbonyl)butyl)pyrroHdine-3 -carboxylic acid ethyl ester The procedure of Fung, et. al., I. Med. Chem., 35(10): 1722-34 (1992) was adapted. The resultant compound from Example 6A (103 mg, 0.279 mmol) was dissolved in 0.7 mL of nitromethane and 0.7 mL of H2O, and ammonium carbonate (34 mg, 0.35 mmol) and
(2S)-benzyl 2-bromopentanoate (78 mg, 0.30 mmol) were added. The reaction was refluxed for 24 hours. The reaction was partitioned between 15 mL of 1 M aqueous Na2CO3 and 25 mL of CH C12. The aqueous phase was extracted with 2 x 10 mL CH2C12, and the combined organic phases were washed with 15 mL brine, dried (Na2SO4), then filtered and concentrated under reduced pressure to a brown oU ( 169 mg) . The crude product was purified by sUica gel chromatography eluting with 3: 1 CH2Cl2-hexane to produce 106 mg
(68%) of the title compound as a waxy solid. H NMR indicated the presence of two diastereomeric products.
Example 75B trans. trans-2-(4-Methoxyphenyl , -4-( 1 ,3-benzodioxol-5-yl)- 1 -(( 1 R) - 1 -(N,N- dipropylaminocarbonyl)-l-butyl)pyrroUdine-3-carboxylic acid ethyl ester The resultant compound from Example 75A (101 mg, 0.180 mmol) and 30 mg of 10% palladium on charcoal were stirred in 2 mL EtOAc under 1 atmosphere of H2 for 4 hours. The reaction mixture was filtered through a plug of Celite, using 15 mL MeOH to wash the catalyst. The combined filtrate and wash were concentrated in vacuo to give 81.4 mg (96%) of the crude acid as a white solid.
The above crude acid was combined with HOBt hydrate (41 mg, 0.27 mmol), dipropylamine (26 mg, 0.26 mmol), and 4-methylmorphoHne (37 mg, 0.37 mmol) in 2 mL dry DMF. The solution was cooled to -15 °C, then l-ethyl-3-(3- dimethylaminopropyl)carbodiimide hydroehloride (44 mg, 0.23 mmol) was added. The mixture was stirred at -15 °C and allowed to warm slowly to room temperature overnight. The solvent was removed by distillation under reduced pressure, and the residue was partitioned between 20 mL EtOAc and 10 mL of 1 M aqueous Na2CO3. The organic phase was washed with 10 mL of brine, dried (Na2SO4), then filtered and concentrated in vacuo. The crude product was purified by flash chromatography on silica gel, eluting with 1:2 Et2θ- hexane. Further purification of overlap fractions by preparative TLC eluting with 1:2 Et2O- hexane yielded 32 mg (34%) of a less polar product, and 44 mg (46%) of a more polar product.
Example 75C
(2R.3R.4RV2-(4-MethoxyphenylV4-(L3-benzodioxol-5-ylVl-((lRVl-(N.N- dipropylaminocarbonyl)-l-butyl)pyrroHdine-3-carboxylic acid The procedure of Example 73 C was foUowed, with the substitution of the less polar isomer from Example 75B for the resultant product from Example 73B, to provide the title compound in 94% yield. [ ]D = -52° (c=0.235, CH3OH). iH NMR ^DsOD, 300 MHz)
0.55 (t, J=7Hz, 3H), 0.87 (t, J=7Hz) and 0.87-0.94 (m, 6H total), 1.03-1.25 (br m, 2H), 1.25-1.68 (br m, 4H), 1.90-2.07 (br m, IH), 2.75-2.94 (br m, 2H), 2.94-3.02 (br m, 2H), 3.20- 3.40 (m, overlapping with CD2HOD signal), 3.40-3.60 (br m, 2H), 3.79 (s, 3H), 4.04 (br d, =9 Hz, IH), 5.92 (dd, J=3,5 Hz, 2H), 6.72 (d, =8 Hz, IH), 6.79 (dd, =1.5,8 Hz, IH), 6.92- 6.98 (br m, 3H), 7.29-7.39 (m, 2H). MS m/z 525 (M+H)+.
Example 76 (2S.3S,4S)-2-(4-Methoxyphenyn-4-(L3-benzodioxol-5-yl)-l-((lRVl-(N,N- dipropylaminocarbonyl)-l-butyl)pyrroHdine-3-carboxylic acid The procedure of Example 73C was foUowed, with the substitution of the more polar isomer from Example 75B for the resultant product from Example 73B, to provide the title compound in 88% yield. [ ]D = +58° (c=0.37, CH3OH). Η N ^CDsOD, 300 MHz)
0.57 (br t, J=7Hz, 3H), 0.88-0.98 (m, 6H), 1.08-1.35 (br m, 2H), 1.35-1.68 (br m, 4H), 1.75-1.90 (br m, IH), 2.75-2.86 (br m, 2H), 3.10-3.30 (br m, 2H), 3.51-3.65 (br m, 2 H), 3.69 (s, 3H), 4.03-4.16 (br m, 2H), 5.91 (s, 2H), 6.71-6.83 (m, 2H), 6.86-6.97 (m, 3H), 7.32 (br d, J=9Hz, 2H). MS m/z 525 (M+H)+.
Example 77 (2S.3S.4S -2-(4-MethoxyphenylV4-(1.3-benzodioxol-5-ylVl-((lS)-l-(N.N- dipropylaminocarbonyl - 1 -butyl)pyrrolidine-3-carboxylic acid
Example 77A trans. tr_.ns-2-(4-Methoxyphenyl -4-( 1 ,3-benzodioxol-5-vD- 1 -(( 1 S - 1 -(N,N- dipropylaminocarbonylVl-butyl)pyrrolidine-3-carboxylic acid ethyl ester (2R)-N,N-dipropyl 2-hydroxypentanamide (106 mg, 0.528 mmol, made by standard procedure) was dissolved in 2 mL THF under an argon atmosphere, dnsopropylethylamine (75 mg, 0.58 mmol) was added, then the solution was cooled to -20 °C. Trifluoromethanesulfonic anhydride (95 μL, 159 mg, 0.565 mmol) was added to the cooled solution over 1 minute, and the reaction mixture was stirred at -20 °C for 1 hour, and at room temperature for an additional 1 hour. The resulting slurry was recooled to 0 °C, and a solution of the resultant compound from Example 6A (195 mg, 0.528 mmol) and dnsopropylethylamine (101 μL, 75 mg, 0.58 mmol) in 3 mL of CH2C12 was added. The reaction was stirred at 0 °C for 3 hours and for an additional 2 days at room temperature. TLC (Et2θ-hexane 1:2) indicated starting materials remained, so the mixture was warmed to reflux for 4 hours. The reaction was cooled, then partitioned between 30 mL EtOAc and 15 mL of 1 M aqueous Na2CO3. The aqueous phase was extracted with 15 mL EtOAc, then the combined organic phases were washed with 20 mL brine, dried (Na2SO4), filtered and concentrated in vacuo to a yellowish oU. Purification by flash chromatography on sUica gel eluting with 1:2 Et2θ-hexane gave 19.9 mg (7%) of a less polar product and 20.1 mg (7%) of a more polar product. *H NMR spectra and MS were the same as those of Example 76B.
Example 77B (2S.3S,4S)-2-(4-MethoxyphenylV4-(1.3-benzodioxol-5-ylVl-((lSVl-(N.N- dipropylaminocarbonyl)-l-butyl)pyrroHdine-3-carboxylic acid The procedure of Example 73 C was foUowed, with the substitution of the less polar isomer from Example 77A for the resultant product from Example 73B, to provide the title compound in 100% yield. XH NMR (CD3OD, 300 MHz) and MS identical to those of
Example 75C.
Example 78 (2R.3R.4RV2-(4-Methoxyphenyl -4-( 1.3-benzodioxol-5-yl , - 1 -(( 1 S 1 -(N.N- dipropylaminocarbonylVl-butyl)pyrrolidine-3-carboxylic acid The procedure of Example 73 C was foUowed, with the substitution of the more polar isomer from Example 77A for the resultant product from Example 73B, to provide the title compound in 88% yield. Η NMR (CD3OD, 300 MHz) and MS identical to those of Example 76.
Example 79 trans.trαns-2-(4-Methoxyphenyl -4-(l,3-benzodioxol-5-yl)-l- N.N-_ t( - butyl)aminocarbonylmethyl)-3-(5-tetrazolyl)Oyn:o]idm.e Carbonyldiirnidaκole (510 mg, 3.148 mmol) was added to 1.020 g (2.00 mmol) of the compound resulting from Example 43 in 2.7 mL THF, and the mixture was heated for 40 minutes at 50 °C. The reaction mixture was cooled in an ice bath, and 25% solution of ammonia in methanol was added. After 30 minutes, the sohd which had formed was filtered, washed with ethanol and finally with ether to yield 850 mg (83%) of the 3-carboxamide compound, mp. 194-196 °C. Phosphorus oxychloride (1.06 g) was added to this amide in 7 mL of pyridine, and the mixture was stirred 1 hour at room temperature. Dichloromethane was added, and the solution was washed with potassium bicarbonate solution, dried over sodium sulfate, and concentrated. The residue was chromatographed on silica gel eluting with 2: 1 hexane-ethyl acetate to give 790 mg (96%) of the 3-carbonitrile compound. To this nitrile in 5 mL toluene was added 385 mg of trimethyl tin chloride and 126 mg sodium azide. The mixture was heated 20 hours at 125 °C (bath temp). After cooHng, methanol (5 mL ) was added, and the solution was concentrated in vacuo. To the resulting residue was added 6 mL of methanol and 6 mL of water containing 0.2 g phosphoric acid. After stirring 1 hour at room temperature, water was added and the mixture extracted with dichloromethane. The combined organic extracts were dried and concentrated, and the resulting residue was crystaUized from ether to give a sohd. The sohd was dissolved in sodium hydroxide solution, filtered from insoluble material and acidified with acetic acid'to get 532 mg (62%) of the title compound, mp. 165-167 °C. lH NMR (CDC13, 300 MHz) 0.85 (t, I=7Hz, 3H), 0.87 (t, J=7Hz, 3H), 1.10-1.50 (m, 8H), 3.0-3.6 (m, 8H), 3.70 (s, 3H), 3.7-3.8 (m, IH), 3.90 (t, J=9Hz, IH), 4.37 (d, J=9Hz, IH), 5.86 (s, 2H), 6.62 (d, I=8Hz, IH), 6.65-6.73 (m, 3H), 6.95 (d, J=2Hz, IH), 7.11 (d, J=9Hz, 2H).
Example 80 tr-.7;s.trans-2-(4-Fluorophenyl)-4-(l,3-benzodioxol-5-yl)-l- N.N--/tCn- butyt")αmmocαrbθ7zv/ et v/)pyrroHdine-3-carboxylic acid
The title compound was prepared as an amorphous sohd from methyl (4- flourobenzoyl) acetate and 5-(2-nitrovinyl)-l,3-benzodioxole using the procedures described in Examples 1 and 43. H MR (CDCI3, 300 MHz) δ 0.81 (t, J=7Hz, 3H), 0.90 (t, J=7Hz, 3H), 1.0-1.55 ( , 8H), 2.81 (d, J=13 Hz, IH), 2.90-3.10 (m, 4H), 3.15-3.30 (m, IH), 3.32- 3.45 (m, 3H), 3.55-3.65 (m, IH), 3.86 (d, J=10Hz, IH), 5.94 (dd, I=2Hz, 4Hz, 2H), 6.72 (d, =8 Hz, IH), 6.86 (d, = 8 Hz, IH), 6.95-7.07 (m, 3H), 7.32-7.45 (m, 2H).
Example 81 trans. trans-2-(4-Methoxyphenyl)-4-( 1 ,3 -benzodioxol-5-yl)- 1 -(Ν,Ν-di(n- butyl . amino carbonylmethy l)pyrroHdine-3 -carboxylic acid N,N-Dibutyl glycine (150 mg, 0.813 mmol), prepared by the method of Bowman, R.E., J. Chem. Soc. 1346 (1950), in 0.7 mL of THF was treated with 138 mg (0.852 mmol) carbonyldiimidazole and heated for 30 minutes at 50 °C. After coohng to room temperature, 250 mg (0.678 mmol) of ethyl trøns,trans-2-(4-methoxyphenyl)-4-(l,3-benzodioxol-5-yl)- pyrrolidine-3 -carboxylate, the compound resulting from Example 6 A, was added, and the mixture was heated at 45 °C for 30 minutes. The product was chromatographed on sUica gel, eluting with 1:1 hexane-ethyl acetate to give 306 mg of the intermediate ethyl ester.
The ester was hydrolyzed with sodium hydroxide in water and ethanol to give 265 mg of the title compound as a white powder. XH NMR (CDCI3, 300 MHz) δ rotational isomers - 0.75 and 0.85 (2 1, J=7Hz, 3H), 1.05-1.5 (m, 8H), 2.65-3.20 (m, 6H) 3.43-3.70 (m, 3H), 3.72 (s, 3H), 3.87 (d, J=15Hz, IH), 4.49 (dd, J=12Hz, 6Hz) and 5.23 (dd, J=12Hz, 8Hz) 2H, 5.90 (dd, I=2Hz, 4Hz, 2H), 6.63-6.78 (m, 3H), 6.86 and 7.04 (d, J=9Hz, 2H), 7.22 (d, J=9Hz, 2H).
Example 82 trans.trans-2-(4-Methoxyphenyl)-4-(l,3-benzodioxol-5-yl)-l-(N-n-butyl)-N-(n- propyl)aminocarbonylmethyl)pyrroHdine-3-carboxylic acid The title compound was prepared using the procedures described in Example 1. m.p. 160-162 °C. iH N R (CDCI3, 300 MHz) rotational isomers δ 0.69, 0.80, 0.84, 0.87 (four triplets, I=7Hz, 6H), 1.00-1.52 (m, 6H), 2.63 and 2.66 (two doublets, I=13Hz, IH), 2.90-3.10 (m, 4H), 3.23-3.61 (m, 5H), 3.71 and 3.75 (two doublets, I=10Hz, IH), 3.78 (s, 3H), 5.92- 5.96 (m, 2H), 6.72 (d, J=8Hz, IH), 6.83-6.89 (m, 3H), 7.03 (d, J=2Hz, IH), 7.81 (d, J=9Hz, 2H).
Example 83 trans.tra7.s-2-(4-Methoxyphenyl)-4-(l,3-benzodioxol-5-yl)-l-[2-(N,N-di(n- propyl)aminocarbonyl)ethyl]pyrrolidine-3-carboxylic acid The compound resulting from Example 6A (250 mg, 0.677 mmol), 205 mg (1.36 mmol) diallyl acrylamide (Polysciences, Inc.), and 10 mg acetic acid were heated at 85 °C in 0.75 mL of methoxyethanol for one hour. Toluene was added, and the solution was washed with bicarbonate solution, dried, and concentrated. Chromatography on sUica gel eluting with 3: 1 hexane-ethyl acetate gave 283 mg (80%) of the diallyl compound.
The diallyl compound was hydrogenated using 10% Pd/C catalyst (27 mg) in ethyl acetate (25 mL) under a hydrogen atmosphere. The catalyst was removed by filtration, and the filtrate was concentrated to afford the dipropyl amide ethyl ester in 100% yield. The ester was hydrolyzed to the title compound by the method of Example ID in 83% yield. Η NMR (CDC13, 300 MHz) δ 0.82 and 0.83 (two triplets, I=7Hz, 6H), 1.39-1.54 (m,
4H), 2.35-2.60 (m, 3H), 2.80-3.07 (m, 5H), 3.14-3.21 (m, 2H), 3.31-3.38 (m, IH), 3.51-3.61 (m, IH), 3.73 (d, J=12H, IH), 3.75 (s, 3H), 5.94 (s, 2H), 6,71 (d, J=9Hz, IH), 6.79-6.85 (m, 3H), 7.04 (d, J=2Hz, 1H)< 7.32 (d, I=9Hz, 2H).
Example 84 trans.trans-2-(4-Methoxyphenyl)-4-(L3-benzodioxol-5-yl)-l-(N,N-di(n- butyl) amino carbonyl)pyrroHdine-3 -carboxylic acid
The title compound was prepared by the procedures described in Example 8 using dibutyl carbamoyl chloride, prepared by the method of Hoshino et al, Syn. Comm., 17:
1887-1892 (1987), as a starting material. H NMR (CDCI3, 300 MHz) δ 0.86 (t, J=7Hz, 6H),
1.14-1.28 (m, 4H), 1.35-1.48 (m, 4H), 2.81-2.94 (m, 2H), 3.11 (t, I=12Hz, IH), 3.30-3.41 (m, 2H), 3.59-3.68 (m, 2H), 3.76 (s, 3H), 3.78-3.85 (m, IH), 5.81 (d, J=9Hz, IH), 5.94 (s, 2H), 6.73-6.86 (m, 5H), 7.24 (d, I=9Hz, 2H).
Example 85 trans.trans-2-(4-Methoxyphenyl)-4-(l,3-benzodioxol-5-yl)-l-tN.N-_/tt - bt.tv/)-.mtnoc_.rbonv/7?.et v/)pyrroHdine-3-carboxylic acid sodium salt Sodium hydroxide (48.2 mg of 98.3% pure, 1.184 mmol) in 2 mL of MeOH was added to the compound resulting from Example 43 (610 mg, 1.196 mmol.) in 5 mL MeOH. The solution was concentrated to dryness, and the resulting powder was stirred with heptane. The heptane was removed in vacuo to give a powder which was dried in the vacuum oven for 2 hours at 60 °C to yield 627.5 mg of the title compound.
Example 86 trans.trαns-2-(4-Methoxyphenyl -4-(l,3-benzodio'xol-5-yl')-l-[2-(Ν,Ν-di(n- butyl)amino)ethyllpyrrolidine-3-carboxylic acid A solution of the bromoethyl compound resulting from Example 61A (150 mg), dibutylamine (150 mg) and sodium iodide (18 mg) in 0.75 mL ethanol was heated at 80 °C for 1 hour. After cooling, toluene was added, and the solution was washed with potassium bicarbonate solution, dried over a2SO4 and concentrated. More toluene was added, and the solution was again concentrated to get rid of excess dibutylamine. The residue was dissolved in warm heptane and filtered from a small amount of insoluble material. The hepane was removed in vacuo to give 143 mg (87%) of the intermediate ethyl ester. The ester was hydrolyzed by the method of Example ID to give the title compound as a white powder. *H NMR (CD3OD, 300 MHz) δ 0.89 (t, J=7Hz, 6H), 1.16-1.30 (m, 4H),
1.44-1.56 (m, 4H), 2.48-2.57 (m, IH), 2.80-3.08 (m, 8H), 3.14-3.25 (m, IH), 3.31-3.38 (m, IH), 3.59-3.60 (m, IH), 3.74 (s, 3H), 3.75 (d, J=10Hz, IH), 5.89 (s, 2H), 6.71 (d, J=9Hz, IH), 6.81 (dd, J=9Hz, 2Hz, IH), 6.90 (d, J=10Hz, 2H), 6.96 (d, J=2Hz, IH), 7.37 (d, J=10Hz, 2H). Example 87 tra7?s,trans-2-(4-Methoxyphenyl)-4-(l,3-benzodioxol-5-yl)-l-{2-[N-(N,N-di(n- butyl)aminocarbonyl)-N-methylamino]ethyl}pyrrolidine-3-carboxy lie acid Dibutyl carbamoyl chloride (135 mg) was added to the compound resulting from Example 6 IB (250 mg) and 150 mg triethylamine in 1 mL dichloromethane. After stirring 1 hour at room temperature, toluene was added, and the solution was washed with potassium bicarbonate solution, dried over Na2SO4 and concentrated. The residue was chromatographed on sUica gel, eluting with a mixture of 38% EtOAc and 62% hexane to give 194 mg of the ethyl ester intermediate. The ester was hydrolyzed by the method of Example ID to afford 141 mg of the title compound. *H NMR (CD3OD, 300 MHz) 0.92 (t, I=7Hz, 6H), 1.21-1.32 (m, 4H), 1.42-
1.53 (m, 4H), 2.62 (s, 3H), 2.65-2.76 (m, IH), 3.00-3.20 (m, 8H), 3.44-3.55 (m, IH), 3.62- 3.78 (m, 2H), 3.80 (s, 3H), 4.07 (d, =12 Hz, IH), 5.93 (s, 2H), 6.75 (d, J=9Hz, IH), 6.87 (dd, I=9Hz, 2Hz, IH), 6.94 (d, =10 Hz, 2H), 7.04 (d, I=2Hz, IH), 7.40 (d, =1 OHz, 2H).
Example 88 trans,trans-2-(4-Methoxyphenyl)-4-(l,3-benzodioxol-5-yl)-l-(N,N-di(n- butyl) amino carbonylmethy l)pyrroUdine-3 -(N-methanesulfonyl)carboxamide Carbonyldiimidazole (75 mg, 0.463 mmol) was added to 150 mg (0.294 mmol) of the compound resulting from Example 43 in 0.4 mL of tetrahydrofuran, and the solution was stirred at 60 °C for 2 hours. After cooling, 50 mg (0.526 mmol) of methanesulfonamide and 68 mg (0.447 mmol) of DBU in 0.3 mL of THF were added. The mixture was stirred at 45 °C for 2 hours. The solvents were removed in vacuo, and the residue was dissolved in water. A few drops of acetic acid were added, and the solution was lyophilizedto give 121 mg (70%) of the title compound, p. 170-173 °C. Η NMR (CDCI3, 300 MHz) 0.82 (t,
J=7Hz, 3H), 0.88 (t, I=7Hz, 3H), 1.05-1.51 (m, 8H), 2.75-2.86 (m, 2H), 2.83-3.25 (m, 4H), 3.17 (s, 3H), 3.32-3.50 (m, 3H), 3.70-3.78 (m, IH), 3.80 (s, 3H), 3.87 (d, I=10Hz, IH), 5.96 (dd, J=2Hz, 4Hz, 2H), 6.74 (d, I=9Hz, IH), 6.84 (dd, I=9Hz, 2Hz, IH), 6.90 (d, J=10 Hz, 2H), 7.01 (d, J=2Hz, IH), 7.34 (d, I=10Hz, 2H).
Example 89 tr-.ns.tr-.ns-2-(4-Methoxyphenyl)-4-(l,3-benzodioxol-5-yl)-l-(N.N-di(n- butyl) amino carbonylmethy l)pyrroHdine-3 -(N-benzenesulfonyl) carboxamide The compound resulting from Example 43 was converted to the title compound by the method of Example 88 substituting benzenesulfonamide for methanesulfonamide. m.p. 169- 171 °C for a sample recrystaUized from acetonitrile. *H NMR (CDCI3, 300 MHz) δ 0.81(t, J=7 Hz, 3H), 0.89 (t, I=7Hz, 3H), 1.02-1.50 (m, 8H), 2.65-2.80 (m, 2H), 2.90-3.25 (m, 4H), 3.80-3.95 (m, 3H), 3.50-3.60 (m, IH), 3.65 (d, J=10Hz, IH), 3.81 (s, 3H), 5.94 (s, 2H), 6.70 (s, 2H), 6.81-6.90 (m, 3H), 7.17 (d, I=10Hz, 2H), 7.55 (t, =7 Hz, 2H), 7.66 (t, I=7Hz, IH), 8.95 (d, I=7Hz, 2H).
Example 90 tr-.ns.trans-2-(4-MethoxyphenylV4-(1.3-benzodioxol-5-ylVl-[TSl,N-di(n-butyl) aminosulfonylmethyl]-pyrroHdine-3-carboχylic acid Chloromethyl sulfenyl chloride, prepared by the method of Brintzinger et. al., Chem. Ber. 85: 455-457 (1952), is reacted with dibutylamine by the method of E. Vilsmaier described in Liebigs Ann. Chem. 1055-1063 (1980) to give N,N-dibutyl chloromethyl sulfenyl chloride. Alternatively dimethyl(methylthio)sulfonium tetraflouroborate is reacted with dibutylamine to give N,N-dibutyl methylsulfenyl chloride which is chlorinated with N- cMorosuccinimide to give chloromethyl sulfenyl chloride by the method of E. VUsmaier, described in the above reference.
The N,N-dibutyl chloromethyl sulfenyl chloride is reacted with the compound resulting from Example 6A to give ethyl trans,tra7zs-2-(4-Methoxyphenyl)-4-(l,3- benzodioxol-5-yl)-l-psf,N-di(n-butyl)aminosulfenylmethyl]-pyrroHdine-3-carboxylate. This is oxidized with osmium tetroxide and N-methyl morphoHne N-oxide by the method of S. Kaldor and M. Hammond, Tet. Lett. 32: 5043-5045 (1991) to give the title compound after hydrolysis of the ethyl ester.
Example 91 trans. tr_.ns-2-(4-Methoxyphenyl)-4-( 1 ,3 -benzodioxol-5-yl)- 1 -[(N,N-di(n- butyl)aminocarbonyl-l-(RS)-ethyl]pyrroUdine-3-carboxylic acid
Example 91 A (±.-Dibutyl 2-bromopropanamide 2-Bromopropanoic acid (510 mg, 3.33 mmol) and 4-methylmorphoHne (0.74 mL, 6.73 mmol) were dissolved in 10 mL of CH2Cl2, the solution was cooled to 0 °C under a N2 atmosphere, and then treated dropwise with isobutyl chloroformate (0.45 mL , 3.5 mmol). After 10 minutes at 0 °C, dibutylamine (0.57 mL, 3.4 mmol) was added. The reaction was stirred at 0 °C for 1 hour and for an additional 16 hours at room temperature. The mixture was partitioned with 25 mL of 1.0 M aqueous Na2CO3 solution, then the organic phase was washed sequentially with 25 mL of 1 M aqueous NaHSO4 and 25 mL brine, dried (Na2SO4), filtered, and concentrated under reduced pressure to afford 698 mg (2.64 mmol, 79 %) of the crude bromoamide as a colorless oil. *H NMR (CDCI3, 300 MHz) 0.93 (t, I=7Hz) and 0.97 (t, J=7.5Hz, 6H total), 1.26-1.60 (m, 7H), 1.60-1.78 (m, IH), 1.82 (d, J=6Hz, 3H), 3.04- 3.27 (m, 2H), 3.42-3.64 (m, 2H), 4.54 (q, J=7H, IH). MS (DCI/NH3) m/e 264 and 266 (M+H)+.
Example 9 IB trans, trans- and cis, trans-2-(4-Methoxyphenyl)-4-( 1 ,3-benzodioxol-5-yl)- 1 -((N.N-di(n- butyl)amino)carbonyl-l-(RS)-ethyl)pyrroUdine-3-carboxylic acid ethyl ester A solution of the resultant mixture of trans Jrans and cisjrans compounds from Example IC (232 mg, 0.628 mmol) and the resultant compound from Example 91 A (183 mg, 0.693 mmol) in 2 mL of CH3CN was treated with dnsopropylethylamine (0.22 mL, 1.3 mmol). The solution was stirred at 60-80 °C under a N2 atmosphere for 16 hours. The reaction was concentrated under reduced pressure, then the residue was partitioned between 30 mL Et2θ and 10 mL of 1 M aqueous Na2CO3 solution. The organic phase was washed with 20 mL water and 20 mL brine, dried over Na2SO4, filtered and concentrated under reduced pressure to afford the crude amino amide as a brown oU (339 mg, 98% crude). The product was obtained by flash chromatography on sUica gel eluting with 20% EtOAc-hexane to provide 224 mg (70%) of the title compounds as a mixture of 4 diastereomers. H NMR (CDCI3, 300 MHz) 0.66-1.55 (several m, 19H), 2.63-3.00 (m, 3H), 3.05-3.39 (m, 2H), 3.40-3.76 (m, 4H), 3.78-3.80 (4 s, 3H), 3.84-4.25 (m, 2.6H), 4.38 (d, I=10.5Hz, 0.2H) and 4.58 (d, I=10.5Hz, 0.2H), 5.90-5.97 (m, 2H), 6.68-6.96 (m, 5H), 7.38-7.43 (m, 2H). MS (DCI/NH3) m/e 553 (M+H)+.
Example 91 C trans.tr-.ns-2-(4-MethoxyphenylV4-(l,3-benzodioxol-5-yl)-l-((N,N-dibutylamino)carbonyl- l-(RS)-ethyl)pyrrolidine-3-carboxylic acid The procedure of Example 73C was used, substituting the resultant compound from Example 9 IB for the resultant compound from Example 73 B to give the title compound in 61% yield. Η NMR (CD3OD, 300 MHz) δ 0.70-1.05 (several m, 8H), 1.14 (d, J=6Hz, 2H), 1.17-1.55 (m, 6H), 2.79-3.03 (m, 3.5H), 3.20-3.65 (br m, 4.6H plus CD2HOD), 3.70-3.78 (m, 0.4H), 3.79 (s, 3H), 3.98 (d, I=8Hz, 0.6H), 4.06 (t, J=7.5Hz, 0.4H), 4.25 (d, I=8Hz, 0.4H), 5.92 (s) and 5.94 (s, 2H total 6H), 6.73 (d, J=2.5Hz) and 6.75 (d, J=3Hz, IH total), 6.78-6.85 (m, IH), 6.91-7.00 (m, 3H), 7.30-7.38 (m, 2H). MS (DCI/NH3) m/e 525 (M+H)+. Anal calcd for C30H40N2O6O.5H2O: C, 67.52; H, 7.74; N, 5.25. Found: C, 67.63; H, 7.65; N, 5.21. Example 92 trans. trans-2-(Pentyl)-4-( 1 ,3-benzodioxol-5-yl)- 1 -(N,N-di(n- butyl)aminocarbonylmethyl)pyrrolidine-3-carboxy lie acid
Example 92A
Methyl 2-(4-hexenoyl)-4-nitro-3-(l ,3-benzodioxole-5-yl)butyrate A solution of methyl 3-oxo-6-octenόate (502 mg, 2.95 mmol) in 10 mL of isopropanol was added to a solution of 5-(2-nitrovinyl)-l,3-benzodioxole (712 mg, 3.69 mmol) in 10 mL THF, then DBU (22 μL, 0.15 mmol) was added. The resulting reddish solution was stirred at room temperature for 20 minutes. TLC (ethyl acetate-hexane, 1:3) indicated complete consumption of ketoester. The solution was concentrated in vacuo said flash chromatographed on sUica gel eluting with 18% ethyl acetate in hexane to produce 879 mg (2.42 mmol, 82%) of the title compound as a mixture of diastereomers in a 1: 1 ratio. *H NMR (CDC13, 300 MHz) 1.55-1.66 (m, 3H), 2.02-2.17 (br m, IH), 2.20-2.37 (m, 1.5H), 2.49-2.76 (m, 1.5H), 3.57 (s, 1.5H), 3.74 (s, 1.5H), 3.97 (d, J=7.5H, 0.5H) and 4.05 (d, I =8Hz, 0.5H), 4.10-4.20 (m, IH), 4.68-4.82 (m, 2H), 5.06-5.52 (m, 2H), 5.95 (2s, 2H), 6.65 (m, IH), 6.68 (br s, IH), 6.75 (d, 7.5Hz, IH). MS (DCI/NH3) m/e 381 (M+NK ÷. Anal calcd for C18H21NO7: C, 59.50; H, 5.82; N, 3.85. Found: C, 59.32; H, 5.71; N, 3.72.
Example 92B
Methyl trans.trans-2-(pentyl)-4-(l,3-benzodioxol-5-yl pyrroHdine-3-carboxylate The procedures of Example IB and Example IC were foUowed, with the substitution of the resultant compound from Example 92 A for the resultant compound from Example 1 A, and the substitution of the this resultant compound for the resultant compound from Example IB, to provide the title compound in crude form as a yellow oU. This crude compound was epimerized under the foUowing conditions. A solution of the crude compound (660 mg, 2.07 mmol) in 3 mL methanol was treated with a solution of sodium methoxide (made by the addition of sodium metal (14 mg, 0.61 mmol) to 1 mL of methanol). The resultant solution was heated at reflux for 18 hours. The reaction was concentrated under reduced pressure, and the residue was partitioned between 25 mL saturated NaHCO3 diluted with 10 mL water and 30 mL of CH2C12- The aqueous phase was extracted (2 x 30 mL CH2C12), then the combined organic phases were washed with 20 mL brine, dried over Na2SO4, filtered and the filtrate concentrated under reduced pressure to afford the crude product. Purification by flash chromatography on silica gel eluting with 3.5% methanol in CH2CI2 gave 336 mg (57%) the title compound as a yellow oil. Η NMR (CDCI3, 300 MHz) 0.90 (br t, 3H), 1.25-1.70 (br m, 8H), 1.83-2.02 (br s, 2H), 2.58 (dd, I=8,9Hz, IH), 2.99 (dd, I=8,14Hz, IH), 3.34-3.45 (m, 2H), 3.53 (q, I=9Hz, IH), 3.66 (s, 3H), 5.94 (s, 2H), 6.65-6.75 (m, 3H). MS (DCI NH3) m/e 320 (M+H)+. Anal calcd for Cι8H25Nθ4: C, 67.69; H, 7.89; N, 4.39. Found: C, 67.39; H, 7.84; N, 4.37.
Example 92C trans. trans-2-(Pentyl)-4-( 1 ,3-benzodioxol-5-yl)- 1 -(N,N-di(n- butyl) amino carbonylmethyl)pyrroHdine-3 -carboxylic acid The procedures of Example IB-ID were used, with the substitution of the resultant compound from Example 92 A for the resultant compound from Example IB, to provide the title compound as a white foam. H NMR (CDCI3, 300 MHz) δ 0.87 (br t) and 0.89 (br t, 6H total), 0.97 (t, I=7.5Hz, 3H), 1.21-1.42 (br m, 10), 1.43-1.78 (br m, 6H), 2.76 (t, I=7Hz, IH), 3.02-3.30 (br m, 6H), 3.40-3.60 (m, 3H), 3.73 (d, J=14Hz, IH), 5.98 (AB, 2H), 6.70 (d, I=7Hz, IH), 6.77 (dd, I=1.5,7Hz, IH), 6.89 (d, J=1.5Hz, IH). MS (DCI/NH3) m/e 475 (M+H)+. Anal calcd for C27H42N205 0.5H2O: C, 67.05; H, 8.96; N, 5.79. Found: C, 67.30; H, 8.77; N, 5.68.
Example 93 trans, trans-2-(PentylV4-( 1 ,3-benzodioxol-5-yl)- 1 - [2-(N-propyl-N- propylsulfonylamino)ethyl]pyrroHdine-3-carboxylic acid
Example 93A Methyl trans,trans-2-(pentylV4-fl,3-benzodioxol-5-yl -l-(2-bromoethyl pyrroHdine-3- carboxylate The procedure of Example 61 A was used, with the substitution of the resultant compound from Example 92B for the resultant compound from Example IC, to provide the title compound as a yellow oU. *H NMR (CDCI3, 300 MHz) δ 0.89 (br t, J=7Hz, 3H), 1.24-
1.40 (br m, 6H), 1.60-1.80 (br m, 2H), 2.61-2.75 (m, 2H), 2.76-2.91 (m, 2H), 3.10-3.22 (m, 2H), 3.36-3.47 (m, 2H), 3.68 (s, 3H), 5.92 (s, 2H), 6.69-6.77 (m, 2H), 6.90-6.94 (m, IH). MS (DCI/NH3) m/e 426, 428 (M+H)+.
Example 93B Methyl trans.trans-2-(PentylV4-(l,3-benzodioxol-5-ylVl-[2-(N-propyl-N- propylsulfonylamino) ethyl]pyrroHdine-3 -carboxylate A solution of the resultant compound from Example 93A (102 mg, 0.24 mmol) and tetrabutylammonium iodide (6 mg, 16 μmol) in 1 mL EtOH was treated with propylamine (60 μL, 0.73 mmol). The solution was warmed to 80 °C for 4 hours. The reaction was concentrated under reduced pressure, then the residue was dissolved in 35 mL ethyl acetate and extracted with 2 x 15 mL of 1 M aqueous Na2CO3. The organic phase was washed with 15 mL brine, then dried over Na2SO4, filtered and concentrated under reduced pressure to provide the crude secondary amine as a yellow oU (94.2 mg). The crude amine was dissolved in 1 mL of CH2CI2, diiosopropylethylamine (65 μL, 0.373 mmol) was added, followed by propylsulfonyl chloride (29 μL, 0.26 mmol). The solution was stirred at room temperature for 4 hours. The reaction was quenched with 10% aqueous citric acid (to pH 4), and the mixture was extracted with 2 x 3 mL CH2CI2. The combined organic extracts were washed with 2 mL brine, then dried over Na2SO4, filtered, concentrated in vacuo. Purification by flash chromatography eluting with 20% ethyl acetate in hexane provided 65.0 mg (53%) of the title compound as a waxy solid. Rf = 0.17 (20%EtOAc-hexane). MS (DCI/NH3) m/e 511 (M+H)+.
Example 93 C trans.trans-2-(Pentyl)-4-(l,3-benzodioxol-5-yl)-l-[2-(N-propyl-N- propylsulfonylamino)ethyl]pyrroHdine-3-carboxy lie acid The procedure of Example 71 C was followed, with the substitution of the resultant compound from Example 93B for the resultant compound from Example 7 IB, to provide the title compound as a white foam (47 mg, 80%), Rf = 0.14 (5%MeOH-CH2Cl2). *H NMR (CDCI3, 300 MHz) δ 0.88 (tart) and 0.92 (t, I=7Hz, 6H total), 1.22-1.52 (br m, 6H), 1.63 (sextet, J=8Hz, 2H), 1.75-2.10 (br m, 4H), 2.89-2.98 (m, 2H), 3.05 (brt, I=9Hz, IH), 3.10- 3.30 (m, 3H), 3.30-3.80 (br m, 7H), 5.94 (s, 2H), 6.71 (t, J=8Hz, IH), 6.77 (dd, J=1.5,8Hz, IH), 6.89 (d, J=1.5Hz, IH). MS (DCI/NH3) m/e 497 (M+H)+.
Example 94 trans. trans-2-(Propyl)-4-( 1 ,3-benzodioxol-5-yl)- 1 -(N,N-di(n- butyl)aminocarbonylmethyl pyrrolidine-3-carboxylic acid
Example 94A Ethyl 2-(4-butanoyl)-4-nitro-3-(l,3-benzodioxole-5-yl)butyrate
The procedure of Example 92A was followed, with the substitution of ethyl butyryl acetate for methyl 3-oxo-6-octenoate, to provide the title compound as a mixture of trans and cis isomers (47 mg, 80%), Rf = 0.28 (25%EtOAc-hexane). Η MR (CDCI3, 300 MHz) δ
0.74 (t, J=7.5Hz) and 0.91 (t, J=7.5Hz, 3H total), 1.08 (t, I=7Hz) and 1.28 (t, I=7Hz, 3H total), 1.45 (sextet, J=7Hz, 1.5H), 1.63 (sextet, J=7Hz, approx. 1.5H), 2.17 (t, I=7Hz) and 2.24 (t, J=7Hz, 0.5H total)2.40-2.54 (m, IH), 2.60 (t, J=7.5Hz) and 2.67 (t, J=7.5Hz, 0.5H total), 3.93-4.09 (m, 2H), 4.10-4.20 (br m, IH), 4.23 (q, I=7Hz, IH), 4.67-4.85 9m, 2H), 5.94 (s, 2H), 6.62-6.75 (m, 3H). MS (DCI/NH3) m/e 369 (M+NH4)+. Anal calcd for Cι7H2ιN07:
C, 58.11; H, 6.02; N, 3.99. Found: C, 58.21; H, 5.98; N, 3.81.
Example 94B Ethyl trans. trans-2-(propyl)-4-(l ,3-benzodioxol-5-yl)pyrroHdine-3-carboxylate The procedure of Example 92B was foUowed, with the substitution of the resultant compound from Example 94A for the resultant compound from Example 92A, to afford the title compound. MS (DCI/NH3) m/e 306 (M+H)+.
Example 94C tr-.ns.trans-2-(Propyl)-4-(l,3-benzodioxol-5-yl)-l-((N,N-di(n-butyl)aminocarbonylmethyl)- pyrrolidine-3 -carboxylic acid The procedure of Example 92C was foUowed, with the substitution of the resultant product from Example 94B for the resultant product from Example 92B, to give the title compound. *H NMR (CDCI3, 300 MHz) 0.89 (t, I=7.5Hz), 0.92 (t, I=7.5Hz), and 0.97 (t,
J=7.5H, 9H total), 1.22-1.80 (br m, 12H), 2.83 (t, I=7.5Hz, IH), 3.40-3.55 (br rn, 2H), 3.55- 3.68 (m, IH), 3.78 (d, I=15Hz, IH), 5.92 (q, J=lHz, 2H), 6.70 (d, I=8Hz, IH), 6.79 (dd, I=lHz,8Hz, IH), 6.90 (d, J=lHz, H). MS (DCI/NΗ3) m/e 447 (M+H)+. Anal calcd for C25H38N205 0.5 H2O: C, 65.91; H, 8.63; N, 6.15. Found: C, 65.91; H, 8.68; N, 5.94.
Example 95 (2R,3R.4S -(+V2-(4-Methoxyphenyl)-4-(1.3-benzodioxol-5-ylVl-(tert-butyloxycarbonyl- aminocarbonylmethyl)-pyιτolidine-3-carboxylic acid
Example 95A trans, trans-2-(4-Methoxyphenyl)-4-( 1 ,3-benzodioxol-5-yl)- 1 -([tert- butyloxycarbonylaminocarbonylmethyl]pyrroHdine-3 -carboxylic acid The resulting mixture of 64% transjrans- and cisjrans- pyrrolidines resulting from Example IC (3.01 g, 8.15 mmol) was dissolved in 50 mL of methylene chloride. To this was added dropwise a solution of di-tert-butyl dicarbonate (1.96 g, 8.97 mmol) in 20 mL methylene chloride under a nitrogen atmosphere, and the resulting solution was stirred 30 minutes at which point TLC (ethyl acetate: hexane, 1 : 1) indicated that aU of the starting material was consumed. The reaction mixture was concentrated and dried under high vacuum to give 3.94 g of the ethyl ester as a yellow-brown oil. XH NMR (CDCL3, 300 MHz)
0.99, 1.07 (br t, br t, J=7 Hz, 3H), 1.11-1.62 (several br m, 9H), 3.05 (br m, IH), 3.44-3.95 (m, 3H), 3.81 (s, 3H), 4.04 (q, J=7 Hz, IH), 4.14-4.28 (br m, IH), 4.89-5.24 (br m, IH), 5.94
(d, J=3 Hz, 2H), 6.69-6.90 (m, 5H), 7.06-7.20 (m, 2H). MS (DCI/NH3) m e 470 (M+H)+. i To the ethyl ester dissolved in 170 mL of ethanol was added a solution of Hthium hydroxide (1.06 g, 25.17 mmol) in 60 mL of water. The reaction mixture was vigorously stirred for 18 hours under a nitrogen atmosphere. The reaction mixture was concentrated to remove ethanol, diluted with 250 mL of water and extracted three times with 250 mL of ether. The organic phase acidified to shght cloudiness (pH ~7) with 1 N hydrochloric acid, then to pH 4 with 10 % citric acid and extracted with 5 % ethanol in methylene chloride (3 x 100 mL). The combined organic layers dried (Na2SO4), filtered, concentrated and dried on high vacuum to give the title compound as a white foam (2.19 g, 60 %). *H NMR (CDCI3, 300 MHz) 1.16 (v br s, 9H), 3.11 (br m, IH), 3.50-3.64 (m, 2H), 3.81 (s, 3H), 4.24 (br m, IH), 4.96 (br m, IH), 5.94 (s, 2H), 6.71-6.79 (m, 3H), 6.84-6.91 (m, 2H), 7.19 (d, =9 Hz, 2H). MS (DCI/NH3) m/e 442 (M+H)+.
Example 95B
(2R.3R.4SV(+V2-(4-MethoxyphenylV4-( 3-benzodioxol-5-yn-l-(tert- butyloxycarbonylaminocarbonylmethyl)-pyrroHdine-3-carboxylic acid The compound resulting from Example 95A (2.15 g, 4.86 mmol) and (+)-cinchonine (1.43 g, 4.86 mmol) were added to 100 mL of methylene chloride; this suspension was swirled with warming as necessary to get all sohds to dissolve. The solution was then concentrated and dried on high vacuum to a white foa This material was crystaUized from a mixture of refluxing chloroform (64 mL) and hexane (360 mL). The resulting crystals were isolated by filtration and recrystalHzed under the same conditions seven additional times. Each time the resulting crystals and filtrate were monitored by *H NMR and chiral HPLC. The amount of (2S,3S,4R)-(-)- enantiomer decreased first in the crystals and then in the filtrate with the predetermined endpoint achieved when the (2S,3S,4R)-(-)- enantiomer could no longer be detected in the filtrate. The pure (2R,3R,4S)-(+)- enantiomer thus obtained was partitioned between 100 mL of 10% citric acid and 100 mL of ether. The aqueous layer was further extracted twice with 100 mL of ether. The combined ether layers were washed with brine, dried (Na2SO4), filtered, concentrated and dried on high vacuum to a white powder (550 mg, 55 % of theoretical 50 % maximum, >99.5 ee). MR (CDCI3, 300 MHz) 1.05-1.50 (br m, 9H), 3.12 (br m, IH), 3.50-3.65 (m, 2H), 3.81 (s, 3H), 4.24 (m, IH), 4.96 (br m, IH), 5.95 (s, 2H), 6.70-6.79 (m, 3H), 6.86 (d, 1=9 Hz, 2H), 7.19 (d, J=9 Hz, 2H). MS (DCI/NH3) m/e 442 (M+H)+.
Example 95C (2R.3R.4SV(+ -Ethyl 2-(4-methoχyphenylV4-(1.3-benzodioxol-5-ylVpyrroHdine-3- carboxylate The compound resulting from Example 95B (251 mg, 0.568 mmol) was dissolved in 20 mL of a saturated solution of anhydrous HCl(g) in anhydrous ethanol. The resulting solution was heated at 50 C. with stirring for 18 hours at which point aU of the precipitated solid had dissolved. The reaction mixture was concentrated to a solid which was partitioned between O.8 M aqueous sodium carbonate (50 mL) and methylene chloride (50 mL). The aqueous layer was further extracted with methylene chloride (2 x 50 mL). The combined organic layers were dried (Na2SO4), filtered, concentrated and dried under high vacuum to give the title compound as an almost colorless oil (158 mg, 69%) . XH NMR (CDCI3,
300MHz) 1.11 (t, J=7 Hz, 3H), 2.18 (vbr s, IH), 2.93 (t, J= 9 Hz, IH), 3.19,3.22 (dd, J=7 Hz, IH), 3.50-3.69 (m, 2H), 3.80 (s, 3H), 4.07 (q, J=7 Hz, 2H), 4.49 (d, =9 Hz, IH), 5.94 (s, 2H), 6.73 (d, J=2 Hz, 2H), 6.81-6.92 (m, 3H), 7.34-7.41 (m, 2H). MS (DCI/NH3) m/e 370
(M+H)+.
Example 95D (2R.3R.4S -(+)-2-(4-Methoxyphenyl.-4-( 3-benzodioxol-5-yl -l-(tert-butyloxycarbonyl- aminocarbonylmethy -pyrroHdine-3-carboxy lie acid To the resulting compound from Example 95C (131 mg, 0.355 mmol) was added, dHsopropylethylamine (137 mg, 185 μL, 1.06 mmol), acetonitrile (2 mL), N,N-di-(n- butyl)bromoacetamide (133 mg, 0.531 mmol), and the mixture was heated at 50 C. for 1.5 hours. The reaction mixture was concentrated to a solid, dried under high vacuum, and purified by chromatography on silica gel eluting with 1:3 ethyl acetate-hexane to give pure ester as a colorless oU. *H NMR (CDCI3, 300MHz) δ 0.81 (t, J=7 Hz, 3H), 0.88 (t, J=7 Hz, 3H), 1.10 (t, J=7 Hz, 3H), 1.00-1.52 (m, 8H), 2.78 (d, J=14 Hz, IH), 2.89-3.10 (m, 4H), 3.23- 3.61 (m, 5H), 3.71 (d, =9 Hz, IH), 3.80 (s, 3H), 4.04 (q, J=7 Hz, 2H), 5.94 (dd, =1.5 Hz, 2H), 6.74 (d, J=9 Hz, IH), 6.83-6.90 (m, 3H), 7.03 (d, J=2 Hz, IH), 7.30 (d, =9 Hz, 2H). MS (DCI NΗ3) m/e 539 (M+H)+.
To the ethyl ester dissolved in 7 mL of ethanol was added a solution of Hthium hydroxide (45 mg, 1.06 mmol) in water (2.5 mL). The mixture was stirred for 1 hour at ambient temperature and then warmed slowly to 40 °C. over 2.5 hours at which point aU of the starting material had been consumed. The reaction mixture was concentrated to remove the ethanol, dUuted with 60 mL water and extracted with ether (3 x 40 mL). The aqueous solution was treated with 1 N aqueous hydrochloric acid untU cloudy, and the pH was then adjusted to ~4-5 with 10% aqueous citric acid. This mixture was extracted with 1:19 ethanol- methylene chloride (3 x 50 mL). The combined extracts were dried (Na2SO4), filtered, concentrated and dried under high vacuum to give the title compound as a white foam (150 mg, 83%). *H NMR (CDC13, 300MHz) δ 0.80 (t, J=7 Hz, 3H), 0.88 (t, =7 Hz, 3H), 1.08
(m, 2H), 1.28 (m, 3H), 1.44 (m, 3H), 2.70-3.77 (svr br m, 12H), 3.79 (s, 3H), 5.95 (m, 2H), 6.75 (d, =8 Hz, IH), 6.87 (br d, =8 Hz, 3H), 7.05 ( br s, IH), 7.33 (v br s, 2H). MS (DCI/NH3) m/e 511 (M+H)+. [α]22 = +74.42° . Anal calcd for C29H38N2O6 -0.5 H2O: C ,67.03; H, 7.56; N, 5.39. Found: C, 67.03; H, 7.59; N, 5.33.
Example 95E Alternate Preparation of (2R.3R.4SV(+V2-(4-MethoxyphenylV4-(1.3-benzodioxol-5-ylVl- (tert-butyloxycarbonylaminocarbonylmethyl)-pyrrolidine-3-carboxylic acid
The product of Example 95A (2.858 g) was suspended in 10 mL of EtOAc. 0.7833 g of R (+) alpha methyl benzy lamine in 3 mL ethyl acetate was added. On swirling aU of the soHds were dissolved. The ethyl acetate was removed in vacuum. Ether (13 ml) was added to the residue. When aU of the residue had dissolved, 5 mg of seed crystals were added and these crystals were crushed with a metal spatula while cooling in ice. The product crystaUized very slowly. After 1 hour the sohd was filtered and washed with ether giving 1.4213 g, p. 163-167°. The filtrate was concentrated, cooled and scratched with a spatula to give a second crop 0.1313 g, mp. 164-168°. The filtrate was concentrated again and put in the refrigerator and let stand overnight giving 1.6906 g, mp. 102-110°. (HPLC of this showed 20%of the desired enantiomer and 80% of the unwanted enantiomer.)
The first two batches of crystaUized material were combined and suspended in 20 mL dichloromethane (Note: the unwanted isomer is more soluble in dichloromethane) and stirred for 2 minutes. The mixture was concentrated, but not to dryness, and ether (10 mL) was added. After stirring for a few minutes the crystals were filtered. Yield: 1.401 g, mp. 164- 172°.
Treatment of the crystalline product with 10% citric acid and ether according the method described in Example 95B provided the title compound.
Example 96 tr_.ns.trans-2-(4-Methoxyphenyl)-4-(l,3-benzodioxol-5-yl)-l-[2-(N-propyl-N- butyrylamino) ethyl]pyι OHdine-3 -carboxylic acid The title compound was prepared by the methods described in Example 61, but substituting propylamine for methylamine in Example 61B and butyryl chloride for isobutyryl chloride in Example 61 C. The product was purified by preparative HPLC (Vydac μC18) eluting with a 10-70% gradient of CH3CN in 0.1% TFA. The desired fractions were lyophilized to give the product as a white sohd. Η NMR (CDCI3, 300 MHz) δ 0.80 (m, 3H), 0.90 (t, 3H, J=8Hz), 1.42 (m, 2H), 1.58 (heptet, 2H, J=8Hz), 2.20 (t, 3H, J=8Hz), 2.94 (br m, 2H), 3.10 (br m, 2H), 3.48 (br m, 4H), 3.76 (br m, 2H), 3.78 (s, 3H), 4.30 (br s, IH), 5.95 (s, 2H), 6.75 (d, IH, I=8Hz), 6.84 (m, IH), 6.85 (d, 2H, J=8Hz), 7.04 (d, IH, J=lHz), 7.40 (d, 2H, I=8Hz). MS (DCI/NH3) m/e 497 (M+H)+. Anal calcd for C28H36N2O6 1.0 TFA: C, 58.82; H, 6.42; N, 4.57. Found: C, 58.77; H, 6.30; N, 4.42.
Example 97 trans.tr-.7.s-2-(4-Methoxyphenyl)-4-(1.3-benzodioxol-5-yl)-l-[2-(N-propyl-N- (ethylaminocarbonyl.amino^ethyl]pyrrolidine-3-carboxylic acid The title compound was prepared by the methods described in Example 61 , but substituting propylamine for methylamine in Example 61B and ethyl isocyanate for isobutyryl chloride in Example 61C. The crude product was purified by trituration with 1: 1 diethyl ether-hexane. The resulting soHd was dissolved in CH3CN and water and lyophilized to give the product as a white solid. 1H NMR (CDCI3, 300 MHz) mixture of rotamers δ 0.80 (t, I=8Hz) and 1.05 (t, I=8Hz) and 1.20 (m) and 1.42 (m) total of 8H for the four peaks, 2.35 (br s, IH), 2.70 (m, IH), 3.0 (m, 3H), 3.2 (m, 3H), 3.25 (dq, IH, I=l,8Hz), 3.42 (m, IH), 3.6 (m, IH), 3.75 (m, IH), 3.78 (s, 3H), 4.8 (br s, IH), 5.95 (s, 2H), 6.74 (d, IH, J=8Hz), 6.85 (m, 3H), 7.00 (s, IH), 7.30 (d, 2H, I=8Hz). MS (DCI/NH3) m/e 498 (M+H)+. Anal calcd for C27H35N3O6 • 0.75 H2O: C, 63.45; H, 7.20; N, 8.22. Found: C, 63.38; H, 7.29; N, 8.44.
Example 98 tr-.ns.tr-.ns-2-(4-Methoxyphenyl)-4-(l,3-benzodioxol-5-yl)-l-[2-(N-butyl-N- butyrylamino . ethylJpyrrolidine-3 -carboxylic acid The title compound was prepared by the methods described in Example 61, but substituting butylamine for methylamine in Example 61B and butyryl chloride for isobutyryl chloride in Example 61C. The crude product was purified by trituration with 1: 1 diethyl ether-hexane. The resulting solid was dissolved in CH3CN and water and lyophilized to give the product as a white sohd. 1H NMR (CDCI3, 300 MHz) δ 0.80 (m, 3H), 0.90 (t, 3H, I=8Hz), 1.45 (m, 4H), 1.6 (m, 2H), 2.20 (t, 3H, J=8Hz), 2.94 (br m, 2H), 3.10 (br m, 2H), 3.5 (br m, 4H), 3.80 (br m, 2H), 3.82 (s, 3H), 4.30 (br s, IH), 5.95 (s, 2H), 6.75 (d, IH, J=8Hz), 6.84 (m, IH), 6.85 (d, 2H, J=8Hz), 7.04 (d, IH, J=lHz), 7.40 (d, 2H, I=8Hz). MS (DCI/NH3) m/e 511 (M+H)+. HRMS calcd for C29H38N2O6: 511.2808. Found: 511.2809
Example 99 tra7zs.trans-2-(4-Methoxyphenyl)-4-(l,3-benzodioxol-5-yl)-l-[2-(N-ρropyl-N- ethoxycarbonylamino)ethyllpyrroHdine-3-carboxy lie acid The title compound was prepared by the methods described in Example 61, but substituting propylamine for methylamine in Example 6 IB and ethyl chloroformate for isobutyryl chloride in Example 61C. The crude product was purified by trituration with 1 : 1 diethyl ether-hexane. The resulting solid was dissolved in CH3CN and water and lyophilized to give the product as a white sohd. 1H NMR (CDCI3, 300 MHz) δ 0.80 (t, 3H, I=8Hz), 1.05 (m, 2H), 1.22 (m, 3H), 1.45 (m, 3H), 2.08 (br s, IH), 2.75 (m, IH), 2.88 (br q, 2H, J=8Hz), 3.08 (br m, 2H), 3.27 (br m, 2H), 3.44 (m, IH), 3.54 (dt, IH, J=l,8Hz), 3.63 (d, IH, J=8Hz), 3.78 (s, 3H), 4.02 (br d, 2H), 5.93 (s, 2H), 6.72 (d, IH, I=8Hz), 6.81 (dd, IH, J=l,8Hz), 6.85 (d, 2H, I=8Hz), 7.00 (s, IH), 7.30 (d, 2H, I=8Hz). MS (DCI/NH3) m/e 499 (M+H)+. Anal calcd for C-27H34N2O7 • 0.5 H2O: C, 63.89; H, 6.95; N, 5.52. Found: C, 64.03; H, 6.71; N, 5.30.
Example 100 tra7.s.trans-2-(4-Methoxyphenyl)-4-(l,3-benzodioxol-5-yl)-l-[2-(N-methyl-N-(2- ethylbutyryl)amino)ethyl]pyrrolidine-3-carboxyHc acid To the compound resulting from Example 6 IB (190 mg) dissolved in THF (2 mL) was added HOBt (60 mg), EDCI (85 mg), N-methylmoipholine (50 μL), and DMF (2 mL). 2-Ethylbutyric acid was added and the solution stirred overnight at ambient temperature. Water (10 mL) was added, and the mixture was extracted with EtOAc (2 x 25 mL). The combined organic extracts were washed with saturated sodium bicarbonate solution, 1 N H3PO4, and brine, dried with Na2SO4, and evaporated to give an oU which was purified by flash chromatography on siHca gel eluting with 1:3 EtOAc-hexane. The resulting ethyl ester was saponified by the procedure described in Example 61C. The crude product was dissolved in CH3CN and water and lyophilized to give the product as a white sohd. H NMR (CDCI3, 300 MHz) (mixture of rotamers) 0.66, 0.74, 0.80, 0.88 (aU triplets, total of 6H, I=8Hz), 1.05 (m, 2H), 1.25-1.75 (m, 5H), 2.16 (m, IH), 2.32 (m, IH), 2.45 (m, IH), 2.70 (m, IH), 2.86, 2.94 (s, total 3H), 2.95 (m, IH), 3.35 (m, IH), 3.52 (m, 2H), 3.65 (m, IH), 3.80 (s, 3H), 5.94, 5.96 (s, total 2H), 6.73 (m, IH), 6.84 (m, 3H), 6.97 (m, IH), 7.30 (m, 2H). MS (DCI NH3) m/e 497 (M+H)+. Anal calcd for C28H36N2O6 ■ 0.25 H2O: C, 67.11; H, 7.34; N, 5.59. Found: C, 67.13; H, 7.24; N, 5.56.
Example 101 tra7.s,trans-2-(4-Methoxypheny -4-(l,3-benzodioxol-5-ylVl-[2-(N-methyl-N-(2- propylvaleryl amino ethyl1pyrrolidine-3-carboxyHc acid The title compound was prepared by the procedure described in Example 100, but substituting 2-propylpentanoic acid for 2-ethylbutyric acid. The crude product was purified by preparative HPLC (Vydac μC18) eluting with a 10-70% gradient of CH3CN in 0.1%
TFA. The desired fractions were lyophilized to give the product as a white solid. 1H NMR (CDCI3, 300 MHz) δ 0.79 (t, 3H, J=8Hz), 0.82 (t, 3H, J=8Hz), 1.10 (m, 4H), 1.2- 1.5 (m, 4H), 2.55 (m, IH), 2.96 (s, 3H), 3.15 (br m, IH), 3.32 (br m, IH), 3.56 (m, 2H), 3.68 (m, IH) 3.68 (s, 3H), 3.70 (m, IH), 3.80 (m, 2H), 4.65 (br d, IH), 5.92 (s, 2H), 6.75 (d, IH, J=8Hz), 6.84 (m, IH), 6.85 (d, 2H, J=8Hz), 7.05 (s, IH), 7.42 (d, 2H, J=8Hz). MS
(DCI/NH3) m/e 525 (M+H)+. Anal calcd for C30H40N2O6 • 1.25 TFA: C, 58.51; H, 6.23; N, 4.20. Found: C, 58.52; H, 6.28; N, 4.33.
Example 102 transJr_.ns-2-(4-Methoxyphenyl)-4-(l,3-benzodioxol-5-yl l-[2-(N-propyl-N-(tert- butyloxycarbonylmethyl) amino . ethyl]pyrroHdine-3 -carboxylic acid The title compound was prepared by the methods described in Example 61, but substituting propylamine for methylamine in Example 61B and t-butyl bromoacetate for isobutyryl chloride in Example 61 C. The crude product was purified by trituration with 1 : 1 diethyl ether-hexane. The resulting solid was dissolved in CH3CN and water and lyophilized to give the product as a white sohd. 1H NMR (CDCI3, 300 MHz) δ 0.82 (t, 3H, J=8Hz), 1.18 (m, 2H), 1.19 (s, 9H), 2.12 (m, IH), 2.46 (m, 2H), 2.70 (m, 3H), 2.85 (m, 2H), 3.20 (s, 2H), 3.40 (dd, IH, I=2,8Hz), 3.50 (dt, IH, I=2,8Hz), 3.62 (d, IH, I=8Hz), 3.78 (s, 3H), 5.95 (s, 2H), 6.72 (d, IH, I=8Hz), 6.84 (m, IH), 6.85 (d, 2H, J=8Hz), 7.05 (s, IH), 7.16 (d, 2H, I=8Hz). MS (DCI/NH3) m/e 541 (M+H)+. Anal calcd for C30H40N2O7 ■ 1.0 H2O: C, 64.50; H, 7.58; N, 5.01. Found: C, 64.75; H, 7.35; N, 4.86.
Example 103 trans.trans-2-(4-Methoxyphenyl)-4-(1.3-benzodioxol-5-yl)-l-[2-(N-propyl-N-(n- propylaminocarbonylmethyl)amino)ethyl]pyrroHdine-3-carboxylic acid The title compound was prepared by the methods described in Example 61, but substituting propylamine for methylamine in Example 6 IB and N-propyl bromoacetamide for isobutyryl chloride in Example 61C. The crude product was purified by preparative HPLC (Vydac Cl 8) eluting with a 10-70% gradient of CH3CN in 0.1 % TFA. The desired fractions were lyophilized to give the product as a white soHd. H NMR (CDCI3, 300 MHz) 0.78 (t, 3H, I=8Hz), 0.88 (t, 3H, I=8Hz), 1.45 (m, 2H), 1.48 (m, 3H, I=8Hz), 2.55-2.7 (m,
2H), 2.90 (m, IH), 3.04 (m, IH), 3.15 (m, 3H), 3.28 (t, IH, J=8Hz), 3.45 (t, IH, I=8Hz), 3.60 (m, 2H), 3.70 (d, 2H, J=8Hz), 3.75 (m, IH), 3.80 (s, 3H), 4.25 (d, IH, I=8Hz), 5.95 (s, 2H), 6.75(d, IH, J=8Hz), 6.86 (dt, IH, I=l,8Hz), 6.88 (d, 2H, J=8Hz), 7.04 (d, IH, J=lHz), 7.40 (d, 2H, I=8Hz). MS (DCI/NH3) m/e 526 (M+H)+. Anal calcd for C29H39N3O6 • 1.85 TFA: C, 53.32; H, 5.59; N, 5.70. Found: C, 53.45; H, 5.62; N, 5.63.
Example 104 trans,tra72s-2-(4-Methoxyphenyl)-4-(l,3-benzodioxol-5-yl)-l-[2-(N-propyl-N-(4- methoxyphenoxycarbony 1) amino) ethyl]pyrrolidine-3 -carboxylic acid The title compound was prepared by the methods described in Example 61, but substituting propylamine for methylamine in Example 6 IB and 4- methoxyphenylchloroformate for isobutyryl chloride in Example 61C. The crude product was purified by trituration with 1 : 1 diethyl ether-hexane. The resulting solid was dissolved in CH3CN and water and lyophilized to give the product as a white sohd. H NMR (CD3OD, 300 MHz) mixture of rotamers δ 0.88 (m,3H), 1.57 (m, 2H), 2.45 (br s) and 2.60 (br s, total of IH), 2.90-3.15 (m, 4H), 3.42-3.7 (m, 5H), 3.78 (s, 3H), 3.80 (s, 3H), 3.85 (m) and 4.0 (m, total of IH), 5.95 (s) and 5.98 (s, total of 2H), 6.63(m, IH), 6.72 (d, IH, J=8Hz), 6.81 (m, 2H), 6.93 (m, 5H), 7.40 (m, 2H). MS (DCI/NH3) m/e 577 (M+H)+. Anal calcd for C32H36N2O8 • 1.0 H2O: C, 64.63; H, 6.44; N, 4.71. Found: C, 64.70; H, 6.38; N, 4.63.
Example 105 trans. trans-2-( 4-Methoxyphenyl)-4-( 1 ,3-benzodioxol-5-yl)- 1 -[2-(N-propyl-N-(4- methoxybenzoyl)amino)ethyl]pyrrolidine-3-carboxy lie acid The title compound was prepared by the methods described in Example 61, but substituting propylamine for methylamine in Example 61B and anisoyl chloride for isobutyryl chloride in Example 61 C. The crude product was purified by trituration with 1 : 1 diethyl ether-hexane. The resulting sohd was dissolved in CH3CN and water and lyophilized to give the product as a white sohd. 1H NMR (CDCI3, 300 MHz) mixture of rotamers δ 0.78 (m) and 0.98 (t, I=8Hz) total of 3H, 1.47 (m) and 1.52 (q, I=8Hz) total of 2H, 2.25 (br s, IH), 2.78 (br s, IH), 2.90 (br t, 2H), 3.12-3.68 (m, 7H), 3.80 (s, 3H), 3.82 (s, 3H), 5.94 (s, 2H), 6.75(d, IH, I=8Hz), 6.83 (m, 5H), 6.94 (m, IH), 7.22 (m, 4H). MS (FAB) m/e 561 (M+H)+. Anal calcd for C32H36N2O7 • 0.75 H2O: C, 66.94; H, 6.58; N, 4.88. Found: C, 67.00; H,
6.38; N, 4.59.
Example 106 trans,tr-.ns-2-(4-Methoxyphenyl -4-(l,3-benzodioxol-5-yl -l-[2-(N-propyl-N- benzoylamino) ethyl]pyrroHdine-3 -carboxylic acid The title compound was prepared by the methods described in Example 61, but substituting propylamine for methylamine in Example 6 IB and benzoyl chloride for isobutyryl chloride in Example 61C. The crude product was purified by trituration with 1 : 1 diethyl ether-hexane. The resulting solid was dissolved in CH3CN and water and lyophilized to give the product as a white sohd. 1H NMR (CDCI3, 300 MHz) mixture of rotamers δ 0.65 and 0.9 ( , total of 3H) , 1.4 and 1.55 (m, total of 2H), 2.05 and 2.15 (m, total of IH), 2.6 - 3.6 (m, 8H), 5.92 (s, 2H), 6.70(d, IH, I=8Hz), 6.82 (m, 4H), 7.2 - 7.4 (m, 6H). MS (DCI/NH3) m/e 531 (M+H)+. Anal calcd for C31H34N2O6 • 0.3 H2O: C, 69.46; H, 6.51; N, 5.23. Found: C, 69.48; H, 6.19; N, 4.84.
Example 107 trans.trans-2-(4-Methoxyphenyl)-4-(l,3-benzodioxol-5-yl)-l-[2-(N-propyl-N- benzyloxycarbonylamino) ethyl]pyιτoHdine-3 -carboxylic acid The title compound was prepared by the methods described in Example 61, but substituting propylamine for methylamine in Example 6 IB and benzyl chloroformate for isobutyryl chloride in Example 61C. The crude product was purified by preparative HPLC (Vydac μC18) eluting with a 10-70% gradient of CH3CN in 0.1% TFA. The desired fractions were lyophilized to give the product as a white sohd. H NMR (CDCI3, 300 MHz) δ 0.8 (m, 3H) 1.45 (m, 2H), 2.20 (br m, IH), 2.75 ( , IH), 2.93 (m, IH), 3.15 (m, 2H), 3.32 (m, 3H), 3.52 (m, 2H), 3.66 (m, IH), 3.78 (s, 3H), 5.00 (m, 2H), 5.94 (s, 2H), 6.72(d, IH, I=8Hz), 6.82 (m, 3H), 7.0 (br d, IH, = 15Hz), 7.2 (s, 4H), 7.30 (m, 3H). MS (FAB) m/e 561 (M+H)+. Anal calcd for C32H36N2O7 • 1.0 TFA: C, 60.53; H, 5.53; N, 4.15. Found: C,
60.66; H, 5.34; N, 4.28.
Example 108 trans. trans-2-(4-Methoxyphenyl)-4-( 1.3-benzodioxol-5-yl)- 1 -[2-(N-propyl-N-(4- methoxybenzyloxycarbonyl)amino)ethyl]pyrroUdine-3-carboxy lie acid The title compound is prepared by the methods described in Example 61, substituting propylamine for methylamine in Example 6 IB and 4-methoxybenzyl chloroformate for isobutyryl chloride in Example 61 C.
Example 109 transJr-.ns-2-(4-Methoxyphenyl)-4-(l,3-benzodioxol-5-yl)-l-[2-(N-butyl-N- ethoxycarbonylamino)ethyl]pyrroHdine-3-carboxy lie acid The title compound was prepared by the methods described in Example 61, but substituting butylamine for methylamine in Example 6 IB and ethyl chloroformate for isobutyryl chloride in Example 61C. The crude product was purified by preparative HPLC (Vydac μC18) eluting with a 10-70% gradient of CH3CN in 0.1% TFA. The desired fractions were lyophilized to give the product as a white sohd. H NMR (CDCI3, 300 MHz) δ 0.82 (t, 3H, J=8Hz), 1.20 (m, 5H), 1.34 (m, 2H), 3.08 (m, 2H), 3.17 (m, 2H), 3.52 (m, 2H), 3.75 (m, 2H), 3.78 (s, 3H), 4.06 (q, 2H, J=8Hz), 4.35 (br s, IH), 5.94 (s, 2H), 6.76 (d, IH, J=8Hz), 6.92 (d, 2H, I=8Hz), 7.03 (br s, IH), 7.17 (br s, IH), 7.7 (br s, 2H). MS (FAB) m/e 513 (M+H)+. Anal calcd for C28H36N2O7 • 0.5 TFA: C, 61.15; H, 6.46; N, 4.92. Found: C, 60.99; H, 6.80; N, 4.93.
Example 110 trans.tr ns-2-(4-Methoxyphenyl)-4-(1.3-benzodioxol-5-ylVl-[2-(N-butyl-N- propoxycartaonylamino)ethyl]pyrroUdine-3-carboxy lie acid The title compound was prepared by the methods described in Example 61, but substituting butylamine for methylamine in Example 6 IB and propyl chloroformate for isobutyryl chloride in Example 61C. The crude product was purified by trituration with 1 : 1 diethyl ether-hexane. The resulting sohd was dissolved in CH3CN and water and lyophilized to give the product as a white sohd. 1H NMR (CDCI3, 300 MHz) 0.80 (br s, IH), 0.85 (t, 3H, J=8Hz), 0.92 (br s, IH), 1.22 (m, 3H), 1.40 (m, 3H), 1.62 (br m, IH), 2.15 (br s, IH), 2.72 (m, IH), 2.87 (m, IH), 3.1-3.45 (m, 5H), 3.55 (m, IH), 3.64 (d, IH, I=8Hz), 3.79 (s, 3H), 3.88 (br s, IH), 3.97 (br s, IH), 5.95 (s, 2H), 6.73(d, IH, I=8Hz), 6.85 (m, 3H, 7.0 (s, IH), 7.30 (d, 2H, J=8Hz). MS (FAB) m/e 527 (M+H)+. Anal calcd for C29H38N2O7 0.15 H2O: C, 65.80; H, 7.29; N, 5.29. Found: C, 65.79; H, 7.30; N, 5.21.
Example 111 tr_.ns,tr-.ns-2-(4-Methoxyphenyl)-4-(l,3-benzodioxol-5-yl)-l-[2-(N-propyl-N- propoxycarbonylamino) ethyl]pyrroUdine-3 -carboxylic acid The title compound was prepared by the methods described in Example 61, but substituting propylamine for methylamine in Example 6 IB and propyl chloroformate for isobutyryl chloride in Example 61 C. The crude product was purified by trituration with 1 : 1 diethyl ether-hexane. The resulting sohd was dissolved in CH3CN and water and lyophilized to give the product as a white soHd. 1H NMR (CDCI3, 300 MHz) 0.80 (t, 3H, I=8Hz), 093 (m, 3H), 1.43 (m, 3H), 1.62 (m, IH), 2.15 (br s, IH), 2.68-3.45 (m, 8H), 3.54 (m, IH), 3.66 (m, IH), 3.78 (s, 3H), 3.94 (m, 2H), 5.94 (s, 2H), 6.72 (d, IH, J=8Hz), 6.82 (m, IH), 6.84 (d, 2H, I=8Hz), 7.00 (br s, IH), 7.33 (m, 2H). MS (DCI/NH3) m/e 513 (M+H)+. Anal calcd for C28H36N2O7 0.15 H2O: C, 65.26; H, 7.10; N, 5.44. Found: C, 65.22; H, 6.74; N, 5.06.
Example 112 tra7.s,trans-l-(K,N-Di(n-butyl)aminocarbonylmethyl)-2,4-di(l,3-benzodioxol-5- yl)pyrrolidine-3 -carboxylic acid Ethyl (3 ,4-methylenedioxybenzoyl) acetate, prepared by the method of Krapcho et al,
Org. Syn. 47, 20 (1967) starting with 3,4-methylenedioxyacetophenone instead of 4- methoxyacetophenone, was reacted by the procedures described in Example 1 to give the title compound as a white soHd. mp. 58-60 °C. 1H NMR (CDCI3, 300 MHz) δ 0.87 (quintet, J=6Hz, 6H), 1.12 (sextet, J=6Hz, 2H), 1.24-1.51 (m, 6H), 2.80 (d, J=13Hz, IH), 2.94-3.12 (m, 4H), 3.28-3.50 (m, 4H), 3.58-3.62 (m, IH), 3.78 (d, I=9Hz, IH), 5.95 (s, 4H), 6.73 (dd, I=8Hz, 3Hz, 2H), 6.84-6.89 (m, 2H), 6.92 (d, I=lHz, IH), 7.01 (d, H=lHz, IH). MS (DCI/NH3) m/e 525 (M+H)+.
Example 113 trans.trans-l-(2-(N-(n-Butyl)-N-propylsulfonylamino)ethyl)-2-(4-methoxyphenyl)-4-(l,3- benzodioxol-5-yl)pyrrolidine-3-carboxylic acid Using the procedures described in Example 66, the title compound was prepared as a white solid, p. 64-65 °C. 1H NMR (CDC13, 300 MHz) δ 0.83 (t, J=7Hz, 3H), 0.98 (t,
I=7Hz, 3H), 1.12-1.25 (m, 2H), 1.32-1.41 (m, 2H), 1.75 (sextet, I=7Hz, 2H), 2.23-2.31 ( , 2H), 2.72-3.32 (m, 8H), 3.43 (dd, J=9Hz, 3Hz, IH), 3.53-3.59 (m, IH), 3.65 (d, I=9Hz, IH), 3.80 (s, 3H), 5.95 (s, 2H), 6.73 (d, J=8Hz, IH), 6.83 (dd, I=8Hz, IHz, IH), 6.88 (d, I=9Hz, 2H), 7.02 (d, I=lHz, IH), 7.33 (d, I=9Hz, 2H). MS (DCI/NH3) m/e 547 (M+H)+.
Example 114 trans, trans- 1 -(N.N-Di(n-butyl.aminocarbonylmethyl)-2-(4-methoxyphenyl -4-( 1.3- benzodioxol-5-yl)pyrrolidine-3-carboxy lie acid
Using the procedures described in Examples 28 and 43, the title compound was prepared as a white sohd. p. 74-76 °C. 1HNMR (CDCI3, 300 MHz) δ 0.80 (t, I=6Hz, 3H), 0.88 (t, J=8Hz, 3H), 1.08 (sextet, J=8Hz, 2H), 1.21-1.48 (m, 6H), 2.75 (d, J=12Hz, IH), 2.95-3.09 (m, 4H), 3.26-3.59 (m, 5H), 3.75 (d, J=9Hz, IH), 3.79 (s, 3H), 4.28 (s, 4H), 6.78 (d, I=9Hz, IH), 6.85 (d, I=9Hz, 2H), 6.91 (d,d, I=3Hz, 9Hz, IH), 6.98 (d, I=3Hz, IH), 7.32 (d, J=9Hz, 2H). MS (DCI/NH3) m/e 525 (M+H)+.
Example 115 transJrans-l-(2-(N-Propyl-N-propylsulfonylamino)ethvπ-2-(4-methoxyphenyl -4-(l,3- taenzodioxol-5-yl)pyrrolidine-3-cartaoxy lie acid
Using the procedures described in Example 66, the title compound was prepared as a white solid, p. 72-73 °C. 1H NMR (CDCI3, 300 MHz) δ 0.79 (t, I=8Hz, 3H), 0.98 (t, J=8Hz, 3H), 1.43 (sextet, J=8Hz, 2H), 1.75 (sextet, I=8Hz, 2H), 2.22-2.32 (m, IH), 2.69-3.32 (m, 9H), 3.42 (dd, I=3Hz, 12Hz, IH), 3.52-3.58 (rn, IH), 3.64 (d, J=12Hz, IH), 3.80 (s, 3H), 5.95 (s, 2H), 6.73 (d, =1 IHz, IH), 6.83 (dd, J=lHz, 1 IHz, IH), 6.87 (d, =1 IHz, 2H), 7.0 (d, J=2Hz, IH), 7.32 (d, =1 IHz, 2H). MS (DCI/NH3) m/e 533 (M+H)+.
Example 116 trans, trans- 1 -(2-(N-Butyl-N-butylsulfonylamino)ethyl)-2-(4-methoxyphenyl)-4-( 1.3- benzodioxol-5-yl)pyrroHdine-3-cartaoxylic acid
Using the procedures described in Example 66, the title compound was prepared as a white solid, p. 62-63 °C. 1H NMR (CDCI3, 300 MHz) δ 0.82 (t, J=6Hz, 3H), 0.91 )t, J=6Hz, 3H), 1.20 (sextet, J=6Hz, 2H), 1.33-1.42 (m, 4H), 1.68 (quintet, I=6Hz, 3H),2.23- 2.32 (m, IH), 2.70-3.28 (m, 9H), 3.41 (d, I=8Hz, IH), 3.52-3.58 (m, IH), 3.65 (d, I=8Hz, 1H), 3.79 (s, 3H), 5.95 (s, 2H), 6.72 (d, J=8Hz, IH), 6.82 (d, J=8Hz, IH), 6.87 (d, I=8Hz, 2H), 7.01 (s, IH), 7.32 (d, I=8Hz, 2H). MS (DCI/NH3) m/e 561 (M+H)+.
Example 117 trans.trans-l-(2-(N,N-Di(n-butyl)aminocarbonylmethyl)-2-(4-methoxymethoxyphenyl)-4-
(1.3-benzodioxol-5-yl.pyrrolidine-3-carboxylic acid 4-Hydroxyacetophenone was treated with chloromethyl methyl ether and triethylamine in THF at room temperature to give ethyl 4-methoxymethoxybenzoylacetate which was treated by the procedures described in Example 1 to afford the title compound as a white sohd. m.p. 48-49 °C. 1H NMR (CDCI3, 300 MHz) δ 0.81 (t, I=7Hz, 3H), 0.88 (t,
J=7Hz, 3H), 1.06 (sextet, J=7Hz, 2H), 1.20-1.35 (m, 4H), 1.44 (quintet, I=7Hz, 2H), 2.75 (d, J=12Hz, IH), 2.94-3.10 (m, 4H), 3.25-3.35 (m, IH), 3.40 (d, J=12Hz, IH), 3.43-3.52 (m, 2H), 3.47 (s, 3H), 3.55-3.62 (m, IH), 3.77 (d, I=9Hz, IH), 5.15 (s, 2H), 5.94 (m, 2H), 6.73 (d, J=8Hz, IH), 6.86 (dd, I=lHz, 8Hz, IH), 7.0 (d, I=8Hz, 2H), 7.04 (d, I=lHz, IH), 7.32 (d, J=8Hz, 2H). MS (DCI/NH3) m/e 541 (M+H)+.
Example 118 trans, trans- 1 -(2-(N,N-Di(n-butyl aminocarbonylmethyl)-2-(4-hvdroxyphenyl -4-( 1,3- benzodioxol-5-yl)ρyrroHdine-3-carboxylic acid hydroehloride salt The compound resulting from Example 116 was treated with concentrated HCl in 1 : 1
THF-isopropanol to give the title compound as a white sohd. mp. 211-212 °C. 1HNMR (CD3OD, 300 MHz) δ 0.90 (t, J=8Hz, 6H), 1.12-1.27 (m, 6H), 1.36-1.45 (m, 2H), 3.04 (bs,
IH), 3.14-3.35 (t, I=9Hz, IH), 3.90 (bs, 3H), 4.17 (d, I=15Hz, IH), 5.96 (s, 2H), 6.82-6.93
(m, 4H), 7.03 (d, J=lHz, IH), 7.42 (bs, 2H). MS (DCI/NH3) m/e 497 (M+H)+.
Example 119 trans.trαns-l-(2-(N-Isobutyl-N-propylsulfonylamino)ethyl)-2-(4-methoxyphenyl)-4-(l,3- benzo dioxol~5-yl)pyrrolidine-3 -carboxylic acid Using the procedures described in Example 66, the title compound was prepared as a white solid, mp. 73-74 °C. 1H NMR (CDCI3, 300 MHz) δ 0.80 (d, J=6Hz, 6H), 0.98 (t,
J=8Hz, 3H), 1.62 (sextet, J=6Hz, IH), 1.74 (sextet, J=8Hz, 2H), 2.23-2.34 (m, IH), 2.68-2.98 (m, 7H), 3.08-3.18 (m, IH), 3.26-3.42 (m, 2H), 3.52-3.58 (m, IH), 3.65 (d, J=9Hz, IH), 3.80 (s, 3H), 5.90 (s, 2H), 6.74 (d, J=8Hz, IH), 6.82 (d, I=8Hz, IH), 6.86 (d, J=8Hz, 2H), 6.98 (d,
J=lHz, IH), 7.33 (d, I=8Hz, 2H). MS (DCI/NH3) m/e 547 (M+H)+. Example 120 trαnsJr_-7zs-l-(2-(N-Beιιzenesulfonyl-N-propylamino)ethyl -2-(4-methoxyphenyl -4-(1.3- benzodioxol-5-y pyrroHdine-3-carboxylic acid Using the procedures described in Example 66, the title compound was prepared as a white soHd. mp. 89-91 °C. 1H NMR (CDC13, 300 MHz) δ 0.74 (t, J=6Hz, 3H), 1.33 (sextet, I=6Hz, 2H), 2.20-2.30 (m, IH), 2.62-2.72 (m, IH), 2.85-3.05 (m, 4H), 3.12-3.22 (m, IH), 3.38 (dd, I=3Hz, 9Hz, IH), 3.49-3.57 (m, IH), 3.62 (d, J=9Hz, IH), 3.82 (s, 3H), 5.96 (s, 2H), 6.73 (d, J=8Hz, IH), 6.84 (dd, J=lHz, 8Hz, IH), 6.85 (d, I=9Hz, 2H), 7.02 (d, I=lHz, IH), 7.28 (d, I=9Hz, 2H), 7.39-7.54 (m, 3H), 7.70 (d, J=7Hz, 2H). MS (DCI/NH3) m/e 567 (M+H)+.
Example 121 trans, trans- 1 -(2-(N-(4-Methoxybenzenesulfonyl)-N-propylamino)ethyl)-2-(4- methoxyphenyl)-4-(l .3-benzodioxol-5-yl)pyrroHdine-3-carboxylic acid Using the procedures described in Example 66, the title compound was prepared as a white solid, p. 96-97 °C. 1H NMR (CDCI3, 300 MHz) δ 0.73 (t, I=7Hz, 3H), 1.34 (sextet, I=7Hz, 2H), 2.20-2.30 (m, IH), 2.62-2.71 (m, IH), 2.82-3.03 (m, 4H), 3.08-3.18 (m, 2H), 3.38 (dd, J=3Hz, 9Hz, IH), 3.48-3.56 (m, IH), 3.62 (d, J=9Hz, IH), 3.81 (s, 3H), 3.86 (s, 3H), 5.95 (s, 2H), 6.73 (d, J=8Hz, IH), 6.81-6.89 (m, 5H), 7.01 (d, J=lHz, IH), 7.28 (d, I=8Hz, 2H), 7.62 (d, I=8Hz, 2H). MS (DCI/NH3) m/e 597 (M+H)+.
Example 122 trans, trans- 1 -(N,N-Di(n-butyl)aminocarbonylmethyl)-2-(2-methoxyethoxy-4- methoxyphenyl)-4-( 1.3-benzodioxol-5-yl)pyrrolidine-3-carboxylic acid 2-Hydroxy-5-methoxyacetophenone was treated with sodium hydride and bromoethyl methyl ether in THF at 70 °C to provide ethyl 2-methoxyethoxy-4-methoxybenzoylacetate which was treated by the procedures described in Example 1 to provide the title compound as a white sohd. m.p. 63-65 °C. 1H NMR (CDCI3, 300 MHz) δ 0.84 (t, I=7Hz, 3H), 0.89 (t, I=7Hz, 3H), 1.16 (sextet, J=7Hz, 2H), 1.28 (sextet, I=7Hz, 2H), 1.45-1.52 (m, 4H), 2.87-2.94 (m, 2H), 3.00-3.16 (m, 3H), 3.26-3.36 (m, 2H), 3.43 (s, 3H), 3.47-3.54 (m, 3H), 3.66-3.72 (m, 2H), 3.78 (s, 3H), 3.76-3.84 (m, IH), 4.02-4.10 (m, 2H), 4.25 (d, J=9Hz, IH), 5.92 (s, 2H), 6.40 (d, J=2Hz, IH), 6.52 (dd, J=2Hz, 9Hz, IH), 6.70 (d, I=8Hz, IH), 6.83 (dd, I=lHz, 8Hz, IH), 5.98 (d, J=2Hz, IH), 7.53 (d, J=9Hz, IH). MS (DCI/NH3) m/e 585 (M+H)+.
Example 123 trans.trans-l-(2-(N-Propyl-N-(2.4-dimethylbenzenesulfonyl amino ethyl)-2-(4- methoxyphenyl. -4-( 1 ,3-benzodioxol-5-yl)pyrrolidine-3-carboxylic acid
Using the procedures described in Example 66, the title compound was prepared as a white sohd. mp. 88-90 °C. 1H NMR (CDC13, 300 MHz) δ 0.69 (t, I=7Hz, 3H), 1.32 (sextet, J=7Hz, 2H), 2.12-2.20 (m, IH), 2.32 (s, 3H), 2.47 (s, 3H), 2.62-2.69 (m, IH), 2.78 (t, J=9Hz, IH), 2.89 (dd, J=8Hz, IH), 3.02 (sextet, J=9Hz, 2H), 3.15-3.32 (m, 3H), 3.46-3.55 (m, IH), 3.60 (d, J=9Hz, IH), 3.82 (s, 3H), 5.96 (s, 2H), 6.72 (d, I=7Hz, IH), 6.80 (dd, I=lHz, 9Hz, IH), 6.86 (d, I=9Hz, 2H), 6.97 (d, J=lHz, IH), 7.03 (bs, 2H), 7.29 (d, I=9Hz, IH). MS (DCI/NH3) m/e 595 (M+H)+.
Example 124 trans.trans-l-(2-(N-Propyl-N-(3-cMoropropylsulfonyl)amino)ethyl)-2-(4-methoxyphenyl)-4- (1.3-benzodioxol-5-yl)pyrroUdine-3-carboxylic acid Using the procedures described in Example 66, the title compound was prepared as a white sohd. mp. 75-76 °C. lR NMR (CDC13) 300 MHz) δ 0.80 (t, J=7Hz, 3H), 1.45 (sextet, I=7Hz, 2H), 2.15-2.31 (m, 3H), 2.70-2.80 (m, IH), 2.85-3.10 (m, 6H), 3.23-3.31 (m, 2H), 3.43 (bd, I=9Hz, IH), 3.55-3.66 (m, 4H), 3.81 (s, 3H), 5.94 (s, 2B), 6.13 (d, J=8Hz, IH), 6.82 (d, J=8Hz, IH), 6.86 (d, J=8Hz, 2H), 7.00 (s, IH), 7.33 (d, I=8Hz, 2H). MS (DCI/NH3) m/e 567 (M+H) +
Example 125 trans.trans-l-(2-(N-Propyl-N-(2-methoxyethylsulfonyl)amino)ethyl)-2-(4-methoxyphenyl)-
4-(l ,3-benzodioxol-5-yfipyrrolidine-3-carboxylic acid
Using the procedures described in Example 66, trans, trans- l-(2-(N-Propyl-N- (vinylsulfonyl)amino)ethyl)-2-(4-methoxyphenyl)-4-(l,3-benzodioxol-5-yl)pyrroHdine-3- carboxylic acid was prepared. Ester hydrolysis using aqueous sodium hydroxide in methanol afforded the title compound as a white solid, mp. 62-64 °C. 1H NMR (CDCI3, 300 MHz) δ 0.78 (t, I=7Hz, 3H), 1.42 (sextet, J=7Hz, 2H), 2.23-2.32 (m, IH), 2.72-2.79 (m, IH), 2.86- 3.05 (m, 4H), 3.10-3.27 (m, 4H), 3.32 (s, 3H), 3.43 (dd, I=3Hz, 9Hz, IH), 3.53-3.58 (m, IH), 3.65 (d, I=9Hz, IH), 3.69 (t, J=6Hz, 2H), 3.80 (s, 3H), 5.94 (s, 2H), 6.73 (d, J=8Hz, IH), 6.82 (dd, I=lHz, 8Hz, IH), 6.87 (d, I=8Hz, 2H), 7.02 (d, I=lHz, IH), 7.33 (d, I=8Hz, 2H).
MS (DCI/NH3) m/e 549 (M+H)+.
Example 126 trans, trans- 1 -(2-(N-Propyl-N-(2-ethoxyethylsulfonyl)amino)ethyl)-2-(4-methoxyphenyl)-4- (1 ,3-benzodioxol-5-yl)pyrrolidine-3-carboxylic acid Using the procedures described in Example 66, the title compound was prepared as a white solid, mp. 58-60 °C. 1H NMR (CDC13, 300 MHz) δ 0.78 (t, J=7Hz, 3H), 1.18 (t, J=7Hz, 3H), 1.43 (sextet, I=7Hz, 2H), 2.24-2.33 (m, IH), 2.70-2.80 (m, IH), 2.87-3.05 (m, 4H), 3.13-3.20 (m, 2H), 3.22-3.32 (m, 2H), 3.42 (dd, J=2Hz, 9Hz, IH), 3.46 (q, J=7Hz, 2H), 3.52-3.58 (m, IH), 3.65 (d J=9Hz, IH), 3.72 (t, J=6Hz, 2H), 3.80 (s, 3H), 5.95 (s, 2H), 6.73 (d, J=7Hz, IH), 6.83 (dd, I=lHz, 7Hz, IH), 6.87 (d, I=8Hz, 2H), 7.00 (d, J=lHz, IH), 7.32
(d, I=8Hz, 2H). MS (DCI/NH3) m/e 563 (M+H)+.
Example 127 trans.tr_-ns-l-(2-(N-Propyl-N-(5-dimethylamino-l-naphthylsulfonyl)amino)ethyl)-2-(4- methoxyphenyl)-4-( 1.3-benzodioxol-5-yl)pyrroHdine-3-carboxylic acid Using the procedures described in Example 66, the title compound was prepared as a yellow sohd. m.p. 102-104 °C. 1H NMR (CDCI3, 300 MHz) δ 0.62 (t, J=7Hz, 3H), 1.28
(sextet, I=7Hz, 2H), 2.12-2.20 (m, IH), 2.78 (t, I=9Hz, IH), 2.88 (s, 6H), 2.72-2.89 (m, IH), 3.05-3.12 (m, 2H), 3.26-3.45 (m, 3H), 3.45-3.52 (m, IH), 3.58 (d, I=9Hz, IH), 6.97 (d, I=lHz, IH), 7.13 (d, I=7Hz, IH), 7.26 (d, J=8Hz, IH), 7.42-7.50 (m, 2H), 8.08 (dd, I=lHz,
7Hz, IH), 8.20 (d, J=8Hz, IH), 8.48 (d, J=8Hz, IH). MS (DCI/NH3) m/e 660 (M+H)+.
Example 128 trans, trans- 1 -(2-(N-Propyl-N-(ethylsulfonyl . amino)ethylV2-(4-methoxyphenyl)-4-( 1,3- benzodioxol-5-yl)pyrroHdine-3-carboxylic acid Using the procedures described in Example 66, the title compound was prepared as a white sohd. mp. 70-72 °C. 1H NMR (CDCI3, 300 MHz) δ 0.79 (t, J=8Hz, 3H), 1.28 (t, J=7Hz, 3H), 1.43 (q, J=8Hz, 2H), 2.22-2.30 (m, IH), 2.71-2.80 (m, IH), 2.82-3.10 (m, 6H), 3.18-3.32 (m, 2H), 3.43 (dd, J=3Hz, 9Hz, IH), 3.53-3.60 (m, IH), 3.65 (d, I=9Hz, IH), 3.80 (s, 3H), 5.96 (s, 2H), 6.73 (d, I=7Hz, IH), 6.82 (dd, J=lHz, 7Hz, IH), 6.88 (d, J=8Hz, 2H),
7.00 (d, J=lHz, IH),. 7.32 (d, I=8Hz, 2H). MS (DCI/NΗ3) m/e 519 (M+H)+.
Example 129 trans.trans-l-(2-(N-Propyl-N-(4-methylbenzenesulfonyl)amino)ethyl)-2-(4-methoxyphenyl)- 4-(l .3-benzodioxol-5-yl)pyrroHdine-3-carboxylic acid Using the procedures described in Example 66, the title compound was prepared as a white solid, mp. 78-79 °C. 1H NMR (CDCI3, 300 MHz) δ 0.73 (t, I=7Hz, 3H), 1.33 (sextet, J=7Hz, 2H), 2.20-2.30 (m, IH), 2.40 (s, 3H), 2.61-2.72 (m, IH), 2.83-3.05 (m, 4H), 3.08-3.19 (m, 2H), 3.48 (dd, J=3Hz, 9Hz, IH), 3.49-3.57 (m, IH), 3.62 (d, I=9Hz, IH), 3.81 (s, 3H), 5.95 (s, 2H), 6.73 (d, J=8Hz, IH), 6.82 (d, J=8Hz, IH), 6.87 (d, I=8Hz, 2H), 7.00 (s, IH), 7.21 (d, J=8Hz, 2H), 7.29 (d, I=8Hz, 2H), 7.57 (d, I=8Hz, 2H). MS (DCI/NH3) m/e 581 (M+H)+.
Example 130 trans.tr_-ns-l-(N.N-Di(n-butyl)aminocarbonylmethyl)-2-(3-pyridyl)-4-(l,3-benzodioxol-5- yl)pyrroUdine-3-carboxylic acid Methyl nicotinoyl acetate was prepared by the method of Wenkert, et al., I. Org.
Chem. 48: 5006 (1983) and treated by the procedures described in Example 1 to provide the title compound as a white solid. m.p. 167-168 °C. 1H MR (CDCI3, 300 MHz) δ 0.82 (t, I- 7Hz, 3H), 0.89 (t, J=7Hz, 3H), 1.14 (sextet, J=7Hz, 2H), 1.23-1.48 (m, 6H), 2.86-3.20 (m, ' 6H), 3.34-3.43 (m, 2H), 3.57 (dd, I=3Hz, 9Hz, IH), 3.75-3.83 (m, IH), 4.08 (d, J=9Hz, IH), 5.93 (s, 2H), 6.73 (d, J=8Hz, IH), 6.90 (dd, J=2Hz, 8Hz, IH), 7.03 (d, J=2Hz, IH), 7.38 (dd, I=4Hz, 8Hz, IH), 8.04 (d, I=8Hz, IH), 8.48 (dd, I=2Hz, 4Hz, 2H). MS (DCI/NH3) m/e 482-
(M+H)+.
Example 131 trαnsJrans-l-(2-( -Propyl-N-(n-butylsulfonyl an_-_no ethyl)-2-(4-methoxyphenyl)-4-(l,3- benzodioxol-5-yl)pyrroHdine-3 -carboxylic acid Using the procedures described in Example 66, the title compound was prepared as a white sohd. mp. 65-66 °C. 1H NMR (CDCI3, 300 MHz) δ 0.78 (t, J=7Hz, 3H), 0.92 (t,
I=7Hz, 3H), 1.31-1.46 (m, 4H), 1.68 (quintet, I=7Hz, 2H), 2.21-2.32 ( , IH), 2.70-3.08 (m, 7H), 3.12-3.23 (m, 2H), 3.42 (dd, J=2Hz, 9Hz, IH), 3.52-3.58 (m, IH), 3.64 (d, J=9Hz, IH), 3.80 (s, 3H), 5.96 (s, 2H), 6.72 (d, I=7Hz, IH), 6.83 (dd, I=lHz, 7Hz, IH), 6.86 (d, I=8Hz, 2H), 7.00 (d, I=lHz, IH), 7.32 (d, J=8Hz, 2H). MS (DCI/NH3) m/e 547 (M+H)+.
Example 132 trans.tr-.ns-l-(2-( -Propyl-N-(4-chlorober-zenesulfonyl amino)ethyl)-2-(4-methoxyphenyl)-
4-(l ,3-benzodioxol-5-yl)pyrrolidine-3-carboxylic acid Using the procedures described in Example 66, the title compound was prepared as a white solid, mp. 105-106 °C. 1HNMR (CDCI3, 300 MHz) 0.72 (t, I=7Hz, 3H), 1.34 (sextet, I=7Hzm 2H), 2.56-2.62 (m, IH), 2.78-2.86 (m, IH), 2.96-3.03 (m, 3H), 3.13-3.26 (m, 3H), 3.51 (dd, I=5Hz, 9Hz, IH), 3.62-3.68 (m, IH), 3.80 (s, 3H), 3.94 (d, J=9Hz, IH), 5.92 (s, 2H), 6.75 (d, J=8Hz, IH), 6.84 (dd, I=2Hz, 8Hz, IH), 6.94 (d, J=8Hz, 2H), 6.98 (d, I=2Hz, IH), 7.36 (d, J=8Hz, IH), 7.49 (d, I=8Hz, IH), 7.68 (d, J=8Hz, IH). MS (DCI/NH3) m/e 601 (M+H)+.
Example 133 trans.trans-l-(2-(N-Propyl-N-(benzylsulfonyl)amino)ethyl)-2-(4-methoxyphenyl)-4-(1.3- benzodioxol-5-yDpyrroHdine-3-carboxylic acid Using the procedures described in Example 66, the title compound was prepared as a white soHd. p. 88-89 °C. lR NMR (CDCI3, 300 MHz) δ 0.72 (t, J=7Hz, 3H), 1.32 (sextet, J=7Hz, 2H), 2.06-2.16 (m, IH), 2.56-2.67 (m, IH), 2.75-3.10 (m, 6H), 3.30 (dd, I=2Hz, 9Hz, IH), 5.95 (s, 2H), 6.73 (d, J=7Hz, IH), 6.80 (dd, I=lHz, 7Hz, IH), 6.86 (d, J=8Hz, 2H), 6.97 (d, J=lHz, IH), 7.27-7.35 (m, IR). MS (DCI/NH3) m/e 581 (M+H)+.
Example 134 transJrans-l-(2-( -Propyl-N-(4-fluorobenzenesulfonyl)amino)ethyl)-2-(4-methoxyphenyl)- 4-(l ,3-benzodioxol-5-yl)pyrroHdine-3-carboxylic acid
Using the procedures described in Example 66, the title compound was prepared as a white soHd. mp. 91-93 °C. 1H NMR (CDCI3, 300 MHz) δ 0.73 (t, I=7Hz, 3H), 1.44 (sextet, I=7Hz, 2H), 2.18-2.27 (m, IH), 2.56-2.61 (m, IH), 2.78-2.87 (m, 2H), 2.97 (septet, I=8Hz, 2H), 3.11-3.16 (m, 2H), 3.33 (dd, J=2Hz, 9Hz, IH), 3.43-3.50 (m, IH), 3.57 (d, J=9Hz, IH), 3.78 (s, 3H), 7.08 (t, J=8Hz, 2H), 7.24 (d, I=8Hz, 2H), 7.69 (dd, I=5Hz, 8Hz, 2H). MS (DCI/NH3) m/e 585 (M+H)+.
Example 135 trans, trans- 1 -(N-Methyl-N-propylaminocarbonylmethyl)-2-(4-methoxyphenyl)-4-(4- benzofuranyl)pyrroUdine-3-carboxy lie acid
Example 135A Benzofuran-4-carboxaldehyde To a suspension of 60% sodium hydride in mineral oil (4.00 g, 100 mmol, 1.25 eq) in DMF (60 mL) at 0 °C was added a solution of 3-bromophenol (13.8 g, 80 mmol) in DMF (5 mL). After 10 minutes, bromoacetaldehyde diethyl acetal (14.9 mL, 96.6 mmol, 1.24 eq) was added, and the resultant mixture then heated at 120 °C for 2.5 hours. The mixture was cooled to room temperature and was poured into water, and extracted once with ether. The organic solution was dried over MgSO4, filtered, evaporated and vacuum distUled to yield a colorless liquid (17.1 g, 74%). b.p. 160-163 °C at 0.4 mm Hg. To warm polyphosphoric acid (15.3 g) was added a solution of the above compound (17.1 g, 59.3 mmol) in benzene (50 mL). The resultant mixture was heated under reflux with vigorous stirring for 4 hours, after which time the benzene layer was carefully decanted off, and the lower layer washed once with hexanes. The combined organic solutions were concentrated in vacuo, and then vacuum distUled to yield a colorless liquid (8.13 g, 70%). b.p. 62-72 °C at 0.6 mmHg.
To a solution of the above compounds (8.11 g, 41.5 mmol) in ether (80 mL) at -78 °C was added 1.7 M t-butyllithium (48.8 mL, 83 mmol, 2 eq) such that the temperature did not exceed -70 °C. After stirring for 15 minutes, a solution of DMF (6.5 mL, 83 mmol, 2 eq) in ether (20 mL) was added, and the mixture aUowed to warm to room temperaure over 2 hours. The mixture was poured into water and the phases separated. The organic solution was dried over MgSU4 and concentated in vacuo. The residue was purified by flash chromatography on sUica gel eluting with 10% ether in hexanes to yield benzofuran-6-carboxaldehyde (1.22 g) and benzofuran-4-carboxaldehyde (1.86 g), both as colorless oUs.
Example 135B trans, trans- 1 -(N-Methyl-N-propylaminocarbonylmethyl)-2-(4-methoxyphenyl . -4-(4- benzo fur anyl. pyrroHdine-3 -carboxy lie acid The title compound was prepared using the procedures described in Examples 1 and 49 substituting the compound resulting from Example 135A in Example 49 A for piperonal. !H NMR (300 MHz, CDC13) (minor rotamer) δ 7.59 (IH, t, J=3Hz), 7.4-7.2 (6H, m), 6.8
(2H, d, J=8Hz), 4.03 (IH, m), 3.94 (IH, dd, J=8Hz, 3Hz), 3.77 (3H, s), 3.61 (IH, dd, I=8Hz, 7 3Hz), 3.42 (IH, dd, J=l lHz, 5Hz), 3.40-2.90 (5H, m), 2.82 (2.81) (3H, s), 1.50 (2H, septet, I=7Hz), 0.82 (0.75) (3H, t, I=7Hz). MS (DCI/NH3) m/e 451 (M+H)+. Anal.calc. for C26H30N2O5 • AcOH: C, 65.87; H, 6.71; N ,5.49. Found: C, 66.04; H, 6.42; N, 5.60. s
Example 136 trans, trans- 1 -(N-Methyl-N-propylaminocarbonylmethyl)-2-(4-methoxyphenyl)-4-(6- benzofuranyl)pyrroHdine-3-carboxylic acid
The title compound was prepared using the procedures described in Examples 1 and 49 substituting benzofuran-6-carboxaldehyde, prepared as described in Example 135A, in Example 49A for piperonal. lR NMR (300 MHz, CDCI3) (minor rotamer) δ 7.65 (IH, bd),
7.60 (IH, d, I=2Hz), 7.55 (IH, d, J=8Hz), 7.35 (3H, m), 6.85 (2H, dd, J=8Hz, 3Hz), 6.75 (IH, dd, I=3Hz, 2Hz), 3.83 (2H, m), 3.79 (3H, s), 3.60-3.0 (7H, m), 2.91 (2.83) (s, 3H), 1.51 (2H, septet, I=7Hz), 0.83 (0.78) (3H, t, I=7Hz). MS (DCI/NH3) m/e 451 (M+H)+. Anal.calc. for C26H30N2O5 • 0.5 H2O: C, 67.96; H, 6.80; N, 6.10. Found: C, 67.90; H, 6.71; N, 6.07.
Example 137 trans.tra7.s-l-(N-Methyl-N-propylaminocarbonylmethyl)-2-(4-methoxyphenyl)-4-(6-benzo-
2,3-dihydrofuranyl)pyrroUdine-3-carboxylic acid The title compound was prepared by catalytic hydrogenation (4 atmospheres of H2 in
AcOH, foUowed by preparative hplc) of the compound resulting from Example 136 H NMR (300 MHz, CDCI3) (minor rotamer) δ 7.49 (7.47) (2H, d, J=8Hz), 7.19 (IH, d, I=8Hz), 7.00 (IH, m), 7.82 (3H, m), 5.40 (IH, dd, =1 IHz, 7Hz), 4.58 (2H, t, J=8Hz), 4.18 (IH, m), 4.10 (IH, m), 3.88 (IH, m), 3.79 (3H, s), 3.60 (IH, m), 3.35 (IH, m), 3.19 (2H, t, J=8Hz), 3.00 (4H, m), 2.91 (2.78) (s, 3H), 1.53 (1.40) (2H, septet, J=7Hz), 0.88 (0.78) (3H, t, J=7Hz). MS (DCI/NH3) m/e 453 (M+H)+. AnaLcalc. for C26H32N2O5 • 1.25 TFA: C, 57.53; H,
5.63; N, 4.71. Found: C, 57.68; H, 5.68; N, 4.70.
Example 138 trans, trans- 1 -(N,N-Di(n-butyl)aminocarbonylmethyl)-2-(4-methoxyphenyl -4-(4- benzofuranyl)pyrrolidine-3-carboxylic acid The title compound was prepared by the procedures described in Examples 1 and 49 substituting benzofuran-4-carboxaldehyde in Example 49A for piperonal and substituting
N,N-dibutyl bromoacetamide for N-methyl-N-propyl bromoacetamide. *H NMR (300 MHz, CDCI3) 7.62 (IH, d, J=3Hz), 7.39 (IH, dt, J=8Hz, 2Hz), 7.34 (3H, m), 7.26 (IH, d,
I=2Hz), 7.23 (IH, d, I=8Hz), 6.84 (2H, d, J=8Hz), 4.02 (IH, ddd, J=8, 6Hz,4Hz), 3.89 (IH, d, J=9Hz) 3.79 (3H, s), 3.67 (IH, dd, J=10Hz, 3Hz), 3.44 (2H, m), 3.35-3.15 (3H, m), 3.00 (2H, m), 2.84 (IH, d, I=14Hz), 1.43 (3H, m), 1.23 (3H, m), 1.08 (2H, m), 0.87 (3H, t,
J=7Hz), 0.82 (3H, t, J=7Hz). MS (DCI/NH3) m/e 507 (M+H)+. Analcalc. for C3oH38N2O5: C, 71.12; H, 7.56; N, 5.53. Found: C, 70.86; H, 7.45; N, 5.24.
Example 139 trans, trans- 1 -(N,N-Di(n-butyl)aminocarbonyhnethyl)-2-(4-methoxyphenyl)-4-(4- benzofurany pyrrolidine-3-carboxylic acid The title compound was prepared by the procedures described in Examples 1 and 49 substituting benzofuran-5-carboxaldehyde, prepared by the procedures described in Example 135A substituted 4-bromophenol for 3-bromophenol, in Example 49A for piperonal and substituting N,N-dibutyl bromoacetamide for N-methyl-N-propyl bromoacetamide. ΪHNMR (300 MHz, CDCI3) δ 7.64 (IH, bd), 7.59 (IH, d, J=2Hz), 7.43 (2H, m), 7.33 (2H, d, I=8Hz), 6.85 (2H, d, J=8Hz), 6.73 (IH, dd, J=3Hz, IHz), 3.82 (IH, d, J=l lHz), 3.89 (IH, d, J=9Hz) 3.79 (3H, s), 3.53 (IH, dd, I=10Hz, 3Hz), 3.44 (2H, m), 3.30 (IH, m), 3.20-2.95 (5H, m), 2.82 (IH, d, J=14Hz), 1.43 (3H, m), 1.23 (3H, m), 1.08 (2H, m), 0.87 (3H, t, I=7Hz), 0.82 (3H, t, J=7Hz). MS (DCI/NH3) m/e 507 (M+H)+. Anal.calc. for C30H38N2O5: C, 71.12; H, 7.56; N, 5.53. Found: C, 70.73; H, 7.45; N, 5.29.
Example 140 trans, trans- 1 -(N,N-Di(n-butyl)aminocarbonylmethyl)-2-(4-methoxyphenyl)-4-(6- benzofuranyl.pyrroHdine-3-carboxylic acid The title compound was prepared by the procedures described in Examples 1 and 49 substituting benzofuran-6-carboxaldehyde in Example 49A for piperonal and substituting
N,N-dibutyl bromoacetamide for N-methyl-N-propyl bromoacetamide. lR NMR (300 MHz,
CDCI3) δ 7.63 (IH, bd), 7.59 (IH, d, I=2Hz), 7.53 (IH, d, J=8Hz), 7.36 (3H, m), 6.85 (2H, d, I=8Hz), 6.73 (IH, dd, J=3Hz, IHz), 3.82 (IH, d, J=l lHz), 3.89 (IH, d, I=9Hz) 3.79 (3H, s), 3.53 (IH, dd, I=10Hz, 3Hz), 3.44 (2H, m), 3.30 (lH, m), 3.20-2.95 (5H, m), 2.80 (IH, d, I=14Hz), 1.43 (3H, m), 1.23 (3H, m), 1.08 (2H, m), 0.87 (3H, t, I=7Hz), 0.82 (3H, t, I=7Hz). MS (DCI/NH3) m/e 507 (M+H)+. Analxalc. for C30H38 2O5 • 0.75 H2O: C, 69.28; H, 7.65; N, 5.39. Found: C, 69.11; H, 7.33; N, 5.32.
Example 141 tr-.ns.trans-l-(N,N-Di(n-butyl)aminocarbonylmethyl)-2-(4-methoxyphenyl)-4-(6-benzo-2,3- dihydrofuranyl)pyrroHdine-3 -carboxylic acid The title compound was prepared by catalytic hydrogenation of the compound resulting from Example 140 (4 atmospheres of H2 in AcOH, foUowed by preparative hplc). !H NMR (300 MHz, CDCI3) 7.40 (2H, d, J=8Hz), 7.16 (IH, d, J=8Hz), 6.97 (IH, dd,
I=8Hz, 2Hz), 6.89 (3H, m), 5.90 (IH, bs) 4.57 (2H, t, J=9Hz), 4.93 (2H, m), 3.80 (3H, s),
3.70-3.58 (2H, m), 3.40 (lH, m), 3.30-2.90 (8H, m), 1.40 (2H, m), 1.29 (3H, m), 1.08 (2H, m), 0.92 (3H, t, J=7Hz), 0.82 (3H, t, I=7Hz). MS (DCI/NH3) m/e 509 (M+H)+ Anal.calc. for C3θH4oN2O5 - 0.85 TFA: C, 62.88; H, 6.80; N, 4.63. Found: C, 63.04; H, 6.66; N, 4.60.
Example 142 trans, trans- 1 -(N-Methyl-N-propylaminocarbonylmethyl)-2-(4-methoxyphenylV4-(5- indanyl,pyrroHdine-3 -carboxylic acid
Example 142A Indane-5-carboxaldehyde Indane-5-carboxaldehyde was prepared by formylation of indane under the conditions described for 2,3-dihydrobenzofuran in Example 52A. The resultant mixture of 4- and 5- carboxaldehydes was purified as follows: to a 6:1 mixture of indane-4-carboxaldehyde and indane-5-carboxaldehyde (3.46 g, 23 mmol) was added aniline (2.20 g, 23 mmol, 1 eq). The resultant solution slowly solidfied to a mixture of imines which was recrystaUized from hot acetonitrile to yield the 5-aldimine as a white soHd. The aldimine (2.65 g) was suspended in water (6 mL), and treated with 4 N hydrochloric dioxane (10 mL). The mixture was boiled for 1 hour, cooled to room temperature, and poured into ether. The organic solution was dried over MgSO4, filtered, and concentated in vacuo. Vacuum distUlation of the residue afforded indane-5-carboxaldehyde (1.54 g, 88%) as a colorless liquid, b.p. 88-90 °C at 0.9 mmHg.
Example 142B trans, trans- 1 -(N-Methyl-N-propylaminocarbonylmethyl)-2-(4-methoxyphenylV4-(5- indanyl)pyrroHdine-3-carboxylic acid The title compound was prepared by the procedures described in Examples 1 and 49 substituting indane-5-carboxaldehyde for piperonal in Example 49A. *H NMR (300 MHz, CDC13) (minor rotamer) δ 7.25-7.1 (5H, m), 6.78 (2H, d, I=8Hz), 3.89 (IH, d, J=8Hz), 3.75 (3H, s), 3.50-2.90 (6H, m), 2.88 (6H, t, I=6Hz), 2.82 (2.80) (3H, s), 2.04 (2H, t, J=8Hz),
1.48 (2H, septet, I=7Hz), 0.83 (0.73) (3H, t, J=7Hz). MS (DCI/NΗ3) m/e 451 (M+H)+, 473 (M+Na)+. AnaLcalc. for C27H34N2O4 • 2.5 H2O : C, 65.44; H, 7.93; N, 5.65. Found: C, 65.36; H, 7.45; N, 5.53.
Example 143 trans, trans -1 -(N-Methyl-N-propyl_ιminocarbonylmethylV2-(4-methoxyphenylV4-(6- indolyl)pyrroHdine-3 -carboxylic acid The title compound was prepared by the procedures described in Examples 1 and 49 substituting indole-6-carboxaldehyde, prepared by the method of Rapoport, J. Org. Chem. 51: 5106 (1986), for piperonal in Example 49A. *H NMR (300 MHz, CDCI3) (minor rotamer) δ 8.43 (IH, brs), 7.57 (IH, d, J=8Hz), 7.43 (IH, s), 7.31 (2H, dd, J=6Hz, 3Hz), 7.22 (IH, d, J=8Hz), 7.1 (IH, t, I=3Hz), 6.78 (2H,dd, J=6Hz, 3Hz), 6.45 (IH, m), 3.93 (IH, dd, I=6Hz, 3Hz), 3.80 (IH, m), 3.73 (3H, s), 3.60-2.90 (6H, m), 2.86 (2.82) (3H, s), 1.47 (2H, septet, I=7Hz), 0.83 (0.73) (3H, t, J=7Hz). MS (DCI/NΗ3) m/e 450 (M+H)+. Anal.calc. for C26H3iN3O4 - 0.75 H2θ: C, 67.44; H, 7.07; N, 9.07. Found: C, 67.42; H, 7.09; N, 8.91. Example 144 trans.trans-l-(N-Methyl-N-propylaminocarbonylmethyl)-2-(4-methoxyphenyl)-4-(3,4- difluorophenyl)pyrroHdine-3-carboxy lie acid The title compound was prepared by the procedures described in Examples 1 and 49 substituting 3,4-difluorobenzaldehyde for piperonal in Example 49 A. *H NMR (300 MHz, CDC13) (minor rotamer) δ 7.60-7.3 (4H, m), 7.13 (IH, q, J=9Hz), 6.90 (2H, d, J=8Hz), 3.90
(IH, m), 3.79 (3H, s), 3.60-2.95 (6H, m), 2.92 (2.78) (3H, s), 1.55 (2H, septet, I=7Hz), 0.88 (0.73) (3H, t, J=7Hz). MS (DCI/NH3) m/e 447 (M+H)+. Anal.calc. for C24H28F2N2O4 • 1.80 H2O: C, 60.19; H, 6.65; N, 5.85. Found: C, 60.13; H, 6.34; N, 5.84.
Example 145 trans, trans- 1 -(N-Methyl-N-propylaminocarbonylmethyl)-2-(4-methoxyphenyl)-4-
(phenyl)pyrroHdine-3 -carboxylic acid The title compound was prepared by the procedures described in Examples 1 and 49 substituting benzaldehyde for piperonal in Example 49A. *H NMR (300 MHz, CDCI3)
(minor rotamer) δ 7.53 (4H, d, J=6Hz), 7.40-7.20 (3H, m), 6.88 (2H, d, I=8Hz), 3.90 (IH, m), 3.79 (3H, s), 3.70-2.95 (8H, m), 2.90 (2.79) (3H, s), 1.50 (2H, sept, I=7Hz), 0.87 (0.72) (3H, t, I=7Hz). MS (DCI/NH3) m/e 411 (M+H)+. AnaLcalc. for C24H30N2O4 • 2.00 H2O:
C, 64.55; H, 7.67; N, 6.27. Found: C, 64.37; H, 7.43; N, 6.29.
Example 146 trans, trans- 1 -(N-Methyl-N-propylaminocarbonylmethyl)-2-(4-methoxyphenyl)-4-(4- hy droxyphenyl)pyrroHdine-3 -carboxylic acid The title compound was prepared by the procedures described in Examples 1 and 49 substituting 4-hydroxybenzaldehyde for piperonal in Example 49A., lR NMR (300 MHz, CDCI3-CD3OD) (minor rotamer) δ 7.35 (2H, d, J=8Hz), 7.28 (2H, dd, J=7Hz, 3Hz), 6.90
(2H, dd, J=7Hz, 3Hz), 6.89 (2H, d, J=8Hz), 3.81 (3H, s), 3.65 (IH, d, J=8Hz), 3.70-3.00 (8H, m), 2.92 (2.83) (3H, s), 1.50 (2H, septet, J=7Hz), 0.87 (0.77) (3H, t, I=7Hz). MS (DCI/NH3) m/e 427 (M+H)+. Anal.calc. for C24H30N2O5 • 1.00 H2O: C, 64.85; H, 7.26; N, 6.30. Found: C, 64.82; H, 7.39; N, 6.46.
Example 147 trans, trans- 1 -(N-Methyl-N-propylaminocarbonylmethyl)-2-(4-methoxyphenylV4-(2,4- dimethoxypheny l)pyrroHdine-3 -carboxylic acid The title compound was prepared by the procedures described in Examples 1 and 49 substituting 2,4-dimethoxybenzaldehyde for piperonal in Example 49A. lR NMR (300 MHz, CDCI3-CD3OD) (minor rotamer) δ 7.61 (IH, d, J=8Hz), 7.30 (2H, d, J=8Hz), 6.82
(2H, d, I=8Hz), 6.55 (IH, d, J=8Hz), 6.45 (IH, d, J=3Hz), 3.90 (IH, m), 3.81 (3H, s), 3.79 (3H, s), 3.77 (3H, s), 3.70-2.90 (8H, m), 2.85 (3H, s), 1.50 (2H, sept, I=7Hz), 0.87 (0.77) (3H, t, I=7Hz). MS (DCI/NH3) m/e 471 (M+H)+. Analcalc. for C26H34 2O6 • 0.75 H2O: C, 64.51; H, 7.39; N, 5.79. Found: C, 64.65; H, 7.07; N, 5.75.
Example 148 trans, trans- 1 -(N,N-Di(n-butyl aminocarbonylmethyl)-2-(4-methoxyphenyl ) -4-(5-benzo-2,3- dihydrofuranyl . pyrroUdine-3 -carboxylic acid The title compound was prepared by the procedures described in Examples 1 and 49 substituting 2,3-dihydrobenzofuran-5-carboxaldehyde for piperonal in Example 49A. lR NMR (300 MHz, CDCI3) δ 7.31 (2H, d, J=8Hz), 7.27 (IH, d, I=2Hz), 7.18 (IH, dd, I=7Hz, 3Hz), 6.86 (2H, d, I=8Hz), 6.72 (IH, d, J=8Hz), 4.56 (2H, t, I=7Hz), 3.78 (3H, s), 3.62 (IH, m), 3.50-3.25 (4H, m), 3.17 (2H, t, J=7Hz), 3.15-2.90 (5H, m), 2.79 (IH, d, J=14Hz), 1.43 (3H, m), 1.26 (3H, m), 1.08 (2H, m), 0.87 (3H, t, I=7Hz), 0.81 (3H, t, I=7Hz). MS (DCI/NH3) m/e 509 (M+H)+. Analcalc. for C30H40N2O5 • 0.25 H2O: C, 70.22; H, 7.95; N,
5.46. Found: C, 70.21; H, 7.92; N, 5.36.
Example 149 trans, trans- 1 -(N.N-Di(n-butyl)aminocarbonylmethyl)-2-(4-methoxyphenyl)-4-(4- methoxyphenyl.pyrroHdine-3-carboxylic acid The title compound was prepared by the procedures described in Examples 1 and 49 substituting 4-methoxybenzaldehyde for piperonal in Example 49A. *H NMR (300 MHz, CDCI3) δ 7.38 (2H, d, J=8Hz), 7.30 (2H, d, J=8Hz), 6.87 (4H, dd, J=7Hz, 3Hz), 3.78 (3H, s), 3.76 (3H, s), 3.63 (IH, m), 3.50-3.20 (4H, m), 3.15-2.90 (5H, m), 2.78 (IH, d, J=14Hz), 1.43 (3H, m), 1.27 (3H, m), 1.09 (2H, m), 0.87 (3H, t, I=7Hz), 0.81 (3H, t, J=7Hz). MS (DCI/NH3) m/e 497 (M+H)+. Analcalc. for C29H40N2O5: C, 70.13; H, 8.12; N, 5.64. Found: C, 69.78; H, 8.10; N, 5.54.
Example 150 trans.trans-l-0S[,N-Di(n-butyl)aminocarbonylmethyl)-2-(4-methoxyphenyl)-4-(3,4- difluorophenyl . pyrroHdine-3 -carboxylic acid The title compound was prepared by the procedures described in Examples 1 and 49 substituting 3,4-difluorobenzaldehyde for piperonal in Example 49 A. lR NMR (300 MHz, CDC13) δ 7.35 (IH, m), 7.30 (2H, d, J=8Hz), 7.20-7.00 (2H, m), 6.87 (2H, d, J=8Hz), 3.78
(3H, s), 3.79 (IH, m), 3.62 (IH, m), 3.50-3.30 (3H, m), 3.23 (IH, m), 3.15-2.90 (4H, m), 2.78 (IH, d, J=14Hz), 1.43 (2H, m), 1.27 (4H, m), 1.08 (2H, m), 0.85 (3H, t, J=7Hz), 0.80 (3H, t, I=7Hz). MS (DCI/NH3) m/e 503 (M+H)+. Analcalc. for C28H36F2N2O4- • 1 H2O: C, 64.60; H, 7.36; N, 5.38. Found: C, 64.59; H, 7.20; N, 5.35.
Example 151 trans, trans- 1 -(N,N-Di(n-butyl)aminocarbonylmethyl)-2-(4-methoxyphenyl)-4-(2,4- dimethoxyphenyl)pyrroHdine-3 -carboxylic acid The title compound was prepared by the procedures described in Examples 1 and 49 substituting 2,4-dimethoxybenzaldehyde for piperonal in Example 49A. lR NMR (300 MHz, CDCI3) δ 7.37 (2H, d, J=8Hz), 7.20 (IH, d, J=8Hz), 6.92 (2H, d, I=8Hz), 6.60 (IH, d, J=3Hz), 6.49 (IH, dd, J=6Hz, 2Hz), 5.35 (IH, d, J=8Hz), 4.20 (3H, m), 4.10 (3H, s), 3.83 (3H, s), 3.81 (3H, s), 3.75 (3H, m), 3.17 (2H, hep, J=7Hz), 3.05 (2H, t, I=7Hz), 1.30 (4H, m), 1.07 (4H, m), 0.87 (3H, t, I=7Hz), 0.80 (3H, t, J=7Hz). MS (DCI/NH3) m/e 527
(M+H)+. Analcalc. for C30H42N2O6 • 1.30 TFA: C, 58.02; H, 6.47; N, 4.15. Found: C,
57.92; H, 6.43; N, 4.07.
Example 152 trans, trans- 1 -(N,N-Di(n-butyl . aminocarbonylmethyl)-2-phenyl-4-( 1 ,3 -benzodioxol-5- yl, pyrrolidine-3 -carboxylic acid The title compound was prepared by the procedures described in Examples 1 and 49 substituting ethyl benzoylacetate in Example 49B. 2H NMR (300 MHz, CDCI3) δ 7.50-7.25
(5H, m), 7.04 (IH, d, J=3Hz), 6.87 (IH, dd, I=7Hz, 3Hz), 6.74 (IH, d, J=8Hz), 5.94 (IH, d, I=4Hz), 5.92 (IH, d, I=4Hz), 3.85 (IH, d, I=8Hz), 3.64 (IH, m), 3.42 (3H, m), 3.27 (2H, m), 3.20-2.90 (5H, m), 2.81 (IH, d, J=14Hz), 1.43 (2H, m), 1.27 (4H, m), 1.05 (2H, m), 0.85 (3H, t, J=7Hz), 0.80 (3H, t, J=7Hz). MS (DCI/NH3) m/e 481 (M+H)+. Anal.calc. for C28H36N2O5: C, 69.98; H, 7.55; N, 5.83. Found: C, 69.69; H, 7.63; N, 5.71.
Example 153 trans.tr-.ns-l-(N,N-Di(n-butyl)aminocarbonylmethyl)-2-phenyl-4-(5-benzo-2,3- dihydrofuranyl.pyrroHdine-3-carboxylic acid The title compound was prepared by the procedures described in Examples 1 and 49 substituting ethyl benzoylacetate in Example 49B and 2,3-dihydrobenzofuran-5- carboxaldehyde for piperonal in Example 49 A. H NMR (300 MHz, CDC13) 7.53 (2H, m), 7.40 (4H, m), 7.13 (IH, dd, J=7Hz, 3Hz), 6.72 (IH, d, J=8Hz), 5.40 (IH, d, I=10Hz), 4.56 (2H, t, J=8Hz), 4.18 (IH, d, J=14Hz), 4.07 (2H, m), 3.79 (2H, m), 3.48 (IH, d,
J=14Hz), 3.35 (IH, m), 3.28 (3H, m), 2.95 (2H, m), 1.47 (2H, m), 1.28 (4H, m), 1.10 (2H, m), 0.93 (3H, t, J=7Hz), 0.78 (3H, t, J=7Hz). MS (DCI/NH3) m/e 479 (M+H)+. Anal.calc. for C29H38N2O4 - 1.10 TFA: C, 62.04; H, 6.52; N, 4.64. Found: C, 61.89; H, 6.44; N, 4.57.
Example 154 tra7ϊs.trans-l-(N,N-Di(n-butyl)aminocarbonylmethyl)-2-(4-t-butylphenyl)-4-(5-benzo-2.3- dihydrofuranyl)pyrroHdine-3 -carboxylic acid The title compound was prepared by the procedures described in Examples 1 and 49 substituting t-butyl benzoylacetate, prepared by the method of Krapcho et al, Org. Syn. 47:20 (1967) starting from 4-t-butylacetophenone, in Example 49B and 2,3- dihydrobenzofuran-5-carboxaldehyde for piperonal in Example 49A. lR NMR (300 MHz, CDCI3) δ 7.60-7.30 (6H, m), 6.90 (IH, m), 4.50 (2H, m), 3.95 (IH, m), 3.85-2.95 (11H, m),
2.90 (IH, d, I=14Hz), 1..58 (2H, m), 1.50 (7H, m), 1.41 (6H, s), 1.10 (2H, m), 1.00 (3H, t, I=7Hz), 0.90 (3H, t, I=7Hz). MS (DCI/NH3) m/e 535 (M+H)+. Anal.calc. for C33H46N2O4 • 0.25 H2O: C, 73.50; H, 8.69; N, 5.19. Found: C, 73.57; H, 8.58; N, 5.14.
Example 155 tra7?s.trans-2-(N,N-Di(n-butyl)aminocarbonylmethyl)-2-(4-methoxyphenyl)-4-(4- fluorophenyl)pyrπ_ Hdine-3 -carboxylic acid The title compound was prepared by the procedures described in Examples 1 and 49 substituting 4-fluorobenzaldehyde for piperonal in Example 49A. *H NMR (300 MHz, CDCI3) 7.50 (IH, m), 7.42 (IH, dd, I=7Hz, 3Hz), 7.36 (2H, d, I=8Hz), 7.01 (3H, t,
I=8Hz), 6.87 (IH, d, I=8Hz), 3.83 (IH, m), 3.8 (3H, s), 3.67 (IH, m), 3.47 (3H, m), 3.30- 2.90 (5H, m), 2.82 (IH, d, J=14Hz), 1.43 (2H, m), 1.28 (4H, m), 1.08 (2H, m), 0.90 (3H, t, J=7Hz), 0.82 (3H, t, J=7Hz). MS (DCI/NH3) m/e 485 (M+H)+. Analcalc. for C28H37FN2O4: C, 69.40; H, 7.70; N, 5.78. Found: C, 69.03; H, 8.00; N, 5.74.
Example 156 tra7;sJrα7;s-l-πS .N-Di(n-butyl)aminocarbonylmethyl)-2-(3-fa-yl)-4-(1.3-benzodioxol-5- yl)pyrroHdine-3-carboxylic acid The title compound was prepared by the procedures described in Examples 1 and 49 substituting β-oxo-3-furanpropionate in Example 49B. lηEL NMR (300 MHz, CDCI3) δ 7.41
(2H, m), 6.97 (IH, d, I=3Hz), 6.85 (IH, dd, I=7Hz, 3Hz), 6.72 (IH, d, J=8Hz), 6.42 (IH, s), 5.94 (IH, d, I=4Hz), 5.92 (IH, d, I=4Hz), 3.90 (IH, m), 3.70-3.25 (5H, m), 3.20-2.90 (4H, m), 2.85 (IH, d, J=14Hz), 1.43 (2H, m), 1.40-1.05 (6H, m), 0.90 (6H, m). MS (DCI/NH3) m/e 471 (M+H)+. Analcalc. for C26H34N2O6: C, 66.36; H, 7.28; N, 5.95. Found: C, 66.09; H, 7.24; N, 5.87.
Example 157 trans, trans- 1 -(N,N-Di(n-butyl)aminocarbonylmethyl)-2-(isopropyl)-4-( 1 ,3-benzodioxol-5- yl)pyrrolidine-3 -carboxylic acid The title compound was prepared by the procedures described in Examples 1 and 49 substituting ethyl isobutyrylacetate in Example 49B. lR NMR (300 MHz, CDCI3) δ 6.85
(IH, d, I=2Hz), 6.76 (IH, dd, J=6Hz, 2Hz), 6.71 (IH, d, I=8Hz), 5.92 (2H, s), 3.75 (IH, d, I=14Hz), 3.66 (IH, q, J=7Hz), 3.42 (3H, m), 3.25 (3H, m), 3.11 (2H,m), 2.83 (IH, t, I=7Hz), 1.88 (IH, m), 1.55 (4H, m), 1.32 (4H, m), 0.92 (12H, m). MS (DCI/NH3) m/e 447 (M+H)+. Analcalc. for C25H38N2O5 • 0.50 H2O: C, 65.91; H, 8.63; N, 6.15. Found: C, 66.07; H, 8.10; N, 6.03.
Example 158 trans, trans- 1 -(N,N-Di(n-butyl)aminocarbonylmethyl)-2-(4-t-butylphenyl)-4-( 1,3- benzodioxol-5-yl)pyrroHdine-3-carboxylic acid The title compound was prepared by the procedures described in Examples 1 and 49 substituting ethyl 4-t-butylbenzoylacetate, prepared by the method of Krapcho et al., Org. Syn. 47: 20 (1967) starting with 4-t-butylacetophenone), in Example 49B. !H NMR (300 MHz, CDCI3) δ 7.32 (4H, d, J=3Hz), 7.04 (IH, d, J=2Hz), 6.87 (IH, dd, J=8Hz, 3Hz), 6.74
(IH, d, I=9Hz), 5.94 (IH, d, J=4Hz), 5.92 (IH, d, I=4Hz), 3.77 (IH, d, J=14Hz), 3.65-3.25 (5H, m), 3.15-2.85 (4H, m), 2.73 (IH, d, I=14Hz), 1.45 (2H, m), 1.29 (13H, s), 1.00 (2H, m), 0.86 (3H, t, I=7Hz), 0.76 (3H, t, I=7Hz). MS (DCI/NH3) m/e 537 (M+H)+. Anal.calc. for C32H44N2O5: C, 71.61; H, 8.26; N, 5.22. Found: C, 71.43; H, 8.09; N, 5.11.
Example 159 trans.tr-.ns-l-(N.N-Di(n-butyl.aminocarbonylmethyl)-2-(4-t-butylphenylV4-(5-benzo-2,3- dihvdrofuranyl)pyrrolidine-3-carboxylic acid The title compound was prepared by the procedures described in Examples 1 and 49 substituting ethyl isobutyrylacetate in Example 49B and 2,3-dihydrobenzofuran-5- carboxaldehyde for piperonal in Example 49A. lR NMR (300 MHz, CDC13) δ 7.30 (IH, s),
7.13 (IH, dd, J=7Hz, 2Hz), 6.82 (IH, d, J=8Hz), 4.68 (2H, t, J=8Hz), 4.48 (IH, s), 3.19 (3H, m), 3.80 (3H, m), 3.48 (2H, m), 3.3 (5H, m), 2.41 (IH, m), 1.65 (4H, m), 1.44 (4H, m), 1.21 (3H, d, J=5Hz), 1.17 (3H, d, J=5Hz), 1.05 (6H, m). MS (DCI/NH3) m/e 445 (M+H)+. Analcalc. for C26H4oN2O4 - 1.2 TFA: C, 58.67; H, 7.14; N, 4.8.2 Found: C, 58.54; H, 7.25; N, 4.74.
Example 160 trans.trans-l-(N,N-Di(n-butyl)aminocarbonylmethyl)-2-(anti-4-methoxycyclohexyl)-4-(l,3- benzodioxol-5-yl)pyrrolidine-3-carboxylic acid
Example 160A syn and anti Ethyl 4-methoxycyclohexanoylacetate
Syn, anti-4-Methoxycyclohexane carboxylic acid (5.00 g, 31.6 mmol) and carbonyldiimidazole (6.15 g, 37.9 mmol, 1.2 eq) were stirred in anhydrous tetrahydrofuran (50 mL) for 6 hours at room temperature. At the same time, magnesium chloride (3.01 g, 31.6 mmol) and ethyl malonate potassium salt (7.52 g, 44.2 mmol, 1.4 equivalents) were stirred in anhydrous tetrahydrofuran (75 mL) for 6 hours at 50 °C. The mixture was cooled to room temperature, and the imidazole-acid mixture added to it. The reaction stirred overnight at room temerature. The solvents were removed under reduced pressure, and the residue was taken up in chloroform/water. The organic phase washed with 5% potassium bisulfate, water, and brine, dried with magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography on 175 g sUica gel, eluting with 20% ethyl acetate in hexanes. Pure fractions of the syn and anti methoxycyclohexyl β-keto esters were obtained. The solvents were removed under reduced pressure to yield the trans-4-methoxycyclohexyl β-keto ester (914 mg) as a colorless oil and the cis 4-methoxycyclohexyl β keto ester (1.07 g) as a colorless oU.
Example 160B trans.tr-.ns-l-(N,N-Di(n-butyl)aminocarbonyhnethyl)-2-(anti-4-methoxycyclohexyl)-4-(l,3- benzodioxol-5-yl)pyrroHdine-3-carboxylic acid The title compound was prepared by the procedures described in Examples 1 and 49 substituting the anti-compound resulting from Example 160A in Example 49B. XH NMR (300 MHz, CDC13) δ 6.84 (IH, d, I=2Hz), 6.76 (IH, dd, J=7Hz, 2Hz), 6.61 (IH, d, I=8Hz), 5.92 (2H, s), 3.69 (2H, m), 3.50-3.27 (5H, m), 3.26 (3H, s), 3.25-3.00 (3H, m), 2.88 (IH, m), 1.95 (2H, m), 1.62 (7H, m), 1.33 (9H, m), 0.97 (3H, t, J=7Hz), 0.92 (3H, t, J=7Hz). MS (DCI/NH3) m/e 517 (M+H)+. Anal.calc. for C29H44N2O6 • 0.50 H2O: C, 66.26; H, 8.63; N, 5.33. Found: C, 66.27; H, 8.50; N, 5.13.
Example 161 trans, trans- 1 -(N,N-Di(n-butyl)aminocarbonylmethyl)-2-(syn-4-methoxycyclohexyl)-4-( 1,3- benzodioxol-5-yl)pyrroHdine-3-carboxylic acid The title compound was prepared by the procedures described in Examples 1 and 49 substituting the syn-compound resulting from Example 160A in Example 49B. H NMR (300 MHz, CDCI3) δ 6.84 (IH, d, J=2Hz), 6.77 (IH, dd, I=6Hz, 2Hz), 6.61 (IH, d, J=8Hz),
5.92 (2H, s), 3.65 (2H, m), 3.42 (2H, m), 3.32 (3H, s), 3.30-3.00 (6H, m), 2.82 (IH, m), 2.10 (2H, m), 1.83 (2H, m), 1.52 (6H, m), 1.33 (4H, m), 1.20-1.00 (4H, m), 0.96 (3H, t, J=7Hz), 0.91 (3H, t, J=7Hz). MS (DCI/NH3) m/e 517 (M+H)+. Analcalc. for C29H44N2O6 • 0.30 H2O: C, 66.72; H, 8.61; N, 5.37. Found: C, 66.76; H, 8.65; N, 5.28.
Example 162 tr ns.trans-l-(TS[,N-Di(n-butyl aminocarbonylmethylV2,4-di(5-benzo-2,3- dihy drofuranyl)pyrroHdine-3 -carboxylic acid
Example 162A 5-Acetyl-2,3-dihydrobenzofuran To a 0 °C solution of acetyl chloride (1.64 mL, 23.0 mmol, 1.3 equivalents) in methylene chloride (30 mL) was added stannic chloride (2.49 mL, 21.3 mmol, 1.2 equivalents), maintaining the temperature below 5 °C. The solution was stirred 15 minutes at 0 °C, and then a solution of 2,3-dihydrofuran (2.00 mL, 17.7 mmol) in methylene chloride (5 mL) was added dropwise whUe maintaining the temperature below 8 °C. The dark red solution was stirred 1 hour at 2 °C and then poured into 50 mL of ice water. The reaction was stirred an additional 30 minutes, and the layers were separated. The organic layer was washed with water and aqueous sodium bicarbonate, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography on 150 g silica gel, eluting with 18% ethyl acetate in hexanes. The solvents were removed under reduced pressure to yield the title compound (2.68 g, 93%) as a yellow soHd.
Example 162B trans.trans-l-(N,N-Di(n-butyl aminocarbonylmethyl)-2.4-di(5-benzo-2,3- dihydrofuranv pyrroHdine-3-carboxy lie acid The title compound was prepared by the procedures described in Examples 1 and 49 substituting the compound resulting from Example 162A in Example 49B and 2,3- dihydrobenzofuran-5-carboxaldehyde for piperonal in Example 49A. XH NMR (300 MHz, CDC1 ) δ 7.43 (IH, s), 7.38 (IH, s), 7.06 (2H, m), 6.75 (IH, d, J=6Hz), 6.70 (IH, d, J=6Hz),
5.40 (IH, d, J=9Hz), 4.58 (4H, q, I=7Hz), 4.16 (IH, d, J=14Hz), 4.09 (2H, m), 3.82 (2H, m), 3.57 (IH, d, J=14Hz), 3.38 (IH, m), 3.30-3.05 (6H, m), 2.95 (2H, q, I=6Hz), 1.50 (2H, m), 1.30 (4H, m), 1.15 (2H, m), 0.94 (3H, t, I=7Hz), 0.83 (3H, t, J=7Hz). MS (DCI/NH3) m/e 521 (M+H)+. Analcalc. for C31H40N2O5 • 1.25 TFA: C, 60.67; H, 6.27; N, 4.22. Found: C, 60.49; H, 6.18; N, 4.13.
Example 163 trans.trans-l-(N,N-Di(n-butyl.aminocarbonylmethyl)-2-(3--uryl)-4-(5-benzo-2,3- dihydrofuranyl)pyrroHdine-3 -carboxylic acid
The title compound was prepared by the procedures described in Examples 1 and 49 substituting ethyl β-oxo-3-furanpropionate in Example 49B and 2,3-dihydrobenzofuran-5- carboxaldehyde for piperonal in Example 49A. lR NMR (300 MHz, CDCI3) δ 7.42 (IH, m),
7.38 (IH, m), 7.13 (IH, s), 7.16 (IH, dd, J=7Hz, 3Hz), 6.70 (IH, d, J=8Hz), 6.41 (IH, m), 4.57 (2H, t, J=7Hz), 3.95 (IH, d, J=8Hz), 3.63 (IH, m), 3.55 (IH, d, =14), 3.50-3.25 (4H, m), 3.18 (2H, t, J=6Hz), 3.15-2.95 (3H, m), 2.87 (IH, d, J=14Hz), 1.45 (4H, m), 1.35-1.10 (4H, m), 0.85 (6H, m). MS (DCI/NH3) m/e 469 (M+H)+. Anal.calc. for C27H36N2O5 ■ 0.25 H2O: C, 68.55; H, 7.78; N, 5.92. Found: C, 68.62; H, 7.68; N, 5.82.
Example 164 tr ns,trans-l-(N,N-Di(n-butyl.aminocarbonylmethyl)-2-(4-methoxyphenyl)-4-(3- fluorophenvπpyrroHdine-3 -carboxylic acid The title compound was prepared by the procedures described in Examples 1 and 49 substituting 3-fluorobenzenecarboxaldehyde for piperonal in Example 49A. *H NMR (300 MHz, CDCI3) δ 7.30 (2H, d, J=8Hz), 7.22 (2H, m), 6.91 (IH, m), 6.86 (2H, d, J=8Hz), 3.79
(IH, m), 3.78 (3H, s), 3.68 (IH, m), 3.55-3.37 (3H, m), 3.29 (IH, m), 3.15-2.90 (5H, m), 2.78 (IH, d, J=14Hz), 1.43 (2H, m), 1.25 (4H, m), 1.07 (2H, m), 0.87 (3H, t, J=7Hz), 0.80 (3H, t, J=7Hz). MS (DCI/NH3) m/e 485 (M+H)+. Anal.calc. for C28H37FN2O4 • 0.25 H2O:
C, 68.76; H, 7.73; N, 5.73. Found: C, 68.87; H, 7.69; N, 5.67. Example 165 trans, trans- 1 -(N,N-Di(n-butyl)aminocarbonylmethyl)-2-(4-methoxyphenylV4-(3- pyridyl)pyrrolidine-3 -carboxylic acid The title compound was prepared by the procedures described in Examples 1 and 49 substituting 3-pyridinecarboxaldehyde for piperonal in Example 49A. The nitro styrene was prepared by the method of Bourguignon ,et al, Can. J. Chem. 63: 2354 (1985). *H NMR (300 MHz, CDCI3) δ 8.82 (IH, bs), 8.73 (IH, bd, J=9Hz), 8.62 (IH, bd, I=7Hz), 7.78 (IH, bdd, I=9Hz, 3Hz), 7.38 (2H, d, I=10Hz), 6.90 (2H, d, J=10Hz), 4.39 (IH, d, I=12Hz), 3.95 (IH, m), 3.80 (3H, s), 3.79 (IH, m), 3.68 (IH, d, I=18Hz), 3.50-3.30 (3H, m), 3.25-2.90 (6H, m), 1.47 (2H, m), 1.31 (4H, m), 1.20 (2H, m), 0.92 (3H, t, J=7Hz), 0.83 (3H, t, I=7Hz). MS (DCI/NH3) m/e 468 (M+H)+. Analcalc. for C27H37N3O4 ■ 1.65 TFA: C, 55.50; H, 5.94; N, 6.41. Found: C, 55.53; H, 5.90; N, 6.27.
Example 166 trans.trans-l-(y,N-Di(n-butyl)aminocarbonylmethyl)-2-(2-fluorophenyl)-4-(l,3- benzodioxol-5-yl)pyrroHdine-3-carboxylic acid The title compound was prepared by the procedures described in Examples 1 and 49 substituting ethyl 2-fluorobenzoylacetate in Example 49B. XH NMR (300 MHz, CDCI3) δ
7.52 (IH, dt, J=7Hz, 3Hz), 7.25 (IH, m), 7.13 (IH, dt, J=7Hz, 3Hz), 7.02 (2H, m), 6.88 (IH, dd, J=7Hz, 3Hz), 6.73 (IH, d, J=8Hz), 5.93 (IH, d, J=4Hz), 5.92 (IH, d, I=4Hz), 4.25 (IH, d, I=9Hz), 3.68 (IH, m), 3.42 (3H, m), 3.39 (IH, m), 3.20-2.95 (4H, m), 2.91 (IH, d, I=14Hz), 1.45 (3H, m), 1.26 (3H, m), 1.08 (2H, m), 0.87 (3H, t, I=7Hz), 0.81 (3H, t, J=7Hz). MS (DCI/NH3) m/e 499 (M+H)+. Anal.calc. for C28H35FN2O5 • 0.25 H2O: C, 66.85; H, 7.11;
N, 5.57. Found: C, 66.51; H, 6.67; N, 5.18.
Example 167 trans.trans-l-( ,N-Di(n-butyl)aminocarbonylmethylV2-(3-fluorophenyl)-4-(l,3- benzodioxol-5-yl)pyrroUdine-3-carboxylic acid The title compound was prepared by the procedures described in Examples 1 and 49 substituting ethyl 3-fluorobenzoylacetate in Example 49B. lR NMR (300 MHz, CDCI3) δ
7.38 (IH, m), 7.18 (IH, d, J=7Hz), 7.15 (IH, m), 7.00 (IH, d, I=2Hz), 6.95 (IH, m), 6.86 (IH, dd, J=7Hz, 2Hz), 6.75 (IH, d, I=8Hz), 5.93 (IH, d, I=4Hz), 5.92 (IH, d, J=4Hz), 3.94 (IH, d, I=14Hz), 3.63 (IH, m), 3.42 (3H, m), 3.35-2.95 (5H, m), 2.87 (IH, d, J=14Hz), 1.44 (3H, m), 1.27 (3H, m), 1.10 (2H, m), 0.88 (3H, t, J=7Hz), 0.81 (3H, t, J=7Hz). MS (DCI NΗ3) m/e 499 (M+H)+. Anal.calc. for C28H35FN2O5: C, 67.45; H, 7.08; N, 5.62. Found: C, 67.32; H, 7.05; N, 5.40.
Example 168 trans, trans- 1 -(4-N,N-Di(n-butyl)aminophenylV2-(4-methoxyphenyl)-4-( 1 ,3-benzodioxol-5-
V-.pyrrolidine-3-carboxylic acid 4-Nitro-l-fluorobenzene, ethyl trans, trans-2-(4-methoxyphenyl)~4-(l,3-benzodioxol- 5-yl)-pyrroHdine-3-carboxylate (the compound resulting from Example 6A), and dnsopropylethylamine are heated in dioxane to give ethyl trans, trans-2-(4-methoxyphenyl)- 4-(l,3-benzodioxol-5-yl)-l-(4-nitrophenyl)-pyrroHdine-3-carboxylate. The nitro compound is hydrogenated to give the corresponding aminophenyl compound. The aminophenyl compound is reacted with butyraldehyde and sodium cyanoborohydride according to the method of Borch, J. Am Chem. Soc. 93: 2897 (1971) to give the corresponding N,N- dibutylaminophenyl compound. Hydrolysis with sodium hydroxide using the method of Example ID affords the title compound.
Example 169 trans,trans-l-(2-N,N-Dibutylaminopyrimidin-4-yl)-2-(4-methoxyphenyl)-4-(l,3- benzodioxol-5-yl pyrroHdine-3-carboxylic acid 2-(Dibutylamino)-4-chloropyrimidine is prepared from 2,4-dichloropyrimidine according to the method of Gershon, I. Heterocyclic Chem. 24: 205 (1987) and reacted with ethyl trans,trαns-2-(4-methoxyphenyl)-4-(l,3-benzodioxol-5-yl)-pyrroHdine-3-carboxylate (the compound resulting from Example 6A) and diisoproplyethylamine in dioxane with heating to give the intermediate ethyl ester, which is hydrolyzed with sodium hydroxide using the method of Example ID to the title compound.
Examples 170-266 Using the procedures described in Examples 1, 4, 5, 7, 8 and 9 and Scheme X, the following compounds can be prepared.
Ex. No. Name
170 trans, trans-2-(4-Methoxyphenyl)-4-( 1 ,3-benzodioxol-5-yl)- 1 - (isopropylaminocarbonylmethyl)-pyrroHdine-3-carboxylic acid;
171 trans, trøns-2-(4-Methoxyphenyl)-4-( 1 ,3-benzodioxol-5-yl)- 1 - (ethylaminocarbonylmethyl)-pyrroHdine-3-carboxylic acid; 172 trans, trans-2-(4-Methoxyphenyl)-4-( 1 ,3-benzodioxol-5-yl)- 1 -( 1 - methylpropylaminocarbonylmethyl)-pyrroHdine-3-carboxylic acid;
173 trans, trans-2-(4-Methoxyphenyl)-4-( 1 ,3-benzodioxol-5-yl)- 1 - (phenylaminocarbonylmethyl)-pyrroHdine-3-carboxylic acid;
174 trans, trans-2-(4-Methoxyphenyl)-4-( 1 ,3-benzodioxol-5-yl)- 1 - (piperidinylcarbonylmethyl)-pyrroHdine-3 -carboxylic acid;
175 trans, tra«s-2-(4-Methoxyphenyl)-4-( 1 ,3-benzodioxol-5-yl)- 1 -( 1 - (propylaminocarbonyl)ethyl)-pyrroHdine-3-carboxylic acid;
176 trans, trans-2-(4-Methoxyphenyl)-4-( 1 ,3-benzodioxol-5-yl)- 1 -( - (piOpylaminocarbonyl)benzyl)-pyπOHdine-3-carboxylic acid;
177 trans, trans-2-(4-Methoxyphenyl)-4-( 1 ,3-benzodioxol-5-yl)- 1 ~(bis- (propylaminocarbonyl)methyl)-pyrroHdine-3-carboxylic acid;
178 trans, trans-2-(4-Methoxyphenyl)-4-( 1 ,3-benzodioxol-5-yl)- 1 -(2- (propylaminocarbonyl)ethyl)-pyrrolidine-3-carboxylic acid;
179 trans, trans-2-(4-Methoxyphenyl)-4-( 1 ,3-benzodioxol-5-yl)- 1 - (propylaminosulfonylmethyl)-pyrroHdine-3-carboxylic acid;
180 trans, trans-2-(4-Methoxyphenyl)-4-( 1 ,3-benzodioxol-5-yl)- 1 -(2- phenethyl)-pyrroHdine-3-carboxy lie acid;
181 trans, trans-2-(4-Methoxyphenyl)-4-( 1 ,3-benzodioxol-5-yl)- 1 - (pentanoylmethyl)-pyrroHdine-3-carboxy lie acid;
182 trans,trans-2-(4-Methoxyphenyl)-4-(l,3-benzodioxol-5-yl)-l- (benzoylmethyl)-pyrrolidine-3-carboxylic acid;
183 trans, trans-2-(4-Methoxyphenyl)-4-( 1 ,3-benzodioxol-5-yl)- 1 - (hexyl)-pyrroHdine-3-carboxylic acid;
184 trans, trans-2-(4-Methoxyphenyl)-4-( 1 ,3-benzodioxol-5-yl)- 1 -(2- hexynyl)-pyrroHdine-3-carboxylic acid;
185 trans, trans-2-(4-Methoxyphenyl)-4-( 1 ,3-benzodioxol-5-yl)- 1 - (propoxymethylcarbonyl-pyrroHdine-3 -carboxylic acid;
186 trans, tra77S-2-(4-Methoxyphenyl)-4-( 1 ,3 -benzodioxol-5-yl)- 1 - (phenylacetyl)-pyrroHdine-3-carboxylic acid;
187 trans, tra7_s-2-(4-Methoxyphenyl)-4~(l ,3-benzodioxol-5-yl)-l- (anilinylcarbonyl)-pyrroHdine-3-carboxylic acid;
188 trans, t/"αns-2-(4-Methoxyphenyl)-4-( 1 ,3-benzodioxol-5-yl)-l -(2- acetylaminoethyl)-pyrroHdine-3-carboxy lie acid;
189 trans, tr_ms-2-(4-Methoxyphenyl)-4-( 1 ,3 -benzodioxol-5-yl)- 1 -(2- phenoxyethyl)-pyrroHdine-3-carboxylic acid; 190 trans, trans-2-(4-Methoxyphenyl)-4-(l ,3-benzodioxol-5-yl)- 1 -(2- benzodioxanylmethyl)-pyrrolidine-3-carboxy lie acid;
191 trans, trans-2-(4-Methoxyphenyl)-4-( 1 ,3-benzodioxol-5-yl)- 1 -(2- tetraHydrofuranylmethyl)-pyrrohdine-3 -carboxylic acid;
192 trans, tra7.s-2-(4-Methoxyphenyl)-4-( 1 ,3-benzodioxol-5-yl)- 1 -(2- (propylaminocarbonylamino)ethenyl)-pyrroHdine-3-carboxyHc acid;
193 trans, trans-2-(4-Methoxyphenyl)-4-( 1 ,3-benzodioxol-5-yl)- 1 -(2- (propylaminocarbonylamino)ethyl)-pyrrolidine-3-carboxy lie acid;
194 t7'-.ns,tra7zs-2-(4-Methoxyphenyl)-4-(l,3-benzodioxol-5-yl)-l-(3- oxohex-l-enyl)-pyrroHdine-3-carboxylic acid;
195 trans, tra72s-2-(2,4-Dimethoxyphenyl)-4-( 1 ,3-benzodioxol-5-yl)- 1 - (propylaminocarbonyHnethyl)-pyrroHdine-3-carboxylic acid;
196 trans,trans-2-(2-Carboxy-4-methoxyphenyl)-4-(l,3-benzodioxol-5- yl)- 1 -(propylaminocarbonylmethyl)-pyrrolidine-3-carboxylic acid;
197 trans, trans-2-(2-Aminocarbonyl-4-methoxyphenyl)-4-( 1,3- benzodioxol-5-yl)- 1 -(propylamino carbonylmethyl) -pyrroHdine-3- carboxylic acid;
198 trans, trø7zs-2-(2-Methanesulfonamido-4-methoxyphenyl)-4-( 1,3- beι_-Zθdioxol-5-yl)-l-(propylaminocarbonylmethyl)-pyrroHdine-3- carboxylic acid;
199 trans, trans-2-(2-Aminocarbonylmethoxy-4-methoxyphenyl)-4- ( 1 ,3-benzodioxol-5-yl)- 1 -(propylaminocarbonylmethyl)- pyrrolidine-3-carboxylic acid;
200 trans,trans-2-(2-Methoxyethoxy-4-methoxyphenyl)-4-(l,3- benzodioxol-5-yl)-l-(propylaminocarbonylmethyl)-pyrrolidine-3- carboxylic acid;
201 trans, tra7zs-2-(2-Carboxymethoxy-4-methoxyphenyl)-4-( 1,3- benzodioxol-5-yl)- 1 -(propylamino carbonylmethyl) -pyrrolidine-3 - carboxylic acid;
202 trans,trans-2-(4-Methoxy-2-tetrazolylmethoxyphenyl)-4-(l,3- benzodioxol-5-yl)-l-(propylaminocarbonylmethyl)-pyrroHdine-3- carboxylic acid;
203 trans, t7^7zs-2-(2-AUyloxy-4-methoxyphenyl)-4-( 1 ,3-benzodioxol- 5-yl)-l-(propylaminocarbonylmethyl)-pyrrolidine-3-carboxylic acid; 204 transjrans 2,4-Bis(4-methoxyphenyl)-l- (propylaminocarbonylmethyl)-pyrrolidine-3-carboxylic acid;
205 transjrans 2,4-Bis(l,3-benzodioxol-5-yl)-l- (piOpylaminocarbonylmethyl)-pyrroHdine-3-carboxylic acid;
206 trans, trans-2-(4-Methoxyphenyl)-4-( 1 ,3-benzodioxol-5-yl)- 1 -(N- methyl-N-propylaminocarbonylmethyl)-pyrrolidine-3-carboxylic acid;
207 trans, tr_.ns-2-(4-Methoxyphenyl)-4-( 1 ,3-benzodioxole-5-yl)- 1 -(N- methyl-N-butylaminocarbonyl)-pyrroHdine-3-carboxylic acid;
208 trans, trans-2-(4-Methoxyphenyl)-4-( 1 ,3-benzodioxol-5-yl)- 1 -(N- methyl-N-(4-methoxyphenyl)aminocarbonyl)-3-pyrroHdine-3- carboxylic acid;
209 tr-.77s,tr-.ns-2-(4-Methoxyphenyl)-4-(l,3-benzodioxol-5-yl)-l-(N- methyl-N-phenylaminocarbonyl)-pyrrolidine-3-carboxy lie acid;
210 trans, tr_zns-2-(4-Methoxyphenyl)-4-( 1 ,3-benzodioxol-5-yl)- 1 -(N- methyl-N-aUylaminocarbonyHnethyl)-pyrroHdine-3-carboxyHc acid;
211 trø7is, tr_zns-2-(4-Methoxyphenyl)-4-( 1 ,3-benzodioxol-5-yl)-l -(TST- methyl-N-(n-butyl) aminocarbonylmethyl)-pyrroHdine-3 -carboxylic acid;
212 tra7.s.tr_zns-2-(4-Methoxyphenyl)-4-(l,3-benzodioxol-5-yl)-l-(N- methyl-N-isobutylaminocarbonyHnethyl)-pyrrolidine-3-carboxylic acid;
213 trans, tr-_ns-2-(4-Methoxyphenyl)-4-( 1 ,3-benzodioxol-5-yl)- 1 -(N- methyl-N-cy clopentylamino carbonylmethy l)-pyrrolidine-3 - carboxylic acid;
214 trans, trøns-2-(4-Methoxyphenyl)-4-( 1 ,3-benzodioxol-5-yl)- 1 -(N- methyl-N-(2-methoxyethyl)aminocarbonyl)-pyιτolidine-3- carboxylic acid;
215 trans, tra72s-2-(4-Methoxyphenyl)-4-( 1 ,3-benzodioxol-5-yl)-l -(N- methyl-N-butoxyethylammocarbonyl)-pyrrolidine-3-carboxyHc acid;
216 trans, trans-2-(l ,3-Be_ιzodioxol-5-yl)-4-(4~methoxyphenyl)- 1 -(N- methyl-N-propylaminocarbonylmethyl)-pyrroHdine-3-carboxylic acid; 217 trans, trans-2-(4-Methoxyphenyl)-4-( 1 ,4-benzodioxan-6-yl)- 1 -(N- methyl-N-propylaminocarbonylmethyl)-pyrrolidine-3-carboxylic acid;
218 trans, trø72s-2-(4-Methoxyphenyl)-4-( 1 ,3-benzodioxol-5-yl)- 1 -(N- methyl-N-isopropylaminocarbonylmethyl)-pyrroHdine-3- carboxylic acid;
219 trans, trø7zs-2-(4-Methoxyphenyl)-4-( 1 ,3-benzodioxol-5-yl)- 1-(N- methyl-N-ethylaminocarbonylmethyl)-pyrrolidine-3-carboxyHc acid;
220 trans,trans-2-(4-Methoxyphenyl)-4-(l,3-benzodioxol-5-yl)-l-(N- methyl-N-( 1 -methylpropyl)aminocarbonylmethyl)-pyrroHdine-3- carboxylic acid;
221 trans, trans-2-(4-Methoxyphenyl)-4-( 1 ,3-benzodioxol-5-yl)- 1 -(N- methyl-N-phenylaminocarbonyHnethyl)-pyrroHdine-3-carboxylic acid;
222 trans, trans-2-(4-Methoxyphenyl)-4-( 1 ,3-benzodioxol-5-yl)- 1 -( 1 - (N-methyl-N-propylaminocarbonyl)ethyl)-pyrroHdine-3-carboxylic acid;
223 trans, tra7zs-2-(4-Methoxyphenyl)-4-( 1 ,3-benzodioxol-5-yl)- 1 -( - (N-methyl-N-propylaminocarbonyl)benzyl)-pyrroHdine-3- carboxylic acid;
224 trans,trans-2-(4-Methoxyphenyl)-4-(l,3-benzodioxol-5-yl)-l-(N- ethyl-N-propylaminocarbonylmethyl)-pyrrolidine-3-carboxylic acid;
225 trans,tra7zs-2-(4-Methoxyphenyl)-4-(l,3-benzodioxole-5-yl)-l-(N- ethyl-N-butylaminocarbonyl)-pyrrolidine-3-carboxylic acid;
226 tra«s,trans-2-(4-Methoxyphenyl)-4-(l,3-benzodioxol-5-yl)-l-(N- ethyl-N-(4-methoxyphenyl)aminocarbonyl)-3-pyrrolidine-3- carboxylic acid;
227 trans,trans-2-(4-Methoxyphenyl)-4-(l,3-benzodioxol-5-yl)-l-(N- ethyl-N-phenylaminocarbonyl)-pyrroHdine-3-carboxylic acid;
228 tra7ϊs,trans-2-(4-Methoxyphenyl)-4-(l,3-benzodioxol-5-yl)-l-(N- ethyl-N-aUylaminocarbonylmethyl)-pyrrolidine-3-carboxy lie acid;
229 trans,tr-.ns-2-(4-Methoxyphenyl)-4-(l,3-benzodioxol-5-yl)-l-(N- ethyl-N-isobutylaminocarbonylm.ethyl)-pyrroHdine-3-carboxylic acid; 230 trans,trans-2-(4-Methoxyphenyl)-4-(l,3-benzodioxol-5-yl)-l-(N- ethyl-N-cyclopentylaminocarbonylmethyl)-pyrroHdine-3- carboxylic acid;
231 trans, trans-2-(4-Methoxyphenyl)-4-( 1 ,3-benzodioxol-5-yl)- 1 -(N- ethyl-N-methoxyethylaminocarbonyl)-pyrroHdine-3-carboxylic acid;
232 trans, tra7?s-2-(4-Methoxyphenyl)-4-( 1 ,3 -benzodioxol-5-yl)- 1 -(N- ethyl-N-butoxyethylaminocarbonyl)-pyrroHdine-3-carboxylic acid;
233 tra7zs,tra72s-2-(l,3-Benzodioxol-5-yl)-4-(4-methoxyphenyl)-l-(N- ethyl-N-propylaminocarbonylmethyl)-pyrroHdine-3-carboxyHc acid;
234 trans, trans-2-(4-Methoxyphenyl)-4-( 1 ,4-benzodioxan-6-yl)- 1 -(N- ethyl-N-propylaminocarbonylmethyl)-pyrroHdine-3-carboxyHc acid;
235 trans, trans-2-(4-Methoxyphenyl)-4-( 1 ,3-benzodioxol-5-yl)- 1 ~(N- ethyl-N-isopropylaminocarbonylmethyl)-pyrroHdine-3-carboxylic acid;
236 trans, trans-2-(4-Methoxypheny 1) -4-( 1 , 3 -benzodioxol-5-yl)- 1 - (N,N-diethylaminocarbonylmethyl)-pyrroHdine-3τcarboxy lie acid;
237 trans,trans-2-(4-Methoxyphenyl)-4-(l,3-benzodioxol-5-yl)-l-(N- ethyl-N-(l-methylpropyl)aminocarbonylmethyl)-pyrroHdine-3- carboxylic acid;
238 trans, trans-2-(4-Methoxyphenyl)-4-( 1 ,3 -benzodioxol-5-yl)- 1 -(N- ethyl-N-phenylaminocarbonylmethyl)-pyrroHdine-3-carboxylic acid; 239 trans, trans-2-(4-Methoxyphenyl)-4-( 1 ,3-benzodioxol-5-yl)- 1 -( 1 -
(N-ethyl-N-propylaminocarbonyl)ethyl)-pyrroHdine-3-carboxylic acid;
240 trans, trans-2-(4-Methoxyphenyl)-4-( 1 ,3-benzodioxol-5-yl)- 1 -( - (N-ethyl-N-propylaminocarbonyl)benzyl)-pyrroHdine-3-carboxylic acid;
241 trans, trans-2-(4-Methoxyphenyl)-4-( 1 ,3-benzodioxol-5-yl)- 1 -(N- methyl-N-isobutylaminocarbonylmethyl)-pyι oHdine-3-carboxylic acid; 242 trans,trα7.s-2-(4-Methoxyphenyl)-4-(l,3-benzodioxol-5-yl)-l-(N- methyl-N-cyclohexylaminocarbonylmethyl)-pyrroHdine-3- carboxylic acid;
243 trans, tr_.ns-2-(4-Methoxyphenyl)-4-( 1 ,3-benzodioxol-5-yl)- 1 - (N,N-dipropylaminocarbonylmethyl)-pyrrolidine-3-carboxyHc acid;
244 trans, tra72s-2-(4-Methoxyphenyl)-4-( 1 ,3-benzodioxol-5-yl)- 1 - (isobutyloxyethyl)-pyrrolidine-3-carboxy lie acid;
245 trans, trans-2-(4-Methoxyphenyl)-4-(l ,3-benzodioxol-5-yl)- 1 - (butylsulfonyl)-pyrroHdine-3-carboxylic acid;
246 trans, trα7.s-2~(4-Methoxyphenyl)-4-( 1 ,3-benzodioxol-5-yl)- 1 - (isopropylsulfonylamino ethyl)-pyrroHdine-3 -carboxylic acid;
247 trans, tr-zns-2-(4-Methoxyphenyl)-4-( 1 ,3-benzodioxol-5-yl)- 1 - (ethoxymethylcarbonylmethyl)-pyιτoHdine-3-carboxylic acid;
248 trans,tr 7.s-2-(4-Methoxyphenyl)-4-(l,3-benzodioxol-5-yl)-l-(2- ethylbutyryHnethyl)-pyrroHdine-3-carboxylic acid;
249 trans, tr_.?.s-2-(4-Methoxyphenyl)-4-( 1 ,3-benzodioxol-5-yl)- 1 -(N- methyl-N-(3,4-dimethoxybenzyl)aminocarbonylmethyl)- pyrroHdine-3 -carboxylic acid;
250 trans,tra7.s-2-(4-Methoxyphenyl)-4-(l,3-benzodioxol-5-yl)-l- [(lR)-l-(N-methyl-N-propylaminocarbonyl)butyl]-pyrroHdine-3- carboxylic acid;
251 trans, tr-.77s-2-(4-Methoxyphenyl)-4-( 1 ,3-benzodioxol-5-yl)- 1 - [(lS)-l-(N-methyl-N-propylaminocarbonyl)butyl]-pyrrolidine-3- carboxylic acid;
252 trans, traτ.s-2-(4-Methoxyphenyl)-4-( 1 ,3-benzodioxol-5-yl)- 1 -(3- isopropoxypropyl)-pvrrolidine-3-carboxylic acid;
253 trans,tra72s-2-(4-Methoxyphenyl)-4-(l,3-benzodioxol-5-yl)-l-(5- methylhexy 1) -pyrroHdine-3 -carboxylic acid;
254 tra72s,trans-2-(4-Methoxyphenyl)-4-(l,3-benzodioxol-5-yl)-l-(5- methyl-2-hexenyl)-pyrroHdine-3 -carboxylic acid;
255 trans,trans-2-(4-Methoxyphenyl)-4-(l,3-benzodioxol-5-yl)-l-(5- methyl-4-hexenyl)-pyrroHdine-3 -carboxylic acid;
256 t7-_.ns,trans-2-(4-Methoxyphenyl)-4-(l,3-benzodioxol-5-yl)-l-(3,5- dimethyl-2-hexenyl)-pyrroHdine-3-carboxylic acid; 257 trans, tr-.ns-2-(4-Methoxyphenyl)-4-( 1 ,3-benzodioxol-5-yl)- 1 -(2- (N-methyl-N-isobutyrylamino)ethyl)-pyrroHdine-3-carboxyHc acid;
258 trans,tr-.ns-2-(4-Methoxyphenyl)-4-(l,3-benzodioxol-5-yl)-l-(N- methyl-N-(2,2-dimethylpropyl)aminocarbonylmethyl)-pyrroHdine- 3 -carboxylic acid;
259 trans,tr_.ns-2-(4-Methoxyphenyl)-4-(l,3-benzodioxol-5-yl)-l-(N- ethyl-N-butylaminocarbonylmethyl)-pyrrolidine-3 -carboxylic acid;
260 trans,tr_.ns-2-(4-Methoxyphenyl)-4-(l,3-benzodioxol-5-yl)-l-(N- methyl-N-benzylaminocarbonylmethyl)-pyrroHdine-3-carboxylic acid;
262 trans, trαns-2-(4-Methoxyphenyl)-4-(5~indanyl)- 1 - N-methyl-N- propylamino carbonylmethyl)-pyrroHdine-3 -carboxylic acid;
262 .raws, tr-.ns-2-(4-Methoxyphenyl)-4-(2,3-dihydiObenzofuran-5-yl)- l-(N-methyl-N-propylaminocarbonylmethyl)-pyrroHdine-3- carboxylic acid;
263 trans, tr_.ns-2-(4-Methoxyphenyl)-4-( 1 -methylindol-5-yl)- 1 -(N- methyl-N-propylaminocarbonylmethyl)-pyrroHdine-3-carboxylic acid;
264 trans, tr-.7.s-2-(4-Methoxyphenyl)-4-(2-naphthyl)- 1 -(N-methyl-N- propylaminocarbonylmethyl)-pyrroHdine-3-carboxylic acid;
265 traws, tr-.ns-2-(4-Methoxyphenyl)-4-( 1 ,2-dimethoxy-4-phenyl)- 1 - (N-methyl-N-propylaminocarbonylmethyl)-pyrroHdine-3- carboxylic acid;
266 trans, trans-2-(4-Methoxyphenyl)-4-( 1 -methoxy-3-phenyl)- 1 -(N- methyl-N-propylaminocarbonylmethyl)-pyrrolidine-3-carboxylic acid; '
Examples 267-288 Following the procedures described in Example 1 and Scheme II, the foUowing compounds can be prepared.
267 t7"_.ns,tr-.72s-3-(4-Methoxyphenyl)-5-(l,3-benzodioxol-5-yl)-l- (propylaminocarbonylmethyl)-piperidine-4-carboxylic acid; 268 trans, trans-3-(4-Methoxyphenyl)-5-( 1 ,3-benzodioxol-5-yl)- 1 - (aminocarbonylmethyl)-piperidine-4-carboxyHc acid;
269 tra72s,trαns-3-(4-Methoxyphenyl)-5-(l,3-benzodioxol-5-yl)-l-(4- fluorobenzyl)-piperidine-4-carboxylic acid;
270 trans, trans-3-(4-Methoxyphenyl)-5-(l ,3-benzodioxol-5-yl)- 1 -(2- ethoxyethyl)-piperidine-4-carboxylic acid;
271 trans, trans-3-(4-Methoxyphenyl)-5-( 1 ,3-benzodioxol-5-yl)- 1 -(2- propoxyethyl)-piperidine-4-carboxylic acid;
272 trans,trans-3-(4-Methoxyphenyl)-5-(l,3-benzodioxol-5-yl)-l-[2-(2- methoxyethoxy)ethyl]-piperidine-4-carboxylic acid;
273 tra7.s,trans-3-(4-Methoxyρhenyl)-5-(l,3-benzodioxol-5-yl)-l-[2-(2- pyridyl)ethyl]-piperidine-4-carboxylic acid;
274 trans, trans-3-(4-Methoxyphenyl)-5-(l ,3-benzodioxol-5-yl)- 1 - (morphoHn-4-ylcai"bonyl)-piperidine-4-carboxylic acid;
275 trans,trans-3-(4-Methoxyphenyl)-5-(l,3-be_ιzodioxole-5-yl)-l- (butylaminocarbonyl)-piperidine-4-carboxylic acid;
276 tra7.s,trβns-3-(4-Methoxyphenyl)-5-(l,3-benzodioxol-5-yl)-l-(4- methoxyphenylaminocarbonyl)-3-piperidine-4-carboxylic acid;
277 trans, trans-3-(4-Methoxyphenyl)-5-( 1 ,3-benzodioxol-5-yl)- 1- acetylpiperidine-3-carboxylic acid;
278 trans, trans-3-(4-Methoxyphenyl)-5-( 1 ,3-benzodioxol-5-yl)- 1 -(2- furoyl)-piperidine-3-carboxylic acid;
279 trans, trans-3-(4-Methoxyphenyl)-5-(l ,3-benzodioxol-5-yl)- 1 - (phenylaminocarbonyl)-piperidine-4-carboxylic acid;
280 tr_.7ts,tr 72s-3-(4-Methoxyphenyl)-5-(l,3-benzodioxol-5-yl)-l- (allylaminocarbonylmethyl)-piperidine-4-carboxy lie acid;
281 t7"αns, tra77s-3-(4-Methoxyphenyl)-5-( 1 ,3-benzodioxol-5-yl)- l-(n- butylaminocarbonylmethyl)-piperidine-4-carboxylic acid;
282 trans, t7-_.ns-3-(4-Methoxyphenyl)-5-( 1 ,3-benzodioxol-5-yl)- 1 -(N-n- butyl-N-methylaminocarbonylmethyl)-piperidine-4-carboxyHc acid;
283 trans, trans-3-(4-Methoxyphenyl)-5-( 1 ,3-benzodioxol-5-yl)- 1 - (pyrroHdin- 1 -ylcarbonylmethyl)-piperidine-4-carboxylic acid;
284 trans,trαns-3-(4-Methoxyphenyl)-5-(l,3-benzodioxol-5-yl)-l- (isobutylaminocarbonylmethyl)-piperidine-4-carboxy lie acid; 285 trans, trans-3-(4-Methoxyphenyl)-5-( 1 ,3 -benzodioxol-5-yl)- 1 - (cyclopentylaminocarbonylmethyl)-piperidine-4-carboxy lie acid;
286 trans, tra7.s-3-(4-Methoxyphenyl)-5-( 1 ,3-benzodioxol-5-yl)- 1 - (morpholin-4-ylaminocarbonylmethyl)-piperidine-4-carboxyHc acid;
287 trans,trans-3-(4-Methoxyphenyl)-5-(l,3-benzodioxol-5-yl)-l-(2- phenoxyethyl)-piperidine-4-carboxylic acid;
288 trans, tra77s-3-(4-Methoxyphenyl)-5-( 1 ,3-benzodioxol-5-yl)- 1- (methoxyethylaminocarbonyl)-piperidine-4-carboxylic acid.
Example 289 transjrans- 2-(4-Methoxyphenyl)-4-(l,3-benzodioxol-5-yl)-l- (4-dibutylaminophenyl)- pyrroHdine-3 -carboxylic acid 4-Nitro-fluorobenzene, ethyl tr_.7.s,trans-2-(4-methoxyphenyl)-4-(l,3-benzodioxol-5- yl)-pyrroHdine-3-carboxylate (example 6A) and di-isopropyl ethylamine are heated in dioxane to give ethyl tr_.ns,trans-2-(4-methoxyphenyl)-4-(l,3-benzodioxol-5-yl)-l-(4- nitrophenyl)-pyrroHdine-3-carboxylate. The nitro compound is hydrogenated to the corresponding aminophenyl compound. This is reacted with butyraldehyde and sodium cyanoborohydride according to the method of Borch (I. Am Chem Soc, 93, 2897, 1971) to give the corresponding N,N-dibutylaminophenyl compound, which is hydrolyzed with sodium hydroxide using the method of example ID to give the title compound.
Example 290 trans.tr-.ns-2-(4-Methoxyphenyl)-4-(l,3-benzodioxol-5-yl)-l-(2-dibutylamino-pyrimidine-4- yl)-pyrroHdine-3-carboxyHc acid 2-(Dibutylamino) 4-chloropyrimidine is prepared from 2-4-dichloropyrimidine according to the method of Gershon (I. Heterocyclic Chem. 24, 205, 1987). This compound, ethyl trans,tra72s-2-(4-methoxyphenyl)-4-(l,3-benzodioxol-5-yl)-pyrroHdine-3-carboxylate (example 6A), and di-isopropyl ethylamine are heated in dioxane to give the intermediate ethyl ester, which is hydrolyzed with sodium hydroxide using the method of example ID to give the title compound.
Example 291 tra72s.tr-.ns-2-(4-Methoxyphenyl)-4-(l,3-benzodioxol-5-ylVl-(N-butyl-N- phenylaminocarbonylmethylVpyrroUdine-3-carboxylic acid The title compound was prepared according to the general procedure of Example 1. *H NMR (CD3OD) : 0.87 (t,3H,J=8); 1.2-1.35 (m,2H); 1.35-1.5 (m,2H); 2.78 (m, 2H);
3.10 (t,lH, J=9); 3.26 (d,lH,J=15); 3.44 (dd,lH,J=5,10); 3.5-3.7 (m,3H); 3.77 (m,lH); 3.78 (s,3H); 5.93 (s,2H); 6.7-6.9 (m,4H); 7.0-7.2 (m,5H); 7.4 (m,3H). MS (DCI/NH3): m/e 531 (M+H)+. Anal calcd for C3 ιH34N2O6: C, 70.17; H, 6.46; N, 5.28. Found: C,70.36; H, 6.52; N, 4.99.
Example 292 Sodium trα7.sJra7is-2-(4-Methoxyphenyl)-4-(l,3-beι_zodioxol-5-yl)-l-ι^.N- /t7.- butyl) aminocarbonylmethyl) -pyrroHdine-3 -carboxylate
Example 292A Ethyl 3-(4-methoxyphenyl)-3-oxopropionate Simultaneous reactions were run in both a 65-L reactor and a 35-L reactor that share the same reflux system. A nitrogen atmosphere was maintained in both. 4.0 kg (100 moles) of 60% sodium hydride in mineral oU and 32 L toluene were charged into the ambient temperature reactors. The mixture was agitated for 5 minutes and allowed to settle. 20 L of the toluene solution was aspirated. 28 L of toluene was added, agitated for 5 minutes, aUowed to settle and 28 L of the toluene solution was aspirated. 68 L of toluene and 8.4 L (69.7 moles) diethyl carbonate were added. The agitation was begun and the flow of Syltherm (Note 4) in reactor jackets was initiated. A solution of 5.0 kg (33.3 moles) 4- methoxy acetophenone in 12 L toluene was added over 20 minutes. When additions were complete, the jacket temperaturewas reduced to 10° C and stirring continued for 16 hours. A solution of 6.7 L (l 17 moles) glacial acetic acid in 23 L deionized water was fed at the same rate that was previously used for the acetophenone solution. When addition was complete, agitation was stopped and the layers separated. The aqueous layer was washed once with 13 L toluene. The combined organic layers were washed twice with 6.7 L portions of 7% (w:w) aqueous sodium bicarbonate. The toluene solution was washed once with 6.7 L of 23% (w:w) aqueous sodium chloride . The organic solution was dried over 10 kg sodium sulfate, filtered, and the solvent removed on the rotary evaporator to provide the desired product.
Example 292B 3 ,4-Methylenedioxy- 1 -(2-nitroethenyl. -benzene In a 45-L cryogenic reactor with a contoured, anchor stirrer was dissolved 5.537 kg
(36.9 moles) piperonal in 9 L methanol and 2.252 kg (36.9 moles) nitromethane at 15°-20° C. The jacket temperature was set to -5° C and the reaction solution cooled to a temperature of +3.5° C. A 21° C solution of 3.10 kg (38.8 moles) 50% (w:w) aquous sodium hydroxide dUuted with 3.7 L water was pumped in. The reaction temperature was maintained between 10°- 15° C. When addition was complete, the jacket temperature was reset to 1° C and stirring continued for 30 minutes. A mixture of 7 kg ice in 19 L water was added to dissolve most of the soHd. The reaction mixture was filtered through canvas and then a 27R10SV Honeycomb filter. The filtered solution was metered into a 21° C mixture of 7.4 L concentrated hydrochloric acid in 11.1 L deionized water. The final reaction temperature was 26° C. The resulting product was centrifuged and washed until the wash pH rose to at least 6 (by pH indicating paper). The crude product was dissolved in 92 L dichloromethane and the layers separated. The aqueous layer was washed once with 8 L dichloromethane. The combined organics were dried over 1.32 kg magnesium sulfate and filtered through Whatman #1 paper. The volume was reduced to 20% and the solution cooled to 4° C. Filtration through Whatman #1 paper, foUowed by ambient temperature drying in vacuo with an air leak afforded 1.584 kg (22%) of a first crop Concentration of the MLS to 25% foUowed by similar coohng, filtration, and drying afforded 0.262 kg (4%) of a second crop. The yellow product darkened on standing in light and air.
Example 292C Ethyl 2-(4-methoxybenzoyD-3-(l,3-benzodioxol-5-yl)-4-nitro-butanoate
Into a 45-L stirred reactor at ambient temperature were charged 5.819 kg (30.1 moles) 3,4-methylenedioxy-l-(2-nitroethenyl)-benzene and 24 L ethyl acetate . A solution of 5.355 kg (24.1 moles) ethyl 3-(4-methoxyphenyl)-3-oxopropionate in 16 L ethyl acetate was added. 280 g (275 ml, 1.84 moles) of l,8-diaza-bicyclo[5.4.0]undec-7-ene in four equal portions was added over a 2.5 hour period. The reaction mixture was filtered tlirough dicalite and the resulting filtered solution was used in the next step without any further purification.
Example 292D Ethyl 2-(4-methoxyphenyl)-4-(l,3-beιιzodioxol-5-yl)-4,5-dihydro-3H-pyrrol-3-carboxy late The product of Example 292C (1316 ml solution consisting of 300 g Ethyl 2-(4- methoxybenzoyl)-3-(3,4-methylenedioxyphenyl)-4 nitrobutanoate in ethyl acetate) was added to a glass reactor containing RaNi # 28 (300 g). The reaction mixture was shaken under a hydrogen environment of 4 atm at room temperature for 18 hoursand filtered through a nylon 0.20 micron 47 mm millipore. The filtrate was concentrated to 1.4 kg of dark solution and purified by normal phase silica gel chromatography eluting with 85: 15, hexanes: ethyl acetate. The pure fractions were combined and concentrated (as above) until crystals formed. The solution was cooled to 0° C and filtered. The solid was washed with 2 L of 85: 15, hexane: ethyl acetate (0° C). The solids were dried zn vacuo at 50° C to a constant weight of 193.4 g (21% yield, melting point 80-81° C) of the title compound. A further 200 g (23% yield) of product was obtained from the mother liquors.
Example 292E Ethyl 2-(4-methoxyphenyl)-4-(l ,3-benzodioxol-5-yl)-pyrroHdine 3-carboxylate Into a 12-L flask equipped with magnetic stirring, addition funnel, temperature probe, and nitrogen inlet was charged 0.460 kg ethyl 2-(4-methoxyphenyl)-4-(3,4- methylenedioxyphenyl)-4,5-dihydro-3H -pyrrole-3 -carboxylate (1.25 mol). The reaction vessel was degassed with nitrogen. Absolute 3.7 L ethanol and 1.12 L of THF were added. 31 mg bromocresol green and 94.26g sodium cyanoborohydride (1.5 mol) were added. A solution containing 400 mL absolute ethanol and 200 mL of 12 M HCl was then added. The reaction mixture was stirred for 30 minutes after addition was complete. After the starting material was consumed, 0.5 L of 7% aq. NaHCO3 was added. The reaction mixture was concentrated and dUuted with 5 L ethyl acetate. The organic layer was washed twice with 2 L of 7% aq. NaHCO3 and once with 2.5 L of 23% aq. NaCl, the dried over 190g MgSO4, filtered, and concentrated to give 447 g of the title compound as a thick yellow oU.
Example 292F Ethyl 2-(4-methoxypheny)-4-(l ,3-benzodioxol-5-yl -l-(N,N-di(n- butyD amino carbonyhnethyl pyrrolidine 3-carboxylate Into a 22-L flask equipped with overhead stirring, nitrogen inlet, and condenser was charged ethyl 2-(4-methoxyphenyl)-4-(3,4-methylenedioxyphenyl)-pyrrolidine-3- carboxylate (2.223 kg,6.02 mol). The reaction vessel was degassed with nitrogen. 13.2 L ofacetonitrile, 3.66 L diisopropylethylamine (2.71 kg, 20.9 mol), and 1.567 kg dibutylamidomethyl bromide (6.26 mol) were added. The mixture was refluxed at 78° C for 17 hrs. After the disappearance of starting material , the mixture was concentrated until crystals formed. The solid was filtered and washed with 4 L ethyl acetate (0° C).
Concentrating of the filtrate was continued as above until all volatiles were removed. The residue was diluted with 40 L ethyl acetate and washed with 20 L deionized water. The organic layer was washed with 8 L of 23% aq. NaCl nad dried over 0.399 kg MgSO4 and filtered. Concentration as above provided 3.112 kg (96 % yield) of the title compound as a dark oil. Example 292G tra77s.tra7ts-2-(4-Methoxyphenyl)-4-(l,3-benzodioxol-5-yl)-pyrroHdine 3-carboxylate and preparation of trans, trans 2-(4-methoxyphenyl)-4-(3 ,4-dioxyphenylVpyrroUdine-3- carboxylic acid ethyl ester Into a 35-L reactor equipped with overhead stirring, nitrogen inlet, and condenser was charged 3.112 kg ethyl 2-(4-methoxyphenyl)-4-(3,4-methylenedioxyphenyl)-pyrroHdine 3- carboxylate (5.78 mol). 16.4 L of absolute ethanol was added and the reaction vessel was degassed with nitrogen. 0.115 kg of sodium ethoxide (1.69 mol) was added and the mixture was refluxed at 79° C for 1 hr. The mixture was cooled to 15° C and 5 L of 7.6 M NaOH solution (38.1 mol) was added. The mixture was stirred at 15° C for 18 hrs. The solvent was evaporated and the residue dissolved in 15.8 L of deionized water and extracted with 28 L of ether. The ether solution was washed with 9.5 L deionized water. The aqueous wash was extracted with 3 L ether. 0.340 L of 12 M HCl was added to the aqueous layer. The aqueous layer was extracted with 24 L of ethyl acetate. The organic layer was washed with 9 L of 23% aq. NaCl, dried with 0.298 kg MgSO4 , filtered, and concentrated to give 2.132 kg of a dark oU. The oil was triturated with 18 L ether. The undesired solids were filtered and saved for later use. The mother Hquors were concentrated to obtain 1.102 kg of Hght foam. The foam was dissolved in 5.5 L ethyl acetate with heating to 65° C. 14 L hexane was added slowly enough to keep the solution refluxing. The reaction mixture was cooled to 10° C and filtered. The crystals were washed with 2 L ether (0° C) and dried to constant weight in vacuo at 50° C to give 0.846 kg (43% yield, melting point 119-120) of crude product, which was further purified by normal phase silica gel chromatography.
Example 292H SocHum tr-.72s.trans-2-(4-methoxyphenyl)-4-(l,3-benzodioxol-5-yl)-l-(N,N-di(n- butyl) amino carbonylmethyl) pyrrolidine 3-carboxylate Into a 20-L flask was charged transjrans 2-(4-methoxyphenyl)-4-(3,4- methyledioxyphenyl)-l-(N,N-dibutylamino- carbonyl methyl) pyrrolidine 3-carboxyHc acid (0.927 kg, 1.819 mol). A solution of 0.0720 kg NaOH (1.80 mol) dissolved in 4.65 L methanol was added. The reaction mixture was concentrated to an oU. Pentane (4 L) was added and the solution concentrated again. Pentane (4 L) was added again and concentration of this solution gave a light tan foam. The foam was dried in vacuo at 50° C to a constant weight of 0.937 kg (97% yield) of the title compound.
Example 293 tr-.ns-tr-.ns-2-(4-Methoxyphenyl)-4-(l,3-benzodioxol-5-yl)-l-[decahydroisoquinoHn-2- carbonylmethyl]-pyrroHdine-3-carboxylic acid.
The title compound was prepared using the procedures described in example 1. NMR (CD OD, 300 MHz) shows a mixture of isomers. MS (DCI/NH3) m/z 521. Anal calcd for C30H36N2O6 . 1.3 TFA: C, 58.54; H, 6.62; N, 4.19 . Found: C, 58.34; H, 5.58; N, 4.00 .
Example 294 trαns-tr-.ns-2-(4-Methoxyphenyl)-4-(l,3-benzodioxol-5-yl)-l-[3,3-dimethylpiperidinyl- carbonylmethyl] -pyrroHdine-3 -carboxylic acid. The title compound was prepared using the procedures described in example 1. NMR
(CD3OD, 300 MHz) indicates presence of rotamers. δ 0.84 (s, 3H), 0.86 (s, 3H), 1.35-1.6
(m, 4H), 3.83 (s, 3H), 5.96 (s, 2H), 6.81 (d, IH, J=8), 6.90 (dd, IH, =1,8), 7.01 (d, 2H, =9), 7.03 (s, IH), 7.47 (d, 2H, J=9). MS (DCI/NH3) m/z 495. Anal calcd for C28H34N2O6 . 1.4 TFA: C, 56.55; H, 5.45; N, 4.28 . Found: C, 56.52; H, 5.83; N, 4.26 .
Example 295 tr_.ns-trans-2-(4-Methoxyphenyl)-4-(l,3-benzodioxol-5-yl)-l-[2-(N-propyl-N-iso- butoxycarbonylamino ethyl]-pyrroHdine-3-carboxylic acid The title compound was prepared by the methods detailed in Example 61, but substituting propylamine for methylamine in Example 6 IB and isobutyl chloroformate for isobutyryl chloride in Example 61C. The crude product was purified by trituration with 1 : 1 diethyl ether/ hexane. The resulting soHd was dissolved in CH3CN and water and lyophilized to give the product as a white sohd. 1H NMR (CDCI3, 300 MHz) δ 0.80 (t, 3H, =7), 0.92 (m, 3H), 1.43 (h, 2H, J=7Hz), 1.7-1.9 (m, IH), 2.72 (m, IH), 2.90 (m, 2H), 3.10 (m, 2H), 3.25 (m, 2H), 3.40 (m, IH), 3.55 (m, IH), 3.62 (m, IH), 3.7-3.9 (m, 2H) 3.78 (s, 3H), 5.95 (s, 2H), 6.72 (d, IH, = 8Hz), 6.82 (m, 3H), 7.00 (s, IH), 7.30 (d, 2H, J=8Hz). MS (DCI NH3) m/e 527 (M+H)+. Anal calcd for C29H38N2O6 ' 0.5 H2O: C, 65.03; H, 7.34; N, 5.23. Found: C, 65.13; H, 6.96; N, 4.95.
Example 296 tra7.s-trans-2-(4-Methoxyphenyl)-4-(l,3-benzodioxol-5-yl)-l-[l,2,3,4-tetrahydroisoquinoHn- 2- carbonylmethyl]-pyrroHdine-3-carboxyHc acid. The title compound was prepared using the procedures described in example 1. NMR (CD3OD, 300 MHz) indicates presence of rotamers. δ 2.97 (m, 2H), 4.68 (s, 3H), 5.97 (s, 2H), 6.83 (d, IH, J=8), 6.9-7.0 (m, 3H), 7.03 (d, IH, =2), 7.1-7.3 (m, 4H), 7.4-7.5 (m, 2H). MS (DCI/NH3) m/z 515. Example 297 tra72s-tr_.ns-2-(4-Methoxyphenyl)-4-(l,3-benzodioxol-5-yl)-l-[2-(N-propyl-N- dimethylaminocarbonylamino)ethyl]-pyrroHdine-3-carboxy lie acid The title compound was prepared by the methods detailed in Example 61, but substituting propylamine for methylamine in Example 6 IB and dimethylcarbamyl chloride for isobutyryl chloride in Example 61C. The crude product was purified by preparative HPLC (Vydac C18) eluting with a 10-70% gradient of CH CN in 0.1% TFA. The desired fractions were lyophilized to give the product as a white sohd. H NMR (CDCI3, 300 MHz) δ 0.70 (t, 3H, J=7), 1.28 (m, 2H), 2.75 (s, 3H), 2.82 (m, 2H), 3.1-3.45 (m, 4H), 3.70 (m, IH), 3.80 (s, 3H), 3.90 ( , 3H), 4.72 (m, IH), 5.95 (s, 2H), 6.75 (d, IH, = 8Hz), 6.87 (m, 3H), 7.05 (s, IH), 7.40 (d, 2H, I=8Hz). MS (DCI/NH3) m/e 498 (M+H)+. Anal calcd for C27H35N3O6 ' 1.25 TFA: C, 55.35; H, 5.71; N, 6.56. Found: C, 55.41; H, 5.71; N, 6.41.
Example 298 trans.trα72s-2-(4-Methoxyphenyl)-4-(l,3-benzodioxol-5-yl)-l-(2-(N-propyl-N-(4- nitrobenzenesulfbnyl . amino^ ethyl ,-pyrroHdine-3 -carboxylic acid Using the procedures described in Eample 66, the title compound was prepared as a yellow sohd. m.p. 85-87°C. 1H NMR (CDC13, 300 MHz) δ 0.77 (t, I=7.5Hz, 3H), 1.38 (sextet, I=7.5Hz, 2H), 2.20-2.29 (m, IH), 2.57-2.66 (m, IH), 2.82-3.15 (m, 4H), 3.22 (t,
J=7.5Hz, 2H) 3.38 (dd, J=3Hz,J=9Hz, IH), 3.49-3.57 (m, IH), 3.59 (d, J=9Hz, IH), 3.83 (s, 3H), 5.96 (s, 2H), 6.73 (d, I=8Hz, IH), 6.82 (dd, J=lHz,I=8Hz, IH), 6.87 (d, I=9Hz, 2H), 6.98 (d, I=lHz, IH), 7.27 (d, I=9Hz, 2H), 7.82 (d, J=9Hz, 2H), 8.23 (d, I=9Hz,2H). MS (DCI/NH3) m/e 612 (M+H)+-
Example 299 trans.t7j-.72s-2-(4-Methoxyphenyl)-4-(l,3-benzodioxol-5-yl)-l-(2-(N-propyl-N-n- pentanesulfonylamino)ethyl)-pyrroHdine-3-carboxylic acid Using the procedures described in Example 66, the title compound was prepared as a white solid. m.p. 59-61°C 1H NMR (CDCI3, 300MHz) δ 0.79 (t, I=7.5Hz, 3H), 0.90 (t,
J=6Hz, 3H), 1.26-1.32 (m, 4H), 1.43 (sextet, I=7.5Hz, 2H), 1.67-1.76 (m, 2H), 2.23-2.32 (m, IH), 2.70-3.08 (m, 7H), 3.15-3.32 (m,2H), 3.42 (dd, I=3Hz,I=9Hz, IH), 3.52-3.57 (m, IH), 3.63 (d, J=9Hz, IH), 3.80 (s, 3H), 5.95 (s, 2H), 6.73 (d, J=7.5Hz, IH), 6.83 (dd, J=lHz,J=7.5Hz, IH), 6.87(d, I=8Hz, 2H), 7.00 (d, I=lHz, IH), 7.32 (d, I=8Hz, 2H). MS (DCI/NH3) m/e 561 (M+EQ+- Example 300 trans. trans-2-(4-Methoxyphenyl)-4-( 1 ,3-benzodioxol-5-yl)- 1 -(2-( N-propyl-N-(4- trifluoromethoxybenzenesulfonyl)amino)ethyl)-pyrroUdine-3-carboxylic acid Using the procedures described in Example 66, the title compound was prepared as a white sohd. m.p.l22-124°C. !H NMR (CD3OD, 300MHz) 0.75 (t, I=7.5Hz, 3H), 1.26-1.45 (m, 2H), 2.96-3.08 (m, 2H), 3.23 (bs, 2H), 3.35-3.45 (m, 2H), 3.52 (t, J=10Hz, IH), 3.81 (d, J=9Hz, 2H), 3.86 (s, 3H), 3.92 (t, I=9Hz, IH), 4.63 (d, J=10Hz, IH), 5.97 (s, 2H), 6.82 (d, J=9Hz, IH), 6.93 (dd, I=3Hz,J=9Hz, IH), 7.06-7.08 (m, 3H), 7.46 (d, J=9Hz, 2H), 7.56 (d, J=9Hz, 2H), 7.89 (d, I=9Hz, 2H). MS (DCI/NH3), m/e 651 (M+H)+.
Example 301 trans.trans-2-(4-Methoxyphenyl)-4-(l,3-benzodioxol-5-yl)-l-(2-(N-piOpyl-N-(2-methyl-2- propenesulfonyl)amino)ethyl)-pyrroHdine-3-carboxylic acid Using the procedures described in Example 66, the title compound was prepared as a white sohd. mp. 69-71°C. 1HNMR (CDCl3, 300MHz) δ 0.79 (t, J=7.5Hz, 3H), 1.93 (sextet, J+7.5HZ, 2H), 1.92 (s, 3H), 2.25-2.35 (m, IH), 2.68-2.77 (m, IH), 2.85-3.28 (m, 7H), 3.40 (d, I=9Hz, IH), 3.52-3.68 (m, 2H), 3.66 (d, J=9Hz, IH), 3.80 (s, 3H), 4.92 (s, IH), 5.07 (s, IH), 5.97 (s, 2H), 6.74 (d, I=7Hz, IH), 6.82-6.89 (m,3H), 7.01 (s,lH), 7.33 (d, I=9Hz, 2H). MS (DCI/NH3), m/e 545 (M+H)+.
Example 302 tr-.7.s-trans-2-(4-Methoxyphenyl)-4-( 1 ,3-benzodioxol-5-yl)- 1 -[2-ethylpiperidinyl- carbonylmethyl]-pyrroHdine-3-carboxylic acid. The title compound was prepared using the procedures described in example 1. NMR
(CD3OD, 300 MHz) shows a mixture of isomers. δ 0.75 (t, 3H, J=7), 1.4-1.7 (m, 8H), 3.84
(s, 3H), 5.96 (s, 2H), 6.83 (d, IH, =8), 6.91 (d, IH, =8), 7.0-7.1 (m, 3H), 7.52 (d, 2H, J=9). MS (DCI/NH3) m/z 495. Anal calcd for C28H34N2O6 . 1.6 TFA: C, 55.35; H, 5.30; N, 4.14.
Found: C, 55.26; H, 5.37; N, 4.01 .
Example 303 trans.tra72s-2-(4-Methoxyphenyl)-4-(l,3-benzodioxol-5-yl)-l-(2-(N-propyl-N-(2- methylpropanesulfonyl)amino.ethyl)-pyrroUdine-3-carboxyHc acid Using the procedures described in Example 66, the title compound was prepared as a white soHd. mp. 72-73°C. !H NMR (CDC13, 300 MHz) δ 0.82 (t, J=7.5Hz, 3H),1.04 (d,
J=6Hz, 6H), 1.44(q, I=7.5Hz, 2H), 2.15-2.33 (m,2H), 2.57-2.75 (m, 2H), 2.84-3.08 (m, 3H), 3.12-3.21 (m, IH), 3.23-3.45 (m, IH), 3.43 (d, 1=1 IHz, IH), 3.55-3.62 (m, IH), 3.66 (d, J=9Hz, IH), 3.80 (s, 3H), 5.95 (s, 2H), 6.75 (d, J=9Hz, IH), 6.83 (dd, I=lHz,J=9Hz, IH), 6.87(d, J=9Hz, 2H), 7.02 (d, I=lHz, IH), 7.33 (d, J=9Hz, 2H). MS (DCI/NH3) m/e 547 M+H)+.
Example 304 trans,trαns-2-(4-Methoxyphenyl -4-(l,3-benzodioxol-5-yl)-l-(2-(N-propyl-N- heptanesulfonylamino)ethyl)-pyrroHdine-3-carboxylic acid Using the procedures described in Example 66, the title compound was prepared as a white solid. m.p.58-59°C. !H NMR (CDC13, 300MHz). δ 0.80(t, J=7.5Hz, 3H), 0.88 (t,
J=7Hz, 3H), 1.23-1.36 (m, 8H), 1.94 (q, J=7.5Hz, 2H), 1.71(quintet, I=7Hz, 2H), 2.23-2.32 (m, IH), 2.70-3.09(m, 7H), 3.13-3.32 (m,2H), 3.43(dd, J=3Hz,I=9Hz, IH), 3.52-3.58(m,lH), 3.65(d, J=9Hz, IH), 3.80 (s, 3H), 5.96(s, 2H), 6.73 (d, I=7Hz, IH), 6.83 (dd, I=lHz, I=7Hz, IH), 6.87(d, J=9Hz, 2H), 7.01(d, J=lHz, IH), 7.32(d, I=9Hz, 2H). MS (DCI/NH3) m/e 589 M+H)+.
Example 305 trans-tr-.ns-2-(4-Methoxyphenyl)-4-(l,3-benzodioxol-5-yl)-l-[2-(N-ethyl-N- ethoxycarbonylamino ethyl]-pyrroUdine-3-carboxylic acid Prepared by the methods detaUed in Example 61, but substituting ethylamine for methylamine in Example 6 IB and ethyl chloroformate for isobutyryl chloride in Example 61C. The crude product was purified by preparative HPLC (Vydac μC18) eluting with a 10- 70% gradient of CH3CN in 0.1% TFA. The desired fractions were lyophilized to give the product as a white solid. 1H NMR (CDCI3, 300 MHz) δ 0.90 (t, 3H, =7), 1.22 (m, 3H), 3.0- 3.2 (m, 4H), 3.42 (m, 2H), 3.78 (s, 3H), 3.82 (m, 4H), 4.10 (q, 2H, I=7Hz), 3.5 (br s, IH), 5.97 (dd, 2H, J=l,7Hz), 6.72 (d, IH, J= 8Hz), 6.84 (m, 3H), 7.00 (s, IH), 7.42 (d, 2H, I=8Hz). MS (DCI/NH3) m/e 485 (M+H)+. Anal calcd for C26H32N2O7 • 1.2 TFA: C, 54.90; H, 5.39; N, 4.51. Found: C, 55.01; H, 5.36; N, 4.56.
Example 306 tr_.ns.tr_tns-2-(4-Methoxyphenyl)-4-(l,3-benzodioxol-5-yl)-l-(2-(N-propyl-N- hexanesulfonylamino.ethyl -pyrrolidine-3-carboxylic acid Using the procedures described in Example 66, the title compound was prepared as a white sohd. m.p.59-60°C. !H NMR (CDC13, 300MHz) δ 0.80(t, J=7.5Hz,3H), 0.89(t, I=7Hz, 3H), 1.25-1.36(m, 6H), 1.53(sextet, J=7.5Hz, 2H), 1.72(quintet, I=7Hz, 2H), 2.23-2.32(m, IH), 2.72-3.08(m, 7H), 3.15-3.32(m, 2H), 3.43(d, I=9Hz, IH), 3.55-3.62(m, IH), 3.65 (d, I=10Hz, IH), 3.80(s, 3H), 5.96(s, 2H), 6.74(d, J=7.5Hz,lH), 6.82(d, I=7.5Hz,lH), 6.87(d, J=9Hz, 2H), 7.01(s,lH), 7.32(d, I=9Hz,2H). MS (DCI/NH3), m/e 575 (M+H)+.
Example 307 trans-trans-2-(4-Ethylphenyl)-4-(l,3-benzodioxol-5-ylVl-[N,N-di(n- butyl) aminocarbonylmethyl] -pyrrolidine-3 -carboxylic acid. The title compound was prepared using the procedures described in examples 1 and 49, substituting ethyl 4-ethylbenzoylacetate (prepared by the method of Krapcho et al., Org. Syn. 47, 20 (1967) starting with 4'-ethylacetophenone) in procedure 49B. NMR (CDCI3, 300 MHz) δ 7.31 (2H, d, I=8Hz), 7.16 (2H, d, I=8Hz), 7.03 (IH, d, I=3Hz), 6.86 (IH, dd, I=8&3Hz), 6.73 (IH, d, J=9Hz), 5.94 (IH, d, J=4Hz), 5.92 (IH, d, J=4Hz), 3.77 (IH, d, I=9Hz), 3.60 (IH, m), 3.53-3.23 (5H, m), 3.13-2.90 (4H, m), 2.73 (IH, d, I=14Hz), 2.62 (2H, q, I=9Hz), 1.45 (2H, m), 1.40-1.10 (6H, m), 1.02 (2H, m), 0.87 (3H, t, I=7Hz), 0.78 (3H, t, J=7Hz). m/e (DCI, NH3) 509 (MH+) Analcalc. for C30H40N2O5 C 70.84, H 7.93, N 5.51. Found C 70.80, H 7.85, N 5.25 .
Example 308 trans-tra72S-2-(4-Methoxyphenyl)-4-(l,3-benzodioxol-5-yl)-l-[2-(N-propyl-N-(2- chloroethoxy)carbonylamino)ethyl]-pyrroHdine-3-carboxylic acid Prepared by the methods detailed in Example 61, but substituting propylamine for methylamine in Example 6 IB and 2-chloroethyl chloroformate for isobutyryl chloride in Example 61C. The crude product was purified by trituration with 1 : 1 diethyl ether/ hexane. The resulting solid was dissolved in CH3CN and water and lyophilized to give the product as a white solid. 1H NMR (CDCI3, 300 MHz) 0.80 (t, 3H, J=7), 1.22 (m, 3H), 2.15 (m, IH), 2.75 (m, IH), 2.85 (m, IH), 3.1 (m, 2H), 3.25 (m, 2H), 3.5 (m, 3H), 3.65 (m, 2H), 3.80 (s, 3H), 4.18 (m, IH), 4.30 (m, IH), 5.98 (s, 2H), 6.72 (m, IH), 6.82 (m, 3H), 7.00 (m, IH), 7.30(m, 2H). MS (DCI/NH3) m/e 533 (M+H)+. Anal calcd for C27H33N2O7CI: C, 60.84; H, 6.24; N, 5.26. Found: C, 60.48; H, 6.04; N, 5.10.
Example 309 tra7.s-trflns-2-(2-Methoxyethyl)-4-( 1 ,3-benzodioxol-5-yl)- 1 -[N,N-di(n- butyl) amino carbonylmethyl] -pyrrolidine-3 -carboxylic acid.
The title compound was prepared using the procedures described in example 1, substituting ethyl 5-methoxy-3-oxopentanoate for ethyl 4-methoxybenzoylacetate in Example IA. The title compound is a yellow foam. !H NMR (CDCI3, 300 MHz) δ 0.91 (t, I=7Hz) and 0.95 (t, J=7Hz, 6H total), 1.28-1.41 (br m, 4H), 1.45-1.63 (br m, 4H), 2.00-2.20 (br m, 2H), 3.06 (br t, J=9Hz, IH), 3.30 (s) and 3.20-3.68 (br m, 1 IH total), 3.72-4.10 (br m, 4H), 5.92 (s, 2H), 6.72 (d, J=8.5Hz, IH), 6.82 (dd, =1.5, 8.5Hz, IH), 6.91 (d, =1.5Hz, IH); MS (FAB) m/e 463 (M+H)+. Anal calcd for C25H38N2O5Η2O: C, 62.48; H, 8.39; N, 5.83.
Found: C, 62.13; H, 8.15; N, 5.69.
Example 310 trans,trans-2-(4-Methoxyphenyl)-4-(l,3-benzodioxol-5-yl)-l-(2-(N-ethyl-N-n- pentanesulfonylamino)ethyl)-pyrroUdine-3-carboxylic acid Using the procedures described in Example 66, the title compound was prepared as a white sohd. m.p.57-58°C. lR NMR (CDC13, 300MHz) 0.89(t, I=7Hz, 3H), 1.06(t, J=7.5Hz, 3H), 1.26-1.37(m, 4H), 1.72(quintet, J=7.5Hz, 2H), 2.22-2.32(m,lH), 2.71- 2.96(m,5H), 3.08-3.30(m,4H), 3.95(d, I=9Hz, IH), 3.53-3.60(m, IH), 3.67(d, J=9Hz,lH), 3.80(s, IH), 5.97(s, 2H), 6.73(d, I=9Hz, IH), 6.82(d, I=9Hz,lH), 6.88(d, I=9Hz,
2H),7.02(s,lH), 7.33(d, I=9Hz, 2H). MS (CDI/NH3) m/e 547 (M+H)+.
Example 311 trans-trans-2-(4-Methoxyphenyl)-4-( 1 ,3-benzodioxol-5-yl)- 1 -[N,N-dicyclohexylamino carbonylmethyl]-pyrroHdine-3-carboxylic acid. The title compound was prepared using the procedures described in example 1. NMR (CD3OD, 300 MHz) δ 1.0-2.0 (m, 20H), 3.0-3.1 (m, 2H), 3.80 (s, 3H), 5.95 (s, 2H), 6.75 (d,
IH, =8), 6.86 (dd, IH, J=2,8), 6.95 (d, 2H, J=9), 7.04 (d, IH, J=2), 7.38 (d, 2H, =9). MS (DCI/NH3) m/z 563. Anal calcd for C33H42N2O6 . 0.5 H2O: C, 69.33; H, 7.58; N, 4.90 . Found: C, 69.42; H, 7.29; N, 4.78.
Example 312 trans-trans-2-(4-Methoxyphenyl)-4-(l,3-benzodioxol-5-yl)-l-[2-(N-propyl-N-tert- butoxycarbonylamino) ethyl] -pyrroHdine-3 -carboxylic acid. The title compound was prepared using the procedures described in example 61, substituting propylamine for aqueous methylamine in Example 6 IB and di-tert- butyldicarbonate for isobutyryl chloride in Example 61C. NMR (CD3OD, 300 MHz) suggests presence of rotamers δ 0.81 (t, 3H, J=7), 1.2-1.5 (m, 11H), 3.78 (s, 3H), 5.92 (dd, 2H, =1,2), 6.74 (d, IH, =8), 6.84 (dd, IH, =2,8), 6.92 (d, 2H, 1=9), 6.99 (bd s, IH), 7.35 (d, 2H, J=9). MS (DCI/NH3) m/z 527. Anal calcd for C29H38N2O7 : C, 66.14; H, 7.27; N, 5.32 . Found: C, 66,05; H, 7.36; N, 5.15.
Example 313 trans-tr-.ns-2-(4-Methoxy-3-fluorophenyl)-4-(l,3-benzodioxol-5-ylVl-[N,N-di(n- butyl)aminocarbonylmethyl]-pyrrolidine-3-carboxylic acid. The title compound was prepared using the methods described in examples 1 and 43, using 4-methoxy-3-fluoro acetophenone in place of 4-methoxy acetophenone. p. 142-143 °C. NMR (CDC13, 300 MHz) δ 0.82 (t, I=7Hz, 3H), 0.88 (t, J=7Hz, 3H), 1.03-1.50 (m, 8H), 2.82 (d, J=13Hz, IH), 2.90-3.13 (m, 4H), 3.20-3.50 (m, 3H), 3.39 (d, I=13H, IH), 3.55-3.65 (m, IH), 3.82 (d, I=10Hz, IH), 3.87 (s, 3H), 5.91 (dd, J=2Hz, 4Hz, 2H), 6.72 (d, I=8Hz, IH), 6.83-6.91 (m, 2H), 6.99 (d, J=2Hz, IH), 7.06 (m, 2H). Anal calcd for C29H37N2O6F : C,
65.89; H, 7.06; N, 5.30 . Found: C, 65.82; H, 7.13; N, 5.29.
Example 314 trans. tr_.ns-2-(Propyl ) -4-( 1 ,3-benzodioxol-5-yl)- 1 -(2-(N-propyl- pentanesulfonylamino)ethyl)pyrroHdine-3-carboxylic acid
Example 314A
Propyl pentanesulfonamide Pentane sulfonyl chloride (687 mg, 4.03 mmol) was dissolved in 5 mL CH2CI2 and added to an ice-cooled solution of n-propylamine (0.40 mL, 4.82 mmol) and ethyldiisopropylamine (0.85 mL, 4.88 mmol) in 5 mL CH2CI2 under a nitrogen atmosphere. The reaction was stirred at 0 °C for 30 min, then at 25 °C for 4 h. The solution was partitioned between 20 mL of 1.0 M aqeous NaHSO4 and 25 mL CH2CI2. The organic phase was washed sequentially with 25 mL H2O and 25 mL brine, then dried (Na2SO4), filtered, and concentrated in vacuo to provide 739 mg (3.83 mmol, 95%) of the title compound as a white solid. TLC (25% EtOAc-hexane) Rf 0.23; *H NMR (CDCI3, 300 MHz) 0.92 (t, J=7Hz, 3H), 0.97 (t, J=7Hz, 3H), 1.28-1.50 (br m, 4H), 1.52-1.68 (m, 2H), 1.75-1.90 (br m, 2H), 2.98-3.06 (m, 2H), 3.08 (q, I=6Hz, 2H), 4.10-4.23 (br m, IH); MS (DCI/NH3) m/e 211
(M+NH4)+.
Example 3149B Ethyl trans. trans— 4-( 1 ,3-benzodioxol-5-yl)- 1 -(2-bromoethyl)-2-propylpyrroHdine-3- carboxylate The title compound was prepared according the procedure of Example 61 A, substituting the compound of Example 94B for the pyrroHdine mixture.
Example 314C Ethyltr-.ns.tra72s-2-(Propyl)-4-(l,3-benzodioxol-5-yl)-l-(2-(N-propyl- pentanesulfonylamino)ethyl)pyrroHdine-3-carboxylate A solution of the compound of Example 314A (6.6 mg, 34 μmol) in 0.1 mL DMF was treated with sodium hydride (2 mg, 60% oil dispersion, 1.2 mg NaH, 50 μmol). The resulting mixture was stirred at room temperature for 15 min, then a solution of the compound of Example 189B (9.0 mg, 22 μmol) in 0.1 mL DMF was added, followed b y 0.5 mg of tetra-n-butylammonium iodide. The reaction was sealed under argon and stirred at 60 °C overnight. The reaction was concentrated under high vacuum, and the residue was partitioned between 2 mL of saturated aqueous NaHCO3, 1 mL water and 5 mL EtOAc. The organic phase was washed with 1 mL brine, dried by passing through a plug of Na2SO4, and the filtrate concentrated in vacuo to an oU. The crude product was purified by preparative TLC (sUica gel, 8 x 20 cm, 0.25 mm thickness, eluting with 20% EtOAc-hexane, providing 8.4 mg (73%) of the title compound as a wax.
Example 314D trans, trans-4-( 1 ,3-benzodioxol-5-yl)-2-(PropylV 1 -(2-(N-propyl- pentanesulfonylamino , ethyl)pyrroHdine-3 -carboxylic acid The title compound was prepared according to the procedure of Example 71C. *H NMR (CDC13, 300 MHz) 0.88-1.00 (m, 9H), 1.20-1.55 (br m, 6H), 1.55-1.68 (m, 3H), 1.70-1.85 (br m, 2H), 1.90-2.16 (br m, 2H), 2.84-3.26 (br m, 6H), 3.26-3.90 (br m, 6H), 5.95 (s, 2H), 6.76 (d, I=8Hz, IH), 6.79 (m, IH), 6.93 (br s, IH); HRMS (FAB) calcd for C25H41N2O6S (M+H)+ 497.2685, found 497.2679.
Example 315 trans, tr_.ns-2-(4-Methoxyphenyl)-4-( 1 ,3-benzodioxol-5-yl)- 1 -(2-(N-propyl-N- dimethylsulfamoylamino)ethyl)-pyrrolidine-3-carboxylic acid Using the procedures described in Example 66, the title compound was preapred as a white solid. m.p.59-61°C. !H NMR (CDC13, 300MHz) δ 0.79 (t, J=7.5Hz, 3H), 1.45(sextet, I=7.5Hz, 2H), 2.22-2.31(m,lH), 2.65(s, 6H), 2.70-2.79(m, IH), 2.85-3.04(m, 4H), 3.09- 3.32(m, 2H), 3.40(d, I=9Hz, 1H),3.55 (t, J=9Hz,lH), 3.65(d, I=9Hz,lH), 3.81(s, 3H),
5.96(s,2H), 6.75(d, J=9Hz, IH), 6.83(d, J=9Hz, IH), 6.88(d, J=9Hz, 2H), 7.02(s, IH), 7.34(d, I=9Hz, 2H). MS (DCI/NH3) m/e534 (M+H)+.
Example 316 tra72s-tr-.ns-2-(4-Methoxphenyl)-4-(l,3-benzodioxol-5-yl)-l-[2-(N-propyl-N-[4- methoxyphenyl]sulfonylamino)propyl]-pyrrolidine-3-carboxylic acid Example 316A Ethyl trans-trans and cis-trans 2-(4-Methoxyphenyl)-4-(l,3-benzodiox-5-yl) -l-(3- bromopropyl) pyrrolidine-3 -carboxylate A 2: 1 mixture of trans-trans and cis-trans ethyl 2-(4-methoxyphenyl)-4-( 1,3- benzodiox-5-yl) -pyrroHdine-3 -carboxylate (4.00 g; prepared according to example IC), 32 ml dibromopropane, and 200 mg sodium iodide, were heated at 100° for 1.25 hrs. The excess dibromopropane was removed in vacuo and the residue was dissolved in toluene. After shaking with potassium bicarbonate, the solution was dried (Na2SO4) and the solution concentrated. The residue was chromatographed on silica gel eluting with 5: 1 hexane:EtOAc. yielding 5.22 (98%) of the title compound.
Example 316B Ethyl trans-trans and cis-trans 2-(4-Methoxyphenyl)-4-(l,3-benzodiox-5-yl) -l-(3- propylaminopropyl) pyrroUdine-3 -carboxylate
The compound described in Example 316A (5.22 g) was heated at 80° for 2 hrs.with 35 ml. ethanol, 2.5 g. propylamine and 35 mg. sodium iodide. The solvents were removed in vacuo. The residue was dissolved in toluene, shaken with potassium bicarbonate solution and dried (Na2SO4). The soUution was concentated in vacuum to give 4.96 g of the title compound as an orange oil. This was used in the next step without purification.
Example 316C tr-.ns-tra7ts-2-(4-Methoxphenyl)-4-(l,3-benzodioxol-5-yl)-l-[2-(N-propyl-N-[4- methoxyphenyl]sulfonylamino)propyl]-pyrroHdine-3-carboxylic acid Using the method described in example 66, the compound prepared in Example 316B was reacted with 4-methoxybenzenesulfonyl chloride in acetonitrile containing dnsopropylethylamine. The resulting product was chromatographed on silica gel (30% EtOAc in hexane), and hydrolyzed to the title compound by the method of example ID. NMR (CDC1 , 300 MHz) 0.83 (t, I=7Hz, 3H), 1.40-1.52 (m, 2H), 1.56-1.70 (m, 2H), 2.00- 2.11 (m, IH), 2.40-2.51 (m, IH), 2.69-2.78 (m, IH), 2.84-3.03 (m, 4H), 3.19-3.34 (m, 2H), 3.48-3.59 (m, 2H), 3.80 (s, 3H), 3.86 (s, 3H), 5.95 (s, 2H), 6.74 (d, I=8Hz, IH), 6.85 (d, J=8Hz, 3H), 6.93 (d, J=8Hz, 2H), 7.02 (d, J=2Hz, IH), 7.29 (d, I=8Hz, 2H), 7.69 (d, J=8Hz, 2H). Anal calcd for C32H38N2O8S : C, 62.93; H, 6.27; N, 4.59. Found: C, 62.97; H, 6.39;
N, 4.45.
Example 317 trans-tra72s-2-(4-Metho_ henyl)-4-(l,3-benzodioxol-5-yl)-l-[2-(N-propyl-N- propylsulfonylamino)propyl]-pyrroHdine-3-carboxylic acid Using the method described in example 66, the propylamino compound prepared in Example 316B was reacted with propanesulfonyl chloride in acetonitrile containing diisopropylethylamine. The resuling product was chromatographed on sUica gel (30% EtOAc in hexane) and hydrolyzed to the title compound by the method of example ID. NMR (CDCI3, 300. MHz) 0.85 (t, J=7Hz, 3H), 1.02 (t, J=7Hz, 3H), 1.47-1.60 (m, 2H),
1.65-1.85 (m, 4H), 2.04-2.16 (m, IH), 2.42-2.57 (m, IH), 2.72-3.11 (m, 5H), 3.25-3.41 (m, 2H), 3.50-3.62 ( , 2H), 3.80 (s, 3H), 5.85 (s, 2H), 6.72 (d, J=8Hz, IH), 6.80-6.90 (m, 3H), 7.02 (d, J=2Hz, IH), 7.30 (d, J=9Hz, 2H). Anal calcd for C28H38N2O7S: C, 61.52; H, 7.01;
N, 5.12 . Found: C, 61.32; H, 7.01; N, 5.01.
Example 318 trans, trans— 2-(3-Fluoro-4~methoxyphenyI)-4-( 1 ,3-benzodioxol-5-yl .1 -(2-(N-propyl-N- pentanesulfonylamino)ethyl)-pyrroUdine-3-carboxy lie acid
Using the procedures described in Example 313 and Example 66, the title compound was prepared as a white sohd. m.p.66-68°C. lR NMR (CDC13, 300MHz) δ 0.81(t,J=7.5Hz, 3H), 0.89(t, J=7Hz, 3H), 1.26-1.35(m, 4H), 1.45(sextet, I=7.5Hz, 2H), 1.68-1.76(m, 2H), 2.25-2.33(m, IH), 2.72-2.92(m, 5H), 2.97-3.12(m, 2H), 3.16-3.33(m,2H), 3.43(dd, J=3Hz,J=9Hz,lH), 3.53-3.60(m, IH), 3.66(d, I=10Hz, IH), 3.88(s, 3H), 5.95(s, 2H), 6.74(d, I=8Hz, IH), 6.82(dd, J=lHz,J=8Hz,l H), 6.92(t, I=8Hz,lH), 6.97(d, J=lHz, IH), 7.12(d, J=8Hz, IH), 7.18(dd, J=lHz,J=12Hz, IH). MS (DCI NH3) m e 579 (M+H)+.
Example 319 trans-tr_.ns-2-(4-Pyridinyl)-4-(l,3-benzodioxol-5-yl)-l-[N.N-di(n- butyl) aminocarbonylm.ethyl]-pyrrolidine-3-carboxylic acid. The title compound was prepared using the methods described in examples 1 and 43, using methyl 3-oxo-3-(4-pyridyl)propanoate (I. Am. Chem. Soc. 1993, 115, 11705) in place of ethyl (4-methoxybenzoyl)acetate. m.p. 131-132 °C. NMR (CDCI3, 300 MHz) δ 0.82 (t, I+7Hz, 3H), 0.88 (t, I=7Hz, 3H), 1.05-1.50 (m, 8H), 2.90 (dd, = 7Hz, 9Hz, IH), 2.97 (d, J=13Hz, IH), 3.00-3.25 (m, 4H), 3.32 (m, IH), 3.39 (d, J=13Hz, IH), 3.45-3.52 (m, IH), 3.67-3.78 (m, IH), 4.10 (d, J=9Hz, IH), 5.92 (dd, J=2Hz, 4 Hz, 2H), 6.75 (d, J=9Hz, IH), 6.90 (dd, I=9Hz, 2Hz, IH), 7.02 (d, I=2Hz, IH), 7.45 (d, J=8Hz, 2H), 8.50 (d, J=8Hz, 2H). Anal calcd for C27H35N3O5 : C, 67.34; H, 7.33; N, 8.73 . Found: C, 67.39; H, 7.45; N, 8.61.
Example 320 tra7;s-tra7?s-2-(4-Methoxyphenyl)-4-(l,3-benzodioxol-5-yl)-l-[2-(N-propyl-N- diethylaminocarbonylamino) ethyl] -pyrroHdine-3 -carboxylic acid.
The title compound was prepared using the procedures described in example 61, substituting propylamine for aqueous methylamine in Example 6 IB and diethylcarbamyl chloride for isobutyryl chloride in Example 61C. NMR (CD3OD, 300 MHz) δ 0.74 (t, 3H,
J=7), 1.09 (t, 6H, =7), 1.33 (m, 2H), 3.17 (q, 4H, =7), 3.78 (s, 3H), 4.04 (m, IH), 5.93 (s, 2H), 6.86 (d, IH, =8), 7.06 (dd, IH, =2,8), 6.94 (d, 2H, =9), 7.04 (d, IH, J=2), 7.40 (d, 2H, =9). MS (DCI/NH3) m/z 526. Anal calcd for C29H39N3O6 . 0.1 TFA: C, 65.31; H, 7.34; N, 7.82 . Found: C, 65.33; H, 7.43; N, 8.14.
Example 321 trans-trans-2-(4-Methoxyphenyl)-4-(l,3-benzodioxol-5-ylVl-[3,5-dimethylpiperidinyl- carbonylmethyl]-pyrroUd_ne-3-carboxylic acid. The title compound was prepared using the procedures described in example 1. NMR (CD3OD, 300 MHz) shows mixture of isomers. δ 0.88 (d, 3H, J=7), 0.93 (d, 3H, =7), 3.82
(s, 3H), 5.95 (s, 2H), 6.82 (d, IH, J=8), 6.89 (dd, IH, J=l,8), 7.00 d, 2H, J=9), 7.03 (m, IH), 7.47 (d, 2H, J=9). MS (DCI/NH3) m/z 495.
Example 322 tra72S-tr-.ns-2-(4-MethoxyphenyD-4-(l,3-benzodioxol-5-yl)-l-[N,N-di(s- butyl)aminocarbonylmethyl]-pyrroUdine-3-carboxylic acid. The title compound was prepared using the procedures described in example 1. NMR (CD3OD, 300 MHz) suggests a mixture of isomers. δ 0.83 (t, 6H, 1=8), 1.27 (d, 6H, =7),
1.6 (m, 2H), 3.79 (s, 3H), 5.93 (s, 2H), 6.75 (d, IH, J=8), 6.86 (d, IH, =8), 6.94 (d, 2H, J=9), 7.03 (d, IH, J=2), 7.35 (d, 2H, =9). MS (DCI/NH3) m/z 511.
Example 323 trans-trans-2-(4-Methoxyphenyl)-4-(l,3-benzodioxol-5-yl -l-pSf-(2-Methylphenyl)-N- butylamino carbonylmethyl]-pyrroHdine-3-carboxylic acid. The title compound was prepared using the procedures described in example 1. MS
(DCI/NH3) m/z 545. Anal calcd for C32H36N2O6 . 0.9 H2O: C, 68.53; H, 6.79; N, 4.99 . Found: C, 68.56; H, 6.62; N, 4.71.
Example 324 trans-trans-2-(4-MethoxyphenylV4-(l,3-benzodioxol-5-yl)-l-[N-(3-Methylphenyl)-N- butylamino carbonylmethyl]-pyrroUdine-3-carboxylic acid. The title compound was prepared using the procedures described in example 1. NMR (CD3OD, 300 MHz) d 0.88 (t, 3H, =7), 1.2-1.5 (m, 4H), 2.31 (s, 3H), 2.8 (m, 2H), 3.14 (t,
IH, J=10), 3.3 (m, IH), 3.44 (dd, IH, =5,10), 3.53 (m, IH), 3.60 (t, 2H, =7), 3.79 (s, 3H), 3.82 (m, IH), 5.93 (s, 2H), 6.74 (d, IH, J=8), 6.8-6.9 (m, 5H), 7.06 (d, IH, J=2), 7.09 (d, 2H, J=9), 7.18 (d, IH, =7), 7.27 (t, IH, =7). MS (DCI/NH3) m/z 545. Anal calcd for C32H36 2O6 . 0.8 H2O: C, 68.75; H, 6.78; N, 5.01 . Found: C, 68.70; H, 6.67; N, 4.85.
Example 325 tr-.72s.tr-.ns-4-(l,3-Benzodioxol-5-yl)-2-(benzyloxymethyl)-l-((N,N- dibutylaminocarbonylmethyl.pyrrolidine-3-carboxylic acid
Example 325A Ethyl tr-.ns.trfl77s-4-(1.3-Benzodioxol-5-yl)-2-(benzyloxymethyl)-l-((N.N-di(n- butyl) amino carbonylmethy l)pyrroHdine-3 -carboxylate The procedures of Example 1A-1D were foUowed, substituting ethyl 4-benzyloxy-3- oxobutyrate for 4-methoxybenzoylacetate in Example 1 A, to afford the title compound as a colorless oU. TLC (30% EtOAc-hexane) Rf 0.18; !R NMR (CDCI3, 300 MHz) δ 0.88 (t,
I=7Hz, 6H), 1.17 (t, J=7Hz, 3H), 1.20-1.34 (br m, 4H), 1.40-1.56 (br m, 3H), 2.85 (t, I=8Hz, IH), 2.98-3.30 (m, 5H), 3.39-3.60 (m, 3H), 3.64-3.75 (m, 2H), 3.92 (d, I-14Hz, IH), 4.10 (two overlapping q, I=6.5Hz, 2H), 4.53 (s, 2H), 5.91 (m, 2H), 6.69 (d, I=9Hz, IH), 6.77 (dd, =1.5, 9Hz, IH), 6.91 (d, =1.5Hz, IH); MS (DCI/NH3) m/e 553 (M+H)+.
Example 325B tra77sJrα72s-4-(l,3-Benzodioxol-5-yl -2-(benzyloxymethyl)-l-((N,N-di(n- butyl)aminocarbonylmethyl)pyrrolidine-3-carboxylic acid
The title compound was prepared according to the procedure of Example 71C, as a colorless glass. TLC (5% MeOH-CH2Cl2) Rf 0.13; iHNMR (CDCI3, 300 MHz) δ 0.86 (t, J=7Hz), and 0.90 (t, I=7Hz, 6H total), 1.15-1.52 (br m, 8H), 2.96-3.35 (br m, 5H), 3.50-3.75 (br m, 2H), 3.80 (dd, J=3, 13Hz, IH), 3.88-4.40 (br m, 6H), 4.45 (AB, 2H), 5.90 (s, 2H), 6.70 (d, J=8Hz, IH), 6.84 (dd, J=l,8Hz, IH), 6.93 (d, J=lHz, IH), 7.28-7.39 (m, 5H); MS (DCI/NH3) m/e 524 (M+H)+.
Example 326 trans. trans-4-(l ,3 -Benzodioxol-5-yl)-2-(hydroxymethyl)- 1 -((N,N-di(n- butyl) amino carbonylmethy l)pyrrolidine-3 -carboxylic acid Example 326A Ethyltrans.trans-4-(l,3-Beιιzodioxol-5-yl -2-(hydroxymethyl -l-((N,N-di(n- butyl) amino carbonylmethyl)pyrroHdine-3 -carboxylate The resultant product from Example 325A (128 mg, 0.232 mmol) and 25 mg of 20% Pd(OH)2 on charcoal in 7 mL EtOH was stirred under 1 atm hydrogen for 48 h. The mixture was filtered through a plug of cehte, and the catalyst was washed with 2 x 10 mL EtOH, then the combined filtrate and washes were concentrated under reduced pressure to afford the crude product. Purification by flash chromatography (40%EtOAc-hexane) provided the title compound.
Example 326B tr-.72s.tra7zs-4-(l,3-Benzodioxol-5-yl)-2-(hydroxymethyl)-l-((N,N- di(butyl)aminocarbonylmethyl)pyrroHdine-3-carboxylic acid
The title compound was prepared according to the procedure of Example 71C.
Example 327 tra7?s.trans--4-(l,3-Benzodioxol-5-yl)-2-(N-methylpropenamid-3-yl)-l-((N,N-di(n- butyl)aminocarbonylmethyl)pyrroHdine-3-carboxylic acid
Example 327A
Ethyl trans.tra7;s--4-(l,3-Benzodioxol-5-ylV2-(formylVl-((N,N-di(n- butyl amino carbonylmethyl pyπOHdine-3 -carboxylate The title compound is made by selective oxidation (e.g. using the Swem oxidation with DMSO, oxalyl chloride, ethyldiisopropylamine or using the Dess-Martin periodinane) of the compound of Example 326A.
Example 327B Ethyl trαns.tr-.ns--4-(l,3-Benzodioxol-5-yl)-2-(O-tert-butylpropenoat-3-yl)-l-((N,N-di(n- butyl) aιninocarbonylmethyl)pyrroHdine-3-carboxylate The title compound is produced by condensing the compound of Example 327A with tert-butyl triphenylphosphoranylidine acetate in CH2CI2 solution.
Example 327C Ethyl trans. trans— 4-(l ,3-Benzodioxol-5-yl)-2-(propenoic acid-3-yP- 1 -(N,N-di(n- butyl) aminocarbonylmethyl)pyrroHdine-3-carboxylate The title compound is produced by reacting the compound of Example 327B with trifluoacetic acid in CH2CI2 (1: 1).
Example 327D Ethyl tmns.tr-.72s--4-(l,3-Benzodioxol-5-yl)-2-(N-methylpropenamid-3-yl)-l-(N,N-di(n- but l) amino carbonylmethy l)pyrroHdine-3 -carboxylate The title compound is produced by condensing the compound of Example 327C with methylamine hydroehloride in the presence of a carbodiimide (e.g. N-ethyl-N-(3- dimethylamino)propylcarbodumide, DCC) .
Example 327E trans, trans— 4-( 1 ,3-Benzodioxol-5-yl)-2-(N-methylpropenamid-3-yl)- 1 -(N,N-di(n- butyl.aminocarbonyhnethyl)pyrroHdine-3-carboxylic acid The title compound is produced by reacting the compound of Example 327D with lithium hydroxide according to the procedure of Example 71 C.
Example 328 transjrans— 4-(l,3-Benzodioxol-5-yl)-2-(l-hvdroxy-2-propen-3-yl)-l-(N,N-di(n- butvD amino carbonylmethyl pyrroHdine-3 -carboxylic acid
Example 328A Ethyl tr-.nsJrans--4-(l,3-Benzodioxol-5-yl)-2-(l-hvdroxy-2-propen-3-yl)-l-(N,N-di(n- butyl aminocarbonylm.ethyl)pyrrolidine-3-carboxylate The title compound is produced by reacting the compound of Example 327C with borane methyl sulfide complex.
Example 328B tr-.nsJra72s--4-(l,3-Benzodioxol-5-yl)-2-(l-hydrox-2-propen-3-yl)-l-(N,N-di(n- butyl) amino carbonylmethy l)pyrroHdine-3 -carboxylic acid The title compound is produced by condensing the compound of Example 328A with lithium hydroxide according to the procedure of Example 71C.
Example 329 trans. trαns--4-(l,3-Benzoά^oxol-5-yl)-2-(N-ben--ylaminomethyl)-l-(N,N-di(n- butyl)aminocarbonylmethyl)pyrrolidine-3-carboxylic acid Example 329A Ethyl trans. trans- 4-( 1 ,3-Benzodioxol-5-yl)-2-(N-benzylaminomethyl)- 1 -(N,N-di(n- but l) amino carbonylmethy I) pyrroHdine-3 -carboxylate The title compound is produced by condensing the compound of Example 327A with benzylamine in the presence of sodium cyanoborohydride in ethanol.
Example 329B trans, trans— 4-( 1 ,3-Benzodioxol-5-yl)-2-(N-benzylaminomethyl)- 1 -(N,N-di(n- butyl)aminocai"bonylmethyl.pyrroHdine-3-carboxy lie acid The title compound is produced by reacting the compound of Example 329A with lithium hydroxide according to the procedure of Example 71C.
Example 330 trans.trans--4-(l,3-Benzoάιoxol-5-yl)-2-(N-acetyl-N-benzylaminomethyl)-l-(N,N-di(n- butyl) aminocarbonyhnethyl)pyrroHdine-3-carboxylic acid
Example 330A Ethyl trans, trans— 4-( 1 ,3-Benzodioxol-5-yl -2-(N-acetyl-N-benzylaminomethyl)- 1 -(N,N- di(n-butyl.aminocarbonylmethyl pyrroHdine-3-carboxylate The title compound is produced by reacting the compound of Example 3294A with acetic anhydride in the presence of pyridine or triethylamine.
Example 330B tra72s,tr-.72s--4-(l,3-Benzodioxol-5-yl)-2-(N-acetyl-N-benzylaminomethyl)-l-(N,N-di(n- butyl) aminocarbonylmethyl pyrrolidine-3-carboxylic acid
The title compound is produced by reacting the compound of Example 330A with lithium hydroxide according to the procedure of Example 71C.
Example 331 trans, trans— 4-( 1 ,3-Benzodioxol-5-yl)-2-(ethynyl)- 1 -(N,N-di(n- butyl)aminocarbonyhnethyl)pyrroUdine-3-carboxylic acid
Example 331 A Ethyl tr-.ns.trans--4-(l,3-Benzodioxol-5-ylV2-(ethynyl)-l-(N,N-di(n- butyl) amino carbonylmethy 1. pyιτolidine-3 -carboxylate The title compound is made by employing the procedure of Corey and Fuchs (Tetrahedron Lett. 1972, 3769-72), using the compound of Example 327 A.
Example 33 IB trans, trans- 4-( 1 ,3-Benzodioxol-5-ylV2-(ethynyl)- 1 -(N,N-di(n- butyπaminocarbonylmethyl)pyrrolidine-3-carboxylic acid The title compound is produced by reacting the compound of Example 331 A with lithium hydroxide according to the procedure of Example 71C.
Example 332 trans, trans— 4-( 1 ,3-Benzodioxol-5-yl)-2-( 1 -pentynyl)- 1 -(N,N-di(n- butyl) amino carbonylmethyl)pyrroUdine-3 -carboxylic acid
Example 332A Ethyl transJrans— 4-(l,3-Benzodioxol-5-ylV2-(pentynyl)-l-(N,N-di(n- butyl)aminocarbonylmethyl.pyrroUdine-3-carboxylate The title compound is made by palladium-catalyzed coupling of the compound of Example 206A and propyl iodide, employing the procedure of Taylor, et. al. (J. Org. Chem. 1989, 54(15), 3618-24).
Example 332B trans, trans— 4-( 1 ,3-Benzodioxol-5-yl)-2-( 1 -pentynyl)- 1 -(N,N-di(n- but l) amino carbonylmethy l)pyrroUdine-3 -carboxylic acid The title compound is produced by reacting the compound of Example 332A with lithium hydroxide according to the procedure of Example 71 C.
Example 333 tr-.ns-trans-2-(4-Methoxphenyl)-4-(l,3-benzodioxol-5-yl)-l-[2-(2,6-dioxopiperidinyl) ethyl} -pyrrolidine-3-carboxylic acid The compound of example 61A is added to a solution of the sodium salt of glutarimide in dimethylformamide. After stirring 24 hours, water is added and the mixture is extracted with ether. The resultant glutarimide is hydrolyzed to the title compound by the method of example ID.
Example 334 tr-tns-trans-2-(4-Methoxyphenyl)-4-(l,3-benzodioxol-5-yl)-l-[N,N- diphenylaminocarbonylmethyl]-pyrrolidine-3-carboxylic acid. The title compound was prepared according to the procedures described in Example 1. 1HNMR (300 MHz, CD3OD) 2.83 (dd, 1, = 8.1, 9.7), 2.99 (d, 1, J = 15.4), 3.19 (t, 1, = 9.5), 3.49 (d, 1, J = 15.3), 3.51 (dd, 1, = 4.6, 9.5), 3.57 (m, 1), 3.79 (s, 3), 3.85 (d, 1, = 9.5), 5.90 (s, 2), 6.71 (d, 1, J = 8.0), 6.84 (m, 3), 7.04 (d, 1, J = 1.6), 7.14-7.16 (m, 6), 7.19- 7.34 (m, 6); MS (DCI/NH3) m/z 551; Anal Calcd for
C33H30N2O6 .65H2O.O.35C2H5OCOCH3: C, 69.77, H, 5.77, N, 4.76. Found: C, 69.75, H, 5.55, N, 4.64.
Example 335 trans-trans-2-(4-Methoxyphenyl)-4-(l,3-benzodioxol-5-yl)-l-[N,N- dnsopropylaminocarbonylmethyl]-pyrroHdine-3-carboxylic acid. The title compound was prepared according to the procedures described in Example 1. 1H NMR (300 MHz, CD3OD) 0.95 (d, 3, J = 6.5), 1.24 (d, 3, J = 6.4), 1.30 (d, 6, J =
6.8), 2.85 (d, 1, J = 12.5), 3.04 (dd, 1, J = 8.1, 9.8), 3.14 (t, 1; J = 9.7), 3.32-3.55 (m, 3), 3.63 (m, 1), 5.92 (s, 2), 6.75 (d, 1, J = 8.1), 6.85 (dd, 1, J = 1.7, 8.1), 6.93 (m, 2), 7.02 (d, 1, J = 1.7), 7.35 (m, 2). MS (DCI/NH3) m/z 483. Anal Calcd for C27H34 2O6 -0.65 EtOAc:
C, 65.86, H, 7.32, N, 5.19. Found: C, 5.74, H, 7.26, N, 5.52.
Example 336 transJrans-2-(3-Fluoro-4-methoxyphenyl)-4-(l,3-benzodioxol-5-yl)-l-(2-N-propyl-N- butanesulfonylamino)ethyl)-pyrroUdine-3-carboxylic acid Using the procedures described in Example 313 and Example 66, the title compound Was prepared as a white solid. mp.65-66°C. lR NMR (CDC13, 300MHz) 0.82(t, I=7.5Hz, 3H), 0.92(t, J=7.5Hz, 3H), 1.34-1.52(m, 4H), 1.72(quintet, J=7.5Hz,2H), 2.25-2.35(m,lH), 2.72-2.94(m, 5H), 2.97-3.12(m, 2H), 3.19-3.46(m, 2H), 3.44(d, I=9Hz,lH), 3.53-3.60(m, IH), 3.67(d, I=9Hz, IH), 3.89(s, 3H), 5.95(s, 2H), 6.74(d, J=8Hz, IH), 6.82(d, J=8Hz, IH), 6.92(t, J=9Hz, IH), 6.97(s, IH), 7.12(d, I=9Hz, IH), 7.18(d, I=12Hz, IH). MS (DCI/NH3) m/e 565 (M+H)+.
Example 337 Using methods described in the above examples, the compounds disclosed in Table 1 can be prepared.
Figure imgf000190_0001
Table 1
Figure imgf000190_0002
3.
Table 1 cont.
R R R
Figure imgf000191_0001
7. 8.
Figure imgf000191_0002
10. 11. 12.
Figure imgf000191_0003
16. 17. 18.
Figure imgf000191_0004
19. 20. 21. Table 1 cont.
R
Figure imgf000192_0001
22. 23. 24.
Figure imgf000192_0002
25. 26. 27.
Figure imgf000192_0003
28. 29. 30.
Figure imgf000192_0004
31. 32. 33.
Figure imgf000192_0005
34. 35. 36.
Figure imgf000192_0006
37. 38. 39. Table 1 cont.
Figure imgf000193_0001
40. 41. 42.
Figure imgf000193_0002
43. 44. 45.
Figure imgf000193_0003
46. 47. 48.
Figure imgf000193_0004
49. 50. 51.
Figure imgf000193_0005
58. 59. 60. Table 1 cont.
R
Figure imgf000194_0001
. .
63.
Figure imgf000194_0002
64. 65. 66.
Figure imgf000194_0003
67. 68. 69.
Figure imgf000194_0004
70. 71. 72.
Figure imgf000194_0005
.73. 74. 75.
Figure imgf000194_0006
Table 1 cont.
Figure imgf000195_0001
79. 80. 81.
Figure imgf000195_0002
82. 83- 84.
Figure imgf000195_0003
86. 87.
85.
Figure imgf000195_0004
88. 89. 90.
Figure imgf000195_0005
91. 92. 93
Figure imgf000195_0006
94. 95. 96. Table 1 cont.
Figure imgf000196_0001
99.
97. 98.
Figure imgf000196_0002
100. 101. 102.
Figure imgf000196_0003
106. 107. 108.
Figure imgf000196_0004
109. 110. 111.
Figure imgf000196_0005
112. 113. 114.
Figure imgf000196_0006
115. 116. 117. Table 1 cont.
R R
Figure imgf000197_0001
118. 119. 120.
Figure imgf000197_0002
124. 125. 126.
Figure imgf000197_0003
133. 134. 135. Table 1 cont.
R R
Figure imgf000198_0001
. 137. 138.
Figure imgf000198_0002
151. 152. 153. Table 1 cont.
R
Figure imgf000199_0001
154.
155. 156.
Figure imgf000199_0002
160. 161. 162.
Figure imgf000199_0003
163. 164. 165.
Figure imgf000199_0004
166.
167. 168. Table 1 cont.
Figure imgf000200_0001
169. 170 171.
Figure imgf000200_0002
172. 17 174.
Figure imgf000200_0003
175. 176. 177
Figure imgf000200_0004
178. 179. 180.
Figure imgf000200_0005
181. 182.
183.
Figure imgf000200_0006
187. 1 88 189. Table 1 cont.
R R
Figure imgf000201_0001
190. 191. 192.
Figure imgf000201_0002
193. 194. 195
Figure imgf000201_0003
199. 200.
201.
Figure imgf000201_0004
Table 1 cont.
R
Figure imgf000202_0001
208. 209. 210.
Figure imgf000202_0002
211. 212. 213.
Figure imgf000202_0003
214. 215. 216.
Figure imgf000202_0004
217. 218. 219.
Figure imgf000202_0005
220. 221. 222. Table 1 cont.
R
Figure imgf000203_0001
223. 224. 225.
Figure imgf000203_0002
228.
226. 227.
Figure imgf000203_0003
229. 230. 231.
Figure imgf000203_0004
232. 233.
234.
Figure imgf000203_0005
235. 236. 237. Table 1 cont.
R R R
Figure imgf000204_0001
244. 245. 246.
Figure imgf000204_0002
247. 248. 249.
Figure imgf000204_0003
250. 251.
252. Table 1 cont.
R R R
Figure imgf000205_0001
253. 254
255.
Figure imgf000205_0002
259. 260. 261.
Figure imgf000205_0003
Figure imgf000205_0004
pjl^rli o
262. 263. 264.
Figure imgf000205_0005
265. 266. 267. Table 1 cont.
R
Figure imgf000206_0001
277.
278. 279.
Figure imgf000206_0002
Table 1 cont.
R R
Figure imgf000207_0001
283. 284. 285.
Figure imgf000207_0002
292. 293. 294.
Figure imgf000207_0003
Table 1 cont.
R
Figure imgf000208_0001
301. 302. 303.
Figure imgf000208_0002
304. 305. 306.
Figure imgf000208_0003
307. 308. 309.
Figure imgf000208_0004
310. 311. 312. Table 1 cont.
R
Figure imgf000209_0001
313. 314. 315.
Figure imgf000209_0002
316. 317. 318.
Figure imgf000209_0003
325. 326. 327. Table 1 cont.
R
Figure imgf000210_0001
328. 329. 330.
Figure imgf000210_0002
331. 332. 333.
Figure imgf000210_0003
Table 1 cont.
R
Figure imgf000211_0001
343. 344. 345.
Figure imgf000211_0002
346. 347. 348.
Figure imgf000211_0003
349. 350. 351.
Figure imgf000211_0004
355. 356. 357. Table 1 cont.
Figure imgf000212_0001
1. 362.
363.
Figure imgf000212_0002
364. 365. 366.
Figure imgf000212_0003
370. 371. 372. Table 1 cont.
R
Figure imgf000213_0001
376. 377. 378.
Figure imgf000213_0002
379. 380. 381.
Figure imgf000213_0003
385. 386. 387. Table 1 cont.
R R R
Figure imgf000214_0001
391. 392 393.
Figure imgf000214_0002
394. 395. 396.
Figure imgf000214_0003
397. 398. 399.
Figure imgf000214_0004
401. 402. Table 1 cont.
R
Figure imgf000215_0001
403. 404. 405.
Figure imgf000215_0002
406 407. 408.
Figure imgf000215_0003
Table 1 cont.
R
Figure imgf000216_0001
418. 419. 420.
Figure imgf000216_0002
421. 422. 423.
Figure imgf000216_0003
424. 425. 426.
Figure imgf000216_0004
427. 428. 429.
Figure imgf000216_0005
431. 432.
430. Table 1 cont.
R
Figure imgf000217_0001
442. 443. 444.
Figure imgf000217_0002
Table 1 cont.
R
Figure imgf000218_0001
448. 449. 450.
Figure imgf000218_0002
451.
452. 453.
Figure imgf000218_0003
454. 455. 456.
Figure imgf000218_0004
460. 461. 462. Table 1 cont.
R R R
Figure imgf000219_0001
466. 467. 468.
Figure imgf000219_0002
. 473. 474.
Figure imgf000219_0003
. Table 1 cont.
R R R
Figure imgf000220_0001
489.
Figure imgf000220_0002
Table 1 cont.
R R R
Figure imgf000221_0001
. 500. 501.
Figure imgf000221_0002
502. 503. 504.
Figure imgf000221_0003
. 5oy_ Table 1 cont.
R R
Figure imgf000222_0001
508. 509. 510.
Figure imgf000222_0002
511. 512. 513.
Figure imgf000222_0003
514. 515. 516.
Figure imgf000222_0004
517. 518. 519.
Figure imgf000222_0005
520. 521.
522. Table 1 cont.
R
Figure imgf000223_0001
529. 530. 531.
Figure imgf000223_0002
. 533.
534.
Figure imgf000223_0003
535. . 537. Table 1 cont.
R
Figure imgf000224_0001
. . 540.
Figure imgf000224_0002
540. 542. 543.
Figure imgf000224_0003
544. 545. 546.
Figure imgf000224_0004
Table 1 cont.
R R R
Figure imgf000225_0001
Frk clo .
Figure imgf000225_0002
Figure imgf000225_0003
559. 560. 561.
Figure imgf000225_0004
565. 566. 567. Table 1 cont.
R R
Figure imgf000226_0001
568. 569. 570.
Figure imgf000226_0002
571. 572. 573.
Figure imgf000226_0003
574. 575. 576.
Figure imgf000226_0004
578. 579.
577.
Figure imgf000226_0005
Table 1 cont.
R R R
Figure imgf000227_0001
592. 593. 594.
Figure imgf000227_0002
595. 596. 597.
Figure imgf000227_0003
598. 599. 600.
Figure imgf000227_0004
601. 602. 603. Table 1 cont.
R
Figure imgf000228_0001
607. 608. 609.
Figure imgf000228_0002
613. 614. 615.
Figure imgf000228_0003
Table 1 cont.
R
Figure imgf000229_0001
622. 623. 624.
Figure imgf000229_0002
625. 626. 627.
Figure imgf000229_0003
628. 629. 630.
Figure imgf000229_0004
631. 632. 633.
Figure imgf000229_0005
634. 635. 636.
Figure imgf000229_0006
Table 1 cont.
R
Figure imgf000230_0001
640. 641. 642.
Figure imgf000230_0002
649. 650. 651.
Figure imgf000230_0003
.
653. 654. Table 1 cont.
R
Figure imgf000231_0001
655. 656. 657.
Figure imgf000231_0002
658. 659. 660.
Figure imgf000231_0003
661. 662. 663.
Figure imgf000231_0004
664. 665. 666.
Figure imgf000231_0005
667. 668. 669. Table 1 cont.
R
Figure imgf000232_0001
670. 671. 672.
Figure imgf000232_0002
676. 677. 678.
Figure imgf000232_0003
684.
682. 683. Table 1 cont.
R R R
Figure imgf000233_0001
685. 686. 687.
Figure imgf000233_0002
Table 1 cont.
R R
Figure imgf000234_0001
706. 707. 708.
Figure imgf000234_0002
709. 710. 711.
Figure imgf000234_0003
712. 713. 714.
Figure imgf000234_0004
715. Example 338 Using methods described in the above examples, compounds comprising a parent structure selected from those disclosed in Table 2A and an R substituent selected from those disclosed in Table 2B can be prepared.
Table 2A
Figure imgf000235_0001
Figure imgf000235_0002
Figure imgf000235_0003
Table 2A cont,
Figure imgf000236_0001
Table 2A cont.
Figure imgf000237_0001
Table 2A cont.
Figure imgf000238_0001
Table 2A cont.
Figure imgf000239_0001
Figure imgf000239_0003
Figure imgf000239_0002
Figure imgf000239_0004
Table 2A cont.
Figure imgf000240_0001
Table 2A cont.
Figure imgf000241_0001
Table 2A cont.
Figure imgf000242_0001
Figure imgf000242_0002
Table 2A cont.
Figure imgf000243_0001
Table 2A cont.
Figure imgf000244_0001
Table 2A cont.
Figure imgf000245_0001
Figure imgf000245_0002
Table 2A cont.
Figure imgf000246_0001
137.
Figure imgf000246_0002
Table 2A cont.
Figure imgf000247_0001
Figure imgf000247_0002
154. 155. Table 2A cont.
Figure imgf000248_0001
Figure imgf000248_0002
Table 2A cont.
Figure imgf000249_0001
Figure imgf000249_0002
Table 2A cont.
Figure imgf000250_0001
192.
190. 191. Table 2A cont.
Figure imgf000251_0001
193. 195.
194.
Figure imgf000251_0002
Table 2A cont.
Figure imgf000252_0001
208. 209. 210.
Hgcq
Figure imgf000252_0002
Figure imgf000252_0003
Figure imgf000252_0004
Table 2A cont.
Figure imgf000253_0001
223. 224. 225.
Figure imgf000253_0002
Table 2A cont.
Figure imgf000254_0001
Table 2A cont.
Figure imgf000255_0001
Table 2A cont.
Figure imgf000256_0001
Table 2A cont.
Figure imgf000257_0001
268. 269. 270.
Figure imgf000257_0002
276.
274. 275.
Figure imgf000257_0003
Table 2A cont.
Figure imgf000258_0001
283. 284. 285.
Figure imgf000258_0002
292. 293. 294. Table 2A cont.
Figure imgf000259_0001
298. 299. 300.
Figure imgf000259_0002
Figure imgf000259_0003
302. 303.
Figure imgf000259_0004
Table 2A cont.
Figure imgf000260_0001
Table 2A cont.
Figure imgf000261_0001
Table 2A cont.
Figure imgf000262_0001
337. 339.
338.
Figure imgf000262_0002
Table 2A cont.
Figure imgf000263_0001
358. 359. 360.
Figure imgf000263_0002
Table 2A cont.
Figure imgf000264_0001
367. 368. 369.
Figure imgf000264_0002
373. 374. 375. Table 2A cont.
Figure imgf000265_0001
378.
376. 377.
Figure imgf000265_0002
382. 383. 384.
Figure imgf000265_0003
. .
Table 2A cont.
Figure imgf000266_0001
390.
388. 389.
Figure imgf000266_0002
Table 2A cont.
Figure imgf000267_0001
.
409.
Figure imgf000267_0002
412. 413. 414. Table 2A cont.
Figure imgf000268_0001
418. 419. 420.
Figure imgf000268_0002
Table 2A cont.
Figure imgf000269_0001
Table 2A cont.
Figure imgf000270_0001
448. 450.
449.
Figure imgf000270_0002
454. 455. 456.
Table 2A cont.
Figure imgf000271_0001
463. 465.
464.
Table 2B
Figure imgf000272_0001
10. 11. 12.
Y
Figure imgf000272_0002
13. 14. 15.
Figure imgf000272_0003
16. 18. 17.
Figure imgf000272_0004
19. 20. 21. Table 2B cont.
R
Figure imgf000273_0001
22. 23. 24.
Figure imgf000273_0002
25. 26. 27.
Figure imgf000273_0003
28. 29. 30.
Figure imgf000273_0004
31 . 32. 33.
Figure imgf000273_0005
34. 35. 36.
Figure imgf000273_0006
40. 41. 42. Table 2B cont.
Figure imgf000274_0001
43. 44. 45.
Figure imgf000274_0002
46. 47. 48.
Figure imgf000274_0003
49. 50. 51.
Figure imgf000274_0004
52. 53. 54.
Figure imgf000274_0005
Table 2B cont.
R
Figure imgf000275_0001
65. 66.
Figure imgf000275_0002
. 68. 69.
Figure imgf000275_0003
. 71. 72.
Figure imgf000275_0004
73. 74. 75.
Figure imgf000275_0005
76. 77. 78. Table 2B cont.
Figure imgf000276_0001
79. 80. 81.
Figure imgf000276_0002
82
83. 84.
Figure imgf000276_0003
85. 86. 87.
Figure imgf000276_0004
91. 92. 93
Figure imgf000276_0005
. 98.
99. Table 2B cont.
Figure imgf000277_0001
103. 104. 105.
Figure imgf000277_0002
106. 107. 108.
Figure imgf000277_0003
109. 110. 111.
Figure imgf000277_0004
Table 2B cont.
R
Figure imgf000278_0001
121. 122.
123.
Figure imgf000278_0002
130. 131. 132. Table 2B cont.
R R
Figure imgf000279_0001
133. 134. 135.
Figure imgf000279_0002
136- 137. 138.
Figure imgf000279_0003
139. 140. 141.
Figure imgf000279_0004
43. 144.
142. 1
Figure imgf000279_0005
145. 146. 147. Table 2B cont.
R R R
Figure imgf000280_0001
148. 149.
150.
Figure imgf000280_0002
151, 152. 153.
Figure imgf000280_0003
160. . 162. Table 2B cont.
Figure imgf000281_0001
163. 164. 165.
Figure imgf000281_0002
166. 167.
168.
Figure imgf000281_0003
169. 170.
171
Figure imgf000281_0004
175. 176. 177. Table 2B cont.
R
Figure imgf000282_0001
178. 179. 180.
Figure imgf000282_0002
183.
181 , 182.
Figure imgf000282_0003
.
188. 189.
Figure imgf000282_0004
192. Table 2B cont.
R
Figure imgf000283_0001
205. 206. 207. Table 2B cont.
R
Figure imgf000284_0001
208.
209. 210.
Figure imgf000284_0002
214. 215. 216.
Figure imgf000284_0003
Table 2B cont.
R
Figure imgf000285_0001
223. 224. 225.
Figure imgf000285_0002
226. 227. 228.
Figure imgf000285_0003
229. 230. 231.
Figure imgf000285_0004
232. 233. 234.
Figure imgf000285_0005
Table 2B cont.
R
Figure imgf000286_0001
241 , 242. 243.
Figure imgf000286_0002
244. 245. 246.
Figure imgf000286_0003
247. 248. 249.
Figure imgf000286_0004
Table 2B cont.
R R R
Figure imgf000287_0001
259. 260. 261.
Figure imgf000287_0002
262. 263. 264.
Figure imgf000287_0003
Table 2B cont.
R
Figure imgf000288_0001
268. 269. 270.
Figure imgf000288_0002
271. 272. 273.
Figure imgf000288_0003
277. 278.
279.
Figure imgf000288_0004
280. 281. 282.
Figure imgf000289_0001
292. 293. 294.
Figure imgf000289_0002
295. 296. 297. Table 2B cont.
R
Figure imgf000290_0001
298. 299. 300.
Figure imgf000290_0002
301. 302. 303.
Figure imgf000290_0003
307. 308. 309.
Figure imgf000290_0004
310. 31 1. 312 Table 2B cont.
R
Figure imgf000291_0001
313. 314. 315.
Figure imgf000291_0002
319. 320. 321.
Figure imgf000291_0003
322. 323. 324.
Figure imgf000291_0004
Table 2B cont.
R
Figure imgf000292_0001
336.
334. 335.
Figure imgf000292_0002
337. 338. 339.
Figure imgf000292_0003
340. 341. 342. Table 2B cont.
R R R
Figure imgf000293_0001
343. 344. 345.
Figure imgf000293_0002
347. 348.
346.
Figure imgf000293_0003
Table 2B cont.
R R R
Figure imgf000294_0001
364. 365.
366.
Figure imgf000294_0002
367
368. 369
Figure imgf000294_0003
370. 37 372 Table 2B cont.
R
Figure imgf000295_0001
376. 377. 378.
Figure imgf000295_0002
379. 380. 381.
Figure imgf000295_0003
383.
382. 384.
Figure imgf000295_0004
388. 389. 390. Table 2B cont.
R R
Figure imgf000296_0001
. 398. 399.
Figure imgf000296_0002
405.
Figure imgf000296_0003
406. 407. 408. Table 2B cont.
R
Figure imgf000297_0001
418. 419. 420.
Figure imgf000297_0002
424. 425.
426. Table 2B cont.
R
Figure imgf000298_0001
427. 428 429.
Figure imgf000298_0002
430. 431. 432.
Figure imgf000298_0003
436. 437.
438.
Figure imgf000298_0004
. .
441.
Figure imgf000298_0005
Table 2B cont.
R
Figure imgf000299_0001
445. 446. 447.
Figure imgf000299_0002
448. 449. 450.
Figure imgf000299_0003
451. 452. 453.
Figure imgf000299_0004
. . 456.
Figure imgf000299_0005
Table 2B cont.
R
Figure imgf000300_0001
460. 461. 462.
Figure imgf000300_0002
463. 464. 465.
Figure imgf000300_0003
Table 2B cont.
R
Figure imgf000301_0001
475. 476. 477.
Figure imgf000301_0002
481. 482. 483.
Figure imgf000301_0003
484. 485. 486.
Figure imgf000301_0004
487. 488. 489. Table 2B cont.
R
Figure imgf000302_0001
490. 491. 492.
Figure imgf000302_0002
Table 2B cont.
R R
Figure imgf000303_0001
508. 509. 510.
Figure imgf000303_0002
511. 512. 513.
Figure imgf000303_0003
514. 515, 516.
Figure imgf000303_0004
517. 518. 519.
Figure imgf000303_0005
Table 2B cont.
R R
Figure imgf000304_0001
523. 524. 525.
Figure imgf000304_0002
. 527. 528.
Figure imgf000304_0003
529. 530. 531.
Figure imgf000304_0004
Table 2B cont.
R
Figure imgf000305_0001
538. 539. 540.
Figure imgf000305_0002
541. 542. 543.
Figure imgf000305_0003
544. 545. 546.
Figure imgf000305_0004
547. 548. 549.
Figure imgf000305_0005
550. 551. 552. Table 2B cont.
R
Figure imgf000306_0001
556. 557. 558.
Figure imgf000306_0002
565. 566. 567 Table 2B cont.
R R R
Figure imgf000307_0001
571. 572. 573.
Figure imgf000307_0002
. 575. 576.
Figure imgf000307_0003
577. 578. 579.
Figure imgf000307_0004
580. 581. 582. Table 2B cont.
R
Figure imgf000308_0001
583. 584. 585.
Figure imgf000308_0002
586. 587. 588.
Figure imgf000308_0003
592. 593. 594.
Figure imgf000308_0004
rfi
Figure imgf000308_0005
595. 596. 597. Table 2B cont.
R R R
Figure imgf000309_0001
598. 599. 600.
Figure imgf000309_0002
. . .
Figure imgf000309_0003
Figure imgf000309_0004
611. 612. Table 2B cont.
R
Figure imgf000310_0001
622. 623. 624.
Figure imgf000310_0002
625. 626. 627. Table 2B cont.
R R R
Figure imgf000311_0001
628. 629. 630.
Figure imgf000311_0002
Example 339
Using methods described in the above examples, compounds comprising a parent structure selected from those disclosed in Table 3A and an R substituent selected from those disclosed in Table 3B can be prepared.
Table 3A
Figure imgf000312_0001
Figure imgf000312_0002
Figure imgf000312_0003
Figure imgf000313_0001
Figure imgf000313_0002
Figure imgf000313_0003
19. 21.
20.
Table 3B
Figure imgf000314_0001
8.
Figure imgf000314_0002
13. 14. 15.
Figure imgf000314_0003
16. 18. 17.
Figure imgf000314_0004
19. 20. 21. Table 3B cont.
R R R
Figure imgf000315_0001
22. 23. 24.
Figure imgf000315_0002
25. 26. 27.
Figure imgf000315_0003
28. 29. 30.
Figure imgf000315_0004
31. 32. 33.
Figure imgf000315_0005
34.
35. 36.
Figure imgf000315_0006
37. 38. 39.
Figure imgf000315_0007
40. 4 . 42. Table 3B cont.
R
Figure imgf000316_0001
43. 44. 45.
Figure imgf000316_0002
46. 47. 48.
Figure imgf000316_0003
49. 50. 51.
Figure imgf000316_0004
52. 53. 54.
Figure imgf000316_0005
Table 3B cont.
R
Figure imgf000317_0001
65. 66.
Figure imgf000317_0002
67. 68. 69.
Figure imgf000317_0003
73. 74. 75.
Figure imgf000317_0004
76. 77. 78. Table 3B cont.
Figure imgf000318_0001
79. 80. 81.
Figure imgf000318_0002
82.
83. 84.
Figure imgf000318_0003
85. 86. 87.
Figure imgf000318_0004
91. 92. 93.
Figure imgf000318_0005
97. 98.
99. Table 3B cont.
H3Ccrfrf
Figure imgf000319_0001
103. 104 105.
Figure imgf000319_0002
106. 107. 108.
Figure imgf000319_0003
115. 116. 117. Table 3B cont.
R
Figure imgf000320_0001
, 122.
123.
Figure imgf000320_0002
124. 125. 126.
Figure imgf000320_0003
127. 128. 129.
Figure imgf000320_0004
130. 131. 132. Table 3B cont.
R R R
Figure imgf000321_0001
133. 134. 135.
Figure imgf000321_0002
136. 137 138.
Figure imgf000321_0003
139. 140. 141 ,
Figure imgf000321_0004
144.
142. 143
Figure imgf000321_0005
145. 146. 147. Table 3B cont.
R
Figure imgf000322_0001
151 152. 153.
Figure imgf000322_0002
1 . 155. 156.
Figure imgf000322_0003
Table 3B cont.
R
Figure imgf000323_0001
. 167.
168.
Figure imgf000323_0002
169. 170.
171
Figure imgf000323_0003
175. 176. 177. Table 3B cont.
R R
Figure imgf000324_0001
178. 179. 180.
Figure imgf000324_0002
82. 183.
181. 1
Figure imgf000324_0003
184. 185. 186.
Figure imgf000324_0004
187.
188. 189.
Figure imgf000324_0005
192. Table 3B cont.
R
Figure imgf000325_0001
193.
194. 195
Figure imgf000325_0002
205. 206. 207. Table 3B cont.
R
Figure imgf000326_0001
X jXYNrf O
208. 209. 210.
Figure imgf000326_0002
214. 215. 216.
Figure imgf000326_0003
Table 3B cont.
R
Figure imgf000327_0001
223. 224. 225.
Figure imgf000327_0002
226. 227. 228.
Figure imgf000327_0003
Table 3B cont.
R
Figure imgf000328_0001
241. 242. 243.
Figure imgf000328_0002
244. 245. 246.
Figure imgf000328_0003
247. 248. 249.
Figure imgf000328_0004
Table 3B cont.
R R
Figure imgf000329_0001
259. 260. 261.
Figure imgf000329_0002
262. 263. 264.
Figure imgf000329_0003
265.
266. 267. Table 3B cont.
R
Figure imgf000330_0001
268. 269. 270.
Figure imgf000330_0002
271. 272. 273.
Figure imgf000330_0003
277. 278.
279.
Figure imgf000330_0004
280. 281. 282.
Figure imgf000331_0001
292. 293. 294.
Figure imgf000331_0002
295. 296. 297. Table 3B cont.
R
Figure imgf000332_0001
298. 299. 300.
Nγ*krfrf
Figure imgf000332_0002
301. 302. 303.
Figure imgf000332_0003
V 'frrfrf
Figure imgf000332_0004
307. 308 309.
Figure imgf000332_0005
310 311 , 312. Table 3B cont.
R R R
Figure imgf000333_0001
317. 318.
Figure imgf000333_0002
319. 320. 321.
Figure imgf000333_0003
322. 323. 324.
Figure imgf000333_0004
Table 3B cont.
R
Figure imgf000334_0001
336.
334. 335.
Figure imgf000334_0002
337. 338. 339.
Figure imgf000334_0003
340. 341. 342. Table 3B cont.
R R R
Figure imgf000335_0001
343. 344. 345.
Figure imgf000335_0002
347. 348.
346.
Figure imgf000335_0003
Table 3B cont.
R R
Figure imgf000336_0001
362. 363.
Figure imgf000336_0002
364. 365
366.
Figure imgf000336_0003
367.
368. 369.
Figure imgf000336_0004
370. 371 - 372. Table 3B cont.
Figure imgf000337_0001
376. 377. 378.
Figure imgf000337_0002
379. 380. 381.
Figure imgf000337_0003
382. 383. 384.
Figure imgf000337_0004
388. 389. 390. Table 3B cont.
R
Figure imgf000338_0001
Figure imgf000338_0002
cl j tt
Figure imgf000338_0003
. 398. 399.
Figure imgf000338_0004
405.
Figure imgf000338_0005
406. 407. 408. Table 3B cont.
R
Figure imgf000339_0001
418. 419. 420.
Figure imgf000339_0002
424. 425.
426. Table 3B cont.
R
Figure imgf000340_0001
427. 428 429.
Figure imgf000340_0002
430. 431. 432.
Figure imgf000340_0003
433. 434. 435.
Figure imgf000340_0004
436. 437.
438.
Figure imgf000340_0005
.
443. 444. Table 3B cont.
R
Figure imgf000341_0001
445. 446. 447.
Figure imgf000341_0002
448. 449. 450.
Figure imgf000341_0003
451. 452. 453.
Figure imgf000341_0004
. . 456.
Figure imgf000341_0005
457. 458. 459. Table 3B cont.
R
Figure imgf000342_0001
460. 461. 462.
Figure imgf000342_0002
463. 464. 465.
Figure imgf000342_0003
.
467. 468.
Figure imgf000342_0004
Table 3B cont.
R
Figure imgf000343_0001
Figure imgf000343_0002
C SY
481. 482. 483.
Figure imgf000343_0003
484. 485. 486.
Figure imgf000343_0004
487. 488. 489. Table 3B cont.
R
Figure imgf000344_0001
490. 491. 492.
Figure imgf000344_0002
Table 3B cont.
R R
Figure imgf000345_0001
508. 509. 510.
Figure imgf000345_0002
511. 512. 513.
Figure imgf000345_0003
514. 515, 516.
Figure imgf000345_0004
517. 518. 519.
Figure imgf000345_0005
Table 3B cont.
R
Figure imgf000346_0001
. 527. 528.
Figure imgf000346_0002
529. 530. 531.
Figure imgf000346_0003
532. 533.
534.
Figure imgf000346_0004
Table 3B cont.
R
Figure imgf000347_0001
538. 539. 540.
Figure imgf000347_0002
544. 545. 546.
Figure imgf000347_0003
547. 548. 549.
Figure imgf000347_0004
550. 551. 552. Table 3B cont.
R R
Figure imgf000348_0001
553. 554. 555.
Figure imgf000348_0002
556. 557. 558.
Figure imgf000348_0003
565. 566. 567. Table 3B cont.
Figure imgf000349_0001
571. 572. 573.
Figure imgf000349_0002
. 575. 576.
Figure imgf000349_0003
577. 578. 579.
Figure imgf000349_0004
Table 3B cont.
R
Figure imgf000350_0001
583. 584. 585.
Figure imgf000350_0002
586. 587. 588.
Figure imgf000350_0003
592. 593. 594.
Figure imgf000350_0004
595. 596. 597. Table 3B cont.
R R R
Figure imgf000351_0001
598. 599. 600.
Figure imgf000351_0002
Table 3B cont.
Figure imgf000352_0001
622. 623. 624.
Figure imgf000352_0002
625. 626. 627. Table 3B cont.
R R R
Figure imgf000353_0001
628. 629. 630.
Figure imgf000353_0002
Example 340 trα^Jr_.n-?-4-(l,3-Benzodioxol-5-yl)-2-(4-methoxyphenyl -l-(N- 3-methγlbut-l-yl)-N- phenyl)aminocarbonylmethyl)-pyrrohdine-3-carboxylic acid Using the procedures described in Example 1, the title compound was prepared. H NMR (300 MHz, CD3OD) δ 0.85 (d, 1=6 Hz, 6H), 1.25 (q, J=7 Hz, 2H), 1.42-1.56 (m, IH),
3.43-3.85 (m, 9H), 3.88s (3), 5.95 (s, 2H), 6.80 (d, J=7 Hz, IH), 6.86 (dd, J=9 Hz, IH), 6.89- 7.00 (m, 2H), 6.97 (d, J=l Hz, IH), 7.04 (d, J=9 Hz, 2H), 7.37 (d, J=9 Hz, 2H), 7.40-7.47 ( , 3H). MS (CI.) m/e C (53.12, 53.11), H (4.63, 4.80), N (3.33, 3.28).
Example 341 trans, trαn^-4-(l,3-Benzodioxol-5-yl)-2-(4-methox phenyl)-l-(N-butyl-N-(4- methylphenylaminocarbonylmethyl)-pyrrolidine-3 -carboxyHc acid Using the procedures described in Example 1, the title compound was prepared. ^H NMR (300 MHz, CD3OD) δ 0.87 (t, J=7 Hz, 3H), 1.20-1.47 (m, 4H), 2.37 (s, 3H), 2.83 (q,
J=7 Hz, 2H), 3.06-3.25 (m, 2H), 3.40-3.50 (m, IH), 3.51-3.63 (m, 3H), 3.80 (s, 3H), 3.87 (d,
J=9 Hz, IH), 5.92 (s, 2H), 6.74 (d, J=8 Hz, IH), 6.80-6.86 (m, 3H), 6.89 (d, J=8 Hz, 2H), 7.04 (d, J=2 Hz, IH), 7.12 (d, J=8 Hz, 2H), 7.19 (d, J=8 Hz, 2H). MS (DCI) m/e 545 (M+H)+ Analysis calcd for C32H36N2O6: C, 70.57; H, 6.66; N, 5.14. Found: C, 70.20; H, 6.81; N, 5.03.
Example 342 trans. trans-4-( 1 ,3-Benzodioxol-5-yl)-2-(4-propoxyphenyl)- 1 -(N.N-di(n- butyl)amino)carbonyl)methylVpyrrolidine-3-carboxylic acid Using the procedures described in Example 1 , the title compound was prepared. ^H
(300MHz, CDCI3 ) δ 7.30 (2H, d, J=9), 7.03 (IH, d, J=2), 6.83 (3H, m), 6.72 (IH, d, J=9), 5.95 (IH, d, 1=2), 5.93 (IH, d, J=2), 3.88 (2H, t, J=7), 3.73 (IH, d, J=12), 3.58 (IH, m),
3.53-3.20 (4H, m), 3.10-2.90 (4H, m), 2.72 (IH, d, J=15), 1.79 (2H, q, J=8), 1.50-1.05 (8H, m), 1.02 (3H, t, J=7), 0.87 (3H, t, 1=1), 0.80 (3H, t, J=7). MS (DCI/NH3) m/e 539 (M+H)X
Anal calcd for C31H42N2O6 O.5H2O: C, 67.98; H , 7.91; N, 5.11. Found: C,68.24; H, 7.70; N, 5.03.
Example 343 tr_.» .trαni-4-(1.3-Benzodioxol-5-γl -2-(4-propγlphenyl -l-(N,N-di(n- butyl)aminocarbonylmethyl pyrrohdine-3-carboxylic acid Using the procedures described in Example 1, the title compound was prepared. H (300MHz, CDCI3 ) δ 7.31(2H, d, 1=9), 7.13 (2H, d, 1=9), 7.03 (IH, d, 1=2), 6.84 (IH, dd,
1=6, 2), 6.13 (IH, d, 1=9), 5.95 (IH, d, 1=2), 5.93 (IH, d, J=2), 3.76 (IH, d, J=10), 3.60 (IH, m), 3.55-3.20 (4H, m), 3.13-2.88 (4H, ), 2.75 (IH, d, J=15), 2.55 (2H, t, J=8),1.62 (2H, q,
J=8), 1.50-1.00 (8H, m), 0.92 (3H, t, 1=1), 0.85 (3H, t, 1=1), 0.78 (3H, t, J=7). MS
(DCI/NH3) m/e 523 (MH+). Anal calcd for C31H42N2O5 O.25 H2O : C, 70.63; H, 8.13; N, 5.31. Found: C, 70.55; H, 8.08; N, 5.18.
Example 344 tr_.rø-trflπi'-2-(4-Methoxyphenyl)-4-(1.3-benzodioxol-5-yl)-l-[3-(N-propyl-N-n- pentanesulfonylamino ,propyl]pyrrolidine-3 -carboxylic acid Using the procedures described in Example 316, the title compound was prepared.
!H MR (300MHz, CDCI3) δ 0.85 (t, J=7Hz, 3H), 0.90 (t, J=7Hz, 3H), 1.3-1.4 (m, 4H),
1.5-1.6 (sextet, 1=1, 2H), 1.65-1.8 (m, 4H), 2.05-2.15 (m, IH), 2.43-2.56 (m, IH), 2.72-3.1 (m, 7H), 3.27-3.4 (m, 2H), 3.5-3.6 (m, 2H), 3.80 (s, 3H), 5.95 (s, 2H), 6.73 (d, J=8Hz, IH), 6.8-6.9 (m, IH), 6. 85 (d, J= 9Hz, 2H), 7.02 (d, J=2Hz, IH), 7.80 (d, J=9Hz, 2H).
Example 345 trans . trans-4- 1.2-Dihydrobenzofiιran-5-yl)-2-(4-ethylphenylV 1 -(N.N-di(n- butyl)aminocarbonylmethyl)-pyriOhdine-3-carboxy lie acid Using the procedures described in Example 1, the title compound was prepared. *H
(300MHz, CDCI3 ) δ 7.40 (3H, m), 7.22 (2H, d, J=8), 7.13 (IH, dd, J=8, 3), 6.72 (IH, d,
1=9), 5.28 (IH, d, 1=12), 4.55 (2H, t, 1=9), 4.15 (IH, d, J=18), 4.03 (2H, m), 3.75 (2H, m),
3.40 (2H, m), 3.20 (2H, t, J=9), 3.15 (IH, m), 3.10-2.90 (2H, m), 2.63 (2H, q, 1=9), 1.47
(2H, m), 1.31 (4H, m), 1.12 (3H, t, J=8), 1.10 (2H,m), 0.92 (3H, t, 1=9), 0.80 (3H, t, 1=9). MS (DCI/ H3) m/e 507 (M+H+). Anal calcd for C31H42N2O4 • 1.0 TFA: C ,63.86 ; H, 6.98; N, 4.51. Found: C, 63.95; H, 7.12; N, 4.43.
Example 346 trans. trans-4-( 1 -Be_-Zθdioxol-5-yl, -2-(4-methoxyphenyl , - 1 -(((N-(3-pentvD -N- phenylamino) carbonyl)methyl)pyrrolidme-3 -carboxylic acid
Using the procedures described in Example 1, the title compound was prepared. 1H
NMR (300 MHz, CD3OD) δ 0.93 (t, J=7.3 Hz, 3H), 0.94 (t, J=7.3 Hz, 3H), 1.33 (m, 4H),
2.72 (d, J=15.2 Hz, IH), 2.81 (m, IH), 3.11-3.23 (m, 2H), 3.45-3.57 (m, 2H), 3.79 (s, 3H),
3.83 (d, J=9.8 Hz, IH), 4.54 (m, IH), 5.92 (s, 2H), 6.73 (d, J=7.8 Hz, IH), 6.83 (m, 3H), 6.98 (bs, 2H), 7.04 (d, J=1.7 Hz, IH), 7.07 (2), 7.37 (m, 3H). MS (DCI) m/e 545 (M+H+). Anal calcd for C32H33 2O6 • 0.35H2O: C, 69.76; H, 6.71; N, 5.08. Found: C, 69.72; H, 6.66; N, 4.94.
Example 347 trans. trans-4-( 13 -Benzodioxol-5-yl)-2-(4-methoxyphenyl)- 1 -(((N-butyl) -N-(3- trifluoromethylphenyl)amino)carbonyl)methyl)pyrrohdine-3-carboxylic acid Using the procedures described in Example 1, the title compound was prepared. ^H
NMR (300 MHz, CD3OD) δ 0.87 (t, J=6.6 Hz, 3H), 1.17-1.45 (m, 4H), 2.65 (d, J=16.5 Hz,
IH), 2.72 (m, IH), 3.10 (t, J=9.5 Hz, IH), 3.21-3.27 (m, IH), 3.40 (dd, J=4.1, 9.9 Hz, IH), 3.54 (m, IH), 3.61-3.74 (m, 3H), 3.77 (s, 3H), 5.93 (s, 2H), 6.73-6.85 (m, 4H), 7.02 (m, 3H), 7.33 (d, J=7.5 Hz, IH), 7.40 (s, IH), 7.58 (t, J=7.8 Hz, IH), 7.69 (d, J=7.5 Hz, IH). MS
(DCI) m/e 599 (M+H+). Anal calcd for C32H33F3N2O6: C, 64.21; H, 5.56; N, 4.68. Found: C, 64.09; H, 5.63; N, 4.57.
Example 348 trans. trø..5'-4-(1.3-Benzodioxol-5-yl)-2-(4-methoxyphenyl)-l-(N-propyl-N-(4- morpholinylcarbonyl aminocarbonylmethyl)-pyrrolidine-3-carboxylic acid Using the procedures described in Example 1, the title compound was prepared. 1H NMR (300 MHz, CD3OD) δ 0.78 (t, 1=1 Hz, 3H), 1.43 (q, 1=1 Hz, 2H), 2.07-3.01 (m, IH),
2.76 (dd, 1=1, 9 Hz, 2H), 2.77-3.00 (m, 5H), 3.05 (3.70, J=m Hz, 11H), 3.76 (s, 3H), 5.88 (s, 2H), 6.67 (d, J=8 Hz, IH), 6.80 (dd, 1=1 Hz, IH), 6.83-6.90 (m, 2H), 6.98 (d, J=2 Hz, IH), 7.32-7.39 (m, 2H). MS m/e calc'd for (M+H) C29H39N3O7: (M+H) 540.2710,. Found (M+H) 540.2713.
Example 349 trans . trans-4-( 1 ,3-Benzodioxol-5-ylV2-(4-methoxyphenyl)- 1 -(ct-?-2.6-dimethylpiperidin- 1- yl) carbonylmethyl) -pyrrolidine-3 -carboxylic acid Using the procedures described in Example 1, the title compound was prepared. H NMR (300 MHz, CD3OD) δ 0.94 (d, 1=1 Hz, 3H), 1.15d (7, 3H), 1.10-1.70 (m, 6H), 1.70-
1.90 (m, IH), 2.9. (d, J=13 Hz, IH), 3.00-3.20 (m, 2H), 3.50 (3.70, J=mHz, 2H), 3.79 (s, 3H), 3.80-4.00 (m, IH), 4.10-4.65 (m, 2H), 5.95 (s, 2H), 6.70 (7.10, J=mHz, 5H), 7.35 (m,
2H). MS m/e calc'd for (M+H)+ C28H35N2O6: (M+H) 495.2495. Found (M+H) 495.2493.
Example 350 trans. trαn_;-2-(4-Methoxymethoxyphenyl)-4-(l,3-benzodioxol-5-yl)-l-(2-(N-propyl-N-w- pentanesulfonylamino)ethyl]pyrrohdine-3-carboxylic acid Using the procedures described in Example 1, the title compound was prepared and isolated as a white solid. m.p. 57-59 °C. 1HNMR (CDCI3, 300 MHz) δ 0.78 (t, J=7Hz,
3H), 0.90 (t, J=7Hz, 3H), 1.28-1.36 (m, 4H), 1.93 (sextet, J=7Hz, IB), 1.72 (t, J=7Hz, 2H), 2.20-2.32 ( , IH), 2.72-3.10 (m, 7H), 3.18-3.41 (m, 2H), 3.43 (dd, J=3Hz, J=9Hz, IH), 3.48 (s, 3H), 3.52-3.59 (m, IH), 3.68 (d, J=9Hz, IH), 5.15 (s, 2H), 5.94 (s,2H), 6.73 (d, J=8Hz, IH), 6.82 (dd, J=lHz, J=8Hz, IH), 6.98-7.02 (m, 3H), 7.32 (d, J=9Hz, 2H). MS (DCI/NH3) m/e 591 (M+H)+
Example 351 tr-.n_?.trø«-.-4-(l,3-Bei-Zθdioxol-5-yl)-2-(4-methoxyphenyl)-l-(((N-(2-butyl)-N- phenylamino carbonyl methyl.pyrrolidine-3-carboxylic acid Using the procedures described in Example 1, the title compound was prepared. ^H NMR (300 MHz, CD3OD) δ 0.79-0.89 (m, 6H), 1.14-1.21 (m, IH), 1.25-1.40 (m, IH), 2.64
(dd, J=4.6, 15.4 Hz, IH), 2.76 (t, J=9.0 Hz, IH), 3.05-3.13 (m, 2H), 3.37-3.49 (m, 2H), 3.70
(s, 3H), 3.80 (d, J=9.8 Hz, IH), 4.53 (m, IH), 5.83 (m, 2H), 6.65 (d, J=8.1 Hz, IH), 6.72 (-
6.76, J=mHz, 3H), 6.87 (m, 2H), 6.95 (d, J=1.7 Hz, IH), 7.03 (m, 2H), 7.29 (m, 3H). MS
(DCI) m/e 531 (M+H+). Anal calcd for C31H34N2O6 • O.4H2O: C, 69.23; H, 6.52; N, 5.21. Found: C, 69.19; H, 6.52; N, 5.03.
Example 352 t/jα«-r.trαn^-4-(l,3-Benzodioxol-5-yl)-2-(4-methoxyphenyl)-l-(((N-(2-propyl)-N- phenylamino carbonyl)methyl)pyrrolidine-3-carboxylic acid Using the procedures described in Example 1, the title compound was prepared. ^H
NMR (300 MHz, CD3OD) δ 0.99 (d, J=6.8 Hz, 6H), 2.71 (d, J=15.6 Hz, IH), 2.84 (m, IH),
3.13-3.18 (m, 2H), 3.45-3.58 (m, 2H), 3.79 (s, 3H), 3.88 (d, J=9.8 Hz, IH), 4.80 (m, IH),
5.92 (s, 2H), 6.74 (d, J=8.1 Hz, IH), 6.83 (m, 3H), 6.96 (br s, 2H), 7.04 (d, J=1.7 Hz, IH),
7.13 (m, 2H), 7.38 (m, 3H). MS (DCI) m/e 517 (M+H+). Anal calcd for C30H32N2O6 • 0.4H2O • O.O8CH3CO2C2H5: C, 68.65; H, 6.28; N, 5.28. Found: C, 68.64; H, 6.35; N, 5.14.
Example 353 trans. trα?.5,-4-(4-Propoxyphenyl)-2- 4-methoxyphenyl)- 1 -(N,N-di(n- butyl)aminocarbonylmethyl)-pyrrolidine-3-carboxylic acid Using the procedures described in Example 1, the title compound was prepared. 1H
(300MHz, CDCI3 ) δ 7.42 (2H, d, J=10Hz), 7.38 (2H, d, J=10Hz), 6.92 (2H, d, J=10Hz),
6.88 (2H, d, J=10Hz), 5.13 (IH, bd, J=12Hz), 4.02 (2H, m), 3.90 (2H, t, J=8Hz), 3.80 (3H, s), 3.71 (3H, m), 3.40 (2H, m), 3.19 (IH, m), 3.10-2.90 (2H, m), 1.80 (2H, m), 1.48 (2H, m), 1.29 (4H, m), 1.13 (2H, m), 1.03 (3H, t, J=8Hz), 0.92 (3H, t, J=9Hz), 0.82 (3H, t, J=9Hz).
MS (DCI/NH3) m/e 525 (MH+). Anal calcd for C3lH44N2θ5- 1 TFA : C, 62.06 H 7.10; N, 4.39 . Found: C, 62.43; H, 7.28; N, 4.39.
Example 354 trans, trans-4- 1.3-Benzodioxol-5-yl)-2-(4-methoxyphenyl, - 1 -(( 1 ,2,3 ,4-tetrahydroquinohn- 1 -yl carbonyl)methyl)pyrrohdine-3-carboxyhc acid Using the procedures described in Example 1, the title compound was prepared. 1H
NMR (300 MHz, CD3OD) δ 1.88 (quintet, J=6.5 Hz, 2H), 2.67 (t, J=6.4 Hz, 2H), 2.87 (t, J=8.6 Hz, IH), 3.14 (m, 2H), 3.42 (dd, J=4.6, 9.7 Hz, IH), 3.53-3.70 (m, 3H), 3.72-3.78 (m, IH), 3.77 (s, 3H), 3.86 (d, J=9.6 Hz, IH), 5.91 (s, 2H), 6.73 (d, J=8.1 Hz, IH), 6.83 (m, 3H), 6.98 (d, J=l.l Hz, IH), 7.02-7.23 (m, 6H). MS (DCI) m/e 515 (M+H+). Anal calcd for C30H30 2O6 - 0.3H2O - 0.15 CH3CO2C2H5: C, 68.93; H, 6.01; N, 5.25. Found: C, 68.91; H, 5.86; N, 5.19.
Example 355 trans, t rans-2-(3 ,4-Dimethoxyphenyl)-4-( 1.3-benzodioxol-5-yl)-l -(N.N-di(n- butyl aminocarbonylmethyl)-pyrroUdine-3-carboxylic acid Using the procedures described in Example 1, the title compound was prepared and isolated as a white solid, mp. 64-65 °C. ΪH NMR (CDCI3, 300MHz) δ 0.79 (t, J=7Hz, 3H), 0.88 (t, J=7Hz, 3H),1.07 (sextet, J=7Hz, 2H), 1.20-1.35 (m, 4H), 1.43 (sextet, J=7Hz, 2H), 2.83 (d, J=13.5Hz, IH), 2.94-3.17 ( , 4H), 3.22-3.42 (m, IH), 3.40-3.48 (m, 3H), 3.58- 3.65 (m, IH), 3.82 (s, 3H), 3.85 (s, 4H),5.92 (s, 2H), 6.73 (d, J=8Hz, IH), 6.81 (d, J=8Hz,
IH), 6.86-6.96 (m, 3H), 7.07 (d, J=3Hz, IH). MS (DCI/NH3) m/e 541 (M+H)+.
Example 356 tra»-.Jr-.n5,-2-(3,4-Dimethoxyphenyl)-4-(1.3-benzodioxol -5-yl)-l-[2-(N-propyl-N-?.- pentanesulfonylamino ethyl]pyrrolidine-3 -carboxylic acid Using the procedures described in Example 1, the title compound was prepared and isolated as a white sohd. mp. 75-86 °C. *H NMR (CD3OD, 300 MHz) δ 0.75 (t, J=7Hz,
3H), 0.82 (t, J=7Hz, 3H), 1.32-1.43 (m, 6H), 1.65-1.77 (m, 2H), 3.0-3.09 (m, 4H), 3.23-3.27 (m, 2H), 3.44 (t, J=6Hz, IH), 3.47-3.56 (m, 2H), 3.78 (d, J=9Hz, IH), 3.83-3.93 (m, 2H), 3.87 (s, 3H), 3.92 (s, 3H), 4.63 (d, J=13Hz, IH), 5.97 (s, 2H), 6.82 (d, J=7Hz, IH), 6.93 (d, J=7Hz, IH), 7.06 (d, J=7Hz, IH), 7.08 (d, J=3Hz, IH), 7.16 (dd, J=3Hz, J=7Hz, IH), 7.27 (d, J=3Hz, IH). MS (DCI/NH3) m/e 591 (M+H)+
Example 357 trans, trans-2-(3 ,4-Dimethoxyphenyl)-4-( 1 ,3-benzodioxol-5-yl)- 1 -[2-(N-propyl-N-n- hexanesulfonylamino)ethyl1pyrrolidine-3-carboxylic acid Using the procedures described in Example 1 , the title compound was prepared and isolated as a white solid. m.p. 65-66 °C. lR NMR (CDCI3, 300 MHz) δ 0.80 (t, J=7Hz,
3H), 0.89 (t, J=7Hz, 3H), 1.23-1.48 (m, 6H), 1.43 (sextet, J=7Hz, 2H), 1.72 (sextet,J=7Hz, 2H), 2.25-2.35 (m, IH), 2.73-3.10 (m, 7H), 3.19-3.32 (m, 2H), 3.45 (dd, J=3Hz, J=9Hz, IH), 3.53-3.59 (m, IH), 3.68 (d, J=9Hz, 1H),3.87 (s, 6H), 5.95 (s, 2H), 6.74 (d, J=8Hz, IH), 6.79- 6.86 (m, 2H), 6.92-6.97 (m, 2H), 7.02 (s, IH). MS (DCI/NH3) m/e 605 (M+H)+. Example 358 trans. tr_ms-2-(4-Methoxyphenyl)-4-( 1 ,3-benzodioxol-5-yl)-l -[2-(phthalimido)ethyl]- pyrrolidine-3-carboxylic acid The compound of Example IC (250 mg), N-bromoethylphthalimide (206 mg), and diisopropylethylamine (175 mg) were dissolved in 1 mL of acetonitrile and heated for 2.5 hours at 95 °C. Toluene was added, and the mixture was washed with KHCO3 solution.
The solution was dried (Na2SO4) and concentrated. The crude product was purified by chromatography on silica gel eluting with 3:1 EtOAc-hexane to give 216 mg of an intermediate ethyl ester which was hydrolyzed by the method of Example ID to give 130 mg of the title compound as a white powder. !H NMR (300 MHz, CDCI3) δ 3.12-3.26 (m, 2H), 3.60-3.75 (m, 2H), 3.70 (s, 3H), 3.98-4.12 (m, 2H), 4.45-4.55 ( , IH), 4.69 (d, J=9Hz, IH), 4.76-4.88 (m, IH), 5.96 (s, 2H), 6.55 (d, J=8Hz, IH), 6.60-6.70 ( , 3H), 6.79 (d, J=8Hz, IH), 7.05-7.45 (m, 5H), 7.75 (d, J=7Hz, IH).
' Example 359 trans , trans-4-( 1 ,3 -Benzodioxol-5-yl)-2-(4-methoxyphenylV 1 -(((N-(2-pentyl)-N- phenylamino carbonyl)methyl)pyrrohdine-3-carboxy lie acid Using the procedures described in Example 1, the title compound was prepared. 1H
NMR (300 MHz, CD3OD) δ 0.86-0.98 (m, 6H), 1.17-1.22 (m, IH), 1.23-1.41 (m, 3H), 2.70 (dd, J=11.2, 15.3 Hz, IH), 2.83 (m, IH), 3.10-3.21 (m, 2H), 3.45-3.60 (m, 2H), 3.79 (s, 3H), 3.86 (m, IH), 4.74 (m, IH), 5.91 (m, 2H), 6.73 (dd, J=l.l, 7.7 Hz, 3H), 6.82 (m, 2H), 7.04-
7.14 (m, 3H), 7.36 (m, 3H). MS (DCI) m/e 545 (M+H+). Anal calcd for C32H36N2O6 • 0.25 CH3CO2C2H5: C, 69.95; H, 6.76; N, 4.94. Found: C, 70.03; H, 6.54; N, 4.78.
Example 360 tr-.n ,.t/*-.n5,-4-π,3-Benzodioxol-5-yl)-2-(4-methoxyphenyl)-l-(N-butyl-N-(2- naphthyl aminocarbonylmethyl -pyrrolidine-3-carboxylic acid Using the procedures described in Example 1, the title compound was prepared. 1H
NMR (300 MHz, CD3OD) δ 0.83 (t, 1=1 Hz, 3H), 1.23-1.39 (m, 4H), 1.40-1.55 (m, 3H), 2.60-2.72 (m, 2H), 3.00-3.80 (m, 5H), 3.66 (s, 3H), 5.87 (s, 2H), 6.39 (d, 1=9 Hz, 2H), 6.74- 6.85 (m, 3H), 7.17 (d, 1=2 Hz, IH), 7.40 (dd, J=8 Hz, IH), 7.52-7.62 (m, 3H), 7.80-7.90 (m, 1H), 7.90-8.00 (m, 2H). MS (DCI) m/e 581 (M+H)+. Analysis calcd for C35H36N2O6 • 0.3 H2O: C, 71.73; H, 6.29; N, 4.78. Found: C, 71.74; H, 6.26; N, 4.72.
Example 361 tr ..-?.tr-.n '-2-( 4-Propoxyphenyl)-4-(l,3-benzodioxol-5-yl -l-[2-(Nrpropyl-N-»- pentanesulfonylamino) ethyl]pyrrolidine-3 -carboxylic acid Using the procedures described in Example 66, the title compound was prepared and isolated as a white sohd. mp. 53-54 °C. *H NMR (CDCI3, 300MHz) 0.79 (t, J=7Hz, 3H), 0.89 (t, J=7Hz, 3H), 1.03 (t, J=7Hz, 3H), 1.24-1.34 (m, 4H), 1.43 (sextet, J=7Hz, 2H), 1.67-1.75 (m, 2H), 1.80 (sextet, 2H), 2.23-2.33 (m, IH), 2.72-2.93 (m, 5H), 3.05 (septet, J=7Hz, 2H), 3.15-3.35 (m, 2H), 3.42 (d, J=9Hz, IH), 3.54-3.62 (m, IH), 3.67 (d, J=9Hz, IH), 4.90 (t, J=7Hz, 2H), 5.95 (s, 2H), 6.73 (d, J=8Hz, IH), 6.85 (d, J=8Hz, 2H), 7.02 (s,
IH), 7.32 (d, J=8Hz, 2H). MS (DCI/NH3) m/e 589 (M+H)+.
Example 362 trans. trans-4-( 1 ,3-Benzodioxol-5-yl)-2-(4-methoxyphenyD- 1 -((2-methylindolin- 1 - yl) carbonyl)methyl)pyrrohdine-3 -carboxylic acid Using the procedures described in Example 1, the title compound was prepared. ^H
NMR (300 MHz, CD3OD) δ mixture of indole C2 diastereomers, 0.95 (m, 1.5 (CH3 )), 1.05 (d, 6.3H, 1.5 (CH3)), 2.62 (m, IH), 3.01 (m, 2H), 3.14-3.25 (m, IH), 3.37-3.52 (m, 1.5H),
3.56-3.80 (m, 2H), 3.65 (s, 1.5 (CH3O)), 3.76 (s, 1.5 (CH3O)), 3.93 (m, 0.5H), 4.05-4.13
(m, 0.5H,), 4.42 (m, 0.5H), 4.65-4.74 ( , IH), 5.91 (m, 2H), 6.72 (d, J=8.1 Hz, 0.5H), 6.75
(m, 0.5H), 6.85 (m, 2H), 6.92 (d, J=8.5 Hz, IH), 7.00-7.06 (m, 2H), 7.14 (t, J=7.7 Hz, IH),
7.21 (t, J=6.6 Hz, IH), 7.38 (m, 2H), 7.99 (m, IH). MS (DCI) m/e 515 (M+H+). Anal calcd for C30H30N2O6 ' 0.35H2O • 0.3 CH3CO2C2H5: C, 68.47; H, 6.10; N, 5.12. Found: C, 68.46; H, 5.97; N, 5.07.
Example 363 trans. trans-4-( 1 ■3-Benzodioxol-5-yl)-2-(4-methoxyphenyl) - 1 -(2-hydroxy-3-propylhex- 1- yl)pyrrolidine-3 -carboxylic acid Using the procedures described in Example 1, the title compound was prepared. ^H NMR (300 MHz, CD3OD) δ 1.06 (m, 6H), 1.26-1.60 (m, 9H), 3.16 (dd, J=10.9, 12.6 Hz, IH), 3.18 (d, J=l l Hz, IH), 3.44 (d, J=2.0 Hz, IH), 3.61 (t, J=l l Hz, IH), 3.73 (t, J=11.0 Hz, IH), 3.85 (m, IH), 3.96-4.17 (m, 2H), 4.02 (s, 1.5 (CH3O diastereomer)), 4.03 (s, 1.5 (CH3O diastereomer)), 6.15 (s, 2H), 7.01 (d, J=8.1 Hz, 0.5H), 7.00 (d, J=8.1 Hz, 0.5H), 7.10
(m, IH), 7.23 ( , 3H), 7.77 (m, 2H). MS (DCI.) m/e 484 (M+H+). Anal calcd for C28H37NO6 • 0.33 H3PO4: C, 65.34; H, 7.44; N, 2.72. Found: C, 65.30; H, 7.40; N, 2.60.
Example 364 trans, trans-4-( 1 ,3-Benzodioxol-5-ylV2-(4-methoxyphenyl)- 1 -(((N-(4-heptyl)-N-(3 ,4- dimethoxybeιιzyl)amino carbonyl)methyl)pyrrohdine-3-carboxylic acid Using the procedures described in Example 1, the title compound was prepared. H
NMR (300 MHz, CD3OD) δ 1: 1 mixture of rotamers, 0.61 (t, J=7.1 Hz, 1.5H), 0.72 (7.3, 1.5H), 0.76 (t, J=7.1, 1.5, 0.83, t, 7.3 Hz, 1.5H), 1.05-1.60 (m, 8H), 2.84-3.10 (m, J=2.5,
3.18, t, 9.7 Hz, 0.5H), 3.41-3.52 (m, 2H), 3.47-3.69 (m, 2H), 3.66 (s, 1.5H), 3.73 (s, 1.5H),
3.77 (s, 1.5H), 3.78 (s, 1.5H), 3.79 (s, 1.5H), 3.86 (d, J=9.8 Hz, 0.5H), 4.19 (d, J=17.7 Hz,
0.5H), 4.29 (d, J=15.2 Hz, 0.5H), 4.40-4.49 (m, 0.5H), 4.47 (d, J=15.3 Hz, 0.5H), 4.60 (d,
J=17.6 Hz, 0.5H), 5.93 (m, 2H), 6.46 (dd, 1=1.7, 8.2 Hz, 0.5H), 6.52 (d, J=2.0 Hz, 0.5H), 6.74 (m, 2.5H), 6.80 (s, IH), 6.83-6.88 (m, IH), 6.92 ( , 1.5H), 7.03 (dd, J=1.7, 6.8 Hz, '
IH), 7.19 (m, IH), 7.36 (m, IH). MS (DCI) m/e 647 (M+H+). Anal calcd for C37H46N2O8: C, 68.71; H, 7.17; N, 4.33. Found: C, 68.41; H, 7.26; N, 4.11.
Example 365 trans . trans-4-( 1 ,3-Benzodioxol-5-yl)-2-(4-methoxyphenyl)- 1 -((indolin-1 - yl)carbonyl)methyl)pyrrolidine-3-carboxylic acid Using the procedures described in Example 1, the title compound was prepared. 1H
NMR (300 MHz, CD3OD) δ 2.97 (dd, J=8.1, 9.5 Hz, IH), 3.10 (t, J=8.1 Hz, 2H), 3.16-3.22
(m, 2H), 3.51-3.68 (m, 3H), 3.73 (m, 3H), 3.83-4.05 (m, 3H), 5.90 (m, 2H), 6.73 (d, J=8.1 Hz, IH), 6.86 (m, 3H), 6.99 (dt, J=l.l, 7.4 Hz, IH), 7.08 (d, J=0.7 Hz, IH), 7.11 (m, IH), 7.18 (d, J=7.1 Hz, IH), 7.38 (d, J=8.5 Hz, 2H), 8.02 (8.1, IH). MS (CI.) m/e 501 (M+H+). Anal calcd for C29H28N2O6 • 0.5 H2O • 0.15 CH3CO2C2H5: C, 68.01; H, 5.82; N, 5.36. Found: C, 68.03; H, 5.65; N, 5.25.
Example 366 trans. trans-4-( 1 ,3-Benzodioxol-5-yl)-2-(4-methoxyphenyl)- 1 -(N-butyl-N-(2- chlorophenyl) amino carbonylmethy l)pyrrolidine-3 -carboxylic acid Using the procedures described in Example 1, the title compound was prepared. *H
NMR (300 MHz, CD3OD) δ 0.89 (dt, 1=1 Hz, 3H), 1.23-1.51 (m, 4H), 2.52-4.00 (m, 8H), 3.78 (d, 1=6 Hz, 3H), 5.92 (d, 1=6 Hz, 2H), 6.70-6.87 (m, 4H), 7.02-7.21 (m, 4H), 7.27-7.52
(m, 3H). MS (DCI) m/e 565 (M+H)+. Analysis calcd for C31H32N2O6CI • O.6H2O: C,
64.66; H, 5.99; N, 4.86. Found: C, 64.59; H, 6.00; N, 4.64.
Example 367 trans. tran,s-2-(4-Methoxphenγl)-4-( 1 ,3-benzodioxol-5-yl)- 1 -
(3 ,4,5-trimethoxybe_-zyl p ohdine-3-carboxγlic acid The compound resulting from Example IC (0.25 g) was reacted with 0.169 g of
3,4,5-trimethoxybenzyl chloride and 0.175 g of diisopropylethylamine in 1 mL of acetonitrile for 2 hours at room temperature. The resulting ester was isolated and then hydrolyzed by the method of Example ID to give 0.193 g of the title compound, mp. 108-
110 °C *H NMR (300 MHz, CDCI3) δ 2.75 (t, J=9Hz, IH), 2.95-3.05 (m, 2H), 3.20 (d,
J=ll Hz, IH), 3.45-3.55 (m, IH), 3.7-3.8 (m, 2H), 3.84 (s, 3H), 5.95 (dd, J=2Hz, 6Hz, 2H), 6.55 (s, 2H), 6.70 (d, J=8Hz, IH), 6.30-6.35 (m, IH), 6.90 (d, J=9Hz, 2H), 7.13 (d, J=2Hz, IH), 7.43 (d, J=9Hz, 2H).
Example 368 trans. trans-4-( 1.3-Benzodioxol-5-yl)-2-(4-methoxyphenyl ) - 1 -fiS[-butyl-N-(3- cMorophenyl)an_dnocarbonylmethyl)-pyrrohdine-3-carboxylic acid Using the procedures described in Example 1, the title compound was prepared. *H NMR (300 MHz, CD3OD) δ 0.89 (t, 1=1 Hz, 3H), 1.20-1.42 (m, 4H), 3.42-3.87 (m, 9H), 3.9
(s, 3H), 5.96 (s, 2H), 6.75 (7.10, J=mHz, 7H), 7.33-7.50 (m, 4H). MS (CI.) m/e 565(M+H). Analysis calcd for C31H33N2O6CM.OCF3COOH: C, 58.37; H, 5.05; N, 4.13. Found: C, 58.41; H, 4.99; N, 4.08.
Example 369 trα7?i.trflrø-2-(4-Methoxphenyl)-4-π.3-benzodioxol-5-yl)-l-[2-(di-n-butylamino)pyrimidin-
4-yl]pyrrolidine-3 -carboxy he acid The compound resulting from Example IC (0.25 g) was reacted with 0.11 g of 2,4- dichloropyrimidine and 0.175 g of diisopropylethylamine in 1 mL of acetonitrile for 2 hours at room temperature to give 0.218 g of ethyl 2-(4-methoxphenyl)-4-( 1 ,3-benzodioxol-5~yl)- l-(2-c oro-4-pyrirnidyl)-pyrroHdine-3-carboxylate. This compound was reacted with 1 mL of dibutylamine in 2 mL of toluene at 125 °C for 17 hours. The resulting ethyl ester was hydrolyzed by the method of Example ID to give 0.142 g of the title comopund as a white powder. 1H NMR (300 MHz, CDCI3) 0.75-0.90 (broad, 6H), 1.1-1.3 (br, 4H), 1.35-1.55 (br, 4H), 3.05 (m, IH), 3.3-3.5 (br, 2H), 3.55-3.67 (m, 2H), 3.75 (s, 3H), 4.6 (br, IH), 5.2 (br, IH), 5.45 (br, IH), 5.87 (s, 2H), 6.3 (br, IH), 6.67 (d, J=8Hz, IH), 6.7-6.85 (m, 4H), 7.10 (d, J=9Hz, 2H).
Example 370 tr rø,tr ^-4-(l,3-Benzodioxol-5-yl)-2-(4-methoxyphenyl)-l-(((N-(2-methylbut-2-yl)-N- phenylamino.carbonyl)methyl)pyιτohdine-3-carboxy lie acid
Using the procedures described in Example 1, the title compound was prepared. H
NMR (300 MHz, CD3OD) 0.90 (t, J=7.5 Hz, 3H), 1.12 (s, 3H), 1.14 (s, 3H), 2.06 (q,
J 7.5 Hz, 2H), 2.73 (d, J=15.3 Hz, IH), 2.91 (t, J=9.5 Hz, IH), 3.11 (d, J=15.6 Hz, IH),
3.21 (t, J=8.8 Hz, IH), 3.50-3.61 (m, 2H), 3.80 (s, 3H), 4.00 (d, J=10.2 Hz, IH), 5.91 (s, 2H), 6.74 (d, J=7.8 Hz, IH), 6.85 (m, 3H), 6.93 (m, IH), 6.98 (m, IH), 7.03 (d, J=1.7 Hz,
IH), 7.17 (m, 2H), 7.36 (m, 3H). MS (DCI) m/e 545 (M+H+). Anal calcd for C32H36N2O6: C, 70.57; H, 6.66; N, 5.14. Found: C, 70.17; H, 6.53; N, 4.97.
Example 371 trans, trarø-2-f 4-Ethylphenyl)-4-(5-indanyr)- 1 -(N.N-di(n-butyl) aminocarbonylmethyl)- pyrrolidine-3 -carboxylic acid Using the procedures described in Example 1, the title compound was prepared. *H (300MHz, CDCI3) 7.25 (3H, m), 7.21 (IH, d, 3Hz), 7.17 (3H, m), 3.80 (IH, d, 10Hz), 3.65 (IH, ddd, 6, 5, 3Hz), 3.4 (4H, m), 3.10 (2H, m), 2.98 (2H, m), 2.88 (5H, m), 2.79 (IH, d, 16Hz), 2.62 (2H, q, 7Hz), 2.05 (2H, m), 1.42 (2H, m), 1.32 (IH, m), 1.21 (3H, t, 7Hz), 1.05 (2H, sext, 7Hz), 0.87 (3H, t, 7Hz), 0.79 (3H, t, 7Hz). MS (DCI, NH3) m/e 505
(M+H+). Anal calcd for C32H44N2O3: C, 76.15; H, 8.79; N 5.55. Found: C, 75.96; H, 8.75; N, 5.36.
Example 372 trans. ra.._f-2-(3.4-Difluorophenyl)-4-(l,3-benzodioxol-5-yl)-l-(N,N-di(n- butyl) amino carbonylmethy 1, -pyrrolidine-3 -carboxylic acid Using the procedures described in Example 1, the title compound was prepared and isolated as a white solid. m.ρ. 62-63 °C lR NMR (CDCI3, 300 MHz), δ 0.83 (t, J=7Hz,
3H), 0.88 (t, J=7Hz, 3H), 1.13 (sextet, J=7Hz, 2H),1.20-1.32 (m,3H), 1.36-1.49 (m,3H), 2.85-2.93 (m,2H), 2.98-3.23 (m, 4H), 3.36-3.45 (m, 3H), 3.58-3.66 (m IH), 3.94 (d, J=8Hz,
IH), 5.93 (s, 2H), 6.72 (d, J=7.5Hz, IH), 6.84 (dd, J=lHz, J=7.5Hz, IH), 6.98 (d, J=7.5Hz,
IH), 7.08-7.15 (m, 2H), 7.22-7.28 (m, IH). MS (CDI/NH3) m/e517 (M+H)+.
Example 373 trαn-?.tr-.n_.-2-(3,4-Difluorophenyl)-4-(l,3-benzodioxol-5-yl)-l-[2-(N-propyl-N-n- pentanesulfonylamino)ethyl]pyrrolidine-3-carboxy lie acid Using the procedures described in Example 1, the title compound was prepared and isolated as a white solid. m.ρ. 71-72 °C 1H NMR (CDCI3, 300 MHz) δ 0.82 (t, J=7Hz,
3H), 0.90 (t, J=7Hz, 3H), 1.25-1.38 (m, 4H), 1.46 (sextet, J=7Hz, 2H), 1.74 (quintett, J=7Hz, 2H), 2.26-2.36 (m, IH), 2.72-2.95 (m, 5H), 2.98-3.12 (m, 2H), 3.15-3.34 (m, 2H), 3.45 (dd, J=3Hz, J=9Hz, IH), 3.53-3.60 (m, IH), 3.71 (d, J=9Hz, IH), 5.96 (s, 2H), 6.75 (d, J=9Hz, IH), 3.82 (dd„ J=2Hz, J=9Hz, IH), 5.96 (d, J=2Hz, IH), 7.09-7.18 (m, 2H), 7.23-7.34 (m, IH). MS (CDI/NH3) m/e567 (M+H)+.
Example 374 trαrøJr_-W-.-4-(1.3-Benzodioxol-5-yl)-2-(ethoxymethyl)-l-(((N,N-di(n- butyl)aminocarbonylmethyl)-pyrroHdine-3-carboxylic acid Using the procedures described in Example 1, the title compound was prepared. TLC (10% MeOH-CH2C_2) Rf = 0.53. 1H NMR (CDCI3, 300 MHz, rotameric forms) δ
0.70 (t, J=7Hz), 0.80 (t, J=7Hz) and 0.96-1.04 (m, 6H total), 1.04-1.75 (m, 11H), 1.34-1.53 (br m, 4H), 2.65 (AB) and 2.80-3.08 (m, 2H total), 3.10-3.82 (br m, 12H), 4.03 (m) and 4.22-4.45 (br m, 2H total), 5.90 (s) and 5.91 (s, 2H total), 6.65-6.84 (m) and 6.93 (m) and 6.99 (m, 3H total). MS (FAB) m/e 463 (M+H)+ Anal calcd for C25H38N2O6 • 1.5 H2O:
C, 61.33; H, 8.44; N, 5.72. Found: C, 61.28; H, 7.78; N, 5.62.
Example 375 tran , trans-4-( 1 ,3-Benzodioxol-5-yl)-2-(n-butyl)- 1 -(N.N- di(n-butyl)aminocarbonylmethyl)-pyrrolidine-3-carboxyhc acid Using the procedures described in Example 1, the title compound was prepared and isolated as a colorless wax. TLC (10% MeOH-CH2Cl2) Rf = 0.37. lR NMR (CDCI3, 300
MHz, rotameric forms) δ 0.71 (t, J=7Hz) and 0.77-1.05 (m, 9H total), 1.05-1.20 (m, 2H), 1.20-1.72 (br m, 13H), 2.48-2.52 (m, IH), 2.87-3.00 (m, IH), 3.05-3.60 (m, 5H), 3.60-3.80 (br m, 2H), 3.88-4.05 (br m, IH), 4.28 (br d, J=15Hz, IH total), 5.90 (s) and 5.92 (s, 2H total), 6.67-6.82 (m, 3H total). MS (FAB) m/e 461 (M+H)+ Anal calcd for C26H40N2O5 1.75 H2O: C, 63.45; H, 8.90; N, 5.69. Found: C, 63.18; H, 8.22; N, 5.60.
Example 376 tr_.?Z '.trαn ,-4- i,3-Benzodioxol-5-yl -2-(2-methylbutyl)-l-(N,N-di(n- butyl)aminocarbonylmethyl)-pyrroHdine-3-carboxylic acid
Using the procedures described in Example 1, the title compound was prepared and isolated as a colorless glass. TLC (10% MeOH-CH2C_2) Rf = 0.49. lR NMR (CDCI3, 300
MHz, rotameric forms and mixture of diastereomers) 0.69 (br t, J=7Hz) and 0.75-2.15 (several br m, approx. 26H total), 2.48-2.65 (br m, IH), 2.87-3.01 (br m, IH), 3.06-3.82 (br m, IR), 3.90-4.40 (br m, 2H), 5.90 (s) and 5.92 (s, 2H total), 6.67-6.90 (m, 3H total). MS (FAB) m/e 475 (M+H)+.
Example 377. tr-.?.-..tr-.π_?-4-(l,3-Benzodioxol-5-ylV2-(3-methylbutyl)-l-(N,N-di(n- butyl. aminocarbonylm.ethyl -pyrrolidine-3 -carboxylic acid Using the procedures described in Example 1, the title compound was prepared. TLC (10% MeOH-CH2Cl2) Rf = 0.41. *H NMR (CDCI3, 300 MHz, rotameric forms) δ 0.73 (t, J=7Hz) and 0.77-1.05 (m, 12H total), 1.07-1.75 (m, approx. 14H plus H2O), 2.48- 2.63 (m, IH), 2.87-3.05 (m, IH), 3.05-3.60 (several br m, 5H), 3.62-4.02 (br m, 2H), 4.29 (br d, J=15Hz, IH), 5.89 (s) and 5.93 (s, 2H total), 6.65-6.90 (m, 3H total). MS (FAB) m/e
475 (M+H)X
Example 378 trα»^.tr-.^ ,-2-(4-Methoxyphenyl)-4-(1.3-benzodioxol-5-yl)-l-[2-(N-propyl-N-((N-methyl-
N-propylamino)sulfonyl)amino)ethyl]pyrrolidine-3-carboxyhc acid Using the procedures described in Example 66, the title compound was prepared and isolated as a white sohd. m.p. 58-59 °C lR NMR (CDCI3, 300MHz) δ 0.78 (t, J=7Hz,
3H), 0.90 (t, J=7Hz, 3H), 1.27 (sextet, J=7Hz, 2H), 1.48 (m, 4H), 2.22-2.30 (m, IH), 2.62 (s,
3H), 2.68-2.78 (m, IH), 2.84-3.03 (m, 5H), 3.08-3.31 (m, 3H),3.39 (dd, J=3Hz, J=9Hz,lH),
3.50-3.58 (m, IH), 3.63 (d, J=9Hz, 1H),3.79 (s, 3H), 5.95 (s, 2H), 3.73 (d, J=8Hz, IH), 6.83
(dd, J=2Hz, J=8Hz, IH), 3.87 (d, J=9Hz, 2H), 7.01 (d, J=2Hz, 1H), 7.33 (d, J=9Hz, 2H). MS (DCI/NH3) m/e 576 (M+H)+. Example 379 trα?.-.trαn--2.4-Di(3,4-difluorophenyl)-l-(N.N-di(n-butyl.aminocarbonylmethyl)- pyrrohdine-3 -carboxylic acid Using the procedures described in Example 1, the title compound was prepared. 1H NMR (300MHz, CDCI3 ) 7.35 (2H, m), 7.18 (4H, m), 4.87 (IH, d, J=12), 4.00-3.60 (5H, m), 3.60-3.10 (3H, m), 3.10-2.90 (2H, m), 1.45 (2H, m), 1.29 (4H, m), 1.15 (2H, m), 0.91 (3H, t, 1=9), 0.83 (3H, t, 1=9). MS (DCI/NH3) m/e 509 (M+H+). Anal calcd for C27H32F4N2O3- 0.75 TFA: C, 57.62; H, 5.56; N, 4.72. Found: C, 57.72; H, 5.67; N, 4.66.
Example 380 trans. trans-4-(3 ,4-Dimethylphenyl)-2-(4-methoxyphenyl)- 1 -(N,N-di(n- butyl) amino carbonylmethy l pyrro lidine-3 -carboxylic acid Using the procedures described in Example 1, the title compound was prepared. 1H
NMR (300 MHz, CDCI3 ) 7.43 (2H, d, 1=9), 7.25 (IH, bs), 7.18 (IH, dd, J=8, 3), 7.11 (IH, d, 1=9), 6.90 (2H, d, J=10), 5.48 (IH, d, J=12), 4.26 (IH, d, J=18), 4.16 (2H, m), 3.83
(2H, m), 3.81 (3H, s), 3.56 (IH, bd, J=18), 3.37 (IH, m), 3.20 (IH, m), 2.96 (2H, m), 2.24
(3H, s), 2.22 (3H, s), 1.47 (2H, m), 1.27 (4H, m), 1.10 (2H, m), 0.93 (3H, t, 1=9), 0.81 (3H, t, J=9). MS (DCI/NH3) m/e 495 (M+HY Anal calcd for C30H42N2O4- 1.25 TFA: C, 61.26; H, 6.84; N, 4.40. Found: C, 61.16; H, 7.05; N, 4.38.
Example 381 tr-.n .tr-.»-.-2,4-Di(3-fluoro-4-methoxyphenyl)-l-(N,N-di(n-butyl aminocarbony)methyl)- pyrrolidine-3 -carboxylic acid Using the procedures described in Example 1, the title compound was prepared. 1H NMR (300MHz, CDCI3 ) 7.20 (2H, m), 7.17 (2H, m), 6.93 (2H, m), 5.48 (IH, m), 4.26
(IH, m), 4.16 (2H, m), 3.83 (2H, m), 3.87 (6H, s), 3.56 (IH, m), 3.37 (IH, m), 3.20 (IH, m),
2.96 (2H, m), 1.47 (2H, m), 1.27 (4H, m), 1.10 (2H, m), 0.93 (3H, t, J=9), 0.81 (3H, t, 1=9).
MS (DCI/NH3) m/e 533 (M+H+). Anal calcd for C29H38F2N2O5- 0.75 H2O: C, 63.78; H, 7.29; N, 5.13. Found: C, 63.77; H, 7.08; N, 4.99.
Example 382 trans . trans-4-( 1.3-Benzodioxol-5-yl)-2-(4-methoxyphenyl) - 1 -(((N-(2-pentyl).N-(3- methylphenyl)amino carbonyl)methyl)pyrrohdine-3-carboxy lie acid Using the procedures described in Example 1, the title compound was prepared. ^H
NMR (300 MHz, CD3OD) δ 0.90 (m, 3H), 0.95 (t, J=7.3 Hz, 3H), 1.13-1.37 (m, 4H), 2.30
(s, 3H), 2.34 (s (CH3 rotamer)), 2.73-2.91 (m, 2H), 3.17-3.26 (m, 2H), 3.32-3.62 (m, 2H),
3.77-4.08 (m, IH), 3.80 (s, 3H), 4.71 (m, IH), 5.92 (m, 2H), 6.61-6.84 (m, 6H), 7.04-7.16
(m, 3H), 7.23-7.29 (m, 2H). MS (DCI) m/e 559 (M+H+). Anal calcd for C33H38N2O6 •
0.35 H2O • 0.05 CH3CO2C2H5: C, 70.03; H, 6.92; N, 4.92. Found: C, 70.08; H, 6.82; N,
4.95.
Example 383 trans . irans-4- 1 ,3-Benzodioxol-5-yl)-2-(4-methoxyphenyl)- 1 -(N-butyl-N-( 1 - naphthyl)aminocarbonylmethyl)pyrrohdine-3-carboxylic acid Using the procedures described in Example 1, the title compound was prepared. ^H NMR (300 MHz, CD3OD) δ 0.87 (t, J=7 Hz, 3H), 1.20-1.40 (m, 2H), 1.40-1.60 (m, 2H),
2.42-2.80 (m, 2H), 2.85-4.00 (m, 6H), 3.77 (d, J=1.5 Hz, 3H), 4.05-4.20 (m, IH), 5.94 (d,
1=2 Hz, 2H), 6.6 (dd, 1=9, 10 Hz, IH), 6.70-6.85 (m, 4H), 6.95-7.02 (m, 2H), 7.17 (dd, 8H,
1/2), 7.25 (dd, 8H, 1/2), 7.38-7.60 (m, 4H), 7.87-8.00 (m, 2H). MS (E.S.I.) m/e (M+H) 581.
Analysis calcd for C35H36N2O6 • 1.4 H2O: C, 69.38; H, 6.45; N, 4.62. Found: C, 69.36; H, 6.07; N, 4.41.
Example 384 tr-.^-f.tr-.» .-2-(4-Methoxyphenyl)-4-(1.3-benzodioxol-5-yl)-l-[2-fN'-phenyl-N-»- hexanesulfonylamino)ethyl]pyιτohdme-3-carboxylic acid Using the procedures described in Example 66, the title compound was prepared and isolated as a tan solid, mp. 67-68 °C 1H MR (CD3OD, 300 MHz) δ 0.88 (t, J=7Hz, 3H),
1.25-1.40 (m, 6H), 1.73 (quintet, J=7Hz, 2H), 2.13-2.23 (m, IH), 2.64-2.88 (m, 3H), 3.02 (sextet, J=8Hz, 2H), 3.44-3.53 ( , 2H), 3.58 (d, J=9Hz, IH), 3.56-3.75 (m, IH), 3.78 (s, 3H), 3.88-3.98 (m, IH), 5.93 (s, 2H), 6.72 (d, J=9Hz, IH), 5.78-5.84 ( , 3H), 6.96 (d, J=2Hz, IH), 7.20 (d, J=9Hz, 2H), 7.27-7.36 (m, 5H). MS (DCI/NH3) m/e 609 (M+H)X Example 385 trans. trans-4-(l ,3-Benzodioxol-5-yl -2-(4-methoxyphenyl)- 1 -(2-methyl- 1 ,2.3.4- tetrahydroquinolin-l-yl carbonylmethyl)pyrrolidine-3-carboxylic acid Using the procedures described in Example 1, the title compound was prepared. ^H
NMR (300 MHz, CD3OD) δ 1.03 (m, 3H), 1.10-1.45 (m, IH), 2.10-2.85 (m, 4H), 2.90-4.00
(m, IR), 3.76 (s, 1.5H), 3.77 (s, 1.5H, isomer), 5.90 (m, 2H), 6.70-7.40 (m, 11H). MS (DCI) m/e 529 (M+H)X Analysis calcd for C31H32N2O6 • 0.3 H2O: C, 69.73; H, 6.15; N, 5.25.
Found: C, 69.74; H, 6.10; N, 5.01.
Example 386 trans. trans-4- 1 ,3-Benzodioxol-5-yl)-2-(4-methoxyphenyl)-l -(3-butyl-hept-2-en- 1 - yl)pyrrohdine-3 -carboxylic acid Using the procedures described in Example 1, the title compound was prepared. H NMR (300 MHz, CD3OD) δ 0.86 (t, J=7.0 Hz, 3H), 0.90 (t, J=7.0 Hz, 3H), 1.20-1.41 (m,
8H), 1.95-2.06 (m, 4H), 3.24 (d, J=11.0 Hz, IH), 3.51-3.59 (m, 3H), 3.60-3.71 (m, IH), 3.77-3.84 (m, IH), 3.81 (s, 3H), 4.45 (d, J=11.0 Hz, IH), 5.52 (t, J=7.4 Hz, IH), 5.93 (s, 2H), 6.77 (d, J=8.1 Hz, IH), 6.87 (dd, J=1.8, 8.1 Hz, IH), 6.99 (m, 3H), 7.46 (m, 2H). MS
(DCI) m/e 494 (M+H+). Anal calcd for C30H39NO5: C, 72.99; H, 7.96; N, 2.84. Found: C, 72.73; H, 7.89; N, 2.64.
Example 387 trans, trαn_.-2-.3-Fluoro-4-methoxyphenyl)-4-(l,3-benzodioxol-5-yπ-l-[2-fiSf-propyl-N-n- hexanesulfonylamino ethyl]pyrrolidine-3 -carboxylic acid Using the procedures described in Example 66, the title compound was prepared and isolated as a white sohd. m.p. 63-65 °C lR NMR (CDC , 300MHz) 0.82 (t, J=7Hz,
3H), 0.88 (t, J=6Hz, 3H), 1.23-1.47 (m, 6H), 1.44 (sextet, J=7Hz, 2H), 1.71 (quintet, J=6Hz,
2H), 2.24-2.34 (m, IH), 2.70-2.93 (m, 5H), 2.96-3.12 (m, 2H), 3.15-3.35 (m, 2H), 3.43 (dd,
J=3Hz, J=9Hz, IH), 3.52-3.59 (m, IH), 3.66 (d, J=9Hz, IH), 3.87 (s, 3H), 5.95 (s, 2H), 6.74 (d, J=8Hz, IH), 6.82 (d, J=8Hz, IH), 6.42 (t, J=8Hz, IH), 6.96 (s, IH), 7.12 (d, J=9Hz, IH),
7.17 (d, J=12Hz, IH). MS (DCI/NH3) m/e 593 (M+H)+. Example 388 tr_.?.^.trø»^-4-(1.3-Benzodioxol-5-yl -2-(4-methoxyphenylVl-(.3- pyridyl)methyl)pyrrolidine-3 -carboxylic acid Using the procedures described in Example 1, the title compound was prepared. ^H
NMR (300 MHz, CD3OD) 2.87 (m, 2H), 3.04 (dd, J=3.2, 9.7 Hz, IH), 3.21 (d, J=13.7
Hz, IH), 3.51 (m, IH), 3.76-3.85 (m, 2H), 3.79 (s, 3H), 5.90 (m, 2H), 6.71 (m, IH), 6.79
(dd, J=1.7 Hz, 7.8H), 6.94 (m, 3H), 7.36-7.45 (m, 3H), 7.81 (m, IH), 8.39 (m, IH), 8.46 (dd,
J=1.4 Hz, IH). Anal calcd for C25H24 2O5 • 0.70 H2O • 0.05 CH3CO2C2H5: C, 67.34; H, 5.79; N, 6.23. Found: C, 67.31; H, 5.63; N, 5.90.
Example 389 trans. trans-2-(n-Rexyϊ)-4-( 1.3-benzodioxol-5-yl)- 1 -(N.N-di(n-butyl)aminocarbonylmethyl)- pyrrohdine-3-carboxylic acid Using the procedures described in Example 1, the title compound was prepared. H
NMR (CDCI3, 300 MHz) 0.82-1.00 (m, 9H), 1.20-1.40 (m, 12H), 1.45-1.60 (m, 4H),
1.70-1.90 (br m, 2H), 3.10-3.46 (m, 6H), 3.65 (t, J=10.8 Hz, IH), 3.76 (t, J=11.0 Hz, IH),
3.92-4.06 (m, 2H), 4.14-4.34 (m, 2H), 5.94 (s, 2H), 6.73 (d, J=8.1 Hz, IH), 6.79 (dd, J=8.1,
1.8 Hz, IH), 6.87 (d, J=1.8 Hz, IH). MS(DCI/NH3) m/e 489 (M+H)+. Anal calcd for C28H44N2O5 • 0.9 TFA: C, 60.53; H, 7.65; N, 4.74. Found: C, 60.62; H, 7.69; N, 4.61.
Example 390 trαn_.tr-.n._'-4-(l,3-Benzodioxol-5-yl)-2-(4-methoxyphenyl)-l-(((N-(2-pentyl)-N-(4-fluoro-3- methylphenyl) amino) carbonyl)methyl)pyrrolidine-3 -carboxyHc acid Using the procedures described in Example 1 , the title compound was prepared. H
NMR (300 MHz, CD3OD) 0.92 ( , 3H), 0.97 (t, J=7.1 Hz, 3H), 1.13-1.40 (m, 4H), 2.22
(m, 3H), 2.58-2.74 (m, IH), 2.78-2.87 (m, IH), 3.09-3.25 (m, 2H), 3.39-3.60 (m, 2H), 3.70-
3.90 (m, IH), 3.80 (s, 3H), 4.70 (m, IH), 5.93 (m, 2H), 6.70-6.76 (m, IH), 6.75 (dd, J=1.4,
8.1 Hz, IH), 6.80-6.94 (m, 4H), 6.96-7.13 (m, 4H). MS (DCI.) m/e 577 (M+H+). Anal calcd for C33H37FN2O6 • 0.25 H2O: C, 68.20; H, 6.50; N, 4.82. Found: C, 68.21; H, 6.46; N, 4.74.
Example 391 trans. trans~4-( 1 ,3-Benzodioxol-5-yl)-2-(4-methoxyphenyl)- 1 -((2- pyridyl)methyl)pyrrohdine-3 -carboxylic acid Using the procedures described in Example 1, the title compound was prepared. H
NMR (300 MHz, CD3OD) 2.97 (dd, J=7.9, 9.7 Hz, IH), 3.04 (t, J=9.6 Hz, IH), 3.18 (dd,
J=4.4 Hz, 9.9H), 3.47 (d, J=14.0 Hz, IH), 3.59 (m, IH), 3.78 (s, 3H), 3.96 (d, J=9.9 Hz, IH), 3.97 (d, J=13.6 Hz, IH), 5.90 (m, 2H), 6.73 (d, J=8.1 Hz, IH), 6.83 (dd, J=1.7, 7.9 Hz, IH), 6.92 ( , 2H), 6.96 (d, J=1.8 Hz, IH), 7.28 (m, IH), 7.44 (m, 2H), 7.53 (d, J=8.1 Hz, IH),
7.80 (dt, J=1.8, 7.7 Hz, IH), 8.42 (m, IH). MS (DCI) m/e 433 (M+H+). Anal calcd for
C25H24N2O5 • 0.35 H2O: C, 68.43; H, 5.67; N, 6.38. Found: C, 68.44; H, 5.61; N, 6.24.
Example 392 trans . tr-.n5-2-(3-Phenylpropyl -4-( 1 -benzodioxol-5-yl)- 1 -(N,N-di(n- butyl)aminocarbonvhnethyl)-pyrrohdine-3-carboxy lie acid Using the procedures described in Example 1, the title compound was prepared. H
NMR (CDCI3, 300 MHz) δ 0.89-0.97 ( , 6H), 1.22-1.36 (m, 4H), 1.41-1.55 (m, 4H), 1.63- 1.95 (m, 4H), 2.62 (dt, J=7.2, 2.1 Hz, 2H), 3.05-3.44 (m, IR), 3.53-3.60 (m, 2H), 3.65-3.76
(m, IH), 3.82-3.90 (m, IH), 3.96-4.10 (m, IH), 5.92 (s, 2H), 6.71 (d, J=8.1 Hz, IH), 6.77
(dd, J=8.1, 1.5 Hz, IH), 6.86(d, J=1.2 Hz, IH), 7.10-7.28 (m, 5H). MS(DCI NH3) m e 523
(M+H)+ Anal calcd for C31H42N2O5 - 0.6 TFA: C, 65.43; H, 7.26; N, 4.74. Found: C, 65.28; H, 7.29; N, 4.50.
Example 393 tr_.?z_.-trαrø-2-(4-Methoxy-3-fluorophenyl)-4-(7-methoxy-l,3-benzodioxol-5-yl)-l-(N.N- di(n-butyl)aminocarbonylmethylVpyrrohdine-3-carboxyhc acid Using the procedures described in Example 1, the title compound was prepared and isolated as a white sohd. m.p. 115-117 °C. lR NMR (300 MHz, CDCI3) δ 0.82 (t, J=7Hz, 3H), 0.88 (t, J=7Hz, 3H), 1.05-1.5 (m, 8H), 2.85 (d, J=13Hz, IH), 2.90-3.17 (m, 5H), 3^20- 3.35 (m, IH), 3.35-3.50 (m, 3H), 3.55-3.65 (m, IH), 3.84 (d, J=10Hz, IH), 3.87 (s, 3H), 3.92 (s, 3H), 5.94 (dd, J=4Hz, 2Hz, 2H), 6.62 (s, IH), 6.70 (s, IH), 6.90 (t, J=8Hz, IH), 7.05-7.20 (m, 2H).
Example 394 trans-trans-2-( 1 ,4-Benzodioxan-6-yl , -4-(7-methoxy- 1 ,3-benzodioxol-5-yl)- 1 -(N.N-di(n- butyl)aminocarbonylmethyl)-pyrroUdine-3-carboxylic acid Using the procedures described in Example 1, the title compound was prepared and isolated as a white sohd. mp. 107-110 °C !H NMR (300 MHz, CDCI3) δ 0.82 (t, J=7Hz,
3H), 0.88 (t, J=7Hz, 3H), 1.05-1.50 (m, 8H), 2.75 (d, J=13Hz, IH), 2.90-3.12 (m, 4H), 3.32-
3.60 ( , 5H), 3.69 (d, J= 8Hz, IH), 3.90 (s, 3H), 4.23 (s, 4H), 5.95 (dd, J=4Hz, 2Hz, 2H),
6.62 (s, IH), 6.70 (s, IH), 6.78-6.93 (m ,3H).
Example 395 trøn-?Jr n5,-4-(l,3-Benzodioxol-5-yl)-2-(4-methoxyphenyl)-l-(3-butyl-2-fluoro-hept-2-en-l- yl. pyrrolidine-3 -carboxylic acid Using the procedures described in Example 1, the title compound was prepared. ^H
NMR (300 MHz, CD3OD) δ 0.84 (t, J=7.0 Hz, 3H), 0.88 (t, J=7.0 Hz, 3H), 1.16-1.37 (m, 8H), 1.83 (t, J=8.5 Hz, 2H), 2.03-2.08 (m, 2H), 2.76-2.92 (m, 2H), 3.02 (t, J=9.3 Hz, IH),
3.32-3.42 (m, 2H), 3.50 (m, IH), 3.71 (d, J=9.2 Hz, IH), 3.78 (s, 3H), 5.91 (m, 2H), 6.72 (d,
J=7.8 Hz, IH), 6.83 (dd, J=1.7, 8.1 Hz, IH), 6.90 (m, 2H), 7.02 (d, J=1.7 Hz, IH), 7.34 (m,
2H). MS (DCI) m/e 512 (M+H+). Anal calcd for C30H38FNO5: C, 70.43; H, 7.49; N, 2.74. Found: C, 70.58; H, 7.54; N, 2.66.
Example 396 tr-.n_?.trαn_.-2-(3-Fluoro-4-ethoxyphenyl)-4- i,3-benzodioxol-5-yl)-l-[2-(N-propyl-N-?.- pentanesulfonylamino ethyl]pyrrohdine-3 -carboxylic acid Using the procedures described in Example 66, the title compound was prepared and isolated as a white solid. m.p. 65-66 °C R NMR (CDCI3, 300 MHz) 0.82 (t, J=7Hz,
3H), 0.90 (t, J=7Hz, 3H), 1.26-1.36 (m, 4H), 1.41-1.52 (m, 5H), 1.73 (quintet, J=7Hz, 2H), 2.23-2.33 (m, IH), 2.69-2.96 (m, 5H), 2.97-3.12 (m, 2H), 3.16-3.37 (m, 2H), 3.43 (d, J=9Hz, IH), 3.52-3.59 (m, IH), 3.66 (d, J=9Hz, IH), 4.08 (q, J=7Hz, 2H), 5.95 (s, 2H), 6.74 (d, J=8Hz, IH), 6.82 (d, J=8Hz, IH), 6.92 (t, J=8Hz, IH), 6.97 (s, IH), 7.07 (d, J=8Hz, IH),
7.15 (d, J=12Hz, IH). MS (DCI/NH3) m/e 593 (M+H)+.
Example 397 tr-.π5,.trαrø-2-(4-Methoxy-3-fluorophenyl)-4-(7-methoxy-1.3-benzodioxol-5-yl)-l-[(N- butyl-N-propylamino)carbonylmethyl]pyrrohdine-3-carboxy lie acid Using the procedures described in Example 1, the title compound was prepared and isolated as a white solid. m.p. 118-120 °C H NMR (300 MHz, CDCI3) δ 0.70-0.90 (4 triplets, J=7Hz), 1.05-1.55 (m, 8H), 2.80-3.50 (m, 9H), 3.55-3.65 (m, IH), 3.82 (d, J= lOHz, IH), 3.85 (s, 3H), 3.92 (s, 3H), 5.96 (s, 2H), 6.62 (s, IH), 6.70 (s, IH), 6.90 (t, J=8Hz, IH), 7.08-7.22 (tn, 2H).
Example 398 trans, trans-4- 1 ,3-benzodioxol-5-yl -2-(4-methoxyphenyl)- 1 -(N-butyl-N-(4- cMorophenyl)aminocarbonyhnethyl)pyrroHdine-3-carboxylic acid Using the procedures described in Example 1, the title compound was prepared. ^H
NMR (300 MHz, CD3OD) 0.87 (t, 1=1 Hz, 3H), 1.20-1.50 (m, 4H), 2.66-4.00 (m, 9H), 3.81 (s, 3H), 5.95 (s, 2H), 6.77 (d, 1=1 Hz, IH), 6.85 (d, J=8 Hz, 3H), 7.05 (m, 5H), 7.33- 7.42 (m, 2H). MS (CI,) m/e 565 (M+H). Analysis calcd for C31H33N2O6CI • 0.25 H3PO4: C, 63.16; H, 5.77; N, 4.75. Found: C, 63.14; H, 5.59; N, 4.53.
Example 399 trø??^.trα?.^-4-(l,3-Benzodioxol-5-yl)-2-.4-methoxyphenyl)-l-(4-methyl-1.2.3.4- tetrahydro quinolin- 1 -yl)carbonylmethyl)pyrrolidine-3-carboxylic acid Using the procedures described in Example 1, the title compound was prepared. H
NMR (300 MHz, CD3OD) δ 1.27 (d, 1=1 Hz, 1.5H), 1.28 (d, 7H, 1.5-diastereomer), 1.39-
1.55 (m, IH), 2.02-2.15 (m, IH), 2.60-3.25 (m, 5H), 3.33-4.00 ( , 5H), 3.78 (s, 3H), 5.92 (d, 1=3 Hz, 2H), 6.73 (dd, J=8 Hz, IH), 6.75-6.90 (m, 3H), 6.91-7.35 (m, 7H). MS (DCI) m/e 529 (M+H)+. Analysis calcd for C31H32N2O6: C, 70.44; H, 6.10; N, 5.30. Found: C, 70.16; H, 6.04; N, 5.04.
Example 400 trαrø.trαrø-2-(3-Fluoro-4-methoxyphenyl)-4-π,3-benzodioxol-5-yl)-l-[2-(N-propyl-N-(2-
(piperidin-l-yl)ethanesulfonylamino)ethyl]pyrrohdine-3-carboxylic acid Using the procedures described in Example 66, the title compound was prepared and isolated as a white sohd. mp. 95-96 °C 1HNMR (CDCI3, 300MHz) δ 0.82 (t, J=7Hz,
3H), 1.43-1.55 (m, 4H), 1.63-1.72 (m, 4H), 2.29-2.38 (m, IH), 2.64-2.78 (m, 5H), 2.87 (t, J=8Hz, IH), 2.95-3.04 (m, 5H), 3.20-3.30 ( , IH), 3.32-3.43 (m, 4H), 3.54-3.63 (m, IH),
3.78 (d, J=8Hz, IH), 3.87 (s, 3H), 5.92 (s, 2H), 6.72 (d, J=8Hz, IH), 6.78 (dd, J=2Hz,
J=8Hz, IH), 6.88 (t, J=8Hz, IH), 6.94 (d, J=2Hz, IH), 7.08-7.20 (m, 2H). MS (DCI/NH3) m/e 620 (M+H)+.
Example 401 trans, tr-.n,s-2-(;.-HeptvD-4-(l ,3-benzodioxol-5-yl)- 1 -(N,N-di(n- butyl) amino carbonylmethy l)-pyrrohdine-3 -carboxylic acid Using the procedures described in Example 1, the title compound was prepared. XH
NMR (CDCI3, 300 MHz) δ 0.83-0.98 (s, 9H), 1.18-1.40 (m, 14H), 1.44-1.60 (m, 4H), 1.72- 1.96 (br m, 2H), 3.12-3.45 (m, 6H), 3.65 (t, J = 10.5 Hz, IH), 3.76 (t, J = 11.2 IH), 3.90-
4.06 (m, 2H), 4.13-4.33 (m, 2H), 5.93 (s, 2H), 6.73 (d, J = 7.8 Hz, IH), 6.79 (dd, J = 7.8, 1.7
Hz, IH), 6.87 (d, J = 1.7 Hz, IH). MS(DCI/NH3) m e 503 (M+H)+. Anal calcd for C29H46N2O5 • 0.75 TFA: C, 62.28; H, 8.01; N, 4.76. Found: C, 62.20; H, 7.99; N, 4.50.
Example 402 trans. trans-4-(l ,3-Benzodioxol-5-yl)-2-(4-methoxyphenyl)- 1 -(3-methyl- 1.2.3.4- tetrahydroquinohn-l-yl)carbonylmethyl)pyrrohdine-3-carboxylic acid Using the procedures described in Example 1, the title compound was prepared. 1H
NMR (300 MHz, CD3OD) δ 0.99 (d, 1.5H), 1.03 (d, 1=6 Hz, 1.5H, second diastereomer), 2.60-4.00m (12), 3.78 (s, 1.5H), 3.79 (s, 1.5H, second diastereomer), 5.92 (s, IH), 5.93 (s, 1H, diastereomer), 6.65-7.40 (m, 11H). MS (DCI) m/e 529 (M+H)+ Analysis calcd for C31H32N2O6 O.8 H2O: C, 68.57; H, 6.24; N, 5.16. Found: C, 70.44; H, 6.10; N, 5.30.
Example 403 trans. trans-4-( 1 ,3-Benzodioxol-5-yl)-2-(4-methoxyphenyl - 1 -(N-butyl-N-(4- fluorophenyl)aminocarbonylmethyl)pyrrohdine-3-carboxy lie acid Using the procedures described in Example 1, the title compound was prepared. ^H
NMR (300 MHz, CD3OD) δ 0.87 (t, 1=1 Hz, 3H), 1.2-1.47 (m, 4H), 2.7 (d, J=12 Hz, IH),
2.80 (t, 1=9 Hz, IH), 3.09 (t, 1=9 Hz, IH), 3.25 (d, J=15 Hz, IH), 3.40-3.47 (m, IH), 3.49- 3.65 (m, 3H), 3.75 (d, J=12 Hz, IH), 3.80 (s, 3H), 5.94 (s, 2H), 6.72-6.86 (m, 4H), 7.00-7.15
(m, 7H). MS (DCI) m/e 549 (M+H)+ Analysis calcd for C31H33N2O6F • 0.4 H2O: C, 66.99; H, 6.13; N, 5.04. Found: C, 66.99; H, 5.94; N, 4.99.
Example 404 trαn ,Jr-. -l-(N-Butyl-N-(3-methylphenyl)aminocarbonylmethyl)-2-(4-methoxyphenyl)-4-
(5-benzofuranyl) olidine-3 -carboxylic acid Using the procedures described in Example 1 , the title compound was prepared. H
NMR (300MHz, CDCI3) δ 7.66 (lH, bs), 7.60 (IH, d, J=3Hz), 7.45 (2H, s), 7.15 (4H, m),
6.75 (5H, m), 3.96 (IH, d, J=10Hz), 3.78 (3H, s), 3.74 (lH, m), 3.59 (3H, m), 3.21 (IH, t, J=9Hz), 3.19 (IH, d, J=16Hz), 2.92 (IH, t, J=9Hz), 2.70 (IH, d, J=16Hz), 2.29 (3H, s), 1.41 (2H, m), 1.24 (2H, m), 0.85 (3H, t, J=7Hz). MS (DCI, NH3) m/e 541 (M+H+).
Anal, calcd for C33H34N2O • 1 H2O: C, 71.21; H, 6.52; N 5.03. Found: C, 71.31; H, 6.30; N, 4.98.
Example 405 tr-.n^.trαnj,-l-π^-Butyl-N-(3-methylphenyl aminocarbonylmethyl)-2-(4-fluorophenyl)-4-(5- benzofuranyl pyrrohdine-3 -carboxylic acid Using the procedures described in Example 1, the title compound was prepared. H
NMR (300 MHz, CDCI3) δ 7.67 (IH, bs), 7.60 (IH, d, J=3Hz), 7.45 (2H, m), 7.18 (3H, m), 7.12 (IH, d, J=7Hz), 6.93 (2H, m), 6.76 (IH, d, J=3Hz), 6.70 (2H, bd), 4.02 (IH, m), 3.77 (lH, m), 3.59 (3H, m), 3.29 (lH, m), 3.19 (lH, m), 2.94 (IH, m), 2.71 (IH, m), 2.30 (3H, s), 1.45 (2H, m), 1.26 (2H, sext, J=7Hz), 0.84 (3H, t, J=7Hz). MS (DCI, NH3) m e 529 (M+H+). Anal, calcd for C33H34N2O5 • 0.2 HOAc: C, 71.98; H, 6.30; N 5.18. Found : C, 71.68; H, 5.89; N, 5.25.
Example 406 trans . trans-4- 1.3-Benzodioxol-5-yl)-2-(4-methoxyphenyl)- 1 -(0rfN-(di-(3 - methylphenyl)amino)carbonyl)methyl)pyrrohdine-3-carboxy lie acid Using the procedures described in Example 1, the title compound was prepared. 1H NMR (300 MHz, CD3OD) δ 2.27 (s, 6H), 2.81 (dd, J=8.1, 9.5 Hz, IH), 2.98 (d, J=15.3 Hz,
IH), 3.20 (t, J=16.6 Hz, IH), 3.47-3.60 (m, 3H), 3.80 (s, 3H), 3.85 (d, j=9.5 Hz, IH), 5.91
(s, 2H), 6.73 (d, J=7.8 Hz, IH), 6.85 (m, 3H), 6.95 (m, 4H), 7.05 (d, J=1.7 Hz, IH), 7.06-
7.24 (m, 6H). MS (DCI) m/e 579 (M+H+). Anal calcd for C35H34N2O6 - 0.15 H2O • 0.20 CH3CO2C2H5: C, 71.79; H, 6.04; N, 4.68. Found: C, 71.81; H, 5.79; N, 4.51.
Example 407 tran..,tr,.n..-4-(l,2-Dihvclrobenzofoan-5^ methylphenyl)ammo)carbonyl)methyl)pyrrohdine-3-carboxyhc acid Using the procedures described in Example 1, the title compound was prepared. 1H (300MHz; CDCI3 ) δ 7.73 (2H, m), 7.40-7.10 (4H, m), 6.92 (2H, m), 6.72 (2H, d, 1=9), 6.63
(IH, ), 5.40 (IH, ), 4.55 (2H, t, J=9), 4.30-4.10 (3H, m), 3.84 (3H, s), 3.82 (IH, ), 3.65 (IH, m), 3.39 (IH, m), 3.21 (2H, t, 1=9), 3.10-2.90 (2H, m), 2.26 (3H, s), 1.55 (2H, m), 1.45
(2H, m), 0.92 (3H, t, J=9). MS (DCI/NH3) m/e 543 (M+H+). Anal calcd for C33H38N2O5
■ 0.65 H2O: C, 71.50; H, 7.15; N, 5.05 . Found: C, 71.47; H, 6.96; N, 4.83.
Example 408 trans. tr-.??--2-(3-Fluoro-4-methoxyphenyl)-4-fl.3-benzodioxol-5-yl)-l-{2-(N-propyl-N-[2- N,N-dimethylamino)]ethanesulfonylamino)ethyl}pyrrohdine-3-carboxylic acid Using the procedures described in Example 66, the title compound was prepared and isolated as a white sohd. p. 81-82 °C lR NMR (CDCI3, 300 MHz) δ 0.80 (t, J=7Hz, 3H), 1.43 (sextet, J=7Hz, 2H), 2.15-2.24 (m, IH), 2.36 (s, 6H), 2.66-2.76 (m, IH), 2.83-3.04 (m, 6H), 3.18-3.41 (m, 5H), 3.55-3.63 (m, IH), 3.72 (d, J=8Hz, IH), 3.85 (s, 3H), 5.90 (d, J=6Hz, 2H), 6.67 (d, J=8Hz, IH), 6.78 (dd, J=2Hz, J=8Hz, IH), 6.84 (t, J=8Hz, IH), 7.94 (d, J=2Hz, IH), 7.09 (d, J=8Hz, IH), 7.20 (dd, J=2Hz, J=12Hz, IH). MS (DCI/NH3) m/e 580 (M+H)+.
Example 409 trans, trans- 1 -(N.N-Dibutylaminocarbonylmethyl)-2-(4-fluorophenylV4-(5- benzofuranyl)pyrrohchne-3-carboxylic acid Using the procedures described in Example 1 , the title compound was prepared. *H
NMR (300 MHz, CDCI3) δ 7.88 (IH, bs), 7.80 (2H, m), 7.61 (IH, d, J=3Hz), 7.55 (IH, bd,
J=8Hz), 7.46 (IH, d, J=8Hz), 7.07 (2H, t, J=8Hz), 6.76 (IH, d, J=3Hz), 5.53 (IH, bd,
J=l lHz), 4.18 (2H, m), 3.91 (3H, m), 3.55 (IH, d, J=16Hz), 3.30 (3H, m), 3.12 (IH, dd,
J=10&9Hz), 2.95 (IH, m), 1.51 (2H, m), 1.31 (4H, m), 1.12 (2H, m), 0.92 (3H, m), 0.83 (3H, t, J=7Hz). MS m/e (DCI, NH3) 595 (M+H+).
Example 410 trαn-?.tr_-n .-4-π-2-Dihydrobenzofυran-5-yl -2-(4-ethylphenyl)-l-(((N-butyl-N-f3- methylpheny 1) amino) carbonyl)methyl pyrrolidine-3 -carboxyHc acid Using the procedures described in Example 1, the title compound was prepared. H
NMR (300 MHz, CDCI3 ) δ 7.35 (2H, m), 7.20-7.00 (7H, m), 6.70 (2H, d, J=9), 5.38 (IH, m), 4.55 (2H, t, 1=9), 4.05 (IH, m), 3.64 (2H, m), 3.45 (IH, m), 3.21 (2H, t, J=9), 2.95 (IH, m), 2.75 (IH, m), 2.63 (2H, q, J=8), 2.38 (2H, m), 2.27 (3H, s), 1.43 (2H, m), 1.30 (2H, m),
1.22 (3H, t, 1=9), 0.89 (3H, t, J=9). MS (DCI/ Η3) m/e 541 (M+H+). Anal calcd for C34H40N2O4 • 1.6 AcOH: C, 70.17; H, 7.34; N, 4.40. Found: C, 70.11; H, 7.06; N, 4.80.
Example 411 trans. trans-4-( 1 ,2-Dihydrobenzofuran-5-yl -2-(4-fluorophenyl)- 1 -OrfN-difn- butyl)aminocarbonylmethyl)-pyrroHdine-3-carboxy lie acid Using the procedures described in Example 1, the title compound was prepared. *H NMR (300 MHz, CDCI3 ) δ 7.40 (2H, m), 7.28 (IH, bs), 7.18 (IH, dd, J=8, 3), 7.00 (2H, t, 1=9), 6.12 (IH, d, 1=9), 4.53 (2H, t, 1=9), 3.92 (IH, m), 3.65 (IH, m), 3.42 (3H, m), 3.19 (2H, t, J=9), 3.15-2.90 (6H, m), 1.43 (3H, m), 1.25 (3H, m), 1.10 (2H, m), 0.90 (3H, t, J=8), 0.83 (3H, t, J=8). MS (DCI/NH3) m/e 497 (M+H+). Anal calcd for C29H37FN2O4 • 0.25 H2O: C, 69.51; H, 7.54; N, 5.59. Found: C, 69.45; H, 7.60; N, 5.44.
Example 412 trans . trans-4-( 1.2-Dihydrobenzofuran-5-yl)-2-(4- fluorophenyl)- 1 -(((N-butyl-N-(3- methylphenyl) amino) carbonyl)methyl)pyrrohdine-3 -carboxyHc acid
Using the procedures described in Example 1, the title compound was prepared. ^H
NMR (300 MHz, CDCI3 ) δ 7.28 (IH, bs), 7.25-7.00 (5H, m), 6.91 (2H, m), 6.72 (3H, d,
1=9), 4.54 (2H, t, 1=9), 4.00 (IH, m), 3.60 (3H, m), 3.45 (IH, m), 3.19 (2H, t, J=9), 3.11 (2H, m), 2.84 (IH, m), 2.67 (IH, bd, J=18), 2.26 (3H,s), 1.42 (2H, m), 1.25 (2H, m), 0.88 (3H, t, J=8). MS (DCI NH3) m/e 531 (M+K.+). Anal calcd for C32H35FN2O4 • 0.25 H2O: C, 71.82; H, 6.69; N, 5.23. Found: C, 71.66; H, 6.55; N, 5.03.
Example 413 trans. tr_.m,-4-(Indan-5-yl)-2-(4-methoxyphenyI, - 1 -fN.N-di(n-butyl)aminocarbonylmethyl)- pyrroHdine-3 -carboxylic acid
Using the procedures described in Example 1 , the title compound was prepared. H
NMR (300 MHz, CDCI3 ) δ 7.32 (3H, m), 7.18 (2H, m), 6.85 (2H, d, 1=9), 3.83 (IH, m),
3.79 (3H, s), 3.67 (IH, m), 3.50-3.20 (4H, m), 3.20-2.92 (4H, m), 2.87 (5H, m), 2.79 (IH, bd, J=15), 2.06 (2H, m), 1.43 (2H, m), 1.27 (4H, m), 1.08 (2H, m), 0.88 (3H, t, J=8), 0.82 (3H, t, J=8). MS (DCI/NH3) m/e 507 (M+H+). Anal calcd for C31H42N2O4: C, 73.49; H, 8.36; N, 5.53. Found: C, 73.18; H, 8.29; N, 5.17.
Example 414 tr ?^.tr_- _.-2- 4-Methoxyphenyl)-4-(3,4-difluorophenylVl-[(N-butyl-N-(3- methylphenyl)amino.carbonylmethyl]pyrroHdine-3-carboxyHc acid Using the procedures described in Example 1 , the title compound was prepared. ^H NMR (300MHz, CDCI3) δ 0.86 (t, J=7Hz, 3H), 1.10-1.35 (m, 2H), 1.35-1.52 (m, 2H), 2.29 (s, 3H), 2.63 (d, J=13Hz, IH), 2.76 (t, J=7Hz, IH), 3.06-3.20 (m, 2H), 3.42-3.53 (m, IH), 3.50-3.64 (m, 3H), 3.80 (s, 3H), 3.86 (d, J=9Hz, IH), 6.66-6.82 (m, 4H), 7.02-7.22 (m, 6H), 7.30-7.40 (m, IH).
Example 415 tr-.w5,.trαrø-l-(N-Butyl-N-.3-cMorophenyl)aminocarbonylmethyl)-2-(4-fluorophenyl)-4-(5- bei zoiuranyl. pyrroHdine-3 -carboxylic acid Using the procedures described in Example 1, the title compound was prepared. *H
NMR (300 MHz, CDCI3) δ 7.64 (IH, d, J=2Hz), 7.61 (IH, d, J=3Hz), 7.47 (IH, d, J=8Hz),
7.41 (IH, dd, J=8&3Hz), 7.30 (IH, dt, J=8&2Hz), 7.21 (IH, d, J=8Hz), 7.19 (2H, m), 7.00
(IH, bs), 6.94 (2H, t, J=8Hz), 6.83 (IH, bd, J=8Hz), 6.74 (IH, dd, J=2&lHz), 3.96 (IH, d,
J=10Hz), 3.75 (IH, ddd, 6, 5&3Hz), 3.59 (3H, m), 3.23 (IH, t, J=10Hz), 3.18 (IH, d, J=16Hz), 2.92 (IH, dd, J=10&9Hz), 2.69 (IH, d, J=16Hz), 1.41 (2H, m), 1.23 (2H, m),
0.87 (3H, t, J=7Hz). MS (DCI, NH3) 549, 551 (M+H+). Anal, calcd for C31H30CIFN2O: C, 67.82; H, 5.51; N, 5.10. Found: C, 67.43; H, 5.33; N, 4.78.
Example 416 tr n_;.tr-.«_.-4-(1.3-Benzodioxol-5-yl)-2- 4-methoxyphenyl)-l-(((N-propyl-N-(4- phenoxybenzyl)amino)carbonyl)methyl)pyrrolidine-3-carboxylic acid Using the procedures described in Example 1, the title compound was prepared. ^H
NMR (300 MHz, CDCI3 ) δ (rotamer) 7.40-7.20 (5H, m), 7.13 (2H, m), 6.98 (2H, m), 6.93-
6.60 (7H, m), 5.93 (IH, d, 1=2), 5.88 (5.85) (IH, d, 1=2), 4.90 (4.50) (IH, d, J=15), 4.10 (4.25) (IH, d, J=15), 3.77 (3.73) (3H, s), 3.72 (IH, m), 3.60 (IH, m), 3.53-3.20 (3H, m),
3.15-2.75 (4H, m), 1.60-1.20 (2H, m), 0.83 (0.64) (3H, t, J=8). MS (DCI/NH3) m/e 623
(M+H+). Anal calcd for C37H38N2O7 .25 H2O: C, 70.85; H, 6.19; N, 4.47. Found: C, 70.68; H, 6.10; N, 4.42.
Example 417 tra..5,Jrflws-4-(1.2-Dihy(irobe_ zofar^ fluoro.-3-methylphenyπamino)carbonyl)methyl)pyrrolidine-3-carboxylic acid Using the procedures described in Example 1, the title compound was prepared. *H
NMR (300 MHz, CDCI3 ) δ 7.30 (IH, bs), 7.20-7.00 (5H, m), 6.87 (IH, m), 6.73 (2H, d,
1=9), 6.51 (IH, m), 4.81 (IH, m), 4.55 (2H, t, 1=9), 3.92 (IH, bd, J=l l), 3.60 (IH, m), 3.43
(IH, m), 3.18 (2H, t, J=9), 3.17 (IH, m), 3.06 (IH, dd, J=15, 6), 2.88 (IH, dd, J=ll, 9), 2.61
(2H, q, J=8), 2.59 (IH, m), 2.18 (3H, m), 1.40-1.10 (4H ,m), 1.22 (3H, t, 1=9), 1.00-0.80
(6H, m). MS (DCI/NH3) m/e 573 (M+H+). Anal calcd for C35H41FN2O4 • 0.75 H2O: C, 71.71; H, 7.31; N, 4.78. Found: C, 71.56; H, 7.33; N, 4.56.
Example 418 tr-.n^.trø _-2-(4-Methoxphenyl)-4-(l,3-benzodioxol-5-yl)-l-[2-(N-propyl-N-[2- pyrimidinyl] amino) ethyl]pyrroHdine-3 -carboxylic acid Ethyl 2-(4-methoxyphenyl)-4-(l,3-benzodioxol-5-yl)-l-[2-(N- propylamino)propyl]pyrroHdine-3 -carboxylate, prepared by the procedures of Example 61 B
(300 mg), 138 mg of 2-bromopyrimidine, and 150 mg of dnsopropylethylamine were heated at 95 °C for 15 hours in 2 mL of acetonitrile. The resulting intermediate trans-trans ethyl ester was isolated by chromatography on silica gel eluting with 5-10% ETOAc in CH2CI2 and hydrolyzed with NaOH in ethanol/water to give 95 mg of the title compound. 1H NMR (300 MHz, CDCI3) δ 0.82 (t, J=7Hz, 3H), 1.50 (sextet, J=7Hz, 2H), 2.15-2.30 (m, IH),
2.75-2.97 (m, 3H), 3.40-3.55 (m ,4H), 3.60-3.70 (m, 3H), 3.75 (s, 3H), 5.95 (s, 2H), 6.34 (t, J=4Hz, IH), 6.65 (d, J=8Hz, IH), 6.75-6.82 (m, IH), 6.78 (d, J=9Hz, 2H), 6.96 (d, J=2Hz, IH), 7.27 (d, J=9Hz, 2H), 8.20 (d, J=4Hz, 2H).
Example 419 tr_. ,.tr-.^-4-(1.3-Benzodioxol-5-yl)-2-(4-methoxyphenyl)-l-(3-butyl-2-chloro-hept-2-en-l- yl)pyrroHdine-3-carboxylic acid Using the procedures described in Example 1 , the title compound was prepared. H NMR (300 MHz, CD3OD) δ 0.84 (t, J=6.8 Hz, 3H), 0.88 (t, J=6.7 Hz, 3H), 1.19-1.39 (m,
8H), 2.05-2.09 (m, 2H), 2.17-2.23 (m, 2H), 2.78 (dd, J=6.6, 9.2 Hz, IH), 2.95 (t, J=9.2 Hz,
IH), 3.32-3.37 (m, 2H), 3.49 (m, IH), 3.70 (d, J=9.2 Hz, IH), 3.77 (s, 3H), 5.91 (m, 2H),
6.72 (d, J=8.1 Hz, IH), 6.85 (dd, J=1.9, 8.1 Hz, IH), 6.89 (m, 2H), 7.08 (d, J=1.5 Hz, IH),
7.36 (m, 2H). MS (DCI) m/e 528 (M+H+). Anal calcd for C30H38CINO5 • 0.25 H2O: C, 67.66; H, 7.29; N, 2.63. Found: C, 67.62; H, 7.18; N, 2.40.
Example 420 tr-.«s.trafts-4-(l,2-Dihydrobe_-Zθfuran-5^ fluoro-3-methylphenyl)amino)carbonyl methyl)pyrroHdine-3-carboxy lie acid Using the procedures described in Example 1, the title compound was prepared. ^H
NMR (300 MHz, CDCI3 ) δ 7.28 (IH, bs), 7.15 (3H, m), 6.90 (IH, m), 6.77 (2H, dd, 1=9,
3), 6.71 (2H, d, 1=9), 6.56 (IH, m), 4.80 (IH, m), 4.53 (2H, t, 1=9), 3.92 (IH, m), 3.79 (3H, s), 3.60 (IH, m), 3.45 (IH, m), 3.19 (2H, t, 1=9), 3.18 (IH, m), 3.03 (IH, dd, J=15, 6), 2.85
(IH, m), 2.55 (IH, m), 2.18 (3H, m), 1.40-1.05 (4H, m), 1.00-0.80 (6H, m). MS (DCI/NH3) m/e 575 (M+H+). Anal calcd for C34H39FN2O5 • 0.35 H2O: C, 70.29; H, 6.89; N, 4.82. Found: C, 70.37; H, 6.92; N, 4.30.
Example 421 trαn_?.trα^-4-(l,2-Dihydrobenzθ-uran-5-yl -2-(4-methoxyphenyl)-l-( (N-butyl-N- 3- cMorophenyl)amino)carbonyl)methyl)pyriOHdine-3-carboxylic acid
Using the procedures described in Example 1, the title compound was prepared. 1H
NMR (300 MHz, CDCI3 ) δ 7.29 (IH, d, J=3), 7.25-7.05 (5H, m), 6.98 (IH, bs), 6.80 (2H, m), 6.72 (2H, d, 1=9), 4.53 (2H, t, 1=9), 3.85 (IH, d, J=10), 3.79 (3H, s), 3.58 (3H, m), 3.42
(IH, dd, J=10, 6), 3.18 (4H, m), 2.87 (IH, m), 2.66 (IH, m), 1.40 (2H, m), 1.25 (2H, m), 0.86 (3H, t, J=9). MS (DCI/NH3) m/e 563 (M+H+). Anal calcd for C32H35CIN2O5 • 0.25 H2O: C, 67.72; H, 6.30; N, 4.94. Found: C, 67.72; H, 6.21; N, 4.55.
Example 422 tr w ,Jr-.^-4- i.3-Benzodioxol-5-yl)-2-(5-ethylfuran-2-yl)-l- N.N-di(n- butyl)aminocarbonylmethyl -pyrroHdine-3-carboxy lie acid Using the procedures described in Example 1, the title compound was prepared. ^H
NMR (300 MHz, CDCI3 ) δ 7.77 (IH, bs), 7.11 (IH, d, J=3), 7.02 (IH, dd, 1=9, 3), 6.82
(IH, d, 1=9), 6.52 (IH, d, 1=4), 6.08 (IH, d, 1=4), 5.98 (2H, s), 5.80 (IH, d, 1=6), 4.70 (IH, bd, J=15), 4.37 (2H, m), 3.70 (2H, m), 3.39 (2H, m), 3.20 (IH, m), 3.10-2.82 (2H, m), 2.76
(2H, q, J=8), 1.45 (2H, m), 1.32 (3H, t, 1=9), 1.30-1.10 (6H, m), 0.87 (3H, t, 1=9), 0.85 (3H, t, J=9). MS (DCI/NH3) m/e 499 (M+H+). Anal calcd for C28H38N2O6 1.75 HCl: C, 59.80; H, 7.12; N, 4.98. Found: C, 59.51; H, 6.96; N, 4.88.
Example 423 trans, trans-4-( 1 ,2-DihydiObenzofuran-5-yl -2-(4-fluorophenyl)- 1 -(((N-(2-pentyl)-N-(4- fluoro-3-methylphenyl amino)carbonyl methyl)pyrroHcHne-3-carboxylic acid Using the procedures described in Example 1, the title compound was prepared. 1H
NMR (300 MHz, CDCI3 ) δ 7.30-7.10 (4H, m), 6.92 (3H, m), 6.73 (2H, d, 1=9), 6.59 (IH, m), 4.80 (IH, m), 4.53 (2H, t, 1=9), 4.00 (IH, bd, J=10), 3.62 (IH, m), 3.45 (IH, m), 3.22
(IH, m), 3.21 (2H, t, J=9), 3.02 (IH, dd, J=15, 6), 3.85 (IH, t, J=10), 2.58 (IH, bd, J=18),
2.20 (3H, bs), 1.40-1.30 (3H, m), 1.15 (IH, m), 1.00-0.80 (6H, m). MS (DCI/ Η3) m/e 563
(M+H+). Anal calcd for C33H36F2N2O4: C, 70.44; H, 6.45; N, 4.98. Found: C, 70.06; H, 6.47; N, 4.71.
Example 424 trans. trans-4-( 1 ,2-Dihydrobenzo_ϋran-5-yl)-2-(4-fluorophenyl)- 1 -(((N-butyl-N-f 3- chlorophenyD amino) carbonyl)methyl)pyrrolidine-3 -carboxy lie acid Using the procedures described in Example 1, the title compound was prepared. 1H NMR (300 MHz, CDCI3 ) δ 7.30 (2H, m), 7.25-7.10 (4H, m), 6.95 (3H, m), 6.82 (IH, bd, 1=9), 6.73 (IH, d, 1=9), 4.55 (2H, t, 1=9), 3.92 (IH, bd, J=l l), 3.60 (3H, m), 3.43 (IH, dd, 1=9, 6), 3.21 (2H, t, 1=9), 3.16 (2H, m), 2.87 (1H, m), 2.69 (IH, m), 1.42 (2H, m), 1.26 (2H, m), 0.87 (3H, t, 1=9). MS (DCI/NΗ3) m/e 551 (M+H+). Anal calcd for C31H32CIFN2O4 • 0.25 H2O: C, 67.02; H, 5.90; N, 5.04. Found: C, 66.98; H, 5.71; N, 4.76.
Example 425 trα»-?Jrøn5,-4-. l,2-Dihy(irobenzofuran-5-yl)-2-(4-ethylphenyl)-l-(((N-butyl-N-(3- cMorophenyl)amino)carbonyl.methyl)pyrroHdine-3-carboxyHc acid Using the procedures described in Example 1, the title compound was prepared. H NMR (300 MHz, CDCI3 ) δ 7.30 (IH, m), 7.21 (IH, d, 1=9), 1.15 (2H, m), 7.09 (4H, bs),
6.96 (IH, bs), 6.80 (IH, bd, 1=9), 6.73 (IH, d, 1=9), 4.54 (2H, t, 1=9), 3.89 (IH, bd, J=ll),
3.60 (3H, m), 3.43 (IH, m), 3.22 (2H, t, 1=9), 3.18 (2H, m), 2.92 (IH, m), 2.72 (IH, m), 2.62
(2H, q, J=8), 1.41 (2H, m), 1.26 (2H, m), 1.23 (3H, t, 1=9), 0.87 (3H, t, J=9). MS
(DCI/NH3) m/e 561 (M+H+). Anal calcd for C33H37CIN2O4 • 0.25 H2O: C, 70.08; H, 6.68; N, 4.95. Found: C, 70.13; H, 6.59; N, 4.65.
Example 426 trαrø,t n_?-l-flS-Butyl-N-(3-cMorophenyl)carboxamidomethyl)-2-('4-methoxyphenyl)-4-(5- benzofuranyl)pyrroHdine-3-carboxylic acid Using the procedures described in Example 1, the title compound was prepared. H
NMR (300 MHz, CDCI3) δ 7.67 (lH, bs), 7.60 (IH, d, J=3Hz), 7.48 (IH, d, J=8Hz), 7.42
(IH, dd, J=8&3Hz), 7.29 (IH, dt, J=8&3Hz), 7.21 (IH, d, J=8Hz), 7.14 (2H, m), 6.99
(IH, bs), 6.76 (4H, m), 3.88 (IH, d, J=10Hz), 3.75 (IH, ddd, J=6, 5&3Hz), 3.59 (2H, m),
3.53 (IH, dd, J=10&3Hz), 3.22 (IH, t, J=9Hz), 3.19 (lH, m), 2.96( lH, m), 2.70 (IH, d, J=16Hz), 1.42 (2H, m), 1.26 (2H, m), 0.87 (3H, t, J=7Hz). MS (DCI, NH3) m/e 563, 561
(M+H+). Anal, calcd for C32H33CIN2O5 • 0.5 H2O: C, 67.42; H, 6.01; N, 4.91. Found: C, 67.45; H, 5.82; N, 4.68.
Example 427 trαn5,.tr_-n-.-4-(l,3-Benzodioxol-5-yl)-2-(4-methoxyphenyl)-l-(((N-cyclohexyl-N- butylamino)carbonyl)methyl)pyrroHdine-3-carboxy lie acid Using the procedures described in Example 1 , the title compound was prepared. ^H
NMR (300 MHz, CDCI3) (rotamer) δ 0.78 (0.86) (t, 3H, J=7Hz), 0.90-1.90 (envelope, 14H), 2.69 (2.80) (d, IH, J=12Hz), 2.9-3.8 (envelope, 10H), 3.78 (3.80) (s, 3H), 5.92 (s,
2H), 6.72 (d, IH, J=9Hz) 6.86 (m, 3H) 7.03 (d, IH, J=6Hz), 7.34 (m, 2H). MS (DCI/NH3) m/e 537 (M+H)+. Anal, calc'd for C31H40N2O6 • 1 H2O: C, 67.13; H, 7.63; N, 5.05. Found: C, 67.09; H, 7.34; N, 4.92.
Example 428 tr_-n ,Jrα^-4-π,3-Benzodioxol-5-yl)-2-(4-ethylphenyl)-l-(((N-(3-methylphenyl)-N- butylamino) carbonyl)methyl)pyιτoHdine-3 -carboxylic acid Using the procedures described in Example 1, the title compound was prepared. ^H
NMR (300 MHz, CDCI3) δ 0.86 (t, 3H, J=7Hz), 1.22 (t, 3H, J=7Hz), 1.25 (m, 2H), 1.43 (m, 2H), 2.26 (s, 3H), 2.6 (q, 2H, J=7Hz), 2.68 (d, IH, J=12Hz), 2.86 (t, IH, J=8Hz), 3.19 (q,
2H, J=7Hz), 3.44 (dd, IH, J= 3Hz,10Hz), 3.59 (m, 3H), 3.94 (d, IH, 9Hz), 5.92 (s, 2H), 6.75
(m, 3H), 6.86 (dd, IH, J= 2Hz, 8Hz), 7.08 (m, 6H), 7.17 (t, IH, J= 8Hz). MS (DCI/NH3) m/e 543 (M+H)+. Anal, calc'd for C33H38N2O5 • 0.60 H2O: C, 71.61; H, 7.14; N, 5.06. Found: C, 71.57; H, 6.80; N, 4.87.
Example 429 trans. trα^_. -4-(Benzofuran-5-yl)-2-f 4-ethylphenyl)- 1 -(((N-f 3-methylphenyl)-N- butylamino)carbonyl)methyl)pyrroHdine-3-carboxylic acid Using the procedures described in Example 1, the title compound was prepared. ^H NMR (300 MHz, CDCI3) δ 0.90 (t, 3H, J=7Hz), 1.30 (t, 3H, J=7Hz), 1.31 (m, 2H), 1.43 (m,
2H), 2.27 (s, 3H), 2.73 (q, 2H, J=7Hz), 3.15 (d, 2H, J=17Hz), 3.61 (t, 2H, J= 8Hz), 3.82 (m,
2H), 4.00 (t, 1 H, 12Hz), 4.26 (m, 2H), 5.53 (br d, IH), 6.54 (br s, 2H), 6.76 (d, IH, J= 2Hz),
7.14 (m, 3H), 7.28 (s, IH), 7.40 (m, 3H), 7.48 (d, IH, J= 8Hz), 7.63 (d, IH, J=2Hz), 7.73 (s,
IH). HRMS. calc'd for C34H39N2O4 (M+H)+: 539.2910. Found: 539.2891 Example 430 tr-.?.5,.tr-??.5'-4-(1.4-Benzodioxan-6-yl)-2-(4-ethylphenyl)-l-(((N-(3-methylphenyl)-N- butylamino)carbonyl)methyl)pyrrolidine-3-carboxy lie acid Using the procedures described in Example 1, the title compound was prepared. H NMR (300 MHz, CDCI3) δ 0.87 (t, 3H, J=7Hz), 1.22 (t, 3H, J=7Hz), 1.24 (m, 2H), 1.42 (m,
2H), 2.30 (s, 3H), 2.61 (q, 2H, J=7Hz), 2.67 (d, IH, J=14Hz), 2.86 (t, IH, J= 8Hz), 3.18 (q,
2H, J=7Hz), 3.41 (dd, 1 H, J=4,10Hz), 3.59 (m, 3H), 3.93 (d, IH, J=10Hz), 4.25 (m, 4H),
6.74 (br s, 2H), 6.80 (d, IH, J=8Hz), 6.93 (dd, IH, J=2Hz,8Hz), 6.99 (d, IH, J=2Hz), 7.07
(m, 5H), 7.17 (t, IH, J=8Hz). MS (DCI/NH3) m/e 557 (M+H)X Anal, calc'd for C34H40N2O5 • 0.40 H2O: C, 72.42; H, 7.29; N, 4.97. Found: C, 72.49; H, 7.16; N, 4.62.
Example 431 trans . tr-.y._.-2-(3-Fluoro-4-methoxyphenyl)-4-( 1 ■3-benzodioxol-5-yl - 1 -[2-(N-propyl-N-2- mesitylenesulfonylamino) ethyljpyrrolidine-3 -carboxylic acid Using the procedures described in Example 66, the title compound was prepared and isolated as a white sohd. p. 80-82 °C 1H NMR (CDCI3, 300 MHz) 0.69 (t, J=7Hz, 3H), 1.37 (sextet, J=7Hz, 2H), 2.09-2.17 (m, IH), 2.24 (s, 3H), 2.53 (s, 6H), 2.54-2.64 (m, IH), 2.73-2.86 (m, 2H), 3.02 (sextet, J=7Hz, 2H), 3.13-3.28 (m, 3H)), 3.44-3.53 (m, IH), 3.57 (d, J=9Hz, IH), 3.89 (s, 3H), 5.94 (s, 2H), 6.74 (d, J=8Hz, IH), 6.78 (dd, J=2Hz, J=8Hz, IH), 6.85 (s, 2H), 6.92 (d, J=8Hz, IH), 9.94 (d, J=2Hz, IH), 7.06 (d, J=8Hz, IH),
7.13 (dd, J=2Hz, J=12Hz, IH). MS (DCI/NH3) m/e 627 (M+EQ+
Example 432 tr_-7. '.trαn '-2-(4-Methoxyphenyl)-4-(3,4-difluorophenyl)-l-[(N-butyl-N-(3- chlorophenyl)amino)carbonylmethyl]pyrroHdine-3-carboxylic acid
Using the procedures described in Example 1, the title compound was prepared. H
NMR (300 MHz, CDCI3) δ 0.86 (t, J=7Hz, 3H), 1.18-1.32 (m, 2H), 1.35-1.48 (m, 2H), 2.64
(d, J=13Hz, IH), 2.71 (t, J= 7Hz, IH), 3.08-3.18 ( , 2H), 3.42-3.48 (m, IH), 3.53-3.64 (m, 3H), 3.77 (s, 3H), 3.80 (d, J=9Hz, IH), 6.73-6.85 (m, 3H), 6.94 (s, IH), 7.04-7.40 (m, 7H).
Example 433 tr_.n5,.trα7._.-2-(3-Fluoro-4-methoxyphenyl)-4-(1.3-benzodioxol-5-ylVl-(2- N-propyl-N-(3- chloropropanesulfonyl) amino) ethyl)pyrroHdine-3 -carboxylic acid Using the procedures described in Example 1, the title compound was prepared. 1H
NMR (CD3OD, 300 MHz) δ 0.80 (t, 3H, 1=1), 1.47 (bd hex, 2H, J=8), 2.15 (pen, 2H, J=7),
2.32 (m, IH), 2.7-3.2 (m, 9H), 3.46 (dd, IH, 1=4, 10), 3.57 (m, IH), 3.64 (t, 2H, J=6), 3.67
(d, IH, 1=9), 3.86 (s, 3H), 5.92 (s, 2H), 6.74 (d, IH, J=8), 6.84 (dd, IH, 1=2, 8), 6.96 (d, IH,
1=2), 7.06 (t, IH, 1=9), 7.18 (m, 2H). MS (DCI/NH3) m/e 585 (M+H; 35C1)+; 587 (M+H;
37C1)+. Anal calcd for C27H34N2O7CIFS: C, 55.43; H, 5.86; N, 4.79. Found: C, 55.65; H, 5.81; N, 4.70.
Example 434 tr__n^.trø '-2-β-Fluoro-4-methoxyphenyl)-4-π.3-benzodioxol-5-yl)-l-(2- N-isobutyl-N-(3- chloropropanesulfonyl)amino)ethyl)pyrrolidine-3-carboxy lie acid Using the procedures described in Example 66, the title compound was prepared. 1H NMR (CD3OD, 300 MHz) δ 0.79 (d, 3H, 1=1), 0.84 (d, 3H, J=7),1.68 (hept, IH, 1=1), 2.18
(pen, 2H, 1=1), 2.8-3.4 (m, 10H), 3.5-3.8 (m, 3H), 3.65 (t, 2H, 1=6), 3.90 (s, 3H), 5.94 (s,
2H), 6.77 (d, IH, J=8), 6.87 (dd, IH, 1=2, 8), 6.99 (d, IH, 1=2), 7.13 (t, IH, J=9), 7.27 (m,
2H). MS (DCI/NH3) m/e 599 (M+H)+. Anal calcd for C28H36N2O7CIFS • 0.3 TFA: C,
54.24; H, 5.78; N, 4.42. Found: C, 54.19; H, 5.71; N, 4.01.
Example 435 trans. traπ-?-2-Propoxymethyl-4-f 1.3 -benzodioxol-5-yl)- 1 -(N.N-di. n- butyl)aminocarbonylmethyl)-pyrrolidine-3-carboxylic acid Using the procedures described in Example 1, the title compound was prepared. 1H NMR (CDCI3, 300 MHz) δ 0.87-0.98 (m, 9H), 1.21-1.39 (m, 4H), 1.43-1.57 (m, 4H), 1.58-
1.70 (m, 2H), 3.13-3.29 ( , 4H), 3.34-3.43 (m, 3H), 3.45-3.55 (m, 3H), 3.69 (dd, J = 10.2,
4.5 Hz, IH), 3.80-4.20 (m, 4H), 5.93 (s, 2H), 6.73 (d, J = 7.8 Hz, IH), 6.84 (dd, J = 8.2, 1.7
Hz, IH), 6.93 (d, J = 1.7 Hz, IH). MS(DCI/NH3) m e 477 (M+H)+. Anal calcd for
C26H40N2O6 .50 TFA: C, 60.77; H, 7.65; N, 5.25. Found: C, 60.73; H, 7.74; N, 5.22. Example 436 trαrø.trα»_.-2-(3-Fluoro-4-methoxyphenylV4-fl.3-benzodioxol-5-yl)-l-[2-(N-propyl-N-(4- methylbutanesulfonyl)amino)ethyl]pyrrolidine-3-carboxylic acid Using the procedures described in Example 66, the title compound was prepared and isolated as a white sohd. m.p. 65-67 °C ^ NMR (CDCI3, 300MHz) 0.82 (t, J=7Hz,
3H), 0.88 (d, J=5Hz, 6H), 1.46 (sextet, J=7Hz, 2H), 1.56-1.64 (m, 3H), 2.24-2.33 (m, IH),
2.68-2.93 (m, 5H), 2.98-3.12 (m, 2H), 3.15-3.35 (m, 2H), 3.43 (dd, J=3Hz, J=9Hz, IH),
3.52-3.58 (, IH), 3.65 (d, J=12Hz, IH), 3.87 (s, 3H), 5.95 (s, 2H), 6.73 (d, J=8Hz, IH), 6.82
(dd, J=2Hz, J=8Hz, IH), 6.92 (t, J=8Hz, IH), 6.97 (d, J=2Hz, IH), 7.10 (d, J=9Hz, IHz) , 7.16 (dd, J=2Hz, J=12Hz, IH). MS (DCI/NH3) m/e 579 (M+H)+.
Example 437 trans. tmfts-2- .4-Methoxy-3-fluorophenylV4-(7-methoxy- 1 ,3-benzodioxol-5-yl)- 1 -[2-(N- propyl-N-(n-pentanesulfonyl)amino ethyl]pyrrolidine-3-carboxylic acid Using the procedures described in Example 66, the title compound was prepared. H
NMR (300MHz, CDCI3) δ 0.81 (t, J=7Hz, 3H), 0.90 (t, J=9Hz, 3H), 1.25-1.35 (m, 4H), 1.44
(sextet, J=7Hz, 2H), 1.67-1.78 (m, 2H), 2.22-2.34 (m, IH), 2.30-2.95 (m, 5H), 2.95-3.10 (m,
2H), 3.15-3.33 (m, 2H), 3.45 (dd, J=3Hz, 9Hz, IH), 3.47-3.56 (m, IH), 3.65 (d, J=9Hz, IH),
3.88 (s, 3H), 3.94 (s, 3H), 5.95 (s, 2H), 6.55 (s, IH), 6.65 (s, IH), 6.92 (t, J=7H, IH), 7.11 (d, J=9Hz,lH), 7.17 (d, J=12Hz, IH).
Example 438 tr-,røJrα _.-2-(3-Fluoro-4-methoxyphenyl)-4-(1.3-benzodioxol-5-yl)-l-[2-(N-propyl-N-
(2,2,3, 3.3-pentafluoropropoxyethanesulfonyl)ammo)ethyl]pyrroHdine-3-carboxyHc acid Using the procedures described in Example 66, the title compound was prepared and isolated as a white soHd. mp. 63-64 °C ΪH NMR (CDCI3, 300MHz) 0.82 (t, J=7Hz, 3H), 1.45 (sextet, J=7Hz, 2H), 2.24-2.33 (m, IH), 2.70-2.82 (m, IH), 2.85-3.09 (m, 5H), 3.14-3.28 (m, 4H), 3.43 (dd, J-3Hz, J=9Hz, IH), 3.52-3.58 (m, IH), 3.65 (d, J=9Hz, IH), 3.87 (s, 3H), 3.92-3.98 (m, 3H), 5.94 (s, 2H), 6.74 (d, J=8Hz, IH), 6.82 (dd, J=2Hz, J=8Hz, IH), 6.92 (t, J=8Hz, IH), 6.97 (d, J=2Hz, IH), 7.10 (d, J=9Hz, IH), 7.17 (dd, J=2Hz,
J=12Hz, IH). MS (DCI/NH3) m/e 685 (M+H)+. Example 439 trans. trans-2-( 1 ,4-Benzodioxan-6-yl -4-(7-methoxy-l ,3-benzodioxol-5-yl - 1 -[2-(N-propyl- N-(n-pentanesulfonyl)amino)ethyl]pyrroHdine-3-carboxylic acid Using the procedures described in Example 66, the title compound was prepared. 1H
NMR (CDCI3) δ 0.81 (t, J=7Hz, 3H), 0.90 (t, J=7Hz, 3H), 1.23-1.36 (m, 4H), 1.45 (sextet, J=7Hz, 2H), 1.65-1.78 (m, 2H), 2.20-2.30 (m, IH), 2.30-2.95 (m, 5H), 2.95-3.10 (m, 2H), 3.15-3.35 (m, 2H), 3.42 (dd, J=3Hz, 9Hz, IH), 3.46-3.56 (m, IH), 3.59 (d, J=9Hz, IH), 3.91 (s, 3H), 4.24 (s, 4H), 5.95 (s, 2H), 6.57 (s, IH), 6.68 (s, IH), 6.82 (d, J=8Hz, IH), 6.88 (dd, J=2Hz, 8Hz, IH), 6.95 (d, J=2Hz, IH).
Example 440 tr-.π-..tr_..?-.-4-(l,3-Benzodioxol-5-yl)-2-(4-methoxyphenyl)-l-(((N-butyl-N-(4- methoxybenzyl)amino)carbonyl)methyl)pyrroHdine-3-carboxylic acid Using the procedures described in Example 1, the title compound was prepared. ^H
NMR (300 MHz, CDCI3 ) δ (rotamer) 7.32 (IH, d, J=10), 7.22 (IH, m), 7.10 (IH, d, 1=9),
7.03 (6.98) (IH, d, J=3), 6.90-6.80 (4H, m), 6.79 (2H, d, 1=9), 6.11 (IH, t, J=8), 5.85 (2H, s), 4.92 (4.10) (IH, d, J=15), 4.42 (4.22) (IH, d, J=15), 3.81 (IH, m), 3.79 (3.78) (3H, s),
3.76 (3H, s), 3.62 (IH, m), 3.43 (2H, m), 3.30-2.70 (5H, m), 1.42 (IH, m), 1.23 (2H, m), 1.01 (IH, m), 0.83 (0.75) (3H, t, J=8). MS (DCI/NΗ3) m/e 575 (M+H+). Anal calcd for C33H38N2O7 - 0.5 H2O: C, 67.91; H, 6.73; N, 4.80. Found: C, 67.78; H, 6.44; N, 4.55.
Example 441 trαn5'.tr-.»_r-2-(3-Fluoro-4-methoxyphenyl)-4-(l,3-benzodioxol-5-yl)-l-(2-(N-isobutyl-N- (pentanesulfonylamino ethyl)pyrroHdine-3-carboxy lie acid
Using the procedures described in Example 66, the title compound was prepared. 1H
NMR (CD3OD, 300 MHz) δ 0.76 (d, 3H, 1=1), 0.84 (d, 3H, 1=1), 0.92 (t, 3H, J=7), 1.36 (m,
4H),1.70 (m, 3H), 2.90 (m, 2H), 3.02 (m, 2H), 3.1-3.8 (m, 7H), 3.84 (d, 2H, J=8), 3.91 (s,
3H), 5.96 (s, 2H), 6.80 (d, IH, J=8), 6.88 (dd, IH, 1=2, 8), 7.00 (d, IH, 1=2), 1.19 (t, IH, 1=9), 7.35 (m, 2H). MS (DCI/NH3) m/e 593 (M+H)+. Anal calcd for C30H41N2O7F • 0.5 TFA: C, 57.31; H, 6.44; N, 4.31. Found: C, 57.08; H, 6.15; N, 3.95. Example 442 trans. trans-4- 1 ,3-Benzodioxol~5-yl)-2-(4-methoxyphenyl)- 1 -(N-butyl-N-(3- fluorophenylamino)carbonylmethyl pyrrolidine-3-carboxylic acid Using the procedures described in Example 1, the title compound was prepared. H
NMR (300 MHz, CD3OD) δ 0.87 (t, 1=1 Hz, 3H), 1.10-1.30 (m, 4H), 2.70-2.90 (m, 2H),
3.13 (t, J=8 Hz, IH), 3.40-3.90 (m, 6H), 3.79 (s, 3H), 5.93 (s, 2H), 6.75 (d, J=8 Hz, IH),
6.80-7.20 (m, 9H), 7.40 (m, IH). MS (DCI) m/e 549 (M+H)+. Anal calcd for
C31H33N2O6F O.8 H2O: C, 66.13; H, 6.19; N, 4.98. Found: C, 66.21; H, 5.83; N, 4.84.
Example 443 tr-.??^Jr-.»-?-4-(l,3-Benzodioxol-5-yl)-2-(4-fluorophenyl -l-(N-butyl-N-(3- chlorophenylamino) carbonylmethy l pyrroHdine-3 -carboxylic acid Using the procedures described in Example 1 , the title compound was prepared. H
NMR (300 MHz, CD3OD) δ 0.87 (t, 1=1 Hz, 3H), 1.20-1.50 (m, 4H), 2.65-2.85 (m, 2H),
3.05-3.85 (m, IR), 5.93 (s, 2H), 6.75 (d, J=8 Hz, IH), 6.85 (dd, J=8 Hz, IH), 6.90-7.10 (m,
4H), 7.10-7.25 (m, 3H), 7.33-7.45 (m, 2H). MS (DCI) m/e 553 (M+H)+. Anal calcd for C30H30N2O5FCI: C, 65.16; H, 5.47; N, 5.07. Found: C, 65.37; H, 5.41; N, 4.98.
Example 444 trα?. ,.tr-.rø-4-(l,3-Benzodioxol-5-yl)-2-(4-methoxyphenyl)-l-(((N-butyl-N-(3,4- dimethoxybenzyl)amino)carbonyl)methyl)pyrroHdine-3-carboxylic acid Using the procedures described in Example 1, the title compound was prepared. H NMR (300 MHz, CDCI3 ) δ (rotamer) 7.33 (IH, d, J=10), 7.23 (IH, m), 7.03 (6.97) (IH, d,
J=3), 6.90-6.60 (6H, m), 6.47 (IH, m), 5.93 (2H, m), 4.83 (4.09) (IH, d, J=15), 4.45 (4.22) (IH, d, J=15), 3.83 (3.86) (3H, s), 3.79 (IH, m), 3.77 (3.76) (3H, s), 3.75 (3.65) (3H, s), 3.60 (IH, m), 3.43 (2H, m), 3.28 (IH, m), 3.20-2.70 (4H, m), 1.43 (IH, m), 1.23 (2H, m), 1.02
(IH, m), 0.84 (0.77) (3H, t, J=8). MS (DCI/NΗ3) m/e 605 (M+H+). Anal calcd for C34H40N2O8: C, 67.53; H, 6.67; N, 4.63. Found: C, 67.28; H, 6.63; N, 4.38. Example 445 trαn^.trα»_.-4-(l,3-Benzodioxol-5-yl)-2-(4-methoxyphenyl)-l-(((N-butyl-N-(2- methoxybenzyl.amino)carbonyl)methyl)pyrroHdine-3-carboxylic acid Using the procedures described in Example 1, the title compound was prepared. 1H
NMR (300 MHz, CDCI3 ) δ (rotamer) 7.33 (IH, d, J=10), 7.11 (2H, m), 7.03 (IH, dd, J=8, 3), 6.90-6.60 (7H, m), 5.93 (2H, m), 4.83 (4.15) (IH, d, J=15), 4.47 (4.30) (IH, d, J=15), 3.81 (IH, m), 3.78 (3.73) (3H, s), 3.72 (3H, s), 3.59 (IH, m), 3.43 (2H, m), 3.30 (IH, m), 3.20-2.70 (4H, m), 1.42 (IH, m), 1.23 (2H, m), 1.01 (IH, m), 0.83 (0.77) (3H, t, J=8). MS (DCI/NH3) m/e 575 (M+H+). Anal calcd for C33H38N2O7: C, 68.97; H, 6.66; N, 4.87. Found: C, 68.70; H, 6.56; N, 4.61.
Example 446 tr-.» .trα»_?-4-π,3-Benzodioxol-5-yl)-2-(4-methoxyphenyl)-l-(((N-butyl-N-(3- methoxybenzyl)amino carbonyl)methyl pyrrolidine-3-carboxylic acid
Using the procedures described in Example 1 , the title compound was prepared. 1H
NMR (300 MHz, CDCI3 ) δ (rotamer) 7.31 (IH, d, J=10), 7.13 (IH, d, 1=9), 7.16 (IH, dt,
J=8, 3), 7.03 (IH, dd, J=10, 2), 6.90-6.60 (6H, m), 6.50 (IH, m), 5.94 (2H, m), 4.82 (4.19)
(IH, d, J=15), 4.50 (4.23) (IH, d, J=15), 3.78 (3.76) (3H, s), 3.77 (IH, m), 3.75 (3.67) (3H, s), 3.59 (IH, m), 3.57-3.35 (2H, m), 3.25 (IH, m), 3.20-2.70 (4H, m), 1.43 (IH, m), 1.23
(2H, m), 1.02 (IH, m), 0.84 (0.77) (3H, t, J=8). MS (DCI/NH3) m/e 575 (M+H+). Anal calcd for C33H38N2O7: C, 68.97; H, 6.66; N, 4.87. Found: C, 68.72; H, 6.55; N, 4.60.
Example 447 trans , trαn_?-2-(3-Fluoro-4-methoxyphenyl)-4-( 1 ,3 -benzodioxol-5-yl) - 1 -(2-(N-(2- methoxyethyl)-N-(3-cMoropropanesulfonyl)amino)ethyl)pyriOHdine-3-carboxyHc acid Using the procedures described in Example 66, the title compound was prepared. 1H
NMR (CD3OD, 300 MHz) δ 2.15 (pen, 2H, J=7), 2.33 (m, IH), 2.81 (m, 2H); 2.93 (t, IH,
1=9); 3.1-3.6 (m, 10H), 3.24 (s, 3H); 3.65 (t, 2H, J=6), 3.70 (d, IH, 1=9), 3.87 (s, 3H), 5.92 (s, 2H), 6.74 (d, IH, J=8), 6.84 (dd, IH, 1=2, 8), 6.97 (d, IH, 1=2), 7.07 (t, IH, 1=9), 7.17 (m, 2H). MS (DCI/NH3) m/e 601 (M+H)+. Anal calcd for C27H34N2O8CIFS: C, 53.95; H, 5.70; N, 4.66. Found: C, 53.65; H, 5.49; N, 4.26.
Example 448 tr ^.trørø-2-(3-Fluoro-4-methoxyphenyl)-4-(l,3-benzodioxol-5-yl)-l-(2-(N-(2- methoxyethyl)-N-(pentanesulfonyl)amino)ethyl)pyrroHdine-3-carboxylic acid Using the procedures described in Example 66, the title compound was prepared. 1H
NMR (CD3OD, 300 MHz) δ 0.93 ( , 3H), 1.34 (m, 4H), 1.69 ( , 2H), 2.33 (m, IH), 2.75-
3.1 (m, IR), 3.23 (s, 3H), 3.3-3.6 (m, 6H), 3.70 (d, IH, 1=9), 3.86 (s, 3H), 5.92 (s, 2H), 6.74 (d, IH, J=8), 6.84 (dd, IH, 1=2, 8), 6.97 (d, IH, J=2), 7.07 (t, IH, 1=9), 7.18 (m, 2H). MS
(DCI/NH3) m/e 595 (M+H)+. Anal calcd for C29H39N2O8FS: C, 58.57; H, 6.61; N, 4.71. Found: C, 58.21; H, 6.29; N, 4.29.
Example 449 trøn^.trø7; -4-(l,3-Benzodioxol-5-yl)-2-(4-methoxyphenyl)-l-(((K-4-heptyl)-N-(4-fluoro-3- methylphenylamino)carbonyl methyl pyrroHdine-3-carboxy lie acid Using the procedures described in Example 1, the title compound was prepared. ^H
NMR (300 MHz, CD3OD) δ 0.89 (m, 6H), 1.18-1.36 (m, 8H), 2.15 (bs, 1.5 (CH3 rotamer)),
2.28 (bs, 1.5 (CH3 rotamer)), 2.64 (t, J=14.9 Hz, IH), 2.82 (m, IH), 3.07-3.29 (m, 2H), 3.32-3.41 (m, IH), 3.53-3.60 (m, IH), 3.70-3.79 ( , IH), 3.79 (s, 3H), 4.68 (m, IH), 5.92
(m, 2H), 6.69-6.90 (m, 6H), 6.93-7.07 (m, 4H). MS (DCI) m/e 605 (M+H+). Anal calcd for C35H41FN2O6: C, 69.52; H, 6.83; N, 4.63. Found: C, 69.31; H, 6.78; N, 4.35.
Example 450 tr-.n ,.trαn^-4-(l,3-Benzodioxol-5-yl)-2-(4-methoxyphenyl.-l-(((N-(5-nonyl)-N-(4-fluoro-3- methylphenyl) amino) carbonyl)methyl)pyιτohdine-3 -carboxyHc acid Using the procedures described in Example 1, the title compound was prepared. H
NMR (300 MHz, CD3OD) δ 0.81-0.90 (m, 6H), 1.30 (m, 12H), 2.14 (s, 1.5 (CH3 rotamer)),
2.30 (s, 1.5 (CH3 rotamer)), 2.60 (t, J=14.8 Hz, IH), 2.80 (m, IH), 3.09-3.24 (m, 2H), 3.33- 3.42 (m, IH), 3.50-3.55 (m, IH), 3.65-3.77 (m, IH), 3.79 (s, 3H), 4.64 (m, IH), 5.93 (m, 2H), 6.70-6.84 (m, 5H), 6.91-7.13 (m, 5H). MS (DCI) m/e 633 (M+H+). Anal calcd for C37H45FN2O6: C, 70.23; H, 7.17; N, 4.43. Found: C, 70.14; H, 7.13; N, 4.19.
Example 451 trα i'.trø?.--4-(1.3-Benzodioxol-5-yl)-2-(4-methoxyphenyl)-l-((N-(5- nonylamino)carbonyl)methyl)pyrrolidine-3-carboxy lie acid Using the procedures described in Example 1 , the title compound was prepared. *H
NMR (300 MHz, CD3OD) δ 0.80 (t, J=7.0 Hz, 3H), 0.84 (t, J=7.1 Hz, 3H), 1.15-1.55 (m,
12H), 2.88 (d, J=15.9 Hz, IH), 3.07 (m, 2H), 3.26 (d, J=16.3 Hz, IH), 3.36 (dd, J=4.4, 9.8 Hz, IH), 3.64 (m, IH), 3.76 (m, IH), 3.79 (s, 3H), 3.98 (d, J=9.5 Hz, IH), 5.93 (m, 2H), 6.77 (d, J=7.8 Hz, IH), 6.85 (dd, J=1.7, 8.1 Hz, IH), 6.93 (m, 2H), 6.99 (d, J=1.7 Hz, IH),
7.39 (m, 2H). MS (DCI) m/e 525 (M+H+). Anal calcd for C30H46N2O6 • 0.35 H2O: C, 67.86; H, 7.73; N, 5.28. Found: C, 67.87; H, 7.63; N, 5.11.
Example 452 trans, tr-.n^.-4-(l,3-Benzodioxol-5-yl -2-(4-methoxyphenyl -l-((N-butyl-N-(2- fluorophenyl)amino)carbonylmethyl)pyrroH(Hne-3 -carboxyHc acid Using the procedures described in Example 1, the title compound was prepared. *H
NMR (300 MHz, CD3OD) δ 0.87 (dt, 1=1 Hz, 3H), 1.15-1.32 (m, 4H), 3.77 (d, 1=2 Hz, 3H), 2.65-5.92 (m, 9H), 5.93 (d, 1=4 Hz, 2H), 6.70-6.90 ( , 4H), 7.00-7.45 (m, 7H). MS (DCI) m/e 549 (M+H)+. Anal calcd for C31H33N2O6 • 0.4 H2O: C, 66.99; H, 6.13; N, 5.04.
Found: C, 67.01; H, 6.23; N, 4.68.
Example 453 trøn-?.tr_.w_.-2- 4-Methoxphenyl)-4-π,3-benzodioxol-5-yl)-l-[2-(N-propyl-N-(2- benzothiazolyl) amino)ethyl]pyrroHdine-3 -carboxylic acid The title compound was prepared by the method of Example 418, substituting 2- chlorobenzothiazole for 2-bromoρyrimidine. !H NMR (300 MHz, CDCI3) δ 0.88 (t, J=7Hz,
3H), 1.59 (sextet, J=7Hz, 2H), 2.25-2.37 (m, IH), 2.85-2.97 (m, 3H), 3.28-3.36 (m, 2H), 3.50-3.58 (m, 3H), 3.60-3.65 (m, IH), 3.67 (d, J=9Hz, 1H),3.71 (s, 3H), 5.87 (d, J=2Hz,
IH), 5.91 (d, J=2Hz, IH), 6.57 (d, J=8Hz, IH), 6.73 (dd, J=2Hz, 9Hz, IH), 6.76 (d, J=8 Hz, 2H), 6.91 (d, J=2Hz, IH), 7.01 (t, J=8Hz, IH), 7.22 (t, J=8Hz, IH), 7.29 (d, J=8Hz, 2H), 7.40 (d, J=7Hz, IH), 7.55 (d, J=7Hz, IH).
Example 454 trα?. '.tr_.n_;-2-(2-Ethoxyethyl)-4-(l,3-benzodioxol-5-yl)-l-(N,N-di(n- butyl)arninocarbonylmethyl)-pyrroHeHne-3-carboxylic acid Using the procedures described in Example 1, the title compound was prepared. ^H
NMR (CDCI3, 300 MHz) δ 0.91 (t, J = 7.4 Hz, 3H), 0.94 (t, J = 7.4 Hz, 3H), 1.19 (t, J = 7.0 Hz, 3H), 1.24-1.38 (m, 5H), 1.46-1.60 (m, 4H), 2.03-2.12 (m, 2H), 3.07 (t, J = 8.0 Hz, IH), 3.07-3.34 (m, 6H), 3.43-3.52 (m, 3H), 3.59-3.74 (m, 3H), 3.80-4.01 (m, 2H), 5.93 (s, 2H), 6.72 (d, J = 8.1 Hz, IH), 6.79 (dd, J = 8.2 Hz, 1.7 Hz, IH), 6.87 (d, J = 1.7 Hz, IH).
MS(DCI/NH3) m/e 477 (M+H)+ Anal calcd for C26H40N2O6 • 0.4 TFA: C, 61.64; H, 7.80; N, 5.36. Found: C, 61.63; H, 7.84; N, 5.29.
Example 455 trø _.Jrøn_-2- 4-Methoxy-3-fluorophenyl)-4-π,3-ber_zodioxol-5-yl)-l-[2-(N-propyl-N-(2-
(morphoHn-4-ylethyl sulfonylamino)ethyl]pyrrolidine-3-carboxylic acid Ethyl 2-(4-methoxy-3-fluorophenyl)-4-( 1 ,3-benzodioxol-5-yl)- 1 -[2-(N-propyl-N-[2- vinylsulfonyl]amino)ethyl]pyrrolidine-3-carboxylic acid, prepared by the procedures of Example 125, was reacted with excess morphoHne for 4 hours at room temperature.
ChiOmatography on silica gel eluting with EtOAc gave a 65% yield of an intermediate ethyl ester which was hydrolyzed to the title compound with NaOH in ethanol/water. 1 H NMR (300 MHz, CDCI3) δ 0.81 (t, J=7Hz, 3H), 1.46 (sextet, J=7Hz, 2H), 2.43-2.52 (m, 4H), 2.70-2.92 (m, 5H), 2.97-3.33 (m, 6H), 3.60 (dd, J=3Hz, 9Hz, IH), 3.51-3.59 (m, IH), 3.62- 3.70 (m, 5H), 3.88 (s, 3H), 5.95 (s, 2H), 6.72 (d, J=8Hz, IH), 6.70 (dd, J=2Hz, 8Hz, IH), 6.90 (t, J=9Hz, IH), 6.96 (d, J=2Hz, IH), 7.10 (d, J=8Hz, IH), 7.18 (dd, J=2Hz, 12Hz, IH).
Example 456 tr_.^,tr_-»-?-2-.3-Fluoro-4-methoxyphenyl)-4-(l,3-benzodioxol-5-ylVl-[2-(N-propyl-N- ((2,2,2-trifluoroethoxyethane)sulfonyl)amino)ethyl]pyrroHdine-3-carboxylic acid Using the procedures described in Example 66, the title compound was prepared and isolated as a white sohd. m.p. 95-96 °C !H NMR (CD3OD, 300MHz) δ 0.80 (t, J=7Hz, 3H), 1.35-1.48 (m, 2H),3.07 (sextet, J=7Hz, 2H), 3.23-3.55 (m, 8H), 3.80-3.87 (m, 2H), 3.93 (s, 3H), 3.94-4.02 (m, 4H), 4.66 (d, J=12Hz, IH), 5.96 (s, 2H), 6.83 (d, J=8Hz, IH), 6.94 (d, J=8Hz, 1H),7.06 (d, J=2Hz, IH), 7.23 (t, J=9Hz, IH), 7.43 (d, J=9Hz, IH), 7.49 (dd,
J=2Hz,J=12Hz, IH). MS (DCI/NH3) m/e 635 (M+H)+.
Example 457 trørøJr-z»_?-4-(l,3-Benzodioxol-5-yπ-2-(4-fluorophenyl)-l-(N-butyl-N-(3- methylphenyl)aminocarbonylmethyπpyrroHdine-3 -carboxyHc acid
Using the procedures described in Example 1, the title compound was prepared. 1H
NMR (300 MHz, CD3OD) δ 0.87 (t, 1=1 Hz, 3H), 1.20-1.50 (m, 4H), 2.31 (s, 3H), 2.65-
2.80 (m, 2H), 3.19 (t, 1=1 Hz, IH), 3.25 (d, J=10 Hz, IH), 3.35-3.65 (m, 4H), 3.79 (d, J=10
Hz, IH), 5.93 (s, 2H), 6.74 (d, 1=1 Hz, IH), 6.80-6.90 (m, 3H), 6.91-7.09 (m, 3H), 7.10-7.35 (m, 4H). MS (DCI) m/e 533 (M+H)X Anal calcd for C31H33N2O5F: C, 69.91; H, 6.25; N, 5.26. Found: C, 69.56; H, 6.26; N, 5.23.
Example 458 trα»-?.tr--«-?-2-(3-Fluoro-4-methoxyphenyl)-4-(l,3-benzodioxol-5-yl)-l-(2-(N-(2- methoxyethyl)-N-(butanesulfonylamino)ethyl)pyrroHdine-3-carboxy lie acid
Using the procedures described in Example 66, the title compound was prepared. ^H
NMR (CD3OD, 300 MHz) δ 0.94 (m, 3H), 1.23 (hex, 2H, J=8), 1.69 (m, 2H), 3.08 (m,2H),
3.20 (s, 3H), 3.3-3.5 (m, 10H), 3.77 (m, 2H), 3.92 (s, 3H), 4.60 (m, IH), 5.96 (s, 2H), 6.81 (d, IH, J=8), 6.88 (dd, IH, 1=2, 8), 6.99 (d, IH, 1=2), 7.22 (t, IH, J=9), 7.38 (m, 2H). MS (APCI) m/e 581 (M+H)+ Anal calcd for C28H37N2O8FS 1.1 TFA: C, 51.37; H, 5.44; N, 3.97. Found: C, 51.27; H, 5.35; N, 4.11.
Example 459 trans, trα^-2- 3-Fluoro-4-methoxyphenyl)-4-(l,3-benzodioxol-5-yl -l-[2-(N-ρropyl-N- 2- methylpropanesulfonyl) amino) ethyl]pyrroHdine-3 -carboxylic acid Using the procedures described in Example 66, the title compound was prepared and isolated as a white sohd. p. 77-78 °C R NMR (CDCI3, 300MHz) δ 0.83 (t, J=7Hz, 3H),1.06 (d, J=6Hz, 6H),1.45 (q, J=7Hz, 2H), 2.20 (septet, J=6Hz, IH), 2.26-2.36 (m, IH), 2.62-2.78 (m, 3H), 2.85-2.95 (m, 2H), 2.97-3.10 (m, 2H), 3.15-3.35 (m, 2H), 3.43 (dd, J=3Hz, J=9Hz, IH), 3.53-3.62 (m, IH), 3.66 (d, J=9Hz, IH), 3.88 (s, 3H), 5.95 (s, 2H), 6.74 (d, J=8Hz, IH), 6.82 (dd, J=2Hz, J=8Hz, IH), 6.92 (t, J=8Hz, IH), 6.97 (d, J=2Hz, IH), 7.12
(d, J=9Hz, IH), 7.18 (dd, J=2Hz, J=12Hz, IH). MS (DCI/NH3) m/e 565 (M+H)+.
Example 460 trøn ,,tr-. -4-(l,3-Benzodioxol-5-yl)-2-(4-methoxyphenyl)-l-(((N-butyl-N-(4- nitrobenzyl)amino)carbonyl)methyl)pyrroHdine-3-carboxylic acid Using the procedures described in Example 1, the title compound was prepared. H
NMR (300 MHz, CDCI3 ) δ (rotamer) 8.11 (2H, m),7.32 (3H, dd, 1=9, 2), 7.16 (7.07) (IH, bd, J=10), 6.98 (6.94) (IH, d, 1=2), 6.85 (2H, d, 1=9), 6.83-6.70 (2H, m), 5.99 (5.97) (2H, d, 1=2), 5.02 (4.18) (IH, d, J=15), 4.63 (4.38) (IH, d, J=15), 3.79 (3.77) (3H, s), 3.72 (IH, d,
J=10), 3.61 (IH, m), 3.48 (IH, bd, J=15), 3.43-3.20 (2H, m), 3.06 (2H, m), 2.90 (IH, ),
3.79 (IH, bd, J=14), 1.43 (IH, m), 1.23 (2H, m), 1.02 (IH, m), 0.84 (0.78) (3H, t, J=8). MS
(DCI/NH3) m/e 590 (M+H+). Anal calcd for C32H35N3O8: C, 65.18; H, 5.98; N, 7.13. Found: C, 65.89; H, 5.85; N, 6.85.
Example 461 trans. tr_.n^.-2-(4-EthylphenylV4-(3 ,4-difluorophenyl - 1 -(N,N-difa- butyl)aminocarbonylmethyl)-pyrroHdine-3-carboxylic acid Using the procedures described in Example 1 , the title compound was prepared. *H NMR (CD3OD, 300 MHz) δ 0.78 (t, 3H, 1=1), 0.87 (t, 3H, 1=1), 1.02 (hex, 2H, J=7), 1.22
(t, 3H, 1=1), 1.27 (m, 2H), 1.45 (m, 2H, J=7), 2.63 (q, 2H, 1=1), 2.77 (d, IH, J=14), 2.94 (dd,
IH, 1=1, 9), 3.05 (m, 3H), 3.3-3.5 m, 3H), 3.44 (d, IH, J=14), 3.66 (m, IH), 3.75 (d, IH,
J=10), 7.20 (td, 2H, J=l,8), 7.22 (m, 2H), 7.32 (td, 2H, J=l,8), 7.43 (ddd, IH, J=2,8,12).
MS (DCI/NH3) m/e 501 (M+H)+. Anal calcd for C29H38N2O3F2 • 0.6 H2O: C, 68.11; H, 7.73; N, 5.48. Found: C, 68.03; H, 7.53; N, 5.37. Example 462 trø« ,Jrø«--4-(l,3-Benzodioxol-5-yl)-2-(4-methoxyphenyl)-l-(N-butyl-N-(4-fluoro-3- methylphenyl)aminocarbonylmethyl pyrroHdine-3 -carboxyHc acid Using the procedures described in Example 1 , the title compound was prepared. 1H
NMR (300 MHz, CD3OD) δ 0.87 (t, 1=1 Hz, 3H), 1.20-1.50 (m, 4H), 2.21 (d, J=2 Hz, 3H),
2.64 (d, J=14 Hz, IH), 2.75 (dd, J=10 Hz, IH), 3.05 (t, 1=1 Hz, IH), 3.25 (d, J=15 Hz, IH), 3.35-3.70 (m, 5H), 3.77 (s, 3H), 5.92 (s, 2H), 6.70-6.92 (m, 6H), 6.96-7.10 (m, 4H). MS
(DCI) m/e 563 (M+H)+. Anal calcd for C32H35N2O6F • 0.5 H2O: C, 67.24; H, 6.35; N, 4.90. Found: C, 67.16; H, 6.06; N, 4.81.
Example 463 tr-.W5,.tr-.»i,-4-(l,3-Benzodioxol-5-yl)-2-(4-methoxyphenylVl-(N-butyl-N-((3- isopropyl)phenyl)amino)carbonylmethyl)-pyrroHdine-3-carboxy lie acid Using the procedures described in Example 1 , the title compound was prepared. *H
NMR (300 MHz, CD3OD) δ 0.87 (t, 3H), 1.17 (d, 1=1 Hz, 6H), 1.20-1.50 (m, 4H), 2.63 (d,
J=15 Hz, IH), 2.75 (t, 1=1 Hz, IH), 2.85 (m, IH), 3.00 (t, 1=1 Hz, IH), 3.25 (d, J=15 Hz,
IH), 3.40-3.70 (m, 5H), 3.75 (s, 3H), 5.90 (s, 2H), 6.65-6.80 (m, 3H), 6.71 (dt, 1=1 Hz, 3H),
7.07 (m, 3H), 7.20-7.35 (m, 2H). MS (DCI) m/e 573 (M+H)+. Anal calcd for C34H40N2O6 • 0.15 H3PO4: C, 69.52; H, 6.94; N, 4.77. Found: C, 63.31; H, 6.72; N, 4.43.
Example 464 trατ._.tr_.π_.-4-(l,3-Benzodioxol-5-yl)-2-(4-methoxyphenyl)-l-(N-butyl-N-(3- ethylphenyl)aminocarbonylmethyl)pyrrolidine-3-carboxylic acid
Using the procedures described in Example 1, the title compound was prepared. 1H
NMR (300 MHz, CD3OD) δ 0.87 (m, 1=1 Hz, 3H), 1.16 (t, 1=1 Hz, 3H), 1.20-1.47 (m, 4H),
2.50 (q, 1=1 Hz, 2H), 2.70-2.85 (m, 2H), 3.13 (t, 1=1 Hz, IH), 3.20-4.5 (m, 6H), 3.78 (s,
3H), 3.83 (d, J=8 Hz, IH), 5.92 (s, 2H), 6.72 (d, J=8 Hz, IH), 6.80-6.90 (m, 5H), 7.02-7.13 (m, 3H), 7.15-7.25 (m, 2H). MS (DCI) m/e 559 (M+H)+ Anal calcd for C33H38N2O6 • 0.3 H2O: C, 70.27; H, 6.90; N, 4.97. Found: C, 70.31; H, 6.63; N, 4.60.
Example 465 trαrø.tr-.n_.-4-(l,3-Benzodioxol-5-yl)-2-(4-ethylphenyl -l-((flS[-(3-chlorophenyl)-N- butylamino)carbonyl)methyl)pyrroHdine-3-carboxylic acid Using the procedures described in Example 1, the title compound was prepared. 1H
NMR (300 MHz, CDCI3) δ 0.87 (t, 3H, J=7Hz), 1.23 (t, 3H, J=7Hz), 1.28 (m, 2H), 1.41 (m,
2H), 2.63 (q, 2H, J=7Hz), 2.67 (m, IH), 2.92 (m, IH), 3.20 (m, 2H), 3.42 (m, 1 H), 3.60 (q, 2H, J=7Hz), 3.93 (m, IH), 5.92 (s, 2H), 6.75 (d, IH, J=8Hz), 6.84 (m, 3H), 6.95 (br s, IH),
7.02 (s, IH), 7.10 (br s, 3H), 7.25 (m, 2H). MS (APCI) m/e 563 (M+H)+. Anal, calc'd for C32H35N2O5CI • 0.80 H3PO4: C, 59.92; H, 5.88; N, 4.37. Found: C, 59.90; H, 5.83; N, 4.07.
Example 466 trans, trans-4- 1 ,4-Benzodioxan-6-yl -2-(4-ethylphenyl)- 1 -(("(N-(3-chlorophenyl)-N- butylamino)carbonyl)methyl)pyrroHdine-3-carboxylic acid Using the procedures described in Example 1, the title compound was prepared. H
NMR (300 MHz, CDCI3) δ 0.86 (t, 3H, J=7Hz), 1.23 (t, 3H, J=7Hz), 1.25 (m, 2H), 1.40 (m, 2H), 2.64 (q, 2H, J=7Hz), 2.70 (m, IH), 2.95 (m, IH), 3.20 (m, 2H), 3.40 (m, 1 H), 3.57 (m,
3H), 3.90 (m, IH), 4.25 (s, 4H), 6.80 (d, IH, J=8Hz), 6.95 (d, IH, J=2Hz), 6.95 (m, 2H),
7.07 (br s, 3H), 7.22 (m, 3H). MS (APCI) m e 577. (M+H)+. Anal, calc'd for C33H37N2O5CI • 0.85 H2O: C, 66.90; H, 6.58; N, 4.73. Found: C, 66.92; H, 6.25; N, 4.36.
Example 467 trans, trans -4-(Benzofuran-5-ylV2-(4-ethylphenyl) - 1 -(((N-(3-chlorophenyl, -N- butylamino)carbonyl)methyl)pyrroHdine-3-carboxylic acid Using the procedures described in Example 1, the title compound was prepared. *H NMR (300 MHz, CDCI3) δ 0.85 (t, 3H, J=7Hz), 1.26 (t, 3H, J=7Hz), 1.30 (m, 2H), 1.40 (m, 2H), 2.60 (q, 2H, J=7Hz), 2.72 (m, IH), 2.93 (m, IH), 3.22 (m, 2H), 3.50 (m, IH), 3.55 (m, 2H), 3.75 (m, IH), 3.90 (br d, IH), 6.75 (d, IH, J=lHz), 6.80 (br d, IH), 6.95 (br s, IH), 7.08 (m, 4H), 7.20 (t, IH, J=8Hz), 7.28 (t, IH, J=8Hz), 7.42 (m, 2H), 7.58 (d, IH, J=lHz),
7.63 (s, IH). MS (APCI) m/e 559 (M+H)+ Anal, calc'd for C33H35N2O4CI • 0.45 H2O: C, 69.88; H, 6.38; N, 4.94. Found: C, 69.83; H, 6.04; N, 4.87.
Example 468 trø^Jr ^-2-(4-Methoxy-3-fluorophenyl)-4-(7-methoxy-l,3-benzodioxol-5-yl)-l-[2-flSf- butyl-N-phenylamino) ethyl]pyrrolidme-3 -carboxylic acid Ethyl 2-(4-methoxy-3-fluorophenyl)-4-(7-methoxy-l,3-benzodioxol-5-yl)-l-[2-
(bromoethyl]-pyrroHdine-3-carboxylate, prepared using the procedures of Example 61 A
(300 mg), was reacted with N-butyl aniline (190 mg) in 1 mL of dioxane containing 130 mg of diisopropylethylamine to give the ethyl ester. The ester was hydroyzed with sodium hydroxide to give 148 mg of the title compound as a white powder. 1 H NMR (300 MHz, CDCI3) δ 0.90 (t, J=9Hz, 3H), 1.28 (sextet, J=7Hz, 2H), 1.46 (quintet, J=7Hz, 2H), 2.20- 2.32 (m, IH), 2.68-2.77 (m, IH), 2.82-2.95 (m, 2H), 3.12-3.22 (m, 2H), 3.30-3.44 (m, 3H), 3.45-3.55 (m, IH), 3.62 (d, J=9Hz, IH), 3.83 (s, 3H), 3.90 (s, 3H), 5.95 (s, 2H), 6.51 (d, J=7Hz, 2H), 6.55-6.62 ( , 2H), 6.69 (d, J=2Hz, IH), 6.84 (t, J=8Hz, IH), 7.02-7.15 (m, 3H), 7.19 (dd, J=2Hz, 12Hz, IH).
Example 469 trans . trans-4-( 1 ,4-Benzodioxan-6-yl)-2-(4-ethylphenyl)- 1 -(((N,N-di(n- butyl)aminocarbonylmethylVpyrrolicHne-3-carboxylic acid Using the procedures described in Example 1, the title compound was prepared. 1H NMR (300 MHz, CDCI3) δ 0.78 (t, 3H, J=7Hz), 0.88 (t, 3H, J=7Hz), 1.05 (q, 2H, J=7Hz),
1.23 (t, 3H, J=7Hz), 1.28 (m, 2H), 1.45 (m, 2H), 2.64 (q, 2H, J=7Hz), 2.78 (m, IH), 2.9-3.2
(envelope, 4H), 3.30 (m, IH), 3.40 (m, 3H), 3.60 (m, IH), 3.80 (m, IH), 4.25 (s, 4H), 6.80
(d, IH, J=8Hz), 6.90 (m, IH), 6.98 (d, IH, J=2Hz), 7.17 (d, 2H, J=8Hz), 7.30 (m, 2H). MS
(APCI) m/e 523 (M+H)X Anal, calc'd for C31H42N2O5 - 1.1 HOAc: C, 67.73; H, 7.94; N, 4.76. Found: C, 67.81; H, 7.55; N, 4.48. Example 470 trαπ^Jrα -?-4-π,4-Benzodioxan-6-yl)-2-(4-methoxyphenyl)-l-((N-butyl-N-(3- methylphenylamino)carbonyl)methyl)pyrrolidine-3-carboxyHc acid Using the procedures described in Example 1, the title compound was prepared. H NMR (300 MHz, CD3OD) δ 0.87 (t, 1=1.1 Hz, 3H), 1.30 (m, 2H), 1.44 (m, 2H), 2.30 (s,
3H), 2.80 (d, J=15.2 Hz, IH), 2.85 (t, J=9.3 Hz, IH), 3.19 (t, J=9.3 Hz, IH), 3.33 (d, J=10.2
Hz, IH), 3.42-3.61 (m, 3H), 3.79 (s, 3H), 3.91 (d, J=9.8 Hz, IH), 4.22 (m, 4H), 6.75-6.86
(m, 6H), 6.95 (d, J=2.0 Hz, IH), 7.09 (d, J=8.8 Hz, 2H), 7.22 (d, J=10.2 Hz, IH), 7.26 (t,
J=7.6 Hz, IH). MS (DCI) m/e 559 (M+H+). Anal calcd for C33H38N2O6 • 0.4 CH3CO2C2H5: C, 69.97; H, 6.99; N, 4.72. Found: C, 0.06; H, 6.66; N, 4.48.
Example 471 trans. trans-4-( 1 ,4-Benzodioxan-6-yl)-2-(4-methoxyphenyl)- 1 -((N-butyl-N-(3- chlorophenylamino . carbonyl)methyl)pyrπ. lidine-3 -carboxyHc acid Using the procedures described in Example 1 , the title compound was prepared. H
NMR (300 MHz, CD3OD) δ 0.87 (t, J=7.0 Hz, 3H), 1.25 (m, 2H), 1.40 (m, 2H), 2.78 (d,
J=14.6 Hz, IH), 2.86 (t, J=9.0 Hz, IH), 3.16 (t, J=9.5 Hz, IH), 3.34-3.43 (m, 2H), 3.48-3.62
(m, 3H), 3.79 (s, 3H), 3.85 (d, J=9.5 Hz, IH), 4.22 (m, 4H), 6.78 (d, J=8.5 Hz, IH), 6.81-
6.86 (m, 3H), 6.93-7.09 (m, 5H), 7.33-7.38 (m, 2H). MS (DCI) m/e 579 (M+H+). Anal calcd for C32H35CIN2O6 - 1.1 CH3CO2C2H5 - 0.15 H3PO4: C, 63.30; H, 6.46; N, 4.06. Found: C, 63.54; H, 6.09; N, 3.98.
Example 472 trørø,tr-.7;_.-4-(l,3-Benzodioxol-5-yl)-2-(4-methoxyphenyl)-l-(4-pyridylmethyl)pyrrolidine- 3 -carboxyHc acid
Using the procedures described in Example 1, the title compound was prepared. 1H
NMR (300'MHz, CD3OD) δ 2.84 (t, J=9.6 Hz, IH), 2.88 (dd, J=9.6, 7.3 Hz, IH), 3.09 (dd,
J=3.3, 9.6 Hz, IH), 3.21 (d, J=14.3 Hz, IH), 3.53 (m, IH), 3.78 (s, 3H), 3.81 (m, 2H), 5.92
(m, 2H), 6.73 (d, J=8.1 Hz, IH), 6.82 (dd, J=1.8, 8.1 Hz, IH), 6.93 (m, 2H), 6.95 (d, J=1.5 Hz, IH), 7.43 (m, 4H), 8.44 (d, J=5.2 Hz, 2H). MS (DCI) m/e 433 (M+H+). Anal calcd for C25H24 2O5 • 0.3 CH3CO2C2H5: C, 68.57; H, 5.80; N, 6.10. Found: C, 68.68; H, 5.60; N, 5.81.
Example 473 tr-.n Jr-. -.-4-(l,3-Benzodioxol-5-yl)-2-(4-methoxyphenyl)-l- (N-butyl-N-(3-tert- butylphenylamino)carbonyl)methyl)pyrroHcHne-3-carboxylic acid Using the procedures described in Example 1, the title compound was prepared. H
NMR (300 MHz, CD3OD) δ 0.88 (t, J=7.2 Hz, 3H), 1.23 (s, 9H), 1.26-1.45 (m, 4H), 2.74 (dd, J=15.1 Hz, IH), 2.84 (m, IH), 3.13 (t, J=9.0 Hz, IH), 3.29 (d, J=15.1 Hz, IH), 3.50- 3.66 (m, 4H), 3.77 (s, 3H), 3.84 (d, J=9.6 Hz, IH), 5.92 (s, 2H), 6.74 (d, J=7.7 Hz, IH), 6.79-6.85 (m, 4H), 6.86-6.90 (m, IH), 6.99 (t, J=1.8 Hz, IH), 7.06 (d, J=1.8 Hz, IH), 7.13
(m, 2H), 7.33 (t, J=7.7 Hz, IH), 7.42 (m, IH). MS (DCI) m/e 587 (M+H+). Anal calcd for C35H42N2O6: C, 71.65; H, 7.22; N, 4.77. Found: C, 71.56; H, 7.33; N, 4.69.
Example 474 tr_.n_:.trøn-.-4-(l,3-Beιιzodioxol-5-yl -2-f4-methoxyphenyl)-l-(flSl-butyl-N-(3-n- butylphenylamino)carbonyl)methyl)pyrrolidine-3-carboxylic acid Using the procedures described in Example 1, the title compound was prepared. ^H
NMR (300 MHz, CD3OD) δ 0.88 (t, J=7.3 Hz, 3H), 0.92 (t, J=7.3 Hz, 3H), 1.23-1.59 (m, 8H), 2.58 (t, JM7.6 Hz, 2H), 2.75 (d, J=15.3 Hz, IH), 2.80 (dd, J=8.5, 9.5 Hz, IH), 3.12 (t, J=9.3 Hz, IH), 3.29 (d, J=15.6 Hz, IH), 3.46 (dd, J=4.9, 9.7 Hz, IH), 3.52-3.64 (m, 3H), 3.78 (s, 3H), 3.83 (d, J=9.8 Hz, IH), 5.92 (s, 2H), 6.74 (d, J=8.1 Hz, IH), 6.79-6.87 (m, 4H), 7.05 (d, J=1.7 Hz, IH), 7.10 (d, J=8.8 Hz, 2H), 7.20 (d, 7.8H), 7.29 (t, J=7.6 Hz, IH). MS
(DCI) m/e 587 (M+H+). Anal calcd for C35H42N2O6: C, 71.65; H, 7.22; N, 4.77. Found: C, 71.33; H, 7.28; N, 4.74.
Example 475 tr-.7Z-?Jr_.?._.-4-(3,4-Difluorophenyl)-2-(4-ethylphenyl.-l-(N- n-butyl -N-(3- methylphenyl)aminocarbonylmethyl)pyrroHdine-3 -carboxylic acid Using the procedures described in Example 1, the title compound was prepared. ^H
NMR (CD3OD. 300 MHz) δ 0.87 (t, 3H, 1=1), 1.19 (t, 3H, 1=1), 1.28 (m, 2H), 1.43 (m, 2H), 2.28 (s, 3H), 2.60 (q, 2H, J=7), 2.66 (m, 2H), 3.06 (m, IH), 3.21 (d, IH, 1=15), 3,42 (dd, IH, J=4,9), 3.58 (m, 3H), 3.71 (d, IH, J=9), 6.80 (s, 2H), 7.06 (s, 4H), 7.18 (m, 4H), 7.45 (m,
IH). MS (APCI) m/e 535 (M+H)+. Anal calcd for C32H36N2O3F2 • 1.3 HOAc: C, 67.83; H, 6.78; N, 4.57. Found: C, 67.83; H, 6.46; N, 4.70.
Example 476 tr-.w-?.tr_.H-?-2-(4-Ethylphenyl)-4-(3,4-difluorophenyl)-l-(N-(n-butyl)-N-(3- cMorophenyl)aminocarbonylmethyl)pyrroHdine-3-carboxy lie acid Using the procedures described in Example 1, the title compound was prepared. 1H NMR (CD3OD, 300 MHz) δ 0.82 (t, 3H, 1=1), 1.16 (t, 3H, J=7), 1.23 (m, 2H), 1.35 (m, 2H),
2.55 (q, 2H, J=7), 2.66 (m, 2H), 3.01 (t, IH, 1=9), 3.16 (d, IH, J=15), 3.32 (dd, IH, J=4,9),
3.56 ( , 3H), 3.67 (d, IH, 1=9), 6.94 (d, IH, 1=1), 7.02 (m, 5H), 7.14 (m, 2H), 7.32 (m, 3H).
MS (APCI) m/e 555 (M+H)X Anal calcd for C31H33N2O3CIF2 • 0.6 TFA: C, 61.88; H, 5.42; N, 4.48. Found: C, 61.90; H, 5.62; N, 3.98.
Example 477 tr-ϋn_.Jrαπ.s'-4-(l,4-Benzodioxan-6-yl)-2-(4-fluorophenyl)-l-(N-butyl-N-(3- chlorophenyl) amino carbonylmethy l)pyrrolicHne-3 -carboxylic acid Using the procedures described in Example 1, the title compound was prepared. H NMR (300 MHz, CD3OD) δ 0.87 (t, 1=1 Hz, 3H), 1.10-1.30 (m, 4H), 2.60-2.75 (m, 2H),
3.03 (t, 1=1 Hz, IH), 3.15-3.75 (m, 6H), 4.02 (m, 4H), 6.75 (d, J=6 Hz, IH), 6.85 (dd, 1=1
Hz, IH), 6.90 (7.19, J=m Hz, 6H), 7.32-7.43 (m, 3H). MS (DCI) m/e 567 (M+H)+. Anal calcd for C31H32N2O5FCI • 1.6 H2O: C, 62.49; H, 5.95; N, 4.70. Found: C, 62.20; H,
5.54; N, 4.42.
Example 478 trans. tr-.n^-4-(Benzo-uran-5-yl)-2-(4-ethylphenyl)- 1 -(N.N-di(n- butyl.aminocarbonylmethyl)-pyrroHdine-3-carboxy lie acid Using the procedures described in Example 1, the title compound was prepared. H NMR (300 MHz, CDCI3) δ 0.78 (t, 3H, J=7Hz), 0.84 (t, 3H, J=7Hz), 1.05 (q, 2H, J=7Hz),
1.21 (t, 3H, J=7Hz), 1.25 (m, 2H), 1.45 (m, 2H), 2.62 (q, 2H, J=7Hz), 2.80 (d, IH, J=13Hz), 3.0 (m, 2H), 3.15 (m, 2H), 3.35 (m, IH), 3.43 (m, 2H), 3.52 (m, IH), 4.40 (m, 2H), 6.73 (d, IH, J=lHz), 7.14 (d, 2H, J=8Hz), 7.26 (s, IH), 7.31 (d, 2H, J=8Hz), 7.44 (s, 2H), 7.60 (d,
IH, J=lHz), 7.65 (s, IH). MS (APCI) m/e 505 (M+H)+. Anal, calc'd for C31H40N2O4: C, 73.78; H, 7.99; N, 5.55. Found: C, 73.69; H, 7.97; N, 5.21.
Example 479 trα^.tr_.» '-2-(4-Methoxy-3-fluorophenyl)-4-(7-methoxy-l,3-benzodioxol-5-yl)-l-[2-(N- propyl-N-(pyrroHdine-l-carbonylmethyl)amino)ethyl]pyrroHdine-3-carboxy lie acid Ethyl 2-(4-methoxy-3-fluorophenyl)-4-(7-methoxy-l,3-benzodioxol-5-yl)-l-[2-(N- propyl-aminoethyl]-pyrroHdine-3 -carboxylate, prepared according to the procedures of
Example 61B (300 mg), N-bromoacetyl pyrrroHdine (132 mg) and dnsopropylethylamine
(154 mg) were heated for 1 hour at 50 °C in 1 mL of acetonitrile to give the intermediate ethyl ester. The ester was hydrolyzed to the title compound by the method of Example ID.
1H NMR (300 MHz, CDCI3) δ 0.88 (t, J=7Hz, 3H), 1.30-1.45 (m, 2H), 1.75-1.92 (m, 4H), 2.30-2.40 (m, IH), 2.47-2.58 (m, 2H), 2.70-3.00 (m, 5H), 3.24-3.45 (m, 6H), 3.50-3.70'(m, 2H), 3.83 (s, 3H), 3.86 (d, J=9Hz, IH), 3.88 (s, 3H), 5.93 (s, 2H), 6.58 (d, J=2Hz, IH), 6.70 (d, J=2Hz, IH), 6.87 (t, J=8Hz, IH), 7.10 (d, J=9Hz, IH), 7.21 (dd, J=2Hz, 12Hz, IH).
Example 480 tr ^.tr-.7.-?-2- 4-Methoxyphenyl)-4-(l,3-benzodioxol-5-yl)-l-(2-((N- erhy(iroazepinylcarbonyl)- D -leucyl.arrdno)ethyl)pyrrolidine-3-carboxylic acid
Example 480A D-Leucine O-benzyl ester Tosylate salt To benzyl alcohol (8.2 g) dissolved in benzene (30 mL) was added D-leucine (5.0 g) and -toluenesulfonic acid monohydrate (8.0 g). The reaction was warmed to reflux with removal of water overnight. Once TLC indicated consumption of starting material, the reaction was cooled, and the resulting sohd was filtered and washed with EtOAc to give the title compound as a white powder (14.26 g, 99%).
Example 480B N-Perhydroazepinylcarbonyl-D-Leucine O-Benzyl ester To the compound resulting from Example 480A (l.O g) dissolved in chloroform (20 mL) was added triethylamine (0.4 mL). The solution was cooled to 0 °C, and carbonyldiimidazole was added. After 1.5 hours, TLC indicated complete consumption of starting material, so hexamethylene imine (0.327 mL) was added. After 1 hour, an additional amount of hexamethylene imine (0.330 mL) was added, and the reaction was stirred at ambient temperature overnight. The solution was washed with sodium bicarbonate (2 x 20 mL), 1 N H3PO4 (2 x 20 mL), and brine (20 mL), dried over Na2SO4, decanted and evaporated. The residue was purified by flash chromatography on silica gel eluting with 25 - 50% EtOAc in hexanes to give the title compound as a crystalline sohd (0.835 g, 89%).
Example 480C N-Perhydroazepinylcarbonyl-D-Leucine To the compound resulting from Example 480B (200 mg) dissolved in dry ethanol (1.0 mL) was added 10% pahadium on carbon (10 mg). After flushing the flask with nitrogen, the reaction was stirred vigorously under an atmosphere of hydrogen for 1 hour. The reaction was filtered through infusorial earth and evaporated to give the title compound (140 mg).
Example 480D trans. trαn-.-2-(4-Methoxyphenyl)-4-( 1 ,3-benzodioxol-5-yl)- 1 -(cyanomethyl)-pyrroHdine-3- carboxylic acid ethyl ester To the compound resulting from Example 1 C (510 mg of a 50 % wt. solution in toluene) dissolved in acetonitrile (2.0 mL) was added dnsopropylethylamine (0.24 mL), followed by bromoacetonitrile (0.072 mL). After 2 hours, TLC indicated complete comsumption of starting material. The solvent was evaporated, and the residue was purified by flash chromatography on silica gel eluting with 20 - 40% EtOAc in hexanes to give the title compound as a colorless oil (0.28 g, 99%).
Example 480E trαπ ,.tr-.n_?-2-(4-Methoxyphenyl)-4-(l,3-benzodioxol-5-yl)-l-(2-aminoethyl)-pyrroHdine-3- carboxylic acid ethyl ester To the compound resulting from Example 480D (275 mg) dissolved in 10 mL each of triethylamine and ethanol was added Raney nickel catalyst (0.2 g), and the reaction was placed under a hydrogen atmosphere (4 atmospheres) for 3 days. The reaction was filtered and evaporated. The residue was dissolved in methylene chloride (10 mL) and extracted with 1 M HCl (5 x 1 mL). The combined aqueous extracts were basified and then extracted with methylene chloride (5 2 mL). The combined organic extracts were dried with MgSO4, filtered and evaporated to give the title compound as an unstable oil (0.14 g).
Example 480F trans . trα^-2-(4-Methoxyphenyl)-4-( 1 ,3-benzodioxol-5-vD- 1 - ( 2-((N-
(perhydroazepinylcarbonyl leucyl)amino)ethyl)-pyrroHdine-3-carboxylic acid, ethyl ester The compound resulting from Example 480E (0, 10 g) was dissolved in methylene chloride (3.0 mL), and the compound resulting from Example 480C (0.07 g) was added. The solution was cooled to 0 °C, and EDCI (0.052 g) was added. After 4 hours, the reaction was evaporated and partitioned between water (1 mL), and EtOAc (10 mL). The orgainc solution was washed with water (1 mL) and brine (1 mL), dried over MgSO4, filtered and evaporated. The residue was purified by flash chromatography on silica gel eluting with 50 - 60% EtOAc in hexanes to give the title compound as a colorless oil (0.075 g, 48%).
Example 480G t n ..tr 7. '-2-(4-Methoxyphenyl)-4-(l,3-benzo(Hoxol-5-yl)-l-(2-((N- (perhydroazepinylcarbonyl)leucyl)amino)ethyl)pyrroHdine-3-carboxylic acid The compound resulting from Example 480F (0.75 g) was dissolved in ethanol (1.0 mL) and 5 M NaOH (0.050 mL) was added. After 2 hours, additional 5 M NaOH (0.090 mL) was added. After an additional 3.5 hours, the reaction was evaporated. The residue was dissolved in water (5 mL) and washed with diethyl ether (2 x 2 mL). The aqueous solution was acidified with 1 N H3PO4 to pH 3. The soHd which precipitated dissolved when the mixture was extracted with chloroform (3 x 3 mL). The chloroform extracts were washed with brine (2 mL), dried with MgSO4, filtered and evaporated to give the title compound as a tan solid (0.053 g). Purification by HPLC (Vydac mC18) eluting with a 10 - 70% gradient of CH3CN in 0.1%TFA provided suitable material (0.049 g) after lyophilization of the desired fractions. !H NMR (CDCI3, 300 MHz) 0.82 (dd, 6.4, 4.4 Hz, 6H), 0.87 (dd, J = 5.7, 5.7 Hz, 6H), 1.04-1.28 (m, 3H), 1.34-1.65 (m, 19H), 2.95 (br m, 2H), 3.15-3.40 (m, 14H), 3.40-3.55 (m, 4H), 3.58-3.68 (m, 2H), 3.70-3.76 (br m, 2H), 3.80 (s, 3H), 3.81 (s, 3H), 4.15 (br m, 2H), 5.10 (br m, 2H), 5.93 (s, 3H), 5.95 (s, 3H), 6.70-6.97 (m, 13H), 7.43-7.56 (br m, 3H), 8.2 (br s, IH), 8.5 (br s, IH). MS(DCI/NH3) m/e 623
(M+H)+ Anal calcd for C34H46N4O7 • 2.00 TFA: C, 53.65; H, 5.69; N, 6.58. Found: C, 53.66; H, 5.66; N, 6.54.
Example 481 trans. trans-4-( 1 ,3-Benzodioxol-5-yl)-2-(4-methoxyphenyl)- 1 -(N.N-di(-.- hexyl)aminocarbonylmethyl)pyrrolidine-3-carboxylic acid Using the procedures described in Example 1, the title compound was prepared. H
NMR (300 MHz, CD3OD) δ 0.80-0.95 (m, 6H), 1.0 (m, 2H), 1.07 (1.55, J=mHz, 14H),
2.70 (d, J=13 Hz, IH), 2.85-3.15 (m, 4H), 3.20-3.60 (m, 9H), 3.64 (d, J=10 Hz, IH), 3.79 (s, 3H), 5.90 (m, 2H), 6.70 (d, 8H), 1, 6.80-6.93 (m, 3H), 7.05 (2, IH), 7.35 (d, J=10 Hz, 2H).
Anal calcd for C33H46N2O6 - 1.7 H2O: C, 66.35; H, 8.34; N, 4.69. Found: C, 66.32; H,
8.04; N, 4.52.
Example 482 trαrø.trα..5,-4-(l,4-Benzodioxan-6-yl)-2-(4-fluorophenyl -l-(N-butyl-N-(3- methylphenyl)aminocarbonylmethyl)pyrrohdine-3 -carboxylic acid Using the procedures described in Example 1, the title compound was prepared. H
NMR (300 MHz, CD3OD) δ 0.87 (t, J=7 Hz, 3H), 1.20-1.35 (m, 2H), 1.35-1.40 (m, 2H),
2.32 (s, 3H), 2.55-2.70 (m, 2H), 2.97 (t, 1=1 Hz, IH), 3.22 (d, J=14 Hz, IH), 3.25-3.70 (m, 5H), 4.20 (m, 4H), 6.97 (d, 1=2 Hz, IH), 7.09 (m, 2H), 7.15-7.35 (m, 2H). MS (DCI) m/e
547 (M+H)+. Anal calcd for C32H35N2O5F • 1.2 H2O: C, 67.64; H, 6.63; N, 4.93. Found: C, 67.73; H, 6.37; N, 4.70.
Example 483 trorø.tr-.7?-.-4-(l,3-Benzodioxol-5-yl)-2-(4-methoxyphenyl)-l-(((N-butyl-N-(3- nitrobenzyl)amino)carbonyl)methyl)pyrrolidine-3-carboxylic acid Using the procedures described in Example 1, the title compound was prepared. *H
NMR (300 MHz, CDCI3 ) δ (rotamer) 8.14 (2H, m), 8.05 (7.83) (IH, m), 7.60-7.30 (3H, m), 7.13 (IH, m), 7.10-6.70 (5H, m), 5.94 (2H, m), 5.43 (5.33) (IH, d, J=12), 4.75 (IH, bd,
J=15), 4.60-4.20 (2H, m), 4.10 (2H, m), 3.80 (3.76) (3H, s), 3.75-3.40 (3H, m), 3.20-2.80
(2H, m), 1.50 (IH, m), 1.30 (IH, m), 1.20-1.00 (2H, m), 0.91 (0.78) (3H, t, J=8). MS
(DCI/NH3) m/e 590 (M+H+). Anal calcd for C32H35N3O8 • 2.1 TFA: C, 52.44; H, 4.51; N, 5.07. Found: C, 52.25; H, 4.83; N, 5.71.
Example 484 trans. trans-4-( 1 ,2-Dihydrobenzofuran-5-yl)-2-(4-ethylphenyl)- 1 -(((N-butyl-N-(3 ,4- dimethoxybenzyl) amino) carbonyl)methyl)pyrroHdine-3 -carboxylic acid Using the procedures described in Example 1, the title compound was prepared. 1H (300MHz, CDCI3 ) δ (rotamer) 7.40 (2H, m), 7.30-7.10 (4H, m), 6.90-6.70 (3H, ), 6.48
(IH, m), 5.45 (IH, m), 4.65 (IH, d, J=15), 4.57 (2H, dt, 1=9, 3), 4.40-4.00 (5H, m), 3.87 (3.85) (3H, s), 3.84 (IH, m), 3.83 (3.79) (3H, s), 3.56 (2H, m), 3.20 (2H, t, J=10), 2.90 (IH, m), 2.64 (2H, q, J=8), 1.52 (IH, m), 1.31 (2H, m), 1.22 (3H, dt, 1=9, 2), 1.07 (IH, m), 0.92
(0.78) (3H, t, J=8). MS (DCI/NH3) m/e 601 (M+H+). Anal calcd for C36H44N2O6 • 1.35 TFA: C, 61.59; H, 6.06; N, 3.71. Found: C, 61.69; H, 6.04; N, 3.63.
Example 485 trans, trans-4- 1 ,3-Benzodioxol-5-yl)-2-(4-methoxyphenyl)- 1 -(((N-butyl-N-(4- heptyl)amino)carbonyl)methyl)pyrroHdine-3-carboxylic acid Using the procedures described in Example 1, the title compound was prepared. *H
NMR (300 MHz, CD3OD) δ 0.71-1.04 (m, 11H), 1.07-1.35 (m, 6H), 1.73-1.53 (m, 4H),
2.79-3.25 (m, 5H), 3.35-3.44 (m, IH), 3.51-3.68 (m, 3H), 3.78-3.89 (m, IH), 3.79 (s, 3H),
5.92 (m, 2H), 6.74 (dd, J=1.7, 8.1 Hz, IH), 6.85 (td, J=1.7, 8.1 Hz, IH), 6.93 (m, 2H), 7.02
(dd, J=1.7, 9.5 Hz, IH), 7.36 (m, 2H). MS (CI.) m/e 553 (M+H+). Anal calcd for C32H44N2O6: C, 69.54; H, 8.02; N, 5.07. Found: C, 69.31; H, 7.89; N, 5.06. Example 486 trans, tr_zrø-2-(4-Methylcyclohexyl)-4-( 1 ,3-benzodioxol-5-yl)- 1 -(N,N-di(n- butyl)aminocarbonylnιethyl)-pyrrolidine-3-carboxylic acid Using the procedures described in Example 1, the title compound was prepared and isolated as an amorphous solid. lR NMR (CDCI3, 300 MHz) δ 0.88 (3H, d, J = 7Hz), 0.92
(3H, t, J = 7Hz), 0.96 (3H, t, J = 7Hz), 1.05 (IH, m), 1.22-1.40 (7H, m), 1.45-1.65 (6H, m), 1.67-1.84 (4H, m), 3.17-3.45 (6H, m), 3.70 (IH, brm), 3.82 (IH, dd, J = 9Hz, 15Hz), 3.86 (IH, d, J = 15Hz), 5.93 (2H, s), 6.73 (IH, d, J = 8Hz), 6.78 (IH, dd, J = 2Hz, 8Hz), 6.88
(IH, d, J = 2Hz). MS (DCI/NH3) m/e 501 (M+H)+ Anal calcd for C29H44N2O5- 0.25 CF3CO2H : C, 66.96; H, 8.43; N, 5.29. Found: C, 66.79; H, 8.60; N, 4.87.
Example 487 tr-.7.-.Jr-.w_?-2-(2-Propylpentyl)-4-(l,3-benzodioxol-5-yl)-l-(N,N-di(n- butyl)aminocarbonylmethyl)-pyrrolidine-3-carboxylic acid Using the procedures described in Example 1 , the title compound was prepared and isolated as an amorphous sohd. lR NMR (CDCI3, 300 MHz) δ 0.85 (6H, m), 0.92 (3H, t, J
= 7Hz), 0.97 (3H, t, J = 7Hz), 1.12-1.40 (13H, m), 1.42-1.68 (6H, m), 2.90 (IH, m), 3.14- 3.30 (2H, m), 3.33 (4H, m), 3.72 (IH, brm), 3.90 (IH, brm), 5.93 (2H, dd, J = 2Hz, 4Hz), 6.73 (IH, d, J = 8Hz), 6.78 (IH, dd, J = 2Hz, 8Hz), 6.88 (IH, d, J = 2Hz). MS (DCI/NH3) m/e 517 (M+H)+ Anal calcd for C3θH48N2θ5- Q.35 CF3CO2H : C, 66.24; H, 8.76; N, 5.03. Found: C, 66.26; H, 8.82; N, 4.98.
Example 488 trans. trans-4- 1 ,4-Benzodioxan-6-yl -2-(4-fluorophenylV 1 -(N,N-di(n- butyl)aminocarbonylmethyl)-pyrroHdine-3-carboxylic acid
Using the procedures described in Example 1, the title compound was prepared. *H
NMR (300 MHz, CD3OD) δ 0.83 (t, J=7 Hz, 3H), 0.89 (t, J=7 Hz, 3H), 0.90-1.17 (m, 4H),
1.20-1.65 (m, 5H), 2.77d (13, IH), 2.87 (dd, J=8, 2 Hz, IH), 2.95-3.60 (m, 7H), 3.71 (d, 1=9
Hz, IH), 4.21 (s, 4H), 6.72 (d, IH), 6.91 (dd, J=8 Hz, IH), 6.97 (d, J=2 Hz, IH), 7.05 (t, 1=1 Hz, 2H), 7.40-7.50 (m, 2H). MS (DCI) m/e 513 (M+H)X Anal calcd for C29H37N2O5F • 1.2C F3COOH: C, 58.07; H, 5.93; N, 4.31. Found: C, 57.94; H, 5.81; N, 4.56.
Example 489 tr-.n^.trørø-2-(3-Methylpentyl)-4-(l,3-benzodioxol-5-yl)-l-(N,N-di(n- butyl)aminocarbonylmethyl)-pyrroHdine-3-carboxy lie acid Using the procedures described in Example 1, the title compound was prepared and isolated as an amorphous solid. !H NMR (CDCI3, 300 MHz) δ 0.83 (3H, t, J = 7Hz), 0.85
(3H, d, J= 7Hz), 0.91 (3H, t, J = 7Hz), 0.97 (3H, t, J = 7Hz), 1.05-1.22 (2H, m), 1.22-1.41 (7H, m), 1.43-1.68 (5H, m), 1.89 (IH, m), 2.94 (IH, t, J = 6Hz), 3.15-3.27 (3H, m), 3.29-
3.60 (5H, m), 3.72 (IH, brd, J = 6Hz), 3.92 (IH, brd, J = 13.5Hz), 5.93 (2H, dd, J = 2Hz,
4Hz), 6.73 (IH, d, J = 8Hz), 6.78 (IH, dd, J = 2Hz, 8Hz), 6.88 (IH, d, J = 2Hz). MS
(DCI/NΗ3) m/e 489 (M+H)+ Anal calcd for C28H44N2O5' 0.30 CF3CO2H: C, 65.70; H, 8.54; N, 5.36. Found: C, 65.93; H, 8.81; N, 4.84.
Example 490 trørø.tr ^-2-.2-Ethylbutyl)-4-π,3-benzodioxol-5-ylVl-flSr,N-di(n- butyl) amino carbonylmethy l)-pyrroHdine-3 -carboxylic acid Using the procedures described in Example 1, the title compound was prepared and isolated as an amorphous sohd. iH NMR ^DC^, 300 MHz) 0.85 (6H, m), 0.92 (3H, t, J
= 7Hz), 0.97 (3H, t, J = 7Hz), 1.13-1.41 (13H, m), 1.43-1.72 (6H, m), 2.96 (IH, brm), 3.12-
3.52 (6H, m), 3.55-3.70 (IH, m), 3.70-3.86 (2H, m), 3.99 (IH, brm), 5.93 (2H, dd, J = 2Hz,
4Hz), 6.73 (IH, d, J = 8Hz), 6.78 (IH, dd, J = 2Hz, 8Hz), 6.88 (IH, d, J = 2Hz). MS
(DCI/NH3) m/e 489 (M+H)X Anal calcd for C28H44N2O5" 0.45 CF3CO2H: C, 64.28; H, 8.30; N, 5.19. Found: C, 64.16; H, 8.38; N, 5.08.
Example 491 trans . trans-2-(3 -Fluoro-4-methoxyphenyl)-4-( 1 ,3-benzodioxol-5-yl)- 1 - 2-(N-isobutyl-N- (butanesulfonylamino))ethyl)pyrroHdine-3-caι-boxylic acid Using the procedures described in Example 66, the title compound was prepared. *H
NMR (CD3OD, 300 MHz) 0.74 (d, 3H, 1=1), 0.83 (d, 3H, 1=1), 0.94 (t, 3H, 1=1), 1.44 (hex, 2H), 1.67 (m, 4H), 2.91 (d, 2H, J=8), 3.04 (dd, 2H, J=8,10), 3.1-3.6 (m, 5H), 3.78 (m, 2H), 3.92 (s, 3H), 4.60 (m, IH), 5.97 (s, 2H), 6.82 (d, IH, J=8), 6.89 (dd, IH, 1=2, 8), 7.01 (d, IH, 1=2), 7.22 (t, IH, 1=9), 1.39 (m, 2H). MS (ESI) m/e 579 (M+H)+.
Example 492 tr-.n^.tr-.7._.-2-(4-Methoxy-3-fluorophenyl)-4-(l,3-benzodioxol-5-yl)-l-[2-(N-propyl-N-[4- ethylpyrimidin-2-yl]amino)ethyl]pyrroHdine-3-carboxylic acid l-Dimethylamino-l-pentene-3-one, prepared by the method described in Syn.
Comm. 12 (1), 35 (1982), was converted to 2-amino-4-ethylpyrimidine with guanidine by the method of Chem. Ber. 97, 3397 (1964). This material was converted to 2-bromo-4- ethyl-pyrimidine with NaNO2 and HBr, using the method of Helv. Chi Acta 75, 1629
( 1992) . This bromopyrimidine was reacted with ethyl 2-(4-methoxphenyl)-4-( 1,3- benzodioxol-5-yl)- 1 -[2-(N-propylamino)propyl]-pyrrohdine-3-caι-boxylate, prepared using the procedures of Example 61B, using the procedure for Example 418, to give the title compound as a white powder. ΪH NMR (300 MHz, CDCI3) δ 0.83 (t, J=7Hz, 3H), 1.11 (t,
J=7Hz, 3H), 1.45 (sextet, J=7Hz, 2H), 2.18-2.27 (m, IH), 2.45 (q, J=7Hz, 2H), 2.80-2.97 (m, 3H), 3.40-3.75 (m, 7H), 3.83 (s, 3H), 5.95 (s, 2H), 6.25 (d, J=4Hz, IH), 6.68 (d, J=8Hz, IH), 6.79 (dd, J=2Hz, 8Hz, IH), 6.82 (t, J=9Hz, IH), 6.92 (d, J=2Hz, IH), 7.05 (d, J=9Hz, IH), 7.15 (dd, J=2Hz, 12Hz, IH), 8.10 (d, J=4Hz, IH).
Example 493 trans . trans-4-( 1 ,3-Benzodioxol-5-yl)-2-(4-methoxyphenyl)- 1 -((N-butyl-N-(3 ,4- dimethylphenyl amino carbonyl)methyl)pyrrolidine-3 -carboxylic acid Using the procedures described in Example 1, the title compound was prepared. ^H NMR (300 MHz, CD3OD) δ 0.87 (t, J=7.3 Hz, 3H), 1.23-1.36 (m, 2H), 1.38-1.43 (m, 2H),
2.22 (s, 3H), 2.29 (s, 3H), 2.79 (d, J=14.9 Hz, IH), 2.84 (dd, J=8.6, 9.7 Hz, IH), 3.16 (t,
J=9.5 Hz, IH), 3.32 (d, J=15.3 Hz, IH), 3.43-3.61 (m, 4H), 3.79 (s, 3H), 3.88 (d, J=9.8 Hz,
IH), 5.93 (s, 2H), 6.74 (m, 3H), 6.83 (m, 3H), 7.04 (d, J=1.7 Hz, IH), 7.11 (m, 3H). MS
(CI.) m/e 559(MH+). Anal calcd for C33H38N2O6O.3H2O: C, 70.27; H, 6.90; N, 4.97. Found: C, 70.24; H, 6.62; N, 4.58. Example 494 trαn_,tr-.7._?-2-(3-Methylpent-3-en-l-yl)-4-(l,3-benzodioxol-5-yl)-l-(N,N-di(n- butyl) amino carbonylmethyl -pyrroHdine-3 -carboxylic acid Using the procedure described in Example 1, the title compound was prepared and isolated as an amorphous sohd. 1H NMR (CDCI3, 300 MHz) 0.92 (3H, t, J = 7Hz), 0.97
(3H, t, J = 7Hz), 1.22-1.40 (5H, m), 1.44-1.61 (8H, m), 1.82 (IH, brm), 2.02 (2H, m), 3.05-
3.30 (4H, m), 3.3.8 (IH, m), 3.55 (IH, brm), 3.85 (2H, m), 4.12 (IH, brd, J = 15Hz), 5.11
(IH, dd, J = 6Hz, 12Hz), 5.93 (2H, s), 6.73 (IH, d, J = 8Hz), 6.78 (IH, dd, J = 2Hz, 8Hz),
6.88 (IH, d, J = 2Hz). MS (DCI/NH3) m/e 487 (M+H)+ Anal calcd for C28H42N2O5" 0.7 CF3CO2H : C, 62.34; H, 7.60; N, 4.95. Found: C, 62.49; H, 7.43; N, 4.73.
Example 495 l-(N-Phenylaminocarbonylmethyl)-2-r4-methoxyphenyl -4-(l,3-benzodioxol-5- yl)pyrrolidine-3-carboxylic acid
Example 495A
N-Phenylbromoacetamide To a stirred solution of aniline (7.40 mmol) in methylene chloride (25 mL) at -50 °C was added successively N.N-dnsopropylethylamine (1.58 mL, 8.14 mmol, 1.1 eq) and bromoacetyl bromide (0.72 mL, 7.40 mmol, 1 eq) such that the temperature did not exceed -
40 °C On completion of the addition, the coohng bath was removed, and the reaction mixture was allowed to warm to room temperature. After stirring for a further 30 minutes, the mixture was diluted with ether (70 mL) and poured into 1 N sodium bisulfate solution.
The phases were separated, and the upper layer was washed successively with water and brine. The organic phase was dried (Na2SO4) and the solvent evaporated to half volume, at which point the product crystaUized. The crystals were removed by vacuum filtration to afford the title compound.
Example 495B trøm.trα77^-l-flSr-Phenylaminocarbonylmethyl)-2-(4-methoxyphenyl.-4-(l,3-benzodioxol-5- yl.pyrrolidine-3 -carboxylic acid Using the procedures described in Example 1 and the compound resulting from
Exampe 495A, the title compound was prepared. !H NMR (300 MHz, CDCI3) δ 8.8 (bs,
IH) 7.49 (2H, d, J=8Hz), 7.38 (4H, m), 7.11 (IH, tt, J=8&2Hz), 6.99 (IH, d, J=2Hz), 6.91 (2H, d, J=8Hz), 6.86 (IH, d, J=2Hz), 6.81 (IH, d, J=8Hz), 5.99 (IH, d, J=2Hz), 5.98 (IH, d, J=2Hz), 3.94 (IH, d, J=10Hz), 3.78 (3H, s), 3.70 (IH, ddd, J=6, 5&3Hz), 3.42 (IH, dd, J=10&3Hz), 3.41 (IH, d,J=16Hz), 3.18 (IH, dd, J=ll&9Hz), 3.01 (IH, t,
J=10Hz), 2.93 (lH, d, J=16Hz). MS (DCI, NH3) m/e 475 (M+H+). Anal. Calc for C27H26N2O6 • 1 H2O: C, 65.85, H, 5.73, N 5.69, Found: C, 65.95, H, 5.52, N, 5.38.
Example 496 trøn^.tr-.7ϊ_:-l-(N-(2,3-Dimethylphenyl)aminocarbonylmethyl)-2-(4-methoxyphenyl)-4-(l,3- benzodioxol-5-yl)pyrroHdine-3-carboxylic acid Using the procedures described in Example 1, the title compound was prepared. 1H
NMR (300 MHz, CDCI3) δ 8.68 (IH, bs), 7.64 (d, J=8Hz), 7.38, (2H, d, J=8Hz), 7.09 (IH, t, J=8Hz), 6.97, (IH, d, J=8Hz), 6.90 (IH, d, J=2Hz), 6.88 (2H, d, J=8Hz), 6.82 (IH, dd,
J=8&3Hz), 6.76 (IH, d, J=8Hz), 5.97 (IH, d, J=2Hz), 5.96 (IH, d, J=2Hz), 3.95 (IH, d,
J=10Hz), 3.80 (3H, s), 3.70 (IH, ddd, J=6, 5&3Hz), 3.48 (IH, dd, J=10&3Hz), 3.44 (IH, d, J=16Hz), 3.18 (IH, dd, J=ll&9Hz), 3.06 (IH, t, J=10Hz), 2.96 (IH, d, J=16Hz), 2.31
(3H, s), 2.16 (3H, s). MS (DCI, NH3) m/e 503 (M+H+). Anal. Calc for 29H30N2O6 • 0.5 H2O: C, 68.09, H, 6.11, N, 5.48. Found: C, 68.13, H, 5.91, N, 5.29.
Example 497 tr n '.tr-.n^-l-(N-(2,4-DimethyIphenyl)aminocarbonylmethyl)-2-(4-methoxyphenyl)-4-(l,3- benzodioxol-5-yl)pyrroHdine-3-carboxylic acid Using the procedures described in Example 1, the title compound was prepared. *H
NMR (300 MHz, CDCI3) δ 8.60 (lH, bs), 7.78 (d, J=8Hz), 7.38, (2H, d, J=8Hz), 6.99
(IH, m), 6.95, (IH, d, J=8Hz), 6.94 (IH, d, J=2Hz), 6.88 (2H, d, J=8Hz), 6.82 (IH, dd,
J=8&3Hz), 6.77 (IH, d, J=8Hz), 5.97 (IH, d, J=2Hz), 5.96 (IH, d, J=2Hz), 3.92 (IH, d,
J=10Hz), 3.79 (3H, s), 3.68 (IH, ddd, J=6, 5&3Hz), 3.43 (IH, dd, J=10&3Hz), 3.42 (IH, d, J=16Hz), 3.18 (IH, dd, J=ll&9Hz), 3.04 (lH, t, J=10Hz), 2.95 (IH, d, J=16Hz), 2.29 (3H, s), 2.24 (3H, s). MS (DCI, NH3)'m/e 503 (M+H+). Anal. Calc for C29H30N2O6 • 0.75 H2O: C, 67.50, H, 6.15, N 5.43. Found: C, 67.42; H, 5.95; N, 5.13.
Example 498 tr-.π_..tr_.n_.-l-(N-(2,5-Dimethylphenyl.aminocarbonylmethyl)-2- 4-methoxyphenyl -4-(1.3- benzodioxol-5-yl)pyrrolidine-3-carboxylic acid Using the procedures described in Example 1, the title compound was prepared. *H
NMR (300 MHz, CDCI3) δ 8.62 (IH, bs), 7.79 (lH, bs), 7.38, (2H, d, J=8Hz), 7.03 (IH, d, J=8Hz), 6.95, (IH, d, J=8Hz), 6.94 (IH, d, J=2Hz), 6.88 (2H, d, J=8Hz), 6.82 (IH, dd, J=8&3Hz), 6.77 (IH, d, J=8Hz), 5.97 (2H, s), 3.92 (IH, d, J=10Hz), 3.78 (3H, s), 3.70
(IH, ddd, J=6, 5&3Hz), 3.48 (IH, dd, J=10&3Hz), 3.42 (IH, d, J=16Hz), 3.18 (IH, dd,
J=ll&9Hz), 3.04 (lH, t, J=10Hz), 2.95 (IH, d, J=16Hz), 2.29 (3H, s), 2.24 (3H, s). MS
(DCI, NH3) m/e 503 (M+H+). Anal. Calc for C29H30N2O6 • 0.5 H2O: C, 68.09; H, 6.11; ' N, 5.48. Found: C, 67.72; H, 5.89; N, 5.25.
Example 499 tr-.n^Jran-?-l-(N-(3,4-Dimethylphenyl)aminocarbonylmethyl)-2-(4-methoxyphenyl)-4-(l,3- benzodioxol-5-yl pyrroHdine-3-carboxylic acid Using the procedures described in Example 1, the title compound was prepared. H NMR (300 MHz, CDCI3) δ 8.73 (IH, bs), 7.38 (2H, bd, J=8Hz), 7.30, (IH, d, J=3Hz), 7.20
(IH, bs), 7.08, (IH, d, J=8Hz), 7.01 (IH, bs), 6.90 (2H, d, J=8Hz), 6.85 (IH, bs), 6.80 (IH, d, J=8Hz), 5.99 (IH, d, J=3Hz), 5.98 (IH, d, J=3Hz), 3.92 (IH, d, J=10Hz), 3.78 (3H, s),
3.70 (IH, ddd, J=6, 5&3Hz), 3.48 (IH, dd, J=10&3Hz), 3.42 (IH, d, J=16Hz), 3.18 (IH, dd, J=l l&9Hz), 3.04 (IH, t, J=10Hz), 2.95 (IH, d, J=16Hz), 2.25 (3H, s), 2.21 (3H, s). MS (DCI, NH3) m/e 503 (M+H+). Anal. Calc for C29H30N2O6 • 0.75 H2O: C, 67.50; H, 6.15; N 5.43. Found: C, 67.24; H, 5.94; N, 5.20.
Example 500 trans, trans- 1 -(N-(3 , 5-Dimethylphenyl) amino carbonylmethyl)-2- .4-methoxyphenylV 4-( 1,3- benzodioxol-5-yl)pyrroHdine-3 -carboxylic acid Using the procedures described in Example 1, the title compound was prepared. *H NMR (300 MHz, CDCI3) δ 8.75 (IH, bs), 7.35, (2H, d, J=8Hz), 7.10 (2H, s), 7.02 (IH, d, J=3Hz), 6.90 (2H, d, J=8Hz), 6.84 (IH, d, J=2Hz), 6.80, (IH, d, J=8Hz), 6.76 (IH, bs), 5.99 (IH, d, J=3Hz), 5.98 (IH, d, J=3Hz), 3.92 (IH, d, J=10Hz), 3.79 (3H, s), 3.68 (IH, ddd, J=6, 5&3Hz), 3.40 (2H, m), 3.18 (IH, dd, J=l l&9Hz), 2.98 (IH, t, J=10Hz), 2.88
(IH, d, J=16Hz), 2.3 (6H, s). MS (DCI, NH3) m/e 503 (M+H+). Anal. Calc for C29H30N2O6 • 0.5 H2O: C, 68.09; H, 6.11; N 5.48. Found: C, 67.93; H, 6.01; N, 5.19.
Example 501 Alternate Preparation of
(+)-tr-.7. .tr-.7.-?-l-(N,N-Di(n-butyl)aminocarbonylmethyl)-2-(4-methoxyphenyl)-4-(l,3- benzodioxol-5-yl)pyrroHdine-3-carboxylic acid Hydroehloride Salt
Example 501 A N, N-Dibutyl bromoacetamide
To a solution of bromoacetyl bromide (72.3 mL, 830 mmol) in toluene (500 mL) cooled to 0 °C was added a solution of dibutylamine (280.0 mL, 1.66 mol) in toluene (220 mL) via an addition funnel maintaining the reaction temperature below 10 °C. Upon completion of the addition, the reaction mixture was stirred at 0 °C for 15 minutes. A solution of 2.5% aqueous H3PO4 (500 mL) was slowly introduced, and the reaction mixture was aUowed to warm to room temperature with vigorous stirring. The solution is 2.5% phosphoric acid by weight. The layers were separated and the organic phase washed with water (500 mL) and concentrated to provide the bromoacetamide as a solution in toluene.
Example 501B
5-(2-Nitrovinγl, - 1 ,3-benzodioxole To piperonal (15.55 kg, 103.5 mol) under mechanical stirring and under nitrogen was added ammonium acetate (13.4 kg, 173.8 mol), acetic acid (45.2 kg), and nitromethane (18.4 kg, 301.4 mol) sequentially. The mixture was warmed to 70 °C. After about 30 minutes, the yellow product began to crystallize. The reaction temperature was raised to 80 °C and stirred for about 10 hours until minimal piperonal remains. The somewhat thick reaction mixture was cooled to 10 °C and filtered. The precipitate was washed with acetic acid (2 x 8 kg) and then water (2 x 90 kg). The product was dried under a nitrogen purge and then in a vacuum oven at 50 °C for 2 days to afford 15.94 kg (80%) of the title compound as a bright yellow sohd.
Example 50 IC
4-Methoxybenzoyl acetate To potassium t-amylate (25 wt %, 50.8 kg, 99.26 mol) in toluene (15.2 kg) cooled to
5 °C under mechanical stirring and under nitrogen was added a mixture of 4- methoxyacetophenone (6.755 kg, 44.98 mol) and diethyl carbonate (6.40 kg, 54.18 mol) in toluene over 1 hour maintaining the temperature below 10 °C The reaction mixture was heated to 60 °C for 8 hours until no 4-methoxyacetophenone was detected by HPLC. The mixture was cooled to 20 °C and quenched by adding to a mixture of acetic acid (8 kg) and water (90 kg) over 30 minutes while maintaining the temperature at <20 °C The layers were separated, and the organic layer was washed with 5% sodium bicarbonate solution (41 kg) and concentrated to 14.65 kg. The temperature is maintained below 50 °C during the distillation. The yellow product concentrate was assayed by HPLC against an external standard and the yield was found to be 9.40 kg (94%).
Example 50 ID Ethyl 2-(4-methoxybenzoyl)-4-nitromethyl-3-( 1 ,3-benzodioxol-5-yl) butyrate
To the compound resulting from Example 50 IB (7.5 kg, 37.9 mol) suspended in
THF (56 kg) with mechanical stirring under nitrogen was added the compound resulting from Example C (8.4 kg, 37.9 mol). The mixture was cooled to 17 °C, sodium ethoxide (6.4 g, 0.095 mol) was added, and the reaction was stirred for 30 minutes. After about 15 minutes, the nitrostyrene was completely dissolved. Sodium ethoxide (6.4 g, 0.095 mol) was added, and the mixture was stirred at 25 °C until HPLC shows less than 1 area % ketoester remaining. The reaction was concentrated to 32.2 kg which was detennined by
HPLC assay to be -14.9 kg (95%).
Example 50 IE
Ethyl cis, c.-?-2-(4-methoxyphenylV4-(l,3-benzodioxol-5-yl) pyrroHdine-3 -carboxylate Raney nickel (20.0 g), from which the water had been decanted, was charged to a stirred hydrogenator equipped with a thermocouple. THF (20 mL), the crude compound resulting from Example 501D (40.82 g, 0.0482 mol), and acetic acid (2.75 mL, 0.0482 mol) were added sequentially. The mixture was put under a hydrogen atmosphere at 60 psi until the hydrogen uptake slowed dramatically. TFA was added, and the mixture was hydrogenated at 200 psi until HPLC shows no residual imine and <2 area % nitrone. The catalyst was filtered away and washed with 100 mL of methanol. The filtrate was assayed by HPLC and found to contain 13.3 g (75% yield) of the cis, cis-pyrroHdine compound. The filtrate was concentrated and chased with additional THF (200 mL) to give a final volume of 100 mL. The mixture was neutraUzed with 2 N NaOH solution (50 mL), diluted with water (200 mL), and extracted with ethyl acetate (2 x 100 mL). The combined nearly colorless ethyl acetate layers were assayed against an external standard by HPLC to bel3.0 g (73%) of the title compound.
Example 50 IF
Ethyl trans, tr »-.-2-(4-methoxyphenyl)-4-(l,3-benzocHoxol-5-yl pyrrolicHne-3 -carboxylate
The solution of the compound resulting from Example 50 IE (38.1 g, 0.103 mol) was chased with ethanol (200 mL) to a final volume of 100 mL and sodium ethoxide (3.40 g,
0.050 mol) was added. The mixture was heated to 75 °C When HPLC shows <3% of the cis,cis isomer remaimng, the mixture was cooled to room temperature. The product was assayed by HPLC against an external standard and found to contain 34.4 g (90% yield) of the title compound. The crude compound solution was concentrated and the residue taken up in isopropyl acetate (400 mL). The organic layer was washed with water (2 x 150 mL) and then extracted with 0.25 M phosphoric acid solution (2 x 400 mL). The combined phosphate layers were stirred with ethyl acetate (200 mL) and neutralized to pH 7 with soHd sodium bicarbonate (21 g). The organic layer was separated and found to contain 32.9 g (87%) of the title compound.
Example 50 IG Ethyl .2R.3R, 4S .-(rfV2-.4-methoxyphenyl.-4-. 1.3-betιzodioxol-5-yl. pyrroHdine-3- carboxylate, (S)-(+) mandelate salt The solution resulting from Example 50 IF was chased with acetonitrile (100 mL) to give a final volume of 50 mL. (S)-(+)-Mandelic acid (2.06 g, 0.0136 mmol) was added and allowed to dissolve. The mixture was seeded with the product and aUowed to stir at room temperature for 16 hours. The reaction mixture was cooled to 0 °C and stirred for 5 hours. The product was filtered and dried in a vacuum oven with a nitrogen purge for 1 day at 50 °C to give 5.65 g (40%) of the title compound. The purity of the product can be determined by chiral HPLC using Chiralpak AS, isocratic elution with 95:5:0.05 hexane-ethanol- diethylamine; flow - 1 mL/min.; UV detection at 227 nm. Retention times: (+)-enantiomer: 15.5 min.; (-)-enantiomer: 21.0 min.
Example 50 IH
(2R.3R,4S)-(+V2-(4-methoxyphenylV4-(1.3-benzodioxol-5-yl l-πS[.N-di(n- butyl) amino carbonylmethyl)- pyrrolidine-3-carboxylic acid The compound resulting from Example 501G (20.0 g, 0.0383 mol) was suspended in ethyl acetate (150 mL) and 5% sodium bicarbonate solution (150 mL). The mixture was stirred at room temperature until the salt dissolved and carbon dioxide evolution had ceased. The organic layer was separated and concentrated. The residue was chased with acetonitrile (200 mL) to a final volune of 100 mL and cooled to 10 °C Dnsopropylethylamine (11.8 mL, 0.0574 mol) and the compound resulting from Example A (10.5 g, 0.0421 mol) were added, and the mixture was stirred for 12 hours at room temperature. The reaction mixture was concentrated and chased with ethanol (200 mL) to a final volume of 100 mL. Sodium hydroxide solution (40%, 20 mL, 0.200 mol) was added, and the mixture was heated at 60 °C for 4" hours until HPLC showed no starting material remaining. The reaction mixture was poured into water (400 mL) and washed with hexanes (2 x 50 mL). The aqueous layer was washed with hexane (2 x 20 mL). A stirred mixture of the aqueous layer and ethyl acetate (400 mL) was neutralized to pH 5 with concentrated HCl (12 mL). The organic layer was separated and found to contain 18.3 g (94% yield) of the title compound.
Example 5011 r2R.3R,4SVf+.-2-r4-methoχyphenylV4-α,3-benzodioxol-5-yl -l-rN,N-dirn- butyl)aminocarbonylmethyl)- pyrroHdine-3 -carboxylic acid hydroehloride salt To a solution of the compound of Example 50 IH in ethyl acetate at room temperature in a mechanically stirred vessel equipped with a thermocouple, was added 39.4 mL of 1 N HCl in ethanol (0.0394 mol) The resultant solution was filtered to remove foreign matter, concentrated in vacuo, and chased with ethyl acetate (400 mL). The solution was seeded repeatedly, as the solvent was removed, until crystaUization was initiated. The mixture was concentrated to a volume of 100 mL, and the product was filtered and washed with ethyl acetate (25 mL). The resultant white solid was dried in a vacuum oven under a nitrogen purge at 50 °C to afford 17.6 g (90%) of the title compound.
Example 502 trans. trαn5-2-(2-Methylpentyl)-4-(l,3-benzodioxol-5-yl)-l-(N,N-di(n- butyl)aminocarbonylmethyl)-pyrroHcHne-3-carboxylic acid
Example 502A (±)-Ethyl 3-methylhexanoate
To a slurry of 60% socHum hydride (2.26g, 57 mmol) in lOmL of hexanes and lOOmL of diethyl ether was added triethylphosphonoacetate (10.3mL, 52mmol). Once gas evolution ceased, 2-pentanone (6.0mL, 64mmol) was added. After 3 hours at room temperature, the reaction was quenched with water, and partitioned into ether. The organic layer was washed with water and brine, dried with anhydrous sodium sulfate, filtered, and the solvent was removed under reduced pressure. The residue was dissolved in 50mL of ethanol and 10% palladium on carbon (6.0g) was added. The vessel was pressurized to 4 atmosphere of hydrogen, and was shaken at room temperature for 3 hours. The reaction was filtered and the solvent was removed under reduced pressure to give 3.0g of the title compound.
Example 502B (rf)-Ethyl 5-methyl-3-oxooctanoate
To a solution of ethyl 3-methylhexanoate in 150mL of ethanol was added sodium hydroxide (2.3g, 57.6mmol). After 48 hours at room temperature, solvent was removed under reduced pressure, and the residue was dissolved in 150mL of water. The solution was washed with ether, then acidified with concentrated hydrochloric acid and washed with methylene chloride. The organic layer was dried with anhydrous magnesium sulfate, filtered, and the solvent was removed under reduced pressure to give 2.7g of the corresponding acid from which 3.9g of the title compound was prepared by the method of Bram and Vilkas, Bui. Chem. Soc. Fr., 945 (1964).
Example 502C trans . trans-2-f 2-Methylpentyl)-4-( 1 ,3-benzodioxol-5-yl)- 1 -(N,N-di(n- butyl) amino carbonylmethy l)-pyrrolidine-3 -carboxylic acid
Using the procedures described in Example 1 and substituting ethyl 5-methyl-3- oxooctanoate for ethyl (4-methoxybenzoyl) acetate afforded the title compound, which was isolated by lyophilization from dUute aqueous TFA/CH3CN. Note that the multipHcity of the signals in the aryl region of the NMR spectrum reflects a 1 : 1 mixture of diastereomers on the alkyl chain. *H NMR (CDCI3, 300 MHz) δ 0.8-1.0 (m, 12H), 1.2-1.4 (m, 7H), 1.45- 1.6 (m, 6H), 1.6-1.74 (m, IH), 1.8-2.0 (m, IH), 3.1-3.4 (m, 5H), 3.67-3.78 (m, IH), 3.8-3.91 (m, IH), 4.0-4.2 (m, 2H), 4.3-4.5 (m, 2H), 5.93 (d, J=1.5 Hz, 2H), 6.73 (dd, J=8.1, 1.2 Hz, IH), 6.79 (ddd, J=7.8, 1.8, 1.8 Hz, IH), 6.86 (dd, J=3.9, 1.5 Hz, IH). MS (DCI/NH3) m/e 489 (M+H)X Anal calcd for C28H44N2θ5*l ,0 TFA* 0.5 H2O: C, 58.91; H, 7.58; N, 4.58. Found: C, 58.91; H, 7.58; N, 4.45.
Example 503 trans. trαn-;-2-(2.2-Dimethylpentyl)-4-(l,3-benzodioxol-5-yl)-l-(N,N-di(n- butyl) aminocarbonylmethyl)-pyrroHdine-3-carboxy lie acid
Ethyl 3,3-dimethylhexanoate was prepared using the general procedure of Cahiez et al., Tetrahedron Lett., 3_1, 7425 (1990). Using the procedures described in Example 502 and substituting ethyl 3,3-dimethylhexanoate for ethyl 3-methylhexanoate afforded the title compound, which was isolated by lyophilization from dilute aqueous TFA/CH3CN. H NMR (CDCI3, 300 MHz) δ 0.80-0.99 (m, 15H), 1.10-1.37 (m, 8H), 1.43-1.58 (m, 4H), 1.77- 1.97 (m, 2H), 3.48-3.12 (m, 5H), 3.60-3.69 (m, IH), 3.75-3.86 (m, IH), 3.95-4.16 ( , 2H), 4.28-4.4 (m, 2H), 5.94 (s, 2H), 6.74 (d, J=7.8 Hz, IH), 6.8 (dd, J=8.1, 1.5 Hz, IH), 6.87 (d,
J=1.8 Hz, IH). MS (DCI/NH3) m/e 503 (M+H)+. Anal calcd for C29H46N2θ5*1.05 TFA: C, 60.01; H, 7.62; N, 4.50. Found: C, 60.21; H, 7.37; N, 4.33.
Example 504 trans. trans-2-(2-(l ,3-Dioxo-2-yl. ethyl 4-. 1 ,3-benzodioxol-5-ylVl -( ,N-di(n- butyl)aminocarbonylmethyl)-pyrroHdine-3-carboxylic acid
Example 504A Ethyl 5-(1.3-dioxolyD-3-oxopentanoate
The title compound was synthesized from ethyl acetoacetate and 2-bromomethyl- 1,3-dioxane, according to the procedure of Huckin and WeUer, Tetrahedron Lett. 3927, (1971).
Sodium hydride 4.97 g (0.124 mol), as a 60% mineral oU dispersion, was weighed into a 250 mL flask, into which 80 ml of tetrahydrofuran was directly added. The flask was capped with septum cap, flushed with nitrogen, and cooled in an ice bath. To above stirred slurry was added dropwise 15.0 mL (0.118 mol) ethyl acetoacetate. After the addition was complete, the resulting mixture was stirred at 0 °C for additional 10 min. To above mixture was then added 48.4 mL (0.121 mol) n-butyl lithium, a 2.50 M solution in hexane, in a dropwise manner. The resulting orange color solution was stirred for 10 min before 13.5 mL (0.130 mol) bromomethyl-l,3-dioxane was added in one portion. The reaction mixture was then allowed to warm to room temperature and stirred for additional 120 min before it was then quenched by slow addition of 9.8 ml (ca. 0.12 mol) concentrated hydrochloric acid. The biphasic mixture was poured to 50 ml of water and extracted with 150 ml of ethyl ether. The aqueous layer was extracted thoroughly with additional ethyl ether. The ethereal extracts were combined, washed with 2x50 ml of saturated brine, dried over anhydrous magnesium sulfate, filtered and evaporated under reduced pressure to give an brown oUy residue. The crude product was purified using silica gel flash chromatography eluting with 20%) ether/hexane to give 5.40 g (20%) of b-keto ester as a Hght yellow oU. Example 504C trans. trans-2-(2-( 1 ,3-Dioxo-2-vDethyl . -4-f 1 ,3-benzodioxol-5-yl , - 1 -flSf,N-difa- butyl) amino carbonylmethyl) -pyrroHdine-3 -carboxylic acid
Using the procedures described in Example 502 and substituting ethyl 5-(l,3- dioxolyl)-2-oxopentanoate for ethyl 3-methylhexanoate afforded the title compound. 1H
NMR (CDC13, 300 MHz) δ 0.93 (t, J = 7.2 Hz, 3H), 0.95 (t, J = 7.2 Hz, 3H), 1.23-1.38 (m,
4H), 1.52 (sextet, J = 7.9 Hz, 4H), 1.85-1.95 ( , 2H), 2.02-2.17 (m, 2H), 3.18 (dd, J = 6.0 Hz, 9.0 Hz, 2H), 3.30 (dd, J = 9.0 Hz, 18.0 Hz, 2H), 3.35 (m, IH), 3.79 (dd, J = 3.6 Hz, 6.9
Hz, IH), 3.83-3.88 (m, 3H), 3.97 (dd, J = 4.8 Hz, 6.0 Hz, IH), 4.05 (q, J = 9.6 Hz, 2H),
4.30-4.40 (m, IH), 4.37 (s, 2H), 4.87 (t, J = 3.6 Hz, IH), 5.94 (s, 2H), 6.73 (d, J = 8.1 Hz,
IH), 6.79 (dd, J = 1.8 Hz, 8.1 Hz, IH), 6.87 (d, J = 1.8 Hz, IH). MS (APCI) (M+H)+ at m/e 505. Anal calcd for C27H40N2O7 1.2 TFA: C, 55.05; H, 6.47; N, 4.37. Found: C, 55.12; H, 6.44; N, 4.27.
Example 505 t »-?,tr π-?-2-(2-(2-Tefrahydro-2H-pyran)ethyl)-4-(l,3-benzodioxol-5-yl)-l-(N,N-di(n- butyl)aminocarbonylmethyl -pyrroHdine-3-carboxylic acid
Example 505A
Ethyl 5-(2-tetrahydro-2H-pyran -3-oxopentanoate
Using the procedure of Huckin and Weiler, Tetrahedron Lett. 3927, (1971), the title compound was prepared from ethyl acetoacetate and 2-(bromomethyl)tetrahydro-2H-pyran as a light yellow oU.
Example 505B trαn_.,trαn--2-(2-.2-Tefrahydro-2H-pyran)ethyl)-4-(l,3-benzodioxol-5-yl)-l-(N,N-di(n- butyl) amino carbonylmethy l)-pyrroHdine-3 -carboxylic acid
Using the procedures described in Example 502 and substituting ethyl 5-(2- tetrahydro-2H-pyran)-2-oxopentanoate for ethyl 3-methylhexanoate afforded the title compound as an amorphous solid. 1H NMR (CDCI3, 300 MHz) as a mixture of two diastereoisomers: δ 0.89 (t, J = 8.1 Hz, 3H), 0.89 (t, J = 8.1 Hz, 3H), 0.91 (t, J = 8.1 Hz, 3H), 0.91 (t, J= 8.1 Hz, 3H), 1.20-1.40 (m, 10H), 1.42-1.66 (m, 18H), 1.71 (brm, 2H), 1.85 (brm, 2H), 1.96-2.23 (brm, 4H), 3.10-3.29 (m. 8H), 3.29-3.52 (m, 6H), 3.54-3.81 (m, 6H), 4.01 (q, J = 9 Hz, 2H), 4.12-4.25 (m, 4H), 4.43 (d, J = 9 Hz, 2H), 4.50 (d, J = 2.7 Hz, 2H), 5.94 (s, 2H), 5.95 (s, 2H), 6.76 (s, 2H), 6.76 (s, 2H), 6.81 (s, IH), 6.81 (s, IH). MS (APCI) (M+H)+ at m/e 517. Anal calcd for C29H44N2O6 1.4 TFA: C, 56.48; H, 6.77; N, 4.14. Found: C, 56.46; H, 6.99; N, 3.83.
Example 506 trans. tr-.π '-2-(2,2,4-Trimethyl-3-pentenylV4-(l,3-benzodioxol-5-ylVl-πS[,N-difa- butyl)aminocarbonylmethyl)-pyrroHdine-3-carboxy lie acid
Example 506A Methyl 3,3, 5-trimethyl-4-hexenoate
To a slurry of isopropyltripenylphosphonium iodide (20.5g, 47mmol) in 200mL of tetrahydrofuran was added n-butyllithium (27mL of a 1.6M solution in hexane, 43mmol), and the solution was briefly warmed to 0°C After recooling, a solution of methyl 3,3- dimethyl-4-oxobutenoate (5.7g, 40mmol), prepared according to the procedure of Hudlicky et al, Synth. Commun., 16 169 (1986) in lOmL of tetrahydrofuran was added, and the reaction was warmed to 0°C for 30min. The reaction was quenched with dilute hydrochloric acid, and partitioned with ethyl acetate. The organic layer was washed with water, and brine, dried with anhydrous magnesium sulfate, filtered, and the solvent was removed under reduced pressure. The residue was purified by flash chromatography on silica gel eluting with 10% ethyl acetate in hexanes to give 2. Ig (30%) of the title compound.
Example 506B trans. tr-.^-2-(2,2,4-Trimethyl-3-pentenyl)-4-(l,3-benzodioxol-5-yl)-l-(N,N-di(n- butyl)aminocarbonylmethyl)-pyιτoHdine-3-carboxylic acid Using the procedures described in Example 502 and substituting methyl 3,3,5- trimethyl-4-hexenoate for ethyl 3-methylhexanoate afforded the title compound, which was isolated by lyophilization from dilute aqueous TFA/CH3CN. *H NMR (CDCI3, 300 MHz) δ 0.92 (t, J=7.2 Hz, 3H), 0.94 (t, J=7.2 Hz, 3H), 1.11 (s, 3H), 1.13 (s, 3H), 1.24-1.37 (m, 4H), 1.46-1.59 (m, 4H), 1.61 (d, J=1.2 Hz, 3H), 1.69 (d, JM1.2 Hz, 3H), 2.04-2.11 ( , 2H), 3.10-3.20 (m, 2H), 3.30-3.39 (m, 3H), 3.67-3.82 (m, 2H), 3.95-4.08 (m, IH), 4.32 (m, 2H), 4.37-4.47 (m? iH), 4.99 (s, IH), 5.95 (s, 2H), 6.73 (d, J=7.8 Hz, IH), 6.78 (dd, J=8.4, 1.2
Hz, IH), 6.84 (d, J=1.2 Hz, IH). MS (DCI/NH3) m/e 515 (M+H)+. Anal calcd for C3θH46N2θ5*1.05 TFA: C, 60.77; H, 7.48; N, 4.42. Found: C, 60.83; H, 7.20; N, 4.43.
Example 507 trans. tr-.7.g-2-(2,2,-Dimethyl-2-(l,3-dioxolan-2-yl)ethyl)-4-(l,3-benzodioxol-5-yπ-l-(N,N- di(n-butyl aminocarbonyhnethyl)-py-Tolidine-3-carboxyHc acid
Example 507A Methyl 3,3-dimethyl-3-(l,3-dioxolan-2-yl)propanoate
Methyl 3,3-dimethyl-4-oxobutanoate (10g, 70mmol), prepared according to the procedure of HudHcky et al, Synth. Commun., 16 169 (1986), was dissolved in 40mL of benzene, followed by addition of ethylene glycol (20mL), and ?-toluenesulfonic acid monohydrate (1.3g). The reaction was refluxed with azeotropic removal of water for 1 hour. The reaction was poured into 200mL of ether, washed with saturated sodium bicarbonate, water and brine, dried with anhydrous magnesium sulfate, filtered, and the solvent was removed under reduced pressure to give 12.4g (94%) of the title compound.
Example 507B trails. tr n_.-2-(2,2,-Dimethyl-2-(l,3-dioxolan-2-yl)ethylV4-π,3-benzodioxol-5-yl)-l-(N,N- di(n-butyl)aminocarbonylmethyl)-pyrroUdine-3-carboxyUc acid Using the procedures described in Example 502 and substituting methyl 3,3- dimethyl-3-(l,3-dioxolan-2-yl)propanoate for ethyl 3-methylhexanoate afforded the title compound, which was isolated by lyophilization from dilute aqueous TFA/CH3CN. H NMR (CDCI3, 300 MHz) δ 0.82-1.00 (m, 12H), 1.24-1.40 (m, 4H), 1.43-1.64 (m, 5H), 1.76- 1.84 (m, IH), 2.93-3.00 (m, IH), 3.15-3.47 (m, 6H), 3.60-3.70 (m, 3H), 3.74-3.95 (m, 5H), 4.48 (s, IH), 5.94 (m, 2H), 6.72 (d, J=8.0 Hz, IH), 6.83 (dd, J=8.0, 1.2 Hz, IH), 6.94 (d,
J=1.2 Hz, IH). MS (DCI/NH3) m/e 533 (M+H)+. Anal calcd for C29H44N2O7 -1.1 TFAO.2 H2O: C, 56.63; H, 6.93; N, 4.23. Found: C, 56.60; H, 6.96; N, 4.25.
Example 508 trα^.trα^-2-(2-π.3-Dioxo-2-yl ethylV4-ri,3-benzodioxol-5-ylVl-[[N-4-heptyl-N-(;2- methy 1-3 -fluorophenyl)] amino carbonylmethyl]-pyrrolidine-3-carboxylic acid
Example 508A 4-Heptanol
To an ice cooled solution of 1.14g (10.0 mmol) of 4-heptanone in 20 mL of diethyl ether was added 370 mg (10.0 mmol) of LiAlH4, in portions to keep ether reflux at a minimum. After 45 minutes, the reaction was quenched by sequential dropwise addition of 0.4 mL H2O, 0.4 mL 15% (w/v) ΝaOH(αg), and 1.2 mL H2O. After stirring another 45 minutes, MgSO4 was added until the salts were free flowing, then the reaction was filtered. The salts were washed with diethyl ether (3 x 5 mL), then the filtrate and washings were concentrated to a colorless oil. Yield 1.16g (100%).
Example 508B
4-Methanesulfonyloxyheptane
To an ice cooled solution of 834 mg (7.19 mmol) of 4-heptanol in 35 mL of CH2CI2 was added 1.5 mL of triethylamine. Next, 0.7 mL (9 mmol) of methanesulfonyl chloride was added, dropwise, over 1 minute. The mixture was stirred at 0 °C for 30 minutes, then extracted with H2O (1 x 15 mL), 5% NH4OH (2 x 15 mL), IM HCl (2 x 15 mL), and brine (1 x 15 mL), dried over MgSO4, filtered, and concentrated to an oil. Yield 1.31g (94%). lR NMR (300 MHz, CDCI3) d 0.96 (t, 6, J= 9), 1.43 (m, 4), 1.64 (m, 4), 3.00 (s, 3), 4.73 (quintet, 1 J= 5).
Example 508C
4-Fluoro-3-methylaniline
To a solution of 20g (129 mmol) of 2-fluoro-5-nitrotoluene in 400 mL of ethanol was added 2g of 10% Pd-C The mixture was shaken under 45 P.S.I. H2 until hydrogen uptake ceased. The catalyst was filtered away and washed with ethanol, then the combined filtrate and washings were concentrated to 15.2 g (94%) of a colorless oU.
Example 508D N-Heptyl-4-fluoro-3 -methylaniline
To a solution of 4.10 g (3.28 mmol) of 4-fluoro-3-methylaniline in 30 mL of acetonitrUe was added 7.64 g (3.93 mmol) of 4-methanesulfonyloxyheptane, and 3.4 g (4.1 mmol) of ΝaHCθ3(_f). The mixture was stirred at reflux for 24 hours, then poured into 150 mL of H2O and extracted with diethyl ether (2 x 30 mL). The combined ether layers were back extracted with brine (1 x 30 mL), dried over MgSO4, filtered, and concentrated to an oU. This was purified via sUica gel chromatography, eluting with 97.5: .2.5 hexanes: ethyl acetate, to give 2.56g (35%) of a pale yellow oil.
Example 508E N,N-(4-Heptyl)-(4-fluoro-3-methyl)phenylbromoacetamide
To an ice cooled solution of 4.88g (21.9 mmol) of Ν-(4-heptyl)-4-fluoro-3- methylaniline and 4.9 mL (61 mmol) of pyridine in 100 mL of toluene was added a solution of 4.90 mL (56.2 mmol) of bromoacetyl bromide in 7 mL of toluene. The solution was stirred for 24 hours, graduaUy warming to 25 °C, then extracted with IM HCl (1 x 100 mL). The aqueous layer was back extracted with diethyl ether (1 x 50 mL), then the combined organic layers were washed with H2O (2 x 50 mL), saturated NaHCθ3(β ) (2 x 50 mL), and brine (1 x 50 mL), dried over MgSO4, filtered, and concentrated in vacuo to an oU. This was purified via silica gel chromatography, eluting with 90: 10 hexanes: ethyl acetate to give 7.48g (99%) of a light yellow oil. JH NMR (300 MHz, CDCI3) d 0.94 (t, 6, J= 5), 1.33 (m, 4), 1.43 (m, 4), 2.30 (s, 1.5), 2.31 (s, 1.5), 3.54 (s, 2), 4.72 (quintet, 1, J= 5), 6.96-7.04 (m, 2), 7.07(d, 1, J= 7).
Example 508F tr-.^.tr-.^-2-.2- .3-Dioxol-2-ynethylV4-ri.3-benzodioxol-5-ylVl-[[N-4-heptyl-N-.2- methyl-3-fluorophenyl)] amino carbonylmethyl] -pyrroHdine-3 -carboxylic acid
Using the procedures described in Example 502, substituting ethyl 5-(l,3-dioxolyl)- 2-oxopentanoate for ethyl 3-methylhexanoate andN,N-(4-heptyl)-(4-fluoro-3- methyl)phenyl-bromoacetamide for N,N-dibutylbromoacetamide afforded the title compound as an amorphous soHd. *H MR (CDCI3, 300 MHz) δ 0.93 (brt, 6H), 1.23-1.47 (m, 8H), 1.67-2.10 (m, 4H), 2.32 (s, 3H), 3.16 (t, 1= 9.0 Hz, IH), 3.52-3.67 (brm, 2H), 3.73 (t, J= 9.0 Hz, IH), 3.81-4.02 (m, 6H), 4.13 (brm, IH), 4.72 (quintet, J= 6.9 Hz, IH), 4.86 (t, j = 4.0 Hz, IH), 5.93 (s, 2H), 6.72 (d, J = 8.1 Hz, IH), 6.78 (dd, J = 1.8 Hz, 8.1 Hz, IH),
6.85 (d, J = 1.8 Hz, IH), 6.96 (m, 2H), 7.08 (t, J = 9.0 Hz, IH). MS (DCI/ΝH3) (M+H)+ at m/e 599. Anal Calcd for C33H43N2O7F 0.8 TFA: C, 60.24; H, 6.40; N, 4.06. Found: C, 60.21; H, 6.14; N, 3.86.
Example 509 trans. trans-2-(2-( 1 ,3-Dioxol-2-vDethvI,-4-( 1 ,3-benzodioxol-5-yl .- 1 -. N.N-di. n- butyl)aminocarbonylmethyl)-pyrroUdine-3-carboxy lie acid
Using the procedures described in Example 502, substituting ethyl 5-(l,3-dioxolyl)-2- oxopentanoate for ethyl 3-methylhexanoate and 6-methoxypiperonal for piperonal afforded the title compound as an amorphous soHd. lR NMR (CDCI3, 300 MHz) δ 0.93 (t, J = 7.8 Hz, 3H), 0.95 (t, J = 7.8 Hz, 3H), 1.31 (m, 4H), 1.53 (m, 4H), 1.90 (m, 2H), 2.09 (m, 2H),
3.19 (dd, J= 8.4 Hz, 8.4 Hz, 2H), 3.30 (q, J = 9.6 Hz, 2H), 3.25-3.42 (m, IH), 3.73 (q, j = 10.5 Hz, IH), 3.78-3.94 (m, 4H), 3.88 (s, 3H), 3.96 (dd, J = 5.1 Hz, 6.0 Hz, IH), 4.03 (dd, J = 3.0 Hz, 6.3 Hz, 2H), 4.33 (m, 3H), 4.87 (t, J = 3.6 Hz, IH), 5.94 (s, 2H), 6.53 (d, J = 1.8
Hz, IH), 6.63 (d, J = 1.8 Hz, IH). MS (DCI/NH3) (M+H)+ at m/e 535. Anal calcd for C28H42N2O8 1.05 TFA: C, 55.25; H, 6.63; N, 4.28. Found: C, 55.39; H, 6.66; N, 4.26.
Example 510 trαrøJ7^-.n '-2-(.2-Methoxyphenoxy)-methyl)-4-(1.3-benzodioxol-5-yl)-l-(N,N-di(n- butyl . amdnocarbonylmethyl)-pytτoHdine-3-carboxylic acid
Using the procedures described in Example 502, substituting o- methoxyphenoxyacetic acid for 3-methylhexanoic acid, the above compound was prepared as an amorphous solid. lR NMR (CDCT3, 300 MHz) δ 0.85 (t, J=7Hz, 3H), 0.90 (t, J=7Hz, 3H), 1.15-1.35 (m, 4H), 1.40-1.55 (m, 4H), 3.05-3.25 (m, 4H), 3.28-3.55 (m, 4H), 3.58-3.68 (m, IH), 3.75-3.80 (m, IH), 3.82 (s, 3H), 3.91 (d, J=14Hz, IH), 4.05-4.15 (m, IH), 4.23- 4.33 (m, 1H),5.91 (s, 2H), 6.70 (d, J=8Hz, IH), 6.82-6.95 (m, 5H), 7.03 (s, IH). MS
(DCI/NH3) (M+H)+ at m/e 541. Anal calcd for C30H40N2O7: C, 66.65; H, 7.46; N, 5.18. Found: C, 66.37; H, 7.61; N, 5.09.
Example 511 t S.3RrfS)-2-(2,2-DimethylpentylV4-(;i,3-benzodioxol-5-yl)-l-rN-4-heptyl-N-(4-fluoro-3- methylphenyl))aminocarbonylmethyl)-pyrroHdine-3-carboxylic acid
Example 511 A trans. tr_.7?..-N-tert-Butoxycarbonyl-2-(2,2-dimethylpentyl)-4-(l,3-benzodioxol-5-yl)- pyrrolidine-3 -carboxylic acid
Ethyl trans, trΩ77S-2-(2,2-dimethylpentyl)-4-( 1 ,3-benzocHoxol-5-yl)-pyrroHdine-3- carboxylate (2.5g, 6.9mmol), prepared according to Example 503, was dissolved in 50mL of methylene chloride and di-tert-butyldicarbonate (1.5g) was added. After stirring overnight at room temperature, the solvent was removed under reduced pressure and the residue was purified by flash chromatography on silica gel eluting with 10% ethyl acetate/hexanes to give the ethyl ester of the title compound (2.8g) as a colorless oil. The ester was dissolved in 50mL of ethanol foUowed by addition of sodium hydroxide (lOmL of a 5M aqueous solution). After stirring for 20 hours at room temperature, the solvent was removed under reduced pressure, and the residue was dissolved in 150mL of water, and acidified with concentrated phosphoric acid. The mixture was extracted with chloroform (3X50mL), and the organic layers were washed wiith brine, dried over anhydrous magnesium sulfate, filtered, and the solvent was removed under reduced pressure to give the title compound (2.4g) as a white foam.
Example 51 IB Methyl trans. tran_.-2-(2,2-dimethylpentyl)-4-(l ,3-benzodioxol-5-yl)-l-(N-4-heptyl-N-(4- fl.uoro-3-methylphenyl))aminocarbonylmethyl)-pyrrolidine-3-carboχylate: As a single enantiomer
The product from Example 510A (1.97g, 4.5 mmol) was dissolved in 20mL of THF and cooled to 0°C, foUowed by addition of DMF (0.017mL, 5%), and oxalyl chloride (0.437mL, 5.00mmol). After 1 hour, solvent was removed at 0°C under a stream of nitrogen. The residue was dissolved in 5mL of benzene and evaporated. In a separate flask, (S)-4-benzyl-2-oxazoHdinone (1.2g, 6.8mmol) was dissolved in 30mL of THF foUowed by addition of n-butyllithium (4.0mL of a 1.6M solution in hexanes) at 0°C, and the slurry was stirred for 15min. The acid chloride was dissolved in 20mL of THF and cooled to 0°C, foUowed by dropwise addition of the Hthium oxazolide suspension via cannula. After 30min, the reaction was partitioned between ether and saturated bicarbonate. The organic phase was washed with water then brine, dried over anhydrous magnesium sulfate, filtered, and the solvent was removed under reduced pressure. The residue was purified by flash chromatography on silica gel eluting with 15% ethyl acetate/hexanes to give the undesired diastereomer (1.17g, 43%), then elution with 20% ethyl acetate/hexanes gave the desired diastereomer (1.04g, 38%). The desired diastereomer of the N-acyloxazoHdinone (0.84g, 1.42mmol) was dissolved in 2.5mL of dichloromethane, and 2.5mL of trifluoroacetic acid was added. After 30min, the volatiles were removed under a stream of nitrogen, and the residue was twice dissolved in 5mL of toluene and evaporated under reduced pressure.
The TFA salt was stirred with 4mL of acetonitrUe foUowed by addition of dnsopropylethyl amine (l.OmL, 5.7mmol), and N-4-heptyl-N-(4-fluoro-3- methylphenyl)bromoacetamide (589mg, 1.7mmol) as a solution in 2mL of acetonitrile. After 21 hours, the reaction was warmed to 50°C for 3.5 hours. The reaction was cooled, the solvent removed under reduced pressure, and the residue was purified by flash chromatography on silica gel eluting with 20-30% ethyl acetate/hexanes to give 0.939g of amide as a colorless oU. The above amide (200mg, 0.26mmol) was dissolved in 2.0mL of THF and 0.7mL of water. Solid lithium hydroxide monohydrate (22mg, 0.53mmol) was added at 0°C, followed by 30% hydrogen peroxide (0.050mL, 0.55mmol). After 1 hour, the reaction was warmed to room temperature. After an additional hour, the reaction was partitioned between 1 : 1 ethyl acetate:hexanes and water, 0.15g of sodium thiosulfate was added and the mixture was mixed thoroughly. The organic layer was washed with water and brine, dried over anhydrous magnesium sulfate, filtered, and the solvent was removed under reduced pressure. The crude residue was dissolved in 2mL of ether, and lmL of methanol. A solution of (trimethylsilyl)diazomethane in hexanes was added dropwise unt the yellow color remained. The reaction was quenched by addition of 2 drops of glacial acetic acid, and the solvent was removed under reduced pressure. The residue was purified by flash chromatography on lOg of sUica gel eluting with 15-20% ethyl acetate/hexanes to give 70mg of the title compound as a crystaUine solid (mpl37.5°C).
Example 51 IC (2S.3R.4S)-trans. trans-2-( 2.2-Dimethylpentyl . -4-f 1.3-benzodioxol-5-yl . - 1 -fN-4-heptyl-N-
(4-fluoro-3-methylphenyl))aminocarbonylmethyl)-pyrroHdine-3-carboxylate
The product from Example 510B (65mg, 0. lOmmol) was dissolved in l.OmL of methanol and sodium hydroxide (0. lmL of a 5M aqueous solution) was added. After 2 hours, the reaction was warmed to reflux. After 6 hours, the reaction was cooled, and the solvent was removed under reduced pressure. The residue was dissolved in water and acidified with concentrated phosphoric acid. The aqueous solution was washed with chloroform (3X5mL), which was then washed with brine, dried with anhydrous magnesium sulfate, filtered and evaporated under reduced pressure. The title compound was isolated by lyophilization from dilute aqueous TFA/CH3CN. !H NMR (CDCI3, 300 MHz) d 0.78-0.95 (m, 15H), 1.04-1.46 (m, 12H), 1.76-2.95 (m, 2H), 2.31 (s, 3H), 3.23-3.33 (m, IH), 3.47-3.58 (m, IH), 3.6-3.75 (m, 2H), 3.80-3.95 (m, 2H), 4.05-4.15 (m, IH), 4.73 (m, IH), 5.94 (s, 2H), 6.70-6.80 (m, 2H), 6.82-6.93 (m, 2H), 6.96-7.14 (m, 2H). MS (DCI/NH3) m/e 597
(M+H)+. Anal calcd for C35H49N2FO5 O.05H2O O.8TFA: C, 63.81; H, 7.30; N, 4.07.
Found: C, 63.84; H, 7.18; N, 3.94. [a]^ =+46° (c 2.7g/L, CHCI3)
Example 512 trans, trans -2-(2-(2-OxopyrroHdin- 1 -yl)ethyl)-4-( 1 ,3-benzodioxol-5-yl)- 1 -(N,N-di(n- butyl) amino carbonylmethy l)-pyrrolidine-3 -carboxylic acid
Example 512A 2-Oxopyrrolidin-l-ylpropionic acid
To a stirred solution of 5.0 mL (40.5 mmol) 2-oxopyrroHdin-l-ylpropionitrUe in 15 mL of dioxane was added 8.1 mL of hydrochloric acid, a 6.0 M aqueous solution. The resulting mixture was then refluxed at 110 °C over night. The reaction mixture was then allowed to cool to room temperature, extracted with methylene chloride three times. The extracts were combined and washed with saturated brine solution once, dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure to give 1.60 g (25%) of acid as a brown oil.
Example 512B
Ethyl 5-(2-oxopyrrolidin- 1 -yl)-3-oxopentanoate The title compound was prepared from the above acid by adapting the method of Bram and VUkas, Bui. Chem. Soc. Fr., 945 (1964).
Example 512C trα7._..t7^77^-2-(2-(2-OxopyιτoHdin-l-yl)ethyl -4-(l,3-benzodioxol-5-yl)-l-flS,N-di(n- butyl aminocarbonylmethyl)-pyrroHdine-3-carboxylic acid ! '
' / Using the procedures^ described in Example 502, substituting ethyl 5-(2- pxopyrroHdin-l-yl)-3-oxopentanoate for ethyl 3-methylhexanoate afforded the title compound as an amorphous sohd. *H NMR (CDCI3, 300 MHz) 0.91 (t, J = 7.5 Hz, 3H), 0.94 (t, J= 7.5 Hz, 3H), 1.23-1.38 (m, 4H), 1.44-1.60 (m ,4H), 2.05 (t, J = 6.9 Hz, 2H), 2.12- 2.25 (m, IH), 2.38 (td, J = 4.2 Hz, 8.4 Hz, 2H), 2.47-2.61 (m, IH), 3.17 (dd, J = 6.0 Hz, 8.7 Hz, 2H), 3.24 (t, J = 9 Hz, IH), 3.32 (t, J = 7.8 Hz, 2H), 3.38-3.48 (m, 3H), 3.52 (t, J = 9 Hz, IH), 3.66 (t, 1= 6.9 Hz, IH), 3.96 ( , 2H), 4.14 (m, IH), 4.38 (brs, 2H), 5.93 (s, 2H), 6.74 (d, J = 8.1 Hz, IH), 6.89 (dd, J = 1.8 Hz, 8.1 Hz, IH), 6.87 (d, J = 1.8 Hz, IH). MS
(DCI/NH3) (M+H)+ at m/e 516. Anal calcd for C28H41N3O6 1.4 TFA: C, 54.78; H, 6.33; N, 6.22. Found: C, 54.69; H, 6.33; N, 6.14.
Example 513 trans. trans-2-(2-( 1 ,3-Dioxol-2-yl. ethv!V4-.7-methoxy- 1 ,3-benzodioxol-5-yl . - 1 -(N-4-heptyl-
N-(4-fluoro-3-methylphenyl))aminocarbonylmethyl)-pyrrolidine-3-carboxy lie acid
Using the procedures described in Example 502, substituting ethyl 5-(l,3-dioxolyl)-
2-oxopentanoate for ethyl 3-methylhexanoate, N-4-heptyl-N-(4-fluoro-3-methylphenyl) bromoacetamide for N,N-dibutyl bromoacetamide and 6-methoxypiperonal for piperonal afforded the title compound as an amorphous solid. 1H NMR (CDCI3, 300 MHz) δ 0.93 (br t, 6H), 1.23-1.47 (m, 8H), 1.67-2.10 (m, 4H), 2.32 (s, 3H), 3.16 (t, J = 9 Hz, IH), 3.60-4.03
(m, 8H), 3.88 (s, 3H), 4.21 (brs, IH), 4.72 (quintet, J = 6.6 Hz, IH), 4.86 (t, J = 3.6 Hz, IH),
5.93 (s, 2H), 6.49 (s, IH), 6.61 (s, IH), 6.96 (m, 2H), 7.08 (t, J = 9 Hz, IH). MS (DCI/NH3)
(M+H)+ at m/e 629. Anal calcd for C34H45N2O8F 1.0 TFA: C, 58.21; H, 6.24; N, 3.77. Found: C, 58.11; H, 6.11; N, 3.58.
Example 514 t7^rø.trατ._;-2-.2,2-Dimethylpentyl)-4-(7-methoxy-l,3-benzodioxol-5-yl)-l-(N,N-di(n- butyl.aminocarbonylmethyl)-pyrroUdine-3-carboxy lie acid
Using the procedures described in Example 502, substituting ethyl 5-methyl-3- oxooctanoate for ethyl 3-methylhexanoate and 6-methoxypiperonal for piperonal afforded the title compound as an amorphous sohd. ΪH NMR (CDCI3, 300 MHz) δ 0.81 (s, 3H), 0.84 (s, 3H), 0.86 (t, J = 6.9 Hz, 3H), 0.93 (t, J= 6.9 Hz, 3H), 0.96 (t, J = 6.9 Hz, 3H), 1.09-1.38 (m, 8H), 1.45-1.59 (m, 4H), 1.84-2.00 (m, 2H), 3.15 (dd, J = 6.9 Hz, 10.0 Hz, 2H), 3.30-3.42 (m, 3H), 3.72 (t, J = 10.5 Hz, IH), 3.86 (t, J = 10.5 Hz, IH), 3.88 (s, 3H), 4.02 (q, J = 10.0 Hz, IH), 4.12 (d, J = 16.8 Hz, IH), 4.29 (d, J = 16.8 Hz, IH), 4.41 (brm, IH), 5.94 (s, IH),
6.52 (d, J = 1.8 Hz, IH), 6.67 (d, J = 1.8 Hz, IH). MS (DCI/NΗ3) (M+H)+ at m/e 533. Anal calcd for C30H48N2O 0.9 TFA: C, 60.12; H, 7.76; N, 4.41. Found: C, 60.18; H,
7.62; N, 4.33.
Example 515 tr-..?-?,trfl7M,-2-(2,2-cUmethylρentyπ butyl) aminocarbonylmethyl)-pyrroUdine-3-carboxylic acid
Using the procedures described in Example 502, substituting ethyl 3,3- dimethylhexanoate for ethyl 3-methylhexanoate and 2,3-dihydro-benzofuran-5-carbaldehyde for piperonal afforded the title compound as an amorphous sohd by lyophyHzation with
CH3CN/TFA/H2O. 1H NMR (300 MHz, CDCI3) δ 0.83 (s, 3H), 0.85 (s, 3H), 0.86 (t, J=7.2 Hz, 3H), 0.92 (t, J=7.2 Hz, 3H), 0.95 (t, J=7.2 Hz, 3H), 1.09-1.39 (m, 8H), 1.44-1.59 (m, 4H), 1.88 (dd, J=15.0, 7.2 Hz, IH), 2.00 (d, J=15.0 Hz, IH), 3.09 (m, 2H), 3.18 (t, J=9.0 Hz, 2H), 3.27-3.38 (m, 3H), 3.65-3.95 (m, 2H), 4.05 (q, J=10.0 Hz, IH), 4.18 (d, J=16.8 Hz, IH), 4.30-4.45 (m, 2H), 4.55 (t, J=9.0 Hz, 2H), 6.70 (d, J=8.4 Hz, IH), 7.04 (dd, J=8.4, 2.1
Hz, IH), 7.23 (brs, IH). MS (DCI/NH3) at m/e 501 (M+H)+. Anal calc'd for C30H48N2O4 1.05 TFA: C, 62.14; H, 7.97; N, 4.51. Found: C, 62.19; H, 8.00; N, 4.43.
Example 516 trø77_;.tr-.77λ-2-.2,2,-Dimethyl-2-(l,3-dioxolan-2-yl)ethyl)-4-(l-methoxy-l,3-benzodioxol-5- yl)-l-(N,N-cH(n-butyl)aminocarbonylmethylVpyrroHdine-3-carboxylic acid
Using the procedures described in Example 502, substituting methyl 3,3-dimethyl-3- (l,3-dioxolan-2-yl)propanoate for ethyl 3-methylhexanoate and 6-methoxypiperonal for piperonal afforded the title compound as an amorphous sohd by lyophyHzation with CH3CN/TFA/H2O. 1H NMR (CDCI3, 300 MHz) δ 0.93 (t, J=7.2 Hz, 3H), 0.94 (t, J=7.2 Hz, 3H), 0.95 (s, 3H), 0.96 (s, 3H), 1.31 (sextet, J=7.2 Hz, 4H), 1.45 (m, 4H), 1.93 (dd, J=15.9, 6.0 Hz, IH), 2.13 (d, J=15.9 Hz, IH), 3.20 (dd, J=7.7, 7.7 Hz, IH), 3.26-3.40 (m, 3H), 3.60 (m, IH), 3.75-3.86 (m, 3H), 3.88 (s, 3H), 3.93-4.01 (m, 3H), 4.00-4.11 (m, IH), 4.23 (d, J=15.9 Hz, IH), 4.37-4.48 (m, 2H), 4.49 (s, IH), 5.94 (s, 2H), 6.51 (d, J=2.1 Hz,
IH), 6.64 (d, J=2.1 Hz, IH). MS (DCI/NH3) at m/e 563 (M+H)+. Anal calcd for C 0H46N2O8 0.9 TFA: C, 57.41; H, 7.11; N, 4.21; found: C, 57.35; H, 6.86; N, 4.05.
Example 517 tr-,7Z ι.tr n^-2-(2-(2-Methoxyphenyl)-ethyπ-4-π,3-benzodioxol-5-yl)-l-(N,N-di(n- butyl)aminocarbonylmethyl)-pyrrolidine-3-carboxylic acid
Using the procedures described in Example 502, substituting o- methoxyphenylpropionic acid for 3-methylhexanoic acid, the above compoxind was prepared as an amorphous solid. H NMR (CDCI3, 300 MHz) δ 0.85 (t, J=7Hz, 3H), 0.91 (t, J=7Hz, 3H), 1.10-1.27 (m, 4H), 1.42-1.60 (m, 4H), 1.72-1.89 (m, IH), 1.91-2.02 (m, IH), 2.55-2.77 (m, 2H), 2.94 (t, J=6Hz, IH), 3.05-330 (m, 6H), 3.59-3.82 (m, 3H), 3.73 (d, J=14Hz, IH), 3.77 (s, 3H), 5.91 (s, 2H), 6.70 (d, J=8Hz, IH), 6.78-6.88 (m, 3H),6.92 (d, J=2Hz, IH), 7.08-
7.19 (m, 2H). MS (DCI/NH3) (M+H)+ at m/e 539. Anal calcd for C31H42N2O6: C, 69.12; H, 7.86; N, 5.20. Found: C, 68.89; H, 7.70; N, 4.99.
Example 518 trans. tr_.rø-2-(2,2-Dimethyl-3-(E)-pentenyl)-4-( 1 -methoxy- 1 ,3-benzodioxol-5-yf)- 1 -(N.N- di(n-butyl aminocarbonylmethyl)-pytτoHdine-3-carboxyHc acid
Example 518A 4-Methyl-3-penten-2-ol
To a stirred solution of 3-methyl-2-butenal (8.7g, 103mmol) in lOOmL of tetrahydrofuran under N2 at 0 °C was added methylmagnesium bromide (38mL of a 3.0M solution in ethyl ether, 114mmol) dropwise. The resulting mixture was aUowed to warm to room temperature slowly and stirred at room temperature for 1 hour before it was quenched with 25mL of saturated NH4CI. The resulting biphasic mixture was partitioned between ethyl ether and water. The organic layer was washed with brine, dried with anhydrous magnesium sulfate, filtered, and the solvent was removed under reduced pressure to give 8.4g (81%) of alcohol as a colorless oil.
Example 518B trans-Ethyl 3 ,3-dimethyl-4-pentenoate
A mixture of 4-methyl-3-penten-2-ol (7.4g, 74mmol), triethyl orthoacetate (13.6mL, 74mmol) and propionic acid (0.28mL, 3.7mmol) was heated at 150 °C for 7 hours. The product was then distilled under normal pressure (200-220 °C) to give 5.0g of crude ester as a colorless oil.
Example 518C trans, trans -2-(2,2-Dimethyl-3-(E)-pentenyl)-4-( 1 -methoxy- 1 ,3-benzodioxol-5-yl)- 1 -(N,N- di(n-butyl aminocarbonylmethyl -pyrrolidine-3-carboxyHc acid
Using the procedures described in Example 502, substituting trans-ethyl 3,3- cHmethyl-4-pentenoate for ethyl 3-methylhexanoate and 6-methoxypiperonal for piperonal afforded the title compound as an amorphous soHd by lyophilization from dilute aqueous
TFA/CH3CN. 1H NMR (CDCI3, 300 MHz) δ 0.92 (t, J=7.2 Hz, 3H), 0.95 (t, J=7.2 Hz,
3H), 0.97 (s, 3H), 0.99 (s, 3H), 1.31 (sextet, J=7.2 Hz, 4H), 1.52 (quintet, J=7.2 Hz, 4H), 1.58 (d, J=5.4 Hz, 3H), 1.92 (dd, J=15.0, 6.6 Hz, IH), 2.04 (d, J=15.0 Hz, IH), 3.15 (dd, J=7.8, 7.8 Hz, IH), 3.30-3.40 (m, 3H), 3.75 (m, 2H), 3.87 (s, 3H), 3.99 (q, J=9 Hz, 2H), 4.11-4.30 (m, 3H), 5.29 (d, J=15.6 Hz, IH), 5.38 (dd, J=15.6, 6 Hz, IH), 5.94 (s, 2H), 6.50
(d, J=1.8 Hz, IH), 6.63 (d, J=1.8 Hz, IH). MS (DCI/NΗ3) at m/e 531 (M+H)+. Analysis calc'd for C30H46N2O6 0.95 TFA: C, 59.95; H, 7.41; N, 4.38; found: C, 60.00; H, 7.33; N, 4.35. Example 519 trans. tr-.n_?-2-(3-(2-pyridyl)ethyl)-4-(l,3-benzodioxol-5-yl)-l-(N,N-di(n- butyl)aminocarbonylmethyl)-pyrroHdine-3-carboxy lie acid
Example 519A
3-(2-Pyridyl)-propionic Acid
In a 50 mL round-bottomed flask equipped with a stirring bar was placed 3-(2- pyridyl)-propanol (1 g, 7.6 mmol), water (13 mL) and concentrated sulfuric acid (0.5 g, 5.1 mmol). To this stirred solution was added over a period of 30 min potassium permanganate (1.8 g, 11.3 mmol) while the reaction temperature was maintained at 50 °C After the addition was completed, the mixture was held at 50 °C until the color of the reaction mixture turned brown, then heated at 80 °C for 1 hour and filtered. The filtrate was evaporated to dryness to yield quantitatively the desired acid (1.14 g) suitable for next step without further purification. To prepare a pure acid, the residue thus obtained was boUed in ethanol (10 mL) in the presence of charcoal (0.1 g) for 5 min, filtered and cooled to give crystalline 3- (2-pyridyl)-ρroρionic acid (0.88 g, 78%).
Example 519B trans. tr ns-2-.3-.2-pyridyl ethyl)-4-.1.3-benzodioxol-5-ylVl-(N,N-di(n- butyl)aminocarbonylmethyl)-pyrroHdine-3-carboxylic acid
Using the procedure described in Example 502, the title compound was isolated by lyophilization from dilute aqueous TFA/CH3CN as an amorphous soHd. H NMR (CDCI3, 300 MHz) δ 8.65 (d, J=6.0 Hz, IH), 8.06 (t, J=6.91 Hz, IH), 7.70 (d, J=9.0 Hz, IH), 7.51 (t, J=6.91 Hz, IH), 6.82-6.66 (m, 3H), 5.91 (s; 2H), 4.45 (s, 2H), 4.29-4.18 (m, IH), 4.04 (dd, J=20.1, 10.5 Hz, 1 H), 3.84 (t, J=Ϊ2.6 Hz, 1 H), 3.62 (dd, J=Ϊ3.8, 9.6 Hz, IH), 3.46-3.13 (m, 7H), 2.51 (broad s, 2H), 1.60-1.43 ( , 4H), 1.37-1.22 (m, 4H), 0.91 (t, J=8.4 Hz, 6H). MS
(DCI/NΗ3) m/e 510 (M+H)+. Anal calcd for C29H39N3θ5'1. 5 TFA: C, 55.04; H, 5.79; N, 5.92. Found: C, 55.08; H, 5.64; N, 5.81. Example 520
(2S. 3R. ^2-(2-(2-oxopyrrolidin-l-Y_)ethyl)-4-( 1.3-benzodio∑ol-5-yl)-l-(N,N-di n- butyl)aminocarbonylmethyl)-pyrrolidine-3-carboxylic acid
Example 520A
(2S. 3R. ^S)-Ethyl-2-(2-.2-oxopγιτolidin-l-y ethyl -4- .3-benzodioxol-5-yl.pyrrolidine-3- carboxylate-(S)-Mandelate
The racemic amino ester from Example 512 (3.45g, 8.98mmol) in lOmL of ethyl acetate was treated with (S)-(+)-mandeHc acid (0.75g, 4.93mmol). Upon the formation of the clear solution, hexane was dropped in slowly with stirring tUl the solution became Hght cloudy. The solution was left stirred at room temperature over night. The crystals was then coUected by filtration, recrystaHzed from ethyl acetate/hexane twice to give a yield of 800 mg (17%) of pure salt.
Example 520B
(2S. 3R, ^S)-Ethyl-2-r2-(2-oxopyιτoH(Hn-l-yl)ethyl -4-(l,3-benzodioxol-5-yl)-l-rN,N-di(n- butyl) amino carbonylmethy l)-pyrroHdine-3 -carboxylate
To a stirred solution of pure mandelate (150 mg, 0.28 mmol) in CH3CN was added
NN-dibutylbromoacetamide(84 mg, 0.34 mmol) and dnsopropylethylamine (98uL, 0.56mmol). The resulting mixture was stirred at room temperature over night. Solvent was then removed under reduced pressure and the crude product was purified by silica gel flash chromatography to give 140 mg (90% yield) of the title compound.
Example 520C
(2S. 3R. S)-2-.2-(;2-oxopyrroHdm-l-yl)ethvn-4-α,3-benzodioxol-5-yl)-l-(;Ν,Ν-di(n- butyl)aminocarbonylmethyl)-pyrrolidine-3-carboxy lie acid
Using the procedures described in Example 502, the title compound was prepared as an amorphous sohd by lyophyHzation with CH3CN/TFA/H2O. lR NMR (CDCI3, 300 MHz) δ 0.91 (t, J = 7.5 Hz, 3H), 0.94 (t, J = 7.5 Hz, 3H), 1.23-1.38 (m, 4H), 1.44-1.60 (m ,4H), 2.05 (t, J = 6.9 Hz, 2H), 2.12-2.25 (m, IH), 2.38 (td, J = 4.2 Hz, 8.4 Hz, 2H), 2.47-2.61 (m, IH), 3.17 (dd, J = 6.0 Hz, 8.7 Hz, 2H), 3.24 (t, J = 9 Hz, IH), 3.32 (t, J = 7.8 Hz, 2H), 3.38-3.48 (m, 3H), 3.52 (t, J = 9 Hz, IH), 3.66 (t, J= 6.9 Hz, IH), 3.96 (m, 2H), 4.14 (m, 1H), 4.38 (brs, 2H), 5.93 (s, 2H), 6.74 (d, J = 8.1 Hz, IH), 6.89 (dd, J = 1.8 Hz, 8.1 Hz, IH), 6.87 (d, J = 1.8 Hz, IH). MS (DCI/NH3) (M+H)+ at m/e 516. Anal calcd for C28H41N3O6 0.85 TFA: C, 58.23; H, 6.89; N, 6.86. Found: C, 58.37; H, 6.90; N, 6.84.
Example 521
(2S. 3R. ^S)-2-(2-(2-oxopγrroHdin-l-yl)ethγlV4-d ,3-benzodioxol-5-ylVl-(N-4- heptyl-N-(4-fluoro-3-methylphenyl))aminocarbonylmethyl)-pyrroHdine-3-carboxy lie acid
Using the procedures described in Example 520, substituting NN-(4-heptyl)-(4- fluoro-3-methyl)phenyl-bromoacetamide for N,N-dibutylbromoacetamide afforded the title compound as an amorphous solid by lyophyHzation with CH3CΝ/TFA H2O. ^H NMR (CDCI3, 300 MHz) δ 0.85-0.98 (m, 6H), 1.22-1.55 (m, 8H), 2.04 (quintet, J=7.9 Hz, 4H), 2.32 (s, 3H), 2.36 (t, J=7.9 Hz, 2H), 2.61 (m, IH), 3.14 (m, IH), 3.25-3.61 (m, 5H), 3.66- 3.77 (m, IH), 3.79-3.90 (m, 2H), 3.92-4.03 (m, IH), 4.69 (quintet, J=6.8 Hz, IH), 5.95 (s, 2H), 6.71 (s, 2H), 6.78 (s, IH), 6.93-7.13 (m, 3H); MS (DCI/NΗ3) at m/e 610 (M+H)X
Anal calc'd for C34H44N3O6F1 1.45 TFA: C, 57.18; H, 5.91; N, 5.42. Found: C, 57.20; H, 5.62; N, 5.52.
Example 522 trans. tr-.ns-2-(2-α-pyrazolyl.ethyl -4-π,3-benzodioxol-5-γlVl-πSf,N-di(n- butyl) amino carbonylmethy l)-pyrroHάjne-3 -carboxylic acid
Example 522A 3-(l-Pyrazolyl)-propionic Acid
In a 10 mL round-bottomed flask equipped with a condenser and a stirring bar was placed pyrazole (0.50 g, 7.3 mmol), acrylic acid (0.50 mL, 7.3 mmol) and triethylamine (3 mL). The reaction mixture was refluxed for 6 hours. After removing triethylamine, the viscous oU was dried on high vacuo during 12 hours to yield quantitatively the desired acid (l.O g) suitable for the next step without further purification. Example 522B trans. tr_.77s-2-(2-(l-pyrazolyl)ethyl)-4-(1.3-beiizodioxol-5-yl)-l-(N,N-di(n- butyl)aminocarbonylrnethyl)-pyrroHdine-3-carboxy lie acid
Using the procedure described in Example 502, the title compound was isolated by lyophilization from dilute aqueous TFA/CH3CN as an amorphous solid H NMR (CDCI3, 300 MHz) 7.56 (d, J=3.0 Hz, IH), 7.50 (d, 1=3 Hz, IH), 6.83-6.66 (m, 3H), 6.28 (t, J=3 Hz, IH), 5.91 (s, 2H), 4.55-3.98 (m, 6H), 3.83-3.72 (t, J=10.5 Hz, IH), 3.61-3.40 (t, J=10.5 Hz, 1 H), 3.36-3.12 (m, 5H), 2.69-2.43 (m, 2H), 1.59-1.42 (m, 4H), 1.38-1.21 (m, 4H), 0.91
(t, J=7.5 Hz, 6H). MS (DCI/NH3) at m/e 499 (M+H)+. Anal calcd for C27H38N4O5O.75 TFA: C, 58.60; H, 6.69; N, 9.59. Found: C, 58.53; H, 6.45; N, 9.67.
Example 523 trans, tr_.ns-2-(4-Methoxyphenyl)-4-π ,3-benzodioxol-5-yl)-l -[(N-butyl-N-(3- hydroxypropyl)amino)carbonylmethyl]-pyrroHdine-3-carboxylic acid
Example 523A N-Butyl-N-(3-hydroxypropyl)-amine
To a solution of 15.9g (100 mmol) of methyl 3-N-(n-butyl)aminopropionate in 150 mL of cHethyl ether at 0 C was added 50 mL (0.35 mmol) of 1.0M LiAlH4 in diethyl ether, keeping reflux at a minimum. The mixture was stirred at 0 C for 2.25 hours, the quenched by sequential dropwise addition of 1.9 mL H2O, 1.9 mL 15%w/vΝaOH(β^), and 5.7 mL H2O. After stirring for 30 min, the salts were filtered and washed with diethyl ether, then the filtrate was concentrated to 11.3 g (86%) of a light yellow oil.
Example 523B N-Butyl-N-(3-hydroxypropylVchloroacetamide To an ice cooled solution of 1.31g (10.0 mmol) of N-butyl,N-(3- hydroxypropyl) amine in 20 mL of ethyl acetate was added a solution of 1.71g (10.0 mmol) of chloroacetic anhydride in lOmL of ethyl acetate. The mixture was stirred, and gradually warmed to room termperature over 18 hours. The reaction was extracted with H2O (1 x 50 mL), saturated ΝaHCθ3 (aq) (2 x 50 mL), and brine (1 x 50 mL), dried over MgSO4, filtered, and concentrated to an oil. The product was purified via silica gel chromatography, eluting with 80:20 hexanes: ethyl acetate to give 723 mg (35%) of a Hght yellow oil.
Example 523C trans. tra77_;-2-(4-Methoxyphenyl)-4-(l,3-benzodioxol-5-yl)-l-[(N-butyl-N-(3- hydroxypropyl)amino)carbonylmethyl]-pyrroHdine-3-carboxylic acid
Using the procedures described in Example ID, substituting N-butyl-N-(3- hydroxypropyl)-chloroacetamide for N-propyl bromoacetamide and adding DMSO as cosolvent, afforded the title compound, which was isolated by lyophilization from dUute aqueous TFA/CH3CN. 1H NMR (CD3OD, 300 MHz) δ 0.78-0.95 (m, 3H), 1.00-1.80 (m, 4H), 2.80-3.65 (m, 15H), 3.80 (d, J=1.5 Hz, 2H), 5.93 (s, 2H), 6.72-7.05 (m, 5H), 7.33-7.40 ( , 2H). MS (DCI NH3) at m e 513 (M+H)+ Anal calc'd for 28H36N2θ7'1.6 H2O: C, 62.12; H, 7.30; N, 5.17. Found: C, 62.04; H, 7.21; N, 4.88.
Example 524 trans. tr-.ns-2-(4-Methoxyphenyl)-4-(l,3-benzodioxol-5-yl)-l-[(N-propyl-N- propoxyamino)carbonylmethyl]-pyrrolidine-3-carboxylic acid
Example 524A
N-Boc-O-allylhydroxylamine
O-AUylhydroxylamine hydroehloride hydrate (5.0g) was dissolved in THF (15 mL). The solution was cooled to 0°C in an ice bath. Diisopropylethylamine (8mL) and di-t- butyldicarbonate (lO.Og) were added. The mixture was stirred at 0°C for 1 hour at which point the bath was removed and the reaction allowed to warm to room temperature and stirred overnight. The THF was removed in vacuo and the residue taken up in EtOAc (25 mL), and washed with water (1 x 50 mL), saturated sodium bicarbonate solution (3 x 50 mL), IN phosphoric acid (3 x 50 mL), and brine (1 x 50 mL). The organic layer was dried with sodium sulfate and evaporated to give a light yellow oU (6.5g) which was used without any further purification.
Example 524B N-Boc-N-propyl-O-allylhydroxylamine
N-Boc-O-aUylhydroxylamine (6.5g) from the above procedure was dissolved in dry THF (25 mL) and the solution cooled to 0°C in an ice bath. Sodium hydride (1.5g, 60% dispersion in oil) was added portionwise over 5 min. The resulting mixture was stirred for 30 min at 0°C. 1-Iodopropane (3.8mL) was added dropwise to the mixture. The reaction was stirred at 0°C for 1 hour, then stirred overnight at room temperature. The THF was removed in vacuo and the residue taken up in EtOAc (50 mL) and washed with water (1 x 50 mL), saturated sodium bicarbonate solution (3 x 50 mL), IN phosphoric acid (3 x 50 mL), and brine (1 x 50 mL). The organic layer was dried with sodium sulfate and evaporated to give a light yellow oU, which was purified by flash chromatography on sUica gel eluting with 5% EtOAc/hexanes to give the title compound as a colorless oil (6.0g).
Example 524C N-Boc-N-propyl-N-propoxyamine
N-Boc-N-propyl-O-allylhydroxylamine (6.0g) was dissolved in EtOAc (100 mL).
10% Palladium-on-carbon (0.5g) was added, and the mixture was purged with nitrogen. The nitrogen line was exchanged for a balloon of hydrogen, and the mixture was stirred at room temperature for 6 hours. The catalyst was removed by filtration through a pad of Cehte and the solvents were removed in vacuo to give a yellow oU which was purified by flash chromatography on silica gel eluting with 5% EtOAc/hexanes to give the title compound as a colorless oU (5.8g). Example 524D N-Propyl-N-propoxyamine hydroehloride
N-Boc-N-propyl-N-propoxyamine (5.8g) was dissolved in 4N HCl/dioxane (l mL) and stirred at room temperature for 7 hours. The solvent was removed in vacuo and the residue triturated with diethyl ether. The resulting yellow solid (2. Ig) was collected by filtration and washed with diethyl ether.
Example 524E N-propyl-N-propoxy-bromoacetamide
N-Propyl-N-propoxyamine hydroehloride (0.30 g) was dissolved in acetonitrUe and cooled to -20°C PyricHne (0.2 mL) was added. Bromoacetyl bromide (0.15g) was added dropwise over 5 min. The solution was stirred at -20°C for 30 min. The bath was removed and the solution was stirred for 6 hours at room temperature. The solvent was removed in vacuo and the residue taken up in EtOAc (50 mL) and washed with water (1 x 25 mL), IN phosphoric acid (3 x 25 mL), and brine (1 x 25 mL). The organic layer was dried with sodium sulfate and evaporated to give a dark orange oU (0.35g). The product is a mixture of chloro- and bromoacetamides in a ratio of ~3:1.
Example 524F trans. tra77s-2-(4-Methoxyphenyl)-4-(l,3-benzodioxol-5-yl)-l-[(N-butyl-N-(3- hydroxypropyl) amino) carbonylmethyl] -pyrrolidine-3-carboxylic acid
Prepared according to the procedure of Example 523C, employing N-propyl-N- propoxy-bromoacetamide and ethyl 2-(4-methoxyphenyl)-4-(l,3-benzodioxol-5-yl)- pyrrolidine-3-carboxylate. The crude product was purified by preparative HPLC (Vydac mC18) eluting with a 10-70% gradient of CH3CN in 0.1% TFA. The appropriate fraction was lyophilized to give the product as a white sohd. H NMR (CDCI3, 300 MHz) 0.87 (m, 6H, J=8Hz), 1.49 (m, 2H, J=8Hz), 1.61 (m, 2H, J=8Hz), 3.55 (m, 6H), 3.80 (m, 2H),
3.81 (s, 3H), 4.00 (m, 2H), 4.13 (d, 2H, J=17Hz), 5.96 (s, 2H), 6.77 (d, IH, J=9Hz), 6.90 (m, 3H), 7.05 (d, IH, J=lHz), 7.44 (d, 2H, J=9Hz). MS (DCI NH3) m/e 499 (M+H)+ Anal calcd for C27H34N2O7 . 1.20 TFA: C, 55.57; H, 5.58; N, 4.41. Found: C, 55.59; H, 5.58; N, 4.55.
Example 525 trans, tran ,-2-(4-Methoxyphenyl)-4-(l,3-benzodioxol-5-yl)-l-[(N-butyl-N- propoxyamino)carbonylmethyl]-pyrroUdine-3-carboxylic acid
Example 525A N-butyl-N-(2-hydroxyethyl)-amine
In a thick walled glass tube 5 ml (100 mmol) of ethylene oxide was condensed at - 78 C. To thisl2.5 ml (120 mmol) of butylamine was added and the tube was sealed. The resultant solution was aUowed to heat in an oU bath at 50 C for 18 hours. Unreacted reagents were removed by evaporation to give the title compound.
Example 525B N-Butyl-N-(2-azidoethyl)-chloroacetamide
To 500 mg of N-butyl,N-2-hydroxyethylamine was added 2 mL of thinoyl chloride, dropwise. After the initial reaction had ceased, the reaction was stirred for 10 min, then concentrated to an oU. Diethyl ether was added and evaporated to aid in removal of the thionyl chloride. The residue was taken up in 10 mL of DMF, and l.Og (16 mmol) of sodium azide was added. The reaction was stirred at 75 C for 2 hours, then poured into 50 mL of 0.6M NaHC03(α^.) and extracted with diethyl ether (3 x 15 mL). The combined ether layers were back extracted with brine (1 x 15 mL), dried over MgSO4, and filtered. To the ether solution was added 850 mg (4.97 mmol) of chloroacetic anhydride. The reaction was stirred for 10 min, then concentrated to an oil. This was taken up in 10 mL of saturated NaHCθ3(α^.) and extracted with diethyl ether (3 5 mL). The combined ether layers were back extracted with brine (1 x 5 mL), dried over MgSO4, filtered, and concentrated to an oU. This was purified via sUica gel chromatography, eluting with 30% ethyl acetate: hexanes, to give 161 mg (17%) of an oU.
Example 525C trans. tra7zs-2-(4-Methoxyphenyl -4-(l,3-benzodioxol-5-yl)-l-[(N-butyl-N-(2- aminoethyl)amino)carbonylmethyl]-pyrroUdine-3-carboxylic acid
According to the procedure of Example 523C, N-butyl-N-(2-azidoethyl)- chloroacetamide was coupled with ethyl 2-(4-Methoxyphenyl)-4-(l,3-benzodioxol-5-yl)- pyrrolidine-3-carboxylate. The crude product was chromatographed on silica, using 40% EtOAc in hexanes to elute. The product was dissolved in a solution of ethanol and aqueous 2.5 N sodium hydroxide and stirred for 3 hours at room temperature. The solution was concentrated in vacuo and water added. The mixture was extracted with ether; the aqueous layer was acidified to pH 4 with IN H3PO4 and extracted with EtOAc. The latter organic extract was washed with brine and dried over Na2S O4. To 100 mg (0.10 mmol) of the azide was added lmL of IM HCl(α^.), 0.5 mL of dioxane, and 5 mg of 10% Pd-C The suspension was stirred under 1 atm. of H2 for 5 hours, then filtered and concentrated to a white soHd. The product was purified via HPLC, eluting with a 0 to 70 CH3CN in 0.1% aqueous TFA gradient to give the title compound as its TFA salt. H NMR (CD3OD, 300 MHz) 0.92 (t, J=7.0 Hz, 3H), 0.96 (t, rotamer), 1.23 ( , 2H), 1.41 (m, 2H), 3.06 ( , 4H), 3.39 (m, 2H), 3.69 (m, 2H), 3.84 (s, 3H), 3.94 (m, 3H), 4.18 (m, 2H), 5.05 (bd, J=10.7 Hz, IH), 5.98 (s, 2H), 6.84 (d, J=7.7 Hz, IH), 6.93 (dd, J=1.8, 8.1 Hz, IH), 7.05 (m, 3H), 7.56
(m, 2H). MS (DCI/NH3) at m/e 498 (M+H)+ Anal calcd for C27H35N3θ6*3.15 TFA: C,
46.68. H, 4.49. N, 4.90. Found: C, 46.61; H, 4.73; N, 4.79.
Example 526 trans. tr_-77_.-2-(4-Methoxyphenyl)-4-(l,3-benzodioxol-5-yl)-l-[(N-butyl-N-(3- aminopropyl) amino) carbonylmethyl] -pyrrolidine-3 -carboxyHc acid To and ice-cold solution of the compound of Example 523C (100 mg, 0.19 mmol) in 1 mL of dichloromethane was added 17mL of methanesulfonyl chloride, and 39 mL of triethylamine. The mixture was stirred for 20 min, then dUuted with 1.5 mL of dichloromethane and extracted once with 5mL of water to which had been added 1 drop of 85% H3PO4, then 5% ammonium hydroxide (1 x 2.5 mL), and brine (1 x 2.5 mL), dried over MgSO4, filtered, and concentrated to an oU. To a solution of 81 mg (0.13 mmol) of the mesylate in lmL of DMF was added 65 mg (10 mmol) of sodium azide. The mixture was stirred for 1 hour at 50 C, then poured into 10 mL of water and extracted with diethyl ether (3 x 5 mL). The combined ether layers were back extracted with brine (1 x 5 mL), dried over MgSO4, filtered, and concentrated to an oil. This was purified via sUica. gel chromatography, eluting with 60:40 hexanes: ethyl acetate to give 57 mg of a colorless oil. The product was dissolved in a solution of ethanol and aqueous 2.5 N sodium hydroxide and stirred for 3 hours at room temperature. The solution was concentrated in vαcuo and water added. The mixture was extracted with ether; the aqueous layer was acidified to pH 4 with IN H3PO4 and extracted with EtOAc. The latter organic extract was washed with brine and dried over Na2SO4. To this azide was added lmL of IM RCl(αq.), 0.5 mL of dioxane, and 5 mg of 10% Pd-C The suspension was stirred under 1 arm. of H2 for 5 hours, then filtered and concentrated to a white sohd. The product was purified via HPLC, eluting with a 0 to
1 70 CH3CN in 0.1% aqueous TFA gradient to give the title compound as its TFA salt. H NMR (D6-DMSO, 300 MHz) δ 0.85 (apparent q, J=6.8 Hz, 3H), 1.17 (m, 2H), 1.30 (m,
2H), 1.67 (m, 2H), 2.71 (m, 2H), 3.04 (m, IH), 3.21 (m, 3H), 3.45 (m, IH), 3.75 (m, 3H),
3.97 (s, 3H), 3.85-4.80 (broad m, 3H), 6.03 (m, 2H), 6.87 (dd, J=1.4, 8.1 Hz, IH), 6.92 (d,
J=7.8 Hz, IH), 7.01 (m, 2H), 7.16 (m,- IH), 7.55 (m, 2H), 7.72 (m, 2H), 7.85 (m, IH); MS
(DCI/NH3) (M+H)+ at m/e 512. Anal calcd for C28H37N3θ6'3.0 TFA: C, 47.84. H, 4.72. N, 4.92. Found: C, 47.86; H, 4.75; N, 4.97.
Example 527 trans. trαns-2-(4-Methoxyphenyl)-4-(l,3-benzodioxol-5-yl)-l-[(N-butyl-N-(3- dimethylaminopropyl) amino) carbonylmethyl] -pyrroHdine-3 -carboxylic acid Example 527A N-butyl-N-(3-bromopropyl)bromoacetamide
To 1.50g (11.4 mmol) of N-butyl-N-(3-hydroxy)propylamine was added 3 mL of 48% RBτ aq.), and 1.5 mL of cone. H2SO4. The reaction was stirred at reflux for 3 hours, then cooled to room temperature and stirred for 22 hours. The mixture was poured over 50 mL of ice, and the solution was treated with 50 mL of 2M NaOH(α^.). The basic solution was extracted with ethyl acetate (3 x 25 mL), then the combined ethyl acetate layers were back extracted with brine (1 x 25 mL), dried, and filtered. To the ice cooled ethyl acetate solution was added 3mL of triethylamine, then 1.5 mL of bromoacetyl bromide as a solution in 3.5 mL of ethyl acetate. The reaction was stirred at 0 C for 30 min, then extracted with IM RCl(aq.) (2 x 25 mL) saturated NaHCθ3(β#.) (1 x 25 mL) and brine (1 x 25 mL). The organic layer was dried over MgSO4, filtered, and concentrated to an oil. This was purified via silica gel chromatography, eluting with 30% ethyl acetate in hexanes to give 1.47g of a colorless oU.
Example 527B
Ethyl trans. tr_t77_:-2-(4-Methoxγphenyl -4-(l,3-benzodioxol-5-yl -l-[fiSf-butyl-N-(3- bromopropyl amino)carbonylmethyl]-pyrrolidine-3-carboxylate
According to the procedure of Example 523C, N-butyl-N-(3-bromopropyl- bromoacetamide was coupled with ethyl 2-(4-Methoxyphenyl)-4-(l,3-benzodioxol-5-yl)- pyrrohdine-3 -carboxylate. The crude product was chromatographed on sUica, using 40%) EtOAc in hexanes to elute.
Example 527C traits. trans-2-(4-Methoxyphenyl)-4-(l,3-benzodioxol-5-yl)-l-[(N-butyl-N-(3- dimethy laminopropyl) amino) carbonylmethyl] -pyrr oHdine-3 -carboxylic acid
To 400 mg (0.663 mmol) of the compound of Example 527B in 4 mL of absolute
EtOH was added 1.2 mL of 2.0 M Me2NH in THF. The reaction was heated at 50 C for 3h, then stirred at room temperature for 18 hours. The mixture was concentrated, then reconcentrated from CH3CN to remove most of the trimethylamine. The product was purified via siHca gel chromatography, eluting with 9: 1 CH2Q2: MeOH over about 20 mL of silica gel to give the ethyl ester. The product was dissolved in a solution of ethanol and aqueous 2.5 N sodium hydroxide and stirred for 3 hours at room temperature. The solution was concentrated in vacuo and water added. The mixture was extracted with ether; the aqueous layer was acidified to pH 4 with IN H3PO4, and the product was purified by preparative HPLC. lR NMR (CD3OD, 300 MHz) 0.92 (t, J=7.0 Hz, 3H), 1.22 (m, 2H), 1.39 (m, 2H), 1.90 (m, 2H), 2.87 (s, 6H), 3.07 ( , 4H), 3.24 (m, IH), 3.43 ( , IH), 3.62 (m, IH), 3.84 (s, 3H), 3.88 (m, 3H), 4.07 (m, IH), 4.17 (m, IH), 4.97 (m, IH), 5.97 (s, 2H), 6.83 (d, J=8.1 Hz, IH), 6.93 (dd, J=1.7, 8.1 Hz, IH), 7.05 (m, 3H), 7.53 ( , 2H). MS (DCI/NH3) at /e 540 (M+H)+ Anal calcd for C3θH4lN3θ6'2.95 TFA: C, 49.22. H, 5.06. N, 4.80. Found: C, 49.16; H, 5.11; N, 4.62.
Example 528 trans, tra7ts-2-(4-Methoxyphenyl)-4-(l,3-benzodioxol-5-yl)-l-[(N-butyl-N-(3- trimethylammoιnbpropyl)amino)carbonylmethyl]-pyrroHdine-3-carboxylic acid
Prepared according to the procedures of Example 527C, substituting aqueous Me3N for Me2NH. lR NMR (CD3OD, 300 MHz) δ 0.91 (m, 3H), 1.24 (m, 2H), 1.40 (m, 2H),
1.99 (m, 2H), 3.13 (s, 9H), 3.18 (s, rotamer), 3.20 (m, 3H), 3.39 (m, 4H), 3.72 (m, IH), 3.84 (s, 3H), 4.03 (m, 3H), 4.35 (m, IH), 5.19 (m, IH), 5.97 (s, 2H), 6.84 (d, J=8.1 Hz, IH), 6.96
(dd, J=1.7, 7.9 Hz, IH), 7.10 (m, 3H), 7.62 (m, 2H). MS (DCI/NH3) at m/e 554 (M+H)+. Anal calcd for C3lH44N3θ6*0.1 H2θ»l. 5 TFA: C, 47.25. H, 4.96. N, 4.32. Found: C, 47.25; H, 4.74; N, 4.75.
Example 529 trans, t7--.77s-2-(4-Methoxyphenyl)-4-(l,3-benzodioxol-5-yl)-l-[(N-butyl-N-(4- aιninobutyl)amino)carbonylmethyl]-pyrroHdine-3-carboxylic acid Example 529A N-butyl-N-(4-hydroxybutyl)-amine
A solution of 8.1 g (110 mmol) of n-butylamine and 8.6 g of butyrolactone in 50 ml toluene was allowed to reflux under nitrogen atmosphere for 50 hours. Volatile solvents were removed in vacuo. To a solution of 3.18 gm (20 mmol) of the resultant N-butyl -4- hydroxybutyramide in 50 ml of toluene were added 120 ml (120 mmol) DIBAL(25%W). The solution was heated with stirring at 70 C for 18 hours. After cooling to 0 C, the reaction was quenched with methanol (1/3 amount of DIBAL solution was used) followed by addition of saturated solution of Rochelle's salt. The mixture was extracted twice with EtOAc; the organic extracts were washed with brine and dried over Na2SO4.
Example 529B N-butyl-N-(4-hydroxybutyl)-chloroacetamide
Pyridine (2 ml) was added to an ice cold solution of 0.58 gm (4 mmol) of N-butyl-N- (4-hydroxybutyl)-amine in 10 ml of EtOAc. To this solution 0.769 gm (4.5 mmol) chloroacetic anhydride was added in small portions. The reaction mixture was allowed to stir for 5 hours at 0 C, and then was aUowed to warm to room temperature. Bicarbonate was added, and the resultant mixture was extracted with EtOAc. The organic layer was washed with water and brine. The crude material was purified by column chromatography.
Example 529C Ethyl trans. trans-2-(4-Methoxyphenyl)-4-(l,3-benzodioxol-5-yl)-l-[(N-butyl-N-(4- hy droxybutyl) amino) carbon lmethyl] -pyrroHdine-3 -carboxylate
According to the procedure of Example 523C, N-butyl-N-(4-hydroxybutyl- chloroacetamide was coupled with ethyl 2-(4-Methoxyphenyl)-4-(l,3-benzodioxol-5-yl)- pyrroHdine-3 -carboxylate. The crude product was chromatographed on sUica gel.
Example 529D Ethyl trans. tra7?_.-2-(4-Methoxyphenyl -4-(l ,3-benzodioxol-5-yl)-l-[(N-butyl-N-(4- bromobutvD amino) carbonylmethyl] -pyrrolidine-3 -carboxylate
To the solution of 0.180 gm (0.33 mmol) of the compound of Example 529C in 2 ml DMF 0.086 gm (1 mmol) of lithium bromide and 0.120 ml (0.66 mmol) of PBr3 was added. The reaction mixture was allowed to stir at 0 C for 2 hours and was slowly warmed to room temperature. Bicarbonate was added, and the resultant mixture was extracted with EtOAc. The organic layer was washed with water and brine. The crude material was purified by column chromatography.
Example 529E trans. trans-2-(4-Methoxyphenyl)-4-( 1 ,3-benzodioxol-5-yl)- 1 -[(N-butyl-N-(4- aminobutyl)amino)carbonyhnethyl]-pyrroHdine-3-carboxylic acid
To a solution of 0.135 gm (0.21 mmol) of the compound of Example 529D in 2 ml
DMF was added 0.1 gm of sodium azide. Reaction was allowed to stir at room temperature for 18 hours under nitrogen atmosphere. After addition of water, the product was extracted into EtOAc. The crude product (117 mg) was dissolved in 10 ml ethanol under nitrogen atmosphere. To this 45 mgs of 10% Pd C catalyst was added, the nitrogen from the reaction flask was evacuated and was flushed with hydrogen by placing a balloon fiUed with hydrogen.
The reaction was allowed to stir for 4 hours under hydrogen atmosphere, and was worked up by filtering through a Celite pad. The product was dissolved in a solution of ethanol and aqueous 2.5 N sodium hydroxide and stirred for 8 hours at room temperature. The solution was concentrated in vacuo and water added. The mixture was extracted with ether; the aqueous layer was acidified to pH 4 with IN H3PO4, and the product was purified by preparative HPLC !H NMR (CD3OD, 300 MHz) δ 0.90 (t, J=7 Hz, 3H), 1.10-1.65 (m,
6H), 2.85-2.95 (m, 2H), 3.00-4.10 (m, 14H), 5.50 (d, 1=3 Hz, 2H), 5.97 (s, 2H), 6.82 (d, J=8 Hz, IH), 6.91 (dd, 1=1 Hz, IH), 7.00-7.06 ( , 3H), 7.45-7.55 (m, 2H). MS (DCI NH3) at m/e 526 (M+H)+. Anal calc'd for C29H39N3O6-2.2 TFA: C, 51.75; H, 5.35; N, 5.41. Found: C, 51.75; H, 5.31; N, 5.30.
Example 530 trans. tmns-2-(4-Methoxyphenyl)-4-(l,3-benzodioxol-5-yl)-l-[(N-butyl-N-(4- dimethylaminobutyl)amino)carbonylmethyl]-pyrrolidine-3-carboxylic acid
The title compound was prepared from the compound of Example 529D, employing the procedures of Example 527C B NMR (CD3OD, 300 MHz) 0.90 (dt, J=7Hz, 3H), 1.1-1.75 (m, 8H), 2.75 (d, 1=1 Hz, 6H), 3.0-4.25 (m, 16H), 5.97 (s, 2H), 6.83 (d, J=8 Hz, IH), 6.93 (dd, J=8 Hz, IH), 7.02-7.08 (m, 3H), 7.49-7.56 (m, 2H). MS (DCI/NH3) at m/e
554 (M+H)+ Anal calc'd for C3lH43N3θ6*2.1 TFA: C, 53.31; H, 5.73; N, 5.30. Found: C, 53.50; H, 5.38; N, 5.34.
Example 531 trans, tran5,-2-(4-Methoxyphenyl)-4-(l,3-benzodioxol-5-yl)-l-[(N-butyl-N-(3- pyridyl)amino)carbonylmethyl]-pyrroUdine-3-carboxylic acid
Example 531 A N-butyl-N-.3-pyridylVamine
To a solution of 941 mg (10 mmol) of 3-aminopyridine and 0.9 mL of butyraldehyde in 30 mL of CH3OH was added 10 mL of glacial acetic acid. The mixture was stirred at room temperature for 1 hour, then the reaction was cooled with an ice bath, and 650 mg (10.3 mmol) of sodium cyanoborohydride was added. The ice bath was removed, and the reaction was stirred for 4.5 hours at room temperature. The mixture was poured into 300 mL of 0.67M NaOH(Ω .), and extracted with ethyl acetate (3 x 50 mL). The combined organic layers were back extracted with brine (1 x 50 mL), dried over MgSO4, filtered, and concentrated to an oil. The product was isolated via silica gel chromatography, eluting with 3:1 ethyl acetate: hexanes to give 1.18g (79%) of a colorless solid. Example 53 IB trans, tmns-2-(4-Methoxyphenyl)-4-( 1 ,3-benzodioxol-5-yl)- 1 -[(N-butyl-N-(3- pyridyl)am-no)carbonylmethyl]-ρyrroUdine-3-carboxylic acid
The compound of Example 53 IA was reacted according to the procedures of
Example 523, to give the title compound. 1H NMR (D6-DMSO, 300 MHz) 0.80 (t, J=6.4 Hz, 3H), 1.15-1.99 (m, 4H), 2.59 (m, IH), 3.05 (m, 2H), 3.26 (m, 2H), 3.49 (m, 2H), 3.56 (t, J=7.1 Hz, 2H), 3.73 (s, 3H), 6.00 (s, 2H), 6.80 (m, 3H), 6.85 (d, J=8.1 Hz, IH), 6.98 (m, 2H), 7.04 (m, IH), 7.41 (dd, J=l, 4.7 Hz, 8.1H), 7.58 (m, IH), 8.36 (bs, IH), 8.54 (bs,
IH), 12.24 (bs, IH). MS (DCI/NH3) at m/e 532 (M+H)+. Anal calcd for C30H33N3θ6*0.1 H3PO4: C, 66.55. H, 6.20. N, 7.76. Found: C, 66.59; H, 6.06; N, 7.60.
Example 532 trans, tr_.?7s-2-(4-Methoxyphenyl)-4-( 1 ,3-benzodioxol-5-yD- 1 -[(N-butyl-N-(3- an_inomethylphenyl)amino carbonylmethyl]-pyrrolidine-3-carboxylic acid
Example 532A N-butyl-N-(3-hydroxymethylphenyl)-amine
To a solution of 3.69 g (30 mmol) of 3-amino benzyl alcohol in 20 ml DMSO was added 3.78 g (45 mmol) solid NaHCO3 and 2.91 ml (27 mmol) 1-bromobutane. The reaction was allowed to stir at 50 C for 18 hours (overnight). Reaction was worked up by adding 250 ml water and product was extracted in ethyl acetate. Water was added, and the resultant mixture was extracted with EtOAc. The organic layer was washed with water and brine.
Example 532B N-butyl-N-(3-hvdroxymethylphenyl)-bromoacetamide To a solution of 3.42 g (19.2 mmol) of the compound of Example 532A in 20 ml toluene, was added 2.42 ml (30 mmol) pyridine. The mixture was cooled to 0 C; 4.025 gm (20.0 mmol) of bromoacetyl bromide (diluted with 5 ml toluene) was added in a dropwise fashion. The reaction mixture was allowed to stir for 5 hours at 0 C and then was aUowed to warm to room temperature. Saturated potassium carbonate solution was added, and the mixture was stirred vigorously for 2 hours. The mixture was extracted with EtOAc; the organic layer was washed with IN H3PO4, water, and brine.
Example 532C
Ethyl trans. tra77s-2-(4-Methoxyphenyl)-4-(l ,3-benzodioxol-5-yl)-l-[(N-butyl-N-(3- chloromethylphenyl)amino)carbonylmethyl]-pyrrolidine-3-carboxylate
According to the procedure of Example 523C, N-butyl-N-(3-hydroxymethylphenyl)- bromoacetamide was coupled with ethyl 2-(4-Methoxyphenyl)-4-( 1 ,3-benzodioxol-5-yl)- pyrroHdine-3-carboxylate. The crude product (129 mg) was dissolved in 0.5 ml of DMF and cooled to 0°C; 19 mg of LiCl was added, foUowed by 85 μl of thionyl chloride. The mixture was aUowed to stir for 30 min; water was added, and the mixture was extracted with EtOAc. The organic extracts were washed with water and brine, and dried over Na2SO4.
Example 532D trans, tr_.n_.-2-(4-Methoxyphenyl)-4-( 1 ,3-benzodioxol-5-yl)- 1 -[(N-butyl-N-(3- aminomethylphenyl) amino) carbonylmethyl] -pyrrolidine-3 -carboxylic acid
The compound of Example 532C (182 mg) was dissolved in 1 mL of DMF. Two drops of water were added, followed by 126 mg (2.0 mmol, 6.5 eq) of sodium azide. The resultant solution was heated at 115 °C for 3 hours. Water was added, and the mixture was extracted with EtOAc. The organic extracts were washed with water and brine, and dried over N 2SO4.
Example 532E trans, trans -2-(4-Methoxyphenyl)-4-( 1 ,3 -benzodioxol-5-yl)- 1 -[(N-butyl-N-(3- aminomethylphenyl)amino.carbonylmethyl]-pyrrolidine-3-carboxy lie acid
In a 50 ml round bottom flask 0.090 gm Tin (II) chloride was suspended in 1 ml acetonitrUe. Triethylamine (0.2 mL) was added, foUowed by 0.19 ml of thiophenol ; the reaction mixture turned yellow. Reaction flask was cooled to 0 C in ice bath; a solution of 0.185 gm of the compound of Example 532D in 2 ml acetonitrile was added. The mixture was allowed to stir for 30 min. Ether (10 ml) was added, foUowed by addition of 10 ml 2N HCl . The aqueous extract was basified with 4N NaOH and extracted with dichloromethane. The organic layer was washed with water and brine. The crude product was dissolved in a solution of ethanol and aqueous 2.5 N sodium hydroxide and stirred for 8 hours at room temperature. The solution was concentrated in vacuo and water added. The mixture was extracted with ether; the aqueous layer was acidified to pH 4 with IN H3PO4, and the product was purified by preparative HPLC ^NMR ^DsOD, 300 MHz) 0.88 (t, 1=7 Hz, 3H), 1.15-1.45 (m, 4H), 3.40-4.20 (m, 14H), 5.97 (s, 2H), 6.82 (d, J=8 Hz, IH), 6.88 (dd, J=8 Hz, IH), 6.97-7.20 (m, 5H), 7.40 (d, J=9 Hz, 2H), 7.56 (d, J=5 Hz, 2H). MS
(DCI/NH3) at m/e 560 (M+H)+. Anal calcd for C32H37N3θ6'4.2 TFA: C, 46.72; H, 4.00; N, 4.05. Found: C, 46.66; H, 4.06; N, 4.00.
Example 533 trans, t7jα775'-2-(4-Methoxyphenyl)-4-(l,3-benzodioxol-5-yl)-l-[(N-butyl-N-(3- trimethylammombmethylphenyl)amino)carbonylmethyl]-pyrroHcHne-3-carboxylic acid
To a stirred solution of 0.128 gm of the compound of Example 532C in 0.5 ml methanol, 0.25 ml of an aqueous solution of trimethylamine was added. The mixture was allowed to stir at room temperature under nitrogen atmosphere for 4 hours. IN HCl was added; the aqueous was washed with ether to extract organic impurities. The aqueous layer was dried azeotropically with toluene, and the residue was dried under high vacuum. Yield 0.115 gm. iH NMR (300 MHz, D6-DMSO) 0.83 (t, 1=1 Hz, 3H), 1.15-1.40 (m, 4H), 2.62 (s, 2H), 3.35 (s, 9H), 3.40-3.80 (m, 10H), 4.47 (s, 2H), 6.00 (s, J=3 Hz, 2H), 6.75-6.90 (m, 3H), 7.25-7.37 (m, 2H), 7.45-7.60 (m, 3H). MS (DCI/NH3) at m/e 602 (M+H)+.
Example 534
(2R.3R. S)-2-f3-Fluoro-4-methoxyphenvι)-4-f 1 ,3-benzodioxol-5-yl .1 -r2-rN-propyl-N- ρentanesulfonylamino)ethyl)-pyrroHdine-3-carboχylic acid
Example 534A Ethyl (3 -fluoro-4-methoxy)benzoylacetate
Sodium hydride (17g of a 60% suspension in mineral oU) is washed three times with toluene. The powder is suspended in 138 mL of toluene, and 35 mL of diethyl carbonate is added. The mixture is heated to 90 °C, and a solution of 25 g of 3-fluoro-4- methoxyacetophenone and 50 ml of diethyl carbonate in 50 ml of toluene was added portionwise. Heating is continued for 30 min, then the reaction is cooled to room temperature. A solution of 50 ml of concentrated HCl in 75 ml of ice water is added slowly, and the mixture is stirred. The mixture is extracted with toluene; the combined organic extracts are washed with brine and bicarbonate solutions. The product is dried over Na2SO4 and decolorized with charcoal to give 34.5 g (97%) of the title compound.
Example 534B Ethyl 2-(3-Fluoro-4-methoxyphenyl)-4-(l,3-benzodioxol-5-yl)-ρyrrolidine-3-carboxylate
The compound of Example 534A (12.5 g) and 5-(nitrovinyl)-l,3-benzodioxole (13.1 g, 20% excess) were suspended in a mixture of 75 ml of THF and 13 ml of iPrOH. DBU (0.25 g) was added, and the mixture was stirred at room temperature for 30 min. An additional 0.1 g of DBU was added, and the solution was stirred for 1 hour. The solvents were removed in vacuo; toluene was added, along with brine containing 3 ml of concentrated HCl. The mixture was extracted twice with toluene; the organics were dried over MgSO4. The residue was flashed on silica, using CH2CI2 to elute. Yield 75%. This material (17.4 g) is combined with 35 g of Raney Nickel (washed) in 250 mL of EtOAc. The mixture is shaken under 4 atm of hydrogen for 18 hours. The solution is concentrated in vacuo; the residue is chromatographed on sUica, eluting with 4% EtOAc in CH2CI2. Yield 10.13 g = 66%. The product is combined with 26 ml of THF and 50 ml of EtOH; 2.18 g of NaBH3CN are added, along with a trace of bromcresol green as indicator. A solution of 1 :2 concentrated HCl/EtOH is added dropwise to maintain pH at green-yellow; after color persists, the reaction mixture is stirred for an additional 20 min. The solvents are removed in vacuo; the residue is stirred with mixture of toluene and KHCO3 solution. The organic phase is washed with water and brine, and dried over MgSO4. The crude product is purified by flash chromatography on sUica, eluting with 2: 1 EtOAc/hexanes. Yield 5.92 g (58%) of a 2: 1 mixture of trans-trans and cis-trans isomers.
Example 534C Ethvπ R.3R. S)-2-(3-Fluoro-4-methoxyphenylV4-(l,3-benzodioxol-5-ylVpyrroHdine-3- carboxylate
To the racemic amino ester above (15.0 g, 38.8 mmol), dissolved in 75 ml methylene chloride and cooled in an ice bath, was added Boc anhydride (9.30 g, 42.7 mmol). After stirring 2 hours at room temperature, the solution was concentrated in vacuo ; the residue was dissolved in 50 ml ethanol and treated with a solution of 3.75 g sodium hyroxide in 19 ml water. The solution was warmed until aU was soluble. After stirring for 2 hours at room temperature, the solution was concentrated and redissolved in 200 ml of water. This was extracted with 75 ml of diethyl ether. The ether layer was extracted with 40 ml of water. The combined aqueous phases were acidified with 7.5 g acetic acid; the mixtiire was stirred untU a solid formed. The solid was filtered, washed with water and dissolved in methylene chloride. After drying with sodium sulfate, the solution was concentrated and the residue crystallized from 1 : 1 etherhexane to get 15.99 g of product, m.p. 200-203 (90% yield). The crude acid was suspended in 80 ml ethyl acetate and treated with 4.00 g (33.1 mmol) of (S)- (-)-a-methylbenzylamine. After heating to dissolve the acid, 80 ml of ether was added. Scratching with a glass rod caused the product to crystallize. The sohds were filtered and washed with ether-ethyl acetate solution to give 8.22 g (81% yield based on 50% maximum recovery) of salt, m.p. 165-168°C After one recrystallization, chiral HPLC analysis, using a Regis Whelk-O column, indicated >99.5 % e.e. The salt was dissolved in 500 ml of 36% HCl in ethanol; a white sohd forms. The resultant suspension was heated for 16 hours at 52°C. After concentrating in vacuo, the residue was combined with toluene and stirred with potassium bicarbonate in water for 30 minutes. The toluene was separated, dried (Na2SO4) and concentrated. The residue was chromatographed on sUica gel, eluting with 33% hexane- 67% ethyl acetate to get 6.9 g (99%) of the resolved amino ester.
Example 534D Ethyl (2R.3R. S^2-(3-Fluoro-4-methoxyρhenyl . -4-f 1.3-benzodioxol-5-yl , 1 -(2- N- propylamino)ethyl)-pyrroHdine-3-carboxylate
The compound of Example 534C was dissolved in 1,2-dibromoethane ( 10 mL per 1 g of starting material ); dnsopropylethylamine (1 mL per 1 g of starting material ) and Nal ( 100 mg per 1 g of starting material) were added, and the mixture was stirred at 100°C for 1 hour. Toluene was added, and the mixture was washed with bicarbonate. The solvents were concentrated, and the resultant black residue was chromatographed on silica gel, eluting with 4: 1 hexane-EtOAc to give the N-(2-bromoethyl)pyrrolidine (85-92%). This compound was combined with n-propylamine (3.5 eq.) and Nal (10% by weight of bromide) in ethanol ( 5 mL per 1 g of bromide), and was heated at 80°C for 2 hours. Toluene was added, and the mixture was washed with bicarbonate, dried (Na2SO4), and concentrated. More toluene was added, and removed in vacuo, to get rid of the primary amine. The residue was dissolved in heptane and filtered to remove a small amount of insoluble material. Evaporation of the solvent gave the desired product (86-93% yield), which was used for the next step without further purification.
Example 534E 1-Pentanesulfonyl chloride
1-Pentanesulfonic acid, sodium salt (10 g, 57.5 mmol) was charged into a 250 ml round bottom flask (allow headroom). Thionyl chloride (20 mL) is added; gas evolves, and a while solid forms. The mixture is heated at 60 °C for 3 hours. The solvents are removed in vacuo; toluene is added and removed in vacuo to remove residue of SOC12- The residue is partitioned between CH2CI2 and ice water; the organic layer is dried over Na2SO4 . The crude product is purified by distillation (bp 54-56 °C @ 0.5 mm Hg) to give a clear oU, 61% yield.
Example 534F
(2R.3R.4S)-2-(3-Fluoro-4-methoxyphenyl>-4-( 1 ,3-benzodioxol-5- yl) 1 -r2-(N-propyl-N- pentanesulfonylamino)ethyl)-pyrrolidine-3-carboxylic acid
The compound of Example 534D (200 mg, 0.43 mmol) was dissolved in 5 mL of
CH3CN; 110 mg (2 eq) ofN,N-dnsopropylethylamine and 72.8 mg (1.2 eq) of 1- pentanesulfonyl chloride were added sequentially, the resultant solution was allowed to stir at room temperature for 30 min. The solvent was evaporated under reduced pressure and the residue was dissolved in EtOAc. The solution was washed with saturated NaHCO3 solution, IN H3PO4, and brine, dried over Na2SO4 and evaporated to give a yellowish oil which was purified by flash chromatography on silica gel eluting with 40% EtOAc/hexane to give 220 mg of product (85%). This ester was dissolved in 5 mL of EtOH, to which was added NaOH (46 mg, 3 eq) solution in 2 mL of H2O. This mixture was stirred for 3 hours at room temperature. The solution was concentrated in vacuo using low (<40°C) heat. Water (10 mL) and ether (50 mL) were added; the ether layer was extracted with 5 mL of water. The combined aqueous mixture was back-extracted with ether and then neutraUzed with acetic acid. This solution was extracted twice with ether. The ether was dried (Na2SO4) and concentrated in vacuo. EtOAc (1 mL) and ether (1 mL) were added to dissolve the product, and hexane was added dropwise to produce a white solid. The solid was collected and dried in vacuo to give 125 mg of the title compound.
Example 534H t2Jg i,rfS;-2-(y3-Fluoro-4-methoxyphenylV4-π.3-benzodioxol-5-vm-f2-(;N-propyl-N- pentanesulfonylamino)ethylVpyrroHdine-3-carboxylic acid, hydroehloride salt The free amine is dissolved in iPrOH; a slight excess of HCl in iPrOH is added, and the solution is concentrated in vacuo. More IP A is added, and the solution is reconcentrated. The resultant sticky
material is stirred with ether overnight to give a white powder, which is coUected by filtration and dried overnight in vacuo at 60 °C Yield 95%.
Example 535
The compounds in Table 3C may be prepared using methods presented in the above Examples.
Table 3C.
Figure imgf000457_0001
Figure imgf000458_0001
Figure imgf000459_0001
Figure imgf000459_0002
10
Figure imgf000459_0003
1 12
Figure imgf000459_0004
13 14
Figure imgf000460_0001
15 16
Figure imgf000460_0002
17 18
Figure imgf000460_0003
20
Figure imgf000461_0001
22
Figure imgf000461_0002
24
Figure imgf000461_0003
26
Figure imgf000462_0001
28
Figure imgf000462_0002
30
Figure imgf000462_0003
32
Figure imgf000463_0001
33 34
Figure imgf000463_0002
5 36
Figure imgf000463_0003
7 38 39
Figure imgf000464_0001
41
Figure imgf000464_0002
43
Figure imgf000464_0003
4 45
Figure imgf000465_0001
6 47
Figure imgf000465_0002
8 49
Figure imgf000465_0003
0 51
Figure imgf000465_0004
52 53
Figure imgf000466_0001
54 55
Figure imgf000466_0002
56 57
Figure imgf000466_0003
8 59
Figure imgf000467_0001
60 61
Figure imgf000467_0002
62 63
64 65
Figure imgf000467_0004
66 67
Figure imgf000468_0001
68 69
Figure imgf000468_0002
70 71
Figure imgf000468_0003
72 73
Figure imgf000469_0001
74 75
Figure imgf000469_0002
76 77
Figure imgf000469_0003
78 79
Figure imgf000469_0004
80 81
Figure imgf000470_0001
82 83
Figure imgf000470_0002
84 85
Figure imgf000470_0003
86 87
Figure imgf000471_0001
88 89
Figure imgf000471_0002
90 91
Figure imgf000471_0003
92 93
Figure imgf000471_0004
94 95
Figure imgf000472_0001
96 97
Figure imgf000472_0002
98 99
Figure imgf000472_0003
100 101
Figure imgf000473_0001
102 103
Figure imgf000473_0002
104 105
Figure imgf000473_0003
106 107
Figure imgf000474_0001
108 109
Figure imgf000474_0002
110 111
Figure imgf000474_0003
112 113
Figure imgf000475_0001
114 115
Figure imgf000476_0001
116 117
Figure imgf000476_0002
118 119
Figure imgf000476_0003
120 121
Figure imgf000477_0001
122 123
Figure imgf000477_0002
124 125
Figure imgf000477_0003
126 127
Figure imgf000477_0004
128 129
Figure imgf000478_0001
130 131
Figure imgf000478_0002
132 133
Figure imgf000478_0003
134 135
Figure imgf000479_0001
136 137
Figure imgf000479_0002
138 139
Figure imgf000480_0001
140 141
Figure imgf000480_0002
142 143
Figure imgf000480_0003
144 145
Figure imgf000481_0001
146 147
Figure imgf000482_0001
148 149
Figure imgf000482_0002
150 151
Figure imgf000482_0003
152 153
Figure imgf000483_0001
154 155
Figure imgf000483_0002
156 157
Figure imgf000483_0003
157 159
Figure imgf000484_0001
160 161
Figure imgf000484_0002
162 163
Figure imgf000484_0003
164 165
Figure imgf000485_0001
166 167
Figure imgf000485_0002
168 169
Figure imgf000485_0003
170 171
Figure imgf000486_0001
172 173
Figure imgf000486_0002
174 175
Figure imgf000486_0003
176 177
Figure imgf000487_0001
178 119
Figure imgf000487_0002
181 180
Figure imgf000487_0003
182 183
Figure imgf000488_0001
184 185
Figure imgf000488_0002
186 187
Figure imgf000488_0003
188 189
Figure imgf000489_0001
190 191
Figure imgf000489_0002
192 193
Figure imgf000489_0003
194 195
Figure imgf000490_0001
196 197
Figure imgf000490_0002
198 199
Figure imgf000490_0003
00 201
Figure imgf000491_0001
202 203
Figure imgf000491_0002
204 205
Figure imgf000491_0003
206 207
Figure imgf000492_0001
208 209
Figure imgf000492_0002
210 211
Figure imgf000492_0003
212 213
Figure imgf000492_0004
214 215
Figure imgf000493_0001
216 217
Figure imgf000493_0002
218 219
Figure imgf000493_0003
220 221
Figure imgf000494_0001
222 223
Figure imgf000494_0002
224 225
Figure imgf000494_0003
226 227
Figure imgf000494_0004
228 229
Figure imgf000495_0001
230 231
Figure imgf000495_0002
232 233
Figure imgf000495_0003
234 235
Figure imgf000496_0001
236 237
Figure imgf000496_0002
238 239
Figure imgf000496_0003
240 241
Figure imgf000497_0001
242 243
Figure imgf000497_0002
244 245
Figure imgf000497_0003
246 247
Figure imgf000497_0004
248 249
Figure imgf000498_0001
250 251
Figure imgf000498_0002
252 253
Figure imgf000498_0003
254 255
Figure imgf000499_0001
256 257
Figure imgf000499_0002
258 259
Figure imgf000499_0003
260 261
Figure imgf000499_0004
262 263
Figure imgf000500_0001
264 265
Figure imgf000500_0002
266 267
Figure imgf000500_0003
268 269
Figure imgf000501_0001
270 271
Figure imgf000501_0002
272 273
Figure imgf000501_0003
274 275
Figure imgf000501_0004
276 277
Figure imgf000502_0001
278 279
Figure imgf000502_0002
280 281
Figure imgf000502_0003
282 283
Figure imgf000503_0001
284 285
Figure imgf000503_0002
286 287
Figure imgf000503_0003
288 289
Figure imgf000504_0001
290 291
Figure imgf000504_0002
292 293
Figure imgf000504_0003
294 295
Figure imgf000504_0004
296 297
Figure imgf000505_0001
298 299
Figure imgf000505_0002
300 301
Figure imgf000505_0003
302 303
Figure imgf000505_0004
304 305
Figure imgf000506_0001
306 307
Figure imgf000506_0002
308 309
Figure imgf000506_0003
310 311
Figure imgf000507_0001
312 313
Figure imgf000507_0002
314 315
Figure imgf000507_0003
316 317
Figure imgf000507_0004
318 319
Figure imgf000508_0001
320 321
Figure imgf000508_0002
322 323
Figure imgf000508_0003
324 325
Figure imgf000509_0001
326 327
Figure imgf000509_0002
328 329
Figure imgf000509_0003
330 331
Figure imgf000509_0004
332 333
Figure imgf000510_0001
334 335
Figure imgf000510_0002
336 337
Figure imgf000510_0003
338 339
Figure imgf000510_0004
340 341
Figure imgf000511_0001
342 343
Figure imgf000511_0002
344 345
Figure imgf000511_0003
346 347
Figure imgf000512_0001
348 349
Figure imgf000512_0002
350 351
Figure imgf000512_0003
352 353
Figure imgf000512_0004
354 355
Figure imgf000513_0001
356 357
Figure imgf000513_0002
358 359
Figure imgf000513_0003
360 361
Figure imgf000514_0001
362 363
Figure imgf000515_0001
364 365
Figure imgf000515_0002
366 367
Figure imgf000515_0003
368 369
Figure imgf000516_0001
370 371
Figure imgf000516_0002
372 373
Figure imgf000516_0003
374 375
Figure imgf000516_0004
376 377
Figure imgf000517_0001
378 379
Figure imgf000517_0002
380 381
Figure imgf000517_0003
382 383
Figure imgf000517_0004
384 385
Figure imgf000518_0001
386 387
Figure imgf000519_0001
388 389
Figure imgf000519_0002
390 391
Figure imgf000519_0003
392 393
Figure imgf000520_0001
394 395
Figure imgf000520_0002
396 397
Figure imgf000520_0003
398 399
Figure imgf000520_0004
400 401
Figure imgf000521_0001
402 403
Figure imgf000521_0002
404 405
Figure imgf000521_0003
406 407
Figure imgf000521_0004
409
Figure imgf000522_0001
410 411
Figure imgf000523_0001
412 413
Figure imgf000523_0002
414 415
Figure imgf000523_0003
416 417
Figure imgf000524_0001
419
Figure imgf000524_0002
420 421
Figure imgf000524_0003
422 423
Figure imgf000525_0001
424 425
Figure imgf000525_0002
426 427
Figure imgf000525_0003
428 429
Figure imgf000526_0001
430 431
Figure imgf000526_0002
432 433
Figure imgf000526_0003
434 435
Figure imgf000527_0001
436 437
Figure imgf000527_0002
438 439
Figure imgf000527_0003
440 441
Figure imgf000528_0001
442 443
Figure imgf000528_0002
444 445
Figure imgf000528_0003
446 447
Figure imgf000528_0004
448 449
Figure imgf000529_0001
450 451
Figure imgf000529_0002
452 453
Figure imgf000529_0003
454 455
Figure imgf000530_0001
456 457
Figure imgf000530_0002
458 459
Figure imgf000530_0003
460 461
Figure imgf000531_0001
462 463
Figure imgf000531_0002
464 465
Figure imgf000531_0003
466 467
Figure imgf000532_0001
468 469
Figure imgf000532_0002
470 471
Figure imgf000532_0003
472 473
Figure imgf000533_0001
474 475
Figure imgf000533_0002
476 477
Figure imgf000533_0003
478 479
Figure imgf000534_0001
480 481
Figure imgf000534_0002
482 483
Figure imgf000534_0003
484 485
Figure imgf000535_0001
486 487
Figure imgf000535_0002
488 489
Figure imgf000535_0003
490 491
Figure imgf000536_0001
493
Figure imgf000536_0002
495
Figure imgf000536_0003
497
Figure imgf000537_0001
498 499
Figure imgf000537_0002
500 501
Figure imgf000537_0003
502 503
Figure imgf000538_0001
504 505
Figure imgf000538_0002
506 507
Figure imgf000538_0003
508 509
Figure imgf000539_0001
510 511
Figure imgf000539_0002
512 513
Figure imgf000539_0003
514 515
Figure imgf000540_0001
516 511
Figure imgf000540_0002
518 519
Figure imgf000540_0003
520 521
Figure imgf000541_0001
522 523
Figure imgf000541_0002
524 525
Figure imgf000541_0003
526 527
Figure imgf000542_0001
528 529
Figure imgf000542_0002
530 531
Figure imgf000543_0001
532 533
Figure imgf000543_0002
534 535
Figure imgf000543_0003
536 537
Figure imgf000544_0001
538 539
Figure imgf000544_0002
540 541
Figure imgf000544_0003
Figure imgf000545_0001
544 545
Figure imgf000545_0002
546 547
Figure imgf000545_0003
548 549
Figure imgf000546_0001
550 551
Figure imgf000546_0002
552 553
Figure imgf000546_0003
Figure imgf000547_0001
556 557
Figure imgf000547_0002
558 559
Figure imgf000547_0003
560 561
Figure imgf000548_0001
562 563
Figure imgf000548_0002
564 565
Figure imgf000548_0003
566 567
Figure imgf000549_0001
568 569
Figure imgf000549_0002
570 571
Figure imgf000549_0003
572 573
Figure imgf000550_0001
574 575
Figure imgf000550_0002
576 577
Figure imgf000550_0003
579
580 581
Figure imgf000551_0002
582 583
Figure imgf000551_0003
584 585
Figure imgf000552_0001
586 587
Figure imgf000552_0002
588 589
Figure imgf000552_0003
590 591
Figure imgf000553_0001
592 593
Figure imgf000553_0002
594 595
Figure imgf000553_0003
596 597
Figure imgf000554_0001
598 599
Figure imgf000554_0002
600 601
Figure imgf000554_0003
602 603
Figure imgf000555_0001
604 605
Figure imgf000555_0002
606 607
Figure imgf000555_0003
608 609
Figure imgf000556_0001
0 611
Figure imgf000556_0002
2 613
Figure imgf000556_0003
4 615
Figure imgf000557_0001
616 611
Figure imgf000557_0002
618 619
Figure imgf000557_0003
620 621
Figure imgf000557_0004
622 623
Figure imgf000558_0001
624 625
Figure imgf000558_0002
626 627
Figure imgf000559_0001
628 629
fto
Figure imgf000559_0002
Figure imgf000559_0003
630 631
fto
Figure imgf000559_0005
Figure imgf000559_0004
632 633 fto
Figure imgf000560_0001
Figure imgf000560_0002
634 635
Figure imgf000560_0003
636 637
Figure imgf000560_0004
638 639
Figure imgf000561_0001
640 641
fto
Figure imgf000561_0002
Figure imgf000561_0003
642 643
Figure imgf000561_0004
644 645
Figure imgf000562_0001
646 647
Figure imgf000562_0002
648 649
Figure imgf000562_0003
650 651
Figure imgf000563_0001
652 653
Figure imgf000563_0002
654 655
Figure imgf000563_0003
656 651
Figure imgf000564_0001
658 659
Figure imgf000564_0002
660 661
Figure imgf000564_0003
662 663
Figure imgf000565_0001
664 665
Figure imgf000565_0002
666 661
Figure imgf000565_0003
668 669
Figure imgf000566_0001
610 671
Figure imgf000566_0002
672 613
Figure imgf000566_0003
614 675
Figure imgf000567_0001
616 611
Figure imgf000567_0002
678 679
Figure imgf000567_0003
680 681
Figure imgf000568_0001
Figure imgf000568_0002
684 685
Figure imgf000568_0003
686 687
Figure imgf000569_0001
688 689
Figure imgf000569_0002
690 691
Figure imgf000569_0003
692 693
Figure imgf000570_0001
694 695
Figure imgf000570_0002
696 697
Figure imgf000570_0003
698 699
Figure imgf000570_0004
700 701
Figure imgf000571_0001
702 703
Figure imgf000571_0002
704 705
Figure imgf000571_0003
706 707
Figure imgf000572_0001
708 709
Figure imgf000572_0002
710 711
Figure imgf000572_0003
712 713
Figure imgf000573_0001
714 715
Figure imgf000573_0002
716 717
Figure imgf000573_0003
718 719
Figure imgf000574_0001
0 721
Figure imgf000574_0002
2 723
Figure imgf000574_0003
4 725
Figure imgf000575_0001
726 727
Figure imgf000575_0002
728 729
Figure imgf000576_0001
730 731
Figure imgf000576_0002
732 733
Figure imgf000576_0003
734 735
Figure imgf000577_0001
736 737
Figure imgf000577_0002
738 739
Figure imgf000577_0003
740 741
Figure imgf000578_0001
742 743
Figure imgf000578_0002
744 745
Figure imgf000578_0003
746 747
Figure imgf000579_0001
748 749
Figure imgf000579_0002
750 751
Figure imgf000579_0003
752 753
Figure imgf000580_0001
754 755
Figure imgf000580_0002
756 757
Figure imgf000580_0003
758 759
Figure imgf000581_0001
760 761
Figure imgf000581_0002
762 763
Figure imgf000581_0003
764 765
Figure imgf000582_0001
766 767
Figure imgf000582_0002
768 769
Figure imgf000582_0003
770 771
Figure imgf000583_0001
772 773
Figure imgf000583_0002
774 775
Figure imgf000583_0003
776 777
Figure imgf000584_0001
778 779
Figure imgf000584_0002
780 781
Figure imgf000584_0003
782 783
Figure imgf000585_0001
784 785
Figure imgf000585_0002
786 787
Figure imgf000585_0003
788 789
Figure imgf000586_0001
790 791
Figure imgf000586_0002
792 793
Figure imgf000586_0003
794 795
Figure imgf000586_0004
796 797
Figure imgf000587_0001
798 799
Figure imgf000587_0002
800 801
Figure imgf000587_0003
802 803
Figure imgf000588_0001
804 805
Figure imgf000588_0002
806 807
Figure imgf000588_0003
808 809
Figure imgf000589_0001
810 811
Figure imgf000589_0002
812 813
Figure imgf000589_0003
814 815
Figure imgf000590_0001
816 817
Figure imgf000590_0002
818 819
Figure imgf000590_0003
820 821
822 823
Figure imgf000591_0002
824 825
Figure imgf000591_0003
826 827
Figure imgf000592_0001
828 829
Figure imgf000592_0002
830 831
Figure imgf000592_0003
832 833
Figure imgf000593_0001
834 835
Figure imgf000593_0002
836 837
Figure imgf000593_0003
838 839
Figure imgf000594_0001
842 843
Figure imgf000594_0002
44 845
Figure imgf000594_0003
6 847
Figure imgf000595_0001
848 849
Figure imgf000596_0001
850 851
Figure imgf000596_0002
852 853
Figure imgf000596_0003
854 855
Figure imgf000597_0001
856 857
Figure imgf000597_0002
858 859
Figure imgf000597_0003
860 861
Figure imgf000598_0001
862 863
Figure imgf000598_0002
864 865
Figure imgf000598_0003
866 867
Figure imgf000599_0001
868 869
Figure imgf000599_0002
870 871
Figure imgf000599_0003
Figure imgf000600_0001
874 875
Figure imgf000600_0002
876 sn
Figure imgf000600_0003
878 879
Figure imgf000601_0001
880 881
Figure imgf000601_0002
882 883
Figure imgf000601_0003
884 885
Figure imgf000602_0001
886 887
Figure imgf000602_0002
888 889
Figure imgf000602_0003
890 891
Figure imgf000603_0001
892 893
Figure imgf000603_0002
894 895
Figure imgf000603_0003
896 897
Figure imgf000604_0001
898 899
Figure imgf000604_0002
900 901
Figure imgf000604_0003
902 903
Figure imgf000605_0001
904 905
Figure imgf000605_0002
906 907
Figure imgf000605_0003
908 909
Figure imgf000606_0001
910 911
Figure imgf000606_0002
912 913
Figure imgf000606_0003
914 915
Figure imgf000607_0001
916 917
Figure imgf000607_0002
918 919
Figure imgf000607_0003
920 921
Figure imgf000608_0001
922 923
Figure imgf000608_0002
924 925
Figure imgf000608_0003
926 927
Figure imgf000609_0001
928 929
Figure imgf000609_0002
930 931
Figure imgf000609_0003
932 933
Figure imgf000610_0001
934 935
Figure imgf000610_0002
936 937
Figure imgf000610_0003
938 939
Figure imgf000611_0001
940 941
fto
Figure imgf000611_0003
Figure imgf000611_0002
942 943
Figure imgf000611_0004
944 945
Figure imgf000612_0001
946 947
Figure imgf000612_0002
948 949
Figure imgf000612_0003
950 951
Figure imgf000613_0001
52 953
Figure imgf000613_0002
954 955
Figure imgf000613_0003
956 957 X fto
Figure imgf000614_0002
Figure imgf000614_0001
958 959
:ryy
Figure imgf000614_0003
960 961
Figure imgf000614_0004
962 963
Figure imgf000615_0001
964 965
Figure imgf000615_0002
966 967
Figure imgf000615_0003
968
969
Figure imgf000616_0001
970
971
fto
Figure imgf000616_0002
Figure imgf000616_0003
972
973
Figure imgf000616_0004
74
975
Figure imgf000617_0001
16 977
Figure imgf000617_0002
978 979
Figure imgf000617_0003
980 981
Figure imgf000618_0001
982 983
Figure imgf000618_0002
984 985
Figure imgf000619_0001
986 987
Figure imgf000619_0002
988 989
Figure imgf000619_0003
990 991
Figure imgf000620_0001
992 993
Figure imgf000621_0001
994 995
Figure imgf000621_0002
996 997
Figure imgf000621_0003
998 999
Figure imgf000622_0001
1000 1001
fto
Figure imgf000622_0002
Figure imgf000622_0003
1002 1003
Figure imgf000622_0004
1004 1005
Figure imgf000623_0001
1006 1007
Figure imgf000623_0002
1008 1009
Figure imgf000623_0003
1010 1011
Figure imgf000624_0001
1012 1013
Figure imgf000624_0002
1014 1015
Figure imgf000624_0003
1016 1017
Figure imgf000625_0001
1018 1019
Figure imgf000625_0002
1020 1021
Figure imgf000625_0003
1022 1023
Figure imgf000626_0001
1024
1025
Figure imgf000626_0002
1026
1027
Figure imgf000626_0003
1028 1029
Figure imgf000627_0001
0 1031
Figure imgf000627_0002
1032 1033
Figure imgf000628_0001
1034 1035
Figure imgf000628_0002
1036 1037
Figure imgf000628_0003
1038 1039
Figure imgf000629_0001
1040 1041
Figure imgf000629_0002
1042 1043
Figure imgf000629_0003
1044 1045
Figure imgf000629_0004
1046 1047
Figure imgf000630_0001
1048 1049
Figure imgf000630_0002
1050 1051
Figure imgf000630_0003
1052 1053
Figure imgf000631_0001
1054 1055
Figure imgf000631_0002
1056 1057
Figure imgf000631_0003
1058 1059
Figure imgf000632_0001
1060 1061
Figure imgf000632_0002
1062 1063
Figure imgf000632_0003
1064 1065
Figure imgf000633_0001
1066 1067
Figure imgf000633_0002
1068 1069
Figure imgf000633_0003
1070 1071
Figure imgf000634_0001
1072 1073
Figure imgf000634_0002
1074 1075
Figure imgf000634_0003
1076 1077
Figure imgf000635_0001
Figure imgf000635_0002
1080 1081
Figure imgf000635_0003
1082 1083
Figure imgf000636_0001
1084 1085
Figure imgf000636_0002
1086 1087
Figure imgf000636_0003
1088 1089
Figure imgf000637_0001
1090 1091
Figure imgf000637_0002
1092 1093
Figure imgf000637_0003
1094 1095
Figure imgf000638_0001
1096 1097
Figure imgf000638_0002
1098 1099
Figure imgf000638_0003
1100 1101
Figure imgf000639_0001
1102 1103
Figure imgf000639_0002
1104 1105
Figure imgf000639_0003
1106 1107
Figure imgf000640_0001
1108 1109
Figure imgf000640_0002
1110 llll
Figure imgf000640_0003
1112 1113
Figure imgf000641_0001
1114 1115
Figure imgf000641_0002
1116 1117
Figure imgf000641_0003
1118 1119
Figure imgf000642_0001
1120 1121
Figure imgf000642_0002
1122 1123
Figure imgf000642_0003
1124 1125
Figure imgf000643_0001
1126 1127
Figure imgf000643_0002
1128 1129
Figure imgf000643_0003
1130 1131
Figure imgf000644_0001
1132 1133
Figure imgf000644_0002
1134 1135
Figure imgf000644_0003
1136 1137
Figure imgf000645_0001
1138 1139
Figure imgf000645_0002
1140 1141
Figure imgf000645_0003
1142 1143
Figure imgf000646_0001
1144 1145
Figure imgf000646_0002
1146 1147
Figure imgf000646_0003
1148 1149
Figure imgf000647_0001
1150 1151
Figure imgf000647_0002
1152 1153
Figure imgf000647_0003
1154 1155
Figure imgf000648_0001
1156 1157
Figure imgf000648_0002
1158 1159
Figure imgf000648_0003
1160 1161
Figure imgf000649_0001
1162 1163
Figure imgf000649_0002
1164 1165
Figure imgf000649_0003
1166 1167
Figure imgf000650_0001
1168 1169
Figure imgf000650_0002
1170 1171
Figure imgf000650_0003
1172 1173
Figure imgf000651_0001
1174 1175
Figure imgf000651_0002
1176 1177
Figure imgf000651_0003
1178 1179
Figure imgf000652_0001
1180 1181
Figure imgf000652_0002
1182 1183
Figure imgf000652_0003
1184 1185
Figure imgf000653_0001
1186 1187
Figure imgf000653_0002
1188 1189
Figure imgf000653_0003
1190 1191
Figure imgf000654_0001
1192 1193
Figure imgf000654_0002
1194 1195
Figure imgf000654_0003
1196 1197
Figure imgf000655_0001
1198 1199
Figure imgf000655_0002
1200 1201
Figure imgf000655_0003
1202 1203
Figure imgf000655_0004
1204 1205
Figure imgf000656_0001
1206 1207
Figure imgf000656_0002
1208 1209
Figure imgf000657_0001
1210 1211
Figure imgf000657_0002
1212 1213
Figure imgf000657_0003
1214 1215
Figure imgf000658_0001
1216 1217
Figure imgf000658_0002
1218 1219
Figure imgf000658_0003
1220 1221
Figure imgf000659_0001
1222 1223
Figure imgf000659_0002
1224 1225
Figure imgf000660_0001
1226 1227
Figure imgf000660_0002
1228 1229
Figure imgf000660_0003
1230 1231
Figure imgf000661_0001
1232 1233
Figure imgf000662_0001
1234 1235
Figure imgf000662_0002
1236 1237
Figure imgf000662_0003
1238 1239
Figure imgf000663_0001
1240 1241
Figure imgf000663_0002
1242 1243
Figure imgf000663_0003
1244 1245
Figure imgf000664_0001
1246 1247
Figure imgf000664_0002
1248 1249
Figure imgf000664_0003
1250 1251
Figure imgf000665_0001
1252 1253
Figure imgf000665_0002
1254 1255
Figure imgf000665_0003
1256 1257
Figure imgf000666_0001
1258 1259
Figure imgf000666_0002
1260 1261
Figure imgf000666_0003
1262 1263
Figure imgf000667_0001
1264 1265
Figure imgf000667_0002
1266 1267
Figure imgf000667_0003
1268 1269
Figure imgf000668_0001
1270 1271
Figure imgf000668_0002
1272 1273
Figure imgf000668_0003
1274 1275
Figure imgf000669_0001
1276 1277
Figure imgf000669_0002
1278 1279
Figure imgf000669_0003
1280 1281
Figure imgf000670_0001
1282 1283
Figure imgf000670_0002
1284 1285
Figure imgf000670_0003
1286 1287 -noryd—
Figure imgf000671_0001
1288 1289
Figure imgf000671_0002
1290 1291
Figure imgf000671_0003
1292 1293
Figure imgf000672_0001
1294 1295
Figure imgf000672_0002
1296 1297
Figure imgf000672_0003
1298 1299
Figure imgf000673_0001
1300 1301
Figure imgf000673_0002
1302 1303
Figure imgf000673_0003
1304 1305
Figure imgf000674_0001
1306 1307
Figure imgf000674_0002
1308 1309
Figure imgf000674_0003
1310 1311
Figure imgf000675_0001
1312 1313
Figure imgf000675_0002
1314 1315
Figure imgf000675_0003
1316 1317
Figure imgf000676_0001
1318 1319
Figure imgf000676_0002
1320 1321
Figure imgf000676_0003
1322 1323
Figure imgf000677_0001
1324 1325
Figure imgf000677_0002
1326 1327
Figure imgf000677_0003
1328 1329
Figure imgf000678_0001
1330 1331
Figure imgf000678_0002
1332 1333
Figure imgf000678_0003
1334 1335
Figure imgf000679_0001
1336 1337
Figure imgf000679_0002
1338 1339
Figure imgf000679_0003
1340 1341
Figure imgf000680_0001
1342 1343
Figure imgf000680_0002
1344 1345
Figure imgf000680_0003
1346 1347
Figure imgf000681_0001
1348 1349
Figure imgf000681_0002
1350 1351
Figure imgf000681_0003
1352 1353
Figure imgf000682_0001
1354 1355
Figure imgf000682_0002
1356 1357
Figure imgf000682_0003
1358 1359
Figure imgf000683_0001
1360 1361
Figure imgf000683_0002
1362 1363
Figure imgf000683_0003
1364 1365
Figure imgf000684_0001
1366 1367
Figure imgf000684_0002
1368 1369
Figure imgf000684_0003
1370 1371
Figure imgf000685_0001
1372 1373
Figure imgf000685_0002
1374 1375
Figure imgf000685_0003
1376 1377
Figure imgf000686_0001
1378 1379
Figure imgf000686_0002
1380 1381
Figure imgf000686_0003
1382 1383
Figure imgf000687_0001
1384 1385
Figure imgf000687_0002
1386 1387
Figure imgf000687_0003
1388 1389
Figure imgf000688_0001
1390 1391
Figure imgf000688_0002
1392 1393
Figure imgf000688_0003
1394 1395
Figure imgf000689_0001
1396 1397
Figure imgf000689_0002
1398 1399
Figure imgf000689_0003
1400 1401
Figure imgf000690_0001
1402 1403
Figure imgf000690_0002
1404 1405
Figure imgf000690_0003
1406 1407
Figure imgf000691_0001
1408 1409
Figure imgf000691_0002
1410 1411
Figure imgf000691_0003
1412 1413
Figure imgf000692_0001
1414 1415
Figure imgf000692_0002
1416 1417
Figure imgf000692_0003
1418 1419
Figure imgf000693_0001
1420 1421
Figure imgf000693_0002
1422 1423
Figure imgf000693_0003
1424 1425
Figure imgf000694_0001
1426 1427
Figure imgf000694_0002
1428 1429
Figure imgf000694_0003
1430 1431
Figure imgf000695_0001
1432 1433
Figure imgf000695_0002
1434 1435
Figure imgf000695_0003
1436 1437
Figure imgf000696_0001
1438 1439
Figure imgf000696_0002
1440 1441
Figure imgf000696_0003
1442 1443
Figure imgf000697_0001
1444 1445
Figure imgf000697_0002
1446 1447
Figure imgf000697_0003
1448 1449
Figure imgf000698_0001
1450 1451
Figure imgf000698_0002
1452 1453
Figure imgf000698_0003
1454 1455
Figure imgf000699_0001
1456 1457
Figure imgf000699_0002
1458 1459
Figure imgf000699_0003
1460 1461
Figure imgf000700_0001
1462 1463
Figure imgf000700_0002
1464 1465
Figure imgf000700_0003
1466 1467
Figure imgf000701_0001
1468 1469
Figure imgf000701_0002
1470 1471
Figure imgf000701_0003
1472 1473
Figure imgf000702_0001
1474 1475
Figure imgf000702_0002
1476 1477
Figure imgf000702_0003
1478 1479
Figure imgf000703_0001
1480 1481
Figure imgf000704_0001
1482 1483
Figure imgf000704_0002
1484 1485
Figure imgf000704_0003
1486 1487
Figure imgf000705_0001
1488 1489
Figure imgf000705_0002
1490 1491
Figure imgf000705_0003
1492 1493
Figure imgf000705_0004
94 1495
Figure imgf000706_0001
1496 1497
Figure imgf000707_0001
1498 1599
Figure imgf000707_0002
1500 1501
Figure imgf000707_0003
1502 1503
Figure imgf000708_0001
1504 1505
Figure imgf000709_0001
1506 1507
Figure imgf000709_0002
1508 1509
Figure imgf000709_0003
1510 1511
Figure imgf000709_0004
709
1512 1513
Figure imgf000711_0001
1514 1515
Figure imgf000711_0002
1516 1517
Figure imgf000711_0003
1518 1519
Figure imgf000711_0004
711
1520 1521
Figure imgf000713_0001
1522 1523
Figure imgf000713_0002
1524 1525
Figure imgf000713_0003
1526 1527
Figure imgf000714_0001
1528 1529
Figure imgf000715_0001
1530 1531
Figure imgf000715_0002
1532 1533
Figure imgf000715_0003
1534 1534
Figure imgf000716_0001
1536 1537
Figure imgf000717_0001
1538 1539
Figure imgf000717_0002
1540 1541
Figure imgf000717_0003
1542 1543
Figure imgf000718_0001
1544 1545
Figure imgf000719_0001
1645 1647
Figure imgf000719_0002
1548 1549
Figure imgf000719_0003
1550 1551
Figure imgf000720_0001
Figure imgf000721_0001
1554 1555
Figure imgf000721_0002
1556 1557
Figure imgf000721_0003
1558 1559
Figure imgf000722_0001
1560 1561
Figure imgf000723_0001
1562 1563
Figure imgf000723_0002
1564 1565
Figure imgf000723_0003
1566 1567
Figure imgf000724_0001
1568 1569
iN
Figure imgf000724_0002
Figure imgf000724_0003
1572 1573
Figure imgf000725_0001
4 1575
Figure imgf000725_0002
1576 1577
Figure imgf000726_0001
1578 1579
Figure imgf000726_0002
1580 1581
Figure imgf000726_0003
1582 1583
Figure imgf000727_0001
Figure imgf000727_0002
1586 1587
Figure imgf000727_0003
1588 1589
Figure imgf000728_0001
1590 1591
Figure imgf000728_0002
1592 1593
Figure imgf000728_0003
1594 1595
Figure imgf000729_0001
1596 1597
Figure imgf000729_0002
Figure imgf000729_0003
1600 1601
1602 1603
Figure imgf000730_0002
1604 1605
Figure imgf000730_0003
1606 1607
Figure imgf000731_0001
1608 1609
Figure imgf000731_0002
1610 1611
Figure imgf000731_0003
1612 1613
Figure imgf000732_0001
1614 1615
Figure imgf000732_0002
1616 1617
Figure imgf000732_0003
1618 1619
Figure imgf000733_0001
1620 1621
Figure imgf000733_0002
1622 1623
Figure imgf000733_0003
1624 1625
Figure imgf000734_0001
1626 1627
Figure imgf000734_0002
1628 1629
Figure imgf000734_0003
1630 1631
Figure imgf000735_0001
1632 1633
Figure imgf000735_0002
1634 1635
Figure imgf000735_0003
1636 1637
Figure imgf000736_0001
1638 1639
Figure imgf000736_0002
1640 1641
Figure imgf000736_0003
1642 1643
Figure imgf000737_0001
1644 1645
Figure imgf000737_0002
1646 1647
Figure imgf000737_0003
1648 1649
Figure imgf000738_0001
1650 1651
Figure imgf000738_0002
1652 1653
Figure imgf000738_0003
1654 1655
Figure imgf000739_0001
1656 1657
Figure imgf000739_0002
1658 1659
Figure imgf000739_0003
1660 1661
Figure imgf000740_0001
1662 1663
Figure imgf000740_0002
1664 1665
Figure imgf000740_0003
1666 1667
Figure imgf000741_0001
1668 1669
Figure imgf000741_0002
1670 1671
Figure imgf000741_0003
1672 1673
Figure imgf000742_0001
1674 1675
Figure imgf000742_0002
1676 1677
Figure imgf000742_0003
1678 1679
Figure imgf000743_0001
1680 1681
Figure imgf000743_0002
1682 1683
Figure imgf000743_0003
1684 1685
Figure imgf000744_0001
1686 1687
Figure imgf000744_0002
1688 1689
Figure imgf000744_0003
1690 1691
Figure imgf000745_0001
1692 1693
Figure imgf000745_0002
1694 1695
Figure imgf000745_0003
1696 1697
Figure imgf000746_0001
1698 1699
Figure imgf000746_0002
1700 1701
Figure imgf000746_0003
1702 1703
Figure imgf000747_0001
1704 1705
Figure imgf000747_0002
1706 1707
Figure imgf000747_0003
1708 1709
Figure imgf000748_0001
1710 1711
Figure imgf000748_0002
1712 1713
Figure imgf000748_0003
1714 1715
Figure imgf000749_0001
1716 1717
Figure imgf000749_0002
1718 1719
Figure imgf000749_0003
1720 1721
Figure imgf000750_0001
1722 1723
Figure imgf000750_0002
1724 1725
Figure imgf000750_0003
1726 1727
Figure imgf000751_0001
1728 1729
Figure imgf000751_0002
1730 1731
Figure imgf000751_0003
1732 1733
Figure imgf000752_0001
1734 1735
Figure imgf000752_0002
1736 1737
Figure imgf000752_0003
1738 1739
Figure imgf000753_0001
1740 1741
Figure imgf000753_0002
1742 1743
Figure imgf000753_0003
1744 1745
Figure imgf000754_0001
1746 1747
Figure imgf000754_0002
1748 1749
Figure imgf000754_0003
1750 1751
Figure imgf000755_0001
1752 1753
Figure imgf000756_0001
1754 1755
Figure imgf000756_0002
1756 1757
Figure imgf000756_0003
1758 1759
Figure imgf000757_0001
1760 1761
Figure imgf000757_0002
1762 1763
Figure imgf000757_0003
1764 1765
Figure imgf000758_0001
66 1767
Figure imgf000758_0002
1768 1769
Figure imgf000759_0001
1770 1771
Figure imgf000759_0002
1772 1773
Figure imgf000759_0003
1774 1775
Figure imgf000760_0001
1776 1777
Figure imgf000761_0001
1778 1779
Figure imgf000761_0002
1780 1781
Figure imgf000761_0003
Example 536 r2S,3i-, S1-2-(2,2-Dimethylpentyl)-4-(7-methoxy-l,3-benzodioxol-5-yl)-l-(N,N-di(n- butyl)aminocarbonylmethyl)-pyrrolidine-3 -carboxylic acid
Example 536 A Ethyl 5,5-dimethyl-3-oxooctanoate Ethyl 3,3-dimethylhexanoate was prepared using the general procedure of Cahiez et al, Tetrahedron Lett., 31_, 7425 (1990). To a solution of 63.8 g (370 mmol) of this compound in 400 mL of ethanol, cooled to 0°C, was added a solution of 30 g of NaOH in 150 mL of water. The resultant solution was warmed to ambient temperature and stirred overnight. Solvents were removed in vacuo; the residue was taken up in 700 mL of water, and extracted twice with 1 : 1 ether/hexanes. The aqueous layer was acidified to pH3 with IN HCl and extracted twice with hexanes. The combined hexane extracts were washed with brine, dried over sodium sulfate, filtered and concentrated. A 20.2 g (150 mmol) sample of the crude product is dissolved in 150 mL of THF; 27.3 g of l, -carbonyldiimidazole is added portionwise, to control gas evolution. In meantime, 33.4 g of potassium ethylmalonate and 13.4 g of magnesium chloride are combined in 350 mL of THF (overhead mechanical stirring) and warmed to 50°C for 3 hrs. This mixture is cooled to ambient temperature, and the above acid imidazolide solution is added. The resultant slurry is stirred overnight. Ether (600 mL), hexanes (600 mL) and aqueous IN phosphoric acid (500 mL) are added, and the mixture is sitrred for 30 min. The aqueous layer is separated; the organics are washed sequentially with bicarb (2X), water and brine. The organics are dried over sodium sulfate, filtered and concentrated to give 30.2 g (95% yield) of a colorless liquid.
Example 536B
4-Methoxy-6-(2-nitrovinyl)-l,3-benzodioxole
3-Methoxypiperonal (50.0 g) is combined with 71.9 mL of nitromethane in 250 mL of acetic acid; 36 g of ammonium acetate is added, and the mixture is heated to 50°C for 4 hrs. Solvents are removed in vacuo; the residue is taken up in water and stirred for 20 min. The solution is filtered; the filtrate is washed with water, then ether, to give 51.8 g of a yellow solid.
Example 536C Ethyl trans, trα?7-.-2-(2,2-Dimethylpentyl)-4-(7-methoxy-l,3-benzodioxol-5-yl)-pyrrolidine-
3 -carboxylate
The compound of Example 536A (6.42 g, 30 mmol) was combined with 5.79 g of the compound of Example 536B in 40 mL of THF. DBU (0.5 mL) was added, and the mixture was stirred at ambient temperature for 6 hrs, during which time it turns reddish brown, and homogeneous. The solvents were removed in vacuo; the residue was taken up in EtOAc and washed sequentially with aqueous IN phosphoric acid and brine. The organic phase was dried over sodium sulfate, filtered and concentrated. The residue was dissolved in 50 mL of THF; 12 g of Raney Nickel catalyst (washed sequentially with water and ethanol) was added, followed by 10 mL of acetic acid. The resultant mixture was hydrogenated under 4 atmospheres of hydrogen until hydrogen uptake ceased (~ 3 hrs). The catalyst was removed by filtration; solvents were removed in vacuo. The residue was dissolved in 90 mL of 2:1 ethanol/THF; 30 mg of bromcresol green indicator was added, followed by 30 mL of IN sodium cyanoborohydride in THF. Concentrated HCl was added dropwise to maintain pH at the indicator point, over 1 hr. The resultant solution was stirred overnight at ambient temperature. Bicarb was added, and the solvents were removed in vacuo; the residue was partitioned between water and EtOAc. The organic material was washed with water (2X) and brine. The organic phase was dried over sodium sulfate, filtered and concentrated. The crude product was dissolved in 100 mL of acetonitrile; 10 mL of Hϋnig's base was added, and the solution was warmed to 40°C overnight. Removal of solvents in vacuo provided 5.0 g of a yellowish oil.
Example 536D Ethyl r S,3R, Sl-2-(:2,2-Dimethylpentyl)-4-(7-methoxy-l,3-benzodioxol-5-yl)-pyrrolidine-3- carboxylate
The crude compound of Example 536C (2.0 g) was combined with 4 mL of triethylamine in 40 mL of THF; 2.0 g of di-tert-butyldicarbonate was added, and the mixture was stirred at ambient temperature for 5 hrs. Solvents were removed in vacuo, and the residue was taken up in 60 mL of ethanol. Aqueous sodium hydroxide (10 mL of 2.5 N solution) was added, and the resultant solution was stirred overnight. Solvents were removed in vacuo; the residue was taken up in water and extracted with ether. The aqueous phase was acidified with aqueous IN phosphoric acid and extracted with EtOAc. The organic extracts were washed with brine, dried over sodium sulfate, filtered, and concentrated to give 1.0 g of a colorless oil. A sample of this material (0.734 g, 1.58 mmol) was combined with 0.35 g of pentafluorophenol and 0.364 g of EDAC in 5 mL of DMF. The resultant solution was stirred at ambient temperature for 1 hr, then was poured onto 50 mL of 0.6M sodium bicarbonate solution and extracted (3 X 15 mL) with ether. The combined ether extracts were washed with brine, dried over magnesium sulfate, filtered, and concentrated in vacuo to give a foam, which was dissolved in 5 mL of THF and cooled to 0°C. Simultaneously, 0.418 g (2.37 mmol) of R-4-benzyl-2-oxazolidinone was combined with ~0.1 mg of pyreneacetic acid in 5 mL of THF and cooled to 0°C. N-butyllithium (1.6M in hexanes) was added to a red endpoint (persists ~10 sec), and the solution was stirred for 10 min. The solution was transferred into the solution of the pentafluorophenyl ester, and the resultant solution was stirred at 0°C for 40 min. Solvents were removed in vacuo; the residue was taken up in bicarb and extracted with ether (3 X 10 mL). The combined ether extracts were washed with brine, dried over magnesium sulfate, filtered, and concentrated in vacuo. The crude mixture of diasteromeric products was separated by flash chromatography on silica gel, eluting with a gradient from 4:1->3:1->2:1 hexanes/EtOAc, giving 423 mg of the faster-moving and 389 mg of the slower-moving diastereomer, respectively. The faster-moving diastereomer was dissolved in 2 mL of a 2.0M solution of sodium methoxide in methanol (freshly prepared, containing 5% methyl formate by volume) and stirred at ambient temperature for 16 hrs.
Solvents were removed in vacuo, and the residue was partitioned between ether and aqueous IN sodium hydroxide. The ether layer was washed with brine, dried over magnesium sulfate, filtered, and concentrated in vacuo. The residue was purified by flash chromatography on silica gel, eluting with 4:1 hexanes/EtOAc. The resultant material was dissolved in 5 mL of TFA and stirred at ambient temperature for 1 hr. Solvents were removed in vacuo; the residue was suspended in bicarb and extracted with EtOAc. The organic phase was washed with brine, dried over magnesium sulfate, filtered, and concentrated in vacuo to give 98 mg of product.
Example 536E
\2S, 3R, Sl-2-(2,2-Dimethylpentyl)-4-(7-methoxy- 1 ,3-benzodioxol-5-yl)-l -(N,N-di(n- butyl)aminocarbonylmethyl)-pyrrolidine-3 -carboxylic acid
The compound of Example 536D (48 mg) was combined with 35 mg of the compound of Example 501A in 3 mL of acetonitrile; 0.5 mL of Hunig's base was added, and the solution was allowed to stir overnight at ambient temperature. Solvents were removed in vacuo; the residue was partitioned between EtOAc and aqueous IN phosphoric acid. The organic layer was washed with bicarb and brine, then dried over sodium sulfate, filtered and concentrated. The residue was purified by flash chromatography on silica gel, eluting with 2:1 hexanes/EtOAc. The product was dissolved in 4 mL of ethanol; 1 mL of 2.5N aqueous sodium hydroxide was added, and the resultant solution was stirred overnight at ambient temperature. Solvents were removed in vacuo; the residue was taken up in water and extracted with ether. The aqueous phase was acidified to pH 3 with aqueous IN phosphoric acid and extracted with EtOAc. The organic extracts were washed with brine, dried over sodium sulfate, filtered and concentrated to give a colorless oil. Lyophilization from acetonitrile/0.1% aqueous TFA gave 56 mg of a white solid. lR NMR (CDCI3, 300 MHz) d 0.81 (s, 3H), 0.84 (s, 3H), 0.86 (t, J = 6.9 Hz, 3H), 0.93 (t, J = 6.9 Hz, 3H), 0.96 (t, J = 6.9 Hz, 3H), 1.09-1.38 (m, 8H), 1.45-1.59 (m, 4H), 1.84-2.00 (m, 2H), 3.15 (dd, J = 6.9 Hz, 10.0 Hz, 2H), 3.30-3.42 (m, 3H), 3.72 (t, J = 10.5 Hz, IH), 3.86 (t, J = 10.5 Hz, IH), 3.88 (s, 3H), 4.02 (q, J = 10.0 Hz, IH), 4.12 (d, J = 16.8 Hz, IH), 4.29 (d, J = 16.8 Hz, IH), 4.41 (brm, IH), 5.94 (s, IH), 6.52 (d, J - 1.8 Hz, IH), 6.67 (d, J = 1.8 Hz, IH). MS (ESI) (M+H)+ at m/e 533. Anal calcd for C30H48N2O6O.7 TFA: C, 61.57; H,
8.01; N, 4.57. Found: C, 61.59; H, 8.20; N, 4.63.
Example 537 \2S, 3R, S|-2-(2,2-Dimethylpentyl)-4-( 1 ,3-benzodioxol-5-yl)- 1 -(N,N-di(n- butyl)aminocarbonylmethyl)-pyrrolidine-3 -carboxylic acid
Example 537A Ethyl trans, tr .w-2-(2,2-Dimethylpentyl)-4-(l ,3-benzodioxol-5-yl)-pyrrolidine-3- carboxylate
Prepared according to the procedures of Example 536C above, substituting the compound of Example 501B (5-(2-nitrovinyl)-l,3-benxodioxole) for 4-methoxy-6-(2- nitrovinyl)- 1 ,3 -benzodioxole.
Example 537B
Ethyl r S,3i.,^Sl-2-('2,2-Dimethylpentyl)-4-(l,3-benzodioxol-5-yl)-pyrrolidine-3-carboxylate
The compound of Example 537A (6.8 g) was dissolved in 100 mL of ether; a solution of 1.6 g of (S)-(+)-mancielic acid in 60 mL of ether was added, the total volume was made up to ~200 mL, and the solution was seeded. The mixture was stirred slowly overnight. The resultant crystals were collected by filtration and recrystallized from ether/EtOAc to give 1.8 g of a white solid. Thsi material was partitioned between bicarb and ether; the ether layer was washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo to give the enantiomerically pure product (>98% e.e.). Example 537C r2S,5i.rS1-2-(2,2-Dimethylpentyl)-4-(l,3-benzodioxol-5-yl)-l-(N,N-di(n- butyl)aminocarbonylmethyl)-pyrrolidine-3 -carboxylic acid
Prepared from the compound of Example 537B according to the procedures of Example 536E. *H NMR (CDCI3, 300 MHz) d 0.80-0.99 (m, 15H), 1.10-1.37 (m, 8H), 1.43- 1.58 (m, 4H), 1.77-1.97 (m, 2H), 3.48-3.12 (m, 5H), 3.60-3.69 (m, IH), 3.75-3.86 (m, IH), 3.95-4.16 (m, 2H), 4.28-4.4 (m, 2H), 5.94 (s, 2H), 6.74 (d, J=7.8 Hz, IH), 6.8 (dd, J=8.1, 1.5 Hz, IH), 6.87 (d, J=1.8 Hz, IH). MS (APCI+) m/e 503 (M+H)+.
Example 538 2S, 3R, S1-2-(2,2-Dimethylpentyr)-4-( 1 ,3-benzodioxol-5-yl)- 1 -((N-propoxy , N-(n- butyl))aminocarbonylmethy l)-pyrrolidine-3 -carboxylic acid
Example 538 A
N-Boc-N-butyl-O-allylhydroxylamine
O-Allylhydroxylamine hydroehloride hydrate (5.0g) was dissolved in THF (15 mL). The solution was cooled to 0°C in an ice bath. Diisopropylethylamine (8mL) and di-t- butyldicarbonate (10. Og) were added. The mixture was stirred at 0°C for one hour at which point the bath was removed and the reaction allowed to warm to room temperature and stirred overnight. The THF was removed in vacuo and the residue taken up in EtOAc (25 mL), and washed with water (1 x 50 mL), saturated sodium bicarbonate solution (3 x 50 mL), IN phosphoric acid (3 x 50 mL), and brine (1 x 50 mL). The organic layer was dried with sodium sulfate and evaporated to give a light yellow oil (6.5g). This crude product was dissolved in dry THF (25 mL) and the solution cooled to 0°C in an ice bath. Sodium hydride (1.5g, 60% dispersion in oil) was added portionwise over five minutes. The resulting mixture was stirred for 30 minutes at 0°C. 1-Iodobutane (4.1 mL) was added dropwise to the mixture. The reaction was stirred at 0°C for one hour, then stirred overnight at room temperature. The THF was removed in vacuo and the residue taken up in EtOAc (50 mL) and washed with water (1 x 50 mL), saturated sodium bicarbonate solution (3 x 50 mL), IN phosphoric acid (3 x 50 mL), and brine (1 x 50 mL). The organic layer was dried with sodium sulfate and evaporated to give a light yellow oil, which was purified by flash chromatography on silica gel eluting with 5% EtOAc/hexanes to give the title compound as a colorless oil (6.0 g).
Example 538B N-butyl-N-propoxy amine trifluoroacetate
The compound of Example 538 A (6.0 g) was dissolved in EtOAc (100 mL). 10% Palladium-on-carbon (0.5 g) was added, and the mixture was purged with nitrogen. The nitrogen line was exchanged for a balloon of hydrogen, and the mixture was stirred at room temperature for 6 hours. The catalyst was removed by filtration through a pad of Celite and the solvents were removed in vacuo to give a yellow oil which was purified by flash chromatography on silica gel eluting with 5% EtOAc/hexanes to give a colorless oil (5.8 g). A sample of the resultant material (1.15 g) was dissolved in CH2CI2 (5 mL) and cooled in an ice bath. Trifluoroacetic acid (3mL) was added and the solution stirred cold for two hours. The solvent was removed in vacuo , care being taken not to allow the solution to warm above room temperature. The residue contained considerable TFA and was used without further purification.
Example 538C
N-butyl-N-propoxy-bromoacetamide
The salt of Example 538B (0.60 g) was dissolved in acetonitrile (5 mL) and cooled to -20°C. Hϋnig's base (5.5 mL) was added slowly. Bromoacetyl bromide (0.5 mL) was added dropwise over five minutes. The solution was stirred at -20°C for 30 minutes. The bath was removed and the solution was stirred for six hours at room temperature. The solvent was removed in vacuo and the residue taken up in EtOAc (50 mL) and washed with water (1 x 25 mL), IN phosphoric acid (3 x 25 mL), and brine (1 x 25 mL). The organic layer was dried with sodium sulfate and evaporated to give a dark orange oil (0.65 g) which was used without further purification.
Example 538D r2S,ii?, S1-2-(2,2-Dimethylpentyl)-4-(l,3-benzodioxol-5-yl)-l-((N- propoxy, N-(n-butyl))aminocarbonylmethyl)-pyrrolidine-3-carboxylic acid
The compound of Example 537B was reacted with the compound of Example 538C according to the procedures of Example 536E.
Example 539
\2S, 3R, S1-2-(2,2-Dimethylpentyl)-4-(l ,3-benzodioxol-5-yl-)- 1 -((N- propoxy, N-(n-propyl))ammocarbonylmethyl)-pyrrolidine-3-carboxylic acid
Example 539 A N-propyl-N-propoxy bromoacetamide
Prepared according to the procedures of Example 538 A-C, substituting iodopropane for iodobutane in Example 538 A.
Example 539B
\2S, 3R, ¥S]-2-(2,2-Dimethylpentyl)-4-q ,3-benzodioxol-5-yl - 1 -((N- propoxy, N-(n-propyl))aminocarbonylmethyl)-pyrrolidine-3-carboxylic acid
The compound of Example 537B was reacted with the compound of Example 539 A according to the procedures of Example 536E.
Example 540 \2S, 3R, S1-2-(2,2-Dimethylpentyl)-4-(7-methoxy-l ,3-benzodioxol-5- yl)-l -((N-propoxy, N-(n-butyl))aminocarbonylmethyl)-pyrrolidine-3- carboxylic acid
The compound of Example 536D was reacted with the compound of Example 538C according to the procedures of Example 536E.
Example 541
\2S, 3R, Sl-2-(2,2-Dimethylpentyl)-4-(7-methoxy-l ,3-benzodioxol-5- yl)- 1 -((N-propoxy, N-(n-propyl))aminocarbonylmethyl)-pyrrolidine-3 - carboxylic acid
The compound of Example 536D was reacted with the compoxxnd of Example 539A according to the procedures of Example 536E.
Example 542 \2S, 3R, S1-2-(2,2-Dimethylpent-3-enyl)-4-(l ,3-benzodioxol-5-yl)-l -
((N-propoxy, N-(n-butyl))aminocarbonylmethyl)-pyrrolidine-3- carboxylic acid
Example 542A trfl/zs-Ethyl 3 ,3 -dimethyl-4-hexenoate
A mixture of 4-methyl-3-penten-2-ol (7.4 g, 74 mmol), triethyl orthoacetate (13.6 mL, 74mmol) and propionic acid (0.28 mL, 3.7 mmol) was heated at 150°C for 7 hr. The product was then distilled under normal pressure (200-220 °C) to give 5.0 g of crude ester as a colorless oil.
Example 542B
Ethyl trans, trα -2-(2,2-Dimethylpent-3-enyl -4-(l ,3-benzodioxol-5- yl)-pyrrolidine-3 -carboxylate
The title compound is prepared according to the procedures of Examples 536A and
536C, substituting the compound of Example 542A for ethyl 3,3-dimethylhexanoate in Example 536A and the compound of Example 501B (5-(2-nitrovinyl)-l,3-benxodioxole) for 4-methoxy-6-(2-nitrovinyl)-l,3-benzodioxole in Example 536C.
Example 542C
Ethyl \2S, 3R, ^S1-2-(2,2-Dimethylpent-3-enyl)-4-d ,3-benzodioxol-5- yl)-pyrrolidine-3-carboxylate
The compound of Example 542B was resolved according to the procedure described in Example 537B.
Example 542D r2S,3R,^S1-2-(2,2-Dimethylpent-3-enyl)-4-(l,3-benzodioxol-5-yl)-l- ((N-propoxy , N-(n-butyl))aminocarbonylmethy l)-pyrrolidine-3 - carboxylic acid
The compound of Example 542C was reacted with the compound of Example 538C according to the procedures of Example 536E.
Example 543
\2S, 3R, S1-2-(2,2-Dimethylpent-3-enyl)-4-q ,3-benzodioxol-5-yl)-l - ((N-propoxy, N-(n-propyl))aminocarbonylmethyl)-pyrrolidine-3- carboxylic acid
The compound of Example 542C was reacted with the compound of Example 539A according to the procedures of Example 536E.
Example 544 \2S, 3R, S1-2-(2,2-Dimethylpent-3-enyl)-4-(7-methoxy- 1 ,3- benzodioxol-5-yl)- 1 -((N-propoxy, N-(n-butyl))aminocarbonylmethyl)- pyrrolidine-3 -carboxylic acid
Example 544A Ethyl trans, trα» -2-(2,2-Dimethylpent-3-enyl)-4-(7-methoxy-l ,3- benzodioxol-5-yl)-pyrrolidine-3-carboxylate
The title compound is prepared according to the procedures of Examples 536A and 536C, substituting the compound of Example 542 A for ethyl 3,3-dimethylhexanoate in
Example 536 A.
Example 544B
Ethyl \2S, 3R, ¥Sl-2-(2,2-Dimethylpent-3-enyl -4-(7-methoxy-l ,3- benzodioxol-5-yl)-pyrrolidine-3-carboxylate
The compound of Example 544A was resolved according to the procedure described in Example 536D.
Example 544C \2S, 3R, Sl-2-(2,2-Dimethylpent-3-enyl)-4-(7-methoxy-l ,3- benzodioxol-5-yl)- 1 -((N-propoxy, N-(n-butyl))aminocarbonylmethyl)- pyrrolidine-3 -carboxylic acid
The compound of Example 544B was reacted with the compound of Example 538C according to the procedures of Example 536E.
Example 545
\2S, 3R, S|-2-(2,2-Dimethylpent-3-enyl)-4-(7-methoxy- 1 ,3- benzodioxol-5-yl)- 1 -((N-propoxy, N-(n-propyl))aminocarbonylmethyl)- pyrrolidine-3 -carboxylic acid
The compound of Example 544B was reacted with the compound of Example 539 A according to the procedures of Example 536E.
Example 546 r2SrR,4S1-2-(2-(2-pyridyl)ethyl)-4-(l,3-benzodioxol-5-yl)-l-rrN-4- heptyl-N-(2-methy 1-3 -fluorophenyl)! amino carbonylmethyl] - pyrrolidine-3 -carboxylic acid
Example 546A Ethyl trans, tr_.^ -2-(2-(2-pyridyl)ethyl)-4-(l ,3-benzodioxol-5-yl)- pyrrolidine-3 -carboxylate
The title compound is prepared according to the procedures of Examples 536 A and 536C, substituting the compound of Example 519A for 3,3-dimethylhexanoic acid in
Example 536A.
Example 546B
Ethyl \2S, 3R, S1-2-(2-(2-pyridyl)ethyl)-4-(l ,3-benzodioxol-5-yl)- pyrrolidine-3 -carboxylate
The compound of Example 546A (1.5 g) was dissolved in CH2CI2 (25 mL). Di-t- butyldicarbonate (0.9 g) was added and the solution stirred overnight at room temperature. The solvent was evaporated in vacuo and the residue taken up in EtOAc (50 mL), washed with water (1x50 mL), saturated sodium bicarbonate solution (3x50 mL), and brine (1x50 mL). The organic layer was dried with sodium sulfate and evaporated in vacuo to give an oil with was purified by flash chromatography on silica gel eluting with 1/10/10 EtOH/EtOAc/hexanes to give a colorless oil (1.5 g). The oil was dissolved in EtOH (10 mL) and 50% ΝaOH solution (0.5 mL) and water (5 mL) were added. The mixture was stirred overnight at room temperature. The solvents were evaporated in vacuo and the residue taken up in EtOAc (25 mL) and acidified with 1 Ν H3PO4 (10 mL). The layers were separated and the organic layer dried with sodium sulfate and evaporated to give a white semi-solid (1.3 g). A sample of the resultant Boc-protected amino acid (0.9 g) was dissolved in DMF (5 mL).
(S)-Phenylalaninol (0.32 g), HOOBt (0.33 g), and EDCI (0.40 g) were added and the solution sixrred overnight at room temperature. Water (50 mL) was added and the mixture extracted with EtOAc (3x25 mL). The organic layers were combined, washed with water (2x50 mL), saturated sodium bicarbonate solution (3x50 mL), and brine (1x50 mL), and evaporated to give a yellow oil; tic indicated the presence of two diastereomeric products. The diastereomeric amides were separated by flash chromatography on silica gel eluting with 1/12/12 EtOH/EtOAc/hexanes to give faster- (450 mg) and slower-moving isomers (400 mg). The faster-moving diastereomer (400 mg) was taken up in 6N HCl and heated at reflux overnight. The solvent was evaporated and the residue was taken up in toluene (75 mL) and evaporated. This was repeated two additional times to give a brown solid, which was dissolved in EtOH (50mL). 4N HCl/dioxane (10 mL) was added and the solution heated at reflux overnight. The EtOH was evaporated and the residue taken up in EtOAc which was treated with saturated sodium bicarbonate solution (3x50 mL), and brine (1x50 mL), and evaporated to give a brown solid. Flash chromatography on silica gel eluting with 30% EtOH/EtOAc gave a mixture of products (130mg) which was approximately 70% desired material. This product was carried forward without additional purification.
Example 546C \2S, 3R, 4Sl-2-(2-(2-pyridyl)ethyl)-4-(l ,3-benzodioxol-5-yl)-l -rrN-4- heptyl-N-(2-methyl-3 -fluorophenyl)] amino carbonylmethy 11- pyrrolidine-3 -carboxylic acid
The compound of Example 546B was reacted with the compound of Example 508E according to the procedures of Example 536E.
Example 547 r2S,3i-, S1-2-(4-Methoxyphenyl)-4-(l,3-benzodioxol-5-yl)-l-r(Ν-butyl- N-(4-dimethylaminobutyl)amino)carbonylmethyl1-pyrrolidine-3- carboxylic acid
Example 547 A
N-butyl-4-hydroxybutyramide
To 30 mL (390 mmol) of g-butyrolactone was added 45 ml (455 mmol) of n- butylamine. The solution was heated at 85°C for 1.5 hr, then the excess n-butylamine was removed in vacuo. The product crystallized on standing to give about 62 g of a colorless, low melting solid. Example 547B N-butyl-4-hydroxybutyl chloroacetamide
To an ice cooled solution of 3.40 g (91.9 mmol) of Li AIH4 in 90 mL of THF was added 2.4 mL of 98% H2SO4, dropwise, with stirring. After bubbling had ceased, a solution of 4.7 g of the compound of Example 547 A in lOmL of THF was added. The mixture was stirred at reflux for 24 hr, then cooled with an ice bath and quenched by sequential dropwise addition of 1.7 mL H2O, and 17 mL of 25% w/v aqueous NaOH. The white precipitate was filtered, and washed with about 50 mL of THF. The combined filtrate and washings were concentrated to 3.85 g of an oil. To an ice cooled solution of this material in 35 mL of ethyl acetate was added a solution of 5.0 g (29.2 mmol) of chloroacetic anhydride in 10 mL of ethyl acetate. The solution was stirred at 0°C for 30 min, then extracted with saturated aqueous NaHCO3 solution (1 x 25 mL), 2M NaOH (1 x 25 mL), 5% NH4OH (1 x 25 mL), IM HCl (1 x 25 mL), and brine (1 x 25 mL), dried over MgSO4, filtered, and concentrated in vacuo to an oil. The product was purified via silica gel chromatography, eluting with 98:2 diethyl ether: methanol, to give 1.52 g (31%) of a colorless oil.
Example 547C Ethyl \2S,3R, Sl-2-(4-Methoxyphenyl)-4-(l,3-benzodioxol-5-yl)-l-r(N- butyl-N-(4-hy droxybutyl)amino)carbonylmethy 1] -pyrrolidine-3 - carboxylate
To 1.52 g (6.85 mmol) of the compound of Example 547B was added 2.75 g (7.44 mmol) of the ethyl [2S,3i?,^Sl-2-(4-Methoxyphenyl)-4-(l,3-benzodioxol-5-yl)-pyrrolidine-3- carboxylate (prepared by neutralization of the compound of Example 50 IG), 10 mL of DMSO, and 2 mL of N,N-diisopropylethylamine. The solution was stirred at ambient temperature for 22 h, then poured into 100 mL of water and extracted with diethyl ether (3 x 25 mL). The combined ether layers were washed with water (1 x 25 mL), 4% (v/v ) H3PO4 (1 x 25 mL), saturated aqueous NaHCO3 solution (1 x 25 mL), and brine (1 x 25 mL), dried over MgSO4, filtered, and concentrated to an oil. This was purified via silica gel chromatography, eluting with 98:2 diethyl ether: methanol to give 3.0g (79%) of a colorless oil.
Example 547D
Ethyl r2S,3RrfS1-2-(4-Methoxyphenyl)-4-(l,3-benzodioxol-5-yl)-l-r(N- butyl-N-(4-bromobutyl)amino)carbony lmethy 11 -pyrrolidine-3 - carboxylate
To an ice cooled solution of 2.80 g (5.05 mmol) of the compound of Example 547C in 27 mL of diethyl ether was added 1.4 mL (10 mmol) of triethylamine, then 0.58 mL of methanesulfonyl chloride. A white precipitate formed, and the suspension was stirred at 0 °C for 20 min. The reaction was diluted with 75 mL of diethyl ether, then extracted with saturated aqueous NaHCO3 solution (2 x 25 mL), 5% NH4OH (2 x 25 mL), and brine (1 x 25 mL), dried over MgSO4, filtered, and concentrated to 3.0 g of a colorless oil. To this material in 45 mL of DMF was added 6.0 g (69 mmol) of LiBr. The reaction warmed to about 50 °C, then gradually cooled. The solution was stirred at ambient temperature for 4h, then poured into 450 mL of water, and extracted with diethyl ether (3 x 100 mL). The combined ether layers were back extracted with water (1 x 100 mL), and brine (1 x 100 mL), dried over MgSO4, filtered, and concentrated in vacuo to an oil. The product was purified via silica gel chromatography, eluting with 3:1 diethyl ether: petroleum ether, to give 2.65 g (90%) of a colorless oil.
Example 547E \2S, 3R, ^S|-2-(4-Methoxyphenyl)-4-(l ,3-benzodioxol-5-yl)-l -r(N-butyl- N-(4-dimethylaminobutyl)amino)carbonylmethyl1-pyrrolidine-3- carboxylic acid
To a solution of the compound of Example 547D (0.825 g, 1.34 mmol) in 3 mL of ethanol was added 5 mL of 4.07M dimethylamine in ethanol; the resultant solution was heated at reflux for 75 min. Solvents were removed in vacuo. The residue was purified by flash chromatography on silica gel, eluting with 9:1 dichloromethane/methanol. The resultant material was taken up in 5 mL of 1.4N NaOH in 5:1 ethanol/water and stirred at ambient temperature for 14 hrs. Solvents were removed in vacuo; the residue was taken up in water, then adjusted to pH 6-7 with IM HCl (~7 mL required). The mixture was extracted with EtOAc (3X); the aqueous layer was concentrated in vacuo. The residue was washed 3X with acetonitrile; the combined washes were filtered through Celite and concentrated to give 596 mg of a white foam.
Example 548 r2S,3R,4S|-2-(2,2-Dimethylpentyl)-4-(l,3-benzodioxol-5-yl -l-r(N- butyl-N-(4-dimethylaminobutyl)amino)carbonylmethyl1 -pyrrolidine-3 - carboxylic acid
Prepared according to the procedures of Example 547, substituting the compound of Example 537B (ethyl [2S3i.rS]-2-(232-Dimethylpentyl)-4-(l,3-benzodioxol-5-yl)- pyrrolidine-3 -carboxylate) in Example 547C.
Example 549 \2S, 3R, 4S1-2- , 2,2-Dimethylpentyl)-4-(7-methoxy- 1 ,3-benzodioxol-5- yl)- 1 -r(N-butyl-N-(4-dimethylaminobutyl)amino)carbonylmethyl1- pyrrolidine-3 -carboxylic acid
Prepared according to the procedures of Example 547, substituting the compound of Example 536D (ethyl [2S,5R,^S]-2-(2,2-Dimethylpentyl)-4-(7-methoxy-l,3-benzodioxol-5- yl)-pyrrolidine-3 -carboxylate) in Example 547C.
Example 550 r2SiR^S1-2-(2,2-Dimethylpent-3-enyl)-4-(l,3-benzodioxol-5-yl)-l- r(N-butyl-N-(4-dimethylaminobutyl)amino)carbonylmethyl1-pyrrolidine-
3 -carboxylic acid
Prepared according to the procedures of Example 547, substituting the compound of Example 542C (ethyl [2S,5i?rS]-2-(2,2-Dimethylpent-3-enyl)-4-(l,3-benzodioxol-5-yl)- pyrrolidine-3 -carboxylate) in Example 547C.
Example 551
\2S, 3R, S1-2-(2,2-Dimethylpent-3-enyl)-4-(7-methoxy-l ,3- benzodioxol-5-yl)-l-r(N-butyl-N-(4- dimethylaminobutyl)amino)carbonylmethyl1 -pyrrolidine-3 -carboxylic acid
Prepared according to the procedures of Example 547, substituting the compound of Example 544A (ethyl [2S3R,^S]-2-(2,2-Dimethylpent-3-enyl)-4-(7-methoxy-l33- benzodioxol-5-yl)-pyrrolidine-3-carboxylate) in Example 547C.
Example 552
\2S, 3R, 4S1-2-,2.2-Dimethylpent-3-enyl)-4-(l ,3-benzodioxol-5-yl)-l - [(N,N-di(nbutyl)amino)carbony lmethyll -pyrrolidine-3 -carboxylic acid
Prepared according to the procedures of Example 1, substituting the compound of Example 541C (ethyl[2S,5R,^S]-2-(2,2-Dimethylpent-3-enyl)-4-(l,3-benzodioxol-5-yl)-pyrrolidine-3- carboxylate).
Example 553 \2S, 3R, S1-2-(2,2-Dimethylpent-3 -enyl)-4-(7-methoxy- 1,3- benzodioxol-5-yl)-l-f(N,N-di(n-butyl)amino)carbonylmethyl1- pyrrolidine-3 -carboxylic acid
Prepared according to the procesures of Example 1, substituting the compound of Example 544B (ethyl [2S,3R,^S]-2-(2,2-Dimethylρent-3-enyl)-4-(7-methoxy-l,3-benzodioxol-5-yl)- pyrrolidine-3 -carboxylate) .
Example 554 trans, trα ,-(4-Methoxyphenyl)-4-(l ,3 -benzodioxol-5-yl)- 1 -(N-(bis-(o- tolyl)methyl)aminio)carbonylmethyl)-(pyrrolidine-3-carboxylic acid
Example 554A through 554E
These compounds were prepared in Examples 501 B-F.
Example 554F Bis-(o-tolyl)methylamine In a 50 mL round-bottom flask were placed 2,2'-dimethylbenzophenone (prepared form commercially available methyl-2-methylbenzoate according to the procedure in J Chem. Soc, 1929, 1631) (2.50 g, 10 mmol), hydroxylamine hydroehloride (0.76 g, 11 mmol), pyridine (5mL) and ethanol (5mL). The mixture was stirred under reflux for 8 h, cooled to r.t. diluted with EtOAc (25mL) and transferred into a separatory funnel. The aqueous layer was removed, and organic layer was washed in turns with CuSO4 (25mL), water 25 (mL) and brine (25 mL). After concentration of the organic phase, the residual oil obtained was purified by column chromatography (elution with 10% EtOAc in Hexanes) to give 1.31 g (73%) of oxime as a white crystalline solid.
To 55mL of ammonia cooled in dry ice-acetone bath was added 130 mg (6 mmol) of sodium metal. To the resulting blue solution at -78 C was added slowly 650 mg (3mmol) of the above oxime in 25 mL of anhydrous THF. The solution was stirred for 1 li followed by the addition of lg of ammonium chloride. The resulting colorless reaction mixture was warmed to r.t, transferred to a separatory funnel, diluted with 50 mL of water and extracted with dichloromethane (3x50 mL). The combined organic layers were dried (Na2SO4) and concentrated to give a yellowish oil. The residue was purified by a column chromatography (elution with 60% EtOAc in hexanes, followed by elution with 2% ET3N in EtOAc) to give 500 mg (66%) of the pure amine.
Example 554G N-(Bis-(o-tolyl)methl) bromacetamide The compound of Example 554F (100 mg, 0.47 mmol) was dissolved in 2mL of 1,2- dichloroethane. To this solution at -78 C was added Et3N (0.05 mL) and then dropwise bromacethy bromide (40 mL, 0.47 mmol in 1 mL of 1,2-dichloroethane). The reaction mixture was stirred at -78 C for 10 min, then at r.t. for 2 h, diluted with water (10 mL), and extracted with 1 ,2-dichloroethane (2x25mL). The combined organic layers was concentrated to give the bromacetamide as a white solid (184 mg, 96%) suitable for further use without additional purification.
Example 554 H Ethyl trα^5,,tr_.^ ,-2-(4-Methoxyphenyl)-4-(l,3-benzodioxol-5-yl)-l-(N-((bis-(o- tolyl)methyl)amino)carbonylmethyl)-pyrrolidine-3-carboxylate
The compound of Example of 554G was dissoleve in 5mL of CH3CN and added to a solution of 0.20 g (0.54 mmol) of the compound of Example IE, N,N-diisopropylethylamine (0.1 mL) and CH3CN (lOmL). The reaction mixture was stirred overnight at r.t., diluted with H2O (25 mL) and extracted with EtOAc (2x25 mL). The combined organic fractions were concentrated to give a yellow oil, which was purified by a column chromatography (elution with 40% of EtOAc in Hexanes) to give 250 mg (73%) of the title compound
Example 554J tr π ,,tr-.rø-2-(4-Methoxyphenyl)-4-(l,3-benzodioxol-5-yl)-l-(N-((bis-(o- toly l)methy l)amino)carbony lmethyl)-pyrrolidine-3 -carboxylic acid
The compound of Example 554H was dissolved in a solution of 50 mL of ethanol and 10 mL of aqueous sodium hydroxide (6N) and stirred overnight at room temperature. The solution was then diluted with 30 mL of water, transferred to a separatory funnel and extracted with a mixture of 20% Hexanes in EtOAc (2x5 OmL). The aqueous phase was treated with hydrochloric acid (3N) until pH=4 and extracted with chloroform (3x50mL). The combined organic fractions containing the acid product were concentrated to get a yellow viscous oil. The title compound was then isolated by lyophylizatin from dilute CH3CN/TFA/H2O as an amorphous solid: 1H NMR (300 MHz, CDCI3) δ 2.14 (s, 3H), 2.20 (s, 3H), 3.02-3.33 (m, 2H), 3.40-3.72 (m, 3H), 3.80 (s, 3H), 4.16-4.24 (broad s, IH), 5.92 (m, 2H), 6.36-6.42 (m, IH), 6.58-6.67 (m, 2H), 6.81 (t, J = 9 Hz, 4H), 6.88-7.00 (m, 2H), 7.05- 7.27 (m, 8H). MS (ESI+) m/e 593 (M+H+). Anal. Calc for C36H36N2O6* 0.4 TFA: C, 69.25 H, 5.75 N, 4.39. Found: C, 69.20 H, 5.68 N, 4.22.
Example 555 trαπ Jr-7 -2-r4-(2-Methoxyethoxy)phenyl1-4-(l,3-benzodioxol-5-yl)-l-(N-(2,2-dimethyl-l- phenylpropy 1)- 1 -amino)carbonylmethyl)-pyrrolidine-3 -carboxylic acid The title compound was prepared by using the procedures of Example 554, substituting 2,2-dimethyl-l-phenylpropan-l-one for 2,2'-dimethylbenzophenone in Example 554F and ethyl [4-(2-methoxyethoxy)benzoyl] acetate for ethyl (4-methoxybenzoyl) acetate in Example IC. lR NMR (300 MHz, CDC13) δ 0.85 (s, 9H, minor diastereomer), 0.88 (s, 9H, major diastereomer), 3.44 (s,2H), 3.10-3.42 (m, 3H), 3.46 (s, 3H), 3.51-3.75 (m, 4H), 4.06- 4.13 (m, 2H), 4.72 (m, IH), 5.97 (m, 2H), 6.77-7.45 (m, 12H). MS (ESI+) m/e 589 (M+H+). Anal. Calc for C34H40 2O7* 0.75 TFA: C, 63.24 H, 6.09 N, 4.15. Found: C, 63.33 H, 6.18 N, 4.05.
Example 556 trα^5,,trα^.s,-2-r4-(2-Methoxyethoxy)phenyl1-4-(l,3-benzodioxol-5-yl)-l-(N-((bis-(o tolyl)methyl)ammo)carbonylmethyl)-pyrrolidine-3-carboxylic acid The title compound was prepared by using the procedures of Example 554, substituting ethyl [4-(2-methoxyethoxy)benzoyl] acetate for ethyl (4-methoxybenzoyl) acetate in Example 554C. 1H NMR (300 MHz, CDC13) δ 2.13 (s, 3H), 2.20 (s, 3H), 2.94- 3.23 (m, 3H), 3.32-3.51 (m, 2H), 3.47 (s, 3H), 3.58-3.69 (braod s, IH), 3.76 (dd , J = 6, 1.5 Hz, 4H), 4.09 (t, J = 4.5 Hz, IH), 5.93 (m 2H), 6.34-6.41 (d, J = 7.5 Hz, 2H), 6.58 (broad s, 2H), 6.72- 6.98 (m,3H), 7.05-7.28 (m, 8H). MS (ESI+) m/e 6.37 (M+H1"). Anal. Calc for C38H40N2O7* 0.2 TFA: C, 69.93 H, 6.14 N, 4.25. Found: C, 70.03 H, 6.08 N, 4.21.
Example 557 t7- π ,tr-.m-2-r4-(2-Isopropoxyethoxy)phenyl1-4-(l,3-benzodioxol-5-yl)-l-(N-(2,2-dimethyl- 1 -phenylpropyl - 1 -amino)carbonylmethyl)-pyrrolidine-3 -carboxylic acid The title compound was prepared by using the procedures of Example 554, substituting 2,2-dimethyl-l-phenylpropan-l-one for 2,2'-dimethylbenzophenone in Example 554F and ethyl[4-)2-isopropoxyethoxy)benzoyl] acetate for ethyl (4-methoxybenzoyl) acetate is Example IC. . 1H NMR (300 MHz, CDC13) δ 0.83 (s, 9H, major diastereomer), 0.88 (s, 9H, minor diastereomer), 1.19 (d, J = 7 Hz, 6H), 3.14-3.83 (m,9H), 4.07 (p, J = 10.5, 4.5 Hz, 2H), 4.27-4.47 (m,lH), 4.70 (t, J = 9 Hz, IH), 5.93-6.00 (m,2H), 6.73-7.38 (m, 12H). MS (ESI+) m/e 617 (M+H+). Anal. Calc for C36H44N2O7* 0.6 TFA: C, 65.21 H, 6.56 N, 4.09. Found: C, 65.15 H, 6.59 N, 4.01.
Example 558 trans, trans-2- ["4-Methoxyphenyl1-4-(l ,3 -benzodioxol-5-yl)- 1 -(N-(3 ,3 -dimethyl- 1 - phenylbutyl)- 1 -amino)carbonylmethyl)-pyrrolidine-3-carboxylic acid The title compound was prepared by using the procedures of Example 554, substituting 3,3-dimethyl-l-phenylbutan-l-one (prepared from commercially available 3,3- dimethyl-butryl chloride according to the procedure inJ Amer. Chem. Soc, 72, 1950, 222- 227) for 2,2'-dimethylbenzophenone in Example 554F. 1H NMR (300 MHz, CDC13) δ 0.84 (s, 9H, minor diastereomer), 0.89 (s, 9H, major diastereomer), 1.68 (t, J = 7.5 Hz, 2H), 3.05- 3.30 (m, 2H), 3.34-3.53 (m, 2h), 3.62-2.74 (m, IH), 3.77 (s, 2H), 3.80 (s, 3H), 4.92-5.02 (m, IH) 5.97-6.01 (m, 2H), 6.77 (t, J = 6 Hz, 2H), 6.88 (q, J = 18, 7.5 Hz, 2H), 6.97 (d, J + 6 Hz, IH), 7.10-7.40 (m, 7H). MS (ESI+) m/e 559 (M+H+). Anal. Calc for C33H38N2O6* 0.45 TFA: C, 65.75 H, 6.35 N, 4.59. Found: C, 66.69 H, 6.32 N, 4.46.
Example 559 trans, tr rø-2-r4-(2-Isopropopoxyethoxy)phenyl1-4 (1 ,3-benzodioxol-5-yl)- 1 -(N-(( 1 -(o-tolyl)- l-(o-ethylphenyl)-methyl)amino)carbonylmethyl)-pyrrolidine-3-carboxylic acid
The title compound was prepared by using the procedures of Example 554, substituting ethyl [4-(2-isopropoxyethoxy)benzoyl] acetate for ethyl (4-methoxybenzoyl) acetate in Example 554C and 2-ethyl-2'-methylbenzophenone (prepared form commercially available methyl-2-methylbenzoate according to the procedure in J Chem. Soc, 1929, 1631) for 2,2'-dimethylbenzophenone in Example 554F. 1H NMR (300 MHz, CDC13) δl .04-1.28 (m, 9H) 2.20 (s, 3H) 2.53 (broad s, 2H), 2.94-3.23 (m, 3H), 3.35-3.87 (m, 6H), 4.08 (board s, 3H), 4.52 (broad s, IH), 5.96 (s, 2H), 6.48-7.35 (m, 15H).. MS (ESI+) m/e 678 (M+H+). Anal. Calc for C41H46N2O7* 0.95 TFA: C, 65.46 H, 6.01 N, 3.46. Found: C, 65.47 H, 6.00 N, 3.10.
Example 560 trans, tra?._.-2-(4-(2-(2-Propoxy)ethoxy)phenyl)-4 (1 ,3-benzodioxol-5-yl -l -(N-phenyl-N-t- butylhydrazino carbonylmethyl)-pyrrolidine-3 -carboxylic acid
Example 560A
N-phenyl-t-butylamine t-Butylamine(2.0 eq.) was stirred in dry THF at r.t. and n-butyllithium(l .2 eq.) was added slowly. The resulting mixture was stirred for 30 min. nad then bromobenzene(1.0 eq.) added, refluxed for 4 hr. After work-up, it was purified and separated by a column(silica) to elute with hexane and ethyl acetate(9:l). Yield 50%.
Example 560B Phenyl-t-butylnitrosamine Phenyl-t-butylamine (6g, 0.04mol) was treated with conc.HCl (5mL) and a solution of NaNo2(6.4g, 2.4 eq.) in 20ml of wather was added slowly. The resulting mixture was stirred for 2hr at r.t. to produce an oily layer which was extracted with EtOAc, washed with brine, and dried over Na2So . Yield 6g (85%). This nitrosoamine was used for the next stop without further purification.
Example 560C N-phenyl-t-butylhydrazine
To a stirred suspension of zinc dust (5.14g, 0.079mol) in water(15ml) was added dropwise a solution of the compound of Example 560B (3.5 g, 0.02mol) in acetic acid(9ml) and the resultant mixture was stirred for lhr at r.t. Dichloromethane(20ml) was added, the mixture was adjusted to pH 8-9 with 15% NaOH, The zinc dust was removed by filtration, and the crude reaction mixture was extracted with dichloromethane. The combined organic layers were dried (MgSO4). Yield 1.97g(60%).
Example 560D N-phenyl-N-t-buty- N'-(bromoacetyl) hydrazine The title compound was prepared by the procedure described Example 554G, substituting the compound of Example 560C.
Example 560E trans, trans -2-(4-(2-(2-Propoxy)ethoxy)phenyl)-4 ( 1 ,3 -benzodioxol-5 -yl)- 1 -(N-phenyl-N-t- butylhydrazino carbonylmethyl)-pyrrolidme-3-carboxylic acid The title compound was prepared by the procedures described in Example 554. H NMR (300MHz, DMSO) δ 0.92 (d, J =24Hz, 6H), 1.10(s,9H), 2.59-2.80(m, 2H), 2.95-3.10 (m,lH), 3.25-3.51(m, 3H), 3.58-3.70(m,3H), 3.73-3.88(m,lH), 4.02-1.07(m,2H), 5.97-6.0(m, 2H), 6.78-6.93(m, 4H), 7.02-7.26(m, 7H), 7.35(d, J=8Hz, IH). MS(ESI+) m/e 618(M+H+). Anal. Calc for C35H43N3O7.O.5H2O: C, 67.07 H, 7.08 N, 6.70. Found: C, 67.21 H, 6.61 N, 6.40.
Example 561 tr-.π ,tr -2-(4-(2-(2-Methoxyethoxy)phenyl -4 (l,3-benzodioxol-5-yl)-l-(N-phenyl-N-t- butylhydrazino carbonylmethyl)-pyrrolidine-3 -carboxylic acid
The title compound was prepared by the procedures described in Example 554 and 560. 1H NMR (300MHz, CD3OD) δ 1.22 (s, 9H), 2.87(d, J =15Hz, IH), 2.98-3.07(m, 2H), 3.27(bs, IH), 3.42(s, 3H), 3.60-3.68(m, 2H), 3.72-3.76(m,2H), 3.92(d, J=9Hz, IH), 4.10- 4.14(m, 2H), 5.95(dd, J=2Hz, 4Hz, 2H) 6.82(d, J=8Hz, IH), 6.90(dd, J=2Hz, 9Hz, IH), 7.96(d, J=8Hz, 2H), 7.07(d, J=2Hz, IH), 7.10-7.23(m, 5H), 7.42(d, J=8Hz, 2H). MS (ESI+) m/e590 (M+H+). Anal. Calc for C33H39N3O7.1.0 AcOH: C, 64.70, H, 6.67, N, 6.47. Found: C, 64.40, H, 6.40 N, 6.70.
As an indication that the compounds described herein act through binding to endothelin receptors, the compounds have been evaluated for their ability to displace endothelin from its receptor.
As an indication that the compounds described herein act through binding to endothelin receptors, the compounds have been evaluated for their ability to displace endothelin from its receptor.
Binding Assay ETA Receptor
Preparation of membranes from MMQ cells: MMQ [MacLeod/MacQueen/Login cell line (prolactin secreting rat pituitary cells)] cells from 150 mL culture flasks were collected by centrifugation (lOOOxg for 10 min) and then homogenized in 25 mL of 10 mM Hepes (pH 7.4) containing 0.25 M sucrose and protease inhibitors [3 mM EDTA , 0.1 mM PMSF, and 5 μg/mL Pepstatin A] by a micro ultrasonic cell disruptor (Kontes). The mixture was centrifuged at lOOOxg for 10 min. The supernatant was collected and centrifuged at 60,000xg for 60 min. The precipitate was resuspended in 20 mM Tris, pH 7.4 containing the above protease inhibitors and centrifuged again. The final pellet was resuspended in 20 mM Tris, pH 7.4 containing protease inhibitors and stored at -80°C until used. Protein content was determined by the Bio-Rad dye-binding protein assay. |"12 i]ET-l binding to membranes:
Binding assays were performed in 96-well microtiter plates pretreated with 0.1% BSA. Membranes prepared from cells were diluted -100 fold in Buffer B (20 mM Tris, 100 mM NaCl, 10 mM MgC_2, pH 7.4, with 0.2% BSA, 0.1 mM PMSF, 5 μg/mL Pepstatin A,
0.025% bacitracin, and 3 mM EDTA) to a final concentration of 0.2 mg/mL of protein. In competition studies, membranes (0.02 mg) were incubated with 0.1 nM of [125J ET-1 in Buffer B (final volume: 0.2 mL) in the presence of increasing concentrations of unlabeled ET-1 or a test compound for 4 hours at 25 °C. After incubation, unbound ligands were separated from bound ligands by a vacuum filtration method using glass-fiber filter strips in PHD cell harvesters (Cambridge Technology, Inc., MA), followed by washing the filter strips with saline (1 mL) for three times. Nonspecific binding was determined in the presence of 1 μM ET-1. The data are shown in Table 4. The per cent inhibition at a concentration of 1 mM is shown. The data show that the compounds of the invention bind to the endothelin receptor.
Table 4 Binding Data
_ample % Inhibition of Example % Inhibition of
ETA at 1 μM ETA at 1 μM
Figure imgf000782_0001
o
o
H U α.
00 r— 1 00 CN CN © © vo o cN oo τt; oo ch eη c f; D CN Ch" rf 00 c oo vo σs σ, σs Ch ch σs © Ch Ch oo oQ
Figure imgf000783_0001
ιn vo t θ τ— i N r m © © © © *— < .— i — ( i— (
Figure imgf000783_0002
o σ, 00 l en vo t- I Tt; r- en vo en Tf Tt- en © en rf CN rf T l CN © v rf inen- © σs © rf t~~ Ch 00 00 oo en VO 00 oo Ch σs o 00 h 00
Figure imgf000783_0003
vo σs © cN en ι t oo oo oo
Figure imgf000783_0004
Figure imgf000784_0001
en vo © .— ι cN in vo t oo oo T_
Figure imgf000784_0002
CN CN CN CN CN CN CN ι
Figure imgf000784_0003
σs τf vo t oo σs υ'—. uN uen Qιn vo t o oo oo oo oo oo ch σs Ch Ch Ch σs O
Figure imgf000785_0001
Tt- vo t '-H en τi- ιn vo ι oo σs © τ— . CN en Tf- in vo ι
00 vo vo σs ch Ch σs σs σs Ch σs © © © © © © © © T— i - ( CN CN CN CN CN CN CN CN en en en en en en en en
Figure imgf000785_0002
τf © o en oo ι o cN τt- o © so vo m CN t σs en oo vo cN oo N in en τ|- en o Ό c~~ © CN t-~ oo σs © σs r~~ o 00 C
CN O en CN oo σs oo oo σ, 00 Ch
Figure imgf000785_0003
en Tt- in vo O oo Ch © r—1 CN en Tt in
Tf Tt Tf Tf Tj- Tf in n in in in in
Figure imgf000785_0005
Figure imgf000786_0001
o
o _5 υ PH oo
Ch
Figure imgf000787_0001
© --ι eN en τt ιn vo ι oo σs © r-ι cN en τt- m 00 CN CN CN CN CN CN CN C CN CN en en en en en en
Figure imgf000787_0002
Tf Tf Tt Tf Tt Tt Tt Tf Tt Tt Tt Tt Tf Tf Tt -ζf
Figure imgf000787_0003
cN en τt m vo f~- © © © © © © τf τf τf τf τf τf
Figure imgf000787_0004
Figure imgf000788_0001
oo σs © -H i vo o σs in o ι - oo σs ©
00 vo o ι ι . t r-. ι t - σs σs σs σ Ch ©
Figure imgf000788_0002
τf τf τf τf τf τf τf τf τf τf τf τf τf ιn
o a o =1
1—1 en en en 00 > Tf © f- 00 en Ch Tf j 00 © © o 00 l vd rf © σs o en
*^ ■8 © © Tf Tf © © © Tf vo Ch m o
© © σs Ch © Ch © © © Ch σs Ch σs © Ch © © Ch σ, σs σ, oo σs :
H rf W
Figure imgf000788_0003
Figure imgf000789_0001
Figure imgf000790_0001
As further demonstration of the efficacy of the described compounds as functional antagonists of endothelin, the ability of the described compounds to inhibit ET-1 -induced phosphatidylinositol hydrolysis was measured.
Determination of Phosphatidylinositol (PI) Hydrolysis MMQ cells (0.4 x 10^ cells/mL) were labeled with 10 μCi/mL of [3H]myo-inositol in RPMI for 16 hours. The cells were washed with PBS, then incubated with Buffer A containing protease inhibitors and 10 mM LiCl for 60 minutes. The cells were then incubated with test compounds for 5 minutes, and then challenged with 1 nM ET-1. ET-1 challenge was terminated by the addition of 1.5 mL of 1 :2 (v/v) chloroform-methanol. Total inositol phosphates were extracted after adding chloroform and water to give final proportions of 1 :1:0.9 (v/v/v) chloroform-methanol-water as described by Berridge (Biochem. J. 206 587- 595 (1982)). The upper aqueous phase (1 mL) was retained and a small portion (100 μL) was counted. The rest of the aqueous sample was analyzed by batch chromatography using anion-exchange resin AG1-X8 (Bio-Rad). The IC50 is the concentration of test compound required to inhibit the ET-induced increase in PI turnover by 50%. The results of the above study clearly indicate that the compounds act as functional ET antagonists.
Table 5 Phosphatidylinositol Hydrolysis
Figure imgf000791_0001
Table 6 ETA/ETB Selectivity
MMQ cells, porcine cerebellar tissues (known to contain ETβ receptors) and Chinese hamster ovary cells (CHO) permanently transfected with the human ETA or ETB receptor were homogenized in 25 ml of 10 mM Hepes (pH 7.4) containing 0.25 M sucrose and a protease inhibitor [50 mM EDTA , 0.1 mM PMSF, 5 μg/ml Pepstatin A, and 0.025% Bacitracin] using a micro ultrasonic cell disrupter. The mixture was centrifuged at lOOOxg for 10 min. The supernatant was collected and centrifuged at 60,000xg for 60 min. The precipitate was resuspended in 20 mM Tris, pH 7.4 containing protease inhibitor and centrifuged again. The final membrane pellet was resuspended in 20 mM Tris, pH 7.4 containing protease inhibitors and stored at -80 °C until used. Protein content was determined by the Bio-Rad dye-binding protein assay.
Binding assays were performed in 96-well microtiter plates pretreated with 0.1% BSA. Membranes prepared from cells were diluted ~100 fold in Buffer B (20 mM Tris, 100 mM NaCl, 10 mM MgC_2, pH 7.4, with 0.2% BSA, 0.1 mM PMSF, 5 μg/mL Pepstatin A, 0.025%) bacitracin, and 50 mM EDTA) to a final concentration of 0.2 mg/mL of protein. In competition binding studies, membranes (0.02 mg) were incubated with 0.1 nM of [125I]ET- 1 (for ETA assay in MMQ or CHO cells transfected with human ETA receptor) or [125I]ET- 3 (for ETB assay in porcine cerebellum or CHO cells transfected with human ETβ receptor) in Buffer B (final volume: 0.2 mL) in the presence of increasing concentrations of the test compound for 3 hours at 25 °C. After incubation, unbound ligands were separated from bound ligands by a vacuum filtration method using glass-fiber filter strips in PHD cell harvesters (Cambridge Technology, Inc., MA), washing the filter strips three times with saline (1 mL). Nonspecific binding was determined in the presence of 1 μM ET-1. IC50 values are calculated using an average of at least two separate determinations. The data shows the selectivity of the compounds of the invention in binding to the endothelin receptors.
Table 6
AMPLE rET-A rET-A pET-B IC50 Selectivity hET-A hET-B IC50 Selectivity
NO. (%I @ IC50 (nM) (rA/pB ratio) IC50 (nM) (hA/hB ratio) lμM) (nM) (nM)
502 95.7 3.0 71,000 23,000
503 97.0 1.4 50,000 35,000 0.92 52,000 56,000
504 97.1 3.1 > 100,000 >32,000 4.6 >100,000 >21,000
505 95.8 2.0 60,000 30,000 , 5.7 68,000 12,000 506 99.7 3.2 >100,000 >31,000 3.0 61,000 20,000
507 99.3 3.0 >100,000 >33,000 1.63 >100,000 >60,000
508 97.6 1.9 45,000 23,000 2.1 51,000 24,000
509 100 0.56 30,000 53,000 0.51 23,000 45,000
510 100 0.50 35,000 68,000 1.0 11,000 11,000
511 99.2 0.81 N.D. — 0.60 15,000 25,000
512 98.9 0.42 >80,000 >190,000 0.58 60,000 >102,000
513 98.0 0.30 8,800 29,000 0.36 14,000 37,000
514 100 1.0 26,000 26,000 0.36 9,800 29,000
515 99.1 1.6 >62,000 >37,000 6.7 >100,000 >15,000
516 99.7 0.71 29,000 40,000 1.8 37,000 21,000
517 94.1 1.0 30,000 30,000 0.43 12,000 29,000
518 96.3 1.3 85,000 63,000 0.31 38,000 124,000
519 99.1 0.38 14,000 36,000 0.23 19,000 83,000
520 97.4 0.20 28,000 130,000
521 100 0.67 37,000 54,000
523 99.0 0.42 360 880 0.33 290 880
524 99.2 0.79 1,700 2,100 0.82 890 1,100 525 100 8.2 560 70
526 100 42 — — 17 7,400 440
527 96.6 7.9 10,000 1,300
528 98.3 11 43,000 3,800
529 98.1 3.6 6,300 1,700
531 99.8 1.2 — — 0.71 870 1,200
532 100 5.1 3,200 630
533 97.9 76 7,900 100 40 22,000 560
534 0.12 0.36 3.0 0.08 0.28 3.5
536 100 0.52 17,000 33,000 0.92 52,000 56,000
537 97.2 0.96 5,900 6,200 0.23 1,900 8,200
552 97.3 0.78 7100,000 7125,000 1.0 >96,000 >96,000
553 100 0.26 42,400 160,000 0.29 39,500 136,000
Determination of Plasma Protein Binding
A stock solution of the test compound in 50% ethanol (2 mg/mL) was diluted 10X • into PBS. A 0.4 mL sample of this secondary stock solution was added to 3.6 mL of fresh plasma, and incubated at room temperature for 1 hour. A 1 mL sample of this incubation mixture was transferred to a Centrifree ultrafiltration tube. The sample was centrifuged in a fixed-bucket rotor for approximately 2 min and the filtrate was discarded. The sample was centrifuged for another 15-30 min. A 100 μL sample of the ultrafiltrate was transfered to a micro HPLC sample vial containing 150 ML of HPLC mobile phase and mixed thoroughly. A 50 μL sample was injected and the concentration of drug in the ultrafiltrate was determined by HPLC analysis compared against a standard sample prepared identically in the absence of plasma. Ultrafiltrate concentrations are calculated from a calibration curve. Protein binding is calculated according to the equation:
%PB = [l-(Cu/Ci)1 * 100%
where Cu is the ultrafiltrate concentration and Ci is the initial plasma concentration. The percent of bound compound is listed in Table 7.
Table 7.
Example #43 > 99.5 % bound
Example #530 78% bound Example #531 92% bound
Example #532 96.8% bound
Example #533 82.6% bound
It has been demonstrated in the literature (Wu-Wong, et al., Life Sci. 1996, 58, 1839-1847, and references contained therein) that compounds which are highly protein bound show decreased potency in vitro in the presence of plasma proteins. A decrease in in vitro potency may correspondingly result in reduced in vivo potency. An endothelin antagonist which has reduced protein binding might be expected to be less susceptible to this effect, and thus be more potent as an in vivo agent. The ability of "reduced protein binding" endothelin antagonists to exhibit enhanced activity the presence of serum albumin has been demonstrated through the following study: A series of bin curves is recorded for a given antagonist, each experiment performed in the presence of increasing concentrations of serum albumin.
Protocol for Albumin-induced binding shift studies: Binding assays were performed in 96- well microtiter plates precoated with 0.1% BSA unless otherwise indicated. Membranes were diluted in Buffer B (20mM Tris, lOOmM NaCl, lOmM MgC12, pH 7.4, 0.1 mM PMSF, 5mg/mL Pepstatin A, 0.025% bacitracin and 3 mM EDTA) to a final concentration of 0.05 mg/ml of protein. Varying concentrations of human serum albumin (HSA) were added as indicated. In competition studies, membranes were incubated with 0.1 nM of [125JJET in Buffer B (final volume: 0.2 ml) in the presence of increasing concentrations of unlabeled test ligands for 4 hours at 25°C. After incubation, unbound ligands were separated from bound ligands by vacuum filtration using glass-fiber filter strips in PHD cell harvesters (Cambridge Technology, Inc., Watertown, MA), followed by washing the filter strips with saline (1 ml) for three times. Nonspecific binding was determined in the presence of 1 μM ET-1.
Figure IA.
Figure imgf000796_0001
[Example 43], M >98% Protein Bound
Figure IB. Figure IC.
Figure imgf000796_0002
[Example 530],
Figure imgf000796_0003
78% Protein Bound
Figure 1
Inhibition of [125I]ET-1 binding to human ETA receptor by ETA antagonists. Each curve was determined in the presence of either 0%, 0.2%, 1%, or 5% HSA, and assays were performed as described above. The results are expressed as % of control binding, with [ I]ET-1 binding in the absence of antagonist defining 100%. Each point represents the mean (±S.D.) of three determinations.
As observed in Figure 1 A, a compound which is highly protein bound (Example 43, >98% bound) shows a rightward shift of the binding curve (toward decreasing potency) in the presence of increasing albumin levels. The compound of Example 531 (Figure IB), in which protein binding i_ reduced to 92%, shows a substantial diminution of this rightward shift; the shift is completely eliminated with the compound of Example 530 (Figure IC), in which protein binding is reduced to 78%. This experiment demonstrates that a reduction in protein binding translates into increased potency in the presence of plasma proteins, and suggests that such compounds may exhibit enhance vivo activity.
The observed reduction in protein binding, in compounds which retain high affinity for endothelin receptors, appears linked to the placement of "basic" functionality (groups which carry ; positive charge at physiological pH).
Such compounds also exhibit improved solubility in aqueous solutions, as demonstrated be (Table 1) in an experiment in which maximum solubility was measured in aqueous media at varyin at about 25°C. These results indicate that compounds that contain charged groups on the amide sidechain exhibit increased solubility over a significant range of pH. Such increased aqueous solut coupled with the enhanced potency resulting from decreased protein binding, might make such compounds preferred for development as parenteral agents. Table 8 presents the pH-Solubility pro for representative compounds of the present invention.
Table 8.
pH [Example 43] (mg/mL) [Example 531] (mg/mL
5.1 0.08 >3.3
6.5 0.51 >3.4
7.1 0.99 3.54
7.6 1.14 3.55 The present invention provides less protein bound compounds having improved in v. and in vivo activity as pharmaceutical agents. The present invention also provides compounds that show that the affinity of hydrophobic acids for plasma protein may be reduced by attaching a counterbalanced charge at a biologically acceptable site. For example, protein binding is reduced b attaching a "basic" functionality (groups which carry a positive charge at physiological pH) on the amide sidechain (see Formula XII wherein R3 has an amide sidechain).
The present invention covers compounds having the formula XII:
Figure imgf000798_0001
XII wherein
Z is ~C(Rι 8)( ι ))- or -C(O)- wherein Ris and R19 are independently selected from hydrogen and loweralkyl; n is 0 or 1 ; R is -(CH2)m-W wherein m is an integer from 0 to 6 and W is
(a) -C(O)2-G wherein G is hydrogen or a carboxy protecting group,
(b) -PO3H2,
(c) -P(O)(OH)E wherein E is hydrogen, loweralkyl or arylalkyl,
(d) -CN, (e) -C(O)NHRi7 wherein R17 is loweralkyl,
(f) alkylaminocarbonyl, .(g) dialkylaminocarbonyl, (h) tetrazolyl, (i) hydroxy,
G) alkoxy,
(k) sulfonamido,
(1) -C(O)NHS(O)2Ri6 wherein Ri6 is loweralkyl, haloalkyl, aryl or dialkylamino,
(m) -S(O)2NHC(O)Ri6 wherein R16 is defined as above,
Figure imgf000799_0001
(n)
Figure imgf000799_0002
Figure imgf000800_0001
Rl and R2 are independently selected from hydrogen, loweralkyl, alkenyl, alkynyl, alkoxyalkyl, alkoxycarbonylalkyl, hydroxyalkyl, haloalkyl, haloalkoxyalkyl, alkoxyalkoxyalkyl, thioalkoxyalkoxyalkyl, cycloalkyl, cycloalkylalkyl, aminocarbonylalkyl, alkylaminocarbonylalkyl, dialkylaminocarbonylalkyl, aminocarbonylalkenyl, alkylaminocarbonylalkenyl, dialkylaminocarbonylalkenyl, hydroxyalkenyl, aryl, arylalkyl, aryloxyalkyl, arylalkoxyalkyl, (N-alkanoyl-N-alkyl)aminoalkyl, alkylsulonylamidoalkyl, heterocyclic, (heterocyclic)alkyl and (Raa)(Rb )N-Rcc- wherein Raa is aryl or arylalkyl, Rbb is hydrogen or alkanoyl and Rcc is alkylene, with the proviso that one or both of Rj and R2 is other than hydrogen;
R3 is (a)R4-C(0)-R5-, R4-C(O)-R5- N(R6)- , wherein R5 is (i) a covalent bond, (ii) alkylene, (iii) alkenylene, (iv) -N(R2o)- s- or -Rsa-
N(R2ø)-R8- wherein Rs and R8a are independently selected from the group consisting of alkylene and alkenylene and R20 is hydrogen, loweralkyl, alkenyl, haloalkyl, alkoxyalkyl, haloalkoxyalkyl, cycloalkyl or cycloalkylalkyl or (v) -O-R9- or -R9a-O-R9- wherein R9 and
R9a are independently selected from alkylene;
R4 and Re are (Ri ι)(Rι 2)N- wherein Ri 1 and R12 are independently selected from
(1) hydrogen,
(2) loweralkyl, (3) haloalkyl,
(4) alkoxyalkyl,
(5) haloalkoxyalkyl,
(6) alkenyl,
(7) alkynyl, (8) cycloalkyl,
(9) cycloalkylalkyl,
(10) aryl,
(11) heterocyclic, (12) arylalkyl,
(13) (heterocy clic)alkyl,
(14) hydroxyalkyl,
(15) alkoxy,
(16) aminoalkyl,
(17) trialkylaminoalkyl,
(18) alkylaminoalkyl,
(19) dialkylaminoalkyl,
(20) carboxyalkyl,
(21) (cycloalkyl)aminoalkyl,
(22) (cycloalkyl)alkylaminoalkyl,
(23) (heterocyclic)aminoalkyl, and
(24) (heterocyclic)aminoalkyl, with the proviso that at least one of Rπ and R12 is selected from heterocyclic, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, trialkylaminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, carboxyalkyl, (cycloalkyl)aminoalkyl, (cycloalkyl)alkylaminoalkyl, (heterocyclic)aminoalkyl, and (heterocyclic)alkylaminoalkyl; or a pharmaceutically acceptable salt thereof.
Preferred compounds having reduced protein binding are shown in Table 9A wherein R may be selected from the substituents shown in Table 9B. Table 9A.
Figure imgf000801_0001
Figure imgf000802_0001
Figure imgf000803_0001
Table 9B.
Figure imgf000804_0001
(CH3)3N' ΪΛΛ
Figure imgf000805_0001
Figure imgf000805_0002
For the purposes of this disclosure, the term "(cycloalkyl)aminoalkyl" as used herein refers a cycloalkyl moiety attached to the parent compound through an aminoalkyl. Examples of (cycloalkyl)aminoalkyl include (cyclohexane)aminopropyl, (cyclohexane)aminoethyl, and the like. The term "(heterocyclic)aminoalkyl" as used herein refers to a heterocyclic moiety attached to the parent compound through an aminoalkyl. Examples of (heterocyclic)aminoalkyl include (pyridine)aminopropyl, (benzofuran)aminopropyl, (tetrahydopyran)aminoethyl, and the like. The term "(cycloalkyl)alkylaminoalkyl" refers to a cycloalkyl moiety attached to the parent compound through an alkylaminoalkyl. Examples of (cycloalkyl)alkylaminoalkyl include (cyclohexane)ethylaminomethyl, (cyclopentane)methylaminoisopropyl, and the like.
The term "(heterocyclic)alkylaminoalkyl" as used herein refers to a heterocyclic moiety attached to the parent compound tlirough an alkylaminoalkyl. Examples of (heterocyclic)alkylaminoalkyl include (pyridine)ethylaminopropyl,
(benzofuran)methylaminoisobutyl, (tetrahydopyran)methylaminoethyl, and the like.
The ability of the compounds of the invention to lower blood pressure can be demonstrated according to the methods described in Matsumura, et al., Eur. J. Pharmacol. 185 103 (1990) and Takata, et al., Clin. Exp. Pharmacol. Physiol. 10 131 (1983). The ability of the compounds of the invention to treat congestive heart failure can be demonstrated according to the method described in Margulies, et al., Circulation 82 2226 (1990).
The ability of the compounds of the invention to treat myocardial ischemia can be demonstrated according to the method described in Watanabe, et al., Nature 344 114 (1990). The ability of the compounds of the invention to treat coronary angina can be demonstrated according to the method described in Heistad, et al., Circ. Res. 54 711 (1984).
The ability of the compounds of the invention to treat cerebral vasospasm can be demonstrated according to the methods described inNakagomi, et al., J. Neurosurg. 66 915 (1987) or Matsumura, et al., Life Sci. 49 841-848 (1991). The ability of the compounds of the invention to treat cerebral ischemia can be demonstrated according to the method described in Hara et al., European. J. Pharmacol. 197: 75-82, (1991).
The ability of the compounds of the invention to treat acute renal failure can be demonstrated according to the method described in Kon, et al., J. Clin. Invest. 83 1762 (1989).
The ability of the compounds of the invention to treat chronic renal failure can be demonstrated according to the method described in Benigni, et al, Kidney Int. 44 440-444 (1993).
The ability of the compounds of the invention to treat gastric ulceration can be demonstrated according to the method described in Wallace, et al., Am. J. Physiol. 256 G661 (1989). The ability of the compounds of the invention to treat cyclosporin-induced nephrotoxicity can be demonstrated according to the method described in Kon, et al., Kidney Int. 37 1487 (1990).
The ability of the compounds of the invention to treat endotoxin-induced toxicity (shock) can be demonstrated according to the method described in Takahashi, et al., Clinical Sci. 79 619 (1990).
The ability of the compounds of the invention to treat asthma can be demonstrated according to the method described in Potvin and Varma, Can. J. Physiol. and Pharmacol. 67 1213 (1989). The ability of the compounds of the invention to treat transplant-induced atherosclerosis can be demonstrated according to the method described in Foegh, et al., Atherosclerosis 78 229-236 (1989).
The ability of the compounds of the invention to treat atherosclerosis can be demonstrated according to the methods described in Bobik, et al., Am. J. Physiol. 258 C408 (1990) and Chobanian, et al, Hypertension 15 327 (1990).
The ability of the compounds of the invention to treat LPL-related lipoprotein disorders can be demonstrated according to the method described in Ishida, et al., Biochem. Pharmacol. 44 1431-1436 (1992).
The ability of the compounds of the invention to treat proliferative diseases can be demonstrated according to the methods described in Bunchman ET and CA Brookshire, Transplantation Proceed. 23 967-968 (1991); Yamagishi, et al., Biochem. Biophys. Res. Comm. 191 840-846 (1993); and Shichiri, et al., J. Clin. Invest. 87 1867-1871 (1991). Proliferative diseases include smooth muscle proliferation, systemic sclerosis, cirrhosis of the liver, adult respiratory distress syndrome, idiopathic cardiomyopathy, lupus erythematosus, diabetic retinopathy or other retinopathies, psoriasis, scleroderma, prostatic hyperplasia, cardiac hyperplasia, restenosis following arterial injury or other pathologic stenosis of blood vessels.
The ability of the compounds of the invention to treat acute or chronic pulmonary hypertension can be demonstrated according to the method described in Bonvallet et al., Am. J. Physiol. 266 H1327 (1994). Pulmonary hypertension can be associated with congestive heart failure, mitral valve stenosis, emphysema, lung fibrosis, chronic obstructive pulmonary disease (COPD), acute repiratory distress syndrome (ARDS), altitude sickness, chemical exposure, or may be idiopathic.
The ability of the compounds of the invention to treat plaletet aggregation, and thrombosis, can be demonstrated according to the method described in McMurdo et al. Eu. J. Pharmacol. 259 51 (1994). The ability of the compounds of the invention to treat cancers can be demonstrated according to the method described in Shichiri, et al., J. Clin. Invest. 87 1867 (1991).
The ability of the compounds of the invention to treat IL-2 (and other cytokine) mediated cardiotoxicity and vascular permeability disorders can be demonstrated according to the method described in Klemm et al., Proc. Nat. Acad. Sci. 92 2691 (1995). The ability of the compounds of the invention to treat nociception can be demonstrated according to the method described in Yamamoto et al., J. Pharmacol. Exp. Therap. 271 156 (1994).
The ability of the compounds of the invention to treat colitis can be demonstrated according to the method described in Hogaboam et al (EUR. J. Pharmacol. 1996, 309, 261- 269).
The ability of the compounds of the invention to treat ischemia-repurfusion injury in kidney transplantation can be demonstrated according to the method described in Aktan et al (Transplant Int 1996, 9, 201-207). The ability of the compounds of the invention to treat angina, pulmonary hypertension, raynaud's disease, and migraine can be demonstrated according to the method described in Ferro and Webb (Drugs 1996, 51,12-27).
The compounds of the present invention can be used in the form of salts derived from inorganic or organic acids. These salts include but are not limited to the following: acetate, adipate, alginate, citrate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, camphorate, camphorsulfonate, digluconate, cyclopentanepropionate, dodecylsulfate, ethanesulfonate, glucoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, fumarate, hydroehloride, hydrobromide, hydroiodide, 2-hydroxy-ethanesulfonate, lactate, maleate, methanesulfonate, nicotinate, 2-naphthalenesulfonate, oxalate, pamoate, pectinate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, succinate, tartrate, thiocyanate, p-toluenesulfonate and undecanoate. Also, the basic nitrogen-containing groups can be quaternized with such agents as loweralkyl halides, such as methyl, ethyl, propyl, and butyl chloride, bromides, and iodides; dialkyl sulfates like dimethyl, diethyl, dibutyl, and diamyl sulfates, long chain halides such as decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides, aralkyl halides like benzyl and phenethyl bromides, and others. Water or oil-soluble or dispersible products are thereby obtained.
Examples of acids which may be employed to form pharmaceutically acceptable acid addition salts include such inorganic acids as hydrochloric acid, sulphuric acid and phosphoric acid and such organic acids as oxalic acid, maleic acid, succinic acid and citric acid. Basic addition salts can be prepared in situ during the final isolation and purification of the compounds of formula (I), or separately by reacting the carboxylic acid function with a suitable base such as the hydroxide, carbonate or bicarbonate of a pharmaceutically acceptable metal cation or with ammonia, or an organic primary, secondary or tertiary amine. Such pharmaceutically acceptable salts include, but are not limited to, cations based on the alkali and alkaline earth metals, such as sodium, lithium, potassium, calcium, magnesium, aluminum salts and the like, as well as nontoxic ammonium, quaternary ammonium, and amine cations, including, but not limited to ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, ethylamine, and the like. Other representative organic amines useful for the formation of base addition salts include diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine and the like.
The compounds of the invention are useful for antagonizing endothelin in a human or other mammal. In addition, the compounds of the present invention are useful (in a human or other mammal) for the treatment of hypertension, acute or chronic pulmonary hypertension, Raynaud's disease, congestive heart failure, myocardial ischemia, reperfusion injury, coronary angina, cerebral ischemia, cerebral vasospasm, chronic or acute renal failure, non- steroidal antiinflammatory drug induced gastric ulceration, cyclosporin induced nephrotoxicity, endotoxin-induced toxicity, asthma, fibrotic or proliferative diseases, including smooth muscle proliferation, systemic sclerosis, cirrhosis of the liver, adult respiratory distress syndrome, idiopathic cardiomyopathy, lupus erythematosus, diabetic retinopathy or other retinopathies, psoriasis, scleroderma, prostatic hyperplasia, cardiac hyperplasia, restenosis following arterial injury or other pathologic stenosis of blood vessels, LPL-related lipoprotein disorders, transplantation-induced atherosclerosis or atherosclerosis in general, platelet aggregation, thrombosis, cancers, prostate cancer, IL-2 and other cytokine mediated cardiotoxicity and permeability disorders, and nociception, especially treatment of bone pain associated with bone cancer.
Total daily dose administered to a host in single or divided doses may be in amounts, for example, from 0.001 to 1000 mg/kg body weight daily and more usually 0.1 to 100 mg/kg for oral administration or 0.01 to 10 mg/kg for parenteral administration. Dosage unit compositions may contain such amounts of submultiples thereof to make up the daily dose. The amount of active ingredient that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated and the particular mode of administration. It will be understood, however, that the specific dose level for any particular patient will depend upon a variety of factors including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, route of administration, rate of excretion, drug combination, and the severity of the particular disease undergoing therapy.
The compounds of the present invention may be administered orally, parenterally, sublingually, by inhalation spray, rectally, or topically in dosage unit formulations containing conventional nontoxic pharmaceutically acceptable carriers, adjuvants, and vehicles as desired. Topical administration may also involve the use of transdermal administration such as transdermal patches or iontophoresis devices. The term parenteral as used herein includes subcutaneous injections, intravenous, intramuscular, intrasternal injection, or infusion techniques.
Injectable preparations, for example, sterile injectable aqueous or oleagenous suspensions may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution or suspension in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-propanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution, and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil may be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid find use in the preparation of injectables.
Suppositories for rectal administration of the drug can be prepared by mixing the drug with a suitable nonirritating excipient such as cocoa butter and polyethylene glycols which are solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum and release the drug. Solid dosage forms for oral administration may include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compound may be admixed with at least one inert diluent such as sucrose lactose or starch. Such dosage forms may also comprise, as is normal practice, additional substances other than inert diluents, e.g., lubricating agents such as magnesium stearate. In the case of capsules, tablets, and pills, the dosage forms may also comprise buffering agents. Tablets and pills can additionally be prepared with enteric coatings.
Liquid dosage forms for oral administration may include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, and elixirs containing inert diluents commonly used in the art, such as water. Such compositions may also comprise adjuvants, such as wetting agents, emulsifying and suspending agents, and sweetening, flavoring, and perfuming agents. The compounds of the present invention can also be administered in the form of liposomes. As is known in the art, liposomes are generally derived from phospholipids or other lipid substances. Liposomes are formed by mono- or multi-lamellar hydrated liquid crystals that are dispersed in an aqueous medium. Any non-toxic, physiologically aceptable and metabohzable lipid capable of forming liposomes can be used. The present compositions in liposome form can contain, in addition to a compound of the present invention, stabilizers, preservatives, excipients, and the like. The preferred lipids are the phospholipids and phosphatidyl cholines (lecithins), both natural and synthetic.
Methods to form liposomes are known in the art. See, for example, Prescott, Ed., Methods in Cell Biology, Volume XIV, Academic Press, New York, N.Y. (1976), p. 33 et seq.
A representative solid dosage form, for example, a tablet or a capsule, comprises: Compound of the invention: 35% w/w Starch, Pregelatinized, NF 50% w/w Microcrystalline Cellulose, NF 10% w/w
Talc, Powder, USP 5% w/w
While the compounds of the invention can be administered as the sole active pharmaceutical agent, they can also be used in combination with one or more cardiovascular agents independently selected from diuretics, adrenergic blocking agents, vasodilators, calcium channel blockers, renin inhibitors, angiotensin converting enzyme (ACE) inhibitors, angiotensin II antagonists, potassium channel activators and other cardiovascular agents.
Representative diuretics include hydrochlorothiazide, chlorothiazide, acetazolamide, amiloride, bumetanide, benzthiazide, ethacrynic acid, furosemide, indacrinone, metolazone, spironolactone, triamterene, chlorthalidone and the like or a pharmaceutically acceptable salt thereof.
Representative adrenergic blocking agents include phentolamine, phenoxybenzamine, prazosin, terazosin, tolazine, atenolol, metoprolol, nadolol, propranolol, timolol, carteolol and the like or a pharmaceutically acceptable salt thereof.
Representative vasodilators include hydralazine, minoxidil, diazoxide, nitroprusside and the like or a pharmaceutically acceptable salt thereof.
Representative calcium channel blockers include amrinone, bencyclane, diltiazem, fendiline, flunarizine, nicardipine, nimodipine, perhexilene, verapamil, gallopamil, nifedipine and the like or a pharmaceutically acceptable salt thereof.
Representative renin inhibitors include enalkiren, zankiren, RO 42-5892, PD-134672 and the like or a pharmaceutically acceptable salt thereof. Representative angiotensin II antagonists include DUP 753, A-81988 and the like.
Representative ACE inhibitors include captopril, enalapril, lisinopril and the like or a pharmaceutically acceptable salt thereof.
Representative potassium channel activators include pinacidil and the like or a pharmaceutically acceptable salt thereof.
Other representative cardiovascular agents include sympatholytic agents such as methyldopa, clonidine, guanabenz, reserpine and the like or a pharmaceutically acceptable salt thereof.
The compounds of the invention and the cardiovascular agent can be administered at the recommended maximum clinical dosage or at lower doses. Dosage levels of the active compounds in the compositions of the invention may be varied so as to obtain a desired therapeutic response depending on the route of administration, severity of the disease and the response of the patient. The combination can be administered as separate compositions or as a single dosage form containing both agents. When administered as a combination, the therapeutic agents can be formulated as separate compositions which are given at the same time or different times, or the therapeutic agents can be given as a single composition.
The foregoing is merely illustrative of the invention and is not intended to limit the invention to the disclosed compounds, processes, compositions and methods. Variations and changes which are obvious to one skilled in the art are intended to be within the scope and nature of the mvention which are defined in the appended claims.

Claims

What is claimed is:
A compound of the
Figure imgf000813_0001
wherein n is zero;
Z is -C(Rjg)(Ri9)- wherein Rig and R19 are hydrogen;
R is -C(O)2-G wherein G is hydrogen;
Rl is aryl substituted with one substituent selected from alkoxy and alkoxyalkoxy;
R2 is heterocycle which is 1,3-benzodioxyl; and
R3 is R4-C(O)-R5 wherein R5 is methylene and R4 is selected from (Rn)(Ri2)N- and
(Rl la)(Rl2a)N-N(H)-;
one of Rn and R12 is hydrogen and the other is selected from arylalkyl and diarylalkyl, wherein each aryl group of the diarylalkyl is substituted with one or two alkyl substituents; and
one of Ri ιa or Ri2a is alkyl and the other is aryl;
or a pharmaceutically acceptable salt thereof.
2. A compound of claim 1 wherein Ri is aryl substituted with one substituent selected from methoxy, methoxyethoxy, and isopropoxyethoxy; R2 is l,3-benzodiox-5-yl; R3 is R4-C(O)-R5 wherein R5 is methylene and R4 is selected from ( n)(Ri2)N- and (Riia)(Ri2a)N-N(H)- wherein one of Rn and R12 is hydrogen and the other is selected from arylalkyl and diarylalkyl wherem each aryl group of the diarylalkyl is substituted with methyl or ethyl.
3. A compound of claim 1 wherein Ri is phenyl substituted with one substituent selected from methoxy, methoxyethoxy, and isopropoxyethoxy; R2 is l,3-benzodiox-5-yl; R3 is R4-C(O)-R5 wherein R5 is methylene and R4 is selected from (Rn)(Ri2)N- and (Rπa)(Ri2a)N-N(H)- wherein one of Rn and R12 is hydrogen and the other is selected from phenylalkyl and diphenylalkyl wherein each phenyl group of the diphenylalkyl is substituted with methyl or ethyl, and one of Ri ιa or Ri2a is alkyl and the other is phenyl.
4. A compound selected from the group consisting of trα«5,,tr_.«5-2-(4-methoxyphenyl)-4-( 1 ,3 -benzodioxol-5-yl)- 1 -(N-((bis-(o- tolyl)methyl)amino)carbonylmethyl)pyrrolidine-3 -carboxylic acid; trαπ5,tr_.«_.-2-[4-(2-methoxyethoxy)phenyl]-4-(l,3-benzodioxol-5-yl)-l-(N-(2,2- dimethy 1- 1 -pheny lpropy 1)- 1 -amino)carbonylmethyl)pyrrolidine-3 -carboxylic acid; tr_.«_.,trα?.5-2-[4-(2-methoxyethoxy)phenyl]-4-(l,3-benzodioxol-5-yl)-l-(N-((bis-(o- tolyl)methyl)amino)carbonylmethyl)pyrrolidine-3 -carboxylic acid; trαrø,trt.«5-2-[4-(2-isopropoxyethoxy)phenyl]-4-(l,3-benzodioxol-5-yl)-l-(N-(2,2- dimethyl- 1 -pheny lpropy 1)- 1 -amino)carbonylmethyl)pyrrolidine-3 -carboxylic acid; tr_.rø,trα«s-2-(4-methoxyphenyl] -4-( 1 ,3 -benzodioxol-5 -yl)- 1 -(N-(3 ,3 -dimethyl- 1 - pheny lbutyl)-l -amino)carbonylmethyl)pyrrolidine-3 -carboxylic acid; trα»5,trα«_.-2-[4-(2-isopropoxyethoxy)phenyl]-4-(l,3-benzodioxol-5-yl)-l-(N-((l-(o- tolyl)- 1 -(o-ethylphenyl)methyl)amino)carbonylmethyl)pyrrolidine-3 -carboxylic acid; tr_7rø,tr-7«j,-2-(4-(2-(2-propoxy)ethoxy)phenyl)-4-(l,3-benzodioxol-5-yl)-l-(N- phenyl-N-t-butylhy drazinocarbonylmethyl)pyrrolidine-3 -carboxylic acid; and trα/.5,,trα«5'-2-(4-(2-methoxyethoxy)phenyl)-4-(l,3-benzodioxol-5-yl)-l-(N-phenyl-N- t-butylhydrazinocarbonylmethyl)pyrrolidine-3-carboxylic acid.
PCT/US2001/027220 2000-08-31 2001-08-31 Endothelin antagonists Ceased WO2002017912A1 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US09/653,563 2000-08-31
US09/653,563 US7208517B1 (en) 1994-08-19 2000-08-31 Endothelin antagonists

Publications (1)

Publication Number Publication Date
WO2002017912A1 true WO2002017912A1 (en) 2002-03-07

Family

ID=24621388

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2001/027220 Ceased WO2002017912A1 (en) 2000-08-31 2001-08-31 Endothelin antagonists

Country Status (1)

Country Link
WO (1) WO2002017912A1 (en)

Cited By (15)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006034085A1 (en) * 2004-09-17 2006-03-30 Abbott Laboratories Crystalline form of atrasentan hydrochloride
WO2006034094A1 (en) * 2004-09-17 2006-03-30 Abbott Laboratories Crystalline form 1 of atrasentan hxdrochloride
WO2006034084A1 (en) * 2004-09-17 2006-03-30 Abbott Laboratories Crystalline form 2 of atrasentan hydrochloride
WO2006034234A1 (en) * 2004-09-17 2006-03-30 Abbott Laboratories Crystalline form 3 of atrasentan hydrochloride
WO2011114103A1 (en) 2010-03-18 2011-09-22 Biolipox Ab Pyrimidinones for use as medicaments
US8569341B2 (en) 2010-06-04 2013-10-29 Amgen Inc. Piperidinone derivatives as MDM2 inhibitors for the treatment of cancer
US8623819B2 (en) 2007-08-22 2014-01-07 AbbVie Deutschland GmbH & Co. KG Therapy for complications of diabetes
US8952036B2 (en) 2013-02-28 2015-02-10 Amgen Inc. Benzoic acid derivative MDM2 inhibitor for the treatment of cancer
US9376386B2 (en) 2013-06-10 2016-06-28 Amgen, Inc. Processes of making and crystalline forms of a MDM2 inhibitor
US9376425B2 (en) 2011-09-27 2016-06-28 Amgen, Inc. Heterocyclic compounds as MDM2 inhibitors for the treatment of cancer
CN105745204A (en) * 2013-09-12 2016-07-06 艾伯维公司 Atrasentan mandelate salts for the treatement of kidney diseases
US9758495B2 (en) 2013-03-14 2017-09-12 Amgen Inc. Heteroaryl acid morpholinone compounds as MDM2 inhibitors for the treatment of cancer
WO2018010656A1 (en) * 2016-07-12 2018-01-18 南京明德新药研发股份有限公司 Pyrrolidine derivative serving as ppar agonist
JP2021504389A (en) * 2017-12-21 2021-02-15 広東衆生睿創生物科技有限公司Ｇｕａｎｇｄｏｎｇ Ｒａｙｎｏｖｅｎｔ Ｂｉｏｔｅｃｈ Ｃｏ．，Ｌｔｄ． Amorphous pyrrolidine derivative used as a PPAR agonist and its production method
US11407721B2 (en) 2013-02-19 2022-08-09 Amgen Inc. CIS-morpholinone and other compounds as MDM2 inhibitors for the treatment of cancer

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1996006095A1 (en) * 1994-08-19 1996-02-29 Abbott Laboratories Endothelin antagonists
WO1997030046A1 (en) * 1996-02-13 1997-08-21 Abbott Laboratories 4-(benzo-1,3-dioxolyl)-pyrrolidine-3-carboxylic acid derivatives as endothelin antagonists
WO1997030045A1 (en) * 1996-02-13 1997-08-21 Abbott Laboratories Novel benzo-1,3-dioxolyl- and benzofuranyl substituted pyrrolidine derivatives as endothelin antagonists

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1996006095A1 (en) * 1994-08-19 1996-02-29 Abbott Laboratories Endothelin antagonists
WO1997030046A1 (en) * 1996-02-13 1997-08-21 Abbott Laboratories 4-(benzo-1,3-dioxolyl)-pyrrolidine-3-carboxylic acid derivatives as endothelin antagonists
WO1997030045A1 (en) * 1996-02-13 1997-08-21 Abbott Laboratories Novel benzo-1,3-dioxolyl- and benzofuranyl substituted pyrrolidine derivatives as endothelin antagonists

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
LIU, GANG ET AL: "Design, Synthesis, and Activity of a Series of Pyrrolidine-3- carboxylic Acid-Based, Highly Specific, Orally Active ETB Antagonists Containing a Diphenylmethylamine Acetamide Side Chain", J. MED. CHEM. (1999), 42(18), 3679-3689, XP002187525 *

Cited By (31)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9051301B2 (en) 2004-09-17 2015-06-09 Abbvie Inc. Crystalline form of a drug
WO2006034094A1 (en) * 2004-09-17 2006-03-30 Abbott Laboratories Crystalline form 1 of atrasentan hxdrochloride
WO2006034084A1 (en) * 2004-09-17 2006-03-30 Abbott Laboratories Crystalline form 2 of atrasentan hydrochloride
WO2006034234A1 (en) * 2004-09-17 2006-03-30 Abbott Laboratories Crystalline form 3 of atrasentan hydrochloride
JP2008513481A (en) * 2004-09-17 2008-05-01 アボット・ラボラトリーズ Crystal form 2 of atrasentan hydrochloride
WO2006034085A1 (en) * 2004-09-17 2006-03-30 Abbott Laboratories Crystalline form of atrasentan hydrochloride
US8865650B2 (en) 2007-08-22 2014-10-21 AbbVie Deutschland GmbH & Co. KG Therapy for complications of diabetes
US8623819B2 (en) 2007-08-22 2014-01-07 AbbVie Deutschland GmbH & Co. KG Therapy for complications of diabetes
US9592231B2 (en) 2007-08-22 2017-03-14 AbbVie Deutschland GmbH & Co. KG Therapy for complications of diabetes
WO2011114103A1 (en) 2010-03-18 2011-09-22 Biolipox Ab Pyrimidinones for use as medicaments
US8569341B2 (en) 2010-06-04 2013-10-29 Amgen Inc. Piperidinone derivatives as MDM2 inhibitors for the treatment of cancer
US9296736B2 (en) 2010-06-04 2016-03-29 Amgen Inc. Piperidinone derivatives as MDM2 inhibitors for the treatment of cancer
US9593129B2 (en) 2010-06-04 2017-03-14 Amgen, Inc. Piperidinone derivatives as MDM2 inhibitors for the treatment of cancer
US9376425B2 (en) 2011-09-27 2016-06-28 Amgen, Inc. Heterocyclic compounds as MDM2 inhibitors for the treatment of cancer
US11407721B2 (en) 2013-02-19 2022-08-09 Amgen Inc. CIS-morpholinone and other compounds as MDM2 inhibitors for the treatment of cancer
US8952036B2 (en) 2013-02-28 2015-02-10 Amgen Inc. Benzoic acid derivative MDM2 inhibitor for the treatment of cancer
US9758495B2 (en) 2013-03-14 2017-09-12 Amgen Inc. Heteroaryl acid morpholinone compounds as MDM2 inhibitors for the treatment of cancer
US9855259B2 (en) 2013-06-10 2018-01-02 Amgen Inc. Processes of making and crystalline forms of a MDM2 inhibitor
US9623018B2 (en) 2013-06-10 2017-04-18 Amgen Inc. Processes of making and crystalline forms of a MDM2 inhibitor
US9757367B2 (en) 2013-06-10 2017-09-12 Amgen Inc. Calcium propane-2-sulfinate dihydrate
US9801867B2 (en) 2013-06-10 2017-10-31 Amgen Inc. Processes of making and crystalline forms of a MDM2 inhibitor
US9376386B2 (en) 2013-06-10 2016-06-28 Amgen, Inc. Processes of making and crystalline forms of a MDM2 inhibitor
CN105745204A (en) * 2013-09-12 2016-07-06 艾伯维公司 Atrasentan mandelate salts for the treatement of kidney diseases
JP2019527730A (en) * 2016-07-12 2019-10-03 広東衆生睿創生物科技有限公司Ｇｕａｎｇｄｏｎｇ Ｒａｙｎｏｖｅｎｔ Ｂｉｏｔｅｃｈ Ｃｏ．，Ｌｔｄ． Pyrrolidine derivatives that are PPAR agonists
CN109563032A (en) * 2016-07-12 2019-04-02 广东众生睿创生物科技有限公司 Pyrrolidin derivatives as PPAR agonist
US10526320B2 (en) 2016-07-12 2020-01-07 Guangdong Raynovent Biotech Co., Ltd. Pyrrolidine derivatives as PPAR agonists
RU2711991C1 (en) * 2016-07-12 2020-01-23 Гуандун Рейновент Биотек Ко., Лтд. Pyrrolidine derivatives as ppar agonists
CN109563032B (en) * 2016-07-12 2022-05-20 广东众生睿创生物科技有限公司 Pyrrolidine derivatives as PPAR agonists
WO2018010656A1 (en) * 2016-07-12 2018-01-18 南京明德新药研发股份有限公司 Pyrrolidine derivative serving as ppar agonist
JP2021504389A (en) * 2017-12-21 2021-02-15 広東衆生睿創生物科技有限公司Ｇｕａｎｇｄｏｎｇ Ｒａｙｎｏｖｅｎｔ Ｂｉｏｔｅｃｈ Ｃｏ．，Ｌｔｄ． Amorphous pyrrolidine derivative used as a PPAR agonist and its production method
US11396493B2 (en) 2017-12-21 2022-07-26 Guangdong Raynovent Biotech Co., Ltd. Amorphous pyrrolidine derivative as PPAR agonist and preparation method thereof

Similar Documents

Publication Publication Date Title
US6462194B1 (en) Endothelin antagonists
JP3741441B2 (en) Endothelin antagonist
EP0885215B1 (en) Novel benzo-1,3-dioxolyl- and benzofuranyl substituted pyrrolidine derivatives as endothelin antagonists
US6946481B1 (en) Endothelin antagonists
WO1999006397A2 (en) Pyrrolidine-3-carboxylic acid derivatives and their use as endothelin antagonists
WO2002017912A1 (en) Endothelin antagonists
US7365093B2 (en) Endothelin antagonists
EP0888340A1 (en) 4-(benzo-1,3-dioxolyl)-pyrrolidine-3-carboxylic acid derivatives as endothelin antagonists
WO1998057933A1 (en) Pyrrolidine carboxylic acid derivatives as endothelin antagonists
AU781355B2 (en) Novel benzo-1,3-dioxolyl-and benzofuranyl substituted pyrrolidine derivatives as endothelin antagonists
AU2005201160B2 (en) Endothelin antagonists
AU725122B2 (en) Endothelin antagonists
NZ514170A (en) Benzo-1, 3-dioxolyl- and benzofuranyl substituted pyrrolidine derivatives as endothelin antagonists
CZ2000348A3 (en) Pyrrolidine-3-karboxylic acid derivatives and their use as endothelin antagonists
NZ514171A (en) Benzo-1,3-dioxolyl- and benzofuranyl substituted pyrrolidine derivatives as endothelin antagonists
AU2008201198A1 (en) Endothelin anatagonists

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

Designated state(s): CA JP MX

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): AT BE CH CY DE DK ES FI FR GB GR IE IT LU MC NL PT SE TR

121 Ep: the epo has been informed by wipo that ep was designated in this application
DFPE Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101)
122 Ep: pct application non-entry in european phase
NENP Non-entry into the national phase

Ref country code: JP