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WO2002017912A1 - Antagonistes de l'endotheline - Google Patents

Antagonistes de l'endotheline Download PDF

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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
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WIPO (PCT)
Prior art keywords
trans
benzodioxol
carboxylic acid
ethyl
pyrrohdine
Prior art date
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PCT/US2001/027220
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English (en)
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
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Abbott Laboratories
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Abbott Laboratories
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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/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • 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

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Abstract

L'invention concerne un composé correspondant à la formule (I), ou un sel pharmaceutiquement acceptable de ce composé, ainsi que des procédés et des intermédiaires pour la préparation de ce composé. L'invention concerne également un procédé pour lutter contre l'action de l'endothéline.
PCT/US2001/027220 2000-08-31 2001-08-31 Antagonistes de l'endotheline Ceased WO2002017912A1 (fr)

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WO2006034094A1 (fr) * 2004-09-17 2006-03-30 Abbott Laboratories Forme cristalline 1 de l’hydrochlorure d’atrasentan
WO2006034084A1 (fr) * 2004-09-17 2006-03-30 Abbott Laboratories Forme cristalline 2 de l’hydrochlorure d’atrasentan
WO2006034234A1 (fr) * 2004-09-17 2006-03-30 Abbott Laboratories Forme cristalline 3 de l’hydrochlorure d’atrasentan
WO2011114103A1 (fr) 2010-03-18 2011-09-22 Biolipox Ab Pyrimidinones pour usage médicamenteux
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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 (zh) * 2013-09-12 2016-07-06 艾伯维公司 用于治疗肾脏疾病的阿曲生坦扁桃酸盐
US9758495B2 (en) 2013-03-14 2017-09-12 Amgen Inc. Heteroaryl acid morpholinone compounds as MDM2 inhibitors for the treatment of cancer
WO2018010656A1 (fr) * 2016-07-12 2018-01-18 南京明德新药研发股份有限公司 Dérivé de pyrrolidine servant d'agoniste de ppar
JP2021504389A (ja) * 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． Ｐｐａｒアゴニストとして用いられるピロリジン誘導体の非晶質及びその製造方法
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US9376386B2 (en) 2013-06-10 2016-06-28 Amgen, Inc. Processes of making and crystalline forms of a MDM2 inhibitor
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US10526320B2 (en) 2016-07-12 2020-01-07 Guangdong Raynovent Biotech Co., Ltd. Pyrrolidine derivatives as PPAR agonists
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