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CN1265097A - Pyrrolidine carboxylic acid derivatives as endothelin antagonists - Google Patents

Pyrrolidine carboxylic acid derivatives as endothelin antagonists Download PDF

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Publication number
CN1265097A
CN1265097A CN98806184A CN98806184A CN1265097A CN 1265097 A CN1265097 A CN 1265097A CN 98806184 A CN98806184 A CN 98806184A CN 98806184 A CN98806184 A CN 98806184A CN 1265097 A CN1265097 A CN 1265097A
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Prior art keywords
phenyl
fluoro
methoxy
methoxyphenyl
hydrogen
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CN98806184A
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A·S·塔斯克
M·温
S·A·波伊德
H·－S·杰
T·W·冯格德恩
B·K·索伦森
K·J·亨赖
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Abbott Laboratories
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Abbott Laboratories
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Priority claimed from US09/087,178 external-priority patent/US6124341A/en
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D207/16—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Furan Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

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

Description

Pyrrolidine carboxylic acid derivatives as endothelin antagonist
The application is the part continuation application of u.s. patent application serial number 08/877187 (on June 17th, 1997 submitted).
Technical field
The present invention relates to for endothelin antagonist compound, prepare the method for this compounds, used synthetic intermediate and method and the composition that is used for the antagonism endothelin in these methods.
Background of the present invention
Endothelin (ET) is 21 amino acid peptides that endotheliocyte produces.ET goes up by enzyme cutting Trp-Val key in the big endothelin of precursor peptide (big ET) to produce.This cutting is caused by endothelin converting enzyme (ECE).Endothelin contraction artery and vein have been shown, increase mean arterial pressure, reduce heart output, the shrinkability of external enhancing heart, the mitotic division of stimulated in vitro vascular smooth muscle cell, the non-vascular smooth muscle of external contraction comprises guinea pig trachea, human uropoiesis bladder band and rat uterus, increase the resistance of tracheae in the body, induce the formation of stomach ulcer, the release of external and body internal stimulus atrial natriuretic peptide, increase the blood plasma level of vassopressin, aldosterone and catecholamine, the release of the release of vitro inhibition renin and stimulated in vitro gonad-stimulating hormone.
Shown that vasoconstriction is (Nature 332 411 (1988), FEBS Letters 231 440 (1988) and Biochem.Biophys.Res.Commun.154 868 (1988)) that cause that combine by acceptor on endothelin and its vascular smooth muscle.Suppress medicine that endothelin produces or combine with endothelin or suppress endothelin and endothelin receptor bonded medicine will bring about a wholesome effect in various treatments field.The antibody of anti-endothelin can alleviate the detrimental action (Kon etc., J.Clin.Invest.83 1762 (1989)) of renal ischaemia to the filterability of renal vascular resistance and renal glomerulus when in fact, having shown in kidney perfusion.In addition, anti-endothelin antibody weakens the renal toxicity effect (Kon etc., Kidney Int.37 1487 (1990)) that vein gives S-Neoral and weakens infarct size coronarius.
(Nature 365:759-761 (1993) report Ro 46-2005 such as Clozel, a kind of ET-A/B antagonist of non-peptide, stop rat ischemia metanephros vasoconstriction, stop rat because the minimizing of the big cerebral blood flow that subarachnoid hemorrhage (SAH) causes and when oral administration, the MAP when reducing Squirrel monkey and arranging sodium.After also having reported SAH recently, the ET-A antagonist BQ-485 of linear tripeptides sample has effect (S.Itoh, the T.Sasaki similar to the artery caliber, K.Ide, K.Ishikawa, M.Nishikibe and M.Yano, Biochem.Biophys.Res.Comm., 195:969-75 (1993).These results show that the medicine of antagonism ET/ET receptors bind provides beneficial therapeutic effect for described disease.
Endothelin receptor relevant on two kinds of structures clone, order-checking and qualitative (Hosada, K. have been carried out; Nakao, K.; Arai, H.; Suga, S.; Ogawa, Y.; Mukoyama, M.; Shirakami, G.; Saito, Y.; Nakanishi, S.; Imura, H.FEBS Lett.1991,187,23-26; Sakamoto, A.; Yanagisawa, M.; Sakurai, T.; Takuwa, Y.; Yanagisawa, H.; Masaki, T.Biochem.Biophys.Res.Commun.1991,178,656-663).Every kind combines with three kinds of different peptides of endothelin with different avidity.ET AAcceptor shows that the avidity to ET-1 and ET-2 surpasses the avidity to ET-3, and ET BThe acceptor right and wrong-different peptide optionally.Being described as the vasorelaxation acceptor at first is because it regulates release (DeNucci, the G. of nitrogen oxide; Thomas, R.; D ' Orleans-Juste, P.; Antunes, E.; Walder, C.; Warner, T.D.; Vane, J.R.Proc.Natl.Acad.Sci.U.S.A.1988,85,9797-9800) clear now, ET BAcceptor is responsible for multiple physiologic function.Present research prompting, ET BPlay conditioned reaction in the some diseases state, these morbid states comprise pulmonary hypertension (McCulloch, the K.M. that makes a definite diagnosis; Maclean, M.R.; J.Cardiovasc.Pharmacol.1995,26 (Suppl.3), S169-S176), contractile dysfunction (Webb, the M.L. relevant with benign prostatauxe; Chao, C.-C.; Rizzo, M.; Shapiro, R.A.; Neubauer, M.; Liu, E.C.K.; Aversa, C.R.; Brittain, R.J.; Treiger, B.Mol.Pharmacol.1995,47,730-737; Webb, M.L.; Meek, T.D.Med.Res.Rev.1997,17,17-67), myocardial infarction (Vitola, J.V.; Forman, M.B.; Holsinger, J.P.; Kawana, M.; Atkinson, J.B.; Quertermous, T.; Jackson, E.K.; Murray, J.J.J.Cardiovasc.Pharmacol.1996,28,774-783) and atherosclerosis (Dagassan, P.H.Breu.V.; Clozel, M.; Kunzli.A.; Vogt, P, Turina, M.; Kiowski, Clozel, J.-P.J.Cardiovasc.Pharmacol.1996,27,147-153).We before once report found effectively a series of and optionally in conjunction with ET AThe tetramethyleneimine of receptor subtype-3-carboxylic acid cpd (Winn, M.; Von Geldern, T.W.; Opgenorth, T.J.; Jae, H.-S.; Tasker.A.S.; Boyd, S.A.; Kester, J.A.; Mantei, R.A.; Bal, R.B.; Sorensen, B.K.; Wu-Wong, J.R.; Chiou, W.J.; Dixon, D.B.; Novosad, E.I.; Hernandez, L.; Marsh, K.C.J.Med.Chem.1996,39,1039-1048).The claimed compound of the present invention is different with previously described compound, and at it effectively with optionally in conjunction with ET BReceptor subtype is blocked described endothelin has uniqueness to the effect aspect of these acceptors character.Can find that like this they have treatment by ET BThe purposes of receptor-mediated disease.
Of the present invention open
According to the invention provides formula (I) compound or its pharmacy acceptable salt:
Figure A9880618400241
Wherein R is-(CH 2) m-W, wherein m is 0 to 6 integer, W is
(a)-C (O) 2-G, wherein G is hydrogen or carboxy protective group,
(b)-PO 3H 2，
(c)-and (OH) E of P (O), wherein E is hydrogen, low alkyl group or arylalkyl,
(d)-CN，
(e)-C (O) NHR 17, R wherein 17Be low alkyl group,
(f) alkyl amino-carbonyl,
(g) dialkyl amino carbonyl,
(h) tetrazyl,
(I) hydroxyl,
(j) alkoxyl group,
(k) sulfonamido,
(l)-C (O) NHS (O) 2R 16, R wherein 16Be low alkyl group, haloalkyl, aryl or dialkyl amido,
(m)-S (O) 2NHC (O) R 16, R wherein 16As above-mentioned definition,
Figure A9880618400251
R 1And R 2Independently be selected from hydrogen, low alkyl group, alkenyl, alkynyl, alkoxyalkyl, alkoxy carbonyl alkyl, hydroxyalkyl, haloalkyl, halogenated alkoxy alkyl, alkoxy alkoxy alkyl, the alkylthio alkoxyalkyl, cycloalkyl, cycloalkylalkyl, the aminocarboxyl alkyl, alkyl amino alkyl carbonyl, the dialkyl amino carbonyl alkyl, the aminocarboxyl alkenyl, the alkyl amino-carbonyl alkenyl, the dialkyl amino carbonyl alkenyl, the hydroxyl alkenyl, aryl, arylalkyl, aryloxy alkyl, alkoxy aryl alkyl, heterocyclic radical, (heterocyclic radical) alkyl and (R Aa) (R Bb) N-R Cc-R wherein AaBe aryl or arylalkyl, R BbBe hydrogen or alkanoyl and R CcBe alkylidene group, prerequisite is R 1And R 2One or both of be not hydrogen; R 3Be R 4-C (O)-R 5-or R 6-S (O) 2-R 7-, R wherein 5Be (i) covalent linkage, (ii) alkylidene group, (iii) alkylene group, (iv)-N (R 20)-R 8-or-R 8a-N (R 20)-R 8-, R wherein 8And R 8aIndependently be selected from alkylidene group and alkylene group; And R 20For hydrogen, low alkyl group, alkenyl, haloalkyl, alkoxyalkyl, halogenated alkoxy alkyl, cycloalkyl or cycloalkylalkyl or (v)-O-R 9-or-R 9a-O-R 9-, R wherein 9And R 9aIndependently be selected from alkylidene group; R 7Be (i) covalent linkage, (ii) alkylidene group, (iii) alkylene group or (iv)-N (R 21)-R 10-or-R 10a-N (R 21)-R 10-, R wherein 10And R 10aIndependently be selected from alkylidene group and alkylene group; And R 21Be hydrogen, low alkyl group, alkenyl, haloalkyl, alkoxyalkyl, halogenated alkoxy alkyl, aryl or arylalkyl; R wherein 4And R 6For
Figure A9880618400261
R wherein 11And R 12Independently be selected from low alkyl group, cyano group, alkoxyl group, halogen, haloalkyl and phenyl, and R 13, R 14And R 15Independently be selected from hydrogen, low alkyl group, hydroxyl, amino, alkoxyl group, aryl, heterocycle, halogen, carboxyl, nitro, alkyl sulphonyl, aryl sulfonyl, thio alkoxy, thio-aryloxy or cyano group; Or
(ii) heterocyclic radical (amino).
The preferred embodiment of the invention is formula (II) compound: Substituting group-R wherein 2,-R and-R 1With trans, trans relation exists, R, R 1, R 2And R 3As above-mentioned definition.
Preferred embodiment of the present invention is formula (I) or formula (II) compound, wherein R 3Be R 4-C (O)-R 5-, R wherein 4As above-mentioned definition, R 5Be alkylidene group or R 3Be R 6-S (O) 2-R 7-, R wherein 7Be alkylidene group, and R 6As above-mentioned definition.
Embodiment that is more preferably of the present invention is formula (I) or formula (II) compound, and wherein R is-C (O) 2-G, wherein G is hydrogen or carboxy protective group, or R is that tetrazyl or R are-C (O)-NHS (O) 2R 16, R wherein 16Be low alkyl group, haloalkyl or aryl, R 1And R 2Independently be selected from (i) low alkyl group, (ii) cycloalkyl, (iii) replace with unsubstituted aryl, (iv) replace or unsubstituted heterocyclic, and R 3Be R 4-C (O)-R 5-, R wherein 4As defined above and R 5Be alkylidene group or R 3Be R 6-S (O) 2-R 7-, R wherein 7Be alkylidene group and R 6As defined above.
The embodiment that the present invention is more preferably is formula (I) or formula (II) compound, and wherein R is-C (O) 2-G, wherein G be hydrogen or carboxy protective group, tetrazyl or-C (O)-NHS (O) 2R 16R wherein 16Be low alkyl group, haloalkyl or aryl, R 1Be (i) alkoxyalkyl, (ii) cycloalkyl, (iii) phenyl, (iv) pyridyl, (v) furyl or (vi) replace or unsubstituted 4-p-methoxy-phenyl, 4-fluoro phenyl, 3-fluoro phenyl, the 4-ethoxyl phenenyl, 4-propoxy-phenyl, the 4-isopropyl phenyl, the 4-trifluoromethyl, 4-pentafluoroethyl group phenyl, 2-fluoro-4-ethoxyl phenenyl, 3-fluoro-4-p-methoxy-phenyl, 3-fluoro-4-ethoxyl phenenyl, 3-fluoro-4-propoxy-phenyl, 3-methoxyl group-4-propoxy-phenyl, 2-fluoro phenyl, 4-methoxymethoxy phenyl, 4-(2-methoxy ethoxy) phenyl, 4-(2-ethoxy ethoxy) phenyl, 4-(2-isopropoxy oxyethyl group) phenyl, the 4-hydroxy phenyl, 1,3-benzo dioxolyl (dioxolyl), 1,4-benzodioxane base or dihydro benzo furyl, wherein said substituting group is selected from alkoxyl group, alkoxyl group alkoxyl group and carboxyl alkoxyl group, R 2For replace or unsubstituted 1,3-benzo dioxolyl, 7-methoxyl group-1,3-benzo dioxolyl, 1,4-benzodioxane base, 8-methoxyl group-1,4-benzodioxane base, dihydro benzo furyl, benzofuryl, 4-p-methoxy-phenyl, Dimethoxyphenyl, fluoro phenyl or phenyl-difluoride base and R 3Be R 4-C (O)-R 5-, R wherein 4As defined above and R 5Be alkylidene group or R 3Be R 6-S (O) 2-R 7-, R wherein 7Be alkylidene group and R 6For as defined above.
Another embodiment that is more preferably of the present invention is formula (I) or formula (II) compound, and wherein R is-C (O) 2-G, wherein G be hydrogen or carboxy protective group, tetrazyl or-C (O)-NHS (O) 2R 16R wherein 16Be low alkyl group, haloalkyl or aryl, R 1Be (i) alkoxyalkyl, (ii) cycloalkyl, (iii) phenyl, (iv) pyridyl, (v) furyl or (vi) replace or unsubstituted 4-p-methoxy-phenyl, 4-fluoro phenyl, 3-fluoro phenyl, the 4-ethoxyl phenenyl, 4-propoxy-phenyl, the 4-isopropyl phenyl, the 4-trifluoromethyl, 4-pentafluoroethyl group phenyl, 2-fluoro-4-ethoxyl phenenyl, 3-fluoro-4-p-methoxy-phenyl, 3-fluoro-4-ethoxyl phenenyl, 3-fluoro-4-propoxy-phenyl, 3-methoxyl group-4-propoxy-phenyl, 2-fluoro phenyl, 4-methoxymethoxy phenyl, 4-(2-methoxy ethoxy) phenyl, 4-(2-ethoxy ethoxy) phenyl, 4-(2-isopropoxy oxyethyl group) phenyl, the 4-hydroxy phenyl, 1,3-benzo dioxolyl, 1,4-benzodioxane base or dihydro benzo furyl, wherein said substituting group is selected from alkoxyl group, alkoxyl group alkoxyl group and carboxyl alkoxyl group, R 2For replace or unsubstituted 1,3-benzo dioxolyl, 7-methoxyl group-1,3-benzo dioxolyl, 1,4-benzodioxane base, 8-methoxyl group-1,4-benzodioxane base, dihydro benzo furyl, benzofuryl, 4-p-methoxy-phenyl, Dimethoxyphenyl, fluoro phenyl or phenyl-difluoride base and R 3Be R 4-C (O)-R 5-, R wherein 4As defined above and R 5Be alkylidene group.
Embodiment that is more preferably of the present invention is formula (I) or formula (II) compound, and wherein R is-C (O) 2-G, wherein G be hydrogen or carboxy protective group, tetrazyl or-C (O)-NHS (O) 2R 16R wherein 16Be low alkyl group or haloalkyl, R 1For replacing or unsubstituted 4-p-methoxy-phenyl, 4-fluoro phenyl, 2-fluoro phenyl, the 4-ethoxyl phenenyl, 4-propoxy-phenyl, the 4-isopropyl phenyl, 3-fluoro-4-p-methoxy-phenyl, 3-fluoro-4-ethoxyl phenenyl, 2-fluoro-4-ethoxyl phenenyl, 3-fluoro-4-propoxy-phenyl, 3-methoxyl group-4-propoxy-phenyl, the 4-trifluoromethyl, 4-pentafluoroethyl group phenyl, 4-methoxymethoxy phenyl, 4-(2-methoxy ethoxy) phenyl, 4-(2-ethoxy ethoxy) phenyl, 4-(2-isopropoxy oxyethyl group) phenyl, the 4-hydroxy phenyl, 1,3-benzo dioxolyl, 1,4-benzodioxane base or dihydro benzo furyl, wherein said substituting group is selected from alkoxyl group, alkoxyl group alkoxyl group and carboxyl alkoxyl group, R 2Be 1,3-benzo dioxolyl, 7-methoxyl group-1,3-benzo dioxolyl, 1,4-benzodioxane base, dihydro benzo furyl, benzofuryl, 4-p-methoxy-phenyl, Dimethoxyphenyl, fluoro phenyl or phenyl-difluoride base and R 3Be R 4-C (O)-R 5-, R wherein 4As defined above and R 5Be alkylidene group.
The most preferred embodiment of the present invention is formula (I) or formula (II) compound, and wherein R is-C (O) 2-G, wherein G is hydrogen or carboxy protective group, R 1For replacing or unsubstituted 4-p-methoxy-phenyl, 4-fluoro phenyl, 2-fluoro phenyl, 3-fluoro-4-ethoxyl phenenyl, 3-fluoro-4-p-methoxy-phenyl, the 4-ethoxyl phenenyl, 4-propoxy-phenyl, the 4-isopropyl phenyl, 2-fluoro-4-ethoxyl phenenyl, 3-fluoro-4-propoxy-phenyl, 3-methoxyl group-4-propoxy-phenyl, 4-methoxymethoxy phenyl, 4-(2-methoxy ethoxy) phenyl, 4-(2-ethoxy ethoxy) phenyl, 4-(2-isopropoxy oxyethyl group) phenyl, the 4-hydroxy phenyl, 1,3-benzo dioxolyl, 1,4-benzodioxane base or dihydro benzo furyl, wherein said substituting group is selected from alkoxyl group, alkoxyl group alkoxyl group and carboxyl alkoxyl group, R 2Be 1,3-benzo dioxolyl, 7-methoxyl group-1,3-benzo dioxolyl, 1,4-benzodioxane base, dihydro benzo furyl, benzofuryl, 4-p-methoxy-phenyl, Dimethoxyphenyl, fluoro phenyl or phenyl-difluoride base and R 3Be R 4-C (O)-R 5-, R wherein 4For
Figure A9880618400291
R wherein 11And R 12Independently be selected from low alkyl group, and R 13, R 14And R 15Independently be selected from hydrogen, low alkyl group, hydroxyl, amino, alkoxyl group, aryl, heterocycle, halogen, carboxyl, nitro, alkyl sulphonyl, aryl sulfonyl, thio alkoxy, thio-aryloxy or cyano group; And R 5Be alkylidene group.
The most preferred embodiment of the present invention is formula (I) or formula (II) compound, and wherein R is-C (O) 2-G, wherein G is hydrogen or carboxy protective group, R 1For replacing or unsubstituted 4-p-methoxy-phenyl, 4-fluoro phenyl, 2-fluoro phenyl, 3-fluoro-4-ethoxyl phenenyl, 3-fluoro-4-p-methoxy-phenyl, the 4-ethoxyl phenenyl, 4-propoxy-phenyl, the 4-isopropyl phenyl, 2-fluoro-4-ethoxyl phenenyl, 3-fluoro-4-propoxy-phenyl, 3-methoxyl group-4-propoxy-phenyl, 4-methoxymethoxy phenyl, 4-(2-methoxy ethoxy) phenyl, 4-(2-ethoxy ethoxy) phenyl, 4-(2-isopropoxy oxyethyl group) phenyl, the 4-hydroxy phenyl, 1,3-benzo dioxolyl, 1,4-benzodioxane base or dihydro benzo furyl, wherein said substituting group is selected from alkoxyl group, alkoxyl group alkoxyl group and carboxyl alkoxyl group, R 2Be 1,3-benzo dioxolyl, 7-methoxyl group-1,3-benzo dioxolyl, 1,4-benzodioxane base, dihydro benzo furyl, benzofuryl, 4-p-methoxy-phenyl, Dimethoxyphenyl, fluoro phenyl or phenyl-difluoride base and R 3Be R 4-C (O)-R 5-, R wherein 4For R wherein 11And R 12Independently be selected from low alkyl group, alkoxyl group and halogen, and R 13, R 14And R 15Independently be selected from hydrogen, low alkyl group, hydroxyl, amino, alkoxyl group, aryl, heterocycle, halogen, carboxyl, nitro, alkyl sulphonyl, aryl sulfonyl, thio alkoxy, thio-aryloxy or cyano group; And R 5Be alkylidene group.
Another the most preferred embodiment of the present invention is formula (I) or formula (II) compound, and wherein R is-C (O) 2-G, wherein G is hydrogen or carboxy protective group, R 1For replacing or unsubstituted 4-p-methoxy-phenyl, 4-fluoro phenyl, 2-fluoro phenyl, 3-fluoro-4-ethoxyl phenenyl, 3-fluoro-4-p-methoxy-phenyl, the 4-ethoxyl phenenyl, 4-propoxy-phenyl, the 4-isopropyl phenyl, 2-fluoro-4-ethoxyl phenenyl, 3-fluoro-4-propoxy-phenyl, 3-methoxyl group-4-propoxy-phenyl, 4-methoxymethoxy phenyl, 4-(2-methoxy ethoxy) phenyl, 4-(2-ethoxy ethoxy) phenyl, 4-(2-isopropoxy oxyethyl group) phenyl, the 4-hydroxy phenyl, 1,3-benzo dioxolyl, 1,4-benzodioxane base or dihydro benzo furyl, wherein said substituting group is selected from alkoxyl group, alkoxyl group alkoxyl group and carboxyl alkoxyl group, R 2Be 1,3-benzo dioxolyl, 7-methoxyl group-1,3-benzo dioxolyl, 1,4-benzodioxane base, dihydro benzo furyl, benzofuryl, 4-p-methoxy-phenyl, Dimethoxyphenyl, fluoro phenyl or phenyl-difluoride base and R 3Be R 4-C (O)-R 5-, R wherein 4For
Figure A9880618400311
R wherein 11And R 12Independently be selected from methyl, ethyl and sec.-propyl, and R 13, R 14And R 15Independently be selected from hydrogen, low alkyl group, hydroxyl, amino, alkoxyl group, aryl, heterocycle, halogen, carboxyl, nitro, alkyl sulphonyl, aryl sulfonyl, thio alkoxy, thio-aryloxy or cyano group; And R 5Be alkylidene group.
Another the most preferred embodiment of the present invention is formula (I) or formula (II) compound, and wherein R is-C (O) 2-G, wherein G is hydrogen or carboxy protective group, R 1For replacing or unsubstituted 4-p-methoxy-phenyl, 4-fluoro phenyl, 2-fluoro phenyl, 3-fluoro-4-ethoxyl phenenyl, 3-fluoro-4-p-methoxy-phenyl, the 4-ethoxyl phenenyl, 4-propoxy-phenyl, the 4-isopropyl phenyl, 2-fluoro-4-ethoxyl phenenyl, 3-fluoro-4-propoxy-phenyl, 3-methoxyl group-4-propoxy-phenyl, 4-methoxymethoxy phenyl, 4-(2-methoxy ethoxy) phenyl, 4-(2-ethoxy ethoxy) phenyl, 4-(2-isopropoxy oxyethyl group) phenyl, the 4-hydroxy phenyl, 1,3-benzo dioxolyl, 1,4-benzodioxane base or dihydro benzo furyl, wherein said substituting group is selected from alkoxyl group, alkoxyl group alkoxyl group and carboxyl alkoxyl group, R 2Be 1,3-benzo dioxolyl, 7-methoxyl group-1,3-benzo dioxolyl, 1,4-benzodioxane base, dihydro benzo furyl, benzofuryl, 4-p-methoxy-phenyl, Dimethoxyphenyl, fluoro phenyl or phenyl-difluoride base and R 3Be R 4-C (O)-R 5-, R wherein 4For R wherein 11And R 12Independently be selected from methyl, ethyl and sec.-propyl, and R 13, R 14And R 15Independently be selected from hydrogen, low alkyl group, hydroxyl, amino, alkoxyl group, aryl, heterocycle, halogen, carboxyl, nitro, alkyl sulphonyl, aryl sulfonyl, thio alkoxy, thio-aryloxy or cyano group; And R 5Be alkylidene group.
The present invention also relates to the method for preparation formula (I) and formula (II) compound and used synthetic intermediate in these methods.
The method of antagonism endothelin in the Mammals that the present invention also relates in this treatment of needs (preferred human), this method comprises formula (I) or formula (II) compound that gives Mammals treatment significant quantity.
The invention further relates to endothelin antagonism composition, they comprise the formula (I) or formula (II) compound of pharmaceutical carrier and treatment significant quantity.
Compound of the present invention comprises the carbon atom of two or more asymmetric replacements.Therefore, the mixture of the racemic mixture of The compounds of this invention, diastereomer and single diastereomer all are included in the scope of the invention.Term " S " and " R " configuration such as IUPAC 1974Recommendations for Section E, (PureAppl.Chem. (1976) 45,13-30) the middle definition for Fundamental Stereochemistry.
Relate to the carboxylic acid protection ester group that other the sense position reaction of described compound the time is used to seal or to protect carboxylic functionality at this used term " carboxy protective group " fingering row.Open carboxy protective group is incorporated herein for referencial use in " Protective Groups in Organic Synthesis " (152-186 page or leaf (1981)) of Greene.In addition, can be with carboxy protective group as prodrug, cracking carboxy protective group at an easy rate in vivo, for example by enzymic hydrolysis, thus the parent of delivery of biologically active.T.Higuchi and V.Stella provide the detailed discussion to the prodrug notion (" Pro-drugs as Novel Delivery Systems ", A.C.S.Symposium Series, American Chemical Society (1975) the 14th volume), be incorporated herein for referencial use.For this type of carboxy protective group well-known to those having ordinary skill in the art, be widely used in the protection of carboxylic group in penicillin and cynnematin field always, as described in United States Patent (USP) 3840556 and 3719667, it is for referencial use to be incorporated herein these disclosed contents.(edit at " Bioreversible Carriers in Drug Design:Theory and Application " by E.B Roche, Pergamon Press publishes, New York (1987)) can find in the 14-21 page or leaf to be incorporated herein for referencial use as the example of the ester that contains carboxylic group compound prodrug.Representational carboxy protective group is C 1To C 8Alkyl (for example methyl, ethyl or the tertiary butyl etc.); Haloalkyl; Alkenyl; The derivative of cycloalkyl and its replacement is cyclohexyl for example, cyclopentyl etc.; Cycloalkylalkyl and its substitutive derivative be cyclohexyl methyl, cyclopentyl-methyl etc. for example; Arylalkyl, for example for example alkoxybenzyl or nitrobenzyl group etc. of the derivative of styroyl or benzyl and its replacement; Aromatic yl alkenyl, for example phenyl vinyl etc.; The derivative of aryl and its replacement, for example 5-(2, the 3-indanyl) etc.; Dialkyl aminoalkyl (for example dimethyl aminoethyl etc.); The alkanoyloxy alkyl group is acetoxy-methyl, butyryl acyloxy methyl, valeryl oxygen ylmethyl, isobutyl acyl-oxygen ylmethyl, isoamyl acyl-oxygen ylmethyl, 1-(propionyloxy)-1-ethyl, 1-(new pentane acyloxy)-1-ethyl, 1-methyl isophthalic acid-(propionyloxy)-1-ethyl, oxy acid methyl neopentyl, propionyloxy methyl etc. for example; Loop chain alkanoyloxy alkyl is cyclopropyl carbonyl oxygen ylmethyl, cyclobutyl carbonyl oxygen ylmethyl, cyclopentylcarbonyl oxygen ylmethyl, cyclohexyl-carbonyl oxygen ylmethyl etc. for example; Aryl acyloxy alkyl, for example benzoyloxy methyl, benzoyloxy ethyl etc.; Aromatic yl alkyl carbonyl oxygen base alkyl, for example benzyloxycarbonyl group oxygen ylmethyl, 2-benzyloxycarbonyl group oxygen base ethyl etc.; Alkoxy carbonyl alkyl, for example methoxycarbonyl methyl, cyclohexyloxy carbonyl methyl, 1-methoxycarbonyl-1-ethyl etc.; Alkoxy-carbonyl oxy alkyl, for example methoxycarbonyl oxygen ylmethyl, tert-butoxycarbonyl oxygen ylmethyl, 1-ethoxy carbonyl Oxy-1-ethyl, 1-cyclohexyl oxygen base ketonic oxygen base-1-ethyl etc.; Alkoxycarbonyl amino alkyl, for example tert-butoxycarbonyl amino methyl etc.; Alkyl amino-carbonyl aminoalkyl group, for example methylamino carbonylamino methyl etc.; Alkanoyl aminoalkyl group, for example acetylamino methyl etc.; Heterocyclic radical ketonic oxygen base alkyl, for example 4-methylpiperazine base ketonic oxygen ylmethyl etc.; Dialkyl amino carbonyl alkyl, for example dimethylamino carbonyl methyl, diethylamino carbonyl methyl etc.; (5-(low alkyl group)-2-oxo-1,3-dioxolen-4-yl) alkyl, for example (the 5-tertiary butyl-2-oxo-1,3-dioxolen-4-yl) methyl etc.; (5-phenyl-2-oxo-1,3-dioxolen-4-yl) alkyl, for example (5-phenyl-2-oxo-1,3-dioxolen-4-yl) methyl etc.
Term used herein " N-protected group " or " N-protected " refer to be used for protect the N-end of amino acid or peptide promptly to protect amino to avoid those groups of unwanted reaction in building-up process.Usually used N-protected group is at Greene " Protective Groups InOrganic Synthesis " (John Wiley ﹠amp; Sons, New York (1981)) open in, be incorporated herein for referencial use.The N-protected group comprises carboxyl groups for example formyl radical, ethanoyl, propionyl, pentanoyl, tertiary butyl ethanoyl, 2-chloro ethanoyl, 2-bromo ethanoyl, trifluoroacetyl group, tribromo-acetyl base, phthaloyl, ortho-nitrophenyl oxygen base ethanoyl, alpha-chloro butyryl radicals, benzoyl, 4-chlorinated benzene formyl radical, 4-bromobenzene formyl radical, 4-nitro benzoyl etc.; The alkylsulfonyl group is benzenesulfonyl, p-toluenesulfonyl etc. for example; Carbamate forms group, benzyloxycarbonyl for example, to the chloro benzyloxy carbonyl, to methoxyl group benzyloxy base carbonyl, to the nitro benzyloxycarbonyl, 2-nitro benzyloxycarbonyl, to the bromo benzyloxycarbonyl, 3,4-dimethoxy benzyloxycarbonyl, 3,5-dimethoxy benzyloxycarbonyl, 2,4-dimethoxy benzyloxycarbonyl, 4-methoxyl group benzyloxy base carbonyl, 2-nitro-4,5-dimethoxy benzyloxycarbonyl, 3,4,5-trimethoxy benzyloxycarbonyl, 1-(to xenyl)-1-methyl ethoxy carbonyl, α, alpha-alpha-dimethyl-3,5-dimethoxy benzyloxycarbonyl, diphenyl-methyl oxygen base carbonyl, tert-butoxycarbonyl, the di-isopropyl methoxycarbonyl, isopropoxy carbonyl, ethoxy carbonyl, methoxycarbonyl, allyloxy carbonyl, 2,2,2-trichlorine ethoxy carbonyl, phenyloxycarbonyl, the 4-nitrophenoxy carbonyl, fluorenyl-9-methoxycarbonyl, the cyclopentyloxy carbonyl, adamantyl oxygen base carbonyl, cyclohexyl oxygen base carbonyl, phenyl thiocarbonyl etc.; Alkyl group is benzyl, trityl group, benzyloxymethyl etc. for example; Silyl-group is three silyls etc. for example.Preferred N-protected group is formyl radical, ethanoyl, benzoyl, pentanoyl, tertiary butyl ethanoyl, benzenesulfonyl, benzyl, tert-butoxycarbonyl (Boc) and benzyloxycarbonyl (Cbz).
Term used herein " alkanoyl " refers to be connected to the alkyl defined herein on the parent molecular moiety by carbonyl (C (O)-).The example of alkanoyl comprises ethanoyl, propionyl etc.
Term used herein " alkanoyl amino " refers to be connected with the alkanoyl group of definition formerly of amino group.The example of alkanoyl amino comprises kharophen, propionamido etc.
Term used herein " alkanoyl aminoalkyl group " refers to R 43-NH-R 44-, R wherein 43Be alkanoyl, R 44Be alkylidene group.
Term used herein " alkanoyloxy alkyl " refers to R 30-O-R 31-, R wherein 30Be alkanoyl group, R 31Be alkylidene group.The example of alkanoyloxy alkyl comprises acetoxy-methyl and acetoxyl group ethyl etc.
The straight or branched hydrocarbyl group that term used herein " alkenyl " refers to contain 2 to 15 carbon atoms and also contains at least one carbon-to-carbon double bond.Alkenyl comprises, for example vinyl, allyl group (propenyl), butenyl, 1-methyl-2-butene-1-base etc.
Term " alkylene group " refers to by containing 2 to 15 carbon atoms and also containing the divalent group of the straight or branched hydrocarbyl derivative of at least one carbon-carbon double bond.The example of alkylene group comprises-CH=CH-,-CH 2CH=CH-,-C (CH 3)=CH-,-CH 2CH=CHCH 2-etc.
Term used herein " alkenyl oxy " refers to that logical peroxide bridge as previously defined (O-) is connected in kiki alkenyl group on the parent molecular moiety.The example of alkenyloxy comprises allyl group oxygen base, butenyl oxygen base etc.
Term used herein " alkoxyl group " refers to R 42O-, wherein R 42For as above-mentioned defined low alkyl group.The example of alkoxyl group includes, but is not limited to methoxyl group, oxyethyl group, propoxy-, isobutoxy, tert.-butoxy etc.
Term used herein " alkoxyl group alkoxyl group " refers to R 80O-R 81O-, wherein R 80For as above-mentioned defined low alkyl group, R 81Be alkylidene group.The representative example of alkoxyl group alkoxy base comprises methoxymethoxy, oxyethyl group methoxy base, tert.-butoxy methoxyl group etc.
Term used herein " alkoxyl group alkoxyl group alkoxyl group " refers to R 82O-R 83O-R 84O-, wherein R 82For as above-mentioned defined low alkyl group, R 83And R 84Be alkylidene group.The representative example of alkoxyl group alkoxyl group alkoxy base comprises methoxy ethoxy methoxyl group, (ethoxymethyl) Oxymethoxy, tert.-butoxy methoxymethoxy etc.
Term used herein " (alkoxyalkyl) alkylsulfonyl " refers to R 85-O-R 86-S (O) 2-, R wherein 85Be low alkyl group and R 86Be alkylidene group.
Term used herein " alkoxy alkoxy alkyl " refers to be connected in the previous defined alkoxyl group alkoxyl group on the alkyl group.The representative example of alkoxy alkoxy alkyl group comprises methoxyethoxyethyl, methoxymethoxy methyl etc.
Term used herein " alkoxyalkyl " refers to be connected in the previous defined alkoxy base on the previous defined alkyl group.The example of alkoxyalkyl includes, but is not limited to methoxymethyl, methoxy ethyl, isopropoxy methyl etc.
Term used herein " alkoxy carbonyl " refers to be connected in previous defined alkoxy base on the parent molecular moiety by carbonyl.The example of alkoxy carbonyl comprises methoxycarbonyl, ethoxy carbonyl, isopropoxy carbonyl etc.
Term used herein " alkoxy carbonyl alkenyl " refers to be connected in the previous defined alkoxycarbonyl groups on the kiki alkenyl group.The alkoxy carbonyl non-limiting examples of alkenyls comprises methoxycarbonyl vinyl, ethoxy carbonyl vinyl etc.
Term used herein " alkoxy carbonyl alkyl " refers to R 34-C (O)-R 35-R wherein 34Be alkoxy base, R 35Be alkylidene group.The example of alkoxy carbonyl alkyl comprises methoxycarbonyl methyl, methoxycarbonyl ethyl, ethoxy carbonyl methyl etc.
Term used herein " alkoxycarbonyl amino alkyl " refers to R 38-C (O)-NH-R 39-, R wherein 38Be alkoxyl group, R 39Be alkylidene group.The example of alkoxycarbonyl amino alkyl comprises methoxycarbonyl amino-ethyl etc.
Term used herein " alkoxy-carbonyl oxy alkyl " refers to R 36-C (O)-O-R 37-, R wherein 36Be alkoxyl group, R 37Be alkylidene group.The example of alkoxy-carbonyl oxy alkyl comprises (ethoxy carbonyl oxygen base) methyl etc.
Term used herein " (alkoxy carbonyl) thio alkoxy " refers to be connected in the previous defined alkoxycarbonyl groups on the thio alkoxy group.The example of (alkoxy carbonyl) thio alkoxy comprises methoxycarbonyl sulfo-methoxyl group, ethoxy carbonyl sulfo-methoxyl group etc.
Term used herein " alkyl " and " low alkyl group " refer to contain the straight or branched alkyl group of 1 to 15 carbon atom, include, but is not limited to methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, isobutyl-, sec-butyl, the tertiary butyl, n-pentyl, 1-methyl butyl, 2,2-dimethylbutyl, 2-methyl amyl, 2,2-dimethyl propyl, n-hexyl etc.
Term used herein " alkylamino " refers to R 51NH-, wherein R 51Be low-grade alkyl group, for example ethylamino, butyl amino etc.
Term used herein " (alkylamino) alkoxyl group " refers to R 52NH-R 53-O-, wherein R 52Be low alkyl group, R 53Be alkylidene group.
Term used herein " alkyl amino-carbonyl " refers to be connected in the previous defined alkylamino group on the parent molecular moiety by ketonic linkage (C (O)-).The example of alkyl amino-carbonyl comprises methylamino carbonyl, ethylamino carbonyl, sec.-propyl aminocarboxyl etc.
Term used herein " alkyl amino-carbonyl alkenyl " refers to be connected with the kiki alkenyl group of alkyl amino-carbonyl group.
Term used herein " alkyl amino alkyl carbonyl " refers to be connected with the low-grade alkyl group of alkyl amino-carbonyl group.
Term used herein " alkyl amino-carbonyl aminoalkyl group " refers to R 40-C (O)-NH-R 41-, R wherein 40Be alkylamino group, R 41Be alkylidene group.
Term " alkylidene group " refers to remove two hydrogen atom institute deutero-divalent groups by the saturated alkyl of straight or branched with 1 to 15 carbon atom, for example-and CH 2-,-CH 2CH 2-,-CH (CH 3)-,-CH 2CH 2CH 2-,-CH 2C (CH 3) 2CH 2-etc.
Term used herein " alkyl sulphonyl " refers to by alkylsulfonyl group (S (O) 2-) be connected in the alkyl group on the parent molecular moiety.The example of alkyl sulphonyl comprises methylsulfonyl, ethylsulfonyl, different third alkylsulfonyl etc.
Term used herein " (alkyl sulphonyl) amino " refers to by sulfuryl amino group (S (O) 2-NH-) be connected in previous defined alkyl group on the parent molecular moiety.(alkyl sulphonyl) amino example comprises methylsulfonyl amino, ethylsulfonylamino, different third sulfuryl amino etc.
Term used herein " (alkyl sulphonyl) alkoxyl group " refers to be connected in previous defined alkyl sulphonyl group on the parent molecular moiety by alkoxy base.The example of (alkyl sulphonyl) alkoxyl group comprises methylsulfonyl methoxyl group, ethylsulfonyl oxyethyl group, the different third alkylsulfonyl isopropoxy etc.
Term used herein " (alkylthio) alkoxyl group " refers to R 54-S-R 55-O-, wherein R 54Be low alkyl group R 55Be alkylidene group.
The straight or branched hydrocarbyl group that term " alkynyl " refers to contain 2 to 15 carbon atoms and also contains at least one carbon-to-carbon triple bond.The example of alkynyl comprises-C ≡ C-H, H-C ≡ C-CH 2-, H-C ≡ C-CH (CH 3)-, CH 3-C ≡ C-CH 2-etc.
Term used herein " aminocarboxyl " refers to H 2N-C (O)-.
Term used herein " aminocarboxyl alkenyl " refers to be connected with aminocarboxyl group (NH 2C (O)-) kiki alkenyl group.
Term used herein " aminocarboxyl alkoxyl group " refers to be connected in the H on the previous defined alkoxy base 2N-C (O)-.The example of aminocarboxyl alkoxyl group comprises aminocarboxyl methoxyl group, aminocarboxyl oxyethyl group etc.
Term used herein " aminocarboxyl alkyl " refers to be connected with aminocarboxyl group (NH 2C (O)-) low-grade alkyl group.
Term used herein " aryl acyloxy alkyl " refers to R 32-C (O)-O-R 33-, R wherein 32Be aromatic yl group, R 33Be alkylidene group.The example of aryl acyloxy alkyl comprises benzoyloxy methyl, benzoyloxy ethyl etc.
Refer to have one or two of one or two aromatic ring at this used term " aryl " and encircle carbon-loop systems, include, but is not limited to phenyl, naphthyl, tetralyl, 2,3-indanyl, indenyl etc.Aromatic yl group can not replace or by one; two or three substituting groups that independently are selected from following groups replace: low alkyl group; halogen; haloalkyl; halogenated alkoxy; hydroxyalkyl; alkenyl oxy; alkoxyl group; the alkoxyl group alkoxyl group; alkoxy carbonyl; alkoxyl group alkoxyl group alkoxyl group; (cycloalkyl) alkoxyl group; cycloalkyloxy; (alkylamino) alkoxyl group; (alkylthio) alkoxyl group; the alkoxy carbonyl alkenyl; (alkoxy carbonyl) thio alkoxy; thio alkoxy; amino; alkylamino; dialkyl amido; (dialkyl amido) alkyl; (dialkyl amido) alkoxyl group; aminocarboxyl; the aminocarboxyl alkoxyl group; alkanoyl amino; alkoxy aryl; aryloxy; sulfydryl; cyano group; nitro; carboxaldehyde radicals; carboxyl; the carboxyl alkenyl; the carboxyl alkoxyl group; formamido-; alkyl sulphonyl; (alkyl sulphonyl) amino; (alkyl sulphonyl) alkoxyl group; (alkoxyalkyl) alkylsulfonyl; cyano alkoxy; (heterocyclic radical) alkoxyl group; hydroxyl; the hydroxy alkoxy base; phenyl and tetrazyl alkoxyl group.In addition, the aromatic yl group of replacement comprises tetrafluoro phenyl and pentafluorophenyl group.
Refer to be connected with the kiki alkenyl group of aromatic yl group, for example phenyl vinyl etc. at this used term " aromatic yl alkenyl ".
Refer to R at this used term " aralkoxy " 45O-, wherein R 45Be arylalkyl, for example benzyloxy etc.
Refer to be connected with the low-grade alkyl group of aralkoxy, for example benzyloxymethyl etc. at this used term " sweet-smelling alkoxy alkyl ".
Said term " aralkyl " refers to be connected with the previous defined aryl of low alkyl group, for example benzyl etc.
Refer to R at this used term " aryloxy " 46O-, wherein R 46Be aromatic yl group, for example phenoxy group etc.
Refer to R at this used term " aromatic alkyl carbonyl oxygen base " 62C (O) O-, wherein R 62Be aromatic alkyl group.
The low-grade alkyl group that refers to be connected with aromatic alkyl carbonyl oxygen base group at this used term " aromatic alkyl carbonyl oxygen base alkyl ".
Term " aryloxy alkyl " refers to be connected in the previous defined aryloxy group on the alkyl group.The example of aryloxy alkyl comprises phenoxymethyl, 2-phenoxy group ethyl etc.
At this used term " carboxaldehyde radicals " nail aldehyde group ,-C (O) H.
Refer to NH at this used term " formamido-" 2-C (O)-.
Refer to hydroxy-acid group at this used term " carboxyl " ,-C (O) OH.
Refer to be connected in previous defined carboxylic group on the previous defined kiki alkenyl group at this used term " carboxyl alkenyl ".The carboxyl non-limiting examples of alkenyls comprises 2-carboxy vinyl, 3-carboxyl-1-propenyl etc.
Refer to be connected in previous defined carboxylic group on the previous defined alkoxy base at this used term " carboxyl alkoxyl group ".The example of carboxyl alkoxyl group comprises carboxyl methoxyl group, carboxyl oxyethyl group etc.
Refer to be connected with cyano group (CN) the previous defined alkoxy base of group at this used term " cyano alkoxy ".The example of cyano alkoxy comprises 3-cyano group propoxy-, 4-cyano group butoxy etc.
Refer to R at this used term " cycloalkanes acyloxy " 60-C (O)-O-, wherein R 60Be group of naphthene base.
The low alkyl group that refers to be connected with cycloalkanes acyloxy group at this used term " cycloalkanes acyloxy alkyl ".
Refer to have the aliphatics loop systems of 3 to 10 carbon atoms and 1 to 3 ring at this used term " cycloalkyl ", include, but is not limited to cyclopropyl, cyclopentyl, cyclohexyl, norborneol alkyl (norbornyl), adamantyl etc.Group of naphthene base can for unsubstituted or by one, two or three independently are selected from following substituting group and replace: low alkyl group, haloalkyl, alkoxyl group, thio alkoxy, amino, alkylamino, dialkyl amido, hydroxyl, halogen, sulfydryl, nitro, carboxaldehyde radicals, carboxyl, alkoxy carbonyl and formamido-.
Refer to R at this used term " cycloalkyloxy " 61-O-, wherein R 61Be cycloalkyl.The example of cycloalkyloxy comprises cyclohexyloxy etc.
Refer to R at this used term " (cycloalkyl) alkoxyl group " 63-R 64-O-is R wherein 63Be connected on the parent molecular moiety for cycloalkyl as defined above and by alkoxy base, wherein R 64Be alkylidene group.The example of (cycloalkyl) alkoxyl group comprises (cyclopropyl) oxyethyl group etc.
Refer to be connected with the cycloalkyl of low alkyl group at this used term " cycloalkylalkyl ", include, but is not limited to cyclohexyl methyl.
Refer to (R at this used term " dialkyl amido " 56) (R 57) N-, wherein R 56And R 57Independently be selected from low alkyl group, for example diethylamino, methyl-propyl amino etc.
The low-grade alkyl group that refers to be connected with dialkyl amino group at this used term " (dialkyl amido) alkyl ".
The alkoxy base that refers to be connected with dialkyl amino group at this used term " (dialkyl amido) alkoxyl group ".
Refer to be connected in the previous defined dialkyl amino group on the parent molecular moiety at this used term " dialkyl amino carbonyl " by ketonic linkage (C (O)-).The example of dialkyl amino carbonyl comprises dimethylamino carbonyl, diethylamino carbonyl etc.
The kiki alkenyl group that refers to be connected with the dialkyl amino carbonyl group at this used term " dialkyl amino carbonyl alkenyl ".
Refer to R at this used term " dialkyl amino carbonyl alkyl " 58-C (O)-R 59-, R wherein 58Be dialkyl amino group, R 59Be alkylidene group.
Refer to I, Br, Cl or F at this used term " halo " or " halogen ".
The kiki alkenyl group that refers to be connected with at least one halogenic substituent at this used term " halogenated alkenyl ".
This used term " halogenated alkoxy " refer to have at least one halogenic substituent as above-mentioned defined alkoxy base, 2-fluoro oxyethyl group, 2,2 for example, 2-three fluoro oxyethyl groups, three fluoro methoxyl groups, 2,2,3,3,3-five fluoro propoxy-etc.
The low alkyl group that refers to be connected with halogenated alkoxy at this used term " halogenated alkoxy alkyl ".
This used term " haloalkyl " refer to be connected with at least one halogenic substituent as above-mentioned defined low-grade alkyl group, for example chloro methyl, fluoro ethyl, trifluoromethyl or pentafluoroethyl group etc.
Refer to contain the heteroatomic any 3 or 4 yuan of rings that are selected from oxygen, nitrogen and sulphur at this used term " heterocyclic ring " or " heterocyclic radical " or " heterocycle "; Or contain one, two or three nitrogen-atoms, a Sauerstoffatom, a sulphur atom, a nitrogen-atoms and a sulphur atom, a nitrogen-atoms and a Sauerstoffatom, in non-adjacent position two Sauerstoffatoms are arranged, on non-adjacent position, a Sauerstoffatom and a sulphur atom are arranged, or 5,6 or 7 yuan of rings of two sulphur atoms on the non-adjacent position.Described 5 yuan of rings have 0-2 two key, and 6 and 7 yuan of rings have 0-3 two key.Nitrogen heteroatom can be chosen wantonly quaternized.Term " heterocyclic radical " or " heterocycle " also comprise bicyclic radicals, wherein any above-mentioned heterocycle and phenyl ring or naphthenic hydrocarbon ring or another heterocyclic fused (for example indyl, indolinyl, quinolyl, isoquinolyl, tetrahydric quinoline group, tetrahydro isoquinolyl, decahydroquinolyl, Decahydroisoquinolinpreparation base, benzofuryl, dihydro benzo furyl or benzothienyl etc.).Heterocyclic radical comprises: aziridinyl, azetidinyl, pyrryl, pyrrolinyl, pyrrolidyl, pyrazolyl, pyrazolinyl, pyrazolidyl, imidazolyl, imidazolinyl, imidazolidyl, pyridyl, piperidyl, homopiperidinyl, pyrazinyl, piperazinyl, pyrimidyl, pyridazinyl oxazolyl oxazolidinyl isoxazolyl isoxazole alkyl, morpholinyl, thio-morpholinyl, thiazolyl, thiazolidyl, isothiazolyl, the isothiazole alkyl, indyl, quinolyl, isoquinolyl, benzimidazolyl-, benzothiazolyl benzoxazolyl, oxa-fourth cyclic group, furyl, tetrahydrofuran base, thienyl, thiazolidyl, isothiazolyl, triazolyl, tetrazyl isoxazolyl oxadiazole base, thiadiazolyl group, pyrryl, pyrimidyl and benzothienyl.Heterocycle also comprises the compound of following formula
Figure A9880618400421
X wherein *For-CH 2-or-O-, Y *For-C (O)-or [C (R ") 2-] vWherein, R " be hydrogen or C 1-C 4Alkyl-, v is 1,2 or 3, for example 1,3-benzo dioxolyl, 1,4-benzodioxane base etc.Heterocyclic radical also comprises for example peaceful cyclic group of quinoline etc. of dicyclo.
Heterocyclic radical can not replace or is selected from independently that following group one replaces, two replacement or three replacements: hydroxyl, halogen, oxo (=O), alkyl imino (R *N=, wherein R *Be low alkyl group), amino, alkylamino, dialkyl amido, alkoxyl group, alkoxyl group alkoxyl group, haloalkyl, cycloalkyl, aryl, phenyl, arylalkyl ,-COOH ,-SO 3H, alkoxy carbonyl, nitro, cyano group and low alkyl group.In addition, can the nitrogenous heterocycle of N-protected.
The heterocyclic radical of above definition that refers to be connected with the alkoxyl group of above-mentioned definition at this used term " (heterocyclic radical) alkoxyl group ".The example of (heterocyclic radical) alkoxyl group comprises 4-pyridyl methoxyl group, 2-pyridyl methoxyl group etc.
Refer to be connected in above-mentioned defined heterocyclic radical group at this used term " (heterocyclic radical) alkyl " as on the above-mentioned defined low-grade alkyl group.The example of (heterocyclic radical) alkyl comprises 2-pyridylmethyl etc.
Refer to R at this used term " heterocyclic radical (amino) " 77-NH-, wherein R 77For being connected in the aromatic heterocyclic radical as defined above on the amino.Described aromatic heterocycle can be by the R on that all be connected in this aromatic heterocycle and the atom nitrogen-atoms next-door neighbour 75And R 76Two substituting groups replace.R 75And R 76For independently being selected from following substituting group: hydroxyl, halogen, oxo (=O), alkyl imino (R *N=, wherein R *Be low alkyl group), amino, alkylamino, dialkyl amido, alkoxyl group, alkoxyl group alkoxyl group, haloalkyl, cycloalkyl, aryl, phenyl, aralkyl ,-COOH ,-SO 3H, alkoxy carbonyl, nitro, cyano group and low alkyl group.This aromatic heterocycle also can be by the 3rd substituting group that is selected from following groups optional replacement: hydroxyl, halogen, oxo (=O), alkyl imino (R *N=, wherein R *Be low alkyl group), amino, alkylamino, dialkyl amido, alkoxyl group, alkoxyl group alkoxyl group, haloalkyl, cycloalkyl, aryl, phenyl, aralkyl ,-COOH ,-SO 3H, alkoxy carbonyl, nitro, cyano group and low alkyl group.The example of heterocyclic radical (amino) comprises 2,4-parvoline-3-amino, 2,4-diethyl thiophene-3-amino, 2,4-parvoline-2-amino etc.
Refer to R at this used term " heterocycle ketonic oxygen base alkyl " 47-C (O)-O-R 48-, R wherein 47Be heterocyclic radical group, R 48Be alkylidene group.
Refer to OH at this used term " hydroxyl ".
The alkenyl that refers to be connected with oh group at this used term " hydroxyl alkenyl ".
Refer to be connected with hydroxyl (OH) the previous defined alkoxy base of group at this used term " hydroxy alkoxy base ".The example of hydroxy alkoxy base comprises 3-hydroxyl propoxy-, 4-hydroxyl butoxy etc.
The low alkyl group that refers to be connected with oh group at this used term " hydroxyalkyl ".
Refer to-SH at this used term " sulfydryl ".
Term " methylene-dioxy " and " ethylenedioxy " refer to be connected in one or two carbon atom chain on the parent molecular moiety by two Sauerstoffatoms.As be methylene-dioxy, then form 5 yuan of rings of condensed.As be ethylenedioxy, then form 6 yuan of rings of condensed.The result formed the benzo dioxolyl when methylene-dioxy was substituted on the phenyl ring
Figure A9880618400431
When ethylenedioxy was substituted on the benzyl ring, the result formed the benzodioxane base
Figure A9880618400432
Refer to 90% or above specific compound at this used term " pure substantially ".
The group or its tautomer that refer to following formula at this used term " tetrazyl ":
Figure A9880618400433
Refer to be connected in above-mentioned defined tetrazyl group on the above-mentioned defined alkoxy base at this used term " tetrazyl alkoxyl group ".The example of tetrazyl alkoxyl group comprises tetrazyl methoxyl group, tetrazyl oxyethyl group etc.
Refer to R at this used term " thio alkoxy " 70S-, wherein R 70Be low alkyl group.The example of thio alkoxy includes, but is not limited to methylthio group, ethylmercapto group etc.
Refer to R at this used term " thio alkoxy alkoxyl group " 71S-R 72O-, wherein R 71Be above-mentioned defined low alkyl group, R 72Be alkylidene group.The representative example of thio alkoxy alkoxyl group comprises CH 3SCH 2O-, CH 3SCH 2SCH 2O-, t-BuSCH 2O-etc.
Refer to be connected in thio alkoxy alkoxy base on the alkyl group at this used term " thio alkoxy alkoxyalkyl ".The representative example of thio alkoxy alkoxy-alkyl group comprises CH 3SCH 2CH 2OCH 2CH 2-, CH 3SCH 2OCH 2-etc.
Refer to substituting group (R at this used term " trans, trans " 1And R 2) with respect to the orientation of the center substituent R that is shown below:
Figure A9880618400441
Refer to substituting group (R at this used term " trans, cis " 1And R 2) with respect to being shown below
Figure A9880618400442
The orientation of center substituent R.This definition comprises R and R 2Be cis, R and R 1Be trans and R 2With R be trans, R and R 1Be two kinds of situations of cis.
Refer to substituting group (R at this used term " cis, cis " 1And R 2) with respect to the orientation of the center substituent R that is shown below:
Figure A9880618400443
Representative compounds of the present invention comprises: anti-, anti--2-(4-p-methoxy-phenyl)-4-(1,3-benzo dioxole-5-yl)-1-((2,4, the 6-trimethylammonium) phenyl amino carbonyl methyl)-tetramethyleneimine-3-carboxylic acid, anti-, instead-2-(3-fluoro-4-p-methoxy-phenyl)-4-(1,3-benzo dioxole-5 base) 1-((2,4, the 6-trimethylammonium) phenyl amino carbonyl methyl)-tetramethyleneimine-3-carboxylic acid, instead, anti--2-(4-propoxy-phenyl)-4-(1,3-benzo dioxole-5-yl)-1-((2,4, the 6-trimethylammonium) phenyl amino carbonyl methyl)-and tetramethyleneimine-3-carboxylic acid, anti-, anti--2-(4-p-methoxy-phenyl)-4-(1,3-benzo dioxole-5-yl)-1-((2, the 6-diethyl) phenyl amino carbonyl methyl)-and tetramethyleneimine-3-carboxylic acid, anti-, anti--2-(4-propoxy-phenyl)-4-(1,3-benzo dioxole-5-yl)-1-((2, the 6-diethyl) phenyl amino carbonyl methyl)-and tetramethyleneimine-3-carboxylic acid, anti-, anti--2-(3-fluoro-4-p-methoxy-phenyl)-4-(1,3-benzo dioxole-5-yl)-1-((2, the 6-diethyl) phenyl amino carbonyl methyl)-and tetramethyleneimine-3-carboxylic acid, anti-, anti--2-(3-fluoro-4-ethoxyl phenenyl)-4-(1,3-benzo dioxole-5-yl)-1-((2, the 6-diethyl) phenyl amino carbonyl methyl)-and tetramethyleneimine-3-carboxylic acid, anti-, anti--2-(3-fluoro-4-p-methoxy-phenyl)-4-(7-methoxyl group-1,3-benzo dioxole-5-yl)-1-((2, the 6-diethyl) phenyl amino carbonyl methyl)-and tetramethyleneimine-3-carboxylic acid, anti-, anti--2-(3-methoxyl group-4-propoxy-phenyl)-4-(1,3-benzo dioxole-5-yl)-1-((2,6-diethyl phenyl) amino carbonyl methyl)-and tetramethyleneimine-3-carboxylic acid, anti-, anti--2-(4-ethoxyl phenenyl)-4-(1,3-benzo dioxole-5-yl)-1-((2,6-diethyl phenyl) amino carbonyl methyl)-and tetramethyleneimine-3-carboxylic acid, anti-, anti--2-(4-p-methoxy-phenyl)-4-(1,3-benzo dioxole-5-yl)-1-((2, the 6-3,5-dimethylphenyl) amino carbonyl methyl)-and tetramethyleneimine-3-carboxylic acid, anti-, anti--2-(4-propoxy-phenyl)-4-(7-methoxyl group-1,3-benzo dioxole-5-yl)-1-((2,6-diethyl phenyl) amino carbonyl methyl)-and tetramethyleneimine-3-carboxylic acid, anti-, anti--2-(3-methoxyl group-4-propoxy-phenyl)-4-(7-methoxyl group-1,3-benzo dioxole-5-yl)-1-((2,6-diethyl phenyl) amino carbonyl methyl)-and tetramethyleneimine-3-carboxylic acid, anti-, anti--2-(4-p-methoxy-phenyl)-4-(1,3-benzo dioxole-5-yl)-1-((2,6-two bromos) phenyl amino carbonyl methyl)-and tetramethyleneimine-3-carboxylic acid, [2R, 3R, 4S] 2-(4-p-methoxy-phenyl)-4-(1,3-benzo dioxole-5-yl)-and 1-(N-(2, the 6-diethyl) phenyl amino carbonyl methyl)-tetramethyleneimine-3-carboxylic acid, anti-, instead-2-(4-p-methoxy-phenyl)-4-(1,3-benzo dioxole-5-yl)-and 1-((2, the 6-dimethoxy) phenyl amino carbonyl methyl)-tetramethyleneimine-3-carboxylic acid, anti-, instead-2-(4-p-methoxy-phenyl)-4-(1,3-benzo dioxole-5-yl)-and 1-((4-bromo-2,6-diethyl) phenyl amino carbonyl methyl)-tetramethyleneimine-3-carboxylic acid, anti-, instead-2-(4-p-methoxy-phenyl)-4-(1,3-benzo dioxole-5-yl)-and 1-((2-ethyl-6-methyl) phenyl amino carbonyl methyl)-tetramethyleneimine-3-carboxylic acid, anti-, anti--2-(4-p-methoxy-phenyl)-4-(1,3-benzo dioxole-5-yl)-1-((2,4, the 6-triethyl) phenyl amino carbonyl methyl)-tetramethyleneimine-3-carboxylic acid, [2R, 3R, 4S] 2-(4-propoxy-phenyl)-4-(1,3-benzo dioxole-5-yl)-1-(N-(2, the 6-diethyl) phenyl amino carbonyl methyl)-tetramethyleneimine-3-carboxylic acid, instead, instead-2-(4-p-methoxy-phenyl)-4-(1,3-benzo dioxole-5-yl)-1-((2, the 6-di-isopropyl) phenyl amino carbonyl methyl)-tetramethyleneimine-3-carboxylic acid, instead, instead-2-(4-p-methoxy-phenyl)-4-(1,3-benzo dioxole-5-yl)-1-((2,6-diethyl-4-methyl) phenyl amino carbonyl methyl)-tetramethyleneimine-3-carboxylic acid, [2R, 3R, 4S]-2-(4-ethoxyl phenenyl)-4-(1,3-benzo dioxole-5-yl)-1-((2, the 6-diethyl) phenyl amino carbonyl methyl)-tetramethyleneimine-3-carboxylic acid, instead, anti--2-(4-first base phenyl)-4-(1,3-benzo dioxole-5-yl)-1-((4-carboxyl-2, the 6-diethyl) phenyl amino carbonyl methyl)-tetramethyleneimine-3-carboxylic acid, instead, anti--2-(4-p-methoxy-phenyl)-4-(1,3-benzo dioxole-5-yl)-1-((4-nitro-2, the 6-diethyl) phenyl amino carbonyl methyl)-tetramethyleneimine-3-carboxylic acid, instead, anti--2-(4-p-methoxy-phenyl)-4-(1,3-benzo dioxole-5-yl)-1-((2-sec.-propyl-6-methyl) phenyl amino carbonyl methyl)-tetramethyleneimine-3-carboxylic acid, instead, instead-and 2-(4-p-methoxy-phenyl)-4-(1,3-benzo dioxole-5-yl)-1-(N-(2-ethyl-6-methoxyl group) phenyl amino carbonyl methyl)-tetramethyleneimine-3-carboxylic acid, anti-, instead-2-(4-isopropyl phenyl)-4-(1,3-benzo dioxole-5-yl)-and 1-(2,6-diethyl phenyl amino carbonyl methyl)-tetramethyleneimine-3-carboxylic acid, anti-, instead-2-(2-fluoro-4-propoxy-phenyl)-4-(1,3-benzo dioxole-5-yl)-and 1-(2,6-diethyl phenyl amino carbonyl methyl)-tetramethyleneimine-3-carboxylic acid, anti-, instead-2-(4-(2-methoxy ethoxy) phenyl)-4-(1,3-benzo dioxole-5-yl)-and 1-(2,6-diethyl phenyl amino carbonyl methyl)-tetramethyleneimine-3-carboxylic acid, anti-, instead-2-(4-(2-ethoxy ethoxy) phenyl)-4-(1,3-benzo dioxole-5-yl)-and 1-(2,6-diethyl phenyl amino carbonyl methyl)-tetramethyleneimine-3-carboxylic acid, [2R, 3R, 4S]-2-(4-(2-methoxy ethoxy) phenyl)-4-(1,3-benzo dioxole-5-yl)-1-(2,6-diethyl phenyl amino carbonyl methyl)-tetramethyleneimine-3-carboxylic acid, [2R, 3R, 4S]-2-(4-(2-ethoxy ethoxy) phenyl)-4-(1,3-benzo dioxole-5-yl)-1-(2,6-diethyl phenyl amino carbonyl methyl)-tetramethyleneimine-3-carboxylic acid, instead, anti--2-(4-(2-isopropoxy oxyethyl group) phenyl)-4-(1,3-benzo dioxole-5-yl)-1-(2,6-diethyl phenyl amino carbonyl methyl)-tetramethyleneimine-3-carboxylic acid, or its pharmacy acceptable salt.
The preferred compound of the present invention is selected from: anti-, instead-2-(4-p-methoxy-phenyl)-4-(1,3-benzo dioxole-5-yl)-1-((2, the 6-diethyl) phenyl amino carbonyl methyl)-tetramethyleneimine-3-carboxylic acid, instead, instead-2-(4-propoxy-phenyl)-4-(1,3-benzo dioxole-5-yl)-1-((2, the 6-diethyl) phenyl amino carbonyl methyl)-tetramethyleneimine-3-carboxylic acid, instead, instead-2-(3-fluoro-4-p-methoxy-phenyl)-4-(1,3-benzo dioxole-5-yl)-1-((2, the 6-diethyl) phenyl amino carbonyl methyl)-tetramethyleneimine-3-carboxylic acid, instead, instead-2-(3-fluoro-4-ethoxyl phenenyl)-4-(1,3-benzo dioxole-5-yl)-1-((2, the 6-diethyl) phenyl amino carbonyl methyl)-tetramethyleneimine-3-carboxylic acid, instead, instead-2-(3-fluoro-4-p-methoxy-phenyl)-4-(7-methoxyl group-1,3-benzo dioxole-5-yl)-1-((2, the 6-diethyl) phenyl amino carbonyl methyl)-and tetramethyleneimine-3-carboxylic acid, anti-, anti--2-(3-methoxyl group-4-propoxy-phenyl)-4-(1,3-benzo dioxole-5-yl)-1-((2, the 6-diethyl) phenyl amino carbonyl methyl)-and tetramethyleneimine-3-carboxylic acid, anti-, anti--2-(4-ethoxyl phenenyl)-4-(1,3-benzo dioxole-5-yl)-1-((2, the 6-diethyl) phenyl amino carbonyl methyl)-and tetramethyleneimine-3-carboxylic acid, anti-, anti--2-(4-propoxy-phenyl)-4-(7-methoxyl group-1,3-benzo dioxole-5-yl)-1-((2, the 6-diethyl) phenyl amino carbonyl methyl)-and tetramethyleneimine-3-carboxylic acid, anti-, anti--2-(3-methoxyl group-4-propoxy-phenyl)-4-(7-methoxyl group-1,3-benzo dioxole-5-yl)-1-((2, the 6-diethyl) phenyl amino carbonyl methyl)-and tetramethyleneimine-3-carboxylic acid, [2R, 3R, 4S] 2-(4-p-methoxy-phenyl)-4-(1,3-benzo dioxole-5-yl)-and 1-(N-(2, the 6-diethyl) phenyl amino carbonyl methyl)-tetramethyleneimine-3-carboxylic acid, [2R, 3R, 4S] 2-(4-propoxy-phenyl)-4-(1,3-benzo dioxole-5-yl)-1-(N-(2, the 6-diethyl) phenyl amino carbonyl methyl)-tetramethyleneimine-3-carboxylic acid, [2R, 3R, 4S]-2-(4-ethoxyl phenenyl)-4-(1,3-benzo dioxole-5-yl)-1-((2, the 6-diethyl) phenyl amino carbonyl methyl)-tetramethyleneimine-3-carboxylic acid, instead, anti--2-(4-isopropyl phenyl)-4-(1,3-benzo dioxole-5-yl)-1-(2,6-diethyl phenyl amino carbonyl methyl)-tetramethyleneimine-3-carboxylic acid, instead, anti--2-(2-fluoro-4-propoxy-phenyl)-4-(1,3-benzo dioxole-5-yl)-1-(2,6-diethyl phenyl amino carbonyl methyl)-tetramethyleneimine-3-carboxylic acid, instead, anti--2-(4-(2-methoxy ethoxy) phenyl)-4-(1,3-benzo dioxole-5-yl)-1-(2,6-diethyl phenyl amino carbonyl methyl)-tetramethyleneimine-3-carboxylic acid, instead, anti--2-(4-(2-ethoxy ethoxy) phenyl)-4-(1,3-benzo dioxole-5-yl)-1-(2,6-diethyl phenyl amino carbonyl methyl)-tetramethyleneimine-3-carboxylic acid, [2R, 3R, 4S]-2-(4-(2-methoxy ethoxy) phenyl)-4-(1,3-benzo dioxole-5-yl)-1-(2,6-diethyl phenyl amino carbonyl methyl)-and tetramethyleneimine-3-carboxylic acid, [2R, 3R, 4S]-2-(4-(2-ethoxy ethoxy) phenyl)-4-(1,3-benzo dioxole-5-yl)-and 1-(2,6-diethyl phenyl amino carbonyl methyl)-tetramethyleneimine-3-carboxylic acid, anti-, instead-2-(4-(2-isopropoxy oxyethyl group) phenyl)-4-(1,3-benzo dioxole-5-yl)-1-(2,6-diethyl phenyl amino carbonyl methyl)-tetramethyleneimine-3-carboxylic acid, or its pharmacy acceptable salt.
Most preferred of the present invention is: anti-, instead-2-(4-propoxy-phenyl)-4-(1,3-benzo dioxole-5-yl)-1-((2, the 6-diethyl) phenyl amino carbonyl methyl)-tetramethyleneimine-3-carboxylic acid, [2R, 3R, 4S] 2-(4-p-methoxy-phenyl)-4-(1,3-benzo dioxole-5-yl)-(N-(2 for 1-, the 6-diethyl) phenyl amino carbonyl methyl)-tetramethyleneimine-3-carboxylic acid, [2R, 3R, 4S] 2-(4-propoxy-phenyl)-4-(1,3-benzo dioxole-5-yl)-(N-(2 for 1-, the 6-diethyl) phenyl amino carbonyl methyl)-tetramethyleneimine-3-carboxylic acid, [2R, 3R, 4S]-2-(4-ethoxyl phenenyl)-4-(1,3-benzo dioxole-5-yl)-1-((2, the 6-diethyl) phenyl amino carbonyl methyl)-tetramethyleneimine-3-carboxylic acid, instead, instead-2-(4-(2-methoxy ethoxy)-4-(1,3-benzo dioxole-5-yl)-1-(2,6-diethyl phenyl amino carbonyl methyl)-tetramethyleneimine-3-carboxylic acid, instead, instead-2-(4-(2-methoxy ethoxy) phenyl)-4-(1,3-benzo dioxole-5-yl)-1-(2,6-diethyl phenyl amino carbonyl methyl)-tetramethyleneimine-3-carboxylic acid, instead, instead-2-(4-(2-ethoxy ethoxy) phenyl)-4-(1,3-benzo dioxole-5-yl)-1-(2,6-diethyl phenyl amino carbonyl methyl)-tetramethyleneimine-3-carboxylic acid, [2R, 3R, 4S]-2-(4-(2-methoxy ethoxy) phenyl)-4-(1,3-benzo dioxole-5-yl)-1-(2,6-diethyl phenyl amino carbonyl methyl)-tetramethyleneimine-3-carboxylic acid, [2R, 3R, 4S]-2-(4-(2-ethoxy ethoxy) phenyl)-4-(1,3-benzo dioxole-5-yl)-1-(2,6-diethyl phenyl amino carbonyl methyl)-tetramethyleneimine-3-carboxylic acid, instead, anti--2-(4-(2-isopropoxy oxyethyl group) phenyl)-4-(1,3-benzo dioxole-5-yl)-1-(2,6-diethyl phenyl amino carbonyl methyl)-tetramethyleneimine-3-carboxylic acid, or its pharmacy acceptable salt.
The method of representing to prepare The compounds of this invention with flow process I-VII.
It is 0 that m is worked as in flow process I explanation, and W is-CO 2The general method for preparing The compounds of this invention during H.At alkali (as 1; 8-diazabicyclo [5.4.0] 11-7-alkene (DBU) or sodium ethylate or sodium hydride etc.) exist down; for example in toluene, benzene, tetrahydrofuran (THF) or the ethanol etc., make 'beta '-ketoester 1 (wherein E is low alkyl group or carboxy protective group) and 2 reactions of nitroethylene based compound at inert solvent.Reduction condensation product 3 (for example using Raney nickel or platinum catalyst hydrogenation).Make the amine cyclisation of generation produce pyrrolin 4.In THF solvent etc. reduction 4 (for example sodium cyanoborohydride or catalytic hydrogenations etc.) obtain into suitable-suitable, anti-, anti-and suitable, the pyrrolidine compound 5 of anti-product mixtures.That chromatographic separation is removed is suitable-along isomer, stay instead, and anti-and suitable, the trans isomer mixture is with its further processing.Can with described suitable-carry out epimerization (for example using sodium ethylate in ethanol or the DBU in toluene) along isomer to obtain instead, trans isomer carries out following reaction then.Tetramethyleneimine nitrogen is used R by (1) 3-X acidylate or sulfonylation (R 3Be R 4-C (O)-or R 6-S (O) 2-, X is for example halogen (preferred Cl) or X and R of leavings group 4-C (O)-or R 6-S (O) 2-form the activatory ester together, comprise by deutero-ester or acid anhydrides such as formic acid, acetate, alkoxy carbonyl halogenide, N-hydroxy-succinamide, N-hydroxyl phthalimide, N-hydroxybenzotriazole, N-hydroxyl-5-norbornylene-2,3-diformamide, 2,4,5-Trichlorophenol etc.) or (2) for example in the presence of diisopropylethylamine or the triethylamine etc., use R at alkali 3-X alkylation, wherein X be leavings group (for example X be halogen (as Cl, Br or I) or X be leavings group for example sulphonate (for example methanesulfonates, tosylate, triflate etc.) obtain N-deutero-tetramethyleneimine 6, it still is anti-, anti-and suitable, the mixture of trans isomer.Optionally hydrolysis is anti-in the hydrolysis of ester 6 (for example using alkali such as sodium hydroxide in ethanol/water), and anti-ester obtains 7 and 8 mixture, and it can easily be separated.
Used many 'beta '-ketoester raw materials can be from commercially available acquisition in the preparation The compounds of this invention.They also can prepare with the described method of flow process VIII.In the method for flow process VIII (a), aromatics, heteroaromatic or α-level Four methyl ketone (for example using sodium hydride or di-isopropyl lithamide) can be handled by deprotonation and with the reagent (as diethyl carbonate, methyl chlorocarbonate or tert-Butyl dicarbonate) that can shift carboxylic group.Perhaps shown in flow process VIII (b), carboxylic acid can be activated (as with carbonyl dimidazoles or oxalyl chloride) and handle (as ethyl acetic acid lithium, Methylpropanedioic acid magnesium or Meldrum ' s acid, following hot alcoholysis) with the Equivalent of acetic ester.
Embodiment preferred is shown among flow process II and the III.With 1; 8-diazabicyclo [5.4.0] 11-7-alkene (DBU) is as alkali in toluene, make the benzoyl acetic ester for example 26 or 4-(2-methoxy ethoxy) benzoyl acetic ester react with nitroethylene base benzo dioxolyl compound 27 and obtain compound 28.The reduction that produces nitro with Raney nickel catalytic hydrogenation obtains amine, and cyclisation subsequently obtains pyrrolin 29.With the two keys of sodium cyanoborohydride reduction obtain into suitable-suitable, anti-, anti-and suitable, the pyrrolidine compound 30 of trans isomer mixture.That chromatographic separation goes out is suitable-along isomer, stay anti-, anti-and suitable, trans isomer (31).
Flow process III explanation is anti-, the further processing of trans isomer.Anti-, anti-and suitable described in the flow process IV, the mixture of anti-tetramethyleneimine (31) in the presence of ethyl diisopropyl amine with Br-CH 2C (O) NHR 4Reaction obtains alkylating tetramethyleneimine mixture 32 in acetonitrile, and it still is anti-, anti-and suitable, the mixture of trans isomer.Anti-with sodium hydroxide hydrolysis in alcohol-water, the ethyl ester of anti-compound but stay not the suitable of contact, therefore the ethyl ester of anti-compound makes instead, and anti-carboxylic acid 33 separates in the anti-ester 34 from suitable.
The preparation of the compound of flow process IV explanation when W is not carboxylic acid.Compound 55 (can prepare according to flow process I method) is transformed (for example use peptide coupling condition such as N-methylmorpholine, EDCl and HOBt, form under reaction conditions in ammonia existence or other acid amides) obtain methane amide 56.This methane amide dehydration (for example using phosphoryl chloride in pyridine) is obtained nitrile 57.(sodiumazide and Triethylammonium chloride or trimethylsilyl azide thing and stannic oxide) makes nitrile 57 reactions obtain tetrazolium 58 under standard tetrazolium formation condition.Perhaps make nitrile 57 for example obtain amidoxim 59 with the oxammonium hydrochloride reaction in DMF, DMSO or the N,N-DIMETHYLACETAMIDE at solvent in the presence of the alkali (for example salt of wormwood, yellow soda ash, sodium hydroxide, triethylamine, sodium methylate or sodium hydride).In the presence of alkali (for example triethylamine, pyridine, salt of wormwood and yellow soda ash), in conventional organic solvent (for example chloroform, methylene dichloride, dioxane, THF, acetonitrile or pyridine), make amidoxim 59 and methyl chlorocarbonate or ethyl ester reaction obtain the O-acyl compounds.Heating O-acyl group amidoxim makes its cyclisation obtain compound 60 in inert solvent (for example benzene,toluene,xylene, dioxane, THF, ethylene dichloride or chloroform etc.).Perhaps in inert solvent (for example chloroform, methylene dichloride, dioxane and THF etc.), make amidoxim 59 and thionyl chloride reaction obtain oxa-thiadiazoles 61.
Flow process V explanation is the method for the synthesis of pyrrolidine of acrylate by azomethine inner salt type [3+2]-cycloaddition.Known with general works such as compound 70 add to unsaturated ester for example in 71 to obtain for example compound 72 (O.Tsuge, S.Kanemasa, K.Matsuda of tetramethyleneimine, Chem, Lett.1131-4 (1983), O.Tsuge, S.Kanemasa, T.Yamada, K.Matsuda, J.Org.Chem.52 2523-30 (1987) and S.Kanemasa, K Skamoto, O.Tsuge, Bull.Chem.Soc.Jpn.62 1960-68 (1989)).In the presence of TMS fluoroform sulfonyl ester and tetrabutyl ammonium fluoride, make silyl imines 73 and acrylate 74 react the required tetramethyleneimine 75 that obtains to isomer mixture.This method can be revised as directly by make 73 and 74 and suitable brominated ethanamide (for example dibutyl bromo ethanamide) in the presence of tetrabutylammonium iodide and cesium fluoride, react and obtain N-kharophen derivative and directly obtain compound 76.
The method of the tetramethyleneimine 80 of flow process VI explanation preparation enantiomer-pure can be with its further processing on tetramethyleneimine nitrogen.Intermediate racemize tetramethyleneimine ester 77 (for example being prepared by the described method of flow process V) is carried out the protection of Boc-nitrogen (for example use Boc 2O handles) then the described ester of hydrolysis (for example in the second alcohol and water with sodium hydroxide or lithium hydroxide) obtain tertiary butyl formamyl pyrrolidine carboxylic acid 78.Described carboxylic acid is converted into its (+)-Alpha-Methyl benzylamine salt, and it can obtain the pure salt of diastereomer by recrystallization (for example from ethyl acetate and hexane or chloroform and hexane).The pure salt of this diastereomer (for example with yellow soda ash or citric acid) that can neutralize obtains the carboxylic acid 79 of enantiomer-pure.Described tetramethyleneimine nitrogen can be gone protection (for example using trifluoroacetic acid), transform described ester with the hydrochloric acid of ethanol system and obtain salt 80.Perhaps can be with the HCl cracking blocking group of ethanol system, a step forms described ester.Described tetramethyleneimine nitrogen further can be processed the compound 81 that (for example in the presence of diisopropylethylamine, with 2 of monobromo-acetic acid, 6-diethylbenzene methane amide is handled in acetonitrile) obtains optically active.Use (-)-Alpha-Methyl benzylamine to obtain opposite enantiomorph.Can also use the amine of other optional optically active.
Flow process VII shows a preferable methods.Alkali for example triethylamine or diisopropylethylamine etc. or amidine for example in the presence of DBU etc. of sodium ethylate etc. or trialkylamine for example, at inert solvent for example in THF, toluene, DMF, acetonitrile, ethyl acetate, isopropyl acetate or the methylene dichloride etc., make nitroethylene based compound (88) and 'beta '-ketoester 89 reactions obtain compound 90, temperature of reaction is about 100 ℃ of about 0-, the reaction times be about 15 minutes to spending the night.Then carry out the reduction cyclisation then of the nitryl group of compound 90 by following condition: for example the about barometric point of hydrogen pressure is to about 300p.s.i., about 1 hour to about 1 day, at inert solvent for example in THF, ethyl acetate, toluene, ethanol, Virahol, DMF or the acetonitrile etc., with hydrogenation catalyst for example Raney nickel, palladium charcoal, platinum catalyst for example platinum oxide, platinum charcoal or platinum consolidate soil etc., or rhodium catalyst for example rhodium charcoal or rhodium consolidate the mixture that catalytic hydrogenation that soil etc. carries out compound 90 obtains intermediate nitrone 91a or nitrone 91a and imines 91b.With acid for example processing such as trifluoroacetic acid or acetate or sulfuric acid or phosphoric acid or methylsulfonic acid contain the described reaction mixture of nitrone or nitrone/imines mixture, continue hydrogenation then and obtain, the pyrrolidine compound 92 of suitable-isomer to suitable.Handle compound 92 and carry out epimerization at C-3 and obtain instead by being used under the following condition, anti-compound 93, described reaction conditions is included in inert solvent for example among ethanol, ethyl acetate, isopropyl acetate, THF, toluene or the DMF etc., in temperature is under about-20 ℃ to about 120 ℃, with alkali for example sodium ethylate, potassium tert.-butoxide, trimethyl carbinol lithium or tertiary amyl alcohol potassium etc. or trialkylamine, for example triethylamine or diisopropylethylamine etc., or for example processing such as DBU of amidine.With X-R 3Can choose wantonly before the reaction compound 93 itself is split as enantiomorph.At solvent for example in acetonitrile, ethyl acetate, isopropyl acetate, ethanol or the Virahol etc.; handle 93 (+)-isomer and (-)-mixture of isomers with S-(+)-phenylglycollic acid, D-tartrate or D-dibenzoyl tartaric acid etc., can obtain (+)-isomer of the optically active of pure substantially (promptly be at least 95% required isomer) compound 93.Optionally make the form crystallization of (+)-isomer of 93, (-)-isomer of 93 is stayed in the solution with salt.Perhaps can make the optionally crystallization of (-)-isomer of the optically active of pure substantially (i.e. at least 95% required isomer) compound 93 by (+)-isomer of 93 and (-)-mixture of isomers and reactions such as L-tartrate, L-dibenzoyl tartaric acid or L-Pyrrolidonecarboxylic acid, (+)-isomer of required compound 93 is stayed in the solution.
Make compound 93 (racemize or optically active) and X-R 3(wherein X is leavings group (for example halogen or a sulphonate), R 3Definition as described above) obtains intermediate ester 94 in reaction under the following condition: at inert solvent for example in acetonitrile, THF, toluene, DMF or the ethanol etc., temperature is under about 0 ℃ to about 100 ℃, with for example processing such as diisopropylethylamine, triethylamine, sodium bicarbonate or salt of wormwood of alkali.With hydrolysising condition for example use alkali (as sodium hydroxide or lithium hydroxide or potassium hydroxide etc.) solvent for example in alcohol-water or the THF-ethanol etc. with as described in ester separate or situ conversion is carboxylic acid (95).
Flow process I
Figure A9880618400541
Flow process II
Figure A9880618400551
Flow process III
Figure A9880618400561
Flow process IV
Figure A9880618400571
Flow process V
Figure A9880618400581
Flow process VI
Figure A9880618400591
Flow process VII
Flow process VIII
Flow process VIIIa
Flow process VIIIb
The midbody compound that is used to prepare The compounds of this invention is following formula: compound or its salt:
Figure A9880618400621
Wherein m is 0 to 6, and W is (a)-C (O) 2-G, wherein G is hydrogen or carboxy protective group,
(b)-PO 3H 2，
(c)-and (OH) E of P (O), wherein E is hydrogen, low alkyl group or aralkyl,
(d)-CN，
(e)-C (O) NHR 17, R wherein 17Be low alkyl group,
(f) alkyl amino-carbonyl,
(g) dialkyl amino carbonyl,
(h) tetrazyl,
(i) hydroxyl,
(j) alkoxyl group,
(k) sulfonamido,
(l)-C (O) NHS (O) 2R 16, R wherein 16Be low alkyl group, haloalkyl, phenyl or dialkyl amido,
(m)-S (O) 2NHC (O) R 16,
Figure A9880618400622
Figure A9880618400631
R 1And R 2Independently be selected from hydrogen, low alkyl group, alkenyl, alkynyl, alkoxyalkyl, alkoxy carbonyl alkyl, hydroxyalkyl, haloalkyl, halogenated alkoxy alkyl, alkoxy alkoxy alkyl, the thio alkoxy alkoxyalkyl, cycloalkyl, cycloalkylalkyl, the aminocarboxyl alkyl, alkyl amino alkyl carbonyl, the dialkyl amino carbonyl alkyl, the aminocarboxyl alkenyl, the alkyl amino-carbonyl alkenyl, the dialkyl amino carbonyl alkenyl, the hydroxyl alkenyl, aryl, arylalkyl, aryloxy alkyl, alkoxy aryl alkyl, heterocyclic radical, (heterocyclic radical) alkyl and (R Aa) (R Bb) N-R Cc-, R wherein AaBe aryl or arylalkyl, R BbBe hydrogen or alkanoyl and R CcBe alkylidene group, prerequisite is R 1And R 2One of or both be not hydrogen; With following formula: compound or its salt:
Figure A9880618400641
Wherein n is 0 or 1; M is 0 to 6; W is (a)-C (O) 2-G, wherein G is hydrogen or carboxy protective group,
(b)-PO 3H 2，
(c)-and (OH) E of P (O), wherein E is hydrogen, low alkyl group or aralkyl,
(d)-CN，
(e)-C (O) NHR 17, R wherein 17Be low alkyl group,
(f) alkyl amino-carbonyl,
(g) dialkyl amino carbonyl,
(h) tetrazyl,
(i) hydroxyl,
(j) alkoxyl group,
(k) sulfonamido,
(l)-C (O) NHS (O) 2R 16, R wherein 16Be low alkyl group, haloalkyl, phenyl or dialkyl amido,
(m)-S (O) 2NHC (O) R 16,
Figure A9880618400651
R 1And R 2Independently be selected from hydrogen, low alkyl group, alkenyl, alkynyl, alkoxyalkyl, alkoxy carbonyl alkyl, hydroxyalkyl, haloalkyl, halogenated alkoxy alkyl, alkoxy alkoxy alkyl, the thio alkoxy alkoxyalkyl, cycloalkyl, cycloalkylalkyl, the aminocarboxyl alkyl, alkyl amino alkyl carbonyl, the dialkyl amino carbonyl alkyl, the aminocarboxyl alkenyl, the alkyl amino-carbonyl alkenyl, the dialkyl amino carbonyl alkenyl, the hydroxyl alkenyl, aryl, arylalkyl, aryloxy alkyl, alkoxy aryl alkyl, heterocyclic radical, (heterocyclic radical) alkyl and (R Aa) (R Bb) N-R Cc-, R wherein AaBe aryl or arylalkyl, R BbBe hydrogen or alkanoyl and R CcBe alkylidene group, prerequisite is R 1And R 2One of or both be not hydrogen.
Preferred intermediate comprises formula (III), (IV) and (V) compound or its pure substantially (+)-isomer or (-)-isomer, and wherein m is 0 or 1; W is-CO 2-G, wherein G is hydrogen or carboxy protective group, R 1And R 2As above-mentioned definition.
Particularly preferred intermediate is formula (III), (IV) and (V) compound or its pure substantially (+)-isomer or (-)-isomer, and wherein m is 0; W is-CO 2-G, wherein G is hydrogen or carboxy protective group; And R 1Be (i) alkoxyalkyl alkyl, (ii) cycloalkyl, (iii) phenyl, (iv) pyridyl, (v) furyl or (vi) replace or unsubstituted 4-p-methoxy-phenyl, 4-fluoro phenyl, 2-fluoro phenyl, 4-three fluoro aminomethyl phenyls, the 4-ethoxyl phenenyl, 3-fluoro-4-p-methoxy-phenyl, 3-fluoro-4-ethoxyl phenenyl, 4-propoxy-phenyl, the 4-isopropyl phenyl, 2-fluoro-4-ethoxyl phenenyl, 4-(2-methoxy ethoxy) phenyl, 4-(2-ethoxy ethoxy) phenyl, 4-(2-isopropoxy oxyethyl group) phenyl, 3-fluoro-4-propoxy-phenyl, 3-methoxyl group-4-propoxy-phenyl, 4-five fluoro ethylphenyls, 4-methoxymethoxy phenyl, the 4-hydroxy phenyl, 1,3-benzo dioxolyl, 7-methoxyl group-1,3-benzo dioxolyl, 1,4-benzodioxane base or dihydro benzo furyl, substituting group wherein is selected from alkoxyl group, alkoxyl group alkoxyl group and carboxyl alkoxyl group, R 2Be 1,3-benzo dioxolyl, 1,4-benzodioxane base, dihydro benzo furyl, benzofuryl, 4-p-methoxy-phenyl, Dimethoxyphenyl, fluoro phenyl or phenyl-difluoride base.
The embodiment that is not intended to limit concept and range of the present invention with reference to following furnishing an explanation can understand foregoing content better.Use following abbreviation: Boc represents tert-butoxycarbonyl, Cbz represents benzyloxycarbonyl, DBU represents 1,8-diazabicyclo [5.4.0] 11-7-alkene, EDCI represent 1-(3-dimethylaminopropyl-3-ethyl-carbodiimide hydrochloride, EtOAc represents ethyl acetate, EtOH represents ethanol, HOBt represents I-hydroxybenzotriazole, Et 3N represents triethylamine, and TFA represents trifluoroacetic acid, and THF represents tetrahydrofuran (THF).
Embodiment 1
Instead, anti--2-(4-p-methoxy-phenyl)-4-(1,3-benzo dioxole-5-yl)-1-((2,4, the 6-trimethylammonium) phenyl amino carbonyl methyl)-tetramethyleneimine-3-carboxylic acid
Embodiment 1A
2-(4-anisoyl)-4-nitro methyl-3-(1,3-benzo dioxole-5-yl) ethyl butyrate
To (4-anisoyl) ethyl acetate (23.0g; 0.104mol) (according to Krapcho etc.; Org.Syn.47; the preparation of 20 (1967) methods), 5-(2-nitroethylene base)-1; (17.0g 0.088mol) is dissolved in 180ml toluene and being heated in 80 ℃ the solution to 3-benzo dioxole, under agitation adds 1; 8-diazabicyclo [5.4.0] 11-7-alkene (DBU, 0.65g).Heat described mixture to all nitro material dissolutions, do not heat down, add 0.65g DBU then in addition described solution stirring 30 minutes.Restir 45 minutes, thin-layer chromatography (dichloromethane solution of 5% ethyl acetate) show that no nitro raw material exists.Add toluene (200ml), with dilute hydrochloric acid and NaCl solution washing organic layer.Use the dried over sodium sulfate organic layer, then concentrating under reduced pressure.The residue that obtains obtains being the needed product 21.22g of isomer mixture and (4-anisoyl) ethyl acetate of 9.98g recovery through silica gel column chromatography (with 3: 1 hexane-eluent ethyl acetates).
Embodiment 1B
2-(4-p-methoxy-phenyl)-4-(1,3-benzo dioxole-5-yl)-4,5-dihydro-3H-pyrroles-3-carboxylic acid, ethyl ester
Under 4 atmospheric hydrogen pressures, with the compound (21g) of Raney nickel 2800 catalyzer (51g) (Raney nickel with preceding with washing with alcohol 3 times) hydrogenation embodiment 1A generation in 500ml ethanol.Filter and remove catalyzer, the solution that concentrating under reduced pressure obtains.The residue that obtains through silica gel column chromatography, is obtained the required product of 12.34g with the eluant solution of 8.5% ethyl acetate in methylene dichloride.
Embodiment 1C
2-(4-p-methoxy-phenyl)-4-(1,3-benzo dioxole-5-yl)-tetramethyleneimine-3-carboxylic acid, ethyl ester as suitable-suitable, anti-, anti-and suitable, anti--mixture of isomers
(11.89g 0.324mol) is dissolved in 27ml tetrahydrofuran (THF) and the 54ml ethanol compound that embodiment 1B is produced.(2.35g is 0.374mol) with the 5mg tetrabromo-mcresolsulfonphthalein to add sodium cyanoborohydride.To keep solution colour is that yellowish-green speed drips the ethanolic soln of 1: 2 dense HCl in this blue solution.When no longer taking off, yellow stops to add HCL, with described solution restir 20 minutes.The described solution of vacuum concentration makes it be allocated between chloroform and the potassium bicarbonate aqueous solution then.Separate organic layer, through dried over sodium sulfate, concentrating under reduced pressure.Through silica gel column chromatography, it is 64% anti-obtaining with 85: 15 ethyl acetate-hexane wash-outs with residue, anti-compound and 34% suitable, the mixture 5.96g of anti-compound.Further obtain the solid of 0.505g the unknown, then be pure suitable, the suitable-compound of 3.044g with pure eluent ethyl acetate.
Embodiment 1D
N-(2,4, the 6-trimethylphenyl) bromo ethanamide
In-50 ℃ to 2 (1g, 7.40mmol) methylene dichloride (25ml) stirred solution in add continuously N, N-diisopropylethylamine (1.58ml, 8.14mmol, 1.1eq) and bromo acetyl bromide (0.72ml, 7.40mmol is leq) so that temperature is no more than-40 ℃.After adding finishes, remove cryostat, make reaction mixture be warmed to room temperature.Behind the restir 30 minutes, dilute this mixture and be poured in the 1N sodium sulfite solution with ether (70ml).Separate each phase, water and salt solution continuous washing upper strata.Dry organic phase (sodium sulfate), evaporating solvent be to half volume, described product crystallization this moment.Vacuum filtration goes out crystal and obtains title compound (1.51g, 80%).
Embodiment 1E
Instead, anti--2-(4-p-methoxy-phenyl)-4-(1,3-benzo dioxole-5-yl)-1-((2,4, the 6-trimethylammonium) phenyl amino carbonyl methyl)-tetramethyleneimine-3-carboxylic acid
Anti-with 64%, anti-suitable with 34%, the mixture of anti-tetramethyleneimine (mixture that produces by embodiment 1C) (5.72g, 15.50mmol), ethyl diisopropyl amine (4.20g, 32.56mmol) and the compound (19.0mmol) that derives from embodiment 1D in the 30ml acetonitrile in 50 ℃ of heating 1 hour.The described solution of vacuum concentration.Residue is dissolved in the toluene,, obtains to instead through dried over sodium sulfate and vacuum concentration with the potassium bicarbonate solution jolting, anti--and suitable, the product of anti--ethyl ester mixture.
Be dissolved in this mixture in the water that 50ml ethanol and 15ml contain 5.00 sodium hydroxide and under room temperature, stirred 3 hours.This solution of vacuum concentration also adds 60ml water.Unreacted suitable with this mixture of extracted with diethyl ether, anti--ethyl ester to remove.Handle water layer to slight haze with hydrochloric acid.Further obtain thick acid product then with the acetate neutralization.Filter this thick product, be dissolved in purifying in the tetrahydrofuran (THF), through dried over sodium sulfate, vacuum concentration, crystallization purifying obtains target compound from ether. 1H?NMR(300MHz，CDCl 3)δ?8.22(1H，bs)，7.78(2H，d，J＝8Hz)，6.95(5H，m)，6.82(1H，bd，J＝8Hz)，6.77(1H，d，J＝8Hz)，5.96(2H，s)，3.97(1H，bd，J＝10Hz)，3.81(3H，s)，3.70(1H，ddd，6，5&3Hz)，3.57(bdd，10&3Hz)，3.45(1H，d，J＝16Hz)，3.13(2H，m)，2.24(3H，s)，2.06(6H，s)。MS(DCl，NH 3)m/e?517(M+H +)。C 30H 32N 2O 6.0.5H 2The analytical calculation value of O: C, 68.56, H, 6.33, N, 5.33.Measured value: C, 68.84, H, 6.20; N, 5.31.
Embodiment 2
Instead, anti--2-(3-fluoro-4-p-methoxy-phenyl)-4-(1,3-benzo dioxole-5-yl)-1-((2,4, the 6-trimethylammonium) phenyl amino carbonyl methyl)-tetramethyleneimine-3-carboxylic acid
Prepare title compound by embodiment 1 described method. 1H?NMR(300MHz，CDCl 3)δ?8.22(1H，bs)，7.21(1H，dd，J＝12&2Hz)，7.12(1H，bd，J＝8Hz)，6.95(1H，t，J＝8Hz)，6.90(2H，bs)，6.84(1H，d，J＝2Hz)，6.80(1H，dd，J＝8&3Hz)，6.76(1H，d，J＝8Hz)，5.93(2H，s)，3.96(1H，d，J＝10Hz)，3.89(3H，s)，3.70(1H，ddd，6，5&3Hz)，3.56(1H，dd，11&5Hz)，3.45(1H，d，J＝16Hz)，3.10(1H，t，J＝10Hz)，3.07(1H，dd，J＝8&6Hz)，3.02(1H，d，J＝16Hz)，2.17(3H，s)，2.07(6H，s)。MS(DCl，NH 3)m/e?535(M+H +)。C 30H 31FN 2O 6.0.75H 2The analytical calculation value of O: C, 65.74, H, 5.98, N, 5.11.Measured value: C, 65.96, H, 5.88, N, 5.16.
Embodiment 3
Instead, anti--2-(4-propoxy-phenyl)-4-(1,3-benzo dioxole-5-yl)-1-((2,4, the 6-trimethylammonium) phenyl amino carbonyl methyl)-tetramethyleneimine-3-carboxylic acid
Prepare title compound by embodiment 1 described method. 1H NMR (300MHz, CDCl 3) δ 8.21 (1H, bs), 7.38 (2H, d, J=8Hz), 6.90 (2H, d, J=8Hz), 6.89 (2H, d, 3Hz), 7.83 (1H, dd, J=8﹠amp; 2Hz), 6.75 (1H, d, J=8Hz), 5.94 (1H, d, J=3Hz), 5.93 (1H, d, J=3Hz), 3.96 (1H, d, J=10Hz), 3.85 (2H, q, J=7Hz), 3.70 (1H, ddd, 6,5﹠amp; 3Hz), 3.58 (1H, dd, 11﹠amp; 5Hz), 3.48 (1H, d, J=16Hz), 3.15 (1H, dd, 8﹠amp; 6Hz), 3.13 (1H, t, J=10Hz), 2.99 (1H, d, J=16Hz), 2.25 (3H, s), 2.05 (6H, s), 1.81 (2H, sextet, J=7Hz), 1.04 (1H, t, J=7Hz).MS(DCl，NH 3)m/e?545(M+H +)。C 32H 36N 2O 6.0.33H 2The analytical calculation value of O: C, 69.79, H, 6.71, N, 5.09.Measured value: C, 69.78, H, 6.73, N, 4.81.
Embodiment 4
Instead, anti--2-(4-p-methoxy-phenyl)-4-(1,3-benzo dioxole-5-yl)-1-((2, the 6-diethyl) phenyl amino carbonyl methyl)-tetramethyleneimine-3-carboxylic acid
Prepare title compound by embodiment 1 described method. 1H?NMR(300MHz，CDCl 3)δ?8.24(1H，bs)，7.39(2H，d，J＝8Hz)，7.21(1H，dd，J＝8&6Hz)，7.11(2H，d，J＝8Hz)，6.92(2H，d，8Hz)，7.89(1H，d，J＝3Hz)，7.82(1H，dd，J＝8&2Hz)，6.75(1H，d，J＝8Hz)，5.94(1H，d，J＝3Hz)，5.93(1H，d，J＝3Hz)，3.96(1H，d，J＝10Hz)，3.82(3H，s)，3.70(1H，ddd，6，5&3Hz)，3.56(1H，dd，11&5Hz)，3.45(1H，d，J＝16Hz)，3.15(1H，dd，8&6Hz)，3.13(1H，t，J＝10Hz)，3.01(1H，d，J＝16Hz)，2.42(4H，q，J＝7Hz)，1.08(6H，t，J＝7Hz)。MS(DCl，NH 3)m/e?559(M+H 4 +)，531(M+H +)。C 31H 34N 2O 6The analytical calculation value: C, 70.17, H, 6.46, N, 5.28.Measured value: C, 69.88, H, 6.42, N, 5.09.
Embodiment 5
Instead, anti--2-(4-propoxy-phenyl)-4-(1,3-benzo dioxole-5-yl)-1-((2, the 6-diethyl) phenyl amino carbonyl methyl)-tetramethyleneimine-3-carboxylic acid
Prepare title compound by embodiment 1 described method. 1H NMR (300MHz, CDCl 3) δ 8.27 (1H, bs), 7.37 (2H, d, J=8Hz), 7.21 (1H, dd, J=8﹠amp; 6Hz), 7.11 (2H, d, J=8Hz), 6.90 (2H, d, 8Hz), 7.86 (1H, d, J=3Hz), 7.83 (1H, dd, J=8﹠amp; 2Hz), 6.75 (1H, d, J=8Hz), 5.93 (1H, d, J=3Hz), 5.92 (1H, d, J=3Hz), 3.96 (1H, d, J=10Hz), 3.85 (2H, q, J=7Hz), 3.70 (1H, ddd, 6,5﹠amp; 3Hz), 3.55 (1H, dd, 11﹠amp; 5Hz), 3.48 (1H, d, J=16Hz), 3.15 (1H, dd, 8﹠amp; 6Hz), 3.13 (1H, t, J=10Hz), 3.01 (1H, d, J=16Hz), 2.43 (4H, q, J=7Hz), 1.82 (2H, sextet, J=7Hz), 1.08 (6H, t, J=7Hz), 1.04 (3H, t, J=7Hz).MS(DCl，NH 3)m/e?559(M+H +)。C 33H 38N 2O 6.0.25H 2The analytical calculation value of O: C, 70.38, H, 6.89, N, 4.97.Measured value: C, 70.49, H, 6.85, N, 4.68.
Embodiment 6
Instead, anti--2-(3-fluoro-4-p-methoxy-phenyl)-4-(1,3-benzo dioxole-5-yl)-1-((2, the 6-diethyl) phenyl amino carbonyl methyl)-tetramethyleneimine-3-carboxylic acid
Prepare title compound by embodiment 1 described method. 1H?NMR(300MHz，CDCl 3)δ8.21(1H，bs)，7.22(1H，dt，J＝8&2Hz)，7.20(1H，d，J＝8Hz)，7.17(1H，dt，J＝8&2Hz)，7.10(2H，d，J＝8Hz)，6.96(1H，t，J＝8Hz)，6.83(1H，dd，J＝8&2Hz)，6.80(1H，d，J＝3Hz)，6.76(1H，d，J＝8Hz)，5.94(1H，d，J＝3Hz)，5.93(1H，d，J＝3Hz)，3.97(1H，d，J＝10Hz)，3.90(3H，s)，3.72(1H，ddd，6，5&3Hz)，3.58(1H，dd，11&5Hz)，3.46(1H，d，J＝16Hz)，3.14(1H，t，J＝10Hz)，3.12(1H，dd，J＝8&6Hz)，3.05(1H，d，J＝1?6Hz)，2.45(4H，q，J＝7Hz)，1.09(6H，t，J＝7Hz)。MS(DCl，NH 3)m/e549(M+H +)。C 31H 33FN 2O 6.0.5H 2The analytical calculation value of O: C, 66.78, H, 6.15, N, 5.02.Measured value: C, 66.81, H, 5.89, N, 4.87.
Embodiment 7
Instead, anti--2-(3-fluoro-4-ethoxyl phenenyl)-4-(1,3-benzo dioxole-5-yl)-1-((2, the 6-diethyl) phenyl amino carbonyl methyl)-tetramethyleneimine-3-carboxylic acid
Prepare title compound by embodiment 1 described method. 1H?NMR(300MHz，CDCl 3)δ8.23(1H，bs)，7.23(1H，d，J＝2Hz)，7.20(1H，dd，J＝8&3Hz)，7.11(3H，m)，6.96(1H，t，J＝8Hz)，6.83(1H，dd，J＝8&2Hz)，6.80(1H，d，J＝3Hz)，6.76(1H，d，J＝8Hz)，5.93(1H，d，J＝3Hz)，5.92(1H，d，J＝3Hz)，4.11(2H，t，J＝7Hz)，3.97(1H，d，J＝10Hz)，3.72(1H，ddd，6，5&3Hz)，3.55(1H，dd，11&5Hz)，3.47(1H，d，J＝16Hz)，3.14(1H，t，J＝10Hz)，3.12(1H，dd，J＝8&6Hz)，3.04(1H，d，J＝16Hz)，2.45(4H，q，J＝7Hz)，1.47(3H，t，J＝7Hz)，1.09(6H，t，J＝7Hz)。MS(DCl，NH 3)m/e?563(M+H +)。C 32H 35FN 2O 6.0.15TFA analytical calculation value: C, 66.92, H, 6.11, N, 4.83.Measured value: C, 67.19, H, 5.75, N, 4.69.
Embodiment 8
Instead, anti--2-(3-fluoro-4-p-methoxy-phenyl)-4-(7-methoxyl group-1,3-benzo dioxole-5-yl)-1-((2, the 6-diethyl) phenyl amino carbonyl methyl)-tetramethyleneimine-3-carboxylic acid
Prepare title compound by embodiment 1 described method. 1H?NMR(300MHz，CDCl 3)δ8.24(1H，s)，7.25(1H，t，J＝3Hz)，7.21(1H，bd)，7.14(1H，m)，7.08(2H，d，J＝8Hz)，6.96(1H，t，J＝8Hz)，6.56(1H，d，J＝3Hz)，6.50(1H，d，J＝3Hz)，5.93(1H，d，J＝2Hz)，5.91(1H，d，J＝2Hz)，3.97(1H，d，J＝10Hz)，3.90(3H，s)，3.72(1H，ddd，6，5&3Hz)，3.58(1H，dd，11&5Hz)，3.46(1H，d，J＝16Hz)，3.14(1H，t，J＝10Hz)，3.12(1H，dd，J＝8&6Hz)，3.05(1H，d，J＝16Hz)，2.45(4H，q，J＝7Hz)，1.09(6H，t，J＝7Hz)。MS(DCl，NH 3)m/e?579(M+H +)。C 32H 35FN 2O 7.1.5H 2The analytical calculation value of O: C, 63.65, H, 6.31, N, 4.64.Measured value: C, 64.00, H, 6.29, N, 4.26.
Embodiment 9
Instead, anti--2-(3-methoxyl group-4-propoxy-phenyl)-4-(1,3-benzo dioxole-5-yl)-1-((2, the 6-diethyl) phenyl amino carbonyl methyl)-tetramethyleneimine-3-carboxylic acid
Prepare title compound by embodiment 1 described method. 1H?NMR(300MHz，CDCl 3)δ8.22(1H，s)，7.21(1H，m)，7.12(2H，d，J＝10Hz)，7.02(1H，dd，J＝9&3Hz)，6.93(1H，d，J＝2Hz)，6.88(1H，d，J＝2Hz)，6.85(1H，m)，6.82(1H，d，J＝2Hz)，6.75(1H，d，J＝9Hz)，5.95(1H，d，J＝2Hz)，5.93(1H，d，J＝2Hz)，3.97(2H，q，J＝9Hz)，3.84(3H，s)，3.72(2H，m)，3.60-3.45(2H，m)，3.15(2H，m)，3.03(1H，d，J＝18Hz)，2.43(4H，q，J＝9Hz)，1.87(2H，m)，1.08(6H，t，J＝9Hz)，1.04(3H，t，J＝9Hz)。MS(DCl，NH 3)m/e?589(MH +)。C 34H 40N 2O 7.0.45H 2The analytical calculation value of O: C, 68.43, H, 6.91, N, 4.69.Measured value: C, 68.45, H, 6.91, N, 4.62.
Embodiment 10
Instead, anti--2-(4-ethoxyl phenenyl)-4-(1,3-benzo dioxole-5-yl)-1-((2, the 6-diethyl) phenyl amino carbonyl methyl)-tetramethyleneimine-3-carboxylic acid
Prepare title compound by embodiment 1 described method. 1H?NMR(300MHz，CDCl 3)δ8.26(1H，bs)，7.36(2H，d，J＝9Hz)，7.21(1H，m)，7.11(2H，d，J＝10Hz)，6.90(2H，d，J＝9Hz)，6.86(1H，d，J＝2Hz)，6.83(1H，dd，J＝8&2Hz)，6.73(1H，d，J＝9Hz)，5.94(1H，d，J＝2Hz)，5.92(1H，d，J＝2Hz)，4.10-3.90(3H，m)，3.71(1H，m)，3.60-3.40(2H，m)，3.15(2H，m)，3.02(1H，d，J＝18Hz)，2.43(4H，q，J＝9Hz)，1.42(3H，t，J＝9Hz)，1.08(6H，t，J＝9Hz)。MS(DCl，NH 3)m/e?545(MH +)。C 32H 36N 2O 6.0.5H 2The analytical calculation value of O: C, 69.42, H, 6.74, N, 5.06.Measured value: C, 69.52, H, 6.52, N, 4.89.
Embodiment 11
Instead, anti--2-(4-p-methoxy-phenyl)-4-(1,3-benzo dioxole-5-yl)-1-((2, the 6-dimethyl) phenyl amino carbonyl methyl)-tetramethyleneimine-3-carboxylic acid
Prepare title compound by embodiment 1 described method. 1H?NMR(300MHz，CDCl 3)δ8.32(1H，bs)，7.37(2H，d，J＝9Hz)，7.08(3H，m)，6.91(2H，d，J＝9Hz)，6.88(1H，d，J＝2Hz)，6.82(1H，dd，J＝8&2Hz)，6.75(1H，d，J＝9Hz)，5.95(1H，d，J＝2Hz)，5.93(1H，d，J＝2Hz)，3.95(1H，d，J＝10Hz)，3.81(3H，s)，3.72(1H，m)，3.55(1H，dd，J＝10&5Hz)，3.46(1H，d，J＝18Hz)，3.13(2H，m)，3.00(1H，d，J＝18Hz)，2.10(6H，s)。MS(DCl，NH 3)m/e?502(MH +)。C 29H 30N 2O 6.0.5H 2The analytical calculation value of O: C, 68.09, H, 6.11, N, 5.48.Measured value: C, 67.98, H, 6.02, N, 5.33.
Embodiment 12
Instead, anti--2-(4-propoxy-phenyl)-4-(7-methoxyl group-1,3-benzo dioxole-5-yl)-1-((2, the 6-diethyl) phenyl amino carbonyl methyl)-tetramethyleneimine-3-carboxylic acid
Prepare title compound by embodiment 1 described method. 1H?NMR(300MHz，CDCl 3)δ8.30(1H，bs)，7.36(2H，d，J＝9Hz)，7.21(1H，m)，7.09(2H，d，J＝10Hz)，6.91(2H，d，J＝9Hz)，6.59(1H，d，J＝2Hz)，6.51(1H，d，J＝2Hz)，5.93(1H，d，J＝2Hz)，5.91(1H，d，J＝2Hz)，3.93(3H，m)，3.80(3H，s)，3.72(1H，m)，3.60-3.50(2H，m)，3.15(2H，m)，3.02(1H，d，J＝18Hz)，2.43(4H，q，J＝9Hz)，1.82(2H，m)，1.08(6H，t，J＝9Hz)，1.05(3H，t，J＝9Hz)。MS(DCl，NH 3)m/e?589(MH +)。C 34H 40N 2O 7.0.25H 2The analytical calculation value of O: C, 68.84, H, 6.88, N, 4.72.Measured value: C, 68.80, H, 6.59, N, 4.52.
Embodiment 13
Instead, anti--2-(3-methoxyl group-4-propoxy-phenyl)-4-(7-methoxyl group-1,3-benzo dioxole-5-yl)-1-((2, the 6-diethyl) phenyl amino carbonyl methyl)-tetramethyleneimine-3-carboxylic acid
Prepare title compound by embodiment 1 described method. 1H?NMR(300MHz，CDCl 3)δ8.22(1H，s)，7.21(1H，m)，7.09(2H，d，J＝10Hz)，7.02(1H，dd，J＝9&3Hz)，6.93(1H，d，J＝2Hz)，6.87(1H，d，J＝9Hz)，6.61(1H，d，J＝2Hz)，6.53(1H，d，J＝2Hz)，5.93(1H，d，J＝2Hz)，5.91(1H，d，J＝2Hz)，3.97(3H，q，J＝9Hz)，3.84(3H，s)，3.82(3H，s)，3.70(1H，m)，3.60-3.45(2H，m)，3.15(2H，m)，3.02(1H，d，J＝18Hz)，2.42(4H，q，J＝9Hz)，1.85(2H，m)，1.08(6H，t，J＝9Hz)，1.05(3H，t，J＝9Hz)。MS(DCl，NH 3)m/e?619(MH +)。C 35H 42N 2O 8The analytical calculation value: C, 67.94, H, 6.84, N, 4.53.Measured value: C, 67.65, H, 6.98, N, 4.44.
Embodiment 14
Instead, anti--2-(4-p-methoxy-phenyl)-4-(1,3-benzo dioxole-5-yl)-1-((2,6-two bromos) phenyl amino carbonyl methyl)-tetramethyleneimine-3-carboxylic acid
Prepare title compound by embodiment 1 described method. 1H?NMR(300MHz，CDCl 3)δ?8.58(1H，bs)，7.58(2H，d，J＝9Hz)，7.40(2H，bd，J＝10Hz)，7.02(1H，t，J＝9Hz)，6.91(2H，d，J＝9Hz)，6.86(1H，m)，6.76(1H，d，J＝9Hz)，5.93(2H，s)，3.98(1H，bd，J＝10Hz)，3.81(3H，s)，3.73(2H，m)，3.55(1H，bd，J＝15Hz)，3.13(2H，m)，3.01(1H，bd，J＝18Hz)。MS(DCl，NH 3)m/e?633(MH +)。C 27H 24Br 2N 2O 6.0.3H 2The analytical calculation value of O: C, 50.85, H, 3.89, N, 4.39.Measured value: C, 50.45, H, 3.48, N, 4.22.
Embodiment 15
[2R, 3R, 4S] 2-(4-p-methoxy-phenyl)-4-(1,3-benzo dioxole-5-yl)-1-(N-(2, the 6-diethyl) phenyl amino carbonyl methyl)-tetramethyleneimine-3-carboxylic acid, hydrochloride
Embodiment 15A-E
Instead, another preparation method of anti--2-(4-p-methoxy-phenyl)-4-(1,3-benzo dioxole-5-yl)-tetramethyleneimine-3-carboxylic acid, ethyl ester
Embodiment 15A
5-(2-nitroethylene base)-1,3-benzo dioxole
Under nitrogen and mechanical stirring, to piperonylaldehyde (15.55kg, 103.5mol) in order add ammonium acetate (13.4kg, 173.8mol), acetate (45.2kg) and Nitromethane 99Min. (18.4kg, 301.4mol).Make this mixture be warmed to 70 ℃.After about 30 minutes, the beginning crystallization goes out yellow product.Temperature of reaction rises to 80 ℃, 10 hours piperonylaldehydes until the reservation minute quantity of stir about.Make some heavy-gravity reaction mixture be cooled to 10 ℃ and filtration.With acetate (2 * 8kg) and water (2 * 90kg) washing precipitates successively.Dry this product under purging with nitrogen gas in 50 ℃ of vacuum ovens dry 2 days then, obtains 15.94kg (80%) glassy yellow solid title compound.
Embodiment 15B
(4-anisoyl) ethyl acetate
Under nitrogen and mechanical stirring, with 1 hour with 4-methoxyacetophenone (6.755kg, 44.98mol) and diethyl carbonate (6.40kg, 54.18mol) toluene in mixture add uncle-valeric acid potassium (potassium the t-amylate) (25wt% be cooled to 5 ℃, 50.8kg, 99.26mol) toluene (15.2kg) solution in, simultaneously holding temperature is lower than 10 ℃.With reaction mixture be heated to 60 ℃ 8 hours until can not detect the 4-methoxyacetophenone through HPLC.This mixture is cooled to 20 ℃, with quenching in the mixture that added to acetate (8kg) and water (90kg) in 30 minutes, Wei Wendu＜20 ℃ simultaneously.Separate each layer, wash organic layer and be concentrated into 14.65kg with 5% sodium hydrogen carbonate solution (41kg).Holding temperature is lower than 50 ℃ during the distillation.Analyze xanchromatic product enriched material, yield 9.40kg (94%) by HPLC with respect to external perimysium reference.
Embodiment 15C
2-(4-anisoyl)-4-nitro methyl-3-(1,3-benzo dioxole-5-yl) ethyl butyrate
Under nitrogen and mechanical stirring, the compound that will from last embodiment 15B, obtain (8.4kg, 37.9mol) add the compound that derives from embodiment 15A be suspended among the THF (56kg) (7.5kg, 37.9mol) in.This mixture is cooled to 17 ℃, and (6.4g 0.095mol), and stirred this reactant 30 minutes to add sodium ethylate.After about 15 minutes, nitrostyrolene dissolves fully.(6.4g 0.095mol), stirs this mixture in 25 ℃ and shows that until HPLC remaining ketone ester is lower than 1% (area) to add sodium ethylate.This reactant is concentrated into 32.2kg, is about 14.9kg (95%) through the HPLC detection.
Embodiment 15D
Suitable, suitable-2-(4-p-methoxy-phenyl)-4-(1,3-benzo dioxole-5-yl)-tetramethyleneimine-3-carboxylic acid, ethyl ester
Raney nickel (20.0g) (therefrom the water decant being gone out) adding is equipped with in hydrogenator thermopair, that stir.The order add THF (20ml), derive from embodiment 15C crude product (40.82g, 0.0482mol) and acetate (2.75ml, 0.0482mol).Place under the 60psi hydrogen this mixture significantly slack-off until absorption of hydrogen.Add TFA, the hydrogenation under 200psi of this mixture is shown do not have remaining imines and nitrone less than 2% (area) until HPLC.The elimination catalyzer is also used the 100ml methanol wash.Measure filtrate through HPLC, find to contain suitable, the suitable-pyrrolidine compound of 13.3g (yield 75%).Concentrated filtrate is also handled (chased) with other THF (200ml) and is obtained final volume 100ml.With 2N sodium hydroxide solution (50ml) this mixture that neutralizes, water (200ml) dilution is with ethyl acetate (2 * 100ml) extractions.Ethyl acetate layer by the HPLC merging almost colourless with respect to the external perimysium reference analysis is the title compound of 13.0g (73%).
Embodiment 15E
Instead, anti--2-(4-p-methoxy-phenyl)-4-(1,3-benzo dioxole-5-yl)-tetramethyleneimine-3-carboxylic acid, ethyl ester
With ethanol (200ml) will derive from embodiment 15D compound (38.1g 0.103mol) handles final volume to 100ml, add sodium ethylate (3.40g, 0.050mol).With this mixture heating up to 75 ℃.When HPLC shows remaining suitablely,, make this mixture be cooled to room temperature along isomer＜3% o'clock.Analyze this product by HPLC with respect to external perimysium reference, find to contain the title compound of 34.4g (yield 90%).Concentrate the solution of crude product and residue is dissolved in the isopropyl acetate (400ml).(2 * 150ml) washing organic layers, (2 * 400ml) extract water to use the 0.25M phosphoric acid solution then.Stir the phosphate layer that merges with ethyl acetate (200ml), (21g) is neutralized to pH7 with solid sodium bicarbonate.Separate organic layer and find to contain 32.9g (87%) title compound.
Embodiment 15F
[2R, 3R, 4S] 2-(4-p-methoxy-phenyl)-4-(1,3-benzo dioxole-5-yl)-tetramethyleneimine-3-carboxylic acid, ethyl ester
The racemic amino esters (32.9g) that derives from embodiment 1 is dissolved in the 50ml acetonitrile.Add (S)-(+)-amygdalic acid (2.06g, 0.0136mmol) and make it dissolving.Inoculating this mixture with described product also at room temperature stirred 16 hours.Make this reaction mixture be cooled to 0 ℃ and stirred 5 hours.Filter this product and under nitrogen wash in vacuum oven in 50 ℃ of dryings 1 day.(20.0g 0.0383mol) is suspended in ethyl acetate (150ml) and 5% sodium hydrogen carbonate solution (150ml) to make the salt of generation.Stirring this mixture under room temperature stops to produce until salt dissolving and carbonic acid gas.Separate organic layer and concentrated.
Embodiment 15G
[2R, 3R, 4S] 2-(4-p-methoxy-phenyl)-4-(1,3-benzo dioxole-5-yl)-1-(N-(2, the 6-diethyl) phenyl amino carbonyl methyl)-tetramethyleneimine-3-carboxylic acid
According to the method for embodiment 1E, by the compound title compound of embodiment 15F.
Embodiment 15H
[2R, 3R, 4S] 2-(4-p-methoxy-phenyl)-4-(1,3-benzo dioxole-5-yl)-1-(N-(2, the 6-diethyl) phenyl amino carbonyl methyl)-tetramethyleneimine-3-carboxylic acid, hydrochloride
The compound (450mg) of embodiment 15G is dissolved in the 10ml Virahol.Add the excessive slightly saturated HCl solution in ethanol, the solution that stirring generates 10 minutes.Vacuum evaporating solvent is driven excessive HCl with Virahol.Residue is dissolved in the ether and filters, and stays the title compound 448mg into white solid.MS(DCl/NH 3)m/e?531(M+H +)。C 31H 35N 2O 6The analytical calculation value of Cl: C, 65.66, H, 6.22, N, 4.94.Measured value: C, 65.72, H, 6.39; N, 4.65.
Embodiment 16
Instead, anti--2-(4-p-methoxy-phenyl)-4-(1,3-benzo dioxole-5-yl)-1-((2, the 6-dimethoxy) phenyl amino carbonyl methyl)-tetramethyleneimine-3-carboxylic acid
Embodiment 16A
Under room temperature, to 2, the 6-dimethoxybenzoic acid (2.00g, 11.0mmol) 1, in the stirred solution of 2-ethylene dichloride (45ml) order add N-methylmorpholine (1.45ml, 13.2mmol) and the diphenylphosphine acyl azide (2.60ml, 12.1mmol).With this mixture in 75 ℃ of heating after 2 hours, add cuprous iodide (150mg) and benzyl alcohol (2.27ml, 22.0mmol) and continue heated overnight.Solvent removed in vacuo, residue obtain intermediate carbamate (1.50g, yield 48%) through silica gel column chromatography with hexane-eluent ethyl acetates of 4: 1, are white crystalline solid.Be dissolved in this solid in the methyl alcohol (15ml) and join in the flask of the usefulness purging with nitrogen gas that contains 10% palladium charcoal (500mg).Place this mixture under the hydrogen-pressure and under room temperature, stirred 4 hours.Filter this mixture by Celite pad, solvent removed in vacuo obtains title compound (800mg, yield 48%).
Embodiment 16B
Instead, anti--2-(4-p-methoxy-phenyl)-4-(1,3-benzo dioxole-5-yl)-1-((2, the 6-dimethoxy) phenyl amino carbonyl methyl)-tetramethyleneimine-3-carboxylic acid
Prepare title compound by embodiment 1 described method, with the 2 among the compound replacement embodiment 1D of embodiment 16A. 1H?NMR(300MHz，CDCl 3)δ?8.18(1H，bs)，7.39(2H，bd，J＝9Hz)，7.17(1H，t，J＝9Hz)，6.99(1H，d，J＝2Hz)，6.90(2H，d，J＝9Hz)，6.86(1H，d，J＝2Hz)，6.75(1H，d，J＝9Hz)，6.56(2H，d，J＝9Hz)，5.93(2H，s)，3.88(1H，bd，J＝10Hz)，3.81(3H，s)，3.71(6H，s)，3.70(2H，m)，3.49(1H，bd，J＝15Hz)，3.03(2H，m)，2.85(1H，bd，J＝18Hz)。NMR(DCl，NH 3)m/e535(MH +)。C 29H 30N 2O 8.0.75AcOH analytical calculation value: C, 63.20, H, 5.74, N, 4.83.Measured value: C, 63.18, H, 5.34, N, 4.79.
Embodiment 17
Instead, anti--2-(4-p-methoxy-phenyl)-4-(1,3-benzo dioxole-5-yl)-1-((4-bromo-2,6-diethyl) phenyl amino carbonyl methyl)-tetramethyleneimine-3-carboxylic acid
Embodiment 17A
4-bromo-2, the 6-Diethyl Aniline
Under room temperature, (10.4ml 201mmol) adds 2, and (10.0g is in the stirred solution of acetate 67.0mmol) (50ml) for the 6-Diethyl Aniline with bromine.Stirring this reactant under room temperature spends the night.With ether (200ml) diluted reaction mixture and with 5% sodium bisulfite (4 * 50ml) with the salt acid elution.With dried over sodium sulfate organic phase and solvent removed in vacuo.Residue is through silica gel column chromatography, and with 9: 1 hexane: eluent ethyl acetate obtained title compound (3.28g, yield 21%).
Embodiment 17B
Instead, anti--2-(4-p-methoxy-phenyl)-4-(1,3-benzo dioxole-5-yl)-1-((4-bromo-2,6-diethyl) phenyl amino carbonyl methyl)-tetramethyleneimine-3-carboxylic acid
Prepare title compound by embodiment 1 described method, with the 2 among the compound replacement embodiment 1D of embodiment 17A. 1H?NMR(300MHz，CDCl 3)δ?8.21(1H，bs)，7.38(2H，d，J＝9Hz)，7.23(2H，s)，6.92(2H，d，J＝9Hz)，6.88(1H，d，J＝2Hz)，6.82(1H，dd，J＝8&2Hz)，6.75(1H，d，J＝9Hz)，5.93(1H，d，J＝2Hz)，5.91(1H，d，J＝2Hz)，3.95(1H，d，J＝9Hz)，3.82(3H，s)，3.72(1H，m)，3.52(1H，m)，3.45(1H，d，J＝18Hz)，3.14(2H，m)，3.00(1H，d，J＝18Hz)，2.39(4H，q，J＝9Hz)，1.07(6H，t，J＝9Hz)。MS(DCl，NH 3)m/e?609(MH +)。C 31H 33BrN 2O 6The analytical calculation value: C, 61.09, H, 5.46, N, 4.60.Measured value: C, 60.80, H, 5.35, N, 4.54.
Embodiment 18
Instead, anti--2-(4-p-methoxy-phenyl)-4-(1,3-benzo dioxole-5-yl)-1-((2-ethyl-6-methyl) phenyl amino carbonyl methyl)-tetramethyleneimine-3-carboxylic acid
Prepare title compound by embodiment 1 described method. 1H?NMR(300MHz，CDCl 3)δ8.32(1H，bs)，7.38(2H，d，J＝9Hz)，7.20-7.10(3H，m)，6.92(2H，d，J＝9Hz)，6.87(1H，d，J＝2Hz)，6.82(1H，dd，J＝8&2Hz)，6.76(1H，d，J＝9Hz)，5.94(1H，d，J＝2Hz)，5.92(1H，d，J＝2Hz)，3.95(1H，d，J＝9Hz)，3.82(3H，s)，3.73(1H，m)，3.55(1H，dd，J＝12&6Hz)，3.47(1H，d，J＝18Hz)，3.14(2H，m)，3.02(1H，d，J＝18Hz)，2.44(2H，q，J＝9Hz)，2.10(3H，s)，1.10(3H，t，J＝9Hz)。MS(DCl，NH 3)m/e?517(MH +)。C 30H 32N 2O 6.0.5H 2The analytical calculation value of O: C, 68.56, H, 6.33, N, 5.33.Measured value: C, 68.58, H, 6.29, N, 5.13.
Embodiment 19
Instead, anti--2-(4-p-methoxy-phenyl)-4-(1,3-benzo dioxole-5-yl)-1-((2,4, the 6-triethyl) phenyl amino carbonyl methyl)-tetramethyleneimine-3-carboxylic acid
Embodiment 19A
Instead, anti--2-(4-p-methoxy-phenyl)-4-(1,3-benzo dioxole-5-yl)-1-((2,4, the 6-triethyl) phenyl amino carbonyl methyl)-tetramethyleneimine-3-carboxylic acid, ethyl ester
Under room temperature; will be anti-; instead-2-(4-p-methoxy-phenyl)-4-(1; 3-benzo dioxole-5-yl)-1-((4-bromo-2; 6-diethyl phenyl) amino carbonyl methyl)-tetramethyleneimine-3-carboxylic acid, ethyl ester (200mg; 0.314mmol; by embodiment 17 preparation) anhydrous tetrahydro furan (8ml) solution add [1; 1 '-two (diphenylphosphine acyl group) ferrocene] dichloro palladium (II) (with 1: 1 mixture of methylene dichloride) is (13mg) and cesium carbonate (307mg; 0.942mmol) at anhydrous N, in the mixture (using purging with nitrogen gas) in the dinethylformamide (2ml).After stirring 10 minutes under the room temperature, be added in 1.0M triethyl borate in the tetrahydrofuran (THF) (0.471ml, 0.471mmol).Stirring this reactant in 65 ℃ under the nitrogen spends the night.With ethyl acetate (100ml) diluted reaction mixture and water (2 * 30ml) and the salt water washing.Use the dried over sodium sulfate organic phase, solvent removed in vacuo.Residue is through silica gel column chromatography, and with 3: 1 hexane: eluent ethyl acetate obtained title compound (110mg, yield 60%).
Embodiment 19B
Instead, anti--2-(4-p-methoxy-phenyl)-4-(1,3-benzo dioxole-5-yl)-1-((2,4, the 6-triethyl) phenyl amino carbonyl methyl)-tetramethyleneimine-3-carboxylic acid
Prepare title compound by the described method of embodiment 1E. 1H?NMR(300MHz，CDCl 3)δ8.22(1H，bs)，7.38(2H，d，J＝9Hz)，6.95(2H，s)，6.91(2H，d，J＝9Hz)，6.84(1H，d，J＝2Hz)，6.82(1H，dd，J＝8&2Hz)，6.75(1H，d，J＝9Hz)，5.93(1H，d，J＝2Hz)，5.91(1H，d，J＝2Hz)，3.95(1H，d，J＝10Hz)，3.82(3H，s)，3.71(1H，m)，3.52(1H，dd，J＝9&2Hz)，3.46(1H，d，J＝18Hz)，3.13(2H，m)，3.00(1H，d，J＝18Hz)，2.60(2H，q，J＝9Hz)，2.40(4H，q，J＝9Hz)，1.22(3H，t，J＝9Hz)，1.08(6H，t，J＝9Hz)。MS(DCl，NH 3)m/e?559(MH +)。C 33H 38N 2O 6.0.25H 2The analytical calculation value of O: C, 70.38, H, 6.89, N, 4.97.Measured value: C, 70.18, H, 7.14, N, 4.63.
Embodiment 20
[2R, 3R, 4S] 2-(4-propoxy-phenyl)-4-(1,3-benzo dioxole-5-yl)-1-(N-((2, the 6-diethyl) phenyl amino carbonyl methyl)-tetramethyleneimine-3-carboxylic acid
Embodiment 20A
[2R, 3R, 4S] 2-(4-propoxy-phenyl)-4-(1,3-benzo dioxole-5-yl)-uncle 1--butoxy carbonyl-tetramethyleneimine-3-carboxylic acid
The racemic amino esters (8.00g) that derives from embodiment 3 is mixed in 100ml THF with the 4.45g tert-Butyl dicarbonate; Add the 10ml triethylamine, and with room temperature under stirred the solution that generates 3 hours.Solvent removed in vacuo; Residue is dissolved among the EtOAc also with 1N phosphate aqueous solution, supercarbonate (bicarb.) and the washing of salt solution order.Crude product is dissolved in the 30ml ethanol; Add 12ml 2.5N sodium hydroxide solution, under room temperature, stir this mixture overnight, be warmed to then 50 ℃ 2 hours.Solvent removed in vacuo is distributed residue between water and ether.Also use the EtOAc extracting twice with 1N phosphate aqueous solution acidifying aqueous extract.With salt water washing organic extract and to obtain 9.2g with dried over sodium sulfate anti-, anti--2-(4-propoxy-phenyl)-4-(1,3-benzo dioxole-5-yl)-1-tert-butoxycarbonyl-tetramethyleneimine-3-carboxylic acid.This material is dissolved among the 30mlEtOAc, adds 1.3ml (R)-(+)-Alpha-Methyl benzylamine.Stirred this solution 10 minutes; Solvent removed in vacuo adds the 50ml ether, the solution that inoculation generates.After the standing over night, solvent removed in vacuo; Make residue be dissolved in the 70ml ether and filtration.Make solid product recrystallization from the EtOAc/ ether.This crystalline material of vigorous stirring in the two-phase mixture of 1N phosphoric acid and EtOAc; Inclining organic layer, uses the salt water washing then and through dried over sodium sulfate.
Embodiment 20B
[2R, 3R, 4S] 2-(4-propoxy-phenyl)-4-(1,3-benzo dioxole-5-yl)-tetramethyleneimine-3-carboxylic acid, ethyl ester
The compound of embodiment 20A is dissolved in the ethanol and in ice bath cools off.Feed gaseous state HCl until saturated to this solution; The solution that generates is warmed to room temperature and under nitrogen, stirs and spend the night.Solvent removed in vacuo; Make residue be dissolved in the supercarbonate and use ethyl acetate extraction.Inclining organic layer, uses the salt water washing then and through dried over sodium sulfate.
Embodiment 20C
[2R, 3R, 4S] 2-(4-propoxy-phenyl)-4-(1,3-benzo dioxole-5-yl)-1-(N-(2,6-diethyl phenyl) amino carbonyl methyl)-tetramethyleneimine-3-carboxylic acid
According to the method for embodiment 1E compound title compound by embodiment 20B.MS(DCl/NH 3)m/e?559(M+H +)。C 33H 38N 2O 6.0.2H 2The analytical calculation value of O: C, 70.49, H, 6.88, N, 4.98.Measured value: C, 70.52, H, 6.78, N, 4.85.
Embodiment 21
Instead, anti--2-(4-p-methoxy-phenyl)-4-(1,3-benzo dioxole-5-yl)-1-((2, the 6-di-isopropyl) phenyl amino carbonyl methyl)-tetramethyleneimine-3-carboxylic acid
Prepare title compound by embodiment 1 described method. 1H?NMR(300MHz，CDCl 3)δ8.29(1H，bs)，7.39(2H，d，J＝9Hz)，7.29(1H，m)，7.15(2H，d，J＝9Hz)，6.93(2H，d，J＝9Hz)，6.85(1H，d，J＝2Hz)，6.83(1H，dd，J＝8&2Hz)，6.74(1H，d，J＝9Hz)，5.93(1H，d，J＝2Hz)，5.91(1H，d，J＝2Hz)，3.96(1H，d，J＝10Hz)，3.83(3H，s)，3.73(1H，m)，3.55(1H，dd，J＝12&6Hz)，3.50(1H，d，J＝18Hz)，3.14(2H，m)，3.01(1H，d，J＝18Hz)，2.84(2H，m)，1.16(6H，d，J＝8Hz)，1.05(6H，d，J＝8Hz)。MS(DCl，NH 3)m/e?559(MH +)。C 33H 38N 2O 6.0.5H 2The analytical calculation value of O: C, 69.82, H, 6.92, N, 4.93.Measured value: C, 69.69, H, 6.63, N, 4.89.
Embodiment 22
Instead, anti--2-(4-p-methoxy-phenyl)-4-(1,3-benzo dioxole-5-yl)-1-((2,6-diethyl-4-methyl) phenyl amino carbonyl methyl)-tetramethyleneimine-3-carboxylic acid
Prepare title compound by embodiment 19 described methods. 1H?NMR(300MHz，CDCl 3)δ8.20(1H，bs)，7.38(2H，d，J＝9Hz)，6.92(4H，m)，6.86(1H，d，J＝2Hz)，6.82(1H，dd，J＝8&2Hz)，6.75(1H，d，J＝9Hz)，5.93(1H，d，J＝2Hz)，5.91(1H，d，J＝2Hz)，3.95(1H，d，J＝10Hz)，3.81(3H，s)，3.72(1H，m)，3.55(1H，dd，J＝9&2Hz)，3.45(1H，d，J＝18Hz)，3.13(2H，m)，3.00(1H，d，J＝18Hz)，2.39(4H，q，J＝9Hz)，2.28(3H，s)，1.07(6H，t，J＝9Hz)。NMR(DCl，NH 3)545?m/e(MH +)。C 32H 36N 2O 6.0.5H 2The analytical calculation value of O: C, 69.42, H, 6.74, N, 5.06.Measured value: C, 69.43, H, 6.57, N, 4.94.
Embodiment 23
[2R, 3R, 4S]-2-(4-ethoxyl phenenyl)-4-(1,3-benzo dioxole-5-yl)-1-((2, the 6-diethyl) phenyl amino carbonyl methyl)-tetramethyleneimine-3-carboxylic acid
According to the method for embodiment 20, prepare title compound by the racemic amino esters of embodiment 10. 1H?NMR(300MHz，CDCl 3)δ8.32(1H，bs)，7.38(2H，d，J＝9Hz)，7.21(1H，m)，7.12(2H，d，J＝10Hz)，6.90(3H，m)，6.83(1H，dd，J＝8&2Hz)，6.74(1H，d，J＝9Hz)，5.94(1H，d，J＝2Hz)，5.92(1H，d，J＝2Hz)，4.05(2H，m)，3.96(1H，d，J＝10Hz)，3.72(1H，m)，3.53(1H，dd，J＝10&3Hz)，3.47(1H，d，J＝18Hz)，3.13(2H，m)，3.02(1H，d，J＝18Hz)，2.44(4H，q，J＝9Hz)，1.42(3H，t，J＝9Hz)，1.08(6H，t，J＝9Hz)。MS(DCl，NH 3)m/e?545(MH +)。C 32H 36N 2O 6.0.5H 2The analytical calculation value of O: C, 69.42, H, 6.74, N, 5.06.Measured value: C, 69.67, H, 6.73, N, 4.98.
Embodiment 24
Instead, anti--2-(4-p-methoxy-phenyl)-4-(1,3-benzo dioxole-5-yl)-1-((4-carboxyl-2,6-diethyl) phenyl amino carbonyl methyl)-tetramethyleneimine-3-carboxylic acid
Prepare title compound by embodiment 19 described methods. 1H?NMR(300MHz，DMSO)δ7.68(2H，bs)，7.54(2H，d，J＝9Hz)，7.27(2H，m)，6.93(2H，d，J＝9Hz)，6.83(2H，m)，5.98(2H，s)，3.92(1H，d，J＝9Hz)，3.76(3H，s)，3.62(1H，m)，3.45-3.00(2H，m)，3.00-2.80(3H，m)，2.44(4H，q，J＝9Hz)，1.04(6H，t，J＝9Hz)。NMR(DCl，NH 3)m/e?575(MH +)。C 32H 34N 2O 8.0.5H 2The analytical calculation value of O: C, 65.85, H, 6.04, N, 4.80.Measured value: C, 66.03, H, 5.84, N, 4.67.
Embodiment 25
Instead, anti--2-(4-p-methoxy-phenyl)-4-(1,3-benzo dioxole-5-yl)-1-((4-nitro-2,6-diethyl) phenyl amino carbonyl methyl)-tetramethyleneimine-3-carboxylic acid
Embodiment 25A
2,6-diethyl-4-N-methyl-p-nitroaniline
In 0 ℃, (15.9M, 2.10ml 34mmol) are added drop-wise to 2, and (5.0g is in the stirred solution of vitriol oil 34mmol) (30ml) for the 6-Diethyl Aniline with concentrated nitric acid.Remove cryostat, under room temperature, stirred this reactant 3 hours.After in the reaction mixture impouring ice, neutralize this solution also with methylene dichloride (3 * 50ml) extractions with 4N sodium hydroxide.Use the dried over sodium sulfate extract, and solvent removed in vacuo, title compound obtained.
Embodiment 25B
Instead, anti--2-(4-p-methoxy-phenyl)-4-(1,3-benzo dioxole-5-yl)-1-((4-nitro-2,6-diethyl) phenyl amino carbonyl methyl)-tetramethyleneimine-3-carboxylic acid
Prepare title compound by embodiment 1 described method, with the 2 among the compound replacement embodiment 1D of embodiment 25A. 1H?NMR(300MHz，CDCl 3)δ8.38(1H，bs)，7.77(1H，d，J＝9Hz)，7.38(2H，d，J＝9Hz)，7.24(1H，d，J＝9Hz)，6.92(2H，d，J＝9Hz)，6.88(1H，d，J＝2Hz)，6.82(1H，dd，J＝8&2Hz)，6.75(1H，d，J＝9Hz)，5.93(1H，d，J＝2Hz)，5.91(1H，d，J＝2Hz)，3.97(1H，d，J＝9Hz)，3.83(3H，s)，3.74(1H，m)，3.48(2H，m)，3.18(2H，m)，3.04(1H，d，J＝18Hz)，2.63(2H，m)，2.44(2H，q，J＝9Hz)，1.10(3H，t，J＝9Hz)，1.08(3H，t，J＝9Hz)。MS(DCl，NH 3)m/e?576(MH +)。C 31H 33N 3O 8.0.75H 2The analytical calculation value of O: C, 63.20, H, 5.90, N, 7.13.Measured value: C, 63.30, H, 5.81, N, 7.14.
Embodiment 26
Instead, anti--2-(4-p-methoxy-phenyl)-4-(1,3-benzo dioxole-5-yl)-1-((2-sec.-propyl-6-methyl) phenyl amino carbonyl methyl)-tetramethyleneimine-3-carboxylic acid
Prepare title compound by embodiment 1 described method. 1H?NMR(300MHz，CDCl 3)δ8.35(1H，bs)，7.39(2H，d，J＝9Hz)，7.18(2H，m)，7.07(1H，dd，J＝9&2Hz)，6.92(2H，d，J＝9Hz)，6.86(1H，d，J＝2Hz)，6.82(1H，dd，J＝8&2Hz)，6.75(1H，d，J＝9Hz)，5.94(1H，d，J＝2Hz)，5.92(1H，d，J＝2Hz)，3.96(1H，d，J＝10Hz)，3.83(3H，s)，3.72(1H，m)，3.50(2H，m)，3.15(2H，m)，3.02(1H，d，J＝18Hz)，2.86(1H，m)，2.09(3H，s)，1.16(3H，d，J＝8Hz)，1.07(3H，d，J＝8Hz)。MS(DCl，NH 3)m/e531(MH +)。C 31H 34N 2O 6.0.5H 2The analytical calculation value of O: C, 69.00, H, 6.54, N, 5.19.Measured value: C, 69.27, H, 6.67, N, 5.21.
Embodiment 27
Instead, anti--2-(4-p-methoxy-phenyl)-4-(1,3-benzo dioxole-5-yl)-1-(N-(2-ethyl-6-methoxyl group) phenyl amino carbonyl methyl)-tetramethyleneimine-3-carboxylic acid
Embodiment 27A
3-oxo-4-(3-methoxyl group-2-nitrophenyl) ethyl propionate
Ethyl malonic acid potassium (3.68g) is mixed in 12ml DMF with the 2.29g magnesium chloride; Reaction mixture was heated 4 hours in 60 ℃.The mixture that generates is cooled to room temperature.3-methoxyl group-2-nitrobenzoic acid (3.4g) is dissolved among the 12ml DMF; Add 3.06g 1,1-carbonyl dimidazoles (disengaging gas) after stirring 4 hours under the room temperature, joins the solution that generates in the mixture of malonate.The slurry that stirring generates under room temperature 14 hours.Solvent removed in vacuo; Residue is dissolved in the ethyl acetate, order 1N phosphoric acid, supercarbonate and salt water washing, and vacuum concentration.
Embodiment 27B
2-nitro-3-(1-hydroxyethyl) methyl-phenoxide
Be dissolved in the compound (3.2g) of embodiment 27A in the 50ml vitriol oil and under room temperature, stirred 48 hours.Reaction mixture is poured in the 300ml ice and with twice of ethyl acetate extraction.Order water, supercarbonate and salt water washing organic extract, and vacuum concentration.This crude product was heated 3 hours in about 160 ℃.Dark-brown residue with the ethyl acetate extraction generation.Concentrate organic extraction.Crude product is dissolved in the 15ml ethanol; Add sodium borohydride (450mg), the solution that stirring generates under room temperature 2 hours.Solvent removed in vacuo; Make residue be dissolved in the 10%HCl aqueous solution and stirred 15 minutes.With this mixture of ethyl acetate extraction; Order supercarbonate and salt water washing organic extract, and vacuum concentration.Crude product, obtains 1.08g (total recovery 32%) and is the title compound of colorless oil with 1: 1 ethyl acetate/hexane wash-out through the flash chromatography on silica gel purifying.
Embodiment 27C
2-ethyl-6-anisidine
The compound (310mg) of embodiment 27B is dissolved among the 10ml THF; Add 1.5ml phosphoric acid, then add the palladium charcoal of 50mg 10%.Mixture with purging with nitrogen gas generates places under the hydrogen then, and stirring is spent the night.Carefully add supercarbonate, and filter this mixture by Celite pad.Use ethyl acetate extraction filtrate; With supercarbonate and salt water washing organic extraction, and vacuum concentration.Crude product through the flash chromatography on silica gel purifying, with 1: 1 ether/hexane wash-out, is obtained the title compound 102mg (yield 43%) into colorless oil.
Embodiment 27D
Instead, anti--2-(4-p-methoxy-phenyl)-4-(1,3-benzo dioxole-5-yl)-1-(N-(2-ethyl-6-methoxyl group) phenyl amino carbonyl methyl)-tetramethyleneimine-3-carboxylic acid
Prepare title compound by the described method of embodiment, with the compound replacement 2 of embodiment 27C. 1H?NMR(300MHz，CD 3OD)δ1.10(t，J＝8Hz，3H)，2.48(d，J＝8Hz，2H)，3.4-3.9(m，7H)，3.73(s，3H)，3.84(s，3H)，5.93(s，2H)，6.80(d，J＝8Hz，1H)，6.86(d，J＝8Hz，2H)，6.93(dd，J＝2.8Hz，1H)，7.03(bd?d，J＝9Hz，2H)，7.07(d，J＝2Hz，1H)，7.23(t，J＝8Hz，1H)，7.53(bd?d，J＝9Hz，2H)。MS(APCl)m/e?533(M+H +)。C 30H 32N 2O 7.0.7TFA analytical calculation value: C, 61.59, H, 5.38, N, 4.57.Measured value: C, 61.27, H, 5.44, N, 4.61.
Embodiment 28
Instead, anti--2-(4-isopropyl phenyl)-4-(1,3-benzo dioxole-5-yl)-1-(2,6-diethyl phenyl amino carbonyl methyl)-tetramethyleneimine-3-carboxylic acid
Prepare title compound by embodiment 1 described method. 1H NMR (300MHz, CDCl 3) δ 7.51 (2H, bd d, J=9Hz), 7.22 (1H, dd, J=8,9Hz), 7.13 (1H, s), 7.11 (1H, dd, J=1,8Hz), 7.05 (1H, d, J=2Hz), 6.99 (2H, bd d, J=9Hz), 6.91 (1H, dd, J=2,8Hz), 6.78 (1H, d, J=8Hz), 5.93 (1H, d, J=3Hz), 5.92 (1H, d, J=3Hz), 4.64 (1H, septet, J=7Hz), 3.80 (3H, m), 3.55 (2H, m), 2.47 (4H, q, J=7Hz), 1.33 (6H, dd, J=2,7Hz), 1.09 (6H, t, J=7Hz).MS(ESI+)m/e?559(M+H +)。C 33H 38N 2O 6.0.7TFA analytical calculation value: C, 64.71, H, 6.11, N, 4.39.Measured value: C, 64.54, H, 5.78, N, 4.21.
Embodiment 29
Instead, anti--2-(2-fluoro-4-propoxy-phenyl)-4-(1,3-benzo dioxole-5-yl)-1-(2,6-diethyl phenyl amino carbonyl methyl)-tetramethyleneimine-3-carboxylic acid
Prepare title compound by embodiment 1 described method. 1H?NMR(300MHz，CDCl 3)δ1.06(t，3H，J＝7Hz)，1.09(t，6H，J＝7Hz)，1.83(m，2H)，2.44(q，4H，J＝7Hz)，3.4-3.9(m，5H)，3.99(t，2H，J＝6Hz)，5.95(dd，2H，J＝1,2Hz)，6.8-6.9(m，4H)，7.03(d，1H，J＝2Hz)，7.11(d，1H，J＝8Hz)，7.13(s，1H)，7.22(dd，1H，J＝7,9Hz)，7.63(t，1H，J＝9Hz)。MS(ESI+)m/e?577(M+H +)。C 33H 37N 2O 6F.1.0TFA analytical calculation value: C, 60.87, H, 5.55, N, 4.06.Measured value: C, 60.74, H, 5.61, N, 3.97.
Embodiment 30
Instead, anti--2-(4-(2-methoxy ethoxy) phenyl)-4-(1,3-benzo dioxole-5-yl)-1-(2,6-diethyl phenyl amino carbonyl methyl)-tetramethyleneimine-3-carboxylic acid
Prepare title compound by embodiment 1 described method. 1H?NMR(300MHz，CDCl 3)δ1.08(t，J＝7Hz，6H)，2.43(q，J＝7Hz，4H)，3.00(d，J＝11Hz，1H)，3.05-3.15(m，2H)，3.44(s，3H)，3.46(d，J＝11Hz，1H)，3.45-3.55(m，1H)，3.65-3.75(m，1H)，3.75-3.80(m，2H)，3.93(d，J＝7Hz，1H)，4.12-4.17(m，2H)，5.94(dd，J＝2Hz，4Hz，2H)，6.75(d，J＝8Hz，1H)，6.82(dd，J＝2Hz，9Hz，1H)，6.87(d，J＝2Hz，1H)，6.95(d，J＝8Hz，1H)，7.10(d，J＝6Hz，2H)，7.19-7.24(m，1H)，7.37(d，d＝8Hz，2H)，8.29(s，1H)。MS(APCl+)m/e?575(M+H +)。C 33H 38N 2O 7The analytical calculation value: C, 68.97, H, 6.67, N, 4.87.Measured value: C, 68.92, H, 6.83, N, 4.77.
Embodiment 30A
[4-(2-methoxy ethoxy) benzoyl]-ethyl acetate
Make 4-methyl hydroxybenzoate and 1-bromo-2-methyl ethyl ether, and in dimethyl formamide, react with salt of wormwood.In ethanol, make the ester of generation be hydrolyzed to acid with sodium hydroxide.This acid and carbonyl dimidazoles are reacted in THF; Make the imidazoles of generation and the sylvite of monoethyl malonate, and and magnesium chloride, title compound obtained into colorless oil.
Embodiment 30B
Instead, anti--2-(4-(2-methoxy ethoxy) phenyl)-4-(1,3-benzo dioxole-5-yl)-1-(2,6-diethyl phenyl amino carbonyl methyl)-tetramethyleneimine-3-carboxylic acid
Prepare title compound by embodiment 1 described method, use aforesaid b-keto esters as raw material. 1H?NMR(300MHz，CDCl 3)δ1.08(t，J＝7Hz，6H)，2.43(q，J＝7Hz，4H)，3.00(d，J＝11Hz，1H)，3.05-3.15(m，2H)，3.44(s，3H)，3.46(d，J＝11Hz，1H)，3.45-3.55(m，1H)，3.65-3.75(m，1H)，3.75-3.80(m，2H)，3.93(d，J＝7Hz，1H)，4.12-4.17(m，2H)，5.94(dd，J＝2Hz，4Hz，2H)，6.75(d，J＝8Hz，1H)，6.82(dd，J＝2Hz，9Hz，1H)，6.87(d，J＝2Hz，1H)，6.95(d，J＝8Hz，1H)，7.10(d，J＝6Hz，2H)，7.19-7.24(m，1H)，7.37(d，d＝8Hz，2H)，8.29(s，1H)。MS(APCl+)m/e?575(M+H +)。C 33H 38N 2O 7The analytical calculation value: C, 68.97, H, 6.67, N, 4.87.Measured value: C, 68.92, H, 6.83, N, 4.77.
Adopt method described in the above embodiment to prepare the compound of the following example 31-857.
Figure A9880618400911
Figure A9880618400921
Figure A9880618400931
Figure A9880618400941
Figure A9880618400981
Figure A9880618400991
Figure A9880618401011
Figure A9880618401021
Figure A9880618401031
Figure A9880618401041
Figure A9880618401061
Figure A9880618401071
Figure A9880618401081
Figure A9880618401091
Figure A9880618401101
Figure A9880618401111
Figure A9880618401131
Figure A9880618401151
Figure A9880618401171
Figure A9880618401201
Figure A9880618401241
Figure A9880618401251
Figure A9880618401271
Figure A9880618401281
Figure A9880618401301
Figure A9880618401311
Figure A9880618401321
Figure A9880618401341
Figure A9880618401351
Figure A9880618401361
Figure A9880618401371
Figure A9880618401381
Figure A9880618401391
Figure A9880618401401
Figure A9880618401411
Figure A9880618401441
Figure A9880618401471
Figure A9880618401491
Figure A9880618401501
Figure A9880618401541
Figure A9880618401551
Figure A9880618401581
Figure A9880618401591
Figure A9880618401611
Figure A9880618401621
Figure A9880618401631
Embodiment 858
Instead, anti--2-(4-methoxyl group) phenyl-4-(1,3-benzo dioxole-5-yl)-1-((N-2,6-diethyl phenyl) aminocarboxyl) amino-tetramethyleneimine-3-carboxylic acid
Embodiment 858A
Instead, anti--2-(4-methoxyl group) phenyl-4-(1,3-benzo dioxole-5-yl)-1-amino-tetramethyleneimine-3-carboxylic acid, ethyl ester
The solution of 1.18g (10.4mmol) hydroxylamine-o-sulfonic acid in 2ml water is added 1.00g (2.71mmol) instead, and anti--2-(4-methoxyl group) phenyl-4-(1,3-benzo dioxole-5-yl)-1-tetramethyleneimine-3-carboxylic acid, ethyl ester is in the solution of 6ml acetonitrile.This uniform reaction mixture spontaneously heats up, and stirs 20 minutes, then vacuum concentration.Residue is dissolved in the 15ml ethyl acetate and (2 * 25ml) extract, and (1 * 10ml) extracts, through dried over mgso, filter and be condensed into thickness oily matter to use salt solution then with the 0.7M sodium hydrogen carbonate solution.This oily matter is the mixture of raw material tetramethyleneimine and corresponding 1-amino-pyrrolidine.This oily matter to 892mg (2.2mmol) adds 700mg (3.21mmol) two-tert.-butoxy carbonic anhydride in the solution of 10ml ethyl acetate.Under room temperature, stirred this mixture 30 minutes, then vacuum concentration.Through silica gel column chromatography, with 30% ethyl acetate/hexane wash-out, it is anti-to obtain 360mg, anti--2-(4-methoxyl group) phenyl-4-(1,3-benzo dioxole-5-yl)-1-(tert-butoxycarbonyl) amino-tetramethyleneimine-3-carboxylic acid, ethyl ester, is colorless oil.Required product is bigger slightly than the polarity of tert-butoxycarbonyl tetramethyleneimine.The 2ml trifluoroacetic acid is added in 360mg (0.768mmol) the Boc-hydrazine (hydazine).After stirring 2 hours under the room temperature, solvent removed in vacuo; Residue is dissolved in the 10ml 0.6M sodium hydrogen carbonate solution also with ethyl acetate (3 * 3ml) extractions.(1 * 3ml) returns the ethyl acetate layer of proposing merging, through dried over mgso, filters and be condensed into almost colourless oily matter 249mg with salt solution.
Embodiment 858B
Instead, anti--2-(4-methoxyl group) phenyl-4-(1,3-benzo dioxole-5-yl)-1-((N-2,6-diethyl phenyl) aminocarboxyl) amino-tetramethyleneimine-3-carboxylic acid
66mg (0.223mmol) triphosgene is joined 100mg (0.670mmol) 2, and the 6-Diethyl Aniline is at 2ml THF and 0.4ml N, in the ice-cooled solution in N-di-isopropyl-ethamine.Stirred this suspension 10 minutes in 0 ℃, it is anti-, anti--2-(4-methoxyl group) phenyl-4-(1,3-benzo dioxole-5-the yl)-1-amino-tetramethyleneimine-solution of 3-carboxylic acid, ethyl ester in 2ml THF to add 249mg (0.645mmol) then.Stir this mixture 1.5 hours, and added 20ml 0.6M sodium hydrogen carbonate solution then.(3 * 5ml) extract this suspension, through dried over mgso, filter and be condensed into beginning crystalline oily matter with ethyl acetate.It is dissolved in a spot of ethyl acetate solution.Make it crystallization, filter and obtain 108mg (30% from this hydrazine) instead, anti--2-(4-methoxyl group) phenyl-4-(1,3-benzo dioxole-5-yl)-1-((N-2,6-diethyl phenyl) aminocarboxyl) amino-tetramethyleneimine-3-carboxylic acid, ethyl ester.Described in other embodiment, this ester is hydrolyzed and obtains title compound into white solid. 1H?NMR(300MHz，d 6-DMSO)δ1.00(t，J＝7.4，6H)，2.33(brt，J＝7.0Hz，4H)，2.90(t，J＝9.9Hz，1H)，3.38-3.50(m，2H)，3.59(m，1H)，3.75(s，3H)，4.11(d，J＝10.3Hz，1H)，5.98(d，J＝0.7Hz，1H)，5.99(d，J＝1.1Hz，1H)，6.82(m，2H)，6.89(d，J＝8.4Hz，2H)，7.03(d，J＝7.0Hz，2H)，7.12(m，1H)，7.33(d，J＝1.5Hz，1H)，7.38(s，1H)，7.53(d，J＝8.8Hz，2H)，8.02(s，1H)，12.3(s，1H)。MS(CDl，m/e)532(MH +)。C 30H 33N 3O 6The analytical calculation value: C, 67.78, H, 6.26, N, 7.90.Measured value: C, 67.71, H, 6.42, N, 7.82.
Embodiment 859
[2R, 3R, 4S]-2-[4-(2-methoxy ethoxy) phenyl]-4-(1,3-benzo dioxole-5-yl)-1-(2,6-diethyl phenyl amino carbonyl methyl)-tetramethyleneimine-3-carboxylic acid
Embodiment 859A
[2R, 3S, 4S]-2-[4-(2-methoxy ethoxy) phenyl]-4-(1,3-benzo dioxole-5-yl)-tetramethyleneimine-3-carboxylic acid, ethyl ester
The anti-of embodiment 30 will be derived from, instead-2-[4-(2-methoxy ethoxy)]-4-(1,3-benzo dioxole-5-yl)-tetramethyleneimine-3-carboxylic acid, ethyl ester and tert-Butyl dicarbonate reaction, and the product water of generation is separated obtain anti-with sodium hydroxide, instead-2-[4-(2-methoxy ethyl)]-4-(1,3-benzo dioxole-5-yl)-1-(tert-butoxycarbonyl)-tetramethyleneimine-3-carboxylic acid.By splitting this acid with R-(+)-α methylbenzylamine salify.The salt that splits with the HCl solution washing is to remove out resolving agent, in ethanol, heat with HCl in 70 ℃ then and obtained [2R in 18 hours, 3S, 4S]-2-[4-(2-methoxy ethoxy)]-4-(1,3-benzo dioxole-5-yl)-tetramethyleneimine-3-carboxylic acid, ethyl ester, it through the silica gel column chromatography purifying, is used eluent ethyl acetate.
Embodiment 859B
[2R, 3S, 4S]-2-[4-(2-methoxy ethoxy) phenyl)-4-(1,3-benzo dioxole-5-yl)-1-(2,6-diethyl phenyl amino carbonyl methyl)-tetramethyleneimine-3-carboxylic acid
Prepare title compound by embodiment 30 described methods, the compound that uses embodiment 859A is as raw material. 1H?NMR(300MHz，CDCl 3)δ1.08(t，J＝7Hz，6H)，2.43(q，J＝7Hz，4H)，3.00(d，J＝11Hz，1H)，3.05-3.15(m，2H)，3.44(s，3H)，3.46(d，J＝11Hz，1H)，3.45-3.55(m，1H)，3.65-3.75(m，1H)，3.75-3.80(m，2H)，3.93(d，J＝7Hz，1H)，4.12-4.17(m，2H)，5.94(dd，J＝2Hz，4Hz，2H)，6.75(d，J＝8Hz，1H)，6.82(dd，J＝2Hz，9Hz，1H)，6.87(d，J＝2Hz，1H)，6.95(d，J＝8Hz，1H)，7.10(d，J＝6Hz，2H)，7.19-7.24(m，1H)，7.37(d，d＝8Hz，2H)，8.29(s，1H)。
Embodiment 860
Instead, anti--2-(4-(2-ethoxy ethoxy))-4-(1,3-benzo dioxole-5-yl)-1-(2,6-diethyl phenyl amino carbonyl methyl)-tetramethyleneimine-3-carboxylic acid
Prepare title compound by embodiment 30 described methods. 1H NMR (300MHz, CD 3OD) δ 1.09 (t, J=7Hz, 6H), 1.23 (t, J=7Hz, 3H), 2.47 (q, J=7Hz, 4H), 3.4-3.55 (broad peak, 2H), 3.62 (q, J=7Hz, 2H), 3.6-3.9 (broad peak, 4H), 3.82 (m, 2H), 4.16 (m, 2H), 4.4 (broad peak, 1H), 5.93 (dd, J=1Hz, 2Hz, 2H), 6.77 (d, J=8Hz, 1H), 6.90 (dd, J=2Hz, 8Hz, 1H), 7.04 (m, 3H), 7.12 (m, 2H), 7.22 (dd, J=7Hz, 9Hz, 2H), 7.44 (m, 2H).MS(ESl+)m/e589(M+H +)。C 34H 40N 2O 7.0.5TFA analytical calculation value: C, 65.11, H, 6.32, N, 4.34.Measured value: C, 64.81, H, 6.36, N, 4.25.
Embodiment 861
Instead, anti--2-(4-(2-isopropoxy oxyethyl group))-4-(1,3-benzo dioxole-5-yl)-1-(2,6-diethyl phenyl amino carbonyl methyl)-tetramethyleneimine-3-carboxylic acid
Prepare title compound by embodiment 30 described methods. 1H NMR (300MHz, CD 3OD) δ 1.10 (t, J=7Hz, 6H), 1.18 (2, J=7Hz, 6H), 2.47 (q, J=7Hz, 4H), 3.4-3.55 (broad peak, 2H), 3.6-3.9 (broad peak, 4H), 3.75 (septets, 1H, J=7Hz), 3.82 (m, 2H), 4.17 (m, 2H), 4.4-4.5 (broad peak, 1H), 5.93 (broad peak s, 2H), 6.78 (d, J=8Hz, 1H), 6.90 (dd, J=2Hz, 8Hz, 1H), 7.05 (m, 3H), 7.12 (m, 2H), 7.20 (dd, J=7Hz, 9Hz, 2H), 7.56 (m, 2H).MS(ESl+)m/e603(M+H +)。C 35H 42N 2O 7.0.6TFA analytical calculation value: C, 64.79, H, 6.40, N, 4.17.Measured value: C, 64.40, H, 6.53, N, 4.20.
Embodiment 862
Instead, anti--2-(4-(2-propoxy-))-4-(1,4-benzodioxane-6-yl)-1-(2,6-diethyl phenyl amino carbonyl methyl)-tetramethyleneimine-3-carboxylic acid
Prepare title compound by embodiment 1 described method. 1H NMR (300MHz, CD 3OD) δ 1.06 (t, J=7Hz, 3H), 1.09 (t, J=7Hz, 6H), 1.81 (m, 2H), 2.46 (q, J=7Hz, 4H), 3.3 (m, 2H), 3.4-3.5 (broad peak, 2H), 3.6-3.9 (broad peak, 4H), 3.95 (t, J=6Hz, 2H), 4.22 (s, 4H), 4.4 (broad peak, 1H), 6.80 (d, J=8Hz, 1H), 6.92 (dd, J=2Hz, 8Hz, 1H), 6.99 (m, 3H), 7.13 (m, 2H), 7.22 (dd, J=7Hz, 9Hz, 2H), 7.44 (m, 2H).MS(ESl+)m/e?573(M+H +)，595(M+Ha +)。C 34H 48N 2O 6.0.6TFA analytical calculation value: C, 65.95, H, 6.38, N, 4.37.Measured value: C, 65.83, H, 6.40, N, 4.31.
Embodiment 863
Instead, anti--2-[(4-butoxy phenyl)]-4-(1,3-benzo dioxole-5-yl)-1-(2,6-diethyl phenyl amino carbonyl methyl)-tetramethyleneimine-3-carboxylic acid
By embodiment 30 described methods, use the 1-butyl bromide to replace 1-bromo-2-methyl ethyl ether to prepare title compound. 1H?NMR(300MHz，CDCl 3)δ0.99(t，J＝7Hz，3H)，1.08(t，J＝7Hz，6H)，1.42-1.57(m，2H)，1.73-1.82(m，2H)，2.42(q，J＝7Hz，4H)，3.00(d，J＝11Hz，1H)，3.05-3.15(m，2H)，3.46(d，J＝11Hz，1H)，3.50-3.55(m，1H)，3.65-3.75(m，1H)，3.93-4.00(m，3H)，5.94(dd，J＝2Hz，4Hz，2H)，6.75(d，J＝8Hz，1H)，6.82(dd，J＝2Hz，9Hz，1H)，6.87(d，J＝2Hz，1H)，6.93(d，J＝8Hz，1H)，7.10(d，J＝7Hz，2H)，7.19-7.24(m，1H)，7.37(d，H＝8Hz，2H)，8.30(s，1H)。MS(APCl+)m/e?573(M+H +)。C 34H 40N 2O 6The analytical calculation value: C, 71.31, H, 7.04, N, 4.89.Measured value: C, 71.05, H, 7.09, N, 4.83.
Embodiment 864
Instead, anti--2-[4-{ (2-methoxy ethoxy) oxyethyl group } phenyl]-4-(1,3-benzo dioxole-5-yl)-1-(2,6-diethyl phenyl amino carbonyl methyl)-tetramethyleneimine-3-carboxylic acid
By embodiment 30 described methods, replace 1-bromo-2-methyl ethyl ether to prepare title compound with 1-bromo-2-(2-methoxy ethoxy) ethane. 1H?NMR(300MHz，CDCl 3)δ1.08(t，J＝7Hz，6H)，2.43(q，J＝7Hz，4H)，3.00(d，J＝11Hz，1H)，3.05-3.15(m，2H)，3.40(s，3H)，3.46(d，J＝11Hz，1H)，3.44-3.55(m，1H)，3.57-3.62(m，2H)，3.65-3.75(m，1H)，3.70-3.75(m，2H)，3.88(t，J＝6Hz，2H)，3.93(d，J＝7Hz，1H)，4.15(t，J＝7Hz，2H)，5.94(dd，J＝2Hz，4Hz，2H)，6.75(d，J＝8Hz，1H)，6.82(dd，J＝2Hz，9Hz，1H)，6.87(d，J＝2Hz，1H)，6.93(t，J＝8Hz，1H)，7.10(d，J＝7Hz，2H)，7.19-7.24(m，1H)，7.37(d，H＝8Hz，2H)，8.30(s，1H)。MS(APCl+)m/e?619(M+H +)。C 35H 42N 2O 8The analytical calculation value: C, 67.94, H, 6.84, N, 4.53.Measured value: C, 67.49, H, 6.90, N, 4.41.
Embodiment 865
Instead, anti--2-[(3-propoxy-phenyl)]-4-(1,3-benzo dioxole-5-yl)-1-(2,6-diethyl phenyl amino carbonyl methyl)-tetramethyleneimine-3-carboxylic acid
By embodiment 30 described methods, replace 1-bromo-2-methyl ethyl ether and replace the 4-nipagin A to prepare title compound with the 3-methyl hydroxybenzoate with 1-bromo propane. 1H?NMR(300MHz，CDCl 3)δ1.02(t，J＝7Hz，3H)，1.08(t，J＝7Hz，6H)，1.75-1.87(m，2H)，2.43(q，J＝7Hz，4H)，3.02(d，J＝11Hz，1H)，3.09-3.20(m，3H)，3.48-3.56(m，2H)，3.65-3.75(M，1H)，3.90(t，J＝7Hz，2H)，3.98(d，J＝8Hz，1H)，5.94(dd，J＝2Hz，4Hz，2H)，6.75(d，J＝8Hz，1H)，6.80-6.89(m，3H)，6.98-7.05(m，2H)，7.10(d，J＝8Hz，2H)，7.19-7.32(m，2H)，8.30(s，1H)。MS(APCl+)m/e?559(M+H +)。C 33H 38N 2O 6The analytical calculation value: C, 70.94, H, 6.86, N, 5.01.Measured value: C, 70.65, H, 6.63, N, 4.92.
Embodiment 866
Instead, anti--2-(4-(2-methoxyl group) ethyl) phenyl-4-(1,3-benzo dioxole-5-yl)-1-((N-2,6-diethyl phenyl) aminocarboxyl) methyl)-tetramethyleneimine-3-carboxylic acid
Embodiment 866A
4-(2-methoxyl group) ethyl benzoate
To be scattered in 800mg (20mmol) 60% sodium hydride in the mineral oil joins one and is equipped with in the 50ml three-necked flask of two barrier films (septa) and nitrogen capsule.With hexane (3 * 5ml) and adopt whole pipet washing and decant to remove oily matter, and keep the interior nitrogen of flask to be barotropic state.Then, add 5ml THF, cool off this suspension, add the solution of 2.01g (10.0mmol) 4-bromobenzene ethanol in 5ml THF by conduit then with ice bath.Remove ice bath, stirred this mixture 10 minutes, add 700ml (11mmol) methyl iodide then.Under room temperature, stirred this mixture 1 hour, add 1ml water then so that excessive sodium hydride quenching.In this reaction solution impouring 50ml water, (3 * 20ml) extract to use ether then.(1 * 20ml) returns the ether layer of proposing merging, through dried over mgso, filters and be condensed into 2.08g (97%) colorless oil with salt solution.With 400mg magnesium chips and I 21.03g (4.78mmol) 4-(2-methoxyl group) ethyl bromobenzene the solution among 10ml THFs of crystallization above adding in.Under nitrogen with this mixture heating up to refluxing 5 minutes, be cooled to room temperature then.Under nitrogen, Grignard reagent is moved in the 50ml 3-neck flask by syringe.Open dioxide capsule after the reaction, this moment the redness yellowly that fades very soon.After stirring 1 hour under the room temperature, this reactant of vacuum concentration.Residue is dissolved in also uses the 12M hcl acidifying to pH=1 in the 20ml water, (3 * 10ml) extract to use ether then.(3 * 5ml) return the ether layer of proposing merging, and (2 * 5ml) extract the sodium hydroxide layer that merges to use ether then with 2M sodium hydroxide.Until pH=1, (2 * 5ml) extract product to use ethyl acetate then with 12M salt acid treatment alkaline layer.(1 * 5ml) returns the ethyl acetate layer of proposing merging, through dried over mgso, filters and be condensed into 427mg (50%) 4-(2-methoxyl group) ethyl benzoate, is yellow solid with salt solution.This yellow impurity does not disturb any reaction subsequently.
Embodiment 866B
Instead, anti--2-(4-(2-methoxyl group) ethyl) phenyl-4-(1,3-benzo dioxole-5-yl)-1-((N-2,6-diethyl phenyl) aminocarboxyl) methyl-tetramethyleneimine-3-carboxylic acid
According to embodiment 1 described method preparation. 1H?NMR(300MHz，d 6-DMSO)δ1.00(t，J＝7.5Hz，6H)，2.40(q，J＝7.5Hz，4H)，2.66(t，J＝8.3Hz，1H)，2.79(t，J＝6.8Hz，2H)，2.87(d，J＝15.6Hz，1H)，3.00(t，J＝9.2Hz，1H)，3.20(d，J＝15.9Hz，1H)，3.24(s，3H)，3.42-3.47(m，1H)，3.53(t，J＝6.9Hz，1H)，3.60(m，1H)，3.91(d，J＝9.5Hz，1H)，5.94(s，2H)，6.76(d，J＝7.8Hz，1H)，6.84(dd，J＝1.4Hz，8.1Hz，1H)，7.08(d，J＝7.5Hz，2H)，7.17(d，J＝6.4Hz，3H)，7.22(d，J＝1.4Hz，1H)，7.51(t，J＝8.1Hz，2H)，9.21(s，1H)。MS(CDl，m/z)559(MH +)。C 33H 38N 2O 6.0.20H 3PO 4The analytical calculation value: C, 68.54, H, 6.73, N, 4.84.Measured value: C, 68.28, H, 6.46, N, 4.82.
Embodiment 867
Instead, anti--2-[3-(2-methoxy ethoxy) phenyl]-4-(1,3-benzo dioxole-5-yl)-1-(2,6-diethyl phenyl amino carbonyl methyl)-tetramethyleneimine-3-carboxylic acid
By embodiment 30 described methods, replace the 4-methyl hydroxybenzoate to prepare title compound with the 3-methyl hydroxybenzoate. 1H?NMR(300MHz，CDCl 3)δ1.08(t，J＝7Hz，6H)，2.43(q，J＝7Hz，4H)，3.00-3.20(m，3H)，3.42(s，3H)，3.50(d，J＝11Hz，1H)，3.53-3.59(m，1H)，3.65-3.75(m，1H)，3.75(t，J＝6Hz，2H)，3.98(d，J＝8Hz，1H)，4.11(t，J＝6Hz，2H)，5.94(dd，J＝2Hz，4Hz，2H)，6.75(d，J＝8Hz，1H)，6.80-6.89(m，3H)，7.05-7.10(m，2H)，7.10(d，J＝8Hz，2H)，7.19-7.32(m，2H)，8.30(s，1H)。MS(APCl+)m/e?575(M+H +)。C 33H 38N 2O 7The analytical calculation value: C, 68.97, H, 6.67, N, 4.87.Measured value: C, 68.78, H, 6.84, N, 4.72.
Embodiment 868
Instead, anti--2-[(2-methyl-4-propoxy-phenyl)]-4-(1,3-benzo dioxole-5-yl)-1-(2,6-diethyl phenyl amino carbonyl methyl)-tetramethyleneimine-3-carboxylic acid
Embodiment 868A
(4-propoxy--2-methyl benzoyl) ethyl acetate
4-hydroxy-2-methyl methyl phenyl ketone and 1-bromo propane and salt of wormwood are reacted in dimethyl formamide obtain 4-propoxy--2-methyl acetophenone.Adopt the described method of embodiment 15B to make this compound and diethyl carbonate reaction obtain title compound.
Embodiment 868B
Instead, anti--2-[(2-methyl-4-propoxy-phenyl)]-4-(1,3-benzo dioxole-5-yl)-1-(2,6-diethyl phenyl amino carbonyl methyl)-tetramethyleneimine-3-carboxylic acid
By embodiment 30 described method preparations, the compound of using embodiment 868A is as raw material. 1H?NMR(300MHz，CDCl 3)δ1.02(t，J＝7Hz，3H)，1.08(t，J＝7Hz，6H)，1.75-1.85(m，2H)，2.33(s，3H)，2.40-2.48(q，J＝7Hz，4H)，2.98(d，J＝11Hz，1H)，3.06-3.18(m，2H)，3.39(d，J＝11Hz，1H)，3.50-3.58(m，1H)，3.65-3.75(m，1H)，3.90(t，J＝7Hz，2H)，4.28(d，J＝8Hz，1H)，5.94(dd，J＝2Hz，4Hz，2H)，6.70-6.88(m，5H)，7.08-7.25(m，3H)，7.48(d，J＝8Hz，1H)，8.28(s，1H)。MS(APCl+)m/e?773(M+H +)。C 34H 40N 2O 6The analytical calculation value: C, 70.56, H, 7.79, N, 4.33.Measured value: C, 70.16, H, 7.70, N, 4.26.
Embodiment 869
Instead, anti--2-(4-(3-methoxyl group) propyl group) phenyl-4-(1,3-benzo dioxole-5-yl)-1-((N-2,6-diethyl phenyl) aminocarboxyl) methyl-tetramethyleneimine-3-carboxylic acid
Embodiment 869A
4-(3-methoxyl group) propylbenzoic acid
In the mixture of 10.0g (46.5mmol) 4-bromobenzene methyl-formiate, 325mg (1.45mmol) acid chloride (II), 15.1g (51.0mmol) tetrabutylammonium chloride and 13.7g (140mmol) potassium acetate, add 200ml DMF.Make this mixture degassing and, add 10ml allyl group methyl ether then with nitrogen back-filling twice.Stirred these reactants 6 hours in 50 ℃, under room temperature, stirred 66 hours then.By TLC (20% ethyl acetate/hexane) monitoring reaction.After this add other Pd catalyzer (319mg), because more remaining bromo esters.In the heating 2 hours down of 50 ℃ and nitrogen, in this reactant impouring 1L water, this suspension separated into two parts is handled being easy to.Each part with ether (3 * 100ml) extractions, then with each several part ether layer water (1 * 100ml), saturated sodium bicarbonate aqueous solution (1 * 100ml) and salt solution (1 * 100ml) returns and carries, and through dried over mgso, filters also vacuum concentration.4-(3-methoxyl group-1-propenyl) methyl benzoate and 4-(3-methoxyl group-2-propenyl) methyl benzoate crude product merge amount for 9.17g.In the mixture of the above-mentioned product of 8.57g (41.6mmol) and 400mg 10%Pd-C, add 75mlTHF.Stirred this mixture 2 hours down in room temperature and 1atm hydrogen, filtration catalizer then, solvent removed in vacuo.Obtain 4-(3-methoxy-propyl) methyl benzoate of 3.35g (39%) through 15% ethyl acetate/hexane column purification, be colorless oil.With the 1.39M sodium hydroxide of this material and 20ml ethanol: mix in the water at 5: 1.This reactant was heated 30 minutes down in refluxing, then vacuum concentration.Residue is dissolved in the 25ml water, adds the HCl of 40ml 1M then.(3 * 25ml) extract this mixture, and (1 * 25ml) returns the ether layer of proposing merging, becomes 3.03g (97%) 4-(3-methoxyl group) propylbenzoic acid through dried over mgso, filtration and vacuum concentration, is white solid to use salt solution then with ether.
Embodiment 869B
Instead, anti--2-(4-(3-methoxyl group) propyl group) phenyl-4-(1,3-benzo dioxole-5-yl)-1-((N-2,6-diethyl phenyl) aminocarboxyl) methyl-tetramethyleneimine-3-carboxylic acid
Method preparation according to embodiment 1. 1H?NMR(300MHz，d 6-DMSO)δ1.00(t，J＝7.5Hz，6H)，1.80(m，2H)，2.41(q，J＝7.5Hz，4H)，2.62(t，J＝7.7Hz，2H)，2.86(t，J＝9.7Hz，1H)，2.93(d，J＝15.8Hz，1H)，3.11(t，J＝9.6Hz，1H)，3.18(d，J＝16.2Hz，1H)，3.23(s，3H)，3.31-3.40(m，2H)，3.50(m，1H)，3.53(m，1H)，3.95(d，J＝9.9Hz，1H)，5.98(s，2H)，6.80(dd，J＝1.5Hz，8.1Hz，1H)，6.85(dd，J＝1.5Hz，8.1Hz，1H)，7.10(d，J＝7.0Hz，2H)，7.18(m，3H)，7.28(d，J＝1.5Hz，1H)，7.53(d，J＝8.1Hz，1H)，9.28(s，1H)。MS(CDl?m/e)571(MH +)。C 34H 40N 2O 6.005H 3PO 4The analytical calculation value: C, 70.70, H, 7.00, N, 4.85.Measured value: C, 70.68, H, 6.91, N, 4.62.
By combining as index, estimate the ability of described compound displacement with compound described herein from the endothelin of endothelin receptor with endothelin receptor.
ET BReceptors bind is measured
Derive from the preparation of the film of pig cerebellum:
The pig cerebellum is passed through 3-10sec polytron with homogenate at interval in 10 seconds with 13500 rpm in the 10mM Hepes (pH7.4) of 25 volumes (w/v) that contain 0.25M sucrose and proteinase inhibitor [3mM EDTA, 0.1mMPMSF and 5 μ g/ml pepstatin A].With described mixture centrifugal 10 minutes with 1000xg.Collect supernatant liquor and centrifugal 30 minutes with 30000xg.With the precipitation resuspending in the Buffer A that contains above-mentioned proteinase inhibitor (pH 7.4 for 20mM Tris, 100mM sodium-chlor, 10mM magnesium chloride) and recentrifuge.Final throw out resuspending is stored to use in the Buffer A that contains proteinase inhibitor and in-80 ℃.Measure proteic content with Bio-Rad dyeing-conjugated protein assay method.
[ 125I] ET-3 combines with film:
Carrying out combination on the pretreated 96 hole microtest plates with 0.1%BSA measures.Will be by the film of cell preparation at buffer B (20mM Tris, 100mM NaCl, 10mM MgCl 2, pH7.4 contains 0.2%BSA, 0.1mM PMSF, 5 μ g/ml pepstatin A, 0.025% bacitracin and 3mM EDTA) in the dilution about 100 times to final concentration be 0.2mg/ml albumen.In competition research, in the presence of the unlabelled ET-3 of rising concentration or test-compound, with film (0.02mg) and 0.1nM[ 125I] ET-3 hatched 4 hours in 25 ℃ in buffer B (final volume 0.2ml).After hatching, with glass-fiber filter bar PHD cell capture device (Cambridge Technology, Inc separate unconjugated part by the vacuum filtration method in MA) with the bonded part, then with salt solution (1ml) with filtering rod washing 3 times.In the presence of 1 μ MET-1, measure non-specific binding.The gained data provide in table 1, have shown the inhibition per-cent under 1 μ M concentration.These data show that The compounds of this invention can combine with endothelin receptor.
Table 1 binding data
ET under the embodiment 1 μ M BInhibiting rate (%) ET under the embodiment 1 μ M BInhibiting rate (%)
??1???????96.4 ??2???????91.5
??3???????82.1 ??4???????94.0
??5???????96.5 ??6???????92.9
??7???????94.5 ??8???????93.6
??9???????94.8 ?10???????95.2
?11???????96.0 ?12???????96.7
?13???????91.3 ?14???????96.6
?15???????93.4 ?16???????92.3
?17???????97.1 ?18???????94.9
?19???????94.9 ?20???????95.5
?21???????97.1 ?22???????95.3
?23???????99.1 ?24???????93.3
?25???????95.7 ?26???????98.0
?27???????98.8 ?28???????97.2
?29???????94.7 ?30???????97.4
858???????98.3 859???????95.6
860???????93.0 861???????96.7
862???????92.8 863???????92.7
864???????96.3 865???????92.1
866???????92.0 867???????93.5
868???????96.1 869???????98.9
Can confirm the ability that compound of the present invention brings high blood pressure down according to (Clin.Exp.Pharmacol.Physiol.10 131 (1983)) described methods such as (Eur.J.Pharmacol.185 103 (1990)) such as Matsumura and Takata.
Can confirm that according to (Circulation 82 2226 (1990)) described methods such as Margulies compound of the present invention can treat the ability of congestive heart failure.
Can confirm that according to (Nature 344 114 (1990)) described methods such as Watanabe compound of the present invention can treat the ability of myocardial ischemia.
Can confirm that according to (Circ.Res.54 711 (1984)) described methods such as Heistad compound of the present invention can treat the anginal ability of coronary artery.
Can confirm that according to (Life Sci.49 841-848 (1991)) described methods such as (J.Neurosurg.66 915 (1987)) such as Nakagomi or Matsumura compound of the present invention can treat the ability of cerebral vasospasm.
Can confirm the ability of compounds for treating cerebral ischemia of the present invention according to (European.J.Pharmacol.197:75-82 (1991)) described methods such as Hara.
Can confirm that according to (J.Clin.Invest.83 1762 (1989)) described methods such as Kon compound of the present invention can treat the ability of acute renal failure.
Can confirm that according to (Kidney Int.44 440-444 (1993)) described methods such as Benigni compound of the present invention can treat the ability of chronic renal failure.
Can confirm that according to (Am.J.Physiol.256 G661 (1989)) described methods such as Wallace compound of the present invention can treat the ability of stomach ulcer.
Can confirm that according to (Kidney Int.37 1487 (1990)) described methods such as Kon compound of the present invention can treat the ability of S-Neoral inductive renal toxicity.
Can confirm that according to (Clinical Sci.79 619 (1990)) described methods such as Takahashi compound of the present invention can treat the ability of the toxicity of endotaxin induction (shock).
Can confirm that according to Potvin and the described method of Varma (Can.J.Physiol. and Pharmacol.67 1213 (1989)) compound of the present invention can treat the ability of asthma.
Can confirm that according to (Atherosclerosis 78 229-236 (1989)) described methods such as Foegh compound of the present invention can treat the ability of transplanting the inductive atherosclerosis.
Can confirm that according to (Hypertension.15 327 (1990)) described methods such as (Am.J.Physiol.258 C408 (1990)) such as Bobik and Chobanian compound of the present invention can treat the ability of atherosclerosis.
Can confirm that according to (Biochem.Pharmacol.44 1431-1436 (1992)) described methods such as Ishida compound of the present invention can treat the ability of the relevant lipoprotein disorder of LPL-.
According to Bunchman ET and CA Brookshire (Transplantation Proceed.23967-968 (1991)); Yamagishi etc. (Biochem.Biophys.Res.Comm.191 840-846 (1993)); Can confirm that with (J.Clin.Invest.87 1867-1871 (1991)) described methods such as Shichiri compound of the present invention can treat the ability of proliferative disease.Proliferative disease comprises that other pathologic of restenosis behind proliferation of smooth muscle, Sjogren's syndrome disease, liver cirrhosis, adult respiratory distress syndrome, idiopathic cardiomyopathy, lupus erythematosus, diabetic retinopathy or other retinopathy, psoriasis, scleroderma, hyperplasia of prostate, cardiac hypertrophy, the arterial injury or blood vessel is narrow.
Can confirm that according to (Am.J.Physiol 266 H1327 (1994)) described methods such as Bonvallet compound of the present invention can treat acute or the hypertensive ability of chronic pulmonary.Pulmonary hypertension is relevant with following disease: congestive heart failure, mitral valve are narrow, pulmonary emphysema, pulmonary fibrosis, chronic obstructive pulmonary disease (COPD), adult respiratory distress syndrome (ARDS), altitude sickness, Chemical exposure or idiopathic.
Can confirm that according to (Eu.J.Pharmacol.259 51 (1994)) described methods such as McMurdo compound of the present invention can treat platelet aggregation and thrombotic ability.
Can confirm that according to (J.Clin.Invest.87 1867 (1991)) described methods such as Shichiri compound of the present invention can treat the ability of cancer.
Can confirm that according to (Nature Medicine, 1, (9) 944 (1995)) described methods such as Nelson compound of the present invention can treat the ability of gland cancer.
Can confirm that according to (Proc.Nat.Acad.Sci.92 2691 (1995)) described methods such as Klemm compound of the present invention can treat the cardiac toxic of IL-2 (with other cytokine) mediation and the ability of vascular permeability disease.
Can confirm that according to (J.Pharmacol.Exp.Therap.271 156 (1994)) described methods such as Yamamoto compound of the present invention can treat the ability of the pain sensation.
According to Hogaboam etc. (EUR.J.Pharmacol.1996,309,261-269) described method can confirm that compound of the present invention can treat the ability of colitis.
(Transplant Int 1996,9,201-207) described method can confirm that compound of the present invention can treat the ability of ischemical reperfusion injury in the renal transplantation according to Aktan etc.
(Drugs 1996,51, and 12-27) described method can confirm that compound of the present invention can treat stenocardia, pulmonary hypertension, Raynaud disease and migrainous ability according to Ferro and Webb.
Compound of the present invention can be used with the form of the salt of organic or inorganic acid.These salt include, but is not limited to: acetate, adipate, alginate, Citrate trianion, aspartate, benzoate, benzene sulfonate, hydrosulfate, butyrates, camphorate, camsilate, two grape hydrochlorates, cyclopentane propionate, dodecyl sulfate, ethane sulfonate, gluceptate, glycerophosphate, Hemisulphate, enanthate, hexanoate, fumarate, hydrochloride, hydrobromate, hydriodate, 2-hydroxyl-ethane sulfonate, lactic acid salt, maleate, methane sulfonates, nicotinate, 2-naphthoic acid sulfonate, oxalate, two hydrogen naphthoates (pamoate), pectinic acid salt, persulphate, 3-phenylpropionic acid salt, picrate, Pivalate, propionic salt, succinate, tartrate, thiocyanate-, p-tosylate and undecylate.Can be alkaline nitrogen-containing group is quaternized: the muriate of low alkyl group halogen such as methyl, ethyl, propyl group and butyl, bromide and iodide with following reagent; Dialkylsulfates such as dimethyl, diethyl, dibutyl and diamyl sulfuric ester, the muriate of the halogenide of long-chain such as decyl, dodecyl, tetradecyl and octadecyl, bromide and iodide, aralkyl halide such as benzyl and styroyl bromination thing etc.Therefore can obtain water or oil-soluble or dispersion product.
The example that can be used to form the acid of pharmaceutically-acceptable acid addition comprises for example for example oxalic acid, toxilic acid, succsinic acid and citric acid of hydrochloric acid, sulfuric acid and phosphoric acid and organic acid of mineral acid.Can the final separation of formula (I) compound and purification phase formation base addition salt on the throne or by make the carboxylic-acid functional group separately with suitable alkali, the oxyhydroxide of for example pharmaceutically acceptable metallic cation or ammonia or organic primary amine, secondary amine or tertiary amine, carbonate or supercarbonate reaction form.This type of pharmacy acceptable salt includes, but is not limited to: basic metal and alkaline-earth metal be sodium, lithium, potassium, calcium, magnesium, aluminium cations salt etc. for example, and atoxic ammonium, quaternary ammonium and amine positively charged ion, include, but is not limited to ammonium, tetramethyl-ammonium, tetraethyl ammonium, methylamine, dimethylamine, Trimethylamine 99, triethylamine, ethamine etc.Other representative organic amine that can be used to form base addition salt comprises diethylamine, quadrol, thanomin, diethanolamine, piperazine etc.
Compound of the present invention can be used in human or other Mammals antagonism endothelin.In addition, compound of the present invention can be used for (human or other Mammals) treatment hypertension, acute or chronic pulmonary hypertension, Raynaud disease, congestive heart failure, myocardial ischemia, reperfusion injury, coronary artery stenocardia, cerebral ischemia, cerebral vasospasm, chronic or acute renal failure, NSAID (non-steroidal anti-inflammatory drug) inductive stomach ulcer, S-Neoral inductive renal toxicity, the toxicity of endotaxin induction, asthma, fiber or proliferative disease comprise proliferation of smooth muscle, Sjogren's syndrome disease, liver cirrhosis, adult respiratory distress syndrome, idiopathic cardiomyopathy, lupus erythematosus, diabetic nephropathy or other ephrosis, psoriasis, scleroderma, hyperplasia of prostate, cardiac hypertrophy, other pathologic of restenosis or blood vessel is narrow behind the arterial injury, the lipoprotein disorder that LPL-is relevant, transplant inductive atherosclerosis or broad sense atherosclerosis, platelet aggregation, thrombosis, cancer, gland cancer, IL-2 and other cytokine mediated Cardiovascular Toxicity and perviousness disease, colitis, the migraine and the pain sensation.
Once or gradation total dose every day that gives the patient can be, for example oral 0.001-1000mg/kg body weight, being preferably 0.1-100mg/kg or enteron aisle external administration is 0.01-10mg/kg.Dosage unit compositions can contain a plurality of sub-doses so that the dosage of every day to be provided.
The amount that can mix the activeconstituents that produces single dose form with carrier substance depends on the patient that treated and concrete administering mode and changes.
Yet, the specific dosage level that is appreciated that concrete patient depends on various factors, comprises the activity, age, body weight, general physical condition, sex, diet, administration time, route of administration, excretion rate, drug combination situation of the particular compound of use, the severity of the concrete disease for the treatment of.
Can give compound of the present invention through following multiple mode with the dosage unit preparations that contains routine, non-toxicity, pharmaceutically acceptable required carrier, auxiliary and solvent: outside per os, the enteron aisle, hypogloeeis, suction spraying, rectum or part.Topical also can comprise the use percutaneous dosing, for example through skin patch or Iontophoretic device.Outside this used term parenteral, comprise subcutaneous injection agent, vein, intramuscular, breastbone inner injection or infusion techn.
Can be according to technology well known in the art, prepare injection formulations with suitable dispersion agent or wetting agent and suspension agent, for example the aseptic injection aqueous solution or oil soluble suspension.Aseptic injection preparation also can for acceptable diluent or solvent outside atoxic enteron aisle for example, 1, aseptic injection solution or suspension in the ammediol solution.Operable acceptable solvent and solvent are water, RingerShi solution and isotonic sodium chlorrde solution.In addition, aseptic fixed oil is conventionally used as solvent or suspension medium.Therefore, the fixed oil of any gentleness be can use, synthetic one or two glyceryl ester comprised.In addition, can when preparing, use injection lipid acid, for example oleic acid.
Described medicine can be made the suppository of rectal administration according to known technology.Can be by for example theobroma oil or polyoxyethylene glycol (at room temperature be solid, is liquid in rectal temperature, therefore can at internal rectum thawing and release medicine) be mixed with the suppository that is used for rectal administration with medicine and suitable nonirritating vehicle.
Peroral administration solid dosage comprises capsule, tablet, pill, powder agent and granule.In this type of solid dosage, can for example sucrose, lactose or starch mix with at least a inert diluent with active compound.This type of formulation can comprise that also (by normal practice) is not the substance of inert diluent, and for example lubricant is as Magnesium Stearate.Under the situation of capsule, tablet and pill, described formulation can comprise buffer reagent.Tablet and pill can be surrounded by enteric coating in addition.
Peroral administration liquid dosage form can comprise and contains the normally used inert diluent in this area for example pharmaceutically acceptable emulsion, solution, suspension, syrup and the elixir of water.This based composition also can comprise auxiliary, for example wetting agent, emulsifying agent and suspension agent, sweeting agent, correctives and perfume compound.
Also can give compound of the present invention with the form of liposome.As known in the art, liposome generally is by phosphatide or other liquid substance deutero-.Can form liposome by the single or multiple lift hydration liquid crystallization that is scattered in the water-bearing media.Can use any atoxic physiologically acceptable and metabolizable lipid that can form liposome.The present composition of liposome form can contain stablizer, sanitas, vehicle etc. except that containing The compounds of this invention.Preferred lipid comprises phosphatide and phosphatidylcholine (Yelkin TTS), comprises natural and synthetic.
The method for preparing liposome is known in the art.For example, see Prescott, Ed, Methods in Cell Biology, XIV volume, Academic Press, New York, N.Y. ((1976), 33 pages etc.).
Representational solid dosage, for example a slice or a capsule, contain: compound of the present invention: 35% w/w starch, pregelatinized, NF 50% w/w Microcrystalline Cellulose, NF 10% w/w talcum powder, USP 5% w/w
Although compound of the present invention can be used as the administration of single active pharmaceutical preparation, yet the cardiovascular agent that also can independently be selected from following material with itself and one or more is united use: diuretic(s), adrenergic blocker, vasodilator, calcium channel blocker, renin inhibitor, angiotensin converting enzyme (ACE) inhibitor, angiotension II antagonists, potassium channel activator and other cardiovascular agent.
Representative diuretic(s) comprises hydrochlorothiazide, gram urine thiophene, acetazolamide, guanamprazine, bumetanide, benzene thiazine, Uregit, furosemide, indacrinone, methaqualone, spironolactone, triamterene, chlorthalidone etc. or its pharmacy acceptable salt.
Representational adrenergic blocker comprises phentolamine, phenoxybenzamine, Prazosin, terazosin, tolazine, Target, metoprolol, nadolol, Propranololum, timolol, carteolol etc. or its pharmacy acceptable salt.
Representative vasodilator comprises hydralazine, U-10858, diazoxide, Sodium Nitroprusside etc. or its pharmacy acceptable salt.
Representative calcium channel blocker comprises Wincoram, bencyclan, sulphur nitrogen ketone, fendiline, fiunarizine, nicardipine, nimodipine, Perhexiline, verapamil, Gallopamil, NIFEDIPINE etc. or its pharmacy acceptable salt.
Representative renin inhibitor comprises enalkiren, zankiren, RO 42-5892, PD-134672 etc. or its pharmacy acceptable salt.
Representative angiotension II antagonists comprises DUP 753, A-81988 etc.
Representative ACE inhibitor comprises captopril, enalapril, lisinopril etc. or its pharmacy acceptable salt.
Representative potassium channel activator comprises Pinacidil etc. or its pharmacy acceptable salt.
Other representative cardiovascular agent comprises antisympathetic for example methyldopa, clonidine, guanabenz, serpentine etc. or its pharmacy acceptable salt.
Can give The compounds of this invention and cardiovascular agent with maximum clinical dosage or the lower dosage of recommending.The dosage level that can change active compound in the present composition is to obtain required therapeutic response according to the severity of route of administration, disease and patient's reaction.Can be to divide other composition or to contain the single dose form Combined Preparation of two kinds of medicines.
When with the array configuration administration, medicine can be made independent composition, administration or at different time administrations at one time perhaps gives medicine as a composition.
Aforementioned only is to explanation of the present invention, does not mean to limit the present invention in the scope of disclosed compound, preparation method, composition and medication.Apparent to those skilled in the art, variations and modifications are included within the defined scope of the invention of accessory claim book and the character.

Claims (36)

1.下式的化合物或其药学上可接受的盐：其中R为-(CH2)m-W，其中m为0至6的整数，W为1. A compound of the following formula or a pharmaceutically acceptable salt thereof: Wherein R is -(CH 2 ) m -W, wherein m is an integer from 0 to 6, and W is (a)-C(O)2-G，其中G为氢或羧基保护基团，(a)-C(O) 2 -G, wherein G is hydrogen or carboxyl protecting group, (b)-PO3H2，(b)-PO 3 H 2 , (c)-P(O)(OH)E，其中E为氢、低级烷基或芳基烷基，(c)-P(O)(OH)E, wherein E is hydrogen, lower alkyl or arylalkyl, (d)-CN，(d)-CN, (e)-C(O)NHR17，其中R17为低级烷基，(e)-C(O)NHR 17 , wherein R 17 is lower alkyl, (f)烷基氨基羰基，(f) alkylaminocarbonyl, (g)二烷基氨基羰基，(g) dialkylaminocarbonyl, (h)四唑基，(h) tetrazolyl, (i)羟基，(i) hydroxyl, (j)烷氧基，(j) alkoxy, (k)亚磺酰氨基，(k) sulfonamido, (l)-C(O)NHS(O)2R16，其中R16为低级烷基、卤代烷基、芳基或二烷基氨基，(l)-C(O)NHS(O) 2 R 16 , wherein R 16 is lower alkyl, haloalkyl, aryl or dialkylamino, (m)-S(O)2NHC(O)R16，其中R16如上述所定义， R1和R2独立选自氢、低级烷基、链烯基、炔基、烷氧基烷基、烷氧基羰基烷基、羟基烷基、卤代烷基、卤代烷氧基烷基、烷氧基烷氧基烷基、硫代烷氧基烷氧基烷基、环烷基、环烷基烷基、氨基羰基烷基、烷基氨基羰基烷基、二烷基氨基羰基烷基、氨基羰基链烯基、烷基氨基羰基链烯基、二烷基氨基羰基链烯基、羟基链烯基、芳基、芳基烷基、芳氧基烷基、芳基烷氧基烷基、杂环基、(杂环基)烷基和(Raa)(Rbb)N-Rcc-其中Raa为芳基或芳基烷基，Rbb为氢或链烷酰基和Rcc为亚烷基，前提为R1和R2之一或二者不为氢；R3为R4-C(O)-R5-或R6-S(O)2-R7-，其中R5为(i)共价键，(ii)亚烷基，(iii)亚链烯基，(iv)-N(R20)-R8-或-R8a-N(R20)-R8-，其中R8和R8a独立选自亚烷基和亚链烯基；和R20为氢、低级烷基、链烯基、卤代烷基、烷氧基烷基、卤代烷氧基烷基、环烷基或环烷基烷基或(v)-O-R9-或-R9a-O-R9-，其中R9和R9a独立选自亚烷基；R7为(i)一个共价键，(ii)亚烷基，(iii)亚链烯基或(iv)-N(R21)-R10-或-R10a-N(R21)-R10-，其中R10和R10a独立选自亚烷基和亚链烯基；而R21为氢、低级烷基、链烯基、卤代烷基、烷氧基烷基、卤代烷氧基烷基、芳基或芳基烷基；其中R4和R6为
Figure A9880618400041
其中R11和R12独立选自低级烷基、氰基、烷氧基、卤素、卤代烷基和苯基，R13、R14和R15独立选自氢、低级烷基、羟基、氨基、烷氧基、芳基、杂环、卤素、羧基、硝基、烷基磺酰基、芳基磺酰基、硫代烷氧基、硫代芳氧基或氰基；或(ii)杂环基(氨基)。(m)-S(O) 2 NHC(O)R 16 , wherein R 16 is as defined above, R and R are independently selected from hydrogen, lower alkyl, alkenyl, alkynyl, alkoxyalkyl, alkoxycarbonylalkyl, hydroxyalkyl, haloalkyl, haloalkoxyalkyl, alkoxy Alkoxyalkyl, thioalkoxyalkoxyalkyl, cycloalkyl, cycloalkylalkyl, aminocarbonylalkyl, alkylaminocarbonylalkyl, dialkylaminocarbonylalkyl, aminocarbonyl chain Alkenyl, alkylaminocarbonylalkenyl, dialkylaminocarbonylalkenyl, hydroxyalkenyl, aryl, arylalkyl, aryloxyalkyl, arylalkoxyalkyl, heterocyclyl , (heterocyclyl)alkyl and (R aa )(R bb )NR cc - where R aa is aryl or arylalkyl, R bb is hydrogen or alkanoyl and R cc is alkylene, provided that One or both of R 1 and R 2 is not hydrogen; R 3 is R 4 -C(O)-R 5 - or R 6 -S(O) 2 -R 7 -, wherein R 5 is (i) Valence bond, (ii) alkylene, (iii) alkenylene, (iv) -N(R 20 )-R 8 - or -R 8a -N(R 20 )-R 8 -, wherein R 8 and R is independently selected from alkylene and alkenylene; and R is hydrogen, lower alkyl, alkenyl, haloalkyl, alkoxyalkyl, haloalkoxyalkyl, cycloalkyl, or cycloalkyl Alkyl or (v) -OR 9 -or -R 9a -OR 9 -, wherein R 9 and R 9a are independently selected from alkylene; R 7 is (i) a covalent bond, (ii) alkylene, (iii) alkenylene or (iv) -N(R 21 )-R 10 - or -R 10a -N(R 21 )-R 10 -, wherein R 10 and R 10a are independently selected from alkylene and alkylene alkenyl; and R is hydrogen, lower alkyl, alkenyl, haloalkyl, alkoxyalkyl, haloalkoxyalkyl, aryl or arylalkyl ; wherein R and R are
Figure A9880618400041
Wherein R 11 and R 12 are independently selected from lower alkyl, cyano, alkoxy, halogen, haloalkyl and phenyl, R 13 , R 14 and R 15 are independently selected from hydrogen, lower alkyl, hydroxyl, amino, alkane oxy, aryl, heterocycle, halogen, carboxy, nitro, alkylsulfonyl, arylsulfonyl, thioalkoxy, thioaryloxy or cyano; or (ii) heterocyclyl (amino ). 2.权利要求1的化合物，其中R3为R4-C(O)-R5-，其中R4为如本文所定义而R5为亚烷基或R3为R6-S(O)2-R7-，其中R7为亚烷基，R6为如本文所定义。2. The compound of claim 1, wherein R3 is R4 -C(O) -R5- , wherein R4 is as defined herein and R5 is alkylene or R3 is R6 -S(O) 2 -R 7 -, wherein R 7 is an alkylene group, and R 6 is as defined herein. 3.根据权利要求1的化合物，其中R为-C(O)2-G，其中G为氢或羧基保护基团，或R为四唑基或R为-C(O)-NHS(O)2R16，其中R16为低级烷基、卤代烷基或芳基，R1和R2独立选自(i)低级烷基、(ii)环烷基、(iii)取代的或未取代的芳基、(iv)取代的或未取代的杂环基，及R3为R4-C(O)-R5-，其中R4如本文所定义和R5为亚烷基或R3为R6-S(O)2-R7-，其中R7为亚烷基和R6如本文所定义。3. The compound according to claim 1, wherein R is -C(O) 2 -G, wherein G is hydrogen or a carboxyl protecting group, or R is tetrazolyl or R is -C(O)-NHS(O) 2 R 16 , wherein R 16 is lower alkyl, haloalkyl or aryl, R 1 and R 2 are independently selected from (i) lower alkyl, (ii) cycloalkyl, (iii) substituted or unsubstituted aryl group, (iv) substituted or unsubstituted heterocyclyl, and R 3 is R 4 -C(O)-R 5 -, wherein R 4 is as defined herein and R 5 is alkylene or R 3 is R 6 -S(O) 2 -R 7 -, wherein R 7 is alkylene and R 6 is as defined herein. 4.根据权利要求1的化合物，其中R为-C(O)2-G，其中G为氢或羧基保护基团、四唑基或-C(O)-NHS(O)2R16，其中R16为低级烷基、卤代烷基或芳基，R1为(i)烷氧基烷基、(ii)环烷基、(iii)苯基，(iv)吡啶基，(v)呋喃基或(vi)取代或未取代的4-甲氧基苯基、4-氟代苯基、3-氟代苯基、4-乙氧基苯基、4-丙氧基苯基、4-异丙氧基苯基、4-三氟甲基苯基、4-五氟乙基苯基、2-氟代-4-乙氧基苯基、3-氟代-4-甲氧基苯基、3-氟代-4-乙氧基苯基、3-氟代-4-丙氧基苯基、3-甲氧基-4-丙氧基苯基、2-氟代苯基、4-甲氧基甲氧基苯基、4-(2-甲氧基乙氧基)苯基、4-(2-乙氧基乙氧基)苯基、4-(2-异丙氧基乙氧基)苯基、4-羟基苯基、1，3-苯并间二氧杂环戊烯基(dioxolyl)、1，4-苯并二氧六环基或二氢苯并呋喃基，其中所述取代基选自烷氧基、烷氧基烷氧基和羧基烷氧基，R2为取代的或未取代的1，3-苯并间二氧杂环戊烯基、7-甲氧基-1，3-苯并间二氧杂环戊烯基、1，4-苯并二氧六环基、8-甲氧基-1，4-苯并二氧六环基、二氢苯并呋喃基、苯并呋喃基、4-甲氧基苯基、二甲氧基苯基、氟代苯基或二氟代苯基和R3为R4-C(O)-R5-，其中R4如本文所定义和R5为亚烷基或R3为R6-S(O)2-R7-，其中R7为亚烷基和R6为如本文所定义。4. The compound according to claim 1, wherein R is -C(O) 2 -G, wherein G is hydrogen or a carboxyl protecting group, tetrazolyl or -C(O)-NHS(O) 2 R 16 , wherein R 16 is lower alkyl, haloalkyl or aryl, R 1 is (i) alkoxyalkyl, (ii) cycloalkyl, (iii) phenyl, (iv) pyridyl, (v) furyl or (vi) Substituted or unsubstituted 4-methoxyphenyl, 4-fluorophenyl, 3-fluorophenyl, 4-ethoxyphenyl, 4-propoxyphenyl, 4-isopropyl Oxyphenyl, 4-trifluoromethylphenyl, 4-pentafluoroethylphenyl, 2-fluoro-4-ethoxyphenyl, 3-fluoro-4-methoxyphenyl, 3 -Fluoro-4-ethoxyphenyl, 3-fluoro-4-propoxyphenyl, 3-methoxy-4-propoxyphenyl, 2-fluorophenyl, 4-methoxy methoxyphenyl, 4-(2-methoxyethoxy)phenyl, 4-(2-ethoxyethoxy)phenyl, 4-(2-isopropoxyethoxy) Phenyl, 4-hydroxyphenyl, 1,3-benzodioxolyl (dioxolyl), 1,4-benzodioxanyl or dihydrobenzofuranyl, wherein the substitution The group is selected from alkoxy, alkoxyalkoxy and carboxyalkoxy, and R is substituted or unsubstituted 1,3-benzodioxol, 7-methoxy-1 , 3-benzodioxolyl, 1,4-benzodioxanyl, 8-methoxy-1,4-benzodioxanyl, dihydrobenzofuranyl , benzofuryl, 4-methoxyphenyl, dimethoxyphenyl, fluorophenyl or difluorophenyl and R 3 is R 4 -C(O)-R 5 -, wherein R 4 as defined herein and R5 is alkylene or R3 is R6 -S(O) 2 - R7- , wherein R7 is alkylene and R6 is as defined herein. 5.根据权利要求1的化合物，其中R为-C(O)2-G，其中G为氢或羧基保护基团、四唑基或-C(O)-NHS(O)2R16其中R16为低级烷基、卤代烷基或芳基，R1选自：(i)烷氧基烷基、(ii)环烷基、(iii)苯基，(iv)吡啶基，(v)呋喃基或(vi)取代或未取代的4-甲氧基苯基、4-氟代苯基、3-氟代苯基、4-乙氧基苯基、4-丙氧基苯基、4-异丙氧基苯基、4-三氟甲基苯基、4-五氟乙基苯基、2-氟代-4-乙氧基苯基、3-氟代-4-甲氧基苯基、3-氟代-4-乙氧基苯基、3-氟代-4-丙氧基苯基、3-甲氧基-4-丙氧基苯基、2-氟代苯基、4-甲氧基甲氧基苯基、4-(2-甲氧基乙氧基)苯基、4-(2-乙氧基乙氧基)苯基、4-(2-异丙氧基乙氧基)苯基、4-羟基苯基、1，3-苯并间二氧杂环戊烯基、1，4-苯并二氧六环基或二氢苯并呋喃基，其中所述取代基选自烷氧基、烷氧基烷氧基和羧基烷氧基，R2为取代的或未取代的1，3-苯并间二氧杂环戊烯基、7-甲氧基-1，3-苯并间二氧杂环戊烯基、1，4-苯并二氧六环基、8-甲氧基-1，4-苯并二氧六环基、二氢苯并呋喃基、苯并呋喃基、4-甲氧基苯基、二甲氧基苯基、氟代苯基或二氟代苯基和R3为R4-C(O)-R5-，其中R4如本文所定义和R5为亚烷基。5. The compound according to claim 1, wherein R is -C(O) 2 -G, wherein G is hydrogen or a carboxyl protecting group, tetrazolyl or -C(O)-NHS(O) 2 R 16 wherein R 16 is lower alkyl, haloalkyl or aryl, R is selected from: (i) alkoxyalkyl, (ii) cycloalkyl, (iii) phenyl, (iv) pyridyl, (v) furyl or (vi) substituted or unsubstituted 4-methoxyphenyl, 4-fluorophenyl, 3-fluorophenyl, 4-ethoxyphenyl, 4-propoxyphenyl, 4-iso Propoxyphenyl, 4-trifluoromethylphenyl, 4-pentafluoroethylphenyl, 2-fluoro-4-ethoxyphenyl, 3-fluoro-4-methoxyphenyl, 3-fluoro-4-ethoxyphenyl, 3-fluoro-4-propoxyphenyl, 3-methoxy-4-propoxyphenyl, 2-fluorophenyl, 4-methyl Oxymethoxyphenyl, 4-(2-methoxyethoxy)phenyl, 4-(2-ethoxyethoxy)phenyl, 4-(2-isopropoxyethoxy ) phenyl, 4-hydroxyphenyl, 1,3-benzodioxolyl, 1,4-benzodioxanyl or dihydrobenzofuranyl, wherein the substituents are selected from from alkoxy, alkoxyalkoxy and carboxyalkoxy, R 2 is substituted or unsubstituted 1,3-benzodioxol, 7-methoxy-1,3 -Benzodioxolyl, 1,4-benzodioxanyl, 8-methoxy-1,4-benzodioxanyl, dihydrobenzofuranyl, benzene Furanyl, 4-methoxyphenyl, dimethoxyphenyl, fluorophenyl or difluorophenyl and R 3 is R 4 -C(O)-R 5 -, wherein R 4 is as herein defined and R 5 is an alkylene group. 6.根据权利要求1的化合物，其中R为-C(O)2-G，其中G为氢或羧基保护基团、四唑基或-C(O)-NHS(O)2R16其中R16为低级烷基或卤代烷基，R1为取代或未取代的4-甲氧基苯基、4-氟代苯基、2-氟代苯基、4-乙氧基苯基、4-丙氧基苯基、4-异丙氧基苯基、3-氟代-4-甲氧基苯基、3-氟代-4-乙氧基苯基、2-氟代-4-乙氧基苯基、3-氟代-4-丙氧基苯基、3-甲氧基-4-丙氧基苯基、4-三氟甲基苯基、4-五氟乙基苯基、4-甲氧基甲氧基苯基、4-(2-甲氧基乙氧基)苯基、4-(2-乙氧基乙氧基)苯基、4-(2-异丙氧基乙氧基)苯基、4-羟基苯基、1，3-苯并间二氧杂环戊烯基、1，4-苯并二氧六环基或二氢苯并呋喃基，其中所述取代基选自烷氧基、烷氧基烷氧基和羧基烷氧基，R2为1，3-苯并间二氧杂环戊烯基、7-甲氧基-1，3-苯并间二氧杂环戊烯基、1，4-苯并二氧六环基、二氢苯并呋喃基、苯并呋喃基、4-甲氧基苯基、二甲氧基苯基、氟代苯基或二氟代苯基和R3为R4-C(O)-R5-，其中R4如本文所定义和R5为亚烷基。6. The compound according to claim 1, wherein R is -C(O) 2 -G, wherein G is hydrogen or a carboxyl protecting group, tetrazolyl or -C(O)-NHS(O) 2 R 16 wherein R 16 is lower alkyl or haloalkyl, R 1 is substituted or unsubstituted 4-methoxyphenyl, 4-fluorophenyl, 2-fluorophenyl, 4-ethoxyphenyl, 4-propane Oxyphenyl, 4-isopropoxyphenyl, 3-fluoro-4-methoxyphenyl, 3-fluoro-4-ethoxyphenyl, 2-fluoro-4-ethoxy Phenyl, 3-fluoro-4-propoxyphenyl, 3-methoxy-4-propoxyphenyl, 4-trifluoromethylphenyl, 4-pentafluoroethylphenyl, 4- Methoxymethoxyphenyl, 4-(2-methoxyethoxy)phenyl, 4-(2-ethoxyethoxy)phenyl, 4-(2-isopropoxyethoxy base) phenyl, 4-hydroxyphenyl, 1,3-benzodioxolyl, 1,4-benzodioxanyl or dihydrobenzofuranyl, wherein the substituent selected from alkoxy, alkoxyalkoxy and carboxyalkoxy, R 2 is 1,3-benzodioxolyl, 7-methoxy-1,3-benzodioxol Oxolyl, 1,4-benzodioxanyl, dihydrobenzofuryl, benzofuryl, 4-methoxyphenyl, dimethoxyphenyl, fluorophenyl or difluorophenyl and R 3 is R 4 —C(O)—R 5 —, wherein R 4 is as defined herein and R 5 is alkylene. 7.根据权利要求1的化合物，其中R为-C(O)2-G，其中G为氢或羧基保护基团，R1为取代或未取代的4-甲氧基苯基、4-氟代苯基、2-氟代苯基、3-氟代-4-乙氧基苯基、3-氟代-4-甲氧基苯基、4-乙氧基苯基、4-丙氧基苯基、4-异丙氧基苯基、3-氟代-4-丙氧基苯基、3-甲氧基-4-丙氧基苯基、4-甲氧基甲氧基苯基、4-(2-甲氧基乙氧基)苯基、4-(2-乙氧基乙氧基)苯基、4-(2-异丙氧基乙氧基)苯基、4-羟基苯基、1，3-苯并间二氧杂环戊烯基、1，4-苯并二氧六环基或二氢苯并呋喃基，其中所述取代基选自烷氧基、烷氧基烷氧基和羧基烷氧基，R2为1，3-苯并间二氧杂环戊烯基、7-甲氧基-1，3-苯并间二氧杂环戊烯基、1，4-苯并二氧六环基、二氢苯并呋喃基、苯并呋喃基、4-甲氧基苯基、二甲氧基苯基、氟代苯基或二氟代苯基和R3为R4-C(O)-R5-，其中R4为
Figure A9880618400071
其中R11和R12独立选自低级烷基，及R13、R14和R15独立选自氢、低级烷基、羟基、氨基、烷氧基、芳基、杂环、卤素、羧基、硝基、烷基磺酰基、芳基磺酰基、硫代烷氧基、硫代芳氧基或氰基；及R5为亚烷基。7. The compound according to claim 1, wherein R is -C(O) 2 -G, wherein G is hydrogen or a carboxyl protecting group, R 1 is substituted or unsubstituted 4-methoxyphenyl, 4-fluoro Substituted phenyl, 2-fluorophenyl, 3-fluoro-4-ethoxyphenyl, 3-fluoro-4-methoxyphenyl, 4-ethoxyphenyl, 4-propoxy Phenyl, 4-isopropoxyphenyl, 3-fluoro-4-propoxyphenyl, 3-methoxy-4-propoxyphenyl, 4-methoxymethoxyphenyl, 4-(2-methoxyethoxy)phenyl, 4-(2-ethoxyethoxy)phenyl, 4-(2-isopropoxyethoxy)phenyl, 4-hydroxybenzene 1,3-benzodioxolyl, 1,4-benzodioxanyl or dihydrobenzofuryl, wherein the substituent is selected from alkoxy, alkoxy Alkoxy and carboxyalkoxy, R 2 is 1,3-benzodioxol, 7-methoxy-1,3-benzodioxol, 1, 4-benzodioxanyl, dihydrobenzofuranyl, benzofuryl, 4-methoxyphenyl, dimethoxyphenyl, fluorophenyl or difluorophenyl and R3 is R 4 -C(O)-R 5 -, wherein R 4 is
Figure A9880618400071
wherein R 11 and R 12 are independently selected from lower alkyl, and R 13 , R 14 and R 15 are independently selected from hydrogen, lower alkyl, hydroxyl, amino, alkoxy, aryl, heterocycle, halogen, carboxyl, nitric acid radical, alkylsulfonyl, arylsulfonyl, thioalkoxy, thioaryloxy, or cyano; and R is alkylene. 8.根据权利要求1的化合物，其中R为-C(O)2-G，其中G为氢或羧基保护基团，R1为取代或未取代的4-甲氧基苯基、4-氟代苯基、2-氟代苯基、3-氟代-4-乙氧基苯基、3-氟代-4-甲氧基苯基、4-乙氧基苯基、4-丙氧基苯基、4-异丙氧基苯基、2-氟代-4-乙氧基苯基、3-氟代-4-丙氧基苯基、3-甲氧基-4-丙氧基苯基、4-甲氧基甲氧基苯基、4-(2-甲氧基乙氧基)苯基、4-(2-乙氧基乙氧基)苯基、4-(2-异丙氧基乙氧基)苯基、4-羟基苯基、1，3-苯并间二氧杂环戊烯基、1，4-苯并二氧六环基或二氢苯并呋喃基，其中所述取代基选自烷氧基、烷氧基烷氧基和羧基烷氧基，R2为1，3-苯并间二氧杂环戊烯基、7-甲氧基-1，3-苯并间二氧杂环戊烯基、1，4-苯并二氧六环基、二氢苯并呋喃基、苯并呋喃基、4-甲氧基苯基、二甲氧基苯基、氟代苯基或二氟代苯基和R3为R4-C(O)-R5-，其中R4为
Figure A9880618400081
其中R11和R12独立选自低级烷基、烷氧基和卤素，及R13、R14和R15独立选自氢、低级烷基、羟基、氨基、烷氧基、芳基、杂环、卤素、羧基、硝基、烷基磺酰基、芳基磺酰基、硫代烷氧基、硫代芳氧基或氰基；及R5为亚烷基。8. The compound according to claim 1, wherein R is -C(O) 2 -G, wherein G is hydrogen or a carboxyl protecting group, R 1 is substituted or unsubstituted 4-methoxyphenyl, 4-fluoro Substituted phenyl, 2-fluorophenyl, 3-fluoro-4-ethoxyphenyl, 3-fluoro-4-methoxyphenyl, 4-ethoxyphenyl, 4-propoxy Phenyl, 4-isopropoxyphenyl, 2-fluoro-4-ethoxyphenyl, 3-fluoro-4-propoxyphenyl, 3-methoxy-4-propoxyphenyl base, 4-methoxymethoxyphenyl, 4-(2-methoxyethoxy)phenyl, 4-(2-ethoxyethoxy)phenyl, 4-(2-isopropyl Oxyethoxy)phenyl, 4-hydroxyphenyl, 1,3-benzodioxolyl, 1,4-benzodioxanyl or dihydrobenzofuranyl, wherein The substituent is selected from alkoxy, alkoxyalkoxy and carboxyalkoxy, R 2 is 1,3-benzodioxolyl, 7-methoxy-1,3- Benzodioxolyl, 1,4-benzodioxanyl, dihydrobenzofuryl, benzofuryl, 4-methoxyphenyl, dimethoxyphenyl, Fluorophenyl or difluorophenyl and R 3 is R 4 -C(O)-R 5 -, wherein R 4 is
Figure A9880618400081
wherein R 11 and R 12 are independently selected from lower alkyl, alkoxy and halogen, and R 13 , R 14 and R 15 are independently selected from hydrogen, lower alkyl, hydroxyl, amino, alkoxy, aryl, heterocyclic , halogen, carboxyl, nitro, alkylsulfonyl, arylsulfonyl, thioalkoxy, thioaryloxy, or cyano; and R is alkylene. 9.根据权利要求1的化合物，其中R为-C(O)2-G，其中G为氢或羧基保护基团，R1为取代或未取代的4-甲氧基苯基、4-氟代苯基、2-氟代苯基、3-氟代-4-乙氧基苯基、3-氟代-4-甲氧基苯基、4-乙氧基苯基、4-丙氧基苯基、4-异丙氧基苯基、2-氟代-4-乙氧基苯基、3-氟代-4-丙氧基苯基、3-甲氧基-4-丙氧基苯基、4-甲氧基甲氧基苯基、4-(2-甲氧基乙氧基)苯基、4-(2-乙氧基乙氧基)苯基、4-(2-异丙氧基乙氧基)苯基、4-羟基苯基、1，3-苯并间二氧杂环戊烯基、1，4-苯并二氧六环基或二氢苯并呋喃基，其中所述取代基选自烷氧基、烷氧基烷氧基和羧基烷氧基，R2为1，3-苯并间二氧杂环戊烯基、7-甲氧基-1，3-苯并间二氧杂环戊烯基、1，4-苯并二氧六环基、二氢苯并呋喃基、苯并呋喃基、4-甲氧基苯基、二甲氧基苯基、氟代苯基或二氟代苯基和R3为R4-C(O)-R5-，其中R4为
Figure A9880618400082
其中R11和R12独立选自甲基、乙基和异丙基，及R13、R14和R15独立选自氢、低级烷基、羟基、氨基、烷氧基、芳基、杂环、卤素、羧基、硝基、烷基磺酰基、芳基磺酰基、硫代烷氧基、硫代芳氧基或氰基；及R5为亚烷基。9. The compound according to claim 1, wherein R is -C(O) 2 -G, wherein G is hydrogen or carboxyl protecting group, R 1 is substituted or unsubstituted 4-methoxyphenyl, 4-fluoro Substituted phenyl, 2-fluorophenyl, 3-fluoro-4-ethoxyphenyl, 3-fluoro-4-methoxyphenyl, 4-ethoxyphenyl, 4-propoxy Phenyl, 4-isopropoxyphenyl, 2-fluoro-4-ethoxyphenyl, 3-fluoro-4-propoxyphenyl, 3-methoxy-4-propoxyphenyl base, 4-methoxymethoxyphenyl, 4-(2-methoxyethoxy)phenyl, 4-(2-ethoxyethoxy)phenyl, 4-(2-isopropyl Oxyethoxy)phenyl, 4-hydroxyphenyl, 1,3-benzodioxolyl, 1,4-benzodioxanyl or dihydrobenzofuranyl, wherein The substituent is selected from alkoxy, alkoxyalkoxy and carboxyalkoxy, R 2 is 1,3-benzodioxolyl, 7-methoxy-1,3- Benzodioxolyl, 1,4-benzodioxanyl, dihydrobenzofuryl, benzofuryl, 4-methoxyphenyl, dimethoxyphenyl, Fluorophenyl or difluorophenyl and R 3 is R 4 -C(O)-R 5 -, wherein R 4 is
Figure A9880618400082
wherein R 11 and R 12 are independently selected from methyl, ethyl and isopropyl, and R 13 , R 14 and R 15 are independently selected from hydrogen, lower alkyl, hydroxyl, amino, alkoxy, aryl, heterocyclic , halogen, carboxyl, nitro, alkylsulfonyl, arylsulfonyl, thioalkoxy, thioaryloxy, or cyano; and R is alkylene. 10.根据权利要求1的化合物，其中R为-C(O)2-G，其中G为氢或羧基保护基团，R1为取代或未取代的4-甲氧基苯基、4-氟代苯基、2-氟代苯基、3-氟代-4-乙氧基苯基、3-氟代-4-甲氧基苯基、4-乙氧基苯基、4-丙氧基苯基、4-异丙氧基苯基、2-氟代-4-乙氧基苯基、3-氟代-4-丙氧基苯基、3-甲氧基-4-丙氧基苯基、4-甲氧基甲氧基苯基、4-(2-甲氧基乙氧基)苯基、4-(2-乙氧基乙氧基)苯基、4-(2-异丙氧基乙氧基)苯基、4-羟基苯基、1，3-苯并间二氧杂环戊烯基、1，4-苯并二氧六环基或二氢苯并呋喃基，其中所述取代基选自烷氧基、烷氧基烷氧基和羧基烷氧基，R2为1，3-苯并间二氧杂环戊烯基、7-甲氧基-1，3-苯并间二氧杂环戊烯基、1，4-苯并二氧六环基、二氢苯并呋喃基、苯并呋喃基、4-甲氧基苯基、二甲氧基苯基、氟代苯基或二氟代苯基和R3为R4-C(O)-R5-，其中R4为
Figure A9880618400091
其中R11和R12独立选自甲基、乙基和异丙基，及R13、R14和R15独立选自氢、低级烷基、羟基、氨基、烷氧基、芳基、杂环、卤素、羧基、硝基、烷基磺酰基、芳基磺酰基、硫代烷氧基、硫代芳氧基或氰基；及R5为亚烷基。10. The compound according to claim 1, wherein R is -C(O) 2 -G, wherein G is hydrogen or a carboxyl protecting group, R 1 is substituted or unsubstituted 4-methoxyphenyl, 4-fluoro Substituted phenyl, 2-fluorophenyl, 3-fluoro-4-ethoxyphenyl, 3-fluoro-4-methoxyphenyl, 4-ethoxyphenyl, 4-propoxy Phenyl, 4-isopropoxyphenyl, 2-fluoro-4-ethoxyphenyl, 3-fluoro-4-propoxyphenyl, 3-methoxy-4-propoxyphenyl base, 4-methoxymethoxyphenyl, 4-(2-methoxyethoxy)phenyl, 4-(2-ethoxyethoxy)phenyl, 4-(2-isopropyl Oxyethoxy)phenyl, 4-hydroxyphenyl, 1,3-benzodioxolyl, 1,4-benzodioxanyl or dihydrobenzofuranyl, wherein The substituent is selected from alkoxy, alkoxyalkoxy and carboxyalkoxy, R 2 is 1,3-benzodioxolyl, 7-methoxy-1,3- Benzodioxolyl, 1,4-benzodioxanyl, dihydrobenzofuryl, benzofuryl, 4-methoxyphenyl, dimethoxyphenyl, Fluorophenyl or difluorophenyl and R 3 is R 4 -C(O)-R 5 -, wherein R 4 is
Figure A9880618400091
wherein R 11 and R 12 are independently selected from methyl, ethyl and isopropyl, and R 13 , R 14 and R 15 are independently selected from hydrogen, lower alkyl, hydroxyl, amino, alkoxy, aryl, heterocyclic , halogen, carboxyl, nitro, alkylsulfonyl, arylsulfonyl, thioalkoxy, thioaryloxy, or cyano; and R is alkylene. 11.具有下式的权利要求1的化合物或其药学上可接受的盐：
Figure A9880618400101
其中R为-(CH2)m-W，其中m为0至6的整数，W为11. A compound of claim 1 having the following formula, or a pharmaceutically acceptable salt thereof:
Figure A9880618400101
Wherein R is -(CH 2 ) m -W, wherein m is an integer from 0 to 6, and W is (a)-C(O)2-G，其中G为氢或羧基保护基团，(a)-C(O) 2 -G, wherein G is hydrogen or carboxyl protecting group, (b)-PO3H2，(b)-PO 3 H 2 , (c)-P(O)(OH)E，其中E为氢、低级烷基或芳基烷基，(c)-P(O)(OH)E, wherein E is hydrogen, lower alkyl or arylalkyl, (d)-CN，(d)-CN, (e)-C(O)NHR17，其中R17为低级烷基，(e)-C(O)NHR 17 , wherein R 17 is lower alkyl, (f)烷基氨基羰基，(f) alkylaminocarbonyl, (g)二烷基氨基羰基，(g) dialkylaminocarbonyl, (h)四唑基，(h) tetrazolyl, (I)羟基，(I) hydroxyl, (j)烷氧基，(j) alkoxy, (k)亚磺酰氨基，(k) sulfonamido, (l)-C(O)NHS(O)2R16，其中R16为低级烷基、卤代烷基、芳基或二烷基氨基，(l)-C(O)NHS(O) 2 R 16 , wherein R 16 is lower alkyl, haloalkyl, aryl or dialkylamino, (m)-S(O)2NHC(O)R16，其中R16如上述所定义，
Figure A9880618400111
R1和R2独立选自氢、低级烷基、链烯基、炔基、烷氧基烷基、烷氧基羰基烷基、羟基烷基、卤代烷基、卤代烷氧基烷基、烷氧基烷氧基烷基、硫代烷氧基烷氧基烷基、环烷基、环烷基烷基、氨基羰基烷基、烷基氨基羰基烷基、二烷基氨基羰基烷基、氨基羰基链烯基、烷基氨基羰基链烯基、二烷基氨基羰基链烯基、羟基链烯基、芳基、芳基烷基、芳氧基烷基、芳基烷氧基烷基、杂环基、(杂环基)烷基和(Raa)(Rbb)N-Rcc-其中Raa为芳基或芳基烷基，Rbb为氢或链烷酰基和Rcc为亚烷基，前提为R1和R2之一或二者不为氢；R3为R4-C(O)-R5-或R6-S(O)2-R7-，其中R5为(i)共价键，(ii)亚烷基，(iii)亚链烯基，(iv)-N(R20)-R8-或-R8a-N(R20)-R8-，其中R8和R8a独立选自亚烷基和亚链烯基；和R20为氢、低级烷基、链烯基、卤代烷基、烷氧基烷基、卤代烷氧基烷基、环烷基或环烷基烷基或(v)-O-R9-或-R9a-O-R9-，其中R9和R9a独立选自亚烷基；R7为(i)一个共价键，(ii)亚烷基，(iii)亚链烯基或(iv)-N(R21)-R10-或-R10a-N(R21)-R10-其中R10和R10a独立选自亚烷基和亚链烯基；而R21为氢、低级烷基、链烯基、卤代烷基、烷氧基烷基、卤代烷氧基烷基、芳基或芳基烷基；其中R4和R6为
Figure A9880618400121
其中R11和R12独立选自低级烷基、氰基、卤素、烷氧基、卤代烷基和苯基，R13、R14和R15独立选自氢、低级烷基、羟基、氨基、烷氧基、芳基、杂环、卤素、羧基、硝基、烷基磺酰基、芳基磺酰基、硫代烷氧基、硫代芳氧基或氰基；或(ii)杂环基(氨基)。(m)-S(O) 2 NHC(O)R 16 , wherein R 16 is as defined above,
Figure A9880618400111
R and R are independently selected from hydrogen, lower alkyl, alkenyl, alkynyl, alkoxyalkyl, alkoxycarbonylalkyl, hydroxyalkyl, haloalkyl, haloalkoxyalkyl, alkoxy Alkoxyalkyl, thioalkoxyalkoxyalkyl, cycloalkyl, cycloalkylalkyl, aminocarbonylalkyl, alkylaminocarbonylalkyl, dialkylaminocarbonylalkyl, aminocarbonyl chain Alkenyl, alkylaminocarbonylalkenyl, dialkylaminocarbonylalkenyl, hydroxyalkenyl, aryl, arylalkyl, aryloxyalkyl, arylalkoxyalkyl, heterocyclyl , (heterocyclyl)alkyl and (R aa )(R bb )NR cc - where R aa is aryl or arylalkyl, R bb is hydrogen or alkanoyl and R cc is alkylene, provided that One or both of R 1 and R 2 is not hydrogen; R 3 is R 4 -C(O)-R 5 - or R 6 -S(O) 2 -R 7 -, wherein R 5 is (i) Valence bond, (ii) alkylene, (iii) alkenylene, (iv) -N(R 20 )-R 8 - or -R 8a -N(R 20 )-R 8 -, wherein R 8 and R is independently selected from alkylene and alkenylene; and R is hydrogen, lower alkyl, alkenyl, haloalkyl, alkoxyalkyl, haloalkoxyalkyl, cycloalkyl, or cycloalkyl Alkyl or (v) -OR 9 -or -R 9a -OR 9 -, wherein R 9 and R 9a are independently selected from alkylene; R 7 is (i) a covalent bond, (ii) alkylene, (iii) alkenylene or (iv) -N(R 21 )-R 10 -or -R 10a -N(R 21 )-R 10 -wherein R 10 and R 10a are independently selected from alkylene and chain alkenyl; and R 21 is hydrogen, lower alkyl, alkenyl, haloalkyl, alkoxyalkyl, haloalkoxyalkyl, aryl or arylalkyl; wherein R 4 and R 6 are
Figure A9880618400121
Wherein R 11 and R 12 are independently selected from lower alkyl, cyano, halogen, alkoxy, haloalkyl and phenyl, R 13 , R 14 and R 15 are independently selected from hydrogen, lower alkyl, hydroxyl, amino, alkane oxy, aryl, heterocycle, halogen, carboxy, nitro, alkylsulfonyl, arylsulfonyl, thioalkoxy, thioaryloxy or cyano; or (ii) heterocyclyl (amino ). 12.权利要求11的化合物，其中R3为R4-C(O)-R5-，其中R4为如本文所定义而R5为亚烷基或R3位R6-S(O)2-R7-，其中R7为亚烷基，R6为如本文所定义。12. The compound of claim 11, wherein R 3 is R 4 -C(O)-R 5 -, wherein R 4 is as defined herein and R 5 is alkylene or R 3 -S(O) 2 -R 7 -, wherein R 7 is an alkylene group, and R 6 is as defined herein. 13.根据权利要求11的化合物，其中R为-C(O)2-G，其中G为氢或羧基保护基团，或R为四唑基或R为-C(O)-NHS(O)2R16，其中R16为低级烷基、卤代烷基或芳基，R1和R2独立选自(i)低级烷基、(ii)环烷基、(iii)取代的或未取代的芳基、(iv)取代的或未取代的杂环基，及R3为R4-C(O)-R5-，其中R4如本文所定义和R5为亚烷基或R3为R6-S(O)2-R7-，其中R7为亚烷基和R6如本文所定义。13. The compound according to claim 11, wherein R is -C(O) 2 -G, wherein G is hydrogen or a carboxyl protecting group, or R is tetrazolyl or R is -C(O)-NHS(O) 2 R 16 , wherein R 16 is lower alkyl, haloalkyl or aryl, R 1 and R 2 are independently selected from (i) lower alkyl, (ii) cycloalkyl, (iii) substituted or unsubstituted aryl group, (iv) substituted or unsubstituted heterocyclyl, and R 3 is R 4 -C(O)-R 5 -, wherein R 4 is as defined herein and R 5 is alkylene or R 3 is R 6 -S(O) 2 -R 7 -, wherein R 7 is alkylene and R 6 is as defined herein. 14.根据权利要求11的化合物，其中R为-C(O)2-G，其中G为氢或羧基保护基团、四唑基或-C(O)-NHS(O)2R16，其中R16为低级烷基、卤代烷基或芳基，R1为(i)烷氧基烷基、(ii)环烷基、(iii)苯基，(iv)吡啶基，(v)呋喃基或(vi)取代或未取代的4-甲氧基苯基、4-氟代苯基、3-氟代苯基、4-乙氧基苯基、4-丙氧基苯基、4-异丙氧基苯基、4-三氟甲基苯基、4-五氟乙基苯基、2-氟代-4-乙氧基苯基、3-氟代-4-甲氧基苯基、3-氟代-4-乙氧基苯基、3-氟代-4-丙氧基苯基、3-甲氧基-4-丙氧基苯基、2-氟代苯基、4-甲氧基甲氧基苯基、4-(2-甲氧基乙氧基)苯基、4-(2-乙氧基乙氧基)苯基、4-(2-异丙氧基乙氧基)苯基、4-羟基苯基、1，3-苯并间二氧杂环戊烯基、1，4-苯并二氧六环基或二氢苯并呋喃基，其中所述取代基选自烷氧基、烷氧基烷氧基和羧基烷氧基，R2为取代的或未取代的1，3-苯并间二氧杂环戊烯基、7-甲氧基-1，3-苯并间二氧杂环戊烯基、1，4-苯并二氧六环基、8-甲氧基-1，4-苯并二氧六环基、二氢苯并呋喃基、苯并呋喃基、4-甲氧基苯基、二甲氧基苯基、氟代苯基或二氟代苯基和R3为R4-C(O)-R5-，其中R4如本文所定义和R5为亚烷基或R3为R6-S(O)2-R7-，其中R7为亚烷基和R6为如本文所定义。14. The compound according to claim 11, wherein R is -C(O) 2 -G, wherein G is hydrogen or a carboxyl protecting group, tetrazolyl or -C(O)-NHS(O) 2 R 16 , wherein R 16 is lower alkyl, haloalkyl or aryl, R 1 is (i) alkoxyalkyl, (ii) cycloalkyl, (iii) phenyl, (iv) pyridyl, (v) furyl or (vi) Substituted or unsubstituted 4-methoxyphenyl, 4-fluorophenyl, 3-fluorophenyl, 4-ethoxyphenyl, 4-propoxyphenyl, 4-isopropyl Oxyphenyl, 4-trifluoromethylphenyl, 4-pentafluoroethylphenyl, 2-fluoro-4-ethoxyphenyl, 3-fluoro-4-methoxyphenyl, 3 -Fluoro-4-ethoxyphenyl, 3-fluoro-4-propoxyphenyl, 3-methoxy-4-propoxyphenyl, 2-fluorophenyl, 4-methoxy methoxyphenyl, 4-(2-methoxyethoxy)phenyl, 4-(2-ethoxyethoxy)phenyl, 4-(2-isopropoxyethoxy) Phenyl, 4-hydroxyphenyl, 1,3-benzodioxolyl, 1,4-benzodioxanyl or dihydrobenzofuryl, wherein the substituent is selected from Alkoxy, alkoxyalkoxy and carboxyalkoxy, R 2 is substituted or unsubstituted 1,3-benzodioxolyl, 7-methoxy-1,3- Benzodioxolyl, 1,4-benzodioxanyl, 8-methoxy-1,4-benzodioxanyl, dihydrobenzofuranyl, benzo Furanyl, 4-methoxyphenyl, dimethoxyphenyl, fluorophenyl or difluorophenyl and R 3 is R 4 -C(O)-R 5 -, wherein R 4 is as herein described Definitions and R 5 is alkylene or R 3 is R 6 -S(O) 2 -R 7 -, wherein R 7 is alkylene and R 6 is as defined herein. 15.根据权利要求11的化合物，其中R为-C(O)2-G，其中G为氢或羧基保护基团、四唑基或-C(O)-NHS(O)2R16其中R16为低级烷基、卤代烷基或芳基，R1选自：(i)烷氧基烷基，(ii)环烷基，(iii)苯基，(iv)吡啶基，(v)呋喃基或(vi)取代或未取代的4-甲氧基苯基、4-氟代苯基、3-氟代苯基、4-乙氧基苯基、4-丙氧基苯基、4-异丙氧基苯基、4-三氟甲基苯基、4-五氟乙基苯基、2-氟代-4-乙氧基苯基、3-氟代-4-甲氧基苯基、3-氟代-4-乙氧基苯基、3-氟代-4-丙氧基苯基、3-甲氧基-4-丙氧基苯基、2-氟代苯基、4-甲氧基甲氧基苯基、4-(2-甲氧基乙氧基)苯基、4-(2-乙氧基乙氧基)苯基、4-(2-异丙氧基乙氧基)苯基、4-羟基苯基、1，3-苯并间二氧杂环戊烯基、1，4-苯并二氧六环基或二氢苯并呋喃基，其中所述取代基选自烷氧基、烷氧基烷氧基和羧基烷氧基，R2为取代的或未取代的1，3-苯并间二氧杂环戊烯基、7-甲氧基-1，3-苯并间二氧杂环戊烯基、1，4-苯并二氧六环基、8-甲氧基-1，4-苯并二氧六环基、二氢苯并呋喃基、苯并呋喃基、4-甲氧基苯基、二甲氧基苯基、氟代苯基或二氟代苯基和R3为R4-C(O)-R5-，其中R4如本文所定义和R5为亚烷基。15. The compound according to claim 11, wherein R is -C(O) 2 -G, wherein G is hydrogen or a carboxyl protecting group, tetrazolyl or -C(O)-NHS(O) 2 R 16 wherein R 16 is lower alkyl, haloalkyl or aryl, R is selected from: (i) alkoxyalkyl, (ii) cycloalkyl, (iii) phenyl, (iv) pyridyl, (v) furyl or (vi) substituted or unsubstituted 4-methoxyphenyl, 4-fluorophenyl, 3-fluorophenyl, 4-ethoxyphenyl, 4-propoxyphenyl, 4-iso Propoxyphenyl, 4-trifluoromethylphenyl, 4-pentafluoroethylphenyl, 2-fluoro-4-ethoxyphenyl, 3-fluoro-4-methoxyphenyl, 3-fluoro-4-ethoxyphenyl, 3-fluoro-4-propoxyphenyl, 3-methoxy-4-propoxyphenyl, 2-fluorophenyl, 4-methyl Oxymethoxyphenyl, 4-(2-methoxyethoxy)phenyl, 4-(2-ethoxyethoxy)phenyl, 4-(2-isopropoxyethoxy ) phenyl, 4-hydroxyphenyl, 1,3-benzodioxolyl, 1,4-benzodioxanyl or dihydrobenzofuranyl, wherein the substituents are selected from from alkoxy, alkoxyalkoxy and carboxyalkoxy, R 2 is substituted or unsubstituted 1,3-benzodioxol, 7-methoxy-1,3 -Benzodioxolyl, 1,4-benzodioxanyl, 8-methoxy-1,4-benzodioxanyl, dihydrobenzofuranyl, benzene Furanyl, 4-methoxyphenyl, dimethoxyphenyl, fluorophenyl or difluorophenyl and R 3 is R 4 -C(O)-R 5 -, wherein R 4 is as herein defined and R 5 is an alkylene group. 16.根据权利要求11的化合物，其中R为-C(O)2-G，其中G为氢或羧基保护基团、四唑基或-C(O)-NHS(O)2R16其中R16为低级烷基或卤代烷基，R1为取代或未取代的4-甲氧基苯基、4-氟代苯基、2-氟代苯基、4-乙氧基苯基、4-丙氧基苯基、4-异丙氧基苯基、3-氟代-4-甲氧基苯基、3-氟代-4-乙氧基苯基、2-氟代-4-乙氧基苯基、3-氟代-4-丙氧基苯基、3-甲氧基-4-丙氧基苯基、4-三氟甲基苯基、4-五氟乙基苯基、4-甲氧基甲氧基苯基、4-(2-甲氧基乙氧基)苯基、4-(2-乙氧基乙氧基)苯基、4-(2-异丙氧基乙氧基)苯基、4-羟基苯基、1，3-苯并间二氧杂环戊烯基、1，4-苯并二氧六环基或二氢苯并呋喃基，其中所述取代基选自烷氧基、烷氧基烷氧基和羧基烷氧基，R2为1，3-苯并间二氧杂环戊烯基、7-甲氧基-1，3-苯并间二氧杂环戊烯基、1，4-苯并二氧六环基、二氢苯并呋喃基、苯并呋喃基、4-甲氧基苯基、二甲氧基苯基、氟代苯基或二氟代苯基和R3为R4-C(O)-R5-，其中R4如本文所定义和R5为亚烷基。16. The compound according to claim 11, wherein R is -C(O) 2 -G, wherein G is hydrogen or a carboxyl protecting group, tetrazolyl or -C(O)-NHS(O) 2 R 16 wherein R 16 is lower alkyl or haloalkyl, R 1 is substituted or unsubstituted 4-methoxyphenyl, 4-fluorophenyl, 2-fluorophenyl, 4-ethoxyphenyl, 4-propane Oxyphenyl, 4-isopropoxyphenyl, 3-fluoro-4-methoxyphenyl, 3-fluoro-4-ethoxyphenyl, 2-fluoro-4-ethoxy Phenyl, 3-fluoro-4-propoxyphenyl, 3-methoxy-4-propoxyphenyl, 4-trifluoromethylphenyl, 4-pentafluoroethylphenyl, 4- Methoxymethoxyphenyl, 4-(2-methoxyethoxy)phenyl, 4-(2-ethoxyethoxy)phenyl, 4-(2-isopropoxyethoxy base) phenyl, 4-hydroxyphenyl, 1,3-benzodioxolyl, 1,4-benzodioxanyl or dihydrobenzofuranyl, wherein the substituent selected from alkoxy, alkoxyalkoxy and carboxyalkoxy, R 2 is 1,3-benzodioxolyl, 7-methoxy-1,3-benzodioxol Oxolyl, 1,4-benzodioxanyl, dihydrobenzofuryl, benzofuryl, 4-methoxyphenyl, dimethoxyphenyl, fluorophenyl or difluorophenyl and R 3 is R 4 —C(O)—R 5 —, wherein R 4 is as defined herein and R 5 is alkylene. 17.根据权利要求11的化合物，其中R为-C(O)2-G，其中G为氢或羧基保护基团，R1为取代或未取代的4-甲氧基苯基、4-氟代苯基、2-氟代苯基、3-氟代-4-乙氧基苯基、3-氟代-4-甲氧基苯基、4-乙氧基苯基、4-丙氧基苯基、4-异丙氧基苯基、3-氟代-4-丙氧基苯基、3-甲氧基-4-丙氧基苯基、4-甲氧基甲氧基苯基、4-(2-甲氧基乙氧基)苯基、4-(2-乙氧基乙氧基)苯基、4-(2-异丙氧基乙氧基)苯基、4-羟基苯基、1，3-苯并间二氧杂环戊烯基、1，4-苯并二氧六环基或二氢苯并呋喃基，其中所述取代基选自烷氧基、烷氧基烷氧基和羧基烷氧基，R2为1，3-苯并间二氧杂环戊烯基、7-甲氧基-1，3-苯并间二氧杂环戊烯基、1，4-苯并二氧六环基、二氢苯并呋喃基、苯并呋喃基、4-甲氧基苯基、二甲氧基苯基、氟代苯基或二氟代苯基和R3为R4-C(O)-R5-，其中R4为
Figure A9880618400151
其中R11和R12独立选自低级烷基，及R13、R14和R15独立选自氢、低级烷基、羟基、氨基、烷氧基、芳基、杂环、卤素、羧基、硝基、烷基磺酰基、芳基磺酰基、硫代烷氧基、硫代芳氧基或氰基；及R5为亚烷基。17. The compound according to claim 11, wherein R is -C(O) 2 -G, wherein G is hydrogen or a carboxyl protecting group, R 1 is substituted or unsubstituted 4-methoxyphenyl, 4-fluoro Substituted phenyl, 2-fluorophenyl, 3-fluoro-4-ethoxyphenyl, 3-fluoro-4-methoxyphenyl, 4-ethoxyphenyl, 4-propoxy Phenyl, 4-isopropoxyphenyl, 3-fluoro-4-propoxyphenyl, 3-methoxy-4-propoxyphenyl, 4-methoxymethoxyphenyl, 4-(2-methoxyethoxy)phenyl, 4-(2-ethoxyethoxy)phenyl, 4-(2-isopropoxyethoxy)phenyl, 4-hydroxybenzene 1,3-benzodioxolyl, 1,4-benzodioxanyl or dihydrobenzofuryl, wherein the substituent is selected from alkoxy, alkoxy Alkoxy and carboxyalkoxy, R 2 is 1,3-benzodioxol, 7-methoxy-1,3-benzodioxol, 1, 4-benzodioxanyl, dihydrobenzofuranyl, benzofuryl, 4-methoxyphenyl, dimethoxyphenyl, fluorophenyl or difluorophenyl and R3 is R 4 -C(O)-R 5 -, wherein R 4 is
Figure A9880618400151
wherein R 11 and R 12 are independently selected from lower alkyl, and R 13 , R 14 and R 15 are independently selected from hydrogen, lower alkyl, hydroxyl, amino, alkoxy, aryl, heterocycle, halogen, carboxyl, nitric acid radical, alkylsulfonyl, arylsulfonyl, thioalkoxy, thioaryloxy, or cyano; and R is alkylene. 18.根据权利要求11的化合物，其中R为-C(O)2-G，其中G为氢或羧基保护基团，R1为取代或未取代的4-甲氧基苯基、4-氟代苯基、2-氟代苯基、3-氟代-4-乙氧基苯基、3-氟代-4-甲氧基苯基、4-乙氧基苯基、4-丙氧基苯基、4-异丙氧基苯基、2-氟代-4-乙氧基苯基、3-氟代-4-丙氧基苯基、3-甲氧基-4-丙氧基苯基、4-甲氧基甲氧基苯基、4-(2-甲氧基乙氧基)苯基、4-(2-乙氧基乙氧基)苯基、4-(2-异丙氧基乙氧基)苯基、4-羟基苯基、1，3-苯并间二氧杂环戊烯基、1，4-苯并二氧六环基或二氢苯并呋喃基，其中所述取代基选自烷氧基、烷氧基烷氧基和羧基烷氧基，R2为1，3-苯并间二氧杂环戊烯基、7-甲氧基-1，3-苯并间二氧杂环戊烯基、1，4-苯并二氧六环基、二氢苯并呋喃基、苯并呋喃基、4-甲氧基苯基、二甲氧基苯基、氟代苯基或二氟代苯基和R3为R4-C(O)-R5-，其中R4为
Figure A9880618400161
其中R11和R12独立选自低级烷基、烷氧基和卤素，及R13、R14和R15独立选自氢、低级烷基、羟基、氨基、烷氧基、芳基、杂环、卤素、羧基、硝基、烷基磺酰基、芳基磺酰基、硫代烷氧基、硫代芳氧基或氰基；及R5为亚烷基。18. The compound according to claim 11, wherein R is -C(O) 2 -G, wherein G is hydrogen or a carboxyl protecting group, R is substituted or unsubstituted 4-methoxyphenyl, 4-fluoro Substituted phenyl, 2-fluorophenyl, 3-fluoro-4-ethoxyphenyl, 3-fluoro-4-methoxyphenyl, 4-ethoxyphenyl, 4-propoxy Phenyl, 4-isopropoxyphenyl, 2-fluoro-4-ethoxyphenyl, 3-fluoro-4-propoxyphenyl, 3-methoxy-4-propoxyphenyl base, 4-methoxymethoxyphenyl, 4-(2-methoxyethoxy)phenyl, 4-(2-ethoxyethoxy)phenyl, 4-(2-isopropyl Oxyethoxy)phenyl, 4-hydroxyphenyl, 1,3-benzodioxolyl, 1,4-benzodioxanyl or dihydrobenzofuranyl, wherein The substituent is selected from alkoxy, alkoxyalkoxy and carboxyalkoxy, R 2 is 1,3-benzodioxolyl, 7-methoxy-1,3- Benzodioxolyl, 1,4-benzodioxanyl, dihydrobenzofuryl, benzofuryl, 4-methoxyphenyl, dimethoxyphenyl, Fluorophenyl or difluorophenyl and R 3 is R 4 -C(O)-R 5 -, wherein R 4 is
Figure A9880618400161
wherein R 11 and R 12 are independently selected from lower alkyl, alkoxy and halogen, and R 13 , R 14 and R 15 are independently selected from hydrogen, lower alkyl, hydroxyl, amino, alkoxy, aryl, heterocyclic , halogen, carboxyl, nitro, alkylsulfonyl, arylsulfonyl, thioalkoxy, thioaryloxy, or cyano; and R is alkylene. 19.根据权利要求11的化合物，其中R为-C(O)2-G，其中G为氢或羧基保护基团，R1为取代或未取代的4-甲氧基苯基、4-氟代苯基、2-氟代苯基、3-氟代-4-乙氧基苯基、3-氟代-4-甲氧基苯基、4-乙氧基苯基、4-丙氧基苯基、4-异丙氧基苯基、2-氟代-4-乙氧基苯基、3-氟代-4-丙氧基苯基、3-甲氧基-4-丙氧基苯基、4-甲氧基甲氧基苯基、4-(2-甲氧基乙氧基)苯基、4-(2-乙氧基乙氧基)苯基、4-(2-异丙氧基乙氧基)苯基、4-羟基苯基、1，3-苯并间二氧杂环戊烯基、1，4-苯并二氧六环基或二氢苯并呋喃基，其中所述取代基选自烷氧基、烷氧基烷氧基和羧基烷氧基，R2为1，3-苯并间二氧杂环戊烯基、7-甲氧基-1，3-苯并间二氧杂环戊烯基、1，4-苯并二氧六环基、二氢苯并呋喃基、苯并呋喃基、4-甲氧基苯基、二甲氧基苯基、氟代苯基或二氟代苯基和R3为R4-C(O)-R5-，其中R4为其中R11和R12独立选自甲基、乙基和异丙基，及R13、R14和R15独立选自氢、低级烷基、羟基、氨基、烷氧基、芳基、杂环、卤素、羧基、硝基、烷基磺酰基、芳基磺酰基、硫代烷氧基、硫代芳氧基或氰基；及R5为亚烷基。19. The compound according to claim 11, wherein R is -C(O) 2 -G, wherein G is hydrogen or a carboxyl protecting group, R 1 is substituted or unsubstituted 4-methoxyphenyl, 4-fluoro Substituted phenyl, 2-fluorophenyl, 3-fluoro-4-ethoxyphenyl, 3-fluoro-4-methoxyphenyl, 4-ethoxyphenyl, 4-propoxy Phenyl, 4-isopropoxyphenyl, 2-fluoro-4-ethoxyphenyl, 3-fluoro-4-propoxyphenyl, 3-methoxy-4-propoxyphenyl base, 4-methoxymethoxyphenyl, 4-(2-methoxyethoxy)phenyl, 4-(2-ethoxyethoxy)phenyl, 4-(2-isopropyl Oxyethoxy)phenyl, 4-hydroxyphenyl, 1,3-benzodioxolyl, 1,4-benzodioxanyl or dihydrobenzofuranyl, wherein The substituent is selected from alkoxy, alkoxyalkoxy and carboxyalkoxy, R 2 is 1,3-benzodioxolyl, 7-methoxy-1,3- Benzodioxolyl, 1,4-benzodioxanyl, dihydrobenzofuryl, benzofuryl, 4-methoxyphenyl, dimethoxyphenyl, Fluorophenyl or difluorophenyl and R 3 is R 4 -C(O)-R 5 -, wherein R 4 is wherein R 11 and R 12 are independently selected from methyl, ethyl and isopropyl, and R 13 , R 14 and R 15 are independently selected from hydrogen, lower alkyl, hydroxyl, amino, alkoxy, aryl, heterocyclic , halogen, carboxyl, nitro, alkylsulfonyl, arylsulfonyl, thioalkoxy, thioaryloxy, or cyano; and R is alkylene. 20.根据权利要求11的化合物，其中R为-C(O)2-G，其中G为氢或羧基保护基团，R1为取代或未取代的4-甲氧基苯基、4-氟代苯基、2-氟代苯基、3-氟代-4-乙氧基苯基、3-氟代-4-甲氧基苯基、4-乙氧基苯基、4-丙氧基苯基、4-异丙氧基苯基、2-氟代-4-乙氧基苯基、3-氟代-4-丙氧基苯基、3-甲氧基-4-丙氧基苯基、4-甲氧基甲氧基苯基、4-(2-甲氧基乙氧基)苯基、4-(2-乙氧基乙氧基)苯基、4-(2-异丙氧基乙氧基)苯基、4-羟基苯基、1，3-苯并间二氧杂环戊烯基、1，4-苯并二氧六环基或二氢苯并呋喃基，其中所述取代基选自烷氧基、烷氧基烷氧基和羧基烷氧基，R2为1，3-苯并间二氧杂环戊烯基、7-甲氧基-1，3-苯并间二氧杂环戊烯基、1，4-苯并二氧六环基、二氢苯并呋喃基、苯并呋喃基、4-甲氧基苯基、二甲氧基苯基、氟代苯基或二氟代苯基和R3为R4-C(O)-R5-，其中R4为
Figure A9880618400172
其中R11和R12独立选自甲基、乙基和异丙基，及R13、R14和R15独立选自氢、低级烷基、羟基、氨基、烷氧基、芳基、杂环、卤素、羧基、硝基或氰基，R5为亚烷基。20. The compound according to claim 11, wherein R is -C(O) 2 -G, wherein G is hydrogen or a carboxyl protecting group, R 1 is substituted or unsubstituted 4-methoxyphenyl, 4-fluoro Substituted phenyl, 2-fluorophenyl, 3-fluoro-4-ethoxyphenyl, 3-fluoro-4-methoxyphenyl, 4-ethoxyphenyl, 4-propoxy Phenyl, 4-isopropoxyphenyl, 2-fluoro-4-ethoxyphenyl, 3-fluoro-4-propoxyphenyl, 3-methoxy-4-propoxyphenyl base, 4-methoxymethoxyphenyl, 4-(2-methoxyethoxy)phenyl, 4-(2-ethoxyethoxy)phenyl, 4-(2-isopropyl Oxyethoxy)phenyl, 4-hydroxyphenyl, 1,3-benzodioxolyl, 1,4-benzodioxanyl or dihydrobenzofuranyl, wherein The substituent is selected from alkoxy, alkoxyalkoxy and carboxyalkoxy, R 2 is 1,3-benzodioxolyl, 7-methoxy-1,3- Benzodioxolyl, 1,4-benzodioxanyl, dihydrobenzofuryl, benzofuryl, 4-methoxyphenyl, dimethoxyphenyl, Fluorophenyl or difluorophenyl and R 3 is R 4 -C(O)-R 5 -, wherein R 4 is
Figure A9880618400172
wherein R 11 and R 12 are independently selected from methyl, ethyl and isopropyl, and R 13 , R 14 and R 15 are independently selected from hydrogen, lower alkyl, hydroxyl, amino, alkoxy, aryl, heterocyclic , halogen, carboxyl, nitro or cyano, R 5 is an alkylene group. 21.化合物选自：反，反-2-(4-甲氧基苯基)-4-(1，3-苯并间二氧杂环戊烯-5-基)-1-((2，6-二乙基)苯基氨基羰基甲基)-吡咯烷-3-羧酸，反，反-2-(4-丙氧基苯基)-4-(1，3-苯并间二氧杂环戊烯-5-基)-1-((2，6-二乙基)苯基氨基羰基甲基)-吡咯烷-3-羧酸，反，反-2-(3-氟代-4-甲氧基苯基)-4-(1，3-苯并间二氧杂环戊烯-5-基)-1-((2，6-二乙基)苯基氨基羰基甲基)-吡咯烷-3-羧酸，反，反-2-(3-氟代-4-乙氧基苯基)-4-(1，3-苯并间二氧杂环戊烯-5-基)-1-((2，6-二乙基)苯基氨基羰基甲基)-吡咯烷-3-羧酸，反，反-2-(3-氟代-4-甲氧基苯基)-4-(7-甲氧基-1，3-苯并间二氧杂环戊烯-5-基)-1-((2，6-二乙基)苯基氨基羰基甲基)-吡咯烷-3-羧酸，反，反-2-(3-甲氧基-4-丙氧基苯基)-4-(1，3-苯并间二氧杂环戊烯-5-基)-1-((2，6-二乙基)苯基氨基羰基甲基)-吡咯烷-3-羧酸，反，反-2-(4-乙氧基苯基)-4-(1，3-苯并间二氧杂环戊烯-5-基)-1-((2，6-二乙基)苯基氨基羰基甲基)-吡咯烷-3-羧酸，反，反-2-(4-丙氧基苯基)-4-(7-甲氧基-1，3-苯并间二氧杂环戊烯-5-基)-1-((2，6-二乙基)苯基氨基羰基甲基)-吡咯烷-3-羧酸，反，反-2-(3-甲氧基-4-丙氧基苯基)-4-(7-甲氧基-1，3-苯并间二氧杂环戊烯-5-基)-1-((2，6-二乙基)苯基氨基羰基甲基)-吡咯烷-3-羧酸，[2R，3R，4S]2-(4-甲氧基苯基)-4-(1，3-苯并间二氧杂环戊烯-5-基)-1-(N-(2，6-二乙基)苯基氨基羰基甲基)-吡咯烷-3-羧酸，[2R，3R，4S]2-(4-丙氧基苯基)-4-(1，3-苯并间二氧杂环戊烯-5-基)-1-(N-(2，6-二乙基)苯基氨基羰基甲基)-吡咯烷-3-羧酸，[2R，3R，4S]-2-(4-乙氧基苯基)-4-(1，3-苯并间二氧杂环戊烯-5-基)-1-((2，6-二乙基)苯基氨基羰基甲基)-吡咯烷-3-羧酸，反，反-2-(4-异丙氧基苯基)-4-(1，3-苯并间二氧杂环戊烯-5-基)-1-(2，6-二乙基苯基氨基羰基甲基)-吡咯烷-3-羧酸，反，反-2-(2-氟代-4-丙氧基苯基)-4-(1，3-苯并间二氧杂环戊烯-5-基)-1-(2，6-二乙基苯基氨基羰基甲基)-吡咯烷-3-羧酸，反，反-2-(4-(2-甲氧基乙氧基)苯基)-4-(1，3-苯并间二氧杂环戊烯-5-基)-1-(2，6-二乙基苯基氨基羰基甲基)-吡咯烷-3-羧酸，反，反-2-(4-(2-乙氧基乙氧基)苯基)-4-(1，3-苯并间二氧杂环戊烯-5-基)-1-(2，6-二乙基苯基氨基羰基甲基)-吡咯烷-3-羧酸，[2R，3R，4S]-2-(4-(2-甲氧基乙氧基)苯基)-4-(1，3-苯并间二氧杂环戊烯-5-基)-1-(2，6-二乙基苯基氨基羰基甲基)-吡咯烷-3-羧酸，[2R，3R，4S]-2-(4-(2-乙氧基乙氧基)苯基)-4-(1，3-苯并间二氧杂环戊烯-5-基)-1-(2，6-二乙基苯基氨基羰基甲基)-吡咯烷-3-羧酸，反，反-2-(4-(2-异丙氧基乙氧基)苯基)-4-(1，3-苯并间二氧杂环戊烯-5-基)-1-(2，6-二乙基苯基氨基羰基甲基)-吡咯烷-3-羧酸，或其药学上可接受的盐。21. The compound is selected from: trans, trans-2-(4-methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1-((2, 6-diethyl)phenylaminocarbonylmethyl)-pyrrolidine-3-carboxylic acid, trans, trans-2-(4-propoxyphenyl)-4-(1,3-benzodiox Helopenten-5-yl)-1-((2,6-diethyl)phenylaminocarbonylmethyl)-pyrrolidine-3-carboxylic acid, trans, trans-2-(3-fluoro- 4-methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1-((2,6-diethyl)phenylaminocarbonylmethyl) -Pyrrolidine-3-carboxylic acid, trans, trans-2-(3-fluoro-4-ethoxyphenyl)-4-(1,3-benzodioxol-5-yl )-1-((2,6-diethyl)phenylaminocarbonylmethyl)-pyrrolidine-3-carboxylic acid, trans, trans-2-(3-fluoro-4-methoxyphenyl) -4-(7-methoxy-1,3-benzodioxol-5-yl)-1-((2,6-diethyl)phenylaminocarbonylmethyl)-pyrrole Alkane-3-carboxylic acid, trans, trans-2-(3-methoxy-4-propoxyphenyl)-4-(1,3-benzodioxol-5-yl) -1-((2,6-diethyl)phenylaminocarbonylmethyl)-pyrrolidine-3-carboxylic acid, trans, trans-2-(4-ethoxyphenyl)-4-(1, 3-Benzodioxol-5-yl)-1-((2,6-diethyl)phenylaminocarbonylmethyl)-pyrrolidine-3-carboxylic acid, trans, trans-2 -(4-propoxyphenyl)-4-(7-methoxy-1,3-benzodioxol-5-yl)-1-((2,6-diethyl ) phenylaminocarbonylmethyl)-pyrrolidine-3-carboxylic acid, trans, trans-2-(3-methoxy-4-propoxyphenyl)-4-(7-methoxy-1, 3-Benzodioxol-5-yl)-1-((2,6-diethyl)phenylaminocarbonylmethyl)-pyrrolidine-3-carboxylic acid, [2R, 3R, 4S] 2-(4-methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1-(N-(2,6-diethyl) Phenylaminocarbonylmethyl)-pyrrolidine-3-carboxylic acid, [2R,3R,4S]2-(4-propoxyphenyl)-4-(1,3-benzodioxolane En-5-yl)-1-(N-(2,6-diethyl)phenylaminocarbonylmethyl)-pyrrolidine-3-carboxylic acid, [2R,3R,4S]-2-(4- Ethoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1-((2,6-diethyl)phenylaminocarbonylmethyl)-pyrrole Alkane-3-carboxylic acid, trans, trans-2-(4-isopropoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1-(2 , 6-diethylphenylaminocarbonylmethyl)-pyrrolidine-3-carboxylic acid, trans, trans-2-(2-fluoro-4-propoxyphenyl)-4-(1,3- Benzodioxol-5-yl)-1-(2,6-diethylphenylaminocarbonylmethyl)-pyrrolidine-3-carboxylic acid, trans, trans-2-(4- (2-methoxyethoxy)phenyl)-4-(1,3-benzodioxol-5-yl)-1-(2,6-diethylphenylaminocarbonyl Methyl)-pyrrolidine-3-carboxylic acid, trans, trans-2-(4-(2-ethoxyethoxy)phenyl)-4-(1,3-benzodioxolane En-5-yl)-1-(2,6-diethylphenylaminocarbonylmethyl)-pyrrolidine-3-carboxylic acid, [2R, 3R, 4S]-2-(4-(2-methyl Oxyethoxy)phenyl)-4-(1,3-benzodioxol-5-yl)-1-(2,6-diethylphenylaminocarbonylmethyl)- Pyrrolidine-3-carboxylic acid, [2R,3R,4S]-2-(4-(2-ethoxyethoxy)phenyl)-4-(1,3-benzodioxolane En-5-yl)-1-(2,6-diethylphenylaminocarbonylmethyl)-pyrrolidine-3-carboxylic acid, trans, trans-2-(4-(2-isopropoxyethyl Oxy)phenyl)-4-(1,3-benzodioxol-5-yl)-1-(2,6-diethylphenylaminocarbonylmethyl)-pyrrolidine- 3-carboxylic acid, or a pharmaceutically acceptable salt thereof. 22.根据权利要求21的化合物，其中所述化合物为反，反-2-(4-丙氧基苯基)-4-(1，3-苯并间二氧杂环戊烯-5-基)-1-((2，6-二乙基)苯基氨基羰基甲基)-吡咯烷-3-羧酸或其药学上可接受的盐。22. The compound according to claim 21, wherein said compound is trans, trans-2-(4-propoxyphenyl)-4-(1,3-benzodioxol-5-yl )-1-((2,6-diethyl)phenylaminocarbonylmethyl)-pyrrolidine-3-carboxylic acid or a pharmaceutically acceptable salt thereof. 23.根据权利要求21的化合物，其中所述化合物为[2R，3R，4S]2-(4-甲氧基苯基)-4-(1，3-苯并间二氧杂环戊烯-5-基)-1-(N-((2，6-二乙基)苯基氨基羰基甲基)-吡咯烷-3-羧酸或其药学上可接受的盐。23. The compound according to claim 21, wherein said compound is [2R, 3R, 4S] 2-(4-methoxyphenyl)-4-(1,3-benzodioxole- 5-yl)-1-(N-((2,6-diethyl)phenylaminocarbonylmethyl)-pyrrolidine-3-carboxylic acid or a pharmaceutically acceptable salt thereof. 24.根据权利要求21的化合物，其中所述化合物为[2R，3R，4S]2-(4-丙氧基苯基)-4-(1，3-苯并间二氧杂环戊烯-5-基)-1-(N-((2，6-二乙基)苯基氨基羰基甲基)-吡咯烷-3-羧酸或其药学上可接受的盐。24. The compound according to claim 21, wherein said compound is [2R, 3R, 4S] 2-(4-propoxyphenyl)-4-(1,3-benzodioxole- 5-yl)-1-(N-((2,6-diethyl)phenylaminocarbonylmethyl)-pyrrolidine-3-carboxylic acid or a pharmaceutically acceptable salt thereof. 25.根据权利要求21的化合物，其中所述化合物为[2R，3R，4S]-2-(4-乙氧基苯基)-4-(1，3-苯并间二氧杂环戊烯-5-基)-1-((2，6-二乙基)苯基氨基羰基甲基)-吡咯烷-3-羧酸或其药学上可接受的盐。25. The compound according to claim 21, wherein said compound is [2R, 3R, 4S]-2-(4-ethoxyphenyl)-4-(1,3-benzodioxole -5-yl)-1-((2,6-diethyl)phenylaminocarbonylmethyl)-pyrrolidine-3-carboxylic acid or a pharmaceutically acceptable salt thereof. 26.根据权利要求21的化合物，其中所述化合物为反，反-2-(4-(2-甲氧基乙氧基)苯基)-4-(1，3-苯并间二氧杂环戊烯-5-基)-1-(2，6-二乙基苯基氨基羰基甲基)-吡咯烷-3-羧酸或其药学上可接受的盐。26. The compound according to claim 21, wherein said compound is trans, trans-2-(4-(2-methoxyethoxy)phenyl)-4-(1,3-benzodioxa Cyclopenten-5-yl)-1-(2,6-diethylphenylaminocarbonylmethyl)-pyrrolidine-3-carboxylic acid or a pharmaceutically acceptable salt thereof. 27.拮抗内皮素的药用组合物，包含治疗有效量的权利要求1的化合物和药学上可接受的载体。27. An endothelin-antagonizing pharmaceutical composition comprising a therapeutically effective amount of the compound of claim 1 and a pharmaceutically acceptable carrier. 28.拮抗内皮素的药用组合物，包含治疗有效量的权利要求11的化合物和药学上可接受的载体。28. An endothelin-antagonizing pharmaceutical composition comprising a therapeutically effective amount of the compound of claim 11 and a pharmaceutically acceptable carrier. 29.拮抗内皮素的方法，包括给予需要此治疗的哺乳动物治疗有效量的权利要求1的化合物。29. A method of antagonizing endothelin comprising administering a therapeutically effective amount of a compound of claim 1 to a mammal in need of such treatment. 30.拮抗内皮素的方法，包括给予需要此治疗的哺乳动物治疗有效量的权利要求11的化合物。30. A method of antagonizing endothelin comprising administering a therapeutically effective amount of a compound of claim 11 to a mammal in need of such treatment. 31.治疗高血压、充血性心力衰竭、动脉损伤后的再狭窄、脑或心肌缺血或动脉粥样硬化症的方法，包括给予需要此治疗的哺乳动物治疗有效量的权利要求1的化合物。31. A method of treating hypertension, congestive heart failure, restenosis after arterial injury, cerebral or myocardial ischemia or atherosclerosis comprising administering a therapeutically effective amount of a compound of claim 1 to a mammal in need of such treatment. 32.治疗高血压、充血性心力衰竭、动脉损伤后的再狭窄、脑或心肌缺血或动脉粥样硬化症的方法，包括给予需要此治疗的哺乳动物治疗有效量的权利要求11的化合物。32. A method of treating hypertension, congestive heart failure, restenosis after arterial injury, cerebral or myocardial ischemia or atherosclerosis comprising administering a therapeutically effective amount of a compound of claim 11 to a mammal in need of such treatment. 33.治疗下列疾病的方法：冠脉心绞痛、脑血管痉挛、急性和慢性肺动脉高血压、急性和慢性肾衰竭、胃溃疡、环孢菌素诱导的肾毒性、内毒素诱导的毒性、哮喘、LPL-相关的脂蛋白紊乱、纤维变性或增生性疾病、血小板凝集、血栓症、IL-2介导的心脏毒性、痛觉、结肠炎、血管渗透性疾病、缺血-再灌注损伤、全身性硬化症、肝硬化、成人呼吸窘迫综合征、特发性心肌病、红斑狼疮、糖尿病性视网膜病或其它视网膜病、牛皮癣、schleroderma、前列腺增生、心脏肥大、雷诺氏病、癌症、腺瘤、心绞痛、移植引起的动脉粥样硬化和偏头痛，该方法包括给予需要此治疗的哺乳动物治疗有效量的权利要求1的化合物。33. The method for treating the following diseases: coronary angina pectoris, cerebral vasospasm, acute and chronic pulmonary hypertension, acute and chronic renal failure, gastric ulcer, cyclosporin-induced nephrotoxicity, endotoxin-induced toxicity, asthma, LPL - Associated lipoprotein disturbances, fibrotic or proliferative disorders, platelet aggregation, thrombosis, IL-2-mediated cardiotoxicity, pain perception, colitis, vascular permeability disorders, ischemia-reperfusion injury, systemic sclerosis , cirrhosis, adult respiratory distress syndrome, idiopathic cardiomyopathy, lupus erythematosus, diabetic retinopathy or other retinopathy, psoriasis, schleroderma, prostatic hyperplasia, cardiac hypertrophy, Raynaud's disease, cancer, adenoma, angina, transplantation atherosclerosis and migraine, the method comprising administering a therapeutically effective amount of a compound of claim 1 to a mammal in need of such treatment. 34.治疗下列疾病的方法：冠脉心绞痛、脑血管痉挛、急性和慢性肺动脉高血压、急性和慢性肾衰竭、胃溃疡、环孢菌素诱导的肾毒性、内毒素诱导的毒性、哮喘、LPL-相关的脂蛋白紊乱、纤维变性或增生性疾病、血小板凝集、血栓症、IL-2介导的心脏毒性、痛觉、结肠炎、血管渗透性疾病、缺血-再灌注损伤、全身性硬化症、肝硬化、成人呼吸窘迫综合征、特发性心肌病、红斑狼疮、糖尿病性视网膜病或其它视网膜病、牛皮癣、schleroderma、前列腺增生、心脏肥大、雷诺氏病、癌症、腺瘤、心绞痛、移植引起的动脉粥样硬化和偏头痛，该方法包括给予需要此治疗的哺乳动物治疗有效量的权利要求11的化合物。34. Method for treating the following diseases: coronary angina pectoris, cerebral vasospasm, acute and chronic pulmonary hypertension, acute and chronic renal failure, gastric ulcer, cyclosporin-induced nephrotoxicity, endotoxin-induced toxicity, asthma, LPL - Associated lipoprotein disturbances, fibrotic or proliferative disorders, platelet aggregation, thrombosis, IL-2-mediated cardiotoxicity, pain perception, colitis, vascular permeability disorders, ischemia-reperfusion injury, systemic sclerosis , cirrhosis, adult respiratory distress syndrome, idiopathic cardiomyopathy, lupus erythematosus, diabetic retinopathy or other retinopathy, psoriasis, schleroderma, prostatic hyperplasia, cardiac hypertrophy, Raynaud's disease, cancer, adenoma, angina, transplantation atherosclerosis and migraine, the method comprising administering a therapeutically effective amount of a compound of claim 11 to a mammal in need of such treatment. 35.治疗高血压、充血性心力衰竭、动脉损伤后的再狭窄、脑或心肌缺血或动脉粥样硬化的方法，该方法包括给予需要此治疗的哺乳动物治疗有效量的权利要求1的化合物以及一种或多种心血管药物。35. A method of treating hypertension, congestive heart failure, restenosis after arterial injury, cerebral or myocardial ischemia or atherosclerosis, which method comprises administering a therapeutically effective amount of a compound of claim 1 to a mammal in need of such treatment and one or more cardiovascular medications. 36.治疗高血压、充血性心力衰竭、动脉损伤后的再狭窄、脑或心肌缺血或动脉粥样硬化的方法，该方法包括给予需要此治疗的哺乳动物治疗有效量的权利要求11的化合物以及一种或多种心血管药物。36. A method of treating hypertension, congestive heart failure, restenosis after arterial injury, cerebral or myocardial ischemia or atherosclerosis, which method comprises administering a therapeutically effective amount of a compound of claim 11 to a mammal in need of such treatment and one or more cardiovascular medications.
CN98806184A 1997-06-17 1998-06-08 Pyrrolidine carboxylic acid derivatives as endothelin antagonists Pending CN1265097A (en)

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US87718797A 1997-06-17 1997-06-17
US08/877,187 1997-06-17
US09/087,178 US6124341A (en) 1996-02-13 1998-05-29 Endothelin antagonists
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CN108569990A (en) * 2018-07-09 2018-09-25 张立国 Polysubstituted pyrrole alkane derivatives and its application as Rho kinase inhibitors in cancer
CN108929258A (en) * 2018-07-09 2018-12-04 张立国 A kind of Rho kinase inhibitor and its application in cancer treatment

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CN117362314B (en) * 2023-10-09 2025-11-04 广东省中医院（广州中医药大学第二附属医院、广州中医药大学第二临床医学院、广东省中医药科学院） Preparation method of 2-aryl-2,3,4,5-tetrahydro-1,4-epoxybenzozazepine compounds

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN108569990A (en) * 2018-07-09 2018-09-25 张立国 Polysubstituted pyrrole alkane derivatives and its application as Rho kinase inhibitors in cancer
CN108929258A (en) * 2018-07-09 2018-12-04 张立国 A kind of Rho kinase inhibitor and its application in cancer treatment

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