发明名称 Acylamino-substituted fused cyclopentanecarboxylic acid derivatives and their use as pharmaceuticals
摘要 The present invention relates to compounds of the formula I,; wherein A, Y, Z, R3 to R6, R20 to R22 and R50 have the meanings indicated in the claims, which are valuable pharmaceutical active compounds. Specifically, they are inhibitors of the endothelial differentiation gene receptor 2 (Edg-2, EDG2), which is activated by lysophosphatidic acid (LPA) and is also termed as LPA1 receptor, and are useful for the treatment of diseases such as atherosclerosis, myocardial infarction and heart failure, for example. The invention furthermore relates to processes for the preparation of the compounds of the formula I, their use and pharmaceutical compositions comprising them.
申请公布号 US9328071(B2) 申请公布日期 2016.05.03
申请号 US201414314780 申请日期 2014.06.25
申请人 SANOFI 发明人 Schaefer Matthias;Pernerstorfer Josef;Kadereit Dieter;Strobel Hartmut;Czechtizky Werngard;Chen L. Charlie;Safarova Alena;Weichsel Aleksandra;Patek Marcel
分类号 C07C237/38;C07D333/38;C07D213/82;C07C235/54;C07C235/62;C07C235/84;C07C317/22;C07C317/46;C07C323/62;C07C255/54;C07C255/57;C07C255/58;C07D207/08;C07D213/81;C07C307/10;C07C309/73;C07C311/08;C07C323/12;C07C323/19;C07D207/09;C07D209/12;C07D209/44;C07D211/22;C07D213/30;C07D213/68;C07D213/74;C07D213/75;C07D221/04;C07D231/12;C07D233/54;C07D233/84;C07D235/12;C07D241/38;C07D249/06;C07D261/04;C07D261/20;C07D263/32;C07D271/08;C07D277/24;C07D277/56;C07D285/06;C07D295/08;C07D295/20;C07D305/06;C07D307/12;C07D309/06;C07D319/06;C07D319/12;C07D333/16;C07D333/56;C07D333/78;C07D413/04;C07D417/04;C07D471/08;A61K31/196;A61K31/216;A61K31/277;A61K31/381;A61K31/439;A61K31/44;A61K31/4409;A61K31/445;A61K31/495;A61K31/4965;C07C231/02;C07C319/20;C07C323/42 主分类号 C07C237/38
代理机构 代理人 Bender Kelly L.
主权项 1. A method for treating a fibrotic disease in a patient in need thereof, comprising administering to the patient a pharmaceutically effective amount of a compound of formula (I), wherein ring A is a benzene ring, wherein the benzene ring is optionally substituted by one or more identical or different substituents chosen from the series consisting of halogen, R1, HO—, R1—O—, R1—C(O)—O—, R1—S(O)2—O—, R1—S(O)m—, H2N—, R1—NH—, R1—N(R1)—, R1—C(O)—NH—, R1—C(O)—N(R71)—, R1—S(O)2—NH—, R1—S(O)2—N(R71)—, R1—C(O)—, HO—C(O)—, R1—O—C(O)—, H2N—C(O)—, R1—NH—C(O)—, R1—N(R1)—C(O)—, H2N—S(O)2—, R1—NH—S(O)2—, R1—N(R1)—S(O)2—, NC—, O2N—, phenyl and Het; Y is chosen from the series consisting of N(R10), S, O, C(R12)═C(R13), N═C(R14) and C(R15)═N; Z is chosen from the series consisting of N and C(R16); R1, R11, R30, R33, R35, R54, R55, R57 and R58 are, independently of each other group R1, R11, R30, R33, R35, R54, R55, R57 and R58, chosen from the series consisting of (C1-C6)-alkyl, (C2-C6)-alkenyl, (C2-C6)-alkynyl, (C3-C7)-cycloalkyl and (C3-C7)-cycloalkyl-(C1-C4)-alkyl- which are all optionally substituted by one or more identical or different substituents R70; R3 and R5 are independently of each other chosen from the series consisting of hydrogen, (C1-C4)-alkyl, phenyl-(C1-C4)-alkyl, phenyl and hydroxy; R4 and R6 are independently of each other chosen from the series consisting of hydrogen and (C1-C4)-alkyl; R10 is chosen from the series consisting of hydrogen and R11; R12, R13, R14, R15 and R16 are independently of each other chosen from the series consisting of hydrogen, (C1-C4)-alkyl, HO—(C1-C4)-alkyl-, (C1-C4)-alkyl-O—, (C1-C4)-alkyl-S(O)m—, H2N—, (C1-C4)-alkyl-NH—, (C1-C4)-alkyl-N((C1-C4)-alkyl), (C1-C4)-alkyl-C(O)—, NC— and O2N—; R20 is chosen from the series consisting of hydrogen and (C1-C4)-alkyl; one of the groups R21 and R22 is a group of the formula II R24—R23—  II and the other of the groups R21 and R22 is chosen from the series consisting of hydrogen, halogen, R30, HO—, R30—O—, R30—C(O)—O—, R30—S(O)2—O—, R30—S(O)m—, H2N—, R30—NH—, R30—N(R30)—, R30—C(O)—NH—, R30—C(O)—N(R71)—, R30—S(O)2—NH—, R30—S(O)2—N(R71)—, R30—C(O)—, HO—C(O)—, R30—O—C(O)—, H2N—C(O)—, R30—NH—C(O)—, R30—N(R30)—C(O)—, H2N—S(O)2—, R30—NH—S(O)2—, R30—N(R30)—S(O)2—, NC—, O2N— and Het1; R23 is a direct bond or a chain consisting of 1 to 5 chain members of which 0, 1 or 2 chain members are identical or different hetero chain members chosen from the series consisting of N(R25), O, S, S(O) and S(O)2, but two hetero chain members can be present in adjacent positions only if one of them is chosen from the series consisting of S(O) and S(O)2 and the other is chosen from the series consisting of N(R25), O and S, and the other chain members are identical or different groups C(R26)(R26), wherein two adjacent groups C(R26)(R26) can be connected to each other by a double bond or a triple bond; R24 is chosen from the series consisting of hydrogen, R31, HO—, R31—O—, R31—C(O)—O—, R31—S(O)m—, H2N—, R31—NH—, R31—N(R31)—, R31—C(O)—NH—, R31—C(O)—N(R71)—, R31—S(O)2—NH—, R31—S(O)2—N(R71)—, R31—C(O)—, HO—C(O)—, R31—O—C(O)—, H2N—C(O)—, R31—NH—C(O)—, R31—N(R31)—C(O)—, H2N—S(O)2—, R31—NH—S(O)2—, R31—N(R31)—S(O)2—, NC— and a 3-membered to 10-membered, monocyclic, bicyclic or tricyclic ring which is saturated or unsaturated and contains 0, 1, 2 or 3 identical or different hetero ring members chosen from the series consisting of N, N(R32), O, S, S(O) and S(O)2, which ring is optionally substituted on ring carbon atoms by one or more identical or different substituents chosen from the series consisting of halogen, R33, HO—, R33—O—, R33—C(O)—O—, R33—S(O)2—O—, R33—S(O)m—, H2N—, R33—NH—, R33—N(R33)—, R33—C(O)—NH—, R33—C(O)—N(R71)—, R33—S(O)2—NH—, R33—S(O)2—N(R71)—, H2N—S(O)2—NH—, R33—NH—S(O)2—NH—, R33—N(R33)—S(O)2—NH—, H2N—S(O)2—N(R71)—, R33—NH—S(O)2—N(R71)—, R33—N(R33)—S(O)2—N(R71)—, R33—C(O)—, HO—C(O)—, R33—O—C(O)—, H2N—C(O)—, R33—NH—C(O)—, R33—N(R33)—C(O)—, H2N—S(O)2—, R33—NH—S(O)2—, R33—N(R33)—S(O)2—, NC—, O2N—, oxo, phenyl and Het, provided that the total number of C, N, O and S atoms which is present in the two groups R23 and R24, is at least 5; R25 is chosen from the series consisting of hydrogen and (C1-C4)-alkyl; R26, independently of each other group R26, is chosen from the series consisting of hydrogen, fluorine, (C1-C4)-alkyl and HO—, or two groups R26 bonded to the same carbon atom together are oxo, or two of the groups R26 or one group R25 and one group R26, together with the comprised chain members, form a 3-membered to 7-membered monocyclic ring which is saturated and contains 0, 1 or 2 identical or different hetero ring members chosen from the series consisting of N, N(R34), O, S, S(O) and S(O)2, which ring is optionally substituted on ring carbon atoms by one more identical or different substituents chosen from the series consisting of fluorine and (C1-C4)-alkyl; R31 is chosen from the series consisting of (C1-C6)-alkyl, (C2-C6)-alkenyl and (C2-C6)-alkynyl which are all optionally substituted by one or more identical or different substituents R70; R32 and R34 are independently of each other chosen from the series consisting of hydrogen, R35, R35—S(O)2—, R35—C(O)—, R35—O—C(O)—, phenyl and Het; R50 is chosen from the series consisting of R51—O— and R52—N(R53)—; R51 is chosen from the series consisting of hydrogen and R54; R52 is chosen from the series consisting of hydrogen, R55, NC— and R56—S(O)2—; R53 is chosen from the series consisting of hydrogen and R57; R56 is chosen from the series consisting of R58 and phenyl; R60, independently of each other group R60, is chosen from the series consisting of hydrogen and (C1-C4)-alkyl; R70 is chosen from the series consisting of HO—, R71—O—, R71—C(O)—O—, R71—S(O)m—, H2N—, R71—NH—, R71—N(R71)—, R71—C(O)—NH—, R71—C(O)—N(R71)—, R71—S(O)2—NH—, R71—S(O)2—N(R71)—, HO—C(O)—, R71—O—C(O)—, H2N—C(O)—, R71—NH—C(O)—, R71—N(R17)—C(O)—, H2N—S(O)2—, R71—NH—S(O)2—, R71—N(R71)—S(O)2—, NC—, oxo, phenyl and Het2; R71, independently of each other group R71, is chosen from (C1-C4)-alkyl, (C3-C4)-cycloalkyl and (C3-C4)-cycloalkyl-(C1-C2)-alkyl-; Het, independently of each other group Het, is a monocyclic 4-membered to 7-membered heterocyclic ring which comprises 1, 2 or 3 identical or different hetero ring members chosen from the series consisting of N, N(R60), O, S, S(O) and S(O)2, which ring is saturated or unsaturated and is optionally substituted by one or more identical or different substituents chosen from the series consisting of halogen, (C1-C4)-alkyl and R70; Het1 is a monocyclic 4-membered to 7-membered heterocyclic ring which comprises 1 or 2 identical or different hetero ring members chosen from the series consisting of N, N(R60), O, S, S(O) and S(O)2, which ring is saturated and is optionally substituted by one or more identical or different substituents chosen from the series consisting of fluorine and (C1-C4)-alkyl; Het2 is a monocyclic 5-membered or 6-membered heterocyclic ring which comprises 1, 2 or 3 identical or different hetero ring members chosen from the series consisting of N, N(R60), O and S, which ring is aromatic and is optionally substituted by one or more identical or different substituents chosen from the series consisting of halogen, (C1-C4)-alkyl, (C1-C4)-alkyl-O— and NC—; m, independently of each other number m, is an integer chosen from the series consisting of 0, 1 and 2; phenyl, independently of each other group phenyl, is optionally substituted by one or more identical or different substituents chosen from the series consisting of halogen, (C1-C4)-alkyl, (C1-C4)-alkyl-O— and NC—, unless specified otherwise; cycloalkyl, independently of each other group cycloalkyl, and independently of any other substituents on cycloalkyl, is optionally substituted by one or more identical or different substituents chosen from fluorine and (C1-C4)-alkyl; and alkyl, alkenyl and alkynyl, independently of each other group alkyl, alkenyl and alkynyl, and independently of any other substituents on alkyl, alkenyl and alkynyl, is optionally substituted by one or more fluorine substituents; in any of its stereoisomeric forms or a mixture of stereoisomeric forms in any ratio, or a physiologically acceptable salt thereof, or a physiologically acceptable solvate of any of them, provided that the compound of the formula I is not 2-[(6,2′,4′-trichlorobiphenyl-3-carbonyl)amino]indane-2-carboxylic acid, 2-[6-chloro-[1,1′,4′,1″]terphenyl-3-carbonyl)amino]indane-2-carboxylic acid, 2-(4-chloro-3-phenylethynyl-benzoylamino)-indane-2-carboxylic acid, 5-(4-chloro-phenyl)-2-[4-(2-methyl-1H-benzoimidazol-1-ylmethyl)-benzoylamino]-indane-2-carboxylic acid or 5-(4-chloro-phenyl)-2-[4-(2-methyl-1H-benzoimidazol-1-ylmethyl)-benzoylamino]-indane-2-carboxylic acid ethyl ester.
地址 Paris FR