Acylamino-substituted fused cyclopentanecarboxylic acid derivatives and their use as pharmaceuticals

Patent metadata

Field	Value
Publication number	US-9328071-B2
Application number	US-201414314780-A
Country	US
Kind code	B2
Filing date	Jun 25, 2014
Priority date	May 5, 2008
Publication date	May 3, 2016
Grant date	May 3, 2016

Abstract

The present invention relates to compounds of the formula I,

wherein A, Y, Z, R 3 to R 6 , R 20 to R 22 and R 50 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 LPA 1 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.

First claim

We claim:

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, R 1 , HO—, R 1 —O—, R 1 —C(O)—O—, R 1 —S(O) 2 —O—, R 1 —S(O) m —, H 2 N—, R 1 —NH—, R 1 —N(R 1 )—, R 1 —C(O)—NH—, R 1 —C(O)—N(R 71 )—, R 1 —S(O) 2 —NH—, R 1 —S(O) 2 —N(R 71 )—, R 1 —C(O)—, HO—C(O)—, R 1 —O—C(O)—, H 2 N—C(O)—, R 1 —NH—C(O)—, R 1 —N(R 1 )—C(O)—, H 2 N—S(O) 2 —, R 1 —NH—S(O) 2 —, R 1 —N(R 1 )—S(O) 2 —, NC—, O 2 N—, phenyl and Het;
Y is chosen from the series consisting of N(R 10 ), S, O, C(R 12 )═C(R 13 ), N═C(R 14 ) and C(R 15 )═N;
Z is chosen from the series consisting of N and C(R 16 );
R 1 , R 11 , R 30 , R 33 , R 35 , R 54 , R 55 , R 57 and R 58 are, independently of each other group R 1 , R 11 , R 30 , R 33 , R 35 , R 54 , R 55 , R 57 and R 58 , chosen from the series consisting of (C 1 -C 6 )-alkyl, (C 2 -C 6 )-alkenyl, (C 2 -C 6 )-alkynyl, (C 3 -C 7 )-cycloalkyl and (C 3 -C 7 )-cycloalkyl-(C 1 -C 4 )-alkyl- which are all optionally substituted by one or more identical or different substituents R 70 ;
R 3 and R 5 are independently of each other chosen from the series consisting of hydrogen, (C 1 -C 4 )-alkyl, phenyl-(C 1 -C 4 )-alkyl, phenyl and hydroxy;
R 4 and R 6 are independently of each other chosen from the series consisting of hydrogen and (C 1 -C 4 )-alkyl;
R 10 is chosen from the series consisting of hydrogen and R 11 ;
R 12 , R 13 , R 14 , R 15 and R 16 are independently of each other chosen from the series consisting of hydrogen, (C 1 -C 4 )-alkyl, HO—(C 1 -C 4 )-alkyl-, (C 1 -C 4 )-alkyl-O—, (C 1 -C 4 )-alkyl-S(O) m —, H 2 N—, (C 1 -C 4 )-alkyl-NH—, (C 1 -C 4 )-alkyl-N((C 1 -C 4 )-alkyl), (C 1 -C 4 )-alkyl-C(O)—, NC— and O 2 N—;
R 20 is chosen from the series consisting of hydrogen and (C 1 -C 4 )-alkyl;
one of the groups R 21 and R 22 is a group of the formula II
R 24 —R 23 —  II

and the other of the groups R 21 and R 22 is chosen from the series consisting of hydrogen, halogen, R 30 , HO—, R 30 —O—, R 30 —C(O)—O—, R 30 —S(O) 2 —O—, R 30 —S(O) m —, H 2 N—, R 30 —NH—, R 30 —N(R 30 )—, R 30 —C(O)—NH—, R 30 —C(O)—N(R 71 )—, R 30 —S(O) 2 —NH—, R 30 —S(O) 2 —N(R 71 )—, R 30 —C(O)—, HO—C(O)—, R 30 —O—C(O)—, H 2 N—C(O)—, R 30 —NH—C(O)—, R 30 —N(R 30 )—C(O)—, H 2 N—S(O) 2 —, R 30 —NH—S(O) 2 —, R 30 —N(R 30 )—S(O) 2 —, NC—, O 2 N— and Het 1 ;
R 23 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(R 25 ), 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(R 25 ), O and S, and the other chain members are identical or different groups C(R 26 )(R 26 ), wherein two adjacent groups C(R 26 )(R 26 ) can be connected to each other by a double bond or a triple bond;
R 24 is chosen from the series consisting of hydrogen, R 31 , HO—, R 31 —O—, R 31 —C(O)—O—, R 31 —S(O) m —, H 2 N—, R 31 —NH—, R 31 —N(R 31 )—, R 31 —C(O)—NH—, R 31 —C(O)—N(R 71 )—, R 31 —S(O) 2 —NH—, R 31 —S(O) 2 —N(R 71 )—, R 31 —C(O)—, HO—C(O)—, R 31 —O—C(O)—, H 2 N—C(O)—, R 31 —NH—C(O)—, R 31 —N(R 31 )—C(O)—, H 2 N—S(O) 2 —, R 31 —NH—S(O) 2 —, R 31 —N(R 31 )—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(R 32 ), 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, R 33 , HO—, R 33 —O—, R 33 —C(O)—O—, R 33 —S(O) 2 —O—, R 33 —S(O) m —, H 2 N—, R 33 —NH—, R 33 —N(R 33 )—, R 33 —C(O)—NH—, R 33 —C(O)—N(R 71 )—, R 33 —S(O) 2 —NH—, R 33 —S(O) 2 —N(R 71 )—, H 2 N—S(O) 2 —NH—, R 33 —NH—S(O) 2 —NH—, R 33 —N(R 33 )—S(O) 2 —NH—, H 2 N—S(O) 2 —N(R 71 )—, R 33 —NH—S(O) 2 —N(R 71 )—, R 33 —N(R 33 )—S(O) 2 —N(R 71 )—, R 33 —C(O)—, HO—C(O)—, R 33 —O—C(O)—, H 2 N—C(O)—, R 33 —NH—C(O)—, R 33 —N(R 33 )—C(O)—, H 2 N—S(O) 2 —, R 33 —NH—S(O) 2 —, R 33 —N(R 33 )—S(O) 2 —, NC—, O 2 N—, oxo, phenyl and Het,
provided that the total number of C, N, O and S atoms which is present in the two groups R 23 and R 24 , is at least 5;
R 25 is chosen from the series consisting of hydrogen and (C 1 -C 4 )-alkyl;
R 26 , independently of each other group R 26 , is chosen from the series consisting of hydrogen, fluorine, (C 1 -C 4 )-alkyl and HO—, or two groups R 26 bonded to the same carbon atom together are oxo, or two of the groups R 26 or one group R 25 and one group R 26 , 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(R 34 ), 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 (C 1 -C 4 )-alkyl;
R 31 is chosen from the series consisting of (C 1 -C 6 )-alkyl, (C 2 -C 6 )-alkenyl and (C 2 -C 6 )-alkynyl which are all optionally substituted by one or more identical or different substituents R 70 ;
R 32 and R 34 are independently of each other chosen from the series consisting of hydrogen, R 35 , R 35 —S(O) 2 —, R 35 —C(O)—, R 35 —O—C(O)—, phenyl and Het;
R 50 is chosen from the series consisting of R 51 —O— and R 52 —N(R 53 )—;
R 51 is chosen from the series consisting of hydrogen and R 54 ;
R 52 is chosen from the series consisting of hydrogen, R 55 , NC— and R 56 —S(O) 2 —;
R 53 is chosen from the series consisting of hydrogen and R 57 ;
R 56 is chosen from the series consisting of R 58 and phenyl;
R 60 , independently of each other group R 60 , is chosen from the series consisting of hydrogen and (C 1 -C 4 )-alkyl;
R 70 is chosen from the series consisting of HO—, R 71 —O—, R 71 —C(O)—O—, R 71 —S(O) m —, H 2 N—, R 71 —NH—, R 71 —N(R 71 )—, R 71 —C(O)—NH—, R 71 —C(O)—N(R 71 )—, R 71 —S(O) 2 —NH—, R 71 —S(O) 2 —N(R 71 )—, HO—C(O)—, R 71 —O—C(O)—, H 2 N—C(O)—, R 71 —NH—C(O)—, R 71 —N(R 17 )—C(O)—, H 2 N—S(O) 2 —, R 71 —NH—S(O) 2 —, R 71 —N(R 71 )—S(O) 2 —, NC—, oxo, phenyl and Het 2 ;
R 71 , independently of each other group R 71 , is chosen from (C 1 -C 4 )-alkyl, (C 3 -C 4 )-cycloalkyl and (C 3 -C 4 )-cycloalkyl-(C 1 -C 2 )-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(R 60 ), 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, (C 1 -C 4 )-alkyl and R 70 ;
Het 1 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(R 60 ), 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 fluorin

Assignees

• Sanofi Sa

Inventors

• Schaefer Matthias
• Pernerstorfer Josef
• Kadereit Dieter
• Strobel Hartmut
• Czechtizky Werngard
• Chen L Charlie
• Safarova Alena
• Weichsel Aleksandra
• Patek Marcel

Classifications

• A61P9/10

  for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis · CPC title

• A61P35/04

  specific for metastasis · CPC title

• A61P37/00

  Drugs for immunological or allergic disorders · CPC title

• A61P9/00

  Drugs for disorders of the cardiovascular system · CPC title

• A61P5/14

  of the thyroid hormones, e.g. T3, T4 · CPC title