Indole carboxamide derivatives as P2X7 receptor antagonists

Patent metadata

Field	Value
Publication number	US-9556117-B2
Application number	US-201314653363-A
Country	US
Kind code	B2
Filing date	Dec 17, 2013
Priority date	Dec 18, 2012
Publication date	Jan 31, 2017
Grant date	Jan 31, 2017

Abstract

The invention relates to indole carboxamide derivatives of formula (I),

wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 and n are as defined in the description, their preparation and their use as pharmaceutically active compounds.

First claim

The invention claimed is:

1. A compound of the formula (I),

wherein
n represents 1, 2, 3 or 4;
R 1 represents hydrogen and R 2 represents hydroxy; hydroxy-(C 1 -C 3 )alkyl; (C 1 -C 3 )alkoxy; —NHR 11 ; —N(CH 3 ) 2 ; —CN; —CONH 2 ; (C 1 -C 4 )alkoxy-carbonyl; (C 1 -C 4 )alkylamino-carbonyl; aryl which is unsubstituted or mono- or di-substituted with (C 1 -C 3 )fluoroalkyl or halogen; or heteroaryl which is unsubstituted or mono- or di-substituted with (C 1 -C 4 )alkyl, (C 1 -C 3 ) fluoroalkyl or halogen; or
R 1 represents (C 1 -C 3 )alkyl or hydroxy-(C 1 -C 3 )alkyl and R 2 represents hydrogen;
R 3 represents hydrogen or fluoro;
R 4 represents hydrogen or fluoro;
R 5 represents hydrogen, (C 1 -C 4 )alkyl or halogen;
R 6 represents hydrogen, (C 1 -C 4 )alkyl, (C 1 -C 4 )alkoxy, (C 1 -C 4 )alkyl-carbonyl, hydroxy-(C 1 -C 4 )alkyl, hydroxy-(C 2 -C 4 )alkoxy, (C 1 -C 2 )alkoxy-(C 1 -C 4 )alkyl, (C 1 -C 4 )alkoxy-(C 2 -C 4 )alkoxy, hydroxy, amino, nitro or halogen;
R 7 represents hydrogen or (C 1 -C 3 )alkyl;
R 8 represents hydrogen, (C 1 -C 4 )alkyl or hydroxy;
R 9 represents hydrogen, (C 1 -C 4 )alkyl, (C 1 -C 4 )alkylthio, formyl or halogen;
R 10 represents fluoro, chloro, methyl, ethyl, (C 1 -C 2 )fluoroalkyl or methoxy; and
R 11 represents hydrogen, benzyl, (C 1 -C 4 )alkyl-carbonyl, (C 1 -C 4 )alkoxy-carbonyl or (C 1 -C 4 )alkyl-sulfonyl which is unsubstituted or mono-substituted with hydroxy or (C 1 -C 4 )alkoxy-carbonyl;
or a salt of such a compound.

2. The compound of formula (I) according to claim 1 , wherein n represents 2, 3 or 4;
R 1 represents hydrogen;
R 2 represents hydroxy; hydroxy-(C 1 -C 3 )alkyl; —NHR 11 ; —CN; or a 5- or 6-membered monocyclic heteroaryl group which group is unsubstituted or mono-substituted with (C 1 -C 4 )alkyl, (C 1 -C 3 ) fluoroalkyl or halogen;
R 3 represents hydrogen or fluoro;
R 4 represents hydrogen or fluoro;
R 5 represents hydrogen;
R 6 represents hydrogen, (C 1 -C 4 )alkyl, (C 1 -C 4 )alkoxy or (C 1 -C 2 )alkoxy-(C 1 -C 4 )alkyl;
R 7 represents hydrogen;
R 8 represents hydrogen;
R 9 represents hydrogen, (C 1 -C 4 )alkyl or halogen;
R 10 represents chloro or methyl; and
R 11 represents (C 1 -C 4 )alkyl-sulfonyl which is unsubstituted or mono-substituted with hydroxy or (C 1 -C 4 )alkoxy-carbonyl;
or a salt of such a compound.

3. The compound of formula (I) according to claim 1 , wherein
n represents 2 or 3;
or a salt of such a compound.

4. The compound of formula (I) according to claim 1 , wherein
R 2 represents hydroxy; hydroxy-(C 1 -C 3 )alkyl; —NHR 11 ; or —CN; and
R 11 represents methyl-sulfonyl which is unsubstituted or mono-substituted with methoxy-carbonyl; or ethyl-sulfonyl which is mono-substituted with hydroxy;
or a salt of such a compound.

5. The compound of formula (I) according to claim 1 , wherein
R 2 represents a 5- or 6-membered monocyclic heteroaryl group which group is unsubstituted or mono-substituted with (C 1 -C 4 )alkyl, (C 1 -C 3 )fluoroalkyl or halogen;
or a salt of such a compound.

6. The compound of formula (I) according to claim 1 , wherein
R 6 represents (C 1 -C 4 )alkyl, (C 1 -C 4 )alkoxy or (C 1 -C 2 )alkoxy-(C 1 -C 4 )alkyl;
or a salt of such a compound.

7. The compound of formula (I) according to claim 1 , wherein
R 5 , R 7 , R 8 and R 9 represent hydrogen;
or a salt of such a compound.

8. The compound of formula (I) according to claim 1 , wherein
R 10 represents chloro;
or a salt of such a compound.

9. The compound of formula (I) according to claim 1 , which is also a compound of formula (I OH )

wherein
n represents 2 or 3;
R 3 represents hydrogen or fluoro;
R 4 represents hydrogen or fluoro;
R 6 represents (C 1 -C 4 )alkyl, (C 1 -C 4 )alkoxy, hydroxy-(C 1 -C 4 )alkyl, hydroxy-(C 2 -C 4 )alkoxy, (C 1 -C 2 )alkoxy-(C 1 -C 4 )alkyl or halogen; and
R 10 represents chloro, methyl or trifluoromethyl;
or a salt of such a compound.

10. The compound of formula (I) according to claim 1 , which is also a compound of formula (I HET )

wherein
n represents 2 or 3;
X represents CH or N;
2S represents hydrogen, (C 1 -C 4 )alkyl, (C 1 -C 3 )fluoroalkyl or halogen;
R 3 represents hydrogen or fluoro;
R 4 represents hydrogen or fluoro; and
R 6 represents hydrogen or (C 1 -C 4 )alkyl;
or a salt of such a compound.

11. The compound of formula (I) according to claim 1 , selected from the group consisting of:
4-Chloro-1H-indole-5-carboxylic acid ((S)-1-cyclohexyl-2-hydroxy-ethyl)-amide;
4-Chloro-1H-indole-5-carboxylic acid (1-hydroxy-cyclohexylmethyl)-amide;
4-Chloro-1H-indole-5-carboxylic acid (1-hydroxy-cycloheptylmethyl)-amide;
4-Chloro-1H-indole-5-carboxylic acid (4,4-difluoro-1-hydroxy-cyclohexylmethyl)-amide;
4-Chloro-1H-indole-5-carboxylic acid [(S)-1-(4,4-difluoro-cyclohexyl)-2-hydroxy-ethyl]-amide;
4-Chloro-l-methyl-1H-indole-5-carboxylic acid (1-hydroxy-cyclohexylmethyl)-amide;
4-Chloro- 1-methyl- 1H-indole-5-carboxylic acid ((S)- 1-cyclohexyl-2-hydroxy-ethyl)-amide;
4-Chloro-3-formyl- 1H-indole-5-carboxylic acid ((S)- 1-cyclohexyl-2-hydroxy-ethyl)-amide;
4-Chloro-3-formyl-1H-indole-5-carboxylic acid (1-hydroxy-cyclohexylmethyl)-amide;
4-Chloro-1H-indole-5-carboxylic acid (1-cycloheptyl-2-hydroxy-ethyl)-amide;
4-Chloro-1H-indole-5-carboxylic acid [1-(2-trifluoromethyl-pyrimidin-5-yl)-cyclohexylmethyl]-amide;
4-Chloro-1H-indole-5-carboxylic acid [1-(6-chloro-pyridin-3-yl)-cyclohexylmethyl]-amide;
4-Chloro-1H-indole-5-carboxylic acid [1-(6-trifluoromethyl-pyridin-3-yl)-cyclohexylmethyl]-amide;
4-Chloro-1H-indole-5-carboxylic acid [1-(6-chloro-pyridin-3-yl)-4,4-difluoro-cyclohexylmethyl ]-amide;
4-Chloro-1H-indole-5-carboxylic acid [1-(4-chloro-phenyl)-cyclohexylmethyl]-amide;
4-Chloro-1H-indole-5-carboxylic acid [1-(4-trifluoromethyl-phenyl)-cyclohexylmethyl]-amide;
4-Chloro-1H-indole-5-carboxylic acid (1-pyridin-3-yl-cyclohexylmethyl)-amide;
4-Chloro-1H-indole-5-carboxylic acid (1-pyridin-3-yl-cyclopentylmethyl)-amide;
4-Chloro-1H-indole-5-carboxylic acid (1-pyridin-3-yl-cycloheptylmethyl)-amide;
4-Chloro-7-methyl-1H-indole-5-carboxylic acid (1-hydroxy-cyclohexylmethyl)-amide;
4-Chloro-2-oxo-2,3-dihydro-1H-indole-5-carboxylic acid (1-hydroxy-cycloheptylmethyl)-amide;
4-Chloro-2-methyl-1H-indole-5-carboxylic acid (1-hydroxy-cyclohexylmethyl)-amide;
4-Chloro-7-iodo-3-methylsulfanyl-1H-indole-5-carboxylic acid (1-hydroxy-cyclohexylmethyl)-amide;
4-Chloro-7-methyl-1H-indole-5-carboxylic acid (4,4-difluoro- l -hydroxy-cyclohexylmethyl)-amide;
4-Chloro-7-methyl-1H-indole-5-carboxylic acid (1-hydroxy-cycloheptylmethyl)-amide;
4-Chloro-3-fluoro-1H-indole-5-carboxylic acid (1-hydroxy-cycloheptylmethyl)-amide;
4-Methoxy-1H-indole-5-carboxylic acid (1-hydroxy-cycloheptylmethyl)-amide;
3,4-Dichloro-1H-indole-5-carboxylic acid (1-hydroxy-cyclohexylmethyl)-amide;
4-Chloro-7-nitro-1H-indole-5-carboxylic acid (1-hydroxy-cyclohexylmethyl)-amide;
1-{[(4-Chloro-1H-indole-5-carbonyl)-amino]-methyl }-cyclohexanecarboxylic acid methyl ester;
4-Chloro-1H-indole-5-carboxylic acid (1-hydroxymethyl-cyclohexylmethyl)-amide;
7-Amino-4-chloro-1H-indo

Assignees

• Actelion Pharmaceuticals Ltd
• Actelion Pharmaceuticals Ltd

Inventors

• Hilpert Kurt
• Hubler Francis
• Renneberg Dorte
• Stamm Simon

Classifications

• A61P37/02

  Immunomodulators · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61P9/00

  Drugs for disorders of the cardiovascular system · CPC title

• A61P37/08

  Antiallergic agents (antiasthmatic agents A61P11/06; ophthalmic antiallergics A61P27/14) · CPC title