Heterocyclic amide derivatives as P2X7 receptor antagonists

Patent metadata

Field	Value
Publication number	US-9388197-B2
Application number	US-201414762692-A
Country	US
Kind code	B2
Filing date	Jan 21, 2014
Priority date	Jan 22, 2013
Publication date	Jul 12, 2016
Grant date	Jul 12, 2016

Abstract

The invention relates to heterocyclic amide derivatives of formula (I),

wherein R 1 , R 2 , R 3 , R 4 , R 5 , n, m, p and X 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 or 3;
m represents 0, 1 or 2;
p represents 0, 1 or 2;
X represents —O— or —CH 2 —;
R 1 represents hydrogen, (C 1 -C 2 )alkyl or hydroxy-(C 1 -C 2 )alkyl and R 2 represents hydrogen or halogen; or R 1 and R 2 together represent a —CH 2 CH 2 — or a —CH 2 CH 2 CH 2 — group;
each R 3 independently represents (C 1 -C 4 )alkyl, (C 3 -C 6 )cycloalkyl, (C 1 -C 4 )alkoxy, hydroxy-(C 1 -C 3 )alkyl, hydroxy-(C 2 -C 3 )alkoxy, hydroxy-(C 2 -C 3 )alkoxy-(C 1 -C 2 )alkyl, (C 1 -C 2 )alkoxy-(C 1 -C 2 )alkyl, (C 1 -C 3 )fluoroalkyl, (C 1 -C 3 )fluoroalkoxy, cyano, halogen or phenoxy;
R 4 represents hydrogen, (C 1 -C 4 )alkyl, (C 1 -C 3 )fluoroalkyl, amino, halogen or phenyl; and
R 5 represents hydrogen or methyl;
or a salt of such a compound.

2. The compound of formula (I) according to claim 1 , that is a compound of formula (Ixo),

wherein
n represents 1, 2 or 3;
m represents 0, 1 or 2;
p represents 1 or 2;
R 1 represents hydrogen, (C 1 -C 2 )alkyl or hydroxy-(C 1 -C 2 )alkyl and R 2 represents hydrogen or halogen; or R 1 and R 2 together represent a —CH 2 CH 2 — or a —CH 2 CH 2 CH 2 — group;
each R 3 independently represents (C 1 -C 4 )alkyl, (C 3 -C 6 )cycloalkyl, (C 1 -C 4 )alkoxy, hydroxy-(C 1 -C 3 )alkyl, hydroxy-(C 2 -C 3 )alkoxy, hydroxy-(C 2 -C 3 )alkoxy-(C 1 -C 2 )alkyl, (C 1 -C 2 )alkoxy-(C 1 -C 2 )alkyl, (C 1 -C 3 )fluoroalkyl, (C 1 -C 3 )fluoroalkoxy, cyano, halogen or phenoxy; and
R 5 represents hydrogen or methyl;
or a salt of such a compound.

3. The compound of formula (I) according to claim 1 , wherein
m represents 0;
or a salt of such a compound.

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

5. The compound of formula (I) according to claim 1 , wherein
R 1 represents hydrogen and R 2 represents chloro;
or a salt of such a compound.

6. The compound of formula (I) according to claim 1 , wherein
R 1 and R 2 together represent a —CH 2 CH 2 — group;
or a salt of such a compound.

7. The compound of formula (I) according to claim 1 , wherein
a first R 3 group is attached in para-position relative to the R 1 -bearing carbon atom and represents chloro; and
a second R 3 group is absent, or is attached in ortho-position relative to the R 1 -bearing carbon atom and represents methyl, cyclopropyl, methoxy, hydroxy-methyl, 2-hydroxy-ethoxy, (2-hydroxy-ethoxy)-methyl, methoxy-methyl, chloro or bromo;
or a salt of such a compound.

8. The compound of formula (I) according to claim 1 , wherein
R 4 represents hydrogen;
or a salt of such a compound.

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

10. The compound of formula (I) according to claim 1 , selected from the group consisting of:
N-(4-chlorobenzyl)-5,6-dihydrofuro[2,3-d]thiazole-6-carboxamide;
N-(2,4-dichlorobenzyl)-5,6-dihydrofuro[2,3-d]thiazole-6-carboxamide;
N-(2-chloro-4-fluorobenzyl)-5,6-dihydrofuro[2,3-d]thiazole-6-carboxamide;
N-(3,4-dichlorobenzyl)-5,6-dihydrofuro[2,3-d]thiazole-6-carboxamide;
N-(2-bromo-4,6-dichlorobenzyl)-5,6-dihydrofuro[2,3-d]thiazole-6-carboxamide;
N-(2,4-dichloro-6-methylbenzyl)-5,6-dihydrofuro[2,3-d]thiazole-6-carboxamide;
N-(2,4-dichlorophenethyl)-5,6-dihydrofuro[2,3-d]thiazole-6-carboxamide;
N-(3-(2,4-dichlorophenyl)propyl)-5,6-dihydrofuro[2,3-d]thiazole-6-carboxamide;
N-(1-(2,4-dichlorophenyl)-2-hydroxyethyl)-5,6-dihydrofuro[2,3-d]thiazole-6-carboxamide;
N-(2,4-dichloro-6-(hydroxymethyl)benzyl)-5,6-dihydrofuro[2,3-d]thiazole-6-carboxamide;
N-(5,7-dichloro-2,3-dihydro-1H-inden-1-yl)-5,6-dihydrofuro[2,3-d]thiazole-6-carboxamide;
N-(2,4-dichloro-6-cyclopropylbenzyl)-5,6-dihydrofuro[2,3-d]thiazole-6-carboxamide;
N-(2-chloro-3-(trifluoromethyl)benzyl)-5,6-dihydrofuro[2,3-d]thiazole-6-carboxamide;
N-(3-chloro-2-(trifluoromethyl)benzyl)-5,6-dihydrofuro[2,3-d]thiazole-6-carboxamide;
N-(2,4-dichloro-6-((2-hydroxyethoxy)methyl)benzyl)-5,6-dihydrofuro[2,3-d]thiazole-6-carboxamide;
N-(4-phenoxybenzyl)-5,6-dihydrofuro[2,3-d]thiazole-6-carboxamide;
N-(2,4-dichlorobenzyl)-5,6-dihydro-4H-cyclopenta[d]thiazole-6-carboxamide;
N-(2-chloro-4-fluorobenzyl)-5,6-dihydro-4H-cyclopenta[d]thiazole-6-carboxamide;
N-(2-bromo-4,6-dichlorobenzyl)-5,6-dihydro-4H-cyclopenta[d]thiazole-6-carboxamide;
N-(2,4-dichloro-6-methylbenzyl)-5,6-dihydro-4H-cyclopenta[d]thiazole-6-carboxamide;
N-(2,4-dichlorophenethyl)-5,6-dihydro-4H-cyclopenta[d]thiazole-6-carboxamide;
N-(2-chloro-3-cyanobenzyl)-5,6-dihydro-4H-cyclopenta[d]thiazole-6-carboxamide;
N-(3-(2,4-dichlorophenyl)propyl)-5,6-dihydro-4H-cyclopenta[d]thiazole-6-carboxamide;
N-(1-(2,4-dichlorophenyl)-2-hydroxyethyl)-5,6-dihydro-4H-cyclopenta[d]thiazole-6-carboxamide;
N-(2,4-dichloro-6-(hydroxymethyl)benzyl)-5,6-dihydro-4H-cyclopenta[d]thiazole-6-carboxamide;
N-(2,4-dichloro-6-methoxybenzyl)-5,6-dihydro-4H-cyclopenta[d]thiazole-6-carboxamide;
N-(5,7-dichloro-2,3-dihydro-1H-inden-1-yl)-5,6-dihydro-4H-cyclopenta[d]thiazole-6-carboxamide;
N-(2-chloro-3-(trifluoromethyl)benzyl)-5,6-dihydro-4H-cyclopenta[d]thiazole-6-carboxamide;
N-(3-fluoro-4-(trifluoromethoxy)benzyl)-5,6-dihydro-4H-cyclopenta[d]thiazole-6-carboxamide;
N-(4-chlorobenzyl)-N-methyl-6,7-dihydro-5H-pyrano[2,3-d]thiazole-7-carboxamide;
N-(2,4-dichlorobenzyl)-6,7-dihydro-5H-pyrano[2,3-d]thiazole-7-carboxamide;
N-(2-chloro-4-fluorobenzyl)-6,7-dihydro-5H-pyrano[2,3-d]thiazole-7-carboxamide;
N-(2,3-dichlorobenzyl)-6,7-dihydro-5H-pyrano[2,3-d]thiazole-7-carboxamide;
N-(2,4-dichloro-6-methylbenzyl)-6,7-dihydro-5H-pyrano[2,3-d]thiazole-7-carboxamide;
N-(2,4-dichlorophenethyl)-6,7-dihydro-5H-pyrano[2,3-d]thiazole-7-carboxamide;
N-(2-chloro-3-cyanobenzyl)-6,7-dihydro-5H-pyrano[2,3-d]thiazole-7-carboxamide;
N-(4-(trifluoromethyl)benzyl)-6,7-dihydro-5H-pyrano[2,3-d]thiazole-7-carboxamide;
N-(3-(2,4-dichlorophenyl)propyl)-6,7-dihydro-5H-pyrano[2,3-d]thiazole-7-carboxamide;
N-((S)-1-(2,4-dichlorophenyl)-2-hydroxyethyl)-6,7-dihydro-5H-pyrano[2,3-d]thiazole-7-carboxamide;
N-(2,4-dichloro-6-(hydroxymethyl)benzyl)-6,7-dihydro-5H-pyrano[2,3-d]thiazole-7-carboxamide;
N-((S)-5,7-dichloro-2,3-dihydro-1H-inden-1-yl)-6,7-dihydro-5H-pyrano[2,3-d]thiazole-7-carboxamide;
N-(2-chloro-3-(trifluoromethyl)benzyl)-6,7-dihydro-5H-pyrano[2,3-d]thiazole-7-carboxamide;
N-(2,4-dichloro-6-(2-hydroxyethoxy)benzyl)-6,7-dihydro-5H-pyrano[2,3-d]thiazole-7-carboxamide;
N-(3-fluoro-4-(trifluoromethoxy)benzyl)-6,7-dihydro-5H-pyrano[2,3-d]thiazole-7-carboxamide;
N-(4-phenoxybenzyl)-6,7-dihydro-5H-pyrano[2,3-d]thiazole-7-carboxamide;
N-(4-chlorobenzyl)-4,5,6,7-tetrahydrobenzo[d]thiazole-7-carboxamide;
N-(4-chlorobenzyl)-N-methyl-4,5,6,7-tetrahydrobenzo[d]thiazole-7-carboxamide;
N-(3-chloro-2-methylbenzyl)-4,5,6,7-tetrahydrobenzo[d]thiazole-7-carboxamide;
2-amino-N-(2,4-dichlorobenzyl)-4,5,6,7-tetrahydrobenzo[d]thiazole-7-carboxamide;
N-(2,4-dichlorobenzyl)-2-methyl-4,5,6,7-tetrahydrobenzo[d]thiazole-7-carboxamide;
2-bromo-N-(2,4-dichlorobenzyl)-4,5,6,7-tetrahydrobenzo[d]thiazole-7-carboxamide;
N-(2,4-dichlorobenzyl)-4,5,6,7-tetrahydrobenzo[d]thiazole-7-carboxamide;
N-(2-chloro-4-fluorobenzyl)-4,5,6,7-tetrahydrobenzo[d]thiazole-7-carboxamide;
N-(2,3-dichlorobenzyl)-4,5,6,7-tetrahydrobenzo[d]thiazo

Assignees

• Actelion Pharmaceuticals Ltd
• Actelion Pharmaceuticals Ltd

Inventors

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

Classifications

• A61P37/08

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

• A61P35/00

  Antineoplastic agents · CPC title

• A61P9/00

  Drugs for disorders of the cardiovascular system · CPC title

• 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

• A61P43/00

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