Benzamide-containing compounds and their use in the treatment of pain

Patent metadata

Field	Value
Publication number	US-9649308-B2
Application number	US-201514744103-A
Country	US
Kind code	B2
Filing date	Jun 19, 2015
Priority date	Oct 12, 2012
Publication date	May 16, 2017
Grant date	May 16, 2017

Abstract

The present invention is directed to benzamide-containing compounds of formula I

or pharmaceutically acceptable salts thereof which inhibit the P2X7 receptor, and their use in the treatment of pain.

First claim

What is claimed:

1. A method of treating pain comprising administering a therapeutically effective amount of at least one compound of formula I

wherein R 1 is pyridyl, pyrazinyl, pyridazinyl, or pyrimidyl, each of which is optionally substituted with one or more C 1-6 alkyl, halogen, hydroxy, C 1-6 hydroxyalkyl, C 1-4 fluoroalkyl, C 3-6 cycloalkyl, C 1-4 fluoroalkoxy, cyano or —SO 2 R 8 ;
wherein R 2 is C 3-6 cycloalkyl, C 3-6 cyclohetalkyl, C 1-4 fluoroalkyl, C 1-4 fluoroalkoxy, C 1-4 alkoxy, C 1-6 alkenyl, C 1-6 alkynyl, 6 membered heteroaryl, phenyl or C 1-4 alkyl optionally substituted with one or more R 9 ;
wherein R 3 is hydrogen, fluorine, C 1-4 alkyl or C 1-4 fluoroalkyl; or
wherein R 2 and R 3 combine with the carbon to which they are attached to form cyclohexyl, tetrahydropyranyl, piperazinyl, piperidinyl, morpholinyl, pyrrolidinyl, pyrrolo, imidazo, azetidinyl, homomorpholinyl, homopiperidinyl or homopiperazinyl each of which is optionally substituted with one or more C 1-6 alkyl, C 1-6 alkenyl, C 3-6 -cycloalkyl, C 1-6 alkoxy, oxo, —NR 6 R 7 or fluorine;
wherein R 4 is halogen, C 1-4 fluoroalkyl, cyano, cyclopropyl, C 1-4 alkyloxy, C 1-4 fluoroalkyloxy, —SO 2 R 8 , —NR 6 R 7 or C 1-6 alkyl;
wherein R 5 is halogen, C 1-6 alkyl, C 1-4 fluoroalkyl, cyano, —SO 2 R 8 , —NR 6 R 7 , C 1-6 alkoxy, C 1-4 fluoroalkoxy or C 3-6 -cycloalkyl;
wherein R 6 and R 7 independently of each other are hydrogen or C 1-6 alkyl;
wherein R 8 is C 1-6 alkyl, C 3-6 cycloalkyl or C 1-4 fluoroalkyl;
wherein R 9 is C 1-6 alkyl, C 3-6 cycloalkyl, —NR 10 R 11 , C 1-4 fluoroalkyl or 3 to 7 membered heterocyclyl which is optionally substituted with one or more C 1-6 alkyl, halogen, hydroxy, C 1-4 fluoroalkyl, C 3-6 cycloalkyl, C 1-4 alkoxy, C 1-4 fluoroalkoxy or cyano;
wherein R 10 and R 11 independently of each other are hydrogen or C 1-6 alkyl; or
wherein R 10 and R 11 combine with the nitrogen to which they are attached to form piperazinyl, piperidinyl, morpholinyl, pyrrolidinyl, azetidinyl, homomorpholinyl, homopiperidinyl or homopiperazinyl each of which is optionally substituted with one or more C 1-6 alkyl, C 1-6 alkoxy, oxo or fluorine; and
wherein n is 0-3; or a pharmaceutically acceptable salt thereof;
to a subject in need thereof.

2. The method of claim 1 wherein the pain is acute pain.

3. The method of claim 1 wherein the pain is chronic pain.

4. The method of claim 1 wherein the pain is inflammatory pain.

5. The method of claim 1 wherein the pain is caused by morphine tolerance, fibromyalgia, neuralgia, osteoarthritis, rheumatoid arthritis, psoriatic arthritis, irritable bowel syndrome or inflammatory bowel disease, or is headache, neuropathic pain or post-operative pain.

6. The method of claim 5 wherein the pain is neuropathic pain.

7. The method of claim 1 , wherein the compound is (−)2-chloro-N-[3-cyclopropyl-2-[2-(trifluoromethyl)pyrimidin-5-yl]propyl]benzamide.

8. The method of claim 1 , wherein the compound is (−)-2-chloro-N-(3-cyclopropyl-2-(2-(trifluoromethyl)pyrimidin-5-yl)propyl)-6-fluorobenzamide.

9. The method of claim 1 , wherein the compound is (−)2,3-dichloro-N-[3-cyclopropyl-2-[2-(trifluoromethyl)pyrimidin-5-yl]propyl]benzamide.

10. The method of claim 1 , wherein the compound is(−)2,6-dichloro-N-[3-cyclopropyl-2[2-(trifluoromethyl)pyrimidin-5-yl]propyl]benzamide.

11. The method of claim 1 , wherein the compound is (+)2-chloro-N-[3-cyclopropyl-2[2-(trifluoromethyl)pyrimidin-5-yl]propyl]-3-fluoro-benzamide.

12. The method of claim 1 , wherein the compound is (+)-2-chloro-N-(3-(1-(trifluoromethyl)cyclopropyl)-2-(2-(trifluoromethyl)pyrimidin-5-yl)propyl)benzamide.

13. The method of claim 1 , wherein the compound is (+)2-chloro-N-[3-[1-(trifluoromethyl)cyclopropyl]-2-[2-(trifluoromethyl)pyrimidin-5-yl]propyl]benzamide.

14. The method of claim 1 , wherein the compound is (+)-2,3-Dichloro-N-(2-(2-(difluoromethyl)pyrimidin-5-yl)-3-(1-(trifluoromethyl)cyclopropyl)propyl)benzamide.

15. The method of claim 1 , wherein the compound is (−)2,3-dichloro-N-[3-cyclopropyl-2-[2-(difluoromethyl)pyrimidin-5-yl]propyl]benzamide.

16. The method of claim 1 , wherein the compound is (+)2,3-dichloro-N-[3-[1-(trifluoromethyl)cyclopropyl]-2-[2-(trifluoromethyl)pyrimidin-5-yl]propyl]benzamide.

17. The method of claim 1 , wherein the compound is (−)-2,6-dichloro-N-(3-cyclopropyl-2-(2-(difluoromethyl)pyrimidin-5-yl)propyl)benzamide.

18. The method of claim 1 , wherein the compound is (−)2-chloro-N-[3-cyclopropyl-2-[2-(trifluoromethyl)pyrimidin-5-yl]propyl]-3-fluoro-benzamide.

19. The method of claim 1 , wherein the compound is (−)-2,3-Dichloro-N-(2-(2-(difluoromethyl)pyrimidin-5-yl)-3-(1-(trifluoromethyl)cyclopropyl)propyl)benzamide.

20. The method of claim 1 , wherein the compound is (−)2,3-dichloro-N-[3-[1-(trifluoromethyl)cyclopropyl]-2[2-(trifluoromethyl)pyrimidin-5-yl]propyl]benzamide.

21. The method of claim 1 , wherein the compound is (−)-2,3-dichloro-N-(3-cyclopropyl-2-methyl-2-(2-(trifluoromethyl)pyrimidin-5-yl)propyl)benzamide.

22. The method of claim 1 , wherein the compound is (+)2-chloro-3-fluoro-N-[3-[1-(trifluoromethyl)cyclopropyl]-2-[2-(trifluoromethyl)pyrimidin-5-yl]propyl]benzamide.

23. The method of claim 1 , wherein the compound is (−)2,6-dichloro-N-[3-cyclopropyl-2-(2-methylpyrimidin-5-yl)propyl]benzamide.

Assignees

• H Lundbeck As

Inventors

• Kilburn John Paul
• Rasmussen Lars Kyhn
• Jessing Mikkel
• Eldemenky Eman Mohamed
• Chen Bin
• Jiang Yu
• Hopper Allen T

Classifications

• A61P43/00

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

• A61P25/18

  Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia · CPC title

• A61P25/04

  Centrally acting analgesics, e.g. opioids · CPC title

• A61P29/00

  Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID] · CPC title

• A61P25/00

  Drugs for disorders of the nervous system · CPC title