Imidazole-substituted arylamides as P2X3 and P2X2/3 antagonists

• US 7,858,654 B2
• Filed: 12/17/2008
• Issued: 12/28/2010
• Est. Priority Date: 12/17/2007
• Status: Active Grant

• Current Assignee: Roche Palo Alto LLC (Roche Holding AG)
• Original Assignee: Roche Palo Alto LLC (Roche Holding AG)
• Inventors: Hawley, Ronald Charles, Feng, Lichun, Chen, Li, Dillon, Michael Patrick, Yang, Minmin
• Primary Examiner(s): Wilson; James O
• Assistant Examiner(s): Willis; Douglas M
• Application Number:
  US12/316,942
• Publication Number:
  US 20090163499A1
• Time in Patent Office: 741 Days
• Field of Search: 514/399, 548/343.5
• US Class Current: 514/399
• CPC Class Codes: A61P 1/00 Drugs for disorders of the alimentary tract or the digestive system
• CPC Class Codes: A61P 1/06 Anti-spasmodics, e.g. drugs for colics, esophagic dyskinesia
• CPC Class Codes: A61P 1/12 Antidiarrhoeals
• CPC Class Codes: A61P 1/16 for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
• CPC Class Codes: A61P 11/00 Drugs for disorders of the respiratory system
• CPC Class Codes: A61P 11/06 Antiasthmatics
• CPC Class Codes: A61P 11/08 Bronchodilators
• CPC Class Codes: A61P 13/08 of the prostate
• CPC Class Codes: A61P 13/10 of the bladder
• CPC Class Codes: A61P 13/12 of the kidneys
• CPC Class Codes: A61P 17/02 for treating wounds, ulcers, burns, scars, keloids, or the like
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/04 Centrally acting analgesics, e.g. opioids
• CPC Class Codes: A61P 25/06 Antimigraine agents
• CPC Class Codes: A61P 25/28 for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• CPC Class Codes: A61P 25/30 for treating abuse or dependence
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07D 233/64 with substituted hydrocarbon radicals attached to ring carbon atoms, e.g. histidine
• CPC Class Codes: C07D 401/14 containing three or more hetero rings
• CPC Class Codes: C07D 403/12 : linked by a chain containing hetero atoms as chain links

Abstract

Compounds of the formula I:

wherein R¹ is optionally substituted imidazolyl, and R², R³, R⁴, R⁵, R⁶, R⁷ and R⁸ are as defined herein. Also provided are methods of using the compounds for treating diseases mediated by a P2X₃ and/or a P2X_2/3 receptor antagonist and methods of making the subject compounds.

Claims

1. A compound of formula I:

2. The compound of claim 1, wherein R¹ is imidazolyl optionally substituted once with C_1-6alkyl or halo-C_1-6alkyl.

3. The compound of claim 1, wherein R² is 4-methyl-phenyl, 2-fluoro-4-methyl-phenyl, 2-chloro-4-fluoro-phenyl, 4-chloro-2-fluoro-phenyl, 2,4-dichloro-phenyl, 2,4-difluoro-phenyl, or 2-chloro-4-methyl-phenyl.

4. The compound of claim 1, wherein R² is 5-methyl-pyridin-2-yl, 5-chloro-pyridin-2-yl, 5-fluoro-pyridin-2-yl, 5-methyl-3-fluoro-pyridin-2-yl, 5-methyl-3-chloro-pyridin-2-yl, 3,5-difluoro-pyridin-2-yl or 3,5-dichloro-pyridin-2-yl.

5. The compound of claim 1, wherein R⁶, R⁷ and R⁸ are hydrogen.

6. The compound of claim 1, wherein R³ is hydrogen.

7. The compound of claim 1, wherein R⁴ is hydrogen.

8. The compound of claim 1, wherein R⁴ is methyl.

9. The compound of claim 1, wherein R⁴ and R⁵ together with the atom to which they are attached form a C_3-6 carbocyclic ring that is optionally substituted with hydroxy.

10. The compound of claim 1, wherein R¹ is a group of formula A1:

11. The compound of claim 1, wherein said compound is of formula IIa or IIb:

12. The compound of claim 1, wherein said compound is of formula III:

13. A pharmaceutical composition comprising:

(a) a pharmaceutically acceptable carrier; and

(b) a compound of claim 1.