Imidazole-substituted arylamides as P2X3 and P2X2/3 antagonists

• US 20090163499A1
• Filed: 12/17/2008
• Published: 06/25/2009
• 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
• Granted Patent: US 7,858,654 B2
• Time in Patent Office: Days
• US Class Current: 514/235.800
• 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, halo-C_1-6alkyl, hetero-C_1-6alkyl, C_1-6alkoxy, phenyl, heterocyclyl, C_3-6-cycloalkyl, C_3-6cycloalkyl-C_1-6alkyl or cyano.

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

4. The compound of claim 1, wherein R² is phenyl substituted at the 4-position with methyl or halo and optionally substituted at the 2- and 6-positions with halo.

5. 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.

6. The compound of claim 1, wherein R² is pyridin 2-yl substituted with methyl or halo at the 5-position and optionally substituted with halo at the 3-position.

7. 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-ppyridin-2-yl.

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

9. The compound of claim 1, wherein R³ hydrogen.

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

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

12. 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.

13. The compound of claim 1, wherein R⁵ is:

C_1-6alkyl;

C_1-6alkyloxy-C_1-6alkyl;

hydroxy-C_1-6alkyl;

C_1-6alkylsulfanyl-C_1-6alkyl;

C_1-6alkylsulfonyl-C_1-6alkyl;

amino-C_1-6alkyl;

N—

C_1-6alkyl-amino-C_1-6alkyl;

N,N-di-C_1-6alkyl-amino-C_1-6alkyl;

C_3-7cycloalkyl;

optionally substituted phenyl;

heteroaryl, or heterocyclyl-C_1-6alkyl.

14. The compound of claim 1, wherein R⁵ is:

C_1-6alkyloxy-C_1-6alkyl;

hydroxy-C_1-6alkyl;

heteroaryl, or heterocyclyl-C_1-6alkyl.

15. The compound of claim 1, wherein R⁵ is:

is hydroxymethyl, methoxymethyl, pyrazin-2-yl, 5-methyl-pyrazin-2-yl, 6-methyl-pyridazin-3-yl, or 1-methyl-6-oxo-1,6-dihydro-pyridin-3-yl.

16. The compound of claim 1, wherein R¹ is a group of formula A1, formula A2 or formula A3:

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

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

19. A composition comprising:

(a) a pharmaceutically acceptable carrier; and

(b) a compound of claim 1.

20. A method for treating a pain condition selected from inflammatory pain, surgical pain, visceral pain, dental pain, premenstrual pain, central pain, pain due to burns, migraine or cluster headaches, nerve injury, neuritis, neuralgias, poisoning, ischemic injury, interstitial cystitis, cancer pain, viral, parasitic or bacterial infection, post-traumatic injury, or pain associated with irritable bowel syndrome, said method comprising administering to a subject in need thereof an effective amount of a compound of claim 1.

21. A method for treating a respiratory disorder selected from chronic obstructive pulmonary disorder (COPD), asthma, and bronchospasm, said method comprising administering to a subject in need thereof an effective amount of a compound of claim 1.