Thiazole and oxazole-substituted arylamides as P2X3 and P2X2/3 antagonists

• US 20080132494A1
• Filed: 11/08/2007
• Published: 06/05/2008
• Est. Priority Date: 11/09/2006
• Status: Active Grant

• Current Assignee: Roche Palo Alto LLC (Roche Holding AG)
• Original Assignee: Roche Palo Alto LLC (Roche Holding AG), Roche R&D Center China, Ltd. (Roche Holding AG)
• Inventors: Hawley, Ronald Charles, Feng, Lichun, Chen, Li, Dillon, Michael Patrick, Yang, Minmin
• Granted Patent: US 7,786,110 B2
• Time in Patent Office: Days
• US Class Current: 514/227.8
• CPC Class Codes: A61P 11/00 Drugs for disorders of the respiratory system
• CPC Class Codes: A61P 13/00 Drugs for disorders of the urinary system
• CPC Class Codes: A61P 13/02 of urine or of the urinary tract, e.g. urine acidifiers
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/02 for peripheral neuropathies
• CPC Class Codes: A61P 25/04 Centrally acting analgesics, e.g. opioids
• CPC Class Codes: A61P 25/06 Antimigraine agents
• 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 263/32 with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
• CPC Class Codes: C07D 277/30 Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
• CPC Class Codes: C07D 277/66 with aromatic rings or ring systems directly attached in position 2
• CPC Class Codes: C07D 401/14 containing three or more hetero rings

Abstract

Compounds of the formula I:

or a pharmaceutically acceptable salt thereof, wherein, R¹ is a group of formula A or formula B,

and X, R², R³, R⁴, R⁵, R⁶, R^a and R^b 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 R² is phenyl substituted at the 4-position with methyl or halo and optionally substituted at the 2-position with halo.

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

4. 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.

5. The compound of claim 4, wherein R⁶ is hydrogen.

6. The compound of claim 5, wherein R³ is hydrogen.

7. The compound of claim 5, wherein R⁴ is hydrogen.

8. The compound of claim 5, wherein R⁴ is methyl.

9. The compound of claim 1, wherein R′

is a group of formula A.

10. The compound of claim 1, wherein X is S.

11. The compound of claim 1, wherein one of R^a and R^b is hydrogen and the other is:

hydrogen;

C_1-6alkyl;

C_1-6alkoxy;

C_1-6alkylsulfonyl-C_1-6alkyl;

halo-C_1-6alkyl;

halo-C_1-6alkoxy;

hetero-C_1-6alkyl;

C_3-6-cycloalkyl;

C_3-6cycloalkyl-C_1-6alkyl;

aminocarbonyl;

C_1-6alkoxycarbonyl;

or cyano.

12. The compound of claim 1, wherein one of R^a and R^b is hydrogen and the other is C_1-6alkyl.

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

C_1-6alkyloxy-C_1-6alkyl;

hydroxy-C_1-6alkyl;

heteroaryl, or heterocyclyl-C_1-6alkyl.

14. The compound of claim 1, wherein R⁵ is hydroxymethyl, methoxymethyl, pyrazin-2-yl or 5-methyl-pyrazin-2-yl.

15. The compound of claim 1, wherein said compound is of formula II:

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

17. A pharmaceutical composition comprising:

(a) a pharmaceutically acceptable carrier; and

(b) a compound of claim 1.

18. A method for treating a urinary tract disease selected from reduced bladder capacity, frequent micturition, urge incontinence, stress incontinence, bladder hyperreactivity, benign prostatic hypertrophy, prostatitis, detrusor hyperreflexia, urinary frequency, nocturia, urinary urgency, overactive bladder, pelvic hypersensitivity, urethritis, prostatitis, pelvic pain syndrome, prostatodynia, cystitis, or idiophatic bladder hypersensitivity, said method comprising administering to a subject in need thereof an effective amount of a compound of claim 1.

19. 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.

20. 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.