Diaminopyrimidines as P2X3 and P2X2/3 modulators

• US 7,531,547 B2
• Filed: 08/25/2006
• Issued: 05/12/2009
• Est. Priority Date: 09/01/2005
• Status: Active Grant

• Current Assignee: Roche Palo Alto LLC (Roche Holding AG)
• Original Assignee: Roche Palo Alto LLC (Roche Holding AG)
• Inventors: Wagner, Paul J., Jahangir, Alam, Dillon, Michael Patrick, Moore, Amy Geraldine
• Primary Examiner(s): Balasubramanian; Venkataraman
• Application Number:
  US11/510,216
• Publication Number:
  US 20070049758A1
• Time in Patent Office: 991 Days
• Field of Search: 544/298, 544/323, 544/324, 514/269, 514/272, 514/275, 513/275
• US Class Current: 514/269
• CPC Class Codes: A61P 1/00 Drugs for disorders of the alimentary tract or the digestive system
• CPC Class Codes: A61P 1/02 Stomatological preparations, e.g. drugs for caries, aphtae, periodontitis
• CPC Class Codes: A61P 1/04 for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
• 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 11/00 Drugs for disorders of the respiratory system
• CPC Class Codes: A61P 11/06 Antiasthmatics
• CPC Class Codes: A61P 13/00 Drugs for disorders of the urinary system
• 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 15/00 Drugs for genital or sexual disorders for disorders of sex hormones A61P5/24; Contraceptives
• CPC Class Codes: A61P 17/02 for treating wounds, ulcers, burns, scars, keloids, or the like
• 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 31/04 Antibacterial agents
• CPC Class Codes: A61P 31/12 Antivirals
• CPC Class Codes: A61P 33/00 Antiparasitic agents
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07D 239/48 : Two nitrogen atoms

Abstract

Compounds and methods for treating diseases mediated by a P2X₃ and/or a P2X_2/3 receptor antagonist, the methods comprising administering to a subject in need thereof an effective amount of a compound of formula (I):

wherein D, X, R¹, R², R³, R⁴, R⁵, R⁶, R⁷ and R⁸ are as defined herein.

Claims

1. A compound of formula (1):

2. The compound of claim 1, wherein X is:

—

O—

;

or —

CH₂—

.

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

4. The compound of claim 2, wherein one of R⁷ and R⁸ is hydrogen and the other is hydrogen, alkyl, hydroxyalkyl or haloalkyl.

5. The compound of claim 3, wherin R³ is:

hydrogen;

halo;

alkoxy;

haloalkoxy;

hydroxy;

or alkylsulfonyl.

6. The compound of claim 5, wherein R¹ is isopropyl.

7. The compound of claim 3, wherein R⁵ is:

hydrogen;

alkyl;

optionally substituted phenyl;

optionally substituted pyridinyl;

optionally substituted thienyl;

optionally substituted imidazolyl;

hydroxyalkyl;

alkoxyalkyl;

aminoalkyl;

cyanoalkyl;

alkylsilyl or cycloalkyl.

8. The compound of claim 3, wherein R⁵ is hydrogen or alkyl.

9. The compound of claim 6, wherein R⁵ is hydrogen or methyl.

10. The compound of claim 3, wherein R⁵ is heteroaryl selected from pyridinyl, pyrimdinyl, thienyl, furanyl, imidazolyl, pyrazolyl and pyrrolyl.

11. The compound of claim 3, wherein R⁵ is:

hydrogen;

methyl;

ethyl;

propyl;

phenyl;

methoxymethyl;

pyridin-2-yl;

pyridin-3-yl;

pyridin-4-yl;

2-hydroxyethyl;

3-hydroxypropyl;

hydroxymenthyl;

methylaminomethyl;

2-cyanoethyl;

thien-3-yl;

1-methylimidazol-5-yl;

trimethylsilyl;

or cyclopropyl.

12. The compound of claim 1 wherein said compound is of the formula (II):

13. The compound of claim 1, wherein said compound is of the formula (III):

14. The compound of claim 1, wherein said compound is of the formula (IV):

16. A method for treating asthma, said method comprising administering to a subject in need thereof an effective amount of a compound of claim 1.

15. A compound of the formula (VII):