Oxazolone and pyrrolidinone-substituted pryidine amides as P2X 3 and P2X 2/3 antagonists

• US 8,093,275 B2
• Filed: 06/22/2010
• Issued: 01/10/2012
• Est. Priority Date: 06/22/2009
• Status: Active Grant

• Current Assignee: Roche Palo Alto LLC (Roche Holding AG)
• Original Assignee: Roche Palo Alto LLC (Roche Holding AG)
• Inventors: Chen, Li, Dillon, Michael Patrick, Feng, Lichun, Yang, Minmin
• Primary Examiner(s): Wilson, James O
• Assistant Examiner(s): Willis, Douglas M
• Application Number:
  US12/820,660
• Publication Number:
  US 20100324069A1
• Time in Patent Office: 567 Days
• Field of Search: 514/357, 544/238, 544/277, 544/333, 544/405, 546/268.1, 548/217, 548/237, 548/306.1, 548/503, 548/518
• US Class Current: 514/357
• CPC Class Codes: A61K 31/497 containing further heterocyclic rings
• 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 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 13/08 of the prostate
• CPC Class Codes: A61P 13/10 of the bladder
• CPC Class Codes: A61P 15/00 Drugs for genital or sexual disorders for disorders of sex hormones A61P5/24; Contraceptives
• CPC Class Codes: A61P 15/08 for gonadal disorders or for enhancing fertility, e.g. inducers of ovulation or of spermatogenesis
• 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 25/30 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 31/04 Antibacterial agents
• CPC Class Codes: A61P 31/12 Antivirals
• CPC Class Codes: A61P 33/00 Antiparasitic agents
• CPC Class Codes: A61P 39/02 Antidotes
• CPC Class Codes: A61P 9/10 for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• CPC Class Codes: C07D 207/27 : with substituted hydrocarbon radicals directly attached to the ring nitrogen atom
• CPC Class Codes: C07D 233/32 : One oxygen atom
• CPC Class Codes: C07D 263/20 : attached in position 2
• 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
• CPC Class Codes: C07D 407/14 : containing three or more hetero rings
• CPC Class Codes: C07D 413/10 : linked by a carbon chain containing aromatic rings
• CPC Class Codes: C07D 413/12 : linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 413/14 : containing three or more hetero rings
• CPC Class Codes: C07D 473/00 : Heterocyclic compounds containing purine ring systems

Abstract

Compounds of the formula I:

or a pharmaceutically acceptable salt thereof, wherein, X, Y, R¹, R², R³, R⁴, R⁵, R⁶ and R⁷ are as defined herein. Also disclosed are methods of using the compounds for treating diseases associated with P2X₃ and/or a P2X_2/3 receptor antagonists and methods of making the compounds.

Claims

1. A compound of formula I:

2. The compound of claim 1, wherein R⁵, R⁶ and R⁷ are hydrogen.

3. The compound of claim 2, wherein R¹ is methyl.

4. The compound of claim 2, wherein R² is:

cyclopropyl;

2-methoxy-1-methyl-ethyl;

2-hydroxy-1-methyl-ethyl;

5-methylpyrazin-2-yl-methyl;

1-pyrazin-2-yl-ethyl;

pyrimidin-5-yl-methyl;

6-methyl-pyridazin-3-yl-methyl;

pyridazin-3-yl-methyl;

5-methyl-pyrimidin-2-yl-methyl;

or 2-methyl-pyrimidin-5-yl-methyl.

5. The compound of claim 2, wherein R² is 2-hydroxy-1-methyl-ethyl;

5-methylpyrazin-2-yl-methyl;

or 1-pyrazin-2-yl-ethyl.

6. The compound of claim 2, wherein R³ is C_1-6alkyl.

7. The compound of claim 2, wherein R³ is ethyl or isopropyl.

8. The compound of claim 2, wherein R⁴ is hydrogen.

9. The compound of claim 2, wherein R³ and R⁴ together with the atoms to which they are attached form a fused phenyl ring.

10. The compound of claim 2, wherein Y is —

O—

.

11. The compound of claim 2, wherein Y is —

CHR^b—

.

12. The compound of claim 2, wherein Y is —

NR^c—

.

13. A pharmaceutical composition comprising:

(a) a pharmaceutically acceptable carrier; and

(b) a compound of claim 1.

14. A compound of formula III:

15. The compound of claim 14, wherein R¹ is methyl.

16. The compound of claim 15, wherein Y is —

O—

.

17. A compound selected from:

N-(5-Methyl-pyrazin-2-ylmethyl)-3-(5-methyl-pyridin-2-yl)-5-(2-oxo-benzooxazol-3-yl)-benzamide;

3-(5-Methyl-pyridin-2-yl)-5-(2-oxo-benzooxazol-3-yl)-N-(1-pyrazin-2-yl-ethyl)-benzamide

N—

((S)-2-Hydroxy-1-methyl-ethyl)-3-(5-methyl-pyridin-2-yl)-5-(2-oxo-benzooxazol-3-yl)-benzamide;

3-(5-Methyl-pyridin-2-yl)-5-(2-oxo-2,3-dihydro-benzoimidazol-1-yl)-N-(1-pyrazin-2-yl-ethyl)-benzamide;

N-(5-Methyl-pyrazin-2-ylmethyl)-3-(5-methyl-pyridin-2-yl)-5-(2-oxo-2,3-dihydro-indol-1-yl)-benzamide;

3-(5-Methyl-pyridin-2-yl)-5-(2-oxo-2,3-dihydro-indol-1-yl)-N-(1-pyrazin-2-yl-ethyl)-benzamide;

3-((R)-4-Isopropyl-2-oxo-oxazolidin-3-yl)-N—

((R)-2-methoxy-1-methyl-ethyl)-5-(5-methyl-pyridin-2-yl)-benzamide;

N-Cyclopropyl-3-((R)-4-isopropyl-2-oxo-oxazolidin-3-yl)-5-(5-methyl-pyridin-2-yl)-benzamide;

N—

((S)-2-Hydroxy-1-methyl-ethyl)-3-((R)-4-isopropyl-2-oxo-oxazolidin-3-yl)-5-(5-methyl-pyridin-2-yl)-benzamide;

3-((R)-4-Isopropyl-2-oxo-oxazolidin-3-yl)-5-(5-methyl-pyridin-2-yl)-N-(1-pyrazin-2-yl-ethyl)-benzamide;

3-((R)-4-Isopropyl-2-oxo-oxazolidin-3-yl)-N-(5-methyl-pyrazin-2-ylmethyl)-5-(5-methyl-pyridin-2-yl)-benzamide;

3-(5-Methyl-pyridin-2-yl)-5-(2-oxo-benzooxazol-3-yl)-N-pyrimidin-5-ylmethyl-benzamide;

N-(6-Methyl-pyridazin-3-ylmethyl)-3-(5-methyl-pyridin-2-yl)-5-(2-oxo-benzooxazol-3-yl)-benzamide;

3-(5-Methyl-pyridin-2-yl)-5-(2-oxo-benzooxazol-3-yl)-N-pyridazin-3-ylmethyl-benzamide;

3-((R)-4-Methyl-2-oxo-oxazolidin-3-yl)-5-(5-methyl-pyridin-2-yl)-N-(1-pyrazin-2-yl-ethyl)-benzamide;

3-((R)-4-Methyl-2-oxo-oxazolidin-3-yl)-N-(5-methyl-pyrazin-2-ylmethyl)-5-(5-methyl-pyridin-2-yl)-benzamide;

3-(4-Ethyl-2-oxo-oxazolidin-3-yl)-N—

((S)-2-hydroxy-1-methyl-ethyl)-5-(5-methyl-pyridin-2-yl)-benzamide;

3-(4-Ethyl-2-oxo-oxazolidin-3-yl)-5-(5-methyl-pyridin-2-yl)-N-(1-pyrazin-2-yl-ethyl)-benzamide;

3-(4-Ethyl-2-oxo-oxazolidin-3-yl)-N-(5-methyl-pyrazin-2-ylmethyl)-5-(5-methyl-pyridin-2-yl)-benzamide;

3-(4,4-Dimethyl-2-oxo-oxazolidin-3-yl)-5-(5-methyl-pyridin-2-yl)-N-(1-pyrazin-2-yl-ethyl)-benzamide;

3-(4,4-Dimethyl-2-oxo-oxazolidin-3-yl)-N-(5-methyl-pyrazin-2-ylmethyl)-5-(5-methyl-pyridin-2-yl)-benzamide;

N—

((S)-2-Hydroxy-1-methyl-ethyl)-3-(5-methyl-pyridin-2-yl)-5-((R)-2-oxo-4-propyl-oxazolidin-3-yl)-benzamide;

3-(5-Methyl-pyridin-2-yl)-5-((R)-2-oxo-4-propyl-oxazolidin-3-yl)-N-(1-pyrazin-2-yl-ethyl)-benzamide;

N-(5-Methyl-pyrazin-2-ylmethyl)-3-(5-methyl-pyridin-2-yl)-5-((R)-2-oxo-4-propyl-oxazolidin-3-yl)-benzamide;

3-(4,4-Dimethyl-2-oxo-oxazolidin-3-yl)-N—

((S)-2-hydroxy-1-methyl-ethyl)-5-(5-methyl-pyridin-2-yl)-benzamide;

N—

((S)-2-Hydroxy-1-methyl-ethyl)-3-(2-methyl-5-oxo-pyrrolidin-1-yl)-5-(5-methyl-pyridin-2-yl)-benzamide;

3-(2-Methyl-5-oxo-pyrrolidin-1-yl)-5-(5-methyl-pyridin-2-yl)-N-(1-pyrazin-2-yl-ethyl)-benzamide;

3-(2-Methyl-5-oxo-pyrrolidin-1-yl)-N-(5-methyl-pyrazin-2-ylmethyl)-5-(5-methyl-pyridin-2-yl)-benzamide;

N-(5-Methyl-pyrazin-2-ylmethyl)-3-(5-methyl-pyridin-2-yl)-5-(5-oxo-6-oxa-4-aza-spiro[2,4]hept-4-yl)-benzamide;

N-(5-Methyl-pyrazin-2-ylmethyl)-3-(5-methyl-pyridin-2-yl)-5-(8-oxo-7,8-dihydro-purin-9-yl)-benzamide;

3-(4,4-Dimethyl-2-oxo-oxazolidin-3-yl)-N-(6-methyl-pyridazin-3-ylmethyl)-5-(5-methyl-pyridin-2-yl)-benzamide;

3-(5-Methyl-pyridin-2-yl)-N-(5-methyl-pyrimidin-2-ylmethyl)-5-(2-oxo-benzooxazol-3-yl)-benzamide; and

3-(5-Methyl-pyridin-2-yl)-N-(2-methyl-pyrimidin-5-ylmethyl)-5-(2-oxo-benzooxazol-3-yl)-benzamide;

or a pharmaceutically acceptable salt thereof.