OXAZOLONE AND PYRROLIDINONE-SUBSTITUTED ARYLAMIDES AS P2X3 AND P2X2/3 ANTAGONISTS

• US 20100324069A1
• Filed: 06/22/2010
• Published: 12/23/2010
• Est. Priority Date: 06/22/2009
• Status: Active Grant

• Current Assignee: Li Chen, Lichun Feng, Michael Patrick Dillon, Minmin Yang
• Original Assignee: Li Chen, Lichun Feng, Michael Patrick Dillon, Minmin Yang
• Inventors: Feng, Lichun, Chen, Li, Dillon, Michael Patrick, Yang, Minmin
• Granted Patent: US 8,093,275 B2
• Time in Patent Office: Days
• US Class Current: 514/255.05
• 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 X is —

N—

.

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

CR^a—

.

12. The compound of claim 11, wherein R^a is hydrogen or halo.

13. The compound of claim 11, wherein R^a is hydrogen.

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

O—

.

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

CHR^b—

.

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

NR^c—

.

17. The compound of claim 9, wherein said compound is of formula III:

18. The compound of claim 1, wherein said compound is 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;

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

4′

-Methyl-5-(2-oxo-pyrrolidin-1-yl)-biphenyl-3-carboxylic acid (2-methoxy-1-methyl-ethyl)-amide;

4′

-Methyl-5-(2-oxo-imidazolidin-1-yl)-biphenyl-3-carboxylic acid (2-methoxy-1-methyl-ethyl)-amide;

4′

-Methyl-5-(2-methyl-5-oxo-pyrrolidin-1-yl)-biphenyl-3-carboxylic acid (2-methoxy-1-methyl-ethyl)-amide;

(S)-1-[5-(2-Methoxy-1-methyl-ethylcarbamoyl)-4′

-methyl-biphenyl-3-yl]-5-oxo-pyrrolidine-2-carboxylic acid methyl ester;

5-((R)-4-Isopropyl-2-oxo-oxazolidin-3-yl)-4′

-methyl-biphenyl-3-carboxylic acid ((S)-2-hydroxy-1-methyl-ethyl)-amide;

5-((R)-4-Isopropyl-2-oxo-oxazolidin-3-yl)-4′

-methyl-biphenyl-3-carboxylic acid (1-pyrazin-2-yl-ethyl)-amide;

5-((R)-4-Isopropyl-2-oxo-oxazolidin-3-yl)-4′

-methyl-biphenyl-3-carboxylic acid (5-methyl-pyrazin-2-ylmethyl)-amide;

5-((R)-4-Isopropyl-2-oxo-oxazolidin-3-yl)-4′

-methyl-biphenyl-3-carboxylic acid cyclopropylamide;

5-((S)-4-Isopropyl-2-oxo-oxazolidin-3-yl)-4′

-methyl-biphenyl-3-carboxylic acid cyclopropylamide;

5-((S)-4-Isopropyl-2-oxo-oxazolidin-3-yl)-4′

-methyl-biphenyl-3-carboxylic acid ((S)-2-hydroxy-1-methyl-ethyl)-amide;

5-((S)-4-Isopropyl-2-oxo-oxazolidin-3-yl)-4′

-methyl-biphenyl-3-carboxylic acid (5-methyl-pyrazin-2-ylmethyl)-amide;

5-((S)-4-Isopropyl-2-oxo-oxazolidin-3-yl)-4′

-methyl-biphenyl-3-carboxylic acid (1-pyrazin-2-yl-ethyl)-amide;

2′

-Fluoro-5-((R)-4-isopropyl-2-oxo-oxazolidin-3-yl)-4′

-methyl-biphenyl-3-carboxylic acid ((S)-2-hydroxy-1-methyl-ethyl)-amide;

2′

-Fluoro-5-((R)-4-isopropyl-2-oxo-oxazolidin-3-yl)-4′

-methyl-biphenyl-3-carboxylic acid (1-pyrazin-2-yl-ethyl)-amide;

2′

-Fluoro-5-((R)-4-isopropyl-2-oxo-oxazolidin-3-yl)-4′

-methyl-biphenyl-3-carboxylic acid (5-methyl-pyrazin-2-ylmethyl)-amide;

2′

-Fluoro-5-((R)-4-isopropyl-2-oxo-oxazolidin-3-yl)-4′

-methyl-biphenyl-3-carboxylic acid cyclopropylamide;

4′

-Methyl-5-(2-oxo-benzooxazol-3-yl)-biphenyl-3-carboxylic acid (1-pyrazin-2-yl-ethyl)-amide;

4′

-Methyl-5-(2-oxo-benzooxazol-3-yl)-biphenyl-3-carboxylic acid (5-methyl-pyrazin-2-ylmethyl)-amide;

4′

-Methyl-5-(2-oxo-imidazolidin-1-yl)-biphenyl-3-carboxylic acid (2-methoxy-1-methyl-ethyl)-amide;

4′

-Methyl-5-(2-oxo-2,3-dihydro-indol-1-yl)-biphenyl-3-carboxylic acid (5-methyl-pyrazin-2-ylmethyl)-amide;

4′

-Methyl-5-(2-oxo-2,3-dihydro-indol-1-yl)-biphenyl-3-carboxylic acid (1-pyrazin-2-yl-ethyl)-amide; and

4′

-Methyl-5-(8-oxo-7,8-dihydro-purin-9-yl)-biphenyl-3-carboxylic acid ((S)-1-pyrazin-2-yl-ethyl)-amide.

19. A pharmaceutical 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.