Tetrazole-substituted arylamides as P2X3 and P2X2/3 antagonists

• US 20080004442A1
• Filed: 06/28/2007
• Published: 01/03/2008
• Est. Priority Date: 06/29/2006
• Status: Active Grant

• Current Assignee: Roche Palo Alto LLC (Roche Holding AG)
• Original Assignee: Roche Palo Alto LLC (Roche Holding AG)
• Inventors: Dillon, Michael, Feng, Lichun, Chen, Li, Yang, Minmin, Hawley, Ronald
• Granted Patent: US 7,595,405 B2
• Time in Patent Office: Days
• US Class Current: 544/132
• CPC Class Codes: A61K 31/41 having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
• CPC Class Codes: A61K 31/4439 containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole nicotine A61K31/465
• CPC Class Codes: A61K 31/497 containing further heterocyclic rings
• CPC Class Codes: A61K 31/5377 not condensed and containing further heterocyclic rings, e.g. timolol
• 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 1/12 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 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 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 29/00 : Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 29/02 : without antiinflammatory effect
• 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 35/00 : Antineoplastic agents
• CPC Class Codes: A61P 39/02 : Antidotes
• CPC Class Codes: A61P 43/00 : Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• 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 241/12 : with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
• CPC Class Codes: C07D 257/04 : Five-membered rings
• CPC Class Codes: C07D 401/10 : linked by a carbon chain containing aromatic rings
• CPC Class Codes: C07D 401/12 : linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 401/14 : containing three or more hetero rings
• CPC Class Codes: C07D 403/10 : linked by a carbon chain containing aromatic rings
• CPC Class Codes: C07D 403/12 : linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 403/14 : containing three or more hetero rings
• CPC Class Codes: C07D 405/12 : linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 407/10 : linked by a carbon chain containing aromatic rings
• CPC Class Codes: C07D 409/12 : linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 413/10 : linked by a carbon chain containing aromatic rings
• CPC Class Codes: C07D 417/10 : linked by a carbon chain containing aromatic rings
• CPC Class Codes: C07D 417/12 : linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 471/04 : Ortho-condensed systems
• CPC Class Codes: C07D 491/10 : Spiro-condensed systems
• CPC Class Codes: C07D 491/107 : with only one oxygen atom as ring hetero atom in the oxygen-containing ring
• CPC Class Codes: C07D 498/08 : Bridged systems

Abstract

Compounds of the formula I:
or a pharmaceutically acceptable salt thereof, wherein, R¹ is optionally substituted tetrazolyl, R² is optionally substituted phenyl, optionally substituted pyridinyl or optionally substituted thienyl, and R³, R⁴, R⁵ and R⁶ are as defined herein. Also provided are methods of using the compounds for treating diseases associated with the P2X₃ and/or a P2X_2/3 receptor antagonist and methods of making the compounds.

Claims

1. A compound of formula I:

2. The compound of claim 1, wherein R² is optionally substituted phenyl.

3. The compound of claim 1, wherein R² is optionally substituted pyridinyl.

4. The compound of claim 1, wherein R³ is hydrogen.

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

6. The compound of claim 1, wherein R⁶ is hydrogen.

7. The compound of claim 1, wherein R¹ is tetrazol-1-yl optionally substituted at the 5-position with C_1-6alkyl, halo-C_1-6alkyl, hetero-C_1-6alkyl, C_3-6-cycloalkyl, C_3-6cycloalkyl-C_1-6alkyl or cyano.

8. The compound of claim 1, wherein R² is phenyl optionally substituted once, twice or three times with a group or groups each independently selected from C_1-6alkyl, C_1-6alkyloxy, halo, C_1-6haloalkyl, hetero-C_1-6alkyl, C_1-6alkylsulfonyl or cyano.

9. The compound of claim 1, wherein R² is pyridin-2-yl optionally substituted once or twice with a group or groups each independently selected from C_1-6alkyl, C_1-6alkyloxy, halo, C_1-6haloalkyl, hetero-C_1-6alkyl, C_1-6alkylsulfonyl or cyano.

10. 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.

11. The compound of claim 1, wherein R⁴ and R⁵ together with the atom to which they are attached form a cyclopropyl group.

12. The compound of claim 1, wherein R¹ is tetrazol-1-yl optionally substituted at the 5-position with methyl, ethyl, n-propyl, n-butyl, isopropyl, isobutyl, tert-butyl, cyclopropyl, cyclopropylmethyl, trifluoromethyl, pentafluoro-ethyl, 1,1-difluoro-ethyl, 1-methoxy-ethyl, 1-ethoxy-ethyl, 2-methoxy-1-methyl-ethyl, 1-hydroxy-ethyl, or dimethylamino-methyl.

13. The compound of claim 1, wherein R⁵ is heteroaryl selected from pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrazolyl or thiazolyl, each of which may be optionally substituted once or twice with a group or groups independently selected from methyl, ethyl, n-propyl, fluoro, chloro, amino, methylamino and dimethylamino.

14. The compound of claim 1, wherein R⁵ is heterocyclyl-C_1-6alkyl selected from morpholinomethyl, piperidinyl-methyl, piperazinyl-methyl, thiomorpholinylmethyl, pyrrolidinylmethyl, or azetidinylmethyl, the heterocyclyl portion of which may be optionally substituted once or twice with a group or groups independently selected from methyl, methoxy, halo, methanesulfonyl, oxo and acetyl.

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