Biphenyl amides as P2X 3 and P2X 2/3 antagonists

• US 8,283,383 B2
• Filed: 06/22/2010
• Issued: 10/09/2012
• 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: Broka, Chris Allen, Hawley, Ronald Charles
• Primary Examiner(s): Wilson, James O
• Assistant Examiner(s): Willis, Douglas M
• Application Number:
  US12/820,577
• Publication Number:
  US 20100324056A1
• Time in Patent Office: 840 Days
• Field of Search: 514/765, 544/162, 544/242, 544/406, 546/245, 546/323, 548/127, 548/202, 548/236, 548/248, 548/374.1, 549/70, 549/425, 549/505, 564/168
• US Class Current: 514/765
• CPC Class Codes: A61P 1/00 Drugs for disorders of the alimentary tract or the digestive system
• 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 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 13/08 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 19/00 Drugs for skeletal disorders
• 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 31/10 Antimycotics
• CPC Class Codes: A61P 31/12 Antivirals
• CPC Class Codes: A61P 33/00 Antiparasitic agents
• CPC Class Codes: A61P 35/04 specific for metastasis
• 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: C07C 237/32 : having the nitrogen atom of the carboxamide group bound to an acyclic carbon atom of a hydrocarbon radical substituted by oxygen atoms
• CPC Class Codes: C07C 237/42 : having nitrogen atoms of amino groups bound to the carbon skeleton of the acid part, further acylated
• CPC Class Codes: C07C 2601/02 : with a three-membered ring
• CPC Class Codes: C07C 2601/08 : the ring being saturated
• CPC Class Codes: C07C 2601/14 : The ring being saturated
• CPC Class Codes: C07D 213/56 : Amides
• CPC Class Codes: C07D 213/61 : Halogen atoms or nitro radicals
• CPC Class Codes: C07D 213/81 : Amides; Imides
• CPC Class Codes: C07D 231/14 : with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
• 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 241/24 : 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 261/18 : Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen
• CPC Class Codes: C07D 263/34 : with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
• CPC Class Codes: C07D 265/30 : not condensed with other rings
• CPC Class Codes: C07D 277/56 : Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
• CPC Class Codes: C07D 285/06 : 1,2,3-Thiadiazoles; Hydrogenated 1,2,3-thiadiazoles
• CPC Class Codes: C07D 295/125 : with the ring nitrogen atoms and the substituent nitrogen atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
• CPC Class Codes: C07D 307/68 : Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
• CPC Class Codes: C07D 309/08 : with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
• CPC Class Codes: C07D 333/38 : 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 401/12 : linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 403/12 : linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 405/14 : containing three or more hetero rings
• CPC Class Codes: C07D 417/12 : linked by a chain containing hetero atoms as chain links

Abstract

Compounds of the formula I:

or a pharmaceutically acceptable salt thereof, wherein, R¹ is optionally substituted phenyl or optionally substituted pyridinyl, and R², R³, R⁴, R⁵, R⁶, R⁷, R⁸ and R⁹ 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 R⁶ , R⁷, and R⁸ are hydrogen.

3. The compound of claim 1, wherein R¹ is 4-methyl-phenyl.

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

5. The compound of claim 4, wherein R² is hydrogen.

6. The compound of claim 4, wherein R² is methyl.

7. The compound of claim 4, wherein R³ is:

C_1-6alkyl;

C_1-6alkyloxy-C_1-6alkyl;

hydroxy-C_1-6alkyl;

C_3-7cycloalkyl;

heteroaryl, or heterocyclyl-C_1-6alkyl.

8. The compound of claim 4, wherein R³ is:

C_1-6alkyloxy-C_1-6alkyl;

hydroxy-C_1-6alkyl;

heteroaryl, or heterocyclyl-C_1-6alkyl.

9. The compound of claim 4, wherein R³ is methoxymethyl.

10. The compound of claim 4, wherein R³ is hydroxymethyl.

11. The compound of claim 4, wherein R³ is heteroaryl selected from pyridinyl, pyrimidinyl, or pyrazinyl, each of which may be unsubstituted or substituted once or twice with methyl.

12. The compound of claim 4, wherein R³ is hydroxymethyl, methoxymethyl, pyrazin-2-yl or 5-methyl-pyrazin-2-yl.

13. The compound of claim 4, wherein R⁵ is C_1-6alkyl or C_3-7cyclalkyl.

14. The compound of claim 4, wherein R⁵ is isopropyl, isobutyl or tert-butyl.

16. A pharmaceutical composition comprising:

(a) a pharmaceutically acceptable carrier; and

(b) a compound of claim 1.

15. A compound selected from the group consisting of:

4-Methyl-thiophene-2-carboxylic acid [5-(2-methoxy-1-methyl-ethylcarbamoyl)-4′

-methyl-biphenyl-3-yl]-amide;

5-Methyl-thiophene-2-carboxylic acid [5-(2-methoxy-1-methyl-ethylcarbamoyl)-4′

-methyl-biphenyl-3-yl]-amide;

Furan-2-carboxylic acid [5-(2-methoxy-1-methyl-ethylcarbamoyl)-4′

-methyl-biphenyl-3-yl]-amide;

Thiophene-2-carboxylic acid [5-(2-methoxy-1-methyl-ethylcarbamoyl)-4′

-methyl-biphenyl-3-yl]-amide;

5-Benzoylamino-4′

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

Pyridine-2-carboxylic acid [5-(2-methoxy-1-methyl-ethylcarbamoyl)-4′

-methyl-biphenyl-3-yl]-amide;

5-(Cyclohexanecarbonyl-amino)-4′

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

5-(2,4-Dimethyl-benzoylamino)-4′

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

5-(2-Chloro-4-fluoro-benzoylamino)-4′

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

5-(2-Chloro-4-trifluoromethyl-benzoylamino)-4′

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

Thiazole-4-carboxylic acid [5-(2-methoxy-1-methyl-ethylcarbamoyl)-4′

-methyl-biphenyl-3-yl]-amide;

5-Methyl-3-phenyl-isoxazole-4-carboxylic acid [5-(2-methoxy-1-methyl-ethylcarbamoyl)-4′

-methyl-biphenyl-3-yl]-amide;

2,5-Dimethyl-oxazole-4-carboxylic acid [5-(2-methoxy-1-methyl-ethylcarbamoyl)-4′

-methyl-biphenyl-3-yl]-amide;

3-Methyl-thiophene-2-carboxylic acid [5-(2-methoxy-1-methyl-ethylcarbamoyl)-4′

-methyl-biphenyl-3-yl]-amide;

2,5-Dimethyl-2H-pyrazole-3-carboxylic acid [5-(2-methoxy-1-methyl-ethylcarbamoyl)-4′

-methyl-biphenyl-3-yl]-amide;

5-Methyl-isoxazole-3-carboxylic acid [5-(2-methoxy-1-methyl-ethylcarbamoyl)-4′

-methyl-biphenyl-3-yl]-amide;

4-Methoxy-thiophene-3-carboxylic acid [5-(2-methoxy-1-methyl-ethylcarbamoyl)-4′

-methyl-biphenyl-3-yl]-amide;

4′

-Methyl-5-(methyl-propionyl-amino)-biphenyl-3-carboxylic acid (2-methoxy-1-methyl-ethyl)-amide;

4′

-Methyl-5-(methyl-propionyl-amino)-biphenyl-3-carboxylic acid ((R)-1-methyl-2-morpholin-4-yl-ethyl)-amide;

5-(Acetyl-methyl-amino)-4′

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

5-(Acetyl-ethyl-amino)-4′

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

5-[(Methoxy-acetyl)-methyl-amino]-4′

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

5-[Ethyl-(2-methoxy-acetyl)-amino]-4′

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

5-(Acetyl-pyrimidin-4-yl-amino)-4′

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

4′

-Methyl-5-(propionyl-pyrimidin-4-yl-amino)-biphenyl-3-carboxylic acid (1-pyrazin-2-yl-ethyl)-amide;

5-(Isobutyryl-pyrimidin-4-yl-amino)-4′

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

Pyrazine-2-carboxylic acid ethyl-[4′

-methyl-5-(1-pyrazin-2-yl-ethylcarbamoyl)-biphenyl-3-yl]-amide;

N-Ethyl-N-[5-(2-methoxy-1-methyl-ethylcarbamoyl)-4′

-methyl-biphenyl-3-yl]-isonicotinamide;

5-[Ethyl-(3-methyl-butyryl)-amino]-4′

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

5-[Ethyl-(3-methyl-butyryl)-amino]-4′

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

N-Ethyl-N-[4′

-methyl-5-(1-pyrazin-2-yl-ethylcarbamoyl)-biphenyl-3-yl]-nicotinamide;

5-[(2,2-Dimethyl-propionyl)-methyl-amino]-4′

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

5-(Isobutyryl-methyl-amino)-4′

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

5-(Cyclopropanecarbonyl-methyl-amino)-4′

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

Ethyl-[4′

-methyl-5-(1-pyrazin-2-yl-ethylcarbamoyl)-biphenyl-3-yl]-carbamic acid isobutyl ester;

4-Methyl-[1,2,3]thiadiazole-5-carboxylic acid methyl-[4′

-methyl-5-(1-pyrazin-2-yl-ethylcarbamoyl)-biphenyl-3-yl]-amide;

Ethyl-[4′

-methyl-5-(1-pyrazin-2-yl-ethylcarbamoyl)-biphenyl-3-yl]-carbamic acid isopropyl ester;

5-(Ethyl-isobutyryl-amino)-4′

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

Ethyl-[4′

-methyl-5-(1 -pyrazin-2-yl-ethylcarbamoyl)-biphenyl-3-yl]-carbamic acid methyl ester;

5-(Isobutyryl-methyl-amino)-4′

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

Tetrahydro-pyran-4-carboxylic acid ethyl-[4′

-methyl-5-(1-pyrazin-2-yl-ethylcarbamoyl)-biphenyl-3-yl]-amide;

5-Isobutyrylamino-4′

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

Tetrahydro-pyran-4-carboxylic acid methyl-[4′

-methyl-5-(1-pyrazin-2-yl-ethylcarbamoyl)-biphenyl-3-yl]-amide;

Morpholine-4-carboxylic acid [4′

-chloro-5-(1-pyrazin-2-yl-ethylcarbamoyl)-biphenyl-3-yl]-methyl-amide;

4′

-Chloro-5-(3-ethyl-1-methyl-ureido)-biphenyl-3 -carboxylic acid (1-pyrazin-2-yl-ethyl)-amide;

4′

-Methyl-5-[methyl-(2-methyl-butyryl)-amino]-biphenyl-3-carboxylic acid (1-pyrazin-2-yl-ethyl)-amide;

5-[(2-Ethyl-butyryl)-methyl-amino]-4′

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

5-[(2,2-Dimethyl-butyryl)-methyl-amino]-4′

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

5-(Ethyl-isobutyryl-amino)-4′

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

5-(Cyclopentanecarbonyl-methyl-amino)-4′

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

5-(Cyclopentanecarbonyl-methyl-amino)-4′

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

5-(Cyclohexanecarbonyl-methyl-amino)-4′

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

4′

-Methyl-5-[methyl-(2-methyl-butyryl)-amino]-biphenyl-3-carboxylic acid ((S)-2-hydroxy-1-methyl-ethyl)-amide;

2′

-Chloro-5-(isobutyryl-methyl-amino)-4′

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

2′

-Chloro-5-(isobutyryl-methyl-amino)-4′

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

2′

-Chloro-5-(isobutyryl-methyl-amino)-4′

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

4′

-Chloro-5-(trimethyl-ureido)-biphenyl-3-carboxylic acid (1-pyrazin-2-yl-ethyl)-amide;

2′

-Fluoro-5-(isobutyryl-methyl-amino)-4′

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

2′

-Fluoro-5-(isobutyryl-methyl-amino)-4′

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

2′

-Fluoro-5-(isobutyryl-methyl-amino)-4′

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

1-Acetyl-piperidine-4-carboxylic acid methyl-[4′

-methyl-5-(1-pyrazin-2-yl-ethylcarbamoyl)-biphenyl-3-yl]-amide;

5-(Isobutyryl-methyl-amino)-4′

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

2′

,4′

-Dichloro-5-(isobutyryl-methyl-amino)-biphenyl-3-carboxylic acid ((R)-2-methoxy-1-methyl-ethyl)-amide;

2′

,4′

-Dichloro-5-(isobutyryl-methyl-amino)-biphenyl-3-carboxylic acid (1-pyrazin-2-yl-ethyl)-amide;

2′

,4′

-Difluoro-5-(isobutyryl-methyl-amino)-biphenyl-3-carboxylic acid ((R)-2-methoxy-1-methyl-ethyl)-amide; and

2′

,4′

-Difluoro-5-(isobutyryl-methyl-amino)-biphenyl-3-carboxylic acid (1-pyrazin-2-yl-ethyl)-amide.