IP Library › Granted Patent US 7,482,469

Granted Patent B2

US 7,482,469 · App. 11/593,741 · Granted Jan 27, 2009

2-(benzimidazol-1-yl)-acetamide bisaryl derivatives

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Quick Facts

Patent No.: US 7,482,469
App. No.: 11/593,741
Granted: Jan 27, 2009
Kind: B2

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Abstract

The invention relates to 2-(benzimidazol-1-yl)-acetamide bisaryl derivative having the general Formula I wherein n is 0 or 1; Ar 1 represents a diradical derived from a 5- or-6-membered aromatic ring, optionally comprising 1-3 heteroatoms selected from N, O and S, said ring being optionally substituted with (C 1-4 )alkyl, (C 1-4 )alkyloxy, halogen, CF 3 or cyano; Ar 2 represents a 6-membered aryl ring, optionally comprising 1-3 nitrogen atoms, said ring being optionally substituted with 1-3 substituents selected from (C 1-4 )alkyl (optionally substituted with 1 or more halogens), (C 1-4 )alkyloxy (optionally substituted with 1 or more halogens), di(C 1-4 )alkylamino, halogen, CF 3 or cyano; or a pharmaceutically acceptable salt thereof; to pharmaceutical compositions comprising the same and to the use of said 2-(benzimidazol-1-yl)-acetamide bisaryl derivatives in the treatment of TRPV1 mediated disorders.

Claims (194)

1. A 2-(benzimidazol-1-yl)-acetamide bisaryl compound of Formula I

wherein n is 0 or 1;

Ar 1 represents a diradical derived from a 5- or-6-membered aromatic ring, optionally comprising 1-3 heteroatoms selected from N, O and S, said ring being optionally substituted with (C 1-4 )alkyl, (C 1-4 )alkyloxy, halogen, CF 3 or cyano;

Ar 2 represents a 6-membered aryl ring, optionally comprising 1-3 nitrogen atoms, said ring being optionally substituted with 1-3 substituents selected from (C 1-4 )-alkyl (optionally substituted with 1 or more halogens), (C 1-4 )alkyloxy (optionally substituted with 1 or more halogens), di(C 1-4 )alkylamino, halogen, CF 3 or cyano; or a pharmaceutically acceptable salt thereof; with the proviso that compounds wherein n is 0 and —Ar 1 — is a 2,4-thiazolylene or —Ar 1 —Ar 2 represents 1,1′biphenyl)-2-yl are excluded.

2. The 2-(benzimidazol-1-yl)-acetamide bisaryl compound according to claim 1 , wherein Ar 1 represents 1,3-phenylene, 2,6-pyridinylene, 1,3-pyrazolylene, 3,5-oxazolylene or 1,2,4-thiadiazol-3,5-diyl.

3. The 2-(benzimidazol-1-yl)-acetamide bisaryl compound according to claim 1 , wherein Ar 2 —Ar 1 — represents 1-phenyl-1H-pyrazol-3-yl, 4-pyridin-2-yl-thiazol-2-yl or 3-phenyl-isoxazol-5-yl.

4. The 2-(benzimidazol-1-yl)-acetamide bisaryl compound according to claim 1 , wherein n is 0 and Ar 2 —Ar 1 — represents 1-phenyl-1H-pyrazol-3-yl.

5. The 2-(benzimidazol-1-yl)-acetamide bisaryl compound according to claim 1 which is selected from the group consisting of:

2-benzimidazol-1-yl-N-biphenyl-3-yl-acetamide;

2-benzimidazol-1-yl-N-(2′-methoxy-biphenyl-3-yl)-acetamide;

2-benzimidazol-1-yl-N-(6-methoxy-biphenyl-3-yl)-acetamide;

2-benzimidazol-1-yl-N-(4-methyl-biphenyl-3-yl)-acetamide;

2-benzimidazol-1-yl-N-(4′-chloro-biphenyl-3-yl)-acetamide;

2-benzimidazol-1-yl-N-(4-methoxy-biphenyl-3-yl)-acetamide;

2-benzimidazol-1-yl-N-(2′-methyl-biphenyl-3-yl)-acetamide;

2-benzimidazol-1-yl-N-(6-phenyl-pyridin-2-yl)-acetamide;

2-benzimidazol-1-yl-N-biphenyl-3-ylmethyl-acetamide;

2-benzimidazol-1-yl-N-(3-phenyl-[1,2,4]thiadiazol-5-yl)-acetamide;

2-benzimidazol-1-yl-N-biphenyl-4-ylmethyl-acetamide;

2-benzimidazol-1-yl-N-biphenyl-2-ylmethyl-acetamide;

2-benzimidazol-1-yl-N-[1-(3-trifluoromethyl-phenyl)-1H-pyrazol-3-yl]-acetamide;

2-benzimidazol-1-yl-N-(1-phenyl-1H-pyrazol-3-yl)-acetamide;

2-benzimidazol-1-yl-N-[1-(4-trifluoromethyl-phenyl)-1H-pyrazol-3-yl]-acetamide;

2-benzimidazol-1-yl-N-[1-(3-methyl-phenyl)-1H-pyrazol-3-yl]-acetamide;

2-benzimidazol-1-yl-N-[1-(3-chloro-4-methyl-phenyl)-1H-pyrazol-3-yl]-acetamide;

2-benzimidazol-1-yl-N-[1-(3,5-difluoro-phenyl)-1H-pyrazol-3-yl]-acetamide;

2-benzimidazol-1-yl-N-[1-(3-fluoro-phenyl)-1H-pyrazol-3-yl]-acetamide;

2-benzimidazol-1-yl-N-[1-(3,4-difluoro-phenyl)-1H-pyrazol-3-yl]-acetamide;

2-benzimidazol-1-yl-N-[3-(6-methyl-pyridin-2-yl)-phenyl]-acetamide;

2-benzimidazol-1-yl-N-(3-m-tolyl-isoxazol-5-yl)-acetamide;

2-benzimidazol-1-yl-N-(2′-chloro-biphenyl-4-yl)-acetamide;

2-benzimidazol-1-yl-N-(3′-chloro-biphenyl-4-yl)-acetamide;

2-benzimidazol-1-yl-N-(3′-methoxy-biphenyl-4-yl)-acetamide;

2-benzimidazol-1-yl-N-(2′-methoxy-biphenyl-4-yl)-acetamide;

2-benzimidazol-1-yl-N-(4′-methyl-biphenyl-3-yl)-acetamide;

2-benzimidazol-1-yl-N-(4′-cyano-biphenyl-3-yl)-acetamide;

2-benzimidazol-1-yl-N-(3′-trifluoromethyl-biphenyl-3-yl)-acetamide;

2-benzimidazol-1-yl-N-(3′-cyano-biphenyl-3-yl)-acetamide;

2-benzimidazol-1-yl-N-(4′-methoxy-biphenyl-3-yl)-acetamide;

2-benzimidazol-1-yl-N-[3-(4-methyl-pyridin-2-yl)-phenyl]-acetamide;

2-benzimidazol-1-yl-N-[3-(4-trifluoromethyl-pyrimidin-2-yl)-phenyl]-acetamide;

2-benzimidazol-1-yl-N-(3′-methoxy-biphenyl-3-yl)-acetamide;

2-benzimidazol-1-yl-N-(3′-methyl-biphenyl-3-yl)-acetamide;

2-benzimidazol-1-yl-N-[3-(5-methyl-pyridin-2-yl)-phenyl]-acetamide;

2-benzimidazol-1-yl-N-[3-(5-trifluoromethyl-pyridin-2-yl)-phenyl]-acetamide;

2-benzimidazol-1-yl-N-[3-(6-trifluoromethyl-pyridin-2-yl)-phenyl]-acetamide;

2-benzimidazol-1-yl-N-(3′-trifluoromethoxy-biphenyl-3-yl)-acetamide;

2-benzimidazol-1-yl-N-[3-(4-trifluoromethyl-pyridin-2-yl)-phenyl]-acetamide;

2-benzimidazol-1-yl-N-(4′-methyl-biphenyl-2-ylmethyl)-acetamide;

2-benzimidazol-1-yl-N-(3′-methyl-biphenyl-2-ylmethyl)-acetamide;

2-benzimidazol-1-yl-N-(4′-chloro-biphenyl-2-ylmethyl)-acetamide;

2-benzimidazol-1-yl-N-(3′-chloro-biphenyl-2-ylmethyl)-acetamide;

2-benzimidazol-1-yl-N-(3′,4′-difluoro-biphenyl-2-ylmethyl)-acetamide;

2-benzimidazol-1-yl-N-(4′-trifluoromethyl-biphenyl-2-ylmethyl)-acetamide;

2-benzimidazol-1-yl-N-(3′-trifluoromethyl-biphenyl-2-ylmethyl)-acetamide;

2-benzimidazol-1-yl-N-(3′-dimethylamino-biphenyl-2-ylmethyl)-acetamide;

2-benzimidazol-1-yl-N-(2′-methyl-biphenyl-4-ylmethyl)-acetamide;

2-benzimidazol-1-yl-N-(3′-methoxy-biphenyl-4-ylmethyl)-acetamide;

2-benzimidazol-1-yl-N-(2′-trifluoromethyl-biphenyl-4-ylmethyl)-acetamide;

2-benzimidazol-1-yl-N-(3′-trifluoromethyl-biphenyl-4-ylmethyl)-acetamide;

2-benzimidazol-1-yl-N-(2′-dimethylamino-biphenyl-4-ylmethyl)-acetamide;

2-benzimidazol-1-yl-N-(3′-methyl-biphenyl-3-ylmethyl)-acetamide;

2-benzimidazol-1-yl-N-(3′-methoxy-biphenyl-3-ylmethyl)-acetamide;

2-benzimidazol-1-yl-N-(2′-trifluoromethyl-biphenyl-3-ylmethyl)-acetamide; and

2-benzimidazol-1-yl-N-(3′-trifluoromethyl-biphenyl-3-ylmethyl)-acetamide;

or pharmaceutically acceptable salt thereof.

6. A pharmaceutical composition comprising a 2-(benzimidazol-1-yl)-acetamide bisaryl compound or a pharmaceutically acceptable salt thereof according to claim 1 in admixture with pharmaceutically acceptable auxiliaries.

7. The pharmaceutical composition according to claim 6 , wherein in the 2-(benzimidazol-1-yl)-acetamide bisaryl compound of formula I, Ar 1 represents 1,3-phenylene, 2,6-pyridinylene, 1,3-pyrazolylene, 3,5-oxazolylene or 1,2,4-thiadiazol-3,5-diyl.

8. The pharmaceutical composition according to claim 6 , wherein in the 2-(benzimidazol-1-yl)-acetamide bisaryl compound of formula I, Ar 2 —Ar 1 — represents 1-phenyl-1H-pyrazol-3-yl, 4-pyridin-2-yl-thiazol-2-yl or 3-phenyl-isoxazol-5-yl.

9. The pharmaceutical composition according to claim 6 , wherein in the 2-(benzimidazol-1-yl)-acetamide bisaryl compound of formula I, n is 0 and Ar 2 —Ar 1 — represents 1-phenyl-1H-pyrazol-3-yl.

10. The pharmaceutical composition according to claim 6 , wherein the 2-(benzimidazol-1-yl)-acetamide bisaryl compound is selected from the group consisting of:

2-benzimidazol-1-yl-N-biphenyl-3-yl-acetamide;

2-benzimidazol-1-yl-N-(2′-methoxy-biphenyl-3-yl)acetamide;

2-benzimidazol-1-yl-N-(6-methoxy-biphenyl-3yl)-acetamide;

2-benzimidazol-1-yl-N-(4-methyl-biphenyl-3-yl) acetamide;

2-benzimidazol-1-yl-N-(4′-chloro-biphenyl-3-yl)-acetamide;

2-benzimidazol-1-yl-N-(4methoxy-biphenyl-3-yl)-acetamide;

2-benzimidazol-1-yl-N-(2′-methyl-biphenyl-3-yl)acetamide;

2-benzimidazol-1-yl-N-(6-phenyl-pyridin-2-yl)-acetamide;

2-benzimidazol-1-yl-N--biphenyl-3-ylmethyl-acetamide;

2-benzimidazol-1-yl-N-(3-phenyl-[1,2,4]thiadiazol-5-yl)-acetamide;

2-benzimidazol-1-yl-N-biphenyl-4-ylmethyl-acetamide;

2-benzimidazol-1-yl-N-biphenyl-2-ylmethyl-acetamide;

2-benzimidazol-1-yl-N-[1-(3-trifluoromethyl-phenyl)-1H-pyrazol-3-yl]-acetamide;

2-benzimidazol-1-yl-N-(1-phenyl-1H-pyrazol-3-yl-acetamide;

2-benzimidazol-1-yl-N-[1-(4-trifluoromethyl-phenyl)-1H-pyrazol-3-yl]-acetamide;

2-benzimidazol-1-yl-N-[1-(3-methyl-phenyl)-1H-pyrazol-3-yl]-acetamide;

2-benzimidazol-1-yl-N-[1-(3-chloro-4-methyl-phenyl)-1H-pyrazol-3-yl]-acetamide;

2-benzimidazol-1-yl-N-[1-(3,5-difluoro-phenyl)-1H-pyrazol-3-yl]-acetamide;

2-benzimidazol-1-yl-N-[1-(3-fluoro-phenyl)-1H-pyrazol-3-yl]-acetamide;

2-benzimidazol-1-yl-N-[1-(3,4-difluoro-phenyl)-1H-pyrazol-3-yl]-acetamide;

2-benzimidazol-1-yl-N-[3-(6-methyl-pyridin-2-yl)-phenyl]-acetamide;

2-benzimidazol-1-yl-N-(3-m-tolyl-isoxazol-5-yl)-acetamide;

2-benzimidazol-1-yl-N-(2′-chloro-biphenyl-4-yl)-acetamide;

2-benzimidazol-1-yl-N-(3′-chloro-biphenyl-4-yl)-acetamide;

2-benzimidazol-1-yl-N-(3′-methoxy-biphenyl-4-yl)-acetamide;

2-benzimidazol-1-yl-N-(2′-methoxy-biphenyl-4-yl)-acetamide;

2-benzimidazol-1-yl-N-(4′-methyl-biphenyl-3-yl)-acetamide;

2-benzimidazol-1-N-(4′-cyano-biphenyl-3-yl)-acetamide:

2-benzimidazol-1-yl-N-(3′-trifluoromethyl-biphenyl-3-yl)-acetamide;

2-benzimidazol-1-yl-N-(3′-cyano-biphenyl-3-yl)-acetamide;

2-benzimidazol-1-yl-N-4′-methoxy-biphenyl-3-yl)-acetamide;

2-benzimidazol-1-yl-N-[3-(4-methyl-pyridin-2-yl)-phenyl]-acetamide;

2-benzimidazol-1-yl-N-[3-(4-trifluoromethyl-pyrimidin-2-yl)-phenyl]-acetamide;

2-benzimidazol-1-yl-N-(3′-methoxy-biphenyl-3-yl)-acetamide;

2-benzimidazol-1-yl-N-(3′-methyl-biphenyl-3-yl)-acetamide;

2-benzimidazol-1-yl-N-[3-(5-methyl-pyridin-2-yl)-phenyl]-acetamide;

2-benzimidazol-1-yl-N-[3-(5-trifluoromethyl-pyridin-2-yl)-phenyl]-acetamide;

2-benzimidazol-1-yl-N-[3-(6-trifluoromethyl-pyridin-2-yl)-phenyl]-acetamide;

2-benzimidazol-1-yl-N-(3′-trifluoromethoxy-biphenyl-3-yl)-acetamide;

2-benzimidazol-1-yl-N-[3-(4-trifluoromethyl-pyridin-2-yl)-phenyl]1-acetamide;

2-benzimidazol-1yl-N-(4′-methyl-biphenyl-2-ylmethyl)-acetamide;

2-benzimidazol-1yl-N-(3′-methyl-biphenyl-2-ylmethyl)-acetamide; 2-benzimidazol-1-yl-N-(4′-chloro-biphenyl-2-ylmethyl)-acetamide;

2-benzimidazol-1-yl-N-(3 40 -chloro-biphenyl-2-ylmethyl)-acetamide;

2-benzimidazol-1yl-N-(3′,4′-difluoro-biphenyl-2-ylmethyl)-acetamide;