IP Library › Granted Patent US 7,345,075

Granted Patent B2

US 7,345,075 · App. 11/305,521 · Granted Mar 18, 2008

1,2 diarylbenzimidazoles and their pharmaceutical use

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Quick Facts

Patent No.: US 7,345,075
App. No.: 11/305,521
Granted: Mar 18, 2008
Kind: B2

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Abstract

Benzimidazoles of general formula I and the use of benzimidazole derivatives for the production of pharmaceutical agents for treatment and prophylaxis of diseases that are associated with a microglia activation are described.

Claims (303)

1. A compound, which is

[(1,2-diphenyl-1H-benzimidazol-6-yl)oxy]acetic acid isopropyl ester,

3-[(1,2-diphenyl-1H-benzimidazol-6-yl)oxy]propanoic acid methyl ester,

2-[(1,2-diphenyl-1H-1-benzimidazol-6-y)oxy]propanoic acid methyl ester,

4-[(1,2-diphenyl-1H-benzimidazol-6-yl)oxyl]butanoic acid isopropyl ester,

5-[(1,2-diphernyl-1H-benzimidazol-6-yl)oxy]pentanoic acid isopropyl ester,

6-[(1,2-diphenyl-1H-benzimidazol-6-yl)oxy]hexanoic acid methyl ester,

6-[(1,2-diphenyl-1H-henzimidazol-6-yl)oxy]hexanoic acid isopropyl ester,

6-[(1,2-diphenyl-1H-benzimidazol-6-yl)oxy]hexanamide,

N-methoxy-6-[(1,2-diphenyl-1H-benzimidazol-6-yl)oxy]hexanamide,

N-(phenylmethoxy)-6-[(1,2-diphenyl-1H-benzimidazol-6-yl)oxy]hexanamide,

N-hydroxy-6-[(1,2-diphenyl-1H-benzimidazol-6-yl)oxy]hexanamide,

7-[(1,2diphenyl-1H-benzimidazol-6-yl)oXy]heptanoic acid methyl ester,

6-[[1-(3-nitrophenyl)-2-phenyl-1H-benzimidazol-6-yl]oxy]hexanoic acid isopropyl ester,

6-[[2-phenyl-1-[3-(trifluoromethyl)phenyl]-1H-benzimidazol-6-yl]oxy]hexanoic acid methyl ester,

6-[[2-phenyl-1-[3-(trifluoromethyl)phenyl]-1H-benzimidazol-6-yl]oxy]hexanoic acid isopropyl ester,

6-[[1-(3-cyanophenyl)-2-phenyl-1H-benzimidazol-6-yl]oxy]hexanoic acid methyl ester,

6-[[1-(3-cyanophenyl)-2-phenyl-1H-benzimidazol-6-yl]oxy]hexanoic acid isopropyl ester,

6-[[1-(3-cyanophenyl)-2-phenyl-1H-benzimidazol-6-yl]oxy]hexanoic acid,

6-[[1-(4-cyanophenyl)-2-phenyl-1H-benzimidazol-6-yl]oxy]hexanoic acid methyl ester,

6-[[1-(4-cyanophenyl)-2-phenyl-1H-benzimidazol-6-yl]oxy]hexanoic acid isopropyl ester,

6-[[1-(3-chlorophenyl)-2-phenyl-1H-benzimidazol-6-yl]oxy]hexanoic acid methyl ester,

6-[[1-(3-chlorophenyl)-2-phenyl-1H-benzimidazol-6-yl]oxy]hexanoic acid isopropyl ester,

6-[[1-(4-chlorophenyl)-2-phenyl-1H-benzimidazol-6-yl]oxy]hexanoic acid methyl ester,

6-[[1-(4-chlorophenyl)-2-phenyl-1H-henzimidazol-6-yl]oxy]hexanoic acid isopropyl ester,

6-[[1-(3-methylpheny)-2-phenyl-1H-benzimidazol-6-yl]oxy]hexanoic acid methyl ester,

6-[[1-(3-methylphenyl)-2-phenyl-1H-benzimidazol-6-yl]oxy]hexanoic acid isopropyl ester,

6-[[1-(4-methylphenyl)-2-phenyl-1H-benzimidazol-6-yl]oxy]hexanoic acid methyl ester,

6-[[1-(4-methylphenyl)-2-phenyl-1H-henzimidazol-6-yl]oxy]hexanoic acid isopropyl ester,

6-[[1-(3,4-dimethylphenyl)-2-phenyl-1H-benzimidazol-6-yl]oxy]hexanoic acid methyl ester,

6-[[1-(3,5-dimethylphenyl)-2-phenyl-1H-benzimidazob-6-yl]oxy]hexanoic acid methyl ester,

6-[[1-(3,5-dimethylphenyl)-2-phenyl-1H-benzimidazol-6-yl]oxy]hexanoic acid isopropyl ester,

6-[[1-(3-methoxyphenyl)-2-phenyl-1H-benzimidazol-6-yl]oxy]hexanoic acid methyl ester,

6-[[1-(4-methoxyphenyl)-2-phenyl-1H-benzimidazol-6-yl]oxy]hexanoic acid methyl ester,

6-[[1-(3,4-dimethoxyphenyl)-2-phenyl-1H-benzimidazol-6-yl]oxy]hexanoic acid methyl ester,

6-[[1-[3,4-(methylenedioxy)phenyl]-2-phenyl-1H-benzimidazol-6-yl]oxy]hexanoic acid methyl ester,

6-[[1-[3,4-(methylenedioxy)phenyl]-2-phenlyl-1H-benizimidazol-6-yl]oxy]hexanoic acid,

6-[[2-phenyl-1-(3,4,5-trimethoxyphenyl)-1H-benzimidazol-6-yl]oxy]hexanoic acid methyl ester,

6-[[2-phenyl-1-(3,4,5-trimethoxyphenyl)-1H-benzimidazol-6-yl]oxy]hexanoic acid,

6-[[2-phenyl-1-(3,4,5-trimethoxyphenyl)-1H-benzimidazol-6-yl]oxy]hexanoic acid isopropyl ester,

6-[[1-[4-(N,N-dimethylamino)phenyl]-2-phenyl-1H-benzimidazol-6-yl]oxy]hexanoic acid methyl ester,

6-[[1-[4-(N,N-dimethylamino)phenyl]-2-phenyl-1H-benzimidazol-6-yl]oxy]hexanoic acid,

6-[[1-phenyl-2-[3-(trfluoromethyl)phenyl]-1H-benzimidazol-6-yl]oxy]hexanoic acid isopropyl ester,

6-[[2-(3-chlorophenyl)-1-phenyl-1H-benzimidazol-6-yl]oxy]hexanoic acid methyl ester,

6-[[2-(3-chlorophenyl)- 1-phenyl-1H-benzimidazol-6-yl]oxy]hexanoic acid isopropyl ester,

6-[[2-(4-chlorophenyl)-1-phenyl-1H-benzimidazol-6-yl]oxy]hexanoic acid methyl ester,

6-[[2-(4-chlorophenyl)-1-phenyl-1H-benzimidazol-6-yl]oxy]hexanoic acid isopropyl ester,

6-[[2-(4-methylphenyl-1-phenyl-1H-benzimidazol-6-yl]oxy]hexanoic acid methyl ester,

6-[[2-(4-methylphenyl)-1-phenyl-1H-benzimidazol-6-yl]oxy]hexanoic acid isopropyl ester,

6-[(1,2-diphenyl-5-nitro-1H-benzimidazol-6-yl)oxy]hexanoic acid methyl ester,

6-[(1,2-diphenyl-5-nitro-1H-benzimidazol-6-yl)oxy]hexanoic acid isopropyl ester,

6-[[5-[[(4-bromophenyl)sulfonyl]amino]-1,2-diphenyl-1H-benzimidazol-6-yl]oxy]hexanoic acid isopropyl ester,

6-[[5-[[(4-chlorophenyl)sulfonyl]amino]-2-diphenyl-1H-benzimidazol-6-yl]oxy]hexanoic acid methyl ester,

6-[[5-[[((4-chlorophenyl)sulfonyl]amino]-1,2-diphenyl-1H-benzimidazol-6-yl]oxy]hexanoic acid isopropyl ester,

6-[[1,2-diphenyl-5-[[(3-methylpheny)sulfonyl]amino]-1H-benzimidazol-6-yl]oxy]hexanoic acid isopropyl ester,

6-[[1,2-diphenyl-5-[[(4-methylphenyl)sulfonyl]amino]-1H-benzimidazol-6-yl]oxy]hexanoic acid isopropyl ester,

6-[[1,2-diphenyl-5-[[(4-methoxyphenyl)sulfonyl]amino]-1H-henzimidazol-6-yl]oxy]hexanoic acid isopropyl ester,

6-[[1,2-diphenyl-5-[[[(4-trifluoromethyl)phenyl]sulfonyl]amino]-1H-benzimidazol-6-yl]oxy]hexanoic acid isopropyl ester,

6-[[5-[[[4-(acetylamino)pheny]sulfonyl]amino]-1,2-diphenyl-1H-benzimidazol-6-yl]oxy]-hexanoic acid isopropyl ester,

6-[[5-[[bis(3-chlorophenyl)sulfonyl]amino]-1,2-diphenyl-1H-benzimidazol-6-yl]oxy]hexanoic acid isopropyl ester,

6-[[1,2-diphenyl-5-[(propylsulfonyl)amino]-1H-benzimidazol-6-yl-6-yl]oxy]hexanoic acid isopropyl ester, 6-[[5-[(benzylsulfonyl)amino]-1,2-diphenyl-1H-benzimidazol-6-yl]oxy]hexanoic acid isopropyl ester,

2-[2[(1,2-diphenyl-1H-benzimidazol-6-yl)oxy]ethoxy]acetic acid methyl ester,

3-[2[(1,2-diphenyl-1H-benzimidazol-6-yl)oxy]ethoxy]propanoic acid methyl ester,

6-[[1(3-nitrophenyl)-2-phenyl-1H-benzimidazol-6-yl]oxy]hexanoic acid ethyl ester,

6-[[4-acetyl-1-(4-methylphenyl)-2-phenyl-1H-benzimidazol-6-yl]oxy]hexanoic acid methyl ester,

6-[[1-(4-methylphenyl)-2-phenyl-1H-benzimidazol-5-yl]oxy]hexanoic acid methyl ester,

6-[[2-phenyl-1-[4-(thiomethyl)phenyl]-1H-benzimidazol-5-yl]oxy]hexanoic acid methyl ester,

6-[[2-phenyl-1-[(4-(thiomethyl)phenyl]-1H-benzimidazol-6-yl]oxy]hexanoic acid methyl ester,

6-[[2-phenyl-1-(3-thienyl)-1H-benzimidazol-5-yl]oxy]hexanoic acid methyl ester,

6-[[2-phenyl-1-(3-thienyl)-1H-benzimidazol-6-yl]oxy]hexanoic acid methyl ester,

4-[(2-diphenyl-1H-benzimidazol-6-yl)oxy]butanoic acid methyl ester,

N-(phenylmethoxy)-6-[[2-phenyl-1-(3,4,5-trimethoxyphenyl)-1H-benzimidazol-6-yl]oxy]-hexanamide,

N,N-dimethyl-6-[(1,2-diphenyl-1H-benzimidazol-6-yl)oxy]hexanamide,

N-isopropyl-6-[(1,2-diphenyl-1H-benzimidazol-6-yl)oxy]hexanamide,

6-[(1,2-diphenyl-1H-benzimidazol-6-yl)oxy]-1-pyrrolidin-1-ylhexan-1-one,

5-[[5-[[(4chloropheny)sulfonyl]amno]-2-diphenyl-1H-benzimidazol-6-yl]oxy]pentanoic acid methyl ester,

6-[[5-[[(4-chlorophenyl)sulfonyl]amino]-1-(4-methylphenyl)-2-phenyl-1H-benzimidazol -6-yl]oxy]hexanoic acid methyl ester,

6-[[5-[[(4-chlorophenyl)sulfonyl]amino]-1(4-methoxyphenyl)-2-phenyl-1H-benzimidazol-6-yl]oxy]hexanoic acid methyl ester,

6-[[4-(acetyloxy)-1-(4-methylphenyl)-2-phenyl-1H-benzimidazol-6-yl]oxy]hexanoic acid methyl ester,

6-[[4-hydroxy-1-(4-methylphenyl)-2-phenyl-1H-benzimidazol-6-yl]oxy]hexanoic acid methyl ester,

6-[[4-hydroxy-1-(4-methylphenyl)-2-phenyl-1H-benzimidazol-6-yl]oxy]hexanoic acid, or

6-[[7-methyl-1-(4-methylphenyl)-2-phenyl-1H-benzimidazol-6-yl]oxy]hexanoic acid methyl ester,

or a pharmaceutically acceptable salt thereof.

2. A compound, which is

6-[[2-(4-fluoro-phenyl)-1-phenyl-1H-benzimidazol-6-yl]oxy]hexanoic acid methyl ester,

6-[[2-(4-methoxyphenyl)-1-phenyl-1H-benzimidazol-6-yl]oxy]hexanoic acid methyl ester,

6-[[2-(4-bromophenyl)-1-phenyl-1H-benzimidazol-6-yl]oxy]hexanoic acid methyl ester,

6-[[2-[4-(trifluoromethy)phenyl]-1-phenyl-1H-benzimidazol-6-yl]oxy]hexanoic acid methyl ester,

6-[[5-hydroxy-1-(4-methylphenyl)-2-pheny-1H-benzimidazol-6-yl]oxy]hexanoic acid isopropyl ester,

6-[[5-hydroxy-1-(4-methylphenyl)-2-phenyl-1H-benzimidazol-6-yl]oxy]hexanoic acid,

6-[[5-methoxy-1-(4-methylphenyl)-2-phenyl-1H-benzimidazol-6-yl]oxy]hexanoic acid isopropyl ester,

6-[[5-hydroxy-1-(4-methylphenyl)-2-phenyl-1H-benzimidazol-6-yl]oxy]hexanoic acid methyl ester,

6-[[5-methoxy-1-(4-methylphenyl)-2-phenyl-1H-benzimidazol-6-yl]oxy]hexanoic acid methyl ester,

6-[[5-[[(4-chlorophenyl)sulfonyl]amino]-1-(3,4-dimethylphenyl)-2-phenyl-1H-benzimidazol-6-yl]oxy]hexanoic acid methyl ester,

6-[[5-[[(4-chlorophenyl)sulfonyl]amino]-2-(4-fluorophenyl)-1-(4-methoxyphenyl)-1H-benzimidazol-6-yl]oxy]-hexanoic acid methyl ester,

6-[[5-[[(4-chlorophenyl)sulfonyl]amino]-1-(4-methoxyphenyl)-2-(4methoxyphenyl)-1H-benzimidazol-6-yl]oxy]hexanoic acid methyl ester,

4-[[5-[[(4-chlorophenyl)sulfonyl]amino]-1-(4-methoxyphenyl)-2-phenyl-1H-benzimidazol-6-yl]oxy]butanoic acid methyl ester,

5-[[5-[[(4-chlorophenyl)sulfonyl]amino]-1-(4-methoxyphenyl)-2-phenyl-1H-benzimidazol-6-yl-oxy]pentanoic acid methyl ester,

5-[[5-[[(4-chlorophenyl)sulfonyl]amino]-1,2-diphenyl-1H-benzimidazol-6-yl]oxy]pentanoic acid methyl ester,

6-[[5-[[(4-(trifluoromethyl)phenyl)sulfonyl]amino]1-(4-methoxyphenyl)-2-phenyl-1H-benzimidazol-6-yl]oxy]hexanoic acid methyl ester,

6-[[5-[[(4-chlorophenyl)sulfonyl]methylamino]-1-(4-methoxyphenyl)-2-phenyl-1H-benzimidazol-6-yl]oxy]hexanoic acid methyl ester,

6-[[1-(3-fluorophenyl)-2-phenyl-1H-benzimidazol-6-yl]oxy]hexanoic acid methyl ester,

6-[[2-(4-nitrophenyl)-1-phenyl-1H-benzimidazol-6-yl]oxy]hexanoic acid methyl ester,

N-(cyclopropylmethoxy)-6-[(1,2-diphenyl-1H-benzimidazol-6-yl)oxy]hexanamide,

N-isobutoxy-6-[(1,2-diphenyl-1H-benzimidazol-6-yl)oxy]hexanamide,

N-(cyclopropylmethoxy)-6-[2-phenyl-1-(3,4,5-trimethoxyphenyl)-1H-benzimidazol-6-yl)oxy]-hexanamide,

N-isobutoxy-6-[2-phenyl-1-(3,4,5-trimethoxyphenyl)-1H-benzimidazol-6-yl)oxy]hexanamide,

N-(2-methoxyethyl)-6-[(1,2-diphenyl-1H-benzimidazol-6-yl)oxy]hexanamide,

N-(3-methoxypropyl)-6-[(1,2-diphenyl-1H-benzimidazol-6-yl)oxy]hexanamide,

N-isobutyl-6-[(1,2-diphenyl-1H-benzimidazol-6-yl)oxy]hexanamide,

N,N-di(-2-methoxyethyl)-6-[(1,2-diphenyl-1H-benzimidazol-6-yl)oxy]hexanamide,

N-isopentyl-6-[(1,2-diphenyl-1H-benzimidazol-6-yl)oxy]hexanamide,

N-isopropyl-6-[[1-(3,4-dimethylphenyl)-2-phenyl-1H-benzimidazol-6-yl]oxy-]hexanamide,

N,N-dimethyl-6-[[1-(3,4-dimethylphenyl)-2-phenyl-1H-benzimidazol-6-yl]oxy]hexanamide,

N,N-diethyl-6-[[1-(3,4-dimethylphenyl)-2-phenyl-1H-benzimidazol-6-yl]oxy]hexanamide,

N-isobutyl-6-[[1-(3,4-dimethylphenyl)-2-phenyl-1H-benzimidazol-6-yl]oxy]hexanamide,

N-cyclopropyl-6-[[1-(3,4-dimethylphenyl)-2-phenyl-1H-benzimidazol-6yl]oxy]hexanamide,

N-cyclobutyl-6-[[1-(3,4-dimethylphenyl)-2-phenyl-1H-benzimidazol-6-yl]oxy]hexanamide, or

N-tert-butyl-6-[[1-(3,4-dimethylphenyl)-2-phenyl-1H-benzimidazol-6-yl]oxy]hexanamide,

or a pharmaceutically acceptable salt thereof

3. A pharmaceutical composition comprising a compounds according to claim 1 and a pharmaceutically acceptable carrier.

4. A pharmaceutical composition comprising a compounds according to claim 2 and a pharmaceutically acceptable carrier.

5. A compound according to claim 1 , which is

6-[(1,2-diphenyl-1H-benzimidazol-6-yl)oxy]hexanamide,

N-methoxy-6-[(1,2-diphenyl-1H-benzimidazol-6-yl)oxy]hexanamide,

N-(phenylmethoxy)-6-[(1,2diphenyl-1H-benzimidazol-6-yl)oxy]hexanamide,

N-hydroxy-6-[(1,2-diphenyl-1H-benzimidazol-6-yl)oxy]hexanamide,

N-(phenylmethoxy)-6-[[2-phenyl-1-(3,4,5-trimethoxyphenyl)-1H-benzimidazol-6-yl]oxy]-hexanamide,

N,N-dimethyl-6-[(1,2-diphenyl-1H-benzimidazol-6yl)oxy]hexanamide, or

N-isopropyl-6-[(1,2-diphenyl-1H-benzimidazol-6-yl)oxy]hexanamide,

or a pharmaceutically acceptable salt thereof.

6. A compound according to claim 1 , which is

[(1,2-diphenyl-1H-benzimidazol-6-yl)oxy]acetic acid isopropyl ester,

3-(1,2-diphenyl-1H-benzimidazol-6-yl)oxy]propanoic acid methyl ester,

2-[(1,2-diphenyl-1H-benzimidazol-6-yl)oxy]propanoic acid methyl ester,

4-[(1,2-diphenyl-1H-benzimidazol-6-yl)oxy]butanoic acid isopropyl ester,

5-[(1,2-diphenyl-1H-benzimidazol-6-yl)oxy]pentanoic acid isopropyl ester,

6-[(1,2-diphenyl-1H-benzimidazol-6-yl)oxy]hexanoic acid methyl ester,

6-[(1,2-diphenyl-1H-benzimidazol-6-yl)oxy]hexanoic acid isopropyl ester,

7-[(1,2-diphenyl-1H-benzimidazol-6-yl)oxy]heptanoic acid methyl ester,