IP Library › Granted Patent US 9,365,550

Granted Patent B2

US 9,365,550 · App. 14/675,404 · Granted Jun 14, 2016

Benzimidazoles as CNS active agents

Inventors: Simona M. Ceccarelli (Basel, CH); Ravi Jagasia (Loerrach, DE); Roland Jakob-Roetne (Inzlingen, DE); Juergen Wichmann (Steinen, DE)

Assignee: Hoffmann-La Roche Inc.

C07D403/04 C07D401/14

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Quick Facts

Patent No.: US 9,365,550
App. No.: 14/675,404
Granted: Jun 14, 2016
Kind: B2

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Abstract

The present invention relates to compounds of general formula wherein R 1 hydrogen, lower alkyl, halogen or lower alkyl substituted by halogen; R 2 is hydrogen or halogen; X 1 is N or CH; X 2 is N or CH; with the proviso that only one of X 1 or X 2 is N; X 3 is C(R) or N; and R is hydrogen, lower alkyl, halogen, lower alkyl substituted by halogen, lower alkoxy or SO 2 -lower alkyl; or to a pharmaceutically acceptable acid addition salt, to a racemic mixture or to its corresponding enantiomer and/or optical isomers thereof. The compounds may be used for the treatment of schizophrenia, obsessive-compulsive personality disorder, major depression, bipolar disorders, anxiety disorders, normal aging, epilepsy, retinal degeneration, traumatic brain injury, spinal cord injury, post-traumatic stress disorder, panic disorder, Parkinson's disease, dementia, Alzheimer's disease, mild cognitive impairment, chemotherapy-induced cognitive dysfunction, Down syndrome, autism spectrum disorders, hearing loss, tinnitus, spinocerebellar ataxia, amyotrophic lateral sclerosis, multiple sclerosis, Huntington's disease, stroke, radiation therapy, chronic stress, abuse of neuro-active drugs, such as alcohol, opiates, methamphetamine, phencyclidine and cocaine.

Claims (104)

1. A Compound of formula I

wherein

R 1 hydrogen, lower alkyl, halogen or lower alkyl substituted by halogen;

R 2 is hydrogen or halogen;

X 1 is N or CH;

X 2 is N or CH;

with the proviso that only one of X 1 or X 2 is N;

X 3 is C(R) or N;

and R is hydrogen, lower alkyl, halogen, lower alkyl substituted by halogen, lower alkoxy or SO 2 -lower alkyl;

or a pharmaceutically acceptable acid addition salt, a racemic mixture or its corresponding enantiomer and/or optical isomers thereof.

2. A compound of formula IA according to claim 1 ,

wherein

R 1 hydrogen, lower alkyl, halogen or lower alkyl substituted by halogen;

R 2 is hydrogen or halogen;

X 3 is C(R) or N;

and R is hydrogen, lower alkyl, halogen, lower alkyl substituted by halogen, lower alkoxy or SO 2 -lower alkyl;

or a pharmaceutically acceptable acid addition salt, a racemic mixture or its corresponding enantiomer and/or optical isomers thereof.

3. The compound of formula IA according to claim 2 , wherein the compound is

1-p-Tolyl-6-(2-p-tolyl-2H-pyrazol-3-yl)-1H-benzoimidazole

1-Phenyl-6-(2-phenyl-2H-pyrazol-3-yl)-1H-benzoimidazole

6-[2-(4-Fluoro-phenyl)-2H-pyrazol-3-yl]-1-phenyl-1H-benzoimidazole

1-Phenyl-6-(2-p-tolyl-2H-pyrazol-3-yl)-1H-benzoimidazole

6-(2-Phenyl-2H-pyrazol-3-yl)-1-p-tolyl-1H-benzoimidazole

6-[2-(4-Fluoro-phenyl)-2H-pyrazol-3-yl]-1-p-tolyl-1H-benzoimidazole

1-(4-Fluoro-phenyl)-6-(2-phenyl-2H-pyrazol-3-yl)-1H-benzoimidazole

1-(4-Fluoro-phenyl)-6-[2-(4-fluoro-phenyl)-2H-pyrazol-3-yl]-1H-benzoimidazole

1-(4-Fluoro-phenyl)-6-(2-p-tolyl-2H-pyrazol-3-yl)-1H-benzoimidazole

1-(4-Fluoro-phenyl)-6-[2-(4-trifluoromethyl-phenyl)-2H-pyrazol-3-yl]-1H-benzoimidazole

6-[2-(4-Chloro-phenyl)-2H-pyrazol-3-yl]-1-(4-fluoro-phenyl)-1H-benzoimidazole

1-(4-Chloro-phenyl)-6-[2-(4-trifluoromethyl-phenyl)-2H-pyrazol-3-yl]-1H-benzoimidazole

1-(4-Chloro-phenyl)-6-[2-(4-chloro-phenyl)-2H-pyrazol-3-yl]-1H-benzoimidazole

6-[2-(4-Chloro-phenyl)-2H-pyrazol-3-yl]-1-(4-trifluoromethyl-phenyl)-1H-benzoimidazole

1-(2,4-Difluoro-phenyl)-6-[2-(4-trifluoromethyl-phenyl)-2H-pyrazol-3-yl]-1H-benzoimidazole

6-[2-(4-Chloro-phenyl)-2H-pyrazol-3-yl]-1-(2,4-difluoro-phenyl)-1H-benzoimidazole

1-(2,4-Difluoro-phenyl)-6-[2-(4-fluoro-phenyl)-2H-pyrazol-3-yl]-1H-benzoimidazole

6-[2-(4-Fluoro-phenyl)-2H-pyrazol-3-yl]-1-(4-trifluoromethyl-phenyl)-1H-benzoimidazole

1-(4-Chloro-phenyl)-6-[2-(4-fluoro-phenyl)-2H-pyrazol-3-yl]-1H-benzoimidazole

6-[2-(4-Fluoro-phenyl)-2H-pyrazol-3-yl]-1-pyridin-4-yl-1H-benzoimidazole

6-[2-(4-Chloro-phenyl)-2H-pyrazol-3-yl]-1-pyridin-4-yl-1H-benzoimidazole

1-(4-Chloro-2-fluoro-phenyl)-6-[2-(4-fluoro-phenyl)-2H-pyrazol-3-yl]-1H-benzoimidazole

1-(4-Chloro-2-fluoro-phenyl)-6-[2-(4-chloro-phenyl)-2H-pyrazol-3-yl]-1H-benzoimidazole

6-[2-(4-Fluoro-phenyl)-2H-pyrazol-3-yl]-1-(4-methoxy-phenyl)-1H-benzoimidazole

6-[2-(4-Chloro-phenyl)-2H-pyrazol-3-yl]-1-(4-methoxy-phenyl)-1H-benzoimidazole

6-[2-(4-Fluoro-phenyl)-2H-pyrazol-3-yl]-1-(4-methanesulfonyl-phenyl)-1H-benzoimidazole or

6-[2-(4-Chloro-phenyl)-2H-pyrazol-3-yl]-1-(4-methanesulfonyl-phenyl)-1H-benzoimidazole.

4. A compound of formula IA-1 according to claim 1

wherein

R 1 hydrogen, lower alkyl, halogen or lower alkyl substituted by halogen;

R 2 is hydrogen or halogen;

R is hydrogen, lower alkyl, halogen, lower alkyl substituted by halogen, lower alkoxy or SO 2 -lower alkyl,

or a pharmaceutically acceptable acid addition salt, a racemic mixture or its corresponding enantiomer and/or optical isomers thereof.

5. A compound of formula IA-1 according to claim 4 wherein the compound is