Benzisoxazoles
The present invention relates to compounds of general formula wherein Ar 1 /Ar 2 are phenyl or a 5 or 6-membered heteroaryl; R 1 /R 2 is hydrogen, halogen, lower alkyl, CF 3 or lower alkoxy; n,m are 1 or 2; or to a pharmaceutically acceptable acid addition salt, to a racemic mixture or to its corresponding enantiomer and/or optical isomers thereof, with the exception of the compound 2,1-benzisoxazole, 3-(4-chlorophenyl)-5-(1-phenyl-1H-pyrazol-5 -yl)-. 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.
1. A compound of formula
wherein
Ar 1 /Ar 2 are phenyl or a 5 or 6-membered heteroaryl;
R 1 /R 2 is hydrogen, halogen, lower alkyl, CF 3 or lower alkoxy;
n,m are 1 or 2;
or a pharmaceutically acceptable acid addition salt, a racemic mixture or its corresponding enantiomer and/or optical isomers thereof, with the exception of the compound 2,1-benzisoxazole, 3-(4-chlorophenyl)-5-(1-phenyl-1H-pyrazol-5-yl).
2. A compound of formula IA encompassed by compounds of formula I according to claim 1
wherein
R 1 /R 2 is hydrogen, halogen, lower alkyl, CF 3 or lower alkoxy;
n,m are 1 or 2;
or a pharmaceutically acceptable acid addition salt, a racemic mixture or its corresponding enantiomer and/or optical isomers thereof, with the exception of the compound 2,1-benzisoxazole, 3-(4-chlorophenyl)-5-(1-phenyl-1H-pyrazol-5-yl).
3. A compound of formula IA according to claim 1 wherein the compounds are:
3-(4-Fluoro-phenyl)-5-[2-(2-fluoro-phenyl)-2H-pyrazol-3-yl]-benzo[c]isoxazole;
3-(3-Fluoro-phenyl)-5-[2-(2-fluoro-phenyl)-2H-pyrazol-3-yl]-benzo[c]isoxazole;
5-[2-(2-Fluoro-phenyl)-2H-pyrazol-3-yl]-3-p-tolyl-benzo[c]isoxazole;
5-[2-(2-Fluoro-phenyl)-2H-pyrazol-3-yl]-3-(4-trifluoromethyl-phenyl)-benzo[c]isoxazol;
3-(4-Chloro-phenyl)-5-[2-(2-fluoro-phenyl)-2H-pyrazol-3-yl]-benzo[c]isoxazole;
5-[2(2-Fluoro-phenyl)-2H-pyrazol-3-yl]-3-(4-methoxy-phenyl)-benzo[c]isoxazole;
3-(4-(4-Bromo-phenyl)-5-[2-(2-fluoro-phenyl)-2-H-pyrazol-3-yl]benzo[c]isoxazole;
3-(4-Fluoro-phenyl)-5-[2-(4-fluoro-phenyl)-2H-pyrazol-3-yl]-benzo[c]isoxazole;
3-(4-Fluoro-phenyl)-5-[2-(4-fluoro-phenyl)-2H-pyrazol-3-yl]-benzo[c]isoxazole;
3-(3-Fluoro-phenyl)-5-[2-(4-fluoro-phenyl)-2H-pyrazol-3-yl]-benzo[c]isoxazole;
5-[2-(4-Fluoro-phenyl)-2H-pyrazol-3-yl]-3-p-tolyl-benzo[c]isoxazole;
3-(4-Chloro-phenyl)-5-(4-fluoro-phenyl)-2H-pyrazol-3-yl)-benzo[c]isoxazole;
5-[2-(4-Fluoro-phenyl)-2H-pyrazol-3-yl]-3-(4-methoxy-phenyl)-benzo[c]isoxazole;
3-(4-Fluoro-phenyl)-5-(2-p-tolyl-2H-pyrazol-3-yl)-benzo[c]isoxazole;
3-(3-Fluoro-phenyl)-5-(2-p-tolyl-2H-pyrazol-3-yl)-benzo[c]isoxazole;
3-p-Tolyl-5-(2-p-tolyl-2H-pyrazol-3-yl)-benzo[c]isoxazole;
5-(2-p-Tolyl-2H-pyrazol-3-yl)-3-(4-trifluoromethyl-phenyl)-benzo[c]isoxazole;
3-(4-Chloro-phenyl)-5-(2-p-tolyl-2H-pyrazol-3-yl)-benzo[c]isoxazole;
3-(4-Methoxy-phenyl)-5-(2-p-tolyl-2H-pyrazol-3-yl)-benzo[c]isoxazole;
3-(4-Fluoro-phenyl)-5-[2-(4-methoxy-phenyl)-2H-pyrazol-3-yl]-benzo[c]isoxazole;
3-(3-Fluoro-phenyl)-5-[2-(4-methoxy-phenyl)-2H-pyrazol-3-yl]-benzo[c]isoxazole;
5-[2-(4-Methoxy-phenyl)-2H-pyrazol-3-yl]-3-p-tolyl-benzo[c]isoxazole;
3-(4-Chloro-phenyl)-5-[2-(4-methoxy-phenyl)-2H-pyrazol-3-yl]-benzo[c]isoxazole;
3-(4-Methoxy-phenyl)-5-[2-(4-methoxy-phenyl)-2H-pyrazol-3-yl]-benzo[c]isoxazole;
5-[2-(4-Chloro-phenyl)-2H-pyrazol-3-yl]-3-(4-fluoro-phenyl)-benzo[c]isoxazole;
5-[2-(4-Chloro-phenyl)-2H-pyrazol-3-yl]-3-(3-fluoro-phenyl)-benzo[c]isoxazole;
3-(4-Chloro-phenyl)-5-[2-(4-chloro-phenyl)-2H-pyrazol-3-yl]-benzo[c]isoxazole;
5-[2-(2,4-Difluoro-phenyl)-2H-pyrazol-3-yl]-3-(4-fluoro-phenyl)-benzo[c]isoxazole;
5-[2-(2,4-Difluoro-phenyl)-2H-pyrazol-3-yl]-3-(3-fluoro-phenyl)-benzo[c]isoxazole;
5-[2-(2,4-Difluoro-phenyl)-2H-pyrazol-3-yl]-3-p-tolyl-benzo[c]isoxazole;
5-[2-(2,4-Difluoro-phenyl)-2H-pyrazol-3-yl]-3-(4-trifluoromethyl-phenyl)-benzo[c]isoxazole;
3-(4-Chloro-phenyl)-5-[2-(2,4-difluoro-phenyl)-2H-pyrazol-3-yl]-benzo[c]isoxazole;
5-[2-(2,4-Difluoro-phenyl)-2H-pyrazol-3-yl]-3-(4-methoxy-phenyl)-benzo[c]isoxazole;
3-Phenyl-5-(2-phenyl-2H-pyrazol-3-yl)-benzo[c]isoxazole;
3-(3-Fluoro-4-methoxy-phenyl)-5-[2-(2-fluoro-phenyl)-2H-pyrazol-3-yl]-benzo[c]isoxazole;
3-(3-Fluoro-4-methoxy-phenyl)-5-[2-(4-fluoro-phenyl)-2H-pyrazol-3-yl]-benzo[c]isoxazole;
3-(3,4-Difluoro-phenyl)-5-(2-p-tolyl-2H-pyrazol-3-yl)-benzo[c]isoxazole;
3-(3-Fluoro-4-methoxy-phenyl)-5-(2-p-tolyl-2H-pyrazol-3-yl)-benzo[c]isoxazole;
5-[2-(2,4-Difluoro-phenyl)-2H-pyrazol-3-yl]-3-(3-fluoro-4-methoxy-phenyl)-benzo[c]isoxazole;
5-[2-(2-Chloro-phenyl)-2H-pyrazol-3-yl]-3-(4-fluoro-phenyl)-benzo[c]isoxazole;
3-(4-Chloro-phenyl)-5-[2-(2-chloro-phenyl)-2H-pyrazol-3-yl]-benzo[c]isoxazole;
5-[2-(2-Chloro-phenyl)-2H-pyrazol-3-yl]-3-p-tolyl-benzo[c]isoxazole.
4. A compound of formula IB encompassed by compounds of formula I according to claim 1
wherein
is a pyridine ring, wherein the N-atom may be in different positions,
R 1 /R 2 is hydrogen, halogen, lower alkyl, CF 3 or lower alkoxy; and
n,m are 1 or 2;
or a pharmaceutically acceptable acid addition salt, a racemic mixture or its corresponding enantiomer and/or optical isomers thereof.
5. A compound of formula I according to claim 1 , which compound is
3-(4-Fluoro -phenyl)-5-(2-pyridin-2-yl-2H-pyrazol-3-yl)-benzo[c]isoxazole.
6. A compound of formula IC encompassed by compounds of formula I according to claim 1
wherein
R 2 is hydrogen, halogen, lower alkyl, CF 3 or lower alkoxy; and
m is 1 or 2;
or a pharmaceutically acceptable acid addition salt, a racemic mixture or its corresponding enantiomer and/or optical isomers thereof.
7. A compound of formula I according to claim 1 , which compound is
5-[2-(4-Fluoro -phenyl)-2H-pyrazol-3-yl]-3-thiophen-2-yl-benzo[c]isoxazole.
8. A process for the manufacture of a compound of formula I as defined in claim 1 , which process comprises reacting a compound of formula
with a compound of formula
to afford a compound of formula (I)
wherein
Ar 1 /Ar 2 are phenyl or a 5 or 6-membered heteroaryl, R 1 /R 2 is hydrogen, halogen, lower alkyl, CF 3 or lower alkoxy and n,m are 1 or 2;
and, if desired, converting the compounds obtained into pharmaceutically acceptable acid addition salts.
9. A pharmaceutical composition comprising a compound according to claim 1 , and a pharmaceutical acceptable carrier and/or adjuvant.