Patent EA-004749-B1 (EA)
Title: Indole derivatives useful for the treatment of cns disorders
Inventor: FELDING JAKOB
IPC: A61K31/4545
Filed: 2001-07-17
Abstract: 1. A substituted indole derivative of formula I wherein R<1> is hydrogen or C1-6-alkyl, C2-6-alkenyl, C2-6-alkynyl, C3-8-cycloalkyl or C3-8-cycloalkyl-C1-6-alkyl, all of which may be substituted one or more times with substituents selected from halogen, cyano, nitro, amino, hydroxy, thiol, C1-6-alkoxy, C1-6-alkylthio, trifluoromethyl, trifluoromethylsulfonyl and C1-6-alkylsulfonyl, or R<1> is aryl, aryl-C1-6-alkyl, heteroaryl, heteroaryl-C1-6-alkyl where the aryl and heteroaryl groups may be substituted one or more times with substituents selected from halogen, cyano, nitro, amino, C1-6-alkyl, C1-6-alkoxy, C1-6-alkylthio, hydroxy, thiol, trifluoromethyl, trifluoromethylsulfonyl and C1-6 alkylsulfonyl, or R<1> is -NR'R" wherein R' and R" are independently selected from hydrogen and C1-6-alkyl, aryl, aryl-C1-6-alkyl, heteroaryl and heteroaryl-C1-6-alkyl, all of which may be substituted one or more times with substituents selected from halogen, cyano, nitro, amino, C1-6-alkyl, C1-6 alkoxy, C1-6-alkylthio, hydroxy, thiol, trifluoromethyl, trifluoromethylsulfonyl and C1-6 alkylsulfonyl, or R<1> is a saturated or partially saturated 5 to 6-membered ring containing one, two or three hetero atoms selected from O or S, and a group N-R<9> wherein R<9> is hydrogen or C1-6-alkyl optionally substituted with substituents selected from halogen, cyano, nitro, amino, C1-6-alkoxy, C1-6-alkylthio, hydroxy, thiol, trifluoromethyl, trifluoromethylsulfonyl and C1-6 alkylsulfonyl; W is a bond or an O, S, CO, CS, SO or SO2 group; n is 0-6, m is 0-6 and n+m is 0-6; provided that when W is O or S, n >= 2, and when W is CO, CS, SO or SO2, n >= 1; X is C, CH or N and the dotted line emanating from X indicates a bond when X is C and no bond when X is N or CH; R<2> is C1-6-alkyl; R<3>-R<7> are selected from hydrogen, halogen, cyano, nitro, amino, C1-6-alkyl, C2-6-alkenyl, C2-6-alkynyl, C3-8-cycloalkyl, C3-8-cycloalkyl-C1-6-alkyl, C1-6-alkoxy, C1-6-alkylthio, hydroxy, thiol, trifluoromethyl, trifluoromethylsulfonyl and C1-6 alkylsulfonyl; R<8> is hydrogen, C1-6-alkyl, C2-6-alkenyl, C2-6-alkynyl, C3-8-cycloalkyl, C3-8-cycloalkyl-C1-6-alkyl, aryl, aryl-C1-6-alkyl, acyl, thioacyl, C1-6-alkylsulfonyl, trifluoromethylsulfonyl, or arylsulfonyl or a pharmaceutically acceptable acid addition salt thereof. 2. The compound according to claim 1, wherein the indole is bound to X via position 3 of the indole. 3. The compound according to claims 1-2, wherein W is a bond. 4. The compound according to claim 3, wherein n + m is 2. 5. The compound according to claims 1-4, wherein R<2> is a methyl group. 6. The compound according to claims 1 or 5, wherein the group -NH-CO-R<1> is attached to the phenyl group in a position para to the position of the R<2> group. 7. The compound according to claims 1 or 6, wherein R<1> is C1-6-alkyl, C3-8-cycloalkyl, C3-8-cycloalkyl-C1-6-alkyl, phenyl, phenyl-C1-6-alkyl, furanyl, tlienyl, pyridyl, pyrrolyl, pyrimidyl, wherein the phenyl groups may be substituted one or more times with substituents selected from halogen, cyano, nitro, amino, C1-6-alkyl, C1-6-alkoxy, C1-6-alkylthio, hydroxy, trifluoromethyl, trifluoromethylsulfonyl and C1-6-alkylsulfonyl, or R<1> is -NR'R" wherein one of R' and R" is hydrogen and the other of R' and R" is selected from C1-6-alkyl, phenyl and phenyl-C1-6-alkyl, wherein the phenyl groups may be substituted one or more times with substituents selected from halogen, cyano, nitro, amino, C1-6-alkyl, C1-6-alkoxy, C1-6-alkylthio, hydroxy, trifluoromethyl, trifluoromethylsulfonyl and C1-6-alkylsulfonyl, or R<1> is a tetrahydropyranyl or a morpholino, thiomorpholino, piperidino, piperazino or a N-(hydroxy-C1-6-alkyl) piperazinyl group. 8. The compound according to claim 1 selected from: 3-(1-{2-[5-(Acetylamino)-2-methylphenyl]ethyl}piperidin-4-yl)-6-chloro-1H-indole; 3-(1-{2-[5-(Cyclobutylmethanoylamino)-2-methylphenyl] ethyl} piperidin-4-yl)-5-fluoro-1H-indole; 3-1-{2-[5-(Acetylamino)-2-methylphenyl]ethyl}piperidin-4-yl)-5-fluoro-1H-indole; 3-1-{2-[2-Methyl-5-(thiophen-2-ylmethanoylamino)phenyl]ethyl}piperidin-4-yl)-5-chloro-1H-indole; 3-{2-[2-Methyl-5-(3-methoxybenzoylamino)phenyl]ethyl}piperidin-4-yl)-5-chloro-1H-indole; 3-1-{2-[5-(Cyclopropylmethanoylamino)-2-methylphenyl]ethyl}piperidin-4-yl)-5-fluoro-1H-indole; 3-(1-{2-[2-Methyl-5-(thiophen-2-ylmethanoylamino)phenyl]ethyl}piperidin-4-yl)-5-fluoro-1H-indole; 3-(1-{2-[5-(Isobutanoylamino)-2-methylphenyl]ethyl}piperidin-4-yl)-5-fluoro-1H-indole; 3-{2-[2-Methyl-5-(pivaloylamino)phenyl]ethyl}piperidin-4-yl)-5-fluoro-1H-indole; 3-(1-{2-[5-(Hexanoylamino)-2-methylphenyl]ethyl}piperidin-4-yl)-5-fluoro-1H-indole; 3-(1-{2-[5-(4-Fluorobenzoylamino)-2-methylphenyl]ethyl}piperidin-4-yl)-5-fluoro-1H-indole; 3-(1-{2-[5-(3-Methoxybenzoylamino)-2-methylphenyl]ethyl}piperidin-4-yl)-5-fluoro-1H-indole; 3-(1-{2-[2-Methyl-5-(pyridin-3-ylmethanoylamino) phenyl]ethyl}piperidin-4-yl)-5-fluoro-1H-indole; 3-(1-{2-[2-Methyl-5-(3-phenylpropanoylamino)phenyl]ethyl}piperidin-4-yl)-5-fluoro-1H-indole; 3-(1-{2-[2-Methyl-5-(4-methylbenzoyIamino)phenyl]ethyl}piperidin-4-yl)-5-fluoro-1H-indole; 3-(1-{2-[2-Methyl-5-(3-Methyl-3-phenylureido)phenyl]ethyl}piperidin-4-yl)-6-chloro-1H-indole; 3-(1-{2-[5-(Cyclopropylmethanoylamino)-2-methylphenyl]ethyl}piperidin-4-yl)-6-chloro-1H-indole; 3-{2-[2-Methyl-5-(thiophen-2-ylmethanoylamino)phenyl]ethyl}piperidin-4-yl)-6-chloro-1H-indole; 3-(1-{2-[5-(Isobutanoylamino)-2-methylphenyl]ethyl}piperidin-4-yl)-6-chloro-1H-indole; 3-(1-{2-[5-(3-Methoxybenzoylamino)-2-methylphenyl]ethyl}piperidin-4-yl)-6-chloro-1H-indole; 3-(1-{2-[2-Methyl-5-(pyridin-3-ylmethanoylamino)phenyl]ethyl}piperidin-4-yl)-6-chloro-1H-indole; 3-[1-(2-{5-[2-(4-Methoxyphenyl)ethanoylamino]-2-methylphenyl}ethyl)piperidin-4-yl]-chloro-1H-indole; 3-(1-{2-[2-Methyl-5-(4-methylbenzoylamino)phenyl]ethyl}piperidin-4-yl)-6-chloro-1H-indole; 3-[1-(2-{5-[(Cyclopentylmethanoyl)amino]-2-methylphenyl}ethyl)piperidin-4-yl]-6-chloro-1H-indole; 3-{2-[2-Methyl-5-(morfolin-4-ylmethanoylamino)phenyl]ethyl}piperidin-4-yl)-5-fluoro-1H-indole; 3-[1-(2-{5-[3-(4-Fluorophenyl)ureido]-2-methylphenyl}ethyl)piperidin-4-yl]-5-fluoro-1H-indole; 3-(1-{2-[5-(Hexanoylamino)-2-methylphenyl]ethyl}piperidin-4-yl)-7-chloro-1H-indole; 3-(1-{2-[2-Methyl-5-(tetrahydropyran-4-ylmethanoylamino)phenyl]ethyl}piperidin-4-yl)-5-fluoro-1H-indole; 3-(1-{2-[5-(4-Chlorobenzoylamino)-2-methylphenyl]ethyl}piperidin-4-yl)-7-chloro-1H-indole; 3-(1-{2-[5-(3-Cyclohexylpropanoylamino)-2-methylphenyl]ethyl}piperidin-4-yl)-5-fluoro-1H-indole; 3-[1-(2-{5-[(3-Phenylpropanoyl)amino]-2-methylphenyl}ethyl)piperidin-4-yl]-7-chloro-1H-indole; 3-[1-(2-{5-[(2-Phenylethanoyl)amino]-2-methylphenyl}ethyl)piperidin-4-yl]-7-chloro-1H-indole; 3-(1-{2-[2-Methyl-5-(4-methylbenzoylamino)phenyl]ethyl}piperidin-4-yl)-7-chloro-1H-indole; 3-(1-{2-[5-(Cyclopropylmethanoylamino)-2-methylphenyl]ethyl}piperidin-4-yl)-7-chloro-1H-indole; 3-[1-(2-{5-[2-(4-Fluorophenyl)ethanoylamino]-2-methylphenyl}ethyl)piperidin-4-yl]-chloro-1H-indole; 3-[1-(2-{5-[2-(4-Methoxyphenyl)ethanoylamino]-2-methylphenyl}ethyl)piperidin-4-yl]-chloro-1H-indole; 3-[1-(2-{5-[(Cyclobutylmethanoyl)amino]-2-methylphenyl}ethyl) piperidin-4-yl]-7-chloro-1H-indole; 3-(1-{2-[5-(benzoylamino)-2-Methylphenyl]ethyl}piperidin-4-yl)-7-chloro-1H-indole; 3-(1-{2-[5-(4-Fluorobenzoylamino)-2-methylphenyl]ethyl}piperidin-4-yl)-7-chloro-1H-indole; 3-(1-{2-[5-(4-Methoxybenzoylamino)-2-methylphenyl]ethyl}piperidin-4-yl)-7-chloro-1H-indole; 3-[1-(2-{2-Methyl-5-[(pyridin-3-ylmethanoyl)amino]phenyl}ethyl)piperidin-4-yl]-7-chloro-1H-indole; 3-[1-(2-{2-Methyl-5-[(pyridin-4-ylmethanoyl)amino]phenyl}ethyl)piperidin-4-yl]-7-chloro-1H-indole; 3-{2-Methyl-5-[(thiophen-2-ylmethanoyl)amino]phenyl}ethyl)piperidin-4-yl]-chloro-1H-indole; 3-[1-(2-{2-Methyl-5-[(thiophen-3-ylmethanoyl)amino]phenyl}ethyl)piperidin-4-yl]-chloro-1H-indole; 3-[1-(2-{2-Methyl-5-[(1-[1,2,3]thiadiazol-5-ylmethanoyl)amino]phenyl}ethyl)-piperidin-yl]-7-chloro-1H-indole; 3-{1-[2-(5-Acetylamino-2-methylphenyl)-ethyl]-3,6-dihydro-2H-pyridin-4-yl}-5-fluoro-1H-indole; 3-[1-(2-{2-Methyl-5-[(pyridin-3-ylmethanoyl)-amino]-phenyl}-ethyl)-3,6-dihydro-2H-pyridin-4-yl]-5-fluoro-1H-indole; 3-[1-(2-{5-[(4-Fluorophenylmethanoyl)-amino]-2-methylphenyl}-ethyl)-3,6-dihydro-2H-pyridin-4-yl]-5-fluoro-1H-indole; 3-{1-[2-(5-Acetylamino-2-methylphenyl)-ethyl]-3,6-dihydro-2H-pyridin-4-yl}-7-fluoro-1H-indole; 3-[1-(2-{2-Methyl-5-[(pyridin-3-ylmethanoyl)-amino]-phenyl}-ethyl)-3,6-dihydro-2H-pyridin-4-yl]-7-chloro-1H-indole and 3-[1-(2-{5-[(4-Fluorophenylmethanoyl)-amino]-2-methylphenyl}-ethyl)-3,6-dihydro-2H-pyridin-4-yl]-7-chloro-1H-indole or a pharmaceutically acceptable salt thereof. 9. A pharmaceutical composition characterised in that it comprises a compound of any of claims 1 to 8 in a therapeutically effective amount together with one or more pharmaceutically acceptable carriers or diluents. 10. Use of a compound of any of claims 1 to 8 for the manufacture of a medicament useful in the treatment of positive and negative symptoms of schizophrenia, other psychoses, anxiety disorders, such as generalised anxiety disorder, panic disorder and obsessive compulsive disorder, depression, aggression, side effects induced by conventional antipsychotic agents, migraine, cognitive disorders, ADHD and in the improvement of sleep. 11. A method of treating the positive and negative symptoms of schizophrenia, other psychoses, anxiety disorders, such as generalised anxiety disorder, panic disorder and obsessive compulsive disorder, depression, aggression, side effects induced by conventional antipsychotic agents, migraine, cognitive disorders, ADHD and in the improvement of sleep comprising administration of a therapeutically acceptable amount of a compound according to any of claims 1 to 8.