US 6,008,219 AGranted

Bicyclic amine derivatives and their use as anti-psychotic agents

AssigneeSmithKline Beech p.l.c.

InventorsGeoffrey Stemp, Christopher Norbert Johnson

Life of this patent

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Abstract

This invention relates to compounds of formula (I) ##STR1## which are useful as modulators of D.sub.3 receptors, in particular as antipsychotic agents.

Claims11

Dependent claims

A compound of formula (I):

##STR13## wherein X represents a single bond or CR.sup.9 R.sup.10 where R.sup.9 and R.sup.10 each independently represent a hydrogen atom or a C.sub.1-4 alkyl group;
R.sup.1a, R.sup.1b and R.sup.1c each independently represent a substituent selected from:
a hydrogen or halogen atom, a hydroxy, cyano, trifluoromethyl, trifluoromethoxy, trifluoromethanesulfonyloxy, C.sub.1-4 alkyl, C.sub.1-4 alkoxy, C.sub.1-4 alkylthio C.sub.1-4 alkoxyC.sub.1-4 alkyl, C.sub.3-6 cycloalkylC.sub.1-4 alkoxy, C.sub.1-4 alkanoyl, C.sub.1-4 alkoxycarbonyl, C.sub.1-4 alkylsulphonyl, C.sub.1-4 alkylsulphonyloxy, or C.sub.1-4 alkylsulphonylC.sub.1-4 alkyl, arylsulphonylarylsulphonyloxy or arylsulphonylC.sub.1 -.sub.4 alkyl group, or a group R.sup.11 OCO(CH2).sub.p, R.sup.11 R.sup.12 NCO(CH2).sub.p or R.sup.11 R.sup.12 NSO.sub.2 (CH.sub.2).sub.p where each of R.sup.11 and R.sup.12 independently represents a hydrogen atom or a C.sub.1-4 alkyl group and p represents zero or an integer from 1 to 4;
R.sup.2, R.sup.3, R.sup.4 and R.sup.5 each independently represent a hydrogen atom or a C.sub.1-4 alkyl group;
R.sup.6 represents a hydrogen atom or a C.sub.1-6 alkyl, C.sub.3-6 alkenyl or arylC.sub.1-4 alkyl group;
R.sup.7 represents a hydrogen atom or a C.sub.1-4 alkyl group;
and
R.sup.8 represents a group of structure (a), (b) or (c):
##STR14## wherein Ar is furyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, oxadiazolyl, thiadiazolyl, pyridyl, trizolyl, trizolyl, triazinyl, pyridazyl, pyrimidinyl or pyrazolyl optionally substituted by one or more substituents selected from a hydrogen or halogen atom, or a hydroxy, cyano, nitro, H.sub.2 NCO, C.sub.1-4 alkyl, C.sub.1-4 alkoxy, C.sub.1-4 alkanoyl or C.sub.1-4 alkylsuslphonyl group;
or a group of structure (d):
##STR15## R.sup.13 represents a hydrogen or halogen atom, or a hydroxy, cyano, nitro, H.sub.2 NCO, C.sub.1-4 alkyl, C.sub.1-4 alkoxy, C.sub.1-4 alkanoyl or C.sub.1-4 alkylsulphonyl group or is furyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, oxadiazolyl, thiadiazolyl, pyridyl, triazolyl, triazinyl, pyridazyl, pyrimidinyl or pyrazolyl optionally substituted by one or more substituents selected from a hydrogen or halogen atom, or a hydroxy, cyano, nitro, H.sub.2 NCO, C.sub.1-4 alkyl, C.sub.1-4 alkoxy, C.sub.1-4 alkanoyl or C.sub.1-4 alkylsuslphonyl group;
each R.sup.14 and R.sup.15 independently represents a substituent selected from a hydrogen or halogen atom, or a hydroxy, cyano, nitro, H.sub.2 NCO, C.sub.1-4 alkyl, C.sub.1-4 alkoxy C.sub.1-4 alkanoyl or C.sub.1-4 alkylsulphonyl, group;
Y represents H.sub.2 or an oxygen atom;
n is a number from 1 to 4;
and
m is a number from 1 to 3;
or a salt thereof.

14 more elements

A compound of formula (I) which is:

N-(4-(4-phenylbenzoylamino)butyl)-2-(R,S)-methylamino-1,2,3,4-tetrahydronap hthalene;
5-methoxy-N-(4-(4-phenylbenzoylamino)butyl)-2-(R,S)-methyl-amino-1,2,3,4-te trahydronaphthalene;
5-hydroxy-N-(4-(4-phenylbenzoylamino)butyl)-2-(R,S)-methylamino-1,2,3,4-tet rahydronaphthalene;
7-Methoxy-N-(4-(4-phenylbenzoylamino)butyl)-2-(R,S)-methylamino-1,2,3,4-tet rahydronaphthalene,
7-Hydroxy-N-(4-(4-phenylbenzoylamino)butyl)-2-(R,S)-methylamino-1,2,3,4-tet rahydronaphthalene,
5-Methoxy-N-(4-(4-phenylbenzoylamino)butyl)-2-(R,S)-propylamino-1,2,3,4-tet rahydronaphthalene,
6-Methoxy-N-(4-(4-phenzylbenzoylamino)butyl)-2-(R,S)-methylamino-1,2,3,4-te trahydronaphthalene,
5-Methoxy-N-(4-(4-phenylbenzoylamino)butyl)-2-(R,S)-ethylamino-1,2,3,4-tetr ahydronaphthalene,
7-Methoxy-N-(4-(4-phenylbenzoylamino)butyl-2-(R,S)-propylamino-1,2,3,4-tetr ahydronaphthalene,
7-Hydroxy-N-(4-(2-methyl-4-phenyl)benzoylamino)butyl-2-(R,S)-methylamino-1, 2,3,4-tetrahydronaphthalene,
7-Hydroxy-N-(4-(3-methyl-4-phenyl)benzoylamino)butyl-2-(R,S)-methylamino-1, 2,3,4-tetrahydronaphthalene,
7-Hydroxy-N-(4-(4-(4-(1,2,3-thiadiazolyl))benzoyi-amino)butyl)-2-(R,S)-meth ylamino-1,2,3,4-tetrahydronaphthalene,
7-Hydroxy-N-(4-(4-(4-acetyl)phenyl)benzoylamino)butyl-2-(R,S)-methylamino-1 ,2,3,4-tetrahydronaphthalene,
7-Hydroxy-N-(4-(2-naphthoyl)amino)butyl-2-(R,S)-methylamino-1,2,3,4-tetrahy dronaphthalene,
7-Hydroxy-N-(4-(4-(4-methanesulfonyl)phenyl)benzoyl-amino)butyl-2-(R,S)-met hylamino-1,2,3,4-tetrahydro-naphthalene,
7-Hydroxy-N-(4-(4-(4-(3-(5-methyl-(1,2,4-oxadiazolyl)))-2-methylphenyl)benz oylamino)butyl)-2-(R,S)-methylamino-1,2,3,4-tetrahydronaphthalene,
5-Hydroxy-N-(4-(4-phenylbenzoylamino)butyl)-2-(R,S)-propylamino-1,2,3,4-tet rahydronaphthalene,
(R or S)-5-Methoxy-N-(4-(4-phenylbenzoylamino)butyl)-2-methylamino-1,2,3,4-tetra hydronaphthalene, (Enantiomer A),
(R or S)-5-Hydroxy-N-(4-(4-phenylbenzoylamino)butyl)-2-methylamino-1,2,3,4-tetra hydronaphthalene, (Enantiomer A),
(R or S)-5-Methoxy-N-(4-(4-phenylbenzoylamino)butyl)-2-methylamino-1,2,3,4-tetra hydronaphthalene, (Enantiomer B),
(R or S)-5-Hydroxy-N-(4-(4-phenylbenzoylamino)butyl)-2-methylamino-1,2,3,4-tetra hydronaphthalene, (Enantiomer B),
2-(4-(4-Phenylbenzoylamino)butylaminoindane,
N-(4-(4-Phenylbenzoylamino)butyl)-2-methylaminoindane,
7-Methoxy-N-(4-(2-(9-oxofluorenyl))carboxamido)butyl-2-(R,S)-methylamino-1, 2,3,4-tetrahydronaphthalene,
7-Methoxy-N-(4-(3-methyl-4-phenyl)benzo1lamino)butyl-2-(R,S)-methylamino-1, 2,3,4-tetrahydronaphthalene,
7-Methoxy-1-(4-(2-methyl-4-phenyl)benzoylamino)butyl-2-(R,S)-methylamino-1, 2,3,4-tetrahydronaphthalene,
7-Methoxy-N-(4-(4-(4-(1,2,3-thiadiazolyl))benzoylamino)-butyl)-2-(R,S)-meth ylamino-1,2,3,4-tetrahydronaphthalene,
7-Methoxy-N-(4-(4-(4-acetyl)phenyl)benzoylamino)butyl-2-(R,S)-methylamino-1 ,2,3,4-tetrahydronaphthalene,
7-Methoxy-N-(4-(4-(4-(3-(5-methyl-(1,2,4-oxadiazolyl)))-2-methylphenyl)benz oylamino)-2-(R,S )-methylamino-1,2,3,4-tetrahydronaphthalene,
N-(4-(4-phenylbenzoylamino)butyl)-2-(R,S)-propylamino-1,2,3,4-tetrahydronap hthalene,
7-Methoxy-N-(4-(2-naphthoyl)amino)butyl-2-(R,S)-methyl-amino-1,2,3,4-tetrah ydronaphthalene,
7-Hydroxy-N-(4-(4-(4-methoxy)phenyl)benzoylamino)butyl-2-(R,S)-methylamino- 1,2,3,4-tetrahydronaphthalene,
7-Hydroxy-N-(4-(4-(4-pyridyl)benzoyl)amino)butyl-2-(R,S)-methylamino-1,2,3, 4-tetrahydronaphthalene,
7-Hydroxy-N-(4-(4-(3-pyridyl)benzoyl)amino)butyl-2-(R,S)-methylamino-1,2,3, 4-tetrahydronaphthalene,
7-Hydroxy-N-(4-(4-(2-pyridyl)benzoyl)amino)butyl-2-(R,S)-methylamino-1,2,3, 4-tetrahydronaphthalene,
7-Hydroxy-N-(4-(2-(9-oxofluorenyl))carboxamido)butyl-2-(R,S)-methylamino-1, 2,3,4-tetrahydronaphthalene,
7-Methoxy-N-(4-(4-(4-methansulfonyl)phenyl)benzoyl-amino)butyl -2-(R,S)-methylamino-1,2,3,4-tetrahydronaphthalene,
N-(4-(4-Phenylbenzoylamino)butyl)-2-(R,S)-propylamino-5-trifluoromethanesul fonyloxy-1,2,3,4-tetrahydronaphthalene,
5-Cyclopropylmethoxy-N-(4-(4-phenylbenzoylamino)butyl)-2-(R,S)-propylamino- 1,2,3,4-tetrahydronaphthalene,
5-Chloro-N-(4-(4-phenylbenzoylamino)butyl)-2-(R,S)-propylamino-1,2,3,4-tetr ahydronaphthalene,
6-Fluoro-N-(4-(4-phenylbenzoylamino)butyl)-2-(R,S )-propylamino-1,2,3,4-tetrahydronaphthalene,
7-Chloro-N-(4-(4-phenylbenzoylanino)butyl)-2-(R,S)-propylamino-1,2,3,4-tetr ahydronaphthalene,
6-Chloro-N-(4-(4-phenylbenzoylanino)butyl)-2-(R,S)-propylamino-1,2,3,4-tetr ahydronaphthalene,
6-Bromo-N-(4-(4-phenylbenzoylamino)butyl)-2-(R,S)-propylamino-1,2,3,4-tetra hydronaphthalene
N-(4-(4-(4-Pyridyl)benzoyl)amino)butyl-2-(R,S)-propylamino-1,2,3,4-tetrahyd ronaphthalene,
N-(4-(4-Phenylbenzoylamino)butyl)-2-propylaminoindane,
N-(4-(4-Phenylbenzoylamino)butyl-2-(2-propenyl)aminoindane,
cis-5-Methoxy-1-methyl-N-(4-(4-phenylbenzoylamino)butyl)-2-(R,S)-propylamin o-1,2,3,4-tetrahydronaphthalene,
N-(4-(4-Phenylbenzoylamino)butyl-2-(R,S )-propylamino-5-trifluoromethoxy-1,2,3,4-tetrahydronaphthalene,
6-Methylthio-N-(4-(4-phenylbenzoylamino)butyl)-2-(R,S)-propylamino-1,2,3,4- tetrahydronaphthalene,
5-Fluoro-N-(4-(4-phenylbenzoylamino)butyl)-2-(R,S)-propylamino-1,2,3,4-tetr ahydronaphthalene,
7-Methylthio-N-(4-(4-phenylbenzoylamino)butyl)-2-(R,S)-propylamino-1,2,3,4- tetrahydronaphthalene,
7-Fluoro-N-(4-(4-phenylbenzoylamino)butyl)-2-(R,S)-propylamino-1,2,3,4-tetr ahydronaphthalene,
N-(4-(4-Phenylbenzoylarnino)butyl)-2-(R,S)-propylamino-6-trifluoromethoxy-1 ,2,3,4-tetrahydronaphthalene,
5-Bromo-N-(4-(4-phenylbenzoylamino)butyl)-2-(R,S)-propylamino-1,2,3,4-tetra hydronaphthalene,
7-Bromo-N-(4-(4-phenylbenzoylamino)butyl)-2-(R,S)-propylamino-1,2,3,4-tetra hydronaphthalene,
6-Methanesulfonylmethyl-N-(4-(4-phenylbenzoylamino)butyl)-2-(R,S)-propylami no-1,2,3,4-tetrahydronaphthalene,
cis-5-Hydroxy-1-methyl-N-(4-(4-phenylbenzoylamino)butyl)-2-(R,S)-propylamin o-1,2,3,4-tetrahydronaphthalene,
5-Methoxy-N-(4-(4-(2-pyrimidyl)benzoylanino)butyl-2-(R,S)-propylamino-1,2,3 ,4-tetrahydronaphthalene,
5-Methoxy-N-(4-(4-(3-pyridyl)benzoylanino)butyl)-9-(R,S)-propylamino-1,2,3, 4-tetrahydronaphthalene,
5-Methoxy-N-(4-(4-(4-pyridyl)benzoylamino)butyl)-2-(R,S)-propylamino-1,2,3, 4-tetrahydronaphthalene,
5-Methoxy-N-(4-(4-(5-pyrimidyl)benzoylamino)butyl)-2-(R,S)-propylamino-1,2, 3,4-tetrahydronaphthalene,
5-Methoxy-N-(4-(4-(4H-1,2,4-triazol)yl)benzoylamino)butyl)-2-(R,S)-propylam ino-1,2,3,4-tetrahydronaphthalene,
5-Methoxy-N-(4-(1-1H,1,2,4-triazol)yl)benzoylamino)butyl)-2-(R,S)-propylami no-1,2,3,4-tetrahydronaphthalene,
5-Methoxy-N-(4-(4-pyridazylbenzoylamino)butyl)-2-(R,S)-propylamino-1,2,3,4- tetrahydronaphthalene,
cis-1-Methyl-N-(4-(4-phenylbenzoylamino)butyl)-2-(R,S)-propylamino-5-triflu oromethanesulfonyloxy-1,2,3,4-tetrahydronapthalene,
5-Methanesulfonyloxy-N-(4-(4-phenylbenzoylamino)butyl)-2-(R,S)-propylamino- 1,2,3,4-tetrahydronaphthalene,
7-Cyano-N-(4-(4-phenylbenzoylamino)butyl)-2-(R,S)-propylamino-1,2,3,4-tetra hydronaphthalene,
5-Cyano-N-(4-(4-phenylbenzoylamino)butyl)-2-(R,S)-propylamino-1,2,3,4-tetra hydronaphthalene,
6-Cyano-N-(4-(4-phenylbenzoylamino)butyl)-2-(R,S)-propylamino-1,2,3,4-tetra hydronaphthalene
7-(R,S)-(N-(4-(4-Phenylbenzoylamino)butyl)propylamino)-5,6,7,8-tetrahydrona phthalene-2-carboxamide
6-(R,S)-(N-(4-(4-Phenylbenzoylamino)butyl)propylamino)-5,6,7,8-tetrahydrona phthalene-1-carboxamide,
6-(R,S)-(N-(4-(4-Phenylbenzoylamino)butyl)propylamino)-5,6,7,8-tetrahydrona pthalene-2-carboxamide
N,N-Dimethyl-(7-(R,S)-(N-(4-(4-phenylbenzoylamino)butyl)propylamino)-5,6,7, 8-tetrahydronaphthalene)-2-carboxamide,
N,N-Dimethyl-(6-(R,S)-(N-(4-(4-phenylbenzoylamino)butyl)propylamino)-5,6,7, 8-tetrahydronaphthalene)-2-carboxamide,
N-Methyl-(7-(R,S)-(N-(4-(4-phenylbenzoylamino)butyl)propylamino-5,6,7,8-tet rahydronaphthalene)-2-carboxamide,
6-Methylsulfonyl-N-(4-(4-phenylbenzoylamino)butyl)-2-(R,S)-propylamino-1,2, 3,4-tetrahydronaphthalene;
N-(4-(4-Phenylbenzoylamino)butyl)-6-(R,S)-propylamino-5,6,7,8-tetrahydronap hthalene-1-acetic acid, ethyl ester;
N-(4-(4-Phenylbenzoylamino)butyl)-6-(R,S)-propylamino-5,6,7,8-tetrahydronap hthalene-2-acetic acid, ethyl ester;
N-(4-(4-Phenylbenzoylamino)butyl)-7-(R,S)-propylamino-5,6,7,8-tetrahydronap hthalene-2-acetic acid, ethyl ester;
or a salt thereof.

78 more elements

Dependencies are inferred from the claim text.

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