US 6,143,762 A · Tetrahydroisoquinoline derivatives and their pharmaceutical use

Abstract

Compounds of formula (I), wherein R.sup.1 represents a substituent selected from: a hydrogen or halogen atom; a hydroxy, cyano, nitro, trifluoromethyl, trifluoromethoxy, trifluoromethanesulfonyloxy, C.sub.1-4 alkyl, C.sub.1-4 alkoxy, arylC.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, C.sub.1-4 alkylsulphonylC.sub.1-4 alkyl, arylsulphonyl, arylsulphonyloxy, arylsulphonylC.sub.1-4 alkyl, C.sub.1-4 alkylsulphonamido, C.sub.1-4 alkylamido, C.sub.1-4 alkylsulphonamidoC.sub.1-4 alkyl, C.sub.1-4 alkylamidoC.sub.1-4 alkyl, arylsulphonamido, arylcarboxamido, arylsulphonamidoC.sub.1-4 alkyl, arylcarboxamidoC.sub.1-4 alkyl, aroyl, aroylC.sub.1-4 alkyl, or arylC.sub.1-4 alkanoyl group; a group R.sup.3 OCO(CH.sub.2).sub.p, R.sup.3 CON(R.sup.4)(CH2)p, R.sup.3 R.sup.4 NCO(CH.sub.2).sub.p or R.sup.3 R.sup.4 NSO.sub.2 (CH.sub.2).sub.p where each of R.sup.3 and R.sup.4 independently represents a hydrogen atom or a C.sub.1-4 alkyl group or R.sup.3 R.sup.4 forms part of a C.sub.3-6 azacyloalkane or C.sub.3-6 (2-oxo)azacycloalkane ring and p represents zero or an integer from 1 to 4; or a group Ar.sup.1 Z, wherein Ar.sup.1 represents an optionally substituted phenyl ring or an optionally substituted 5- or 6-membered aromatic heterocyclic ring and Z represents a bond, O, S, or CH.sub.2 ; represents a hydrogen atom or a C.sub.1-4 alkyl group; q is 1 or 2; Ar represents an optionally substituted phenyl ring or an optionally substituted 5- or 6-membered aromatic ring; or an optionally substituted bicyclic aromatic or heteroaromatic ring system; and salts thereof. Compounds of formula (I) and their salts have affinity for dopamine receptors, in particular the D.sub.3 receptor, and thus potential in the treatment of conditions wherein modulation of the D.sub.3 receptor is beneficial, e.g. as antipsychotic agents.

Claims10

Dependent claims

A compound of formula (I):

##STR10## wherein:
R.sup.1 represents a substituent selected from:
a hydrogen or halogen atom;
a hydroxy, cyano, nitro, trifluoromethyl, trifluoromethoxy, trifluoromethanesulfonyloxy, C.sub.1-4 alkyl, C.sub.1-4 alkoxy, arylC.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, C.sub.1-4 alkylsulphonylC.sub.1-4 alkyl, arylsulphonyl, arylsulphonyloxy, arylsulphonylC.sub.1-4 alkyl, C.sub.1-4 alkylsulphonamido, C.sub.1-4 alkylamido, C.sub.1-4 alkylsulphonamidoC.sub.1-4 alkyl, C.sub.1-4 alkylamidoC.sub.1-4 alkyl, arylsulphonamido, arylcarboxamido, arylsulphonamidoC.sub.1-4 alkyl, arylcarboxamidoC.sub.1-4 alkyl, aroyl, aroylC.sub.1-4 alkyl, or arylC.sub.1-4 alkanoyl group;
a group R.sup.3 OCO(CH.sub.2).sub.p, R.sup.3 CON(R.sup.4)(CH2)p, R.sup.3 R.sup.4 NCO(CH.sub.2).sub.p or R.sup.3 R.sup.4 NSO.sub.2 (CH.sub.2).sub.p where each of R.sup.3 and R.sup.4 independently represents a hydrogen atom or a C.sub.1-4 alkyl group or R.sup.3 R.sup.4 forms part of a C.sub.3-6 azacyloalkane or C.sub.3-6 (2-oxo)azacycloalkane ring and p represents zero or an integer from 1 to 4;
or a group Ar.sup.1 Z, wherein Ar.sup.1 represents an optionally substituted phenyl ring or an optionally substituted 5- or 6-membered aromatic heterocyclic ring and Z represents a bond, O, S, or CH.sub.2 ;
R.sup.2 represents a hydrogen atom or a C.sub.1-4 alkyl group;
q is 1 or 2;
Ar represents an optionally substituted phenyl ring or an optionally substituted 5- or 6-membered aromatic heterocyclic ring;
or an optionally substituted bicyclic aromatic or heteroaromatic ring system;
or a salt thereof.

8 more elements

A compound of formula (I) which is:

(E)-7-Methoxy-2-(4-(3-phenylpropenoyl)aminobutyl)-1,2,3,4-tetrahydroisoquin oline;
(E)-7-Hydroxy-2-(4-(3-phenylpropenoyl)aminobutyl)-1,2,3,4-tetrahydroisoquin oline;
(E)-2-(4-(3-Phenylpropenoyl)aminobutyl)-7-trifluoromethylsulfonyloxy-1,2,3, 4-tetrahydroisoquinoline;
(E)-2-(4-(3-(3-Nitrophenyl)propenoyl)aminobutyl)-7-trifluoromethylsulfonylo xy-1,2,3,4-tetrahydroisoquinoline;
(E)-2-(4-(3-(4-Methoxyphenyl)propenoyl)aminobutyl)-7-trifluoromethylsulfony loxy-1,2,3,4-tetrahydroisoquinoline;
(E)-2-(4-(3-(4-Bromophenyl)propenoyl)aminobutyl)-7-trifluoromethylsulfonylo xy-1,2,3,4-tetrahydroisoquinoline;
(E)-2-(4-(3-(2-Thienyl)propenoyl)aminobutyl)-7-trifluoromethylsulfonyloxy-1 ,2,3,4-tetrahydroisoquinoline;
(E)-2-(4-(3-(2-Naphthyl)propenyl)aminobutyl)-7-trifluoromethylsulfonyloxy-1 ,2,3,4-tetrahydroisoquinoline;
(E)-2-(4-(3-(3-Furyl)propenoyl)aminobutyl)-7-trifluoromethylsulfonyloxy-1,2 ,3,4-tetrahydroisoquinoline;
(E)-2-(4-(3-(4-Chlorophenyl)propenoyl)aminobutyl)-7-trifluoromethylsulfonyl oxy-1,2,3,4-tetrahydroisoquinoline;
(E)-2-(4-(3-(4-Dimethylaminophenyl)propenoyl)aminobutyl)-7-trifluoromethyls ulfonyloxy-1,2,3,4-tetrahydroisoquinoline;
(E)-2-(4-(3-(3,4-Methylenedioxyphenyl)propenoyl)aminobutyl)-7-trifluorometh ylsulfonyloxy-1,2,3,4-tetrahydroisoquinoline;
(E)-2-(4-(3-(3-(1-Methyl)indolyl)propenoyl)aminobutyl)-7-trifluoromethylsul fonyloxy-1,2,3,4-tetrahydroisoquinoline;
(E)-2-(4-(3-(1-Naphthyl)propenoyl)aminobutyl)-7-trifluoromethylsulfonyloxy- 1,2,3,4-tetrahydroisoquinoline;
(E)-2-(4-(3-(2-Methylphenyl)propenoyl)aminobutyl)-7-trifluoromethylsulfonyl oxy-1,2,3,4-tetrahydroisoquinoline;
(E)-2-(4-(3-(3-Cyanophenyl)propenoyl)aminobutyl)-7-trifluoromethylsulfonylo xy-1,2,3,4-tetrahydroisoquinoline;
(E)-2-(4-(3-(2-Quinolinyl)propenoyl)aminobutyl)-7-trifluoromethylsulfonylox y-1,2,3,4-tetrahydroisoquinoline;
(E)-2-(4-(3-(2-Methoxyphenyl)propenoyl)aminobutyl)-7-trifluoromethylsulfony loxy-1,2,3,4-tetrahydroisoquinoline;
(E)-2-(4-(3-(3-Indolyl)propenoyl)aminobutyl)-7-trifluoromethylsulfonyloxy-1 ,2,3,4-tetrahydroisoquinoline;
(E)-2-(4-(3-(2-Benzofuranyl)propenoyl)aminobutyl)-7-trifluoromethylsulfonyl oxy-1,2,3,4-tetrahydroisoquinoline;
(E)-2-(4-(3-(4-Acetylphenyl)propenoyl)aminobutyl)-7-trifluoromethylsulfonyl oxy-1,2,3,4-tetrahydroisoquinoline;
(E)-2-(4-(3-(3-Methoxyphenyl)propenoyl)aminobutyl)-7-trifluoromethylsulfony loxy-1,2,3,4-tetrahydroisoquinoline;
(E)-2-(4-(3-(3-Quinolinyl)propenoyl)aminobutyl)-7-trifluoromethylsulfonylox y-1,2,3,4-tetrahydroisoquinoline;
(E)-2-(4-(3-(5-(2,3-Dihydro)benzofuranyl)propenoyl)aminobutyl)-7-trifluorom ethylsulfonyloxy-1,2,3,4-tetrahydroisoquinoline;
(E)-2-(4-(3-(6-(1,4-benzodioxanyl)propenoyl)aminobutyl)-7-trifluoromethylsu lfonyloxy-1,2,3,4-tetrahydroisoquinoline;
(E)-2-(4-(3-(3-Acetylphenyl)propenoyl)aminobutyl)-7-trifluoromethylsulfonyl oxy-1,2,3,4-tetrahydroisoquinoline;
(E)-2-(4-(3-(3-Acetamidophenyl)propenoyl)aminobutyl)-7-trifluoromethylsulfo nyloxy-1,2,3,4-tetrahydroisoquinoline;
(E)-2-(4-(3-(3-Dimethylaminophenyl)propenoyl)amninobutyl)-7-trifluoromethyl sulfonyloxy-1,2,3,4-tetrahydroisoquinoline;
(E)-2-(4-(3-(2-Quinoxalinyl)propenoyl)aminobutyl)-7-trifluoromethylsulfonyl oxy-1,2,3,4-tetrahydroisoquinoline;
(E)-2-(4-(3-(2-Benzothiazolyl)propenoyl)aminobutyl)-7-trifluoromethylsulfon yloxy-1,2,3,4-tetrahydroisoquinoline;
(E)-2-(4-(3-(3,4-Dichlorophenyl)propenoyl)aminobutyl)-7-trifluoromethylsulf onyloxy-1,2,3,4-tetrahydroisoquinoline;
(E)-2-(4-(3-(2-(1-Methyl)pyrrolyl)propenoyl)aminobutyl)-7-trifluoromethylsu lfonyloxy-1,2,3,4-tetrahydroisoquinoline;
(E)-2-(4-(3-(5-Pyrido[2,3-b]indolyl)propenoyl)aminobutyl)-7-trifluoromethyl sulfonyloxy-1,2,3,4-tetrahydroisoquinoline;
(E)-2-(4-(3-(5-(2-Dimethylamino)pyrimidinyl)propenoyl)aminobutyl)-7-trifluo romethylsulfonyloxy-1,2,3,4-tetrahydroisoquinoline;
(E)-2-(4-(3-(2-Benzoxazolyl)propenoyl)aminobutyl)-7-trifluoromethylsulfonyl oxy-1,2,3,4-tetrahydroisoquinoline;
(E)-2-(4-(3-(4-(1-Pyrrolidinyl)phenyl)propenoyl)aminobutyl)-7-trifluorometh ylsulfonyloxy-1,2,3,4-tetrahydroisoquinoline;
(E)-2-(4-(3-(3-Methylaminocarbonylphenyl)propenoyl)aminobutyl)-7-trifluorom ethylsulfonyloxy-1,2,3,4-tetrahydroisoquinoline;
(E)-2-(4-(3-(3,4-Methylenedioxyphenyl)propenoyl)aminobutyl)-7-trifluorometh ylsulfonyloxy-1,2,3,4-tetrahydroisoquinoline;
(E)-2-(4-(3-(3-Aminocarbonylphenyl)propenoyl)aminobutyl)-7-trifluoromethyls ulfonyloxy-1,2,3,4-tetrahydroisoquinoline;
(E)-2-(4-(3-(2-Acetamidophenyl)propenoyl)aminobutyl)-7-trifluoromethylsulfo nyloxy-1,2,3,4-tetrahydroisoquinoline;
(E)-2-(4-(3-(2-Naphthyl)propenoyl)aminobutyl)-7-(2-thiophene)sulfonyloxy-1, 2,3,4-tetrahydroisoquinoline;
(E)-2-(4-(3-(4-Dimethylaminophenyl)propenoyl)aminobutyl)-7-(2-thiophene)sul fonyloxy-1,2,3,4-tetrahydroisoquinoline;
(E)-2-(4-(3-(2-Naphthyl)propenoyl)aminobutyl)-7-methylsulfonyloxy-1,2,3,4-t etrahydroisoquinoline;
(E)-2-(4-(3-(4-Dimethylaminophenyl)propenoyl)aminobutyl)-7-methylsulfonylox y-1,2,3,4-tetrahydroisoquinoline;
(E)-2-(4-(3-(2-Naphthyl)propenoyl)aminobutyl)-7-acetyl-1,2,3,4-tetrahydrois oquinoline;
(E)-2-(4-(3-(2-Naphthyl)propenoyl)aminobutyl)-7-bromo-1,2,3,4-tetrahydroiso quinoline;
(E)-2-(4-(3-(2-Naphthyl)propenoyl)aminobutyl)-7-(4-cyanophenyl)sulfonyloxy- 1,2,3,4-tetrahydroisoquinoline;
(E)-2-(4-(3-(2-Naphthyl)propenoyl)aminobutyl)-7-methoxy-1,2,3,4-tetrahydroi soquinoline;
(E)-7-Phenylsulfonylmethyl-2-(4-(3-(2-naphthyl)propenoly)aminobutyl)-1,2,3, 4-tetrahydroisoquinoline;
(E)-7-Methylsulfonamido-2-(4-(3-(2-naphthyl)propenoly)aminobutyl)-1,2,3,4-t etrahydroisoquinoline;
(E)-2-(4-(3-(2-Naphthyl)propenoyl)aminobutyl)-7-phenylsulfonamido-1,2,3,4-t etrahydroisoquinoline;
(E)-7-(4-Cyanophenyl)sulfonamido-2-(4-(3-(2-naphthyl)propenoly)aminobutyl)- 1,2,3,4-tetrahydroisoquinoline;
(E)-2-(4-(3-(5-Indolyl)propenoyl)aminobutyl)-7-trifluoromethylsulfonyloxy-1 ,2,3,4-tetrahydroisoquinoline;
(E)-2-(4-(3-(5-Benzimidazolyl)propenoly)aminobutyl)-7-trifluoromethylsulfon yloxy-1,2,3,4-tetrahydroisoquinoline;
(E)-7-Methylsulfonylmethyl-2-(4-(3-(2-naphthyl)propenoly)aminobutyl)-1,2,3, 4-tetrahydroisoquinoline;
(E)-2-(4-(3-(2-Naphthyl)propenoly)aminobutyl)-7-trifluoromethoxy-1,2,3,4-te trahydroisoquinoline;
(E)-7-Cyano-2-(4-(3-(2-naphthyl)propenoly)aminobutyl)-1,2,3,4-tetrahydroiso quinoline;
(E)-2-(4-(3-(3-Indolyl)propenoly)aminobutyl)-7-trifluoromethoxy-1,2,3,4-tet rahydroisoquinoline;
(E)-2-(4-(3-(4-Dimethylaminophenyl)propenoly)-7-trifluoromethoxy-1,2,3,4-te trahydroisoquinoline;
(E)-2-(4-(3-(4-Aminophenyl)propenoly)aminobutyl)-7-trifluoromethylsulfonylo xy-1,2,3,4-tetrahydroisoquinoline;
(E)-2-(4-(3-(4-Nitrophenyl)propenoly)aminobutyl)-7-trifluoromethylsulfonylo xy-1,2,3,4-tetrahydroisoquinoline;
(E)-7-Cyano-2-(4-(3-(3-indolyl)propenoyl)aminobutyl)-1,2,3,4-tetrahydroisoq uinoline;
(E)-2-(4-(3-(3-(7-Methyl)indolyl)propenoyl)aminobutyl)-7-trifluoromethylsul fonyloxy-1,2,3,4-tetrahydroisoquinoline;
(E)-2-(4-(3-(2-(6-Acetyl)naphthyl)propenoyl)aminobutyl)-7-trifluoromethylsu lfonyloxy-1,2,3,4-tetrahydroisoquinoline;
(E)-7-Cyano-2-(4-(3-(3-(7-methyl)indolyl)propenoyl)aminobutyl)-1,2,3,4-tetr ahydroisoquinoline;
(E)-7-Cyano-2-(4-(3-(5-benzimidazolyl)propenoyl)aminobutyl)-1,2,3,4-tetrahy droisoquinoline;
(E)-7-Cyano-2-(4-(3-(5-indolyl)propenoyl)aminobutyl)-1,2,3,4-tetrahydroisoq uinoline;
(E)-2-(4-(3-(2-(6-Acetyl)naphthyl)propenoyl)aminobutyl)-7-cyano-1,2,3,4-tet rahydroisoquinoline;
(E)-7-Cyano-2-(4-(3-(6-indolyl)propenoyl)aminobutyl)-1,2,3,4-tetrahydroisoq uinoline;
(E)-7-Cyano-2-(4-(3-(3-(7-fluoro)indolyl)propenoyl)aminobutyl)-1,2,3,4-tetr ahydroisoquinoline;
(E)-2-(4-(3-(3-(7-Bromo)indolyl)propenoyl)aminobutyl)-7-trifluoromethoxy-1, 2,3,4-tetrahydroisoquinoline;
(E)-2-(4-(3-(3-(7-Bromo)indolyl)propenoyl)aminobutyl)-7-cyano-1,2,3,4-tetra hydroisoquinoline;
(E)-2-(4-(3-(3-(7-Cyano)indolyl)propenoyl)aminobutyl)-7-cyano-1,2,3,4-tetra hydroisoquinoline;
(E)-7-Cyano-2-(4-(3-(5-(2-methyl)indolyl)propenoyl)aminobutyl)-1,2,3,4-tetr ahydroisoquinoline;
(E)-2-(4-(3-(5-(2-Methyl)indolyl)propenoyl)aminobutyl)-7-trifluoromethoxy-1 ,2,3,4-tetrahydroisoquinoline;
(E)-2-(4-(3-(3-(7-Acetyl)indolyl)propenoyl)aminobutyl)-7-cyano-1,2,3,4-tetr ahydroisoquinoline;
(E)-7-Cyano-2-(4-(3-(6-(2-methyl)indolyl)propenoyl)aminobutyl)-1,2,3,4-tetr ahydroisoquinoline;
(E)-7-Cyano-2-(4-(3-(5-(2,3-dihydro-2-oxo)-1H-indolyl)propenoyl)aminobutyl) -1,2,3,4-tetrahydroisoquinoline;
(E)-2-(4-(3-(6-(1,2-Dihydro-2-oxo)quinolinyl)propenoyl)aminobutyl)-7-triflu oromethoxy-1,2,3,4-tetrahydroisoquinoline;
(E)-2-(4-(3-(5-(2-Acetyl)indolyl)propenoyl)aminobutyl)-7-cyano-1,2,3,4-tetr ahydroisoquinoline;
(E)-7-Chloro-2-(4-(3-(6-indolyl)propenoyl)aminobutyl)-1,2,3,4-tetrahydroiso quinoline;
(E)-7-Cyano-2-(4-(3-(5-(3-methyl)indolyl)propenyl)aminobutyl)-1,2,3,4-tetra hydroisoquinoline;
(E)-2-(4-(3-(6-(3-Methyl)indolyl)propenoyl)aminobutyl)-7-trifluoromethoxy-1 ,2,3,4-tetrahydroisoquinoline;
(E)-7-Cyano-2-(4-(3-(5-(1-methyl)indolyl)propenoyl)aminobutyl)-1,2,3,4-tetr ahydroisoquinoline;
(E)-2-(4-(3-(2-(1-Methyl)indolyl)propenoyl)aminobutyl)-7-trifluoromethylsul fonyloxy-1,2,3,4-tetrahydroisoquinoline;
(E)-2-(4-(3-(5-Indolyl)propenoyl)aminobutyl)-1,2,3,4-tetrahydroisoquinoline ;
(E)-7-Cyano-2-(4-(3-(5-(2-methyl)benzimidazolyl)propenoyl)aminobutyl)-1,2,3 ,4-tetrahydroisoquinoline;
(E)-2-(4-(3-(5-(2-Methyl)benzimidazolyl)propenoyl)aminobutyl)-7-trifluorome thoxy-1,2,3,4-tetrahydroisoquinoline;
(E)-2-(4-(3-(5-Indolyl)propenoyl)aminobutyl)-7-trifluoromethyl-1,2,3,4-tetr ahydroisoquinoline;
(E)-2-(4-(3-(5-Indolyl)propenoyl)aminobutyl)-7-methylsulfonamido-1,2,3,4-te trahydroisoquinoline;
(E)-2-(4-(3-(5-Indolyl)propenoyl)aminobutyl)-7-methylaminosulfonyl-1,2,3,4- tetrahydroisoquinoline;
(E)-2-(4-(3-(3-(7-Methyl)indolyl)propenoyl)aminobutyl)-7-trifluoromethoxy-1 ,2,3,4-tetrahydroisoquinoline;
(E)-7-Cyano-2-(4-(3-(5-(3-dimethylaminomethyl)indolyl)propenoyl)aminobutyl) -1,2,3,4-tetrahydroisoquinoline;
or a salt thereof.

91 more elements

Dependencies are inferred from the claim text.

Tetrahydroisoquinoline derivatives and their pharmaceutical use

Life of this patent

Tetrahydroisoquinoline derivatives and their pharmaceutical use

Life of this patent

Abstract

Claims10