US 2003/0191314 A1 · Tetrahydroisoquinoline derivatives as modulators of dopamine D3 receptors

Abstract

Compounds of formula (I): 1 wherein: R1 represents a substituent selected from: a hydrogen or halogen atom; a hydroxy, cyano, nitro, trifluoromethyl, trifluoromethoxy, trifluoromethanesulfonyloxy, pentafluoroethyl, C1-4alkyl, C1-4alkoxy, arylC1-4alkoxy, C1-4alkylthio, C1-4alkoxyC1-4alkyl, C3-6cycloalkylC1-4alkoxy, C1-4alkanoyl, C1-4alkoxycarbonyl, C1-4alkylsulfonyl, C1-4alkylsulfonyloxy, C1-4alkylsulfonylC1-4alkyl, arylsulfonyl, arylsulfonyloxy, arylsulfonylC1-4alkyl, C1-4alkylsulfonamido, C1-4alkylamido, C1-4alkylsulfonamidoC1-4alkyl, C1-4alkylamidoC1-4alkyl, arylsulfonamido, arylcarboxamido, arylsulfonamidoC1-4alkyl, arylcarboxamidoC1-4alkyl, aroyl, aroylC1-4alkyl, or arylC1-4alkanoyl group; a group R3OCO(CH2)p, R3CON(R4)(CH2)p, R3R4NCO(CH2)p or R3R4NSO2(CH2)p where each of R3 and R4 independently represents a hydrogen atom or a C1-4alkyl group or R3R4 forms part of a C3-6azacyloalkane or C3-6(2-oxo)azacycloalkane ring and p represents zero or an integer from 1 to 4; or a group Ar1—Z, wherein Ar1 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 CH2; R2 represents a hydrogen atom or a C1-4alkyl group; q is 1 or 2; A represents a group of formula (a) or (b) 2 wherein T, U, V and Y independently represent CH or a nitrogen atom; R5 is a group selected from: a hydrogen or halogen atom, cyano, C1-4 alkyl or C1-4 alkoxy group s is 1 or 2. Ar2 represents an optionally substituted phenyl ring or an optionally substituted 5- or 6-membered aromatic heterocyclic ring; and salts thereof. The compounds are useful for the treatment of conditions which require modulaton of a dopamine receptor such as schizophrenia.

Claims12

Dependent claims

A compound of formula (I):

23
wherein:
R1 represents a substituent selected from:
a hydrogen or halogen atom;
a hydroxy, cyano, nitro, trifluoromethyl, trifluoromethoxy, trifluoromethanesulfonyloxy, pentafluoroethyl, C1-4alkyl, C1-4alkoxy, arylC1-4alkoxy, C1-4alkylthio, C1-4alkoxyC1-4alkyl, C3-6cycloalkylC1-4alkoxy, C1-4alkanoyl, C1-4alkoxycarbonyl, C1-4alkylsulfonyl, C1-4alkylsulfonyloxy, C1-4alkylsulfonylC1-4alkyl, arylsulfonyl, arylsulfonyloxy, arylsulfonylC1-4alkyl, C1-4alkylsulfonamido, C1-4alkylamido, C1-4alkylsulfonamidoC1-4alkyl, C1-4alkylamidoC1-4alkyl, arylsulfonamido, arylcarboxamido, arylsulfonamidoC1-4alkyl, arylcarboxamidoC1-4alkyl, aroyl, aroylC1-4alkyl, or arylC1-4alkanoyl group;
a group R3OCO(CH2)p, R3CON(R4)(CH2)p, R3R4NCO(CH2)p or R3R4NSO2(CH2)p where each of R3 and R4 independently represents a hydrogen atom or a C1-4alkyl group or R3R4 forms part of a C3-6azacyloalkane or C3-6(2-oxo)azacycloalkane ring and p represents zero or an integer from 1 to 4;
or a group Ar1—Z, wherein Ar1 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 CH2;
R2 represents a hydrogen atom or a C1-4alkyl group;
q is 1 or2;
A represents a group of formula (a) or (b)
24
wherein
T, U, V and Y independently represent CH or a nitrogen atom;
R5 is a group selected from:
a hydrogen or halogen atom, cyano, C1-4 alkyl or C1-4 alkoxy group
s is 1 or2.
Ar2 represents an optionally substituted phenyl ring or an optionally substituted 5- or 6-membered aromatic heterocyclic ring;
and salts thereof.

15 more elements

A process for preparing compounds of formula (I) which process comprises:

(a) reacting a compound of formula (II):
25
wherein R1, R2 and q are as hereinbefore defined, with a compound of formula (III):
A—COX
Formula (III)
wherein A is as hereinbefore defined and X is a halogen atom or the residue of an activated ester;
(b) to prepare a compound of formula (I) wherein R1 is Ar1—Z and Z is a bond, reacting a compound of formula (IV):
26
wherein R2 and A are as hereinbefore defined and one R1a represents a group W wherein W is a halogen atom or a trifluoromethylsulfonyloxy group, or W is a group M selected from a boron derivative e.g. a boronic acid function B(OH)2 or a metal function such as trialkylstannyl e.g. SnBu3, zinc halide or magnesium halide, and when q is 2 the other R1a is R1;
with a compound Ar1—W1, wherein W1 is a halogen atom or a trifluoromethylsulfonyloxy group when W is a group M or W 1 is a group M when W is a halogen atom or a trifluoromethylsulfonyloxy group;
(c) to prepare a compound of formula (I) wherein R1 is Ar1—Z and Z is O or S, reacting a compound of formula (V):
27
wherein R2 and A are as hereinbefore defined and one R1b represents a group ZH and when q is 2 the other R1b represents R1;
with a reagent serving to introduce the group Ar1;
(d) interconversion of one compound of formula (I) to a different compound of formula (I) e.g. (i) alkylation of a compound (I) wherein R2 represents hydrogen, (ii) conversion of one R1 from alkoxy (e.g. methoxy) to hydroxy, or (iii) conversion of R1 from hydroxy to sulfonyloxy, eg alkylsulfonyloxy or trifluoromethanesulfonyloxy;
(e) separation of cis- and trans-isomers of compounds of formula (I) by conventional methods, e.g. chromatography or crystallisation;
and optionally thereafter forming a salt of formula (I).

14 more elements

Dependencies are inferred from the claim text.

Tetrahydroisoquinoline derivatives as modulators of dopamine D3 receptors

Life of this patent

Tetrahydroisoquinoline derivatives as modulators of dopamine D3 receptors

Life of this patent

Abstract

Claims12