Patent EA-005098-B1 (EA)
Title: Bicyclic heterocycles, and pharmaceutical compositions containing these compounds
Inventor: HIMMESBACH FRANK
IPC: A61P17/00
Filed: 2000-03-14
Abstract: 1. Bicyclic heterocycles of general formula wherein Ra denotes a hydrogen atom, Rb denotes a phenyl, benzyl or 1-phenylethyl group wherein the phenyl nucleus is substituted in each case by the groups R1 to R3, whilst R1 and R2 which may be identical or different, each denote a hydrogen, fluorine, chlorine or bromine atom, a methyl, trifluoromethyl, methoxy, ethynyl or cyano group and R3, denotes a hydrogen atom, Rc and Rd in each case denote a hydrogen atom, X denotes a nitrogen atom, A denotes an -O-C1-C4-alkylene or -O-CH2-CH(OH)-CH2 group, whilst the oxygen atom of the above-mentioned groups in each case is linked to the bicyclic heteroaromatic ring, B denotes an -NR5-O-CO-alkylene-NR6 group wherein the alkylene moiety, which is straight-chained and contains 1 or 2 carbon atoms, may additionally be substituted by an R6O-CO or R6O-CO-methyl group, whilst R5 denotes a hydrogen atom, a C1-C2-alkyl group which may be substituted by an R6O-CO group, a C2-C4 alkyl group which is substituted from position 2 onwards by a hydroxy group, a C3-C6 cycloalkyl or C3-C6-cycloalkylmethyl group and R6 denotes a hydrogen atom, a C1-C6 alkyl, cyclopentyl, cyclopentylmethyl, cyclohexyl, cyclohexylmethyl, phenyl, benzyl, 5-indanyl or RgCO-O-, (ReCRf) group, whilst Re denotes a hydrogen atom or a C1-C4 alkyl group, Rf denotes a hydrogen atom and Rg denotes a C1-C4 alkyl, cyclopentyl, cyclohexyl, C1-C4 alkoxy, cyclopentyloxy or cyclohexyloxy group, a pyrrolidino or piperidino group which is substituted by an R6O-CO or R6-O-CO-C1-C2-alkyl group wherein Rg is as hereinbefore defined, H a pyrrolidino or piperidino group which is substituted by two R6O-CO or R6-O-CO-C1-C2-alkyl groups wherein R6 is as hereinbefore defined, a piperazino group which is substituted in the 4 position by the group R10 and additionally at a cyclic carbon atom by an R6O-CO or R6-O-CO-C1-C2-alkyl group wherein R6 is as hereinbefore defined and R10 denotes a hydrogen atom, a methyl or ethyl group, a piperazino group which is substituted in the 4 position by an R6O-CO or R6-O-CO-C1-C4-alkyl group wherein R6 is as hereinbefore defined, a piperazino group which is substituted in the 4 position by an R6O-CO or R6-O-CO-C1-C2-alkyl group and is additionally substituted at a cyclic carbon atom by an R6O-CO or R6-O-CO-C1-C2-alkyl group wherein R6 is as hereinbefore defined, a morpholino group which is substituted by an R6O-CO or R6-O-CO-C1-C2-alkyl group, whilst R6 is as hereinbefore defined, a pyrrolidinyl or piperidinyl group substituted in the 1 position by an R6-O-CO-C1-C4-alkyl, bis-(R6O-CO)-C1-C4alkyl group wherein R6 is as hereinbefore defined, a 2-oxo-morpholino group which may be substituted by 1 or 2 methyl groups, a 2-oxo-morpholinyl group which is substituted in the 4 position by a methyl, ethyl or R6-O-CO-C1-C2 alkyl group, whilst R6 is as hereinbefore defined and the above-mentioned 2-oxo-morpholinyl groups in each case are linked to a carbon atom of the group A, or a R11N(C1-C2 alkyl) group wherein R11 denotes a 2-oxo-tetrahydro-furan-3-yl or 2-oxo-tetrahydrofuran-4-yl group, and C and D together denote a hydrogen atom, a methoxy, ethoxy, 2-methoxy-ethoxy, C4-C6cycloalkoxy or C3-C6cycloalkyl-C1-C3-alkoxy group, the tautomers, the stereoisomers and the salts thereof. 2. Bicyclic heterocycles of general formula (I), according to claim 1wherein Ra denotes a hydrogen atom, Rb denotes a phenyl, benzyl or 1-phenylethyl group wherein the phenyl nucleus is substituted in each case by the groups C1-C3, whilst R1 and R2 which may be identical or different, each denote a hydrogen, fluorine, chlorine or bromine atom, a methyl, trifluoromethyl, methoxy, ethynyl or cyano group and R3 denotes a hydrogen atom, Rc and Rd in each case denote a hydrogen atom, X denotes a nitrogen atom, A and B together denote a hydrogen atom, a methoxy, ethoxy, 2-methoxy-ethoxy, C4-C6-cycloalkoxy or C3-C6-cycloalkylC1-C3 alkoxy group, C denotes an -O-C1-C4alkylene or -O-CH2-CH(OH)-CH2 group, whilst the oxygen atom of the above-mentioned groups in each case is linked to the bicyclic heteroaromatic ring, and D denotes an R6O-CO-alkylene-NR5 group wherein the alkylene moiety, which is straight-chained and contains 1 or 2 carbon atoms, may additionally be substituted by an R6O-CO or R6O-CO-methyl group, whilst R5 denotes a hydrogen atom, a C1-C2 alkyl group which may be substituted by an R6O-CO group, a C2-C4 alkyl group which is substituted from position 2 by a hydroxy group, a C3-C6-cycloalkyl or C3-C6-cycloalkylmethyl group and R6 denotes a hydrogen atom, a C1-C6-alkyL, cyclopentyl, cyclopentylmethyl, cyclohexyl, cyclohexylmethyl, phenyl, benzyl, 5-indanyl or RgCO-O-(ReCRf) group, whilst Re denotes a hydrogen atom or a C1-C4 alkyl group, Rf denotes a hydrogen atom and Rg denotes a C1-C4 alkyl, cyclopentyl, cyclohexyl, C1-C4 alkoxy, cyclopentyloxy or cyclohexyloxy group, a pyrrolidino or piperidino group which is substituted by an R6O-CO or R6-O-CO-C1-C2 alkyl group wherein R6 is as hereinbefore defined, a pyrrolidino or piperidino group which is substituted by two R6O-CO or R6-O-CO-C1-C2 alkyl groups wherein R6 is as hereinbefore defined, a piperazino group which is substituted in the 4 position by the group R10 and additionally at a cyclic carbon atom by an R6O-CO or R6-O-CO-C1-C2 alkyl group wherein R6 is as hereinbefore defined and R10 denotes a hydrogen atom, a methyl or ethyl group, a piperazino group which is substituted in the 4 position by an R6-O-CO-C1-C4alkyl group, bis-(R6O-CO)-C1-C4alkyl group wherein R6 is as hereinbefore defined, a piperazino group which is substituted in the 4 position by an R6-O-CO-C1-C2alkyl group and is additionally substituted at a cyclic carbon atom by an R6O-CO or R6O-CO-C1-C2-alkyl group wherein R6 is as hereinbefore defined, a morpholino group which is substituted by an R6O-CO or R6-O-CO-C1-C2alkyl group, whilst R6 is as hereinbefore defined, a pyrrolidinyl or piperidinyl group substituted in the 1 position by an R6-O-CO-C1-C4 alkyl group, bis-(R6O-CO)-C1-C4 alkyl group wherein R6 is as hereinbefore defined, a 2-oxo-morpholino group which may be substituted by 1 or 2 methyl groups, a 2-oxo-morpholinyl group which is substituted in the 4 position by a methyl, ethyl or R6-O-CO-C1-C2 alkyl group, whilst R6 is as hereinbefore defined and the above-mentioned 2-oxo-morpholinyl groups are in each case linked to a carbon atom of the group C, or a R11N(C1-C2 alkyl) group wherein R11 denotes a 2-oxo-tetrahydro-furan-3-yl or 2-oxo-tetrahydrofuran-4-yl group, the tautomers, stereoisomers and salts thereof. 3. Bicyclic heterocycles of general formula I according to claim 1, wherein Ra denotes a hydrogen atom, Rb denotes a phenyl group wherein the phenyl nucleus is substituted in each case any the groups R1 to R3, whilst R1 and R2 which may be identical or different, each denote a hydrogen, fluorine, chlorine or bromine atom and R3 denotes a hydrogen atom, Rc and Rd in each case denote a hydrogen atom, X denotes a nitrogen atom, A denotes an -O- C1-C4 alkylene or -O-CH2-CH(OH)-CH2 group, whilst the oxygen atom of the above-mentioned groups in each case is linked to the bicyclic heteroaromatic ring, B denotes an R6O-CO-CH2-NR5 group wherein R5 denotes a hydrogen atom or a methyl group which may be substituted by an R6O-CO group, or a C2-C4 alkyl group substituted from position 2 onwards by a hydroxy group, and R6 denotes a hydrogen atom, a methyl or ethyl group, a pyrrolidino or piperidino group which is substituted by an R6O-CO group, whilst R6 is as hereinbefore defined, a piperazino group which is substituted in the 4 position by an R6OCOCH2 or bis-(R6O-CO)-C1-C3 alkyl group, whilst R6 is as hereinbefore defined, a pyrrolidinyl or piperidinyl group substituted in the 1 position by an R6O-CO-CH, group, whilst R6 is as hereinbefore defined, a 2-oxo-morpholino group which may be substituted by one or two methyl groups, or a R11N(C1-C2 alkyl) group wherein R11 denotes a 2-oxo-tetrahydro-furan-3-yl or 2-oxo-tetrahydrofuran-4-yl group, and C and D together denote a methoxy, C4-C6 cycloalkoxy or C3-C6 cycloalkylmethoxy group, the tautomers, stereoisomers and salts thereof. 4. Bicyclic heterocycles of general formula I according to claim 2, wherein Ra denotes a hydrogen atom, Rb denotes a phenyl group wherein the phenyl nucleus is substituted in each case any the groups R1 to R3, whilst R1 and R2 which may be identical or different, each denote a hydrogen, fluorine, chlorine or bromine atom and R3 denotes a hydrogen atom, Rc and Rd in each case denote a hydrogen atom, X denotes a nitrogen atom, A and B together denote a C4-C6 cycloalkoxy or C3-C6 cycloalkyl-methoxy group, C denotes an -O-CH2CH, group, whilst the oxygen atom of the above-mentioned group is linked to the bicyclic heteroaromatic ring, D denotes an R6O-CO-CH2NR5 group wherein R5 denotes a C2-C4-alkyl group substituted from position 2 onwards by a hydroxy group, and R6 denotes a methyl or ethyl group, a 2-oxo-morpholino group which may be substituted by one or two methyl groups, or a R11N(C1-C2 alkyl) group wherein R11 denotes a 2-oxo-tetrahydro-furan-3-yl or 2-oxo-tetrahydrofuran-4-yl group, the tautomers, stereoisomers and salts thereof. 5. The following bicyclic heterocycles of general formula I according to claim 1 or 2 selected from the group consisting of: (1) 4-(3-chloro-4-fluorophenylamino)-6-(3-[4-(methoxycarbonyl-methyl)-1-piperazinyl]propyloxy}-7-methoxy-quinazoline, (2) 4-[(3-bromophenyl)amino]-6-(2-{4-[(ethoxycarbonyl)methyl]-piperazin-1-yl}ethoxy)-7-methoxy-quinazoline, (3) (S)-4-[(3-bromophenyl)amino1-6-[3-(2-methoxycarbonyl-pyrrolidin-1-yl)propyloxy]-7-methoxy-quinazoline, (4) 4 -[(3-bromophenyl)amino]-6-(3-{4-[(ethoxycarbonyl)methyl]-piperazin-1-yl)-2-hydroxy-propyloxy)-7-methoxy-quinazoline, (5) (S)-4-[(3-bromophenyl)amino]-6-({1-[(ethoxycarbonyl)methyl]-pyrrolidine-2-yl}methoxy)-7-methoxy-quinazoline and (6) 4-[(3-bromophenyl)amino]-6-(2-{4-[1,2-bis(methoxycarbonyl)-ethyl]-piperazin-1-yl