Patent EA-004981-B1 (EA)
Title: Bicyclic heterocycles, medicaments containing these compounds, their use and methods for the production thereof
Inventor: HIMMELSBACH FRANK
IPC: A61P35/00
Filed: 2000-06-16
Abstract: 1. Bicyclic heterocycles of general formula wherein Ra denotes a hydrogen atom or a C1-4alkyl group, 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, in each case denote a hydrogen, fluorine, chlorine, bromine or iodine atom, a C1-4-alkyl, hydroxy, C1-4alkoxy, C3-6cycloalkyl, C4-6cycloalkoxy, C1-5alkenyl or C2-5alkynyl group, an aryl, aryloxy, arylmethyl or arylmethoxy group, a C3-5alkenyloxy or C3-5alkynyloxy group, whilst the unsaturated moiety may not be linked to the oxygen atom, a C1-4-alkylsulphenyl, C1-4alkylsulphinyl, C1-4alkylsulphonyl, C1-4alkylsulphonyloxy, trifluoromethylsulphenyl, trifluoromethylsulphinyl or trifluoromethylsulphonyl group, methyl or methoxy group substituted by 1 to 3 fluorine atoms, an ethyl or ethoxy group substituted by 1 to 5 fluorine atoms, a cyano or nitro group or an amino group optionally substituted by one or two C1-4alkyl groups, wherein the substituents may be identical or different, or R1 together with R2, if they are bound to adjacent carbon atoms, denote a -CH=CH-CH=CH-, -CH=CH-NH or -CH=N-NH group and R3 denotes a hydrogen, fluorine, chlorine or bromine atom, a C1-4alkyl, trifluoromethyl or C1-4alkoxy group, X denotes a methine group substituted by a cyano group or a nitrogen atom, A denotes an imino group optionally substituted by a C1-4alkyl group, B denotes a carbonyl or sulphonyl group, C denotes a 1,3-allenylene, 1,1- or 1,2-vinylene group which may be substituted in each case by one or two methyl groups or by a trifluoromethyl group, an ethynylene group or a 1,3-butadien-1,4-ylene group optionally substituted by 1 to 4 methyl groups or by a trifluoromethyl group, D denotes an alkylene, -CO-alkylene or -SO2-alkylene group wherein the alkylene moiety in each case contains 1 to 8 carbon atoms and additionally 1 to 4 hydrogen atoms in the alkylene moiety may be replaced by fluorine atoms, whilst the linking of the -CO-alkylene or -SO2-alkylene group to the adjacent group C in each case must take place via the carbonyl or sulphonyl group, a -CO-O-alkylene, -CO-NR4-alkylene or -SO2-NR4-alkylene group wherein the alkylene moiety in each case contains 1 to 8 carbon atoms, whilst the linking to the adjacent group C in each case must take place via the carbonyl or sulphonyl group, wherein R4 denotes a hydrogen atom or a C1-4alkyl group, or, if D is bound to a carbon atom of the group E, it may also denote a bond or, if D is bound to a nitrogen atom of the group E, it may also denote a carbonyl or sulphonyl group, E denotes an amino, C1-4-alkyl amino or di-(C1-4alkyl)-amino group wherein the alkyl moieties may be identical or different, a C2-4-alkylamino group wherein the alkyl moiety is substituted in beta-, gamma- or delta-position with regard to the nitrogen atom of the amino group by the group R5, whilst R5 denotes a hydroxy, C1-4alkoxy, amino, C1-4alkylamino or di-(C1-4alkyl)-amino group, a 4- to 7-membered alkyleneimino group optionally substituted by one or two methyl groups or a 6- to 7-membered alkyleneimino group optionally substituted by one or two methyl groups wherein in each case a methylene group in position 4 is replaced by an oxygen or sulphur atom, by a sulphinyl, sulphonyl, imino or N-(C1-4-alkyl)-imino group, an N-(C1-4-alkyl)-N-(C2-4-alkyl)-amino group wherein the C2-4alkyl moiety is substituted in beta-, gamma- or delta-position with regard to the nitrogen atom of the amino group by the group R5, whilst R5 is as hereinbefore defined, a di-(C2-4alkyl)-amino group wherein the two C2-4alkyl moieties are substituted in each case in beta-, gamma- or delta- position with regard to the nitrogen atom of the amino group by the group R5, whilst the substituents may be identical or different and R5 is as hereinbefore defined, a C3-7cycloalkylamino or C3-7cycloalkyl-C1-3alkyl amino group wherein in each case the nitrogen atom may be substituted by a further C1-4alkyl group, an amino or C1-4alkylamino group wherein in each case the nitrogen atom is substituted by a tetrahydrofuran-3-yl, tetrahydropyran-3-yl, tetrahydropyran-4-yl, tetrahydrofuranylmethyl, 1-(tetrahydrofuran-3-yl)-piperidin-4-yl, 1-(tetrahy-dropyran-3-yl)-piperidin-4-yl, 1-(tetrahydropyran-4-yl)-piperidin-4-yl, 3-pyrrolidinyl, 3-piperidinyl, 4-piperidinyl, 3-hexahydro-azepinyl or 4-hexahydro-azepinyl group optionally substituted by 1 to 3 C1-4alkyl groups, a 4- to 7-membered alkyleneimino group optionally substituted by 1 to 4 C1-2alkyl groups, which may be substituted by the group R5 either at a cyclic carbon atom or at one of the alkyl groups, whilst R5 is as hereinbefore defined, a piperidino group substituted by a tetrahydrofuranyl, tetrahydropyranyl or tetrahydrofuranylmethyl group, a 6- to 7-membered alkyleneimino group optionally substituted by 1 or 2 C1-2alkyl groups wherein a methylene group in each case is replaced in the 4 position by an oxygen or sulphur atom, by an imino group substituted by the group R6, or by a sulphinyl or sulphonyl group, whilst R6 denotes a hydrogen atom, a C1-4alkyl, 2-methoxy-ethyl, 3-methoxy-propyl, C3-7-cycloalkyl, C3-7cycloalkyl-C1-4alkyl, tetrahydrofuran-3-yl, tetrahydropyran-3-yl, tetrahydropyran-4-yl, tetrahydrofuranylmethyl, formyl, C1-4alkylcarbonyl, C1-4alkylsulphonyl, aminocarbonyl, C1-4alkylamino-carbonyl or di-(C1-4alkyl)-aminocarbonyl group, an imidazolyl group optionally substituted by 1 to 3 methyl groups, a C5-7cycloalkyl group wherein a methylene group is replaced by an oxygen or sulphur atom, by an imino group substituted by the group R6, by a sulphinyl or sulphonyl group, whilst R6 is as hereinbefore defined, or D together with E denotes a hydrogen, fluorine or chlorine atom, a C1-4alkyl group optionally substituted by 1 to 5 fluorine atoms, a C3-6cycloalkyl group, an aryl, heteroaryl, C1-4alkylcarbonyl or arylcarbonyl group, a carboxy, C1-4alkoxycarbonyl, aminocarbonyl, C1-4alkylamino-carbonyl or di-(C1-4alkyl)-aminocarbonyl group or a carbonyl which is substituted by a 4- to 7-membered alkyleneimino group, whilst in the above mentioned 6- to 7-membered alkyleneimino groups in each case a methylene group may be replaced in the 4 position by an oxygen or sulphur atom, by animino group substituted by the group R6, by a sulphinyl or sulphonyl group, whilst R6 is as hereinbefore defined, and Rc denotes a C4-7cycloalkoxy or C3-7cycloalkyl-C1-6alkoxy group wherein the cycloalkyl moiety in each case may be substituted by a C1-3alkyl, hydroxy, C1-4alkoxy, amino, C1-4alkylamino, di (C1-4alkyl)-amino, pyrrolidino, piperidino, morpholino, piperazino, N-(C1-2alkyl)-piperazino, hydroxy-C1-2alkyl, C1-4alkoxy-C1-2alkyl, amino-C1-2alkyl, C1-4alkyl amino-C1-2alkyl, di (C1-4alkyl)-amino-C1-2alkyl, pyrrolidino-C1-2alkyl, piperidino C1-2alkyl, morpholino-C1-2alkyl, piperazino-C1-2alkyl or N-(C1-2alkyl)-piperazino-C1-2alkyl group, whilst the above mentioned mono substituted cycloalkyl moieties may additionally be substituted by a C1-3alkyl group, a tetrahydrofuran-3-yloxy, tetrahydropyran-3-yloxy, tetrahydropyran-4-yloxy or tetrahydrofuranylmethoxy group, an C2-4alkoxy group substituted in beta-, gamma- or delta- position with regard to the oxygen atom by an azetidin-1-yl, 4-methyl-homo-piperazino or 4-ethyl-homopiperazino group, a 3-pyrrolidinyloxy, 2-pyrrolidinyl-C1-4alkyloxy, 3-pyrrolidinyl-C1-4alkyloxy, 3-piperidinyloxy, 4-piperidinyloxy, 2-piperidinyl-C1-4alkyloxy, 3-piperidinyl-C1-4alkyloxy, 4-piperidinyl-C1-4alkyloxy, 3-hexahydro-azepinyloxy, 4-hexahydro-azepinyloxy, 2-hexahydro-azepinyl-C1-4alkyloxy, 3-Hexahydro-azepinyl-C1-4alkyloxy or 4-hexahydro-azepinyl-C1-4alkyloxy group wherein in each case the cyclic nitrogen atom is substituted by the group R6, where R6 is as hereinbefore defined, whilst by the aryl moieties mentioned in the definition of the above mentioned groups is meant a phenyl group which in each case may be monosubstituted by R7, mono-, di- or trisubstituted by R8 or mono substituted by R7 and additionally mono- or disubstituted by R8, wherein the substituents may be identical or different and R7 denotes a cyano, carboxy, C1-4alkoxycarbonyl, aminocarbonyl; C1-4alkylaminocarbonyl, di-(C1-4alkyl)-aminocarbonyl, C1-4alkylsulphenyl, C1-4alkylsulphinyl, C1-4alkylsulphonyl, hydroxy, C1-4alkylsulphonyloxy, trifluoromethyloxy, nitro, amino, C1-4alkyl amino, di-(C1-4alkyl)-amino, C1-4alkyl-carbonylamino, N-(C1-4alkyl)-C1-4alkylcarbonylamino, C1-4al-kylsulphonylamino, N-(C1-4alkyl)-C1-4alkylsulphonylamino, aminosulphonyl, C1-4alkylaminosulphonyl or di-(C1-4alkyl)-aminosulphonyl group or a carbonyl group which is substituted by a 5- to 7-membered alkyleneimino group, whilst in the above mentioned 6- to 7-membered alkyleneimino groups in each case a methylene group in the 4 position may be replaced by an oxygen or sulphur atom, by a sulphinyl, sulphonyl, imino or N-(C1-4alkyl)-imino group, and R8 denotes a fluorine, chlorine, bromine or iodine atom, a C1-4alkyl, trifluoromethyl or C1-4alkoxy group or two groups R8, if they are bound to adjacent carbon atoms, together denote a C3-5alkylene, methylenedioxy or 1,3-butadien-1,4-ylene group, and the heteroaryl groups mentioned in the definition of the above mentioned groups include a 5-membered heteroaromatic group which contains an imino group, an oxygen or sulphur atom or an imino group, an oxygen or sulphur atom and one or two nitrogen atoms, or a 6-membered heteroaromatic group which contains one, two or three nitrogen atoms, whilst the above mentioned 5-membered heteroaromatic groups may be substituted in each case by 1 or 2 methyl or ethyl groups and the above mentioned 6-membered heteroaromatic groups may be substituted in each case by 1 or 2 methyl or ethyl groups or by a fluorine, chlorine, bromine or iodine atom or by a trifluoromethyl, hydroxy, methoxy or ethoxy group, the tautomers, stereoisomers and salts thereof. 2. Bicyclic heterocycles of general formula I