Patent EA-003532-B1 (EA)
Title: Substituted indolinones having an inhibiting effect on kinases and cycline/cdk complexes
Inventor: HECKEL ARMIN
IPC: C07D413/12
Filed: 1999-04-10
Abstract: 1. Substituted indolinones of general formula I, wherein X denotes an oxygen atom, R1 denotes a hydrogen atom, a C1-4-alkoxy-carbonyl group, R2 denotes a carboxy-, C1-4-alkoxy-carbonyl or aminocarbonyl group wherein the amino moiety may be substituted by one or two C1-3-alkyl groups and the substitutes may be identical or different, R3 denotes a phenyl group which may be optionally substituted by fluorine, chlorine or bromine atoms, by methyl, cyano- or aminomethyl group, R4 denotes a hydrogen atom or a methyl group and R5 denotes a hydrogen atom, a C1-5-alkyl group or benzyl group optionally substituted by a carboxy or C1-3-alkoxy-carbonyl group, a C3-7-cycloalkyl group optionally substituted by a methyl group, an indanyl, pyridyl, oxazolyl, thiazolyl or imidazolyl group optionally substituted by a methyl group, to which a phenyl ring may additionally be fused via two adjacent carbon atoms, a methylphenyl group or dimethoxyphenyl group optionally substituted by a fluorine, chlorine or bromine atom, or by a methoxy, carboxy, C1-3-alkyloxycarbonyl, nitro or aminosulphonyl group, or a dimethoxyphenyl group, a pyrrolidinyl or piperidinyl group linked via a carbon atom, which may be substituted at the nitrogen atom by a C1-3alkyl group, a phenyl group which is substituted by a trifluoromethoxy group, by a fluorine, chlorine, bromine or iodine atom, by a C1-3alkoxy group which may be substituted in the 2- or 3-position by an amino, C1-3alkylamino, di-(C1-3alkyl)amino, phenyl-C1-3alkylamino, N-(C1-3alkyl)phenyl-C1-3alkylamino, pyrrolidino or piperidino group, by a phenyl-C1-3alkylamino-C1-3alkyl group which may be [substituted] in the phenyl nucleus by a fluorine, chlorine, bromine or iodine atom, by a C1-5alkyl, C1-3alkoxy or trifluoromethyl group and additionally at the amine nitrogen atom by a C1-3alkyl group wherein the hydrogen atoms from position 2 may be wholly or partially replaced by fluorine atoms, by a C1-5alkyl, phenyl, imidazolyl, C3-7cycloalkyl, C1-3alkoxy-C1-3alkoxy, phenyl-C1-3alkoxy, carboxy-C1-3alkyl, C1-3alkoxycarbonyl-C1-3alkyl, carboxy- C1-3alkoxycarbonyl, aminocarbonyl, C1-3alkylaminocarbonyl, di-(C1-3alkyl)-aminocarbonyl, phenyl-C1-3alkylaminocarbonyl, N-(C1-3alkyl)phenyl-C1-3alkylaminocarbonyl, piperazinocarbonyl, N-(C1-3alkyl)-piperazinocarbonyl, nitro, amino, C1-3alkylamino, di-(C1-3alkyl)amino-, pyrrolidino, piperidino, morpholino, C2-4-alkanoylamino, N-(C1-3-alkyl)-C2-4-alkanoylamino, benzoylamino- or N-(C1-3-alkyl)-benzoylamino group, by an N-(C1-3-alkyl) -C2-4-alkanoylamino group which is additionally substituted in the alkyl moiety by a carboxy or C1-3-alkoxycarbonyl group, by a C1-3-alkylaminocarbonyl or di-(C1-3-alkyl)-aminocarbonyl group wherein an alkyl moiety is additionally substituted by a di-(C1-3-alkyl)amino group, or by an N- (C1-3-alkyl)-C1-3alkylsulphonylamino or N-(C1-3-alkyl)-phenylsulphonylamino group wherein the alkyl moiety may additionally be substituted by a cyano, carboxy, C1-3-alkoxycarbonyl, C1-3-alkylamino, di-(C1-3-alkyl)-amino group, aminocarbonyl, C1-3-alkylaminocarbonyl, di-(C1-3-alkyl)aminocarbonyl, piperidinocarbonyl or 2-[di-(C1-3-alkylamino)]-ethylaminocarbonyl group, a phenyl group optionally substituted by a C1-3-alkyl group wherein the alkyl moiety is substituted by a hydroxy, C1-3-alkoxy, carboxy, C1-3-alkoxy-carbonyl, amino, C1-5-alkylamino, di-(C1-5alkyl) -amino, C2-4-alkanoylamino, N-(C1-3-alkyl)-C2-4alkanoylamino, pyrrolidino, dehydropyrrolidino, piperidino, dehydropiperidino, 3-hydroxypiperidino, 4-hydroxypiperidino, hexamethyleneimino, morpholino, thiomorpholino, piperazino, 4-(C1-3-alkyl)-piperazino, 4-phenyl-piperazino, 4-(C2-4-alkanoyl)-piperazino, 4-benzoyl-piperazino or imidazolyl group, whilst the above mentioned saturated cycloalkyleneimino rings, C1-5-alkylamino or di-(C1-5-alkyl)-amino groups may additionally be substituted by one or two C1-5-alkyl groups, by a C3-7-cycloalkyl, hydroxy, C1-3-alkoxy, carboxy, C1-3-alkoxycarbonyl, aminocarbonyl, C1-3-alkylaminocarbonyl or di-(C1-3-alkyl)-aminocarbonyl group, by a phenyl-C1-3-alkyl or phenyl group optionally mono- or disubstituted in the phenyl nucleus by fluorine, chlorine, bromine or iodine atoms or by C1-3-alkyl or cyano groups, whilst the substituents may be identical or different, or a methylene group adjacent to the nitrogen atom in the above mentioned cycloalkyleneimino rings may be replaced by a carbonyl or sulphonyl group, and the above mentioned monosubstituted phenyl groups may additionally be substituted by a fluorine, chlorine or bromine atom or by a methyl, amino, C1-3-alkylamino or di-(C1-3-alkyl)-amino group, or a phenyl ring optionally substituted by one or two C1-3-alkoxy groups may be fused to one of the above mentioned unsubstituted cycloalkyleneimino rings via two adjacent carbon atoms, the isomers and the salts thereof. 2. Substituted indolinones of general formula I according to claim 1, wherein X denotes an oxygen atom, R1 denotes a hydrogen atom, R2 denotes a carboxy, C1-4-alkoxycarbonyl or aminocarbonyl group wherein the amino moiety may be substituted by one or two C1-3-alkyl groups and the substituents may be identical or different, R3 denotes a phenyl group optionally substituted by a methyl group, R4 denotes a hydrogen atom or a methyl group and R5 denotes a hydrogen atom, a C1-3-alkyl group, a benzyl group or a methyl or ethyl group substituted by a carboxy or C1-3-alkoxycarbonyl group, a C3-7-cycloalkyl group optionally substituted by a methyl group, an indanyl, pyridyl, oxazolyl, thiazolyl or imidazolyl group optionally substituted by a methyl group, to which a phenyl ring may additionally be fused via two adjacent carbon atoms, a methylphenyl group optionally substituted by a fluorine, chlorine or bromine atom, or by a methoxy, carboxy, C1-3-alkyloxycarbonyl, nitro or aminosulphonyl group, or a dimethoxyphenyl group, a 3-pyrrolidinyl or 4-piperidinyl group which may be substituted at the nitrogen atom by a C1-3-alkyl group, a phenyl group which is substituted by a trifluoromethoxy, benzyloxy, cyano or nitro group, by a fluorine, chlorine, bromine or iodine atom, by a C1-3-alkoxy group, whilst the ethoxy and n-propoxy groups may each be terminally substituted by a dimethylamino, diethylamino, N-ethyl-methylamino, N-benzyl-methylamino or piperidino group, by a phenyl-C1-3-alkylamino-C1-3-alkyl group which may be substituted in the phenyl nucleus by a fluorine, chlorine, bromine or iodine atom, by a methyl, methoxy or trifluoromethyl group and additionally at the amine nitrogen atom by a C1-5-alkyl or 2,2,2-trifluoroethyl group, by a C1-4-alkyl, phenyl, imidazolyl, cyclohexyl, methoxymethyl, carboxymethyl, C1-3-alkoxycarbonyl-methyl, carboxy, C1-3-alkoxycarbonyl, aminocarbonyl, C1-3-alkylaminocarbonyl, di-(C1-3-alkyl)-aminocarbonyl, phenyl-C1-3-alkylaminocarbonyl, N-(C1-3-alkyl)-phenyl-C1-3-alkylaminocarbonyl, piperazinocarbonyl, N-(C1-3-alkyl)-piperazinocarbonyl, amino, C1-3-alkylamino, di-(C1-3-alkyl)-amino, pyrrolidino, piperidino, morpholino, C2-4-alkanoyl-amino, N-(C1-3-alkyl) -C2-4-alkanoylamino, benzoylamino or -(C1-3-alkyl)-benzoylamino group, by an N-(C1-3-alkyl) -C2-4-alkanoylamino group which is additionally substituted in the alkyl moiety by a carboxy or C1-3-alkoxycarbonyl group, by a C1-3-alkylaminocarbonyl or di-(C1-3-alkyl)-aminocarbonyl group wherein an alkyl moiety is additionally substituted by a di-(C1-3-alkyl)-amino group, or by an N-(C1-3-alkyl)-C1-3-alkylsulphonylamino or N-(C1-3-alkyl)-phenylsulphonylamino group wherein the alkyl moiety may additionally be substituted by a cyano, carboxy, C1-3-alkoxycarbonyl, C1-3-alkylamino, di-(C1-3-alkyl)-amino group, aminocarbonyl, C1-3-alkylaminocarbonyl, di-(C1-3-alkyl)-aminocarbonyl, piperidinocarbonyl or 2-[di-(C1-3-alkylamino)]-ethylaminocarbonyl group, a phenyl group optionally substituted by a C1-3-alkyl group wherein the alkyl moiety is substituted by a hydroxy, C1-3-alkoxy, carboxy, C1-3-alkoxy-carbonyl, amino, C1-5-alkylamino, di-(C1-5-alkyl)-amino, C2-4-alkanoylamino, N-(C1-3-alkyl)-C2-4-alkanoylamino, pyrrolidino, dehydropyrrolidino, piperidino, dehydropiperidino, 4-hydroxypiperidino, hexamethyleneimino, morpholino, thiomorpholino, piperazino, 4-(C1-3-alkyl)-piperazino, 4-phenylpiperazino, 4-(C2-4alkanoyl)-piperazino, 4-benzoylpiperazino or imidazolyl group, whilst the above mentioned saturated cycloalkyleneimino rings may additionally be substituted by a phenyl group or by one or two methyl groups, the above mentioned C1-5-alkylamino and di-(C1-5-alkyl)-amino groups may additionally be substituted by one or two C1-3-alkyl groups, by a cyclohexyl, hydroxy, C1-3-alkoxy, carboxy, C1-3-alkoxycarbonyl, aminocarbonyl, C1-3-alkylaminocarbonyl or di-(C1-3-alkyl)-aminocarbonyl group, by a phenyl-C1-3-alkyl or phenyl group optionally substituted in the phenyl nucleus by a fluorine, chlorine, bromine or iodine atom or by a methyl or cyano group, or a methylene group adjacent to the nitrogen atom in the above mentioned cycloalkyleneimino rings may be replaced by a carbonyl or sulphonyl group, and the above mentioned monosubstituted phenyl groups may additionally be substituted by a fluorine, chlorine or bromine atom or by a methyl, amino, C1-3-alkylamino or di-(C1-3-alkyl)-amino group, or a phenyl ring optionally substituted by one or two C1-3-alkoxy groups may be fused to one of the above mentioned unsubstituted cycloalkyleneimino rings via two adjacent carbon atoms, the isomers and salts thereof. 3. Substituted indolinones of general formula I according to claim 1, wherein X denotes an oxygen atom, R1 denotes a hydrogen atom, R2 denotes a carboxy or aminocarbonyl group wherein the amino moiety may be substituted by one or two C1-3-alkyl groups and the substituents may be identical or different, R3 denotes a phenyl group optionally substituted by a methyl group, R4 denotes a hydrogen atom and R5 denotes a hydrogen atom, a 3-pyrrolidinyl or 4-piperidinyl group which may be substituted at the nitr