Patent EA-003514-B1 (EA)
Title: Substituted indolinones, the production thereof and their use as medicaments
Inventor: HECKEL ARMIN
IPC: C07D417/12
Filed: 1999-05-28
Abstract: 1. Substituted indolinones of general formula wherein X denotes an oxygen or sulphur atom, R1 denotes a hydrogen atom, a C1-C4-alkoxy-carbonyl or C2-C4-alkanoyl group, R2 denotes a carboxy or C1-C4-alkoxy-carbonyl group or an aminocarbonyl group optionally substituted by one or two C1-C3-alkyl groups, whilst the substituents may be identical or different, R3 denotes a hydrogen atom or a C1-C6-alkyl group which may be substituted at the 2 position, in relation to the carbon atom of the R3-C(R4NR5) = group by a fluorine, chlorine or bromine atom, by a hydroxy, C1-C3-alkoxy, C1-C3-alkylsulphenyl, C1-C3-alkylsulphinyl, C1-C3-alkylsulphonyl, phenylsulphenyl, phenylsulphinyl, phenylsulphonyl, amino, C1-C3-alkylamino, di-(C1-C3-alkyl) -amino, C2-C5-alkanoylamino or N-(C1-C3-alkyl amino) - C2-C5-alkanoylamino group, R4 denotes a hydrogen atom, a C1-C6-alkyl group or a C5-C7-cycloalkyl group optionally substituted by a C1-C3-alkyl group wherein a methylene group in the 3 or 4 position in relation to the carbon atom of the R3-C(R4NR5)= group may be substituted by an imino group optionally substituted by a C1-C3-alkyl group, a phenyl or naphthyl group which may be substituted -by a fluorine, chlorine, bromine or iodine atom, -by a methoxy group optionally substituted by 1 to 3 fluorine atoms, -by a C2-C3-alkoxy which may be substituted in the 2 or 3 position by a C1-C3-alkyl amino, di-(C1-C3-alkyl)-amino or 5- to 7-membered cycloalkyleneimino group, whilst additionally an alkyl moiety in the above mentioned alkylamino and dialkylamino groups may be substituted by a phenyl group, -by a trifluoromethyl, amino, C1-C3-alkylamino, di-(C1-C3-alkyl) -amino, C2-C5-alkanoylamino, N-(C1-C3-alkyl)- C2-C5-alkanoylamino, C1-C5-alkylsulphonylamino, N-(C1-C5-alkyl)- C1-C5-alkylsulphonylamino, phenylsulphonylamino, N-(C1-C3-al-kyl)-phenylsulphonylamino, aminosulphonyl, C1-C3-alkylamino-sulphonyl or di-(C1-C3-alkyl)-aminosulphonyl group, whilst additionally an alkyl moiety in the above mentioned alkyl-amino and dialkylamino groups may be substituted by a phenyl group, by a carbonyl group which is substituted by a hydroxy, C1-C3-alkoxy, amino, C1-C3-alkylamino or N-(C1-C5-alkyl)- C1-C3-alkylamino group, whilst additionally an alkyl moiety in the above mentioned groups may be substituted by a carboxy, C1-C3-alkoxycarbonyl or phenyl group or in the 2 or 3 position by a di-(C1-C3-alkyl)-amino, piperazino, N-(C1-C3-alkyl)-piperazino or 5- to 7-membered cycloalkyleneimino group, -by a C1-C3-alkyl group which is substituted by an amino, C1-C7-alkylamino, C5-C7-cycloalkylamino, C5-C7-cycloalkyl- C1-C3--alkylamino or phenyl- C1-C3--alkylamino group which may additionally be substituted at the amino nitrogen atom by a C1-C3-alkyl group wherein the hydrogen atoms are wholly or partially replaced by fluorine atoms, by a C5-C7-cycloalkyl, C2-4-alkenyl or C1-C4-alkyl group, whilst the above mentioned C1-C4-alkyl substituent may in each case be additionally mono, di- or trisubstituted by a cyano, carboxy, C1-C3-alkoxycarbonyl, pyridyl, imidazolyl, benzo[1,3]dioxole or phenyl group, wherein the phenyl group may be substituted by fluorine, chlorine or bromine atoms, by methyl, methoxy, trifluoromethyl, cyano or nitro groups and the substituents may be identical or different, or may be substituted in the 2, 3 or 4 position by a hydroxy group, by a C1-C3 -alkyl group which may be substituted by a hydroxy, carboxy, thiomorpholino, 1-oxido-thiomorpholino, 1,1-dioxido-thiomorpholino, piperazino, N-(C1-C3-alkyl)-piperazino or N-phenyl-piperazino group, by a 5- to 7-membered cycloalkenyleneimino group or by a 4- to 7-membered cycloalkyleneimino group, wherein the above mentioned 5- to 7-membered cycloalkyleneimino groups may be substituted by one or two C1-C3-alkyl groups, by a C5-C7-cycloalkyl or phenyl group, by a C1-C3-alkyl, C5-C7-cycloalkyl, phenyl, carboxy or C1-C4-alkoxy-carbonyl group and by a hydroxy group and in the above mentioned cycloalkyleneimino groups a methylene group adjacent to the nitrogen atom may be replaced by a carbonyl group, -by a C1-C3-alkyl group which is substituted by a 5- to 7-membered cycloalkyleneimino group, whilst a phenyl group optionally mono- or disubstituted by fluorine, chlorine or bromine atoms or by methyl or methoxy groups, wherein the substituents may be identical or different, or an oxazolo, imidazolo, thiazolo, pyridino, pyrazino or pyrimidino group, optionally substituted by a fluorine, chlorine, bromine or iodine atom or by a methyl, methoxy or amino group, may be fused to the above mentioned 5- to 7-membered cycloalkyleneimino groups via two adjacent carbon atoms, whilst additionally the above mentioned monosubstituted phenyl groups may be substituted by a fluorine, chlorine or bromine atom or by a methyl, methoxy or vitro group, 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- and 6-membered heteroaromatic groups may additionally be substituted by a chlorine or bromine atom or by a methyl group, or a phenyl ring may be fused to the above mentioned 5- or 6-membered heteroaromatic groups via two adjacent carbon atoms, and R5 denotes a hydrogen atom or a C1-C3-alkyl group with proviso that X denotes an oxygen atom, R1 and R5 each denotes hydrogen atom, R4 does not denote a phenyl group which is substituted by C1-C3-alkylamino, di-(C1-C3-alkyl)-amino, C1-C5-alkylsulfonylamino, phenylsulfonylamino, aminosulfonyl, C1-C3-alkylaminosulfonyl, di-(C1-C3-alkyl)-aminosulfonyl or N-(C1-C5-alkyl)- C1-C3alkylaminocarbonyl group, whilst any carboxy, amino or imino groups present may be substituted by groups which can be cleaved in vivo, their enantiomers and/or diasteriomers and 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 an aminocarbonyl group, R3 denotes a hydrogen atom or a C1-C4-alkyl group which may be substituted, at the 2 position in relation to the carbon atom of the R3-C (R4NR5) = group, by a chlorine or bromine atom or by a phenylsulphonyl group, R4 denotes a hydrogen atom, a C1-C3-alkyl group or a cyclopentyl or cyclohexyl group optionally substituted by a methyl group, whilst in the cyclopentyl and cyclohexyl group a methylene group in the 3 or 4 position in relation to the carbon atom of the R3-C(R4NR5) = group may be optionally replaced by an imino group or a methyl group, a phenyl group which is optionally substituted -by a fluorine, chlorine, bromine or iodine atom, -by a methoxy group optionally substituted by 1 to 3 fluorine atoms, -by a C2-C3-alkoxy which is substituted in the 2 or 3 position by methylamino, dimethylamino or 5- to 7-membered cycloalkyleneimino group, whilst additionally a methyl group in the above mentioned amino groups may be substituted by a phenyl group, -by a trifluoromethyl, amino, C2-C5-alkanoylamino, N-(C1-C3-alkyl) - C2-C5-alkanoylamino, C1-C5-alkylsulphonylamino, N-(C1-C3-alkyl) - C1-C5-alkylsulphonylamino, phenylsulphonylamino, N-(C1-C3-alkyl)-phenylsulphonylamino or aminosulphonyl group, whilst additionally an alkyl moiety in the above mentioned alkylamino and dialkylamino groups may be substituted by a phenyl group, -by a carbonyl group which is substituted by a hydroxy, C1-C3-alkoxy, amino, C1-C3-alkyl amino or N-(C1-C5-alkyl)- C1-C3-alkylamino group, whilst additionally an alkyl moiety in the above mentioned groups may be substituted by a carboxy, C1-C3-alkoxycarbonyl or phenyl group or in the 2 or 3 position by a di-(C1-C3-alkyl)-amino, piperazino, N-(C1-C3-alkyl)-piperazino or 5- to 7-membered cycloalkyleneimino group, -by a C1-C3-alkyl group which is substituted by an amino, C1-C7-alkyl amino, C5-C7-cycloalkylamino, C5-C7-cycloalkyl- C1-C3-alkylamino or phenyl- C1-C3-alkylamino group which may additionally be substituted at the amino nitrogen atom by a C1-C3-alkyl group wherein the hydrogen atoms are wholly or partially replaced by fluorine atoms, by a C5-C7-cycloalkyl, C2-C4-alkenyl or C1-C4-alkyl group, whilst the above mentioned C1-C4-alkyl substituent may in each case be additionally substituted by a cyano, carboxy, C1-C3-alkoxycarbonyl, pyridyl, imidazolyl, benzo[1,3]di-oxole or phenyl group, wherein the phenyl group may be monosubstituted by a fluorine, chlorine or bromine atom or by a methyl, methoxy, cyano, trifluoromethyl or nitro group, or di- or trisubstituted by fluorine, chlorine or bromine atoms or by methyl or methoxy groups, and the substituents may be identical or different, or may be substituted in the 2, 3 or 4 position by a hydroxy group, -by a C1-C3-alkyl group which may be substituted by a hydroxy, carboxy, thiomorpholino, 1-oxido-thiomor-pholino, 1,1-dioxido-thiomorpholino, piperazino, N-(C1-C3-alkyl)-piperazino or N-phenyl-piperazino group, by a 5- to 7-membered cycloalkenyleneimino group or by a 4- to 7-membered cycloalkyleneimino group, wherein the above mentioned 5- to 7-membered cycloalkyleneimino groups may be substituted by one or two C1-C3-alkyl groups, by a cyclohexyl or phenyl group, by a C1-C3-alkyl, cyclohexyl, phenyl, carboxy or C1-C4-alkoxy-carbonyl group and by a hydroxy group and in the above mentioned cycloalkyleneimino groups a methylene group adjacent to the nitrogen atom may be replaced by a carbonyl group, -by a C1-C3-alkyl group which is substituted by a 5- to 7-membered cycloalkyleneimino group, whilst a phenyl group optionally mono- or disubstituted by fluorine, chlorine or bromine atoms or by methyl or methoxy groups, wherein the substituents may be identical or different, or a pyrazino or thiazolo group, optionally substituted by an amino group, may be fused to the above mentioned 5- to 7-membered cycloalkyleneimino groups via two adjacent carbon atoms condensed by optionally mono- or