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CA2387013A1 - 6-position substituted indolinones, the preparation thereof and their use as pharmaceutical compositions - Google Patents

6-position substituted indolinones, the preparation thereof and their use as pharmaceutical compositions Download PDF

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CA2387013A1
CA2387013A1 CA002387013A CA2387013A CA2387013A1 CA 2387013 A1 CA2387013 A1 CA 2387013A1 CA 002387013 A CA002387013 A CA 002387013A CA 2387013 A CA2387013 A CA 2387013A CA 2387013 A1 CA2387013 A1 CA 2387013A1
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alkyl
amino
phenyl
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CA2387013C (en
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Armin Heckel
Gerald Jurgen Roth
Rainer Walter
Jacobus Van Meel
Norbert Redemann
Ulrike Tontsch-Grunt
Walter Spevak
Frank Hilberg
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Boehringer Ingelheim Pharma GmbH and Co KG
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Priority claimed from DE19949208A external-priority patent/DE19949208A1/en
Priority claimed from DE2000142696 external-priority patent/DE10042696A1/en
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Abstract

The invention relates to a 6-substituted indoline of formula (I), wherein R1 to R5 and X are as defined in claim 1, isomers and salts of said compound, i n particular physiologically compatible salts of said compound having pharmacologically important characteristics, in particular inhibiting action on different receptor-tyrosine kinases and cyclin/CDK complexes in addition to inhibiting the proliferation of endothelial cells and different tumor cells. The invention also relates to medicaments containing said compounds, the use of said compounds and a method for the production thereof.

Claims (10)

1. Indolinones of general formula substituted in the 6 position, wherein X denotes an oxygen or sulphur atom, R1 denotes a hydrogen atom or a prodrug group, R2 denotes a carboxy group, a straight-chain or branched C1-6-alkoxy-carbonyl group, a C4-7-cycloalkoxy-carbonyl or an aryloxycarbonyl group, a straight-chain or branched C1-6-alkoxy-carbonyl group, which is terminally substituted in the alkyl moiety by a phenyl, heteroaryl, carboxy, C1-3-alkoxy-carbonyl, aminocarbonyl, C1-3-alkyl amino-carbonyl or di-(C1-3-alkyl)-aminocarbonyl group, a straight-chain or branched C2-6-alkoxy-carbonyl group, which is terminally substituted in the alkyl moiety by a chlorine atom or a hydroxy, C1-3-alkoxy, amino, C1-3-alkylamino or di-(C1-3-alkyl)-amino group, an aminocarbonyl or methylaminocarbonyl group, an ethylaminocarbonyl group optionally substituted in the 2 position of the ethyl group by a hydroxy or C1-3-alkoxy group or, if R4 does not denote an aminosulphonyl-phenyl or N- (C1-5-alkyl) -C1-3-alkylaminocarbonyl-phenyl group, it may also denote a di-(C1-2-alkyl)-aminocarbonyl group, R3 denotes a hydrogen atom, a C1-6-alkyl, C3-7-cycloalkyl, trifluoromethyl or heteroaryl group, a phenyl or naphthyl group, a phenyl or naphthyl group mono-or disubstituted by a fluorine, chlorine, bromine or iodine atom, by a trifluoromethyl, C1-3-alkyl or C1-3-alkoxy group, whilst in the event of disubstitution the substituents may be identical or different and wherein the abovementioned unsubstituted as well as the mono- and disubstituted phenyl and naphthyl groups may additionally be substituted by a hydroxy, hydroxy-C1-3-alkyl or C1-3-alkoxy-C1-3-alkyl group, by a cyano, carboxy, carboxy-C1-3-alkyl, C1-3-alkoxycarbonyl, aminocarbonyl, C1-3-alkylamino-carbonyl or di- (C1-3-alkyl) -aminocarbonyl group, by a nitro group, by an amino, C1-3-alkyl amino, di- (C1-3-alkyl) -amino or amino-C1-3-alkyl group, by a C1-3-alkylcarbonylamino, N- (C1-3-alkyl) -C1-3-alkyl-carbonylamino, C1-3-alkylcarbonylamino-C1-3-alkyl, N- (C1-3-alkyl) -C1-3-alkylcarbonylamino-C1-3-alkyl, C1-3-alkyl-sulphonylamino, C1-3-alkylsulphonylamino-C1-3-alkyl, N- (C1-3-alkyl) -C1-3-alkylsulphonylamino-C1-3-alkyl or aryl-C1-3-alkylsulphonylamino group, by a cycloalkylamino, cycloalkyleneimino, cyclo-alkyleneiminocarbonyl, cycloalkyleneimino-C1-3-alkyl, cycloalkyleneiminocarbonyl-C1-3-alkyl or cycloalkyleneiminosulphonyl-C1-3-alkyl group having 4 to 7 ring members in each case, whilst in each case the methylene group in position 4 of a 6- or 7-membered cycloalkyleneimino group may be replaced by an oxygen or sulphur atom, by a sulphinyl, sulphonyl, -NH or -N(C1-3-alkyl) group, or by a heteroaryl or heteroaryl-C1-3-alkyl group, R4 denotes a C3-7-cycloalkyl group, whilst the methylene group in the 4 position of a 6- or 7-membered cycloalkyl group may be substituted by an amino, C1-3-alkylamino or di- (C1-3-alkyl) -amino group or replaced by an -NH or -N(C1-3-alkyl) group, or a phenyl group substituted by the group R6, which may additionally be mono- or disubstituted by fluorine, chlorine, bromine or iodine atoms, by C1-5-alkyl, trifluoromethyl, hydroxy, C1-3-alkoxy, carboxy, C1-3-alkoxycarbonyl, amino, acetylamino, C1-3-alkyl-sulphonylamino, aminocarbonyl, C1-3-alkyl-aminocarbonyl, di- (C1-3-alkyl) -aminocarbonyl, aminosulphonyl, C1-3-alkyl-aminosulphonyl, di-(C1-3-alkyl)-aminosulphonyl, nitro or cyano groups, wherein the substituents may be identical or different and wherein R6 denotes a hydrogen, fluorine, chlorine, bromine or iodine atom, a cyano, nitro, amino, C1-5-alkyl, C3-7-cycloalkyl, trifluoromethyl, phenyl, tetrazolyl or heteroaryl group, the group of formula wherein the hydrogen atoms bound to a nitrogen atom may in each case be replaced independently of one another by a C1-3-alkyl group, a C1-3-alkoxy group, a C1-3-alkoxy-C1-3-alkoxy, phenyl-C1-3-alkoxy, amino-C2-3-alkoxy, C1-3-alkyl amino-C2-3-alkoxy, di-(C1-3-alkyl)-amino-C2-3-alkoxy, phenyl-C1-3-alkylamino-C2-3-alkoxy, N-(C1-3-alkyl)-phenyl-C1-3-alkyl amino-C2-3-alkoxy, C5-7-cycloalkyleneimino-C2-3-alkoxy or C1-3-alkylmercapto group, a carboxy, C1-4-alkoxycarbonyl, aminocarbonyl, C1-3-alkyl-amino-carbonyl, N-(C1-5-alkyl)-C1-3-alkylaminocarbonyl, phenyl-C1-3-alkylamino-carbonyl, N-(C1-3-alkyl)-phenyl-C1-3-alkyl amino-carbonyl, piperazinocarbonyl or N-(C1-3-alkyl)-piperazinocarbonyl group, a C1-3-alkylaminocarbonyl or N-(C1-5-alkyl)-C1-3-alkylaminocarbonyl group wherein an alkyl moiety is substituted by a carboxy or C1-3-alkoxycarbonyl group or in the
2 or 3 position by a di-(C1-3-alkyl)-amino, piperazino, N-(C1-3-alkyl)-piperazino or a 4- to 7-membered cycloalkyleneimino group, a C3-7-cycloalkyl-carbonyl group, wherein the methylene group in the 4 position of the 6- or 7-membered cycloalkyl moiety may be substituted by an amino, C1-3-alkyl amino or di-(C1-3-alkyl)-amino group or replaced by an -NH or -N(C1-3-alkyl) group, a 4- to 7-membered cycloalkyleneimino group wherein a methylene group linked to the imino group may be replaced by a carbonyl or sulphonyl group or the cycloalkylene moiety may be fused to a phenyl ring or one or two hydrogen atoms may each be replaced by a C1-3-alkyl group and/or in each case the methylene group in the 4 position of a 6-or 7-membered cycloalkyleneimino group may be substituted by a carboxy, C1-3-alkoxycarbonyl, aminocarbonyl, C1-3-alkylaminocarbonyl, di- (C1-3-alkyl) -aminocarbonyl, phenyl-C1-3-alkylamino or N- (C1-3-alkyl) -phenyl-C1-3-alkylamino group or may be replaced by an oxygen or sulphur atom, by a sulphinyl, sulphonyl, -NH, -N(C1-3-alkyl), -N(phenyl), -N(C1-3-alkyl-carbonyl) or -N(benzoyl) group, a C1-4-alkyl group substituted by the group R7, wherein R7 denotes a C3-7-cycloalkyl group, whilst the methylene group in the 4 position of a 6- or 7-membered cycloalkyl group may be substituted by an amino, C1-3-alkyl amino or di- (C1-3-alkyl) -amino group or replaced by an -NH or -N(C1-3-alkyl) group or in a 5- to 7-membered cycloalkyl group a -(CH2)2 group may be replaced by a -CO-NH group, a -(CH2)3 group may be replaced by a -NH-CO-NH or -CO-NH-CO group or a -(CH2)4 group may be replaced by a -NH-CO-NH-CO group, whilst in each case a hydrogen atom bound to a nitrogen atom may be replaced by a C1-3-alkyl group, an aryl or heteroaryl group, a hydroxy or C1-3-alkoxy group, an amino, C1-7-alkyl amino, di-(C1-7-alkyl)-amino, phenyl amino, N-phenyl-C1-3-alkyl-amino, phenyl-C1-3-alkyl-amino, N-(C1-3-alkyl)-phenyl-C1-3-alkyl amino or di-(phenyl-C1-3-alkyl)-amino group, an .omega.-hydroxy-C2-3-alkyl-amino, N-(C1-3-alkyl)-.omega.-hydroxy-C2-3-alkyl-amino, di-(.omega.-hydroxy-C2-3-alkyl)-amino, di-(.omega.-(C1-3-alkoxy)-C2-3-alkyl)-amino or N-(dioxolan-2-yl)-C1-3-alkyl-amino group, a C1-3-alkylcarbonylamino-C2-3-alkyl-amino or C1-3-alkylcarbonylamino-C2-3-alkyl-N-(C1-3-alkyl)-amino group, a C1-3-alkylsulphonylamino, N-(C1-3-alkyl)-C1-3-alkyl-sulphonylamino, C1-3-alkylsulphonylamino-C2-3-alkyl-amino or C1-3-alkylsulphonylamino-C2-3-alkyl-N-(C1-3-alkyl)-amino group, a hydroxycarbonyl-C1-3-alkyl amino or N-(C1-3-alkyl)-hydroxycarbonyl-C1-3-alkyl-amino group, a guanidino group wherein one or two hydrogen atoms may each be replaced by a C1-3-alkyl group, a group of formula -N(R8)-CO-(CH2)n-R9 ~(II), wherein R8 denotes a hydrogen atom or a C1-3-alkyl group, n denotes one of the numbers 0, 1, 2 or 3 and R9 denotes an amino, C1-4-alkylamino, di-(C1-4-alkyl)-amino, phenylamino, N-(C1-4-alkyl)-phenylamino, benzylamino, N-(C1-4-alkyl)-benzylamino or C1-4-alkoxy group, a 4- to 7-membered cycloalkyleneimino group, whilst in each case the methylene group in the 4 position of a 6- or 7-membered cycloalkyleneimino group may be replaced by an oxygen or sulphur atom, by a sulphinyl, sulphonyl, -NH, -N(C1-3-alkyl), -N(phenyl), -N(C1-3-alkyl-carbonyl) or -N(benzoyl) group, or, if n denotes one of the numbers 1, 2 or 3, it may also denote a hydrogen atom, a group of formula -N(R10)-(CH2)m-(CO)o-R11 ~~(III), wherein R10 denotes a hydrogen atom, a C1-3-alkyl group, a C1-3-alkylcarbonyl, arylcarbonyl, phenyl-C1-3-alkyl-carbonyl, C1-3-alkylsulphonyl, arylsulphonyl or phenyl-C1-3-alkylsulphonyl group, m denotes one of the numbers 1, 2, 3 or 4, o denotes the number 1 or, if m denotes one of the numbers 2, 3 or 4, o may also denote the number 0 and R11 denotes an amino, C1-4-alkylamino, di-(C1-4-alkyl)-amino, phenylamino, N-(C1-4-alkyl)-phenyl amino, benzylamino, N-(C1-4-alkyl)-benzylamino, C1-4-alkoxy or C1-3-alkoxy-C1-3-alkoxy group, a di-(C1-4-alkyl)-amino-C1-3-alkylamino group optionally substituted in the 1 position by a C1-3-alkyl group or a 4- to 7-membered cycloalkyleneimino group, wherein the cycloalkylene moiety may be fused to a phenyl ring or in each case the methylene group in the 4 position of a 6- or 7-membered cycloalkyleneimino group may be replaced by an oxygen or sulphur atom, by a sulphinyl, sulphonyl, -NH, -N(C1-3-alkyl), -N(phenyl), -N(C1-3-alkyl-carbonyl) or -N(benzoyl) group, a C4-7-cycloalkylamino, C4-7-cycloalkyl-C1-3-alkyl amino or C4-7-cycloalkenylamino group wherein position 1 of the ring is not involved in the double bond and wherein the abovementioned groups may each additionally be substituted at the amino-nitrogen atom by a C5-7-cycloalkyl, C2-4-alkenyl or C1-4-alkyl group, a 4- to 7-membered cycloalkyleneimino group, wherein the cycloalkylene moiety may be fused to a phenyl group or to an oxazolo, imidazolo, thiazolo, pyridino, pyrazino or pyrimidino group optionally substituted by a fluorine, chlorine, bromine or iodine atom, by a nitro, C1-3-alkyl, C1-3-alkoxy or amino group, and/or one or two hydrogen atoms may each be replaced by a C1-3-alkyl, C5-7-cycloalkyl or phenyl group and/or the methylene group in the 3 position of a 5-membered cycloalkyleneimino group may be substituted by a hydroxy, hydroxy-C1-3-alkyl, C1-3-alkoxy or C1-3-alkoxy-C1-3-alkyl group, the methylene group in the 3 or 4 position of a 6- or 7-membered cycloalkyleneimino group may in each case be substituted by a hydroxy, hydroxy-C1-3-alkyl, C1-3-alkoxy, C1-3-alkoxy-C1-3-alkyl, carboxy, C1-4-alkoxycarbonyl, aminocarbonyl, C1-3-alkylaminocarbonyl, di-(C1-3-alkyl)-aminocarbonyl, phenyl-C1-3-alkylamino or N-(C1-3-alkyl)-phenyl-C1-3-alkyl-amino group or may be replaced by an oxygen or sulphur atom, by a sulphinyl, sulphonyl, -NH, -N(C1-3-alkyl-), -N(phenyl), -N(phenyl-C1-3-alkyl-), -N(C1-3-alkyl-carbonyl-), -N(C1-4-hydroxy-carbonyl-), -N(C1-4-alkoxy-carbonyl-), -N(benzoyl-) or -N(phenyl-C1-3-alkyl-carbonyl-) group, wherein a methylene group linked to an imino-nitrogen atom of the cycloalkyleneimino group may be replaced by a carbonyl or sulphonyl group or in a 5-to 7-membered monocyclic cycloalkyleneimino group or a cycloalkyleneimino group fused to a phenyl group the two methylene groups linked to the imino-nitrogen atom may each be replaced by a carbonyl group, or R6 denotes a C1-4-alkyl group which is substituted by a carboxy, C1-3-alkoxycarbonyl, aminocarbonyl, C1-3-alkylaminocarbonyl or di-(C1-3-alkyl)-aminocarbonyl group or by a 4- to 7-membered cycloalkyleneiminocarbonyl group, 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, a group of formula -N(R12)-CO-(CH2)p-R13 ~~(IV).
wherein R12 denotes a hydrogen atom, a C1-6-alkyl or C3-7-cycloalkyl group or a C1-3-alkyl group terminally substituted by a phenyl, heteroaryl, trifluoromethyl, hydroxy, C1-3-alkoxy, aminocarbonyl, C1-4-alkylamino-carbonyl, di-(C1-4-alkyl)-amino-carbonyl, C1-3-alkyl-carbonyl, C1-3-alkyl-sulphonyl-amino, N-(C1-3-alkyl)-C1-3-alkyl-sulphonylamino, C1-3-alkyl-aminosulphonyl or di-(C1-3-alkyl)-aminosulphonyl group and p denotes one of the numbers 0, 1, 2 or 3 and R13 assumes the meanings of the abovementioned group R7, or, if p denotes one of the numbers 1, 2 or 3, it may also denote a hydrogen atom, a group of formula -N(R14)-(CH2)q-(CO)r-R15 ~~~(V), wherein R14 denotes a hydrogen atom, a C1-4-alkyl group, a C1-3-alkylcarbonyl, arylcarbonyl, phenyl-C1-3-alkylcarbonyl, heteroarylcarbonyl, heteroaryl-C1-3-alkylcarbonyl, C1-4-alkylsulphonyl, arylsulphonyl, phenyl-C1-3-alkylsulphonyl, heteroarylsulphonyl or heteroaryl-C1-3-alkyl-sulphonyl group, q denotes one of the numbers 1, 2, 3 or 4, r denotes the number 1 or, if q is one of the numbers 2, 3 or 4, it may also denote the number 0 and R15 assumes the meanings of the abovementioned group R7, a group of formula -N(R16)-SO2-R17 ~(VI), wherein R16 denotes a hydrogen atom or a C1-4-alkyl group optionally terminally substituted by a cyano, trifluoromethyl-carbonylamino or N-(C1-3-alkyl)-trifluoromethyl-carbonyl-amino group and R17 denotes a C1-3-alkyl group, an amino group substituted by a di-(C1-3-alkyl)-amino-C1-3-alkyl-carbonyl or di-(C1-3-alkyl)-amino-C1-3-alkyl-sulphonyl group and a di-(C1-3-alkyl)-aminocarbonyl-C1-3-alkyl group, or an N- (C1-3-alkyl) -C1-5-alkylsulphonylamino or N-(C1-3-alkyl)-phenylsulphonylamino group wherein the alkyl moiety is additionally substituted by a cyano or carboxy group, wherein all the single-bonded or fused phenyl groups contained in the groups mentioned under R6 may be mono- or disubstituted by fluorine, chlorine, bromine or iodine atoms, by C1-5-alkyl, trifluoromethyl, hydroxy, C1-3-alkoxy, carboxy, C1-3-alkoxycarbonyl, aminocarbonyl, C1-4-alkyl amino-carbonyl, di-(C1-4-alkyl)-amino-carbonyl, aminosulphonyl, C1-3-alkyl-aminosulphonyl, di-(C1-3-alkyl)-aminosulphonyl, C1-3-alkyl-sulphonylamino, nitro or cyano groups, wherein the substituents may be identical or different, or two adjacent hydrogen atoms of the phenyl groups may be replaced by a methylenedioxy group, and R5 denotes a hydrogen atom or a C1-3-alkyl group, wherein by an aryl group is meant a phenyl or naphthyl group optionally mono- or disubstituted by a fluorine, chlorine, bromine or iodine atom, by a cyano, trifluoromethyl, nitro, carboxy, aminocarbonyl, C1-3-alkyl or C1-3-alkoxy group and by a heteroaryl group is meant a monocyclic 5- or 6-membered heteroaryl group optionally substituted by a C1-3-alkyl group in the carbon skeleton, wherein the 6-membered heteroaryl group contains one, two or three nitrogen atoms and the 5-membered heteroaryl group contains an imino group optionally substituted by a C1-3-alkyl or phenyl-C1-3-alkyl group, an oxygen or sulphur atom or an imino group optionally substituted by a C1-3-alkyl or phenyl-C1-3-alkyl group or an oxygen or sulphur atom and additionally a nitrogen atom or an imino group optionally substituted by a C1-3-alkyl or phenyl-C1-3-alkyl group and two nitrogen atoms, and moreover a phenyl ring may be fused to the abovementioned monocyclic heterocyclic groups via two adjacent carbon atoms and the bonding takes place via a nitrogen atom or via a carbon atom of the heterocyclic moiety or a fused phenyl ring, some or all of the hydrogen atoms in the abovementioned alkyl and alkoxy groups or in the alkyl moieties contained in the above-defined groups of formula I may be replaced by fluorine atoms, and the hydrogen atom of any carboxy group present or a hydrogen atom bound to a nitrogen atom may each be replaced by a group which can be cleaved in vivo, the tautomers, the diastereomers, the enantiomers, the mixtures thereof and the salts thereof.

2. Indolinones of general formula I according to claim 1, wherein R1 and R3 are as hereinbefore defined and X denotes an oxygen atom, R2 denotes a carboxy group, a straight-chain or branched C1-6-alkoxy-carbonyl group, a C5-7-cycloalkoxycarbonyl or a phenoxycarbonyl group, a straight-chain or branched C1-3-alkoxy-carbonyl group, which is terminally substituted in the alkyl moiety by a phenyl, heteroaryl, carboxy, C1-3-alkoxycarbonyl, aminocarbonyl, C1-3-alkylaminocarbonyl or di-(C1-3-alkyl)-aminocarbonyl group, a straight-chain or branched C2-3-alkoxy-carbonyl group, which is terminally substituted in the alkyl moiety by a chlorine atom, by a hydroxy, C1-3-alkoxy, amino, C1-3-alkyl amino or di-(C1-3-alkyl)-amino group, an aminocarbonyl or methylaminocarbonyl group, an ethylaminocarbonyl group optionally substituted in the 2 position of the ethyl group by a hydroxy or C1-3-alkoxy group or, if R4 does not denote an aminosulphonyl-phenyl or N-(C1-5-alkyl)-C1-3-alkylaminocarbonyl-phenyl group, it may also denote a di-(C1-2-alkyl)-aminocarbonyl group, R4 denotes a C3-7-cycloalkyl group, whilst the methylene group in the 4 position of a 6- or 7-membered cycloalkyl group may be substituted by an amino, C1-3-alkyl amino or di-(C1-3-alkyl)-amino group or replaced by an -NH or -N(C1-3-alkyl) group, or a phenyl group substituted by the group R6, which may additionally be mono- or disubstituted by fluorine, chlorine or bromine atoms, by C1-3-alkyl, trifluoromethyl, hydroxy, C1-3-alkoxy, carboxy, C1-3-alkoxycarbonyl, amino, acetylamino, aminocarbonyl, C1-3-alkyl-aminocarbonyl, di-(C1-3-alkyl)-aminocarbonyl, nitro or cyano groups, wherein the substituents may be identical or different and wherein R6 denotes a hydrogen, fluorine, chlorine, bromine or iodine atom, a cyano, nitro, amino, C1-5-alkyl, C3-7-cycloalkyl, trifluoromethyl, phenyl, tetrazolyl or heteroaryl group, the group of formula wherein a hydrogen atom bound to the nitrogen atom may be replaced by a C1-3-alkyl group, a C1-3-alkoxy group, an amino-C2-3-alkoxy, C1-3-alkylamino-C2-3-alkoxy, di-(C1-3alkyl)-amino-C2-3-alkoxy, phenyl-C1-3-alkylamino-C2-3-alkoxy, N-(C1-3-alkyl)-phenyl-C1-3-alkylamino-C2-3-alkoxy, pyrrolidino-C2-3-alkoxy, piperidino-C2-3-alkoxy or C1-3-alkylmercapto group, a carboxy, C1-4-alkoxycarbonyl, aminocarbonyl, C1-3-alkyl-amino-carbonyl, phenyl-C1-3-alkylamino-carbonyl or N-(C1-3-alkyl)-phenyl-C1-3-alkylamino-carbonyl group, a C3-7-cycloalkyl-carbonyl group, wherein the methylene group in the 4 position of the 6- or 7-membered cycloalkyl moiety may be replaced by an -NH or -N(C1-3alkyl) group, a 4- to 7-membered cycloalkyleneimino group, wherein a methylene group linked to the imino group may be replaced by a carbonyl or sulphonyl group or one or two hydrogen atoms may each be replaced by a C1-3-alkyl group and/or in each case the methylene group in the 4 position of a 6-or 7-membered cycloalkyleneimino group may be substituted by a carboxy, C1-3-alkoxycarbonyl, aminocarbonyl, C1-3-alkylaminocarbonyl , di-(C1-3-alkyl)-aminocarbonyl, phenyl-C1-3-alkyl amino or N-(C1-3-alkyl)-phenyl-C1-3-alkyl amino group or may be replaced by an oxygen or sulphur atom, by a sulphinyl, sulphonyl, -NH or -N(C1-3-alkyl) group, a C1-4-alkyl group terminally substituted by the group R7, wherein R7 denotes a C5-7-cycloalkyl group, whilst the methylene group in the 4 position of a 6- or 7-membered cycloalkyl group may be replaced by an -NH
or -N(C1-3-alkyl) group or in a 5- to 7-membered cycloalkyl group a -(CH2)2 group may be replaced by a -CO-NH group, a -(CH2)3 group may be replaced by a -NH-CO-NH- or a -(CH2)4 group may be replaced by a -NH-CO-NH-CO group, whilst in each case a hydrogen atom bound to a nitrogen atom may be replaced by a C1-3-alkyl group, a phenyl or heteroaryl group, a hydroxy or C1-3-alkoxy group, an amino, C1-6-alkyl amino, di-(C1-6-alkyl)-amino, phenylamino, N-phenyl-C1-3-alkyl-amino, phenyl-C1-3-alkyl amino, N-(C1-3-alkyl)-phenyl-C1-3-alkylamino or di-(phenyl-C1-3-alkyl)-amino group, a .omega.-hydroxy-C2-3-alkyl-amino, N-(C1-3-alkyl)-.omega.-hydroxy--C2-3-alkyl-amino, di-(.omega.-hydroxy-C2-3-alkyl)-amino, di-(.omega.-(C1-3-alkoxy)-C2-3-alkyl)-amino or N-(dioxolan-2-yl)-C1-3-alkyl-amino group, a C1-3-alkyl carbonyl amino-C2-3-alkyl-amino or C1-3-alkylcarbonylamino-C2-3-alkyl-N-(C1-3-alkyl)-amino group, a C1-3-alkylsulphonylamino, N-(C1-3-alkyl)-C1-3-alkylsulphonylamino, C1-3-alkylsulphonylamino--C2-3-alkyl-amino or C1-3-alkylsulphonylamino-C2-3-alkyl--N-(C1-3-alkyl)-amino group, a hydroxycarbonyl-C1-3-alkylamino or N-(C1-3-alkyl)-hydroxycarbonyl-C1-3-alkyl-amino group a guanidino group wherein a hydrogen atom may be replaced by a C1-3-alkyl group, a group of formula -N (R8) -CO- (CH2) n-R9 (II) , wherein R8 denotes a hydrogen atom or a C1-3-alkyl group, n denotes one of the numbers 0, 1, 2 or 3 and R9 denotes an amino, C1-3-alkyl amino, di-(C1-3-alkyl)-amino, phenylamino, benzylamino or C1-4-alkoxy group, a 5- to 7-membered cycloalkyleneimino group, wherein the methylene group in position 4 of the piperidino group may be replaced by an oxygen or sulphur atom, by an -NH, -N(C1-3-alkyl), -N(phenyl), -N(C1-3-alkyl-carbonyl) or -N(benzoyl) group, or, if n denotes one of the numbers 1, 2 or 3, it may also denote a hydrogen atom, a group of formula -N(R10)-(CH2)m-(CO)o-R11 (III), wherein R10 denotes a hydrogen atom, a C1-3-alkyl group, a C1-3-alkylcarbonyl or C1-3-alkylsulphonyl group, m denotes one of the numbers 1, 2 or 3, o denotes the number 1 or, if m is one of the numbers 2 or 3, o may also denote the number 0 and R11 denotes an amino, C1-3-alkyl amino, di-(C1-3-alkyl)-amino, C1-4-alkoxy or C1-3-alkoxy-C1-3-alkoxy group or a 5- to 7-membered cycloalkyleneimino group, wherein the methylene group in position 4 of the piperidino group may be replaced by an oxygen or sulphur atom, by an -NH, -N(C1-3-alkyl), -N (phenyl), -N(C1-3-alkyl-carbonyl) or -N(benzoyl) group, a C4-7-cycloalkylamino or C4-7-cycloalkenylamino group wherein position 1 of the ring is not involved in the double bond, a 4- to 7-membered cycloalkyleneimino group, wherein the cycloalkylene moiety may be fused to a phenyl group or one or two hydrogen atoms may each be replaced by a C1-3-alkyl group and/or the methylene group in position 3 of the pyrrolidino group may be substituted by a hydroxy or C1-3-alkoxy group, in each case the methylene group in the 4 position of a 6- or 7-membered cycloalkyleneimino group may be substituted by a hydroxy, hydroxy-C1-3-alkyl, C1-3-alkoxy, carboxy, C1-3-alkoxycarbonyl, aminocarbonyl, C1-3-alkylaminocarbonyl, di-(C1-3-alkyl)-aminocarbonyl, phenyl-C1-3-alkyl amino or N-(C1-3-alkyl)-phenyl-C1-3-alkyl-amino group or may be replaced by an oxygen or sulphur atom, by a sulphinyl, sulphonyl, -NH, -N(C1-3-alkyl), -N(phenyl), -N(phenyl-C1-3-alkyl), -N(C1-3-alkyl-carbonyl), -N(C1-4-alkoxy-carbonyl), -N(benzoyl) or -N (phenyl-C1-3-alkyl-carbonyl) group, wherein a methylene group linked to an imino-nitrogen atom of the cycloalkyleneimino group may be replaced by a carbonyl or sulphonyl group or in a 5-to 6-membered monocyclic cycloalkyleneimino group or a cycloalkyleneimino group fused to a phenyl group the two methylene groups linked to the imino-nitrogen atom may each be replaced by a carbonyl group, or R6 denotes a C1-4-alkyl group which is terminally substituted by a carboxy, C1-3-alkoxycarbonyl, aminocarbonyl, C1-3-alkylaminocarbonyl or di-(C1-3-alkyl)-aminocarbonyl group or by a 4- to 7-membered cycloalkyleneiminocarbonyl group, a group of formula -N(R12)-CO-(CH2)p-R13 (IV), wherein R12 denotes a hydrogen atom, a C1-3-alkyl, C5-7-cycloalkyl, phenyl-C1-3-alkyl or heteroaryl-C1-3-alkyl group and p denotes one of the numbers 0, 1, 2 or 3 and R13 assumes the meanings of the abovementioned group R7, or, if p denotes one of the numbers 1, 2 or 3, it may also denote a hydrogen atom, a group of formula -N(R14) - (CH2) q- (CO) r-R15 (V), wherein R14 denotes a hydrogen atom, a C1-4-alkyl group, a C1-3-alkylcarbonyl, phenylcarbonyl, phenyl-C1-3-alkyl-carbonyl, heteroarylcarbonyl, heteroaryl-C1-3-alkylcarbonyl, C1-4-alkylsulphonyl, phenylsulphonyl, phenyl-C1-3-alkylsulphonyl-heteroarylsulphonyl or heteroaryl-C1-3-alkyl-sulphonyl group, q denotes one of the numbers 1, 2, 3 or 4, r denotes the number 1 or, if q is one of the numbers 2, 3 or 4, it may also denote the number 0 and R15 assumes the meanings of the abovementioned group R7, a group of formula -N(R16)-SO2-R17 (VI), wherein R16 denotes a hydrogen atom or a C1-4-alkyl group optionally terminally substituted by a cyano, trifluoromethyl-carbonylamino or N- (C1-3-alkyl) -trifluoromethyl--carbonyl-amino group and R17 denotes a C1-3-alkyl group, an amino group substituted by a di-(C1-3-alkyl)-amino-C1-3-alkyl-carbonyl or di-(C1-3-alkyl)-amino-C1-3-alkyl-sulphonyl group and a di-(C1-3-alkyl)-aminocarbonyl-C1-3-alkyl group, wherein all the single-bonded or fused phenyl groups contained in the groups mentioned under R6 may be mono-or disubstituted by fluorine, chlorine or bromine atoms, by C1-3-alkyl, trifluoromethyl, hydroxy, C1-3-alkoxy, carboxy, C1-3-alkoxycarbonyl, aminocarbonyl, C1-3-alkyl-aminocarbonyl, aminosulphonyl, C1-3-alkyl-aminosulphonyl, nitro or cyano groups, wherein the substituents may be identical or different, or two adjacent hydrogen atoms of the phenyl groups may be replaced by a methylenedioxy group, and R5 denotes a hydrogen atom or a C1-3-alkyl group, whilst by a heteroaryl group as mentioned above is meant a pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrrolyl, furyl, thienyl, oxazolyl, thiazolyl, pyrazolyl, imidazolyl or triazolyl group optionally substituted in the carbon skeleton by a C1-3-alkyl group wherein a hydrogen atom bound to a nitrogen atom may be replaced by a C1-3-alkyl or phenyl-C1-3-alkyl group and wherein the 5-membered heteroaryl groups containing at least one imino group are bound via a carbon or nitrogen atom, a hydrogen atom bound to a nitrogen atom in the abovementioned groups may be replaced by a group which can be cleaved in vivo, the carboxy groups contained in the abovementioned groups may each be substituted by a group which can be cleaved in vivo, some or all of the hydrogen atoms in the abovementioned alkyl and alkoxy groups or in the alkyl moieties contained in the above-defined groups of formula I may be replaced by fluorine atoms and the tautomers, the diastereomers, the enantiomers, the mixtures thereof and the salts thereof.
3. Indolinones of general formula I according to claim 1, wherein X denotes an oxygen atom, R1 denotes a hydrogen atom, R2 denotes a carboxy group, a straight-chain or branched C1-4-alkoxycarbonyl group or a phenoxycarbonyl group, a straight-chain or branched C1-3-alkoxy-carbonyl group, which is terminally substituted in the alkyl moiety by a phenyl, carboxy, C1-3-alkoxycarbonyl, aminocarbonyl, C1-3-alkylaminocarbonyl or di- (C1-3-alkyl)-aminocarbonyl group, a straight-chain or branched C2-3-alkoxy-carbonyl group which is terminally substituted in the alkyl moiety by a hydroxy, C1-3-alkoxy, amino, C1-3-alkylamino or di-(C1-3-alkyl)-amino group, an aminocarbonyl or methylaminocarbonyl group, an ethylaminocarbonyl group optionally substituted in the 2 position of the ethyl group by a hydroxy or C1-3-alkoxy group or, if R4 does not denote an aminosulphonyl-phenyl or N- (C1-5-alkyl) -C1-3-alkylaminocarbonyl-phenyl group, it may also denote a di-(C1-2-alkyl)-aminocarbonyl group, R3 denotes a C1-4-alkyl group or a phenyl group which may be substituted by a fluorine, chlorine or bromine atom, by a trifluoromethyl, C1-3-alkyl, hydroxy or C1-3-alkoxy group, R4 denotes a C5-6-cycloalkyl group, wherein the methylene group in position 4 of the cyclohexyl group may be substituted by an amino, C1-3-alkyl amino or di-(C1-3-alkyl)-amino group or replaced by an -NH or -N(C1-3-alkyl) group, a phenyl group, a phenyl group disubstituted by C1-3-alkyl, C1-3-alkoxy or nitro groups, wherein the substituents may be identical or different, or a phenyl group substituted by the group R6, which may additionally be substituted by a fluorine, chlorine or bromine atom or by an amino or nitro group, wherein R6 denotes a fluorine, chlorine or bromine atom, a C1-3-alkyl, C1-3-alkoxy, nitro, amino or C5-6-cycloalkyl group, a pyrrolyl, pyrazolyl, imidazolyl, triazolyl or tetrazolyl group bound via a carbon atom, wherein the abovementioned heteroaromatic groups in the carbon skeleton may be substituted by a C1-3-alkyl group or a hydrogen atom bound to a nitrogen atom may be replaced by a C1-3-alkyl or phenyl-C1-3-alkyl group, the group of formula a carboxy, C1-4-alkoxycarbonyl, phenyl-C1-3-alkylamino-carbonyl or C5-7-cycloalkyl-carbonyl group, a 5 or 6-membered cycloalkyleneimino group, wherein the methylene group in position 4 of the piperidino group may be replaced by an oxygen or sulphur atom, by an -NH or -N(C1-3-alkyl) group, an unbranched C1-3-alkyl group terminally substituted by the group R7, wherein R7 denotes a C5-7-cycloalkyl group, wherein in a 5 or 6-membered cycloalkyl group a -(CH2)2 group may be replaced by a -CO-NH group, a -(CH2)3 group may be replaced by an -NH-CO-NH- or a -(CH2)4 group may be replaced by an -NH-CO-NH-CO group, whilst in each case a hydrogen atom bound to a nitrogen atom may be replaced by a C1-3-alkyl group, a phenyl or pyridinyl group or a pyrrolyl, pyrazolyl, imidazolyl or triazolyl group bound via a carbon or nitrogen atom, wherein the abovementioned heteroaromatic groups in the carbon skeleton may be substituted by a C1-3-alkyl group or a hydrogen atom bound to a nitrogen atom may be replaced by a C1-3-alkyl group, a hydroxy or C1-3-alkoxy group, an amino, C1-6-alkyl amino, di- (C1-6-alkyl) -amino, phenylamino, N-phenyl-C1-3-alkylamino, phenyl-C1-3-alkylamino or N- (C1-3-alkyl) -phenyl-C1-3-alkyl amino group, a .omega.-hydroxy-C2-3-alkyl-amino, N- (C1-3-alkyl) -.omega.-hydroxy-C2-3-alkylamino, di- (.omega.-hydroxy-C2-3-alkyl) -amino or di- (.omega.- (C1-3-alkoxy) -C2-3-alkyl) -amino group, a C1-3-alkylcarbonylamino-C2-3-alkyl-amino or C1-3-alkylcarbonylamino-C2-3-alkyl-N-(C1-3-alkyl)-amino group, a C1-3-alkylsulphonylamino, N-(C1-3-alkyl)-C1-3-alkylsulphonylamino, C1-3-alkylsulphonylamino--C2-3-alkylamino or C1-3-alkylsulphonylamino--C2-3-alkyl-N-(C1-3-alkyl)-amino group, a hydroxycarbonyl-C1-3-alkylamino or N-(C1-3-alkyl)-hydroxycarbonyl-C1-3-alkyl-amino group, a guanidino group wherein a hydrogen atom may be replaced by a C1-3-alkyl group, a group of formula -N(R8)-CO-(CH2)n-R9 (II), wherein R8 denotes a hydrogen atom or a C1-3-alkyl group, n denotes one of the numbers 0, 1, 2 or 3 and R9 denotes an amino, C1-3-alkylamino, di-(C1-3-alkyl)-amino or C1-4-alkoxy group, a 5- or 6-membered cycloalkyleneimino group, wherein the methylene group in position 4 of the piperidino group may be replaced by an -NH, -N(C1-3-alkyl) or -N(C1-3-alkyl-carbonyl) group, or, if n denotes one of the numbers 1, 2 or 3, R9 may also denote a hydrogen atom, a group of formula -N(R10)-(CH2)m-(CO)o -R11 (III), wherein R10 denotes a hydrogen atom or a C1-3-alkyl group, m denotes one of the numbers 1, 2 or 3, o denotes the number 1 or, if m is one of the numbers 2 or 3, o may also denote the number 0 and R11 denotes an amino, C1-3-alkylamino, di-(C1-3-alkyl)-amino, C1-4-alkoxy or methoxy-C1-3-alkoxy group or a 5- or 6-membered cycloalkyleneimino group, wherein the methylene group in position 4 of the piperidino group may be replaced by an -NH, -N(C1-3-alkyl) or -N(C1-3-alkyl-carbonyl) group, an azetidino, pyrrolidino, piperidino, 2,6-dimethyl-piperidino, 3,5-dimethyl-piperidino or azepino group, wherein the methylene group in position 3 of the pyrrolidino group may be substituted by a hydroxy group, the methylene group in position 4 of the piperidino group may be substituted by a hydroxy, hydroxy-C1-3-alkyl or C1-3-alkoxy group or may be replaced by an oxygen or sulphur atom, by a sulphinyl, sulphonyl, -NH, -N (C1-3-alkyl), -N(C1-3-alkyl-carbonyl), -N(benzoyl) or -N(phenyl-C1-3-alkyl-carbonyl) group, wherein a methylene group linked to an imino-nitrogen atom of the pyrrolidino, piperidino or piperazino group may be replaced by a carbonyl group, or R6 denotes a straight-chain C1-3-alkyl group which is terminally substituted by a carboxy or C1-3-alkoxy-carbonyl group, a group of formula -N(R12)-CO-(CH2)p-R13 (IV), wherein R12 denotes a hydrogen atom, a C1-3-alkyl or phenyl-C1-3-alkyl group, p denotes one of the numbers 0, 1 or 2 and R13 denotes an amino, C1-4-alkylamino, di-(C1-4-alkyl)-amino, benzylamino, N-(C1-3-alkyl)-benzylamino, C1-3-alkoxy-C1-3-alkylamino, N-(C1-3-alkyl)-C1-3-alkoxy-C1-3-alkylamino, di-(2-methoxy-ethyl)-amino, di-(.omega.-hydroxy-C2-3-alkyl)-amino or aminocarbonyl-methyl-N-(methyl)-amino group, a pyrrolyl, pyrazolyl or imidazolyl group bound via a nitrogen atom and optionally substituted by a C1-3-alkyl group, a pyrrolidino, piperidino, morpholino, thiomorpholino or a piperazino group optionally substituted in the 4 position by a C1-3-alkyl, phenyl-C1-3-alkyl, C1-3-alkylcarbonyl or C1-4-alkoxycarbonyl group or, if n denotes the number 1 or 2, it may also denote a hydrogen atom, a group of formula -N(R14)-(CH2)q-(CO)r-R15 (V), wherein R14 denotes a hydrogen atom, a C1-4-alkyl, C1-3-alkyl-carbonyl, phenylcarbonyl, phenyl-C1-3-alkylcarbonyl, furyl-carbonyl, pyridinyl-carbonyl, furyl-C1-3-alkylcarbonyl, pyridinyl-C1-3-alkylcarbonyl, C1-4-alkylsulphonyl, phenylsulphonyl or phenyl-C1-3-alkylsulphonyl group, q denotes one of the numbers 1, 2 or 3, r denotes the number 1 or, if q is one of the numbers 2 or 3, it may also denote the number 0 and R15 denotes an amino, C1-4-alkylamino, di-(C1-4-alkyl)-amino, phenylamino, N-(C1-4-alkyl)-phenylamino, benzylamino or N-(C1-4-alkyl)-benzylamino group, or a group of formula -N(R16)-SO2-R17 (VI), wherein R16 denotes a hydrogen atom or a C1-3-alkyl group optionally terminally substituted by a cyano, trifluoromethyl-carbonylamino or N-(C1-3-alkyl)-trifluoromethyl-carbonyl-amino group and R17 denotes a C1-3-alkyl group, wherein all the single-bonded or fused phenyl groups contained in the groups mentioned under R6 may be substituted by a fluorine, chlorine or bromine atom, by a methyl, trifluoromethyl, methoxy, nitro or cyano group and R5 denotes a hydrogen atom, wherein a hydrogen atom bound to a nitrogen atom in the abovementioned groups may be replaced by an acetyl or tert.butoxycarbonyl group, the carboxy groups contained in the abovementioned groups may also be present in the form of the tert.butoxycarbonyl precursor group, the tautomers, the diastereomers, the enantiomers, the mixtures thereof and the salts thereof.
4. Indolinones of general formula I according to claim 1, wherein X denotes an oxygen atom, R1 and R5 each denote a hydrogen atom, R2 denotes a methoxycarbonyl, ethoxycarbonyl or aminocarbonyl group, R3 denotes a phenyl group and R4 denotes a phenyl group monosubstituted by the group R6, wherein R6 denotes an N-methyl-imidazol-2-yl group, an unbranched C1-3-alkyl group which is terminally substituted by a C1-4-alkylamino, di-(C1-4-alkyl)-amino, piperidino or 2,6-dimethyl-piperidino group, a group of formula -N(R12)-CO-(CH2)p-R13 (IV), wherein R12 denotes a C1-3-alkyl group, p denotes one of the numbers 1 or 2 and R13 denotes a di-(C1-3-alkyl)-amino group, or a group of formula -N(R14)-(CH2)q-(CO)r-R15 (V), wherein R14 denotes a C1-3-alkyl-carbonyl or C1-3-alkylsulphonyl group, q denotes one of the numbers 1, 2 or 3, r denotes the number 1 or, if q is one of the numbers 2 or 3, r may also denote the number 0 and R15 denotes a di-(C1-3-alkyl)-amino group, the tautomers, the diastereomers, the enantiomers, the mixtures thereof and the salts thereof.
5. The following substituted indolinones of general formula I
according to claim 1:
(a) 3-Z-[1-(4-(piperidin-1-yl-methyl)-anilino)-1-phenyl-methylene]-6-ethoxycarbonyl-2-indolinone, (b) 3-Z-[(1-(4-(piperidin-1-yl-methyl)-anilino)-1-phenyl-methylene]-6-carbamoyl-2-indolinone, (c) 3-Z-[1-(4-(piperidin-1-yl-methyl)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone, (d) 3-Z-[1-(4-(dimethylaminomethyl)-anilino)-1-phenyl-methylene]-6-ethoxycarbonyl-2-indolinone, (e) 3-Z-[1-(4-((2,6-dimethyl-piperidin-1-yl)-methyl)-anilino)-1-phenyl-methylene]-6-ethoxycarbonyl-2-indolinone, (f) 3-Z-[1-(4-(N-(2-dimethylamino-ethyl)-N-acetyl-amino)-ani-lino)-1-phenyl-methylene]-6-ethoxycarbonyl-2-indolinone, (g) 3-Z-[1-(4-(N-(3-dimethylamino-propyl)-N-acetyl-amino)-ani-lino)-1-phenyl-methylene]-6-ethoxycarbonyl-2-indolinone, (h) 3-Z-[1-(4-(N-(2-dimethylamino-ethyl)-N-methylsulphonyl-amino)-anilino)-1-phenyl-methylene]-6-ethoxycarbonyl-2-indolinone, (i) 3-Z-[1-(4-(dimethylaminomethyl)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone, (j) 3-Z-[1-(4-(N-acetyl-N-dimethylaminocarbonylmethyl-amino)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone, (k) 3-Z-[1-(4-ethylaminomethyl-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone, (l) 3-Z-[1-(4-(1-methyl-imidazol-2-yl)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone, (m) 3-Z-[1-(4-(N-dimethylaminomethylcarbonyl-N-methyl-amino)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone, (n) 3-Z-[1-(4-(N-(2-dimethylamino-ethyl)-N-methylsulphonyl-amino)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone, (o) 3-Z-[1-(4-(N-(3-dimethylamino-propyl)-N-methylsulphonyl-amino)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone, (p) 3-Z-[1-(4-(N-dimethylaminocarbonylmethyl-N-methylsulphonyl-amino)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone, (q) 3-Z-[1-(4-(N-((2-dimethylamino-ethyl)-carbonyl)-N-methyl-amino)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone, (r) 3-Z-[1-(4-(N-(2-dimethylamino-ethyl)-N-acetyl-amino)-ani-lino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone and (s) 3-Z-[1-(4-methylaminomethyl-anilino)-1-phenyl-methylene]-
6-methoxycarbonyl-2-indolinone, the tautomers, the mixtures and the salts thereof.
6. Physiologically acceptable salts of the compounds according to claims 1 to 5.
7. Pharmaceutical compositions containing a compound according to at least one of claims 1 to 5 or a salt according to claim 6 optionally together with one or more inert carriers and/or diluents.
8. Use of a compound according to at least one of claims 1 to or a salt according to claim 6 for preparing a pharmaceutical composition which is suitable for treating excessive or anomalous cell proliferation.
9. Process for preparing a pharmaceutical composition according to claim 7, characterised in that a compound according to at least one of claims 1 to 5 or a salt according to claim 6 is incorporated in one or more inert carriers and/or diluents by a non-chemical method.
10. Process for preparing the compounds according to claims 1 to 6, characterised in that a. a compound of general formula wherein X and R3 are defined as in claims 1 to 5, R2' has the meanings given for R2 in claims 1 to 5, R18 denotes a hydrogen atom or a protecting group for the nitrogen atom of the lactam group, wherein one of the groups R2' and R18 may also denote a bond to a solid phase optionally formed via a spacer and the other one of the groups R2' and R18 has the abovementioned meanings, and Z1 denotes a halogen atom, a hydroxy, alkoxy or aryl-alkoxy group, is reacted with an amine of general formula wherein R4 and R5 are defined as in claims 1 to 5, and subsequently, if required, any protecting group used for the nitrogen atom of the lactam group is cleaved or a compound thus obtained is cleaved from a solid phase, or b. in order to prepare a compound of general formula I wherein R2 has the meanings given in claims 1 to 5, with the exception of the carboxy group, a compound of general formula wherein R1 and R3 to R5 are defined as in claims 1 to 5, or a reactive derivative thereof, is reacted with a compound of general formula H - R19 (X), wherein R19 denotes a C1-6-alkanol, a C4-7-cycloalkanol or an aromatic alcohol, a C1-6-alkanol which is terminally substituted in the alkyl moiety by a phenyl, heteroaryl, carboxy, C1-3-alkoxy-carbonyl, aminocarbonyl, C1-3-alkylamino-carbonyl or di-(C1-3-alkyl)-aminocarbonyl group, a C2-6-alkanol which is terminally substituted in the alkyl moiety by a chlorine atom or a hydroxy, C1-3-alkoxy, amino, C1-3-alkylamino or di-(C1-3-alkyl)-amino group, an amino or methylamino group, an ethylamino group optionally substituted in the 2 position of the ethyl group by a hydroxy or C1-3-alkoxy group or a di-(C1-2-alkyl)-amino group, or c. in order to prepare a compound of general formula I, wherein R4 denotes a C1-4-alkyl group substituted by the group R7, wherein R7 denotes an amino, C1-7-alkyl amino, di-(C1-7-alkyl)-amino, phenylamino, N-phenyl-C1-3-alkyl-amino, phenyl-C1-3-alkyl-amino, N-(C1-3-alkyl)-phenyl-C1-3-alkylamino or di-(phenyl-C1-3-alkyl)-amino group, a .omega.-hydroxy-C2-3-alkyl-amino, N-(C1-3-alkyl)-.omega.-hydroxy-C2-3-alkyl-amino, di-(.omega.-hydroxy-C2-3-alkyl)-amino, di-(.omega.-(C1-3-alkoxy)-C2-3-alkyl)-amino or N-(dioxolan-2-yl)-C1-3-alkyl-amino group, a C1-3-alkylcarbonylamino-C2-3-alkyl-amino or C1-3-alkylcarbonylamino-C2-3-alkyl-N-(C1-3-alkyl)-amino group, a C1-3-alkylsulphonylamino, N-(C1-3-alkyl)-C1-3-alkylsulphonylamino, C1-3-alkylsulphonylamino-C2-3-alkyl-amino or C1-3-alkylsulphonylamino-C2-3-alkyl-N-(C1-3-alkyl)-amino group, a group of formula -N(R10)-(CH2)m-(CO)o-R11 (III), wherein R10 denotes a hydrogen atom, a C1-3-alkyl group, a C1-3-alkylcarbonyl, arylcarbonyl, phenyl-C1-3-alkyl-carbonyl, C1-3-alkylsulphonyl, arylsulphonyl or phenyl-C1-3-alkylsulphonyl group, m denotes one of the numbers 1, 2, 3 or 4, o denotes the number 1 and R11 denotes an amino, C1-4-alkylamino, di-(C1-4-alkyl)-amino, phenylamino, N-(C1-4-alkyl)-phenylamino, benzylamino, N-(C1-4-alkyl)-benzylamino, C1-4-alkoxy or C1-3-alkoxy-C1-3-alkoxy group, a di-(C1-4-alkyl)-amino-C1-3-alkylamino group optionally substituted in the 1 position by a C1-3-alkyl group, or a 4- to 7-membered cycloalkyleneimino group, wherein the cycloalkylene moiety may be fused to a phenyl ring or in each case the methylene group in the 4 position of a 6- or 7-membered cycloalkyleneimino group may be replaced by an oxygen or sulphur atom, by a sulphinyl, sulphonyl, -NH, -N(C1-3-alkyl), -N(phenyl), -N(C1-3-alkyl-carbonyl) or -N(benzoyl) group, a C4-7-cycloalkylamino, C4-7-cycloalkyl-C1-3-alkylamino or C4-7-cycloalkenylamino group wherein position 1 of the ring is not involved in the double bond and wherein the abovementioned groups may each additionally be substituted at the amino-nitrogen atom by a C5-7-cycloalkyl, C2-4-alkenyl or C1-4-alkyl group, or a 4- to 7-membered cycloalkyleneimino group, wherein the cycloalkylene moiety may be fused to a phenyl group or to an oxazolo, imidazolo, thiazolo, pyridino, pyrazino or pyrimidino group optionally substituted by a fluorine, chlorine, bromine or iodine atom, by a nitro, C1-3-alkyl, C1-3-alkoxy or amino group, and/or one or two hydrogen atoms may each be replaced by a C1-3-alkyl, C5-7-cycloalkyl or phenyl group and/or the methylene group in the 3 position of a 5-membered cycloalkyleneimino group may be substituted by a hydroxy, hydroxy-C1-3-alkyl, C1-3-alkoxy or C1-3-alkoxy-C1-3-alkyl group, in each case the methylene group in the 3 or 4 position of a 6- or 7-membered cycloalkyleneimino group may be substituted by a hydroxy, hydroxy-C1-3-alkyl, C1-3-alkoxy, C1-3-alkoxy-C1-3-alkyl, C1-4-alkoxycarbonyl, aminocarbonyl, C1-3-alkylaminocarbonyl, di-(C1-3-alkyl)-aminocarbonyl, phenyl-C1-3-alkyl amino or N-(C1-3-alkyl)-phenyl-C1-3-alkylamino group or may be replaced by an oxygen or sulphur atom, by a sulphinyl, sulphonyl, -NH, -N(C1-3-alkyl-), -N(phenyl), -N(phenyl-C1-3-alkyl-), -N(C1-3-alkyl-carbonyl-), -N(C1-4-alkoxy-carbonyl-), -N(benzoyl-) or -N(phenyl-C1-3-alkyl-carbonyl-) group, wherein a methylene group linked to an imino-nitrogen atom of the cycloalkyleneimino group may be replaced by a carbonyl or sulphonyl group or in a 5-to 7-membered monocyclic cycloalkyleneimino group or a cycloalkyleneimino group fused to a phenyl group the two methylene groups linked to the imino-nitrogen atom may each be replaced by a carbonyl group, a compound of general formula wherein R3, R5 and X are defined as in claims 1 to 5, R2' has the meanings given for R2 in claims 1 to 5, R18 denotes a hydrogen atom or a protecting group for the nitrogen atom of the lactam group, wherein one of the groups R2' and R18 may also denote a bond to a solid phase optionally formed via a spacer and the other one of the groups R2' and R18 has the abovementioned meanings, A denotes a C1-4-alkyl group and Z2 denotes a leaving group, is reacted with an amine of general formula H~R7, (XII), wherein R7, has the meanings given for R7 hereinbefore, and subsequently, if necessary, any protecting group used for the nitrogen atom of the lactam group is cleaved, or a compound thus obtained is cleaved from a solid phase, and subsequently, if desired, a compound of general formula I thus obtained which contains an alkoxycarbonyl group is converted by hydrolysis into a corresponding carboxy compound, or a compound of general formula I thus obtained which contains an amino or alkylamino group is converted by reductive alkylation into a corresponding alkylamino or dialkylamino compound, or a compound of general formula I thus obtained which contains an amino or alkylamino group is converted by acylation or sulphonation into a corresponding aryl or sulphonyl compound or a compound of general formula I thus obtained which contains a carboxy group is converted by esterification or amidation into a corresponding ester or aminocarbonyl compound or a compound of general formula I thus obtained which contains a cycloalkyleneimino group wherein a methylene group is replaced by a sulphur atom is converted by oxidation into a corresponding sulphinyl or sulphonyl compound, or a compound of general formula I thus obtained which contains a nitro group is converted by reduction into a corresponding amino compound, or a compound of general formula I thus obtained wherein R4 denotes a phenyl group substituted by an amino, alkylamino, aminoalkyl or N-alkyl-amino group is converted, by reaction with a corresponding cyanate, isocyanate or carbamoyl halide, into a corresponding urea compound of general formula I or a compound of general formula I thus obtained wherein R4 denotes a phenyl group substituted by an amino, alkylamino, aminoalkyl or N-alkyl-amino group is converted, by reaction with a corresponding compound which transfers the amidino group or by reaction with a corresponding nitrile, into a corresponding guanidino compound of general formula I, or if necessary any protecting group used during the reactions to protect reactive groups is cleaved or subsequently, if desired, a compound of general formula I thus obtained is resolved into the stereoisomers thereof or a compound of general formula I thus obtained is converted into the salts thereof, particularly, for pharmaceutical use, into the physiologically acceptable salts thereof with an inorganic or organic acid or base.
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