Title of Invention

NOVEL INDOLINONE COMPOUNDS HAVING AN INHIBITING EFFECT ON KINASES AND CYCLINE/CDK COMPLEXES

Abstract

The present invention relates to indolinone compounds of general formula wherein R1 to R5 and X are defined as claim 1, the isomers thereof and the salts thereof, particularly the physiologically acceptable salts thereof which have valuable pharmacological properties, particularly an inhibitory effect on various kinases and cycline/CDK complexes and on the proliferation of various tumour cells, and processes for preparing them.

Full Text

FORM 2 THE PATENTS ACT 1970 [39 OF 1970] & THE PATENTS RULES, 2003 COMPLETE SPECIFICATION [See Section 10; rule 13] NOVEL INDOLINONE COMPOUNDS HAVING AN INHIBITING EFFECT ON KINASES AND CYCLINE/CDK COMPLEXES" BOEHRINGER INGELHEIN PHARMA GMBH 6B CO. KG, a German company of Binger Strasse 173, D-55216 Ingelheim am Rhein, Germany, The following specification particularly describes the invention and the manner in which it is to be performed: This invention relates to novel indolinone compounds having an inhibiting effect on kinases and cycline/cdk complexes. The present invention relates to new substituted indolinones of general formula the isomers thereof, the salts thereof.,.particularly the physiologically acceptable salts thereof which have valuable properties. The above compounds of general formula I wherein Rx denotes a hydrogen atom or a prodrug 'group have valuable pharmacological properties, particularly an inhibiting effect on various kinases, especially complexes of CDKS (CDK1, CDK2, CDK3, CDK4, CDK6, CDK7, CDK8 and CDK9) with their specific cyclines (A, Bl, B2, C, Dl, D2, D3, E, F, Gl, G2, H, I and K) and on viral cycline (cf. L. Mengtao in J. Virology 21(3), 1984-1991 (1997)), and the other compounds of the above general formula I wherein R1 does not represent a hydrogen atom or a prodrug group are valuable intermediate products for preparing the abovementioned compounds. Thus, the present invention relates to the above compounds of general formula I (the compounds wherein R1 denotes a hydrogen atom or a prodrug group having valuable pharmacological properties) , the pharmaceutical compositions containing the pharmacologically active compounds, their use and processes for preparing them. In the above general formula I X denotes an oxygen or sulphur atom, R1 denotes a hydrogen atom, a C1-4-alkoxy-carbonyl or C2-4-alkanoyl 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 substitutents may be identical or different, R3 denotes a phenyl or naphthyl group which may be substituted by fluorine, chlorine or bromine atoms, by C1-3-alkyl, C1-3-alkoxy, cyano, trifluoromethyl, nitro, amino, C1_3-alkylamino, di-(C1-3-alkyl) -amino, C2-4-alkanoyl-amino, N-(C1-3-alkyl)-c2-4-alkanoylamino, N-(C1-3-alkyl)-C2-4-alkanoylamino c1-3-alkylsulphonylamino, amino-C1-3-alkyl, C1-3-alkylamino-C1-3-alkyl, di- (C1-3-alkyl) -amino-C1-3-alkyl, N- (C2-4-alkanoyl) -amino-C1-3-alky1 or N-(C2-4-alkanoyl)-c1-3-alkylamino-C1-3-alkyl groups and the substituents may be identical or different, R4 denotes a hydrogen atom or a C1-3-alkyl group and R5 denotes a hydrogen atom, a C1-5-alkyl group optionally substituted by a phenyl, carboxy or C1-3-alkoxy-carbonyl group, a C3-7-cycloalkyl group optionally substituted by a C1-3-alkyl group, an indanyl group optionally substituted by a C1-3-alkyl group, a 5-membered heteroaryl group which contains an imino group optionally substituted by a C1-3-alkyl group, an oxygen or sulphur atom or an imino group optionally substituted by a C1-3-alkyl group and an oxygen, sulphur or nitrogen atom or two nitrogen atoms or a 6-membered heteroaryl group which contains 1 to 3 nitrogen atoms, whilst additionally a 1,3-butadienylene bridge may be attached via two adjacent carbon atoms or via one carbon atom and an adjacent imino group of the abovementioned 5-and 6-membered heteroaryl groups and the carbon skeleton of the abovementioned mono- and bicyclic rings may be mono or disubstituted by fluorine, chlorine, bromine or iodine atoms, by C1-5-alkyl or cyano groups and the substituents may be identical or different, a pyrrolidinyl or piperidinyl group linked via a carbon atom, which may be substituted at the nitrogen atom by a C1-3-alkyl group, a phenyl group optionally(mono or disubstituted by \ fluorine, chlorine, bromine or iodine atoms, by C1-3-alkyl or cyano groups, whilst the substituents may be identical or different, a phenyl, pyridyl, pyrimidyl or thienyl group each of which is substituted by a C3-7cycloalkyl, C1-3-alkoxy, phenyl-C1-3-alkoxy, carboxy-C1-3-alkyl, C1-3-alkoxy-carbonyl-C1-3-alkyl, carboxy, C1-3-alkoxycarbonyl, aminocarbonyl, C1-3-alkylaminocarbonyl, di- (C1-3-alkyl) -aminocarbonyl, nitro, amino, C1-3-alkylamino, di-(C1-3alkyl)-amino, C2-4-alkanoyl-amino, N- (C1-3-alkyl) -C2-4-alkanoylamino or N-(C1-3-alkyl)-C2-4-alkanoylamino group, by a C1-3-alkylaminocarbonyl group wherein the alkyl moiety additionally substituted by a di-(C1-3-alkyl)-amino group, or by a N- (C1-3-alkyl) -C1-3-alkylsulphonylamino group wherein the alkyl moiety may additionally be substituted by a cyano, carboxy, C1-3-alkoxycarbonyl, C1-3-alkylamino or di- (C1-3-alkyl) -amino group, a phenyl or thienyl group 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, C1-3-alkylamino, di- (C1-3-alkyl) -amino, C2-4-alkanoylamino, N-(C1-3-alkyl) -C2-4-alkanoylamino, pyrrolidino, piperidino, hexamethyleneimino, morpholino, piperazino, 4- (C1-3-alkyl) -piperazino, 4-(C2-4-alkanoyl)-piperazino, 4-benzoyl-pipera¬zino or imidazolyl group, whilst the abovementioned cycloalkyleneimino rings, C1-3-alkylamino or di-(C1-3-alkyl)-amino groups may additionally be substituted by a C1-5-alkyl, C3-7-cycloalkyl, hydroxy, C1-3-alkoxy, carboxy, C1-3-alkoxycarbonyl, aminocarbonyl, C1-3-alkylaminocarbonyl or di- (d-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 abovementioned cycloalkyleneimino rings may be replaced by a carbonyl or sulphonyl group, and the abovementioned monosubstituted phenyl group may additionally be substituted by a fluorine, chlorine or bromine atom or by a methyl group. Moreover, the carboxy, amino or imino groups present in a compound of the above general formula I may be substituted by groups which can be cleaved in vivo. A group which can be split off from an imino or amino group in vivo might be, for example, a hydroxy group, an acyl group such as the benzoyl or pyridinoyl group or a d1-16-alkanoyl group such as the formyl, acetyl, propionyl, butanoyl, pentanoyl or hexanoyl group, an allyloxycarbonyl group, a C1-16-alkoxycarbonyl group such as the methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, tert.butoxycarbonyl, pentoxycarbonyl, hexyloxycarbonyl, octyloxycarbonyl, nonyloxycarbonyl, decyloxycarbonyl, undecyloxycarbonyl, dodecyloxycarbonyl or hexadecyloxycarbonyl group, a phenyl-C1-6-alkoxycarbonyl group such as the benzyloxycarbonyl, phenylethoxycarbonyl or phenylpropoxycarbonyl group, a C1-3-alkylsulphonyl-C2-4-alkoxycarbonyl, C1-3-alkoxy-C2-4-alkoxy-C2-4-alkoxycarbonyl or RcCO-0- (RdCRe) -O-C0 group wherein Rc denotes a C1-8-alkyl, C5-7-cycloalkyl, phenyl or phenyl-C1-3-alkyl group, Re denotes a hydrogen atom, a C1-3-alkyl, C5-7-cycloalkyl or phenyl group and R4 denotes a hydrogen atom or a C1-3-alkyl group or the RcCO-O-(RdCRe)-o- group, whilst the abovementioned ester groups may also be used as a group which can be converted in vivo into a carboxy group. Preferred compounds of general formula I are those wherein v rv /■■■ 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 or naphthyl group which may be substituted by fluorine, chlorine or bromine atoms, by C1-3-alkyl, C1-3-alkoxy, cyano, trif luoromethyl, nitro, amino, C1-3-alkylamino, di- (C1-3-alkyl) -amino, C2-4-alkanoyl-amino, N- (C1-3-alkyl) -C2-4-alkanoylamino, N-(C1-3-alkyl)-C2-4-alkanoylamino, C1-3-alkylsulphonylamino, amino- C1-3-aIkyl, C1-3-alkylamino-C1-3-alkyl, di- (C1-3-alkyl) -amino-C1-3-alkyl, N-(C2-4-alkanoyl)-amino-C1-3-alkyl or N-(C2-4-alkanoyl)-C1-3-alkylamino-C1-3-alkyl groups and the substituents may be identical or different, R4 denotes a hydrogen atom or a C1-3-alkyl group and R5 denotes a hydrogen atom, a C1-5-alkyl group optionally substituted by a phenyl, carboxy or C1-3-alkoxycarbonyl group, a C3-7-cycloalkyl group optionally substituted by a C1-3-alkyl group, an indanyl, pyridyl, pyrimidyl, oxazolyl, thiazolyl or imidazolyl group optionally substituted by a C1-3-alkyl group, to which a phenyl ring may additionally be fused via two adjacent carbon atoms, a pyrrolidinyl or piperidinyl group linked via a carbon atom, which may be substituted at the nitrogen atom by a C1-3-alkyl group, ■ i a phenyl, pyridyl, pyrimidyl or thienyl group each of which may be substituted by a fluorine, chlorine, bromine or iodine atom, by a C1-5-alkyl, C3-7-cycloalkyl, C1-3-alkoxy, phenyl-C1-3-alkoxy, carboxy-C1-3-alkyl, C1-3-alkoxy-carbonyl-C1-3-alkyl, carboxy, C1-3-alkoxycarbonyl, aminocarbonyl, C1-3-alkylaminocarbonyl, di-(C1-3-alkyl)-aminocarbonyl, nitro, amino, C1.3-alkylamino, di- (C1-3-alkyl) -amino, C2-4-alkanoyl-amino, N- C1-3-alkyl) -C2-4-alkanoylamino or N-(C1-3-alkyl) - C2-4-alkanoylamino group, by a C1-3-alkylaminocarbonyl group wherein the alkyl moiety is additionally substituted by a di- (C1-3-alkyl) -amino group, or by a N- (C1-3-alkyl) -C1-3-alkylsulphonylamino group wherein the alkyl moiety may additionally be substituted by a cyano, carboxy, C1-3-alkoxycarbonyl, C1-3-alkylamino or di- (C1-3-alkyl) -amino group, a phenyl or thienyl group 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, d1-5-alkylamino, di- (C1-5-alkyl) -amino, C2_4-alkanoylamino, N- (C1-3-alkyl) -C2-4-alkanoylamino, pyrrolidine, piperidino, hexamethyleneimino, morpholino, piperazino, 4-(C1-3-alkyl)-piperazino, 4-(C2-4-alkanoyl)-piperazino, 4-benzoyl-pipe¬razino or imidazolyl group, whilst the abovementioned cycloalkyleneimino rings, C1-5-alkylamino or di-(C1-5-alkyl) -amino groups may additionally be substituted by a C1-3-alkyl, C3-7-cycloalkyl, phenyl-C1-3-alkyl, phenyl, hydroxy, C1-3-alkoxy, carboxy, C1-3-alkoxy-carbonyl, aminocarbonyl, C1-3-alkylaminocarbonyl or di-(C1-3-alkyl)-aminocarbonyl group or a methylene group adjacent to the nitrogen atom may be replaced in the abovementioned cycloalkyleneimino rings by a carbonyl or sulphonyl group, and the abovementioned monosubstituted phenyl group may additionally be substituted by a fluorine, chlorine or bromine atom or by a methyl group, and the salts thereof. Particularly preferred compounds of the above general formula I are those wherein X denotes an oxygen atom, R1 denotes a hydrogen atom or a C1-4-alkoxycarbonyl group, 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 fluorine, chlorine or bromine atom, by a methyl, cyano or aminomethyl group, R4 denotes a hydrogen atom or a methyl group and R5 denotes a hydrogen atom, a C1-3-alkyl group optionally substituted by a carboxy or C1-3-alkoxycarbonyl group, a C3-7-cycloalkyl group optionally substituted by a methyl group, an indanyl, pyriflyl, 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 benzyl, methyl-bromophenyl or 1-methyl-4-piperidinyl group, a phenyl group which is optionally substituted by a fluorine, chlorine, bromine or iodine atom, by a methanesulphonylamino group which is substituted at the nitrogen atom by a methyl, cyanomethyl, ethoxycarbonyl or 2-dimethylaminoethyl group, by a C1-4-alkyl, cyclohexyl, methoxy, ethoxy, benzyloxy, carboxymethyl, ethoxycarbonylmethyl, carboxy, methoxycarbonyl, aminocarbonyl, C1-3-alkylaminocarbonyl, di-(C1-3-alkyl)-aminocarbonyl, nitro, amino, methylamino, dimethylamino, acetylamino, N-miethyl-acetylamino or N-(2-diethylaminoethyl)-aminocarbonyl group, a phenyl group substituted by a methyl or ethyl group wherein the alkyl moiety is substituted by a carboxy, ethoxycarbonyl, amino, C1-3-alkylamino, di-(C1-3-alkyl)-amino, acetylamino, pyrrolidino, 2-oxo-pyrrolidino, piperidino, 2-oxo-piperidino, hexamethyleneimino, morpholino, piperazino, 4-C1-3-alkyl-piperazino, 4-acetyl-piperazino, 4-benzoyl-piperazino or imidazolyl group, whilst the abovementioned piperidino ring may additionally be substituted by a C1-3-alkyl, cyclohexyl, hydroxy, C1-3-alkoxy or C1-3-alkoxycarbonyl group or by a benzyl or phenyl group optionally substituted in the phenyl nucleus by a fluorine, chlorine, bromine or iodine atom or by a methyl or cyano group, and the salts thereof. Most particularly preferred compounds of the above general formula I are those wherein X denotes an oxygen atom, R1 denotes a hydrogen atom, R2 denotes a aminocarbonyl group wherein the amino moiety may be substituted by one or two methyl 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 phenyl group substituted by a methyl group, wherein the methyl group is substituted by an amino, C1-3-alkylamino, di- (C1-3-alkyl) -amino, pyrrolidino, piperidino, hexamethyleneimino, morpholino, piperazino or 4-(C1-3-alkyl)-piperazino group, whilst the abovementioned cyclo-alkyleneimino rings may additionally be substituted by a C1-3-alkyl, C5-7-cycloalkyl, benzyl, phenyl, hydroxy, C1-3-alkoxy, carboxy or C1-3-alkoxy-carbonyl group, particularly those compounds wherein X denotes an oxygen atom, R1 denotes a hydrogen atom, R2 denotes an aminocarbonyl group, R3 denotes a phenyl group, R4 denotes a hydrogen atom and R5 denotes a phenyl group which is substituted in the 4-position by a bromine atom, by an aminomethyl, dimethylaminomethyl, diethylaminomethyl, pyrrolidinomethyl, piperidinomethyl, hexamethyleneiminomethyl, 4-phenyl-piperidino or 4-benzyl-piperidino group is substituted, and the salts thereof. The following are mentioned as examples of particularly preferred compounds: (a) 3-Z-[1-(4-aminomethyl-phenylamino)-1-phenyl-methylene]-5-amido-2-indolinone, (b) 3-Z-(1-phenylamino)-1-phenyl-methylene)-5-amido-2-indolinone, (c) 3-Z-[1-(4-bromophenylamino)-1-phenyl-methylene]-5- amido-2 -indolinone, (d) 3-Z- [1-(4-dimethylamino-methyl)-phenylamino)-1-phenyl-methylene]-5-amido-2-indolinone, (e) 3-Z- [1-(4-pyrrolidinomethyl-phenylamino)-1-phenyl-methylene]-5-amido-2 -indolinone, (f) 3-Z-[1-(4-piperidinomethyl-phenylamino)-1-phenyl-methylene]-5-amido-2-indolinone, (g) 3-Z- [1-(4-hexamethyleneiminomethyl-phenylamino)-1-phenyl-methylene]-5 -amido-2 -indolinone-1ri fluoroacetate, (h) 3-Z- [1-(4-(4-benzyl-piperidino)-methyl)-phenylamino)-1-phenyl-methylene]-5-amido-2-indolinone and the salts thereof. According to the invention the new compounds are obtained for example using the following methods known in principle from the literature: a. reacting a compound of general formula (ID, wherein X, R2 and R3 are as hereinbefore defined, R6 denotes a hydrogen atom, a protecting group for the nitrogen atom of the lactam group or a bond to a solid phase and Z1 denotes a halogen atom, a hydroxy, alkoxy or aralkoxy group, e.g. a chlorine or bromine atom, a methoxy, ethoxy or benzyloxy group, with an amine of general formula (III) , wherein R4 and R5 are as hereinbefore defined, and if necessary subsequently cleaving any protecting group used for the nitrogen atom of the lactam group, or cleaving from a solid phase. A suitable protecting group for the nitrogen atom of the lactam group might be for example an acetyl, benzoyl, ethoxycarbonyl, tert butyloxycarbonyl or benzyloxycarbonyl group and a suitable solid phase might be a Rink resin such as a p- ' benzyloxybenzylalcohol resin, whilst the bond may usefully be via an intermediate such as a 2,5-dimethoxy-4-hydroxy- . benzyl derivative. The reaction is conveniently carried out in a solvent such as dimethylformamide, toluene, acetonitrile, tetrahydrofuran, dimethylsulphoxide, methylene chloride or mixtures thereof, optionally in the presence of an inert base such as triethylamine, N-ethyl-diisopropylamine or sodium hydrogen carbonate at temperatures between 2 0 and 175°C carried out, whilst any protecting group used can be cleaved simultaneously by transamidation. If Z1 in a compound of general formula II denotes a halogen atom, the reaction is preferably carried out in the presence of an inert base at temperatures between 20 and 120°C. If Z1 in a compound of general formula II denotes a hydroxy, alkoxy or aralkoxy group, the reaction is preferably carried out at temperatures between 2 0 and 200°C. If any protecting group used subsequently has to be cleaved, this is conveniently carried out either hydro-lytically in an aqueous or alcoholic solvent, e.g. in methanol/water, ethanol/water, isopropanol/water, tetrahydrofuran/water, dioxane/water, dimethylformamide/water, methanol or ethanol in the presence of an alkali metal base such as lithium hydroxide, sodium hydroxide or potassium hydroxide at temperatures between 0 and 100°C, preferably at temperatures between 10 and 50°C, or advantageously by transamidation with a primary or secondary organic base such as methylamine, butylamine, dimethylamine or piperidine in a solvent such as methanol, ethanol, dimethylformamide and mixtures thereof or in an excess of the amine used at temperatures between 0 and 100°C, preferably at temperatures between 10 and 50°C. Any solid phase used is preferably cleaved using trifluoroacetic acid and water in the presence of a dialkylsulphide such as dimethylsulphide at temperatures between 0 and 35°C, preferably at ambient temperature. b. In order to prepare a compound of general formula I which contains an aminomethyl group and X denotes an oxygen atom: Reduction of a compound of general formula (IV) , wherein R1 to R4 are as hereinbefore defined and R7 has the meanings given for R5 hereinbefore with the proviso that R5 contains a cyano group. The reduction is preferably carried out by catalytic hydrogenation with hydrogen in the presence of a catalyst such as palladium/charcoal or platinum in a solvent such as methanol, ethanol, ethyl acetate, dimethylformamide, dimethylformamide/acetone or glacial acetic acid optionally with the addition of an acid such as hydrochloric acid at temperatures between 0 and 50°C, but preferably at ambient temperature, and at a hydrogen pressure from 1 to 7 bar, but preferably from 3 to 5 bar. If according to the invention a compound of general formula I is obtained which contains an alkoxycarbonyl group, this can be converted by hydrolysis into a corresponding carboxy compound, or If a compound of general formula I is obtained which contains an amino or alkylamino group, this may be converted by alkylation or reductive alkylation into a corresponding alkylamino or dialkylamino compound, or If a compound of general formula I is obtained which contains an amino or alkylamino group, this may be converted by acylation into a corresponding acyl compound, or If a compound of general formula I is obtained which contains a carboxy group, this can be converted by esterification or amidation into a corresponding ester or aminocarbonyl compound. The subsequent hydrolysis is preferably carried out in an aqueous solvent, e.g. in water, isopropanol/water, tetrahydrofuran/water or dioxane/water, in the presence of an acid such as trifluoroacetic acid, hydrochloric acid or sulphuric acid or in the presence of an alkali metal base such as lithium hydroxide, sodium hydroxide or potassium hydroxide at temperatures between 0 and 100°C, preferably at temperatures between 10 and 50°C. The subsequent reductive alkylation is preferably carried out in a suitable solvent such as methanol, methanol/water, methanol/water/ammonia, ethanol, ether, tetrahydrofuran, dioxane or dimethylformamide optionally with the addition of an acid such as hydrochloric acid in the presence of catalytically activated hydrogen, e.g. hydrogen in the presence of Raney nickel, platinum or palladium/charcoal, or in the presence of a metal hydride such as sodium borohydride, lithium borohydride or lithium; aluminium hydride at temperatures between 0 and 100°C, preferably at temperatures between 2 0 and 80°C. The subsequent alkylation is carried out with an alkylating agent such as an alkyl halide or dialkyl sulphate such as methyliodide, dimethylsulphate or propylbromide preferably in a solvent such as methanol, ethanol, methylene chloride, tetrahydrofuran, toluene, dioxane, dimethylsulphoxide or dimethylformamide optionally in the presence of an inorganic or a tertiary organic base such as triethylamine, N-ethyl- diisopropylamine or dimethylaminopyridine, preferably at temperatures between 20°C and the boiling temperature of the solvent used. The subsequent acylation is preferably carried out in a solvent such as methylene chloride, diethylether, tetrahydrofuran, toluene, dioxane, acetonitrile, dimethylsulphoxide or dimethylformamide, optionally in the presence of an inorganic or a tertiary organic base, preferably at temperatures between 20°C and the boiling temperature of the solvent used. The acylation with a corresponding acid is preferably carried out in the presence of a dehydrating agent, e.g. in the presence of isobutyl chloroformate, tetraethyl orthocarbonate, trimethyl orthoacetate, 2,2-dimethoxypropane, tetramethoxysilane, thionyl chloride, trimethylchlorosilane, phosphorus trichloride, phosphorus pentoxide, N,N'-dicyclohexylcarbodiimide, N,N'-dicyclohexyl-carbodiimide/N-hydroxysuccinimide, N,N'-dicyclohexylcarbodiimide/1-hydroxy-benzotriazole, 2-(lH-benzotriazol-1-yl)-l,1,3,3-tetramethyluronium-tetrafluoroborate, 2-(lH-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium-tetrafluoroborate/1-hydroxy-benzotriazole, N,N'-carbonyldiimidazole or triphenylphosphine/carbon tetrachloride, and optionally with the addition of a base such as pyridine, 4-dimethylamino-pyridine, N-methyl-morpholine or triethylamine, conveniently at temperatures between 0 and 150°C, preferably at temperatures between 0 and 100°C, and the acylation with a corresponding reactive compound such as an anhydride, ester, imidazolide or halide thereof is optionally carried out in the presence of a tertiary organic base such as triethylamine, N-ethyl-diisopropylamine or N-methyl-morpholine at temperatures between 0 and 150°c, preferably at temperatures between 50 and 100°C. The subsequent esterification or amidation is conveniently carried out by reacting a corresponding reactive carboxylic acid derivat ive with a corresponding alcohol or amine as described hereinbefore. In the reactions described hereinbefore, any reactive groups present such as carboxy, amino, alkylamino or imino groups may be protected during the reaction by conventional protecting groups which are cleaved again after the reaction. For example, a protecting group for a carboxyl group may be a trimethylsilyl, methyl, ethyl, tert.butyl, benzyl or tetrahydropyranyl group and protecting groups for an amino, alkylamino or imino group may be an acetyl, trifluoroacetyl, benzoyl, ethoxycarbonyl, tert.butoxycarbonyl, benzyloxycarbonyl, benzyl, methoxybenzyl or 2,4-dimethoxybenzyl group and additionally, for the amino group, a phthalyl group. Any protecting group used is optionally subsequently cleaved for example by hydrolysis in an aqueous solvent, e.g. in water, isopropanol/water, acetic acid/water, tetrahydrofuran/water or dioxane/water, in the presence of an acid such as trifluoroacetic acid, hydrochloric acid or sulphuric acid or in the presence of an alkali metal base such as lithium hydroxide, sodium hydroxide or potassium hydroxide, at temperatures between 0 and 100°C, preferably at temperatures between 10 and 50°C. However, a benzyl, methoxybenzyl or benzyloxycarbonyl group is cleaved, for example, hydrogenolytically, e.g. with hydrogen in the presence of a catalyst such as palladium/charcoal in a solvent such as methanol, ethanol, ethyl acetate, dimethylformamide, dimethylformamide/acetone or glacial acetic acid, optionally with the addition of an acid such as ■i hydrochloric acid or glacial acetic acid at temperatures between 0 and 50°C, but preferably at ambient temperature, and at a hydrogen pressure of 1 to 7 bar, but preferably 3 to 5 bar. A methoxybenzyl group may also be cleaved in the presence of an oxidising agent such as cerium(IV)ammonium nitrate in a solvent such as methylene chloride, acetonitrile or acetonitrile/water at temperatures of between 0 and 50°C, but preferably at ambient temperature. A 2,4-dimethoxybenzyl group, however, is preferably cleaved in trifluoroacetic acid in the presence of anisole. A tert butyl or tert butyloxycarbonyl group is preferably cleaved by treating with an acid such as trifluoroacetic acid or hydrochloric acid, optionally using a solvent such as methylene chloride, dioxane, ethyl acetate or ether. A phthalyl group is preferably cleaved in the presence of hydrazine or a primary amine such as methylamine, ethylamine or n-butylamine in a solvent such as methanol, ethanol, isopropanol, toluene/water or dioxane at temperatures between 2 0 and 50°C. Moreover, chiral compounds of general formula I obtained i may be resolved into their enantiomers and/or diastereomers. Thus, for example, the compounds of general formula I obtained which occur as racemates may be separated by methods known per se (cf. Allinger N. L. and Eliel E. L. in "Topics in Stereochemistry", Vol. 6, Wiley Interscience, 1971) into their optical antipodes and compounds of general formula I with at least 2 asymmetric carbon atoms may be resolved into their diastereomers on the basis of their physical-chemical differences using methods known per se, e.g. by chromatography and/or fractional crystallisation, and, if these compounds are obtained in racemic form, they may subsequently be resolved into the enantiomers as mentioned above. The enantiomers are preferably separated by column separation on chiral phases or by recrystallisation from an optically active solvent or by reacting with an optically active substance which forms salts or derivatives such as e.g. esters or amides with the racemic compound, particularly acids and the activated derivatives or alcohols thereof, and separating the diastereomeric mixture of salts or derivatives thus obtained, e.g. on the basis of their differences in solubility, whilst the free antipodes may be released from the pure diastereomeric salts or derivatives by the action of suitable agents. Optically active acids in common use are e.g. the D- and L-forms of tartaric acid or dibenzoyltartaric acid, di-o-tolyltartaric acid, malic acid, mandelic acid, camphorsulphonic acid, glutamic acid, N-acetylglutamic acid, aspartic acid, N-acetylaspartic acid or quinic acid. An optically active alcohol may be for example (+) or (-)-menthol and an optically active acyl group in amides, for example, may be a (+)-or (-)-menthyloxycarbonyl group. Furthermore, the compounds of formula I obtained may be converted into the salts thereof, particularly for pharmaceutical use into the physiologically acceptable salts with inorganic or organic acids. Acids which may be used for this purpose include for example hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid, fumaric acid, succinic acid, lactic acid, citric acid, tartaric acid, maleic acid or methanesulphonic acid. Moreover, if the new compounds of formula I thus obtained contain a carboxy group they may subsequently, if desired, be converted into the salts thereof with inorganic or organic bases, particularly for phar¬ maceutical use into the physiologically acceptable salts thereof. Suitable bases for this purpose include for example sodium hydroxide, potassium hydroxide, cyclohexylamine, ethanolamine, diethanolamine and triethanolamine . The compounds of general formulae I to/VII used as starting materials are known from the literature in some cases or may be obtained by methods known from the literature or are described in the Examples. As already mentioned, the new compounds of general formula I wherein R1 represents a hydrogen atom or a prodrug group have valuable pharmacological properties, particularly inhibitory effects on various kinases and cycline/CDK-complexes, on the proliferation of cultivated human tumour cells and, when administered orally, on the growth of tumours in nude mice infected with human tumour cells. For example, the compounds listed in Table 1 Vere tested for their biological properties as follows: Test 1 Inhibition of cycline/CDK enzyme, in vitro activity High Five™ insect cells (BTI-TN-5B1-4) which had been infected with a high titre of recombinant baculovirus were used to produce active human cycline/CDK holoenzymes. By using a baculovirus vector which contained two promoters (polyhedrin enhancer promoter, P10 enhancer promoter), GST-tagged cyclines (e.g. cycline Dl or cycline D3) with the corresponding His6-tagged CDK subunit (e.g. for CDK4 or CDK6) were expressed in the same cell. The active holoenzyme was isolated by affinity chromatography on glutathione sepharose. Recombinant GST-tagged pRB (aa 379-928) was produced in E. coli and purified by affinity chromatography on glutathione sepharose. The substrates used for the kinase assays depended on the specific kinases. Histone H1 (Sigma) was used as the substrate for cycline E/CDK2, cycline A/CDK2, cycline B/CDK1 and for v-cycline/CDK6. GST-tagged pRB (aa 379-928) was used as substrate for cycline D1/CDK4, cycline D3/CDK4, cycline D1/CDK6 and for cycline D3/CDK6. Lysates of the insect cells infected with recombinant baculovirus or recombinant kinases (obtained from the lysates by purification) were incubated together with radiolabelled ATP in the presence of a suitable substrate with various concentrations of the inhibitor in a 1% DMSO solution (dimethyl sulphoxide) for 45 minutes at 30°C. The substrate proteins with associated radioactivity were precipitated with 5% TCA (trichloroacetic acid) in water-repellent PVDF multi-well microtitre plates (Millipore) or with 0.5% phosphoric acid solution on Whatman P81 filters. After the addition of scintillation liquid the radioactivity was measured in a Wallace 1450 Microbeta Liquid Scintillation Counter. For each concentration of the substance double measurements were carried out; IC50 values were calculated for the enzyme inhibition. (2) 3-Z-(1-phenylamino)-1-phenyl-methylene)-5-amido-2- indolinone Yield: 27 % of theory, Rf value: 0.53 (silica gel; methylene chloride/methanol = 9:1) C22H17N3O2 Mass spectrum: m/z = 355 (M+) (3) 3-Z-[1-(4-acetylamino-phenylamino)-1-phenyl- methylene]-5-amido-2-indolinone Yield: 28 % of theory, Rf value: 0.35 (silica gel; methylene chloride/methanol = 9:1) C24H20N4O3 Mass spectrum: m/z = 412 (M+) (4) 3-Z-[1-(4-acetyl-N-methyl-amino-phenylamino)-1-phenyl-methylene]-5-amido-2-indolinone Yield: 15 % of theory, Rf value: 0.36 (silica gel; methylene chloride/methanol = 9:1) C25H22N4O3 Mass spectrum: m/z = 426 (M+) (5) 3-Z-[1-(4-(2-amino-ethyl)-phenylamino)-1-phenyl-methylene]-5-amido-2-indolinone Yield: 30 % of theory, Rf value: 0.04 (silica gel; methylene chloride/methanol = 9:1) C24H22N4O2 Mass spectrum: m/z = 398 (M+) (6) 3-Z-[1-(4-methoxy-phenylamino)-1-phenyl-methylene]-5-amido-2 -indolinone Yield: 32 % of theory, Rf value: 0.48 (silica gel; methylene chloride/methanol = 9:1) C23H19N3O3 Mass spectrum: m/z = 385 (M+) (7) 3-Z-[1-(4-biphenylamino)-1-phenyl-methylene]-5-amido- 2-indolinone Yield: 22 % of theory, Rf value: 0.51 (silica gel; methylene chloride/methanol = 9:1) C28H21N3O2 Mass spectrum: m/z = 431 (M+) (8) 3-Z-[1-(3-pyridylamino)-1-phenyl-methylene]-5-amido- 2-indolinone Yield: 35 % of theory, Rf value: 0.41 (silica gel; methylene chloride/methanol = 9:1) C21H16N4O2 Mass spectrum: m/z = 356 (M+) (9) 3-Z-[1-(4-dimethylamino-phenylamino)-1-phenyl- methylene] -5-amido-2-indolinone Yield: 19 % of theory, Rf value: 0.49 (silica gel; methylene chloride/methanol = 9:1) C24H22N4O2 Mass spectrum: m/z = 3 98 (M+) (10) 3-Z-[1-(4-morpholino-phenylamino)-1-phenyl- methylene]-5-amido-2-indolinone Yield: 42 % of theory, Rf value: 0.48 (silica gel; methylene chloride/methanol = 9:1) C26H24N4O3 Mass spectrum: m/z = 440 (M+) (11) 3-Z-[1-(4-tert butyl-phenylamino)-1-phenyl- methylene]-5-amido-2-indolinone Yield: 32 % of theory, Rf value: 0.48 (silica gel; methylene chloride/methanol = 9:1) C26H25N3O2 Mass spectrum: m/z = 411 (M+) (12) 3-Z-[1-(2-amino-phenylamino)-1-phenyl-methylene]-5- amido-2 -indolinone Yield: 28 % of theory, Rf value: 0.52 (silica gel; methylene chloride/methanol = 9:1) C22H18N4O2 Mass spectrum: m/z = 370 (M+) (13) 3-Z-[1-(4-phenyl-phenylamino)-1-phenyl-methylene]-5- amido-2-indolinone Yield: 40 % of theory, Rf value: 0.4 (silica gel; methylene chloride/methanol = 9:1) C29H23N3O3 Mass spectrum: m/z = 461 (M+) (l4) 3-Z- [1- (4-bromophenylamino) -1-phenyl-methylene] -5- amido-2 -indolinone Yield: 35 % of theory, Rf value: 0.46 (silica gel; methylene chloride/methanol = 9:1) C22H16BrN3O2 Mass spectrum: m/z = 433/435 (M+) (15) 3-Z-[1-(4-methoxycarbonyl-phenylamino)-1-phenyl-methylene]-5-amido-2-indolinone Yield: 34 % of theory, Rf value: 0.36 (silica gel; methylene chloride/methanol = 9:1) C24H19N3O4 Mass spectrum: m/z = 413 (M+) (16) 3-Z-[1-(3-amido-phenylamino)-1-phenyl-methylene]-5-amido- 2-indolinone Yield: 32 % of theory, Rf value: 0.32 (silica gel; methylene chloride/methanol = 9:1) C23H18N4O3 Mass spectrum: m/z = 398 (M+) (17) 3-Z-[1-(3-methyl-phenylamino)-1-phenyl-methylene]-5-amido-2-indolinone Yield: 12 % of theory, Rf value: 0.5 (silica gel; methylene chloride/methanol = 9:1) C23H19N3O2 Mass spectrum: m/z = 369 (M+) (18) 3-Z-[1-(2-methyl-phenylamino)-1-phenyl-methylene]-5-amido-2 -indolinone Yield: 21 % of theory, Rf value: 0.5 (silica gel; methylene chloride/methanol = 9:1) C23H19N3O2 Mass spectrum: m/z = 369 (M+) (19) 3-Z- [1- (3-methoxy-phenylamino) -1-phenyl-methylene] -5-amido-2-indolinone Rf value: 0.49 (silica gel; methylene chloride/methanol = 9:1) C23H19N3O3 Mass spectrum: m/z = 385 (M+) (20) 3-Z-[1-(3-ethoxycarbonyl-phenylamino)-1-phenyl-methylene]-5-amido-2-indolinone Rf value: 0.48 (silica gel; methylene chloride/methanol = 9:1) C25H21N3O4 Mass spectrum: m/z = 427 (M+) (21) 3-Z- [1-(3-nitro-phenylamino)-1-phenyl-methylene]-5-amido-2-indolinone Yield: 32 % of theory, Rf value: 0.56 (silica gel; methylene chloride/methanol = 9:1) C22H16N4O4 Mass spectrum: m/z = 400 (M+) (22) 3-Z-[1-(4-amido-phenylamino)-1-phenyl-methylene]-5-amido-2-indolinone Yield: 26 % of theory, Rf value: 0.47 (silica gel; methylene chloride/methanol = 9:1) C23H18N4O3 Mass spectrum: m/z = 398 (M+) (23) 3-Z-[1-(4-pyridylamino)-1-phenyl-methylene]-5-amido-2-indolinone Yield: 15 % of theory, Rf value: 0.42 (silica gel; methylene chloride/methanol = 9:1) C21H16N4O2 Mass spectrum: m/z = 356 (M+) (24) 3-Z- [1-(4-methyl-phenylamino)-1-phenyl-methylene]-5-amido-2 -indolinone Yield: 45 % of theory, Rf value: 0.54 (silica gel; methylene chloride/methanol = 9:1) C23H19N3O2 Mass spectrum: m/z = 369 (M+) (25) 3-Z- [1-(4-ethoxy-phenylamino)-1-phenyl-methylene]-5-amido-2 -indolinone Yield: 40 % of theory, Rf value: 0.51 (silica gel; methylene chloride/methanol = 9:1) C24H21N3O3 Mass spectrum: m/z = 399 (M+) (26) 3-Z-[1-(3-bromophenylamino)-1-phenyl-methylene]-5- amido-2 -indolinone Yield: 41 % of theory, R£ value: 0.53 (silica gel; methylene chloride/methanol = 9:1) C22H16BrN3O2 Mass spectrum: m/z = 433/435 (M+) (27) 3-Z-[1-(4-chlorophenylamino)-1-phenyl-methylene]-5- amido-2-indolinone Yield: 50 % of theory, Rf value: 0.49 (silica gel; methylene chloride/methanol = 9:1) C22H16C1N3O2 Mass spectrum: m/z = 38 9 (M+) (28) 3-Z-[1-(4-isopropyl-phenylamino)-1-phenyl- methylene]-5-amido-2-indolinone Yield: 48 % of theory, Rf value: 0.65 (silica gel; methylene chloride/methanol = 9:1) C25H23N3O2 Mass spectrum: m/z = 397 (M+) (29) 3-Z-[1-(2-fluorenylamino)-1-phenyl-methylene]-5- amido-2-indolinone Yield: 43 % of theory, Rf value: 0.58 (silica gel; methylene chloride/methanol = 9:1) C29H21N3O2 Mass spectrum: m/z = 443 (M+) (30) 3-Z-[1-(4-(2-hydroxyethyl)-phenylamino)-1-phenyl- methylene]-5-amido-2-indolinone Yield: 22 % of theory, Rf value: 0.3 7 (silica gel; methylene chloride/methanol = 9:1) C24H21N3O3 Mass spectrum: m/z = 398 (M-H) '(31) 3-Z- [1- (4- (4-imidazolyl) -phenylamino) -1-phenyl- methylene]-5-amido-2-indolinone Yield: 23 % of theory, Rf value: 0.5 (silica gel; methylene chloride/methanol = 9:1) C25H19N502 Mass spectrum: m/z = 421 (M+) r(32) 3-Z-[1-(4-ethoxycarbonylmethyl-phenylamino)-1-phenyl-methylene]-5-amido-2-indolinone C26H23N3O4 Mass spectrum: m/z = 442 (M+H)+ (33) 3-Z- [1-(4-bromo-3-methyl-phenylamino)-1-phenyl- methylene]-5-amido-2-indolinone C23H18BrN3O2 Mass spectrum: m/z = 447/449 (M+) (34) 3-Z-[1-(4-cyclohexyl-phenylamino)-1-phenyl- methylene] -5-amid.o-2-indolinone C28H27N3o2 Mass spectrum: m/z = 437 (M+) (35) 3-Z-[1-(4-bromo-2-methyl-phenylamino)-1-phenyl- methylene] -5-amido-2-indolinone C23H18BrN3O2 Mass spectrum: m/z = 447/449 (M+) (36) 3-Z-(1-amino-1-phenyl-methylene)-5-amido-2- indolinone Rf value: 0.3 (silica gel; methylene chloride/methanol = 9:1) C16H13N3O2 Mass spectrum: m/z = 279 (M+) (37) 3-Z-(1-cyclohexylamino-l-phenyl-methylene)-5-amido- 2-indolinone Rf value: 0.55 (silica gel; methylene chloride/methanol = 9:1) C22H23N3O2 Mass spectrum: m/z = 361 (M+) ' (38) 3-Z-(1-cyclopentylamino-l-phenyl-methylene)-5-amido- 2-indolinone Rf value: 0.53 (silica gel; methylene chloride/methanol = 9:1) C21H21N3O2 Mass spectrum: m/z = 347 (M+) (39) 3-Z-(1-methylamino-l-phenyl-methylene)-5-amido-2- indolinone Rf value: 0.5 (silica gel; methylene chloride/methanol = 9:1) C17H15N3O2 Mass spectrum: m/z = 293 (M+) (40) 3-Z-(1-ethylamino-l-phenyl-methylene)-5-amido-2- indolinone Rf value: 0.52 (silica gel; methylene chloride/methanol = 9:1) C18H17N3O2 Mass spectrum: m/z = 307 (M+) (41) 3-Z-(1-isopropylamino-l-phenyl-methylene)-5-amido-2- indolinone Rf value: 0.44 (silica gel; methylene chloride/methanol = 9:1) C19H19N3O2 Mass spectrum: m/z = 321 (M+) (42) 3-Z-(1-dimethylamino-l-phenyl-methylene)-5-amido-2-indolinone Rf value: 0.39 (silica gel; methylene chloride/methanol = 9:1) C18H17N3O2 Mass spectrum: m/z = 307 (M+) (43) 3-Z-(1-cyclopropylamino-l-phenyl-methylene)-5-amido-2-indolinone Rf value: 0.47 (silica gel; methylene chloride/methanol = 9:1) C19H17N3O2 Mass spectrum: m/z = 319 (M+) '" (44) 3-Z- (1-cycloheptylamino-l-phenyl-methylene) -5-amido-2-indolinone Rf value: 0.58 (silica gel; methylene chloride/methanol = 9:1) C23H25N3O2 Mass spectrum: m/z = 375 (M+) (45) 3-Z-(1-cyclobutylamino-l-phenyl-methylene)-5-amido- 2-indolinone Rf value: 0.49 (silica gel; methylene chloride/methanol = 9:1) C20H19N3O2 Mass spectrum: m/z = 333 (M+) (46) 3-Z-[1-(4-methylcyclohexylamino)-1-phenyl- methylene]-5-amido-2-indolinone Rf value: 0.67 (silica gel; methylene chloride/methanol = 9:1) C23H25N3O2 Mass spectrum: m/z = 375 (M+) (47) 3-Z- [1- (1- (R, S) -indanylamino) -1-phenyl-methylene] -5-amido-2-indolinone Rf value: 0.59 (silica gel; methylene chloride/methanol = 9:1) C25H21N3O2 Mass spectrum: m/z = 395 (M+) (48) 3-Z- [1- (methoxycarbonylmethylamino)-1-phenyl-methylene]-5-amido-2-indolinone Rf value: 0.46 (silica gel; methylene chloride/methanol = 9:1) C19H17N304 Mass spectrum: m/z = 351 (M+) (49) 3-Z-[1-((2-methoxycarbonyl-ethyl)-amino)-1-phenyl-methylene]-5-amido-2-indolinone Rf value: 0.45 (silica gel; methylene chloride/methanol = 9:1) C20H19N3O4 Mass spectrum: m/z = 365 (M+) (50) 3-Z- [1- (4-aminomethyl-phenylamino) - 1-phenyl- methylene]-5-amido-2-indolinone Yield: 32 % of theory, Rf value: 0.46 (silica gel; methylene chloride/methanol = 9:1) C23H20N4O2 Mass spectrum: m/z = 384 (M+) (61) 3-Z-[1-(4-pyrrolidinomethyl-phenylamino)-1-phenyl-methylene]-5-amido-2-indolinone-trifluoroacetate Yield: 60 % of theory, /,,Rf value: 0.07 (silica gel; methylene chloride/methanol = 9:1) C27H26N4O2 Mass spectrum: m/z = 438 (M+) (52) 3-Z-[1-(4-morpholinomethyl-phenylamino)-1-phenyl- methylene]-5-amido-2-indolinone Yield: 65 % of theory, Rf value: 0.46 (silica gel; methylene chloride/methanol = 9:1) C27H26N4O Mass spectrum: m/z = 454 (M+) (53) 3-Z- [1-(4-piperidinomethyl-phenylamino)-1-phenyl- methylene]-5-amido-2-indolinone-trifluoroacetate Yield: 60 % of theory, Rf value: 0.08 (silica gel; methylene chloride/methanol = 9:1) C28H28N402 Mass spectrum: m/z = 452 (M+) (54) 3-Z-[1-(4-hexamethyleneiminomethyl-phenylamino)-1- phenyl-methylene]-5-amido-2-indolinone-trifluoroacetate C29H3oN4O2 Mass spectrum: m/z = 466 (M+) (55) 3-Z-[1-(4-(4-hydroxy-piperidinomethyl)-phenylamino)-1-phenyl-methylene]-5-amido-2-indolinone C28H28N4O3 Mass spectrum: m/z = 468 (M+) (56) 3-Z-[1-(4-(4-methyl-piperidinomethyl)-phenylamino)- 1-phenyl-methylene]-5-amido-2-indolinone C29H30N4O2 Mass spectrum: m/z = 466 (M+) (57) 3-Z- [1-(4-(4-ethyl-piperidinomethyl)-phenylamino)-1- phenyl-methylene]-5-amido-2-indolinone C30H32N4O2 Mass spectrum: m/z = 480 (M+) (58) 3-Z- [1-(4-(4-isopropyl-piperidinomethyl)-phenylamino)-1-phenyl-methylene]-5-amido-2-indolinone C31H34N4O2 Mass spectrum: m/z = 4 94 (M+) (59) 3-Z- [1-(4-(4-phenyl-piperidinomethyl)-phenylamino)-1-phenyl-methylene]- 5 -amido-2 -indolinone C34H32N4O2 Mass spectrum: m/z = 528 (M+) r(60) 3-Z-[1-(4-(4-benzyl-piperidinomethyl)-phenylamino)-1-phenyl-methylene]-5-amido-2-indolinone C35H34N4O2 Mass spectrum: m/z 0 542 (M+) (61) 3-Z-[1-(4-(4-ethoxycarbonyl-piperidinomethyl)-phenylamino)-1-phenyl-methylene]-5-amido-2-indolinone C31H32N4O4 Mass spectrum: m/z = 524 (M+) (62) 3-Z-[1-(4 -dimethylaminomethyl-phenylamino)-1-phenyl-methylene]-5-amido-2-indolinone C25H24N4O2 Mass spectrum: m/z = 412 (M+) (63) 3-Z-[1-(4-dipropylaminomethyl-phenylamino)-l-phenyl- methylene]-5-amido-2-indolinone C29H32N402 Mass spectrum: m/z = 468 (M+) (64) 3-Z-[1-(4-piperazinylmethyl-phenylamino)-1-phenyl-'methylene]-5-amido-2-indolinone C27H27N5O2 Mass spectrum: m/z = 453 (M+) (65) 3-Z-[1-(3-dimethylaminomethyl-phenylamino)-1-phenyl-methylene]-5-amido-2-indolinone C25H24N4O2 Mass spectrum: m/z = 412 (M+) (66) 3-Z-[1-(4-(2-diethylamino-ethyl)-phenylamino)-1- phenyl-methylene]-5-amido-2-indolinone C28H30N4O2 Mass spectrum: m/z = 454 (M+) (67) 3-Z-[1-(4-(2-morpholino-ethyl)-phenylamino)-1- phenyl-methylene]-5-amido-2-indolinone C28H28N4O3 Mass spectrum: m/z = 468 (M+) (68) 3-Z- [1-(4-(2-pyrrolidinyl-ethyl)-phenylamino)-1- phenyl-methylene]-5 -amido-2 -indolinone C28H28N4O2 Mass spectrum: m/z = 452 (M+) (69) 3-Z- [1-(4-(2-piperidinyl-ethyl)-phenylamino)-1- phenyl-methylene]-5-amido-2-indolinone C29H30N4O2 Mass spectrum: m/z = 466 (M+) (70) 3-Z- [1-(2-thiazolylamino)-1-phenyl-methylene]-5- amido-2 -indolinone Yield: 30 % of theory, Rf value: 0.48 (silica gel; methylene chloride/methanol = 9:1) C19H14N4O2S Mass spectrum: m/z = 362 (M+) (71) 3-Z- [1-(2-benzimidazolylamino)-1-phenyl-methylene]- 5-amido-2-indolinone Yield: 29 % of theory, Rf value: 0.44 (silica gel; methylene chloride/methanol = 9:1) C23H17N5O2 Mass spectrum: m/z = 395 (M+) (72) 3-Z-[1-(5-methyl-isoxazol-3-yl-amino)-1-phenyl- methylene]-5-amido-2-indolinone Yield: 39 % of theory, Rf value: 0.43 (silica gel; methylene chloride/methanol = 9:1) C21H18N4O3 Mass spectrum: m/z = 374 (M+) (73) 3-Z-(1-benzylamino-l-phenyl-methylene)-5-amido-2- indolinone Rf value: 0.63 (silica gel; methylene chloride/methanol = 9:1) C23H19N3O2 Mass spectrum: m/z = 369 (M+) (74) 3-Z-[1-(4-(1-imidazolyl-methyl)-phenylamino)-1- phenyl-methylene]-5 -amido-2 -indolinone Rf value: 0.45 (silica gel; methylene chloride/methanol = 9:1) C26H21N5O2 Mass spectrum: m/z = 436 (M+H) (75) 3-Z-[1-(4-((2-diethylamino-ethyl)-aminocarbonyl)- phenylamino)-1-phenyl-methylene]-5-amido-2-indolinone- trifluoroacetate Yield: 27 % of theory, Rf value: 0.05 (silica gel; methylene chloride/methanol = 9:1) C29H31N5O3 Mass spectrum: m/z = 497 (M+) (76) 3-Z-[1-(4-acetylaminomethyl-phenylamino)-1-phenyl- methylene]-5-amido-2-indolinone Rf value: 0.4 (silica gel; methylene chloride/methanol = 9:1) C25H22N4O3 Mass spectrum: m/z = 426 (M+) (77) 3-Z-[1-(4-((2-dimethylaminoethyl)-N-methanesulphonyl-amino)-phenylamino)-1-phenyl-methylene] 5-amido-2-indolinone Rf value: 0.1 (silica gel; methylene chloride/methanol = 9:1) C27H29N5O4S Mass spectrum: m/z = 519 (M+) (78) 3-Z- [1- (4- (N-(ethoxycarbonylmethyl) -N-methanesulphonyl-amino)-phenylamino)-1-phenyl-methylene] 5-amido-2-indolinone Rf value: 0.57 (silica gel; methylene chloride/methanol = 9:1) C27H26N4O6 Mass spectrum: m/z = 534 (M+) Y (79) 3-Z-[1-(4-(N-(cyanomethyl)-N-methanesulphonyl- amino)-phenylamino)-1-phenyl-methylene] -5-amido-2- indolinone Rf value: 0.49 (silica gel; methylene chloride/methanol = 9:1) C25H21N5O4S Mass spectrum: m/z = 487 (M+) (80) 3-Z-[1-(4-(N-methyl-N-methanesulphonyl-amino)- phenylamino)-1-phenyl-methylene] -5-amido-2-indolinone Rf value: 0.46 (silica gel; methylene chloride/methanol = 9:1) C24H22N4O4S Mass spectrum: m/z = 462 (M+) (81) 3-Z-[1-(4-(2-oxo-pyrrolidin-1-yl-methyl)- phenylamino)-1-phenyl-methylene]-5-amido-2-indolinone C27H24N4O3 Mass spectrum: m/z = 452 (M+) Example 5 3-Z-T1-(4-(4-acetyl-piperazinylmethyl)-phenylamino)-1-phenyl-methylene!-5-amido-2-indolinone 25 mg of 3-Z-[1-(4-(4-piperazinylmethyl)-phenylamino)-1-phenyl-methylene]-5-amido-2-indolinone and 0.02 g of triethylamine are dissolved in 10 ml of methylene chloride and mixed with 5 mg of acetyl chloride and the solution is stirred for 16 hours at ambient temperature. Then it is washed with water and the organic phase is then evaporated down. Yield: 15 mg g [sic] (68 % of theory), C29H29N5O3 Mass spectrum: m/z = 495 (M+) The following compound is prepared analogously: (1) 3-Z- [1-(4-(4-benzoyl-piperazinylmethyl)-phenylamino)-1-phenyl-methylene]-5-amido-2-indolinone Prepared from 3-Z-[1-(4-(4-piperazinyl-methyl- phenylamino)-1-phenyl-methylene]-5-amido-2-indolinone and benzoyl chloride. Yield: 91 % of theory, C34H31N5O3 Mass spectrum: m/z = 557 (M+) Example 6 Dry ampoule containing 75 mg of active substance per 10 ml Composition: Active substance 75.0 mg Mannitol 50.0 mg water for injections ad 10.0 ml Preparation: Active substance and mannitol are dissolved in water. After packaging the solution is freeze-dried. To produce the solution ready for use, the product is dissolved in water for injections. Example 7 Dry ampoule containing 3 5 mg of active substance per 2 ml Composition: Active substance 35.0 mg Mannitol 100.0 mg water for injections ad 2.0 ml Preparation: Active substance and mannitol are dissolved in water. After packaging, the solution is freeze-dried. To produce the solution ready for use, the product is dissolved in water for injections. Example 8 Tablet containing 50 mg of active substance Composition: (1) Active substance 50.0 mg (2) Lactose 98.0 mg (3) Maize starch 50.0 mg (4) Polyvinylpyrrolidone 15.0 mg (5) Magnesium stearate 2.0 ma 215.0 mg Preparation: (1), (2) and (3) are mixed together and granulated with an aqueous solution of (4). (5) is added to the dried granulated material. From this mixture tablets are pressed, biplanar, faceted on both sides and with a dividing notch on one side. Diameter of the tablets: 9 mm. Example 9 Tablet containing 350 mg of active substance Preparation: (1) Active substance 350.0 mg (2) Lactose 136.0 mg (3) Maize starch 80.0 mg (4) Polyvinylpyrrolidone 3 0.0 mg (5) Magnesium stearate 4.0 mg 600.0 mg (1), (2) and (3) are mixed together and granulated with an aqueous solution of (4). (5) is added to the dried granulated material. From this mixture tablets are pressed, biplanar, faceted on both sides and with a dividing notch on one side. Diameter of the tablets: 12 mm. Example 10 Capsules containing 50 mg of active substance Composition: (1) Active substance 50.0 mg (2) Dried maize starch 58.0 mg (3) Powdered lactose 50.0 mg (4) Magnesium stearate 2,0 mg 160.0 mg Preparation: (1) is triturated with (3). This trituration is added to the mixture of (2) and (4) with vigorous mixing. This powder mixture is packed into size 3 hard gelatin capsules in a capsule filling machine. Example 11 Capsules containing 3 50 mg of active substance Composition: (1) Active substance 350.0 mg (2) Dried maize starch 46.0 mg (3) Powdered lactose 3 0.0 mg (4) Magnesium stearate 4.0 mg 43 0.0 mg Preparation: (1) is triturated with (3). This trituration is added to the mixture of (2) and (4) with vigorous mixing. This powder mixture is packed into size 0 hard gelatin capsules in a capsule filling machine. Example 12 Suppositories containing 100 mg of active substance 1 suppository,contains: Active substance 100.0 mg Polyethyleneglycol (M.W. 1500) 600.0 mg Polyethyleneglycol (M.W. 6000) 460.0 mg Polyethylenesorbitan monostearate 84 0.0 mg 2,000.0 mg Preparation: The polyethyleneglycol is melted together with polyethylene sorbitanmonostearate. At 40°C the ground active substance is homogeneously dispersed in the melt It is cooled to 38°C and poured into slightly chilled suppository moulds. We Claim: 1. Novel indolinone compounds of general formula (I), wherein X represents an oxygen atom, R1 represents a hydrogen atom, R2 represents an aminocarbonyl group wherein the amino moie¬ty may be substituted by one or two C1-3-alkyl groups and the substituents may be identical or different, or a carboxy, methoxycarbonyl or ethoxycarbonyl group, R3 represents a phenyl group, R4 represents a hydrogen atom or a methyl group, and R5 represents a hydrogen atom, a C1-3-alkyl or benzyl group, or a methyl or ethyl group substituted by a methoxycarbonyl group, a C3-7-cycloalkyl group optionally substituted by a methyl group, a l-methyl-4-piperidinyl, dimathoxphenyl, indanyl, fluorenyl, methyloxazolyl, thiazolyl, imidazolyl or benzimidazolyl group, a pyridyl group optionally substituted by a methyl group, by a chlorine or bromine atom, a phenyl group optionally substituted by a C1-4-alkyl, cyclo¬hexyl, 4-phenyl-4-hydroxy-piperidinomethyl, 6,7-dimethoxy-1,2,3,4-tetrahydro-isoquinolin-2-ylmethyl, phenyl, methoxy, ethoxy, trifluoromethoxy, benzyloxy, morpholino, cyano or nitro group, by a chlorine or bromine atom, a phenyl group substituted by a methyl group which itself is substituted by a methoxy, carboxy, methoxycarbonyl, ethoxy-carbonyl, pyrrolidino, 2-methoxycarbonyl-pyrrolidino, de-hydropyrrolidino, 2-oxo-pyrrolidino, dehydropiperidino, pi-peridino, dimethylpiperidino, 2-oxo-piperidino, morpholino, thiomorpholino, 1-oxo-thiomorpholino, hexamethylenimino, imidazolyl, aminophenyl or methylaminophenyl group or by a piperazino group optionally substituted in position 4 by a phenyl, acetyl or benzoyl group, a phenyl group substituted by a methyl group which itself is substituted by a piperidino group substituted by a C1-3-al-kyl, cyclohexyl, benzyl, phenyl, hydroxy, methoxycarbonyl or ethoxycarbonyl group, a phenyl group substituted by a methyl group which itself is substituted by an amino, C1-3-alkylamino or acetylamino group wherein one hydrogen atom of the amino moieties may be re¬placed by a C1-4-alkyl, cyclohexyl, benzyl, chlorobenzyl, phenyl, methoxycarbonylmethyl or ethoxycarbonylmethyl group, a phenyl group substituted by an ethyl group which itself is terminally substituted by a hydroxy, amino, dimethylamino, diethylamino, pyrrolidino. piperidino or morpholino group, a phenyl group substituted by a methyl group which itself is substituted by an acetylamino group wherein the remaining hydrogen atom of the amino moieties is replaced by a methyl group optionally substituted by methoxycarbonyl, ethoxycarbonyl, aminocarbonyl, methylaminocarbonyl, morpholinocarbonyl, 2--dimethylaminoethyl or N- (2-dimethylaminoethyl) -aminocarbonyl group, a phenyl group substituted by a n-c2-3-alkoxy group terminally substituted by a dimethylamino, diethyl amino, N-methyl-benzylamino or piperidino group, a phenyl group substituted by a carbonyl group which itself is substituted by a hydroxy, methoxy, ethoxy, piperidino or 4-methyl-piperazino group, or by an amino group wherein one hydrogen atom of the amino moieties may be replaced by a benzyl, methoxycarbonylmethyl, 2-dimethylaminethyl or 2-diethylaminethyl group, or a methylphenyl group substitured by a chlorine or bromine atom, or by a methoxy, carboxy, methoxycarbonyl, nitro or aminosulfonyl group, the isomers and salts thereof. 2. Novel indolinone compounds of general formula I as claimed in claim 1, wherein X and R1 to R4 are as hereinbefore defined in claim 1 and R5 represents a a l-methyl-4-piperidinyl group, a phenyl group optionally substituted by a c1-4-alkyl, cyclo-hexyl, 4-phenyl-4-hydroxy-piperidinomethyl, 6,7-dimethoxy-1,2,3,4-tetrahydro-isoquinolin-2-ylmethyl, phenyl, methoxy, ethoxy, trifluoromethoxy, benzyloxy, morpholino, cyano or nitro group, by a chlorine or bromine atom, a phenyl group substituted by a methyl group which itself is substituted by a methoxy, carboxy, methoxycarbonyl, ethoxy-carbonyl, pyrrolidine 2-methoxycarbonyl-pyrrolidine de-hydropyrrolidino, 2-oxo-pyrrolidino, dehydropiperidino, pi-peridino, dimethylpiperidino, 2-oxo-piperidino, morpholino, thiomorpholino, 1-oxo-thiomorpholino, hexamethyleniraino, imidazolyl, aminophenyl or methylaminophenyl group or by a piperazino group optionally substituted in position 4 by a phenyl, acetyl or benzoyl group, a phenyl group substituted by a methyl group which itself is substituted by a piperidino group substituted by a C1-3-al-kyl, cyclohexyl, benzyl, phenyl, hydroxy, methoxycarbonyl or ethoxycarbonyl group, a phenyl group substituted by a methyl group which itself is substituted by an amino, C1-3-alkylamino or acetylamino group wherein one hydrogen atom of the amino moieties may be re¬placed by a C1-4-alkyl, cyclohexyl, benzyl, chlorobenzyl, phenyl, methoxycarbonylmethyl or ethoxycarbonylmethyl group, a phenyl group substituted by an ethyl group which itself is terminally substituted by a hydroxy, amino, dimethyl amino, diethylamino, pyrrolidine, piperidino or morpholino group, a phenyl group substituted by a methyl group which itself is substituted by an acetylamino, C1-3-alkylsulfonylamino or phenylsulfonylamino group wherein the remaining hydrogen atom of the amino moieties is replaced by a methyl group optionally substituted by methoxycarbonyl, ethoxycarbonyl, aminocarbonyl, methylaminocarbonyl, morpholinocarbonyl, 2--dimethylaminoethyl or N- (2-dimethylaminoethyl) -aminocarbonyl group, a phenyl group substituted by a n-C2-3-alkoxy group terminally substituted by a dimethylamino, diethylamino, N-methyl-benzylamino or piperidino group, a phenyl group substituted by a carbonyl group which itself is substituted by a hydroxy, methoxy, ethoxy, piperidino or 4-methyl-piperazino group, or by an amino, methylamino or ethylamino group wherein one hydrogen atom of the amino moieties may be replaced by a methyl, ethyl, benzyl, methoxycarbonylmethyl, 2-dimethyl amine thy1 or 2-diethyl-aminethyl group, or a methylphenyl group substitured by a chlorine or bromine atom, or by a methoxy, carboxy, methoxycarbonyl, nitro or aminosulfonyl group, the isomers and salts thereof. 3. Novel indolinone compounds of general formula I as claimed in at least one of claims 1 or 2, wherein the group R2 is in the 5 position 4. Novel indolinone compounds of general formula I as claimed in claim 1, said compounds being: (a) 3-Z- [1- (4-aminomethyl-phenylamino) -1-phenyl-methylene] -5-amido-2-indolinone, (b) 3-Z- (1-phenylamino) -1-phenyl-methylene) -5-amido-2- indolinone, (c) 3-Z- [1- (4-brpmophenylamino)-1-phenyl-methylene]-5-amido-2-indolinone, (d) 3-Z- [1- (4-dimethyl amino-methyl) -phenyl amino) -1-phenyl-methylene]-5-amido-2-indolinone, (e) 3-Z- [1- (4-pyrrolidinomethyl-phenylamino) -1-phenyl-methylene]-5-amido-2-indolinone, (f) 3-Z-[1-(4-piperidinomethyl-phenylamino)-l-phenyl-methylene]-5-amido-2-indolinone, (g) 3-Z- [1- (4-hexamethyleneiminomethyl-phenylamino)-l-phenyl-methylene] -5-amido-2-indolinone, (h) 3-Z-[1-(4-(4-ben2yl-piperidino)-methyl)-phenylamino)-1-phenyl-methylene]-5-amido-2-indolinone, (i) 3-z- [1- (4-(N-butyl-aminomethyl) -phenylamino) -1-phenyl-methylene] -5-amido-2-indolinone, (j) 3-Z-[l- (4- (N-.(phenyl-methyl) -aminomethyl) -phenylamino) -1-phenyl-methylene] -5-amido-2-indolinone, (k) 3-Z-[l-(4- (N-methyl-N-benzyl-amino-methyl)-phenyl amino) -1 -phenyl -methyl ene ]- 5 - amido- 2 - indol inone, (1) 3-Z- [1- (4-piperidino-methyl-phenylamino) -1-phenyl-methy¬lene ] -5-dimethylcarbamoyl-2-indolinone, (m) 3-Z-[l-(4-piperidino-methyl-phenylamino)-1-phenyl-methy¬lene] -5-diethylcarbamoyl-2-indolinone, (n) 3-Z-[1-(4-(3-diethylamino-propoxy)-phenylamino) -1-phenyl-methylene]-5-amido-2-indolinone and the salts thereof. 5. Physiologically acceptable salts of the novel indolinone compounds as claimed in claims 1 to 4. 6. Process for preparing the novel indolinone compounds as claimed in claims 1 to 5, characterised in that a. a compound of general formula (II, wherein X, R2 and R3 are defined as mentioned in claims 1 to 4, R6 denotes a hydrogen atom, a protecting group for the nitrogen atom of the lactam group or a bond to a solid phase and z1 denotes a halogen atom, a hydroxy, alkoxy or aralkoxy group, is reacted with an amine of general formula (III), wherein R4 and R5 are defined as in claims 1 to 4, 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 or b. in order to prepare a compound of general formula I which contains an aminomethyl group and where X denotes an oxygen atom, a compound of general formula wherein. R1 to R4 are defined as in claims 1 to 4 and R, has the meanings given for R5 in claims 1 to 4, with the proviso that R5 contains a cyano group, is reduced 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 alkylation or 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 into a corresponding acyl 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 if necessary a 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. Dated this 31st day of August, 2000 [DEEPAK. TIKU] OF REMFRY & SAGAR ATTORNEY FOR THE APPLICANTS

Documents:

in-pct-2000-00351-mum-abstract(18-12-2007).doc

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