NO317298B1 - Substituted indolines with an inhibitory effect on kinases and cyclin / CDK complexes - Google Patents

Abstract

Substituted indolinones of the general formula are described. Wherein R 1 to Rog X is defined as in claim 1, their isomers and their salts, in particular their physiologically tolerable salts, which have valuable pharmacological properties, have an inhibitory effect on various kinases and cyclin / CDK complexes as well as on proliferation of various tumor cells. There are further described medicaments containing these compounds, their use and process for their preparation.

Description

The present invention relates to substituted indolinones with an inhibitory effect on kinases and cyclin/CDK complexes, methods for the production and use thereof as well as physiologically tolerable salts and pharmaceuticals.

The present invention therefore relates to new substituted indolinones, characterized in that they have the general formula

in which

X is an oxygen atom,

Ri is a hydrogen atom,

R 2 is a carboxy, C 1-4 alkoxycarbonyl or aminocarbonyl group, the amino part may be substituted with one or two C 1-3 alkyl groups and the substituents may be the same or different,

R3 is a phenyl group,

R 4 is a hydrogen atom or a C 10 -alkyl group and

R5 is a hydrogen atom,

a C 1-5 alkyl group optionally substituted with a phenyl or C 1-3 alkoxycarbonyl group,

a C3-7 cycloalkyl group optionally substituted with a C10 alkyl group,

a fluorenyl group,

an indanyl group optionally substituted with a C 1-3 alkyl group,

a heteroaryl group chosen from thiazolyl, isoxazolyl, pyridyl and benzimidazolyl, which optionally is mono- and bicyclic ring is mono- or disubstituted with Q-s alkyl groups and the substituents can be the same or different,

a piperidinyl group, each of which may be substituted on the nitrogen atom by a

C 1-3 alkyl group,

a phenyl group optionally disubstituted with fluorine, chlorine, bromine or iodine atoms, C 1-5 -alkyl, C 1-3 -alkoxy, carboxy-, C 1-3 -alkoxycarbonyl, aminosulfonyl, nitro or cyano groups, wherein the substituents may be the same or different,

a phenyl or pyridyl group, each of which may be substituted with a trifluoromethoxy group, with a fluorine, chlorine, bromine or iodine atom,

with a C1-3-alkyl group, which can be substituted in the 2- or 3-position with an amino-, do-alkylamino-, di-(C1-3-alkyl)-amino-, phenyl-C1-3-alkylamino- , N-(C10-alkyl)-phenyl-C1-3-alkylamino, pyrrolidino or piperidino group,

with a phenyl-C1-3-alkylamino-C1-3-alkyl group, which in the phenyl nucleus can be mono- or disubstituted with fluorine, chlorine, bromine or iodine atoms, the substituents can be the same or different,

with a C 1-5 -alkyl-, phenyl-, imidazolyl-, C 3-7 -cycloalkyl-, C 1-3 -alkyl-C 1-3 -alkyl-, phenyl-C 1-3 -alkyl-, C 1-3 -alkyl-carbonyl- C1-3-alkyl-, carboxy-, C1-3-alkylaminocarbonyl-, aminocarbonyl-, C1-3-alkylaminocarbonyl-, di-(C1-3-alkyl)-aminocarbonyl-, phenyl-C1-3-alkylaminocarbonyl-, N-( C 1-3-alkyl)-phenyl-C 1-3-alkylamino-carbonyl-, C 1-3-alkylamino-carbonyl-C 1-3-alkylaminocarbonyl-, piperidinocarbonyl-, N-(C 1-3-alkyl)-piperazino-carbonyl-, nitro-, amino-, C10-alkylamino-, di-(C1-3-alkyl)-amino-, morpholino-, C2-4-alkanoylamino-, N-(C1-3-alkyl)-C2-4-alkanoylamino -, cyano, hydroxy-Ci-3-alkyl or N-(Ci-3-alkyl)-benzoylamino group,

with an N-(C1_3-alkyl)-C2^-alkanoylamino group, which in the alkyl part is additionally

substituted with a carboxy or Cu-alkylcarbonyl group,

with a C 1-3 alkylaminocarbonyl or di-(C 1-3 alkyl)aminocarbonyl group, i

in which an alkyl part is additionally substituted with a di-(C1-3-alkyl)-amino group, or

with an N-(C(.3-alkyl)-Ci-3-alkylsulfonylamino- or N-(Ci.3-alkyl)-phenylsulfonyl-amino group, in which the alkyl part may additionally be substituted with a cyano-, Ci-3 - alkoxycarbonyl, di-(C1-3-alkyl)amino, C1-3-alkylaminocarbonyl or piperidinocarbonyl group,

a phenyl group substituted with a C 1-3 alkyl group, in which the alkyl part is substituted with a C 1-3 alkoxycarbonyl-, amino-, C 1-5 -alkylamino-, di-(C 1-5 -alkyl)-amino-, C 2 -alkanoylamino-, N-(C1-3-alkyl)-C2-4-alkanoylamino-, pyrrolidino-, dehydro-pyrrolidino-, piperidino-, dehydropiperidino-, 3-hydroxypiperidino-, 4-hydroxypiperidino-, hexamethyleneimino-, aminophenyl- or C3-7 cycloalkylamino, phenylamino group,

with one in the phenyl part, optionally with a halogen atom or a Cu-alkoxy group

substituted N-phenyl-C1-3-alkyl-N-C1-3-alkylamino group,

with an N-halo-Ci-3-alkyl-N-phenyl-Ci-3-alkyl-amino group optionally substituted with a halogen atom in the phenyl part,

with an N-phenyl-C10-alkylamino group optionally substituted with a halogen atom in the phenyl part,

or with an N-C2^-alkanyl-N-C1-3- alkoxycarbonyl-C1-3-alkylamino-, N-phenyl-N-C1-3-alkylamino-, C1-3-alkylcarbonyl-C1-3-alkylamino- , morpholino-, thiomorpholino-, 1-oxothiomorpholino-, piperazino-, 4-(C].3-alkyl)-piperazino-, 4-phenyl-piperazino-, 4-(C2-4-alkanoyl)-piperazino-, 4 -benzoylpiperazino or imidazolyl group,

wherein the above-mentioned saturated cycloalkyleniminorings may additionally be substituted with one or two Cj-s alkyl groups, with a C3-7 cycloalkyl, hydroxy, C1-3 alkoxycarbonyl, benzyl or a phenyl group or with a hydroxy and a phenyl group,

or a methylene group adjacent to the nitrogen atom in the aforementioned cycloalkylene diminomer rings may be replaced by a carbonyl group, or

on one of the aforementioned unsubstituted cycloalkylene diminomer rings, a phenyl ring optionally substituted with one or two C1-3 alkoxy groups can be condensed over two neighboring carbon atoms,

as well as their isomers and their pharmaceutically acceptable salts.

The above-mentioned compounds of the general formula I, where Ri is a hydrogen atom, show valuable pharmacological properties, in particular an inhibitory effect on various kinases, especially on complexes of CDK (CDK1, CDK2, CDK3, CDK4, CDK6, CDK7, CDK8 and CDK9) with their specific cyclins (A, Bl, B2, C, Dl, D2, D3, E, F, Gl, G2, H, I and K) and on viral cyclin (see L. Mengtao in J. Virology 71(3) , 1984-1991

(1997)), and the other compounds of the above-mentioned general formula I, constitute valuable intermediates for the preparation of the aforementioned compounds.

The object of the present invention is thus the above-mentioned compounds of the general formula I, wherein the compounds, in which R[ is a hydrogen atom, have valuable pharmacological properties.

The present invention further relates to substituted indolinones of general formula I according to claim 1, characterized in that

X is an oxygen atom,

Ri is a hydrogen atom,

R 2 is a carboxy, C 1 -C 6 -alkylcarbonyl or aminocarbonyl group, in which the amino part may be substituted by one or two C 1-3 alkyl groups and the substituents may be the same or different,

R3 is a phenyl group,

R 4 is hydrogen or a methyl group and

R 5 is hydrogen,

a C1.5-alkyl group or a benzyl group optionally substituted with a carboxy- or C1-3-alkoxycarbonyl group,

a C3-7 cycloalkyl group optionally substituted with a methyl group,

an indanyl, pyridyl, isoxazolyl, thiazolyl or benzimidazolyl group optionally substituted with a methyl group,

a methylphenyl group optionally substituted with a fluorine, chlorine or bromine atom, with a methoxy, carboxy, C1.3-alkyloxycarbonyl, nitro or aminosulfonyl group or a dimethoxyphenyl group,

a piperidinyl group, each of which is substituted at the nitrogen atom with a Cu-alkyl group,

a phenyl group, which may be substituted

with a trifluoromethoxy group, with a fluorine, chlorine, bromine or iodine atom,

with a C 1-3 alkoxy group, which can be substituted in the 2- or 3-position with an amino-, C 1-3 -alkylamino-, di-(C 1-3 -alkyl)-amino-, phenyl-C 1-3 - alkylamino, N-(Ci-3-alkyl)-phenyl-Ci-3-alkylamino, pyrrolidino or piperidino group,

with a phenyl-Ci.3-alkylamino-Ci.3-alkyl group, which in the phenyl nucleus may be substituted with a fluorine, chlorine, bromine or iodine atom,

with a C 1-8 -alkyl-, phenyl-, imidazolyl-, C 3-7 -cycloalkyl-, C 1-3 -alkyl-C 1-3 -alkyl-, phenyl-C 1-3-alkoxy-, C 1-3 - Alkoxycarbonyl-Ci-3-alkyl-, carboxy-, Qo-Alkoxy-carbonyl-, aminocarbonyl-, Cu-alkylaminocarbonyl-, di-(Ci-3-alkyl)-aminocarbonyl-, phenyl-Ci-3-alkylaminocarbonyl-, N -(C1.3-alkyl)-phenyl-C1.3-alkylamino-carbonyl-, piperidinocarbonyl-, N-(C1.3-alkyl)-piperazinocarbonyl-, nitro-, amino-, C1-3-alkylamino- , di-(C1-3-alkyl)-amino-, morpholino-, C2-4-alkanoylamino-, N-(C1-3-alkyl)-C2-4-alkanoylamino- or N-(C1-3-alkyl) -benzoylamino group,

with an N-(C1-3-alkyl)-C2-3-alkanoylamino group, which in the alkyl part is additionally substituted with a carboxy- or Cu-alkoxycarbonyl group,

with a C1-3-alkylaminocarbonyl or di-(C1-3-alkyl)aminocarbonyl group, in which an alkyl part is additionally substituted with a di-(C1-3-alkyl)amino group, or

with an N-(Ci-3-alkyl)-C].3-alkylsulfonylamino- or N-(Ci-3-alkyl)-phenylsulfonyl-amino group in which the alkyl part can additionally be substituted with a cyano-, Cu- carbonyl, di-(C 1-3 alkyl)amino, C 1-3 alkylaminocarbonyl or piperidinocarbonyl group,

a phenyl group optionally substituted with a C 1-3 alkyl group, in which the alkyl part is substituted with a C 1-3 alkoxycarbonyl-, amino-, C 1-5 -alkylamino-, di-(C 1-5 alkyl)-amino-, C2-4-alkanoylamino-, N-(C1-3-alkyl)-C2-4-alkanoylamino-, pyrrolidino-, dehydro-pyrrolidino-, piperidino-, dehydro-piperidino-, 3-hydroxypiperidino-, 4-hydroxypiperidino-, hexamethyleneimino-, morpholino-, thiomorpholino-, piperazino-, 4-(C1.3-alkyl)-piperazino-, 4-phenyl-piperazino-, 4-(C2^-alkanoyl)-piperazino-, 4-benzoyl-piperazino - or imidazolyl group,

wherein the aforesaid saturated cycloalkyleniminorings may additionally be substituted with one or two C 1-5 alkyl groups, with a C 3-7 cycloalkyl, hydroxy, C 1-3 alkoxycarbonyl, benzyl or phenyl,

or a methylene group adjacent to the nitrogen atom in the aforementioned cycloalkylenimine ring may be replaced by a carbonyl group, or

on one of the aforementioned unsubstituted cycloalkylenimine rings over two neighboring carbon atoms, a phenyl ring optionally substituted with one or two C1-3 alkoxy groups can be condensed on,

as well as their isomers and their pharmaceutically acceptable salts.

The present invention further relates to substituted indolinones with the general formula I according to claim 1, characterized in that

X is an oxygen atom,

Ri is a hydrogen atom,

R 2 is a carboxy, C 1 -C 6 -alkylcarbonyl or aminocarbonyl group, in which the amino part may be substituted by one or two C 1-3 alkyl groups and the substituents may be the same or different,

R3 is a phenyl group,

R4 is a hydrogen atom or a methyl group and

R5 is a hydrogen atom,

a C1-3 alkyl group, a benzyl group or a methyl or ethyl group substituted with a C1-3 alkoxycarbonyl group,

a C3.7-cycloalkyl group optionally substituted with a methyl group,

an indanyl, pyridyl, isoxazolyl, thiazolyl or benzimidazolyl group optionally substituted with a methyl group,

a methylphenyl group optionally substituted with a fluorine, chlorine or bromine atom, with a methoxy-, carboxy-, C1-3-alkyloxycarbonyl, nitro or aminosulfonyl group or a dimethoxyphenyl group,

a 4-piperidinyl group, which is substituted on the nitrogen atom with a C 1-3 alkyl group,

a phenyl group, which is substituted

with a trifluoromethoxy, benzyloxy, cyano or nitro group, a fluorine, chlorine or bromine atom,

with a C 1-3 alkoxy group, wherein the terminal ethoxy and n-propoxy groups may each be substituted with a dimethylamino, diethylamino, N-ethylmethylamino, N-benzylmethylamino or piperidino group,

with a phenyl-Ci-3-alkylamino-Ci-3-alkyl group, which in the phenyl nucleus may be substituted with a fluorine, chlorine, bromine or iodine atom,

with a C1-3-alkyl-, phenyl-, imidazolyl-, cyclohexyl-, methoxymethyl-, C1-6-alkyl-carbonyl-methyl-, carboxy-, C1-3-alkoxycarbonyl-, amino-carbonyl-, Cu-alkylaminocarbonyl-, di-(Ci-3-alkyl)-aminocarbonyl-, phenyl-Ci-3-alkylaminocarbonyl-, N-(Ci-3-alkyl)-phenyl-C[.3-alkylaminocarbonyl-, piperidinocarbonyl-, N-(Ci. 3-alkyl)-piperazinocarbonyl-, amino-, Cu-alkylamino-, di-(Ci-3-alkyl)-amino-, morpholino-, C2-4-alkanoylamino-, N-(Ci-3-alkyl)-C2 ^- alkanoylamino-, benzoylamino- or N-(C1-3-alkyl)-benzoylamino group,

with an N-(C1.3-alkyl)-C2-3-alkanoylamino group, which in the alkyl part is additionally substituted with a carboxy- or Cu-alkoxycarbonyl group,

with a Cu-alkylaminocarbonyl or di-(Ci-3-alkyl)-aminocarbonyl group, in which an alkyl part is additionally substituted with a di-(Ci-3-alkyl)-amino group, or

with an N-(C1.3-alkyl)-C1-3-alkylsulfonylamino- or N-(C1-3-alkyl)-phenylsulfonyl-amino group, in which the alkyl part can additionally be substituted with a cyano-, carboxy-, C 1-3 -Alkoxycarbonyl-, di-(C 1-3 -alkyl)-amino-, Cu-alkylaminocarbonyl- or piperidino-carbonyl group,

a phenyl group optionally substituted with a Cu-alkyl group, in which the alkyl group is substituted with a C 1-3 -alkoxycarbonyl-, amino-, C 1-5 -alkylamino-, di-(C 1-5 -alkyl)-arnino-, C 2-3 -alkanoylamino -, N-(C1.3-alkyl)-C2^-alkanoylamino-, pyrrolidino-, dehydro-pyrrolidino-, piperidino-, dehydro-piperidino-, 4-hydroxypiperidino-, hexamethyleneimino-, morpholino-, thiomorpholino-, piperazino -, 4-(C1-3-alkyl)-piperazino-, 4-phenyl-piperazino-, 4-(C2-3-alkanoyl)-piperazino-, 4-benzoyl-piperazino- or imidazolyl group,

wherein the aforementioned saturated cycloalkylene diminor rings may additionally be substituted with a phenyl group or with one or two methyl groups,

or a methylene group adjacent to the nitrogen atom in the aforesaid cycloalkylene ring may be replaced by a carbonyl, or

on one of the aforementioned unsubstituted cycloalkylenimine rings, a phenyl ring optionally substituted with one or two C 1-3 alkoxy groups can be condensed over two neighboring carbon atoms,

as well as their isomers and their pharmaceutically acceptable salts.

The present invention further relates to substituted indolinones with the general formula I according to claim 1, characterized in that

X is an oxygen atom,

Ri is a hydrogen atom,

R2 is a carboxy or aminocarbonyl group, in which the amino part may be substituted with one or two Cu-alkyl groups and the substituents may be the same or different,

R3 is a phenyl group,

R4 is a hydrogen atom and

Rj is a hydrogen atom,

a 4-piperidinyl group, which is substituted on the nitrogen atom with a C 10 alkyl group,

a phenyl group, which may be substituted

with a C 1-3 alkoxy group, wherein each terminal ethoxy and n-propoxy group may be substituted with a dimethylamino, diethylamino, N-ethylmethylamino, N-benzylmethylamino or piperidino group,

with a phenyl-C]-3-alkylamino-Ci-3-alkyl group, which in the phenyl nucleus may be substituted with a fluorine, chlorine, bromine or iodine atom,

a phenyl group optionally substituted with a C 1-3 alkyl group, in which the alkyl group is substituted with a Cu-alkylamino-, amino-, Cu-alkylamino-, di-(Ci-5-alkyl)-amino-, C 2Jj-alkanoylamino-, N -(C].3-alkyl)-C2^-alkanoylamino-, pyrrolidino-, dehydro-pyrrolidino-, piperidino-, dehydro-piperidino-, 4-hydroxypiperidino-, hexamethyleneimino-, morpholino-, thiomorpholino-, piperazino-, 4 -(C1-3-alkyl)-piperazino-, 4-phenyl-piperazino-, 4-(C2-4-alkanoyl)-piperazino-, 4-benzoyl-piperazino- or imidazolyl group,

wherein the aforementioned saturated cycloalkylene diminor rings may additionally be substituted with a phenyl group or with one or two methyl groups,

or a methylene group adjacent to the nitrogen atom in the aforesaid cycloalkylenimine ring may be replaced with a carbonyl group, and the aforesaid monosubstituted phenyl groups may additionally be substituted with a fluorine, chlorine or bromine atom, a methyl, amino, Ci.3- alkylamino or di-(C 1-3 alkyl) amino group, or

on one of the aforementioned unsubstituted cycloalkylene diminomer rings, a phenyl ring optionally substituted with one or two C1-3 alkoxy groups can be condensed over two neighboring carbon atoms,

as well as their isomers and their pharmaceutically acceptable salts.

Particularly preferred compounds with the above-mentioned general formula I are those in which the residue R.2 is in the 5-position.

Particularly preferred are the following 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-bromo-phenylamino)-1-phenyl-methylene]-5-amido-2-indolinone,

(d) 3-Z-[l-(4-dimethylamino-methyl)-phenylamino)-1-phenyl-methylene]-5-amido-2-indolinone, (e) 3-Z-[l-(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-[l-(4-hexamethyleneiminomethyl-phenylamino)-l-phenyl-methylene]-5-amido-2-indolinone, (h) 3-Z-[l-(4-(4 -benzyl-piperidino)-methyl)-phenylamino)-l-phenyl-methylene]-5-amido-2-indolinone, (i) 3-Z-[l-(4-(N-butyl-aminomethyl)-phenylamino) -l-phenyl-methylene]-5-amido-2-indolinone, (j) 3-Z-[l -(4-(N-(phenyl-methyl)-aminomethyl)-phenylamino)-l -phenyl-methylene] -5-amido-2-indolinone, (k) 3-Z-[l-(4-(N-methyl-N-benzyl-amino-methyl)-phenylamino)-1-phenyl-methylene]-5-amido- 2-indolinone, (1) 3-Z-[l-(4-piperidino-methyl-phenylamino)-1-phenyl-methylene]-5-dimethylcarbamoyl-2-indolinone, (m) 3-Z-[l-( 4-piperidino-methyl-phenylamino)-1-phenyl-methylene]-5-diethylcarbamoyl-2-indolinone,

(n) 3-Z-[1-(4-(3-diethylamino-propoxy)-phenylamino)-1-phenyl-methylene]-5-amido-2-indolinone

and their pharmaceutically acceptable salts.

The present invention further relates to physiologically tolerable salts, characterized in that they are of compounds according to claims 1 to 6.

The invention further relates to pharmaceuticals, characterized in that they contain a compound according to at least one of claims 1 to 6 or a salt according to claim 7, next to possibly one or more inert carriers and/or diluents.

It is also described the use of a compound according to at least one of claims 1 to 6 or a salt according to claim 7 for the production of a drug which is suitable for the treatment of extensive or abnormal cell proliferations.

The present invention further relates to a method for producing a medicinal product according to claim 8, characterized in that, by non-chemical means, one or more inert carriers are incorporated into a compound according to at least one of claims 1 to 6 or a salt according to claim 7 and/or diluent.

The invention also relates to a method for producing compounds according to claims 1 to 7, characterized in that a. a compound with the general formula

in which

X, R-2 and R3 are defined as in claims 1 to 6,

Rg is a hydrogen atom, a protecting group for the nitrogen atom of the lactam group or a bond on a solid phase and

Zi is a halogen atom, a hydroxy, alkoxy or aralkyl group, is reacted with an amine of the general formula

in which

R4 and R5 are defined as in claims 1 to 6,

and if necessary, a protecting group used for the nitrogen atom of the lactam group or a compound thus obtained is then cleaved from the solid phase, or

b. for the preparation of a compound of the general formula I, which contains an aminomethyl group and X is an oxygen atom, a compound of the general formula is reduced

in which

Ri to R4 are defined as in claims 1 to 6 and

R7 has the same meaning as R5 in claims 1 to 6, provided that R5 contains a cyano group,

and, if desired, subsequently transfers a compound of the general formula I obtained in this way, which contains an alkoxycarbonyl group, by means of hydrolysis to a corresponding carboxy compound or

a compound of the general formula I obtained in this way, which contains an amino or alkylamino group, is transferred by means of alkylation or reductive alkylation to a corresponding alkylamino or dialkylamino compound or

a compound of the general formula I obtained in this way, which contains an amino or alkylamino group, is transferred by means of acylation to a corresponding acyl compound or

a compound of the general formula I obtained in this way, which contains a carboxy group, is transferred by means of esterification or amidation to a corresponding ester or aminocarbonyl compound or

if necessary, a protective residue used during the reaction to protect reactive groups is cleaved off, or

if desired, such an obtained compound of the general formula I is then cleaved into their stereoisomers, or

such an obtained compound of the general formula I is transferred to their salts, in particular for pharmaceutical use in their physiologically tolerable salts with an inorganic or organic acid or base.

As a protecting group for the nitrogen atom of the lactam group comes, for example, an acetyl, benzoyl, ethoxycarbonyl, tert-butyloxycarbonyl or benzyloxycarbonyl group and

as solid phase a "Rink" or Sikter resin in consideration.

The reaction is conveniently carried out in a solvent such as dimethylformamide, toluene, acetonitrile, tetrahydrofuran, dimethylsulfoxide, methylene chloride or their mixture, optionally in the presence of an inert base such as triethylamine, N-ethyl-diisopropylamine or sodium bicarbonate at temperatures between 20 and 175°C, during which an applied protecting group can simultaneously be cleaved due to reamidation.

The possibly necessary subsequent cleavage of an applied protecting group is conveniently carried out either hydrolytically 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 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 preferably with reamidation with a primary or secondary organic base such as ammonia, methylamine, butylamine, dimethylamine or piperidine in a solvent such as methanol, ethanol, dimethylformamide and mixtures thereof or in an excess of added amine at temperatures between 0 and 100°C, preferably at temperatures between 10 and 50°C.

Separation of a used solid phase preferably takes place with the aid of trifluoroacetic acid and water in the presence of a dialkyl sulphide such as dimethyl sulphide at temperatures between 0 and 35°C, preferably at room temperature.

Reduction is preferably carried out by means of 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, preferably at room temperature, and at a hydrogen pressure of 1 to 7 bar, preferably from 3 to 5 bar.

Hydrolysis preferably takes place 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 sulfuric acid or in the presence of an alkali 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.

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 by adding an acid such as hydrochloric acid in the presence of catalytically activated hydrogen, e.g. of hydrogen in the presence of Raney nickel, platinum or palladium/carbon, or in the presence of a metal hydride such as sodium borohydride, lithium borohydride or lithium aluminum hydride at temperatures between 0 and 100°C, preferably at temperatures between 20 and 80°C.

Alkylation is carried out with an alkylating agent such as alkyl halide or dialkyl sulfate such as methyl iodide, dimethyl sulfate or propyl bromide, preferably in a solvent such as methanol, ethanol, methylene chloride, tetrahydrofuran, toluene, dioxane, dimethyl sulfoxide or dimethyl formamide, optionally in the presence of an inorganic or a tertiary organic base which triethylamine, N-ethyl-diisopropylamine or dimethylaminopyridine, preferably at temperatures between 20°C and the boiling temperature of the solvent used.

Acylation is preferably carried out in a solvent such as methylene chloride, diethyl ether, tetrahydrofuran, toluene, dioxane, acetonitrile, dimethylsulfoxide 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. Thus, the acylation is carried out with a corresponding acid, preferably in the presence of a water-attracting agent, e.g. in the presence of chloroformic acid isobutyl ester, orthocarboxylic acid tetra-ethyl ester, orthoacetic acid trimethyl ester, 2,2-dimethoxy-propane, tetramethoxysilane, thionyl chloride, trimethylchlorosilane, phosphorus trichloride, phosphorus pentoxide, N,N'-dicyclohexylcarbodiimide, N,N'-dicyclohexylcarbodiimide/ N-hydroxysuccinimide, N ^N-dicyclohexylcarbodiimide/ 1-hydroxy-benzotriazole, 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium tetrafluoro-borate, 2-(1H-benzotriazol-1-yl)-1, 1,3,3-tetramethyluronium tetrafluoroborate/1-hydroxybenz-triazole, N,N'-carbonyldiimidazole or triphenylphosphine/tetrachlorocarbon, and optionally with the addition of a base such as pyridine, 4-dimethylaminopyridine, N-methylmorpholine or triethylamine appropriately at temperatures between 0 and 150°C, preferably at temperatures between 0 and 100°C, and the acylation is carried out with a correspondingly reactive compound such as their anhydride, ester, imidazolides or halides, optionally in the presence of a tertiary organic base such as triethylamine, N-ethyldiisopropyl amine or N-methylmorpholine at temperatures between 0 and 150°C, preferably at temperatures between 50 and 100°C.

Esterification or amidation is conveniently carried out by reacting a reactive corresponding carboxylic acid derivative with a corresponding alcohol or amine as stated above.

In the above-mentioned reaction, any reactive groups such as carboxy, amino, alkylamino or imino groups which are protected during the reaction with normal protective groups which are cleaved off again after the reaction can be used.

Examples of protective residues for a carboxyl group are trimethylsilyl, methyl, ethyl, tert.butyl, benzyl or tetrahydropyranyl group and

as a protecting residue for an amino, alkylamino or imino group, acetyl, trifluoroacetyl, benzoyl, ethoxycarbonyl, tert-butoxycarbonyl, benzyloxycarbonyl, benzyl, methoxybenzyl or 2,4-dimethoxybenzyl group and for the amino group in addition the phthalyl group.

The possibly subsequent cleavage of an applied protective residue takes place, for example, hydrolytically 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 sulfuric acid or in the presence of an alkali 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.

Cleavage of a benzyl, methoxybenzyl or benzyloxycarbonyl residue, on the other hand, takes place, for example, hydrogenolytically, e.g. with hydrogen in the presence of a catalyst such as palladium/carbon in a solvent such as methanol, ethanol, acetic acid ethyl ester, dimethylformamide, dimethylformamide/acetone or vinegar optionally with the addition of an acid such as hydrochloric acid or acetic acid at temperatures between 0 and 50°C, preferably on the other hand, at room temperature, and at a hydrogen pressure of 1 to 7 bar, preferably on the other hand from 3 to 5 bar.

Cleavage of a methoxybenzyl group can also take place in the presence of an oxidizing agent such as Cer(IV) ammonium nitrate in a solvent such as methylene chloride, acetonitrile or acetonitrile/water at temperatures between 0 and 50°C, preferably at room temperature.

Cleavage of a 2,4-dimethoxybenzyl residue, on the other hand, preferably takes place in trifluoroacetic acid in the presence of anisole.

Cleavage of a tert-butyl or tert-butyloxycarbonyl residue preferably takes place by treatment with an acid such as trifluoroacetic acid or hydrochloric acid, optionally by using a solvent such as methylene chloride, dioxane, ethyl acetate or ether.

Cleavage of a phthalyl residue preferably takes place 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 20 and 50°C.

Furthermore, obtained chiral compounds of general formula I can be separated into their enantiomers and/or diastereomers.

Thus, for example, it is possible to separate the obtained compounds of general formula I, which occur in racemates, according to the per se known method (see Allinger N. L. and Eliel E. L. in "Topics in Stereochemistry", Vol. 6, Wiley Interscience, 1971) in their optical antipodes and compounds of general formula I with at least 2 asymmetric carbon atoms due to their physicochemical differences according to per se known methods, e.g. with chromatography and/or fractional crystallization, in their diastereomers, and if they exist in racemic form, then as indicated above be separated into the enantiomers.

Enantiomer separation takes place preferably by column separation on chiral phases and by recrystallization from an optically active solvent or by reaction with one, with racemic compound salts or derivatives such as e.g. ester or amide-forming optically active compounds, especially acids and their activated derivatives or alcohols, and separating the thus obtained mixtures of diastereomeric salts or derivatives, e.g. due to different solubility, since the free antipodes can be liberated from the pure diastereomeric salts or derivatives by the action of a suitable agent. Particularly applicable, optically active acids are e.g. The D and L form of tartaric acid, dibenzoyltartaric acid, di-o-tolyltartaric acid, malic acid, mandelic acid, camphorsulphonic acid, glutamic acid, N-acetyl-glutamic acid, aspartic acid, N-acetyl-aspartic acid or quinic acid. As an optically active alcohol, (+)- or (-)-menthol can be mentioned, for example, and as an optically active acyl residue in amides, for example (+)- or (-)-menthyloxycarbonyl residue.

Furthermore, the obtained compounds of formula I can be their salts, especially for pharmaceutical use in their physiologically tolerable salts with inorganic or organic acids. Examples of acids that come into consideration are hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, fumaric acid, Bernstein acid, lactic acid, citric acid, tartaric acid, maleic acid or methanesulphonic acid.

Moreover, the thus obtained new compounds of formula I, if they contain a carboxy group, can, if desired, finally be transferred into their salts with inorganic or organic bases, especially for pharmaceutical use in their physiologically tolerable salts. Examples of bases that can be mentioned are sodium hydroxide, potassium hydroxide, cyclohexylamine, ethanolamine, diethanolamine and triethanolamine.

The compounds of general formula I to VIII used as starting products are partly known in the literature or can be obtained according to methods known in the literature or described in the examples.

As indicated above, the compounds of general formula I, in which Ri is a hydrogen atom or a prodrug residue, exhibit valuable pharmacological properties, in particular inhibition of the action on various kinases and cyclin/CDK complexes, on proliferative cultured human tumor cells as well as after oral administration on the growth course of tumors in nude mice that had been infected with human tumor cells.

For example, the compounds listed in Table 1 were investigated in terms of their biological properties:

TEST 1

Inhibition of cvklin/CDK enzyme activity in vitro

High Five™ insect cells (BTI-TN-5B1-4), which were infected with a high titer of recombinant Baculovirus, were used for the production of active human cyclin/CDK holoenzymes. Using a Baculovirus vector containing two promoters (polyhedrin enhancer promoter, P10 enhancer promoter), GST-linked cyclin (e.g. cyclin D1 or cyclin D3) with corresponding Hise-linked CDK subunit (e.g. for CDK4 or CDK6) expressed in the same cells. The active holoenzyme was isolated by affinity chromatography on Glutathione-Sepharose. Recombinant GST-linked pRB (aa 379-928) was produced in E. coli and purified by affinity chromatography on Glutathione-Sepharose.

The substrate used in a kinase assay depended on the specific kinases. Histone H1 (Sigma) was used as substrate for cyclin E/CDK2, cyclin A/CDK2, cyclin B/CDK1 and for v-cyclin/CDK6. GST-linked pRB (aa 379-928) was used as substrate for cyclin D1/CDK4, cyclin D3/CDK4, cyclin D1/CDK6 and for cyclin D3/CDK6.

Lysates with recombinant Baculovirus-infected insect cells or also recombinant kinases (obtained from the lysates by purification) were incubated together with radiolabeled ATP in the presence of a suitable substrate with different concentrations of the Inhibitor in a 1% DMSO (dimethyl sulfoxide) solution for 45 minutes at 30°C. The substrate proteins with associated radioactivity were filled with 5% TCA (trichloroacetic acid) in hydrophobic PVDF multi-well microtiter plates (millipore) or with 0.5% phosphoric acid solution on Whatman P81 filters. After addition of scintillation liquid, radioactivity was maintained in a Wallace 1450 microbeta liquid scintillation counter.

Per concentration of substance, a double measurement was carried out; The IC 50 values for the enzyme inhibition were calculated.

TEST 2

Inhibition of profiling by dried human tumor cells

The cell from the Leiomyosarcoma tumor cell line SK-UT-1B (obtained from the American Type Culture Collection (ATCC)) was grown in minimal essential medium with non-essential amino acids (Gibco), reduced with sodium pyruvate (1 mMol), Glutamine (2 mMol) and 10% fetal calf serum (Gibco) and harvested in the log growth phase. Finally, the SK-UT-1B cells were placed in Cytostar® multi-well plates (Amersham) at a density of 4000 cells per well. well and incubated overnight in an incubator. Different concentrations of the compounds (dissolved in DMSO; final concentration: <1%) were added to the cells. After 48 hours of incubation, ^C-Thymidine (Amersham) was added to each well, and this was further incubated for 24 hours. The amount of ^C-Thymidine, which was incorporated in the presence of the inhibitors into the tumor cells and which represents the number of cells in S phase, was measured in a Wallace 1450 microbeta liquid scintillation counter. The IC 50 values were calculated for inhibition of proliferation (= inhibition of incorporated <1>^C-Thymidine), while correcting for background radiation. All measurements were carried out twice.

TEST 3

In vivo effect on tumor-bearing nude mice

IO<6> cells [SK-UT-1B, or non-small cell lung tumorNCI-H460 (obtained from ATCC)] in a volume of 0.1 ml were subcutaneously injected into male and/or female nude mice (NMRI nu/nu; 25-35 g; N = 10-20); alternatively, small pieces of SK-UT-1B or NCI-H460 cell clumps were implanted subcutaneously. One to three weeks after injection, respectively. implantation, a kinase inhibitor was applied daily for a duration of 2 to 4 weeks orally (per feeding tube). Tumor size was measured three times per week with a digital caliper. The effect of a kinase inhibitor on the course of tumor growth was determined as percent inhibition compared to a placebo-treated control group.

The table indicated below contains the obtained results of in vitro test 2:

Due to their biological properties, the novel compounds of general formula I, as well as their isomers and their physiologically tolerable salts, are suitable for the treatment of diseases characterized by extensive or abnormal cell proliferation.

Such diseases include (without claim to completeness): Viral infections (eg HIV and Kaposi's Sarcoma); inflammation and autoimmune diseases (eg Colitis, Arthritis, Alzheimer's disease, Glomerulonephritis and wound healing); bacterial, fungal and/or parasitic infections; leukemias, lymphomas and solid tumors; skin diseases (eg psoriasis); joint diseases; cardiovascular diseases (eg restenosis and hypertrophy). Furthermore, they are useful as protection of proliferative cells (eg hair, gut, blood and progenitor cells) against DNA damage by radiation, UV treatment and/or cytostatic treatment.

The new compounds can be used for short- or long-term treatment of the above-mentioned diseases, possibly also in combination with other "known" compounds such as other cytostatics.

Dosage which is necessary to achieve a corresponding effect contains preferably in the case of intravenous administration 0.1 to 30 mg/kg, preferably 0.3 to 10 mg/kg, and in the case of oral administration 0.1 to 100 mg/kg, preferably 0, 3 to 30 mg/kg, each 1 to 4 times daily. Compound with formula I produced according to the invention can be mixed together with one or more inert common carriers and/or diluents, e.g. with corn starch, milk sugar, cane sugar, microcrystalline cellulose, magnesium stearate, polyvinylpyrrolidone, citric acid, tartaric acid, water, water/ethanol, water/glycerin, water/sorbitol, water/polyethylene glycol, propylene glycol, cetyl stearyl alcohol, carboxymethyl cellulose or fatty compounds such as hard fat or suitable mixtures thereof, in usual galenic preparations such as tablets, dragees, capsules, powders, suspensions, juices and as solutions for injections or infusions.

The examples given below shall explain the invention in more detail:

Example I

1- acetyl- 2- indolinone- 5- carboxylic acid methyl ester

10.5 g of 2-Indolinone-5-carboxylic acid methyl ester (Prepared analogously to Ogawa et al. Chem.farm.Bull 36,2253-2258 (1988)) is stirred in 30 ml of acetic anhydride for 4 hours at 140°C. It is then allowed to cool, poured into ice water and the sediment is sucked off. The product is washed once more with water, then taken up in methylene chloride, dried over sodium sulfate and evaporated.

Yield: 11 g (86% of theoretical),

Rf value: 0.63 (silica gel; methylene chloride/methanol = 50:1)

Example II

I - acetyl- 3-( l - ethoxy- 1 - phenyl- methylene)- 2- indolinone- 5- carboxylic acid methyl ester

II g of 1-acetyl-2-indolinone-5-carboxylic acid methyl ester is stirred in 110 ml of acetic anhydride and 30 ml of orthobenzoic acid triethyl ester for 2 hours at 100°C. It is then inverted, the residue washed with ether and filtered off.

Yield: 11.5 g (67% of theoretical),

Rf value: 0.55 (silica gel, methylene chloride/petroleum ether/acetic ester = 4:5:1)

Example III

28.0 g of Rink-Harz (MBHA-Harz, Firma Novobiochem) is allowed to swell in 330 ml of dimethylformamide. 330 ml of 30% piperidine in dimethylformamide is then added and stirred for 7 minutes, in order to cleave the FMOC protecting group. The resin is then washed several times with dimethylformamide. Finally, 7.3 g of 2-Indolinone-5-carboxylic acid, 5.6 g of hydroxybenzotriazole, 13.3 g of O-Cbenzotriazole-1-y^-NjNjN^N-tetramethyluronium-tetrafluoroborate and 5.7 ml of N-ethyl-diisopropylamine are added in 300 ml of dimethylformamide and stir for 1 hour. Now the solution is filtered off and the resin is washed five times with 300 ml of dimethylformamide and three times with 300 ml of methylene chloride. For drying, nitrogen is blown through the resin.

Yield: 28 g of charged resin

Example IV

5 g of coated resin prepared according to Example III is stirred with 15 ml of acetic anhydride at 80°C for 1 hour. 15 ml of orthobenzoic acid triethyl ester is then added and stirred for a further 3 hours at 110°C. The resin is then filtered off and washed with dimethylformamide, methanol and finally with methylene chloride.

Yield: 7 g moist resin

Example V

4-(ethylaminomethyl)-nitrobenzene

6 g of 4-nitrobenzyl bromide is dissolved in 25 ml of ethanol, mixed with 25 ml of 10% ethanolic ethylamine solution and heated at reflux for 2 hours. The solution is then inverted, the residue is taken up with methylene chloride and washed with dilute caustic soda. Finally, the organic phase is evaporated.

Yield: 2.3 g (46% of theoretical),

Rf value: 0.2 (silica gel; methylene chloride/methanol = 9:1)

Analogously, it is produced:

4-[N-(4-chlorophenyl-methyl)-amino-methyl]-nitrobenzene

4-(N-cyclohexyl-amino-methyl)-nitrobenzene

4-(N-isopropyl-amino-methyl)-nitrobenzene

4-(N-butyl-amino-methyl)-nitrobenzene

4-(N-Methoxycarbonyl-methyl-amino-methyl)-nitrobenzene

4-(N-(phenyl-methyl)-amino-methyl)-nitrobenzene

4-(Pyrrolidino-methyl)-nitrobenzene

4-(morpholino-methyl)-nitrobenzene

4-(piperidino-methyl)-nitrobenzene

4-(hexamethyleneimino)-nitrobenzene

4-(4-hydroxy-piperidino-methyl)-nitrobenzene

4-(4-methyl-piperidino-methyl)-nitrobenzene

4-(4-ethyl-piperidino-methyl)-nitrobenzene

4-(4-isopropyl-piperidino-methyl)-nitrobenzene

4-(4-phenyl-piperidino-methyl)-nitrobenzene

4-(4-benzyl-piperidino-methyl)-nitrobenzene

4-(4-ethoxycarbonyl-piperidino-methyl)-nitrobenzene

4-(Dimethylamino-methyl)-nitrobenzeri

4-(Dipropylamino-methyl)-nitrobenzene

4-(4-tert.butyloxycarbonyl-piperazino-methyl)-nitrobenzene 3 -(dimethylamino-methyl)-nitrobenzene

4-(2-diethylamino-ethyl)-nitrobenzene

4-(2-morpholinyl-ethyl)-nitrobenzene

4-(2-pyrTolidinyl-ethyl)-nitrobenzene

4-(2-piperidinyl-ethyl)-nitrobenzene

4-(N-ethyl-N-benzyl-amino-methyl)-nitrobenzene

4-(N-propyl-N-benzyl-amino-methyl)-nitrobenzene

4-|^-methyl-N-(4-chlorophenylmethyl)-amino-methyl])-nitrobenzene 4-|N-methyl-N-(4-bromophenylmethyl)-amino-methyl]-nitro 4- [N-methyl- N-(3-chlorophenylmethyl)-amino-methyl]-nitrobenzene 4-[N-methyl-N-(3,4-dimethoxyphenylmethyl)-amino-methyl]-nitrober^ 4-|^-methyl-N-(4- methoxyphenylmethyl)-amino-methyl]-nitrobenz^ 4-|N-2,2,2-trifluoroethyl-N-(phenylmethyl)-amino-methyl]-nitrobenzene 4-|N-2,2,2-trifluoroethyl-N- (4-chlorophenylmethyl)-amine^

Example VI

4- fN- etvl- N- tert. butoxcarbonvl- amino- metvlVnitrobenzene 2.2 g of 4-(ethylamino-methyl)-nitrobenzene is dissolved in 50 ml of acetic ester and stirred with 2.6 g of di-tert-butyl dicarbonate for 30 minutes at room temperature. The solution is then washed with water and evaporated.

Yield: 3.4 g,

Rf value: 0.9 (silica gel, methylene chloride/methanol = 9:1)

Analogously, it is prepared: 4-|N-(4-chlorophenyl-methyl)-N-tert.butoxycarbonyl-amino-methyl)-nitrobenzene 4-(N-cyclohexyl-N-tert.butoxycarbonyl-amino-methyl)-nitrobenzene 4 -(N-isopropyl-N-tert.butoxycarbonyl-amino-methyl)-nitrobenzene 4-(N-butyl-N-tert.butoxycarbonyl-amino-methyl)-nitrobenzene 4-(N-methoxycarbonyl-methyl-N-tert. butoxycarbonyl-amino-methyl)-nitrobenzene 4-(N-(phenyl-methyl)-N-tert.butoxycarbonyl-amino-methyl)-nitrobenzene

Example VII

4- 0>iJ- etvl- N- tert. butoxycarbonyl-amino-methyl)-aniline 6.4 g of 4-(N-ethyl-N-tert.butoxycarbonyl-amino-methyl)-nitrobenzene is dissolved in 60 ml of methanol and hydrated with 1.5 g of Raney-Nickel at room temperature and 3 bars. The catalyst is then filtered off and the solution evaporated.

Yield: 4.78 g,

Rf value: 0.7 (silica gel, methylene chloride/methanol 50:1)

Analogously, it is prepared: 4-[N-(4-chlorophenyl-methyl)-N-tert.butoxycarbonyl-amino-methyl]-aniline 4-(N-cyclohexyl-N-tert.butoxycarbonyl-amino-methyl)-aniline 4 -(N-isopropyl-N-tert.butoxycarbonyl-amino-methyl)-aniline 4-(N-butyl-N-tert.butoxycarbonyl-amino-methyl)-aniline 4-(N-methoxycarbonyl-methyl-N-tert. butoxycarbonyl-amino-methyl)-aniline 4-(N-(phenyl-methyl)-N-tert.butoxycarbonyl-amino-methyl)-amline 4-(pyrrolidino-methyl)-aniline

4-(morpholinomethyl)-aniline

4-(piperidino-methyl)-aniline

4-(hexamethyleneimino-methyl)-aniline

4-(4-hydroxy-piperidino-methyl)-aniline

4-(4-methyl-piperidino-methyl)-aniline

4-(4-Ethyl-piperidino-methyl)-aniline

4-(4-isopropyl-piperidino-methyl)-aniline

4-(4-phenyl-piperidino-methyl)-aniline

4-(4-benzyl-piperidino-methyl)-aniline

4-(4-ethoxycarbonyl-piperidino-methyl)-amline

4-(2-morpholinyl-ethyl)-aniline

4-(2-pyrrolidinyl-ethyl)-aniline

4-(2-piperidinyl-ethyl)-aniline

4-(N-ethyl-N-benzyl-amino-methyl)-aniline

4-(N-propyl-N-benzyl-amino-methyl)-aniline

4-[N-methyl-N-(4-chlorophenylmethyl)-amino-methyl]-aniline 4-[N-methyl-N-(4-bromophenylmethyl)-amino-methyl]-aniline 4-[N-methyl-N -(3-chlorophenylmethyl)-amino-methyl]-aniline 4-[N-methyl-N-(3,4-dimethoxyphenylmethyl)-amino-methyl]-aniline 4-[N-methyl-N-( 4-Methoxyphenylmethyl)-amino-methyl]-aniline 4-[N-2,2,2-trifluoroethyl-N-(phenylmethyl)-amino-methyl]-aniline 4-n-2,2,2-trifluoroethyl-N- (4-chlorophenylmethyl)-amino-methyl]-aniline Preparation of end products: Example 1

3- Z-[ 1 -( 1 - methyl- piperidin- 4- yl- aminoV 1 - phenyl- methylene 1- 2- indolinone- 5- carboxylic acid methyl ester

11. 5 g l- acetvl- 3- n- ethoxyl- l- phenyl- methylene V2- indolinone- 5- carboxyl svremethyl ester

is dissolved in 115 ml of methylene chloride and stirred with 10.8 g of 4-amino-N-methylpiperidine for 5 hours at room temperature. 20 ml of methanolic ammonia is then added and left to stand overnight. The solution is evaporated and the residue washed with ether.

Yield: 11.9 g (97% of theoretical),

Rf value: 0.20 (silica gel; methylene chloride/methanol = 9:1)

C23H25N3O3

Mass spectrum: m/z = 391 (M<*>)

Analogously, it is produced:

(1) 3-Z-[1-(4-(piperidino-methyl)-phenylamino)-1-phenyl-methylene]-2-indolinone-5-carboxylic acid methyl ester

Rr value: 0.4 (silica gel, methylene chloride/methanol = 9:1)

C29H29N3O3

Mass spectrum: m/z = 467 (M^)

(2) 3-Z-[1-(4-(N-phenylmethyl-N-methylamino-methyl)-phenylamino)-1-phenyl-methylene]-2-indolinone-5-carboxylic acid methyl ester

C32H29N3O3

Mass spectrum: m/z = 503 (M<4>)

(3) 3-Z-[1-(4-(dimethylamino-methyl)-phenylamino)-1-phenyl-methylene]-2-indolinone-5-carboxylic acid methyl ester

C26<H>25N3O3

Mass spectrum: m/z = 427 (M<*>)

(4) 3-Z-[1-(3-(Dimethylamino-methyl)-phenylamino)-1-phenyl-methylene]-2-indolinone-5-carboxylic acid methyl ester

C26H25N3O3

Mass spectrum: m/z = 427 (M<*>)

(5) 3-Z-[ 1 -(4-chloro-phenylamino)-l -phenyl-methylene]-2-indolinone-5-carboxylic acid methyl ester (6) 3-Z-(l-phenylamino-l-phenyl-methylene) -2-indolinone-5-carboxylic acid methyl ester Example 2

3-Z-n-n-methyl-piperimin-4-yl-a^ 11.9 g 3-Z-[1-(1-methyl-piperidin-4-yl-amino)-1-phenyl-methylene]- 2-Indolinone-5-carboxylic acid methyl ester is heated at reflux in 300 ml of methanol and 150 ml of 1N sodium hydroxide solution for 4 hours. It is then neutralized with 150 ml IN hydrochloric acid and evaporated to dryness. The rest is washed several times with water and dried.

Yield: 86% of theoretical,

Rf value: 0.17 (silica gel; methylene chloride/methanol = 4:1)

C22<H>23N3O3

Mass spectrum: m/z = 377 (M<4>)

Analogously, it is produced:

(1) 3-Z-[ 1 -(4-(piperidino-methyl)-phenylamino)-1-phenyl-methylene]-2-indolinone-5-carboxylic acid

Rf value: 0.15 (silica gel, methylene chloride/methanol = 9:1)

C2<g>H27N303

Mass spectrum: m/z = 453 (M<+>)

(2) 3-Z-[1-(4-(N-phenylmethyl-N-methylamino-methyl)-phenylamino)-1-phenyl-methylene)-2-indolinone-5-carboxylic acid

<C>3iH27<N>303

Mass spectrum: m/z = 489 (M<*>)

(3) 3-Z-[1-(4-(dimethylamino-methyl)-phenylamino)-1-phenyl-methylene]-2-indolinone-5-carboxylic acid

C2SH23N3O3

Mass spectrum: m/z = 413 (M<4>)

(4) 3-Z-[1-(3-(Dimethylamino-methyl)-phenylamino)-1-phenyl-methylene)-2-indolinone-5-carboxylic acid

C25H23N303

Mass spectrum: m/z = 413 (M<4>)

(5) 3-Z-[1-(4-chloro-phenylamino)-1-phenyl-methylene]-2-indolinone-5-carboxylic acid

(6) 3-Z-[1-phenylamino-1-phenyl-methylene)-2-indolinone-5-carboxylic acid

Example 3

3-Z-fl-n-methyl-piperidin-4-^ 2 g 3-Z-[ 1 -(1-methyl-piperidin-4-yl-amino)-1-phenyl-methylene]-2-indolinone-5 -carboxylic acid

is heated with 5 ml of thionyl chloride for 2 hours at reflux. It is then stirred in and the residue washed with ether. 0.5 g of this acid chloride is taken up without further purification in 5 ml of methylene chloride and mixed with 0.5 ml of dimethylamine in 5 ml of methylene chloride and stirred overnight at room temperature. The product is chromatographed over a silica gel column with methylene chloride/methanol/ammonia (4:1:0.1).

Yield: 50% of theoretical,

Rf value: 0.14 (silica gel: methylene chloride/methanol = 9:1)

C24H2<g>N402

Mass spectrum: m/z = 404 (M<4>)

Analogously, the following compounds are produced:

(1) 3-Z-[1-(1-methyl-piperidin-4-yl-amino)-1-phenyl-methylene]-5-methylcarbamoyl-2-indolinone

Yield: 49% of theoretical,

Rf value: 0.19 (silica gel; methylene chloride/methanol = 4:1)

C23H26N402

Mass spectrum: m/z = 390 (M<4>)

(2) 3-Z-[l-(1-methyl-piperidin-4-yl-amino)-l-phenyl-methylene]-5-carbamoyl-2-indolinone Yield: 58% of theory,

Rf value: 0.15 (silica gel; methylene chloride/methanol = 4:1)

C22H24N4O2

Mass spectrum: m/z = 376 (M<*>)

(3) 3-Z-[ 1 -(4-piperidino-methyl-phenylamino)-1-phenyl-methylene]-5-dimethylcarbamoyl-2-indolinone

Prepared from 3-Z-[l-(4-piperidino-methyl-phenylamino)-l-phenyl-methylene]-2-indolinone-5-carboxylic acid and dimethylamine or 0.64 g of Z-[l-(4- piperidino-methyl-phenylamino)-! -phenyl-methylene]-2-indolinone-5-carboxylic acid, 0.34 g dimethylamine hydrochloride, 0.9 g 0-benzotriazol-1-yl-N,N,N',N'-tetramethyluronium tetrafluoroborate), 0.4 g 1-hydroxy -1H-benztriazole and 2.9 g of diisopropylethylamine stirred in 20 ml of dimethylformamide for 20 hours at room temperature. It is then evaporated and the remainder suspended in water.

The precipitate is filtered off.

Yield: 600 mg (88% of theoretical),

Rf value: 0.2 (silica gel, methylene chloride/ethanol = 9:1)

C30H32N4O2

Mass spectrum: m/z = 481 (M+H)<+>

(4) 3-Z-[l-(4-piperidino-methyl-phenylamino)-l-phenyl-m indolinone

Prepared from 3-Z-[1-(4-piperidino-methyl-phenylamino)-1-phenyl-methylene]-2-indolinone-5-carboxylic acid and methylamine analogously to Example 3(3).

Rr value: 0.2 (silica gel, methylene chloride/ethanol = 9:1)

C29H30N4O2

Mass spectrum: m/z = 467 (M+H)<+>

(5) 3-Z-[1-(4-piperidino-methyl-phenylamino)-1-phenyl-methylene]-5-methylethylcarbamoyl-2-indolinone

Prepared from 3-Z-[1-(4-piperidino-methyl-phenylamino)-1-phenyl-methylene]-2-indolinone-5-carboxylic acid and methyl-ethylamine analogously to Example 3(3).

Rf value: 0.55 (silica gel, methylene chloride/ethanol = 9:1)

C31H34N4O2

Mass spectrum: m/z = 495 (M+H)<+>

(6) 3-Z-[I-(4-piperidino-methyl-phenylamino)-1-phenyl-methylene]-5-propylcarbamoyl-2-indolinone

Prepared from 3-Z-[1-(4-piperidino-methyl-phenylamino)-1-phenyl-methylene]-2-indolinone-5-carboxylic acid and propylamine analogously to Example 3(3).

Rf value: 0.31 (silica gel, methylene chloride/ethanol = 9:1)

C31<H>34N4O2

Mass spectrum: m/z = 495 (M+H)<+>

(7) 3-Z-[1-(4-piperidino-methyl-phenylamino)-1-phenyl-methylene]-5-diethylcarbamoyl-2-indolinone

Prepared from 3-Z-[1-(4-piperidino-methyl-phenylamino)-1-phenyl-methylene]-2-indolinone-5-carboxylic acid and diethylamine analogously to Example 3(3).

Rf value: 0.55 (silica gel, methylene chloride/ethanol = 9:1)

C32H36N4O2

Mass spectrum: m/z = 509 (M+H)<+>

(8) 3-Z-[1-(4-(N-phenylmethyl-N-methyl-aminomethyl)-phenylamino)-1-phenyl-methylene]-5-methylcarbamoyl-2-indolinone (9) 3-Z-[ l -(4-(N-phenylmethyl-N-methyl-aminomethyl)-phenylamino)-l -phenyl-methylene]-5-dimethylcarbamoyl-2-indolinone (10) 3-Z-[l-(4-(N- phenylmethyl-N-methyl-aminomethyl)-phenylamino)-l-phenyl-methylene]-5-diethylcarbamoyl-2-indolinone (11) 3-Z-[l-(4-(N-phenylmeryl-N-methyl-aminomethyl) -phenylam propylcarbamoyl-2-indolinone (12) 3 -Z- [ 1 -(4-(N-phenylmethyl-N-methyl 1-aminomethyl)-phenylamino)-1 -phenyl-methylene]-5-dipropylcarbamoyl-2- indolinone (13) 3-Z-[ 1 -(4-(dimethylamino-methyl)-phenylarnino)-1 -phenyl-methylene]-5-methylcarbamoyl-2-indolinone (14) 3-Z-[ 1 -(4- (dimethylarnino-methyl)-phenylarnino)-1-phenyl-methylene]-5-dimethyl-carbamoyl-2-indolinone (15) 3-Z-[l-(4-(dimethylamino-methyl)-phenylam 2-indolinone (16 ) 3-Z-[1-(4-(dimethylamino-methyl)-phenylamino)-1-phenyl-m 2-indolinone (17) 3-Z-[ 1 -(4-(dimethylamino-methyl)-phenylamino)- 1 -phenyl-methylene]-5-dipropyl-carbamoy 1 -2-indolinone (18) 3-Z-[1-(3-(dimethylamino-methyl)-phenylami no)-1-phenyl-methylene]-5-methylcarbamoyl-2-indolinone (19) 3-Z-[ 1 -(3-(dimethylamino-methyl)-phenylamino)-1-phenyl-methylene]-5-dimethyl- carbamoyl-2-indolinone (20) 3-Z-[l -(3-(dimethylamino-methyl)-phenylamino)-1 -phenyl-methylene]-5-diethylcarbamoyl-2-indolinone (21) 3 -Z- [ 1 -(3 -(dimethylamino-methyl)-phenylamino)-1 -phenyl-methylene]-5-propylcarbamoyl-2-indolinone (22) 3-Z-[l -(3-(dimeth<y>lamino-methyl)- phenylamino)-1-phen<y>l-methylene]-5-dipropyl-carbamoyl-2-indolinone

(23) 3-Z-[1-(4-chloro-phenylamino)-1-phenyl-methylene]-5-methylcarbamoyl-2-indolinone

(24) 3-Z-[1-(4-chloro-phenylamino)-1-phenyl-methylene]-5-dimethylcarbamoyl-2-indolinone

(25) 3-Z-[1-(4-chloro-phenylamino-1-phenyl-methylene]-5-diethylcarbamoyl-2-indolinone

(26) 3-Z-[1-(4-chloro-phenylamino)-1-phenyl-methylene]-5-propylcarbamoyl-2-indolinone

(27) 3-Z-[1-(4-chloro-phenylamino)-1-phenyl-methylene]-5-dipropylcarbamoyl-2-indolinone

(28) 3-Z-(1-phenylamino-1-phenyl-methylene)-5-methylcarbamoyl-2-indolinone

(29) 3-Z-(1-phenylamino-1-phenyl-methylene)-5-dimethylcarbamoyl-2-indolinone

(30) 3-Z-(1-phenylamino-1-phenyl-methylene)-5-diethylcarbamoyl-2-indolinone

(31) 3-Z-(1-phenylamino-1-phenyl-methylene)-5-propylcarbamoyl-2-indolinone

(32) 3-Z-(1-phenylamino-1-phenyl-methylene)-5-dipropylcarbamoyl-2-indolinone

Example 4

3- Z-[ l- f4- amino- phenvlaminoVl- phenyl- metvlen1- 5- amido- 2- indolinone

800 mg of the resin prepared according to Example IV is suspended in 4 ml of methylene chloride and stirred with 0.8 g of 1,4-phenylenediamine for 16 hours at room temperature. It is filtered off and the resin washed several times with methylene chloride, methanol and dimethylformamide. 3 ml of methanolic ammonia is then added for 2 hours to remove the acetyl groups. Then, after further washing, 4 ml of 10% trifluoroacetic acid in methylene chloride are added over the course of 90 minutes, the resin is separated off and the solution is reduced. The residue is taken up with a little IN caustic soda and extracted with methylene chloride. The organic phase is dried over sodium sulfate and inverted.

Yield: 45 mg (30% of theoretical over all stages),

Rf value: 0.26 (silica gel; methylene chloride/methanol = 9:1)

C22H18N4O2

Mass spectrum: m/z = 370 (M<*>)

Analogously, the following compounds are produced:

(1) 3-Z-[1-(3-amino-phenylamino)-1-phenyl-methylene]-5-amido-2-indolinone

Yield: 24% of theoretical,

Rf value: 0.44 (silica gel; methylene chloride/methanol = 9:1)

C22H18N402

Mass spectrum: m/z = 370 (M<+>)

(2) 3-Z-(1-phenylamino-1-phenyl-methylene)-5-amido-2-indolinone

Yield: 27% of theoretical,

Rf value: 0.53 (silica gel; methylene chloride/methanol = 9:1)

C22H,7N3O2

Mass spectrum: m/z = 355 (M<4>)

(3) 3-Z-[l-(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)

C 24 H 2 o N 4 O 3

Mass spectrum: m/z = 412 (M<4>)

(4) 3-Z-[1-(4-acetyl-N-methyl-amino-phenylamino)-1-phenyl-methylene]-5-amido-2-indolinone

Yield: 15% of theoretical,

Rf value: 0.36 (silica gel; methylene chloride/methanol = 9:1)

. C25H22N403

Mass spectrum: m/z = 426 (M<+>)

(5) 3-Z-[l-(4-(2-amino-ethyl)-phenylamino)-l-phenyl-methylene]-5-amido-2-indolinone Yield: 30% of theoretical,

Rf value: 0.04 (silica gel; methylene chloride/methanol = 9:1)

C24H22N4O2

Mass spectrum: m/z = 398 (M<4>)

(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)

C23H19N303

Mass spectrum: m/z = 385 (M<+>)

(7) 3-Z-[l-(4-Biphenylamino)-l-phenyl-methylene]-5-amido-2-indolinone

Yield: 22% of theoretical,

Rf value: 0.51 (silica gel; methylene chloride/methanol = 9:1)

C28H2iN3O2

Mass spectrum: m/z = 431 (M<+>)

(8) 3-Z-[1-(3-pyridylamino)-1-phenyl-methylene]-5-amido-2-indolinone

Yield: 35% of theoretical,

Rf value: 0.41 (silica gel; methylene chloride/methanol = 9:1)

C 2 i H 16 N 4 O 2

Mass spectrum: m/z = 356 (M<+>)

(9) 3-Z-[l-(4-dimethylamino-phenylamino)-l-phenyl-methylene]-5-amido-2-indolinone Yield: 19% of theory,

Rf value: 0.49 (silica gel; methylene chloride/methanol = 9:1) C24H22N402

Mass spectrum: m/z = 398 (M<+>)

(10) 3-Z-[l-(4-morpholino-phenylamino)-l-phenyl-methylene]-5-amido Yield: 42% of theory,

Rf value: 0.48 (silica gel; methylene chloride/methanol = 9:1)

C26H24N4O3

Mass spectrum: m/z = 440 (M<4>)

(11) 3-Z-[l-(4-tert.butyl-phenylamino)-l-phenyl-methylene]-5-amido-2-indolinone Yield: 32% of theoretical,

Rf value: 0.48 (silica gel; methylene chloride/methanol = 9:1)

C26H25N302

Mass spectrum: m/z = 411 (M<4>)

(12) 3-Z-[l-(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)

C22H,8<N>402

Mass spectrum: m/z = 370 (M<4>)

(13) 3-Z-[1-(4-benzyloxy-phenylamino)-1-phenyl-methylene]-5-amido-2-indolinone Yield: 40% of theoretical,

Rf value: 0.4 (silica gel; methylene chloride/methanol = 9:1)

C29H23N3O3

Mass spectrum: m/z = 461 (M<4>)

(14) 3-Z-[l-(4-bromo-phenylamino)-l-phenyl-methylene]-5-amido-2-indolinone Yield: 35% of theoretical,

Rf value: 0.46 (silica gel; methylene chloride/methanol = 9:1)

C22Hi6BrN3O2

Mass spectrum: m/z = 433/435 (M<4>)

(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)

C24H19N304

Mass spectrum: m/z = 413 (M<4>)

(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)

C23H18N403

Mass spectrum: m/z = 398 (M<4>)

(17) 3-Z-[l-(3-methyl-phenylamino)-l-phenyl-methylene]-5-amido-2-indolinone Yield: 12% of theoretical,

Rf value: 0.5 (silica gel; methylene chloride/methanol = 9:1)

C^HigN-jO^

Mass spectrum: m/z = 369 (M4)

(18) 3-Z-[l-(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)

C23H19N302

Mass spectrum: m/z = 369 (M<1>")

(19) 3-Z-[1-(3-methoxy-phenylamino)-1-phenyl-methylene]-5-amido-2-indolinone Rr value: 0.49 (silica gel; methylene chloride/methanol = 9:1)

C23H19N303

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)

C2SH21N3O4

Mass spectrum: m/z = 427 (M<+>)

(21) 3-Z-[l-(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)

C22H16N404

Mass spectrum: m/z = 400 (M<+>)

(22) 3-Z-[l-(4-Amido-phenylamino)-l-phenyl-methylene]-5-amido-2-indolinone Yield: 26% of theory,

Rf value: 0.47 (silica gel; methylene chloride/methanol = 9:1) C23Hi8N4O3

Mass spectrum: m/z = 398 (M<+>)

(23) 3-Z-[l-(4-pyridylamino)-l-phenyl-methylene]-5-amido-2-indolinone Yield: 15% of theory,

Rf value: 0.42 (silica gel; methylene chloride/methanol = 9:1)

C 2 i H 16 N 4 O 2

Mass spectrum: m/z = 356 (M<*>)

(24) 3-Z-[l-(4-methyl-phenylamino)-l-phenyl-methylene]-5-amido-2-indolinone Yield: 45% of theory,

Rf value: 0.54 (silica gel; methylene chloride/methanol = 9:1)

C23<H>19N302

Mass spectrum: m/z = 369 (M<*>)

(25) 3 -Z- [ 1 -(4-ethoxy-phenylamino)-1-phenyl-methylene] -5-amido-2-indolinone Yield: 40% of theoretical,

Rf value: 0.51 (silica gel; methylene chloride/methanol = 9:1)

C24H21N3O3

Mass spectrum: m/z = 399 (M<*>)

(26) 3-Z-[1-(3-bromo-phenylamino)-1-phenyl-methylene]-5-arnido-2-indolinone

Yield: 41% of theoretical,

Rf value: 0.53 (silica gel; methylene chloride/methanol = 9:1)

C22Hi6BrN3O2

Mass spectrum: m/z = 433/435 (M<+>)

(27) 3-Z-[1-(4-chloro-phenylamino)-1-phenyl-methylene]-5-amido-2-indolinone

Yield: 50% of theoretical,

Rf value: 0.49 (silica gel; methylene chloride/methanol = 9:1)

C22H16CIN3O2 Mass spectrum: m/z = 389/391 (M<+>)

(28) 3-Z-[l-(4-isopropyl-phenylamino)-l-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 theoretical,

Rf value: 0.58 (silica gel; methylene chloride/methanol = 9:1)

C29H21N3O2

Mass spectrum: m/z = 443 (M<+>)

(30) 3-Z-[l-(4-(2-Hydroxyethyl)-phenylamino)-l-phenyl-methylene]-5-amido-2-indolinone Yield: 22% of theory,

Rf value: 0.37 (silica gel; methylene chloride/methanol = 9:1)

C24H21N3O3

Mass spectrum: m/z - 398 (M-H)

(31) 3-Z-[l-(4-(4-imidazolyl)-phenylamino)-l-phenyl-methylene]-5-amido-2-indolinone Yield: 23% of theory,

Rf value: 0.5 (silica gel; methylene chloride/methanol = 9:1)

C25H,9N502

Mass spectrum: m/z = 421 (M<*>)

(32) 3-Z-[1-(4-ethoxycarbonylmethyl-phenylamino)-1-phenyl-methylene]-5-amido-2-indolinone C26<H>23N3O4

Mass spectrum: m/z = 442 (M+H)<+>

(33) 3-Z-[1-(4-bromo-3-methyl-1-phenylamino)-1-phenyl-methylene]-5-amido-2-indol inone C23H,8BrN302

Mass spectrum: m/z = 447/449 (M<+>)

(34) 3-Z-[ 1 -(4-cyclohexyl-phenylamino)-1-phenyl-methylene]-5-amido-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 C23Hi8BrN3O2

Mass spectrum: m/z = 447/449 (M<+>)

(36) 3-Z-[l-amino-l-phenyl 1-methylene]-5-amido-2-indol inone

Rr value: 0.3 (silica gel; methylene chloride/methanol = 9:1) C.6<H>13<N>302

Mass spectrum: m/z = 279 (M<4>)

(37) 3-Z-[1-cyclohexylamino-1-phenyl-methylene]-5-amido-2-indo-linone Rf value: 0.55 (silica gel; methylene chloride/methanol = 9:1)

C22H23N3O2

Mass spectrum: m/z = 361 (M<4>)

(3 8) 3 -Z- [ 1 -cyclopentylamino-1-phenyl 1-methylene]-5-amido-2-indo-linone Rf value: 0.53 (silica gel; methylene chloride/methanol = 9:1) C2 .H21N3O2

Mass spectrum: m/z = 347 (M*)

(39) 3-Z-[1-methylamino-1-phenyl-methylene]-5-amido-2-indoIinone Rf value: 0.5 (silica gel; methylene chloride/methanol = 9:1) C]7Hi5N3O2

Mass spectrum: m/z = 293 (M<*>)

(40) 3-Z-[1-ethylamino-1-phenyl-methylene]-5-amido-2-indolinone Rf value: 0.52 (silica gel; methylene chloride/methanol = 9:1) Ci8Hi7N3O2

Mass spectrum: m/z = 307 (M<*>)

(41) 3-Z-[l -isopropylamino-l-phenyl-methylene]-5-amido-2-indolinone Rf value: 0.44 (silica gel; methylene chloride/methanol = 9:1) C19H,9N3O2

Mass spectrum: m/z = 321 (M<+>)

(42) 3-Z-[1-dimethylamino-1-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-1-phenyl-methylene]-5-amido-2-indolinone Rf value: 0.47 (silica gel; methylene chloride/methanol = 9:1) C9H17N3O2

Mass spectrum: m/z = 319 (M<1>")

(44) 3-Z-[1-cycloheptylamino-1-phenyl-methylene]-5-amido-2-indolinone Rf value: 0.58 (silica gel; methylene chloride/methanol = 9:1) C23H25N302

Mass spectrum: m/z = 375 (M<*>)

(45) 3-Z-f 1 -cyclobutylamino-1-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-[I -(4-methylcyclohexylamino)-1-phenyl-methylene]-5-amido-2-indolinone Rf value: 0.67 (silica gel; methylene chloride/methanol = 9:1)

C23H25N302

Mass spectrum: m/z = 375 (M<4>)

(47) 3-Z-[l-(l-(R,S)-indanylamino)-l-phenyl-methylene]-5-amido-2-indolinone

Rf value: 0.59 (silica gel; methylene chloride/methanol = 9:1)

C 2 s H 2 i N 3 O 2

Mass spectrum: m/z = 395 (M<4>)

(48) 3-Z-[ 1 -(Methoxycarbonylmethylamino)-1-phenyl-methylene]-5-amido-2-indolinone Rf value: 0.46 (silica gel; methylene chloride/methanol = 9:1)

C] 9 H 17 N 3 O 4

Mass spectrum: m/z = 351 (M<4>)

(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)

C 2 oH] 9 N 3 O 4

Mass spectrum: m/z = 365 (M<4>)

(50) 3-Z-[l-(4-aminomethyl-phenylamino)-l-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<+>)

(51) 3-Z-[1-(4-pyrrolidinomethyl-phenylamino)-1-phenyl-methylene]-5-amido-2-indolinone-trifluoroacetate

Yield: 60% of theoretical,

Rr value: 0.07 (silica gel; methylene chloride/methanol = 9:1)

C27H2eN402

Mass spectrum: m/z = 438 (M<4>)

(52) 3-Z-[l-(4-morpholinomethyl-phenylamino)-l-phenyl-methylene]-5-amido-2-indolinone Yield: 65% of theory,

Rf value: 0.46 (silica gel; methylene chloride/methanol = 9:1)

C27H26N403

Mass spectrum: m/z = 454 (M<*>)

(53) 3-Z-[1-(4-piperidinomethyl-phenylamino)-1-phenyl-methylene]-5-amido-2-indolinone-trifluoroacetate

Yield: 60% of theoretical,

Rf value: 0.08 (silica gel; methylene chloride/methanol = 9:1)

C2<gH>2gN4O2

Mass spectrum: m/z = 452 (M<4>)

(54) 3-Z-[1-(4-hexamethyleneiminomethyl-phenylamino)-1-phenyl-methylene]-5-amido-2-indolinone-trifluoroacetate

C 29 H 3 o N 4 O 2

Mass spectrum: m/z = 466 (M4)

(55) 3-Z-[1-(4-(4-hydroxy-piperidine) 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 (M4)

(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

C3,H34N402

Mass spectrum: m/z = 494 (M<4>)

(59) 3-Z-[1-(4-(4-phenyl-piperidinomethyl)-phenylamino)-1-phenyl-methylene]-5-amido-2-indolinone

C34H32N402

Mass spectrum: m/z = 528 (M<4>)

(60) 3-Z-[1-(4-(4-benzyl-piperidinomethyl)-phenylamino)-1-phenyl-methylene]-5-amido-2-indolinone

C3SH34N4O2

Mass spectrum: m/z = 542 (M<4>)

(61) 3-Z-[1-(4-(4-ethoxycarbonyl-piperidinomethyl)-phenylamino)-1-phenyl-methylene]-5-amido-2-indolinone

C31H32N4O4

Mass spectrum: m/z = 524 (M<4>)

(62) 3-Z-[ 1 -(4-Dimethylaminomethyl-phenylamino)-1-phenyl-methylene]-5-amido-2-indolinone C25H24N402

Mass spectrum: m/z = 412 (M<4>)

(63) 3-Z-[1-(4-Dipropylaminomethyl-phenylamino)-1-phenyl-methylene]-5-amido-2-indolinone C29H32N402

Mass spectrum: m/z = 468 (M<4>)

(64) 3-Z-[ 1 -(4-piperazinylmethyl-phenylamino)-1-phenyl-methylene]-5-amido-2-indolinone C27H27N502

Mass spectrum: m/z = 453 (M<4>)

(65) 3-Z-[ 1 -(3-Dimethylaminomethyl-phenylamino)-1-phenyl-methylene]-5-amido-2-indolinone C25H24N4O2

Mass spectrum: m/z = 412 (M4)

(66) 3-Z-[1-(4-(2-diethylamino-ethyl)-phenylamino)-1-phenyl-methylene]-5-amido-2-ind 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<4>)

(68) 3-Z-[1-(4-(2-pyrrolidinyl-ethyl)-phenylamino)-1-phenyl-methylene]-5-amido-2-indolinone C28H28N4O2

Mass spectrum: m/z = 452 (M<4>)

(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 theoretical,

Rr value: 0.48 (silica gel; methylene chloride/methanol = 9:1)

C19HHN4O2S

Mass spectrum: m/z = 362 (M<4>)

(71) 3-Z-[1-(benzimidazol-2-ylamino)-1-phenyl-methylene]-5-amido-2-indolinone

Yield: 29% of theoretical,

Rf value: 0.44 (silica gel; methylene chloride/methanol = 9:1)

C23H,7N502

Mass spectrum: m/z = 395 (M<4>)

(72) 3-Z-[l-(5-methyl-isoxazol-3-yl-amino)-l-phenyl-methylene]-5-amido-2-indolinone Yield: 39% of theory,

Rf value: 0.43 (silica gel; methylene chloride/methanol = 9:1)

C 2 i H 18 N 4 O 3

Mass spectrum: m/z = 374 (M<4>)

(73) 3-Z-[1-benzylamino-1-phenyl-1-methylene]-5-amido-2-indolinone

Rf value: 0.63 (silica gel; methylene chloride/methanol = 9:1)

C23H19N302

Mass spectrum: m/z = 369 (M<4>)

(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 theoretical,

Rf value: 0.05 (silica gel; methylene chloride/methanol = 9:1)

C29H31N5O3

Mass spectrum: m/z = 497 (M<4>)

(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)

C2SH22N4O3

Mass spectrum: m/z = 426 (M<*>)

(77) 3-Z-[1-(4-((2-dimethylaminoethyl)-N-methanesulfonyl-amino)-phenylamino)-1-phenyl-methylene]-5-amido-2-indolinone

Rf value: 0.1 (silica gel; methylene chloride/methanol = 9:1)

C27<H>29N504S

Mass spectrum: m/z =519 (M<+>)

(78) 3-Z-[1-(4-(N-(Ethoxycarbonylmethyl)-N-methanesulfonyl-amino)-phenylamino)-1-phenyl-methylene]-5-amido-2-indolinone

Rf value: 0.57 (silica gel; methylene chloride/methanol = 9:1)

C27H26N406

Mass spectrum: m/z = 534 (M1")

(79) 3-Z-[l-(4-(N-(cyanomethyl)-N-methanesulfonyl-amino)-phenylamino)-l-phenyl-methylene]-5-amido-2-indolinone

Rf value: 0.49 (silica gel; methylene chloride/methanol = 9:1)

C2sH21N504S

Mass spectrum: m/z = 487 (M<*>)

(80) 3-Z-[1-(4-(N-methyl-N-methanesulfonyl-amino)-phenylamino)-1-phenyl-methylene]-5-amido-2-indolinone

Rf value: 0.46 (silica gel; methylene chloride/methanol = 9:1)

C24<H>22N404S

Mass spectrum: m/z = 462 (M<1>")

(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<*>)

(82) 3-Z-[1-(4-(2-oxo-piperidin-1-yl-methyl)-phenylamino)-1-phenyl-methylene]-5-amido-2-indolinone

C28H26N403

Mass spectrum: m/z = 466 (M1")

(83) 3-Z-[1-(4-(4-cyclohexyl-piperidino-methyl)-phenylamino)-1-phenyl-methylene]-5-amido-2-indolinone-trifluoroacetate

C34H38N402

Mass spectrum: m/z = 534 (M<*>)

(84) 3-Z-[1-(4-(2,6-Dimethyl-piperidino-methyl)-phenylamino)-1-phenyl-methylene]-5-amido-2-indolinone-trifluoroacetate

C30H32N4O2

Mass spectrum: m/z: 480 (M<*>)

(85) 3-Z-[1-(4-(4-phenyl-4-hydroxy-piperidino-methyl)-phenylamino)-1-phenyl-methylene]-5-amido-2-indolinone-trifluoroacetate

C34H32N4O3

Mass spectrum: m/z = 545 (M<+>)

Rf value: 0.66 (silica gel, methylene chloride/methanol = 4:1)

(86) 3-Z-[1-(4-(2-Methoxycarbonyl-pyrrolidino-methyl)-phenylamino)-1-phenyl-methylene]-5-amido-2-indolinone-trifluoroacetate

C29H28N4O4

Mass spectrum: m/z = 497 (M+H)<+>

Rf value: 0.65 (silica gel, methylene chloride/methanol = 4:1)

(87) 3-Z-[ 1 -(4-(1-oxo-thiomorpholin-4-ylmethyl)-phenylamino)-1-phenyl-methylene]-5-amido-2-indolinone-trifluoroacetate

C27H26N403S

Mass spectrum: m/z = 487 (M+H)<+>

Rf value: 0.68 (silica gel, methylene chloride/methanol = 4:1)

(88) 3-Z-[1-(4-(3,6-dihydro-2H-pyridin-1-ylmethyl)-phenylamino)-1-phenyl-methylene]-5-amido-2-indolinone-trifluoroacetate

C28H26N4O2

Mass spectrum: m/z = 451 (M+H)<+>

(89) 3-Z-[1-(4-(2,5-dihydro-pyrrol-1-ylmethyl)-phenylamino)-1-phenyl-methylene]-5-amido-2-indolinone-trifluoroacetate

C27H24N402

Mass spectrum: m/z = 437 (M+H)<+>

Rf value: 0.49 (silica gel, methylene chloride/methanol = 4:1)

(90) 3-Z-[ 1 -(4-(Thiomorpholin-4-ylmethyl)-phenylamino)-1-phenyl-methylene]-5-amido-2-indolinone-trifluoroacetate

C27H26N402S

Mass spectrum: m/z = 471 (M+H)<+>

Rf value: 0.78 (silica gel, methylene chloride/methanol = 4:1)

(91) 3-Z-[1^(4-(6,7-dimethoxy-tetrahydroisoquinolin-2-ylmethyl)-phenylamino)-1-phenyl 1-methylene]-5-amido-2-indolinone-trifluoroacetate

C34H32N4O4

Mass spectrum: m/z = 561 (M+H)<+>

Rf value: 0.8 (silica gel, methylene chloride/methanol = 4:1)

(92) 3-Z-[1-(4-(4-phenyl-piperazin-1-ylmethyl))-phenylamino)-1-phenyl-methylene]-5-amido-2-indolinone-trifluoroacetate

C33H31NSO2

Mass spectrum: m/z =530 (M+H)<+>

Rf value: 0.78 (silica gel, methylene chloride/methanol = 4:1)

(93) 3-Z-[1-(4-(3,5-Dimethyl-piperidino-methyl)-phenylamino)-1-phe^indolinone-trifluoroacetate

C30H32N4O2

Mass spectrum: m/z = 480 (M<+>)

Rf value: 0.54 (silica gel, methylene chloride/methanol = 4:1)

(94) 3-Z-[1-(4-(N-methyl-N-benzyl-amino-methyl)-phenylamino)-1-phenyl-methylene]-5-amido-2-indolinone-trifluoroacetate

C3]H29N4O4

Mass spectrum: m/z = 488 (M<4>)

(95) 3-Z-[1-(3,4-dimethoxy-phenylamino)-1-phenyl-methylene]-5-amido-2-indolinone C24H21N3O4

Mass spectrum: m/z = 415 (M<4>)

Rf value: 0.5 (silica gel, methylene chloride/methanol = 9:1)

(96) 3-Z-[1-(4-trifluoromethoxy-phenylamino)-1-phenyl-methylene]-5-amido-2-indolinone C23<H>16F3<N>303

Mass spectrum: m/z = 439 (M<4>)

Rf value: 0.5 (silica gel, methylene chloride/methanol = 9:1)

(97) 3-Z-[1-(3-ethoxycarbonyl-phenylamino)-1-phenyl-methylene]-5-amido-2-indolinone C25<H>21N3O4

Mass spectrum: m/z = 427 (M<4>)

Rf value: 0.52 (silica gel, methylene chloride/methanol = 9:1)

(98) 3-Z-[1-(3-carboxy-phenylamino)-1-phenyl-methylene]-5-amido-2-indolinone C23H17N304

Mass spectrum: m/z = 399 (M<4>)

Rf value: 0.14 (silica gel, methylene chloride/methanol = 9:1)

(99) 3-Z-[1-(3-Diethylcarbamoyl-phenylamino)-1-phenyl-methylene]-5-amido-2-indolinone C27H26N403

Mass spectrum: m/z = 454 (M<4>)

Rf value: 0.48 (silica gel, methylene chloride/methanol = 9:1)

(100) 3-Z-[1-(3-ethylcarbamoyl-phenylamino)-1-phenyl-methylene]-5-amido-2-indolinone C25H22N4O3

Mass spectrum: m/z = 426 (M<4>)

Rf value: 0.42 (silica gel, methylene chloride/methanol = 9:1)

(101) 3-Z-[1-(3-trifluoromethoxy-phenylamino)-1-phenyl-methylene]-5-amido-2-indolinone C23Hi6F3N303

Mass spectrum: m/z = 439 (M<4>)

Rf value: 0.5 (silica gel, methylene chloride/methanol = 9:1)

(102) 3-Z-[1-(3-ethoxy-phenylamino)-1-phenyl-methylene]-5-amido-2-indolinone

C24H21N3O3

Mass spectrum: m/z = 399 (M<4>)

Rf value: 0.49 (silica gel, methylene chloride/methanol = 9:1)

r

(103) 3-Z-[1-(4-Methoxymethyl-phenylamino)-1-phenyl-methylene]-5-am C24H21N3O3

Mass spectrum: m/z = 399 (M<4>)

Rr value: 0.4 (silica gel, methylene chloride/methanol = 4:1)

(104) 3-Z-[1-(4-ethyl-phenylamino)-1-phenyl-methylene]-5-amido-2-indolinone C24H2|N302

Mass spectrum: m/z = 383 (M4)

Rf value: 0.52 (silica gel, methylene chloride/methanol = 4:1)

(105) 3-Z-[1-(4-methyl-3-nitro-phenylamino)-1-phenyl-methylene]-5-amido-2-indolinone C23H18N404

Mass spectrum: m/z = 414 (M<4>)

(106) 3-Z-[1-(4-methyl-3-methoxy-phenylamino)-1-phenyl-methylene]-5-amido-2-indolinone C24H2,N303

Mass spectrum: m/z = 399 (M4)

(107) 3-Z-[1-(4-(4-aminophenyl-methyl)-phenylamino)-1-phenyl-methylene]-5-amido-2-indolinone-trifluoroacetate

C29H24N4O2

Mass spectrum: m/z = 460 (M<4>)

(108) 3-Z-[1-(4-Methoxycarbonyl-3-methyl-phenylamino)-1-phenyl-methylene]-5-amido-2-indolinone

C 25 H 2 , N 3 O 4

Mass spectrum: m/z = 427 (M4)

Rf value: 0.56 (silica gel, methylene chloride/methanol = 4:1)

(109) 3-Z-[1-(4-cyanophenylamino)-1-phenyl-methylene]-5-amido-2-indolinone C23Hi6N4O2

Mass spectrum: m/z = 380 (M<4>)

Rr value: 0.65 (silica gel, methylene chloride/methanol = 9:1)

(110) 3-Z-[1-(5-methyl-pyridin-2-yl-amino)-1-phenyl-methylene]-5-amido-2-indolinone Rf value: 0.6 (silica gel, methylene chloride/ methanol = 9:1)

C22H18N4O2

Mass spectrum: m/z = 370 (M<+>)

111) 3-Z-[1-(5-bromo-pyridin-2-yl-amino)-1-phenyl-methylene]-5-amido-2-indolinone Rf value: 0.65 (silica gel, methylene chloride/methanol = 9:1)

C2iHi5BrN4O2

Mass spectrum: m/z = 434/436 (M4)

112) 3-Z-[1-(2-chloro-pyridin-5-yl-amino)-1-phenyl-methylene]-5-amido-2-indolinone Rf value: 0.49 (silica gel, methylene chloride/methanol = 9:1)

Mass spectrum: m/z = 390/392 (M<4>)

113) 3-Z- [ 1 -(3-cyanophenylamino)-1-phenyl 1-methylene]-5-amide o-2-indolinone C23H16N402

Mass spectrum: m/z = 380 (M<*>)

Rr value: 0.57 (silica gel, methylene chloride/methanol = 9:1)

(114) 3-Z-[l-(4-(N-phenyl-amino-methyl)-phenylamino)-l-phenyl-methylene]-5-amido-2-indolinone

C29H24N402

Mass spectrum: m/z = 460 (M<+>)

Rr value: 0.74 (silica gel, methylene chloride/methanol = 9:1)

(115) 3-Z-[1-(4-(N-methyl-N-phenyl-aminomethyl)-phenylamino)-1-phenyl-methylene]-5-amido-2-indolinone

C 3 o H 2 6 N 4 O 2

Mass spectrum: m/z = 474 (M<+>)

Rf value: 0.75 (silica gel, methylene chloride/methanol = 9:1)

(116) 3-Z-[1-(4-(N-ethyl-aminomethyl)-phenylamino)-1-phenyl-methylene]-5-amido-2-indolinone-trifluoroacetate

C25<H>24N402

Mass spectrum: m/z = 412 (M<4>)

(117) 3-Z-[ 1 -(4-(N-(4-chlorophenyl-methyl)-aminomethyl)-phenyl-amino)-1-phenyl-methylene]-5-amido-2-indolinone-trifluoroacetate

C3oH25ClN4O2

Mass spectrum: m/z = 508/510 (M<4>)

(118) 3-Z-[1-(4-(N-cyclohexyl-aminomethyl)-phenylamino)-1-phenyl-methylene]-5-amido-2-indolinone-trifluoroacetate

C 29 H 3 o N 4 O 2

Mass spectrum: m/z = 466 (M<4>)

(119) 3-Z-[1-(4-(N-isopropyl-aminomethyl)-phenylamino)-1-phenyl-methylene]-5-amido-2-indolinone-trifluoroacetate

C26H26N402

Mass spectrum: m/z = 426 (M<4>)

(120) 3-Z-[1-(4-(N-butyl-aminomethyl)-phenylamino)-1-phenyl-methylene]-5-amido-2-indolinone-trifluoroacetate

C27H28N4O2

Mass spectrum: m/z = 440 (M<4>)

(121) 3-Z-[ 1 -(4-(N-Methoxycarbonyl-methylamino-methyl)-phenyl-amino)-1-phenyl-methylene]-5-amido-2-indolinone-trifluoroacetate

C26H24N404

Mass spectrum: m/z = 456 (M<+>)

(122) 3-Z-[1-(4-(N-(phenyl-methyl)-aminomethyl)-phenylamino)-1-phenyl-methylene]-5-amido-2-indolinone-trifluoroacetate

C 3 o H 2 6 N 4 O 2

Mass spectrum: m/z = 464 (M<4>)

(123) 3-Z-[l-(4-(N-acetyl-N-ethoxycarbonylmethyl-amino)-phenyl-amino)-l-phenyl-methylene]-5-amido-2-indolinone

C28H26N4O5

Mass spectrum: m/z = 498 (M<4>)

(124) 3-Z-[l-(4-methyl-3-sulfamoyl-phenylamino)-l-phenyl-methylene]-5-amido-2-indolinone C23H20N4O4S

Mass spectrum: m/z = 448 (M<4>)

(125) 3-Z-[1-(4-(N-methanesulfonyl-N-(methylcarbamoylmethyl)-amino)-phenylamino)-1-phenyl-methylene]-5-amido-2-indolinone

C26H25N5O5S

Mass spectrum: m/z =519 (M<4>)

(126) 3-Z-[1-(4-(N-methanesulfonyl-N-(piperidine-carbonyl-methyl)amino)-phenylamino)-1-phenyl-methylene]-5-amido-2-indolinone

C 3 o H 3 , N 5 O 5 S

Mass spectrum: m/z = 573 (M<4>)

(127) 3-Z-[1-(4-carboxy-phenylamino)-1-phenyl-methylene]-5-amido-2-indolinone C23H17N304

Mass spectrum: m/z = 398 (M-H<4>)

(128) 3-Z-[1-(4-carboxy-3-methyl-phenylamino)-1-phenyl-methylene]-5-amido-2-indolinone C24H19N304

Mass spectrum: m/z =412 (M-H<4>)

(129) 3-Z-[1-(4-(3-diethylamino-propoxy)-phenylamino)-1-phenyl-methylene]-5-amido-2-indolinone-trifluoroacetate

C29H32N4O3

Mass spectrum: m/z = 484 (M<4>)

(130) 3-Z-[1-(4-(2-piperidino-ethoxy)-phenylamino)-1-phenyl-methylene]-5-amido-2-indolinone-trifluoroacetate

C29H30N4O3

Mass spectrum: m/z = 483 (M+H)<4>

(131) 3-Z-[ 1 -(4-(3-piperidino-propoxy)-phenylamino)-1-phenyl-methylene]-5-amido-2-indolinone-thyrofluoroacetate

C30H32N4O3

Mass spectrum: m/z = 496 (M<4>)

(132) 3-Z-[1-(4-(3-Dimethylamino-propoxy)-phenylamino)-1-phenyl 1-methylene]-5-amido-2-indolinone-trifluoroacetate

C27H28N4O3

Mass spectrum: m/z = 457 (M+H)4*

(133) 3-Z-[1-(4-(3-N-methyl-N-benzylamino-propoxy)-phenylamino)-1-phenyl 1-methylene]-5-amido-2-indolinone-trifluoroacetate

C33H32N4O3

Mass spectrum: m/z = 533 (M+H)<4>

(134) 3-Z-[1-(4-(2-Dimethylamino-ethoxy)-phenylamino)-1-phenyl-methylene]-5-amido-2-indolinone-trifluoroacetate

C26H26N4O3

Mass spectrum: m/z = 443 (M+H)<+>

(135) 3-Z-[1-(4-(N-ethyl-N-benzyl-aminomethyl)-phenylamino)-1-phenyl-methylene]-5-amido-2-indolinone

(136) 3-Z-[1-(4-(N-propyl-N-benzyl-aminomethyl)-phenylamino)-1-phenyl-methylene]-5-amido-2-indolinone

(137) 3-Z-[1-(4-(N-methyl-N-(4-chlorophenyl-methyl)-aminomethyl)-phenylamino)-1-phenyl-methylene]-5-amido-2-indolinone

(138) 3-Z-[l-(4-(N-methyl-N-(4-bromophenyl-methyl)-amino-methyl)-phenylamino)-1-phenyl-methylene]-5-amido-2-indolinone

(139) 3-Z-j 1 -(4-(N-methyl-N-(3-chlorophenyl-methyl)-amino-methyl)-phenylamino)-1-phenyl 1-methylene]-5-amido-2-indolinone

(140) 3-Z-[ 1 -(4-(N-methyl-N-(3,4-dimethoxyphenyl-methyl)-amino-methyl)-phenylamino)-1 -

phenyl-methylene]-5-amido-2-indolinone

(141) 3-Z-[ 1 -(4-(N-methyl-N-(4-methoxyphenyl-methyl)-amino-methyl)-phenylamino)-1-phenyl-methylene"|-5-amido-2- indolinone

(142) 3-Z-[1-(4-(N-trifluoroethyl-N-(phenyl-methyl)-amino-methyl)-phenylamino)-1-phenyl-methylene]-5-amido-2-indolinone

(143) 3-Z-[1-(4-(N-trifluoroethyl-N-(4-chlorophenyl-methyl)-aminomethyl)-phenylamino)-1-phenyl-methylene]-5-amido-2-indolinone

EXAMPLE 5

3-Z-fl -( 4-( 4- acetyl- piperazinylmethyl)- phenylamino)- 1 - phenyl- methylene- 1- 5- amido- 2- indolinone 25 mg 3-Z-[1-(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 was stirred for 16 hours at room temperature. It is then washed with water and then the organic phase is inverted.

Yield: 15 mg (68% of theoretical),

C29H29N5O3

Mass spectrum: m/z = 495 (M<*>)

Analogously, the following compound is prepared:

(1) 3-Z-[1-(4-(4-benzoyl-piperazinylmethyl)-phenylamino)-1-phenyl-methylene]-5-amido-2-indolinone

Prepared from 3-Z-[1-(4-(piperazinyl-methyl-phenylamino)-1-phenyl-methylene]-5-amido-2-indolinone and benzoyl chloride.

Yield: 91% of theoretical,

C34H31N5O3

Mass spectrum: m/z = 557 (M<4>)

EXAMPLE 6

3- Z- IT -( 4- diethylcarbamoyl- phenylamino- 1 - phenyl- methylene-1- 5- amido- 2- indolinone

7 g of resin from step IV is reacted analogously to Example 4 with 4-aminobenzoic acid ethyl ester. Moisture-stressed resin is suspended in 30 ml of dioxane and 30 ml of methanol and stirred with 25 ml of 1 N caustic soda for 40 hours. It is then neutralized with dilute hydrochloric acid and washed with methylene chloride, methanol and dimethylformamide. Then 300 mg of the resin is suspended in 3 ml of dimethylformamide, allowed to stand with 0.2 ml of diethylamine, 0.5 g of O-Crjenzotriazol-l-ylJ-N.NjN^N-tetramethyl-uronium-tetrafluoroborate and 0.8 ml of ethyldiisopropylamine 60 hours at room temperature. Finally, the product is cleaved from the resin as described in Example 4.

Yield: 29 mg,

Rf value: 0.46 (silica gel, methylene chloride/methanol = 9:1)

C27H26N403

Mass spectrum: m/z = 454 (M<4>)

Analogously, it is produced:

(1) 3-Z-[1-(4-(piperidinocarbonyl)-phenylamino)-1-phenyl-methylene]-5-amido-2-indolinone Rf value: 0.43 (silica gel, methylene chloride/methanol = 9: 1)

C28H26N403

Mass spectrum: m/z = 466 (M<4>)

(2) 3-Z-[1-(4-(4-methylpiperazinecarbonyl)-phenylamino)-1-phenyl-methylene]-5-amido-2-indolinone-trifluoroacetate

Rf value: 0.84 (silica gel, methylene chloride/methanol = 4:1)

C28H27N503

Mass spectrum: m/z = 481 (M<4>)

(3) 3-Z-[1-(4-(N-(2-dimethylamino-ethyl)-N-methyl-carbamoyl)-phenylamino)-1-phenyl-methylene]-5-amido-2-indolinone-trifluoroacetate

Rf value: 0.25 (silica gel, methylene chloride/methanol = 9:1)

C28H29N5O3

Mass spectrum: m/z = 484 (M+H)<+>

(4) 3-Z-[ 1 -(4-(N-Methoxycarbonylmethyl-carbamoyl)-phenylamino)-1-phenyl-methylene]-5-amido-2-indolinone

Rf value: 0.4 (silica gel, methylene chloride/methanol = 9:1)

C26H22N405

Mass spectrum: m/z = 470 (M<4>)

(5) 3-Z-[1-(4-benzylcarbamoyl-phenylamino)-1-phenyl-methylene]-5-amido-2-indolinone Rf value: 0.48 (silica gel, methylene chloride/methanol = 9:1)

C30<H>24N4O3

Mass spectrum: m/z = 488 (M<4>)

EXAMPLE 7

3- 2-[ l -( 4-( N- methvl- benzovlaminoVphenylaminoV 1 - phenvt- methylene1- 5- amido- 2- indolinone

4.5 g of resin from step IV is reacted analogously to Example 4 with 3.4 g of 4-(9H-fluoren-9-yl-methoxycarbonyl)-methyl-amino)-aniline in dimethylformamide. The 9H-fluorene protecting group is then cleaved off with 4 ml of 30% piperidine in dimethylformamide and the resin washed several times. Then 400 mg of harapiks are suspended in 4 ml of dimethylformamide and 0.3 ml of triethylamine and reacted with 0.3 ml of benzoyl chloride for one hour at room temperature. Finally, the product is separated from the resin as described in Example 4.

Yield: 33 mg.

Rf value: 0.45 (silica gel, methylene chloride/methanol = 9:1)

C30H24N4O3

Mass spectrum: m/z = 488 (M<4>)

Analogously, it is produced:

(1) 3-Z-[l-(4-(N-methyl-propionylamino)-phenylamino)-l-phenyl-methylene]-5-amido-2-indolinone

Rr value: 0.42 (silica gel, methylene chloride/methanol = 9:1)

C26H24N403

Mass spectrum: m/z = 440 (M1")

(2) 3-Z-[1-(4-(N-methyl-butyrylamino)-phenylamino)-1-phenyl-methylene]-5-amido-2-indolinone

Rf value: 0.44 (silica gel, methylene chloride/methanol = 9:1)

C27H26N403

Mass spectrum: m/z = 453 (M-H<4>)

(3) 3-Z-[1-(4-(N-methyl-ethylsulfonylamino)-phenylamino)-1-phenyl-methylene]-5-amido-2-indolinone

Rf value: 0.42 (silica gel, methylene chloride/methanol = 9:1)

C25H24N4O4S

Mass spectrum: m/z = 475 (M-H<4>)

(4) 3-Z-[l-(4-(N-methyl-propylsulfonylamino)-phenylamino)-l-phenyl-methylene]-5-amido-2-indolinone

Rr value: 0.44 (silica gel, methylene chloride/methanol = 9:1)

C25H26N4O4S

Mass spectrum: m/z = 491 (M+H)<4>

(5) 3-Z-[1-(4-(N-methyl-phenylsulfonylamino)-phenylamino)-1-phenyl-methylene]-5-amido-2-indolinone

Rf value: 0.53 (silica gel, methylene chloride/methanol = 9:1)

C29H24N4O4 S

Mass spectrum: m/z = 524 (M<4>)

EXAMPLE 8

Dry ampoule with 75 mp Active substance per 10 ml

Composition:

Manufacturing:

Active ingredient and mannitol are dissolved in water. After filling, it is freeze-dried. Dissolution into a ready-to-use solution is done with water for injection purposes.

EXAMPLE 9

Dry ampoule with 35 mg active ingredient per 2 ml

Composition:

Manufacturing:

Active ingredient and mannitol are dissolved in water. After filling, it is freeze-dried. Dissolution into a ready-to-use solution is done with water for injection purposes.

EXAMPLE 10

Tablets with 50 me active ingredient

Composition:

Manufacturing:

(1), (2) and (3) are mixed and granulated with an aqueous solution of (4). The dried granules are (5) added and mixed. From this mixture, tablets are pressed, biplane with two-sided facets and a dividing line on one side.

Diameter of the tablets: 9 mm.

Example 11

Tablets with 350 mg Active ingredient

Composition:

Manufacturing:

(1), (2) and (3) are mixed and granulated with an aqueous solution of (4). Dried granules are (5) added. From this mixture, tablets are pressed, biplane with two-sided facets and one-sided dividing line.

Diameter for tablets: 12 mm.

EXAMPLE 12

Capsules with 50 mg active ingredient

Composition:

Manufacturing:

(1) is rubbed with (3). The mixture from (2) and (4) is added to this rubbing under intensive mixing.

This powder mixture is filled on a capsule filling machine for hard gelatin capsules size 3.

EXAMPLE 13

Capsules with 350 mg active ingredient

Composition:

Manufacturing:

(1) is rubbed with (3). This rub-in is added to the mixture from (2) and (4) under intensive mixing.

This powder mixture is filled on a capsule filling machine for size 0 hard gelatin capsules.

EXAMPLE 14

Suppositories with 100 mg active ingredient

1 suppository contains:

Manufacturing:

Polyethylene glycol is melted together with polyethylene sorbitan monostearate. At 40°C, the ground active compounds are dispersed homogeneously in the melt. It is cooled at 38°C and poured into slightly cooled suppository forms.

Claims (11)

1. Substituted indolinones, characterized in that they have the general formula in which X is an oxygen atom, Ri is a hydrogen atom, R 2 is a carboxy, C 1-4 alkoxycarbonyl or aminocarbonyl group, the amino part may be substituted with one or two C 1-3 alkyl groups and the substituents may be the same or different, R3 is a phenyl group, R 4 is a hydrogen atom or a C 1-3 alkyl group and Rj is a hydrogen atom, a C 1-6 alkyl group optionally substituted with a phenyl or C 1-3 alkoxycarbonyl group, a C3-7 cycloalkyl group optionally substituted with a C1-3 alkyl group, a fluorenyl group, an indanyl group optionally substituted with a C 1-3 alkyl group, a heteroaryl group selected from thiazolyl, isoxazolyl, pyridyl and benzimidazolyl, which optionally is mono- and bicyclic ring is mono- or disubstituted with C 1-5 alkyl groups and the substituents may be the same or different, a piperidinyl group, each of which may be substituted on the nitrogen atom by a C 1-3 alkyl group, a phenyl group optionally disubstituted with fluorine, chlorine, bromine or iodine atoms, C 1-5 -alkyl, C 1-3 -alkoxy, carboxy-, C 1 -alkoxycarbonyl, aminosulfonyl, nitro or cyano groups, wherein the substituents may be same or different, a phenyl or pyridyl group, each of which may be substituted with a trifluoromethoxy group, with a fluorine, chlorine, bromine or iodine atom, with a C1-3-alkyloxy group, which can be substituted in the 2- or 3-position with an amino-, C1-3-alkylamino-, di-(C1-3-alkyl)amino-, phenyl-C[ .3-alkylamino-, N-(Ci-3-alkyl)-phenyl-Ci-3-alkylamino-, pyrrolidino- or piperidino group, with a phenyl-Ci-3-alkylamino-Ci-3-alkyl group, which in the phenyl nucleus can be mono- or disubstituted with fluorine, chlorine, bromine or iodine atoms, the substituents can be the same or different, with a C 1-5 -alkyl-, phenyl-, imidazolyl-, C 3-7 -cycloalkyl-, C 1-3 -alkyl-C 1-3 -alkyl-, phenyl-Cu- alkoxy-, C 1-3 - alkoxycarbonyl-Ci -3-alkyl-, carboxy-, C1-3-alkylaminocarbonyl-, aminocarbonyl-, C1-3-alkylaminocarbonyl-, di-(Cu-alkyl)-aminocarbonyl-, phenyl-C1-3-alkylaminocarbonyl-, N-( C 1-3-alkyl)-phenyl-C 1-3-alkylamino-carbonyl-, C 1-3-alkoxy-carbonyl-C 1-3-alkylaminocarbonyl, piperidinocarbonyl-, N-(C 1-3-alkyl)-piperazino-carbonyl -, nitro-, amino-, C10-alkylamino-, di-(C1-3-alkyl)-amino-, morpholino-, C2-3-alkanoylamino-, N-(C1-3-alkyl)-C2-4-alkanoylamino -, cyano, hydroxy-Cu-alkyl or N-(Ci-3-alkyl)-benzoylamino group, with an N-(C1-3-alkyl)-C2-3-alkanoylamino group, which in the alkyl part is additionally substituted with a carboxy- or C1-3-alkoxycarbonyl group, with a Cu-alkylaminocarbonyl or di-(Ci-3-alkyl)-aminocarbonyl group, in which an alkyl part is additionally substituted with a di-(Ci-3-alkyl)-amino group, or with an N-(Ci-3-alkyl)-Ci-3-alkylsulfonylamino- or N-(C[.3-alkyl)-phenylsulfonyl-amino group, in which the alkyl part may additionally be substituted with a cyano-, Cu- -carbonyl-, di-(Ci-3-alkyl)-amino-, Cu-alkylaminocarbonyl- or piperidinocarbonyl group, a phenyl group substituted with a Cu-alkyl group, in which the alkyl part is substituted with a C1-3-alkoxycarbonyl-, amino-, C1-5-alkylamino-, di-(C1-5-alkyl)-amino-, C2-4- alkanoylamino-, N-(C].3-alkyl)-C2-*-alkanoylamino-, pyrrolidino-, dehydro-pyrrolidino-, piperidino-, dehydropiperidino-, 3-hydroxypiperidino-, 4-hydroxypiperidino-, hexamethyleneimino-, aminophenyl- or C3-7 cycloalkylamino, phenylamino group, with an N-phenyl-Ci-3-alkyl-N-Ci-3-alkylamino group optionally substituted in the phenyl part with a halogen atom or a C 1-3 alkoxy group, with an N-halo-Ci-3-alkyl-N-phenyl-Ci-3-alkyl-amino group optionally substituted with a halogen atom in the phenyl part, with an N-phenyl-Ci-3-alkylamino group optionally substituted with a halogen atom in the phenyl part, or with an N-C 2 3 -alkanyl-N-C 1-3 -alkoxycarbonyl-C 1-3 -alkylamino-, N-phenyl-N-C 1-3 -alkylamino-, C 1-3-alkoxycarbonyl-C 1-3 -alkylamino -, morpholino-, thiomorpholino-, 1-oxothiomorpholino-, piperazino-, 4-(C1-3-alkyl)-piperazino-, 4-phenyl-piperazino-, 4-(C2^t-alkanoyl)-piperazino-, 4 -benzoylpiperazino or imidazolyl group, wherein the above-mentioned saturated cycloalkylene diminomer rings may additionally be substituted with one or two C 1-6 alkyl groups, with a C 3.7 cycloalkyl, hydroxy, C 1-3 alkoxycarbonyl, benzyl, or a phenyl group or with a hydroxy and a phenyl group, or a methylene group adjacent to the nitrogen atom in the aforementioned cycloalkylene diminomer rings may be replaced by a carbonyl group, or on one of the aforementioned unsubstituted cycloalkylene diminomer rings, a phenyl ring optionally substituted with one or two C]-3-alkoxy groups can be condensed over two neighboring carbon atoms, as well as their isomers and their pharmaceutically acceptable salts. 2. Substituted indolinones of general formula I according to claim 1, characterized by that X is an oxygen atom, Ri is a hydrogen atom, R 2 is a carboxy, C 1 - 4 -alkoxycarbonyl or aminocarbonyl group, in which the amino part may be substituted with one or two Cu alkyl groups and the substituents may be the same or different, R3 is a phenyl group, R 4 is hydrogen or a methyl group and R 5 is hydrogen, a C1.5-alkyl group or a benzyl group optionally substituted with a carboxy- or C1-3-alkyl-carbonyl group, a C3-7 cycloalkyl group optionally substituted with a methyl group, an indanyl, pyridyl, isoxazolyl, thiazolyl or benzimidazolyl group optionally substituted with a methyl group, a methylphenyl group optionally substituted with a fluorine, chlorine or bromine atom, with a methoxy-, carboxy-, C 1-3-alkyloxycarbonyl-, nitro- or aminosulfonyl group or a dimethoxyphenyl group, a piperidinyl group, each of which is substituted at the nitrogen atom with a C 1-3 alkyl group, a phenyl group, which may be substituted with a trifluoromethoxy group, with a fluorine, chlorine, bromine or iodine atom, with a C 1-3-alkyl group, which can be substituted in the 2- or 3-position with an amino-, C 1-3-alkylamino-, di-(C 1-3-alkyl)-amino-, phenyl-C 1 3-alkylamino-, N-(Ci-3-alkyl)-phenyl-Ci-3-alkylamino-, pyrrolidino- or piperidino group, with a phenyl-C1.3-alkylamino-C13-alkyl group, which in the phenyl nucleus can be substituted with a fluorine, chlorine, bromine or iodine atom, with a C 1-5 -alkyl-, phenyl-, imidazolyl-, C 3-7 -cycloalkyl-, C 1-3 -alkyl-, C 1-3 -alkyl-, phenyl-C 1-3 -alkyl-, C 1-3 -alkyl-, C 1-3 -alkoxycarbonyl -C1-3-alkyl-, carboxy-, C1-3-alkylaminocarbonyl-, aminocarbonyl-, C1-3-alkylaminocarbonyl-, di-(C1-3-alkyl)-aminocarbonyl-, phenyl-C10-alkylaminocarbonyl-, N- (C1-3-alkyl)-phenyl-C1-3-alkylaminocarbonyl-, piperidinocarbonyl-, N-(C1-3-alkyl)-piperazinocarbonyl-, nitro-, amino-, C1-3-alkylamino-, di-(Ci .3-alkyl)-amino-, morpholino-, C2-4-alkanoylamino-, N-(C1-3-alkyl)-C2-4-alkanoylamino- or N-(C1-3-alkyl)-benzoylamino group, with an N-(C1-3-alkyl)-C2-4-alkanoylamino group, which in the alkyl part is additionally substituted with a carboxy- or C1-3-alkoxycarbonyl group, with a Cu-alkylaminocarbonyl or di-(Ci-3-alkyl)-aminocarbonyl group, in which an alkyl part is additionally substituted with a di-(Ci-3-alkyl)-amino group, or with an N-(C1-3-alkyl)-C1-3-alkylsulfonylamino- or N-(C1-3-alkyl)-phenylsulfonyl-amino group in which the alkyl part may additionally be substituted with a cyano-, Cu- carbonyl, di-(C 1-3 alkyl)amino, C 1-3 alkylaminocarbonyl or piperidinocarbonyl group, a phenyl group optionally substituted with a C 1-3 alkyl group, in which the alkyl part is substituted with a Cu-alkyl carbonyl-, amino-, C 1-5 -alkylamino-, di-(C 1-5 alkyl)-amino-, C2-4-alkanoylamino-, N-(C1-3-alkyl)-C2-4-alkanoylamino-, pyrrolidino-, dehydro-pyrrolidino-, piperidino-, dehydro-piperidino-, 3-hydroxypiperidino-, 4-hydroxypiperidino-, hexamethyleneimino-, morpholino-, thiomorpholino-, piperazino-, 4-(Ci-3-alkyl)-piperazino-, 4-phenyl-piperazino-, 4-(C2-4-alkanoyl)-piperazino-, 4-benzoyl-piperazino - or imidazolyl group, wherein the aforesaid saturated cycloalkyleniminorings may additionally be substituted with one or two C 1-5 alkyl groups, with a C 3-7 cycloalkyl, hydroxy, C 1-3 alkoxycarbonyl, benzyl or phenyl, or a methylene group adjacent to the nitrogen atom in the aforementioned cycloalkylenimine ring may be replaced by a carbonyl group, or on one of the aforementioned unsubstituted cycloalkylene diminomer rings over two neighboring carbon atoms, a phenyl ring optionally substituted with one or two Cu-alkoxy groups can be condensed, as well as their isomers and their pharmaceutically acceptable salts. 3. Substituted indolinones with the general formula I according to claim 1, characterized in that X is an oxygen atom, Ri is a hydrogen atom, R 2 is a carboxy, C 1-3 alkoxycarbonyl or aminocarbonyl group, in which the amino part may be substituted by one or two C 1-3 alkyl groups and the substituents may be the same or different, R3 is a phenyl group, R4 is a hydrogen atom or a methyl group and R5 is a hydrogen atom, a C 1-3 alkyl group, a benzyl group or a methyl or ethyl group substituted with a C 1-3 alkoxycarbonyl group, a C3-7 cycloalkyl group optionally substituted with a methyl group, an indanyl, pyridyl, isoxazolyl, thiazolyl or benzimidazolyl group optionally substituted with a methyl group, a methylphenyl group optionally substituted with a fluorine, chlorine or bromine atom, with a methoxy, carboxy, C 1-3 alkyloxycarbonyl, nitro or aminosulfonyl group or a dimethoxyphenyl group, a 4-piperidinyl group, which is substituted on the nitrogen atom with a C 1-3 alkyl group, a phenyl group, which is substituted with a trifluoromethoxy, benzyloxy, cyano or nitro group, a fluorine, chlorine or bromine atom, with a C 1-3 alkoxy group, wherein the terminal ethoxy and n-propoxy groups may each be substituted with a dimethylamino, diethylamino, N-ethylmethylamino, N-benzylmethylamino or piperidino group, with a phenyl-C1-3-alkylamino-C1-3-alkyl group, which in the phenyl atom can be substituted with a fluorine, chlorine, bromine or iodine atom, with a C1-4-alkyl-, phenyl-, imidazolyl-, cyclohexyl-, methoxymethyl-, Cu-alkyl-carbonyl-methyl-, carboxy-, C1-3-alkyl-carbonyl-, amino-carbonyl-, Cu-alkylaminocarbonyl-, di-(Ci-3-alkyl)-aminocarbonyl-, phenyl-Ci-3-alkylaminocarbonyl-, N-(Ci-3-alkyl)-phenyl-Ci-3-alkylaminocarbonyl-, piperidinocarbonyl-, N-(Ci-3 -alkyl)-piperazinocarbonyl-, amino-, Cu-alkylamino-, di-(Ci-3-alkyl)-amino-, morpholino-, C2-»-alkanoylamino-, N-(Ci-3-alkyl)-C2^ - alkanoylamino, benzoylamino or N-(Ct-3-alkyl)-benzoylamino group, with an N-(C1-3-alkyl)-C2-4-alkanoylamino group, which in the alkyl part is additionally substituted with a carboxy- or C1-3-alkoxycarbonyl group, with a C1-3-alkylaminocarbonyl or di-(C1-3-alkyl)aminocarbonyl group, in which an alkyl part is additionally substituted with a di-(C1-3-alkyl)amino group, or with an N-(Ci.3-alkyl)-Ci.3-alkylsulfonylamino- or N-(C[.3-alkyl)-phenylsulfonyl-amino group, in which the alkyl part may additionally be substituted with a cyano-, carboxy-, C1-3-Alkoxycarbonyl-, di-(C1-3-alkyl)-amino-, C1-3-alkylaminocarbonyl- or piperidino-carbonyl group, a phenyl group optionally substituted with a C 1-3 alkyl group, in which the alkyl group is substituted with a C 1-3 -alkylcarbonyl-, amino-, C 1-3 -alkylamino-, di-(C 1-5 -alkyl)-amino-, C 2-3 -alkanoy lamino-, N-(C[.3-alkyl)-C2^-alkanoylamino-, pyrrolidino-, dehydro-pyrrolidino-, piperidino-, dehydro-piperidino-, 4-hydroxypiperidino-, hexamethyleneimino-, morpholino-, thiomorpholino -, piperazino-, 4-(C1-3-alkyl)-piperazino-, 4-phenyl-piperazino-, 4-(C2-4-alkanoyl)-piperazino-, 4-benzoyl-piperazino- or imidazolyl group, wherein the aforementioned saturated cycloalkylene diminor rings may additionally be substituted with a phenyl group or with one or two methyl groups, or a methylene group adjacent to the nitrogen atom in the aforesaid cycloalkylene ring may be replaced by a carbonyl, or on one of the aforementioned unsubstituted cycloalkylene diminomer rings, a phenyl ring optionally substituted with one or two Qo-alkoxy groups can be condensed over two neighboring carbon atoms, as well as their isomers and their pharmaceutically acceptable salts. 4. Substituted indolinones with the general formula I according to claim 1, characterized in that X is an oxygen atom, Ri is a hydrogen atom, R 2 is a carboxy or aminocarbonyl group, in which the amino part may be substituted with one or two C 1-4 alkyl groups and the substituents may be the same or different, R3 is a phenyl group, R4 is a hydrogen atom and Rs is a hydrogen atom, a 4-piperidinyl group, which is substituted on the nitrogen atom with a C 1-3 alkyl group, a phenyl group, which may be substituted with a C 1-3 alkoxy group, wherein each terminal ethoxy and n-propoxy group may be substituted with a dimethylamino, diethylamino, N-ethylmethylamino, N-benzylmethylamino or piperidino group, with a phenyl-Ci-3-alkylamino-Ci-3-alkyl group, which in the phenyl nucleus may be substituted with a fluorine, chlorine, bromine or iodine atom, a phenyl group optionally substituted with a C 1-3 alkyl group, in which the alkyl group is substituted with a C 1-3 alkoxycarbonyl-, amino-, C 1-5 -alkylamino-, di-(C 1-5 -alkyl)-amino-, C 2 ^ -alkanoy lamino-, N-(C 1 j -alkyl)-C 2^ -alkanoylamino-, pyrrolidino-, dehydro-pyrrolidino-, piperidino-, dehydro-piperidino-, 4-hydroxypiperidino-, hexamethyleneimino-, morpholino-, thiomorpholino-, piperazino-, 4-(C1-3-alkyl)-piperazino-, 4-phenyl-piperazino-, 4-(C2-3-alkanoyl)-piperazino-, 4-benzoyl-piperazino- or imidazolyl group, wherein the aforementioned saturated cycloalkylene diminor rings may additionally be substituted with a phenyl group or with one or two methyl groups, or a methylene group adjacent to the nitrogen atom in the aforesaid cycloalkylenimine ring may be substituted with a carbonyl group, and the aforesaid monosubstituted phenyl groups may additionally be substituted with a fluorine, chlorine or bromine atom, a methyl, amino, Ci-3- alkylamino or di-(Ci-3-alkyl)amino group, or on one of the aforementioned unsubstituted cycloalkylene diminomer rings, a phenyl ring optionally substituted with one or two C 1-3 alkoxy groups can be condensed over two neighboring carbon atoms, their isomers and their pharmaceutically acceptable salts. 5. Substituted indolinones of the general formula I according to at least one of claims 1 to 4, characterized in that the radical R2 is in the 5-position. 6. Substituted indolinones with the general formula I according to claim 1, characterized in that they comprise: (a) 3-Z-[ 1 -(4-aminomethyl-phenylamino)-1-phenyl-methylene]-5-amido-2- indolinone, (b) 3-Z-[l -phenylamino)-1 -phenyl-methylene]-5-amido-2-indolinone, (c) 3 -Z- [ 1 -(4-bromo-phenylamino)-1 -pheny 1-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-phenylmethylene]-5-amido-2-indolinone, (g) 3-Z-[1-(4-hexamethyleneiminomethyl-phenylamino)-1-phenylmethylene]-5-amido-2-indolinone, (h) 3-Z-[1-(4-(4-benzyl-piperidino)-methyl)-phenylamino)-1-phenyl-methylene]-5-amido-2-indolinone, (i) 3-Z- [l-(4-(N-butyl-aminomethyl)-phenylamino)-l-phenyl-methylene]-5-amido-2-indolinone, (j) 3-Z-[l-(4-(N-(phenyl -methyl)-aminomethyl)-phenylamino)-l-phenyl-methylene]-5-amido-2-indolinone, (k) 3-Z-[l -(4-(N-methyl-N-benzyl-amino-methyl )-phenylamino)-1-phenyl 1-methylene]-5-amido-2-indolinone, (1) 3-Z-[1-(4-piperidino-methyl-phenylamino)-1-phenyl-methylene]-5-dimethylcarbamoyl-2-indolinone, (m) 3-Z-[1-(4-piperidino- methyl-phenylamino)-1-phenyl-methylene]-5-diethylcarbamoyl-2-indolinone, (n) 3-Z-[1-(4-(3-diethylamino-propoxy)-phenylamino)-1-phenyl-methylene] -5-amido-2-indolinone and their pharmaceutically acceptable salts. 7. Physiologically tolerable salts, characterized in that they are of compounds according to claims 1 to 6. 8. Medicine, characterized in that it contains a compound according to at least one of claims 1 to 6 or a salt according to claim 7, next to possibly one or more inert carriers and/or diluents. 9. Use of a compound according to at least one of claims 1 to 6 or a salt according to claim 7 for the production of a medicinal product which is suitable for the treatment of extensive or abnormal cell proliferations. 10. Method for producing a medicinal product according to claim 8, characterized in that, by non-chemical means, one or more inert carriers and/or diluents are incorporated into a compound according to at least one of claims 1 to 6 or a salt according to claim 7. 11. Method for producing compounds according to claims 1 to 7, characterized in that a. a compound with the general formula in which X, R.2 and R-3 are defined as in claims 1 to 6, R<5 is a hydrogen atom, a protecting group for the nitrogen atom of the lactam group or a bond on a solid phase and Z\ is a halogen atom, a hydroxy-, alkoxy- or aralkyl group, is reacted with an amine of the general formula in which R4 and R5 are defined as in claims 1 to 6, and if necessary, a protecting group used for the nitrogen atom of the lactam group or a compound thus obtained is then cleaved from the solid phase, or b. for the preparation of a compound of the general formula I, which contains an aminomethyl group and X is an oxygen atom, a compound with the general formula is reduced formula in which Ri to R" are defined as in claims 1 to 6 and R7 has the same meaning as R5 in claims 1 to 6, under the condition that R5 contains a cyano group and if desired then transfer a compound of the general formula I obtained in this way, which contains an alkoxycarbonyl group, by means of hydrolysis to a corresponding carboxy compound or a compound of the general formula I obtained in this way, which contains an amino or alkylamino group, is transferred by means of alkylation or reductive alkylation to a corresponding alkylamino or dialkylamino compound or a compound of the general formula I obtained in this way, which contains an amino or alkylamino group, is transferred by means of acylation to a corresponding acyl compound or a compound of the general formula I obtained in this way, which contains a carboxy group, is transferred by means of esterification or amidation to a corresponding ester or aminocarbonyl compound or if necessary, a protective residue used during the reaction to protect reactive groups is cleaved off, or if desired, such an obtained compound of the general formula I is then cleaved into their stereoisomers, or such obtained compound of the general formula I is transferred to their salts, in particular for pharmaceutical use in their physiologically tolerable salts with an inorganic or organic acid or base.