UA63009C2 - Substituted indolinones and medicaments based thereon - Google Patents

Abstract

The invention relates to substituted indolinones of general formula (I), wherein R1 to R5 and X have the meanings given in claim 1, to their isomers and to their salts, especially their physiologically compatible salts. The inventive compounds have valuable pharmacological properties, especially an inhibitory effect on various kinases and cycline/CDK complexes, and on the proliferation of various tumour cells. The invention also relates to medicaments containing these compounds, to their use and to methods for producing them.

Description

The present invention relates to new substituted indolinones of the general formula

EH ra "t her a

eat

She

In their isomers and salts, first of all, their physiologically acceptable salts, compounds with valuable properties.

Compounds of the general formula !, in which Ki represents a hydrogen atom or a prodrug residue, are characterized by valuable pharmacological properties, in particular, they are capable of inhibiting various kinases, primarily SOC complexes (SOKI, SOK2, SOKZ, SOKa, sok, SOKU, SOKAV and SOKU ) with their specific cyclins (A, B1, B2, C, 01, 02, 03, E, E, 01, 52, H, | and K) and viral cyclin (see G. Mepdiaso in

U9oigp. Migoiodu 71(3), p. 1984-1991 (1997)), and other compounds of the above general formula I, in which Ki has values different from the hydrogen atom and the prodrug residue, are valuable intermediates for the preparation of the first compounds.

Based on this, the object of this invention is the mentioned compounds of the general formula I, while the compounds in which Ki means a hydrogen atom or a prodrug residue are characterized by valuable pharmacological properties, and medicinal products containing these compounds applicable in pharmacology, as well as their use and the method of obtaining them.

In the above general formula

X stands for an oxygen or sulfur atom,

Bi means a hydrogen atom, a C1i-C--Alkoxycarbonyl or Co-Szalkanoyl group,

Ag means a carboxy, C 1 -C 3 carboxycarbonyl or aminocarbonyl group, where the amine moiety may be substituted by one or two C 1 -C 3 -alkyl groups, and the substituents may be identical or different from each other,

Az means a phenyl or naphthyl group that can be replaced by fluorine, chlorine or bromine atoms, C1-

C3-alkyl, C1-C3-alkoxy-, cyano-, trifluoromethyl, nitro-, amino-, C1i-C3-alkylamino-, di(C1-C3-alkyl)amino-, C2-C--alkanoylamino-, /- M-(C1-C3-alkyl)-C0-C--alkanoylamino-, C1-C3-alkylsulfonylamino-, amino-C1-C3-alkyl, C1-C3-alyusamino-C1-C3-alkyl, di(C1-C3 -alkylamino-Ci-C3-alkyl, M-(C2-

Ca-alkanoyl)amino-Ci-C3-alkyl or M-(C2-C4-alkanoyl)-C1-C3-alkylamino-C1i-C3-alkyl groups and substituents can be identical or different from each other,

Ba means a hydrogen atom or a C1-C3-alkyl group and

A5 means a hydrogen atom, a C1-C6-alkyl group optionally substituted by a phenyl, carboxy- or C1-C3-alkoxycarbonyl group, an optionally substituted C3-C7-cycloalkyl group, an optionally substituted C1- C3-alkyl group means an indanyl group, a 5-membered heteroaryl group containing an imino group optionally substituted by a C1-C3-alkyl group, an oxygen or sulfur atom, or an imino group optionally substituted by a C1-C3-alkyl group and an oxygen atom, sulfur or nitrogen, or two nitrogen atoms, or means a 6b-membered heteroaryl group containing 1-3 nitrogen atoms, with the help of two adjacent carbon atoms or one carbon atom and an adjacent imino group in the composition of the above 5- and b-membered heteroaryl groups can additionally be joined by a 1,3-butadienylene bridge, and the carbon skeleton of the mentioned mono- and bicyclic rings can be mono- or disubstituted by fluorine, chlorine, bromine or iodine atoms, Ci-Cv-alkyl or cyano groups, and the substituents can be identical or different separated from each other, a pyrrolidinyl or piperidinyl group attached to a carbon atom, which can be substituted for a nitrogen atom

C1i-C3-alkyl group, optionally disubstituted by fluorine, chlorine, bromine or iodine atoms, C1i-C5-alkyl, C1-C3-alkoxy-, carboxy-, C1-C3-alkoxycarbonyl, aminosulfonyl, nitro- or cyano groups, phenyl group , while the substituents can be identical or different from each other, a phenyl, pyridyl, pyrimidyl or thienyl group, each of which is substituted by a trifluoromethoxy group, a fluorine, chlorine, bromine or iodine atom, a C1i-C3-alkoxy group, which in the 2nd or 3 - position can be replaced by amino-, C1i-C3-alkylamino-, di(Ci-C3-alkyl)amino-, phenyl-C1-C3-alkylamino-, M- (C1-C3-alkylphenyl-C1-C3-alkylamino- , pyrrolidine or piperidine group, phenyl-C1-C3-alkylamino-C1-

a C3-alkyl group, which can be a trifluoromethyl group mono- or disubstituted in the phenyl nucleus, fluorine, chlorine, bromine or iodine atoms, C1-C3-alkyl or C1-C3-alkoxy groups, while the substituents can be identical or different from each other , and additionally, the nitrogen atom of the amine is replaced by Si-

C3-alkyl group, in which hydrogen atoms, starting from the 2nd position, can be partially or completely replaced by fluorine atoms,

C1-C3-alkyl, phenyl, imidazolyl, C3-C3-cycloalkyl, C1-C3-alkyl, C1-C3-alkyl, phenyl-C1-C3-alkyl, carboxy-C1-C3-alkyl, C1-C3- alkoxycarbonyl-C1-C3-alkyl, carboxy-, C1-C3- alkoxycarbonyl, aminocarbonyl, C1-C3-alkylaminocarbonyl, di(C1-C3-alkyl)aminocarbonyl, phenyl-C1-C3-alkylaminocarbonyl, M-(C1-C3- alkyl)uphenyl-C1-C3-alkylaminocarbonyl, piperazinecarbonyl, M-(C1-C3-alkyl)piperazinecarbonyl, nitro-, amino-, C1-C3-alkylamino-, di(C1-C3-alkyl)amino-, pyrrolidine, piperidine , morpholine, C2-C4-alkanoylamino-, M-(C1-C3-alkyl)-

C2-Ca-alkanoylamino-, benzoylamino- or M-(C1-C3-alkyl) benzoylamino group,

M-(C1-C3-alkyl)-C2-Ca-alkanoylamino group, which in the alkyl fragment is additionally replaced by a carboxy- or C3-C3- alkoxycarbonyl group,

by a C-C3-alkylaminocarbonyl or di(C1-C3-alkyl)aminocarbonyl group, in which one alkyl fragment is additionally replaced by a di(C1-C3-alkylamino group, or

M-(C1-C3-alkyl)-C1-C3-alkylsulfonylamino- or M-(C1-C3-alkylphenylsulfonylamino) group, in which the alkyl fragment can additionally be replaced by cyano-, carboxy-, C1i-C3-alkylsulfonyl, C1-C3-alkylamino -, di(C1i-C3-alkyl)amino-, aminocarbonyl, C1-C3-alkylaminocarbonyl, di(C1-C3-alkylaminocarbonyl, piperidinocarbonyl or 2-Idi(C1i-C3-alkylamino))ethylaminocarbonyl group substituted by C1i-C3 - an alkyl group is a phenyl or thienyl group, in which the alkyl fragment is replaced by hydroxy-, C-C3-alkyl, carboxy-, C1-C3-alkyloxycarbonyl, amino-, C1-C3-alkylamino-, di(C1-C5-alkyl) amino-, C2-C-alkanoylamino-, M-(C1-C3-alkyl)-Co-C--alkanoylamino-, pyrrolidine, dehydropyrrolidine, piperidine, dehydropiperidine, 3-hydroxypiperidine, 4-hydroxypiperidine, hexamethyleneimino-, morpholine, thiomorpholine , piperazine, 4-(C1-C3-alkyl)piperazine, 4-phenylpiperazine, 4-(C2-C«-alkanoyl)piperazine, 4-benzoylpiperazine or imidazolyl groups oy, while the above-mentioned saturated cycloalkylenimine rings, C1-C8-alkylamino- or di(C1-C5- alkylamino groups) can be additionally replaced by one or two C-C3-alkyl groups, C3-C7- cycloalkyl, hydroxy-, C1-C3 -Alkoxy-, carboxy-, C-C3-Alkoxycarbonyl, aminocarbonyl, C1-

C3-alkylaminocarbonyl or di(C1i-C3-alkyl)aminocarbonyl group, in the phenyl nucleus - fluorine, chlorine, bromine or iodine atoms, mono- or disubstituted C1i-C3-alkyl or cyano groups, phenyl-C1-C3-alkyl or phenyl group, while the substituents can be identical or different from each other, or the methylene group adjacent to the nitrogen atom in the above cycloalkyleneimine rings can be substituted by a carbonyl or sulfonyl group, and the mentioned monosubstituted phenyl groups can be additionally substituted by a fluorine, chlorine or bromine atom, a metal, amino -, C-C3-alkylamino- or di(C1-C3-alkyl)iamino group, or one of the above unsubstituted cycloalkylenimine rings with the help of two adjacent carbon atoms, a phenolic ring optionally substituted by one or two C1-C3- alkoxy groups can be condensed, when therefore, the carboxyl groups given in the decoding of the mentioned residues can be additionally replaced by a group that is converted directly into a carboxy group, and the ones given in the decoding The residues of the mentioned amino- and imino-group residues can be additionally replaced by a cleavable ip mimo residue.

In addition, the above-mentioned saturated alkyl and alkyl fragments in compounds containing more than two carbon atoms also include their branched isomers, such as isopropyl, tert-butyl, isobutyl, etc.

It is desirable to use compounds of the general formula I, in which

X stands for an oxygen or sulfur atom,

Bi means a hydrogen atom, a C1i-C4-alkoxycarbonyl or a Co-C4-alkanoyl group,

Ag means a carboxy, C 1 -C 6 -alkoxycarbonyl or aminocarbonyl group, where the amine fragment may be substituted by one or two C 1 -C 3 -alkyl groups and the substituents may be identical or different from each other,

Az means a phenyl or naphthyl group that can be substituted by fluorine, chlorine or bromine atoms,

C1i-C3-alkyl, C1i-C3-alkoxy-, cyano-, trifluoromethyl, nitro-, amino-, C1-C3-alkylamino-, di(C1-C3-alkyl)amino-, C2-C--alkanoylamino-, /- M-(C1-C3-alkyl)-C0-C--alkanoylamino-, C1-C3-alkylsulfonylamino-, amino-C1-C3-alkyl, C1-C3-alkylamino-C1-C3-alkyl, di(C1 -C3-alkylamino-C1-C3-alkyl, M-(C2-

C4-alkanoyl)amino-Ci-C3-alkyl or M-(C2-C4a-alkanoyl)-C1-C3-alkylamino-Ci-C3-alkyl groups and substituents can be identical or different from each other,

Ba means a hydrogen atom or a C1-C3-alkyl group and

A5 means a hydrogen atom, a C1-C6-alkyl group optionally substituted by a phenyl, carboxy- or C1-C3-alkoxycarbonyl group, an optionally substituted C3-C7-cycloalkyl group, an optionally substituted C1- C3-alkyl group means an indanyl group, a 5-membered heteroaryl group containing an imino group optionally substituted by a C1-C3-alkyl group, an oxygen or sulfur atom, or an imino group optionally substituted by a C1-C3-alkyl group and an oxygen atom, sulfur or nitrogen or two nitrogen atoms, or means a 6b-membered heteroaryl group containing 1-3 nitrogen atoms, with the help of two adjacent carbon atoms or one carbon atom and an adjacent imino group in the composition of the above 5- and b-membered heteroaryl groups a 1,3-butadienylene bridge can be additionally attached, and the carbon skeleton of the mentioned mono- and bicyclic rings can be mono- or disubstituted by fluorine, chlorine, bromine or iodine atoms, C1-C8-alkyl or cyano groups, and the substituents can be identical or different from each other, a pyrrolidinyl or piperidinyl group attached by a carbon atom, which can be replaced by a C1-C3-alkyl group at the nitrogen atom, optionally mono- or disubstituted by fluorine, chlorine, bromine or iodine atoms, Ci-C3-alkyl or cyano groups a phenol group, wherein the substituents may be identical or different from each other, a phenyl, pyridyl, pyrimidyl or thienyl group, each of which is substituted

C3-C-cycloalkyl, C1-C3-alkyl, phenyl-C1i-C3-alkyl, carboxy-C1-C3-alkyl, /C1-C3- carboxycarbonyl-C1-C3-alkyl, carboxy- alkoxycarbonyl, aminocarbonyl, C1-C3-alkylaminocarbonyl, di(C1-C3-alkylaminocarbonyl, nitro-, amino-, C1-C3-alkylamino-, di(C1-C3-alkyl)amino-, Co-C--alkanylamino- or M-(C1-C3-alkyl)-Co-C--alkanoylamino group,

a C1-C3-alkylaminocarbonyl group, in which the alkyl fragment is additionally replaced by a di(C1-C3-alkyl)iamino group, or

M-(C1-C3-alkyl)-C1-C3-alkylsulfonylamino group, in which the alkyl fragment can be additionally substituted by cyano-, carboxy-, C1-C3- alkoxycarbonyl, C1-C3-alkylamino- or di(C1-C3-alkyl) an laminocarbonyl group substituted by a C1i-C3-alkyl group, a phenyl or thienyl group in which the alkyl fragment is replaced by a hydroxy-, C1-C3-alkyloxy-, carboxy-, C1-C3-alkyloxycarbonyl, amino-, C1-C3-alkylamino-, di (C1-C5- alkylamino-, C2-C-akanoylamino-, M-(C1-C3-alkyl)-Co-C--alkanoylamino-, pyrrolidine, piperidine, hexamethyleneimino-, morpholine, piperazine, 4-(C1-C3) -alkyl)piperazine, 4-(C2-C4-alkanoyl)piperazine, 4-benzoylpiperazine or imidazolyl group, while the above-mentioned cycloalkylenimine rings, C1-C3-alkylamino or di(C1-C4-alkyl)amino groups can be additionally substituted by C1i- C3-alkyl, C3-SU-cycloalkyl, hydroxy-, C1-C3-alkoxy-, carboxy-,

C1-C3-alkoxycarbonyl, aminocarbonyl, C1-C3-alkylaminocarbonyl or di(C1-C3-alkylaminocarbonyl group, fluorine, chlorine, bromine or iodine atoms in the phenolic core, mono- or disubstituted C1-C3-alkyl or cyano groups of phenyl-C1 -C3-alkyl or phenyl group, while the substituents can be identical or different from each other, or the methylene group adjacent to the nitrogen atom in the above cycloalkylenimine rings can be replaced by a carbonyl or sulfonyl group, and the mentioned monosubstituted phenyl groups can be additionally replaced by a fluorine, chlorine atom or bromine or a metal group, primarily compounds of the general formula I, in which

X stands for oxygen atom,

Bi means a hydrogen atom or a C1-C4-alkoxycarbonyl group,

Ag means a carboxy, C 1 -C 6 -alkoxycarbonyl or aminocarbonyl group, where the amine fragment may be substituted by one or two C 1 -C 3 -alkyl groups and the substituents may be identical or different from each other,

Az means a phenyl group optionally substituted by a fluorine, chlorine or bromine atom, a metal, cyano- or aminomethyl group,

Va means a hydrogen atom or metal group and

A5 means a hydrogen atom, a C-C3-alkyl group optionally substituted by a carboxy or C1-C3-alkoxycarbonyl group or a benzyl group, a C3-C7-cycloalkyl group optionally substituted by a methyl group, an indanyl, pyridyl group optionally substituted by a methyl group , an oxazolyl, thiazolyl or imidazolyl group, with which two adjacent carbon atoms can additionally condense a phenyl ring, optionally substituted by a fluorine, chlorine or bromine atom, a methoxy-, carboxy-, C1-C3-alkyloxycarbonyl, nitro- or aminosulfonyl group a methylphenyl group or a dimethoxyphenyl group attached via a carbon atom, a pyrrolidinyl or piperidinyl group substituted by a C1-C3-alkyl group at a nitrogen atom, a phenyl group substituted by a trifluoromethoxy group, a fluorine, chlorine, bromine or iodine atom, a C1i-C3-alkyl group that amino-, C1-C3-alkylamino-, di(C1-C3-alkyl)amino-, phenyl-C1-C3-alkylamino-, M- (C1-C3-alkylphenyl- C1-C3-alkylamino -, pyrrolidine or piperidine group, phenyl-C1-C3-alkylamino-C1-

C3-alkyl group, which in the phenyl nucleus is replaced by a fluorine, chlorine, bromine, or iodine atom, C1-C5-alkyl, C1-C3-alkoxy- or trifluoromethyl group, and additionally in the nitrogen atom of the amine is replaced by C1-

C3-alkyl group, in which hydrogen atoms, starting from the 2nd position, can be completely or partially replaced by fluorine atoms, C3-C3-alkyl, phenyl, imidazolyl, C3-C7-cycloalkyl, C1-C3-alkoxy-C1-C3 -Alkoxy-, phenyl-C1-C3-Alkoxy-, carboxy-C1-C3-Alkyl, C1-C3-Alkoxycarbonyl-C1-C3-Alkyl, Carboxy-C1-C3-Alkoxycarbonyl, Aminocarbonyl, C1-C3-Alkylaminocarbonyl, di(C1-

C3-alkylaminocarbonyl, phenyl-C1-C3-alkylaminocarbonyl, M-(C1-C3-alkyl)uphenyl-C1-C3-alkylaminocarbonyl, piperazinecarbonyl, M-(C1-C3-alkyl)piperazinecarbonyl, nitro-, amino-,

C-C3-alkylamino-, di(C1i-C3-alkylamino-, pyrrolidine, piperidine, morpholine, /C2-C4-alkanoylamino-, M-(C1-C3-alkyl)-Co-C-alkanoylamino-, benzoylamino- or M-(C1-C3-alkyl)benzoylamino group,

M-(C1-C3-alkyl)-Co-C-alkanoylamino group, which in the alkyl fragment is additionally replaced by a carboxy- or C1-C3-alkoxycarbonyl group,

C-C3-alkylaminocarbonyl or di(C1-C3-alkyl)aminocarbonyl group, in which one almyl fragment is additionally replaced by a di(C1-C3-alkyl)amino group, or M-(C1-C3-alkyl)-C1-C3-alkylsulfonylamino - or M-(C1-C3-alkylphenylsulfonylamino), in which the alkyl fragment can be additionally replaced by cyano-, carboxy-, C1-C3-alukoxycarbonyl, C1-C3-alkylamino-, di(C1-C3-alkyl)luamino-, aminocarbonyl, /Ci-C3-alkylaminocarbonyl, di(Ci-C3-alkylaminocarbonyl, piperidinocarbonyl or 2-Idi(Ci-C3-alkylamino))ethylaminocarbonyl group, a phenyl group optionally substituted by a Ci-C3-alkyl group, in which the alkyl fragment is replaced by hydroxy -, C1-C3-Alkoxy-, carboxy-, C1i-C3-Alkoxycarbonyl, amino-, C1i-C8-alkylamino-, di(Ci-C8-alkyl)amino-, C2-C-alkanoylamino-, M-(C1 -C3-alkyl)-Co-C--alkanoylamino-, pyrrolidine, dehydropyrrolidine, piperidine, dehydropiperidine, 3-hydroxypiperidine, 4-hydroxypiperidine, hexamethyleneimino-, morpholine, thiom orpholine, piperazine, 4-(C1-C3-alkyl)piperazine, 4-phenylpiperazine, 4-(Co-Ca-alkanoyl)piperazine, 4-benzoylpiperazine or imidazolyl group, while the above-mentioned saturated cycloalkyleneimine rings, C1-C3-alkylamino- or di(C1-C5- alkylamino groups can be additionally substituted by one or two C1i-C3-alkyl groups, C3-C7- cycloalkyl, hydroxy-, C1-C3- alkoxy-, carboxy-, C1-C3- alkoxycarbonyl, aminocarbonyl, C1-

C3-alkylaminocarbonyl or di(C1i-C3-alkyl)aminocarbonyl group, fluorine, chlorine, bromine or iodine atoms in the phenolic nucleus, mono- or disubstituted C1i-C3-alkyl or cyano groups, phenyl-C1-C3-alkyl or phenyl group, in this case, the substituents may be identical or different from each other, or the methylene group adjacent to the nitrogen atom in the above-mentioned cycloalkylenimine rings may be substituted by a carbonyl or sulfonyl group, and the mentioned monosubstituted phenyl groups may be additionally substituted by a fluorine, chlorine or bromine atom, methyl, amino, C-C3-alkylamino or di(C1-C3-alkyl)amino group, or with one of the above unsubstituted cycloalkylenimine rings with the help of two adjacent carbon atoms, a phenyl ring optionally substituted by one or two C1-C3- alkoxy groups can condense, as well as their isomers and salts.

It is recommended to use compounds of the above general formula I, in which

X stands for oxygen atom,

Vi stands for hydrogen atom,

Ag means a carboxy-, C1-C1-C3-carboxycarbonyl or aminocarbonyl group, in which the amine fragment may be substituted by one or two C1-C3-alkyl groups and the substituents may be identical or different from each other,

Az means a phenyl group optionally substituted by a methyl group,

Va means a hydrogen atom or a methyl group and

A5 means a hydrogen atom,

a C1-C3-alkyl group, a benzyl group or a metal or ethyl group substituted by a carboxy- or C1i-C3-aluoxycarbonyl group, optionally substituted by a metal group C3-C7-cycloalkyl group, optionally substituted by a metal group indanyl, pyridyl, oxazolyl, a thiazolyl or imidazolyl group, with which a phenolic ring can be condensed with the help of two adjacent carbon atoms, optionally substituted by a fluorine, chlorine or bromine atom, a methoxy-, carboxy-, C1-C3-alkyloxycarbonyl, nitro- or aminosulfonyl group, metalphenyl or dimethoxyphenyl group,

A 3-pyrrolidinyl or 4-piperidinyl group, which is substituted in the nitrogen atom by a C1i-C3-alkyl group, a phenyl group substituted by a trifluoromethoxy-, benzyloxy-, cyano- or nitro group, a fluorine, chlorine or bromine atom,

C1i-C3-alkoxy group, and each of the ethoxy- and n-propoxy groups in the terminal position can be replaced by a dimethylamino-, diethylamino-, M-ethylmethylamino-, M-benzylmethylamino- or piperidine group, phenyl-C1-C3-alkylamino-C1i-C3 - an alkyl group that can be substituted in the phenolic nucleus by a fluorine, chlorine, bromine or iodine atom, a metal, methoxy or trifluoromethyl group, and additionally in the nitrogen atom of the amine can be replaced by a C1i-C3-alkyl or 2,2,2-trifluoroethyl group,

C-C4-alkyl, phenyl, imidazolyl, cyclohexyl, methoxymethyl, carboxymethyl, C1-C3-alkoxycarbonylmethyl, carboxy-, C1-C3-alkoxycarbonyl, aminocarbonyl, //C1-C3-alkylaminocarbonyl, di(C1i1-C3-alkylaminocarbonyl, / phenyl-C1-C3-alkylaminocarbonyl, M-(C1-C3-alkyl)phenyl-C1-C3-alkylaminocarbonyl, piperazinecarbonyl, M-(C1-C3-alkyl)upiperazinecarbonyl, amino-, C1-C3-alkylamino-, di( Ci-C3-alkyl)damino-, pyrrolidine, piperidine, morpholine, C2-Ca-alkanoylamino-, M-(C1-C3-alkyl)-Co-C--alkanoylamino-, benzoylamino- or M-(C1-C3) bezoylamino group,

M-(C1-C3-alkyl)-Co-C-alkanoylamino group, which in the alkyl fragment is additionally replaced by a carboxy- or C1-C3-alkoxycarbonyl group,

C-C3-alkylaminocarbonyl or di(C1-C3-alkyl)uaminocarbonyl group, in which one alkyl fragment is additionally replaced by a di(C1-C3-alkyl)amino group, or M-(C1-C3-alkyl)-C1-C3-alkylsulfonylamino - or M-(C1-C3-alkylphenylsulfonylamino group), in which the alkyl fragment can be additionally substituted by cyano-, carboxy-, C1-C3-alkoxycarbonyl, C1-C3-alkylamino-, di(C1-C3-alkyl)amino-, aminocarbonyl, /Ci-C3-alkylaminocarbonyl, di(Ci-C3-alkylaminocarbonyl, piperidinocarbonyl or 2-Idi(Ci-C3-alkylamino))ethylaminocarbonyl group, a phenyl group optionally substituted by a C1i-C3-alkyl group, in which the alkyl group is replaced by hydroxy -, C-C3-alkyl-, carboxy-, C1-C3-alkoxycarbonyl, amino-, C1-C3-alkylamino-, di(C1-C5-alkyl)amino-, C2-C-alkanoylamino-, M-(C1 -C3-alkyl)-Co-C-alkanoylamino-, pyrrolidine, dehydropyrrolidine, piperidine, dehydropiperidine, 4-cproxypiperidine, hexamethyleneimino-, morpholine, thiomorpholine, piperazine, 4-(С 1-C3-alkyl)piperazine, 4-phenylpiperazine, 4-(C2-Ca-alkanoyl)piperazine, 4-benzoylpiperazine or imidazolyl group, while the above-mentioned saturated cycloalkyleneimine rings can be additionally substituted by a phenyl group or one or two methyl groups, the above-mentioned Si -Cv-alkylamino- and di(Ci-Cv-alkylamino groups can be additionally substituted by one or two Ci-Ci-alkyl groups, cyclohexyl, hydroxy-, Ci-Ci-alkyl, carboxy-, C1-Ci- alkoxycarbonyl, aminocarbonyl, C1 -C3-alkylaminocarbonyl or di(C1-C3-alkyl)laminocarbonyl group, optionally substituted in the phenyl nucleus by a fluorine, chlorine, bromine or iodine atom, a metal or cyano group, a phenyl-C1-C3-alkyl or phenyl group, or adjacent to an atom nitrogen, the methylene group in the above-mentioned cycloalkylenimine rings can be replaced by a carbonyl or sulfonyl group, and the mentioned monosubstituted phenyl groups can be additionally replaced by a fluorine, chlorine or bromine atom, a metal, amino-, C-C3 -alkylamino- or di(C1-C3-alkyl)amino group, or with one of the above unsubstituted cycloalkylenimine rings with the help of two adjacent carbon atoms, a phenyl ring optionally substituted by one or two C1-C3- alkoxy groups can be condensed, as well as their isomers and salt

It is also desirable to use compounds of the above formula I, in which

X stands for oxygen atom,

Vi stands for hydrogen atom,

Ag means a carboxyl or aminocarbonyl group, in which the amine fragment can be substituted by one or two C1-C3-alkyl groups and the substituents can be identical or different from each other,

Az means a phenyl group optionally substituted by a metal group,

Va means a hydrogen atom and

A5 means a hydrogen atom,

A 3-pyrrolidinyl or 4-piperidinyl group substituted in the nitrogen atom by a C-C3-alkyl group, a phenyl group substituted

C1i-C3-alkoxy group, and each of the ethoxy- and n-propoxy groups in the terminal position can be replaced by a dimethylamino-, diethylamino-, M-ethylmethylamino-, M-benzylmethylamino- or piperidine group, phenyl-C1-C3-alkylamino-C1i-C3 - an alkyl group, which can be replaced in the phenyl nucleus by a fluorine, chlorine, bromine or iodine atom, a methyl, methoxy or trifluoromethyl group, and additionally in the nitrogen atom of the amine - a C-Cv-alkyl or 2,2,2-trifluoroethyl group, a phenyl group necessarily substituted by a C1i-C3-alkyl group, in which the alkyl group is replaced by a hydroxy-, C1-C3-alkyl group - alkyl)amino-, C2-C-alkanoylamino-, M-(C1-C3-alkyl)-Co-C--alkanoylamino-, pyrrolidine, dehydropyrrolidine, piperidine, dehydropiperidine, 4-hydroxypiperidine, hexamethyleneimino-, morpholine, thiomorpholine, piperazine, 4-(C1-C3-alkyl)piperazine, 4-phenylpiperazine, 4-(C2-Ca-alkanoyl)piperazine, 4-benzoylpiperazine or an imidazolyl group, while the above-mentioned saturated cycloalkylenimine rings may be additionally substituted by a phenyl group or one or two methyl groups, the mentioned C-Cv-alkylamino and di(C1-Cv-alkyl)amino groups may be additionally substituted by one or two

C-C3-alkyl groups, cyclohexyl, hydroxy-, C1-C3-alkoxy-, carboxy-, C1-C3- alkoxycarbonyl, aminocarbonyl, C1-C3-alkylaminocarbonyl or di(C1-C3-alkyl)aminocarbonyl group, optional substituted in the phenyl nucleus by a fluorine, chlorine, bromine or iodine atom, a metal or cyano group, a phenyl-C1-C3-alkyl or phenyl group, or a methylene group adjacent to a nitrogen atom in the above-mentioned cycloalkylenimine rings can be replaced by a carbonyl or sulfonyl group, and the mentioned monosubstituted phenyl groups can be additionally substituted by a fluorine, chlorine or bromine atom, a methyl, amino, C-C3-alkylamino- or di(C1-C3-alkyl)amino group, or with one of the above unsubstituted cycloalkyleneimine rings with the help of two adjacent carbon atoms can be condensed a phenyl ring necessarily substituted by one or two C1-C3- alkoxy groups, as well as their isomers and salts.

The most optimal of the above compounds are compounds in which the K2 residue is in the 5th position, primarily the following: (a) 3-2-1-(4-aminomethylphenylamino)-1-phenylmethylene|-5-amido-2-indolinone, (6) 3-2-P1-phenylamino-1-phenylmethylene|-5-amido-2-indolinone, (c) 3-2-(1-(4-6bromophenylamino)-1-phenylmethylene|-5-amido-2 -indolinone, (d) 3-2-(1-(4-dimethylaminomethyl)phenylamino-1-phenylmethylene|-5-amido-2-indolinone, (d) 3-2-(1-(4-pyrrolidinomethylphenylamino)-1 -phenylmethylene|-5-amido-2-indolinone, (is) 3-2-1-(4-piperidinomethylphenylamino)-1-phenylmethylene|-5-amido-2-indolinone, (is) 3-2-(1- (4-hexamethyleneiminomethylphenylamino)-1-phenylmethylene|-5-amido-2-indolinone, byu) 3-2-(1-(4-(4-benzylpiperidinomethyl)phenylamino)-1-phenylmethylene|-5-amido-2- indolinone, (c) 3-2-I(1-(4-(m-butylaminomethyl)phenylamino)-1-phenylmethylene|-5-amido-2-indolinone, (i) 3-2-11-(4-M -(phenylmethyl)aminomethyl)phenylamino)-1-phenylmethylene|-5-amido-2-indolinone, (in 3-2-11-(4-(M-methyl-M-benzylaminomethyl)phenylamino)-1-phenylmethylene|- 5-amido-2-indolinone, (3-2-11-(4-piper dinomethylphenylamino)-1-phenylmethylene|-5-dimethylcarbamoyl-2-indolinone, (l) 3-2-I1-(4-piperidinomethylphenylamino)-1-phenylmethylene|-5-diethylcarbamoyl-2-indolinone, (m) 3-2 -11-(4-(3-diethylaminopropoxy)phenioamino)-1-phenylmethylene|-5-amido-2-indolinone and their salts.

According to this invention, new compounds can be obtained, for example, in the following ways, generally known from the literature. a) By introducing a compound of the general formula r (1) i, ih

She

Kk, in which X, EC" and Az have the above meanings, does not represent a hydrogen atom, a protecting group for a nitrogen atom of a lactam group, or a bond with a solid phase, and 71 represents a halogen atom, a hydroxy-, hydroxy-, or aralkyl group, e.g. , a chlorine or bromine atom, a methoxy-, ethoxy-, or benzyloxy group, in the reaction with an amine of the general formula

N- Well (1)

Kk in which Ka and K5 have the above values, if necessary, followed by cleavage of the used protecting group for the nitrogen atom of the lactam group or cleavage from the solid phase.

The function of the protecting group for the nitrogen atom of the lactam group can be performed, for example, by an acetyl, benzoyl, ethoxycarbonyl, tert.-butoxycarbonyl, or benzyloxycarbonyl group, and as a solid phase, Rinka's resin or Sieber's resin is used.

The reaction is preferably carried out in a solvent such as dimethylformamide, toluene, acetonitrile, tetrahydrofuran, dimethylsulfoxide, methylene chloride, or in mixtures thereof, optionally in the presence of an inert base such as triethylamine, M-ethyldiisopropylamine or sodium bicarbonate, at temperatures in the range from 20 to 1757"С, while the protective group used can be cleaved as a result of peramidation.

If 21 in the compound of the general formula I represents a halogen atom, the reaction is preferably carried out in the presence of an inert base at a temperature in the range from 20 to 12076.

If 71 in the compound of the general formula II means a hydroxy, alkoxy or aralkyl group, it will be appropriate to carry out the reaction at a temperature in the range from 20 to 20070.

The subsequent cleavage of the optional protective group is expedient to be carried out by a hydrolytic method in an aqueous or alcoholic solvent, for example, in a mixture of methanol/water, ethanol/water, isopropanol/water, tetrahydrofuran/water, dioxane/water, dimethylformamide/water, in methanol or ethanol , in the presence of an alkali metal base, such as lithium hydroxide, sodium hydroxide or potassium hydroxide, at temperatures in the range from 0 to 100"C, preferably from 10 to 50"C, or, preferably, by peramidation using 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, alternatively, using an excess of the applied amine at temperatures in the range from O to 100"C, in the preferred version from 10 to 507C.

Cleavage from the solid phase used is preferably carried out using trifluoroacetic acid and water in the presence of a dialkyl sulfide, such as dimethyl sulfide, at temperatures ranging from

О to 35"С, in the desired version at room temperature. b) 3 with the aim of obtaining a compound of the general formula I containing an aminomethyl group, where X is an oxygen atom: by reducing the compound of the general formula i. a region in which Ki-B" have the above values and K7 has a value analogous to that of K5, provided that K5 is a cyano group.

In a preferred embodiment, the reduction is carried out by catalytic hydrogenation using hydrogen in the presence of a catalyst such as palladium on carbon 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 in the range from 0 to 50"C, preferably at room temperature, and at a hydrogen pressure from 1 to 7 bar, preferably from 3 to 5 bar.

In the case when the method according to the present invention produces a compound of the general formula I containing an alkoxycarbonyl group, this compound can be converted into the corresponding carboxy compound by the method of hydrolysis; if a compound of the general formula ! containing an amino or alkylamino group is obtained, by alkylation or reductive alkylation this compound can be converted into a corresponding alkylamino or dialkylamino compound; in the case of obtaining a compound of the general formula !/ containing an amino or alkylamino group by the acylation method, the first can be converted into the corresponding acyl compound; finally, if a compound of the general formula I containing a carboxy group is obtained, by esterification or amidation this compound can be converted into the corresponding ester or aminocarbonyl compound.

In a preferred embodiment, the subsequent hydrolysis is carried out in an aqueous solvent, for example 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 metal base , such as lithium hydroxide, sodium hydroxide or potassium hydroxide, at temperatures in the range from 0 to 100"C, preferably from 10 to 5076.

The subsequent reductive alkylation is preferably carried out in a suitable solvent such as methanol, methanol/water, methanol/water/ammonia, ethanol, ether, tetrahydrofuran, dioxane or dimethylformamide, optionally with the addition of an acid such as hydrochloric acid in the presence catalytically initiated hydrogen, for example, hydrogen in the presence of Raney, platinum or palladium on carbon, or in the presence of a metal hydride, such as sodium borohydride, lithium borohydride or lithium aluminum hydride, at temperatures in the range of 0 to 100"C, in a preferred embodiment from 20 to 807C.

The subsequent alkylation is preferably carried out using a suitable alkylating agent, such as an alkyl halide or dialkyl sulfate, for example, methyl iodide, dimethyl sulfate, or propyl bromide, 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 tertiary organic base, such as triethylamine, M-ethyldisopropylamine or dimethylaminopyridine, preferably at temperatures in the range from 207C to the boiling point of the solvent used.

The subsequent acylation is recommended to be 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 tertiary organic base, preferably at temperatures in the range from 207C to the boiling point used solvent. At the same time, it is advisable to carry out acylation using a suitable acid, preferably in the presence of a dehydrating agent, for example, chloroformic acid isobutyl ether, orthocarbonic acid tetraethyl ether, orthoacetic acid trimethyl ether, 2,2-dimethoxypropane, tetramethoxysilane, thionyl chloride, trimethylchlorosilane;, phosphorus trichloride , phosphorus pentoxide,

M,M'-dicyclohexylcarbodiimide, mixtures of M,M'-dicyclohexylcarbodiimide and M-hydroxysuccinimide, M,M'-

dicyclohexylcarbodiimide and 1-hydroxybenztriazole, 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate, mixtures of 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetrafluoroborate -t-tetramethyluronium and 1-hydroxybenztriazole, M,M'-carbonyldimidazole or a mixture of triphenylphosphine and tetrachloromethane, and optionally with the addition of a base such as pyridine, 4-dimethylaminopyridine, M-methylmorpholine or triethylamine, at temperatures in the range from 0 to 150"С, in the preferred version from О to 100"С. Acylation using the appropriate reactive compound, in particular, its anhydride, ester, imidazolides or halides, is carried out, if necessary, in the presence of a tertiary organic base, such as triethylamine,

M-ethyldissopropylamine or M-methylmorpholine, at temperatures in the range from 0 to 150"C, preferably from 50 to 10070.

The subsequent esterification or amidation is preferably carried out by introducing a suitable reactive carboxylic acid derivative into the reaction with the corresponding above alcohol or amine.

When carrying out the reactions described above, optional reactive groups, such as carboxy-, amino-, alkylamino- or imino groups, can be protected during the reaction with ordinary protective groups, and after the reaction is completed, they can be cleaved off again. So, for example, a trimethylsilyl, methyl, ethyl, tert.-butyl, benzyl, or tetrahydropyranyl group can be used to protect a carboxyl group, and an acetyl, trifluoroacetyl, benzoyl, ethoxycarbonyl, tert.-butoxycarbonyl group is used to protect an amino, alkylamino, or imino group. a benzyloxycarbonyl, benzyl, methoxybenzyl or 2,4-dimethoxybenzyl group, and a phthalic group is also suitable for protecting the amino group.

Subsequent cleavage of the optional protecting group is carried out, for example, by a hydrolytic method in an aqueous solvent, for example 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 alkali metal bases, such as lithium hydroxide, sodium hydroxide or potassium hydroxide, at temperatures in the range from 0 to 100"C, preferably from 10 to 507C.

Cleavage of the benzyl, methoxybenzyl or benzyloxycarbonyl group is carried out, for example, by hydrogenolysis, in particular, using hydrogen in the presence of a catalyst such as palladium on carbon in a solvent such as methanol, ethanol, ethyl acetic acid, dimethylformamide, a mixture of dimethylformamide and acetone or glacial acetic acid, optionally with the addition of an acid such as hydrochloric acid or glacial acetic acid, at temperatures in the range of 0 to 50°C, preferably at room temperature, and at a hydrogen pressure of 1 to 7 bar, preferably from 3 to 5 bar.

Cleavage of the methoxybenzyl group can also be carried out in the presence of an oxidant, such as cerium(IM)-ammonium nitrate, in a solvent such as methylene chloride, acetonitrile, or an acetonitrile/water mixture, at temperatures in the range from 0 to 50"C, in a preferred variant at room temperature.

Cleavage of the 2,4-dimethoxybenzyl group is advisable in trifluoroacetic acid in the presence of anisole.

Cleavage of the tert-butyl or tert-butyloxycarbonyl group is preferably carried out by treatment with an acid such as trifluoroacetic acid or hydrochloric acid, in which case a solvent such as methylene chloride, dioxane, acetic ether or ether can be used.

Cleavage of the phthalic group is recommended 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 ranging from 20 to 5070 .

Further, obtained chiral compounds of the general formula ! can be divided into enantiomers and/or diastereomers. For example, compounds of general formula I obtained in the form of racemates can be divided into optical antipodes, and the compounds of the general formula I with at least 2 asymmetric carbon atoms, thanks to their physicochemical differences, using known methods, for example, by chromatography and/or by fractional crystallization, can be separated into diastereomers, which, if they are obtained in racemic form, can be separated into enantiomers in the above manner.

In a preferred embodiment, the enantiomers are separated by column chromatography on chiral phases, by recrystallization from an optically active solvent, or by interaction with an optically active substance that forms with the racemic compound salts or derivatives, for example, esters or amides, primarily with acids and their activated derivatives or alcohols. It is recommended to separate the mixture of diastereomeric salts or derivatives obtained in this way, for example, based on their different degrees of solubility, while free antipodes can be released from pure diastereomeric salts or derivatives under the action of appropriate means. Examples of optimal optically active acids include O- and Y-forms of tartaric acid, dibenzoyltartaric acid, di-o-tolyltartaric acid, malic acid, mandelic acid, camphorsulfonic acid, glutamic acid, M-acetylglutamic acid, aspartic acid, M-acetylaspartic acid acid or quinic acid. As an optically active alcohol, for example, (x)- or (-)-menthol is used, and as an optically active acyl group in amides, you can use, for example, (x)- or (-y-methyloxycarbonyl.

Further, obtained compounds of the formula | can be translated into their salts, primarily for the purpose of pharmaceutical use - into their physiologically acceptable salts, for which organic or inorganic acids are used. Such acids can be, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, fumaric acid, succinic acid, lactic acid, citric acid, tartaric acid, maleic acid or methanesulfonic acid.

In addition, the new compounds of formula I obtained in the above manner, if they contain a carboxy group, can then be converted into salts using organic or inorganic bases, primarily for use in pharmaceuticals - into physiologically acceptable salts. As such bases can be used, for example, sodium hydroxide, potassium hydroxide, cyclohexylamine, ethanolamine, diethanolamine and triethanolamine.

The compounds of general formulas I-MIII used as starting products are generally known from the literature or can be obtained by methods known from the state of the art or described in the examples.

As mentioned above, the new compounds of the general formula I, in which Ki is a hydrogen atom or a prodrug residue, have valuable pharmacological properties, first of all, they are able to inhibit various kinases and cyclin/SOC complexes, as well as suppress the proliferation of human cancer cells and tumor growth, which was established by the results of an experiment when the above compounds were orally administered to hairless mice infected with human cancer cells.

The compounds given as examples in the table were tested for their biological effectiveness as follows:

Test 1

Inhibition of the enzymatic activity of the cyclin/SRK complex by migo

Nidp insect cells were used to produce active human cyclin/SOC holoenzymes

Rimetm (VTI-TM-581-4), infected with a high titer of recombinant baculovirus. Using a baculovirus vector containing two promoters (polyhedrin enhancer, P10 enhancer), labeled О5T (glutathione-5-transferase) was expressed in the same cell together with the appropriate Nizv-labeled SOC subunit (for example, SOCA or SOCb) cyclins (for example, cyclin O1 or cyclin OZ). The active holoenzyme was isolated by affinity chromatography on sepharose containing glutathione. Recombinant pEV labeled with O5T (amino acid residues in positions 379-928) was produced in E. soya and purified by affinity chromatography on Sepharose containing glutathione.

The substrates used for the analysis of kinase activity were chosen based on the properties of specific kinases. As a substrate for cyclin E/SOK2, cyclin A/SOK2, cyclin B/SOK2 complexes! and m-cyclin/SVKb used histone NO (bidta company). As a substrate for the complexes cyclin 01/SOKA, cyclin O3Z/SOKA, cyclin 01/SOKb and cyclin 03/SOKb, pKV labeled with O51T (amino acid residues in positions 379-928) was used.

Lysates of recombinant, baculovirus-infected insect cells or recombinant kinases (obtained by purification from lysates) together with the ATP-carrier of the radioactive label were incubated in a 195% solution of DMSO (dimethyl sulfoxide) for 45 minutes. at 30"C in the presence of a suitable substrate with different inhibitor concentrations. Substrate proteins with bound radioactivity were precipitated using

Basic THC (trichloroacetic acid) was deposited in hydrophobic multi-cell titration microplates made of polyvinylidene fluoride (MiPiroge company) or, using a 0.595% solution of phosphoric acid, precipitated on filters of the UUpaytap P8Z1 type. After adding the scintillation liquid, the radioactivity was measured using a liquid scintillation counter of the M/ayase 1450 Misgoreia type. For each concentration of the substance, the measurements were carried out twice, after which the value of ICzo was calculated, which characterizes the inhibition of the enzyme.

Test 2

Inhibition of proliferation of cultured human cancer cells

Leiomyosarcoma cells of the line 5K-OT-18 (obtained from the American Type Culture Collection (ATSC)) were cultured in minimal essential medium with substituted amino acids (Sirso) supplemented with sodium pyruvate (1 mmol), glutamine (2 mmol) and fetal bovine 10956 serum (Sibrso) and collected in the logarithmic phase of growth. Then cells of the 52K-OT-18 line were introduced at a density of 4,000 cells per cell into the cells of a Suiovziage type multicellular tablet (Ategzpat) and incubated overnight in a thermostat. Compounds were added to the cells at various concentrations (dissolved in DMSO; final concentration: "195"). At the end of the 48-hour incubation, c-thymidine (Ategepat) was added to each cell and incubated for another 24 hours. The amount of "C-thymidine injected into the tumor cells in the presence of the inhibitor, and the number of cells that were in the 5th phase (synthesis phase) of cell growth, were determined using a liquid scintillation counter of the U/aNyase 1450 type

Misgoreia. The value of ISzo inhibition of proliferation (inhibition of incorporation of "C-thymidine") was calculated with correction for background radiation. All measurements were performed twice.

Test Z

Study of the effect on hairless (thymusless) mice affected by tumors, i.p. mimo

Male and/or female athymic mice (MMREI mouse line pi/pi; weight 25-35g; number of individuals in the group

М-10-20) by subcutaneous injection with a volume of 0.1 ml, 109 cells each (cells of the 5K-OT-18 line or large cell lung cancer of the MSI-H4b6O line (obtained from ATCC) were injected; in an alternative version, small cells were implanted subcutaneously pieces of tumor tissue in the form of clusters of cells of the ZK-OT-18 or MCI-H4b0 line.

After 1-3 weeks, starting from the moment of injection or implantation, the animals were administered a kinase inhibitor daily for 2-4 weeks orally (using a gastric tube). Tumor growth was assessed three times a week using a digital caliper. The effect of the kinase inhibitor on tumor growth was expressed as percent inhibition of the placebo-treated control group.

The table below summarizes the results of the 2 ip migo test.

Table (Mo example) ZK-OT-18 ISvo (μMI

Due to their biological properties, the new compounds of the general formula I, their isomers and physiologically acceptable salts can be successfully used for the treatment of diseases caused by excessive or abnormal cell proliferation.

Such diseases include, for example, viral infections (for example, HIV infection and sarcoma

Kaposi), 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), osteopathy, diseases cardiovascular system (for example, restenosis and hypertrophy). In addition, they can be used to protect rapidly proliferating cells (eg, hair, intestinal, blood, and progenitor cells) from DNA damage that can be caused by radiation, UV radiation, and/or chemotherapy.

The course of treatment with new compounds of the above diseases can be both short and long, and these compounds can be combined with other known drugs, in particular, cytostatics.

To achieve the desired effect, the dosage for intravenous administration should be from 0.1 to 10 mg/kg, preferably from 0.3 to 10 mg/kg, and for oral administration - from 0.1 to 100 mg/kg, preferably from 0.3 to

Zomg/kg, with 1-4 times a day. For this purpose, from the compounds of formula I! according to the present invention, if necessary, combining them with other active substances, using one or more known inert carriers and/or diluents, such as corn starch, milk sugar, sucrose, microcrystalline cellulose, magnesium stearate, polyvinylrolidone, citric acid, tartaric acid, water/ethanol, water/glycerin, water/sorbitol, water/polyethylene glycol, propylene glycol, cetyl stearyl alcohol, carboxymethyl cellulose, or fatty substances such as solid fat, or their mixtures, are made into conventional galenic preparations in the form of tablets, dragees, capsules, powders, suspensions, suppositories or solutions for injections or infusions.

Below, the present invention is illustrated in more detail by examples.

Example 1

Methyl ether of 1-acetyl-2-indolinone-5-carboxylic acid 10.5 g of methyl ether of 2-indolinone-5-carboxylic acid (obtained in a method similar to this

Odama et al., Spet. Rpagt. Howl! 36, p. 2253-2258 (1988)) is stirred in 3 mL of acetic anhydride for 4 hours. at 140"C. Then the mixture is allowed to cool, poured into ice water, and the precipitate is filtered using a vacuum filter. The product is washed again with water, then dissolved in methylene chloride, dried over sodium sulfate, and concentrated.

Yield: 11g (8695 from theoretical),

Determination: 0.63 (silica gel, methylene chloride/methanol 50:1).

Example of II

Methyl ether of 1-acetyl-3-(1-ethoxy-1-phenylmethylene)-2-indolinone-5-carboxylic acid 11 g of methyl ether of 1-acetyl-2-indolinone-5-carboxylic acid is mixed in 110 ml of adethane and

ZOml of orthobenzoic acid triethyl ether for 2 hours. at 100"C. Then centrifuge, the residue is washed with ether and filtered using a vacuum filter.

Yield: 11.5g (6795 from theoretical),

Concentration: 0.55 (silica gel, methylene chloride/petroleum ether/acetic ether 4:5:1).

Example of PIA 28.0g of Rice resin (MVNA-resin, MomoBiospet company) is placed in 300ml of dimethylformamide, where it swells. Then add 30 ml of 3095-th piperidine in dimethylformamide and shake for 7 minutes, initiating the cleavage of the protective ERitos group, after which the resin is washed several times with dimethylformamide. Then add 7.3 g of 2-indolinone-5-carboxylic acid, 5.6 g of hydroxybenzotriazole, 13.3 g of O-(benzotriazol-1-yl)-M,M,M',M'-tetramethyluronium tetrafluoroborate and 5.7 ml of M- ethaldiisopropylamine in

300 ml of dimethylformamide and shake for an hour. Then the solution is filtered using a vacuum filter and the resin is washed five times with 300 ml of dimethylformamide and three times with 300 ml of methylene chloride.

To dry the resin, a stream of nitrogen is passed through it.

Yield: 28g of saturated resin.

Example IM 5 g of the saturated resin obtained in Example III is mixed in 15 ml of acetic anhydride at 80 "С for an hour.

Then add 15 ml of triethyl ether of orthobenzoic acid and shake for the following minutes. at 1107"C. After that, the resin is filtered using a vacuum filter and washed successively with dimethylformamide, methanol and methylene chloride.

Yield: 7g of wet resin.

Example M 4-(ethylaminomethyl)nitrobenzene bg 4-nitrobenzyl bromide is dissolved in 25 ml of ethanol, mixed with 25 ml of a 1095-th solution of ethylamine in ethanol and for 2 hours. heated under reflux. Then the mixture is centrifuged, the residue is dissolved in methylene chloride and washed with diluted caustic soda. At the end, the organic phase is concentrated.

Yield: 2.3g (4695 from theoretical),

Concentration: 0.2 (silica gel, methylene chloride/methanol 9:1).

The following compounds are obtained in a similar way: 4-(IM-(4-chlorophenylmethyl)aminomethyl|nitrobenzene, 4-(M-cyclohexylaminomethyl)nitrobenzene, 4-(M-isopropylaminomethyl)nitrobenzene, 4-(M-butylaminomethyl)nitrobenzene, 4- (M-methoxycarbonylmethylaminomethyl)nitrobenzene,

4-(m-(phenylmethyl)aminomethyl)nitrobenzene, 4-(pyrrolidinomethyl)nitrobenzene, 4-(morpholinomethyl)nitrobenzene, 4-(piperidinomethyl)nitrobenzene, 4-(hexamethyleneimino)nitrobenzene, 4-(4-hydroxypiperidinomethyl)nitrobenzene, 4 -(4-methylpiperidinomethyl)nitrobenzene, 4-(4-ethylpiperidinomethyl)nitrobenzene, 4-(4-isopropylpiperidinomethyl)nitrobenzene, 4-(4-phenylpiperidinomethyl)nitrobenzene, 4-(4-benzylpiperidinomethyl)nitrobenzene, 4-(4-ethoxycarbonylpiperidinomethyl) )nitrobenzene, 4-(dimethylaminomethyl)nitrobenzene, 4-(dipropylaminomethyl)nitrobenzene, 4-(4-tert.-butyloxycarbonylpiperazinomethyl)nitrobenzene,

3-(dimethylaminomethyl)nitrobenzene, 4-(2-diethylaminoethyl)nitrobenzene, 4-(2-morpholinylethyl)nitrobenzene, 4-(2-pyrrolidinylethyl)nitrobenzene, 4-(2-piperidinylethyl)nitrobenzene, 4-(M-ethyl- M-benzylamnomethyl)nitrobenzene, 4-(M-propyl-M-benzylaminomethyl)nitrobenzene, 4-|M-methyl-M-(4-chlorophenylmethyl)aminomethylnitrobenzene, 4-(M-methyl-M-(4-bromophenylmethyl)aminomethyl |nitrobenzene, 4-|M-methyl-M-(3-chlorophenylmethyl)aminomethylnitrobenzene, 4-|M-methyl-M-(3,4-dimethoxyphenyl)aminomethyl|nitrobenzene, 4-|M-methyl-M-(4 -methoxyphenylmethyl)aminomethyl|nitrobenzene, 4-(M-2,2,2-trifluoroethyl-M-(phenylmethyl)aminomethyl|nitrobenzene, 4-(M-2,2,2-trifluoroethyl-M-(4-chlorophenylmethyl)aminomethyl) |nitrobenzene.

Example MI 4-(M-ethyl-M-tert.-butoxycarbonylaminomethyl)nitrobenzene 2.2 g of 4-(-ethylaminomethyl)nitrobenzene are dissolved in 50 ml of acetic ether and during ZOkhv. mix at room temperature with 2.6 g of di-tert.-butyl dicarbonate. Then the solution is washed with water and concentrated. Output: Z, 4g,

Determination: 0.9 (silica gel, methylene chloride/methanol 9:1).

In a similar way, the following compounds are obtained: 4-(M-(4-chlorophenylmethyl)-M-tert.-butoxycarbonylaminomethylnitrobenzene, 4-(M-cyclohexyl-M-tert.-butoxycarbonylaminomethyl)nitrobenzene, 4-(M-isopropyl-M- tert.-butoxycarbonylaminomethyl)nitrobenzene, 4-(M-butyl-M-tert.-butoxycarbonylaminomethyl)nitrobenzene, 4-(M-methoxycarbonylmethyl-M-tert.-butoxycarbonylaminomethyl)nitrobenzene, 4-(M-(phenylmethyl)-M- tert.-butoxycarbonylaminomethyl)nitrobenzene.

Example MY 4-M-ethyl-M-tert.-butoxycarbonylaminomethyl)aniline 6b, 4 g of 4-M-ethyl-M-tert.-butoxycarbonylaminomethyl)nitrobenzene is dissolved in 00 ml of methanol and hydrogenated in the presence of 1.5 g of Raney nickel at room temperature and pressure Z bar. Then the catalyst is filtered off and the solution is concentrated.

Output: 4.7 8g,

Density: 0.7 (silica gel, methylene chloride/methanol 50:1).

In a similar way, the following compounds are obtained: 4-(IM-(4-chlorophenylmethyl)-M-tert.-butoxycarbonylaminomethylaniline, 4-(M-cyclohexyl-M-tert.-butoxycarbonylaminomethyl)aniline, 4-(M-isopropyl-M- tert.-butoxycarbonylaminomethyl)aniline, 4-(M-butyl-M-tert.-butoxycarbonylaminomethyl)aniline, 4-(M-methoxycarbonylmethyl-M-tert.-butoxycarbonylaminomethyl)aniline, 4-(M-(phenylmethyl)- M- tert.-butoxycarbonylaminomethyl)aniline, 4-(pyrrolidinomethyl)aniline, 4-(morpholinomethyl)aniline, 4-(piperidinomethyl)aniline, 4-(hexamethylenenimnomethyl)aniline, 4-(4-hydroxypiperidinomethyl)aniline, 4-(4-methylpiperidinomethyl)aniline )aniline, 4-(4-ethylpiperidinomethyl)aniline, 4-(4-isopropylpiperidinomethyl)aniline, 4-(4-phenylpiperidinomethyl)aniline, 4-(4-benzylpiperidinomethyl)aniline, 4-(4-ethoxycarbonylpiperidinomethyl)aniline, 4- (2-morpholinylethyl)aniline, 4-(2-(pyrrolidinylethyl)aniline, 4-(2-piperidinylethyl)aniline, 4-(M-ethyl-M-benzylaminomethyl)aniline, 4-(M-propyl-M-benzylaminomethyl) aniline, 4-(m-(4-chlorophenylmethyl)aminomethylaniline,

4-|(M-methyl-M-(4-bromophenylmethyl)aminomethylaniline, 4-|M-methyl-M-(3-chlorophenylmethyl)aminomethylaniline, 4-|M-methyl-Ich-(3,4-dimethoxyphenylmethyl)aminomethylaniline . M-(4-chlorophenylmethyl)aminomethylaniline.

Obtaining final products

Example 1

Methyl ether of 3-2-11-(1-methylpiperidin-4-ylamino)-1-phenylmethylene|-2-indolinone-5-carboxylic acid 11.5 g of methyl ether 1-acetyl-3-(1-ethoxy-1-phenylmethylene) )-2-indolinone-5-carboxylic acid is dissolved in 115 ml of methylene chloride and stirred for 5 hours. at room temperature from 10.8 g of 4-amino-M-methylpiperidine. Then add 20 ml of ammonia in methanol and leave overnight. At the end, the solution is evaporated and the residue is washed with ether.

Yield: 11.9g (9795 from theoretical),

Determination: 0.20 (silica gel, methylene chloride/methanol 91),

SgzNag5MzOz, mass spectrum: t/2-391 (MU).

In a similar way, the following compounds are obtained: (1) methyl ester of 3-2-(1-(4-(piperidinomethyl)phenylamino)-1-phenylmethylene|-2-indolinone-5-carboxylic acid:

Concentration: 0.4 (silica gel, methylene chloride/methanol 9:1),

SgoNgeMzOz, mass spectrum: t/2-467 (MU); (2) 3-2-(11--(4-M-phenylmethyl-M-methylaminomethyl)phenylamino)-1-phenylmethylene|-2-indolinone-5-carboxylic acid methyl ester:

SzaNgeMzOz, mass spectrum: t/2-503 (MU); (3) methyl ester of 3-2-11-(4--dimethylaminomethyl)phenylamino)-1-phenylmethylene|-2-indolinone-5-carboxylic acid:

SgvNag5MzOz, mass spectrum: t/2-427 (MU); (4) methyl ester of 3-2-11-(3--dimethylaminomethyl)phenylamino)-1-phenylmethylene|-2-indolinone-5-carboxylic acid:

SgvNag5MzOz, mass spectrum: t/2-427 (MU); (5) methyl ether of 3-2-(1-(4-chlorophenylamino)-1-phenylmethylene|-2-indolinone-5-carboxylic acid; (6) methyl ether of 3-2-(1-phenylamino-1-phenylmethylene) -2-indolinone-5-carboxylic acid.

Example 2 3-2-11-(1-methylpiperidin-4-ylamino)-1-phenylmethylene|-2-indolinone-5-carboxylic acid 11.9 g of methyl ether 3-2-(1-(1-methylpiperidine-4- ylamino)-1-phenylmethylene|-2-indolinone-5-carboxylic acid is heated for 4 hours in 300 ml of methanol and 150 ml of sodium hydroxide under reflux.

Then neutralize 150 ml of Mn. of hydrochloric acid and concentrate to dryness. The residue is washed several times with water and dried.

Output 8695 from the theoretical,

Determination: 0.17 (silica gel, methylene chloride/methanol 41),

Sg2NgziMzOz, mass spectrum: t/2-:377 (MU).

The following compounds are obtained in a similar way: (1) 3-2-11-(4-(piperidinomethyl)phenylamino)-1-phenylmethylene|-2-indolinone-5-carboxylic acid:

Determination: 0.15 (silica gel, methylene chloride/methanol 91),

SgvNag?MzOz, mass spectrum: t/2-453 (MU); (2)... 3-2-11-(4--(M-phenylmethyl-M-methylaminomethyl)phenylamino)-1-phenylmethylene|-2-indolinone-5-carboxylic acid:

SziH2?7MzOz, mass spectrum: t/2-489 (MU); (3) 3-2-1-(4--dimethylaminomethyl)phenylamino)-1-phenylmethylene|-2-indolinone-5-carboxylic acid:

Sg5NaziMzOz, mass spectrum: t/2-413 (MU); (4) 3-2-1-(3--dimethylaminomethyl)phenylamino)-1-phenylmethylene|-2-indolinone-5-carboxylic acid:

Sg5NaziMzOz, mass spectrum: t/2-413 (MU); (5) 3-2-11-(4-chlorophenylamino)-1-phenylmethylene|-2-indolinone-5-carboxylic acid; (6) 3-2-P-phenylamino-1-phenylmethylene|-2-indolinone-5-carboxylic acid.

Example C 3-2-11-(1-methyllyperidin-4-ylamino)-1-phenylmethylene|-5-dimethylcarbamoyl-2-indolinone 2g 3-2-11-(1-methylpiperidin-4-ylamino)-1-phenylmethylene |-2-indolinone-5-carboxylic acid is heated with bBml of thionyl chloride for an hour. with a return cooler. Then it is centrifuged and the residue is washed with ether. 0.5 g of this acid chloride without further purification is dissolved in 5 ml of methylene chloride and mixed with 0.5 ml of dimethylamine in 5 ml of methylene chloride, after which it is stirred overnight at room temperature. Finally, the product is chromatographed on a silica gel column using a methylene chloride/methanol/ammonia solvent system in the ratio 4:1:0.1.

Output 5095 from the theoretical,

Determination: 0.14 (silica gel, methylene chloride/methanol 91),

SgaNgvimaO", mass spectrum: t/2 404 (MU).

In a similar way, the following compounds are obtained: (1) 3-2-11-(1-methylpiperidin-4-ylamino)-1-phenylmethylene|-5-methylcarbamoyl-2-indolinone: yield: 4995 from theoretical,

Determination: 0.19 (silica gel, methylene chloride/methanol 41),

С2зНовМаО»2 mass spectrum: m/2-390 (MU), (2) 3-2-(1-(1-methylpiperidin-4-ylamino)-1-phenylmethylene|-5-carbamoyl-2-indolinone: yield : 5895 from the theoretical,

Concentration: 0.15 (silica gel, methylene chloride/methanol 41),

Sg2Nga Mao", mass spectrum: t/2-:376 (MU); (3) 3-2-P1-(4-piperidinomethylphenylamino)-1-phenylmethylene|-5-dimethylcarbamoyl-2-indolinone: preparation: from 3-2-(1-(4-piperidinomethylphenylamino)-1-phenylmethylene|-2 -indolinone-5-carboxylic acid and dimethylamine or by stirring for 20 hours at room temperature 0.64g of 2-|1-(4-piperidinomethylphenylamino)-1-phenylmethylene|-2-indolinonecarboxylic acid, 0.Za4g of dimethylamine hydrochloride, 0. 9g of O-benzotriazol-1-yl-M,M,M',M'-tetramethyluronium tetrafluoroborate), 0.4g of 1-hydroxy-1H-benzotriazole and 2.9g of isopropylethylamine in 20ml of dimethylformamide, concentration of the resulting mixture, suspension of the residue in water and filtering the sediment using a vacuum filter, output: b0Omg (8895 from theoretical),

Concentration: 0.2 (silica gel, methylene chloride/ethanol 91),

SzoNzgiMaO", mass spectrum: t/2-481 (MN); (4) 3-2-(1-(4-piperidinomethylphenylamino)-1-phenylmethylene|-5-methylcarbamoyl-2-indolinone: preparation: from 3-2-(1-(4-piperidinomethylphenylamino)-1-phenylmethylene|- of 2-indolinone-5-carboxylic acid and methylamine in a manner similar to that given in example 3(3),

Concentration: 0.2 (silica gel, methylene chloride/ethanol 91),

SgoNzoMaO", mass spectrum: t/2-467 (MN); (5) 3-2-(1-(4-piperidinomethylphenylamino)-1-phenylmethylene|-5-methylethylcarbamoyl-2-indolinone: preparation: from 3-2-(1-(4-piperidinomethylphenylamino)-1-phenylmethylene|- of 2-indolinone-5-carboxylic acid and methylethylamine in a manner similar to that given in example C3(3),

Concentration: 0.55 (silica gel, methylene chloride/ethanol 9:1),

SziNzaMaO", mass spectrum: t/2-495 (MN); (6) 3-2-(1-(4-piperidinomethylphenylamino)-1-phenylmethylene|-5-propylcarbamoyl-2-indolinone: preparation: from 3-2-(1-(4-piperidinomethylphenylamino)-1-phenylmethylene|- of 2-indolinone-5-carboxylic acid and propylamine in a manner similar to that given in example 3(3),

Concentration: 0.31 (silica gel, methylene chloride/ethanol 9:1),

SziNzaMaO", mass spectrum: t/2-495 (MN); (7) 3-2-P1-(4-piperidinomethylphenylamino)-1-phenylmethylene|-5-diethylcarbamoyl-2-indolinone: preparation: from 3-2-(1-(4-piperidinomethylphenylamino)-1-phenylmethylene|-2 -indolinone-5-carboxylic acid and diethylamine in a manner similar to that given in example 3(3),

Concentration: 0.55 (silica gel, methylene chloride/ethanol 9:1),

Sz2NzeMaO", mass spectrum: t/2-509 (MN); (8) 3-2-11-(4--(M-phenylmethyl-M-methylaminomethyl)phenylamino)-1-phenylmethylene|-5-methylcarbamoyl-2-indolinone; (993 3-2-(1-(4-M-phenylmethyl-M-methylaminomethyl)phenylamino)-1-phenylmethylene|-5-dimethylcarbamoyl-2- indolinone; (10) 3-2-11-(4--( M-phenylmethyl-M-methylaminomethyl)phenylamino)-1-phenylmethylene|-5-diethylcarbamoyl-2-indolinone; (11) 3-2-11-(4--«M-phenylmethyl-M-methylaminomethyl)phenylamino)-1 -phenylmethylene|-5-propylcarbamoyl-2-indolinone; (12). 3-2-11-(4-(M-phenylmethyl-M-methylaminomethyl)phenylamino)-1-phenylmethylene|-5-dipropylcarbamoyl-2-indolinone; (13) 3-2-I1-(4-(dimethylaminomethyl)phenylamino)-1-phenylmethylene|-5-methylcarbamoyl-2-indolinone; (14) 3-2-I1-(4-(dimethylaminomethyl)phenylamino)-1-phenylmethylene|-5-dimethylcarbamoyl-2-indolinone; (15) 3-2-(1-(4-(dimethylaminomethyl)phenylamino)-1-phenylmethylene|-5-diethylcarbamoyl-2-indolinone; (16) 3-2-(1-(4-(dimethylaminomethyl)phenylamino) -1-phenylmethylene|-5-propylarbamoyl-2-indolinone; (17) 3-2-I1-(4-(dimethylaminomethyl)phenylamino)-1-phenylmethylene|-5-dipropylcarbamoyl-2-indolinone; (18) 3- 2-(1-(3-(dimethylaminomethyl)phenylamino)-1-phenylmethylene|-5-methylcarbamoyl-2-indolinone; (19) 3-2-(1-(3-(dimethylaminomethyl)phenylamino)-1-phenylmethylene| -5-dimethylcarbamoyl-2-indolinone; (20) 3-2-(1-(3-(dimethylaminomethyl)phenylamino)-1-phenylmethylene|-5-diethylcarbamoyl-2-indolinone; (21) 3-2-I1- (3-(Dimethylaminomethyl)phenylamino)-1-phenylmethylene|-5-propylcarbamoyl-2-indolinone; (22) 3-2-11-(3--(dimethylaminomethyl)phenylamino)-1-phenylmethylene|-5-dipropylcarbamoyl- 2-indolinone; (23) 3-2-(I1-(4-chlorophenylamino)-1-phenylmethylene|-5-methylcarbamoyl-2-indolinone; (24) 3-2-(I1-(4-chlorophenylamino)-1 -phenylmethylene|-5-dimethylcarbamoyl-2-indolinone; (25) 3-2-(/1-(4-chlorophenylamino)-1-phenylmethylene|-5-diethylcarbamoyl-2-indolinone; (26) 3-2-( /1 -(4-chlorophenylamino)-1-phenylmethylene|-5-propylcarbamoyl-2-indolinone;

(27) 3-2-(/1-(4-chlorophenylamino)-1-phenylmethylene|-5-dipropylcarbamoyl-2-indolinone; (28) 3-2-(1-phenylamino-1-phenylmethylene)-5-methylcarbamoyl -2-indolinone; (29) 3-2-(1-phenylamino-1-phenylmethylene)-5-dimethylcarbamoyl-2-indolinone; (30) 3-2-(1-phenylamino-1-phenylmethylene)-5-diethylcarbamoyl -2-indolinone; (31) 3-2-(1-phenylamino-1-phenylmethylene)-5-propylcarbamoyl-2-indolinone; (32) 3-2-(1-phenylamino-1-phenylmethylene)-5-dipropylcarbamoyl -2-indolinone.

Example 4 3-2-(I1-(4-aminophenylamino)-1-phenylmethylene|-5-amido-2-indolinone 80 mg of the resin obtained in example IM is suspended in 4 ml of methylene chloride and shaken with 0.8 g of 1,4-phenylenediamine for 16 hours . at room temperature. Then the resin is filtered and washed several times with methylene chloride, methanol, and dimethylformamide. Then, to remove the acetyl group, add 3 ml of ammonia in methanol for 2 hours. After repeated washing, add 4 ml of 1095 trifluoroacetic acid in methylene chloride for 90 minutes, the resin is separated and the solution is concentrated.The residue is dissolved in a small amount of 1N caustic soda and extracted with methylene chloride.The organic phase is dried over sodium sulfate and centrifuged.

Output 45 mg (3095 from the theoretical after completion of all stages),

Determination: 0.26 (silica gel, methylene chloride/methanol 91),

Sg2NiviMaO", mass spectrum: t/2-:370 (MU).

In a similar way, the following compounds are obtained: (1) 3-2-11-(3-aminophenylamino)-1-phenylmethylene|-5-amido-2-indolinone: yield: 2495 from theoretical,

Determination: 0.44 (silica gel, methylene chloride/methanol 91),

Sg2NiviMaO", mass spectrum: t/2-:370 (MU); (2) 3-2-(1-phenylamino-1-phenylmethylene)-5-amido-2-indolinone: yield: 2795 from theoretical,

Determination: 0.53 (silica gel, methylene chloride/methanol 91),

Sg2Ni?MzO", mass spectrum: t/2-:355 (MU); (3) 3-2-I1-(4-acetylaminophenylamino)-1-phenylmethylene|-5-amido-2-indolinone: yield 2895 from the theoretical,

Concentration: 0.35 (silica gel, methylene chloride/methanol 91),

SgaNgoMaOz mass spectrum: t/2-412 (MU); (4) 3-2-1-(4-acetyl-M-methylaminophenylamino)-1-phenylmethylene|-5-amido-2-indolinone: yield. 1595 from theoretical,

Determination: 0.36 (silica gel, methylene chloride/methanol 91),

C25NggMaOz, mass spectrum: t/2-426 (MU); (5) 3-2-11-(4-(2-aminoethyl)phenylamino)-1-phenylmethylene|-5-amido-2-indolinone: yield: 3095 from theoretical,

Determination: 0.04 (silica gel, methylene chloride/methanol 91),

SgaNogiMaOz, mass spectrum: t/2-398 (MU); (6) 3-2-(1-(4-methoxyphenylamino)-1-phenylmethylene|-5-amido-2-indolinone: yield: 3295 from theoretical,

Determination: 0.48 (silica gel, methylene chloride/methanol 91),

SgzNivMzOz, mass spectrum: t/2-:385 (MU); (7) 3-2-(1-(4-biphenylamino)-1-phenylmethylene|-5-amido-2-indolinone: yield: 2295 from theoretical,

Determination: 0.51 (silica gel, methylene chloride/methanol 91),

SgvNai MzO»5, mass spectrum: t/2-431 (MU); (8) 3-2-/1-(3-pyridylamino)-1-phenylmethylene|-5-amido-2-indolinone: yield 3595 from the theoretical,

Determination: 0.41 (silica gel, methylene chloride/methanol 91),

SaiNiviMaO", mass spectrum: t/2-356 (MU); (9) 3-2-1-(4-dimethylaminophenylamino)-1-phenylmethylene|-5-amido-2-indolinone: output in 1995 from the theoretical,

Determination: 0.49 (silica gel, methylene chloride/methanol 91),

SgaNogMaO", mass spectrum: t/2-398 (MU); (10) 3-2-/1-(4-morpholinophenylamino)-1-phenylmethylene|-5-amido-2-indolinone: yield 4295 from the theoretical,

Determination: 0.48 (silica gel, methylene chloride/methanol 91),

SovNgaMaOz, mass spectrum: t/2-440 (MU); (11) 3-2-(1-(4-tert.-butylphenylamino)-1-phenylmethylene|-5-amido-2-indolinone: yield 3295 from theoretical,

Determination: 0.48 (silica gel, methylene chloride/methanol 91),

SveNg5MzO»5, mass spectrum: t/2-411 (MU); (12) 3-2-(1-(2-aminophenylamino)-1-phenylmethylene|-5-amido-2-indolinone: emission 28905 from theoretical,

Determination: 0.52 (silica gel, methylene chloride/methanol 91),

Sg2NiviMaO", mass spectrum: t/2-:370 (MU); (13) 3-2-(1-(4-benzyloxyphenylamino)-1-phenylmethylene|-5-amido-2-indolinone: yield 4095 from theoretical,

Concentration: 0.4 (silica gel, methylene chloride/methanol 9:1),

SgeNgziMzOz, mass spectrum: t/2-461 (MU); (14) 3-2-(1-(4-bromophenylamino)-1-phenylmethylene|-5-amido-2-indolinone: yield 3595 from theoretical,

Determination: 0.46 (silica gel, methylene chloride/methanol 91),

Sg22NivVg MzO", mass spectrum: t/2-433/435 (MU); (15) 3-2-(I1-(4-Methoxycarbonylphenylamino)-1-phenylmethylene|-5-amido-2-indolinone: yield 3495 from theoretical,

Determination: 0.36 (silica gel, methylene chloride/methanol 91),

SgaNizMzOkh, mass spectrum: t/2-413 (MU); (16) 3-2-(1-(3-amidophenylamino)-1-phenylmethylene|-5-amido-2-indolinone: yield 3295 from theoretical,

Determination: 0.32 (silica gel, methylene chloride/methanol 91),

SgzNiviMaOz, mass spectrum: t/2-398 (MU); (17) 3-2-(1-(3-methylphenylamino)-1-phenylmethylene|-5-amido-2-indolinone: yield 1295 from theoretical,

Ve-value: 0.5 (silica gel, methylene chloride/methanol 9:1),

SgzNivMzO", mass spectrum: t/2-369 (MU); (18) 3-2-(1-(2-methylphenylamino)-1-phenylmethylene|-5-amido-2-indolinone: yield 2195 from theoretical,

Concentration: 0.5 (silica gel, methylene chloride/methanol 9:1),

SgzNivMzO", mass spectrum: t/2-369 (MU); (19) 3-2-(1-(3-methoxyphenylamino)-1-phenylmethylene|-5-amido-2-indolinone:

Determination: 0.49 (silica gel, methylene chloride/methanol 91),

SgzNizMzOz, mass spectrum: t/2-:385 (MU); (20) 3-2-(1-(3-ethoxycarbonylphenylamino)-1-phenylmethylene|-5-amido-2-indolinone:

Determination: 0.48 (silica gel, methylene chloride/methanol 91),

C25Naii MzOh, mass spectrum: t/2-427 (MU); (21) 3-2-11-(3-nitrophenylamino)-1-phenylmethylene)|-5-amido-2-indolinone: yield 3295 from theoretical,

Determination: 0.56 (silica gel, methylene chloride/methanol 91),

Sg2NiviMaOx, mass spectrum: t/2-400 (MU); (22) 3-2-(1-(4-amidophenylamino)-1-phenylmethylene|-5-amido-2-indolinone: yield 2695 from theoretical,

Determination: 0.47 (silica gel, methylene chloride/methanol 91),

SgzNiviMaOz, mass spectrum: t/2-398 (MU); (23) 3-2-(1-(4-pyridylamino)-1-phenylmethylene|-5-amido-2-indolinone: yield 1595 from theoretical,

Determination: 0.42 (silica gel, methylene chloride/methanol 91),

SgiNiviMaO", mass spectrum: t/2-356 (MU); (24) 3-2-(/1-(4-methylphenylamino)-1-phenylmethylene|-5-amido-2-indolinone: yield. 4595 from theoretical,

BaA value: 0.54 (silica gel, methylene chloride/methanol 91),

SgzNivMzO", mass spectrum: t/2-369 (MU); (25) 3-2-(1-(4-ethoxyphenylamino)-1-phenylmethylene|-5-amido-2-indolinone: yield: 4095 from theoretical,

Determination: 0.51 (silica gel, methylene chloride/methanol 91),

SgaNai MzOz, mass spectrum: t/2-399 (MU); (26) 3-2-(1-(3-bromophenylamino)-1-phenylmethylene|-5-amido-2-indolinone: yield 41 95 from theoretical,

Determination: 0.53 (silica gel, methylene chloride/methanol 91),

Sg2NivVi MzO", mass spectrum: t/2-433/435 (MU); (27) 3-2-I11-(4-chlorophenylamino)-1-phenylmethylene|-5-amido-2-indolinone: yield 5095 from theoretical,

Determination: 0.49 (silica gel, methylene chloride/methanol 91),

Sg2NivSiIMzO", mass spectrum: t/2-389/391 (MU); (28) 3-2-11-(4-isopropylphenylamino)-1-phenylmethylene|-5-amido-2-indolinone: yield: 4895 from theoretical,

Determination: 0.65 (silica gel, methylene chloride/methanol 91),

Sg25No2ziMzO", mass spectrum: t/2-397 (MU); (29) 3-2-11-(2-fluorenylamino)-1-phenylmethylene|-5-amido-2-indolinone: yield: 4395 from theoretical,

Determination: 0.58 (silica gel, methylene chloride/methanol 91),

Sg2oNai MzO", mass spectrum: t/2-443 (MU); (30) 3-2-11-(4-(2-hydroxyethylphenylamino)-1-phenylmethylene|-5-amido-2-indolinone: yield: 2295 from theoretical,

Determination: 0.37 (silica gel, methylene chloride/methanol 91),

SgaNai MzOz mass spectrum: t/2-398 (M-N); (31) 3-2-(11-(4-(4-imidazolyl)uphenylamino)-1-phenylmethylene|-5-amido-2-indolinone: yield: 2395 from theoretical,

Concentration: 0.5 (silica gel, methylene chloride/methanol 9:1),

C25NIz MO", mass spectrum: t/2-421 (MU); (32) 3-2-(/1-(4-ethoxycarbonylmethylphenylamino)-1-phenylmethylene|-5-amido-2-indolinone:

SgvNgziMzOkha, mass spectrum: t/2-442 (MN); (33) 3-2-(1-(4-bromo-3-methylphenylamino)-1-phenylmethylene|-5-amido-2-indolinone:

S2zNivVi MzO", mass spectrum: t/2-:447/449 (MU); (34) 3-2-I/1-(4-cyclohexylphenylamino)-1-phenylmethylene|-5-amido-2-indolinone:

С2вН2?МзО», mass spectrum: t/2-437 (MU); (35) 3-2-(1-(4-bromo-2-methylphenylamino)-1-phenylmethylene|-5-amido-2-indolinone:

SgzNiviMzO", mass spectrum: t/2-447/449 (MU); (36) 3-2-|1-amino-1-phenylmethylene|-5-amido-2-indolinone:

Ag value: 0.3 (silica gel, methylene chloride/methanol 91),

StvNiziMzO", mass spectrum: t/2-279 (MU); (37) 3-2-|/1-cyclohexylamino-1-phenylmethylene|-5-amido-2-indolinone:

Ag value: 0.55 (silica gel, methylene chloride/methanol 91),

Sg2NaziMzO", mass spectrum: t/2-:361 (MU); (38) 3-2-|/1-cyclopentylamino-1-phenylmethylene|-5-amido-2-indolinone:

Determination: 0.53 (silica gel, methylene chloride/methanol 91),

Sa Na MzO", mass spectrum: t/2-347 (MU); (39) 3-2-|1-methylamino-1-phenylmethylene|-5-amido-2-indolinone:

Concentration: 0.5 (silica gel, methylene chloride/methanol 9:1),

Si7Ni5MzO", mass spectrum: t/2-293 (MU); (40) 3-2-|1-ethylamino-1-phenylmethylene|-5-amido-2-indolinone:

Determination: 0.52 (silica gel, methylene chloride/methanol 91),

SivNi?MzO", mass spectrum: t/2-:307 (MU); (41) 3-2-|1-isopropylamino-1-phenylmethylene|-5-amido-2-indolinone:

Determination: 0.44 (silica gel, methylene chloride/methanol 91),

SieNivMzO", mass spectrum: t/2-:321 (MU); (42) 3-2-/1-dimethylamino-1-phenylmethylene|-5-amido-2-indolinone:

Determination: 0.39 (silica gel, methylene chloride/methanol 91),

SivNi?MzO", mass spectrum: t/2-:307 (MU); (43) 3-2-/1-cyclopropylamino-1-phenylmethylene|-5-amido-2-indolinone:

Determination: 0.47 (silica gel, methylene chloride/methanol 91),

St9Ni?MzO", mass spectrum; t/2-:319 (MU); (44) 3-2-|1-cycloheptylamino-1-phenylmethylene|-5-amido-2-indolinone:

Determination: 0.58 (silica gel, methylene chloride/methanol 91),

SgzNag5MzO", mass spectrum: t/2-:375 (MU); (45) 3-2-(1-cyclobutylamino-1-phenylmethylene|-5-amido-2-indolinone:

Weights: 0.49 (silica gel, methylene chloride/methanol 91),

SgoNivMzO", mass spectrum: t/2-333 (MU); (46) 3-2-I/1-(4-methylcyclohexylamino)-1-phenylmethylene|-5-amido-2-indolinone:

Determination: 0.67 (silica gel, methylene chloride/methanol 91),

SgzNag5MzO", mass spectrum: t/2-:375 (MU); (47) 3-2-I11-(1-(8,5)-indanylamino)-1-phenylmethylene|-5-amido-2-indolinone:

Determination: 0.59 (silica gel, methylene chloride/methanol 91),

C25Nai MzO»5, mass spectrum: t/2-395 (MU); (48) 3-2-(1-(Methoxycarbonylmethylamino)-1-phenylmethylene|-5-amido-2-indolinone:

Determination: 0.46 (silica gel, methylene chloride/methanol 91),

Sti9Ni?MzOm, mass spectrum: t/2-:351 (MU); (49) 3-2-I1-(2-methoxycarbonylethyl)amino)-1-phenylmethylene|-5-amido-2-indolinone:

Determination: 0.45 (silica gel, methylene chloride/methanol 91),

SgoNioMzOa, mass spectrum: t/2-365 (MU); (50) 3-2-/1-(4-aminomethylphenylamino)-1-phenylmethylene)-5-amido-2-indolinone: yield: 3295 from theoretical,

Determination: 0.46 (silica gel, methylene chloride/methanol 91),

С2зНгоМаО», mass spectrum: t/2-384 (MU); (51) trifluoroacetate 3-2-(1-(4-pyrrolidinomethylphenylamino)-1-phenylmethylene|-5-amido-2-indolinone: yield: 6095 from theoretical,

Determination: 0.07 (silica gel, methylene chloride/methanol 91),

C27NoviMaO", mass spectrum: t/2-438 (MU); (52) 3-2-/1-(4-morpholinomethylphenylamino)-1-phenylmethylene|-5-amido-2-indolinone: yield: 6595 from theoretical,

Determination: 0.46 (silica gel, methylene chloride/methanol 91),

C27NgviMaOz, mass spectrum: t/2-454 (MU); (53) 3-2-(1-(4-piperidinomethylphenylamino)-1-phenylmethylene|-5-amido-2-indolinone trifluoroacetate: yield: 6095 from theoretical,

Determination: 0.08 (silica gel, methylene chloride/methanol 91),

S2vNoviMaO", mass spectrum: t/2-452 (MU); (54) 3-2-I(1-(4-hexamethyleneiminomethylphenylamino)-1-phenylmethylene|-5-amido-2-indolinone trifluoroacetate:

SgoNzoMaO", mass spectrum: t/2-466 (MU); (55) 3-2-11-(4-(4-hydroxypiperidinomethyl)phenylamino)-1-phenylmethylene|-5-amido-2-indolinone:

SgvNgviMmaOz mass spectrum: t/2-468 (MU); (56) 3-2-11-(4-(4-methylthyperidinomethyl)phenylamino)-1-phenylmethylene|-5-amido-2-indolinone:

SgoNzoMaO", mass spectrum: t/2-466 (MU); (57) 3-2-11-(4-(4-ethylpiperidinomethyl)phenylamino)-1-phenylmethylene)|-5-amido-indolinone:

SzoNz2gMaO", mass spectrum: t/2-480 (MU); (58) 3-2-11-(4-(4-isopropylpiperidinomethyl)phenylamino)-1-phenylmethylene|-5-amido-2-indolinone:

SziNzaMaO", mass spectrum: t/2-494 (MU); (59) 3-2-11-(4--4-phenylpiperidinomethyl)phenylamino)-1-phenylmethylene|-5-amido-2-indolinone:

SzaNzgiMaO", mass spectrum: t/2-528 (MU); (60) 3-2-I(1-(4-(4-benzylpiperidinomethyl)phenylamino)-1-phenylmethylene|-5-amido-2-indolinone:

Sz5NzaMaO", mass spectrum: t/2-542 (MU); (61) 3-2-(1-(4-(4-ethoxycarbonylpiperidinomethyl)phenylamino)-1-phenylmethylene|-5-amido-2-indolinone:

SziNz2gMaOx, mass spectrum: t/2-:524 (MU); (62) 3-2-I1-(4-dimethylaminomethylphenylamino)-1-phenylmethylene|-5-amido-2-indolinone:

Sg25NgaMaO", mass spectrum: t/2-412 (MU); (63) 3-2-/1-(4-dipropylaminomethylphenylamino)-1-phenylmethylene|-5-amido-2-indolinone:

SgeNzaMaO", mass spectrum: t/2-468 (MU);

(64) 3-2-I/1-(4-piperazinylmethylphenylamino)-1-phenylmethylene|-5-amido-2-indolinone:

С27Н2?М5О», mass spectrum: t/2-453 (MU); (65) 3-2-(/1-(3-dimethylaminomethylphenylamino)-1-phenylmethylene|-5-amido-2-indolinone:

Sg25NgaMaO", mass spectrum: t/2-412 (MU); (66) 3-2-(1-(4-(2-diethylaminoethyl)phenylamino)-1-phenylmethylene|-5-amido-2-indolinone:

SgviNzoiMaO", mass spectrum: t/2-454 (MU); (67) 3-2-11-(4-(2-morpholinoethyl)phenylamino)-1-phenylmethylene|-5-amido-2-indolinone:

SgvNgviMaOz, mass spectrum: t/2-468 (MU); (68) 3-2-11-(4-(2-pyrrolidinylethyl)phenylamino)-1-phenylmethylene|-5-amido-2-indolinone:

S2vNoviMaO", mass spectrum: t/2-452 (MU); (69) 3-2-11-(4-(2-piperidinylethyl)phenylamino)-1-phenylmethylene|-5-amido-2-indolinone:

SgoNzoMaO", mass spectrum: t/2-466 (MU); (70) 3-2-(1-(2-thiazolylamino)-1-phenylmethylene|-5-amido-2-indolinone: yield: 3095 from theoretical,

Determination: 0.48 (silica gel, methylene chloride/methanol 91),

SizNia Ma", mass spectrum: t/2-362 (MU); (71) 3-2-(1-(benzimidazol-2-ylamino)-1-phenylmethylene|-5-amido-2-indolinone: yield: 2995 from theoretical,

Determination: 0.44 (silica gel, methylene chloride/methanol 91),

SgziNi?7M5O", mass spectrum: t/2-395 (MU); (72) 3-2-(1-(5-methylisoxazol-3-ylamino)-1-phenylmethylene|-5-amido-2-indolinone: yield 3995 from the theoretical,

Determination: 0.43 (silica gel, methylene chloride/methanol 91),

SaiNiviMaOz, mass spectrum: t/2-:374 (MU); (73) 3-2-11-benzylamino-1-phenylmethylene|-5-amido-2-indolinone:

Determination: 0.63 (silica gel, methylene chloride/methanol 91),

SgzNivMzO", mass spectrum: t/2-369 (MU); (74) 3-2-11-(4-(1-imidazolylmethyl)phenylamino)-1-phenylmethylene|-5-amido-2-indolinone;

Determination: 0.45 (silica gel, methylene chloride/methanol 91),

SgvNai MO", mass spectrum: t/2-436(MaN)U; (75) trifluoroacetate 3-2-(11-(4-(2-diethylaminoethyl)aminocarbonyl)phenylamino)-1-phenylmethylene|-5-amido-2-indolinone: yield 2195 from theoretical,

Determination: 0.05 (silica gel, methylene chloride/methanol 91),

SgeNziM5Oz, mass spectrum: t/2-497 (MU); (76) 3-2-I/1-(4-acetylaminomethylphenylamino)-1-phenylmethylene|-5-amido-2-indolinone:

Concentration: 0.4 (silica gel, methylene chloride/methanol 9:1),

Sg25NggMaOz, mass spectrum: t/2-426 (MU); (77) 3-2-(1-(4-(2-dimethylaminoethyl)-M-methanesulfonylamino)phenylamino)-1-phenylmethylene|-5-amido-2-indolinone:

Concentration: 0.1 (silica gel, methylene chloride/methanol 9:1),

C27NgoM5045, mass spectrum: t/2-:519 (MU); (78). 3-2-11-(4-(M-(ethoxycarbonylmethyl)-M-methanesulfonylamino)phenylamino)-1-phenylmethylene|-5-amido-2-indolinone:

Determination: 0.57 (silica gel, methylene chloride/methanol 91),

C27 NagviMma Ob mass spectrum: t/2-534 (MU); (79) 3-2-I11-(4-(M-(cyanomethyl)-M-methanesulfonylamino)phenylamino)-1-phenylmethylene|-5-amido-2-indolinone:

Determination: 0.49 (silica gel, methylene chloride/methanol 91),

C25Ngai M5045, mass spectrum: t/2-487 (MU); (80) 3-2-11-(4-(«M-methyl-M-methanesulfonylamino)phenylamino)-1-phenylmethylene|-5-amido-2-indolinone:

Determination: 0.46 (silica gel, methylene chloride/methanol 91),

SgaNggMaOa5, mass spectrum: t/2-462 (MU); (81) 3-2-11-(4-(2-oxopyrrolidin-1-ylmethyl)phenylamino)-1-phenylmethylene|-5-amido-2-indolinone:

C27NgaMaOz, mass spectrum: t/2-452 (MU);

(82) 3-2-11-(4-(2-oxopiperidin-1-ylmethyl)phenylamino)-1-phenylmethylene|-5-amido-2-indolinone:

SgvNgvimaOz, mass spectrum: t/2-466 (MU); (83) trifluoroacetate 3-2-(11-(4-(4-cyclohexylpiperidinomethyl)phenylamino)-1-phenylmethylene|-5-amido-2-insolinone:

SzaNzviMaO", mass spectrum. t/2-534 (MU); (84) 3-2-|(1-(4--2,6-dimethylpiperidinomethyl)phenylamino)-1-phenylmethylene|-5-amido-2-indolinone trifluoroacetate:

SzoNzaMaO", mass spectrum t/2-480 (MU); (85) trifluoroacetate /-3-2-(1-(4-(4-phenyl-4-hydroxypiperidinomethyl)phenylamino)-1-phenylmethylene|-5-amido-2-indolinone:

SzaNz2gMaOz, mass spectrum: t/2-545 (MU),

Determination: 0.66 (silica gel, methylene chloride/methanol 41); (86) 3-2-(11-(4-(2-methoxycarbonylpyrrolidinomethyl)phenylamino)-1-phenylmethylene|-5-amido-2-indolinone trifluoroacetate:

SgoNgvima Ohm, mass spectrum t/2-497 (MAN),

Determination: 0.65 (silica gel, methylene chloride/methanol 41); (87) 3-2-11-(4-(1-oxothiomorpholin-4-ylmethyl)phenylamino)-1-phenylmethylene|-5-amido-2-indolinone trifluoroacetate:

C27NoviMaOz5, mass spectrum: t/2-487 (Ma-H)",

Ve-value: 0.68 (silica gel, methylene chloride/methanol 41); (88) 3-2-11-(4-(3,6-dihydro-2H-pyridin-1-ylmethyl)phenylamino)-1-phenylmethylene|-5-amido-2-indolinone trifluoroacetate:

SovNovMaO", mass spectrum: t/2-451 (MN); (89) 3-2-(11-(4-(2,5-dihydropyrrol-1-ylmethyl)phenylamino)-1-phenylmethylene|-5-amido-2-indolinone trifluoroacetate:

C27NgaMaO", mass spectrum: t/2-437 (MN),

Determination: 0.49 (silica gel, methylene chloride/methanol 41); (90) 3-2-(1-(4-«thiomorpholin-4-ylmethyl)phenylamino)-1-phenylmethylene|-5-amido-2-indolinone trifluoroacetate:

C27NgvM4O»5, mass spectrum t/2-471 (MN),

Determination: 0.78 (silica gel, methylene chloride/methanol 41); (91) trifluoroacetate 3-2-(1-(4-(6,7-dimethoxytetrahydroisoquinolin-2-ylmethyl)phenylamino)-1-phenylmethylene|-5-amido-2-indolinone:

SzaNzagMaOm. mass spectrum: t/2-561 (MN),

Ve-value: 0.8 (silica gel, methylene chloride/methanol 4:1); (92) trifluoroacetate /3-2-(11-(4-(4-phenylpiperazin-1-ylmethyl))phenylamino)-1-phenylmethylene|-5-amido-2-indolinone:

SzzNaiM5O", mass spectrum: t/2-530 (Ma-N)",

Determination: 0.78 (silica gel, methylene chloride/methanol 41); (93) 3-2-|1-(4--3,5-dimethylpiperidinomethyl)phenylamino)-1-phenylmethylene|-5-amido-2-indolinone trifluoroacetate:

SzoNz2gMaO", mass spectrum: t/2-480 (MU),

Determination: 0.54 (silica gel, methylene chloride/methanol 41); (94) 3-2-(1-(4-(M-methyl-M-benzylaminomethyl)phenylamino)-1-phenylmethylene|-5-amido-2-indolinone trifluoroacetate:

SziNgoMaOh, mass spectrum: t/2-488 (MU); (95) 3-2-(1-(3,4-dimethoxyphenylamino)-1-phenylmethylene|-5-amido-2-indolinone:

SgaNai MzOa, mass spectrum: t/2-415 (MU),

Concentration: 0.5 (silica gel, methylene chloride/methanol 9:1); (96) 3-2-11-(4-trifluoromethoxyphenylamino)-1-phenylmethylene|-5-amido-2-indolinone:

SgzNivEzMzOz, mass spectrum: t/2-439 (MU),

Concentration: 0.5 (silica gel, methylene chloride/methanol 9:1); (97) 3-2-(1-(3-ethoxycarbonylphenylamino)-1-phenylmethylene|-5-amido-2-indolinone:

C25 Naii MzOh, mass spectrum: t/2-427 (MU),

Determination: 0.52 (silica gel, methylene chloride/methanol 9:1); (98) 3-2-I(1-(3-carboxyphenylamino)-1-phenylmethylene|-5-amido-2-indolinone:

Sg2zNi?7MzOx,

mass spectrum: t/2-399 (MU),

Concentration: 0.14 (silica gel, methylene chloride/methanol 9:1); (99) 3-2-(1-(3-diethylcarbamoylphenylamino)-1-phenylmethylene|-5-amido-2-indolinone:

Sg27NavimaOz, mass spectrum: t/2-454 (MU),

Determination: 0.48 (silica gel, methylene chloride/methanol 9:1); (100) 3-2-(1-(3-ethylcarbamoylphenylamino)-1-phenylmethylene|-5-amido-2-indolinone:

C25NggMaOz, mass spectrum: t/2-426 (MU),

Determination: 0.42 (silica gel, methylene chloride/methanol 9:1); (101) 3-2-(1-(3-trifluoromethoxyphenylamino)-1-phenylmethylene|-5-amido-2-indolinone:

SgzNivEzMzOz, mass spectrum: t/2-439 (MU),

Weight: 0.5 (silica gel, methylene chloride/methanol 9:1); (102) 3-2-(11-(3-ethoxyphenylamino)-1-phenylmethylene|-5-amido-2-indolinone:

SgaNai MzOz, mass spectrum: t/2-399 (MU),

Determination: 0.49 (silica gel, methylene chloride/methanol 9:1); (103) 3-2-(11-(4-methoxymethylphenylamino)-1-phenylmethylene|-5-amido-2-indolinone:

SgaNai MzOz, mass spectrum: t/2-399 (MU),

Concentration: 0.4 (silica gel, methylene chloride/methanol 4:1); (104) 3-2-(11-(4-ethylphenylamino)-1-phenylmethylene|-5-amido-2-indolinone:

SgaNai MzO", mass spectrum: t/2-383 (MU),

Determination: 0.52 (silica gel, methylene chloride/methanol 41); (105) 3-2-I(I1-(4-methyl-3-nitrophenylamino)-1-phenylmethylene|-5-amido-2-indolinone:

Sg2NiviMa Oh, mass spectrum: t/2-414 (MU); (106) 3-2-(/1-(4-methyl-3-methoxyphenylamino)-1-phenylmethylene|-5-amido-2-indolinone:

SgaNai MzOz, mass spectrum: t/2-399 (MU); (107) 3-2-(1-(4-(4-aminophenylmethyl)phenylamino)-1-phenylmethylene|-5-amido-2-indolinone trifluoroacetate:

SgoNgaMaO", mass spectrum: t/2-460 (MU); (108) 3-2-(/1-(4-Methoxycarbonyl-3-methylphenylamino)-1-phenylmethylene|-5-amido-2-indolinone:

C25 Naii MzOh, mass spectrum: t/2-427 (MU),

Determination: 0.56 (silica gel, methylene chloride/methanol 41); (109) 3-2-(1-(4-cyanophenylamino)-1-phenylmethylene|-5-amido-2-indolinone:

Sg2NiviMaO", mass spectrum: t/2-380 (MU),

Concentration: 0.65 (silica gel, methylene chloride/methanol 9:1); (110) 3-2-11-(5-methylpyridin-2-ylamino)-1-phenylmethylene|-5-amido-2-indolinone:

Concentration: 0.6 (silica gel, methylene chloride/methanol 9:1),

Sg2NiviMaO", mass spectrum: t/2-:370 (MU); (111) 3-2-11-(5-bromopyridin-2-ylamino)-1-phenylmethylene|-5-amido-2-indolinone:

Determination: 0.65 (silica gel, methylene chloride/methanol 91),

SgiNizVig Mao", mass spectrum: t/2-434/436 (M); (112) 3-2-I1-(2-chloropyridin-5-ylamino)-1-phenylmethylene|-5-amido-2-indolinone:

Determination: 0.49 (silica gel, methylene chloride/methanol 91),

C21Ni5SIMaO", mass spectrum: t/2-390/392 (MU); (113) 3-2-(1-(3-cyanophenylamino)-1-phenylmethylene|-5-amido-2-indolinone:

C2zNivMaO", mass spectrum: t/2-380 (MU),

Determination: 0.57 (silica gel, methylene chloride/methanol 91); (114) 3-2-I(1-(4-M-phenylaminomethyl)phenylamino)-1-phenylmethylene|-5-amido-2-indolinone:

SgoNgaMaO", mass spectrum: t/2-460 (MU),

Determination: 0.74 (silica gel, methylene chloride/methanol 9:1); (115) 3-2-I(1-(4-(M-methyl-M-phenylaminomethyl)phenylamino)-1-phenylmethylene|-5-amido-2-indolinone:

SzoNovimaO", mass spectrum: t/2-474 (MU),

Concentration: 0.75 (silica gel, methylene chloride/methanol 9:1); (116) 3-2-(1-(4-M-ethylaminomethyl)phenylamino)-1-phenylmethylene|-5-amido-2-indolinone trifluoroacetate:

C25NgaMaO", mass spectrum: t/2-412 (MU); (117) 3-2-|1-(4-(4-(4-chlorophenylmethyl)aminomethyl)phenylamino)-1-phenylmethylene|-5-amido-2-indolinone trifluoroacetate:

SzoN25SIMAO",

mass spectrum: t/2-508/510 (MU); (118) trifluoroacetate /3-2-I1-(4-(-«M-cyclohexylaminomethyl)phenylamino)-1-phenylmethylene|-5-amido-2-indolinone:

SgoNzoMaO", mass spectrum: t/2-466 (MU); (119) 3-2-I1-(4-M-isopropylaminomethyl)phenylamino)-1-phenylmethylene|-5-amido-2-indolinone trifluoroacetate:

SgvNovimaO", mass spectrum: t/2-426 (MU); (120) trifluoroacetate 3-2-(11-(4-(M-butylaminomethyl)phenylamino)-1-phenylmethylene|-5-amido-2-indolinone:

Sg27NgvimaO", mass spectrum: t/2-440 (MU); (121) 3-2-(1-(4-M-methoxycarbonylmethylaminomethyl)phenylamino)-1-phenylmethylene|-5-amido-2-indolinone trifluoroacetate:

SovNgaMaOa, mass spectrum: t/2-456 (MU); (122) trifluoroacetate /3-2-I1-(4-M-(phenylmethyl)aminomethyl)phenylamino)-1-phenylmethylene|-5-amido-2-indolinone:

SzoNovimaO", mass spectrum: t/2-464 (MU); (123) 3-2-11-(4-(M-acetyl-M-ethoxycarbonylmethylamino)phenylamino)-1-phenylmethylene|-5-amido-2-indolinone;

SgvNavima Ob, mass spectrum: t/2-498 (MU); (124) 3-2-(/1-(4-methyl-3-sulfamoylphenylamino)-1-phenylmethylene)|-5-amido-2-indolinone:

Sg2zNgoMmaO45, mass spectrum: t/2-448 (MU); (125) 3-2-11-(4--(M-methanesulfonyl-M-(methylcarbamoylmethyl)amino)phenylamino)-1-phenylmethylene|-5-amido-2-indolinone:

SgvNg5M5O55, mass spectrum: t/2-:519 (MU); (126) 3-2-11-(4--(M-methanesulfonyl-M-(piperidinecarbonylmethyl)amino)phenylamino)-1-phenylmethylene|-5-amido-2-indolinone:

SzoNzi M5O55, mass spectrum: t/2-:573 (MU); (127) 3-2-(1-(4-carboxyphenylamino|-1-phenylmethylene)-5-amido-2-indolinone:

Cg2zNi?7MzOx, mass spectrum: m/2-398 (М-Н)"; (128) 3-2-(11-(4-carboxy-3-methylphenylamino)-1-phenylmethylene|-5-amido-2 -indolinone:

SgaNgoMzOkh, mass spectrum: t/2-412 (M-N)"; (129) 3-2-I1-(4-(3-diethylaminopropoxy)phenylamino)-1-phenylmethylene|-5-amido-2-indolinone trifluoroacetate:

SgoNzagMaOz, mass spectrum: t/2-484 (MU); (130) 3-2-(1-(4-(2-piperidinoethoxy)phenylamino)-1-phenylmethylene|-5-amido-2-indolinone trifluoroacetate:

SgoNzoMaOz, mass spectrum: t/2-483 (MN); (131) 3-2-I(1-(4-(3-piperidinopropoxy)phenylamino)-1-phenylmethylene|-5-amido-2-indolinone trifluoroacetate:

SzoNz2gMaOz, mass spectrum: t/2-496 (MU); (132) 3-2-(1-(4--3-dimethylaminopropoxy)phenylamino)-1-phenylmethylene|-5-amido-2-indolinone trifluoroacetate:

Sg27Ngvima Oz, mass spectrum: t/2-457 (MN); (133) trifluoroacetate /3-2-(11-(4-(3-M-methyl-M-benzylaminopropoxy)phenylamino)-1-phenylmethylene|-5-amido-2-indolinone:

SzzNzgMaOz, mass spectrum: t/2-533 (MN); (134) 3-2-I(1-(4--(2-dimethylaminoethoxy)phenylamino)-1-phenylmethylene|-5-amido-2-indolinone trifluoroacetate:

SgvNgvimaOz, mass spectrum: t/2-443 (MN); (135) 3-2-(1-(4-(M-ethyl-M-benzylaminomethyl)phenylamino)-1-phenylmethylene)-5-amido-2-indolinone; (136) 3-2-(11-(4-(M-propyl-M-benzylaminomethyl)phenylamino)-1-phenylmethylene|-5-amido-2-indolinone; (197) 3-2-11-(4- (M-methyl-M-(4-chlorophenylmethyl)aminomethyl)phenylamino)-1-phenylmethylene|-5-amido-2-indolinone; (138) 3-2-11-(4-(M-methyl-M-( 4-bromophenylmethyl)aminomethyl)phenylamino)-1-phenylmethylene|-5-amido-2- indolinone: (139) 3-2-11-(4-M-methyl-M-(3-chlorophenylmethyl)aminomethyl)phenylamino)- 1-phenylmethylene|-5-amido-2-indolinone; (140) 3-2-(11-(4-M-methyl-M-(3,4-dimethoxyphenylmethyl)aminomethyl)phenylamino)-1-phenylmethylene|-5-amido-

2-indolinone; (141) 3-2-(11-(4-(M-(4-methoxyphenylmethyl)aminomethyl)phenylamino)-1-phenylmethylene|-5-amido-2-indolinone; (142) 3-2-11-(4 -M-trifluoroethyl-M-(phenylmethyl)aminomethyl)phenylamino)-1-phenylmethylene|-5-amido-2-indolinone; (143) 3-2-11-(4-(M-trifluoroethyl-M-(4-chlorophenylmethyl)aminomethyl)phenylamino)-1-phenylmethylene|-5-amido-2-indolinone.

Example 5 3-2-I1-(4-4-acetylpiperazinylmethyl)phenylamino)-1-phenylmethylene|-5-amido-2-indolinone 25 mg 3-2-I(1-(4-piperazinylmethyl)phenylamino)-1-phenylmethylene |-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, after which the solution is stirred for 1 hour. at room temperature Then wash with water and finally centrifuge the organic phase. output: 15mg (6895 from theoretical),

SgoNgeM5Oz, mass spectrum: t/2-495 (MU).

In a similar way, the following compound is obtained: (1) 3-2-11-(4-(4-benzoylpiperazinylmethyl)phenylamino)-1-phenylmethylene|-5-amido-2-indolinone: obtaining: C 3-2-(I1- (4-(piperazinylmethyl)phenylamino)-1-phenylmethylene|-5-amido-2-indolinone and benzoyl chloride, yield: 91 95 from theoretical,

SzaNzi M5Oz, mass spectrum: t/2-557 (MU).

Example 6 3-2-11-(4-diethylcarbamoylphenylamino)-1-phenylmethylene|-5-amido-2-indolinone 7g of resin from stage IM similarly to example 4 is introduced into the reaction with ethyl ether of 4-aminobenzoic acid. Wet saturated resin is suspended in 30 ml of dioxane and 30 ml of methanol and mixed with 25 ml of Mn. caustic soda for 40 hours. Then it is neutralized with dilute hydrochloric acid and washed with methylene chloride, methanol and dimethylformamide. Next, 30 mg of the resin is suspended in 3 ml of dimethylformamide and with 0.2 ml of diethylamine, 0.5 g of O-(benzotriazol-1-yl)-M,M,M',M'-tetramethyluronium tetrafluoroborate and 00.d8 ml of ethyldisopropylamine are kept for two days. at room temperature.

At the end, a product similar to that given in example 4 is separated from the resin.

Output: 29mg,

Determination: 0.46 (silica gel, methylene chloride/methanol 91),

Sg27NavimaOz, mass spectrum: t/2-454 (MU).

The following compounds are obtained in a similar way: (1) 3-2-11-(4-(piperidinocarbonyl)phenylamino)-1-phenylmethylene|-5-amido-2-indolinone:

Determination: 0.43 (silica gel, methylene chloride/methanol 91),

SgvNovima Oz, mass spectrum: t/2-466 (MU); (2) 3-2-I1-(4--4-methylpiperazinecarbonyl)phenylamino)-1-phenylmethylene|-5-amido-2-indolinone trifluoroacetate:

Determination: 0.84 (silica gel, methylene chloride/methanol 41),

SgvNg?M5Oz, mass spectrum: t/2-481 (MU); (3) 3-2-(11-(4-(M-(2-dimethylaminoethyl)-M-methylcarbamoyl)phenylamino)-1-phenylmethylene-5-amido-2-indolinone trifluoroacetate:

Concentration: 0.25 (silica gel, methylene chloride/methanol 91),

SgvNgoM5Oz, mass spectrum: t/2-484 (MN); (4) 3-2-11-(4-(-M-methoxycarbonylmethylcarbamoyl)phenylamino)-1-phenylmethylene|-5-amido-2-indolinone:

Concentration: 0.4 (silica gel, methylene chloride/methanol 91),

SoviNg2MaSz5, mass spectrum: t/2-470 (MU); (5) 3-2-(1-(4-benzylcarbamoylphenylamino)-1-phenylmethylene|-5-amido-2-indolinone:

Determination: 0.48 (silica gel, methylene chloride/methanol 91),

SzoNgaMaOz, mass spectrum: t/2-488 (MU).

Example 7 3-2-11-(4-(M-methylbenzoylamino)phenylamino)-1-phenylmethylene|-5-amido-2-indolinone 4.5 g of resin from stage IM similarly to example 4 is introduced into the reaction with 3.4 g of 4- (9H-fluoren-9-ylmethoxycarbonyl)methylamino)aniline in dimethylformamide. Then the ZN-fluorene protecting group is cleaved off using 4 ml of 3095 piperidine in dimethylformamide and the resin is washed several times. Next, 400 mg of resin is suspended in 4 ml of dimethylformamide and 0.3 ml of triethylamine, after which it is introduced into the reaction with

About 3 ml of benzoyl chloride, which lasts for an hour. at room temperature. At the end, a product similar to that given in example 4 is separated from the resin.

Exit ЗЗмг,

Determination: 0.45 (silica gel, methylene chloride/methanol 91),

SzoNgaMaOz, mass spectrum: t/2-488 (MU).

In a similar way, the following compounds are obtained: (1) 3-2-11-(4-(«M-methylpropionylamino)phenylamino)-1-phenylmethylene)|-5-amido-2-indolinone:

Determination: 0.42 (silica gel, methylene chloride/methanol 91),

SovNgaMaOz, mass spectrum: t/2-440 (MU); (2) 3-2-11-(4--"M-methylbutyrylamino)phenylamino)-1-phenylmethylene|-5-amido-2-indolinone:

Determination: 0.44 (silica gel, methylene chloride/methanol 91),

Cg27NavimaOz, mass spectrum: m/2-453 (M-H)"; (3) 3-2-11-(4-M-methylethylsulfonylamino)phenylamino)-1-phenylmethylene|-5-amido-2-indolinone:

Determination: 0.42 (silica gel, methylene chloride/methanol 91),

Co5HgaMaOa5, mass spectrum: m/2-475 (M-H)"; (4) 3-2-M11-(4-("M-methylpropylsulfonylamino)phenylamino)-1-phenylmethylene|-5-amido-2- indolinone:

Determination: 0.44 (silica gel, methylene chloride/methanol 91),

C25NoviMmaO45, mass spectrum: t/2-491 (MN); (5) 3-2-11-(4-(«M-methylphenylsulfonylamino)phenylamino)-1-phenylmethylene|-5-amido-2-indolinone:

Determination: 0.53 (silica gel, methylene chloride/methanol 91),

SgoNgaMaO45, mass spectrum: t/2-524 (MU).

Example 8

An ampoule with a dry preparation containing 75 mg of active substance per 10 ml

Composition: active substance 75.0 mg mannitol 50.0 mg water for injections up to 10, Oml

Preparation The active substance and mannitol are dissolved in water. After filling the ampoule, its contents are dried by freezing. Before use, the latter is diluted with special water for injections.

Example 9

An ampoule with a dry preparation containing 35 mg of the active substance per 2 ml

Composition: active substance 35.0mg mannitol 100.Omg water for injections up to 2.0ml

Preparation: The active substance and mannitol are dissolved in water. After filling the ampoule, its contents are dried by freezing. Before use, the latter is diluted with special water for injections.

Example 10

A tablet containing 50 mg of active substance

Composition: (1) active ingredient 50.0 mg (2) milk sugar 98.0 mg (3) corn starch 50.0 mg (4) polyvinylpyrrolidone 15.0 mg (5) magnesium stearate 2.0 mg 215.0 mg

Preparation: Ingredients (1), (2) and (3) are mixed and granulated using an aqueous solution of ingredient (4). Add ingredient (5) to the dried granulate. From this mixture, tablets are pressed in the form of a biplane with a one-sided facet and a notch on both sides. Diameter of tablets: 9 mm.

Example 11

A tablet containing 3500 mg of active substance

Composition: (1) active substance 350.0 mg (2) milk sugar 136.0 mg (3) corn starch 80.0 mg (4) polyvinylpyrrolidone 30.0 mg (5) magnesium stearate 4.0 mg 600.0 mg

Preparation: Ingredients (1), (2) and (3) are mixed and granulated using an aqueous solution of ingredient (4). Add ingredient (5) to the dried granulate. From this mixture, tablets are pressed in the form of a biplane with a one-sided facet and a notch on both sides. The diameter of the tablets is 12 mm.

Example 12

Capsules containing 50 mg of active substance

Composition: (1) active substance 50.0 mg (2) dried corn starch 58.0 mg (3) powdered milk sugar 50.0 mg (4) magnesium stearate 2.0 mg 160.Omg

Production: Ingredient (1) is ground with ingredient (3). Stirring intensively, this ground mass is added to the mixture of ingredients (2) and (4). At the end, the resulting powder mixture is packed into C-sized capsules with a hard gelatin coating using a suitable dosing device.

Example 13

Capsules containing 350 mg of active substance

Composition: (1) active ingredient 350.0 mg (2) dried corn starch 46.0 mg (3) powdered milk sugar 30.0 mg (4) magnesium stearate 4.0 mg 430.0 mg

Production: Ingredient (1) is ground with ingredient (3). Stirring intensively, this ground mass is added to the mixture of ingredients (2) and (4). At the end, the resulting powder mixture is packed into size 0 capsules with a hard gelatin coating using a suitable dosing device.

Example 14

Suppositories with 100 mg of active substance

One suppository contains: active substance 100.Omg polyethylene glycol (mol. mass 1500) 600.Omg polyethylene glycol (mol. mass 6000) 460.Omg polyethylene sorbitan monostearate 840, Omg 2000.0mg

Production: Polyethylene glycol is melted with polyethylene sorbitan monostearate. At a temperature of 40"C, the crushed active substance is dispersed in the melt until homogeneity is achieved. Then it is cooled to 38"C and poured into previously slightly cooled forms.

Claims (8)

1. Substituted indolinones of the general formula From the rest in And in x (t) , Y Kk in which X represents an oxygen or sulfur atom, Vi represents a hydrogen atom, a C1i-Ca-alkoxycarbonyl or C2-C4-alkanoyl group, Ag represents a carboxy-, C-C--alkoxycarbonyl or aminocarbonyl group, where the amine fragment can be substituted by one or two Ci-C3-alkyl groups and substituents can be identical or different from each other, Az means a phenyl or naphthyl group that can be substituted by fluorine, chlorine or bromine atoms, C1-C3-alkyl, Ci1-C3-alkyl, cyano-, trifluoromethyl, nitro-, amino-, C1i-C3-alkylamino-, di(C1-C3-alkyl)amino-, C2o-C--alkanoylamino-, M-(C1-C3-alkyl)-Co-C--alkanoylamino -, C1-C3-alkylsulfonylamino-, amino-C1-C3-alkyl, C1-C3-alkylamino-C1-C3-alkyl, di(C1i-C3-alkylamino-C1i-C3-alkyl, M- (C2o-Ca- alkanoyl)amino-Ci-C3-alkyl or / M-(C2o-C--alkanoyl)-C1-C3-alkylamino-Ci-C3-alkyl groups and the substituents can be identical or different from each other, Ba means a hydrogen atom or Ci-C3-alkyl group and A5 means a hydrogen atom, no necessarily substituted by a phenyl, carboxy- or C1i-C3-alkoxycarbonyl group, a C1i-C3-alkyl group, optionally substituted by a C1i-C3-alkyl group, a C3-C7-cycloalkyl group, an indanyl group optionally substituted by a C1i-C3-alkyl group group, a 5-linked heteroaryl group containing an imino group optionally substituted by a C1-C3-alkyl group, an oxygen or sulfur atom, or an imino group optionally substituted by a C1-C3-alkyl group and an oxygen, sulfur or nitrogen atom, or two nitrogen atoms, or means a 6b-membered heteroaryl group containing 1-3 nitrogen atoms, while with the help of two adjacent carbon atoms or one carbon atom and an adjacent imino group in the composition of the above 5- and b-membered heteroaryl groups, 1 can be additionally attached, 3-butadienylene bridge, and the carbon skeleton of the mentioned mono- and bicyclic rings can be mono- or di-substituted by fluorine, chlorine, bromine or iodine atoms, C1-C3-alkyl or cyano groups, and the substituents can be identical or different from each other, attached with the help of a carbon atom, a pyrrolidinyl or piperidinyl group, which can be replaced by a C1-C3-alkyl group at the nitrogen atom, optionally disubstituted by fluorine, chlorine, bromine or iodine atoms, C1-C3-alkyl, C1i-C3-alkyl, carboxy -, C-C3-alkoxycarbonyl, aminosulfonyl, nitro- or cyano groups, a phenyl group, while the substituents can be identical or different from each other, a phenyl, pyridyl, pyrimidyl or thienyl group, each of which is substituted by a trifluoromethoxy group, a fluorine, chlorine, bromine atom or iodine, a C1i-C3-alkoxy group, which can be substituted in the 2nd or 3rd position by amino-, C1-C3-alkylamino-, di(C1-C3-alkyl)amino-, phenyl-C1-C3-alkylamino- , M-(C1-C3-alkyl)/phenyl-C1-C3-alkylamino-, pyrrolidine or piperidine group, phenyl-C1-C3-alkylamino-C1-C3-alkyl group that can be mono- or disubstituted in the phenyl nucleus trifluoromethyl group, fluorine, chlorine, bromine or iodine atoms, C-C3-alkyl or C1-C3- alkoxy groups, while the substituents may may be identical or different from each other, and in addition, the nitrogen atom of the amine can be replaced by a C-C3-alkyl group, in which hydrogen atoms, starting from the 2nd position, can be partially or completely replaced by fluorine atoms, C-C5-alkyl, phenyl, imidazolyl, C3-C7-cycloalkyl, C1-C3-alkoxy-C1i-C3-alkoxy-, phenyl-C1-C3-alkoxy-, carboxy-C1-C3-alkyl, C1i-C3-alkoxycarbonyl-C1-C3- alkyl, carboxy-, C1-C3-alkoxycarbonyl, aminocarbonyl, C1-C3-alkylaminocarbonyl, di(C1-C3-alkyl)aminocarbonyl, phenyl-C1-C3-alkylaminocarbonyl, M-(C1-C3-alkyl)uphenyl-C1 -C3-alkylaminocarbonyl, piperazinecarbonyl, /M-(C1-C3-alkyl)piperazinecarbonyl, nitro-, amino-, C1-C3-alkylamino-, di(C1i-C3-alkyl)amino-, pyrrolidine, piperidine, morpholine, C2 -Ca4- alkanoylamino-, M-(C1-C3-alkyl)-C2-C4-alkanoylamino-, benzoylamino- or M-(C1-C3-alkyl)benzoylamino group, M-(C1-C3-alkyl)u-C» o-C-alkanoylamino group, which is additionally substituted in the alkyl fragment is replaced by a carboxy- or C1-C3-alkoxycarbonyl group, a C1-C3-alkylaminocarbonyl group or a di(C1-C3-alkylaminocarbonyl group, in which one alkyl fragment is additionally replaced by a di(C1-C3-alkylamino group), or M-(C1-C3 -alkyl)-C1-C3-alkylsulfonylamino- or M-(C1-C3-alkyl/uphenylsulfonylamino group, in which the alkyl fragment can be additionally substituted by cyano-, carboxy-, C1-C3-alkylsulfonyl, C1-C3-alkylamino-, di( C1i-C3-alkyl)amino-, aminocarbonyl, C1-C3-alkylaminocarbonyl, di(C1-C3-alkyl)aminocarbonyl, piperidinocarbonyl or 2-Idi(C1i1-C3-alkylamino))ethylaminocarbonyl group, a phenyl or thienyl group substituted by a C-C3-alkyl group, in which the alkyl fragment is replaced by hydroxy-, C1-C3-alkyloxy-, carboxy-, C1-C3-alkyloxycarbonyl, amino-, C1-C3-alkylamino-, di(C1- C5-alkyl)amino-, C-C-alkanoylamino-, M-(C1-C3-alkyl)-Co-C-alkanoylamino-, pyrrolidine, dehydropyrrolidine, piperidine, dehydropiperidine, 3-hydroxypiperidine, 4-hydroxypiperidine, hexamethyleneimino-, morpholine, thiomorpholine, piperazine, 4-(C1-C3-alkyl)upiperazine, 4-phenylpiperazine, 4-(C2-C«-alkanoyl)piperazine, 4-benzoylpiperazine or imidazolyl group, while the above-mentioned saturated cycloalkylenimine rings, C-Cv -alkylamino- or di(C1i-C5- alkyl)iamino groups can be additionally substituted by one or two C1i-C3-alkyl groups, C3-C7- cycloalkyl, hydroxy-, C1-C3-alkyl-, carboxy-, C1-C3-alkyloxycarbonyl , aminocarbonyl, C1-C3-alkylaminocarbonyl or di(C1i-C3-alkyl)aminocarbonyl group, in the phenyl nucleus - neoob' necessarily by fluorine, chlorine, bromine or iodine atoms, mono- or disubstituted C1i-C3-alkyl or cyano groups, phenyl-Ci-C3-alkyl or phenyl group, while the substituents can be identical or different from each other, or a methylene adjacent to the nitrogen atom the group in the above cycloalkylenimine rings may be substituted by a carbonyl or sulfonyl group, and the mentioned monosubstituted phenyl groups may be additionally substituted by a fluorine, chlorine or bromine atom, a methyl, amino, C1-C3-alkylamino or di(C1-C3-alkyl)amino group, or with one of the above unsubstituted cycloalkyleneimine rings with the help of two adjacent carbon atoms, a phenyl ring optionally substituted by one or two C1i-C3-alkoxy groups can be condensed, while the carboxyl groups mentioned in the decoding of the above-mentioned residues can be additionally replaced by a group that can be converted into a carboxyl group, and the amino and imino groups given in the decipherment of the mentioned residues can be additionally substituted by cleavage nim ip mimo residue, as well as their isomers and salts. 2. Substituted indolinones of the general formula I according to claim 1, in which X denotes an oxygen atom, B denotes a hydrogen atom or a C1i-C4-alkoxycarbonyl group, Ag denotes a carboxy-, C-C-alkoxycarbonyl or aminocarbonyl group, where the amine fragment can be substituted by one or two C-C3-alkyl groups and the substituents can be identical or different from each other, Az means a phenyl group optionally substituted by a fluorine, chlorine or bromine atom, a methyl, cyano- or aminomethyl group, Ba means a hydrogen atom or a methyl group and A5 means a hydrogen atom, a C1-C6-alkyl group optionally substituted by a carboxy or C1-C3-alkoxycarbonyl group, or a benzyl group optionally substituted by a methyl group, a C3-C7-cycloalkyl group, an indanyl group optionally substituted by a methyl group, a pyridyl, oxazolyl, thiazolyl or imidazolyl group, with which a phenyl ring, optionally substituted by a fluorine, chlorine or bromine atom, can be condensed with the help of two adjacent carbon atoms y, methoxy-, carboxy-, C1-C3-alkyloxycarbonyl, nitro- or aminosulfonyl group, a methylphenyl group or a dimethoxyphenyl group, attached with the help of a carbon atom, a pyrrolidinyl or piperidinyl group, which is replaced at a nitrogen atom by a C1-C3-alkyl group, a phenyl group, substituted by a trifluoromethoxy group, a fluorine, chlorine, bromine or iodine atom, a C1i-C3-alkoxy group, which in the 2nd or 3rd position can be substituted by amino-, C1-C3-alkylamino-, di(C1-C3-alkyl)amino- , phenyl-C1-C3-alkylamino-, M-(C1-C3-alkyl)uphenyl-C1-C3-alkylamino-, pyrrolidine or piperidine group, phenyl-C1-C3-alkylamino-C1-C3-alkyl group, which in the phenyl nucleus is replaced by a fluorine, chlorine, bromine or iodine atom, a C1i-Cv-alkyl, C1-C3-alkoxy- or trifluoromethyl group, and additionally at the nitrogen atom of the amine - a Ci-C3-alkyl group, in which hydrogen atoms, starting from 2- th position, can be completely or partially replaced by fluorine, C-C-alkyl, phenyl, imidazolyl, C-C7-cycloalkyl, C1-C3-alkyl -C1-C3-Alkoxy-, phenyl-C1-C3-Alkoxy-, carboxy-C1-C3-Alkyl, C1-C3-Alkoxycarbonyl-C1-C3-Alkyl, carboxy-, C1-C3-aluoxycarbonyl, aminocarbonyl, C1- C3-alkylaminocarbonyl, di(C1-C3-alkylaminocarbonyl, phenyl-C1-C3-alkylaminocarbonyl, -M- (C1-C3-alkyl)uphenyl-C1-C3-alkylaminocarbonyl, piperazinecarbonyl, M-(C1-C3-alkyl) )piperazinecarbonyl, nitro-, amino-, C1-C3-alkylamino-, di(C1-C3-alkyl)amino-, pyrrolidine, piperidine, morpholine, C2-C.-alkanoylamino-, M-(C1-C3-alkyl) -Co-C--alkanoylamino-, benzoylamino- or M-(C1-C3-alkyl)benzoylamino group, M-(C1-C3-alkyl)u-C»o-C--alkanoylamino group, which in the alkyl fragment is additionally replaced by carboxy - or a C-C3-alkoxycarbonyl group, a C1-C3-alkylaminocarbonyl or a di(C1-C3-alkylaminocarbonyl group, in which one alkyl fragment is additionally replaced by a di(C1-C3-alkylamino group), or M-(C1-C3-alkyl )-C1-C3-alkylsulfonylamino- or M-(C1-C3-alkyl/uphenylsulfonylamino), in which al ring fragment can be additionally substituted by cyano-, carboxy-, C1-C3-alkoxycarbonyl, C1-C3-alkylamino-, di(C1i-C3-alkyl)amino-, aminocarbonyl, C1-C3-alkylaminocarbonyl, di(C1-C3-alkyl )uaminocarbonyl, piperidinocarbonyl or 2-Idi(C1i1-C3-alkylamino))ethylaminocarbonyl group, optionally substituted by a C1-C3-alkyl group, a phenyl group in which the alkyl fragment is replaced by hydroxy-, C1-C3-alkylamino-, carboxy-, C1-C3-alkoxycarbonyl, amino-, C1-C3-alkylamino-, di(C1-C3-alkyl)amino-, C2-C4-alkanoylamino-, /M-(C1-C3-alkyl)u-Co-C- -alkanoylamino-, pyrrolidine, dehydropyrrolidine, piperidine, dehydropiperidine, 3-hydroxypiperidine, 4-hydroxypiperidine, hexamethyleneimino-, morpholine, thiomorpholine, piperazine, 4-(C1-C3-alkyl)upiperazine, 4-phenylpiperazine, 4-(C2-C«-alkanoyl)piperazine, 4-benzoylpiperazine or imidazolyl group, while the above-mentioned saturated cycloalkyleneimine rings, Ci-Cv-alkylamino or di(C1i-Cv5-alkyl)amino groups can be additionally replaced by one or two Ci1i-C3-alkyl groups, C3-C7-cycloalkyl, hydroxy -, C1-C3-alkoxy-, carboxy-, C1-C3-alkoxycarbonyl, aminocarbonyl, C1-C3-alkylaminocarbonyl or di(C1i-C3-alkyl)aminocarbonyl group, in the phenyl nucleus - optionally fluorine, chlorine, bromine atoms or iodine, mono- or disubstituted by C1i-C3-alkyl or cyano groups, phenyl-Ci-C3-alkyl or phenyl group, while the substituents can be identical or different from each other, or the methylene group adjacent to the nitrogen atom in the above cyclo alkylenimine rings can be substituted by a carbonyl or sulfonyl group, and the mentioned monosubstituted phenyl groups can be additionally substituted by a fluorine, chlorine or bromine atom, a methyl, amino-, C1-C3-alkylamino- or di(C1-C3-alkyl)amino group, or with one of of the above unsubstituted cycloalkyleneimine rings with the help of two adjacent carbon atoms, a phenyl ring optionally substituted by one or two C1-C3-alkoxy groups, as well as their isomers and salts, can be condensed. 3. Substituted indolinones of the general formula | zap 1, in which X represents an oxygen atom, B represents a hydrogen atom, Ag represents a carboxy-, C-C--alkoxycarbonyl or aminocarbonyl group, in which the amine fragment can be replaced by one or two C-C3-alkyl groups and the substituents can be identical or differ from each other, Az means a phenyl group optionally substituted by a methyl group, Ba means a hydrogen atom or a methyl group, and A5 means a hydrogen atom, a C1-C3-alkyl group, a benzyl group, or a methyl group substituted by a carboxy- or C1-C3-alkoxycarbonyl group or an ethyl group, optionally substituted by a methyl group, a C3-C7-cycloalkyl group, optionally substituted by a methyl group, an indanyl, pyridyl, oxazolyl, thiazolyl, or imidazolyl group, with which a phenyl ring can be condensed with the help of two adjacent carbon atoms, optionally a methylphenyl or dimethoxyphenyl group necessarily substituted by a fluorine, chlorine or bromine atom, methoxy-, carboxy-, C1-C3-alkyloxycarbonyl, nitro- or aminosulfonyl group pu, a 3-pyrrolidinyl or 4-piperidinyl group substituted by a C1-C3-alkyl group at the nitrogen atom, a phenyl group substituted by a trifluoromethoxy-, benzyloxy-, cyano- or nitro group, a fluorine, chlorine or bromine atom, a C1i-C3-alkyl group , and each of the ethoxy and n-propoxy groups in the terminal position can be replaced by a dimethylamino-, diethylamino-, M-ethylmethylamino-, M-benzylmethylamino- or piperidine group, a phenyl-C1-C3-alkylamino-Ci-C3-alkyl group, which in the phenyl nucleus it can be replaced by a fluorine, chlorine, bromine or iodine atom, a methyl, methoxy- or trifluoromethyl group, and additionally in the nitrogen atom of the amine - a C-Cv-alkyl or 2,2,2-trifluoroethyl group, a C-C-alkyl, phenyl , imidazolyl, cyclohexyl, methoxymethyl, carboxymethyl, /C1-C3- alkoxycarbonylmethyl, carboxy-, C1i-C3-alkoxycarbonyl, aminocarbonyl, /-C1-C3- alkylaminocarbonyl, di(C1-C3-alkylal'aminocarbonyl, phenyl-C1-C3 -alkylaminocarbonyl, -M- (C1-C3-alkyl)uphenyl-C1-C3-alkylaminocarb onylic, piperazinecarbonyl, M-(C1-C3-alkyl)piperazinecarbonyl, amino-, C1-C3-alkylamino-, di(C1i-C3-alkylamino-, pyrrolidine, piperidine, morpholine, C2-C-alkanoylamino-, M- (C1-C3-alkyl)-Co-C--alkanoylamino-, benzoylamino- or M-(C1-C3)benzoylamino group, M-(C1-C3-alkyl)u-C»o-C--alkanoylamino group, which in an alkyl fragment is additionally substituted by a carboxy- or C-C3-alkylcarbonyl group, a C-C3-alkylaminocarbonyl group or a di(C1-C3-alkylaminocarbonyl group), in which one alkyl fragment is additionally substituted by a di(C1-C3-alkylamino group, or M-( C1-C3-alkyl)-C1-C3-alkylsulfonylamino- or M-(C1-C3-alkyl/uphenylsulfonylamino) group, in which the alkyl fragment can be additionally substituted by cyano-, carboxy-, C1-C3-alkoxycarbonyl, C1-C3-alkylamino- , di(C1i-C3-alkyl)amino-, aminocarbonyl, C1-C3-alkylaminocarbonyl, di(C1-C3-alkyl)aminocarbonyl, piperidinocarbonyl or 2-Idi(C1i1-C3-alkylamino))ethylaminocarbonyl group, optionally substituted Well, the C1i-C3-alkyl group is a phenyl group in which the alkyl group is replaced by hydroxy-, C1-C3-alkoxy-, carboxy-, C1-C3-alkyloxycarbonyl, amino-, C1-C3-alkylamino-, di(C1-C5- alkyl)amino-, Co-C-alkanoylamino-, M-(C1-C3-alkyl)-Co-C-alkanoylamino-, pyrrolidine, dehydropyrrolidine, piperidine, dehydropiperidine, 4-hydroxypiperidine, hexamethyleneimino-, morpholine, thiomorpholine, piperazine, 4-(C1-C3-alkyl)piperazine, 4-phenylpiperazine, 4-(C2-C4-alkanoyl)piperazine, 4-benzoylpiperazine or imidazolyl group, while the above saturated cycloalkyleneimine rings can be additionally substituted by a phenyl group or one or two methyl groups , the above Ci-Cv-alkylamino and di(C1-Cv-alkyl)amino groups can be additionally substituted by one or two Ci-C3-alkyl groups, cyclohexyl, hydroxy-, C1-C3- alkoxy-, carboxy-, C1-C3- alkoxycarbonyl , aminocarbonyl, C1-C3-alkylaminocarbonyl or di(C1-C3-alkyl)aminocarbonyl group, optionally substituted in the phenyl nucleus by a fluorine, chlorine, bromine or iodine atom, methyl or cyano group, phenyl-C1-C3-alkyl or phenyl group, or the methylene group adjacent to the nitrogen atom in the mentioned cycloalkylenimine rings can be replaced by a carbonyl or sulfonyl group, and the above-mentioned monosubstituted phenyl groups can be additionally replaced by a fluorine, chlorine or bromine atom, methyl, amino-, C-C3-alkylamino- or di(C1i-C3 -alkyl)l'amino group, or with one of the above unsubstituted cycloalkylenimine rings with the help of two adjacent carbon atoms, a phenyl ring optionally substituted by one or two C1-C3-alkyl groups can be condensed, as well as their isomer and salt. 4. Substituted indolinones of the general formula I according to claim 1, in which X means an oxygen atom, B means a hydrogen atom, Ag means a carboxy- or aminocarbonyl group, in which the amine fragment can be replaced by one or two C1-C3-alkyl groups and the substituents can be identical or different from each other, Az means a phenyl group optionally substituted by a methyl group, Ba means a hydrogen atom and A5 means a hydrogen atom, a 3-pyrrolidinyl or 4-piperidinyl group substituted at a nitrogen atom by a C-C3-alkyl group, a phenyl group , substituted by a C1i-C3-alkoxy group, and each of the ethoxy- and n-propoxy groups in the terminal position can be replaced by a dimethylamino-, diethylamino-, M-ethylmethylamino-, M-benzylmethylamino- or piperidine group, phenyl-C1-C3-alkylamino-C1 -C3-alkyl group, which in the phenyl nucleus can be replaced by a fluorine, chlorine, bromine or iodine atom, a methyl, methoxy- or trifluoromethyl group, and additionally in the nitrogen atom of the amine - a Ci-Cv-alkyl or 2,2,2-trifluoroethyl group, optional to a phenyl group substituted by a C1i-C3-alkyl group, in which the alkyl group is replaced by a hydroxy-, C1-C3-alkyl group - alkyl)amino-, Co-C-alkanoylamino-, M-(C1-C3-alkyl)-Co-C-alkanoylamino-, pyrrolidine, dehydropyrrolidine, piperidine, dehydropiperidine, 4-hydroxypiperidine, hexamethyleneimino-, morpholine, thiomorpholine, piperazine , 4-(C1-C3-alkyl)piperazine, 4-phenylpiperazine, 4-(C2-C4-alkanoyl)piperazine, 4-benzoylpiperazine or imidazolyl group, while the above saturated cycloalkyleneimine rings can be additionally substituted by a phenyl group or one or two methyl groups, the above Ci-Cv-alkylamino- and di(C1-Cv-alkyl) amino groups can be additionally replaced by one or two Ci-C3-alkyl groups, cyclohexyl, hydroxy-, C1-C3-alkyl-, carboxy-, C1-C3 - alkoxycarbonyl, aminocarbonyl, C1-C3-alkylaminocarbonyl or di(C1-C3-alkyl)aminocarb an onyl group, optionally substituted in the phenyl nucleus by a fluorine, chlorine, bromine or iodine atom, a methyl or cyano group, a phenyl-Ci1-C3-alkyl or phenyl group, or a methylene group adjacent to a nitrogen atom in the mentioned cycloalkylenimine rings can be replaced by a carbonyl or sulfonyl group , and the above-mentioned monosubstituted phenyl groups can be additionally substituted with a fluorine, chlorine or bromine atom, a methyl, amino-, C-C3-alkylamino- or di(C1i-C3-alkyl)lamino group, or with one of the above-mentioned unsubstituted cycloalkylenimine rings using of two adjacent carbon atoms can condense a phenyl ring optionally substituted by one or two C1-C3-alkoxy groups, as well as their isomers and salts. 5. Substituted indolinones of the general formula I according to any of claims 1-4, in which the K2 residue is in the 5th position. 6. Substituted indolinones of the general formula I according to claim 1 from the group including (a) 3-2-I1-(4-aminomethylphenylamino)-1-phenylmethylene)|-5-amido-2-indolinone, (6) 3-2 -P-phenylamino-1-phenylmethylene|-5-amido-2-indolinone, (c) 3-2-(1-(4-bromophenylamino)-1-phenylmethylene|-5-amido-2-indolinone, (g) 3-4-M-(4-dimethylaminomethyl)phenylamino-1-phenylmethylene)|-5-amido-2-indolinone, (d) 3-2-(11-(4-pyrrolidinomethylphenylamino)-1-phenylmethylene|-5- amido-2-indolinone, (e) 3-2-I1-(4-piperidinomethylphenylamino)-1-phenylmethylene|-5-amido-2-indolinone, (e) 3-2-(1-(4-hexamethyleneiminomethylphenylamino)- 1-phenylmethylene|-5-amido-2-indolinone, (w) 3-2-(1-(4--4-benzylpiperidinomethyl)phenylamino)-1-phenylmethylene|-5-amido-2-indolinone, (h) 3-2-11-(4-(M-butylaminomethyl)phenylamino)-1-phenylmethylene|-5-amido-2-indolinone, () 3-2-11-(4-M-(phenylmethyl)aminomethyl)phenylamino) -1-phenylmethylene|-5-amido-2-indolinone, (in 3-2-11-(4-(-«M-methyl-M-benzylaminomethyl)phenylamino)-1-phenylmethylene|-5-amido-2- indolinone, (ju. 3-2-11-(4-piperidinomethylphenylamino)-1-phenylmethylene|-5-dimethylcarbamoyl-2-indolinone, (l) 3-2-11-(4-piperidinomethylphenylamino)-1-phenylmethylene|-5- diethylcarbamoyl-2-indolinone, (m) 3-2-I(1-(4-(3-diethylaminopropoxy)phenylamino)-1-phenylmethylene|-5-amido-2-indolinone, and their salts. 7. Compounds according to any of claims 1-6, which are physiologically acceptable salts of substituted indolinones of the general formula I. 8. A medicinal product for the treatment of excessive or abnormal cell proliferation, which contains a compound according to any one of claims 1-7, and, if necessary, one or more inert carriers and/or diluents.