HRP20000831A2 - New substituted indolinones, the preparation thereof and their use as pharmaceutical compositions - Google Patents

Description

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

[image]

to their isomers and to their salts, especially to their physiologically acceptable salts, which have valuable properties.

The above compounds of the general formula I in which R1 denotes a hydrogen atom, or a prodrug group, have valuable pharmacological properties, especially inhibitory effects on various kinases, especially on CDRs complexes (CDK1, CDK2, CDK3, CDK4, CDK6, CDK7, CDKB and CDK9) with their specific cyclins (A, B1, B2, C, D1, D2, D3, E, F, G1, G2, H, 1 and K) and viral cyclin (see. L. Mengtao in J. Virology; 7JL(3) , 1984-1991 (1997)), and other compounds of the above general formula I, in which R 1 does not represent a hydrogen atom or a prodrug group, are valuable intermediates for the preparation of the above-mentioned compounds.

The proposed invention therefore relates to the above compounds of the general formula I, because compounds in which R1 represents a hydrogen atom or a prodrug group have valuable pharmacological properties, to pharmaceutical preparations containing pharmacologically active compounds, their use and procedures for their preparation.

In the above general I

X denotes an oxygen or sulfur atom,

R1 is a hydrogen atom, a C1-4-alkoxy-carbonyl or a C1-4-alkanoyl group,

R2 denotes a carboxy or C1-4-alkoxy-carbonyl group or an aminocarbonyl group, optionally substituted with one or two C1-4-alkyl groups, while the substituents may be the same or different,

R3 denotes a hydrogen atom or a C1-6-alkyl group which can be substituted in position 2 in relation to the carbon atom of the acupine R3-C(R4NR5)= with fluorine, chlorine or a bromine atom, with hydroxy, C1-3-alkoxy, C1- 3-alkyl-sulfenyl, C1-3-alkylsulfinyl, C1-3-alkylsulfonyl, phenylsulfenyl, phenylsulfinyl, phenylsulfonyl, amino, C1-4-alkylamino, di-(C1-4-alkyl)-amino, C2-5-alkanoyl- amino or N-(C1-3-alkylamino)-C1-5-alkanoylamino group,

R4 is a hydrogen atom, a C1-6-alkyl group or a C5-7-cycloalkyl group, optionally substituted with a C1-3-alkyl group, wherein one methylene group is in position 3 or 4 in relation to the carbon atom of the group R3-C( R4NR5)= can be substituted with an imino group optionally substituted with a C1-3-alkyl group,

a phenyl or naphthyl group which can be substituted with a fluorine, chlorine, bromine or iodine atom, with a methoxy group optionally substituted with 1 to 3 fluorine atoms,

with C2-3-Alkoxy which can be substituted in position 2 or 3 with C1-3-alkylamino, di-(C1-3-alkyl)-amino or 5- to 7-membered cycloalkylenimine group, while additionally one alkyl group in the above the mentioned alkylamino and dialkylamino groups can be substituted with a phenyl group,

with trifluoromethyl, amino, C1-3-alkylamino, di-(C1-3-alkyl)-amino, C2-5-alkanoylamino, N-(C1-3-alkyl)-C2-5-alkanoylamino, C1-5-alkylsulfonylamino , N-(C1-3-alkyl) C1-5-alkylsulfonylamino, phenylsulfonylamino, N-(C1-3-alkyl)-phenylsulfonylamino, aminosulfonyl, C1-3-alkylamino-sulfonyl or di-(C1-3-alkyl)- aminosulfonyl group, while additionally one alkyl group in the aforementioned alkylamino and dialkylamino groups can be substituted with a phenyl group,

with a carbonyl group substituted with a hydroxy, C1-3-alkoxy, amino, C1-4-alkylamino or N-(C1-5-alkyl)-C1-3-alkylamino group, while additionally the alkyl group in the aforementioned groups can be substituted with a carboxy, C1-3-alkylcarbonyl or phenyl group or in position 2 or 3 with di-(C1-3-alkyl)-amino, piperazine, N-(C1-4-alkyl)-piperazine or 5- to 7- member cycloalkylenimine group,

with a C1-3-alkyl group that is substituted with an amino, C1-7-alkylamino, C5-7-cycloalkylamino, C5-7-cycloalkyl-C1-3-alkylamino or phenyl-C1-3-alkylamino group which can additionally be substituted on the nitrogen atom with a C1-3-alkyl group, wherein the hydrogen atoms are completely or partially replaced by fluorine atoms, with a C5-7-cycloalkyl, C2-4-alkenyl or C1-4-alkyl group, while

the above-mentioned C1-4-alkyl substituent can in any case be additionally mono-, di- or trisubstituted with a cyano, carboxy, C1-3-alkoxycarbonyl, pyridyl, imidazolyl, benzo[1,3]dioxole or phenyl group, wherein the phenyl the group can be substituted with fluorine, chlorine or bromine atoms, with methyl, methoxy, trifluoromethyl, cyano or nitro groups, and the substituents can be identical or different, or it can be substituted in position 2, 3 or 4 with a hydroxy group,

with a C1-4-alkyl group which may be substituted with hydroxy, carboxy, thiomorpholino, 1-oxido-thiomorpholino, 1,1-dioxido-thiomorpholino, piperazine, N-(C1-3-alkyl)-piperazine or N-phenyl- piperazine group, with 5- to 7-membered. with a cycloalkenylenimino group or with a 4- to 7-membered cycloalkylenimino group, whereby the above-mentioned 5- to 7-membered cycloalkylenimino groups can be substituted with one or two C1-3-alkyl groups, with a C5-7-cycloalkyl or phenyl group, with With a C1-3-alkyl, C5-7-cycloalkyl, phenyl, carboxy or C1-4-alkoxy-carbonyl group and with a hydroxy group and in the above-mentioned cycloalkylenimino groups, the methylene group adjacent to the nitrogen atom can be replaced with a carbonyl group,

with a C1-3-alkyl group which is substituted with a 5- to 7-membered cycloalkylenimine group, while the phenyl group can be mono- or di-substituted as necessary with fluorine, chlorine or bromine atoms or with methyl or methoxy groups, whereby these substituents can be identical or different, or an oxazolo, imidazolo, thiazolo, pyridino, pyrazino or pyrimidino group, optionally substituted with fluorine, chlorine, bromine or iodine atoms or with a methyl, methoxy or amino group, can be fused to the above-mentioned 5- to 7 -members of the cycloalkylenimine group through two adjacent carbon atoms,

while, additionally, the above-mentioned monosubstituted phenyl groups can be substituted with a fluorine, chlorine or bromine atom or with a methyl, methoxy or nitro group,

A 5-membered heteroaromatic group containing an imino group, an oxygen or sulfur atom, or an imino group, an oxygen or sulfur atom and one or two nitrogen atoms, or a 6-membered heteroaromatic group containing one, two or three nitrogen atoms, while the above-mentioned 5 - and 6-membered heteroaromatic groups can be additionally substituted with a chlorine or bromine atom or with a methyl group, or the phenyl ring can be fused to the above-mentioned 6-membered heteroaromatic groups via two adjacent carbon atoms, and

R5 denotes a hydrogen atom or a C1-3-alkyl group.

Furthermore, the carboxy, amino or imino groups present in the above-mentioned compound of general formula 1 may be substituted with groups that can be cleaved in vivo.

In addition to the alkoxycarbonyl and alkanoyl groups already mentioned above, groups that can be cleaved in vivo include an acyl group such as a benzoyl, pyridinoyl, pentanoyl or hexanoyl group, an allyloxycarbonyl group, a C1-16-alkoxycarbonyl group such as a pentoxycarbonyl, a hexyloxycarbonyl, octyloxycarbonyl, nonyloxycarbonyl, decyloxycarbonyl, undecyloxycarbonyl, dodecyloxycarbonyl or hexadecyloxycarbonyl group, a phenyl-C1-6-alkyloxycarbonyl group such as a benzyloxycarbonyl, phenyl-ethoxycarbonyl or phenylpropoxycarbonyl group, a C1-3-alkylsulfonyl-C2-4-alkyloxycarbonyl group , C1-3-Alkoxy-C2-4-Alkoxy-C2-4-Alkoxycarbonyl or RCCO-O-(RdCRe)-O-CO-group, in which

RC represents a C1-8-alkyl, C5-7-cycloalkyl, phenyl or phenyl-C1-3-alkyl group,

Re represents a hydrogen atom, C1-3-alkyl, C5-7-cycloalkyl or phenyl group and

Rd represents a hydrogen atom or a C1-3-alkyl group, or an RCCO-O-(RdCRe)-O- group,

while the above-mentioned ester groups can also be used as groups that can be - in vivo converted into carboxy groups.

Preferred compounds of general formula I are, however, those in which

X represents an oxygen or sulfur atom,

R1 is a hydrogen atom,

R2 represents an aminocarbonyl group,

R3 represents a hydrogen atom or a C1-4-alkyl group which can be substituted in position 2 in relation to the carbon atom of the group R3-C(R4NR5)= with chlorine or a bromine atom, or with a phenylsulfonyl group,

R4 represents a hydrogen atom, a C1-3-alkyl group or a cyclopentyl or cyclohexyl group, optionally substituted with a methyl group, whereby in the cyclopentyl or cyclohexyl group the methylene group is in position 3 or 4 in relation to the carbon atom of the group R3-C(R4NR5) = may be substituted with an imino group, optionally substituted with a methyl group,

a phenyl group substituted with a fluorine, chlorine, bromine or iodine atom,

with a methoxy group optionally substituted with 1 to 3 fluorine atoms,

with C2-3 alkoxy which can be substituted in position 2 or 3 with methylamino, dimethylamino or a 5- to 7-membered cycloalkylenimine group, while additionally one methyl group in the above-mentioned amino groups can be substituted with a phenyl group,

with trifluoromethyl, amino, C2-5-alkanoylamino, N-(C1-3-alkyl)-C2-5-alkanoylamino, C1-5-alkylsulfonylamino, N-(C1-3-alkyl)-C1-5-alkylsulfonylamino, phenylsulfonylamino , N-(C1-3-alkyl)-phenylsulfonylamino or aminosulfonyl group, while additionally one alkyl group in the aforementioned alkylamino and dialkylamino groups can be substituted with a phenyl group,

with a carbonyl group substituted with a hydroxy, C1-3-alkoxy, amino, C1-4-alkylamino or N-(C1-5-alkyl)-C1-3-alkylamino group, while additionally the alkyl group in the aforementioned groups can be substituted with a carboxy, C 1-3 -alkoxycarbonyl or phenylnora group or in position 2 or 3 with di-(C 1-3 -alkyl)-amino, piperazine, N-(C 1-3 -alkyl)-piperazine or 5- to 7- member cycloalkylenimine group,

with a C1-3-alkyl group that is substituted with an amino, C1-7-alkylamino, C5-7-cycloalkylamino, C5-7-cycloalkyl-C1-3-alkylamino or phenyl-C1-3-alkylamino group, which can additionally be by substituents on the nitrogen atom with a C1-3-alkyl group, wherein the hydrogen atoms are completely or partially replaced by fluorine atoms, with a C5-7-cycloalkyl, C2-4-alkenyl or C1-4-alkyl group, while

The above-mentioned C1-4-alkyl substituent can in any case be additionally substituted with a cyano, carboxy, C1-3-alkoxycarbonyl, pyridyl, imidazolyl, benzo-[1,3]dioxole or phenyl group, whereby the phenyl group can be substituted with with fluorine, chlorine or bromine atoms, or with a methyl, methoxy, cyano, trifluoromethyl or nitro group, or di- or trisubstituted with fluorine, chlorine or bromine atoms or with methyl or methoxy groups, and the substituents may be identical or different, or may be substituted in position 2, 3 or 4 with a hydroxy group,

with a C1-3-alkyl group, which may be substituted with hydroxy, carboxy, thiomorpholino, 1-oxido-thiomorpholino, 1,1-dioxido-thiomorpholino, piperazine, N-(C1-3-alkyl)-piperazine or N-phenyl -piperazine group, with a 5- to 7-membered cycloalkenylenimino group or with a 4- to 7-membered cycloalkylenimino group, whereby the aforementioned 5- to 7-membered cycloalkylenimino groups can be substituted with one or two C1-3-alkyl groups, with a cyclohexyl or phenyl group, with a C1-3-alkyl, cyclohexyl, phenyl, carboxy or C1-4-alkoxy-carbonyl group and with a hydroxy group, and in the above-mentioned cycloalkylenimine groups, the methylene group adjacent to the nitrogen atom can be replaced with a carbonyl group ,

with a C1-3-alkyl group which is substituted with a 5- to 7-membered cycloalkylenimine group, while the phenyl group can be mono- or di-substituted as necessary with fluorine, chlorine or bromine atoms or with methyl or methoxy groups, whereby these substituents can be identical or different, or a pyrazino or thiazolo group, optionally substituted with an amino group, can be fused to the above-mentioned 5- to 7-membered cycloalkylenimine groups via two adjacent carbon atoms,

while additionally the above-mentioned monosubstituted phenyl groups can be substituted with a fluorine, chlorine or bromine atom or with a methyl, methoxy or nitro group,

pyridyl group, optionally substituted with a chlorine or bromine atom or with a methyl group,

an oxazolyl, isoxazolyl, imidazolyl or thiazolyl group, optionally substituted with a methyl group, to which the phenyl ring may be fused via two adjacent carbon atoms, and

R5 represents a hydrogen atom or a C1-3-alkyl group,

especially those compounds of the general formula I in which R1 to R3 and R5 are defined as above, i

R4 represents a hydrogen atom, a C1-6-alkyl group or

a C5-7-cycloalkyl group, optionally substituted with a C1-3-alkyl group, whereby one methylene group in position 3 or 4 in relation to the carbon atom of the group R3-C(R4NR5)= can be substituted with an imino group optionally substituted with a C1-3-alkyl group,

a phenyl or naphthyl group, which can be substituted with a fluorine, chlorine, bromine or iodine atom, with C1-3-Alkoxy, amino, C1-3-alkylamino, di-(C1-3-alkyl)-amino, C2-5- alkanoylamino, C1-5-alkylsulfonylamino, N-(C1-3-alkyl) C1-5-alkylsulfonylamino, phenylsulfonylamino or N-(C1-3-alkyl)-phenylsulfonylamino group or with a C1-3-alkyl group which may be substituted with C1-5-alkylamino, di-(C1-3-alkyl)-amino, thiomorpholino, 1-oxido-thiomorpholino, 1,1-dioxido-thiomorpholino, piperazino, N-phenyl-piperazino, C5-7-cycloalkenylenimino group or with C4-7-cycloalkylene-imino group, whereby the aforementioned C5-7-cycloalkylene-imino groups can be substituted with one or two C1-3-alkyl groups, with a C5-7-cycloalkyl or phenyl group, with C1-3- with an alkyl, C5-7-cycloalkyl, phenyl, carboxy or C1-4-alkoxy-carbonyl group and with a hydroxy group, and their isomers in their salts,

Particularly preferred compounds of general formula 1 are those in which R1 to R5 are as defined above, and R2 is in position 5,

especially those compounds in which

X represents an oxygen atom,

R1 is a hydrogen atom,

R2 in position 5 denotes an aminocarbonyl group,

R3 is a hydrogen atom or a C1-4-alkyl group which can be terminally substituted with a chlorine or bromine atom or with a phenylsulfonyl group,

R4 is a hydrogen atom, a C1-3-alkyl group or a cyclopentyl or cyclohexyl group optionally substituted with a methyl group, while in the cyclohexyl group the methylene group in position 4 in relation to the carbon atom of the group R3-C(R4NR5)= can be replaced with an imino group, optionally substituted with a methyl group,

a phenyl group which may be substituted

with a fluorine, chlorine, bromine or iodine atom,

with a methyl or ethyl group, which in each. may be substituted with C1-3-alkylamino, di-(C1-3-alkyl)-amino, thiomoRfolino, 1-oxido-thiomorpholino, 1,1-dioxido-thiomorpholino, N-phenyl-piperazine, 5- to 6- member with a cyclo-alkenylenimino group or with a 5- to 7-membered cycloalkylene-imino group, while the above-mentioned 5- to 7-membered cyclo-alkyleneimino groups can be substituted with one or two methyl groups, with a cyclohexyl or phenyl group, with a methyl, with a cyclohexyl or phenyl group and with a hydroxy group, or

with a methyl or ethyl group that can be substituted with a phenyl group that is substituted with a 5- to 7-membered cycloalkyleneimino group, while additionally the phenyl ring is fused to the above-mentioned cycloalkylene-imino group via 2 adjacent carbon atoms,

with a methyl or ethyl group substituted with an amino, methylamino or ethylamino group, each of which is additionally substituted on the amino nitrogen atom with a benzyl or phenylethyl group, whereby the phenyl group in the above-mentioned groups can be monosubstituted with a fluorine, chlorine or bromine atom or with with a methyl, methoxy, cyano, trifluoromethyl or nitro group, or is di- or tri-substituted with fluorine, chlorine or bromine atoms or with methyl or methoxy groups, and these substituents can be identical or different,

while additionally the above-mentioned monosubstituted phenyl groups may be substituted with a fluorine, chlorine or bromine atom or with a methyl, methoxy or nitro group, and

R5 represents a hydrogen atom or a C1-3-alkyl group, their isomers and their salts.

The greatest preference is given to compounds of the general formula I in which

X represents an oxygen atom,

R1 is a hydrogen atom,

R2 in position 5 denotes an aminocarbonyl group,

R3 is a hydrogen atom or a C1-3-alkyl group,

R4 is a phenyl group that can be substituted with a fluorine, chlorine, bromine or iodine atom,

with a methyl or ethyl group, which in any case can be substituted with C1-3-alkylamino, di-(C1-3-alkyl)-amino, thiomoRfolino, 1-oxido-thiomorpholino, 1,1-dioxido-thiomorpholino, N- phenyl-piperazine, with a 5- to 6-membered cyclo-alkenylenimino group or with a 5- to 7-membered cycloalkylene-imino group, while the aforementioned 5- to 7-membered cyclo-alkyleneimino groups can be substituted with one or two methyl groups, with a cyclohexyl or phenyl group, with a methyl, cyclohexyl or phenyl group and with a hydroxy group, or

with a methyl or ethyl group that can be substituted with a phenyl group, which is substituted in position 4 with a 5- to 7-membered cycloalkylenimine group, while additionally the phenyl ring is fused to the aforementioned cycloalkylenimine groups via 2 adjacent carbon atoms,

with a methyl or ethyl group substituted with an amino, methylamino or ethylamino group, each of which is additionally substituted on the amino nitrogen atom with a benzyl or phenylethyl group, and where the phenyl group may be monosubstituted with a fluorine, chlorine or bromine atom or with methyl, methoxy, cyano, trifluoromethyl or nitro group, disubstituted with methyl or methoxy groups or trisubstituted with methyl or methoxy groups, and the substituents can be identical or different,

while additionally the above-mentioned monosubstituted phenyl groups may be substituted with a fluorine, chlorine or bromine atom or with a methyl, methoxy or nitro group, and

R5 represents a hydrogen atom or a C1-3-alkyl group, their isomers and their salts.

The following compounds are listed as particularly favorable compounds:

(a) 3-Z-[1-(4-piperidinomethyl-phenylamino)-1-methyl-methylene]-5-amido-2-indolinone,

(b) 3-Z-[1-(4-bromo-phenylamino)-1-methyl-methylene]-5-amido-2-indolinone,

(c) 3-Z-[1-(4-piperidinomethyl-phenylamino)-1-butyl-methylene]-5-amido-2-indolinone,

(d) 3-Z-(1-(4-chlorophenylamino)-1-methyl-methylene]-5-amido-2-indolinone and

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

(f) 3-Z-[1-(4-(N-benzyl-N-methyl-aminomethyl)-phenylamino)-1-methyl-methylene]-5-amido-2-indolinone,

(g) 3-Z-[1-(4-(N-(4-chlorobenzyl)-aminomethyl)-phenylamino)-1-methyl-methylene]-5-amido-2-indolinone,

(h) 3-Z-[1-(4-(N-benzyl-N-ethyl-aminomethyl)-phenylamino]-1-methyl-methylene]-5-amido-2-indolinone,

(i) 3-Z-[1-(4-(N-benzyl-aminomethyl)-phenylamino)-1-methyl-methylene]-5-amido-2-indolinone,

(j) 3-Z-[1-(4-(N-benzyl-N-methyl-aminomethyl)-phenyl-amino)-methylene]-5-amido-2-indolinone,

(k) 3-Z-[1-(4-(2,3,4,5-tetrahydro-benzo(d)azepin-3-yl-methyl)-phenylamino)-1-methyl-methylene]-5-amido -2-indolinone,

(1) 3-Z-[1-(4-piperidinomethyl-3-nitro-phenylamino)-1-methyl-methylene]-5-amido-2-indolinone and

(m) 3-Z-[1-(4-methyl-3-nitro-phenylamino)-1-methyl-methylene)-5-amido-2-indolinone as well as their isomers and their salts.

In accordance with the invention, new compounds can be obtained, for example, in accordance with the following procedures, which are generally known from the literature:

a) by the reaction of a compound of the general formula

[image]

in which they are

X and R3 defined as above,

R2' has the meaning given above for R2,

R6 represents a hydrogen atom or a protecting group for the nitrogen atom of the lactam group, while one group R2' or rg can also denote a bond with the solid phase, formed as necessary via a spacer group, and the terminated group R2' or R6 is defined as previously, and

Z1 represents a halogen atom, a hydroxy, alkoxy or aralkyl group, for example a chlorine or bromine atom or a methoxy, ethoxy or benzyloxy group, with an amine of the general formula

[image]

in which they are

R 4 and R 5 are defined as before, and then, as appropriate, by cleaving each protecting group used on the nitrogen atom of the lactam group or from the solid phase.

A suitable protecting group for the nitrogen atom of the lactam group will be, for example, an acetyl, benzoyl, ethoxycarbonyl, tert-butyloxycarbonyl or benzyloxycarbonyl group.

A suitable solid phase can be, for example, a resin such as 4-(2',4'-dimethoxyphenylaminomethyl)-phenoxy resin, wherein the coupling is carried out primarily via an amino group, or a p-benzyloxybenzyl alcohol resin, whereby the coupling is carried out via an intermediate moiety such as the 2,5-di-methoxy-4-hydroxy-benzyl deriv.

The reaction is advantageously carried out in a solvent such as dimethylformamide, toluene, acetonitrile, tetrahydrofuran, dimethylsulfoxide, methylene chloride or a mixture thereof, in the presence of an inert base such as triethylamine, N-ethyl-diisopropylamine or sodium hydrogen carbonate at temperatures between 20 and 175° C, while any protecting group used can be cleaved simultaneously as a result of transamidation.

If Z1 in the compound of formula II represents a halogen atom, the reaction preferably takes place in the presence of an inert base at temperatures between 20 and 120°C.

If Z1 in the compound of the general formula II represents a hydroxy, alkoxy or aralkyl group, the reaction preferably takes place at temperatures between 20 and 200°C.

Subsequent removal of the protecting group used, if necessary, is conveniently carried out hydrolytically in an aqueous or alcoholic solvent, e.g. methanol/water, ethanol/water, isopropanol/water, tetrahydrofuran/water, dioxane/water, dimethylformamide/water, methanol or ethanol in the presence of an alkali metal base such as lithium hydroxide, sodium hydroxide or potassium hydroxide at temperatures between 0 and 100°C, preferably at temperatures between 10 and 50°C,

or even more advantageously, by transamidation with an organic base such as ammonia, methylamine, butylamine, dimethylamine or piperidine in a solvent such as methanol, ethanol, dimethylformamide and their mixture, or in an excess of the amine used, at temperatures between 0 and 100°C , preferably at temperatures between 10 and 50°C.

Any solid phase used is preferably separated using trifluoroacetic acid and water at temperatures between 0 and 35°C, preferably at room temperature.

b. To prepare the compound of the general formula I in which R2 represents the above-mentioned aminocarbonyl groups, the following is done:

amidation of a compound of the general formula

[image]

wherein R 1 and R 3 are as defined above, or a reactive derivative thereof with an amine of the general formula

H-(R7NR8) (V)

in which R7 and R8 can be identical or different and represent a hydrogen atom or C1-3-alkyl groups.

Amidation is preferably carried out in a solvent such as methylene chloride, diethyl ether, tetrahydrofuran, toluene, dioxane, acetonitrile, dimethylsulfoxide or dimethylformamide, if necessary in the presence of an inorganic or tertiary organic base, preferably at temperatures between 20°C and the boiling point of the solvent used. Amidation is carried out with a suitable acid, preferably in the presence of a dehydrating agent, e.g. in the presence of isobutyl chloroformate, tetraethyl orthocarbonate, trimethyl orthoacetate, 2,2-di-methoxypropane, tetramethyloxysilane, thionyl chloride, trimethylchlorosilane, phosphorus trichloride, phosphorus pentoxide, N,N1 -dicyclohexylcarbodiimide, N,N'-dicyclohexylcarbodiimide/N-hydroxysuccinimide, N,N'-dicyclohexylcarbodiimide/1-hydroxy-benzotriazole, 2-(1H-benzo-triazol-1-yl)-1,1,3 ,3-tetramethyluronium tetrafluoroborate, 2-(1H-benzo-triazol-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate/1-hydroxy-benzotriazole, N,N'-carbonyldiimidazole or triphenylphosphine/ of carbon tetrachloride, and optionally with the addition of a base such as pyridine, 4-dimethyl-aminopyridine, N-methylmorpholine or triethylamine, suitably at temperatures between 0 and 150°C, preferably at temperatures between 0 and 100°C, and the acylation is carried out with appropriate by a reactive compound such as an anhydride, ester, imidazolide or the like v halide, optionally in the presence of a tertiary organic base such as triethylamine, N-ethyldiisopropylamine or N-methylmorpholines at temperatures between 0 and 150°C, preferably at temperatures between 50 and 100°C.

If, according to the invention, a compound of the general formula 1 containing an alkoxycarbonyl group is obtained, it can be converted by hydrolysis into the corresponding carboxy compound, or if a compound of the general formula I containing an amino or alkylamino group is obtained, it can be converted by alkylation or reductive alkylation into a corresponding alkylamino or dialkylamino compound, or

if a compound of the general formula I containing an amino or alkylamino group is obtained, it can be converted by acylation into the corresponding acyl compound, or

if a compound of the general formula I containing a carboxy group is obtained, it can be converted by esterification or amidation into the corresponding ester or aminocarbonyl compound, or

if a compound of the general formula I containing a nitro group is obtained, it can be converted by reduction into the corresponding amino compound.

The subsequent hydrolysis is preferably carried out in an aqueous solvent, such as water, isopropanol/water, tetrahydrofuran/water or dioxane/water, in the presence of an acid such as trifluoroacetic acid or sulfuric acid or in the presence of an alkali metal base such as lithium hydroxide, sodium hydroxide or potassium hydroxide at temperatures between 0 and 100°C, preferably at temperatures between 10 and 50°C.

The subsequent reductive alkylation is conveniently carried out in a suitable solvent such as methanol, methanol/water, methanol/water/ammonia, ethanol ether, tetrahydrofuran, dioxane or dimethylformamide, optionally with the addition of an acid such as hydrochloric acid, in the presence of catalytically activated hydrogen, eg hydrogen in the presence of Raney nickel, platinum or palladium/carbon, or in the presence of a metal hydride such as sodium borohydride, lithium borohydride or lithium aluminum hydride, at temperatures between 0 and 100°C, preferably at temperatures between 20 and 80°C .

The subsequent alkylation is carried out with an alkylating agent such as an alkyl halide or dialkyl sulfate, such as methyl iodide, dimethylsulfate or propyl bromide, preferably in a solvent such as methanol, ethanol, methylene chloride, tetrahydrofuran, toluene, dioxane, dimethylsulfoxide or dimethylformamide, according to if necessary in the presence of an inorganic or organic base such as triethylamine, N-ethyl-di-isopropylamine or dimethylaminopyridine, preferably at temperatures between 20°C and the boiling point of the solvent used.

The subsequent acylation is advantageously carried out in a solvent such as methylene chloride, diethyl ether, tetrahydrofuran, toluene, dioxane, acetonitrile, dimethylsulfoxide or dimethyl formamide, if necessary in the presence of an inorganic or tertiary organic base, preferably at temperatures between 20°C and the boiling point of the solvent used . Acylation is carried out with a suitable acid, preferably in the presence of a dehydrating agent, e.g. in the presence of isobutyl chloroformate, tetraethyl orthocarbonate, trimethyl orthoacetate, 2,2-dimethoxypropane, tetramethoxysilane, thionyl chloride, trimethylchlorosilane, phosphorus trichloride, phosphorus pentoxide, N,N' -dicyclohexylcarbodiimide, N,N'-dicyclohexylcarbodiimide,N-hydroxysuccinimide, N,N'-di-cyclohexylcarbodiimide/1-hydroxybenzotriazole, 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium tetrafluoro- borate, 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyl-uronium tetrafluoroborate/1-hydroxy-benzotriazole, N,N'-carbonyldiimidazole or triphenylphosphine/carbon tetrachloride, and if necessary with the addition bases such as pyridine, 4-dimethylamino-pyridine, N-methylmorpholine or triethylamine, preferably at temperatures between 0 and 150°C, preferably at temperatures between 0 and 100°C, and the acylation is carried out with a suitable reactive compound such as anhydride , ester, imidazole or its hal ogenide, if necessary in the presence of a tertiary organic base such as triethylamine, N-ethyl-diisopropylamine or N-methyl-morpholine, at temperatures between 0 and 150°C, preferably at temperatures between 50 and 100°C.

Subsequent esterification or amidation is conveniently carried out by reacting the appropriate reactive carboxylic acid derivative with the appropriate alcoholone or amine as described above.

Subsequent reduction of the nitro group is carried out by hydrogenolysis, e.g. with hydrogen in the presence of a catalyst such as palladium/carbon or Raney nickel, in a solvent such as methanol, ethanol, ethyl acetate, dimethylformamide, dimethylformamide/acetone or glacial acetic acid, according if necessary with the addition of an acid such as HCl or glacial acetic acid, at temperatures between 0 and 50°C, but preferably at room temperature, and under a hydrogen pressure of 1 to 7 bar, and preferably of 3 to 5 bar.

In the reactions described above, all reactive groups present, such as carboxy, amino, alkylamino or imino groups, can be protected during the reaction with the usual protecting groups, which are cleaved off again after the reaction.

For example, a protecting group for a carboxy group can be trimethylsilyl, methyl, ethyl, tert-butyl, benzyl, or tetrahydropyranyl, and a protecting group for an amino, alkylamino, or imino group can be acetyl, trifluoroacetyl, benzoyl, ethoxycarbonyl, tert-butoxycarbonyl, benzyloxycarbonyl. , benzyl, methoxybenzyl or 2,4-dimethoxybenzyl group and, in addition, for the amino group, also a phthalyl group.

Each protecting group used is cleaved as needed, for example by hydrolysis 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 in the presence of an alkali metal base such as lithium hydroxide, sodium hydroxide or potassium hydroxide, at temperatures between 0 and 100°C, preferably at temperatures between 10 and 50°C.

However, the benzyl, methoxybenzyl or benzyloxy-carbonyl group is cleaved hydrogenolytically, eg with hydrogen in the presence of a catalyst such as palladium/charcoal in a suitable solvent such as methanol, ethanol, ethyl acetate, dimethylformamide, dimethyl formamide/acetone or glacial acetic acid , if necessary with the addition of an acid such as hydrochloric acid or glacial acetic acid, at temperatures between 0 and 50°C, and preferably at room temperature, and under a hydrogen pressure of 1 to 7 bar, and preferably 3 to 5 bar.

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

However, the 2,4-dimethoxybenzyl group is preferably cleaved in trifluoroacetic acid in the presence of anisole.

The tert-butyl or tert-butyloxycarbonyl group is conveniently cleaved off by treatment with an acid such as trifluoroacetic acid or hydrochloric acid, if necessary using a solvent such as methylene chloride, dioxane, ethyl acetate or ether.

The phthalyl group is conveniently cleaved in the presence of hydrazine or a primary amine such as methylamine, ethylamine or n-butylamine in a solvent such as methanol, ethanol, isopropanol, toluene/water or dioxane at temperatures between 20 and 50°C.

In addition, the obtained chiral compounds of the general formula I can be separated into enantiomers and/or diastereomers.

Thus, for example, the obtained compounds of the general formula I, which appear as racemates, can be resolved by methods known as such (see Allinger N. L. and Eliel E. L. in "Topics in Stereochemistry", Vol. 6, Wiley Interscience, 1971) into their optical antipodes, and the compounds of formula 1 with at least 2 asymmetric carbon atoms can be separated into their diastereomers on the basis of their physicochemical differences using methods known as such, for example, chromatography and/or fractional crystallization, and, if these compounds are obtained in racemic form, they can then be resolved into their enantiomers as described above.

Enantiomers are separated primarily on a column with chiral phases or by recrystallization from an optically active solvent, or by reaction with an optically active substance that forms salts or derivatives such as esters or amides with racemic ones. compound, especially with acids and their activated derivatives or alcohols and by breaking down the diastereomeric mixture of salts or derivatives thus obtained. eg on the basis of their different solubilities, while the free antipodes can be liberated from the pure diastereomeric salts or derivatives by the action of suitable agents. Optically active acids that are generally used are, for example, D- and L-forms of tartaric acid or dibenzoyltartaric acid, di-o-tolylvic acid, malic acid, mandelic acid, camphorsulfuric acid, glutamic acid, aspartic acid, N-acetyl-aspartic acid or quinic acid. An optically active alcohol can be, for example, (+) or (-)-inenthol, and an optically active acid group in amides can be, for example, a (+)- or (-)-menthyloxycarbonyl group.

In addition, the compounds of formula I can be translated into their salts, in particular, for pharmaceutical use, into physiologically acceptable salts with inorganic or organic acids. Acids that can be used for this purpose include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, fumaric acid, succinic acid, lactic acid, citric acid, tartaric acid, maleic or methanesulfonic acid.

In addition, if the new compounds of formula I contain a carboxy group, they can later, if desired, be converted into their salts with inorganic or organic bases, especially for pharmaceutical use, into their physiologically acceptable salts. Suitable bases for this purpose include, for example, sodium hydroxide, potassium hydroxide, arginine, cyclohexylamine, ethanolamine, diethanolamine and triethanolamine. The compounds of the general formulas 1 to V, used as starting materials, are in some cases known from the literature or are described in the examples.

As already mentioned, new compounds of the general formula I, in which R1 represents a hydrogen atom or a prodrug group, have valuable pharmacological properties, in particular the inhibitory effect on various kinases and cyclin/CDK complexes, on the proliferation of cultured human tumor cells and, given orally, on tumor growth in hairless mice infected with human tumor cells.

For example, the biological properties of the compounds listed in Table 1 were tested as follows.

Examination 1

Inhibition of cyclin/CDK enzymes, action In vitro

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

The media used for kinase assays depend on the specific kinases. Histone H1 (Sigma) was used as a substrate for cyclin E/CDK2, cyclin A/CDK2, cyclin B/CDK1 and for v-cyclins/CDKG. GST-tagged pRB (aa 379-928) was used as a substrate for cyclin D1/CDK4, cyclin D3/CDK4, cyclin D1/CDK6 and for cyclin D3/CDK6.

Cell lysates from insects infected with recombinant baculoviruses or with recombinant baculoviruses. kinases (obtained from lysates by purification) were incubated together with radiolabeled ATP in the presence of a suitable medium with various inhibitor concentrations in a 1% solution in DMSO (dimethyl sulfoxide) for 45 minutes at 30°C. Substrate proteins with bound radioactivity were precipitated with 5% TCA (trichloroacetic acid) in hydrophobic PVDF wells of multiple microtiter plates (Millipore) or with 0.5% phosphoric acid solution on Whatman P81 filters. After the addition of the scintillation liquid, the radioactivity was measured in a Wallace 1450 Microbeta liquid scintillation counter. Two measurements were made for each substance concentration; IC50 values were calculated for enzyme inhibition.

Examination 2

Inhibition of proliferation of cultured human tumor cells

Leiomyosarcoma tumor line SK-UT-1B cells (obtained from the American Type Culture Collection (ATCC)) were grown in Minimum Essential Medium with non-essential amino acids (Gibco), supplemented with sodium pyruvate (1 mmol), glutamine (2 minola) and 10% fetal bovine serum and were collected during the log growth phase. SK-UT-1B cells were then added to wells of Cytostar® (Amersham) multiple plates at a density of 4000 cells per well and incubated overnight in an incubator. Various concentrations of compounds (dissolved in DMSO; final concentration: <1%) were added to the cells. After 48 hours of incubation, 14C-thymidine (Amersham) was added to each well and incubation was continued for another 24 hours. The amount of 14C-thymidine incorporated into tumor cells in the presence of the inhibitor, which represents the number of cells present in S phase, was measured in a Wallace 1450 Microbeta liquid scintillation counter. IC50 values for inhibition of proliferation (=inhibition of incorporated "C-thymidine) corrected for baseline radiation were calculated. All measurements were performed twice.

Examination 3

In vivo effect on tumor-bearing hairless mice

106 cells [SK-UT-1B, or non-small lung tumor cells NCI-H460 (obtained from ATCC)] in a volume of 0.1 ml were injected subcutaneously into male and/or female hairless mice (NMRI nu/nu; 25 -35g; N = 10-20); alternatively, small fragments of SK-UT-IB or NC1-H460 cell clumps were implanted subcutaneously. One to three weeks after injection or implantation, the kinase inhibitor is administered orally daily for a period of 2 to 4 weeks (using a tube through the esophagus). Tumor size was measured three times a week using a digital caliper. The effect of kinase inhibitors on tumor growth was determined as percent inhibition compared to the placebo control group.

Table 2, which follows, contains the results obtained in the In vitro experiment.

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Considering their biological properties, the compounds of the general formula I, their isomers and their physiologically acceptable salts are suitable for the treatment of diseases characterized by excessive or abnormal cell proliferation.

These diseases include (but are not limited to): viral infections (eg HIV and Kaposi's sarcoma); inflammatory and autoimmune diseases (eg colitis, arthritis, Alzheimer's disease, glomerulonephritis and healed wounds); bacterial, fungal and/or parasitic infections; leukemia, lymphoma and hard tumors; skin diseases (eg psoriasis); bone diseases; cardiovascular diseases (eg restenosis and hypertrophy). They can also be used to protect proliferative cells (eg, hair, intestinal, blood and progenitor cells) from DNA damage caused by radiation, UV treatment and/or treatment with cytostatics.

The new compounds can be used for short-term or long-term treatment of the above-mentioned diseases, if necessary together with other compounds from the "state of the art" such as other cytostatics.

To achieve the appropriate effect, when administered intravenously, the required dosage is expediently 0.1 to 30 mg/kg, preferably 0.3 to 10 mg/kg, and 0.1 to 100 mg/kg, preferably 0.3 to 30 mg/kg in the case of oral administration, in any case, the application is made 1 to 4 times a day. For this purpose, the compounds of formula I, produced according to the invention, can be formulated, if necessary, together with other active substances, with one or more inert conventional carriers and/or diluents, such as, for example, starch, lactose, glucose, microcrystalline cellulose, magnesium stearate, polyvinylpyrrolidone, citric acid, tartaric acid, water, water/ethanol, water/glycerol, water/sorbitol, water/polyethylene glycol, propylene glycol, cetylstearyl alcohol, carboxymethylcellulose or fatty substances such as hard fats or their suitable mixtures, for the production of common galenic preparations such as flat or coated tablets, capsules, powders, suspensions or suppositories.

The following examples are intended to illustrate the invention.

Examples

Methyl 1-acetyl-2-indolinone-5-carboxylate

10.5 g of methyl 2-indolinone-5-carboxylate (produced analogously to the procedure according to Ogawa, Hidenori et al. in Chem.Pharm.Bull 36, 2253-2258 (1988)), was stirred for 4 hours in 30 ml of acetic anhydride at 140 °C. The mixture is allowed to cool in ice water and the precipitate is collected by filtration with suction. The product is washed once with water, then taken up in methylene chloride, dried over sulfate and concentrated by evaporation. Yield: 11 g (86% of theoretical), Rf value: 0.63 (silica gel, methylene chloride/methanol = 50:1)

Example II

Methyl 1-acetyl-3-(1-ethoxy-1-butyl-methylene]-2-indolinone-5-carboxylate

11 g of methyl 1-acetyl-2-indolinone-5-carboxylate in 110 ml of acetic anhydride and 30 ml of triethyl orthovalerate are mixed for 2 hours at 100°C. It is then concentrated by rotary evaporation, the residue is washed with ether and filtered off with suction. Yield: 11.5 g (67% of theoretical), Rf value: 0.55 (silica gel, methylene chloride/petroleum ether/ethyl acetate = 4:5:1)

The following compounds were produced analogously to example II:

(1) methyl 1-acetyl-3-(1-ethoxy-methylene]-2-indolinone-5-carboxylate,

it is produced from methyl 1-acetyl-2-indolinone-5-carboxylate and trimethyl orthoformate,

(2) methyl 1-acetyl-3-(1-ethoxy-1-methyl-methylene]-2-indolinone-5-carboxylate,

it is produced from methyl 1-acetyl-2-indolinone-5-carboxylate and triethyl orthoacetate,

(3) methyl 1-acetyl-3-(1-ethoxy-1-ethyl-methylene]-2-indolinone-5-carboxylate,

it is produced from methyl 1-acetyl-2-indolinone-5-carboxylate and triethyl otopropionate.

Examples III

28.0 g of Rink resin (MBHA resin produced by Novobiochem) is allowed to swell in 330 ml of dimethyl formamide. Then 330 ml of 30% piperidine in dimethyl formamide was added and the mixture was shaken for 7 minutes to cleave the 9H-fluoren-9-yl-methoxycarbonyl group. The resin is then washed several times with dimethylformamide. Finally, 7.3 g, 10.5 g of 2-indolinone-5-carboxylic acid (produced analogously to Ogawa, Hidenori et al., Chem. Pharm. Bull 36, 2253-2258 (1988)), 5.6 g hydroxybenzotriazole, 13.3 g of 0"(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate and 5.7 ml of N-ethyl-diisopropylamine in 300 ml of dimethyl formamide and the mixture is shaken 1 hour. The solution is filtered with suction and the resin is washed several times with 300 ml of dimethylorinamide and three times with 300 ml of methylene chloride. Nitrogen is passed through the resin for drying. Yield: 20 g of loaded resin.

Example IV

0.4 g of loaded resin produced in example III was mixed for 1 hour with 2.5 ml of acetic anhydride at 90°C. Then 2.5 ml of trimethyl orthovalerate is added and the mixture is shaken for another 3 hours at 110°C. Then the resin is filtered off with suction and washed with dimethylformamide, methanol and finally with methylene chloride. Yield: 0.6 g of wet resin.

The following loaded resins were produced analogously to example IV:

(1) resin loaded with 3-Z-(1-ethoxy-methylene)-5-amido-2-indolinone, the reaction of the product from example 1 and triethyl orthoformate,

(2) resin loaded with 3-Z-(1-methoxy-1-methyl-methylene)-5-amido-2-indoline, the reaction of the product from example 1 and trimethyl orthoformate,

(3) resin loaded with 3-Z-(1-methoxy-1-ethyl-methylene)-5-amido-2-indolinone, the reaction of the product from example 1 and trimethyl orthopropionate,

(4) resin loaded with 3-Z-(1-rethoxy-1-propyl-methylene)-5-amido-2-indolinone, the reaction of the product from example 1 and trimethyl orthobutyrate,

(5) resin loaded with 3-Z-(1-methoxy-1-ethenyl-methylene)-5-amido-2-indolinone, the reaction of the product from example 1 and 3,3,3-triethoxyprop-1-ene,

(6) resin loaded with 3-Z-(1-methoxy-1-(3-bromo-propyl)-methylene)-5-amido-2-indolinone, the reaction of the product from example 1 and trimethyl 4-bromo-orthobutyrate,

(7) resin loaded with 3-Z-(1-methoxy-1-(2-phenylsulfonyl-ethyl)-methylene)-5-amido-2-indolinone, the reaction of the product from example 1 and triethyl 3-phenylsulfonyl-orthopropionate.

Example V

4-(N-ethyl-aminomethyl)-nitrobenzene

6 g of 4-nitrobenzyl bromide is dissolved in 25 ml of ethanol, mixed with 25 ml of a 10% ethanolic solution of ethylamine and refluxed for 2 hours< Then the solution is concentrated by rotary evaporation, the residue is taken up in methylene chloride and washed with a dilute solution of sodium hydroxide. Then the organic phase is concentrated by evaporation. Yield: 2.3 g (46% of theoretical). Rf value: 0.20 (silica gel, methylene chloride/methanol = 9:1)

The following compounds were produced analogously to example V:

4-[N-(4-chlorophenyl-methyl)-aminomethyl]-nitrobenzene,

4-(N-cyclohexyl-aminomethyl)-nitrobenzene,

4-(N-isopropyl-aminomethyl)-nitrobenzene,

4-(N-butyl-aminomethyl)-nitrobenzene,

4-(N-methoxycarbonylmethyl-aminomethyl)-nitrobenzene,

4-(N-benzyl-aminomethyl)-nitrobenzene,

4-(pyrrolidino-methyl)-nitrobenzene,

4-(morpholino-methyloxy)-nitrobenzene,

4-(piperidino-methyl)-nitrobenzene,

4-(hexamethyleneimino-methyl)-nitrobenzene,

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

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

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

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

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

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

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

4-(dimethylamino-methyl)-nitrobenzene,

4-(di-n-propylamino-methyl)-nitrobenzene,

4-(4-tert-butoxycarbonyl-piperazine-methyl)-nitrobenzene,

3-(dimethylamino-methyl)-nitrobenzene,

4-(2-diethylamino-ethyl)-nitrobenzene,

4-(2-morpholino-ethyl)-nitrobenzene,

4-(2-pyrrolidino-ethyl)-nitrobenzene,

4-(2-piperidino-ethyl)-nitrobenzene,

4-(N-ethyl-N-benzyl-aminomethyl)-nitrobenzene,

4-(N-n-propyl-N-benzyl-aminomethyl)-nitrobenzene,

4-[N-methyl-N-(4-chlorophenylmethyl)-aminomethyl]-nitrobenzene,

4-[N-methyl-N-(4-bromophenylmethyl)-aminomethyl]-nitrobenzene,

4-[N-methyl-N-(3-chlorophenylmethyl)-aminomethyl]-nitrobenzene,

4-[N-methyl-N-(3,4-dimethoxyphenylmethyl)-aminomethyl]-nitrobenzene,

4-[N-methyl-N-(4-methoxyphenylmethyl)-aminomethyl)-nitrobenzene,

4-[N-(2,2,2-trifluoroethyl)-N-benzyl-aminomethyl]-nitrobenzene,

4-[N-(2,2,2-trifluoroethyl)-N-(4-chlorophenylmethyl)-aminomethyl]-nitrobenzene,

4-(2,6-dimethyl-piperidino-methyl)-nitrobenzene,

4-(thiomorpholino-methyl)-nitrobenzene,

4-(S-oxido-thiomorpholino-methyl)-nitrobenzene,

4-(S,S-dioxido-thiomorpholino-methyl)-nitrobenzene,

4-(azetidino-methyl)-nitrobenzene,

4-(2,5-dihydropyrrol-1-yl-methyl)-nitrobenzene,

4-(3,6-dihydro-2H-pyridin-1-yl-methyl)-nitrobenzene,

4-(2-methoxycarbonyl-pyrrolidino-methyl)-nitrobenzene,

4-(3,5-dimethyl-piperidino-methyl)-nitrobenzene,

4-(4-phenyl-piperazinyl-methyl)-nitrobenzene,

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

4-[n-(3,4,5-trimethoxy-benzyl)-N-methyl-aminomethyl]-nitrobenzene,

4-[N-(3,4-dimethoxy-benzyl)-N-ethyl-aminomethyl]-nitrobenzene,

4-[N-(3-chlorobenzyl)-N-methyl-aminomethyl]-nitrobenzene,

4-[N-(2,6-dichlorobenzyl)-N-methyl-aminomethyl]-nitrobenzene,

4-[N-(4-trifluoromethylbenzyl)-N-methyl-aminomethyl]-nitrobenzene,

4-(N-benzyl-N-isopropyl-aminomethyl)-nitrobenzene,

4-(N-benzyl-N-tert-butyl-aminomethyl)-nitrobenzene,

4-(diisopropylainino-methyl)-nitrobenzene,

4-(di-n-propylamino-methyl)-nitrobenzene,

4-(diisobutylamino-methyl)-nitrobenzene,

4-(2,3,4,5-tetrahydro-benzo(d)azepin-3-yl-methyl)-nitrobenzene,

4-(2,3-dihydro-isoindol-2-yl-methyl)-nitrobenzene, 4-(6,7-dimethoxy-1,2,3,4-tetrahydro-isoquinolin-2-yl-methyl)-nitrobenzene,

4-(1,2,3,4-tetrahydro-isoquinolin-2-yl-methyl)-nitrobenzene,

4-[N-(2-hydroxyethyl)-N-benzyl-aminomethyl]-nitrobenzene,

4-[N-(1-ethyl-pentyl)-N-(pyridin-2-yl-methyl)-amino-methyl]-nitrobenzene,

4-(N-phenethyl-N-methyl-aminomethyl)-nitrobenzene,

4-[N-(3,4-dihydroxy-phenethyl)-N-methyl-aminomethyl]-nitrobenzene,

4-[N-(3,4,5-trimethoxy-phenethyl)-N-methyl-aminomethyl]-nitrobenzene,

4-[N-(3,4-dimethoxy-phenethyl)-N-methyl-aminomethyl]-nitrobenzene,

4-[N-(4-nitro-phenethyl)-N-methyl-aminomethyl]-nitro-benzene,

4-(N-phenethyl-N-benzyl-aminomethyl)-nitrobenzene,

4-(N-phenethyl-N-cyclohexyl-aminomethyl)-nitrobenzene,

4-[N-(2-(pyridin-2-yl)-ethyl)-N-methyl-aminomethyl]-nitrobenzene,

4-[N-(2-(pyridin-4-yl)-ethyl)-N-methyl-aminomethyl]-nitrobenzene,

4-[N-(pyridin-4-yl-methyl)-N-methyl-aminomethyl]-nitrobenzene,

4-(dibenzylamino-methyl)-nitrobenzene-4-[N-(4-nitro-benzyl)-N-propyl-aminomethyl]-nitrobenzene,

4-[N-benzyl-N-(3-cyano-propyl)-aminomethyl]-nitrobenzene,

4-(N-benzyl-N-allyl-aminomethyl)-nitrobenzene,

4-[N-(benzo(1,3)dioxol-5-yl-methyl)-N-methyl-amino-methyl]-nitrobenzene,

4-(7-chloro-2,3,4,5-tetrahydro-benzo(d)azepin-3-yl-methyl)-nitrobenzene,

4-(7,8-dichloro-2,3,4,5-tetrahydro-benzo(d)azepin-3-yl-methyl)-nitrobenzene,

4-(7-methoxy-2,3,4,5-tetrahydro-benzo(d)azepin-3-yl-methyl)-nitrobenzene,

4-(7-methyl-2,3,4,5-tetrahydro-benzo(d)azepin-3-yl-methyl)-nitrobenzene,

4-(7,8-dimethoxy-2,3,4,5-tetrahydro-benzo(d)azepin-3-yl-methyl)-nitrobenzene,

4-(6,7-dichloro-1,2,3,4-tetrahydro-isoquinolin-2-yl-methyl)-nitrobenzene,

4-(6,7-dimethyl-1,2,3,4-tetrahydro-isoquinolin-2-yl-methyl)-nitrobenzene,

4-(6-chloro-1,2,3,4-tetrahydro-isoquinolin-2-yl-methyl)-nitrobenzene,

4-(7-chloro-1,2,3,4-tetrahydro-isoquinolin-2-yl-methyl)-nitrobenzene,

4-(6-methoxy-1,2,3,4-tetrahydro-isoinolin-2-yl-methyl)-nitrobenzene,

4-(7-methoxy-1,2,3,4-tetrahydro-isoquinolin-2-yl-methyl)-nitrobenzene,

4-(2,3,4,5-tetrahydro-azepino(4,5-b)pyrazin-3-yl)-methyl)-nitrobenzene,

4-(7-amino-2,3,4,5-tetrahydro-azepino (4,5-b)pyrazin-3-yl-methyl)-nitrobenzene,

4-(2-amino-5,6,7,8-tetrahydro-azepino(4,5-d)thiazol-6-yl-methyl)-nitrobenzene,

4-(5,6,7,8-tetrahydro-azepino(4,5-d)thiazol-6-yl-methyl)-nitrobenzene.

Example VI

4-(N-ethyl-N-tert-butoxycarbonyl-aminomethyl)-nitrobenzene

2.2 g of 4-(N-ethyl-aminomethyl)-nitrobenzene is dissolved in 50 ml of ethyl acetate and mixed for 30 minutes with 2.6 g of di-tert-butyl dicarbonate at room temperature. The solution is then washed with water and concentrated by evaporation. Yield: 3.4 g (97% of theoretical, Rf value: 0.90 (silica gel, methylene chloride/methanol = 9:1)

The following compounds were produced analogously to Example VI:

4-[N-(4-chlorophenylmethyl)-N-tert-butoxycarbonyl-amino-methyl]-nitrobenzene,

4-(N-cyclohexyl-N-tert-butoxycarbonyl-aminomethyl)-nitrobenzene,

4-(N-isopropyl-N-tert-butoxycarbonyl-aminomethyl)-nitrobenzene,

4-(N-butyl-N-tert-butoxycarbonyl-aminomethyl)-nitrobenzene,

4-(N-methoxycarbonylmethyl-N-tert-butoxy-carbonyl-aminomethyl)-nitrobenzene,

4-(N-benzyl-N-tert-butoxycarbonyl-aminomethyl)-nitrobenzene,

4-(N-ethyl-N-tert-butoxycarbonyl-aminomethyl)-nitrobenzene.

Example VII

4-(N-ethyl-N-tert-butoxycarbonyl-aminomethyl)-aniline

6.4 g of 4-(N-ethyl-N-tert-butoxycarbonyl-aminomethyl)-nitrobenzene are dissolved in 60 ml of methanol and hydrogenated with 1.5 g of Raney nickel at room temperature under 3 bar. Then the catalyst is filtered off and the solvent is evaporated. Yield: 4.78 g

Rf value: 0.70 (silica gel, methylene chloride/methanol = 50:1)

The following compounds were produced analogously to Example VII:

4-[N-(4-chlorophenylmethyl)-N-tert-butoxycarbonyl-amino-methyl)-aniline,

4-(N-cyclohexyl-N-tert-butoxycarbonyl-aminomethyl)-aniline,

4-(N-isopropyl-N-tert-butoxycarbonyl-aminomethyl)-aniline,

4-(N-butyl-N-tert-butoxycarbonyl-aminomethyl)-aniline,

4-(N-methoxycarbonylmethyl-N-tert-butoxycarbonyl-aminomethyl)-aniline,

4-(N-benzyl-N-tert-butoxycarbonyl-aminomethyl)-aniline,

4-(pyrrolidino-methyl)-aniline,

4-(morpholino-methyl)-aniline,

4-(piperidino-methyl)-aniline,

4-(hexamethyleneimino-methyl)-aniline,

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

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

4-(4-ethyl-piperidino-methyl)-aniline,

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

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

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

4-(4-ethoxycarbonyl-piperidino-methyl)-aniline,

4-(dimethylamino-methyl)-aniline,

4-(di-n-propylamino-methyl)-aniline,

4-(4-tert-butoxycarbonyl-piperazine-methyl)-aniline,

3-(dimethylamino-methyl)-aniline,

4-(2-diethylamino-ethyl)-aniline,

4-(2-morpholino-ethyl)-aniline,

4-(2-pyrrolidino-ethyl)-aniline,

4-(2-piperidino-ethyl)-aniline,

4-(N-ethyl-N-benzyl-aminomethyl)-aniline,

4-(N-propyl-N-benzyl-aminomethyl)-aniline,

4-(N-methyl-N-(4-chlorophenylmethyl)-aminomethyl)-aniline,

4-(N-methyl-N-(4-bromophenylmethyl)-aminomethyl)-aniline,

4-(N-methyl-N-(3-chlorophenylmethyl)-aminomethyl)-aniline,

4-(N-methyl-N-(3,4-dimethoxyphenylmethyl)-aminomethyl)-aniline,

4-(N-methyl-N-(4-methoxyphenylmethyl)-aminomethyl)-aniline,

4-(N-(2,2,2-trifluoroethyl)-N-benzyl-aminomethyl]-aniline,

4-[N-(2,2,2-trifluoroethyl)-N-(4-chlorophenylmethyl)-amino-methyl]-aniline,

4-(2,6-dimethyl-piperidino-methyl)-aniline,

4-(thiomorpholino-methyl)-aniline,

4-(S-oxido-thiomorpholino-methyl)-aniline,

4-(S,S-dioxido-thiomorpholino-methyl)-aniline,

4-(azetidino-methyl)-aniline,

4-(2,5-dihydropyrrol-1-yl-methyl)-aniline,

4-(3,6-dihydro-2H-pyridin-1-yl-methyl)-aniline

4-(2-methoxycarbonyl-pyrrolidino-methyl)-aniline,

4-(3, 5-dimethyl-piperidino-methyl)-aniline,

4-(4-phenyl-piperazino-methyl)-aniline,

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

4-[N-(3,4,5-trimethoxybenzyl)-N-methyl-aminomethyl]-aniline,

4-[N-(3,4-dimethoxybenzyl)-N-ethyl-aminomethyl]-aniline,

4-(N-benzyl-N-ethyl-aininomethyl)-aniline,

4-[N-(3-chlorobenzyl)-N-methyl-aminomethyl]-aniline,

4-[N-(2,6-dichlorobenzyl)-N-methyl-aminomethyl]-aniline,

4-[N-(4-trifluoromethylbenzyl)-N-methyl-aminomethyl)-aniline,

4-(N-benzyl-N-isopropyl-aminomethyl)-aniline,

4-(N-benzyl-N-tert-butyl-aminomethyl)-aniline,

4-(diisopropylamino-methyl)-aniline,

4-(di-n-propylamino-methyl)-aniline,

4-(diisobutylamino-methyl)-aniline,

4-(2,3,4,5-tetrahydro-benzo(d)azepin-3-yl-methyl)-aniline,

4-(2,3-dihydro-isoindol-2-yl-methyl)-aniline,

4-(6,7-dimethoxy-1,2,3,4-tetrahydro-isoquinolin-2-yl-methyl)-aniline,

4-(1,2,3,4-tetrahydro-isoquinolin-2-yl-methyl)-aniline,

4-[N-(2-hydroxyethyl)-N-benzyl-aminomethyl]-aniline,

4-[N-(1-ethyl-pentyl)-N-(pyridin-2-yl-methyl)-amino-methyl]-aniline,

4-(N-phenethyl-N-methyl-aminoinethyl)-aniline,

4-[N-(3,4-dihydroxy-phenethyl)-N-methyl-aminomethyl)-aniline,

4-[N-(3,4,5-trimethoxy-phenethyl)-N-methyl-aininomethyl]-aniline,

4-[N-(3,4-dimethoxy-phenethyl)-N-methyl-aminomethyl)-aniline,

4-[N-(4-nitro-phenethyl)-N-methyl-aminomethyl)-aniline,

4-(N-phenethyl-N-benzyl-aminomethyl)-aniline,

4-(N-phenethyl-N-cyclohexyl-aminomethyl)-aniline,

4-[N-(2-(pyridin-2-yl)-ethyl)-N-methyl-aminomethyl]-aniline,

4-[N-(2-(pyridin-4-yl)-ethyl)-N-methyl-aminomethyl]-aniline,

4-[N-(pyridin-4-yl-methyl)-N-methyl-aminomethyl]-aniline,

4-(dibenzylamino-methyl)-aniline,

4-[N-(4-nitro-benzyl)-N-propyl-aminomethyl]-aniline,

4-[N-benzyl-N-(3-cyano-propyl)-aminomethyl)-aniline,

4-(N-benzyl-N-allyl-aminomethyl)-aniline,

4-[N-benzyl-N-(2,2,2-trifluoroethyl)-aminomethyl]-aniline,

4-[N-(benzo(1,3)dioxol-5-yl-methyl)-N-methyl-amino-methyl]-aniline,

4-(7-chloro-2,3,4,5-tetrahydro-benzo(d)azepin-3-yl-methyl)-aniline,

4-(7,8-dichloro-2,3,4,5-tetrahydro-benzo(d)azepin-3-yl-methyl)-aniline,

4-(7-methoxy-2,3,4,5-tetrahydro-benzo(d)azepin-3-yl-methyl)-aniline,

4-(7-methyl-2,3,4,5-tetrahydro-benzo(d)azepin-3-yl-methyl)-aniline,

4-(7,S-dimethoxy-2,3,4,5-tetrahydro-benzo(d)azepin-3-yl-methyl)-aniline,

4-(6,7-dichloro-1,2,3,4-tetrahydro-isoquinolin-2-yl-methyl)-aniline,

4-(6,7-dimethyl-1,2,3,4-tetrahydro-isoquinolin-2-yl-methyl)-aniline,

4-(6-chloro-1,2,3,4-tetrahydro-isoquinolin-2-yl-methyl)-aniline,

4-(7-chloro-1,2,3,4-tetrahydro-isoquinolin-2-yl-methyl)-aniline,

4-(6-methoxy-1,2,3,4-tetrahydro-isoquinolin-2-yl-methyl)-aniline,

4-(7-methoxy-1,2,3,4-tetrahydro-isoquinolin-2-yl-methyl)-aniline,

4-(2,3,4,5-tetrahydro-azepino(4,5-b)pyrazin-3-yl-methyl)-aniline,

4-(7-amino-2,3,4,5-tetrahydro-azepino(4,5-b)pyrazin-3-yl-inethyl)-aniline,

4-(2-amino-5,6,7,8-tetrahydro-azepino(4,5-d)thiazol-6-yl-methyl)-aniline,

4-(5,6,7,8-tetrahydro-azepino(4,5-d)thiazol-6-yl-methyl)-aniline.

PREPARATION OF END PRODUCTS

Example 1

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

600 g of the resin produced according to example IV is suspended in 3 ml of dimethylformamide and shaken with 0.4 g of aniline for 10 hours at 70°C. Then the mixture is filtered and the resin is washed several times with methylene chloride, methanol and dimethylformamide. Methanolic ammonia is then added to cleave the acetyl group over 2 hours. Finally, after further washing with dimethylformamide and methylene chloride, 4 ml of 10% trifluoroacetic acid in methylene chloride are added for 90 minutes, the resin is separated and the solution is concentrated by evaporation. The residue is taken up in a little 1N sodium hydroxide solution and extracted with a little methylene chloride. The organic phase is dried over sodium sulfate and concentrated by rotary evaporation. Yield: 37 mg.

Rf value: 0.6 (silica gel, methylene chloride/methanol = 9:1).

C20H21N3O2, mass spectrum: m/z = 335 (M+)

The following compounds were produced analogously to example 1:

(1) 3-Z-(1-phenylamino-methylene)-5-amido-2-indolinone, was prepared from the resin prepared in accordance with Example IV(1) and aniline.

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

Cl6H13N3O2

mass spectrum: m/z = 279 (M+)

(2) 3-Z-[1-(4-methyl-phenylamino)-1-methyl-methylene]-5-amido-2-indolinone, was produced from the resin produced in accordance with Example IV(2) and 4-i methylaniline.

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

C18H17N3O2

mass spectrum: m/z = 307 (M+)

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

was prepared from the resin prepared in accordance with Example IV(2) and 4-chloroaniline.

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

Cl7H14ClN3O2

mass spectrum: m/z = 327/329 (M+)

(4) 3-Z-[1-(4-ethyl-phenylamino)-1-methyl-methylene]-5-amido-2-indolinone,

was prepared from the resin prepared in accordance with Example IV(2) and 4-ethylaniline.

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

Cl9H19N3O2

mass spectrum: m/z = 321 (M+)

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

was prepared from the resin prepared in accordance with Example IV(2) and 4-methoxyaniline.

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

C18H17N3O3

mass spectrum: m/z = 323 (M+)

(6) 3-Z-[1-(4-iodo-phenylamino)-1-methyl-methylene]-5-amido-2-indolinone,

is produced from resin prepared in accordance with the example

IV(2) and 4-iodaniline.

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

Cl7H14JN3O2

mass spectrum: m/z 419 (M+)

(7) 3-Z-[1-(4-fluoro-phenylamino)-1-methyl-methylene]-5-amido-2-indolinone,

was produced from the resin prepared in accordance with example IV(2) and 4-fluoroaniline.

Rf value; 0.60 (silica gel, methylene chloride/methanol = 9:1)

Cl7H14FN3O2

mass spectrum: m/z = 311 (M+)

(8) 3-Z-[1-(4-bromo-phenylamino)-1-methyl-methylene]-5-amido-2-indolinone,

was produced from the resin prepared in accordance with example IV(2) and 4-bromoaniline.

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

C17H14BrN3O2 mass spectrum: m/z = 371/373 (M+)

(9) 3-Z-(1-phenylamino-1-methyl-methylene)-5-amido-2-

indolinone,

was produced from prepared according to example IV(2) and aniline.

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

Cl7H15N3O2

mass spectrum: m/z = 293 (M+)

(10) 3-Z-(1-amino-1-methyl-methylene)-5-amido-2-indolinone, was produced from the resin prepared in accordance with example IV(2) and ammonia.

Rf (value: 0.23 (silica gel, methylene chloride/methanol = 9:1)

C11H11N3O2

mass spectrum: m/z 217 (M+)

(11) 3-Z-[1-(4-piperidinomethyl-phenylamino)-1-methyl-methylene]-5-amido-2-indolinone, was produced from the resin prepared in accordance with example IV (2) and 4-( piperidinomethyl)-aniline.

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

C23H26N4O2

mass spectrum: m/z = 390 (M+)

(12) 3-Z-[1-(4-pyrrolidinomethyl-phenylamino)-1-methyl-methylene]-5-amido-2-indolinone, was produced from the resin prepared in accordance with example IV(2) and 4-pyrrolidinomethyl - aniline.

Rf value: 0.20 (silica gel, methylene chloride/methanol = 4:1)

C22H24N4O2

mass spectrum: m/z =376 (M+)

(13) 3-Z-[1-(4-Dipropylaminomethyl-phenylamino)-1-methyl-methylene]-5-amido-2-indolinone, was produced from the resin prepared in accordance with example 11(2) and 4-dipropylaminomethyl - aniline.

Rf value: 0.71 (silica gel, methylene chloride/methanol = 4:1)

C24H30N4O2

mass spectrum: m/z = 406 (M+)

(14) 3-Z-[1-[4-(2-piperidinoethyl)-phenylamino]-1-methyl-methylene]-5-amido-2-indolinone, was produced from the resin prepared in accordance with example IV(2) and 4-(2-piperidinoethyl)-aniline.

Rf value: 0.38 (silica gel, methylene chloride/methanol = 4:1)

C24H28N4O2

mass spectrum: m/z = 404 (M+)

(15) 3-Z-[1-[4-(2-diethylaminoethyl)-phenylamino]-1-methyl-methylene]-5-amido-2-indolinone, was produced from the resin prepared in accordance with example IV(2) and 4-(2-diethylaminoethyl)-aniline.

Rf value: 0.33 (silica gel, methylene chloride/methanol = 4:1)

C23H28N4O2

mass spectrum: m/z =393 (M+)

(16) 3-Z-[1-(4-hexamethyleneiminomethyl-phenylamino)-1-methyl-methylene]-5-amido-2-indolinone, was produced from the resin prepared in accordance with example IV (2) and 4-hexamethyleneiminomethyl - aniline.

Rf value: 0.34 (silica gel, methylene chloride/methanol = 4:1)

C24H28N3O2

mass spectrum: m/z = 404 (M+)

(17) 3-Z-[1-[4-(N-methyl-N-methanesulfonyl-amino)-phenylamino]-1-methyl-methylene]-5-amido-2-indolinone, was produced from resin prepared in accordance with with example IV(2) and 4-(N-methyl-N-methanesulfonyl-amino)-aniline.

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

C19H20N4O4S

mass spectrum: m/z = 400 (M+)

(18) 3-Z-[1-(4-methanesulfonylamino-phenylamino)-1-methyl-methylene]-5-amido-2-indolinone, was produced from the resin prepared in accordance with example IV(2) and 4-methanesulfonylamino - aniline.

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

C18H18N4O4S

mass spectrum: m/z = 386 (M+)

(19) 3-Z-[1-(4-bromophenylamino)-1-ethyl-methylene]-5-amido-2-indolinone, was produced from the resin prepared in accordance with example IV(3) and 4-bromoaniline.

Rf value: 0.52 (silica gel, methylene chloride/methanol = 5 9:1)

C18H16BrN3O2

mass spectrum: m/z = 385/387 (M+/M+2+)

(20) 3-Z-[1-(4-piperidinomethyl-phenylamino)-1-ethyl-methylene]-5-amido-2-indolinone, was produced from the resin prepared in accordance with example IV(3) and 4-piperidinomethyl - aniline. Rf value: 0.42 (silica gel, methylene chloride/methanol = 4:1)

C24H28N4O2

mass spectrum: m/z = 404 (M+)

(21) 3-Z-[1-(4-piperidinomethyl-phenylamino)-1-propyl-

methylene]-5-amido-2-indolinone, was prepared from the resin prepared in accordance with Example IV(4) and 4-piperidinomethyl-aniline.

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

C25H30N4O2

mass spectrum: m/z = 418 (M+)

(22) 3-Z-[1-(4-bromophenylamino)-1-propyl-methylene]-5-amido-2-indolinone,

was produced from the resin prepared in accordance with example IV(4) and 4-bromoaniline.

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

C19H18BrN3O2

mass spectrum: m/z = 399/401 (M+/M+2+)

(23) 3-Z-[(4-bromophenylamino)-methylene]-5-amido-2-indolinone, was produced from the resin prepared in accordance with example IV(1) and 4-bromoaniline.

C16H12BrN3O2

mass spectrum: m/z = 357/359 (M+/M+2+)

(24) 3-Z-[(4-piperidinomethyl-phenylamino)-methylene]-5-amido-2-indolinone, was produced from the resin prepared in accordance with example IV (1) and 4-piperidinomethyl-aniline.

C24H24N4O2

mass spectrum: m/z = 376 (M+)

(25) 3-Z-[1-(4-bromophenylamino)-1-butyl-methylene]-5-amido-2-indolinone was prepared from the resin prepared in accordance with Example IV and 4-bromoaniline.

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

C20H20BrN3O2

mass spectrum: m/z = 413/415 (M+/M+2+)

(26) 3-Z-[1-(4-piperidinomethyl-phenylamino)-1-butyl-methylene]-5-amido-2-indolinone was prepared from the resin prepared in accordance with Example IV and piperidinomethyl-aniline.

Rf value: 0.48 (silica gel, methylene chloride/methanol = 4:1)

C26H32N4O2

mass spectrum: m/z = 432 (M+)

(27) 3-Z-[1-(4-piperidinomethyl-phenylamino)-1-ethenyl-methylene]-5-amido-2-indolinone, was produced from the resin prepared in accordance with example IV(5) and 4-piperidinomethyl - aniline.

(28) 3-Z-[1-(4-piperidinomethyl-phenylamino)-1-(3-bromo-propyl)-methylene]-5-amido-2-indolinone,

is produced from the resin prepared in accordance with example IV (6) and 4-piperidinomethyl-aniline.

(29) 3-Z-[1-(4-piperidinomethyl-phenylamino)-1-(2-phenyl-sulfonylethyl)-methylene]-5-amido-2-indolinone,

was produced from resin prepared according to example IV(7) and 4-piperidinomethyl-aniline.

(30) 3-Z-[1-[4-(2,6-dimethylpiperidinomethyl)-phenylamino]-1-methyl-methylene]-5-amido-2-indolinone,

was produced from the resin prepared in accordance with example IV(2) and 4-(2,6-dimethylpiperidinomethyl)-aniline.

(31) 3-Z-[1-(4-thiomorpholinomethyl-phenylamino)-1-methyl-methylene]-5-amido-2-indolinone,

it is produced from the resin prepared in accordance with example IV(2) and 4-thiomorpholinomethyl-aniline.

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

C22H24N4O2S

mass spectrum: m/z = 408 (M+)

(32) 3-Z-[1-[(4-thiomorpholino-S-oxido-methyl)-phenylamino]-1-methyl-methylene]-5-amido-2-indolinone,

was produced from the resin prepared in accordance with example IV(2) and 4-(thiomorpholino-S-oxido-methyl)-aniline.

Rf value: 0.21 (silica gel, methylene chloride/methanol 9:1)

C22H24N4O3S

resolved spectrum: m/z = 424 (M+)

(33) 3-Z-[1-[4-(thiomorpholino-S,S-dioxido-methyl)-phenyl-amino]-1-methyl-methylene]-5-amido-2-indolinone,

is produced from the resin prepared in accordance with example IV(2) and 4-thiomorpholino-S,S-dioxido-methyl)-aniline.

(34) 3-Z-[1-(4-azetidionomethyl-phenylamino)-1-methyl-methylene]-5-amido-2-indolinone,

is produced from the resin prepared in accordance with example IV(2) and 4-azetidionomethyl-aniline.

(35) 3-Z-[1-[4-(2,5-dihydropyrrol-1-yl-methyl)-phenylamino]-1-methyl-methylene]-5-amido-2-indolinone,

is produced from the resin prepared in accordance with example IV(2) and 4-(2,5-dihydropyrrol-1-yl-methyl)-aniline.

Rf value: 0.10 (silica gel, methylene chloride/methanol 9:1)

C22H22N4O2

mass spectrum: m/z = 375 (M+)

(36) 3-Z-[1-[4-(3,6-dihydro-2H-pyridin-1-yl-methyl)-phenyl-amino]-1-methyl-methylene]-5-amido-2-indolinone ,

is produced from the resin prepared according to example IV(2) and 4-(3,6-dihydro-2H-pyridin-1-yl-methyl)-aniline.

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

C23H24N4O2

mass spectrum: m/z = 389 (M+H)+

(37) 3-Z-[1-[4-(2-ethoxycarbonyl-pyrrolidinomethyl)-phenyl-amino]-1-methyl-methylene]-5-amido-2-indolinone,

was produced from the resin prepared according to example IV(2) and 4-(2-ethoxycarbonyl-pyrrolidinomethyl)-aniline.

Rf value: 0.50 (silica gel, methylene chloride/methanol = 9:1)

C24H26N4O4

mass spectrum: m/z = 435 (M+H)+

(38) 3-Z-[1-[4-(3,5-dimethyl-piperidinomethyl)-phenylamino]-1-methyl-methylene]-5-amido-2-indolinone, was produced from the resin prepared in accordance with the example IV(2) and 4-(3,5-dimethyl-piperidinomethyl)-aniline.

Rf value: 0.16 (silica gel, methylene chloride/methanol = 9:1)

C25H30N4O2

mass spectrum: m/z = 418 (M+)

(39) 3-Z-[1-[4-(4-phenyl-piperazinylmethyl)-phenylamino]-1-methyl-methylene]-5-amido-2-indolinone-trifluoroacetate,

was produced from the resin prepared in accordance with example IV(2) and 4-(4-phenyl-piperazinylmethyl)-aniline.

Rf value: 0.40 (silica gel, methylene chloride/methanol = 9:1)

C28H29N5O2

mass spectrum: m/z = 468 (M+H)+

(40) 3-Z-[1-[4-(4-phenyl-4-hydroxy-piperidinylmethyl)-phenyl-amino]-1-methyl-methylene]-5-amido-2-indolinone-trifluoro-acetate,

was produced from the resin prepared in accordance with Example IV(2) and 4-(4-phenyl-4-hydroxy-piperidinylmethyl)-aniline.

C29H30N4O3

mass spectrum: m/z = 483 (M+H)+

(41) 3-Z-[1-(3-methoxy-phenylamino)-1-methyl-methylene]-5-amido-2-indolinone,

is produced from the resin prepared in accordance with example IV(2) and 3-methoxy-aniline.

Rf value: 0.40 (silica gel, methylene chloride/methanol = 9:1)

C18H17N3O3

mass spectrum: m/z =323 (M+)

(42) 3-Z-[1-(3-ethoxycarbonyl-phenylamino)-1-methyl-methylene]-5-amido-2-indolinone,

it is produced from the resin prepared in accordance with example IV(2) and ethyl 3-amino-benzoate.

C20H19N3O4

mass spectrum: m/z = 365 (M+)

(43) 3-Z-[1-(4-dimethylaminomethyl-phenylamino)-1-methyl-methylene]-5-amido-2-indolinone trifluoroacetate,

is produced from the resin prepared in accordance with example IV(2) and 4-dimethylaminomethyl-aniline.

C20H22N4O2

mass spectrum: m/z = 351 (M+)

(44) 3-Z-[1-[4-(4-cyclohexyl-piperidinylmethyl)-phenyl-amino]-1-methyl-methylene]-5-amido-2-indolinone,

was produced from the resin prepared according to example IV(2) and 4-(4-cyclohexyl-piperidinylmethyl)-aniline.

(45) 3-Z-[1-(4-morpholinyl-phenylamino)-1-methyl-methylene]-5-amido-2-indolinone,

is produced from the resin prepared in accordance with example IV(2) and 4-morpholinyl-aniline.

C21H22N4O3

mass spectrum: m/z = 378 (M+)

(46) 3-Z-[1-(N-methyl-piperidin-4-ylamino)-1-methyl-methylene)-5-amido-2-indolinone,

is produced from the resin prepared according to example IV(2) and 4-amino-N-methyl-piperidine.

Cl7H22N4O2

mass spectrum: m/z = 314 (M+)

(47) 3-Z-[1-(4-methylcyclohexylamino)-1-methyl-methylene]-5-amido-2-indolinone,

is produced from the resin prepared in accordance with example IV(2) and 4-methyl-cyclohexylamine.

C18H23N3O2

mass spectrum: m/z = 313 (M+)

(48) 3-Z-(1-cyclopentylamino-1-methyl-methylene)-5-amido-2-indolinone,

was produced from the resin prepared in accordance with example IV(2) and cyclopentylamine.

Rf value: 0.70 (silica gel, methylene chloride/methanol = 4:1)

Cl6H19N3O2

mass spectrum: m/z = 285 (M+)

(49) 3-Z-(1-isopropylamino-1-methyl-methylene)-5-amido-2-indolinone,

is produced from the resin prepared in accordance with example IV(2) and isopropylamine.

C14H17N3O2

mass spectrum: m/z = 259 (M+)

(50) 3-Z-[1-(4-ethoxycarbonylmethylaminomethyl-phenylamino)-1-methyl-methylene]-5-amido-2-indolinone,

is produced from the resin prepared in accordance with example IV (2) and 4-(ethoxycarbonylmethyl-N-tert-butyloxycarbonyl-amino-methyl)-aniline.

C21H22N4O4

mass spectrum: m/z = 394 (M+)

(51) 3-Z-[1-(4-benzylaminomethyl-phenylamino)-1-methyl-methylene]-5-amido-2-indolinone,

was produced from the resin prepared in accordance with example IV(2) and 4-(N-benzyl-N-tert-butyloxycarbonyl-aminomethyl)-aniline.

Rf value: 0.24 (silica gel, methylene chloride/methanol = 9:1)

C25H24N4O2

mass spectrum: m/z = 412 (M+)

(52) 3-Z-[1-(4-butylaminomethyl-phenylamino)-1-methyl-methylene]-5-amido-2-indolinone trifluoroacetate,

was produced from the resin prepared in accordance with example IV(2) and 4-(N-butyl-N-tert-butyloxycarbonyl-aminomethyl)-aniline.

Rf value: 0.40 (silica gel, methylene chloride/methanol = 4:1)

C22H26N4O2

mass spectrum: m/z =378 (M+)

(53) 3-Z-[1-(4-ethylaminomethyl-phenylamino)-1-methyl-methylene]-5-amido-2-indolinone trifluoroacetate,

was produced from the resin prepared in accordance with example IV (2) and 4-(N-ethyl-N-tert-butyloxycarbonyl-aminomethyl)-aniline.

Rf value: 0.20 (silica gel, methylene chloride/methanol = 4:1)

C20H22N4O2

mass spectrum: m/z = 351 (M+H+)

(54) 3-Z-[1-(4-cyclohexylaminoethyl-phenylamino)-1-methyl-methylene]-5-amido-2-indolinone trifluoroacetate,

is produced from the resin prepared in accordance with example IV(2) and 4-(cyclohexyl-(N-tert-butyloxycarbonyl-amino-methyl)-aniline.

C24H28N4O2

mass spectrum: m/z = 405 (M+)

(55) 3-Z-[1-(4-isopropylaminomethyl-phenylamino)-1-methyl-methylene]-5-amido-2-indolinone trifluoroacetate,

is produced from the resin prepared in accordance with example IV (2) and 4-(N-isopropyl-N-tert-butyloxycarbonyl-amino-methyl)-aniline.

C21H24N4O2

mass spectrum: m/z = 365 (M+)

(56) 3-Z-[1-(4-trifluoromethoxy-phenylamino)-1-methyl-methylene]-5-amido-2-indolinone,

was produced from the resin prepared in accordance with example IV(2) and 4-trifluoromethoxy-aniline.

Cl8H14F3N3O3

mass spectrum: m/z =377 (M+)

(57) 3-Z-[1-(4-difluoromethoxy-phenylamino)-1-methyl-methylene]-5-amido-2-indolinone,

was produced from the resin prepared in accordance with example IV(2) and 4-difluoromethoxy-aniline.

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

Cl8Hl5F2N3O3

mass spectrum: m/z = 359 (M+H)+

(58) 3-Z-[1-(4-bromo-3-chloro-phenylamino)-1-methyl-methylene]-5-amido-2-indolinone,

was produced from the resin prepared in accordance with example IV(2) and 4-bromo-3-chloroaniline.

C17H13BrClN3O2

mass spectrum: m/z 405/407/409 (M+/m+2+/M+4+)

(59) 3-Z-[1-(4-trifluoromethyl-3-bromo-phenylamino)-1-methyl-methylene]-5-amido-2-indolinone, was produced from the resin prepared in accordance with example IV(2) and 4-trifluoromethyl-3-bromo-aniline.

C18H13BrF3N3O2

mass spectrum: m/z = 439/441 (M+/M+2+)

(60) 3-Z-[1-(4-chloro-phenylamino)-methylene]-5-amido-2-indolinone,

was produced from the resin prepared in accordance with example IV(1) and 4-chloroaniline.

C16Hl2ClN3O2

mass spectrum: m/z = 312/314 (M+)

(61) 3-Z-[1-(3-bromo-phenylamino)-1-methyl-methylene]-5-amido-2-indolinone,

is produced from the resin prepared in accordance with example IV(2) and 3-bromo-aniline.

C17H14N3O2

mass spectrum: m/z = 371/373 (M+)

(62) 3-2-[1-(3-chloro-phenylamino)-1-methyl-methylene]-5-amido-2-indolinone,

is produced from the resin prepared in accordance with example IV(2) and 3-chloroaniline.

C17H14ClN3O2

mass spectrum: m/z = 327/329 (M+)

(63) 3-Z-[1-(2-chloro-phenylamino)-1-methyl-methylene]-5-amido-2-indolinone,

is produced from the resin prepared in accordance with example IV(2) and 2-chloroaniline.

C14H14BrN3O2

mass spectrum: m/z = 327/329 (M+)

(64) 3-Z-[1-(4-bromo-3-methyl-phenylamino)-1-methyl-methylene]-5-amido-2-indolinone,

is produced from the resin prepared in accordance with example IV (2) and 4-broin-3-methyl-aniline.

Rf value: 0.60 (silica gel, methylene chloride/methanol = 9:1)

C18H16BrN3O2

mass spectrum: m/z = 385/387 (M+)

(65) 3-Z-[1-(4-bromo-3-methoxy-phenylamino)-1-methyl-methylene]-5-amido-2-indolinone,

is produced from the resin prepared in accordance with example IV (2) and 4-bromo-3-methoxy-aniline.

Rf value: 0.60 (silica gel, methylene chloride/methanol 9:1)

C18H16BrN3O3

mass spectrum: m/z = 401/403 (M+)

(66) 3-Z-[1-(4-fluoro-3-nitro"phenylamino)-1-methyl-methylene]-5-amido-2-indolinone,

was produced from the resin prepared in accordance with example IV(2) and 4-fluoro-3-nitro-aniline.

Rf value: 0.40 (silica gel, methylene chloride/methanol 9:1)

Cl7H13FN4O4

mass spectrum: m/z = 356 (M+)

(67) 3-Z-[1-(4-bromo-3-nitro-phenylamino)-1-methyl-methylene]-5-amido-2-indolinone,

was produced from the resin prepared in accordance with example IV(2) and 4-bromo-3-nitro-aniline.

Rf value: 0.50 (silica gel, methylene chloride/methanol 9:1)

C17H13BrN4O4

mass spectrum: m/z = 416/418 (M+)

(68) 3-Z-[1-(4-ethyl-3-nitro-phenylamino)-1-methyl-methylene]-5-amido-2-indolinone,

is produced from the resin prepared in accordance with example IV(2) and 4-ethyl-3-nitro-aniline.

Rf value: 0.70 (silica gel, methylene chloride/methanol 9:1)

Cl9H18N4O4

mass spectrum: m/z = 366 (M+)

(69) 3-Z-[1-(4-chloro-3-nitro-phenylamino)-1-methyl-methylene]-5-amido-2-indolinone,

was produced from the resin prepared in accordance with example IV(2) and 4-chloro-3-nitro-aniline.

C17H13ClN4O4

mass spectrum: m/z = 371/373 (M+)

(70) 3-Z-[1-(3-nitro-phenylamino)-1-methyl-methylene]-5-amido-2-indolinone,

is produced from the resin prepared in accordance with example IV(2) and 3-nitro-aniline.

Cl7H14N4O4

mass spectrum: m/z = 338 (M+)

(71) 3-Z-[1-(4-methyl-3-nitro-phenylamino)-1-methyl-methylene]-5-amido-2-indolinone,

was produced from the resin prepared in accordance with example IV(2) and 4-methyl-3-nitro-aniline.

Rf value: 0.50 (silica gel, methylene chloride/methanol = 9:1)

C18H17N4O4

mass spectrum: m/z = 352 (M+)

(72) 3-Z-[1-(4-bromo-3-methoxycarbonyl-phenylamino)-1-methyl-methylene]-5-amido-2-indolinone,

was produced from the resin prepared in accordance with example IV(2) and methyl 2-bromo-5-aminobenzoate.

Rf value: 0.50 (silica gel, methylene chloride/methanol = 9:1)

C19H16BrN3O4

mass spectrum: m/z = 429/431 (M+)

(73) 3-Z-[1-(4-carbamoyl-phenylamino)-1-methyl-methylene]-5-amido-2-indolinone,

is produced from resin prepared in accordance with example IV(2) and 4-aminobenzamide,

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

Cl8Hl6N4O3

mass spectrum: m/z =1= 336 (M+)

(74) 3-Z-[1-(4-(piperidino-carbonyl)-phenylamino)-1-methyl-methylene]-5-amido-2-indolinone, was produced from the resin prepared in accordance with example IV(2) and 1-(4-amino-benzoyl)-piperidine.

Rf value: 0.50 (silica gel, methylene chloride/methanol 9:1)

C23H24N4O3

mass spectrum: m/z = 404 (M+)

(75) 3-Z-[1-(4-(2-(diethylamino)-ethyl-carbamoyl)-phenyl-amino)-1-methyl-methylene]-5-amido-2-indolinone trifluoroacetate,

was prepared from the resin prepared according to example IV(2) and 4-amino-N-[2-(diethylamino)-ethyl]-benzamide.

Rf value: 0.30 (silica gel, methylene chloride/methanol 9:1)

C24H29N5O2

mass spectrum: m/z =436 (M+)

(76) 3-Z-[1-(4-trifluoromethyl-phenylamino)-1-methyl-methylene]-5-amido-2-indolinone,

is produced from resin prepared in accordance with the example

IV(2) and 4-trifluoromethyl-aniline.

C18H14F3N3O2

mass spectrum: m/z =361 (M+)

(77) 3-Z-[1-(3-hydroxymethyl-phenylamino)-1-methyl-methylene]-5-amido-2-indolinone,

it is produced from resin prepared in accordance with example IV (2) and 3-aminobenzylalcohol.

Cl8H17N3O3

mass spectrum: m/z = 323 (M+)

(78) 3-Z-[1-(4-(hydroxycarbonyl-phenylamino)-1-methyl-methylene]-5-amido-2-indolinone,

it is produced from resin prepared in accordance with example IV(2) and 4-aminobenzoic acid.

Rf value: 0.20 (silica gel, methylene chloride/methanol = 4:1)

Cl8H15N3O4

mass spectrum: m/z = 336 (M+)

(79) 3-Z-[1-(4-ethoxycarbonylmethyl-3-nitro-phenylamino)-1-methyl-methylene]-5-amido-2-indolinone,

was produced from the resin prepared in accordance with example IV(2) and ethyl 4-amino-2-nitro-phenylacetate.

Rf value: 0.70 (silica gel, methylene chloride/methanol = 9:1)

C21H20N4O6

mass spectrum: m/z 424 (M+)

(80) 3-Z-[1-(3-methoxycarbonyl-4-methyl-phenylamino)-1-methyl-methylene]-5-amido-2-indolinone,

is produced from the resin prepared in accordance with example IV(2) and methyl 3-amino-6-methyl-benzoate.

Rf value: 0.70 (silica gel, methylene chloride/methanol = 9:1)

C30Hl9N3O4

mass spectrum: m/z = 365 (M+)

(81) 3-Z-[1-(3-diethylcarbamoyl-4-methyl-phenylamino)-1-methyl-methylene]-5-amido-2-indolinone, was produced from the resin prepared in accordance with example IV(2) and 3-amino-6-methyl-benzoic acid diethylamide.

Rf (value: 0.50 (silica gel, methylene chloride/methanol = 9:1)

C23H26N4O3

mass spectrum: m/z = 406 (M+)

(82) 3-Z-[1-(3-ethylcarbamoyl-4-methyl-phenylamino)-1-methyl-methylene]-5-amido-2-indolinone, was produced from the resin prepared in accordance with example IV (2) and 3-amino-6-methyl-benzoic acid ethylamide.

Rf value: 0.40 (silica gel, methylene chloride/methanol = 9:1)

C21H22N4O3

mass spectrum: m/z = 378 (M+)

(83) 3-Z-[1-(3-sulfanoyl-4-methyl-phenylamino)-1-methyl-methylene]-5-amido-2-indolinone, It is produced from the resin prepared in accordance with example IV (2) and 3-amino-6-methyl-phenylsulfonic acid amide.

Rf value: 0.30 (silica gel, methylene chloride/methanol = 9:1)

C18Hl8N4O4S

mass spectrum: m/z = 386 (M+)

(84) 3-Z-[1-(3-acetylamino-4-methyl-phenylamino)-1-methyl-methylene]-5-amido-2-indolinone,

was produced from the resin prepared in accordance with example IV(2) and 4-amino-2-acetylamino-toluene.

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

C20H20N4O3

mass spectrum: m/z = 364 (M+)

(85) 3-Z-[1-(4-(2-dimethylamino-ethoxy)-phenylamino)-1-methyl-methylene]-5-amido-2-indolinone-trifluoroacetate, was produced from the resin prepared in accordance with example IV(2) and 4-(2-dimethylamino-ethoxy)-aniline.

Rf value: 0.10 (silica gel, methylene chloride/methanol 4:1)

C21H24N4O3

mass spectrum: m/z = 380 (M+)

(86) 3-Z-[1-(4-(2-piperidino-ethoxy)-phenylamino)-1-methyl-methylene]-5-amido-2-indolinone-trifluoroacetate, was produced from the resin prepared in accordance with example IV(2) and 4-(2-piperidino-ethoxy)-aniline.

Rf value: 0.70 (silica gel, methylene chloride/methanol 4:1)

C24H28N4O3

mass spectrum: la/z = 420 (M+)

(87) 3-Z-[1-(4-(3-dimethylamino-propoxy)-phenylamino)-1-methyl-methylene]-5-amido-2-indolinone-trifluoroacetate,

is produced from the resin prepared in accordance with example IV(2) and 4-(3-dimethylamino-propoxy)-aniline.

Rf value: 0.10 (silica gel, methylene chloride/methanol 4:1)

C22H26N4O3

mass spectrum: m/z =394 (M+)

(88) 3-Z-[1-(4-(3-piperidino-propoxy)-phenylamino)-1-methyl-methylene]-5-amido-2-indolinone-trifluoroacetate, was produced from the resin prepared in accordance with the example IV(2) and 4-(3-piperidino-propoxy)-aniline.

Rf value: 0.20 (silica gel, methylene chloride/methanol 4:1)

C25H30N4O3

mass spectrum: m/z = 434 (M+)

(89) 3-Z-[1-(4-(3-(N-benzyl-N-methylamino)-propoxy)-phenyl-amino)-1-methyl-methylene]-5-amido-2-indolinone-trifluoro -

acetate,

was produced from the resin prepared in accordance with example IV(2) and 4-[3-(N-benzyl-N-methylamino)-propoxy]-aniline.

Rf value: 0.60 (silica gel, methylene chloride/methanol 4:1)

C28H30N4O3

mass spectrum: m/z = 470 (M+)

(90) 3-Z-[1-(4-(N-benzyl-aminomethyl)-phenylamino)-methylene]-

5-amido-2-indolinone-trifluoroacetate was prepared from the resin prepared in accordance with Example IV (1) and 4-(N-benzyl-N-tert-butoxcarbonyl-aminomethyl)-aniline.

C24H22N4O32

mass spectrum: m/z = 399 (M+H)+

(91) 3-Z-[1-(4-(N-(4-chlorobenzyl)-aminomethyl)-phenylamino)-1-methyl-methylene]-5-amido-2-indolinone-trifluoroacetate, was produced from resin prepared according to example IV(2) and 4-[N-(4-chlorobenzyl-N-tert-butoxycarbonyl-amino-methyl)-aniline.

Rf value: 0.40 (silica gel, methylene chloride/methanol 9:1)

C25H23ClN4O2

mass spectrum: m/z = 446/448 (M+)

(92) 3-Z-[1-(4-(N-(3,4,5-trimethoxybenzyl)-N-methyl-amino-methyl)-phenylamino)-1-methyl-methylene]-5-amido-2 -indolinone-trifluoroacetate,

was produced from the resin prepared in accordance with Example IV(2) and 4-[N-((3,4,5-trimethoxy-benzyl)-N-methyl-amino-methyl]-aniline).

Rf value: 0.50 (silica gel, methylene chloride/methanol 9:1)

C29H32N4O35

mass spectrum: m/z = 516 (M+)

(93) 3-Z-[1-(4-(N-(3,4-dimethoxy-benzyl)-N-methyl-amino-methyl)-phenylamino)-1-methyl-methylene]-5-amido-2 -indolinone-trifluoroacetate

was produced from the resin prepared in accordance with example IV(2) and 4-[N-(3,4-dimethoxy-benzyl)-N-methyl-aminomethyl]-aniline.

Rf value: 0.40 (silica gel, methylene chloride/methanol 9:1)

C28H30N4O4

mass spectrum: m/z = 486 (M+)

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

was produced from the resin prepared in accordance with example IV(2) and 4-[N-(3,4-dimethoxy-benzyl)-N-ethyl-aminomethyl]-aniline.

Rf value: 0.40 (silica gel, methylene chloride/methanol 9:1)

C29H32N4O4

mass spectrum: m/z = 500 (M+)

(95) 3-Z-[1-(4-(N-benzyl-N-ethyl-aminomethyl)-phenylamino)-1-methyl-methylene]-5-ainido-2-indolinone-trifluoroacetate, was produced from resin prepared according to example IV(2) and 4-(N-benzyl-N-ethyl-aminomethyl)-aniline.

Rf value: 0.50 (silica gel, methylene chloride/methanol 9:1)

C27H28N4O2

mass spectrum: m/z = 440 (M+)

(96) 3-Z-[1-(4-(N-Benzyl-N-methyl-aminomethyl)-phenylamino)-1-methyl-methylene]-5-amido-2-indolinone-trifluoroacetate,

was produced from the resin prepared in accordance with example IV(2) and 4-(N-benzyl-N-methyl-aminomethyl)-aniline.

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

C26H26N4O2

mass spectrum: m/z = 426 (M+)

(97) 3-Z-[1-(4-(N-benzyl-N-methyl-aminomethyl)-phenylamino)-1-

ethyl-methylene]-5-amido-2-indolinone-trifluoroacetate, was prepared from the resin prepared in accordance with Example IV(3) and 4-(N-benzyl-N-methyl-aminomethyl)-aniline. Rf value: 0.50 (silica gel, methylene chloride/methanol = 9:1)

C26H26N4O2

mass spectrum: m/z = 440 (M+)

(98) 3-Z-[1-(4-(N-benzyl-N-methyl-aminomethyl)-phenylamino)-1-propyl-methylene]-5-amido-2-indolinone-trifluoroacetate, was produced from resin prepared according to example IV(4) and 4-(N-benzyl-N-methyl-amino-methyl)-aniline.

Rf value: 0.50 (silica gel, methylene chloride/methanol = 9:1)

C28H30N4O2

mass spectrum: m/z = 454 (M+)

(99) 3-Z-[1-(4-(N-(4-chlorobenzyl)-N-methyl-aminomethyl)-phenyl-amino)-1-methyl-methylene]-5-amido-2-indolinone-trifluoro -

acetate,

is produced from the resin prepared in accordance with example IV(2) and 4-[N-(4-chlorobenzyl)-N-methyl-aminomethyl]-aniline.

Rf value: 0.40 (silica gel, methylene chloride/methanol = 9:1)

C26H25C1N4O2

mass spectrum: m/z = 460/462 (M+)

(100) 3-Z-[1-(4-(N-(3-chlorobenzyl)-N-methyl-aminomethyl)-phenylamino)-1-methyl-methylene]-5-amido-2-indolinone-trifluoroacetate,

was produced from the resin prepared in accordance with example IV(2) and 4-[N-(3-chlorobenzyl)-N-methyl-aminomethyl]-aniline.

Rf value: 0.40 (silica gel, methylene chloride/methanol = 9:1)

C26H25C1N4O2

mass spectrum: m/z = 460/462 (M+)

(101) 3-Z-[1-(4-(N-(2,6-dichlorobenzyl)-N-methyl-aminomethyl)-phenylamino)-1-methyl-methylene]-5-amido-2-indolinone-

trifluoroacetate,

was produced from the resin prepared according to example IV(2) and 4-[N-(2,6-dichlorobenzyl)-N-methyl-aminomethyl]-aniline.

Rf value: 0.38 (silica gel, methylene chloride/methanol = 9:1)

C26H24C12N4O2

mass spectrum: m/z = 494/496/498 (M+2+/M+4+)

(102) 3-Z-[1-(4-(N-(4-trifluoromethylbenzyl)-M-methyl-amino-methyl)-phenylamino)-1-methyl-methylene]-5-amido-2-indolinone-trifluoroacetate ,

was produced from the resin prepared in accordance with Example IV(2) and 4-[N-(4-trifluoromethylbenzyl)-N-methyl-aminomethyl]-aniline.

Rf value: 0.38 (silica gel, methylene chloride/methanol = 9:1)

C27H25F3N4O2

mass spectrum: m/z = 494 (M+)

(103) 3-Z-[1-(4-(N-benzyl-N-isopropyl-aminomethyl)-phenyl-amino)-1-methyl-methylene]-5-amido-2-indolinone-trifluoroacetate,

is produced from the resin prepared in accordance with example IV (2) and 4-(N-benzyl-N-isopropyl-aminomethyl)-aniline.

Rf value: 0.50 (silica gel, methylene chloride/methanol = 9:1)

C28H30N4O2

mass spectrum: m/z = 454 (M+)

(104) 3-Z-[1-(4-(N-benzyl-N-tert-butyl-aminomethyl)-phenyl-amino)-1-methyl-methylene]-5-amido-2-indolinone-

trifluoroacetate,

was produced from the resin prepared in accordance with example IV(2) and 4-(N-benzyl-N-tert-butyl-aminomethyl)-aniline.

Rf value: 0.50 (silica gel, methylene chloride/methanol = 9:1)

C29H32N4O2

mass spectrum: m/z = 468 (M+)

(105) 3-Z-[1-(4-(N-benzyl-N-methyl-aminomethyl)-phenylamino)-methylene]-5-amido-2-indolinone-trifluoroacetate,

was produced from the resin prepared in accordance with example IV(1) and 4-(N-benzyl-N-methyl-aminomethyl)-aniline.

C25H24N4O2

mass spectrum; m/z = 413 (M+H+)

(106) 3-Z-[1-(4-(N-benzyl-N-ethyl-aminomethyl)-phenylamino)-1-methyl-methylene]-5-amido-2-indolinone-trifluoroacetate, was produced from resin prepared according to example IV(1) and 4-(N-benzyl-N-ethyl-aminomethyl)-aniline.

C26H26N4O2

mass spectrum; m/z = 427 (M+H+)

(107) 3-Z-[1-(4-(diisopropylamino-methyl)-phenylamino)-1-methyl-methylene]-5-amido-2-indolinone-trifluoroacetate, was produced from the resin prepared in accordance with example IV ( 2) and 4-(diisopropylamino-methyl)-aniline.

Rf value: 0.50 (silica gel, methylene chloride/methanol = 4:1)

C24H30N4O2

mass spectrum: m/z = 406 (M+)

(108) 3-Z-[1-(4-(di-n-propylamino-methyl)-phenylamino)-methylene]-5-amido-2-indolinone-trifluoroacetate,

is produced from the resin prepared in accordance with example IV (2) and 4-(di-n-propylamino-methyl)-aniline.

C23H28N4O2

mass spectrum: m/z = 393 (M+H+)

(109) 3-Z-[1-(4-(diisobutylamino-methyl)-phenylamino)-1-methyl-methylene]-5-amido-2-indolinone-trifluoroacetate,

is produced from the resin prepared in accordance with example IV(2) and 4-(diisobutylamino-methyl)-aniline.

Rf value: 0.50 (silica gel, methylene chloride/methanol = 9:1)

C26H34N4O2

mass spectrum: m/z = 434 (M+)

(110) 3-Z-[1-(4-(2,3,4,5-tetrahydro-benzo(d)azepin-3-yl-methyl)-phenylamino)-1-methyl-methylene]-5-amido -2-indolinone-trifluoroacetate,

is produced from the resin prepared in accordance with example IV(2) and 4-(2,3,4,5-tetrahydro-benzo(d)azepin-3-yl-methyl)-aniline.

Rf value: 0.30 (silica gel, methylene chloride/methanol = 9:1)

C28H28N4O2

mass spectrum: m/z = 452 (M+)

(111) 3-Z-[1-(4-(1,3-dihydro-isoindol-2-yl-methyl)-phenyl-amino)-1-methyl-methylene]-5-amido-2-indolinone-trifluoroacetate ,

is produced from the resin prepared according to example IV(2) and 4-(1, 3-dihydro-isoindol-2-yl-methyl)-aniline.

Rf value: 0.35 (silica gel, methylene chloride/methanol = 9:1)

C26H24N4O2

mass spectrum: m/z = 425 (M+H+)

(112) 3-Z-[1-(4-(6,7-dimethoxy-1,2,3,4-tetrahydro-iso-quinolin-2-yl-methyl)-phenylamino)-1-methyl-methylene] -5-amido-2-indolinone-trifluoroacetate, was produced from the resin prepared in accordance with example IV(2) and 4-(6,7-dimethoxy-1,2,3,4-tetrahydro-isoquinoin-2-yl- methyl)-aniline.

Rf value: 0.50 (silica gel, methylene chloride/methanol = 9:1)

C29H30N4O4

mass spectrum: m/z = 499 (M+)

(113) 3-Z-[1-(4-(1,2,3,4-tetrahydro-isoquinolin-2-yl-methyl)-phenylamino)-1-methyl-methylene]-5amido-2-indolinone-trifluoroacetate ,

is produced from the resin prepared according to example IV(2) and 4-(1,2,3,4-tetrahydro-isoquinolin-2-yl-methyl)-aniline.

(114) 3-Z-[1-(4-(N-(ethoxycarbonylmethyl)-N-benzyl-aminomethyl)-phenylamino)-1-methyl-methylene]-5-amido-2-indolinone-trifluoroacetate,

was prepared from the resin prepared in accordance with Example IV(2) and 4-[N-(ethoxycarbonylmethyl)-N-benzylaminomethyl)-aniline.

Rf value: 0.60 (silica gel, methylene chloride/methanol = 9:1)

C29H30N4O4

mass spectrum: m/z = 498 (M+)

(115) 3-Z-[1-(4-(N-(2-hydroxyethyl)-N-benzyl-aminomethyl)-phenylamino)-1-methyl-methylene]-5-amido-2-indolinone-trifluoroacetate,

is produced from the resin prepared in accordance with example IV (2) and 4-[N-(2-hydroxyethyl)-N-benzyl-aminomethyl)-aniline.

Rf value: 0.40 (silica gel, methylene chloride/methanol = 9:1)

C27H28N4O3

mass spectrum: m/z = 456 (M+)

(116) 3-Z-[1-(4-(N-(1-ethyl-pentyl)-N-(pyridin-2-yl-methyl)-aminomethyl)-phenylamino)-1-methyl-methylene]-5 -amido-2-indolinone

-trifluoroacetate,

was prepared from the resin prepared in accordance with Example IV(2) and 4-[N-(1-ethyl-pentyl)-N-(pyridin-2-yl-methyl)-amino-methyl]-aniline.

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

C31H37N5O2

mass spectrum: m/z = 511 (M+)

(117) 3-Z-[1-(4-(piperidino-methyl)-3-nitro-phenylamino)-1-methyl-methylene]-5-amido-2-indolinone, was produced from the resin prepared in accordance with example IV(2) and 4-(piperidino-methyl)-3-nitro-aniline.

Rf value: 0.70 (silica gel, methylene chloride/methanol = 9:1)

C23H25N5O4

mass spectrum: in/z =436 (M+H+)

(118) 3-Z-[1-(4-(N-phenethyl-N-methyl-aminoethyl)-phenylamino)-1-methyl-methylene]-5-amido-2-indolinone-trifluoroacetate, was produced from resin prepared according to example IV(2) and 4-(N-phenethyl-N-methyl-aminomethyl)-aniline.

Rf value: 0.50 (silica gel, methylene chloride/methanol = 9:1)

C27H28N4O2

mass spectrum: m/z = 441 (M+H+)

(119) 3-Z-[1-(4-(N-phenethyl-N-ethyl-aminomethyl)-phenylamino)-1-methyl-methylene]-5-amido-2-indolinone,

(120) 3-Z-[1-(4-(N-(3,4-dihydroxy-phenethyl)-N-methyl-amino-methyl)-phenylamino)-1-methyl-methylene]-5-amido-2 -indolinone,

(121) 3-Z-[1-(4-(N-(3,4,5-trimethoxy-phenethyl)-N-methyl-aminomethyl)-phenylamino)-1-methyl-methylene]-5-amido-2 -indolinone,

(122) 3-Z-[1-(4-(N-(3,4-dimethoxy-phenethyl)-N-methyl-amino-methyl)-phenylamino)-1-methyl-methylene]-5-amido-2 -indolinone,

(123) 3-Z-[1-(4-(N-(4-nitro-phenethyl)-N-methyl-aminomethyl)-phenylamino)-1-methyl-methylene]-5-amido-2-indolinone,

(124) 3-Z-[1-(4-(N-phenethyl-N-benzyl-aminomethyl)-phenyl-amino)-1-methyl-methylene]-5-amido-2-indolinone,

C33H32N4O2

mass spectrum: m/z = 517 (M+H+)

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

(125) 3-Z-[1-(4-(N-phenethyl-N-cyclohexyl-aminomethyl)-phenylamino)-1-methyl-methylene]-5-amido-2-indolinone,

(126) 3-Z-[1-(4-(N-(4-nitro-phenethyl)-N-isopropyl-amino-methyl)-phenylamino)-1-methyl-methylene]-5-amido-2-indolinone ,

(127) 3-Z-[1-(4-(N-(2-(pyridin-2-yl)-ethyl)-N-methyl-amino-methyl)-phenylamino)-1-methyl-methylene]-5 -amido-2-indolinone,

C26H27N5O2

mass spectrum: m/z = 441 (M+)

Rf value: 0.51 (silica gel, methylene chloride/methanol 4:1)

(128) 3-Z-[1-(4-(N-(2-(pyridin-4-yl)-ethyl)-N-methyl-amino-methyl)-phenylamino)-1-methyl-methylene]-5 -amido-2-indolinone,

(129) 3-Z-[1-(4-(N-(pyridin-2-yl-methyl)-N-methyl-amino-methyl)-phenylamino)-1-methyl-methylene]-5-amido-2 -indolinone,

(130) 3-Z-[1-(4-(N-(pyridin-3-yl-methyl)-N-methyl-amino-methyl)-phenylamino)-1-methyl-methylene]-5-amido-2 -indolinone,

(131) 3-Z-[1-(4-(N-(pyridin-4-yl-methyl)-N-methyl-amino-methyl)-phenylamino)-1-methyl-methylene]-5-amido-2 -indolinone,

(132) 3-Z-[1-(4-(dibenzylamino-methyl)-phenylamino)-1-methyl-methylene]-5-amido-2-indolinone,

C32H30N4O2

mass spectrum: m/z = 503 (M+H+)

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

(133) 3-Z-[1-(4-(N-(4-nitro-benzyl)-N-propyl-aminomethyl)-phenylamino)-1-methyl-methylene]-5-amido-2-indolinone,

(134) 3-Z-[1-(4-(N-benzyl-N-(3-cyano-propyl)-aminomethyl)-phenylamino)-1-methyl-methylene]-5-amido-2-indolinone,

(135) 3-Z-[1-(4-(N-benzyl-N-allyl-aminomethyl)-phenylamino)-1-methyl-methylene]-5-amido-2-indolinone,

C28H26N4O2

mass spectrum: m/z = 451 (M+H+)

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

(136) 3-Z-[1-(4-(imidazol-1-yl-methyl)-phenylamino)-1-methyl-methylene]-5-amido-2-indolinone,

C2lH20N6O2

mass spectrum: m/z = 389 (M+H+)

Rf value: 0.20 (silica gel, methylene chloride/methanol = 4:1)

(137) 3-Z-[1-(4-(imidazol-2-yl-amino-methyl)-phenylamino)-1-methyl-methylene]-5-amido-2-indolinone,

(138) 3-Z-[1-(4-(N-benzyl-N-(2,2,2-trifluoroethyl)-amino-methyl)-phenylamino)-1-methyl-methylene]-5-amido-2 -indolinone,

(139) 3-Z-[1-(4-(N-(benzo(1,3)dioxol-5-yl-methyl)-N-methyl-aminomethyl)-phenylamino)-1-methyl-methylene]-5 -amido-2-indolinone,

C27H26N4O2

mass spectrum: m/z = 470 (M+H+)

Rf value: 0.50 (silica gel, methylene chloride/methanol = 9:1)

(140) 3-Z-[1-(4-(7-chloro-2,3,4,5-tetrahydro-benzo(d)azepin-3-yl-methyl)-phenylamino)-1-methyl-methylene] -5-amido-2-indolinone,

(141) 3-Z-[1-(4-(7,8-dichloro-2,3,4,5-tetrahydro-benzo(d)-azepin-3-yl-methyl)-phenylamino)-1-methyl -methylene]-5-amido-2-indolinone,

(142) 3-Z-[1-(4-(7-bromo-2,3,4,5-tetrahydro-benzo(d)azepin-3-yl-methyl)-phenylamino)-1-methyl-methylene] -5-amido-2-indolinone,

(143) 3-Z-[1-(4-(7-fluoro-2,3,4,5-tetrahydro-benzo(d)azepin-3-yl-methyl)-phenylamino)-1-methyl-methylene] -5-amido-2-indolinone,

(144) 3-Z-[1-(4-(7-methoxy-2,3,4,5-tetrahydro-benzo (d)-azepin-3-yl-methyl)-phenylamino)-1-methyl-methylene ]-5-amido-2-indolinone,

(145) 3-Z-[1-(4-(7-methyl-2,3,4,5-tetrahydro-benzo(d)azepin-3-yl-methyl)-phenylamino)-1-methyl-methylene] -5-amido-2-indolinone,

(146) 3-Z-[1-(4-(7,8-dimethoxy-2,3,4,5-tetrahydro-benzo(d)-azepin-3-yl-methyl)-phenylamino)-1-methyl -methylene]-5-amido-2-indolinone,

(147) 3-Z-[1-(4-(6,7-dichloro-1,2,3,4-tetrahydro-isoquinolin-2-yl-methyl)-phenylamino)-1-methyl-methylene]-5 -amido-2-indolinone,

(148) 3-Z-[1-(4-(6,7-dimethyl-1,2,3,4-tetrahydro-isoquinolin-2-yl-methyl)-phenylamino)-1-methyl-methylene]-5 -amido-2-indolinone,

(149) 3-Z-[1-(4-(6,7-difluoro-1,2,3,4-tetrahydro-isoquinolin-2-yl-methyl)-phenylamino)-1-methyl-methylene]-5 -amido-2-indolinone,

C27H26N4O2

mass spectrum: m/z =439 (M+H+)

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

(150) 3-Z-[1-(4-(6-chloro-1,2,3,4-tetrahydro-isoquinolin-2-yl-methyl)-phenylamino)-1-methyl-methylene]-5-amido -2-indolinone,

(151) 3-Z-[1-(4-(7-chloro-1,2,3,4-tetrahydro-isoquinolin-2-yl-methyl)-phenylamino)-1-methyl-methylene]-5-amido -2-indolinone,

(152) 3-Z-[1-(4-(6-methoxy-1,2,3,4-tetrahydro-isoquinolin-2-yl-methyl)-phenylamino)-1-methyl-methylene]-5-amido -2-indolinone,

(153) 3-Z-[1-(4-(7-methoxy-1,2,3,4-tetrahydro-isoquinolin-2-yl-methyl)-phenylamino)-1-methyl-methylene]-5-amido -2-indolinone,

(154) 3-Z-[1-(4-(2,3,4,5-tetrahydro-azepino(4,5-b)pyrazin-3-yl-methyl)-phenylamino)-1-methyl-methylene] -5-amido-2-indolinone,

(155) 3-Z-[1-(4-(7-amino-2,3,4,5-tetrahydro-azepino(4,5-b)-pyrazin-3-yl-methyl)-phenylamino)-1 -methyl-methylene]-5-amido-2-indolinone,

(156) 3-Z-[1-(4-(2-amino-5,6,7,8-tetrahydro-azepino(4,5-d)thiazol-6-yl-methyl)-phenylamino)-1- methyl-methylene]-5-amido-2-indolinone,

(157) 3-Z-[1-(4-(5,6,7,8-tetrahydro-azepino(4,5-d)thiazol-6-yl-methyl)-phenylamino)-1-methyl-methylene] -5-amido-2-indolinone,

(158) 3-Z-[1-(pyridin-3-yl-amino)-1-methyl-methylene]-5-amido-2-indolinone,

(159) 3-Z-[1-(thiazol-2-yl-amino)-1-methyl-methylene]-5-amido-2-indolinone,

(160) 3-Z-[1-(benzimidazol-2-yl-amino)-1-methyl-methylene]-5-amido-2-indolinone,

(161) 3-Z-[1-(5-methyl-isoxazol-3-yl-amino)-1-methyl-methylene]-5-amido-2-indolinone,

(162) 3-Z-[1-(imidazol-2-yl-amino)-1-methyl-methylene]-5-amido-2-indolinone,

(163) 3-Z-[1-(5-methyl-pyridin-2-yl-amino)-1-methyl-methylene]-5-amido-2-indolinone,

(164) 3-Z-[1-(5-bromo-pyridin-2-yl-amino)-1-methyl-methylene]-5-amido-2-indolinone,

(165) 3-Z-[1-(2-chloro-pyridin-5-yl-amino)-1-methyl-methylene]-5-amido-2-indolinone,

(166) 3-Z-[1-(4-(N-butyl-N-methyl-aminomethyl)-phenylamino)-1-methyl-methylene]-5-amido-2-indolinone,

C23H28N4O2

mass spectrum: m/z = 392 (M+)

(167) 3-Z-[1-(4-(N-isobutyl-aminomethyl)-phenylamino)-1-methyl-methylene]-5-amido-2-indolinone,

C22H26N4O2

mass spectrum: m/z = 378 ((M+)

(168) 3-Z-[1-(4-(N-cyclohexylmethyl-aminomethyl)-phenyl-amino)-1-methyl-methylene]-5-amido-2-indolinone,

C25H30N4O2

mass spectrum: m/z = 418

Rf value: 0.26 (silica gel, methylene chloride/methanol = 4:1)

Example 2

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

2 g of resin produced in accordance with example IVb reacts analogously to example 1 with 2 g of ethyl 4-aminobenzoate in dimethylformamide at 110°C. The wet loaded resin is suspended in 15 ml of dioxane and 15 ml of methanol and stirred for 40 hours with 12 ml of 1N sodium hydroxide solution. The mixture is then neutralized with dilute hydrochloric acid and washed with methylene chloride, methanol and dimethylformamide. 300 mg of resin is then suspended in 3 ml of dimethylformamide and allowed to stand with 0.2 ml of diethylamine, 0.5 g of TBTU (0-benzo-triazol-1-yl-N.N.N'.N'-tetramethyluronium tetrafluoro-borate) and 0.8 ml of N-ethyl-diisopropylamine for 40 hours at room temperature. Finally, the product is separated from the resin as described in Example 1. Yield: 61 mg,

Rf value: 0.30 (silica gel, methylene chloride/methanol = 9:1)

C22H24N4O3

mass spectrum: m/z =392 (M+)

The following compounds were produced analogously to example 2:

(1) 3-Z-[1-(4-benzylcarbamoyl-phenylamino)-1-phenyl-methylene]-5-amido-2-indolinone, was produced analogously to example 2 with benzylamine.

Rf value: 0.30 (silica gel, methylene chloride/methanol = 9:1)

C25H22N4O3

mass spectrum: m/z = 426 (M+)

(2) 3-Z-[1-(4-(N-methoxycarbonylmethyl-carbamoyl)-phenyl-amino)-1-phenyl-methylene]-5-amido-2-indolinone,

was produced analogously to example 2 with benzylamine.

Rf value: 0.50 (silica gel, methylene chloride/methanol = 9:1)

C21H20N4O5

mass spectrum: m/z = 408 (M+)

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

was produced analogously to example 2 with dimethylamine.

Rf value: 0.40 (silica gel, methylene chloride/methanol = 9:1)

C20H20N4O3

mass spectrum: m/z = 364 (M+)

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

was produced analogously to example 2 with 1-(2-amino-ethyl)-piperidine.

Rf value: 0.30 (silica gel, methylene chloride/methanol = 4:1)

C25H29N5O3

mass spectrum: m/z = 448 (M+H+)

(5) 3-Z-[1-(4-(N-methyl-piperazine-carbamoyl)-phenylamino)-1-phenyl-methylene]-5-amido-2-indolinone-trifluoroacetate, was produced analogously to example 2 with N -methyl-piperazine.

Rf value: 0.40 (silica gel, methylene chloride/methanol = 4:1)

C23H25N5O3

mass spectrum: m/z = 419 (M+)

(6) 3-Z-[1-(4-(N-(2-diethylamino-ethyl)-N-methyl-carbamoyl)-phenylamino)-1-phenyl-methylene]-5-amido-2-indolinone-trifluoroacetate ,

was produced analogously to example 2 with N,N-diethyl-N'-methyl-ethylenediamine.

Rf value: 0.20 (silica gel, methylene chloride/methanol = 4:1)

C25H31N5O3

mass spectrum: m/z =449 (M+)

(7) 3-Z-[1-(4-butylcarbamoyl-phenylamino)-1-phenyl-methylene]-5-amido-2-indolinone, was produced analogously to example 2 with butylamine.

Rf value: 0.80 (silica gel, methylene chloride/methanol = 4:1)

C22H24N4O3

mass spectrum: m/z = 392 (M+)

Example 3

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

4.5 g of the resin produced according to example IVb is reacted analogously to example 1 with 3.4 g of 4-(9H-fluoren-9-yl-methoxycarbonyl)-methylamino)-aniline in dimethylformamide. Then the 9H-fluoren-9-yl-methoxycarbonyl group is cleaved with 40 ml of 30% piperidine in dimethylformamide and the resin is washed several times. zatiin 400 mg of resin is suspended in 4 ml of dimethylformamide and 0.3 ml of triethylamine and reacted with 0.3 ml of benzoyl chloride for one hour at room temperature. Finally, the product is cleaved from the resin with trifluoroacetic acid as described in Example 1. Yield: 25 mg,

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

C30H24N4O3

mass spectrum: m/z = 426 (M+)

The following compounds were produced analogously to example 3:

(1) 3-Z-[1-(4-(N-methyl-N-propionyl-amino)-phenylamino)-1-methyl-methylene]-5-iaido-2-indolinone,

was produced analogously to example 3 with propionic acid chloride.

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

C21H22N4O3

mass spectrum: m/z = 378 (M+)

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

was produced analogously to example 3 with butyric acid chloride.

Rf value: 0.28 (silica gel, methylene chloride/methanol = 9:1)

C22H24N4O3

mass spectrum: m/z = 392 (M+)

(3) 3-Z-[1-(4-(N-methyl-N-ethanesulfonyl-amino)phenylamino)-

1-methyl-methylene]-5-amido-2-indolinone, was produced analogously to example 3 with ethanesulfonic acid chloride,

Rf value: 0.30 (silica gel, methylene chloride/methanol = 9:1)

C20H22N4O4S

mass spectrum: m/z = 413 (M-H+)

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

was produced analogously to example 3 with propanesulfonic acid chloride.

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

C21H24N4O4S

mass spectrum: m/z = 451 (M+Na+)

(5) 3-Z-[1-(4-(N-methyl-N-phenylsulfonylamino)-phenylamino-1-methyl-methylene]-5-amido-2-indolinone, was produced analogously to example 3 with phenylsulfonic acid chloride.

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

C24H22N4O4S

mass spectrum: m/z = 462 (M+)

(6) 3-Z-[1-(4-(N-methyl-N-acetyl-amino)-phenylamino)-1-methyl-methylene]-5-amido-2-indolinone, was produced analogously to example 3 with acetyl chloride .

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

C20H20N4O3

mass spectrum: m/z = 364 (M+)

(7) 3-Z-[1-(4-(N-methyl-N-phenylmethylsulfonyl-amino)-phenyl-amino)-1-methyl-methylene]-5-amido-2-indolinone, was produced analogously to example 3 with phenylmethanesulfonic acid chloride.

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

C25H24N4O4S

mass spectrum: m/z = 475 (M-H+)

Example 4

Methyl 3-Z-[1-(4-(N-benzyl-N-methyl-aminomethyl)-phenylamino)-1-methyl-methylene]-2-indolinone-5-carboxylate

8.0 g (28 mmol) of methyl 1-acetyl-3-(1-ethoxy-1-methyl-methylene)-2-indolinone-5-carboxylate is dissolved in 60 ml of dimethylformamide and mixed with 6.3 g (28 mmol) 4-(N-benzyl-N-methyl-aminomethyl)-aniline for 6 hours at 80°C. Then add 30 ml conc. of ammonia and let the mixture stand for 2 hours at 45°C. The solution was evaporated and the residue was washed with ethanol and ether. It is then chromatographed over a small column of silica gel with ethyl acetate/ethanol (9:1). Yield: 8.6 g (70% of theoretical), melting point: 150-152°C,

C27H27N3O3

mass spectrum: m/z = 442 (M+)

The following compounds were produced analogously to example 4:

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

C24H27N3O3

mass spectrum: m/z = 406 (M+H+)

(2) methyl 3-Z-[1-(4-bromo-phenylamino)-1-methyl-methylene]-2-indolinone-5-carboxylate,

C18H15BrN2O3

mass spectrum: m/z = 386/388 (M+)

(3) methyl 3-Z-[1-(4-chloro-phenylamino)-1-methyl-methylene]-2-indolinone-5-carboxylate,

C18H15ClN3O3

mass spectrum: m/z = 342/344 (M+)

(4) methyl 3-Z-[1-(4-(N-methyl-N-methylsulfonyl-amino)-phenylamino)-1-ethyl-methylene]-2-indolinone-5-carboxylate,

C20H21N3O5S

mass spectrum: m/z =415

(5) methyl 3-2-[1-(4-(2,3,4,5-tetrahydro-benzo(d)azepin-3-yl-methyl)-phenylamino)-1-methyl-methylene]-2- indolinone-5-carboxylate,

C29H29N3O2

mass spectrum: m/z = 467 (M+)

Example 5

3-Z-[1-(4-(N-benzyl-N-methyl-aminomethyl)-phenylamino)-1-methyl-methylene]-2-indolinone-5-carboxylic acid

2.3 g (5 mmol) of methyl 3-Z-[1-(4-(N-benzyl-N-methyl-aminomethyl)-phenylamino)-1-methyl-methylene]-2-indolinone-5-carboxylate are dissolved in 50 ml of methanol and 50 ml of dioxane and mixed with 25 ml of 1N sodium hydroxide solution for 1 hour at 70°C. The mixture is then neutralized with 25 ml of 1N hydrochloric acid and evaporated to dryness. The residue is washed several times and evaporated to dryness. Yield: 1.9 g (85% of theoretical),

C26H25N3O3

mass spectrum: m/z = 428 (M+H+)

The following compounds were produced analogously to example 5:

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

C23H25N3O3

mass spectrum: m/z =392 (M+H+)

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

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

Cl7H13ClN2O3

mass spectrum: m/z = 327/329 (M-H+)

(4) 3-Z-[1-(4-(N-methyl-N-methylsulfonyl-amino)-phenylamino)-1-methyl-methylene]-2-indolinone-5-carboxylic acid,

Cl9H19N3O5S

mass spectrum: m/z =401 (M+)

(5) 3-Z-[1-(4-(2,3,4,5-tetrahydro-benzo(d)azepin-3-yl-methyl)-phenylamino)-1-methyl-methylene]-2-indolinone -5-carboxylic acid

C28H27N3O3

mass spectrum: m/z = 453 (M+)

Example 6

3-Z-[1-(4-(N-benzyl-N-methyl-aminomethyl)-phenylamino)-1-methyl-methylene]-2-indolinone-5-diethylcarbamoyl-2-indolinone 0.3 g 3-Z -[1-(4-(N-benzyl-N-methyl-aminomethyl)-phenyl-amino)-1-methyl-methylene]-2-indolinone-2-indolinone-5-carboxylic acid is dissolved with 1.2 g of N-ethyl-diisopropylethylamine in 8 ml of dimethylformamide. Then 0.1 g of diethylamine and 0.4 g of TBTU (O-benzotriazol-1-yl-N.N.N',N'-tetramethyluronium tetrafluoroborate) were added and the mixture was stirred for 20 hours at room temperature. It is then evaporated and the residue is suspended in water and extracted with methylene chloride. The organic phase is evaporated and chromatographed over a silica gel column with methylene chloride/ethanol (19:1).

Utilization: 0.2 g (68% of theoretical),

Rf value: 0.36 (silica gel, methylene chloride/ethanol = 19:1)

C30H34N4O2

mass spectrum: m/z =482 (M+)

The following compounds were produced analogously to example 6:

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

produced from the compound prepared in Example 5(1) and diethylamine.

C27H34N4O2

mass spectrum: m/z =446 (M+)

(2) 3-Z-[1-(4-(N-methyl-N-methylsulfonyl-amino)-phenylamino)-1-methyl-methylene]-2-indolinone-5-diethylcarbamoyl-2-indolinone

produced from the compound prepared in Example 5(4) and diethylamine.

C23H28N4O4S

mass spectrum: m/z = 457 (M+H+)

(3) 3-Z-[1-(4-(2,3,4,5-tetrahydro-benzo(d)azepin-3-yl-methyl)-phenylamino)-1-methyl-methylene]-5-diethylcarbamoyl -2-indolinone,

(4) 3-2-[1-(4-(2,3,4,5-tetrahydro-benzo(d)azepin-3-yl-methyl)-phenylamino)-1-methyl-methylene]-5-dimethyl -carbamoyl-2-indolinone,

(5) 3-Z-[1-(4-(N-phenylmethyl-N-methylamino-methyl)-phenyl-amino)-1-methyl-methylene]-5-methylcarbamoyl-2-indolinone,

(6) 3-Z-[1-(4-(N-phenylmethyl-N-methylamino-methyl)-phenyl-amino)-1-methyl-methylene]-5-dimethylcarbamoyl-2-indolinone,

(7) 3-Z-[1-(4-(N-phenylmethyl-N-methylamino-methyl)-phenyl-amino)-1-methyl-methylene]-5-diethylcarbamoyl-2-indolinone,

(8) 3-Z-[1-(4-(N-phenylmethyl-N-methylamino-methyl)-phenyl-amino)-1-methyl-methylene]-5-propylcarbamoyl-2-indolinone,

(9) 3-Z-[1-(4-(N-phenylmethyl-N-methylamino-methyl)-phenyl-amino)-1-methyl-methylene]-5-dipropylcarbamoyl-2-indolinone,

(10) 3-Z-[1-(4-(dimethylamino-methyl)-phenylamino)-1-methyl-methylene]-5-methylcarbamoyl-2-indolinone,

(11) 3-Z-[1-(4-(dimethylamino-methyl)-phenylamino)-1-methyl-methylene]-5-dimethylcarbamoyl-2-indolinone,

(12) 3-Z-[1-(4-(dimethylamino-methyl)-phenylamino)-1-methyl-methylene]-5-diethylcarbamoyl-2-indolinone,

(13) 3-Z-[1-(4-(dimethylamino-methyl)-phenylamino)-1-methyl-methylene]-5-propylcarbamoyl-2-indolinone,

(14) 3-Z-[1-(4-(dimethylamino-methyl)-phenylamino)-1-methyl-methylene]-5-dipropylcarbamoyl-2-indolinone,

(15) 3-Z-[1-(3-(dimethylamino-methyl)-phenylamino)-1-methyl-methylene]-5-methylcarbamoyl-2-indolinone,

(16) 3-Z-[1-(3-(dimethylamino-methyl)-phenylamino)-1-methyl-methylene]-5-dimethylcarbamoyl-2-indolinone,

(17) 3-Z-[1-(3-(dimethylamino-methyl)-phenylamino)-1-methyl-methylene]-5-diethylcarbamoyl-2-indolinone,

(18) 3-Z-[1-(3-(dimethylamino-methyl)-phenylamino-1-methyl-methylene]-5-propylcarbamoyl-2-indolinone,

(19) 3-Z-[1-(3-(dimethylamino-methyl)-phenylamino)-1-methyl-methylene]-5-dipropylcarbamoyl-2-indolinone,

(20) 3-Z-[1-(4-chloro-phenylamino)-1-methyl-methylene]-5-methyl-carbamoyl-2-indolinone,

(21) 3-Z-[1-(4-chloro-phenylamino)-1-methyl-methylene]-5-dimethyl-carbamoyl-2-indolinone,

(22) 3-Z-[1-(4-chloro-phenylamino)-1-methyl-methylene]-5-diethyl-carbamoyl-2-indolinone,

(23) 3-Z-[1-(4-chloro-phenylamino)-1-methyl-methylene]-5-propyl-carbamoyl-2-indolinone,

(24) 3-Z-[1-(4-chloro-phenylamino)-1-methyl-methylene]-5-di-propyl-carbamoyl-2-indolinone,

(25) 3-Z-(1-phenylamino-1-methyl-methylene)-5-methylcarbamoyl-2-indolinone,

(26) 3-Z-(1-phenylamino-1-methyl-methylene)-5-dimethylcarbamoyl-2-indolinone,

(27) 3-Z-(1-Phenylamino-1-methyl-methylene)-5-diethylcarbamoyl-2-indolinone.

Example 7

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

130 mg of 3-Z-[1-(4-methyl-3-nitro-phenylamino)-1-methyl-methylene]-5-amido-2-indolinone were dissolved in 9 ml of methanol and hydrogenated with 50 mg of Raney nickel at room temperature under 3 bar hydrogen pressure. The catalyst is filtered off and the solution is evaporated.

Utilization: 97 mg (70% of theoretical),

Rf value: 0.60 (silica gel, methylene chloride/ethanol = 4:1)

Cl8H18N4O2

mass spectrum: m/z = 322 (M+)

The following compound was produced analogously to example 7:

(1) 3-Z-[1-(4-(piperidino-methyl)-3-amino-phenylamino)-1-methyl-methylene]-5-amido-2-indolinone, was produced from 3-Z-[1 -(4-(piperidino-methyl)-3-nitro-phenyl-amino)-1-methyl-inethylene]-5-amido-2-indolinone.

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

C23H27N5O2

mass spectrum: m/z = 406 (M+H+)

Example 8

Dry ampoules containing 75 mg of active substance in 10 ml of preparation:

Preparation:

active substance 75.0 mg

mannitol 50.0 mg

water for injections ad 10.0 ml

Preparation:

The active substance and mannitol dissolve in water. After filling, the solution is freeze-dried. To prepare a ready-to-use solution, the product is dissolved in water for injections.

Example 9

Dry ampoules containing 35 mg of active substance in 2 ml

active substance 35.0 mg

mannitol 100.0 mg

water for injections ad 2.0 ml

Preparation:

The active substance and mannitol dissolve in water. After filling, the solution is freeze-dried. To prepare a ready-to-use solution, the product is dissolved in water for injections.

Example 10

Tablet containing 50 mg of active substance

Preparation:

(1) active substance 50.0 mg

(2) lactose 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 together and granulated with an aqueous solution of ingredient (4). Ingredient (5) is added to the dry granulated material. Tablets are pressed from this mixture, flat and hemmed on both sides with a dividing notch on one side. Tablet diameter: 9 mm.

Example 11

Tablet containing 350 mg of active substance

Preparation:

(1) active substance 350.0 mg

(2) lactose 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 together and granulated with an aqueous solution of ingredient (4). Ingredient (5) is added to the dry granulated material. Tablets are pressed from this mixture, flat and hemmed on both sides with a dividing notch on one side. Tablet diameter: 12 mm.

Example 12

Capsules containing 50 mg of active substance

Preparation:

(1) active substance 50.0 mg

(2) dry corn starch 58.0 mg

(3) powdered lactose 50.0 mg

(4) magnesium stearate __2.0 mg

150.0 mg

Preparation:

Component (1) is triturated with (3). This trituration product is added to the mixture of substances (2) and (4) with vigorous stirring.

The resulting powdery mixture is packed using a capsule filling machine into size 3 hard gelatin capsules.

Example 13

Capsules containing 350 mg of active substance

Preparation:

(1) active substance 350.0 mg

(2) dry corn starch 46.0 mg

(3) powdered lactose 30.0 mg

(4) magnesium stearate ___4.0 mg

430.0 mg

Preparation:

Component (1) is triturated with (3). This trituration product is added to the mixture of substances (2) and (4) with vigorous stirring.

The resulting powdery mixture is packed using a capsule filling machine into size 0 hard gelatin capsules.

Example 14

Suppositories containing 100 mg of active substance

1 suppository contains:

active substance 100.0 mg

polyethylene glycol (M.M. 1500) 600.0 mg

polyethylene glycol (M.M. 6000) 460.0 mg

polyethylene sorbitan monostearate __840.0 mg

2,000.0 mg

Preparation:

Polyethylene glycol was dissolved with polyethylene sorbitan monostearate. The ground active substance is homogeneously dispersed in the melt at 40°C. The melt is cooled to at least 38°C and poured into slightly cooled suppository molds.

Claims (13)

1. Substituted indolinones of the general formula [image] indicated by that X denotes an oxygen or sulfur atom, R1 is a hydrogen atom, a C1-4-alkoxy-carbonyl or a C1-4-alkanoyl group, R2 denotes a carboxy or C1-4-alkoxy-carbonyl group or an aminocarbonyl group, optionally substituted with one or two C1-4-alkyl groups, while the substituents may be the same or different, R3 denotes a hydrogen atom or a C1-6-alkyl group which can be substituted in position 2 in relation to the carbon atom of the acupine R3-C(R4NR5)= with fluorine, chlorine or a bromine atom, with hydroxy, C1-3-alkoxy, C1- 3-alkyl-sulfenyl, C1-3-alkylsulfinyl, C1-3-alkylsulfonyl, phenylsulfenyl, phenylsulfinyl, phenylsulfonyl, amino, C1-4-alkylamino, di-(C1-4-alkyl)-amino, C2-5-alkanoyl- amino or N-(C1-3-alkylamino)-C1-5-alkanoylamino group, R4 is a hydrogen atom, a C1-6-alkyl group or a C5-7-cycloalkyl group, optionally substituted with a C1-3-alkyl group, wherein one methylene group is in position 3 or 4 in relation to the carbon atom of the group R3-C( R4NR5)= can be substituted with an imino group optionally substituted with a C1-3-alkyl group, a phenyl or naphthyl group which can be substituted with a fluorine, chlorine, bromine or iodine atom, with a methoxy group optionally substituted with 1 to 3 fluorine atoms, with C2-3-Alkoxy which can be substituted in position 2 or 3 with C1-3-alkylamino, di-(C1-3-alkyl)-amino or 5- to 7-membered cycloalkylenimine group, while additionally one alkyl group in the above the mentioned alkylamino and dialkylamino groups can be substituted with a phenyl group, with trifluoromethyl, amino, C1-3-alkylamino, di-(C1-3-alkyl)-amino, C2-5-alkanoylamino, N-(C1-3-alkyl)-C2-5-alkanoylamino, C1-5-alkylsulfonylamino , N-(C1-3-alkyl) C1-5-alkylsulfonylamino, phenylsulfonylamino, N-(C1-3-alkyl)-phenylsulfonylamino, aminosulfonyl, C1-3-alkylamino-sulfonyl or di-(C1-3-alkyl)- aminosulfonyl group, while additionally one alkyl group in the aforementioned alkylamino and dialkylamino groups can be substituted with a phenyl group, with a carbonyl group substituted with a hydroxy, C1-3-alkoxy, amino, C1-4-alkylamino or N-(C1-5-alkyl)-C1-3-alkylamino group, while additionally the alkyl group in the aforementioned groups can be substituted with a carboxy, C1-3-alkylcarbonyl or phenyl group or in position 2 or 3 with di-(C1-3-alkyl)-amino, piperazine, N-(C1-4-alkyl)-piperazine or 5- to 7- member cycloalkylenimine group, with a C1-3-alkyl group that is substituted with an amino, C1-7-alkylamino, C5-7-cycloalkylamino, C5-7-cycloalkyl-C1-3-alkylamino or phenyl-C1-3-alkylamino group which can additionally be substituted on the nitrogen atom with a C1-3-alkyl group, wherein the hydrogen atoms are completely or partially replaced by fluorine atoms, with a C5-7-cycloalkyl, C2-4-alkenyl or C1-4-alkyl group, while the above-mentioned C1-4-alkyl substituent can in any case be additionally mono-, di- or trisubstituted with a cyano, carboxy, C1-3-alkoxycarbonyl, pyridyl, imidazolyl, benzo[1,3]dioxole or phenyl group, wherein the phenyl the group can be substituted with fluorine, chlorine or bromine atoms, with methyl, methoxy, trifluoromethyl, cyano or nitro groups, and the substituents can be identical or different, or it can be substituted in position 2, 3 or 4 with a hydroxy group, with a C1-4-alkyl group which may be substituted with hydroxy, carboxy, thiomoRfolino, 1-oxido-thiomorpholino, 1,1-dioxido-thiomoRfolino, piperazine, N-(C1-3-alkyl)-piperazino or N-phenyl- piperazine group, with 5- to 7-membered. with a cycloalkenylenimino group or with a 4- to 7-membered cycloalkylenimino group, whereby the above-mentioned 5- to 7-membered cycloalkylenimino groups can be substituted with one or two C1-3-alkyl groups, with a C5-7-cycloalkyl or phenyl group, with With a C1-3-alkyl, C5-7-cycloalkyl, phenyl, carboxy or C1-4-alkoxy-carbonyl group and with a hydroxy group and in the above-mentioned cycloalkylenimino groups, the methylene group adjacent to the nitrogen atom can be replaced with a carbonyl group, with a C1-3-alkyl group which is substituted with a 5- to 7-membered cycloalkylenimine group, while the phenyl group can be mono- or di-substituted as necessary with fluorine, chlorine or bromine atoms or with methyl or methoxy groups, whereby these substituents can be identical or different, or an oxazolo, imidazolo, thiazolo, pyridino, pyrazino or pyrimidino group, optionally substituted with fluorine, chlorine, bromine or iodine atoms or with a methyl, methoxy or amino group, can be fused to the above-mentioned 5- to 7 -members of the cycloalkylenimine group through two adjacent carbon atoms, while, additionally, the above-mentioned monosubstituted phenyl groups can be substituted with a fluorine, chlorine or bromine atom or with a methyl, methoxy or nitro group, A 5-membered heteroaromatic group containing an imino group, an oxygen or sulfur atom, or an imino group, an oxygen or sulfur atom and one or two nitrogen atoms, or a 6-membered heteroaromatic group containing one, two or three nitrogen atoms, while the above-mentioned 5 - and 6-membered heteroaromatic groups can be additionally substituted with a chlorine or bromine atom or with a methyl group, or the phenyl ring can be fused to the above-mentioned 6-membered heteroaromatic groups via two adjacent carbon atoms, and R5 denotes a hydrogen atom or a C1-3-alkyl group. Furthermore, the carboxy, amino or imino groups present in the above-mentioned compound of general formula 1 may be substituted with groups that can be cleaved in vivo, and their isomers and their salts. 2. Substituted indolinones of the general formula 1 according to claim 1, characterized in that X represents an oxygen or sulfur atom, R1 is a hydrogen atom, R2 represents an aminocarbonyl group, R3 represents a hydrogen atom or a C1-4-alkyl group which can be substituted in position 2 in relation to the carbon atom of the group R3-C(R4NR5) = with chlorine or a bromine atom, or with a phenylsulfonyl group, R4 represents a hydrogen atom, a C1-3-alkyl group or a cyclopentyl or cyclohexyl group, optionally substituted with a methyl group, whereby in the cyclopentyl or cyclohexyl group the methylene group is in position 3 or 4 in relation to the carbon atom of the group R3-C(R4NR5) = can be substituted with imino group, optionally substituted with a methyl group, a phenyl group substituted with a fluorine, chlorine, bromine or iodine atom, with a methoxy group optionally substituted with 1 to 3 fluorine atoms, with C2-3-Alkoxy which can be substituted in position 2 or 3 with methylamino, dimethylamino or 5- to 7-membered cycloalkylenimine group, while additionally one methyl group in the above-mentioned amino groups can be substituted with a phenyl group, with trifluoromethyl, amino, C2-5-alkanoylamino, N-(C1-3-alkyl)-C2-5-alkanoylamino, C1-5-alkylsulfonylamino, N-(C1-3-alkyl)-C1-5-alkylsulfonylamino, phenylsulfonylamino , N-(C1-3-alkyl)-phenylsulfonylamino or aminosulfonyl group, while additionally one alkyl group in the aforementioned alkylamino and dialkylamino groups can be substituted with a phenyl group, with a carbonyl group substituted with a hydroxy, C1-3-alkoxy, amino, C1-4-alkylamino or N-(C1-5-alkyl)-C1-3-alkylamino group, while additionally the alkyl group in the aforementioned groups can be substituted with a carboxy, C 1-3 -alkoxycarbonyl or phenyl group or in position 2 or 3 with di-(C 1-3 -alkyl)-amino, piperazine, N-(C 1-3 -alkyl)-piperazine or 5- to 7- member cycloalkylenimine group, with a C1-3-alkyl group that is substituted with an amino, C1-7-alkylamino, C5-7-cycloalkylamino, C5-7-cycloalkyl-C1-3-alkylamino or phenyl-C1-3-alkylamino group, which can additionally be by substituents on the nitrogen atom with a C1-3-alkyl group, whereby the hydrogen atoms are completely or partially replaced by fluorine atoms, with a C5-7-cycloalkyl, C2-4-alkenyl or C1-4-alkyl group, while The above-mentioned C1-4-alkyl substituent can in any case be additionally substituted with a cyano, carboxy, C1-3-alkoxycarbonyl, pyridyl, imidazolyl, benzo-[1,3]dioxole or phenyl group, whereby the phenyl group can be substituted with with fluorine, chlorine or bromine atoms, or with a methyl, methoxy, cyano, trifluoromethyl or nitro group, or di- or trisubstituted with fluorine, chlorine or bromine atoms or with methyl or methoxy groups, and the substituents may be identical or different, or may be substituted in position 2, 3 or 4 with a hydroxy group, with a C1-3-alkyl group, which may be substituted with hydroxy, carboxy, thiomoRfolino, 1-oxido-thiomorpholino, 1,1-dioxido-thiomorpholino, piperazine, N-(C1-3-alkyl)-piperazino or N-phenyl -piperazine group, with a 5- to 7-membered cycloalkenylenimino group or with a 4- to 7-membered cycloalkylenimino group, whereby the aforementioned 5- to 7-membered cycloalkylenimino groups can be substituted with one or two C1-3-alkyl groups, with a cyclohexyl or phenyl group, with a C1-3-alkyl, cyclohexyl, phenyl, carboxy or C1-4-alkoxy-carbonyl group and with a hydroxy group, and in the above-mentioned cycloalkylenimine groups, the methylene group adjacent to the nitrogen atom can be replaced with a carbonyl group , with a C1-3-alkyl group which is substituted with a 5- to 7-membered cycloalkylenimine group, while the phenyl group can be mono- or di-substituted as necessary with fluorine, chlorine or bromine atoms or with methyl or methoxy groups, whereby these substituents can be identical or different, or a pyrazino or thiazolo group, optionally substituted with an amino group, can be fused to the above mentioned 5- to 7-membered cycloalkylenimine groups via two adjacent carbon atoms, while additionally the above-mentioned monosubstituted phenyl groups can be substituted with a fluorine, chlorine or chlorine atom or with a methyl, methoxy or nitro group, pyridyl group, optionally substituted with a chlorine or bromine atom or with a methyl group, an oxazolyl, isoxazolyl, imidazolyl or thiazolyl group, optionally substituted with a methyl group, to which the phenyl ring may be fused via two adjacent carbon atoms, and R5 represents a hydrogen atom or a C1-3-alkyl group, and their isomers and their salts. 3. Substituted indolinones of the general formula I according to claim 2, characterized in that R5 is in the 5 position. 4. Substituted indolinones of the general formula I according to claim 1, characterized in that X represents an oxygen atom, R1 is a hydrogen atom, R2 in position 5 denotes an aminocarbonyl group, R3 is a hydrogen atom or a C1-4-alkyl group which can be terminally substituted with a chlorine or bromine atom or with a phenylsulfonyl group, R4 is a hydrogen atom, a C1-3-alkyl group or a cyclopentyl or cyclohexyl group optionally substituted with a methyl group, while in the cyclohexyl group the methylene group in position 4 in relation to the carbon atom of the group R3-C(R4NR5)= can be replaced with an imino group, optionally substituted with a methyl group, a phenyl group which may be substituted with a fluorine, chlorine, bromine or iodine atom, with a methyl or ethyl group, which in any case can be substituted with C1-3-alkylamino, di-(C1-3-alkyl)-amino, thiomorpholino, 1-oxido-thiomorpholino, 1,1-dioxido-thiomorpholino, N- phenyl-piperazine, with a 5- to 6-membered cyclo-alkenylenimino group or with a 5- to 7-membered cycloalkylene-imino group, while the aforementioned 5- to 7-membered cyclo-alkyleneimino groups can be substituted with one or two methyl groups, with a cyclohexyl or phenyl group, with a methyl, cyclohexyl or phenyl group and with a hydroxy group, or with a methyl or ethyl group that can be substituted with a phenyl group that is substituted with a 5- to 7-membered cycloalkyleneimino group, while additionally the phenyl ring is fused to the above-mentioned cycloalkylene-imino group via 2 adjacent carbon atoms, with a methyl or ethyl group substituted with an amino, methylamino or ethylamino group, each of which is additionally substituted on the amino nitrogen atom with a benzyl or phenylethyl group, whereby the phenyl group in the above-mentioned groups can be monosubstituted with a fluorine, chlorine or bromine atom or with with a methyl, methoxy, cyano, trifluoromethyl or nitro group, or is di- or tri-substituted with fluorine, chlorine or bromine atoms or with methyl or methoxy groups, and these substituents can be identical or different, while additionally the above-mentioned monosubstituted phenyl groups may be substituted with a fluorine, chlorine or bromine atom or with a methyl, methoxy or nitro group, and R5 represents a hydrogen atom or a C1-3-alkyl group, their isomers and their salts. 5. Substituted indolinones of the general formula 1 according to claim 1, characterized in that X represents an oxygen atom, R1 is a hydrogen atom, R2 in position 5 denotes an aminocarbonyl group, R3 is a hydrogen atom or a C1-3-alkyl group, R4 is a phenyl group that can be substituted with a fluorine, chlorine, bromine or iodine atom, with a methyl or ethyl group, which in any case can be substituted with C1-3-alkylamino, di-(C1-3-alkyl)-amino, thiomorpholino, 1-oxido-thiomorpholino, 1,1-dioxido-thiomorpholino, N- phenyl-piperazine, with a 5- to 6-membered cyclo-alkenylenimino group or with a 5- to 7-membered cycloalkylene-imino group, while the aforementioned 5- to 7-membered cyclo-alkyleneimino groups can be substituted with one or two methyl groups, with a cyclohexyl or phenyl group, with a methyl, cyclohexyl or phenyl group. group and with a hydroxy group, or with a methyl or ethyl group that can be substituted with a phenyl group, which is substituted in position 4 with a 5- to 7-membered cycloalkylenimine group, while additionally the phenyl ring is fused to the aforementioned cycloalkylenimine groups via 2 adjacent carbon atoms, with a methyl or ethyl group substituted with an amino, methylamino or ethylamino group, each of which is additionally substituted on the amino nitrogen atom with a benzyl or phenylethyl group, and where the phenyl group may be monosubstituted with a fluorine, chlorine or bromine atom or with methyl, methoxy, cyano, trifluoromethyl or nitro group, disubstituted with methyl or methoxy groups or trisubstituted with methyl or methoxy groups, and the substituents can be identical or different, while additionally the above-mentioned monosubstituted phenyl groups may be substituted with a fluorine, chlorine or bromine atom or with a methyl, methoxy or nitro group, and R5 represents a hydrogen atom or a C1-3-alkyl group, their isomers and their salts. 6. The following substituted indolinones of the general formula 1 according to claim 1, characterized in that they are (a) 3-Z-[1-(4-piperidinomethyl-phenylamino)-1-methyl-methylene]-5-amido-2-indolinone, (b) 3-Z-[1-(4-bromo-phenylamino)-1-methyl-methylene]-5-amido-2-indolinone, (c) 3-Z-[1-(4-piperidinomethyl-phenylamino)-1-butyl-methylene]-5-amido-2-indolinone, (d) 3-Z-(1-(4-chlorophenylamino)-1-methyl-methylene]-5-amido-2-indolinone and (e) 3-Z-(1-phenylamino-methylene)-5-amido-2-indolinone, (f) 3-Z-[1-(4-(N-benzyl-N-methyl-aminomethyl)-phenylamino)-1-methyl-methylene]-5-amido-2-indolinone, (g) 3-Z-[1-(4-(N-(4-chlorobenzyl)-aminomethyl)-phenylamino)-1-methyl-methylene]-5-amido-2-indolinone, (h) 3-Z-[1-(4-(N-benzyl-N-ethyl-aminomethyl)-phenylamino]-1-methyl-methylene]-5-amido-2-indolinone, (i) 3-Z-[1-(4-(N-benzyl-aminomethyl)-phenylamino)-1-methyl-methylene]-5-amido-2-indolinone, (j) 3-Z-[1-(4-(N-benzyl-N-methyl-aminomethyl)-phenyl-amino)-methylene]-5-amido-2-indolinone, (k) 3-Z-[1-(4-(2,3,4,5-tetrahydro-benzo(d)azepin-3-yl-methyl)-phenylamino)-1-methyl-methylene]-5-amido -2-indolinone, (1) 3-Z-[1-(4-piperidinormethyl-3-nitro-phenylamino)-1-methyl-methylene]-5-amido-2-indolinone and (m) 3-Z-[1-(4-methyl-3-nitro-phenylamino)-1-methyl-methylene)-5-amido-2-indolinone, as well as their isomers and their salts. 7. A compound characterized by the fact that it is 3-Z-[1-(4-(N-benzyl-N-methyl-aminomethyl)-phenylamino)-1-methyl-methylene]-5-amido-2-indolinone and its salts. 8. A compound characterized by the fact that it is 3-Z-[1-(4-(2,3,4,5-tetrahydro-benzo(d)azepin-3-ylmethyl)-phenylamino)-1-methyl-methylene ]-5-amido-2-indolidinon and its salts. 9. Physiologically acceptable salts indicated by the fact that they are salts of compounds in accordance with requirements 1 to 8. 10. Pharmaceutical preparations, characterized in that they contain a compound according to at least one of claims 1 to 8 or a salt according to claim 9 and one and/or more inert carriers and/or diluents. 11. Use of a compound according to at least one of claims 1 to 8, characterized in that it is used for the production of pharmaceutical preparations suitable for the treatment of excessive or abnormal cell proliferation. 12. Process for the production of pharmaceutical preparations according to claim 10, characterized in that the compound according to at least one claim from 1 to 8 or its salt according to claim 9 is incorporated by a non-chemical method into one or more inert carriers and/or diluents. 13. Process for the production of compounds according to claims 1 to 9, characterized in that a) a compound of the general formula [image] where X and R 3 are defined as in claims 1 to 8, R2' has the meaning given for R2 in claims 1 to 8, R6 is a hydrogen atom or a nitrogen protecting group atom of the lactam group, while one of the groups R2 or rg it can also indicate a connection with a solid phase formed during processing if necessary via a spacer and the remaining group R2' or R 6 is defined as before, and Z 1 denotes a halogen atom, hydroxy, alkoxy or aralkyl group, reacts with an amine of the general formula [image] where R 4 and R 5 are defined as in claims 1 to 8, and if necessary, any protecting group used or the compound thus obtained is cleaved from the solid phase, or to prepare a compound of the general formula 1 in which R 2 denotes the aminocarbonyl groups mentioned in claims 1 to 8, a compound of the general formula [image] in which R1 and R3 are defined as in claims 1 to 6, or a reactive derivative thereof, is amidated with an amine of the general formula H-(R7NR8) (V) in which R 7 and R 8 , which may be identical or different, denote hydrogen atoms or C 1-3 -alkyl groups, and then, preferably, the thus obtained compound of the general formula I containing an alkoxycarbonyl group can be converted by hydrolysis into the corresponding carboxy compound, or the thus obtained compound of the general formula I containing an amino alkylamino group can be converted by alkylation or reductive alkylation into the corresponding alkylamino or dialkylamino compound, or the thus obtained compound of the general formula I containing an amino alkylamino group can be converted by acylation into the corresponding acyl compound, or the thus obtained compound of the general formula I containing a carboxy group can be converted by esterification or amidation into the corresponding ester or aminocarbonyl compound, or the thus obtained compound of the general formula I containing a nitro group can be converted by reduction into the corresponding amino compound, or if necessary, each protecting group, used during the reactions to protect reactive groups, is cleaved off, or the thus obtained compound of general formula I is separated into its stereoisomers, or the thus obtained compound of the general formula I is translated into its salts, more precisely into salts for pharmaceutical use, into its physiologically acceptable salts with an inorganic or organic acid or base.