# Patent

## Title
Substituted indolinones

## Abstract

The present invention relates to indolinones substituted in the 6-position of general formula 




wherein

R1 to R5 and X are defined as in claim 1, the isomers and the salts thereof, particularly the physiologically acceptable salts thereof which have valuable pharmacological properties, in particular an inhibiting effect on various receptor tyrosine kinases and cyclin/CDK complexes and on the proliferation of endothelial cells and various, pharmaceutical compositions containing these compounds, their use and processes for preparing them.

## Background
The present invention relates to new indolinones substituted in the 6-position of general formula 




the tautomers, diastereomers, enantiomers and mixtures thereof and the salts thereof, particularly the physiologically acceptable salts thereof which have valuable properties.

The above compounds of general formula I wherein R1 denotes a hydrogen atom or a prodrug group have valuable pharmacological properties, in particular an inhibiting effect on various kinases, especially receptor tyrosine kinases such as VEGFR2, VEGFR3, PDGFRα, PDGFRβ, FGFR1, FGFR3, EGFR, HER2, IGF1R and HGFR, as well as complexes of CDK's (Cyclin Dependent Kinases) such as CDK1, CDK2, CDK3, CDK4, CDK5, CDK6, CDK7, CDK8 and CDK9 with their specific cyclins (A, B 1, B2, C, D1, D2, D3, E, F, G1, G2, H, I and K) and on viral cyclin (cf. L. Mengtao in J. Virology 71(3), 1984-1991 (1997)), on the proliferation of cultivated human cells, in particular endothelial cells, e.g. in angiogenesis, but also on the proliferation of other cells, in particular tumour cells.
The other compounds of the above general formula I wherein R1 does not denote a hydrogen atom or a prodrug group are valuable intermediate products for preparing the abovementioned compounds.
The present invention thus relates to the above compounds of general formula I, whilst those compounds wherein R1 denotes a hydrogen atom or a prodrug group have valuable pharmacological properties, pharmaceutical compositions containing the pharmacologically active compounds, the use thereof and processes for preparing them.
In the above general formula I
X denotes an oxygen or sulphur atom,
R1 denotes a hydrogen atom or a group which can be cleaved in vivo such as a C1-4-alkoxycarbonyl or C2-4-alkanoyl group,
R2 denotes a carboxy group, a straight-chain or branched C1-6-alkoxycarbonyl group, a C4-7-cycloalkoxycarbonyl or an aryloxycarbonyl group,
R3 denotes a hydrogen atom, a C1-6-alkyl, C3-7-cycloalkyl, trifluoromethyl or heteroaryl group,
a phenyl or naphthyl group, or a phenyl or naphthyl group mono- or disubstituted by a fluorine, chlorine, bromine or iodine atom, by a trifluoromethyl, C1-3-alkyl or C1-3-alkoxy group, while in the event of disubstitution the substituents may be identical or different,
R4 denotes a phenyl, pyrrolyl or furanyl group substituted by the group R6, which may additionally be mono- or disubstituted by fluorine, chlorine, bromine or iodine atoms, by C1-5-alkyl, trifluoromethyl, hydroxy, C1-3-alkoxy, carboxy, C1-3-alkoxycarbonyl, amino, acetylamino, C1-3-alkyl-sulphonylamino, aminocarbonyl, C1-3-alkyl-aminocarbonyl, di-(C1-3-alkyl)-aminocarbonyl, aminosulphonyl, C1-3-alkyl-aminosulphonyl, di-(C1-3-alkyl)-aminosulphonyl, nitro or cyano groups, while the substituents may be identical or different and wherein
R6 denotes an aminocarbonyl, C1-4-alkylamino-carbonyl, N—(C1-5-alkyl)-N—C1-3-alkyl-aminocarbonyl, C3-7-cycloalkylamino-carbonyl, N—(C1-5-alkyl)-N—C3-7-cycloalkylamino-carbonyl, (phenyl-C1-3-alkyl)amino-carbonyl, N—(C1-3-alkyl)-N-phenyl-C1-3-alkylamino-carbonyl group,
a C1-3-alkylaminocarbonyl or N—(C1-3-alkyl)-N—C1-3-alkylaminocarbonyl group wherein one or two alkyl moieties are substituted independently of one another by a nitro, cyano, carbamoyl, N—(C1-3-alkyl)-carbamoyl, di-N—(C1-3-alkyl)-carbamoyl, carboxy or C1-3-alkoxycarbonyl group or are substituted in the 2- or 3-position by an amino, (C1-3-alkyl)-amino, di-(C1-3-alkyl)-amino, (C1-4-alkoxycarbonyl)-amino, N—(C1-4-alkoxycarbonyl)-N—(C1-3-alkyl)-amino, piperazino, N—(C1-3-alkyl)-piperazino, a 4- to 7-membered cycloalkyleneimino group, a hydroxy or methoxy group,
a 4- to 7-membered cycloalkyleneiminocarbonyl group wherein

    
    
        the cycloalkylene moiety may be fused to a phenyl ring via two adjacent ring atoms or may form a bridge to a methylene or ethylene group via two non-adjacent ring atoms or
        one or two hydrogen atoms may each be replaced by a C1-3-alkyl group and/or
        in each case the methylene group in the 4 position of a 6- or 7-membered cyclo-alkyleneiminocarbonyl group may be substituted by a carboxy, C1-4-alkoxycarbonyl, aminocarbonyl, C1-3-alkylaminocarbonyl, di-(C1-3-alkyl)-aminocarbonyl, di-(C1-3-alkyl)-amino-C1-3-alkyl, di-(C1-3-alkyl)-amino, phenyl-C1-3-alkylamino or N—(C1-3-alkyl)-N-phenyl-C1-3-alkylamino group, a hydroxy or methoxy group or
        may be replaced by an oxygen or sulphur atom, by a sulphinyl, sulphonyl or —NH group or by a nitrogen atom which is substituted by a C1-3-alkyl, phenyl, C1-3-alkyl-carbonyl, C1-4-alkoxy-carbonyl, di-(C1-3-alkyl)-amino-C1-3-alkyl, ω-hydroxy-C2-3-alkyl or benzoyl group,
        while all the single-bonded or fused phenyl groups contained in the groups mentioned under R6 may be mono- or disubstituted by fluorine, chlorine, bromine or iodine atoms, by C1-5-alkyl, trifluoromethyl, hydroxy, C1-3-alkoxy, carboxy, C1-3-alkoxycarbonyl, aminocarbonyl, C1-4-alkylamino-carbonyl, di-(C1-4-alkyl)-amino-carbonyl, aminosulphonyl, C1-3-alkyl-aminosulphonyl, di-(C1-3-alkyl)-aminosulphonyl, C1-3-alkyl-sulphonylamino, nitro or cyano groups, while the substituents may be identical or different, or two adjacent hydrogen atoms of the phenyl groups may be replaced by a methylenedioxy group,

and

    
    


R5 denotes a hydrogen atom or a C1-3-alkyl group,
while by the term aryl group is meant a phenyl or naphthyl group optionally mono- or disubstituted by a fluorine, chlorine, bromine or iodine atom, by a cyano, trifluoromethyl, nitro, carboxy, aminocarbonyl, C1-3-alkyl or C1-3-alkoxy group and
by the term heteroaryl group is meant a monocyclic 5- or 6-membered heteroaryl group optionally substituted in the carbon skeleton by a C1-3-alkyl group, wherein

    
    
        the 6-membered heteroaryl group contains one, two or three nitrogen atoms and
        the 5-membered heteroaryl group contains an imino group optionally substituted by a C1-3-alkyl or phenyl-C1-3-alkyl group, an oxygen or sulphur atom or
        an imino group optionally substituted by a C1-3-alkyl or phenyl-C1-3-alkyl group or an oxygen or sulphur atom and additionally a nitrogen atom or
        an imino group optionally substituted by a C1-3-alkyl or phenyl-C1-3-alkyl group and two nitrogen atoms,
        and moreover a phenyl ring may be fused to the abovementioned monocyclic heterocyclic groups via two adjacent carbon atoms and the bond is via a nitrogen atom or via a carbon atom of the heterocyclic moiety of a fused phenyl ring,
    
    


the hydrogen atoms in the abovementioned alkyl and alkoxy groups or in the alkyl moieties contained in the above-defined groups of formula I may be wholly or partly replaced by fluorine atoms,
the saturated alkyl and alkoxy moieties containing more than 2 carbon atoms present in the groups defined above, also include the branched isomers thereof such as for example the isopropyl, tert.butyl, isobutyl group, unless otherwise stated, and
wherein additionally the hydrogen atom of any carboxy group present or a hydrogen atom bound to a nitrogen atom, for example an amino, alkylamino or imino group or a saturated N-heterocycle such as the piperidinyl group, may be replaced in each case by a group which can be cleaved in vivo,
the tautomers, diastereomers, enantiomers and mixtures thereof and the salts thereof.
By a group which can be cleaved in vivo from an imino or amino group is meant, for example, a hydroxy group, an acyl group such as the benzoyl or pyridinoyl group or a C1-16-alkanoyl group such as the formyl, acetyl, propionyl, butanoyl, pentanoyl or hexanoyl group, an allyloxycarbonyl group, a C1-16-alkoxycarbonyl group such as the methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, tert.butoxycarbonyl, pentoxycarbonyl, hexyloxycarbonyl, octyloxycarbonyl, nonyloxycarbonyl, decyloxycarbonyl, undecyloxycarbonyl, dodecyloxycarbonyl or hexadecyloxycarbonyl group, a phenyl-C1-6-alkoxycarbonyl group such as the benzyloxycarbonyl, phenylethoxycarbonyl or phenylpropoxycarbonyl groups, a C1-3-alkylsulphonyl-C2-4-alkoxycarbonyl, C1-3-alkoxy-C2-4-alkoxy-C2-4-alkoxycarbonyl or ReCO—O—(RfCRg)—O—CO group wherein

    
    
        Re denotes a C1-8-alkyl, C5-7-cycloalkyl, phenyl or phenyl-C1-3-alkyl group,
        Rf denotes a hydrogen atom, a C1-3-alkyl, C5-7-cycloalkyl or phenyl group and
        Rg denotes a hydrogen atom, a C1-3-alkyl or ReCO—O—(RfCRg)—O group wherein Re to Rg are as hereinbefore defined,
    
    


wherein additionally the amino group may be a phthalimido group, while the ester groups mentioned above may also be used as a group which can be converted in vivo into a carboxy group.
An essential feature of the present invention is that R6 denotes an unsubstituted aminocarbonyl group or an aminocarbonyl group which is substituted as defined hereinbefore or hereinafter.
Preferred compounds of general formula I are those wherein
X denotes an oxygen atom,
R1 denotes a hydrogen atom, a C1-4-alkoxycarbonyl or C2-4-alkanoyl group,
R2 denotes a carboxy group or a straight-chain or branched C1-4-alkoxycarbonyl group,
R3 denotes a hydrogen atom, a C1-6-alkyl or C3-7-cycloalkyl group,
a phenyl or naphthyl group, or a phenyl or naphthyl group mono- or disubstituted by a fluorine, chlorine or bromine atom, by a trifluoromethyl, C1-3-alkyl or C1-3-alkoxy group, while in the case of disubstitution the substituents may be identical or different,
R4 denotes a furanyl group substituted by an aminocarbonyl, C1-4-alkylaminocarbonyl or N—(C1-4-alkyl)-N—C1-3-alkylaminocarbonyl group, wherein the C1-4-alkylaminocarbonyl or N—(C1-4-alkyl)-N—C1-3-alkylaminocarbonyl group may be substituted from position 2 in one or both alkyl moieties by an amino, C1-3-alkylamino or di-(C1-3-alkyl)amino group,
a pyrrolyl group substituted by an aminocarbonyl, C1-4-alkylaminocarbonyl or N—(C1-4-alkyl)-N—C1-3-alkylaminocarbonyl group, wherein the C1-4-alkylaminocarbonyl or N—(C1-4-alkyl)-N—C1-3-alkylaminocarbonyl group may be substituted from position 2 in one or both alkyl moieties by an amino, C1-3-alkylamino or di-(C1-3-alkyl)amino group and the nitrogen atom of the pyrrolyl ring is optionally substituted by a C1-3-alkyl group, or
a phenyl group substituted by the group R6, which may additionally be mono- or disubstituted by fluorine, chlorine or bromine atoms, by C1-5-alkyl, trifluoromethyl, hydroxy, C1-3-alkoxy, carboxy, C1-3-alkoxycarbonyl, amino, acetylamino, C1-3-alkyl-sulphonylamino, aminocarbonyl, C1-3-alkyl-aminocarbonyl, di-(C1-3-alkyl)-aminocarbonyl, aminosulphonyl, C1-3-alkyl-aminosulphonyl, di-(C1-3-alkyl)-aminosulphonyl, nitro or cyano groups, while the substituents may be identical or different and wherein
R6 denotes an aminocarbonyl, C1-4-alkylamino-carbonyl, N—(C1-5-alkyl)-N—C1-3-alkyl-aminocarbonyl, C3-7-cycloalkylamino-carbonyl, N—(C1-5-alkyl)-N—C3-7-cycloalkylamino-carbonyl, (phenyl-C1-3-alkyl)amino-carbonyl, N—(C1-3-alkyl)-N-phenyl-C1-3-alkyl-amino-carbonyl group,
a C1-3-alkylaminocarbonyl or N—(C1-3-alkyl)-N—C1-3-alkylaminocarbonyl group wherein one or two alkyl moieties are substituted independently of one another by a nitro, cyano, carbamoyl, N—(C1-3-alkyl)-carbamoyl, di-N—(C1-3-alkyl)-carbamoyl, carboxy or C1-3-alkoxycarbonyl group or are substituted in the 2- or 3-position by an amino, (C1-3-alkyl)-amino, di-(C1-3-alkyl)-amino, (C1-4-alkoxycarbonyl)-amino, N—(C1-4-alkoxycarbonyl)-N—(C1-3-alkyl)-amino, piperazino, N—(C1-3-alkyl)-piperazino, a piperazinyl or piperidinyl group, a hydroxy or methoxy group,
a 4- to 7-membered cycloalkyleneiminocarbonyl group wherein

    
    
        the cycloalkylene moiety may be fused to a phenyl ring via two adjacent ring atoms or via two non-adjacent ring atoms may form a bridge to a methylene or ethylene group or
        one or two hydrogen atoms may each be replaced by a C1-3-alkyl group and/or in each case the methylene group in the 4 position of a 6- or 7-membered cyclo-alkyleneiminocarbonyl group may be substituted by a carboxy, C1-4-alkoxycarbonyl, aminocarbonyl, C1-3-alkylaminocarbonyl, di-(C1-3-alkyl)-aminocarbonyl, di-(C1-3-alkyl)-amino-C1-3-alkyl, di-(C1-3-alkyl)-amino, phenyl-C1-3-alkylamino or N—(C1-3-alkyl)-N-phenyl-C1-3-alkylamino group, a hydroxy or methoxy group or
        may be replaced by an oxygen or sulphur atom, by a sulphinyl, sulphonyl or —NH group or by a nitrogen atom, which is substituted by a C1-3-alkyl, phenyl, C1-3-alkyl-carbonyl, C1-4-alkoxy-carbonyl, di-(C1-3-alkyl)-amino-C1-3-alkyl, ω-hydroxy-C2-3-alkyl or benzoyl group,

and

    
    


R5 denotes a hydrogen atom or a C1-3-alkyl group,
wherein the hydrogen atoms in the abovementioned alkyl and alkoxy groups or in the alkyl moieties contained in the above-defined groups of formula I may be wholly or partly replaced by fluorine atoms,
the saturated alkyl and alkoxy moieties containing more than 2 carbon atoms present in the groups defined above also include the branched isomers thereof such as for example the isopropyl, tert.butyl, isobutyl group, unless otherwise stated, and
additionally the hydrogen atom of any carboxy group present or a hydrogen atom bound to a nitrogen atom, for example an amino, alkylamino or imino group or a saturated N-heterocycle such as the piperidinyl group, may be replaced in each case by a group which can be cleaved in vivo,
the tautomers, diastereomers, enantiomers and mixtures thereof and the salts thereof.
A preferred sub-group relates to compounds of general formula I wherein
X denotes an oxygen atom,
R1 denotes a hydrogen atom,
R2 denotes a carboxy group or a C1-2-alkoxycarbonyl group,
R3 denotes a phenyl or naphthyl group, or a phenyl group monosubstituted by a fluorine, chlorine or bromine atom, by a trifluoromethyl, C1-3-alkyl or C1-3-alkoxy group,
R4 denotes a pyrrolyl group substituted by an aminocarbonyl, C1-4-alkylaminocarbonyl or N—(C1-4-alkyl)-N—C1-3-alkylaminocarbonyl group, wherein the C1-4-alkylaminocarbonyl or N—(C1-4-alkyl)-N—C1-3-alkylaminocarbonyl group may be substituted from position 2 in one or both alkyl moieties by an amino, C1-3-alkylamino or di-(C1-3-alkyl)amino group and the nitrogen atom of the pyrrolyl ring is optionally substituted by a C1-3-alkyl group, or
a phenyl group substituted in the 3- or 4-position by the group R6, wherein
R6 denotes an aminocarbonyl, C1-4-alkylamino-carbonyl, N—(C1-3-alkyl)-N—C1-3-alkyl-aminocarbonyl, C5-6-cycloalkylamino-carbonyl, N—(C1-5-alkyl)-N—C5-6-cycloalkylamino-carbonyl group,
a C1-3-alkylaminocarbonyl or N—(C1-3-alkyl)-N—C1-3-alkylaminocarbonyl group wherein one or two alkyl moieties are substituted independently of one another by a carbamoyl, N—(C1-3-alkyl)-carbamoyl, di-N—(C1-3-alkyl)-carbamoyl, C1-3-alkoxycarbonyl group or are substituted in the 2- or 3-position by an amino, (C1-3-alkyl)-amino, di-(C1-3-alkyl)-amino, (C1-4-alkoxycarbonyl)-amino, N—(C1-4-alkoxycarbonyl)-N—(C1-3-alkyl)-amino, piperazino, N—(C1-3-alkyl)-piperazino, a piperazinyl or piperidinyl group, a hydroxy or methoxy group,
a piperidinocarbonyl, piperazinocarbonyl, homopiperazinocarbonyl or 2,3,4,5-tetrahydro-1(H)-azepino-carbonyl group,

    
    
        which may be fused to a phenyl ring via two adjacent unsubstituted carbon atoms or
        may be substituted in the 4 position by a C1-3-alkyl, C1-4-alkoxycarbonyl, di-(C1-3-alkyl)-amino, di-(C1-3-alkyl)-amino-C1-3-alkyl, 2-hydroxy-ethyl, hydroxy or methoxy group,
    
    


or a 2,5-diaza-bicyclo[2.2.1]hept-2-yl-carbonyl group which may be substituted in the 5 position by a C1-3-alkyl group,
and
R5 denotes a hydrogen atom or a C1-3-alkyl group,
wherein the hydrogen atoms in the abovementioned methyl and methoxy groups may be replaced by 1, 2 or 3 fluorine atoms, and
the saturated alkyl and alkoxy moieties containing more than 2 carbon atoms which are present in the groups defined above also include the branched isomers thereof, such as, for example, the isopropyl, tert.butyl and isobutyl group,
the tautomers, diastereomers, enantiomers and mixtures thereof and the salts thereof.
Particularly preferred compounds of general formula I are those wherein
X denotes an oxygen atom,
R1 and R5 each denote a hydrogen atom,
R2 denotes a methoxycarbonyl group,
R3 denotes a phenyl group and
R4 denotes a phenyl group which is monosubstituted in the 3- or 4-position by the group R6, wherein
R6 denotes an aminocarbonyl, C1-3-alkylamino-carbonyl, N—(C1-5-alkyl)-N—C1-3-alkyl-aminocarbonyl, cyclohexylaminocarbonyl, N—(C1-5-alkyl)-N-cyclohexylaminocarbonyl, phenyl-C1-3-alkylamino-carbonyl, N—(C1-3-alkyl)-N-phenyl-C1-3-alkylamino-carbonyl,
a piperidinocarbonyl, 4-hydroxy-piperidinocarbonyl, 4-[di-(C1-3-alkyl)-amino]-piperidinocarbonyl, 4-[di-(C1-3-alkyl)-amino-C1-3-alkyl]-piperidinocarbonyl, piperazinocarbonyl, N—(C1-3-alkyl)-piperazinocarbonyl, N—(C1-4-alkoxycarbonyl)-piperazinocarbonyl, N-[di-(C1-3-alkyl)-amino-C1-3-alkyl]-piperazinocarbonyl, N-(2-hydroxy-ethyl)-piperazinocarbonyl, homopiperazinocarbonyl, N—(C1-3-alkyl)-homopiperazinocarbonyl, 2,3,4,5-tetrahydro-1(H)-benzo[d]azepino-carbonyl or 5-methyl-2,5-diaza-bicyclo[2.2.1]hept-2-yl-carbonyl group,
a C1-3-alkylaminocarbonyl or N—(C1-5-alkyl)-N—C1-3-alkylaminocarbonyl group wherein one or two alkyl moieties are substituted by a carbamoyl group or are substituted in the 2-or 3-position by an amino, (C1-3-alkyl)-amino, di-(C1-3-alkyl)-amino, hydroxy or methoxy group,
the tautomers, diastereomers, enantiomers and mixtures thereof and the salts thereof.
The following are mentioned as examples of most particularly preferred compounds:
(a) methyl 3-(Z)-[1-{4-[N-(2-dimethylamino-ethyl)-N-methyl-carbamoyl]-phenylamino}-1-phenyl-methylidene]-2-indolinone-6-carboxylate
(b) methyl 3-(Z)-[1-{4-[N-(3-dimethylamino-propyl)-N-methyl-carbamoyl]-phenylamino}-1-phenyl-methylidene]-2-indolinone-6-carboxylate
(c) methyl 3-(Z)-[1-{4-[(4-methyl-piperazin-1-yl)-carbonyl]-phenylamino}-1-phenyl-methylidene]-2-indolinone-6-carboxylate
(d) methyl 3-(Z)-[1-{4-[(4-hydroxy-piperidin-1-yl)-carbonyl]-phenylamino}-1-phenyl-methylidene]-2-indolinone-6-carboxylate
(e) methyl 3-(Z)-[1-{4-[(piperazin-1-yl)-carbonyl]-phenylamino}-1-phenyl-methylidene]-2-indolinone-6-carboxylate
(f) methyl 3-(Z)-[1-{4-[N-(2-methylamino-ethyl)-N-methyl-carbamoyl]-phenylamino}-1-phenyl-methylidene]-2-indolinone-6-carboxylate
(g) methyl 3-(Z)-[1-{4-[(4-dimethylamino-piperidin-1-yl)-carbonyl]-phenylamino}-1-phenyl-methylidene]-2-indolinone-6-carboxylate
(h) methyl 3-(Z)-[1-{4-[(4-ethyl-piperazin-1-yl)-carbonyl]-phenylamino}-1-phenyl-methylidene]-2-indolinone-6-carboxylate
(i) methyl 3-(Z)-[1-{4-[(4-(2-hydroxy-ethyl)-piperazin-1-yl)-carbonyl]-phenylamino}-1-phenyl-methylidene]-2-indolinone-6-carboxylate

    
    
        (k) methyl 3-(Z)-{1-[4-(5-methyl-2,5-diaza-bicyclo[2.2.1]hept-2-yl-carbonyl)-phenylamino]-1-phenyl-methylidene}-2-indolinone-6-carboxylate
    
    


the tautomers, mixtures and salts thereof.
According to the invention, the new compounds are obtained, for example, using the following methods known in principle from the literature:
a. reacting a compound of general formula 




wherein

X and R3 are as hereinbefore defined,
R2′ has the meanings given for R2 hereinbefore,
R18 denotes a hydrogen atom or a protecting group for the nitrogen atom of the lactam group, wherein one of the groups R2′ and R18 may also denote a bond to a solid phase optionally formed via a spacer and the other of the groups R2′ and R18 has the meanings given hereinbefore, and Z1 denotes a halogen atom, a hydroxy, alkoxy or aryl-alkoxy group, e.g. a chlorine or bromine atom, a methoxy, ethoxy or benzyloxy group, with an amine of general formula 




wherein

R4 and R5 are as hereinbefore defined,
and if necessary subsequently cleaving any protecting group used for the nitrogen atom of the lactam or imino group or from a solid phase.
A protecting group for the nitrogen atom of the lactam group might be for example an acetyl, benzoyl, ethoxycarbonyl, tert.butyloxycarbonyl or benzyloxycarbonyl group and
the solid phase might be a resin such as a 4-(2′,4′-dimethoxyphenylaminomethyl)-phenoxy resin, whilst the bond may conveniently be formed via the amino group, or a p-benzyloxybenzylalcohol resin, whilst the bond may conveniently be formed via an intermediate member such as a 2,5-dimethoxy-4-hydroxy-benzyl derivative.
The reaction is conveniently carried out in a solvent such as dimethylformamide, toluene, acetonitrile, tetrahydrofuran, dimethylsulphoxide, methylene chloride or mixtures thereof, optionally in the presence of an inert base such as triethylamine, N-ethyl-diisopropylamine or sodium hydrogen carbonate at temperatures between 20 and 175° C., whilst any protecting group used can be cleaved simultaneously by transamidation.
If Z1 in a compound of general formula VII denotes a halogen atom, the reaction is preferably carried out in the presence of an inert base at temperatures between 20 and 120° C.
If Z1 in a compound of general formula VII denotes a hydroxy, alkoxy or aralkoxy group, the reaction is preferably carried out at temperatures between 20 and 200° C.
If any protecting group used subsequently has to be cleaved, this is conveniently carried out either hydrolytically in an aqueous or alcoholic solvent, e.g. in methanol/water, ethanol/water, isopropanol/water, tetrahydrofuran/water, dioxane/water, dimethylformamide/water, methanol or ethanol in the presence of an alkali metal base such as lithium hydroxide, sodium hydroxide or potassium hydroxide at temperatures between 0 and 100° C., preferably at temperatures between 10 and 50° C.,
or advantageously by transamidation with an organic base such as ammonia, butylamine, dimethylamine or piperidine in a solvent such as methanol, ethanol, dimethylformamide and mixtures thereof or in an excess of the amine used at temperatures between 0 and 100° C., preferably at temperatures between 10 and 50° C.
Any solid phase used is preferably cleaved using trifluoroacetic acid and water at temperatures between 0 and 35° C., preferably at ambient temperature.
b. In order to prepare a compound of general formula I wherein R2 has the meanings given hereinbefore with the exception of the carboxy group:
reacting a compound of general formula 




wherein

R1 and R3 to R5 are as hereinbefore defined, or the reactive derivatives thereof with a compound of general formula

H—R19  (X),

wherein

R19 denotes a straight-chain or branched C1-6-alkanol, a C4-7-cycloalkanol or an aromatic alcohol.
The esterification is preferably carried out in a solvent such as methylene chloride, diethyl ether, tetrahydrofuran, toluene, dioxane, acetonitrile, dimethylsulphoxide or dimethylformamide, optionally in the presence of an inorganic or tertiary organic base, is preferably at temperatures between 20° C. and the boiling temperature of the solvent used. The reaction is carried out with a corresponding acid, preferably in the presence of a dehydrating agent, e.g. in the presence of isobutyl chloroformate, thionyl chloride, tetraethyl orthocarbonate, trimethyl orthoacetate, 2,2-dimethoxypropane, tetramethoxysilane, thionyl chloride, trimethylchlorosilane, phosphorus trichloride, phosphorus pentoxide, N,N′-dicyclohexylcarbodiimide, N,N′-dicyclohexyl carbodiimide/N-hydroxysuccinimide, N,N′-dicyclohexyl carbodiimide/1-hydroxybenzotriazole, 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate, 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium tetrafluooborate/1-hydroxybenotriazole, N,N′-carbonyldiimidazole or triphenylphosphine/carbon tetrachloride, and optionally with the addition of a base such as pyridine, 4-dimethylaminopyridine, N-methyl-morpholine or triethylamine, expediently at temperatures between 0 and 150° C., preferably at temperatures between 0 and 100° C., and the acylation is carried out with a corresponding reactive compound such as the anhydride, ester, imidazolide or halide thereof, optionally 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.
If according to the invention a compound of general formula I is obtained which contains an alkoxycarbonyl group, this can be converted by hydrolysis into a corresponding carboxy compound, or
if a compound of general formula I is obtained which contains an amino or alkylamino group, this may be converted by reductive alkylation into a corresponding alkylamino or dialkylamino compound, or
if a compound of general formula I is obtained which contains an amino or alkylamino group, this may be converted by acylation or sulphonylation into a corresponding acyl or sulphonyl compound, or
if a compound of general formula I is obtained which contains a carboxy group, this may be converted by esterification or amidation into a corresponding ester or aminocarbonyl compound, or
if a compound of general formula I is obtained which contains a cycloalkyleneimino group wherein a methylene group is replaced by a sulphur atom, this may be converted by oxidation into a corresponding sulphinyl or sulphonyl compound, or
if a compound of general formula I is obtained which contains a nitro group, this may be converted by reduction into a corresponding amino compound, or
if a compound of general formula I is obtained wherein R4 denotes a phenyl group substituted by an amino, alkylamino or aminoalkyl group, this may subsequently be converted by reacting with a corresponding cyanate, isocyanate or carbamoyl halide into a corresponding urea compound of general formula I or
if a compound of general formula I is obtained wherein R4 denotes a phenyl group substituted by an amino, alkylamino or aminoalkyl group, this may subsequently be converted by reacting with a corresponding compound which transfers the amidino group or by reacting with a corresponding nitrile into a corresponding guanidino compound of general formula I.
The subsequent hydrolysis is preferably carried out in an aqueous solvent, e.g. in water, methanol/water, ethanol/water, isopropanol/water, tetrahydrofuran/water or dioxane/water, in the presence of an acid such as trifluoroacetic acid, hydrochloric acid or sulphuric acid or in the presence of an alkali metal base such as lithium hydroxide, sodium hydroxide or potassium hydroxide at temperatures between 0 and 100° C., preferably at temperatures between 10 and 50° C.
The subsequent reductive alkylation is preferably carried out in a suitable solvent such as methanol, methanol/water, methanol/water/ammonia, ethanol, ether, tetrahydrofuran, dioxane, methylene chloride or dimethylformamide optionally with the addition of an acid such as hydrochloric acid in the presence of catalytically activated hydrogen, e.g. hydrogen in the presence of Raney nickel, platinum or palladium/charcoal, or in the presence of a metal hydride such as sodium borohydride, sodium cyanoborohydride, lithium borohydride or lithium aluminium hydride at temperatures between 0 and 100° C., preferably at temperatures between 20 and 80° C.
The subsequent acylation or sulphonylation is conveniently carried out with the corresponding free acid or a corresponding reactive compound such as an anhydride, ester, imidazolide or halide thereof, preferably in a solvent such as methylene chloride, diethyl ether, tetrahydrofuran, toluene, dioxane, acetonitrile, dimethylsulphoxide or dimethylformamide, optionally in the presence of an inorganic or a tertiary organic base, preferably at temperatures between −20° C. and 200° C., preferably at temperatures between 20° C. and the boiling temperature of the solvent used. The reaction with the free acid may optionally be carried out in the presence of an acid activating agent or a dehydrating agent, e.g. in the presence of isobutyl chloroformate, tetraethyl orthocarbonate, trimethyl orthoacetate, 2,2-dimethoxypropane, tetramethoxysilane, thionylchloride, trimethylchlorosilane, phosphorus trichloride, phosphorus pentoxide, N,N′-dicyclohexylcarbodiimide, N,N′-dicyclohexyl-carbodiimide/N-hydroxysuccinimide, N,N′-dicyclohexylcarbodiimide/1-hydroxybenzotriazole, 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate, 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate/1-hydroxybenzotriazole, N,N′-carbonyldiimidazole or triphenylphosphine/carbon tetrachloride, and optionally with the addition of a base such as pyridine, 4-dimethylaminopyridine, N-methyl-morpholine or triethylamine, conveniently at temperatures between 0 and 150° C., preferably at temperatures between 0 and 100° C. The reaction with a corresponding reactive compound may optionally be carried out in the presence of a tertiary organic base such as triethylamine, N-ethyl-diisopropylamine, N-methyl-morpholine or pyridine, or, if an anhydride is used, in the presence of the corresponding acid, at temperatures between 0 and 150° C., preferably at temperatures between 50 and 100° C.
The subsequent esterification or amidation is expediently carried out by reacting a corresponding reactive carboxylic acid derivative with a corresponding alcohol or amine as described hereinbefore.
The subsequent reduction of a nitro group is preferably carried out by hydrogenolysis, e.g. with hydrogen in the presence of a catalyst such as palladium/charcoal or Raney nickel in a solvent such as methanol, ethanol, ethyl acetate, dimethylformamide, dimethylformamide/acetone or glacial acetic acid, optionally with the addition of an acid such as hydrochloric acid or glacial acetic acid at temperatures between 0 and 50° C., but preferably at ambient temperature, and at a hydrogen pressure of 1 to 7 bar, but preferably 3 to 5 bar.
The subsequent preparation of a corresponding urea compound of general formula I is conveniently carried out with an inorganic cyanate or a corresponding isocyanate or carbamoylchloride, preferably in a solvent such as dimethylformamide and optionally in the presence of a tertiary organic base such as triethylamine at temperatures between 0 and 50° C., preferably at ambient temperature.
The subsequent preparation of a corresponding guanidino compound of general formula I is conveniently carried out by reacting with a compound that transfers the amidino group, such as 3,5-dimethylpyrazol-1-carboxylic acid amidine, preferably in a solvent such as dimethylformamide and optionally in the presence of a tertiary organic base such as triethylamine at temperatures between 0 and 50° C., preferably at ambient temperature.
In the reactions described hereinbefore, any reactive groups present such as carboxy, hydroxy, amino, alkylamino or imino groups may be protected during the reaction by conventional protecting groups which are cleaved again after the reaction.
For example, a protecting group for a carboxyl group may be a trimethylsilyl, methyl, ethyl, tert.butyl, benzyl or tetrahydropyranyl group and
protecting groups for a hydroxy, amino, alkylamino or imino group may be an acetyl, trifluoroacetyl, benzoyl, ethoxycarbonyl, tert.butoxycarbonyl, benzyloxycarbonyl, benzyl, methoxybenzyl or 2,4-dimethoxybenzyl group and additionally, for the amino group, a phthalyl group.
Any protecting group used is optionally subsequently cleaved for example by hydrolysis in an aqueous solvent, e.g. in water, isopropanol/water, tetrahydrofuran/water or dioxane/water, in the presence of a acid such as trifluoroacetic acid, hydrochloric acid or sulphuric acid or in the presence of an alkali metal base such as lithium hydroxide, sodium hydroxide or potassium hydroxide, at temperatures between 0 and 100° C., preferably at temperatures between 10 and 50° C.
However, a benzyl, methoxybenzyl or benzyloxycarbonyl group is cleaved, for example, hydrogenolytically, e.g. with hydrogen in the presence of a catalyst such as palladium/charcoal in a solvent such as methanol, ethanol, ethyl acetate, dimethylformamide, dimethylformamide/acetone or glacial acetic acid, optionally with the addition of an acid such as hydrochloric acid or glacial acetic acid at temperatures between 0 and 50° C., but preferably at ambient temperature, and at a hydrogen pressure of 1 to 7 bar, but preferably 3 to 5 bar.
A methoxybenzyl group may also be cleaved in the presence of an oxidising agent such as cerium(IV) ammonium nitrate in a solvent such as methylene chloride, acetonitrile or acetonitrile/water at temperatures of between 0 and 50° C., but preferably at ambient temperature.
A 2,4-dimethoxybenzyl group, however, is preferably cleaved in trifluoroacetic acid in the presence of anisol.
A tert.butyl or tert.butyloxycarbonyl group is preferably cleaved by treating with an acid such as trifluoroacetic acid or hydrochloric acid, optionally using a solvent such as methylene chloride, dioxane, ethyl acetate or ether.
A phthalyl group is preferably cleaved in the presence of hydrazine or a primary amine such as methylamine, ethylamine or n-butylamine in a solvent such as methanol, ethanol, isopropanol, toluene/water or dioxane at temperatures between 20 and 50° C.
Moreover, chiral compounds obtained of general formula I may be resolved into their enantiomers and/or diastereomers.
Thus, for example, the compounds of general formula I obtained which occur as racemates may be separated by methods known per se (cf. Allinger N. L. and Eliel E. L. in “Topics in Stereochemistry”, Vol. 6, Wiley Interscience, 1971) into their optical antipodes and compounds of general formula I with at least 2 asymmetric carbon atoms may be resolved into their diastereomers on the basis of their physical-chemical differences using methods known per se, e.g. by chromatography and/or fractional crystallisation, and, if these compounds are obtained in racemic form, they may subsequently be resolved into the enantiomers as mentioned above.
The enantiomers are preferably separated by column separation on chiral phases or by recrystallisation from an optically active solvent or by reacting with an optically active substance which forms salts or derivatives such as e.g. esters or amides with the racemic compound, particularly acids and the activated derivatives or alcohols thereof, and separating the diastereomeric mixture of salts or derivatives thus obtained, e.g. on the basis of their differences in solubility, whilst the free antipodes may be released from the pure diastereomeric salts or derivatives by the action of suitable agents. Optically active acids in common use are e.g. the D- and L-forms of tartaric acid or dibenzoyltartaric acid, di-o-tolyltartaric acid, malic acid, mandelic acid, camphorsulphonic acid, glutamic acid, N-acetylglutamic acid, aspartic acid, N-acetylaspartic acid or quinic acid. An optically active alcohol may be, for example, (+)- or (−)-menthol and an optically active acyl group in amides may be, for example, a (+)- or (−)-menthyloxycarbonyl group.
Furthermore, the compounds of formula I obtained may be converted into the salts thereof, particularly for pharmaceutical use into the physiologically acceptable salts with inorganic or organic acids. Acids which may be used for this purpose include for example hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid, fumaric acid, succinic acid, lactic acid, citric acid, tartaric acid, maleic acid or methanesulphonic acid.
Moreover, if the new compounds of formula I thus obtained contain a carboxy group, they may subsequently, if desired, be converted into the salts thereof with inorganic or organic bases, particularly for pharmaceutical use into the physiologically acceptable salts thereof. Suitable bases for this purpose include for example sodium hydroxide, potassium hydroxide, cyclohexylamine, ethanolamine, diethanolamine and triethanolamine.
The compounds of general formulae VII to X used as starting materials are known from the literature in some cases or may be obtained by methods known from the literature or may be obtained by methods as described hereinbefore and in the Examples.
As already mentioned, the new compounds of general formula I wherein R1 denotes a hydrogen atom or a prodrug group have valuable pharmacological properties, particularly inhibitory effects on various kinases, especially on receptor-tyrosine kinases such as VEGFR2, VEGFR3, PDGFRα, PDGFRβ, FGFR1, FGFR3, EGFR, HER2, IGF1R and HGFR, as well as on complexes of CDK's (Cyclin Dependent Kinases) such as CDK1, CDK2, CDK3, CDK4, CDK5, CDK6, CDK7, CDK8 and CDK9 with their specific cyclins (A, B1, B2, C, D1, D2, D3, E, F, G1, G2, H, I and K) and on viral cyclin, on the proliferation of cultivated human cells, particularly endothelial cells, e.g. in angiogenesis, but also on the proliferation of other cells, particularly tumour cells.
The biological properties of the new compounds were tested by the following standard procedure, as follows:
Human umbilical endothelial cells (HUVEC) were cultivated in IMDM (Gibco BRL), supplemented with 10% foetal calf serum (FBS) (Sigma), 50 μM of β-mercaptoethanol (Fluka), standard antibiotics, 15 μg/ml of endothelial cell growth factor (ECGS, Collaborative Biomedical Products) and 100 μg/ml of heparin (Sigma) on gelatine-coated culture dishes (0.2% gelatine, Sigma) at 37° C., under 5% CO2 in a water-saturated atmosphere.
In order to investigate the inhibitory activity of the compounds according to the invention the cells were “starved” for 16 hours, i.e. kept in culture medium without growth factors (ECGS+heparin). The cells were detached from the culture dishes using trypsin/EDTA and washed once in serum-containing medium. Then they were seeded out in amounts of 2.5×103 cells per well.
The proliferation of the cells was stimulated with 5 ng/ml of VEGF165 (vascular endothelial growth factor; H. Weich, GBF Braunschweig) and 10 μg/ml of heparin. As a control, 6 wells in each dish were not stimulated.
The compounds according to the invention were dissolved in 100% dimethylsulphoxide and added to the cultures in various dilutions as triple measurements, the maximum dimethylsulphoxide concentration being 0.3%.
The cells were incubated for 76 hours at 37° C., then for a further 16 hours 3H-thymidine (0.1 μCi/well, Amersham) was added in order to determine the DNA synthesis. Then the radioactively labelled cells were immobilised on filter mats and the radioactivity incorporated was measured in a β-counter. In order to determine the inhibitory activity of the compounds according to the invention the mean value of the non-stimulated cells was subtracted from the mean value of the factor-stimulated cells (in the presence or absence of the compounds according to the invention).
The relative cell proliferation was calculated as a percentage of the control (HUVEC without inhibitor) and the concentration of active substance which inhibits the proliferation of the cells by 50% (IC50) was determined.
The test results of the following compounds (a) to (f) of general formula I are provided by way of example:
(a) methyl 3-(Z)-[1-{4-[N-(2-dimethylamino-ethyl)-N-methyl-carbamoyl]-phenylamino}-1-phenyl-methylidene]-2-indolinone-6-carboxylate
(b) methyl 3-(Z)-[1-{4-[N-(3-dimethylamino-propyl)-N-methyl-carbamoyl]-phenylamino}-1-phenyl-methylidene]-2-indolinone-6-carboxylate
(c) methyl 3-(Z)-[1-{4-[(4-methyl-piperazin-1-yl)-carbonyl]-phenylamino}-1-phenyl-methylidene]-2-indolinone-6-carboxylate
(d) methyl 3-(Z)-[1-{4-[(4-hydroxy-piperidin-1-yl)-carbonyl]-phenylamino}-1-phenyl-methylidene]-2-indolinone-6-carboxylate
(e) methyl 3-(Z)-[1-{4-[(piperazin-1-yl)-carbonyl]-phenylamino}-1-phenyl-methylidene]-2-indolinone-6-carboxylate
(f) methyl 3-(Z)-[1-{4-[N-(2-methylamino-ethyl)-N-methyl-carbamoyl]-phenylamino}-1-phenyl-methylidene]-2-indolinone-6-carboxylate
(g) methyl 3-(Z)-[1-{4-[(4-dimethylamino-piperidin-1-yl)-carbonyl]-phenylamino}-1-phenyl-methylidene]-2-indolinone-6-carboxylate
(h) methyl 3-(Z)-[1-{4-[(4-ethyl-piperazin-1-yl)-carbonyl]-phenylamino}-1-phenyl-methylidene]-2-indolinone-6-carboxylate
(i) methyl 3-(Z)-[1-{4-[(4-(2-hydroxy-ethyl)-piperazin-1-yl)-carbonyl]-phenylamino}1-phenyl-methylidene]-2-indolinone-6-carboxylate
(k) methyl 3-(Z)-{1-[4-(5-methyl-2,5-diaza-bicyclo[2.2.1]hept-2-yl-carbonyl)-phenylamino]-1-phenyl-methylidene}-2-indolinone-6-carboxylate
The Table that follows contains the results found:














compound
IC50 [μM]









(a)
0.04



(b)
0.02



(c)
0.03



(d)
0.05



(e)
0.01



(f)
0.01



(g)
0.01



(h)
0.02



(i)
0.02



(k)
0.01










In view of their inhibitory effect on the proliferation of cells, particularly endothelial cells and tumour cells, the compounds of general formula I are suitable for treating diseases in which the proliferation of cells, particularly endothelial cells, plays a part.
Thus, for example, the proliferation of endothelial cells and the concomitant neovascularisation constitute a crucial stage in tumour progression (Folkman J. et al., Nature 339, 58-61, (1989); Hanahan D. and Folkman J., Cell 86, 353-365, (1996)). Furthermore, the proliferation of endothelial cells is also important in haemangiomas, in metastasisation, rheumatoid arthritis, psoriasis and ocular neovascularisation (Folkman J., Nature Med. 1, 27-31, (1995)). The therapeutic usefulness of inhibitors of endothelial cell proliferation was demonstrated in the animal model for example by O'Reilly et al. and Parangi et al. (O'Reilly M. S. et al., Cell 88, 277-285, (1997); Parangi S. et al., Proc Natl Acad Sci USA 93, 2002-2007, (1996)).
The compounds of general formula I, their tautomers, their stercoisomers or the physiologically acceptabie salts thereof are thus suitable for treating diseases or conditions characterized by excessive or anomalous cell proliferation, for example, for treating tumours (e.g. plate epithelial carcinoma, astrocytoma, Kaposi's sarcoma, glioblastoma, lung cancer, bladder cancer, neck carcinoma, melanoma, ovarian cancer, prostate cancer, breast cancer, small-cell lung cancer, glioma, colorectal cancer, urogenital cancer and gastrointestinal cancer as well as haematological cancers such as multiple myeloma), psoriasis, arthritis (e.g. rheumatoid arthritis), haemangioma, angiofibroma, eye diseases (e.g. diabetic retinopathy), neovascular glaucoma, kidney diseases (e.g. glomerulonephritis), diabetic retinopathy, malignant nephrosclerosis, thrombic microangiopathic syndrome, transplant rejections and glomerulopathy, fibrotic diseases (e.g. cirrhosis of the liver), mesangial cell proliferative diseases, arteriosclerosis, damage to the nerve tissue and for inhibiting the reocclusion of blood vessels after treatment with a balloon catheter, in vascular prosthetics or after the fitting of mechanical devices for holding the blood vessels open (e.g. stents), or other diseases in which cell proliferation or angiogenesis are involved.
By reason of their biological properties the compounds according to the invention may be used on their own or in conjunction with other pharmacologically active compounds, for example in tumour therapy, in monotherapy or in conjunction with other anti-tumour therapeutic agents, for example in combination with topoisomerase inhibitors (e.g. etoposide), mitosis inhibitors (e.g. vinblastin, taxol), compounds which interact with nucleic acids (e.g. cisplatin, cyclophosphamide, adriamycin), hormone antagonists (e.g. tamoxifen), inhibitors of metabolic processes (e.g. 5-FU etc.), cytokines (e.g. interferons), kinase inhibitors, antibodies, or in conjunction with radiotherapy, etc. These combinations may be administered either simultaneously or sequentially.
For pharmaceutical use the compounds according to the invention are generally used for warm-blooded vertebrates, particularly humans, in doses of 0.01-100 mg/kg of body weight, preferably 0.1-20 mg/kg. For administration they are formulated with one or more conventional inert carriers and/or diluents, e.g. with corn starch, lactose, glucose, microcrystalline cellulose, magnesium stearate, polyvinylpyrrolidone, citric acid, tartaric acid, water, water/ethanol, water/glycerol, water/sorbitol, water/polyethyleneglycol, propyleneglycol, stearylalcohol, carboxymethylcellulose or fatty substances such as hard fat or suitable mixtures thereof in conventional galenic preparations such as plain or coated tablets, capsules, powders, suspensions, solutions, sprays or suppositories.
The following Examples are intended to illustrate the present invention without restricting it:
Preparation of the starting compounds:
Abbreviations used:

    
    
        TBTU=O-(benzotriazol-1-yl)-N,N,N′,N′-bis(tetramethylene-uronium-hexafluorophosphate
        HOBt=1-hydroxy-1H-benzotriazole
    
    




EXAMPLE I
N-(2-dimethylamino-ethyl)-4-nitro-benzamide
1.25 ml of 2-(N,N-dimethylamino)-ethylamine are dissolved with 3 ml of triethylamine in 20 ml of methylene chloride and cooled to 0° C. Then 2 g of 4-nitrobenzoic acid chloride are added batchwise and the mixture is stirred for 5 min in the cold and for 20 min at ambient temperature. Finally, the precipitate is separated off by suction filtering and the organic phase is washed with water, dried over sodium sulphate and concentrated by rotary evaporation.
Yield: 1.8 g (70% of theoretical)
Rf value: 0.78 (silica gel, methylene chloride/methanol=9:1)
C11H15N3O3 
Mass spectrum: m/z=238 [M+H]+
The following compounds are prepared analogously to Example I:

    (1) N-(2-dimethylamino-ethyl)-N-methyl-4-nitro-benzamide
    (2) N-(3-dimethylamino-propyl)-4-nitro-benzamide
    (3) N-(3-dimethylamino-propyl)-N-methyl-4-nitro-benzamide
    (4) N-(2-dimethylamino-ethyl)-N-ethyl-4-nitro-benzamide
    (5) N-(2-(tert-butyloxycarbonyl-methylamino-ethyl)-N-methyl-4-nitro-benzamide
    (6) N,N-bis-(2-diethylamino-ethyl)-4-nitro-benzamide
    (7) N-(2-tert-butyloxycarbonyl-amino-ethyl)-4-nitro-benzamide
    (8) N-(2-dimethylamino-ethyl)-3-nitro-benzamide
    (9) N-(2-dimethylamino-ethyl)-N-methyl-3-nitro-benzamide
    (10) N-(3-dimethylamino-propyl)-3-nitro-benzamide
    (11) N-(3-dimethylamino-propyl)-N-methyl-3-nitro-benzamide
    (12) 2-N-(dimethylamino-methyl)-carbamoyl-5-nitro-furan
    (13) 4-(4-methyl-piperazin-1-yl-carbonyl)-nitrobenzene
    (14) 4-(piperidin-1-yl-carbonyl)-nitrobenzene
    (15) N-cyclohexyl-N-methyl-4-nitro-benzamide
    (16) N-isopropyl-4-nitro-benzamide
    (17) 4-(2,3,4,5-tetrahydro-1(H)-benzo[d]azepin-3-yl-carbonyl)-nitrobenzene
    (18) 4-(4-hydroxy-piperidin-1-yl-carbonyl)-nitrobenzene
    (19) 4-(4-tert-butyloxycarbonyl-piperazin-1-yl-carbonyl)-nitrobenzene
    (20) 4-(4-tert-butyloxycarbonyl-[1,4]diazepan-1-yl-carbonyl)-nitrobenzene
    (21) N-carbamoylmethyl-N-methyl-3-nitro-benzamide
    (22) N-(2-methoxy-ethyl)-N-methyl-3-nitro-benzamide
    (23) N-(2-carbamoylethyl)-3-nitro-benzamide
    (24) N,N-(bis-(2-hydroxy-ethyl))-3-nitro-benzamide
    (25) 4-(4-dimethylamino-piperidin-1-yl-carbonyl)-nitrobenzene
    (26) 4-(4-ethyl-piperazin-1-yl-carbonyl)-nitrobenzene
    (27) 4-(4-(2-dimethylamino-ethyl)-piperazin-1-yl-carbonyl)-nitrobenzene
    (28) 4-(4-(2-hydroxy-ethyl)-piperazin-1-yl-carbonyl)-nitrobenzene
    (29) 4-(5-methyl-2,5-diaza-bicyclo[2.2.1]hept-2-yl-carbonyl)-nitrobenzene
    (30) 4-(4-tert-butyloxycarbonyl-trans-2,5-dimethyl-piperazin-1-yl-carbonyl)-nitrobenzene
    (31) 4-(4-dimethylaminomethyl-piperidin-1-yl-carbonyl)-nitrobenzene
    (32) 4-(cis-2,5-dimethyl-piperazin-1-yl-carbonyl)-nitrobenzene
    (33) (R)-4-(3,4-dimethyl-piperazin-1-yl-carbonyl)-nitrobenzene
    (34) 4-(4-(2-diethylamino-ethoxy)-piperidin-1-yl-carbonyl)-nitrobenzene
    (35) 4-(3-(2-diethylamino-ethoxy)-pyrrolidin-1-yl-carbonyl)-nitrobenzene
    (36) 4-(3-dimethylamino-pyrrolidin-1-yl-carbonyl)-nitrobenzene


EXAMPLE II
4-Nitro-1-methyl-2-[(2-dimethylamino-ethyl)-N-methyl-carbamoyl]-pyrrole
5.4 ml of 2-(N,N-dimethylamino)-ethylamine and 5.8 g of 1-methyl-4-nitro-pyrrol-2-carboxylic acid are dissolved in 200 ml of dimethylformamide and 5.7 ml of triethylamine, 13.1 g of TBTU and 5.5 g of HOBt are added. The mixture is stirred for 24 hours at ambient temperature. Finally, the solvent is substantially removed, water is added and the mixture is extracted with methylene chloride. The organic phase is dried over sodium sulphate and concentrated by rotary evaporation. The residue is purified on a silica gel column with methylene chloride/methanol/ammonia 8:2:0.1 as eluant.
Yield: 9.2 g (100% of theoretical)
Rf value: 0.70 (silica gel, methylene chloride/methanol/ammonia=8:1:0.1)
C11H18N4O3 
Mass spectrum: m/z=255 [M+H]+
EXAMPLE III
4-amino-N-(2-dimethylamino-ethyl)-benzamide
1.8 g of N-(2-dimethylamino-ethyl)-4-nitro-benzamide are dissolved in 30 ml of methanol and hydrogenated over 0.2 g of palladium/charcoal at 50 psi of hydrogen for 2 hours at ambient temperature. The catalyst is filtered off and the filtrate is concentrated by rotary evaporation.
Yield: 1.5 g (95% of theoretical)
Rf value: 0.38 (silica gel, methylene chloride/methanol=9:1)
C11H17N3O
Mass spectrum: m/z=208 [M+H]+
The following compounds are prepared analogously to Example III:

    (1) 4-amino-N-(2-dimethylamino-ethyl)-N-methyl-benzamide
    (2) 4-amino-N-(3-dimethylamino-propyl)-benzamide
    (3) 4-amino-N-(3-dimethylamino-propyl)-N-methyl-benzamide
    (4) 4-amino-N-(2-dimethylamino-ethyl)-N-ethyl-benzamide
    (5) 4-amino-N-(2-(tert-butyloxycarbonyl-methylamino)-ethyl)-N-ethyl-benzamide
    (6) 4-amino-N,N-bis-(2-diethylamino-ethyl)-benzamide
    (7) 4-amino-N-(2-(tert-butyloxycarbonyl-amino)-ethyl)-benzamide
    (8) 3-amino-N-(2-dimethylamino-ethyl)-benzamide
    (9) 3-amino-N-(2-dimethylamino-ethyl)-N-methyl-benzamide
    (10) 3-amino-N-(3-dimethylamino-propyl)-benzamide
    (11) 3-amino-N-(3-dimethylamino-propyl)-N-methyl-benzamide
    (12) 5-amino-2-N-(dimethylamino-methyl)-carbamoyl-furan
    (13) 4-(4-methyl-piperazin-1-yl-carbonyl)-aniline
    (14) 4-(piperidin-1-yl-carbonyl)-aniline
    (15) 4-amino-N-cyclohexyl-N-methyl-benzamide
    (16) 4-amino-N-isopropyl-benzamide
    (17) 4-(2,3,4,5-tetrahydro-1(H)-benzo[d]azepin-3-yl-carbonyl)-aniline
    (18) 4-(4-hydroxy-piperidin-1-yl-carbonyl)-aniline
    (19) 4-(4-tert-butyloxycarbonyl-piperazin-1-yl-carbonyl)-aniline
    (20) 4-(4-tert-butyloxycarbonyl-[1,4]diazepan-1-yl-carbonyl)-aniline
    (21) 3-amino-N-carbamoylmethyl-N-methyl-benzamide
    (22) 3-amino-N-(2-methoxy-ethyl)-N-methyl-benzamide
    (23) 3-amino-N-(2-carbamoylethyl)-benzamide
    (24) 3-amino-N,N—(bis-(2-hydroxy-ethyl))-benzamide
    (25) 4-amino-1-methyl-2-[(2-dimethylamino-ethyl)-N-methyl-carbamoyl]-pyrrole
    (26) 4-(4-dimethylamino-piperidin-1-yl-carbonyl)-aniline
    (27) 4-(4-ethyl-piperazin-1-yl-carbonyl)-aniline
    (28) 4-(4-(2-dimethylamino-ethyl)-piperazin-1-yl-carbonyl)-aniline
    (29) 4-(4-(2-hydroxy-ethyl)-piperazin-1-yl-carbonyl)-aniline
    (30) 4-(5-methyl-2,5-diaza-bicyclo[2.2.1]hept-2-yl-carbonyl)-aniline
    (31) 4-(4-tert-butyloxycarbonyl-trans-2,5-dimethyl-piperazin-1-yl-carbonyl)-aniline
    (32) 4-(4-dimethylaminomethyl-piperidin-1-yl-carbonyl)-aniline
    (33) 4-(cis-3,5-dimethyl-piperazin-1yl-carbonyl)-aniline
    (34) (R)-4-(3,4-dimethyl-piperazin-1-yl-carbonyl)-aniline
    (35) 4-(4-(2-diethylamino-ethoxy)-piperidin-1-yl-carbonyl)-aniline
    (36) 4-(3-(2-diethylamino-ethoxy)-pyrrolidin-1-yl-carbonyl)-aniline
    (37) 4-(3-dimethylamino -pyrrolidin-1-yl-carbonyl)-aniline


EXAMPLE IV
Methyl 4-methoxycarbonylmethyl-3-nitro-benzoate
54.3 g of methyl 3-nitro-benzoate and 29.0 g of methyl chioroacetate are dissolved in 100 ml of dimethylformamide and this solution is added dropwise at −10° C. to a solution of 78.5 g of potassium tert.butoxide in 500 ml of dimethylformamide. The mixture is stirred for another 10 minutes at ambient temperature and after this time the solution is poured onto 350 ml of concentrated hydrochloric acid in 2 l of iced water. The solution is stirred for 0.5 hours and the precipitate obtained is suction filtered and washed with water. The product is recrystallised from 150 ml of methanol and dried in vacuo at 40° C. Yield: 48.3 g (51% of theoretical), contains about 20% of methyl 6-methoxycarbonylmethyl-3-nitro-benzoate
Rf value: 0.7 (silica gel, petroleum ether/ethyl acetate=1:1)
Melting point: 65-73° C.
The following compound is prepared analogously to Example IV:
(1) ethyl 4-methoxycarbonylmethyl-3-nitro-benzoate Prepared from ethyl 4-methoxycarbonylmethyl-3-nitro-benzoate
EXAMPLE V
Methyl 2-indolinone-6-carboxylate
48.3 g of methyl 4-methoxycarbonylmethyl-3-nitro-benzoate are dissolved in 800 ml of concentrated acetic acid, 5.0 g of palladium on charcoal (10%) are added and the solution is hydrogenated for 2.5 hours at ambient temperature and 50 psi. The catalyst is filtered off and the filtrate is evaporated down. The residue is taken up in 150 ml of tert.-butylmethylether, filtered again and dried in vacuo at 100° C.
Yield: 28.6 g (98% of theoretical),
Rf value: 0.4 (silica gel, methylene chloride/methanol=10:1)
Melting point: 208-211° C.
The following compound is prepared analogously to Example V:
(1) ethyl 2-indolinone-6-carboxylate
Prepared from ethyl 4-methoxycarbonylmethyl-3-nitro-benzoate
EXAMPLE VI
1-acetyl-3-(1-ethoxy-1-phenylmethylene)-6-ethoxycarbonyl-2-indolinone
15.0 g of ethyl 2-indolinone-6-carboxylate, 49.6 ml of triethyl orthobenzoate and 150 ml of acetic anhydride are stirred for 4 hours at 110° C. After this time the solvent is removed, the residue is recrystallised from petroleum ether and dried in vacuo at 50° C.
Yield: 16.9 g (61% of theoretical),
Rf value: 0.5 (silica gel, petroleum ether/methylene chloride/ethyl acetate=5:4:1)
Melting point: 98-100° C.
C22H21NO5 
The following compound is prepared analogously to Example VI:
(1) 1-acetyl-3-(1-ethoxy-1-phenylmethylene)-6-methoxycarbonyl-2-indolinone Prepared from methyl 2-indolinone-6-carboxylate, triethyl orthobenzoate and acetic anhydride
Preparation of the final compounds:
Example 1
Methyl 3-(Z)-[1-{4-[N-(2-dimethylamino-ethyl)-N-methyl-carbamoyl]-phenylamino}-1-phenyl-methylidene]-2-indolinone-6-carboxylate
0.3 g of 1-acetyl-3-(1-ethoxy-1-phenylmethylene)-6-methoxycarbonyl-2-indolinone and 0.2 g of 4-amino-N-(2-dimethylamino-ethyl)-N-methyl-benzamide are dissolved in 5 ml of dimethylfornamide and stirred for 4 hours at 70° C. After cooling 3 ml of conc. ammonia are added and the mixture is stirred for another 30 minutes at ambient temperature. Then 1 ml of water is added, the precipitate formed is suction filtered, stirred with a little methanol and ether and then the solid substance is collected.
Yield: 0.1 g (24% of theoretical),
Rf value: 0.22 (silica gel, methylene chloride/methanol=9:1)
C29H30N4O4 
Mass spectrum: m/z=499 [M+H]+
The following compounds are prepared analogously to Example 1:
(1) methyl 3-(Z)-[1-{4-[(2-dimethylamino-ethyl)-carbamoyl]-phenylamino}-1-phenyl-methylidene]-2-indolinone-6-carboxylate
Prepared from 1-acetyl-3-(1-ethoxy-1-phenylmethylene)-6-methoxycarbonyl-2-indolinone and 4-amino-N-(2-dimethylamino-ethyl)-benzamide.
Yield: 0.15 g (36% of theoretical),
Rf value: 0.26 (silica gel, methylene chloride/methanol=9:1)
C28H28N4O4 
Mass spectrum: m/z=483 [M−H]−
(2) methyl 3-(Z)-[1-{4-[(3-dimethylamino-propyl)-carbamoyl]-phenylamino}-1-phenyl-methylidene]-2-indolinone-6-carboxylate
Prepared from 1-acetyl-3-(1-ethoxy-1-phenylmethylene)-6-methoxycarbonyl-2-indolinone and 4-amino-N-(3-dimethylamino-propyl)-benzamide.
Yield: 0.18 g (42% of theoretical)
Rf value: 0.25 (silica gel, methylene chloride/methanol=9:1)
C29H30N4O4 
Mass spectrum: m/z=497 [M−H]−
(3) methyl 3-(Z)-[1-{4-[N-(3-dimethylamino-propyl)-N-methyl-carbamoyl]-phenylamino}-1-phenyl-methylidene]-2-indolinone-6-carboxylate
Prepared from 1-acetyl-3-(1-ethoxy-1-phenylmethylene)-6-methoxycarbonyl-2-indolinone and 4-amino-N-(3-dimethylamino-propyl)-N-methyl-benzamide.
Yield: 0.18 g (41% of theoretical)
Rf value: 0.22 (silica gel, methylene chloride/methanol=9:1)
C30H32N4O4 
Mass spectrum: m/z=513 [M+H]+
(4) methyl 3-(Z)-[1-{4-[(2-dimethylamino-ethyl)-N-ethyl-carbamoyl]-phenylamino}-1-phenyl-methylidene]-2-indolinone-6-carboxylate
Prepared from 1-acetyl-3-(1-ethoxy-1-phenylmethylene)-6-methoxycarbonyl-2-indolinone and 4-amino-N-(2-dimethylamino-ethyl)-N-ethyl-benzamide.
Yield: 36% of theoretical
Rf value: 0.6 (silica gel, methylene chloride/methanol=4:1)
C30H32N4O4 
Mass spectrum: m/z=513 [M+H]+
(5) methyl 3-(Z)-[1-{4-[(2-(tert-butyloxycarbonyl-N-methylamino)-ethyl)-N-methyl-carbamoyl]-phenylamino}-1-phenyl-methylidene]-2-indolinone-6-carboxylate
Prepared from 1-acetyl-3-(1-ethoxy-1-phenylmethylene)-6-methoxycarbonyl-2-indolinone and 4-amino-N-(2-(tert-butyloxycarbonyl-methylamino-ethyl)-N-ethyl-benzamide.
Yield: 25% of theoretical
Rf value: 0.8 (silica gel, methylene chloride/methanol=4:1)
C33H36N4O6 
Mass spectrum: m/z=584 [M]+
(6) methyl 3-(Z)-[1-{4-[N,N-bis-(2-diethylamino-ethyl)-carbamoyl]-phenylamino}-1-phenyl-methylidene]-2-indolinone-6-carboxylate
Prepared from 1-acetyl-3-(1-ethoxy-1-phenylmethylene)-6-methoxycarbonyl-2-indolinone and 4-amino-(N,N-bis-(2-diethylamino-ethyl)-benzamide.
Yield: 68% of theoretical
Rf value: 0.5 (silica gel, methylene chloride/methanol=4:1)
C36H45N5O4 
(7) methyl 3-(Z)-[1-{3-[(2-dimethylamino-ethyl)-carbamoyl]-phenylamino}-1-phenyl-methylidene]-2-indolinone-6-carboxylate
Prepared from 1-acetyl-3-(1-ethoxy-1-phenylmethylene)-6-methoxycarbonyl-2-indolinone and 3-amino-N-(2-dimethylamino-ethyl)-benzamide.
Yield: 51% of theoretical,
Rf value: 0.6 (silica gel, methylene chloride/methanol=4:1)
C28H28N4O4 
Mass spectrum: m/z=483 [M−H]−
(8) methyl 3-(Z)-[1-{3-[(2-dimethylamino-ethyl)-N-methyl-carbamoyl]-phenylamino}-1-phenyl-methylidene]-2-indolinone-6-carboxylate
Prepared from 1-acetyl-3-(1-ethoxy-1-phenylmethylene)-6-methoxycarbonyl-2-indolinone and 3-amino-N-(2-dimethylamino-ethyl)-N-methyl-benzamide.
Yield: 21% of theoretical,
Rf value: 0.35 (silica gel, methylene chloride/methanol=9:1)
C29H30N4O4 
Mass spectrum: m/z=497 [M−H]−
(9) methyl 3-(Z)-[1-{3-[(3-dimethylamino-propyl)-carbamoyl]-phenylamino}-1-phenyl-methylidene]-2-indolinone-6-carboxylate
Prepared from 1-acetyl-3-(1-ethoxy-1-phenylmethylene)-6-methoxycarbonyl-2-indolinone and 3-amino-N-(3-dimethylamino-propyl)-benzamide.
Yield: 53% of theoretical,
Rf value: 0.2 (silica gel, methylene chloride/methanol=4:1)
C29H30N4O4 
Mass spectrum: m/z=497 [M−H]−
(10) methyl 3-(Z)-[1-{3-[(3-dimethylamino-propyl)-N-methyl-carbamoyl]-phenylamino}-1-phenyl-methylidene]-2-indolinone-6-carboxylate
Prepared from 1-acetyl-3-(1-ethoxy-1-phenylmethylene)-6-methoxycarbonyl-2-indolinone and 3-amino-N-(3-dimethylamino-propyl)-N-methyl-benzamide.
Yield: 25% of theoretical,
Rf value: 0.5 (silica gel, methylene chloride/methanol=4:1)
C30H32N4O4 
Mass spectrum: m/z=513 [M+H]+
(11) methyl 3-(Z)-[1-{4-[(4-methyl-piperazin-1-yl)-carbonyl]-phenylamino}-1-phenyl-methylidene]-2-indolinone-6-carboxylate
Prepared from 1-acetyl-3-(1-ethoxy-1-phenylmethylene)-6-methoxycarbonyl-2-indolinone and 4-(4-methyl-piperazin-1-yl-carbonyl)-aniline.
Yield: 0.1 g (23% of theoretical),
Melting point: 196-197° C.
C29H28N4O4 
Mass spectrum: m/z=495 [M−H]−
(12) methyl 3-(Z)-[1-{4-[(piperidin-1-yl)-carbonyl]-phenylamino}-1-phenyl-methylidene]-2-indolinone-6-carboxylate
Prepared from 1-acetyl-3-(1-ethoxy-1-phenylmethylene)-6-methoxycarbonyl-2-indolinone and 4-(piperidin-1-yl-carbonyl)-aniline.
Yield: 0.25 g (60% of theoretical),
Melting point: 268-269° C.
C29H27N3O4 
Mass spectrum: m/z=480 [M−H]−
(13) methyl 3-(Z)-[1-{4-[N-cyclohexyl-N-methyl-carbamoyl]-phenylamino}-1-phenyl-methylidene]-2-indolinone-6-carboxylate
Prepared from 1-acetyl-3-(1-ethoxy-1-phenylmethylene)-6-methoxycarbonyl-2-indolinone and 4-amino-N-cyclohexyl-N-methyl-benzamide.
Yield: 0.25 g (57% of theoretical),
Melting point: 263-265° C.
C31H31N3O4 
Mass spectrum: m/z=508 [M−H]−
(14) methyl 3-(Z)-[1-{4-[isopropyl-carbamoyl]-phenylamino}-1-phenyl-methylidene]-2-indolinone-6-carboxylate
Prepared from 1-acetyl-3-(1-ethoxy-1-phenylmethylene)-6-methoxycarbonyl-2-indolinone and 4-amino-N-isopropyl-benzamide.
Yield: 0.18 g (46% of theoretical),
Melting point: 273-274° C.
C27H25N3O4 
Mass spectrum: m/z=454 [M−H]−
(15) methyl 3-(Z)-[1-{4-[2,3,4,5-tetrahydro-1 (H)-benzo[d]azepin-3-yl-carbonyl]-phenyl-amino}-1-phenyl-methylidene]-2-indolinone-6-carboxylate
Prepared from 1-acetyl-3-(1-ethoxy-1-phenylmethylene)-6-methoxycarbonyl-2-indolinone and 4-(2,3,4,5-tetrahydro-1(H)-benzo[d]azepin-3-yl-carbonyl)-aniline.
Yield: 0.19 g (40% of theoretical),
Melting point: 278-279° C.
C34H29N3O4 
Mass spectrum: m/z=542 [M−H]−
(16) methyl 3-(Z)-[1-{4-[(4-hydroxy-piperidin-1-yl)-carbonyl]-phenylamino}-1-phenyl-methylidene]-2-indolinone-6-carboxylate
Prepared from 1-acetyl-3-(1-ethoxy-1-phenylmethylene)-6-methoxycarbonyl-2-indolinone and 4-(4-hydroxy-piperidin-1-yl-carbonyl)-aniline.
Yield: 0.21 g (49% of theoretical),
Melting point: from 320° C. decomposition
C29H27N3O5 
Mass spectrum: m/z=496 [M−H]−
(17) methyl 3-(Z)-[1-{4-[(4-tert-butyloxycarbonyl-piperazin-1-yl)-carbonyl]-phenylamino}-1-phenyl-methylidene]-2-indolinone-6-carboxylate
Prepared from 1-acetyl-3-(1-ethoxy-1-phenylmethylene)-6-methoxycarbonyl-2-indolinone and 4-(4-tert-butyloxycarbonyl-piperazin-1-yl-carbonyl)-aniline.
Yield: 0.45 g (45% of theoretical),
Melting point: from 238° C. decomposition
C33H34N4O6 
Mass spectrum: m/z=581 [M−H]−
(18) methyl 3-(Z)-[1-{4-[(4-tert-butyloxycarbonyl-[1,4]diazepan-1-yl)-carbonyl]-phenyl-amino}-1-phenyl-methylidene]-2-indolinone-6-carboxylate
Prepared from 1-acetyl-3-(1-ethoxy-1-phenylmethylene)-6-methoxycarbonyl-2-indolinone and 4-(4-tert-butyloxycarbonyl-[1,4]diazepan-1-yl-carbonyl)-aniline.
Yield: 0.58 g (56% of theoretical),
Melting point: from 213° C. decomposition
C34H36N4O6 
Mass spectrum: m/z=595 [M−H]−
(19) methyl 3-(Z)-[1-(4-carbamoyl-phenylamino)-1-phenyl-methylidene]-2-indolinone-6-carboxylate
Prepared from 1-acetyl-3-(1-ethoxy-1-phenylmethylene)-6-methoxycarbonyl-2-indolinone and 4-amino-benzamide.
Yield: 71% of theoretical
Rf value: 0.5 (silica gel, methylene chloride/methanol=9:1)
C24H19N3O4 
Mass spectrum: m/z=412 [M−H]−
(20) methyl 3-(Z)-[1-(4-propylcarbamoyl-phenylamino)-1-phenyl-methylidene]-2-indolinone-6-carboxylate
Prepared from 1-acetyl-3-(1-ethoxy-1-phenylmethylene)-6-methoxycarbonyl-2-indolinone and 4-amino-N-propylbenzamide.
Yield: 56% of theoretical,
Rf value: 0.4 (silica gel, methylene chloride/methanol=9:1)
C27H25N3O4 
Mass spectrum: m/z=456 [M+H]+
(21) methyl 3-(Z)-[1-(4-dimethylcarbamoyl]-phenylamino)-1-phenyl-methylidene]-2-indolinone-6-carboxylate
Prepared from 1-acetyl-3-(1-ethoxy-1-phenylmethylene)-6-methoxycarbonyl-2-indolinone and 4-amino-N,N-dimethylbenzamide.
Yield: 82% of theoretical,
Rf value: 0.6 (silica gel, methylene chloride/methanol=9:1)
C26H23N3O4 
Mass spectrum: m/z=440 [M−H]−
(22) methyl 3-(Z)-[1-{3-[N-(carbamoyl-methyl)-N-methyl-carbamoyl]-phenylamino}-1-phenyl-methylidene]-2-indolinone-6-carboxylate
Prepared from 1-acetyl-3-(1-ethoxy-1-phenylmethylene)-6-methoxycarbonyl-2-indolinone and 3-amino-N-carbamoylmethyl-N-methyl-benzamide.
Yield: 39% of theoretical,
Rf value: 0.35 (silica gel, methylene chloride/methanol=9:1)
C27H24N4O5 
Mass spectrum: m/z=483 [M−H]−
(23) methyl 3-(Z)-[1-{3-[N-(2-methoxy-ethyl)-N-methyl-carbamoyl]-phenylamino}-1-phenyl-methylidene]-2-indolinone-6-carboxylate
Prepared from 1-acetyl-3-(1-ethoxy-1-phenylmethylene)-6-methoxycarbonyl-2-indolinone and 3-amino-N-(2-methoxy-ethyl)-N-methyl-benzamide.
Yield: 59% of theoretical,
Rf value: 0.45 (silica gel, methylene chloride/methanol=9:1)
C28H27N3O5 
Mass spectrum: m/z=484 [M−H]−
(24) methyl 3-(Z)-[1-{3-[(2-carbamoyl-ethyl)-carbamoyl]-phenylamino}-1-phenyl-methylidene]-2-indolinone-6-carboxylate
Prepared from 1-acetyl-3-(1-ethoxy-1-phenylmethylene)-6-methoxycarbonyl-2-indolinone and 3-amino-N-(2-carbamoylethyl)-benzamide.
Yield: 40% of theoretical,
Rf value: 0.35 (silica gel, methylene chloride/methanol=9:1)
C27H24N4O5 
Mass spectrum: m/z=483 [M−H]−
(25) methyl 3-(Z)-[1-{3-[N,N-bis-(2-hydroxy-ethyl)-carbamoyl]-phenylamino}-1-phenyl-methylidene]-2-indolinone-6-carboxylate
Prepared from 1-acetyl-3-(1-ethoxy-1-phenylmethylene)-6-methoxycarbonyl-2-indolinone and 3-amino-N,N—(bis-(2-hydroxy-ethyl))-benzamide.
Yield: 67% of theoretical,
Rf value: 0.30 (silica gel, methylene chloride/methanol=9:1)
C28H27N3O6 
Mass spectrum: m/z=500 [M−H]−
(26) methyl 3-(Z)-[1-{1-methyl-2-[(2-dimethylamino-ethyl)-N-methyl-carbamoyl]-pyrrol-4-yl-amino}-1-phenyl-methylidene]-2-indolinone-6-carboxylate
Prepared from 1-acetyl-3-(1-ethoxy-1-phenylmethylene)-6-methoxycarbonyl-2-indolinone and 4-amino-1-methyl-2-[(2-dimethylamino-ethyl)-N-methyl-carbamoyl]-pyrrole.
Yield: 77% of theoretical,
Rf value: 0.70 (silica gel, methylene chloride/methanol/ammonia=8:2:0,1)
C28H31N5O4 
Mass spectrum: m/z=502 [M+H]+
(27) methyl 3-(Z)-[1-{4-[(4-dimethylamino-piperidin-1-yl)-carbonyl]-phenylamino}-1-phenyl-methylidene]-2-indolinone-6-carboxylate
Prepared from 1-acetyl-3-(1-ethoxy-1-phenylmethylene)-6-methoxycarbonyl-2-indolinone and 4-(4-dimethylamino-piperidin-1-yl-carbonyl)-aniline.
Yield: 57% of theoretical,
Rf value: 0.65 (silica gel, methylene chloride/methanol=9:1)
C31H32N4O4 
Mass spectrum: m/z=523 [M−H]−
(28) methyl 3-(Z)-[1-{4-[(4-ethyl-piperazin-1-yl)-carbonyl]-phenylamino}-1-phenyl-methylidene]-2-indolinone-6-carboxylate
Prepared from 1-acetyl-3-(1-ethoxy-1-phenylmethylene)-6-methoxycarbonyl-2-indolinone and 4-(4-ethyl-piperazin-1-yl-carbonyl)-aniline.
Yield: 41% of theoretical,
Rf value: 0.30 (silica gel, methylene chloride/methanol=9:1)
C30H30N4O4 
Mass spectrum: m/z=511 [M+H]+
(29) methyl 3-(Z)-[1-{4-[(4-(2-dimethylamino-ethyl)-piperazin-1-yl)-carbonyl]-phenylamino}-1-phenyl-methylidene]-2-indolinone-6-carboxylate
Prepared from 1-acetyl-3-(1-ethoxy-1-phenylmethylene)-6-methoxycarbonyl-2-indolinone and 4-(4-(2-dimethylamino-ethyl)-piperazin-1-yl-carbonyl)-aniline.
Yield: 31% of theoretical,
Rf value: 0.35 (silica gel, methylene chloride/methanol=9:1)
C32H35N5O4 
Mass spectrum: m/z=554 [M+H]+
(30) methyl 3-(Z)-[1-{4-[(4-(2-hydroxy-ethyl)-piperazin-1-yl)-carbonyl]-phenylamino}1-phenyl-methylidene]-2-indolinone-6-carboxylate
Prepared from 1-acetyl-3-(1-ethoxy-1-phenylmethylene)-6-methoxycarbonyl-2-indolinone and 4-(4-(2-hydroxy-ethyl)-piperazin-1-yl-carbonyl)-aniline.
Yield: 78% of theoretical,
Rf value: 0.35 (silica gel, methylene chloride/methanol=9:1)
C30H30N4O5 
Mass spectrum: m/z=525 [M−H]−
(31) methyl 3-(Z)-{1-[4-(5-methyl-2,5-diaza-bicyclo[2.2.1]hept-2-yl-carbonyl)-phenylamino]-1-phenyl-methylidene}-2-indolinone-6-carboxylate
Prepared from 1-acetyl-3-(1-ethoxy-1-phenylmethylene)-6-methoxycarbonyl-2-indolinone and 4-(5-methyl-2,5-diaza-bicyclo[2.2.1]hept-2-yl-carbonyl)-aniline.
Yield: 66% of theoretical,
Rf value: 0.25 (silica gel, methylene chloride/methanol/ammonia=9:1:0,1 [sic])
C30H28N4O4 
Mass spectrum: m/z=509 [M+H]+
(32) methyl 3-(Z)-[1-{4-[(4-tert-butyloxycarbonyl-trans-2,5-dimethyl-piperazin-1-yl)-carbonyl]-phenylamino}-1-phenyl-methylidene]-2-indolinone-6-carboxylate
Prepared from 1-acetyl-3-(1-ethoxy-1-phenylmethylene)-6-methoxycarbonyl-2-indolinone and 4-(4-tert-butyloxycarbonyl-trans-2,5-dimethyl-piperazin-1-yl-carbonyl)-aniline.
Yield: 63% of theoretical,
Rf value: 0.55 (silica gel, methylene chloride/methanol/ammonia=9:1:0,1 [sic])
C35H38N4O6 
Mass spectrum: m/z=611 [M+H]+
(33) methyl 3-(Z)-[1-{4-[(4-dimethylaminomethyl-piperidin-1-yl)-carbonyl]-phenylamino}-1-phenyl-methylidene]-2-indolinone-6-carboxylate
Prepared from 1-acetyl-3-(1-ethoxy-1-phenylmethylene)-6-methoxycarbonyl-2-indolinone and 4-(4-dimethylaminomethyl-piperidin-1-yl-carbonyl)-aniline.
Yield: 10% of theoretical,
Melting point: 235-236° C.
C32H34N4O4 
Mass spectrum: m/z=539 [M+H]+
(34) methyl 3-(Z)-[1-{4-[(cis-3,5-dimethyl-piperazin-1-yl)-carbonyl]-phenylamino}-1-phenyl-methylidene]-2-indolinone-6-carboxylate
Prepared from 1-acetyl-3-(1-ethoxy-1-phenylmethylene)-6-methoxycarbonyl-2-indolinone and 4-(cis-3,5-dimethyl-piperazin-1-yl-carbonyl)-aniline.
Yield: 41% of theoretical,
Melting point: 265-266° C.
C30H30N4O4 
Mass spectrum: m/z=511 [M+H]+
(35) methyl (R)-3-(Z)-[1-{4-[(3,4-dimethyl-piperazin-1-yl)-carbonyl]-phenylamino}-1-phenyl-methylidene]-2-indolinone-6-carboxylate
Prepared from 1-acetyl-3-(1-ethoxy-1-phenylmethylene)-6-methoxycarbonyl-2-indolinone and (R)-4-(3,4-dimethyl-piperazin-1-yl-carbonyl)-aniline.
Yield: 36% of theoretical,
Melting point: 265-266° C.
C30H30N4O4 
Mass spectrum: m/z=511 [M+H]+
(36) methyl 3-(Z)-[1-{4-[(4-(2-diethylamino-ethoxy)-piperidin-1-yl)-carbonyl]-phenylamino}-1-phenyl-methylidene]-2-indolinone-6-carboxylate
Prepared from 1-acetyl-3-(1-ethoxy-1-phenylmethylene)-6-methoxycarbonyl-2-indolinone and 4-(4-(2-diethylamino-ethoxy)-piperidin-1-yl-carbonyl)-aniline.
Yield: 12% of theoretical,
Melting point: 114° C.
C35H40N4O5 
Mass spectrum: m/z=597 [M+H]+
(37) methyl 3-(Z)-[1-{4-[(3-(2-diethylamino-ethoxy)-pyrrolidin-1-yl)-carbonyl]-phenylamino}-1-phenyl-methylidene]-2-indolinone-6-carboxylate
Prepared from 1-acetyl-3-(1-ethoxy-1-phenylmethylene)-6-methoxycarbonyl-2-indolinone and 4-(3-(2-diethylamino-ethoxy)-pyrrolidin-1-yl-carbonyl)-aniline.
Yield: 38% of theoretical,
Melting point: 133-134° C.
C34H38N4O5 
Mass spectrum: m/z=583 [M+H]+
(38) methyl 3-(Z)-[1-{4-[(3-dimethylamino-pyrrolidin-1-yl)-carbonyl]-phenylamino}-1-phenyl-methylidene]-2-indolinone-6-carboxylate
Prepared from 1-acetyl-3-(1-ethoxy-1-phenylmethylene)-6-methoxycarbonyl-2-indolinone and 4-(3-dimethylamino-pyrrolidin-1-yl-carbonyl)-aniline.
Yield: 32% of theoretical,
Melting point: 259-260° C.
C30H30N4O4 
Mass spectrum: m/z=511 [M+H]+
Example 2
Methyl 3-(Z)-[1-{4-[(piperazin-1-yl)-carbonyl]-phenylamino}-1-phenyl-methylidene]-2-indolinone-6-carboxylate-trifluoroacetate
A solution of 0.2 g (0.343 mmol) of methyl 3-(Z)-[1-{4-[(4-tert-butyloxycarbonyl-piperazin-1-yl)-carbonyl]-phenylamino}-1-phenyl-methylidene]-2-indolinone-6-carboxylate and 0.079 ml of trifluoroacetic acid in 20 ml of dichloromethane is stirred for 50 hours at ambient temperature. Then the solvent is distilled off in vacuo and the residue is combined with diisopropyl ether. The precipitate is filtered off and washed with diisopropyl ether.
Yield: 0.19 g (92% of theoretical),
Melting point: 270-271° C.
C28H26N4O4 
Mass spectrum: m/z=483 [M+H]+
The following compounds are prepared analogously to Example 2:
(1) methyl 3-(Z)-[1-{4-[([1,4]diazepan-1-yl)-carbonyl]-phenylamino}-1-phenyl-methylidene]-2-indolinone-6-carboxylate-trifluoroacetate
A solution of 0.25 g (0.419 mmol) of methyl 3-(Z)-[1-{4-[(4-tert-butyloxycarbonyl-[1,4]diazepan-1-yl)-carbonyl]-phenylamino}-1-phenyl-methylidene]-2-indolinone-6-carboxylate and 0.4 ml of trifluoroacetic acid in 20 ml of dichloromethane is stirred for 48 hours at ambient temperature and for two hours at 45° C. The solvent is distilled off in vacuo and the residue is combined with diisopropyl ether. The precipitate is filtered off and washed with diisopropyl ether.
Yield: 0.23 g (89% of theoretical),
Melting point: 261-262° C.
C29H28N4O4 
Mass spectrum: m/z=497 [M+H]+
(2) methyl 3-(Z)-[1-{4-[N-(2-methylamino)-ethyl)-N-methyl-carbamoyl]-phenylamino}-1-phenyl-methylidene]-2-indolinone-6-carboxylate
Prepared from methyl 3-(Z)-[1-{4-[(2-(tert-butyloxycarbonyl-methylamino)-ethyl)-N-methyl-carbonyl]-phenylamino}-1-phenyl-methylidene]-2-indolinone-6-carboxylate by treating with trifluoroacetic acid at ambient temperature in methylene chloride.
Yield: 86% of theoretical
Rf value: 0.5 (silica gel, methylene chloride/methanol=4:1)
C28H28N4O4 
Mass spectrum: m/z=485 [M+H]+
(3) methyl 3-(Z)-[1-{4-[(trans-2,5-dimethyl-piperazin-1-yl)-carbonyl]-phenylamino}-1-phenyl-methylidene]-2-indolinone-6-carboxylate-trifluoroacetate
Prepared from methyl 3-(Z)-[1-{4-[(4-tert-butyloxycarbonyl-trans-2,5-dimethyl-piperazin-1-yl)-carbonyl]-phenylamino}-1-phenyl-methylidene]-2-indolinone-6-carboxylate by treating with trifluoroacetic acid at ambient temperature in methylene chloride.
Yield: 100% of theoretical
Rf value: 0.4 (silica gel, methylene chloride/methanol/ammonia=9:1:0,1 [sic])
C30H30N4O4 
Mass spectrum: m/z=511 [M+H]+
Example 3
3-(Z)-[1-{4-[(4-methyl-piperazin-1-yl)-carbonyl]-phenylamino}-1-phenyl-methylidene]-2-indolinone-6-carboxylic acid
155 mg (310 mmol) of methyl 3-(Z)-[1-{4-[(4-methyl-piperazin-1-yl)-carbonyl]-phenylamino}-1-phenyl-methylidene]-2-indolinone-6-carboxylate are dissolved in 5 ml of methanol, 0.5 ml of 10N sodium hydroxide solution are added and the mixture is stirred for 8 hours at 50° C. Then the mixture is neutralised with dilute hydrochloric acid and water is added. The precipitate is filtered off and purified through an RP18-column with a gradient of acetonitrile and water as eluant.
Yield: 13 mg (9% of theoretical),
Melting point: 218° C.
C28H26N4O4 
Mass spectrum: m/z=483 [M+H]+
The following compounds may be prepared analogously to the foregoing Examples:

    (1) methyl 3-(Z)-[1-{4-[N,N-bis-(2-dimethylamino-ethyl)-carbamoyl]-phenylamino}-1-phenyl-methylidene]-2-indolinone-6-carboxylate
    (2) methyl 3-(Z)-[1-{4-[N,N-bis-(3-diethylamino-propyl)-carbamoyl]-phenylamino}-1-phenyl-methylidene]-2-indolinone-6-carboxylate
    (3) methyl 3-(Z)-[1-{4-[(2-diethylamino-ethyl)-carbamoyl]-phenylamino}-1-phenyl-methylidene]-2-indolinone-6-carboxylate
    (4) methyl 3-(Z)-[1-{4-[N,N-bis-(2-hydroxy-ethyl)-carbamoyl]-phenylamino}-1-phenyl-methylidene]-2-indolinone-6-carboxylate
    (5) methyl 3-(Z)-[1-{4-[N-(carbamoyl-methyl)-N-methyl-carbamoyl]-phenylamino}-1-phenyl-methylidene]-2-indolinone-6-carboxylate
    (6) methyl 3-(Z)-[1-{4-[(2-carbamoyl-ethyl)-carbamoyl]-phenylamino}-1-phenyl-methylidene]-2-indolinone-6-carboxylate
    (7) methyl 3-(Z)-[1-{3-[N-(2-hydroxy-ethyl)-N-methyl-carbamoyl]-phenylamino}-1-phenyl-methylidene]-2-indolinone-6-carboxylate
    (8) methyl 3-(Z)-[1-{3-[N-(2-methylamino-ethyl)-N-methyl-carbamoyl]-phenylamino}-1-phenyl-methylidene]-2-indolinone-6-carboxylate
    (9) methyl 3-(Z)-[1-{3-[N(2-aminoethyl)-carbamoyl]-phenylamino}-1-phenyl-methylidene]-2-indolinone-6-carboxylate
    (10) methyl 3-(Z)-[1-{4-[(2-(tert-butyloxycarbonyl-amino)-ethyl)-carbamoyl]-phenylamino}-1-phenyl-methylidene]-2-indolinone-6-carboxylate
    (11) methyl 3-(Z)-[1-{5-[(2-dimethylamino-ethyl)-N-methyl-carbamoyl]-furan-2-yl-amino}-1-phenyl-methylidene]-2-indolinone-6-carboxylate
    (12) methyl 3-(Z)-[1-{4-[(2-amino-ethyl)-carbamoyl]-phenylamino}-1-phenyl-methylidene]-2-indolinone-6-carboxylate
    (13) methyl 3-(Z)-[1-{4-[(4-(2-dimethylamino-ethoxy)-piperidin-1-yl)-carbonyl]-phenylamino}-1-phenyl-methylidene]-2-indolinone-6-carboxylate
    (14) methyl 3-(Z)-[1-{4-[(3-(2-dimethylamino-ethoxy)-pyrrolidin-1-yl)-carbonyl]-phenylamino}-1-phenyl-methylidene]-2-indolinone-6-carboxylate
    (15) methyl (S)-3-(Z)-[1-{4-[(3,4-dimethyl-piperazin-1-yl)-carbonyl]-phenylamino}-1-phenyl-methylidene]-2-indolinone-6-carboxylate


The compounds synthesised or capable of being synthesised according to Examples 1 and 2 are listed in Table 1.







TABLE 1







Compounds of general formula
















Example
R4
R6





1





—(C═O)—N(CH3)—(CH2)2—N(CH3)2


1(1)





—(C═O)—NH—(CH2)2—N(CH3)2


1(2)





—(C═O)—NH—(CH2)3—N(CH3)2


1(3)





—(C═O)—N(CH3)—(CH2)3—N(CH3)2


1(4)





—(C═O)—N(CH2CH3)—CH2CH2—N(CH3)2


1(5)





—(C═O)—N(CH3)—CH2CH2—N(CH3)—COOC(CH3)3


1(6)





—(C═O)—N[CH2CH2—N(CH2CH3)2]2


1(7)





—(C═O)—NH—CH2CH2—N(CH3)2


1(8)





—(C═O)—N(CH3)—CH2CH2—N(CH3)2


1(9)





—(C═O)—NH—CH2CH2CH2—N(CH3)2


1(10)





—(C═O)—N(CH3)—CH2CH2CH2—N(CH3)2


1(11)












1(12)












1(13)












1(14)





—(C═O)—NH—CH(CH3)2


1(15)












1(16)












1(17)












1(18)












1(19)





—(C═O)—NH2


1(20)





—(C═O)—NH—CH2CH2CH3


1(21)





—(C═O)—N(CH3)2


1(22)





—(C═O)—N(CH3)—CH2—(C═O)—NH2


1(23)





—(C═O)—N(CH3)—CH2CH2—OCH3


1(24)





—(C═O)—NH—CH2CH2—CONH2


1(25)





—(C═O)—N[CH2CH2—OH]2


1(26)





—(C═O)—N(CH3)—CH2CH2—N(CH3)2


1(27)












1(28)












1(29)












1(30)












1(31)












1(32)












1(33)












1(34)












1(35)












1(36)












1(37)












1(38)












2












2(1)












2(2)





—(C═O)—N(CH3)—CH2CH2—NH(CH3)


2(3)












(1)





—(C═O)—N[CH2CH2—N(CH3)2]2


(2)





—(C═O)—NH—CH2CH2CH2—N(CH2CH3)2


(3)





—(C═O)—NH—CH2CH2—N(CH2CH3)2


(4)





—(C═O)—N(CH2CH2OH)2


(5)





—(C═O)—N(CH3)—CH2—(C═O)—NH2


(6)





—(C═O)—NH—CH2CH2—CONH2


(7)





—(C═O)—N(CH3)—CH2CH2—OH


(8)





—(C═O)—N(CH3)—CH2CH2—NH—CH3


(9)





—(C═O)—NH—CH2CH2—NH2


(10)





—(C═O)—NH—CH2CH2—NH—COOC(CH3)3


(11)





—(C═O)—N(CH3)—CH2CH2—N(CH3)2


(12)





—(C═O)—NH—CH2CH2—NH2


(13)












(14)












(15)



















Example 4
Dry Ampoule Containing 75 mg of Active Substance per 10 ml













Composition:




















Active substance
75.0
mg



Mannitol
50.0
mg



water for injections
ad 10.0
ml










Preparation:
Active substance and mannitol are dissolved in water. After packaging, the solution is freeze-dried. To produce the solution ready for use, the product is dissolved in water for injections.
Example 5
Dry Ampoule Containing 35 mg of Active Substance per 2 ml













Composition:




















Active substance
35.0
mg



Mannitol
100.0
mg



water for injections
ad 2.0
ml










Preparation:
Active substance and mannitol are dissolved in water. After packaging, the solution is freeze-dried.
To produce the solution ready for use, the product is dissolved in water for injections.
Example 6
Tablet Containing 50 mg of Active Substance













Composition:



















(1) Active substance
50.0 mg



(2) Lactose
98.0 mg



(3) Maize starch
50.0 mg



(4) Polyvinylpyrrolidone
15.0 mg



(5) Magnesium stearate
 2.0 mg




215.0 mg 










Preparation:
(1), (2) and (3) are mixed together and granulated with an aqueous solution of (4). (5) is added to the dried granulated material. From this mixture tablets are pressed, biplanar, faceted on both sides and with a dividing notch on one side. Diameter of the tablets: 9 mm.
Example 7
Tablet Containing 350 mg of Active Substance













Composition:



















(1) Active substance
350.0 mg



(2) Lactose
136.0 mg



(3) Maize starch
 80.0 mg



(4) Polyvinylpyrrolidone
 30.0 mg



(5) Magnesium stearate
 4.0 mg




600.0 mg










Preparation
(1), (2) and (3) are mixed together and granulated with an aqueous solution of (4). (5) is added to the dried granulated material. From this mixture tablets are pressed, biplanar, faceted on both sides and with a dividing notch on one side. Diameter of the tablets: 12 mm.
Example 8
Capsules containing 50 mg of active substance













Composition:



















(1) Active substance
50.0 mg



(2) Dried maize starch
58.0 mg



(3) Powdered lactose
50.0 mg



(4) Magnesium stearate
 2.0 mg




160.0 mg 










Preparation:
(1) is triturated with (3). This trituration is added to the mixture of (2) and (4) with vigorous mixing.
This powder mixture is packed into size 3 hard gelatine capsules in a capsule filling machine.
Example 9
Capsules containing 350 mg of active substance













Composition:



















(1) Active substance
350.0 mg



(2) Dried maize starch
 46.0 mg



(3) Powdered lactose
 30.0 mg



(4) Magnesium stearate
 4.0 mg




430.0 mg










Preparation:
(1) is triturated with (3). This trituration is added to the mixture of (2) and (4) with vigorous mixing.
This powder mixture is packed into size 0 hard gelatine capsules in a capsule filling machine.
Example 10
Suppositories containing 100 mg of active substance













1 suppository contains:



















Active substance
100.0 mg



Polyethyleneglycol (M.W. 1500)
600.0 mg



Polyethyleneglycol (M.W. 6000)
460.0 mg



Polyethylenesorbitan monostearate
840.0 mg




2,000.0 mg 










Preparation:
The polyethyleneglycol is melted together with polyethylene sorbitan monostearate. At 40° C. the ground active substance is homogeneously dispersed in the melt. It is cooled to 38° C. and poured into slightly chilled suppository moulds.

## Claims

1. A compound of formula (I): 




wherein
X denotes an oxygen or sulphur atom, 
R1 denotes a hydrogen atom or a group which can be cleaved in vivo, 
R2 denotes a carboxy group, a straight-chain or branched C1-6-alkoxycarbonyl group, a C4-7-cycloalkoxycarbonyl or an aryloxycarbonyl group, 
R3 denotes a hydrogen atom, a C1-6-alkyl, C3-7-cycloalkyl, trifluoromethyl or heteroryl group, 
or a phenyl or naphthyl group, or a phenyl or naphthyl group each mono- or disubstituted by a fluorine, chlorine, bromine or iodine atom, by a trifluoromethyl, C1-3-alkyl or C1-3-alkoxy group, while in the event of disubstitution the substituents may be identical or different, 
R4 denotes a phenyl, pyrrolyl or furanyl group, each substituted by R6, which R4 group may additionally be mono- or disubstituted by fluorine, chlorine, bromine or iodine atoms, by 
C1-5-alkyl, trifluoromethyl, hydroxy, C1-3-alkoxy, carboxy, C1-3-alkoxycarbonyl, amino, acetylamino, C1-3-alkyl-sulphonylamino, aminocarbonyl, C1-3-alkyl-aminocarbonyl, di-(C1-3-alkyl)-aminocarbonyl, aminosulphonyl, C1-3-alkyl-aminosulphonyl, di-(C1-3-alkyl)-aminosulphonyl, nitro or cyano groups, while the substituents may be identical or different and wherein 
R6 denotes an aminocarbonyl, C1-4-alkylamino-carbonyl, N—(C1-5-alkyl)-N—C1-3-alkylamino-carbonyl, C3-7-cycloalkylamino-carbonyl, N—(C1-5-alkyl)-N—C3-7-cycloalkylaminocarbonyl, (phenyl-C1-3-alkyl)amino-carbonyl, N—(C1-3-alkyl)-N-phenyl-C1-3-alkylamino-carbonyl group, 
or a C1-3-alkylaminocarbonyl or N—(C1-3-alkyl)-N—C1-3-alkylaminocarbonyl group, wherein one or two alkyl moieties are substituted independently of one another by a nitro, cyano, carbamoyl, N—(C1-3-alkyl)-carbamoyl, di-N—(C1-3-alkyl)-carbamoyl, carboxy or C1-3-alkoxycarbonyl group or are substituted in the 2- or 3-position by an amino (C1-3-alkyl)-amino, di-(C1-3-alkyl)-amino, (C1-4-alkoxycarbonyl)-amino, N—(C1-4-alkoxycarbonyl)-N—(C1-3-alkyl)-amino, piperazino, N—(C1-3-alkyl)-piperazino, a 4- to 7-membered cyclo-alkyleneimino group, a hydroxy or methoxy group, 
or a 4- to 7-membered cycloalkyleneiminocarbonyl group wherein 
the cycloalkylene moiety may be fused to a phenyl ring via two adjacent ring atoms or may form a bridge to a methylene or ethylene group via two non-adjacent ring atoms or 
one or two hydrogen atoms may each be replaced by a C1-3-alkyl group and/or 
in each case the methylene group in the 4 position of a 6- or 7-membered cyclo-alkyleneiminocarbonyl group may be substituted by a carboxy, C1-4-alkoxycarbonyl, aminocarbonyl, C1-3-alkylaminocarbonyl, di-(C1-3-alkyl)-aminocarbonyl, di-(C1-3-alkyl)-amino-C1-3-alkyl, di-(C1-3-alkyl)-amino, phenyl-C1-3-alkylamino or N—(C1-3-alkyl)-N-phenyl-C1-3-alkylamino group or a hydroxy or methoxy group or may be replaced by an oxygen or sulphur atom, by a sulphinyl, sulphonyl or —NH group or by a nitrogen atom which is substituted by a C1-3-alkyl, phenyl, C1-3-alkyl-carbonyl, C1-4-alkoxy-carbonyl, di-(C1-3-alkyl)-amino-C1-3-alkyl, ω-hydroxy-C2-3-alkyl or benzoyl group, 
wherein all the single-bonded or fused phenyl groups contained in the R6 groups may be mono- or disubstituted by fluorine, chlorine, bromine or iodine atoms, by C1-5-alkyl, trifluoromethyl, hydroxy, C1-3-alkoxy, carboxy, C1-3-alkoxycarbonyl, aminocarbonyl, C1-4-alkylamino-carbonyl, di-(C1-4-alkyl)-amino-carbonyl, aminosulphonyl, C1-3-alkyl-aminosulphonyl, di-(C1-3-alkyl)-aminosulphonyl, C1-3-alkyl-sulphonylamino, nitro or cyano groups, wherein the substituents may be identical or different, or two adjacent hydrogen atoms of the phenyl groups may be replaced by a methylenedioxy group, 


and
R5 denotes a hydrogen atom or a C1-3-alkyl group, 
wherein by the term aryl in the aryloxycarbonyl group is meant a phenyl or naphthyl group, each optionally mono- or disubstituted by a fluorine, chlorine, bromine or iodine atom, by a cyano, trifluoromethyl, nitro, carboxy, aminocarbonyl, C1-3-alkyl or C1-3-alkoxy group and 
by the term heteroaryl group is meant a monocyclic 5- or 6-membered heteroary group optionally substituted in the carbon skeleton by a C1-3-alkyl group, wherein 
the 6-membered heteroaryl group contains one, two or three ring nitrogen atoms and 
the 5-membered heteroaryl group contains a ring atom selected from an imino group optionally substituted by a C1-3-alkyl or phenyl-C1-3-alkyl group, an oxygen or sulphur atom or 
a ring atom selected from an imino group optionally substituted by a C1-3-alkyl or phenyl-C1-3-alkyl group or an oxygen or sulphur atom, and additionally a ring nitrogen atom or 
an imino ring atom group optionally substituted by a C1-3-alkyl or phenyl-C1-3-alkyl group and two ring nitrogen atoms, 
and wherein a phenyl ring may be fused to the abovementioned monocyclic heteroaryl groups via two adjacent carbon atoms of the phenyl ring and via a nitroge atom or via a carbon atom of the heteroaryl group, 

wherein the hydrogen atoms in the abovementioned alkyl and alkoxy groups or in any alkyl moieties contained in the above-defined groups R1, R2, R3, R4 or R5 may be wholly or partly replaced by fluorine atoms, 
any saturated alkyl and alkoxy moieties containing more than 2 carbon atoms in the groups defined above also include the branched isomers thereof, and 
wherein a hydrogen atom of any carboxy group or a hydrogen atom bound to a nitrogen atom may each be replaced by a group which can be cleaved in vivo, 
or a tautomer, diastereomer, enantiomer, mixture thereof or a salt thereof, 
with the proviso that when R2 denotes a carboxy group or a straight-chain or branched C1-4-alkoxycarbonyl group, then R3 does not denote a hydrogen atom, a C1-6-alkyl, or a triftluoromethyl group.

2. A compound of formula I according to claim 1, wherein
X denotes an oxygen atom, 
R1 denotes a hydrogen atom, a C1-4-alkoxycarbonyl or C2-4-alkanoyl group, 
R2 denotes a carboxy group or a straight-chain or branched C1-4-alkoxycarbonyl group, 
R3 denotes a hydrogen atom, a C1-6-alkyl or C3-7-cycloalkyl group, 
or a phenyl or naphthyl group, or a phenyl or naphthyl group each mono- or disubstituted by a fluorine, chlorine or bromine atom, by a trifluoromethyl, C1-3-alkyl or C1-3-alkoxy group, while in the case of disubstitution the substituents ay be identical or different, 
R4 denotes a furanyl group substituted by an aminocarbonyl, C1-4-alkylaminocarbonyl or N—(C1-4-alkyl)-N—C1-3-alkylaminocarbonyl group, wherein the C1-4-alkyl-aminocarbonyl or N—(C1-4-alkyl)-N—C1-3-alkylaminocarbonyl group each may be substituted at position 2 in one or both alkyl moieties by an amino, C1-3-alkylamino or di-(C1-3-alkyl)amino group, 
or a pyrrolyl group substituted by an aminocarbonyl, C1-4-alkylaminocarbonyl or N—(C1-4-alkyl)-N—C1-3-alkylaminocarbonyl group, wherein the C1-4-alkyl-aminocarbonyl or N—(C1-4-alkyl)-N—C1-3-alkylaminocarbonyl group may each be substituted at position 2 in one or both alkyl moieties by an amino, C1-3-alkylamino or di-(C1-3-alkyl)amino group and the nitrogen atom of the pyrrolyl ring is optionally substituted by a C1-3-alkyl group, or 
a phenyl group substituted by the group R6, which phenyl group may additionally be mono- or disubstituted by fluorine, chlorine or bromine atoms, by C1-5-alkyl, trifluoromethyl, hydroxy, C1-3-alkoxy, carboxy, C1-3-alkoxycarbonyl, amino, acetylamino, C1-3-alkyl-sulphonylamino, aminocarbonyl, C1-3-alkyl-aminocarbonyl, di-(C1-3-alkyl)-aminocarbonyl, aminosulphonyl, C1-3-alkyl-aminosulphonyl, di-(C1-3-alkyl)-aminosulphonyl, nitro or cyano groups, while the substituents may be identical or different and wherein 
R6 denotes an aminocarbonyl, C1-4-alkylamino-carbonyl, N—(C1-5-alkyl)-N—C1-3-alkyl-aminocarbonyl, C3-7-cycloalkylamino-carbonyl, N—(C1-5-alkyl)-N—C3-7-cycloalkyl-aminocarbonyl, (phenyl-C1-3-alkyl)amino-carbonyl, N—(C1-3-alkyl)-N-phenyl-C1-3-alkylamino-carbonyl group, 
or a C1-3-alkylaminocarbonyl or N—(C1-3-alkyl)-N—C1-3-alkylaminocarbonyl group, wherein one or two alkyl moieties are substituted independently of one a other by a nitro, cyano, carbamoyl, N—(C1-3-alkyl)-carbamoyl, di-N—(C1-3-alkyl)-carbamoyl, carboxy or C1-3-alkoxycarbonyl group or are substituted in the 2- or 3-position by an amino, (C1-3-alkyl)-amino, di-(C1-3-alkyl)-amino, (C1-4-alkoxycarbonyl)-amino, N—(C1-4-alkoxycarbonyl)-N—(C1-3-alkyl)-amino, piperazino, N—(C1-3-alkyl)-piperazino, a piperazinyl or piperidinyl group, a hydroxy or methoxy group, 
or a 4- to 7-membered cycloalkyleneiminocarbonyl group wherein 
the cycloalkylene moiety may be fused to a phenyl ring via two adjacent ring atoms or two non-adjacent ring atoms may form a bridge to a methylene or ethylene group or 
one or two hydrogen atoms may each be replaced by a C1-3-alkyl group and/or 
in each case the methylene group in the 4 position of a 6- or 7-membered cycloalkyleneiminocarbonyl group may be substituted by a carboxy, C1-4-alkoxycarbonyl, aminocarbonyl, C1-3-alkylaminocarbonyl, di-(C1-3-alkyl)-aminocarbonyl, di-(C1-3-alkyl)-amino-C1-3-alkyl, di-(C1-3-alkyl)-amino, phenyl-C1-3-alkylamino or C1-3-alkyl)-N-phenyl-C1-3-alkylamino group, a hydroxy or methoxy group, or may be replaced by an oxygen or sulphur atom, by a sulphinyl, sulphonyl or —NH group or by a nitrogen atom, which is substituted by a C1-3-alkyl, phenyl, C1-3-alkyl-carbonyl, C1-4-alkoxy-carbonyl, di-(C1-3-alkyl)-amino-C1-3-alkyl, ω-hydroxy-C2-3-alkyl or benzoyl group, 


and
R5 denotes a hydrogen atom or a C1-3-alkyl group, 
wherein the hydrogen atoms in the abovementioned alkyl and alkoxy groups or any alkyl moieties contained in the above-defined groups R1, R2, R3, R4 or R5 may be wholly or partly replaced by fluorine atoms, 
any saturated alkyl and alkoxy moieties containing more than 2 carbon atoms in the groups defined above also include the branched isomers thereof, and 
wherein a hydrogen atom of any carboxy group or a hydrogen atom bound to a nitrogen atom may each be replaced by a group which can be cleaved in vivo, 
or a tautomer, diastereomer, enantiomer, mixture thereof or a salt thereof.

3. A compound of formula I according to claim 1, wherein
X denotes an oxygen atom, 
R1 denotes a hydrogen atom, 
R2 denotes a carboxy group or a C1-2-alkoxycarbonyl group, 
R3 denotes a phenyl or naphthyl group, or a phenyl group monosubstituted by a fluorine, chlorine or bromine atom, by a trifluoromethyl, C1-3-alkyl or C1-3-alkoxy group, 
R4 denotes a pyrrolyl group substituted by an aminocarbonyl, C1-4-alkylaminocarbonyl or N—(C1-4-alkyl)-N—C1-3-alkylaminocarbonyl group, wherein the C1-4-alkylaminocarbonyl or N—(C1-4-alkyl)-N—C1-3-alkylaminocarbonyl group may be substituted at position 2 in one or both alkyl moieties by an amino, C1-3-alkylamino or di-(C1-3-alkyl)amino group and the nitrogen atom of the pyrrolyl ring is optionally substituted by a C1-3-alkyl group, or 
a phenyl group substituted in the 3- or 4-position by the group R6, wherein 
R6 denotes an aminocarbonyl, C1-4-alkylamino-carbonyl, N—(C1-3-alkyl)-N—C1-3-alkylamino-carbonyl, C5-6-cycloalkylamino-carbonyl, N—(C1-5-alkyl)-N—C5-6-cycloalkylaminocarbonyl group, 
or a C1-3-alkylaminocarbonyl or N—(C1-3-alkyl)-N—C1-3-alkylaminocarbonyl group, wherein one or two alkyl moieties are substituted independently of one another by a carbamoyl, N—(C1-3-alkyl)-carbamoyl, di-N—(C1-3-alkyl)-carbamoyl, C1-3-alkoxycarbonyl group or are substituted in the 2- or 3-position by an amino, (C1-3-alkyl)-amino, di-(C1-3-alkyl)-amino, (C1-4-alkoxycarbonyl)-amino, N—(C1-4-alkoxycarbonyl)-N—(C1-3-alkyl)-amino, piperazino, N—(C1-3-alkyl)-piperazino, a piperazinyl or piperidinyl group, a hydroxy or methoxy group, 
or a piperidinocarbonyl, piperazinocarbonyl, homopiperazinocarbonyl or 2,3,4,5-tetrahydro-1(H)-azepino-carbonyl group, 
each of which may be fused to a phenyl ring via two adjacent unsubstitute carbon atoms or 
each may be substituted in the 4 position by a C1-3-alkyl, C1-4-alkoxycarbonyl, di-(C1-3-alkyl)-amino, di-(C1-3-alkyl)-amino-C1-3-alkyl, 2-hydroxy-ethyl, hydroxy or methoxy group, 

or a 2,5-diaza-bicyclo[2.2.1]hept-2-yl-carbonyl group which may be substituted in the 5 position by a C1-3-alkyl group, 

and
R5 denotes a hydrogen atom or a C1-3-alkyl group, 
wherein the hydrogen atoms in the abovementioned methyl and methoxy groups may be replaced by 1, 2 or 3 fluorine atoms, and 
any saturated alkyl and alkoxy moieties containing more than 2 carbon atoms which are present in the groups defined above also include the branched isomers thereof, 
or a tautomer, diastereomer, enantiomer or mixture thereof or a salt thereof.

4. A compound of formula I according to claim 1, wherein
X denotes an oxygen atom, 
R1 and R5 each denote a hydrogen atom, 
R2 denotes a methoxycarbonyl group, 
R3 denotes a phenyl group and 
R4 denotes a phenyl group which is monosubstituted in the 3- or 4-position by the group R6, wherein 
R6 denotes an aminocarbonyl, C1-3-alkylamino-carbonyl, N—(C1-5-alkyl)-N—C1-3-alkylamino-carbonyl, cyclohexylaminocarbonyl, N—(C1-5-alkyl)-N-cyclohexylaminocarbonyl, phenyl-C1-3-alkylamino-carbonyl, N—(C1-3-alkyl)-N-phenyl-C1-3-alkylamino-carbonyl, 
or a piperidinocarbonyl, 4-hydroxy-piperidinocarbonyl, 4-[di-(C1-3-alkyl)-amino]-piperidinocarbonyl, 4-[di-(C1-3-alkyl)-amino-C1-3-alkyl]-piperidinocarbonyl, piperazinocarbonyl, N—(C1-3-alkyl)-piperazinocarbonyl, N—(C1-4-alkoxycarbonyl)-piperazinocarbonyl, N-[di-(C1-3-alkyl)-amino-C1-3-alkyl]-piperazinocarbonyl, N-(2-hydroxy-ethyl)-piperazinocarbonyl, homopiperazinocarbonyl, N—(C1-3-alkyl)-homopiperazinocarbonyl, 2,3,4,5-tetrahydro-1(H)-benzo[d]azepino-carbonyl or 5-methyl-2,5-diaza-bicycl[2.2.1]hept-2-yl-carbonyl group, 
or a C1-3-alkylaminocarbonyl or N—(C1-5-alkyl)-N—C1-3-alkylaminocarbonyl group wherein one or two alkyl moieties are substituted by a carbarnoyl group or are substitute in the 2- or 3-position by an amino, (C1-3-alkyl)-amino, di-(C1-3-alkyl)-amino, hydroxy or methoxy group, 
or a tautomer, diastereomer, enantiomer, or mixture thereof or a salt thereof.

5. A compound according to claim 1 which is:
(a) methyl 3-(Z)-[1-{4-[N-(2 -dimethylamino-ethyl)-N-methyl-carbamoyl]-phenylamino}-1-phenyl-methylidene]-2-indolinone-6-carboxylate; 
(b) methyl 3-(Z)-[1-{4-[N-(3-dimethylamino-propyl)-N-methyl-carbamoyl]-phenylamino}-1-phenyl-methylidene]-2-indolinone-6-carboxylate; 
(c) methyl 3-(Z)-[1-{4-[(4-methyl-piperazin-1-yl)-carbonyl]-phenylamino}-1-phenyl-methylidene]-2-indolinone-6-carboxylate; 
(d) methyl 3-(Z)-[1-{4-[(4-hydroxy-piperidin-1-yl)-carbonyl]-phenylamino}-1-phenyl-methylidene]-2-indolinone-6-carboxylate; 
(e) methyl 3-(Z)-[1-{4-[(piperazin-1-yl)-carbonyl]-phenylamino}-1-phenyl-methylidene]-2-indolinone-6-carboxylate; 
(f) methyl 3-(Z)-[1-{4-[N-(2-methylamino-ethyl)-N-methyl-carbamoyl]-phenylamino}-1-phenyl-methylidene]-2-indolinone-6-carboxylate; 
(g) methyl 3-(Z)-[1-{4-[(4-dimethylamino-piperidin-1-yl)-carbonyl]-phenylamino}-1-phenyl-methylidene]-2-indolinone-6-carboxylate; 
(h) methyl 3-(Z)-[1-{4-[(4-ethyl-piperazin-1-yl)-carbonyl]-phenylamino}-1-phenyl-methylidene]-2-indolinone-6-carboxylate; 
(i) methyl 3-(Z)-[1-{4-[(4-(2-hydroxy-ethyl)-piperazin-1-yl)-carbonyl]-phenylamino}-1-phenyl-methylidene]-2-indolinone-6-carboxylate; or 
(j) methyl 3-(Z)-{1-[4-(5-methyl-2,5-diaza-bicyclo[2.2.1]hept-2-yl-carbonyl)-phenylamino]-1-phenyl-methylidene}-2-indolinone-6-carboxylate; 
or a tautomer, mixture or salt thereof.

6. Methyl 3-(Z)-[1-{4-[(4-methyl-piperazin-1-yl)-carbonyl]-phenylamino}-1-phenyl-methylidene]-2-indolinone-6-carboxylate or a salt thereof.

7. A physiologically acceptable salt of a compound according to claim 1.

8. A pharmaceutical composition comprising a compound according to claim 1 optionally together with one or more inert carriers and/or diluents.

9. A method of treating a disease or condition characterized by excessive or anomalous endothelial cell proliferation in a patient comprising administering to said patient having said disease or condition an effective amount of a compound according to claim 1.