EP1379501A1 - Indolinones, substituted in position 6, and their use as kinase inhibitors - Google Patents

Abstract

The invention relates to indolinones, substituted in position 6, of general formula (I), in which R1 to R5 and X are defined as per claim (1). The invention also relates to their isomers and salts, in particular to their physiologically compatible salts, which have valuable pharmacological properties, specifically an inhibiting action on various receptor tyrosine kinases and cyclin/CDK complexes, in addition to on the proliferation of endothelium cells and various tumour cells. The invention further relates to medicaments containing said compounds, to the use of said medicaments and to a method for their production.

Description

 INDOLINES SUBSTITUTED IN 6-POSITION AND THEIR USE

AS KINASE INHIBITORS

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

their tautomers, their diastereomers, their enantiomers, their mixtures and their salts, in particular their physiologically tolerable salts, which have valuable properties.

The above compounds of general formula I, in which Rt represents a hydrogen atom or a prodrug residue, have valuable pharmacological properties, in particular an inhibitory effect on various kinases, especially on receptor tyrosine kinases such as VEGFR2, VEGFR3, PDGFRα, PDGFRß, FGFR1, FGFR3 , EGFR, HER2, IGF1 R and HGFR, and 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 (see L. engtao in J. Virology 71 (3), 1984-1991 (1997)), as well as on the Proliferation of cultivated human cells, in particular that of endothelial cells, for example in angiogenesis, but also on the proliferation of other cells, in particular tumor cells. The remaining compounds of the above general formula I, in which Ri represents no hydrogen atom and no prodrug residue, represent valuable intermediates for the preparation of the compounds mentioned above.

The present invention thus relates to the above compounds of the general formula I, the compounds in which R 1 represents a hydrogen atom or a prodrug residue have valuable pharmacological properties, the medicaments containing the pharmacologically active compounds, their use and processes for their preparation.

In the above general formula I mean

X is an oxygen or sulfur atom,

Ri is a hydrogen atom or a prodrug group such as a C _1- alkoxycarbonyl or C _2-4 alkanoyl group,

R _{2 is} a carboxy group, a linear or branched Cι. ₆ alkoxycarbonyl group, a C ₄ - ₇ -Cycloalkoxycarbonyl- or an aryloxycarbonyl group,

R _{3 is} a hydrogen atom, a Cι. ₆ alkyl, C _3-7 cycloalkyl, trifluoromethyl or heteroaryl group,

a phenyl or naphthyl group, or a mono- or disubstituted phenyl or naphthyl group by a fluorine, chlorine, bromine or iodine atom, by a trifluoromethyl, C-ι- ₃ alkyl or Cι- ₃ alkoxy group, where in the case of disubstitution, the substituents can be the same or different,

R _{4 is} a phenyl, pyrrolyl or furanyl group substituted by the group R ₆ , which is additionally substituted by fluorine, chlorine, bromine or iodine atoms, by C _-5 alkyl, trifluoromethyl, hydroxy, C _1-3 - alkoxy, carboxy, Cι _-3 alkoxycarbonyl, amino, acetyl amino, Cι-3-alkyl-sulfonylamino, aminocarbonyl, d- _C3 alkyl-aminocarbonyl, di- (C _-3 alkyl ) aminocarbonyl, aminosulfonyl, C ₃ alkyl alkyl aminosulfonyl, Di- (Cι- ₃ alkyl) aminosulfonyl, nitro or cyano groups can be mono- or disubstituted, where the substituents can be the same or different and where

R _δ an aminocarbonyl, Cι _-4 -alkylamino-carbonyl-, N- (Cι _-5 -alkyl) -Cι _-3 -alkylamino- carbonyl-, C _3-7 -cycloalkylamino-carbonyl-, N- (Cι- _5th -Alkyl) -C ₃ - ₇ -cycloalkylamino-carbonyl-, (phenyl-Cι _-3 -alkyl) amino-carbonyl-, N- (C _1-3 -alkyl) -phenyl-Cι _-3 -alkylamino- carbonyl group .

a Cι. ₃ -Alkylaminocarbonyl- or N- ^ is-alkyl -ds-alkylaminocarbonyl group in which one or two alkyl parts independently of one another by a nitro, cyano, carbamoyl, N- (Cι- ₃ alkyl) carbamoyl, di- N- (-C ₃ alkyl) carbamoyl, carboxy or C _f . ₃ -alkoxycarbonyl group or in the 2- or 3-position by an amino-, (-Cι- ₃ -alkyl) -amino-, di- (Cι- ₃ -alkyl) -amino-, (Cι- ₄ -alkoxycarbonyl) -amino- , N- (Ci ^ -alkoxycarbony -N - ^^ s-alkyamino-, piperazino-, N- (-Cι. ₃ alkyl) -piperazino-, a 4- to 7-membered cycloalkyleneimino group, a hydroxy or methoxy - are substituted,

a 4- to 7-membered cycloalkyleneiminocarbonyl group in which

the cycloalkylene part can be condensed with a phenyl ring via two adjacent ring atoms or can be bridged with a methylene or ethylene group via two non-adjacent ring atoms or

one or two hydrogen atoms can each be replaced by a Cι _-3 alkyl group or / and

each the methylene group in position 4 of a 6- or 7-membered cycloalkyleneiminocarbonyl group by a carboxy, Cι _-4 -alkoxycarbonyl, aminocarbonyl, Cι _-3 -alkylaminocarbonyl-, di- (C _1-3 -alkyl) -aminocarbonyl -, Di- (Ci-s-alkyamino-cis-alkyl-, di- (Cι_ ₃ -alkyl) -amino-, phenyl-C _1-3 -alkylamino- or N- (C _1-3 -alkyl) -phenyl-Cι.3-alkylamino group, a hydroxy or methoxy group substituted or by an oxygen or sulfur atom, by a sulfinyl, sulfonyl or -NH group or by a nitrogen atom by a Cι- alkyl, phenyl, Cι- ₃ alkyl carbonyl, Cι. ₄ -alkoxy-carbonyl-, di- (-Cι- ₃ -alkyl) -amino-Cι. ₃ -alkyl-, ω- hydroxy-C _2-3 -alkyl or benzoyl group is substituted, can be replaced,

wherein all contained in the groups mentioned under R ₆ residues single-bonded or fused phenyl groups by fluorine, chlorine, bromine or iodine atoms, by C-ι- ₅ alkyl, trifluoromethyl, hydroxy, Cι- ₃ alkoxy -, Carboxy-, Cι- ₃ -alkoxycarbonyl-, aminocarbonyl-, C _1-4 -alkylamino-carbonyl-, D C- -alkyO-amino-carbonyl-, aminosulfonyl-, Cι. _3- alkylaminosulfonyl-,

Di- (-C ₃ alkyl) aminosulfonyl, C ₃ alkyl sulfonylamino, nitro or cyano groups can be mono- or disubstituted, where the substituents can be the same or different, or two adjacent hydrogen atoms of the phenyl groups by a methylenedioxy group can be replaced,

and

R _{5 is} a hydrogen atom or a C _-3 alkyl group,

where under the expression an aryl group, optionally by a fluorine, chlorine, bromine or iodine atom, by a cyano, trifluoromethyl, nitro, carboxy, aminocarbonyl, C 1 -C ₃ alkyl or C ^ alkoxy group mono- or disubstituted phenyl or naphthyl group and

under the expression a heteroaryl group, a monocyclic 5- or 6-membered heteroaryl group optionally substituted by a C _1-3 alkyl group in the carbon skeleton, where

the 6-membered heteroaryl group has one, two or three nitrogen atoms and

the 5-membered heteroaryl group is an imino group optionally substituted by a C ₃ alkyl or phenyl C 3 C 3 alkyl group, an oxygen or sulfur atom or an imino group optionally substituted by a C ₃ alkyl or phenyl C ₃ alkyl group or an oxygen or sulfur atom and additionally a nitrogen atom or

contains an imino group optionally substituted by a C ₃ alkyl or phenyl C ₃ alkyl group and two nitrogen atoms,

and in addition a phenyl ring may be fused to the above-mentioned monocyclic heterocyclic groups via two adjacent carbon atoms and the binding takes place via a nitrogen atom or via a carbon atom of the heterocyclic part or a fused-on phenyl ring,

to understand

the hydrogen atoms in the alkyl and alkoxy groups mentioned above or in the alkyl parts contained in the groups of formula I defined above can be partially or completely replaced by fluorine atoms,

the saturated alkyl and alkoxy parts present in the groups defined above, which contain more than 2 carbon atoms, including their branched isomers, such as, for example, the isopropyl, tert-butyl, isobutyl group, unless stated otherwise, and

where in addition the hydrogen atom of an existing carboxy group or a hydrogen atom bonded to a nitrogen atom, for example an amino, alkylamino or imino group or a saturated N-heterocycle such as the piperidinyl group, can in each case be replaced by a radical which can be split off in vivo,

their tautomers, their diastereomers, their enantiomers, their mixtures and their salts. Among a group that can be split off from an imino or amino group in vivo is, for example, a hydroxy group, an acyl group such as the benzoyl or pyridinoyl group or a Cι.ι ₆ alkanoyl group such as the formyl, acetyl, propionyl, butanoyl -, Pentanoyl or hexanoyl group, an allyloxycarbonyl group, a C-ι- ₁₆ alkoxycarbonyl group such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, tert.butoxycarbonyl, pentoxycarbonyl, hexyloxycarbonyl, Octyloxycarbonyl, nonyloxycarbonyl, decyloxycarbonyl, undecyloxycarbonyl, dodecyloxycarbonyl or hexadecyloxycarbonyl group, a phenyl-C ₆ alkoxycarbonyl group such as the benzyloxycarbonyl, phenyl-ethoxycarbonyl or phenylpropoxycarbonyl group, a Gι- _3- alkyl ₄ -alkoxycarbonyl-, Cι- ₃ -alkoxy-C ₂ -4-alkoxy-C ₂ - ₄ -alkoxycarbonyl or R _e CO-O- (R _f CRg) -O-CO group, in the

R _{e is} a Cig-alkyl, C ₅ - ₇ cycloalkyl, phenyl or phenyl-C-ι- ₃ alkyl group,

R _{f is} a hydrogen atom, a C _-3 alkyl, C ₅ . _7- cycloalkyl or phenyl group and

R _{g represents} a hydrogen atom, a C _-3 alkyl or R _e CO-O- (R _f CR _g ) -O group, in which R _e to R _{g are} as defined above,

where the phthalimido group is additionally to be considered for an amino group, the ester radicals mentioned above also being able to be used as a group which can be converted into a carboxy group in vivo.

An essential feature of the present invention is that Rβ denotes an unsubstituted or substituted aminocarbonyl group as defined above or below.

Preferred compounds of general formula I are those in which

X is an oxygen atom, Ri is a hydrogen atom, a Cι _{-4-Alkoxycarbony} -.! Or C _2-4 alkanoyl,

R _{2 is} a carboxy group or a linear or branched C _-4 alkoxycarbonyl group,

R _{3 is} a hydrogen atom, a Ci-β-alkyl or C _3-7 cycloalkyl group,

a phenyl or naphthyl group, or by a fluorine, chlorine or bromine atom, by a trifluoromethyl, Cι. ₃ -alkyl or C-ι. ₃ -alkoxy group mono- or disubstituted phenyl or naphthyl group, where in the case of disubstitution the substituents can be the same or different,

R _{4 is} a furanyl group substituted by an aminocarbonyl, C 1 -C -alkylaminocarbonyl or N- (C ₄ alkyl) - C ₃ alkylaminocarbonyl group, the C 1 -C ₄ -alkyl aminocarbonyl or N- (C ₄ alkyl) ) -Cι _-3 -alkylaminocarbonylgruppe in one or both alkyl parts from position 2 can be substituted by an amino, C-ι_ ₃ alkylamino or di- (C-ι- ₃ - alkyl) amino group,

a pyrrolyl group substituted by an aminocarbonyl, C- _M- alkylaminocarbonyl or N- (-C _-4 -alkyl) - Cι-3-alkylaminocarbonyl group, the C ₁ . ₄ -alkyl- aminocarbonyl- or N- (-Cι- ₄ -alkyl) -Cι- ₃ -alkylaminocarbonylgruppe in one or both alkyl parts from position 2 through an amino-, d- ₃ -alkylamino- or di- (Cι_ ₃ - alkyl) can be substituted amino group and the nitrogen atom of the pyrrolyl ring is optionally substituted by a C-ι- ₃ alkyl group, or

a phenyl group substituted by the group R ₆ , additionally by fluorine, chlorine or bromine atoms, by Cι. ₅ -Alkyl-, trifluoromethyl-, hydroxy-, Cι _-3 -alkoxy-, carboxy-, C-ι-3-alkoxycarbonyl-, amino-, acetylamino-, Cι. _3- alkyl-sulfonylamino-, aminocarbonyl-, -C-3-alkyl-aminocarbonyl-, di- (Cι- ₃ -alkyl) -aminocarbonyl-, amino-sulfonyl-, Cι-3-alkyl-aminosulfonyl-, di- (Cι - _3- alkyl) -aminosulfonyl, nitro or cyano groups can be mono- or disubstituted, where the substituents can be the same or different and where Rβ is an aminocarbonyl, C ₄ alkylamino carbonyl, N (C ₅ alkyl) -C ₃ alkylamino carbonyl, C ₃ - ₇ cycloalkylamino carbonyl, N (C ₅ alkyl) ) -C _3- 7-cycloalkylamino-carbonyl-, (phenyl-Cι. ₃ -alkyl) amino-carbonyl-, N- (Cι- _3- alkyl) -phenyl-Cι _-3 -alkyl- amino-carbonyl group,

a Cι-3-alkylaminocarbonyl or N- (Cι- ₃ alkyl) -Cι ^ alkylaminocarbonyl group, in which one or two alkyl parts independently of one another by a nitro, cyano, carbamoyl, N- (Cι " ₃ alkyl ) -carbamoyl-, di-N- (Cι _-3 -alkyl) -carbamoyl, carboxy or Cι- ₃ alkoxycarbonyl group or in 2- or 3-position by an amino-, (Cι _-3- alkyl) -amino- , Di- (Cι. ₃ -alkyl) -amino-, (Cι- ₄ -alkoxycarbonyl) -amino-, N-

(Cι _-4 -alkoxycarbonyl) -N- (Cι _-3 -alkyl) -amino-, piperazino, N- (Cι. -Alkyl) -piperazino-, a piperazinyl or piperidinyl group, a hydroxy or methoxy group are substituted,

a 4- to 7-membered cycloalkyleneiminocarbonyl group in which

the cycloalkylene part can be condensed with a phenyl ring via two adjacent ring atoms or can be bridged with a methylene or ethylene group via two non-adjacent ring atoms or

one or two hydrogen atoms can each be replaced by a d-3-alkyl group or / and

each the methylene group in position 4 of a 6- or 7-membered cycloalkyleneiminocarbonyl group by a carboxy, Cι _-4 -alkoxycarbonyl,

Aminocarbonyl, Cι _-3 alkylaminocarbonyl, di- ₍₃ Cι- alkyl) aminocarbonyl, di- ₍₃ Cι- alkyl) amino-Cι _-3 alkyl, di- (Cι _-3 alkyl ) -amino-, phenyl-Cι_ ₃ -a! kylamino- or N- (Cι_3-alkyl) -phenyl-Cι- ₃ -alkylamino group, a hydroxy or methoxy group substituted or

by an oxygen or sulfur atom, by a sulfinyl, sulfonyl or -NH group or by a nitrogen atom by a Cι. _3- alkyl-, phenyl-, C _1-3 -alkyl-carbonyl-, C _1-4 -alkoxy-carbonyl-, di- (Cι- ₃ -alkyl) -amino-Cι _-3 -alkyl-, ω- hydroxy-C ₂ - ₃ -alkyl- or benzoyl group is substituted, can be replaced,

and

R _{5 is} a hydrogen atom or a Cι. ₃ -alkyl group,

where the hydrogen atoms in the alkyl and alkoxy groups mentioned above or in the alkyl parts contained in the groups of formula I defined above can be partially or completely replaced by fluorine atoms,

the saturated alkyl and alkoxy parts present in the groups defined above, which contain more than 2 carbon atoms, including their branched isomers, such as, for example, the isopropyl, tert-butyl, isobutyl group, unless stated otherwise, and

where in addition the hydrogen atom of an existing carboxy group or a hydrogen atom bonded to a nitrogen atom, for example an amino, alkylamino or imino group or a saturated N-heterocycle such as the piperidinyl group, can in each case be replaced by a radical which can be split off in vivo,

mean, their tautomers, their diastereomers, their enantiomers, their mixtures and their salts.

A preferred subgroup relates to compounds of the general formula I in which

X is an oxygen atom,

Ri is a hydrogen atom,

R _{2 is} a carboxy group or a Cι. alkoxycarbonyl group, R _{3 is} a phenyl or naphthyl group, or a phenyl group monosubstituted by a fluorine, chlorine or bromine atom, by a trifluoromethyl, C ₃ alkyl or C ₃ alkoxy group,

R _{4 is} a pyrrolyl group which is substituted by an aminocarbonyl, C ₄ alkylaminocarbonyl or N (C ₄ alkyl) C ₃ alkylaminocarbonyl group, the C ₄ alkyl aminocarbonyl or N (C ₄ - ₄ - Alkyl) -Cι- ₃ -alkylaminocarbonylgruppe in one or both alkyl parts from position 2 can be substituted by an amino, Cι- ₃ alkylamino or di- (Cι _-3 - alkyl) amino group and the nitrogen atom of the pyrrolyl ring optionally by a Cι_ ₃ alkyl group is substituted, or

a phenyl group substituted in the 3- or 4-position by the group R, where

Rβ is an aminocarbonyl, C ₄ alkylamino carbonyl, N (C ₃ alkyl) C ₃ alkylamino carbonyl, Cs β cycloalkylamino carbonyl, N (C ₅ alkyl) ) -C ₅ - ₆ -cycloalkylamino-carbonyl group,

a Cι. ₃ -Alkylaminocarbonyl- or N- (-Cι- ₃ -alkyl) -Cι- ₃ -alkylaminocarbonylgruppe, in which one or two alkyl parts independently of one another by a carbamoyl, N- (-Cι. ₃ -alkyl) carbamoyl, di-N- (Cι- ₃ -alkyl) -carbamoyl, Cι- ₃ alkoxycarbonyl group or in 2- or 3-position by an amino, (Cι. ₃ -alkyl) -amino-, di- (Cι _-3 -alkyl) - amino -, (Cι _-4 alkoxycarbonyl) amino, N- (Cι- ₄ alkoxycarbonyl) -N- (. _Cι-C3 alkyl) -amino, piperazino, N- ₍₃ Cι- alkyl) -piperazino -, a piperazinyl or piperidinyl group, a hydroxy or methoxy group are substituted,

a piperidinocarbonyl, piperazinocarbonyl, homopiperazinocarbonyl or 2,3,4,5-tetrahydro-1 (H) -azepino-carbonyl group,

each condensed with a phenyl ring via two adjacent unsubstituted carbon atoms or in position 4 by a C 3 alkyl, C ₄ alkoxycarbonyl, di (C ₃ alkyl) amino, di (C ₃ alkyl) amino C 1. _3- alkyl, 2-hydroxyethyl, hydroxy or methoxy group can be substituted,

or a 2,5-diaza-bicyclo [2.2.1] hept-2-yl carbonyl group, which can be substituted in position 5 by a C 1 -C ₃ -alkyl group,

and

R _{5 is} a hydrogen atom or a C ₃ alkyl group,

wherein the hydrogen atoms in the aforementioned methyl and methoxy groups can be replaced by 1, 2 or 3 fluorine atoms, and

the saturated alkyl and alkoxy parts present in the groups defined above which contain more than 2 carbon atoms, including their branched isomers, such as, for example, the isopropyl, tert-butyl, isobutyl group,

mean, their tautomers, their diastereomers, their enantiomers, their mixtures and their salts.

Particularly preferred compounds of the general formula I are those in which

X is an oxygen atom,

Ri and R ₅ each represent a hydrogen atom,

R _{2 is} a methoxycarbonyl group,

R _{3 is} a phenyl group and R _{4 is} a phenyl group which is monosubstituted in the 3- or 4-position by the Re group, where

Rβ an aminocarbonyl, Cι. ₃ -alkylamino-carbonyl-, N-CCi-s-alkyl-Ci-s-alkylamino-carbonyl-, cyclohexylaminocarbonyl-, N- (Cι_ _5- alkyl) -cyclohexylaminocarbonyl-, phenyl-C-ι- ₃ -alkylamino -carbonyl-, N- (C _1-3 -alkyl) -phenyl-Cι-3-alkylamino-carbonyl-,

a piperidinocarbonyl-, 4-hydroxy-piperidinocarbonyl-, 4- [di- (Cι- ₃ -alkyl) - aminoj-piperidinocarbonyl-, 4- [di- (Cι. ₃ -alkyl) -amino-Cι- ₃ -alkyl] -piperidinocarbonyl-, piperazinocarbonyl-, N- (Cι. ₃ -alkyl) -piperazinocarbonyl-, N- (Cι _-4 -alkoxycarbonyl) - piperazinocarbonyl-, N- [di- (Cι _-3 -alkyl) -amino-Cι. _3- alkyl] -piperazinocarbonyl-, N- (2-hydroxy-ethyl) -piperazinocarbonyl-, homopiperazinocarbonyl-, N- (Cι_ 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 Cι- ₃ alkylaminocarbonyl or N- (Cι- ₅ alkyl) -Cι- ₃ alkylaminocarbonyl group in which one or two alkyl parts by a carbamoyl group or in the 2- or 3-position by an amino, (Cι_ ₃ -Alkyl) -amino-, di- (Cι _-3 -alkyl) -amino-, hydroxyl or methoxy group are substituted,

their tautomers, their diastereomers, their enantiomers, their mixtures and their salts.

The following are particularly preferred compounds:

(a) 3- (Z) - [1 - {4- [N- (2-Dimethylamino-ethyl) -N-methyl-carbamoyl] phenylamino} -1 - phenyl-methylidene] -2-indolinone-6-carboxylic acid methyl ester

(b) 3- (Z) - [1 - {4- [N- (3-Dimethylamino-propyl) -N-methyl-carbamoyl] -phenylamino} -1 ^■ phenyl-methylidene] -2-indolinone-6-carboxylic acid methyl ester

(c) 3- (Z) - [1 - {4 - [(4-methylpiperazin-1-yl) carbonyl] phenylamino} -1-phenylmethylidene] -2-indolinone-6-carboxylic acid methyl ester (d) 3- (Z) - [1 - {4 - [(4-Hydroxy-piperidin-1-yl) carbonyl] phenylamino} -1-phenylmethylidene] -2-indolinone-6-carboxylic acid methyl ester

(e) 3- (Z) - [1 - {4 - [(piperazin-1-yl) carbonyl] phenylamino} -1-phenylmethylidene] -2-indolinone-6-carboxylic acid methyl ester

(f) 3- (Z) - [1 - {4- [N- (2-Methylamino-ethyl) -N-methyl-carbamoyl] phenylamino} -1 - phenyl-methylidene] -2-indolinone-6-carboxylic acid methyl ester

(g) 3- (Z) - [1 - {4 - [(4-Dimethylamino-piperidin-1-yl) carbonyl] phenylamino} -1-phenylmethylidene] -2-indolinone-6-carboxylic acid, methyl ester

(h) 3- (Z) - [1- {4 - [(4-ethyl-piperazin-1-yl) carbonyl] phenylamino} -1-phenylmethylidene] -2-indolinone-6-carboxylic acid methyl ester

(i) 3- (Z) - [1 - {4 - [(4- (2-Hydroxyethyl) piperazin-1-yl) carbonyl] phenylamino} -1-phenylmethylidene] -2-indolinone -6-carbonsäuremethylester

(k) 3- (Z) - {1- [4- (5-Methyl-2,5-diaza-bicyclo [2.2.1] hept-2-ylcarbonyl) phenylamino] -1-phenylmethylidene} -2-indolinone-6-carbonsäuremethylester

their tautomers, their mixtures and their salts.

According to the invention, the new compounds are obtained, for example, by the following processes which are known in principle from the literature:

a. Implementation of a compound of the general formula

in the

X and R ₃ are defined as mentioned at the beginning,

R ₂ 'has the meanings mentioned above for R ₂ ,

Ris is a hydrogen atom or a protecting group for the nitrogen atom of the

Lactam group, where one of the radicals R ₂ 'and R-ι _{8 can} also represent a bond to a solid phase which may be formed via a spacer and the other of the radicals R ₂ ' and Ris has the meanings mentioned above, and Z ₁

Halogen atom, a hydroxy, alkoxy or arylalkoxy group, e.g. a chlorine or

Bromine, a methoxy, ethoxy or benzyloxy group,

with an amine of the general formula

in the

R ₄ and R ₅ are defined as mentioned at the beginning, and if necessary subsequent cleavage of a protective group used for the nitrogen atom of the lactam or imino group or from a solid phase.

A protective group for the nitrogen atom of the lactam group is, for example, an acetyl, benzoyl, ethoxycarbonyl, tert.butyloxycarbonyl or benzyloxycarbonyl group and

as a solid phase, a resin such as a 4- (2 ', 4'-dimethoxyphenylaminomethyl) phenoxy resin, the binding advantageously taking place via the amino group, or a p- Benzyloxybenzyl alcohol resin, the binding advantageously taking place via an intermediate member such as a 2,5-dimethoxy-4-hydroxy-benzyl derivative.

The reaction is advantageously carried out in a solvent such as dimethylformamide, toluene, acetonitrile, tetrahydrofuran, dimethyl sulfoxide, 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. carried out, a protective group used can be split off simultaneously as a result of transamidation.

If Zi in a compound of the 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 Zi in a compound of the general formula VII denotes a hydroxyl, alkoxy or arylalkoxy group, the reaction is preferably carried out at temperatures between 20 and 200 ° C.

The subsequent splitting off of a protective group that may be required is advantageously carried out either hydrolytically in an aqueous or alcoholic solvent, e.g. in methanol / water, ethanol / water, isopropanol / water, tetrahydrofuran / water, dioxane / water, dimethylformamide / water, methanol or ethanol in the presence of an alkali base such as lithium hydroxide, sodium hydroxide or potassium hydroxide at temperatures between 0 and 100 ° C., preferably at temperatures between 10 and 50 ° C,

or advantageously by Umamidierung 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. A solid phase used is preferably cleaved off using trifluoroacetic acid and water at temperatures between 0 and 35 ° C., preferably at room temperature.

b. For the preparation of a compound of the general formula I in which R _2, with the exception of the carboxy group, is defined as mentioned at the beginning:

Implementation of a compound of the general formula

in the

Ri and R ₃ to R ₅ are defined as mentioned above, or their reactive

Derivatives with a compound of the general formula

H - R 19 (X),

in the

Rt _{9 is} a Ytnearer or branched Cι- ₆ alkanol, a C _4-7 cycloalkanol or an aromatic alcohol.

The esterification is preferably carried out in a solvent such as methylene chloride, diethyl ether, tetrahydrofuran, toluene, dioxane, acetonitrile, dimethyl sulfoxide or dimethylformamide, optionally in the presence of an inorganic or a tertiary organic base, preferably at temperatures between 20 ° C. and the boiling point of the solvent used. The reaction with a corresponding acid is preferably carried out in the presence of a dehydrating agent, for example in the presence of isobutyl chloroformate, tetraethyl orthocarboxylate, trimethyl orthoacetic acid, 2,2-di- methoxypropane, tetramethoxysilane, thionyl chloride, trimethylchlorosilane, phosphorus trichloride, phosphorus pentoxide, N.N'-dicyclohexylcarbodiimide, N, N'-dicyclohexylcarbodiimide / N-hydroxysuccinimide, N.N'-dicyclohexylcarbol diimide (N.N'-dicyclohexylcarbodiimide 1 H-benzotriazol-1 -yl) -1, 1, 3,3-tetramethyluronium tetrafluoroborate, 2- (1 H-benzotriazol-1 -yl) -1, 1, 3,3-tetramethyluronium tetrafluoroborate / 1 -Hydroxy-benzotriazole, N, N'-carbonyldiimidazole or triphenylphosphine / carbon tetrachloride, and optionally with the addition of a base such as pyridine, 4-dimethylaminopyridine, N-methylmorpholine or triethylamine, advantageously at temperatures between 0 and 150 ° C., preferably at temperatures between 0 and 100 ° C, and the acylation with a corresponding reactive compound such as its anhydride, ester, imidazolide or halide, 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, performed.

If a compound of the general formula I which contains an alkoxycarbonyl group is obtained according to the invention, this can be converted into a corresponding carboxy compound by means of hydrolysis, or

a compound of the general formula I which contains an amino or alkylamino group, this can be converted into a corresponding alkylamino or dialkylamino compound by means of reductive alkylation, or

a compound of the general formula I which contains an amino or alkylamino group, this can be converted into a corresponding acyl or sulfonyl compound by means of acylation or sulfonation, or

a compound of the general formula I which contains a carboxy group, this can be converted into a corresponding ester or aminocarbonyl compound by esterification or amidation, or

a compound of the general formula I which contains a cycloalkyleneimino group in which a methylene group has been replaced by a sulfur atom these are converted into a corresponding sulfinyl or sulfonyl compound by means of oxidation, or

a compound of the general formula I which contains a nitro group, this can be converted into a corresponding amino compound by reduction, or

a compound of the general formula I in which R represents a phenyl group substituted by an amino, alkylamino or aminoalkyl group, this can then be converted into a corresponding urea compound of the general formula I by reaction with a corresponding cyanate, isocyanate or carbamoyl halide or

a compound of the general formula I in which R _{4 represents} a phenyl group substituted by an amino, alkylamino or aminoalkyl group, this can then be converted into a corresponding one by reaction with a corresponding compound transferring the amidino group or by reaction with a corresponding nitrile Guanidino compound of the general formula I can be converted.

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 sulfuric acid or in the presence of an alkali base such as lithium hydroxide, sodium hydroxide or potassium hydroxide at temperatures between 0 and 100 ° C, preferably at temperatures between 10 and 50 ° C.

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

The subsequent acylation or sulfonylation is advantageously carried out with the corresponding free acid or a corresponding reactive compound such as its anhydride, ester, imidazolide or halide, preferably in a solvent such as methylene chloride, diethyl ether, tetrahydrofuran, toluene, dioxane, acetonitrile, dimethyl sulfoxide or dimethylformamide, optionally in the presence of a inorganic or a tertiary organic base at temperatures between -20 and 200 ° C, preferably at temperatures between 20 ° C and the boiling point of the solvent used. The reaction with the free acid may optionally be in the presence of an acid activating agent or a dehydrating agent, e.g. in the presence of isobutyl chloroformate, tetraethyl orthocarbonic acid, trimethyl orthoacetic acid, 2,2-dimethoxypropane, tetramethoxysilane, thionyl chloride, trimethylchlorosilane, phosphorus trichloride, phosphorus pentoxide, N, N'-dicyclohexylnodimidodimidodimidium carbodiimide, nododicyclide, carbodiimide, nodoxydimide, carbodiimide, carbodiimide, carbodiimide, carbodiimide, carbodiimide, nodicyclide, carbodiimide, carbodiimide, carbodiimide, nodicyclide, carbodiimide, nodicyclide '-Dicyclohexyl-carbodiimide / 1-hydroxy-benzotriazole, 2- (1H-benzotriazol-1-yl) -1, 1, 3,3-tetramethyl-uronium tetrafluoroborate, 2- (1 H-benzotriazol-1-yl) -1, 1, 3,3-tetramethyluronium tetrafluoroborate / 1-hydroxy-benzotriazole, N, N'-carbonyldiimidazole or triphenylphosphine / carbon tetrachloride, and optionally with the addition of a base such as pyridine, 4-dimethylamino-pyridine, N -Methyl-morpholine or triethylamine expediently at temperatures between 0 and 150 ° C, preferably at temperatures between 0 and 100 ° C. The reaction with a corresponding reactive compound can optionally in the presence of a tertiary organic base such as triethylamine, N-ethyl-diisopropylamine, N-methyl-morpholine or pyridine or when using an anhydride 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 advantageously carried out by reacting a reactive corresponding carboxylic acid derivative with an appropriate alcohol or amine as described above.

The subsequent reduction of a nitro group is preferably carried out hydrogenolytically, e.g. with hydrogen in the presence of a catalyst such as palladium / carbon or Raney nickel in a solvent such as methanol, ethanol, ethyl acetate, dimethylformamide, dimethylformamide / acetone or glacial acetic acid, 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 room temperature, and at a hydrogen pressure of 1 to 7 bar, but preferably from 3 to 5 bar.

The subsequent preparation of a corresponding urea compound of the general formula I is advantageously carried out with an inorganic cyanate or a corresponding isocyanate or carbamoyl chloride, 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 Room temperature.

The subsequent preparation of a corresponding guanidino compound of the general formula I is advantageously carried out by reaction with a

Amide / nogroup compound such as 3,5-dimethylpyrazole-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 room temperature ,

In the reactions described above, any reactive groups present, such as carboxy, hydroxyl, amino, alkylamino or imino groups, can be protected during the reaction by customary protective groups which are split off again after the reaction.

For example, the trimethylsilyl, methyl, ethyl, tert-butyl, benzyl or tetrahydropyranyl group and comes as a protective radical for a carboxy group as a protective radical for a hydroxyl, amino, alkylamino or imino group, the acetyl, trifluoroacetyl, benzoyl, ethoxycarbonyl, tert.butoxycarbonyl, benzyloxycarbonyl, benzyl, methoxybenzyl or 2,4-dimethoxybenzyl group and for the amino group additionally the phthalyl group into consideration.

The subsequent subsequent splitting off of a protective residue used takes place, for example, hydrolytically in an aqueous solvent, e.g. in water, isopropanol / water, tetrahydrofuran / water or dioxane / water, in the presence of an acid such as trifluoroacetic acid, hydrochloric acid or sulfuric acid or in the presence of an alkali base such as lithium hydroxide, sodium hydroxide or potassium hydroxide at temperatures between 0 and 100 ° C., preferably at temperatures between 10 and 50 ° C.

However, a benzyl, methoxybenzyl or benzyloxycarbonyl radical is cleaved off, for example, by hydrogenolysis, e.g. with hydrogen in the presence of a catalyst such as palladium / carbon in a solvent such as methanol, ethanol, ethyl acetate, dimethylformamide, dimethylformamide / acetone or glacial acetic acid, optionally with addition of an acid such as hydrochloric acid or glacial acetic acid at temperatures between 0 and 50 ° C., but preferably at room temperature, and at a hydrogen pressure of 1 to 7 bar, but preferably from 3 to 5 bar.

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

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

The cleavage of a tert-butyl or partial. Butyloxycarbonylrest.es is preferably carried out by treatment 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 radical 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.

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

For example, the compounds of general formula I obtained which occur in racemates can be converted into their optical antipodes and by known methods (see Allinger NL and Eliel EL in "Topics in Stereochemistry", Vol. 6, Wiley Interscience, 1971) Compounds of general formula I with at least 2 asymmetric carbon atoms due to their physico-chemical differences according to methods known per se, for example by chromatography and / or fractional crystallization, into their diastereomers, which, if they occur in racemic form, can then be separated into the enantiomers as mentioned above.

The enantiomers are separated preferably by column separation on chiral phases or by recrystallization from an optically active solvent or by reaction with an optically active substance which forms salts or derivatives, such as esters or amides, for example esters or amides, in particular acids and their activated derivatives or alcohols, and Separation of the mixture of diastereomeric salts or derivatives obtained in this way, for example due to different solubilities, it being possible for the free antipodes to be released from the pure diastereomeric salts or derivatives by the action of suitable agents. Particularly common, optically active acids are, for example, the D and L forms of tartaric acid, dibenzoyl tartaric acid, di-o-tolyltartaric acid, malic acid, mandelic acid, camphorsulfonic acid, glutamic acid, N-acetylglutamic acid, aspartic acid, N-acetyl-aspartic acid or quinic acid. As optically more active Alcohol is, for example, (+) - or (-) - menthol, and the optically active acyl radical in amides is, for example, the (+) - or (-) - menthyloxycarbonyl radical.

Furthermore, the compounds of the formula I obtained can be converted into their salts, in particular for pharmaceutical use into their physiologically tolerable salts with inorganic or organic acids. Examples of suitable acids for this purpose are hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, fumaric acid, succinic acid, lactic acid, citric acid, tartaric acid, maleic acid or methanesulfonic acid.

In addition, if the new compounds of formula I thus obtained contain a carboxy group, they can, if desired, subsequently be converted into their salts with inorganic or organic bases, in particular for their pharmaceutical use into their physiologically tolerable salts. Bases which can be used here are, for example, sodium hydroxide, potassium hydroxide, cyclohexylamine, ethanolamine, diethanolamine and triethanolamine.

Some of the compounds of the general formulas VII to X used as starting products are known from the literature or can be obtained by processes known from the literature or can be obtained by the processes described above and in the examples. For example, the compounds of general formula IX are described in German patent application 198 24 922.5.

As already mentioned at the beginning, the new compounds of the general formula I, in which Ri represents a hydrogen atom or a prodrug residue, have valuable pharmacological properties, in particular an inhibitory effect on various kinases, especially on receptor tyrosine kinases such as VEGFR2, VEGFR3, PDGFR, PDGFRß, FGFR1, FGFR3, EGFR, HER2, IGF1R and HGFR, as well as on complexes of CDKs (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 cultured human cells, especially those of endothelial cells Rows, for example in angiogenesis, but also on the proliferation of other cells, especially tumor cells.

The biological properties of the new compounds were tested according to the following standard procedure as follows:

Human umbilical cord endothelial cells (HUVEC) were in IMDM (Gibco BRL), supplemented with 10% fetal bovine serum (FBS) (Sigma), 50 μM ß-mercaptoeethanol (Fluka), standard antibiotics, 15 μg / ml endothelial cell growth factor (ECGS, Collaborative Biomedical Products) and 100 μg / ml heparin (Sigma) on gelatin-coated culture bottles (0.2% gelatin, Sigma) at 37 ° C, 5% CO2 in a water-saturated atmosphere.

To investigate the inhibitory activity of the compounds according to the invention, the cells were "starved" for 16 hours, ie kept in culture medium without growth factors (ECGS + heparin). The cells were detached from the culture bottles using trypsin / EDTA and washed once in serum-containing medium. Then 2.5 × 10 ³ cells were sown per well.

The proliferation of the cells was stimulated with 5 ng / ml VEGF165 (vascular endothelial growth factor; H. Weich, GBF Braunschweig) and 10 μg / ml heparin. As a control value, 6 wells were not stimulated per plate.

The compounds according to the invention were dissolved in 100% dimethyl sulfoxide and added to the cultures as triple determinations in various dilutions, the maximum dimethyl sulfoxide concentration being 0.3%.

The cells were incubated for 76 hours at 37 ° C., then ³ H-thymidine (0.1 μCi / well, Amersham) was added for a further 16 hours in order to determine the DNA synthesis. The radioactively labeled cells were then immobilized on filter mats and the radioactivity incorporated was determined in a ß-counter. To determine the inhibitory activity of the compounds according to the invention, the mean value of the non-stimulated cells was determined from the mean value of the Factor-stimulated cells (in the presence or absence of the compounds of the invention) subtracted.

The relative cell proliferation was calculated as a percentage of the control (HUVEC without inhibitor) and the drug concentration, which inhibits cell proliferation by 50% (IC50), was derived.

The test results of the following compounds (a) to (f) of the general formula I are given by way of example:

(a) 3- (Z) - [1 - {4- [N- (2-Dimethylamino-ethyl) -N-methyl-carbamoyl] phenylamino} -1 - phenyl-methylidene] -2-indolinone-6-carboxylic acid methyl ester

(b) 3- (Z) - [1 - {4- [N- (3-Dimethylamino-propyl) -N-methylcarbamoyl] phenylamino} -1 - phenylmethylidene] -2-indolinone-6-carboxylic acid methyl ester

(c) 3- (Z) - [1 - {4 - [(4-methylpiperazin-1-yl) carbonyl] phenylamino} -1-phenylmethylidene] -2-indolinone-6-carboxylic acid methyl ester

(d) 3- (Z) - [1 - {4 - [(4-Hydroxy-piperidin-1-yl) carbonyl] phenylamino} -1-phenylmethylidene] -2-indolinone-6-carboxylic acid methyl ester

(e) 3- (Z) - [1 - {4 - [(piperazin-1-yl) carbonyl] phenylamino} -1-phenylmethylidene] -2-indolinone-6-carboxylic acid methyl ester

(f) 3- (Z) - [1 - {4- [N- (2-Methylamino-ethyl) -N-methyl-carbamoyl] phenylamino} -1 - phenyl-methylidene] -2-indolinone-6-carboxylic acid methyl ester

(g) 3- (Z) - [1 - {4 - [(4-Dimethylamino-piperidin-1-yl) carbonyl] phenylamino} -1-phenylmethylidene] -2-indolinone-6-carboxylic acid, methyl ester

(h) 3- (Z) - [1 - {4 - [(4-ethyl-piperazin-1-yl) carbonyl] phenylamino} -1-phenylmethylidene] -2-indolinone-6-carboxylic acid, methyl ester (i) 3- (Z) - [1- {4 - [(4- (2-Hydroxyethyl) piperazin-1-yl) carbonyl] phenylamino} -1-phenylmethylidene] -2-indolinone -6-carbonsäuremethylester

(k) 3- (Z) - {1- [4- (5-Methyl-2,5-diaza-bicyclo [2.2.1] hept-2-ylcarbonyl) phenylamino] -1-phenylmethylidene} -2-indolinone-6-carbonsäuremethylester

The following table contains the results found:

Because of their inhibitory effect on the proliferation of cells, in particular endothelial cells and tumor cells, the compounds of general formula I are suitable for the treatment of diseases in which the proliferation of cells, in particular that of endothelial cells, plays a role.

For example, the proliferation of endothelial cells and the associated neovascularization represent a crucial step in tumor progression (Folkman J. et al., Nature 339, 58-61, (1989); Hanahan D. and Folkman J., Cell 86, 353 -365, (1996)). The proliferation of endothelial cells is also important in hemangiomas, metastasis, rheumatoid arthritis, psoriasis and ocular neovascularization (Folkman J., Nature Med. 1, 27-31, (1995)). The therapeutic benefit of inhibitors of endothelial cell proliferation has been described in the animal model, for example by O'Reilly et al. and Parangi et al. (O'Reilly MS et al., Cell 88, 277-285, (1997); Parangi S. et al., Proc Natl Acad Sei USA 93, 2002-2007, (1996)).

The compounds of the general formula I, their tautomers, their stereoisomers or their physiologically tolerable salts are thus suitable, for example, for the treatment of tumors (e.g. squamous cell carcinoma, astrocytoma, Kaposi's sarcoma, glioblastoma, lung cancer, bladder cancer, neck and neck cancer, Melanoma, ovarian carcinoma, prostate carcinoma, breast cancer, small cell lung carcinoma, glioma, colorectal carcinoma, urogenital cancer and gastrointestinal carcinoma as well as haematological cancers, such as multiple myeloma), psoriasis, arthritis (e.g. rheumatoid arthritis, angiopathy), hemi-angioma (hemiangioma), hemi-angioma ), neovascular glaucoma, kidney diseases (eg glomerulonephritis), diabetic nephropathy, malignant nephrosclerosis, thrombic microangiopathic syndromes, transplant rejection and glomerulopathy, fibrotic diseases (eg cirrhosis of the liver), mesangial cell proliferative diseases, injuries degenerative nerve tissue and to inhibit the reocclusion of vessels after balloon catheter treatment, in vascular prosthetics or after the insertion of mechanical devices to keep vessels open (e.g. Stents), or other diseases in which cell proliferation or angiogenesis play a role.

Because of their biological properties, the compounds according to the invention can be used alone or in combination with other pharmacologically active compounds, for example in tumor therapy in monotherapy or in combination with other anti-tumor therapeutic agents, for example in combination with topoisomerase inhibitors (for example Etoposides), mitotic inhibitors (e.g. vinblastine, taxol), compounds interacting with nucleic acids (e.g. cis-platinum, 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 combination with radiation therapy etc. These combinations can be administered either simultaneously or sequentially.

In pharmaceutical use, the compounds according to the invention are generally used in warm-blooded vertebrates, in particular in humans, in doses of 0.01-100 mg / kg of body weight, preferably at 0.1-20 mg / kg. For administration, these are mixed with one or more conventional inert carriers and / or diluents, e.g. with corn starch, milk sugar, cane sugar, microcrystalline cellulose, magnesium stearate, polyvinyl pyrrolidone, citric acid, tartaric acid, water, water / ethanol, water / glycerin, water / sorbitol, water / polyethylene glycol, propylene glycol, stearyl alcohol, carboxymethyl cellulose or fat-containing substances such as hard fat or their suitable mixtures are incorporated into conventional pharmaceutical preparations such as tablets, dragées, capsules, powders, injection solutions, ampoules, suspensions, solutions, sprays or suppositories.

The following examples are intended to explain the invention in more detail:

Preparation of the starting compounds:

Used abbreviations:

TBTU = O- (benzotriazol-1-yl) -N, N, N ', N'-bis (tetramethylene uronium hexafluorophosphate

HOBt = 1-hydroxy-1 H-benzotriazole

Example I:

N- (2-dimethylamino-ethvD-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 in portions and the mixture is stirred for 5 minutes in the cold and 20 minutes in a room. temperature. Finally, the precipitate is filtered off and the organic phase is washed with water, dried over sodium sulfate and evaporated. Yield: 1.8 g (70% of theory) R _f value: 0.78 (silica gel, methylene chloride / methanol = 9: 1)

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-methylpiperazin-1-ylcarbonyl) 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-yi-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-hydroxyethyl)) -3-nitrobenzamide

(25) 4- (4-Dimethylamino-piperidin-1-yl-carbonyl) -nitrobenzene

(26) 4- (4-ethyl-piperazin-1-yl-carbonyl) -nitrobenzene

(27) 4- (4- (2-Dimethylaminoethyl) piperazin-1-ylcarbonyl) nitrobenzene

(28) 4- (4- (2-Hydroxyethyl) piperazin-1-ylcarbonyl) nitrobenzene

(29) 4- (5-Methyl-2,5-diaza-bicyclo [2.2.1] hept-2-ylcarbonyl) 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-Diethylaminoethoxy) piperidin-1-ylcarbonyl) nitrobenzene

(35) 4- (3- (2-Diethylaminoethoxy) pyrrolidin-1-ylcarbonyl) nitrobenzene

(36) 4- (3-Dimethylamino-pyrrolidin-1-yl-carbonyl) -nitrobenzene

Example II:

4-nitro-1-methyl-2-r (2-dimethylamino-ethyl) -N-methyl-carbamovn-pyrrole

5.4 ml of 2- (N, N-dimethylamino) ethylamine and 5.8 g of 1-methyl-4-nitro-pyrrole-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 HOBt added. The mixture is allowed to stir at room temperature for 24 hours. Finally, the solvent is largely removed, water is added and the mixture is extracted with methylene chloride. The organic phase is dried over sodium sulfate and evaporated. The residue is purified on a silica gel column using methylene chloride / methanol / ammonia 8: 2: 0.1 as the eluent. Yield: 9.2 g (100% of theory) Rr value: 0.70 (silica gel, methylene chloride / methanol / ammonia = 8: 1: 0.1) 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 over 0.2 g of palladium / carbon Hydrogenated 50 psi of hydrogen for 2 hours at room temperature. Then the catalyst is filtered off and the mixture is rotated in. Yield: 1.5 g (95% of theory) R _f value: 0.38 (silica gel, methylene chloride / methanol = 9: 1) CnHι ₇ N ₃ O

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-diethylaminoethyl) benzamide

7) 4-Amino-N- (2- (tert-butyloxycarbonylamino) 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-methylpiperazin-1-ylcarbonyl) aniline

(14 4- (Piperidin-1-ylcarbonyl) 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-ylcarbonyl) aniline

(18 4- (4-Hydroxy-piperidin-1-yl-carbonyl) -anι ^* lin

(19 4- (4-tert-Butyloxycarbonyl-piperazin-1-yl-carbonyl) aniline

(20 4- (4-tert-Butyloxycarbonyl- [1, 4] diazepan-1 -ylcarbonyl) 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-hydroxyethyl)) benzamide

(25 4-Amino-1-methyl-2 - [(2-dimethylamino-ethyl) -N-methyl-carbamoyl] pyrrole

(26 4- (4-Dimethylamino-piperidin-1-ylcarbonyl) aniline (27) 4- (4-ethyl-piperazin-1-yl-carbonyl) -aniline

(28) 4- (4- (2-Dimethylaminoethyl) piperazin-1-ylcarbonyl) aniline

(29) 4- (4- (2-Hydroxyethyl) piperazin-1-ylcarbonyl) aniline

(30) 4- (5-Methyl-2,5-diaza-bicyclo [2.2.1] hept-2-ylcarbonyl) aniline

(31) 4- (4-tert-Butyloxycarbonyl-trans-2,5-dimethyl-piperazin-1 -ylcarbonyl) aniline

(32) 4- (4-Dimethylaminomethyl-piperidin-1-yl-carbonyl) aniline

(33) 4- (cis-3,5-Dimethyl-piperazin-1-yl-carbonyl) aniline

(34) (7? -4- (3,4-Dimethyl-piperazin-1-yl-carbonyl) aniline

(35) 4- (4- (2-Diethylaminoethoxy) piperidin-1-ylcarbonyl) aniline

(36) 4- (3- (2-Diethylaminoethoxy) pyrrolidin-1-ylcarbonyl) aniline

(37) 4- (3-Dimethylamino-pyrrolidin-1-yl-carbonyl) aniline

Example IV

4-methoxycarbonylmethyl-3-nitro-benzoic acid methyl ester

54.3 g of 3-nitro-benzoic acid methyl ester and 29.0 g of methyl chloroacetate 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 a further 10 minutes at room temperature and, after this time, the solution is poured onto 350 ml of concentrated hydrochloric acid in 2 l of ice water. The solution is stirred for 0.5 hours, the precipitate obtained is filtered off with suction Washed water. The product is recrystallized from 150 ml of methanol and dried in vacuo at 40 ° C.

Yield: 48.3 g (51% of theory), contains approx. 20% methyl 6-methoxycarbonylmethyl-3-nitro-benzoate R _f 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) 4-Methoxycarbonylmethyl-3-nitro-benzoic acid ethyl ester

Made from 4-methoxycarbonylmethyl-3-nitro-benzoic acid ethyl ester

Example V

2-indolinone-6-carbonsäuremethylester

48.3 g of 4-methoxycarbonylmethyl-3-nitro-benzoic acid methyl ester are dissolved in 800 ml of concentrated acetic acid, 5.0 g of palladium on carbon (10 percent) are added and the solution is hydrogenated for 2.5 hours at room temperature and 50 psi. The catalyst is filtered off and the filtrate is evaporated. The residue is taken up in 150 ml of tert-butyl methyl ether, filtered again and dried in vacuo at 100 ° C.

Yield: 28.6 g (98% of theory),

R _f value: 0.4 (silica gel, methylene chloride / methanol = 10: 1) melting point: 208-211 ° C

The following connection is established analogously to Example V:

(1) 2-Indolinone-6-carboxylic acid ethyl ester Made from 4-methoxycarbonylmethyl-3-nitro-benzoic acid ethyl ester Example VI

1-acetyl-3-d-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 at 110 ° C. for 4 hours. After this time, the solvent is stripped off, the residue is recrystallized from petroleum ether and dried in vacuo at 50 ° C. Yield: 16.9 g (61% of theory),

R _f value: 0.5 (silica gel, petroleum ether / methylene chloride / ethyl acetate = 5: 4: 1) melting point: 98-100 ° CC ₂₂ H2iNO ₅

The following compound is produced analogously to Example VI:

(1) 1-Acetyl-3- (1-ethoxy-1-phenylmethylene) -6-methoxycarbonyl-2-indolinone Made from methyl 2-indolinone-6-carboxylate, triethyl orthobenzoate and acetic anhydride

Making the end connections:

Example 1 :

3- (ZVf1- {4-fΛ / - (2-dimethylamino-ethyl) - / V-methyl-carbamoyll-phenylamino> -1-phenyl-methylidenl-2-indolinone-6-carboxylic acid methyl ester

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 dimethylformamide and stirred at 70 ° C for 4 hours. After cooling, 3 ml of conc. Ammonia added and stirred for a further 30 minutes at room temperature. Then 1 ml of water is added, the precipitate formed is filtered off with suction, stirred with a little methanol and ether and then the solid substance is collected. Yield: 0.1 g (24% of theory), R _f value: 0.22 (silica gel, methylene chloride / methanol = 9: 1)

Mass spectrum: m / z = 499 [M + Hj ⁺

The following compounds are prepared analogously to Example 1:

(1) 3- (Z) - [1 - {4 - [(2-dimethylaminoethyl) carbamoyl] phenylamino} -1-phenylmethylidene] -2-indolinone-6-carboxylic acid methyl ester

Made 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 theory),

R _f value: 0.26 (silica gel, methylene chloride / methanol = 9: 1)

Mass spectrum: m / z = 483 [MH] ^"

(2) 3- (Z) - [1- {4 - [(3-Dimethylamino-propyl) -carbamoyl] -phenylamino} -1-phenyl-methylidene] -2-indolinone-6-carboxylic acid, methyl ester

Made 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 theory)

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

Mass spectrum: m / z = 497 [MH] ^"

(3) 3- (Z) - [1 - {4- [V- (3-Dimethylamino-propyl) -V-methyl-carbamoyl] -phenylamino} -1-phenyl-methylidene] -2-indolinone-6-carboxylic acid methyl ester Made 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 theory) R _f value: 0.22 (silica gel, methylene chloride / methanol = 9: 1)

Mass spectrum: m / z = 513 [M + H] ⁺ (4) 3- (Z) - [1 - {4 - [(2-Dimethylamino-ethyl) - / V-ethyl-carbamoyl] -phenylamino} -1-phenyl-methylidene] -2-indolinone-6-carboxylic acid, methyl ester

Made 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 theory

R _f value: 0.6 (silica gel, methylene chloride / methanol = 4: 1)

Mass spectrum: m / z = 513 [M + H] ⁺

(5) 3- (Z) - [1 - {4 - [(2- (tert-Butyloxycarbonyl-N-methylamino) -ethyl) -N-methyl-carbamoyl] -phenylamino} -1-phenyl-methylidene] Methyl -2-indolinone-6-carboxylate Made from 1-acetyl-3- (1-ethoxy-1-phenylmethylene) -6-methoxycarbonyl-2-indolinone and 4-amino-N- (2- (tert-butyloxycarbonylmethylamino- ethyl) -N-ethyl-benzamide Yield: 25% of theory

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

Mass spectrum: m / z = 584 [M] ⁺

(6) 3- (Z) - [1- {4- [N, N-bis (2-diethylaminoethyl) carbamoyl] phenylamino} -1-phenylmethylidene] -2-indolinone-6-carboxylic acid methyl ester

Made 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 theory Rf value: 0.5 (silica gel, methylene chloride / methanol = 4: 1)

(7) 3- (Z) - [1 - {3 - [(2-Dimethylamino-ethyl) -carbamoyl] -phenylamino} -1-phenyl-methylidene] -2-indolinone-6-carboxylic acid methyl ester made from 1-acetyl- 3- (1-ethoxy-1-phenylmethylene) -6-methoxycarbonyl-2-indolinone and 3-amino-N- (2-dimethylamino-ethyl) -benzamide. Yield: 51% of theory, R _f value: 0.6 (silica gel, methylene chloride / methanol = 4: 1)

Mass spectrum: m / z = 483 [MH] ^"

(8) 3- (Z) - [1 - {3 - [(2-Dimethylamino-ethyl) -N-methyl-carbamoyl] -phenylamino} -1 - phenyl-methylidene] -2-indolinone-6-carboxylic acid, methyl ester

Made 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 theory,

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

Mass spectrum: m / z = 497 [MH] ^"

(9) 3- (Z) - [1 - {3 - [(3-Dimethylamino-propyl) -carbamoyl] -phenylamino} -1-phenyl-methylidene] -2-indolinone-6-carboxylic acid methyl ester Made from 1-acetyl- 3- (1-ethoxy-1-phenylmethylene) -6-methoxycarbonyl-2-indolinone and 3-amino-N- (3-dimethylamino-propyl) -benzamide.

Yield: 53% of theory,

R _f value: 0.2 (silica gel, methylene chloride / methanol = 4: 1) Mass spectrum: m / z = 497 [MH] ^"

(10) 3- (Z) - [1- {3 - [(3-Dimethylamino-propyl) -N-methyl-carbamoyl] -phenylamino} -1-phenyl-methylidene] -2-indolinone-6-carboxylic acid methyl ester Manufactured 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 theory,

R _f value: 0.5 (silica gel, methylene chloride / methanol = 4: 1) C ₃ oH ₃₂ N ₄ O ₄ mass spectrum: m / z = 513 [M + H] ⁺

(11) 3- (Z) - [1- {4 - [(4-methylpiperazin-1-yl) carbonyl] phenylamino} -1-phenylmethylidene] -2-indolinone-6-carboxylic acid, methyl ester Made 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 theory), melting point: 196-197 ° C C2 ₉ H2 ₈ N4O4

Mass spectrum: m / z = 495 [MH] ^"

(12) 3- (Z) - [1 - {4 - [(Piperidin-1 -yl) -carbonyl] -phenylamino} -1 -phenyl-methylidene] -2-indolinone-6-carboxylic acid methyl ester made from 1-acetyl- 3- (1-ethoxy-1-phenylmethylene) -6-methoxycarbonyl-2-, indolinone and 4- (piperidin-1-ylcarbonyl) aniline.

Yield: 0.25 g (60% of theory),

Melting point: 268-269 ° C

C2 ₉ H ₂ 7N ₃ O4 mass spectrum: m / z = 480 [MH] ^"

(13) 3- (Z) - [1 - {4- [N-Cyclohexyl-N-methyl-carbamoyl] -phenylamino} -1-phenyl-methylidene] -2-indolinone-6-carboxylic acid methyl ester

Made 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 theory), melting point: 263-265 ° C

Mass spectrum: m / z = 508 [MH] ^"

(14) 3- (Z) - [1- {4- [Isopropyl-carbamoyl] phenylamino} -1-phenyl-methylidene] -2-indolinone-6-carboxylic acid methyl ester

Made from 1-acetyl-3- (1-ethoxy-1-phenylmethylene) -6-methoxycarbonyl-2-indolinone and 4-amino-N-isopropyl-benzamide. Yield: 0.18 g (46% of theory),

Melting point: 273-274 ° C

C2 ₇ H ₂₅ NsO

Mass spectrum: m / z = 454 [MH] ^" (15) 3- (Z) - [1 - {4- [2,3,4,5-tetrahydro-1 (H) -benzo [d] azepin-3-yl-carbonyl] phenylamino} -1 -phenyl-methylidene] -2-indolinone-6-carboxylic acid methyl ester Made 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 theory), melting point: 278-279 ° C

Mass spectrum: m / z = 542 [MH] ^"

(16) 3- (Z) - [1 - {4 - [(4-Hydroxy-piperidin-1-yl) carbonyl] phenylamino} -1-phenylmethylidene] -2-indolinone-6-carboxylic acid methyl ester

Made 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 theory), melting point: from 320 ° C decomposition Mass spectrum: m / z = 496 [MH] ^"

(17) 3- (Z) - [1 - {4 - [(4-tert-Butyloxycarbonyl-piperazin-1-yl) -carbonyl] -phenylamino} -1 • phenyl-methylidene] -2-indolinone-6-carboxylic acid, methyl ester Made 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 theory), melting point: decomposition from 238 ° C. Mass spectrum: m / z = 581 [MH] ^"

(18) 3- (Z) - [1 - {4 - [(4-tert-butyloxycarbonyl- [1, 4] diazepan-1-yl) carbonyl] phenylamino} -1-phenylmethylidene] - 2-indolinone-6-carboxylic acid methyl ester

Made 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 theory), Melting point: decomposition from 213 ° C Mass spectrum: m / z = 595 [MH] ^"

(19) 3- (Z) - [1 - (4-Carbamoyl-phenylamino) -1-phenyl-methylidene] -2-indolinone-6-carboxylic acid methyl ester

Made from 1-acetyl-3- (1-ethoxy-1-phenylmethylene) -6-methoxycarbonyl-2-indolinone and 4-amino-benzamide. Yield: 71% of theory R _f value: 0.5 (silica gel, methylene chloride / methanol = 9: 1) Mass spectrum: m / z = 412 [MH] ^"

(20) 3- (Z) - [1- (4-Propylcarbamoylphenylamino) -1-phenylmethylidene] -2-indolinone-6-carboxylic acid methyl ester

Made from 1-acetyl-3- (1-ethoxy-1-phenylmethylene) -6-methoxycarbonyl-2-indolinone and 4-amino-N-propylbenzamide.

Yield: 56% of theory,

R _f value: 0.4 (silica gel, methylene chloride / methanol = 9: 1) C ₂₇ H ₂₅ N ₃ O ₄

Mass spectrum: m / z = 456 [M + H] ⁺

(21) 3- (Z) - [1 - (4-Dimethylcarbamoyl] phenylamino) -1-phenyl-methylidene] -2-indolinone-

6-carboxylic acid methyl ester Made from 1-acetyl-3- (1-ethoxy-1-phenylmethylene) -6-methoxycarbonyl-2-indolinone and 4-amino-N, N-dimethylbenzamide.

Yield: 82% of theory,

R _f value: 0.6 (silica gel, methylene chloride / methanol = 9: 1) Mass spectrum: m / z = 440 [MH] ^"

(22) 3- (Z) - [1- {3- [N- (Carbamoyl-methyl) -N-methyl-carbamoyl] phenylamino} -1-phenyl-methylidene] -2-indolinone-6-carboxylic acid methyl ester Made from 1-acetyl-3- (1-ethoxy-1-phenylmethylene) -6-methoxycarbonyl-2-indolinone and 3-amino-N-carbamoylmethyl-N-methyl-benzamide. Yield: 39% of theory,

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

Mass spectrum: m / z = 483 [MH] ^"

(23) 3- (Z) - [1 - {3- [N- (2-methoxy-ethyl) -N-methylcarbamoyl] phenylamino} -1-phenylmethylidene] -2-indolinone-6-carboxylic acid methyl ester Made 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 theory,

R _f value: 0.45 (silica gel, methylene chloride / methanol = 9: 1) Mass spectrum: m / z = 484 [MH] ^"

(24) 3- (Z) - [1 - {3 - [(2-carbamoyl-ethyl) -carbamoyl] -phenylamino} -1-phenyl-methylidene] -2-indolinone-6-carboxylic acid, methyl ester

Made from 1-acetyl-3- (1-ethoxy-1-phenylmethylene) -6-methoxycarbonyl-2-indolinone and 3-amino-N- (2-carbamoylethyl) benzamide.

Yield: 40% of theory,

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

C27H24N4O5

Mass spectrum: m / z = 483 [MH] ^"

(25) 3- (Z) - [1- {3- [N, N-bis (2-hydroxyethyl) carbamoyl] phenylamino} -1-phenylmethylidene] -2-indolinone-6-carboxylic acid, methyl ester

Made 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 theory,

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

Mass spectrum: m / z = 500 [MH] ^" (26) 3- (Z) - [1 - {1-Methyl-2 - [(2-dimethylamino-ethyl) -N-methyl-carbamoyl] pyrrol-4-yl-amino} -1-phenyl-methylidene] Methyl -2-indolinone-6-carboxylate Made 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 theory,

R _f value: 0.70 (silica gel, methylene chloride / methanol / ammonia = 8: 2: 0.1) Mass spectrum: m / z = 502 [M + H] ⁺

(27) 3- (Z) - [1 - {4 - [(4-Dimethylamino-piperidin-1-yl) carbonyl] phenylamino} -1-phenylmethylidene] -2-indolinone-6-carboxylic acid, methyl ester

Made from 1-acetyl-3- (1-ethoxy-1-phenylmethylene) -6-methoxycarbonyl-2-indolinone and 4- (4-dimethylamino-piperidin-1-yl-carbonyl) aniline.

Yield: 57% of theory,

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

Mass spectrum: m / z = 523 [MH] ^"

(28) 3- (Z) - [1 - {4 - [(4-ethyl-piperazin-1-yl) carbonyl] phenylamino} -1-phenylmethylidene] -2-indolinone-6-carboxylic acid, methyl ester

Made from 1-acetyl-3- (1-ethoxy-1-phenylmethylene) -6-methoxycarbonyl-2-indolinone and 4- (4-ethyl-piperazin-1-yl-carbonyl) aniline. Yield: 41% of theory,

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

Mass spectrum: m / z = 511 [M + H] ⁺

(29) 3- (Z) - [1 - {4 - [(4- (2-Dimethylaminoethyl) piperazin-1-yl) carbonyl] phenylamino} - 1-phenylmethylidene] -2-indolinone -6-Carboxylic acid methyl ester Made 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 theory,

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

Mass spectrum: m / z = 554 [M + H] ⁺

(30) 3- (Z) - [1- {4 - [(4- (2-Hydroxyethyl) piperazin-1-yl) carbonyl] phenylamino} -1-phenylmethylidene] -2-indolinone -6-Carboxylic acid methyl ester Made 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 theory,

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

Mass spectrum: m / z = 525 [MH] ^'

(31) 3- (Z) - {1 - [4- (5-Methyl-2,5-diaza-bicyclo [2.2.1] hept-2-yl-carbonyl) -phenylamino] - 1-phenyl-methylidene} Methyl -2-indolinone-6-carboxylate Made 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 theory, R _f value: 0.25 (silica gel, methylene chloride / methanol / ammonia = 9: 1: 0.1) Mass spectrum: m / z = 509 [M + H] ⁺

(32) 3- (Z) - [1 - {4 - [(4-tert-Butyloxycarbonyl-trans-2,5-dimethyl-piperazin-1-yl) - carbonyl] -phenylamino} -1-phenyl-methylidene] -2-indolinone-6-carbonsäuremethylester

Made 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 theory, R _f value: 0.55 (silica gel, methylene chloride / methanol / ammonia = 9: 1: 0.1)

Mass spectrum: m / z = 611 [M + H] ⁺ (33) 3- (Z) - [1 - {4 - [(4-Dimethylaminomethyl-piperidin-1-yl) -carbonyl] -phenylamino} -1 - phenyl-methylidene] -2-indolinone-6-carboxylic acid methyl ester Manufactured from 1-acetyl-3- (1-ethoxy-1-phenylmethylene) -6-methoxycarbonyl-2-indolinone and 4- (4-dimethylaminomethyl-piperidin-1 -ylcarbonyl) aniline. Yield: 10% of theory, melting point: 235-236 ° C Mass spectrum: m / z = 539 [M + H] ⁺

(34) 3- (Z) - [1- {4 - [(cis-3,5-dimethyl-piperazin-1-yl) carbonyl] phenylamino} -1-phenylmethylidene] -2-indolinone-6 -carboxylate

Made 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 theory, melting point: 265-266 ° C

Mass spectrum: m / z = 511 [M + H] ⁺

(35) (R) -3- (Z) - - {4 - [(3,4-dimethylpiperazin-1-yl) carbonyl] phenylamino} -1-phenylmethylidene] -2-indolinone-6 -carboxylate

Made 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 theory, melting point: 265-266 ° C

Mass spectrum: m / z = 511 [M + H] ⁺

(36) 3- (Z) - [1 - {4 - [(4- (2-Diethylaminoethoxy) piperidin-1-yl) carbonyl] phenylamino} - 1-phenylmethylidene] -2-indolinone -6-Carboxylic acid methyl ester Made from 1-acetyl-3- (1-ethoxy-1-phenylmethylene) ~ 6-methoxycarbonyl-2-indolinone and 4- (4- (2-diethylamino-ethoxy) -pjperidin-1 -yl-carbonyl )-aniline. Yield: 12% of theory, melting point: 114 ° C Mass spectrum: m / z = 597 [M + H] ⁺

(37) 3- (Z) - [1 - {4 - [(3- (2-diethylaminoethoxy) pyrrolidin-1-yl) carbonyl] phenylamino} - 1-phenylmethylidene] -2-indolinone -6-carbonsäuremethylester

Made 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 theory, melting point: 133-134 ° C

Mass spectrum: m / z = 583 [M + H] ⁺

(38) 3- (Z) - [1 - {4 - [(3-Dimethylamino-pyrrolidin-1-yl) -carbonyl] -phenylamino} -1 -phenyl-methylidene] -2-indolinone-6-carboxylic acid methyl ester Manufactured from 1-acetyl-3- (1-ethoxy-1-phenylmethylene) -6-methoxycarbonyl-2-indolinone and 4- (3-dimethylamino-pyrrolidin-1-yl-carbonyl) aniline.

Yield: 32% of theory,

Melting point: 259-260 ° C Mass spectrum: m / z = 511 [M + H] ⁺

Example 2:

3- (Z) - [1 - {4 - [(piperazin-1-yl) carbonyl] phenylamino} -1-phenylmethylidene] -2-indolinone-6-carboxylic acid methyl ester trifluoroacetate

A solution of 0.2 g (0.343 mmol) of 3- (Z) - [1- {4 - [(4-tert-Butyloxycarbonyl-piperazin-1-yl) -carbonyl] -phenylamino} -1-phenyl-methylidene] -2-indolinone-6-carboxylic acid methyl ester and 0.079 ml trifluoroacetic acid in 20 ml dichloromethane is stirred for 50 hours at room temperature. The solvent is then distilled off in vacuo and diisopropyl ether is added to the residue. The precipitate is filtered off and washed with diisopropyl ether. Yield: 0.19 g (92% of theory), melting point: 270-271 ° C 2 ₈ H ₂₆ N4O4 mass spectrum: m / z = 483 [M + H] ⁺

The following compounds are prepared analogously to Example 2:

(1) 3- (Z) - [1- {4 - [([1, 4] diazepan-1-yl) carbonyl] phenylamino} -1-phenylmethylidene] -2-indolinone-6-carboxylic acid methyl ester- trifluoroacetate

A solution of 0.25 g (0.419 mmol) of 3- (Z) - [1- {4 - [(4-tert-butyloxycarbonyl-

[1, 4] diazepan-1 -yl) -carbonyl] -phenylamino} -1 -phenyl-methylidene] -2-indolinone-6-carboxylic acid methyl ester and 0.4 ml trifluoroacetic acid in 20 ml dichloromethane is 48 hours at room temperature and two hours stirred at 45 ° C. The solvent is then distilled off in vacuo and diisopropyl ether is added to the residue. The precipitate is filtered off and washed with diisopropyl ether. Yield: 0.23 g (89% of theory), melting point: 261-262 ° C C2 ₉ H28 4O4 mass spectrum: m / z = 497 [M + H] ⁺

(2) 3- (Z) - [1- {4 - [/ V- (2-methylamino) -ethyl) - / V-methyl-carbamoyl] -phenylamino} -1-phenyl-methylidene] -2-indolinone- 6-carbonsäuremethylester

Made from 3- (Z) - [1 - {4 - [(2- (tert-Butyloxycarbonyl-methylamino) -ethyl) -N-methyl-carbonyl] -phenylamino} -1-phenyl-methylidene] -2-indolinone- 6-carboxylic acid methyl ester by treatment with trifluoroacetic acid at room temperature in methylene chloride.

Yield: 86% of theory Rf value: 0.5 (silica gel, methylene chloride / methanol = 4: 1)

C ₂₈ H2 ₈ N ₄ O4

Mass spectrum: m / z = 485 [M + H] ⁺

(3) 3- (Z) - [1 - {4 - [(trans-2,5-dimethylpiperazin-1-yl) carbonyl] phenylamino} -1-phenylmethylidene] -2-indolinone-6 -carboxylate trifluoroacetate

Made from 3- (Z) - [1 - {4 - [(4-tert-Butyloxycarbonyl-trans-2,5-dimethyl-piperazin-1 - yl) -carbonyl] -phenylamino} -1-phenyl-methylidene] - 2-indolinone-6-carboxylic acid methyl ester by treatment with trifluoroacetic acid at room temperature in methylene chloride. Yield: 100% of theory

R _f value: 0.4 (silica gel, methylene chloride / methanol / ammonia = 9: 1: 0.1)

Mass spectrum: m / z = 511 [M + H] ⁺

Example 3:

3- (Z) - [1 - (4-r (4-methyl-piperazin-1-yl-carbonylphenphenyl-1-phenyl-methylidene-2-indolinone-6-carboxylic acid

155 mg (310 mmol) 3- (Z) - [1- {4 - [(4-methyl-piperazin-1-yl) carbonyl] phenylamino} -1-phenyl-methylidene] -2-indolinone-6- carboxylic acid methyl ester are dissolved in 5 ml of methanol, 0.5 ml of 10N sodium hydroxide solution is added and the mixture is stirred at 50 ° C. for 8 hours. The mixture is then neutralized with dilute hydrochloric acid and water is added. The precipitate is filtered off and purified on an RP18 column using a gradient of acetonitrile and water as the eluent. Yield: 13 mg (9% of theory), melting point: 218 ° C.

Mass spectrum: m / z = 483 [M + H] ⁺

The following compounds can be prepared analogously to the examples above:

(1) 3- (Z) - [1- {4- [N, N-bis (2-dimethylaminoethyl) carbamoyl] phenylamino} -1-phenylmethylidene] -2-indolinone-6-carboxylic acid methyl ester

(2) 3- (Z) - [1- {4- [N, N-bis (3-diethylamino-propyl) carbamoyl] phenylamino} -1-phenylmethylidene] -2-indolinone-6-carboxylic acid methyl ester (3) 3- (Z) - [1- {4 - [(2-Diethylaminoethyl) carbamoyl] phenylamino} -1-phenylmethylidene] -2-indolinone-6-carboxylic acid methyl ester

(4) 3- (Z) - [1- {4- [N, N-bis (2-hydroxyethyl) carbamoyl] phenylamino} -1-phenylmethylidene] -2-indolinone-6-carboxylic acid methyl ester

(5) 3- (Z) - [1 - {4- [N- (Carbamoyl-methyl) -N-methyl-carbamoyl] -phenylamino} -1-phenyl-methylidene] -2-indolinone-6-carboxylic acid methyl ester

(6) 3- (Z) - [1- {4 - [(2-carbamoyl-ethyl) -carbamoyl] -phenylamino} -1-phenyl-methylidene] - 2-indolinone-6-carboxylic acid methyl ester

(7) 3- (Z) - [1- {3- [N- (2-Hydroxyethyl) -N-methylcarbamoyl] phenylamino} -1-phenylmethylidene] -2-indolinone-6-carboxylic acid methyl ester

(8) 3- (Z) - [1 - {3- [N- (2-Methylamino-ethyl) -N-methyl-carbamoyl] phenylamino} -1 - phenyl-methylidene] -2-indolinone-6-carboxylic acid methyl ester

(9) 3- (Z) - [1 - {3- [N- (2-Aminoethyl) carbamoyl] phenylamino} -1-phenyl-methylidene] -2-indolinone-6-carboxylic acid methyl ester

(10) 3- (Z) - [1 - {4 - [(2- (tert-Butyloxycarbonylamino) ethyl) carbamoyl] phenylamino} -1 - phenylmethylidene] -2-indolinone-6-carboxylic acid methyl ester

(11) 3- (Z) - [1- {5 - [(2-Dimethylamino-ethyl) -N-methyl-carbamoyl] furan-2-yl-amino} -1-phenyl-methylidene] -2-indolinone -6-carbonsäuremethylester

(12) 3- (Z) - [1 - {4 - [(2-amino-ethyl) carbamoyl] phenylamino} -1-phenyl-methylidene] -2-indolinone-6-carboxylic acid methyl ester

(13) 3- (Z) - [1 - {4 - [(4- (2-Dimethylaminoethoxy) piperidin-1-yl) carbonyl] phenylamino} -1-phenylmethylidene] -2-indolinone -6-carbonsäuremethylester (14) 3- (Z) - [1- {4 - [(3- (2-Dimethylaminoethoxy) pyrrolidin-1-yl) carbonyl] phenylamino} -1-phenylmethylidene] -2-indolinone -6-carbonsäuremethylester

(15) CS -3- (Z) - [1 - {4 - [(3,4-dimethylpiperazin-1-yl) carbonyl] phenylamino} -1-phenylmethylidene] -2-indolinone-6 -carboxylate

The compounds synthesized or synthesizable according to Examples 1 and 2 are summarized in Table 1.

Table 1: Compounds of the general formula

Example 4

Dry ampoule with 75 mg of active ingredient per 10 ml

Composition:

Active ingredient 75.0 mg mannitol 50.0 mg

Water for injections ad 10.0 ml

production:

Active ingredient and mannitol are dissolved in water. After filling, freeze-drying. The ready-to-use solution is dissolved with water for injections.

Example 5

Dry ampoule with 35 mg of active ingredient per 2 ml

Composition:

Active ingredient 35.0 mg

Mannitol 100.0 mg

Water for injections ad 2.0 ml production:

Active ingredient and mannitol are dissolved in water. After filling, freeze-drying.

The ready-to-use solution is dissolved with water for injections.

Example 6

Tablet with 50 mg of active ingredient

Composition:

(1) Active ingredient 50.0 mg

(2) milk sugar 98.0 mg

(3) Corn starch 50.0 mg

(4) Polyvinylpyrrolidone 15.0 mg

(5) Magnesium stearate 2.0 mg

215.0 mg

production:

(1), (2) and (3) are mixed and granulated with an aqueous solution of (4). (5) is added to the dried granulate. Tablets are pressed from this mixture, biplan with a facet on both sides and a partial notch on one side. Tablet diameter: 9 mm.

Example 7

Tablet with 350 mα active ingredient

Composition: (1) Active ingredient 350.0 mg

(2) milk sugar 136.0 mg

(3) corn starch 80.0 mg

(4) Polyvinylpyrrolidone 30.0 mg

(5) Magnesium stearate 4.0 mg

600.0 mg

Preparation: (1), (2) and (3) are mixed and granulated with an aqueous solution of (4). (5) is added to the dried granulate. Tablets are pressed from this mixture, biplan with a facet on both sides and a partial notch on one side. Tablet diameter: 12 mm.

Example 8

Capsules with 50 mg of active ingredient

Composition:

(1) Active ingredient 50.0 mg

(2) Corn starch dried 58.0 mg

(3) Milk sugar powdered 50.0 mg

(4) Magnesium stearate 2.0 mg

160.0 mg

production:

(1) is triturated with (3). This trituration is added to the mixture of (2) and (4) with intensive mixing.

This powder mixture is filled in a size 3 hard gelatin capsule on a capsule filling machine. Example 9

Capsules with 350 mg of active ingredient

Composition:

(1) Active ingredient 350.0 mg

(2) Corn starch dried 46.0 mg

(3) Milk sugar powdered 30.0 mg (4) Magnesium stearate 4.0 mg

430.0 mg

production:

(1) is triturated with (3). This trituration is added to the mixture of (2) and (4) with intensive mixing.

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

Example 10

Suppositories with 100 mg of active ingredient

1 suppository contains: active ingredient 100.0 mg

Polyethylene glycol (M.G. 1500) 600.0 mg

Polyethylene glycol (M.G. 6000) 460.0 mg

Polyethylene sorbitan monostearate 840.0 mg

2,000.0 mg

production:

The polyethylene glycol is melted together with polyethylene sorbitan monostearate. At 40 ° C, the ground active substance is melted homogeneously dispersed. It is cooled to 38 ° C and poured into weakly pre-cooled suppository molds.

Claims

claims

Indolinones of the general formula substituted in the 6-position

in the

X is an oxygen or sulfur atom,

Ri is a hydrogen atom or a prodrug residue,

R _{2 is} a carboxy group, a linear or branched Ci-β-alkoxycarbonyl group, a C ₄ -7-cycloalkoxycarbonyl or an aryloxycarbonyl group,

R _{3 is} a hydrogen atom, a C _1-6 alkyl, C _3-7 cycloalkyl, trifluoromethyl or heteroaryl group,

a phenyl or naphthyl group, or one by a fluorine, chlorine, bromine or iodine atom, by a trifluoromethyl, C- |. ₃ -alkyl or Cι_ ₃ -alkoxy group mono- or disubstituted phenyl or naphthyl group, where in the case of disubstitution the substituents may be the same or different,

R _{4 is} a phenyl, pyrrolyl or furanyl group substituted by the group R ₆ , which is additionally substituted by fluorine, chlorine, bromine or iodine atoms, by d- ₅ -alkyl, trifluoromethyl, hydroxyl, d _-3 -Alkoxy-, carboxy-, d. ₃ -alkoxy-carbonyl-, amino-, acetylamino-, d _-3 -alkyl-sulfonylamino-, aminocarbonyl-, Cι- ₃ alkyl aminocarbonyl, di (Cι _-3 alkyl) aminocarbonyl, aminosulfonyl, Cι _-3 alkyl aminosulfonyl, di (d _-3 alkyl) aminosulfonyl, nitro or Cyano groups can be mono- or disubstituted, where the substituents can be the same or different and where

Rβ an aminocarbonyl, Cι- alkylamino-carbonyl-, N- (Cι- ₅ alkyl) -Cι _-3 -alkyl- aminocarbonyl-, C ₃ - ₇ cycloalkylamino-carbonyl-, N- (Cι _-5 -alkyl) ) -C ₃ - ₇ -cycloalkylaminocarbonyl-, (phenyl-Cι. ₃ -alkyl) amino-carbonyl-, N- (d _-3- alkyl) - phenyl-d-3-alkylamino-carbonyl group,

a C _-3 -alkylaminocarbonyl- or N- (Cι- ₃ -alkyl) -Cι- ₃ -alkylaminocarbonyl- group, in which one or two alkyl parts independently of one another by a nitro, cyano, carbamoyl, N- (Cι- ₃ -alkyl) -carbamoyl, di-N- (C _{1. 3} -alkyl) - carbamoyl, carboxy or d- _3- alkoxycarbonyl group or in the 2- or 3-position by an amino, (-C. ₃ -alkyl ) -amino-, di- (Cι_ ₃ -alkyl) -amino-,

(-Cι -alkoxycarbonyl) -amino-, N- (-Cι. ₄ -alkoxycarbonyl) -N- (Cι. ₃ -alkyl) -amino-, piperazino-, N- (C ₁ - ₃ -alkyl) -piperazino-, a 4- to 7-membered cycloalkylene imino group, a hydroxyl or methoxy group are substituted,

a 4- to 7-membered cycloalkyleneiminocarbonyl group in which

the cycloalkylene part can be condensed with a phenyl ring via two adjacent ring atoms or can be bridged with a methylene or ethylene group via two non-adjacent ring atoms or

one or two hydrogen atoms can each be replaced by a C _1-3 alkyl group or / and

each the methylene group in position 4 of a 6- or 7-membered

Cycloalkyleneiminocarbonyl group by a carboxy, C _1-4 alkoxycarbonyl, aminocarbonyl, d _-3 alkylaminocarbonyl, di (d _-3 alkyl) aminocarbonyl, di (d _-3 alkyl) amino -d_ ₃ -alkyl-, di- (d _-3 -alkyl) -amino-, Phenyl-C _-3 alkylamino or N- (Cι. ₃ alkyl) phenyl -C. _3- alkylamino group, a hydroxy or methoxy group substituted or

by an oxygen or sulfur atom, by a sulfinyl, sulfonyl or -NH group or by a nitrogen atom by a Cι. -Alkyl-, phenyl-, Cι- ₃ -alkyl-carbonyl-, Cι _-4 -alkoxy-carbonyl-, di- (d. ₃ -alkyl) -amino-Cι _-3 -alkyl-, ω-hydroxy-C _{2 3-} alkyl or benzoyl group is substituted, can be replaced,

all of the phenyl groups contained in the radicals mentioned under R ₆ or simply fused by fluorine, chlorine, bromine or iodine atoms, by Cι. ₅ -alkyl-, trifluoromethyl-, hydroxy-, Cι _-3 -alkoxy-, carboxy-, d- ₃ -alkoxycarbonyl-, aminocarbonyl-, d- ₄ -alkylamino-carbonyl-, di- (Cι- ₄ -alkyl) - amino-carbonyl, aminosulfonyl, C ₃ alkyl alkyl aminosulfonyl, di (C ₃ alkyl) amino sulfonyl, C ₃ alkyl sulfonylamino, nitro or cyano groups may be mono- or disubstituted where the substituents can be the same or different, or two adjacent hydrogen atoms of the phenyl groups can be replaced by a methylenedioxy group,

and

R _{5 represents} a hydrogen atom or a C _1-3 alkyl group,

where under the expression an aryl group, optionally by a fluorine, chlorine, bromine or iodine atom, by a cyano, trifluoromethyl, nitro, carboxy, aminocarbonyl, C _-3 alkyl or C 3 alkoxy group mono- or disubstituted phenyl or naphthyl group and

under the expression a heteroaryl group, a monocyclic 5- or 6-membered heteroaryl group optionally substituted by a d_ ₃ -alkyl group in the carbon skeleton, where the 6-membered heteroaryl group has one, two or three nitrogen atoms and

the 5-membered heteroaryl group, optionally by one

Cι- ₃ -alkyl or phenyl-Cι _-3 -alkyl group substituted imino group, an oxygen or sulfur atom or

an imino group optionally substituted by a C ₃ alkyl or phenyl C _1-3 alkyl group or an oxygen or sulfur atom and additionally a nitrogen atom or

a possibly by a Cι. Contains _3- alkyl or phenyl-C _1-3 -alkyl- substituted imino group and two nitrogen atoms,

and in addition a phenyl ring may be fused to the above-mentioned monocyclic heterocyclic groups via two adjacent carbon atoms and the binding takes place via a nitrogen atom or via a carbon atom of the heterocyclic part or a fused-on phenyl ring,

to understand

the hydrogen atoms in the alkyl and alkoxy groups mentioned above or in the alkyl parts contained in the groups of formula I defined above can be partially or completely replaced by fluorine atoms,

the saturated alkyl and alkoxy parts which contain more than 2 carbon atoms in the groups defined above, including their branched isomers, such as, for example, the isopropyl, tert-butyl, isobutyl group, unless stated otherwise, and where in addition the hydrogen atom of an existing carboxy group or a hydrogen atom bonded to a nitrogen atom, for example an amino, alkylamino or imino group or a saturated N-heterocycle such as the piperidinyl group, can in each case be replaced by a radical which can be split off in vivo,

their tautomers, their diastereomers, their enantiomers, their mixtures and their salts.

2. Indolinones of the general formula I according to claim 1, in which

X is an oxygen atom,

Ri is a hydrogen atom, a C _-4 alkoxycarbonyl or C _2-4 alkanoyl group,

R _{2 is} a carboxy group or a linear or branched d- ₄ -alkoxycarbonyl group,

R _{3 is} a hydrogen atom, a Cι. ₆ alkyl or C _3-7 cycloalkyl group,

a phenyl or naphthyl group, or one by a fluorine, chlorine or bromine atom, by a trifluoromethyl, d _-3 alkyl or Cι. ₃ -alkoxy group mono- or disubstituted phenyl or naphthyl group, where in the case of disubstitution the substituents can be the same or different,

R is a furanyl group substituted by an aminocarbonyl, C, _M alkylaminocarbonyl or N (C ₄ alkyl) C _1-3 alkylaminocarbonyl group, the Cu alkylaminocarbonyl or N (C ₄ alkyl) group Cι.3-alkylamino-carbonyl group in one or both alkyl parts from position 2 by one

Amino, C ₃ alkyl alkyl or di (C ₃ alkyl) amino group can be substituted, a pyrrolyl group substituted by an aminocarbonyl, C ₄ alkylaminocarbonyl or N (C ₄ alkyl) d ₃ alkylaminocarbonyl group, the d 4-alkylaminocarbonyl or N (C ₄ alkyl) Cι-3-alkylaminocarbonyl group in one or both alkyl parts from position 2 by an amino, C ₁ - ₃ - alkylamino or di (d- ₃ -alkyl) amino group and can be substituted

Nitrogen atom of the pyrrolyl ring is optionally substituted by a d- ₃ alkyl group, or

a phenyl group substituted by the group Rβ, additionally by fluorine, chlorine or bromine atoms, by Cι. _5- alkyl-, trifluoromethyl-, hydroxy-, d- ₃ -alkoxy-, carboxy-, d- ₃ -alkoxycarbonyl-, amino-, acetylamino-, d-3-alkyl-sulfonylamino-, aminocarbonyl-, d- ₃ - Alkyl aminocarbonyl, di (Cι.3-alkyl) aminocarbonyl, aminosulfonyl, Cι- ₃ alkylaminosulfonyl, di (Cι-3-alkyl) aminosulfonyl, nitro or cyano groups mono- or may be disubstituted, the substituents being the same or different, and wherein

R ₆ is aminocarbonyl, d- ₄ alkylamino-carbonyl, N- ₍₅ Cι- alkyl) -Cι- ₃ alkyl aminocarbonyl, C _3-7 cycloalkylamino-carbonyl, N- (d- ₅ -Alkyl) -C ₃ - ₇ - cycloalkylaminocarbonyl-, (phenyl-Cι. ₃ -alkyl) amino-carbonyl-, N- (Cι. ₃ -alkyl) - phenyl-d-3-alkylamino-carbonyl group,

a Cι. ₃ -Alkylaminocarbonyl- or N- (-Cι. ₃ -alkyl) -Cι _-3 -alkylaminocarbonyl- group, in which one or two alkyl parts independently of one another by a nitro, cyano, carbamoyl, N- (C _1-3 - alkyl) carbamoyl, di-N- (Cι _-3 alkyl) - carbamoyl, carboxy or Cι-3-alkoxycarbonyl group or in the 2- or 3-position by an amino, (Cι. ₃ alkyl) amino -, di (Cι- ₃ alkyl) amino, (Cι _-4 alkoxycarbonyl) amino, N- (C _1-4 alkoxycarbonyl) -N- (alkyl C _{1. 3)} -amino- _I piperazino, N- (d _-3- alkyl) -piperazino, a piperazinyl or piperidinyl group, a hydroxyl or methoxy group are substituted,

a 4- to 7-membered cycloalkyleneiminocarbonyl group in which the cycloalkylene part can be condensed with a phenyl ring via two adjacent ring atoms or can be bridged with a methylene or ethylene group via two non-adjacent ring atoms or

one or two hydrogen atoms can each be replaced by a C ₃ alkyl group or / and

each the methylene group in position 4 of a 6- or 7-membered cycloalkyleneiminocarbonyl group through a carboxy, d- alkoxycarbonyl, aminocarbonyl, Cι-3-alkylaminocarbonyl, di (Cι _-3 alkyl) aminocarbonyl, Di- (Cι. ₃ -alkyl) -amino-Cι. ₃ -alkyl-, di- (Cι. ₃ -alkyl) -amino-, phenyl-Cι.3-alkylamino- or N- (Cι- ₃ -alkyl) -phenyl-Cι. _3- alkylamino group, a hydroxy or methoxy group substituted or

by an oxygen or sulfur atom, by a sulfinyl, sulfonyl or -NH group or by a nitrogen atom by a d- ₃ -alkyl, phenyl, Cι _-3- alkyl carbonyl, Di- (d- ₃ -alkyl) amino -CC. ₃ -alkyl-, ω-hydroxy-C ₂ - ₃ -alkyl or benzoyl group is substituted, can be replaced,

and

R _{5 is} a hydrogen atom or a C ₃ alkyl group,

where the hydrogen atoms in the alkyl and alkoxy groups mentioned above or in the alkyl parts contained in the groups of formula I defined above can be partially or completely replaced by fluorine atoms,

the saturated alkyl and alkoxy parts which contain more than 2 carbon atoms in the groups defined above, including theirs include branched isomers such as the isopropyl, tert-butyl, isobutyl group, unless otherwise mentioned, and

where in addition the hydrogen atom of an existing carboxy group or a hydrogen atom bonded to a nitrogen atom, for example an amino, alkylamino or imino group or a saturated N-heterocycle such as the piperidinyl group, can in each case be replaced by a radical which can be split off in vivo,

mean, their tautomers, their diastereomers, their enantiomers, their mixtures and their salts.

3. Indolinones of the general formula I according to claim 1, in which

X is an oxygen atom,

Ri is a hydrogen atom,

R2 is a carboxy group or a C ₂ alkoxycarbonyl group,

R _{3 is} a phenyl or naphthyl group, or a phenyl group monosubstituted by a fluorine, chlorine or bromine atom, by a trifluoromethyl, C _1-3 alkyl or d _-3 alkoxy group,

R4 one through an aminocarbonyl, d- ₄ -alkylaminocarbonyl or N- (Cι.4-alkyl) -Cι. _3- alkylaminocarbonyl group substituted pyrrolyl group, where the d- ₄ -alkylaminocarbonyl or N- (-C _-4 alkyl) -Cι- ₃ alkylamino carbonyl group in one or both alkyl parts from position 2 by an amino, Cι. ₃ -Alkylamino- or di- (C _-3 -alkyl) amino group can be substituted and the nitrogen atom of the pyrrolyl ring is optionally substituted by a d-3-alkyl group, or a phenyl group substituted in the 3- or 4-position by the group R ₆ , where

R _{6 is} an aminocarbonyl-, d- ₄ -alkylamino-carbonyl-, N- (Cι _-3- alkyl) -Cι- ₃ -alkyl- aminocarbonyl-, C _5- 6-cycloalkylamino-carbonyl-, N- (Cι _-5 Alkyl) C _5-6 cycloalkylaminocarbonyl group,

a Cι _-3 -alkylaminocarbonyl- or N- (Cι- ₃ -alkyl) -Cι _-3 -alkylaminocarbonyl- group, in which one or two alkyl parts independently of one another by a carbamoyl, N- (Cι- ₃ -alkyl) -carbamoyl , Di-N- (-Cι. ₃ -alkyl) -carbamoyl, d- ₃ -alkoxycarbonyl group or in the 2- or 3-position by an amino-, (-Cι. ₃ -alkyl) -amino-, di- (C _{1- 3} -alkyl) -amino-, (Cι. ₄ -alkoxycarbonyl) -amino-, N- (Cι ^ -alkoxycarbonyl) -N- (Cι- ₃ -alkyl) -amino-, piperazino-, N- (Cι. ₃ Alkyl) - piperazino, a piperazinyl or piperidinyl group, a hydroxyl or methoxy group,

a piperidinocarbonyl, piperazinocarbonyl, homopiperazinocarbonyl or 2,3,4,5-tetrahydro-1 (H) -azepino-carbonyl group,

each condensed with a phenyl ring via two adjacent unsubstituted carbon atoms or

in position 4 by a Cι_ ₃ alkyl, C _1-4 alkoxycarbonyl, di (Cι _-3 alkyl) amino, di (Cι. ₃ alkyl) amino C _1-3 alkyl -, 2-hydroxyethyl, hydroxy or methoxy group can be substituted,

or a 2,5-diaza-bicyclo [2.2.1] hept-2-yl-carbonyl group, which can be substituted in position 5 by ad _-3 -alkyl group,

and

R5 is a hydrogen atom or a C _1-3 alkyl group, wherein the hydrogen atoms in the above-mentioned methyl and methoxy groups can be replaced by 1, 2 or 3 fluorine atoms, and

the saturated alkyl and alkoxy parts present in the groups defined above which contain more than 2 carbon atoms, including their branched isomers, such as, for example, the isopropyl, tert-butyl, isobutyl group,

mean, their tautomers, their diastereomers, their enantiomers, their mixtures and their salts.

4. Indolinones of the general formula I according to claim 1, in which

X is an oxygen atom,

Ri and R ₅ each represent a hydrogen atom,

R _{2 is} a methoxycarbonyl group,

R _{3 is} a phenyl group and

R4 is a phenyl group in the 3- or 4-position is substituted by mono- the group _R, wherein

R _{6 is} an aminocarbonyl-, d _-3 -alkylamino-carbonyl-, N- (-Cι _-5 -alkyl) -Cι- ₃ -alkyl- aminocarbonyl-, cyclohexylaminocarbonyl-, N- (Cι_ ₅ -alkyl) -cyclohexylamino- carbonyl- , Phenyl-Cι. ₃ -alkylamino-carbonyl-, N- (d _-3- alkyl) -phenyl-Cι _-3 -alkylamino-carbonyl-,

a piperidinocarbonyl-, 4-hydroxy-piperidinocarbonyl-, 4- [di- (Cι _-3 -alkyl) - amino] -piperidinocarbonyl-, 4- [di- (C _1-3 -alkyl) -amino-Cι- ₃ - alkyl] -piperidino-carbonyl-, piperazinocarbonyl-, N- (C _1-3 -alkyl) -piperazinocarbonyl-, N- (d_4-Alkoxycarbonyl) -piperazinocarbonyl-, N- [Di- (Cι.3-alkyl) amino-Cι-3-alkyl] - piperazinocarbonyl-, N- (2-hydroxy-ethyl) -piperazinocarbonyl-, homopipera- zinocarbonyl -, N- (-Cι- _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 Cι- ₃ alkylaminocarbonyl or N- (Cι- ₅ alkyl) -Cι. ₃ -alkylaminocarbonyl- group, in which one or two alkyl parts by a carbamoyl group or in the 2- or 3-position by an amino-, (d _-3- alkyl) -amino-, di- (Cι_ ₃ -alkyl) - amino- , Hydroxy or methoxy group are substituted,

their tautomers, their diastereomers, their enantiomers, their mixtures and their salts.

5. The following substituted indolinones of the general formula I according to claim 1:

(a) 3- (Z) - [1- {4- [N- (2-Dimethylamino-ethyl) -N-methyl-carbamoyl] - phenylamino} -1-phenyl-methylidene] -2-indolinone-6-carboxylic acid methyl ester

(b) 3- (Z) - [1- {4- [N- (3-Dimethylamino-propyl) -N-methyl-carbamoyl] phenylamino} -1-phenyl-methylidene] -2-indolinone-6-carboxylic acid methyl ester

(c) 3- (Z) - [1 - {4 - [(4-methylpiperazin-1-yl) carbonyl] phenylamino} -1-phenylmethylidene] -2-indolinone-6-carboxylic acid methyl ester

(d) 3- (Z) - [1 - {4 - [(4-Hydroxy-piperidin-1-yl) carbonyl] phenylamino} -1-phenylmethylidene] -2-indolinone-6-carboxylic acid methyl ester

(e) 3- (Z) - [1 - {4 - [(piperazin-1-yl) carbonyl] phenylamino} -1-phenylmethylidene] - 2-indolinone-6-carboxylic acid methyl ester (f) 3- (Z) - [1 - {4- [N- (2-Methylamino-ethyl) -N-methyl-carbamoyl] -phenylamino} -1 ■ phenyl-methylidene] -2-indolinone-6-carboxylic acid methyl ester

(g) 3- (Z) - [1- {4 - [(4-Dimethylamino-piperidin-1-yl) carbonyl] phenylamino} -1-phenylmethylidene] -2-indolinone-6-carboxylic acid methyl ester

(h) 3- (Z) - [1 - {4 - [(4-ethyl-piperazin-1-yl) carbonyl] phenylamino} -1-phenylmethylidene] -2-indolinone-6-carboxylic acid, methyl ester

(i) 3- (Z) - [1- {4 - [(4- (2-Hydroxyethyl) piperazin-1-yl) carbonyl] phenylamino} -1-phenylmethylidene] -2-indolinone -6-carbonsäuremethylester

(k) 3- (Z) - {1- [4- (5-Methyl-2,5-diaza-bicyclo [2.2.1] hept-2-ylcarbonyl) phenylamino] -1-phenyl- methylidene} -2-indolinone-6-carbonsäuremethylester

their tautomers, their mixtures and their salts.

6. 3- (Z) - [1 - {4 - [(4-methyl-piperazin-1-yl) -carbonyl] -phenylamino} -1-phenyl-methylidene] -2-indolinone-6-carboxylic acid methyl ester and its salts ,

7. Physiologically acceptable salts of the compounds according to claims 1 to 6.

8. Medicament containing a compound according to at least one of claims 1 to 6 or a salt according to claim 7 in addition to optionally one or more inert carriers and / or diluents.

9. Use of a compound according to at least one of claims 1 to 6 or a salt according to claim 7 for the manufacture of a medicament which is suitable for the treatment of excessive or abnormal cell proliferation.

10. A method for producing a medicament according to claim 8, characterized in that a compound according to at least one of claims 1 to 6 or a salt according to claim 7 is incorporated in one or more inert carriers and / or diluents by a non-chemical route.

11. A process for the preparation of the compounds according to claims 1 to 7, characterized in that

a. a compound of the general formula

in the

X and R3 are as defined in claims 1 to 6, R ₂ 'has the meanings mentioned for R2 in claims 1 to 6, Ris is a hydrogen atom or a protective group for the nitrogen atom of the lactam group, one of the radicals R ^ and Rι _{8 can} also represent a bond to a solid phase which may be formed via a spacer and the other of the radicals R 'and R- | _{8 has} the meanings mentioned above, and Z _{1 represents} a halogen atom, a hydroxyl, alkoxy or arylalkoxy group,

with an amine of the general formula in the

R ₄ and R _{5 are} as defined in claims 1 to 6, implemented and, if necessary, a protective group used for the nitrogen atom of the lactam or imino group or a compound thus obtained is cleaved from a solid phase, or

b. for the preparation of a compound of general formula I in which

R _2, with the exception of the carboxy group as defined in claims 1 to 6, is a compound of the general formula

in the

Ri and R ₃ to R _{5 are} as defined in claims 1 to 6, or their reactive derivatives with a compound of the general formula

in the

R19 a d _-6 alkanol, a C ₄ - ₇ means cycloalkanol or an aromatic alcohol is reacted and

if desired, a compound of the general formula I thus obtained which contains an alkoxycarbonyl group is subsequently converted into a corresponding carboxy compound by means of hydrolysis or a compound of the general formula I thus obtained, which contains an amino or alkylamino group, is converted into a corresponding alkylamino or dialkylamino compound by means of reductive alkylation, or

a compound of the general formula I thus obtained, which contains an amino or alkylamino group, is converted into a corresponding acyl or sulfonyl compound by means of acylation or sulfonation, or

a compound of the general formula I thus obtained, which contains a carboxy group, is converted into a corresponding ester or aminocarbonyl compound by esterification or amidation, or

a compound of the general formula I thus obtained, which contains a cycloalkyleneimino group in which a methylene group is replaced by a sulfur atom, is converted into a corresponding sulfinyl or sulfonyl compound by oxidation, or

a compound of the general formula I thus obtained, which contains a nitro group, is converted into a corresponding amino compound by reduction or

a compound of the general formula I thus obtained, in which R _{4 represents} a phenyl group substituted by an amino, alkylamino, aminoalkyl or N-alkylamino group, by reaction with a corresponding one

Cyanate, isocyanate or carbamoyl halide is converted into a corresponding urea compound of the general formula I or

a compound of the general formula I thus obtained, in which R _{4 represents} a phenyl group substituted by an amino, alkylamino or aminoalkyl group, by reaction with a corresponding compound which transfers the amidino group or by reaction with a corresponding the nitrile is converted into a corresponding guanidino compound of the general formula I or

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

if desired, a compound of the general formula I thus obtained is subsequently separated into its stereoisomers or

a compound of the general formula I thus obtained is converted into its salts, in particular for pharmaceutical use into its physiologically tolerable salts with an inorganic or organic acid or base.