WO2000073297A1

WO2000073297A1 - Substituted indolinone as tyrosine kinase inhibitors

Info

Publication number: WO2000073297A1
Application number: PCT/EP2000/004685
Authority: WO
Inventors: Armin Heckel; Rainer Walter; Gerald Roth; Jacobus C. A. Van Meel; Norbert Redemann; Ulrike Tontsch-Grunt; Walter Spevak
Original assignee: Boehringer Ingelheim Pharma Kg
Priority date: 1999-05-27
Filing date: 2000-05-23
Publication date: 2000-12-07
Also published as: DE19924401A1; AU5215700A

Abstract

The invention relates to substituted indolinones of general formula (I), wherein R1- R5 and X have the meaning defined in claim 1, to their isomers and salts, especially their physiologically acceptable salts, which have valuable pharmacological properties, especially an inhibiting effect on different kinase and cyclone/CD complexes and on the proliferation of different tumor cells. The invention also relates to the medicaments containing said compounds, to the use and to a method for the production thereof.

Description

SUBSTITUTED INDOLINONES AS TYROSINKINASE INHIBITORS

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

their isomers, their salts, in particular their physiologically tolerable salts, which have valuable properties.

The above compounds of general formula I, in which R _{x 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, PDGFR, FGFR1, EGFR, HER2, IGFIR and HGFR, as well as complexes of CDK's (Cyclin Dependent Kinases) such as CDKl, CDK2, CDK3, CDK, CDK6, CDK7, CDK8 and CDK9 with their specific cyclins (A, B1, B2, C, Dl, D2, D3, E , F, Gl, G2, H, I and K) and on viral cyclin (see L. Mengtao in J. Virology 21 (3), 1984-1991 (1997)), on the proliferation of cultured human cells, in particular those of endothelial cells, for example in angiogenesis, but also on the proliferation of other cells, in particular tumor cells, and the other compounds of the general formula I above, in which R _x does not represent a hydrogen atom or a prodrug residue. represents valuable intermediates for the preparation of the aforementioned compounds.

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

In the above general formula I mean

X is an oxygen or sulfur atom,

R _{x is} a hydrogen atom, a C - ^ - alkoxycarbonyl or C ₂ . ₄ -alkanoyl group,

R _{2 is} one on the amide nitrogen atom by a

Substituted aminocarbonyl or C- _L .g-alkylaminocarbonyl group, in which one or both of the alkyl parts present in each case by a carboxy group or from position 2 by a hydroxy, C- ₃ alkoxy, amino, C- ^ -Alkylamino- or di- (C ^ alkyl) - amino group can be substituted, but in a C ₁ _ ₃ alkylaminocarbonyl or di- (C ₁ - ₃ alkyl) aminocarbonyl group at least one alkyl part by a carboxy group or ab Position 2 must be substituted by an amino, C ₁ _ ₃ alkylamino or di (C _1. ₃ alkyl) amino group,

one on the amide nitrogen atom by a C ₃ . _6- alkyl-, C ₅ _ ₇ -cycloalkyl-, phenyl-, phenyl-C ₁ . _3- alkyl-, C ₅ -, - cycloalkyl-C ₁ _ ₃ -alkyl or naphthyl-C ₁ . _3- alkyl group substituted aminocarbonyl or C - ^ - alkylaminocarbonyl group, in each of which the phenyl part by fluorine, chlorine or bromine atoms, by C - ^ - alkyl or C - ^ - alkoxy groups mono- or disubstituted, the substituents can be the same or different, by three methoxy groups or by one trifluoromethyl, carboxy, C ^ alk- oxycarbonyl-, cyano-, aminocarbonyl-, C-_ ₃ -alkylaminocarbonyl-, di- (C - ^ - alkyl) -aminocarbonyl-, C ₃ . _7- Cycloalkylaminocarbonyl-, N- (Ci- _j -alkyl) -C ₃ _ ₇ -cycloalkylaminocarbonyl-, Di- (C ₃ _ ₇ -cycloalkyl) -aminocarbonyl- or nitro group may be substituted, and the alkyl part of those mentioned above C ₁ _ ₆ alkylaminocarbonyl group additionally by a carboxy group or from position 2 by a hydroxy, C ₁ _ ₃ alkoxy, amino, C ₁ _ ₃ alkylamino or di (C _1. ₃ -Alkyl) -amino group can be substituted, or

a 3- to 7-membered cycloalkyleneimino carbonyl group optionally substituted by a C ₃ alkyl group, a methylene group in a 6 or 7-membered cycloalkyleneimino group in the 4-position being represented by an oxygen or sulfur atom, by a sulfinyl or Sulphonyl group or by an optionally by a C ^ alkyl, formyl or C _. _3- alkyl-carbonyl-substituted imino group can be replaced,

R _{3 is} a hydrogen atom, a C ₁ . ₆ alkyl group or a _j is optionally substituted by a fluorine, chlorine or bromine atom, by a Ci alkyl, hydroxy, C ₁ _ ₃ alkoxy, C ₁ _ ₃ -Alkylsulfenyl-, C ₁ _ ₃ alkylsulfinyl -, C - ^ - Alkylsulfonyl-, Phenylsulfenyl-, Phenylsulfinyl-, Phenylsulfonyl-, Amino-, C - ^ - Alkylamino-, Di- (C ₁ _ ₃ -Alkyl) -amino-, C ₂ . ₅ -alkanoylamino or N- (C - ^ - alkylamino) -C ₂ _ ₅ -alkanoylamino group substituted phenyl group,

R ₄ represents a C- _{^ g} alkyl group or an optionally substituted by a C ^ alkyl group, C ₅ _ ₇ cycloalkyl group, wherein a methylene group in the 3- or 4-position relative to the carbon atom of the R ₃ -C (R ₄ NR ₅ ) = group can be replaced by an imino group optionally substituted by a C - ^ - alkyl group,

a thiophenyl group optionally substituted by a fluorine, chlorine or bromine atom or by a C 1-4 alkyl group,

a phenyl or naphthyl group, the by a fluorine, chlorine, bromine or iodine atom,

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

by a C ₂ _ ₃ alkoxy group which can be substituted in the 2- or 3-position by a C - ^ - alkylamino, di- (C - ^ - alkyl) -amino or 5- to 7-membered cycloalkyleneimino group, where in each case an alkyl part in the above-mentioned alkylamino and dialkylamino groups can be substituted by a phenyl group

by a trifluoromethyl, amino, C - ^ - alkylamino, di- (C - ^ - alkyl) amino, C ₂ . ₅ -alkanoylamino-, N- (C - ^ - alkyl) - C ₂ . _s -alkanoylamino-, C - ^ - alkylsulfonylamino-, N- (C - ^ - alkyl) - C ^ -alkylsulfonylamino-, phenylsulfonylamino-, N- (C ₁ _ ₃ -alkyl) - phenylsulfonylamino-, aminosulfonyl-, C ₁ _ ₃ -Alkylaminosulfonyl- or di- (C - ^ - Alkyl) -aminosulfonylgruppe, where in each case an alkyl part in the above-mentioned alkylamino and dialkylamino groups can be substituted by a phenyl group,

by a C ₂ _ ₄ -alkylamino group which is terminally substituted in the 2-, 3- or 4-position by a di- (C ₁ _ ₃ -alkyl) -amino group and in which the hydrogen amine atom is additionally substituted by a C ₂ . ₅ -alkanoyl or C - ^ - alkylsulfonyl group can be replaced,

by a carbonyl group which is substituted by a hydroxy, C ₁ _ ₃ alkoxy, amino,

- C - ^ - Alkylamino group is substituted, in each case an alkyl part in the groups mentioned above by a carboxy, C ₁ _ ₃ -alkoxycarbonyl or phenyl group or in the 2- or 3-position by a di- (C ₁ _ ₃ Alkyl) amino, piperazino, N- (C 1-4 alkyl) piperazino or 5- to 7-membered cycloalkyleneimino group, by a C ₁ . ₃ alkyl group, which is replaced by an amino, C - ^ - alkylamino, C ₅ . _7- Cycloalkylamino- or phenyl-C ₃ alkylamino group is substituted, each additionally on the amine nitrogen atom by a C ₃ alkyl group, in which the hydrogen atoms are partially or completely replaced by fluorine atoms, by a C _5.7 cycloalkyl -, C ₂ . ₄ alkenyl or C ₁ _ ₄ alkyl group may be substituted, wherein

the above-mentioned C ₁ _ ₄ -alkyl substituent each additionally by a cyano, carboxy, C ₁ _ ₃ -alkoxycarbonyl, pyridyl, imidazolyl, benzo [1, 3] dioxole or phenyl group, the phenyl group being substituted by fluorine , Chlorine or bromine atoms, may be mono-, di- or tri-substituted by methyl, methoxy, trifluoromethyl, cyano or nitro group and the substituents may be the same or different, or in 2-, 3- or 4- Position can be substituted by a hydroxy group,

by a C - ^ - alkyl group, which by a hydroxy, carboxy, thiomorpholino, 1-oxothiomorpholino, 1,1-dioxothiomorpholino, piperazino, N- (C - ^ - alkyl) -piperazino - or N-phenyl-piperazino group, by a 5- to 7-membered cycloalkenyleneimino group or by a 4- to 7-membered cycloalkyleneimino group, the above-mentioned 5- to 7-membered cycloalkyleneimino groups being substituted by one or two C - ^ - alkyl groups, through a C ₅ _ ₇ cycloalkyl or phenyl group, through a C ₁ _ ₃ alkyl, C ₅ _ ₇ cycloalkyl, phenyl, carboxy or C - ^ - alkoxy-car- bonyl group and can be substituted by a hydroxyl group and in the above-mentioned cycloalkyleneimino groups a methylene group adjacent to the nitrogen atom can be replaced by a carbonyl group,

by a C - ^ - alkyl group which is substituted by a 5- to 7-membered cycloalkyleneimino group, the above-mentioned 5- to 7-membered cycloalkyleneimino group being Pen over 2 adjacent carbon atoms one phenyl group which is mono- or disubstituted by fluorine, chlorine or bromine atoms, by methyl or methoxy groups, where the substituents can be the same or different, or one by fluorine, chlorine, bromine or or iodine atom, is fused on by a methyl, methoxy or amino group substituted oxazolo, idazolo, thiazolo, pyridino, pyrazino or pyrimidino group, or

by a di- -C (C ₂ H ₄ alkylamino.) - ^ - alkyl group in which the C ₂ _ ₄ -Alkylteile each substituted in the 2-, 3- or 4-position by a hydroxy group,

may be substituted, in addition the monosubstituted phenyl groups mentioned above may be substituted by a fluorine, chlorine or bromine atom, by a methyl, methoxy or nitro group,

a 5-membered heteroaromatic group which contains an imino group, an oxygen or sulfur atom or an imino group, an oxygen or sulfur atom and one or two nitrogen atoms, or

a 6-membered heteroaromatic group which contains one, two or three nitrogen atoms, it being possible for the abovementioned 5- and 6-membered heteroaromatic groups to be additionally substituted by a chlorine or bromine atom or by a methyl group or to which the above-mentioned 5- and 6-membered heteroaromatic groups can be fused to a phenyl ring via 2 adjacent carbon atoms, and

R ₅ is a Wassersto fatom or a C _{_1-3} alkyl group, wherein R _{2 is} preferably in position 5 or 6 represents

as well as those compounds of the general formula I above in which X, R _lf R ₃ and R ₅ are defined as mentioned at the outset,

R ₄ with the exception of a thiophenyl group optionally substituted by a fluorine, chlorine or bromine atom or by a C ₁ _ ₃ alkyl group, one on the amide nitrogen atom by a C ₅ _ ₇ cycloalkyl, phenyl-C - ^ - alkyl-, C ₅ _ _7- cycloalkyl-C ₁ _ ₃ -alkyl and naphthyl-C ₁ _ ₃ -alkyl group substituted aminocarbonyl and C ₇ -alkylaminocarbonyl groups and the radicals containing a phenyl group substituted by three methoxy groups has the meanings mentioned for R ₄ and

R ₅ with the exception of one by a C ₂ - ₄ -alkylamino group which is terminally substituted in the 2-, 3- or 4-position by a di- (C - ^ - alkyl) - amino group and in which the amine hydrogen atom is additionally substituted by a C ₂ _ ₅ alkanoyl or C - ^ - alkylsulfonyl group can be replaced, and that by a di (C ₂ _ ₄ alkylamino) -C - ^ - alkyl group in which the C ₂ . ₄ -alkyl parts each in the 2-, 3- or 4-position are substituted by a hydroxyl group, substituted phenyl and naphthyl groups have the meanings mentioned for R ₅ at the outset,

Furthermore, the carboxy, amino or imino groups present in a compound of the above general formula I can be substituted by residues which can be split off in vivo.

Here, in addition to the alkoxycarbonyl and alkanoyl groups already mentioned, in-cleavable residues such as an acyl group such as the benzoyl, pyridinoyl, pentanoyl or hexanoyl group, an allyloxycarbonyl group, a ^c _ι -i ₆ ~ alkoxycarbonyl group such as the pentoxycarbonyl, hexyloxy - Carbonyl, octyloxycarbonyl, nonyloxycarbonyl, decyloxycarbonyl, undecyloxycarbonyl, dodecyloxycarbonyl or hexadecyloxycarbonyl group, a phenyl-C ₁ _-- alkoxycarbonyl group such as benzyloxycarbonyl, phenylethoxycarbonyl or phenylpropoxycarbonyl group, a -Alkylsulfonyl-C ₂ _ ₄ -alkoxy- carbonyl, C ₁ . ₃ -alkoxy-C ₂ . ₄ -alkoxy-C ₂ . ₄ -alkoxycarbonyl or R _c CO-0- (R _d CR _e ) -O-CO group, in which

R _c a

kyl group,

R _{e is} a hydrogen atom, a C ₁ _ ₃ alkyl, C ₅ _ ₇ cycloalkyl or phenyl group and

R _{d represents} a hydrogen atom or a C ₁ _ ₃ alkyl group or the R _c CO-0- (R _d CR _e ) -O radical,

to understand, wherein the above-mentioned ester residues can also be used as a group which can be converted into a carboxy group in vivo.

Preferred compounds of general formula I are those in which

X is an oxygen atom,

R _{x is} a hydrogen atom,

R ₂ in position 5 or 6 is one on the amide nitrogen atom by a C ₁ . ₆ -alkyl group substituted aminocarbonyl or C- _L .g-alkyl aminocarbonyl group in which one of the alkyl parts present by a carboxy group or from position 2 by an amino, C - ^ - alkylamino or di- (C ^ alkyl) -amino group can be substituted, but in a C - ^ - alkylaminocarbonyl or di (C ^ alkyl) aminocarbonyl group at least one alkyl part by a carboxy or C - ^ - alkoxycarbonyl group or from position 2 by an amino, C _1st ₃ -Alkylamino- or di- (C - ^ - Alkyl) - amino group must be substituted,

one on the amide nitrogen atom by a C ₃ _-- alkyl, C _s _ ₇ cycloalkyl, phenyl, phenyl C - ^ - alkyl, C ₅ _ ₇ cycloalkyl C ₁ . _3- alkyl or naphthylmethyl group substituted aminocarbonyl or C ₁ . ₇ -Alkylaminocarbonyl group, in each of which the phenyl part by three methoxy groups or by a fluorine, chlorine or bromine atom, by a C ₁ _ ₃ alkyl, C ₁ _ ₃ alkoxy, carboxy, C - ^ - alkoxycarbonyl , Cyano or nitro group, and the alkyl part of the

additionally by a carboxy group or from position 2 by an amino, C _x. --Alkylamino- or di- (C ₁ _ ₃ alkyl) amino group may be substituted, or

may be group-alkyl substituted imino group replaced, - an optionally by a C ₁ _ ₃ alkyl substituted 6-membered Cycloalkyleniminocarbonylgruppe, in which a methylene group in the 4 position by an oxygen or sulfur atom or by an optionally by a C - ^

R _{3 is} a C 1-4 alkyl group or a phenyl group which is optionally substituted by a fluorine, chlorine or bromine atom, by a C ₁ _ ₃ -alkyl, hydroxy or C ₁ _ ₃ -alkoxy group,

R _{4 is} a C 1-4 alkyl group or a cyclopentyl or cyclohexyl group which is optionally substituted by a methyl group, in the cyclopentyl and cyclohexyl group a methylene group in the 3 or 4 position based on the carbon atom of the R ₃ -C (R ₄ NR ₅ ) = Group can be replaced by an imino group optionally substituted by a methyl group,

a phenyl group that

by a fluorine, chlorine, bromine or iodine atom,

by a methoxy group optionally substituted by 1 to 3 fluorine atoms, by a C ₂ _ ₃ alkoxy group which is substituted in the 2- or 3-position by a methylamino, dimethylamino or 5- to 7-membered cycloalkyleneimino group, in each case additionally a methyl group in the above-mentioned amino groups by a phenyl group can be substituted

through a trifluoromethyl, amino, C ₂ _ ₅ alkanoylamino, N- (C - ^ - alkyl) -C ₂ _ ₅ alkanoylamino, C ₁ _ ₅ alkylsulfonylamino, N- (C _1. ₃ - Alkyl) -C - ^ - alkylsulfonylamino, phenylsulfonylamino, N- (C ₁ _ ₃ -alkyl) -phenylsulfonylamino or aminosulfonyl group, where in each case an alkyl part in the above-mentioned alkylamino and dialkylamino groups can be substituted by a phenyl group,

by a C _2.4 alkylamino group which is terminally substituted in the 2-, 3- or 4-position by a di- (C ^ alkyl) amino group and in which the hydrogen amine atom is additionally substituted by a C ₂ _ _s -alkanoyl or C ^ Alkylsulfonyl group can be replaced,

by a carbonyl group which is substituted by a hydroxy, C ₁ _ ₃ alkoxy, amino, C ^ alkylamino or N- (C- _. - ₅ alkyl) - C ^ alkylamino group, each having an alkyl part of the groups mentioned above additionally by a carboxy, C ₁ . ₃ alkoxycarbonyl or phenyl group or in the 2 or 3 position by a di- (c._ ₃ alkyl) -amino, piperazino, N- (C- _^ - _j alkyl) or 5- -piperazino- can be substituted to 7-membered cycloalkyleneimino group,

by a C - ^ - alkyl group which is substituted by an amino, C - ^ - alkylamino, C _5.7 -cycloalkylamino or phenyl-C ₁ _ ₃ -alkylamino group, each of which is additionally on the amine nitrogen atom by a C ^ -Alkylgruppe, in which the hydrogen atoms are partially or completely replaced by fluorine atoms, can be substituted by a cyclohexyl, C ₂ _ ₄ alkenyl or C - ^ - alkyl group, wherein the aforementioned C ₁ _ ₄ alkyl substituent each additionally by a cyano, carboxy, C ₁ _ ₃ alkoxycarbonyl, pyridyl, imidazolyl, benzo [1, 3] dioxole or phenyl group, the phenyl group being substituted by a fluorine -, Chlorine or bromine atom, may be monosubstituted by a methyl, methoxy, cyano, trifluoromethyl or nitro group or may be di- or tri-substituted by fluorine, chlorine or bromine atoms, by methyl or methoxy groups and the substituents may be the same or different , or can be substituted in the 2-, 3- or 4-position by a hydroxy group,

by a C ₁ _ ₃ alkyl group which is replaced by a hydroxy, carboxy, thiomorpholino, 1-oxothiomorpholino, 1,1-dioxothiomorpholino, piperazino, N- (C ₁ _ ₃ -alkyl) -piperazino or N-phenyl-piperazino group, by a 5- to 7-membered cycloalkenyleneimino group or by a 4- to 7-membered cycloalkyleneimino group, the above-mentioned 5- to 7-membered cycloalkyleneimino groups being substituted by one or two C ₁ _ ₃ alkyl groups, by a cyclohexyl or phenyl group, by a C ₁ _ ₃ alkyl, cyclohexyl, phenyl, carboxy or C ₁ _ ₄ alkoxy-carbonyl group and substituted by a hydroxy group and in the cycloalkyleneimino groups mentioned above, a methylene group adjacent to the nitrogen atom can be replaced by a carbonyl group,

by a C ₁ _ ₃ -alkyl group which is substituted by a 5- to 7-membered cycloalkyleneimino group, the abovementioned 5- to 7-membered cycloalkyleneimino groups having 2 adjacent carbon atoms, optionally by fluorine, chlorine or bromine atoms, by Methyl or methoxy groups mono- or disubstituted phenyl group, where the substituents can be the same or different, or a pyrazino or thiazole group optionally substituted by an amino group is fused on, or by a di- (C ₂ _ ₄ -alkylamino) -C - ^ - alkyl group, in which the C _2.4 -alkyl parts are each substituted in the 2-, 3- or 4-position by a hydroxy group,

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

an oxazolyl, isoxazolyl, imidazolyl or thiazolyl group optionally substituted by a methyl group, to which a phenyl ring can be fused via 2 adjacent carbon atoms, and

R _{5 represents} a hydrogen atom a C - ^ - alkyl group,

in particular those compounds of the general formula I in which R _x to R ₃ and R ₅ are defined as mentioned above and

R ₄ a

or an optionally by a C - ^ - alkyl substituted C ₅ _ ₇ cycloalkyl group, wherein a methylene group in the 3- or 4-position relative to the carbon atom of the R ₃ -C (R ₄ NR ₅₎ = group by an optionally a C - ^ - alkyl substituted imino group can be replaced,

a phenyl or naphthyl group, the

by a fluorine, chlorine, bromine or iodine atom,

by a C - ^ - alkoxy-, amino-, C - ^ - alkylamino-, di- (C - ^ - alkyl) -anino-, C ₂ . ₅ -alkanoylamino-, N- (C ₁ _ ₃ -alkylamino) -C ₂ . ₅ -al- kanoylamino-, C ^ -alkylsulfonylamino-, N- (C - ^ - alkyl) -C - ^ - al- kylsulfonylamino, phenylsulfonylamino or N- (C ₁ _ ₃ -alkyl) phenylsulfonylamino group,

by a C ₂ _ ₄ -alkylamino group which is terminally substituted in the 2-, 3- or 4-position by a di- (C ₁ _ ₃ -alkyl) -amino group and in which the hydrogen amine atom is additionally substituted by a C ₂ . ₅ -alkanoyl or C ₁ _ ₅ -alkylsulfonyl group can be replaced,

by a C ₁ _ ₃ alkyl group, which by a C ₁ _ ₅ alkylamino, di (C - ^ - alkyl) amino, thiomorpholino, 1-oxo-thiomorpholino-, 1, 1-dioxo -thiomorpholino-, piperazino-, N- (C - ^ - alkyl) - piperazino-, N-phenyl -piperazino-, C ₅ _ ₇ -cycloalkenyleneimino or C ₄ _ ₇ -cycloalkyleneimino group, where the above-mentioned C ₅ _ ₇ cycloalkyleneimino groups through one or two C ₁ _ ₃ alkyl groups, through a C ₅ . ₇ -cycloalkyl or phenyl group, can be substituted by a C ₁ _ ₃ alkyl, C _s _ ₇ cycloalkyl, phenyl, carboxy or C ₁ _ ₄ alkoxy-carbonyl group and by a hydroxy group , or

by a di (C _2. ₄ alkylamino) -C ₁ _ ₃ alkyl group in which the C ₂ . ₄ -alkyl parts are each substituted in the 2-, 3- or 4-position by a hydroxyl group,

can be substituted

means, their isomers and their salts.

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

X is an oxygen atom,

R _{x is} a hydrogen atom,

R ₂ in position 5 or 6 is an aminocarbonyl or C - ^ - alkyl substituted on the amide nitrogen atom by a C - ^ - alkyl group aminocarbonyl group in which one of the alkyl parts present can be substituted by a carboxy or methoxycarbonyl group or from position 2 by a di (C _1, ₃ alkyl) amino group, but in a C ₁ _ ₃ alkyl aminocarbonyl or di (C _x _ ₃ alkyl) aminocarbonyl group at least one alkyl part must be substituted by a carboxy or methoxycarbonyl group or from position 2 by a di (C ₁ _ ₃ alkyl) amino group,

an amine nitrogen atom substituted by a C ₃ _ ₅ alkyl, cyclohexyl, phenyl, phenyl -C ₁ _ ₂ alkyl or cyclohexyl-C - ^ - alkyl group, aminocarbonyl or C- _^ .-alkylaminocarbonyl group, in each of which the phenyl part by three methoxy groups or by a fluorine, chlorine or bromine atom, by a C - ^ - alkyl, C- _^ - _j alkoxy, carboxy, C- _^ - _j alkoxycarbonyl, cyano or nitro group and the alkyl part of the C ₁ _ ₄ -alkylaminocarbonyl group can additionally be substituted by a carboxy or methoxycarbonyl group or from position 2 by a di- (C ₁ , ₃ -alkyl) amino group, or

a 6-membered cycloalkyleneiminocarbonyl group optionally substituted by a C ₁ _ ₃ -alkyl group, in which a methylene group in the 4-position can be replaced by an oxygen atom,

R _{3 is} a C 1-4 alkyl group or a phenyl group which is optionally substituted by a fluorine, chlorine or bromine atom, by a C ₁ _ ₃ alkyl or C ₁ _ ₃ alkoxy group,

R _{4 is} a C ₁ _ ₃ alkyl group or a cyclopentyl or cyclohexyl group which is optionally substituted by a methyl group, in the cyclohexyl group a methylene group in the 4-position based on the carbon atom of the R ₃ -C (R ₄ NR ₅ ) = group by a can optionally be replaced by a methyl group-substituted imino group,

a phenyl group that by a fluorine, chlorine, bromine or iodine atom,

by a methyl or ethyl group, each by a C ₁ _ ₃ alkylamino, di (C ₁ _ ₃ alkyl) amino, diethanolamino, thiomorpholino, 1-oxothiomorpholino, 1, 1- Dioxo-thiomorpholino, N-phenylpiperazino, 5- to 6-membered cycloalkenimino or 5- to 7-membered cycloalkyleneimino group may be substituted, the above-mentioned 5 to 7-membered cycloalkylene groups being substituted by one or two methyl groups, can be substituted by a cyclohexyl or phenyl group, by a methyl, cyclohexyl or phenyl group and by a hydroxyl group, or

by a methyl or ethyl group, each by a phenyl group which is substituted by a 5 to 7-membered cycloalkyleneimino group, a phenyl ring being additionally fused to the above-mentioned cycloalkyleneimino groups via 2 adjacent carbon atoms,

by a methyl or ethyl group, which are substituted by an amino, methylamino or ethylamino group, each of which is additionally substituted on the amine nitrogen atom by a benzyl or phenylethyl group, the phenyl part of the above-mentioned groups in each case by a fluorine, chlorine or Bromine, may be monosubstituted by a methyl, methoxy, cyano, trifluoromethyl or nitro group or may be di- or trisubstituted by fluorine, chlorine or bromine atoms, by methyl or methoxy groups and the substituents may be the same or different,

by a C ₂ . ₄ alkylamino group which is terminally substituted in the 2-, 3- or 4-position by a di- (C _1. ₃ -alkyl) -amino group and in which the hydrogen amine atom is additionally substituted by a C ₂ _ _s -alkanoyl or C 1 -C 4 -Alkylsulfonylgruppe can be replaced, may be substituted, in addition the monosubstituted phenyl groups mentioned above may be substituted by a fluorine, chlorine or bromine atom, by a methyl, methoxy or nitro group, and

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

their isomers and their salts.

Very particularly preferred compounds of general formula I are those in which

X is an oxygen atom,

R _{τ is} a hydrogen atom,

R ₂ in position 5 or 6 is an aminocarbonyl or C - ^ - alkyl aminocarbonyl group substituted on the amide nitrogen atom in which one of the alkyl parts present is substituted by a carboxy or methoxycarbonyl group or from position 2 by a di ( C _x _ ₃ alkyl) amino group may be substituted, but in a C ₁ _ ₃ alkylaminocarbonyl or di (C - ^ - alkyl) aminocarbonyl group at least one alkyl part by a carboxy or methoxycarbonyl group or from position 2 by a di (C 1-4 alkyl) amino group must be substituted,

one on the amide nitrogen atom by a C ₃ . _5- alkyl-, cyclohexyl-, phenyl-, phenyl-C - ^ - alkyl- or cyclohexyl-C ₁ . _2- alkyl group substituted aminocarbonyl or C ₁ _ ₄ -alkylaminocarbonyl group, in each of which the phenyl part by a fluorine, chlorine or bromine atom, by a C - ^ - alkyl, C - ^ - alkoxy, carboxy, C- ^ -Alkoxycarbonyl, cyano or nitro group and the alkyl part of the C - ^ - alkylaminocarbonyl group can additionally be substituted by a carboxy or methoxycarbonyl group or from position 2 by a di- (C ^ -alkyl) amino group, or a 6-membered cycloalkyleneiminocarbonyl group optionally substituted by a C 1-4 alkyl group, in which a methylene group in the 4 position can be replaced by an oxygen atom,

R _{3 is} a C - ^ - alkyl group or a phenyl group which is optionally substituted by a fluorine, chlorine or bromine atom, by a C ₁ _ ₃ -alkyl or C ₁ - ₃ -alkoxy group,

R _{4 is} a cyclohexyl group which is optionally substituted by a methyl group, in which a methylene group in the 4 position relative to the carbon atom of the R ₃ -C (R ₄ NR ₅ ) = group is replaced by an imino group which is optionally substituted by a methyl group,

a phenyl group that

by a fluorine, chlorine, bromine or iodine atom,

by a methyl or ethyl group, each by an amino, C ₁ _ ₃ alkylamino, di (C ^ alkyl) amino, diethanolamino, N- (phenyl-C ^ -, - alkyl ) -C - ^ - alkylamino-, thio-morpholino-, 1-oxo-thiomorpholino-, 1, 1-dioxo-thiomorpholino-, N-phenyl-piperazino-, 5 to 6-membered cycloalkenylene imino or 5 to 7-membered cycloalkyleneimino group may be substituted, wherein the above-mentioned 5 to 7-membered cycloalkyleneimino groups may be substituted by one or two methyl groups, by a cyclohexyl or phenyl group, by a methyl, cyclohexyl or phenyl group and by a hydroxy group, or

by a C _2.4 alkylamino group which is terminally substituted in the 2-, 3- or 4-position by a di- (C - ^ - alkyl) amino group and in which the hydrogen amine atom is additionally substituted by a C ₂ . ₅ -alkanoyl or C ₁ _ ₅ -alkylsulfonyl group may be replaced, may be substituted, and R _{5 represents} a hydrogen atom,

in particular those compounds of the general formula I in which

X is an oxygen atom,

R _{x is} a hydrogen atom,

R ₂ in position 5 or 6 is an aminocarbonyl or C ₁ _ ₄ alkyl aminocarbonyl group substituted on the amide nitrogen atom by a C ₁ _ ₄ alkyl group, in which one of the alkyl parts present is replaced by a methoxycarbonyl group or from position 2 by a di (C ₁ _ ₃ alkyl) amino group can be substituted, but in a C _1.3 alkylaminocarbonyl or di (C - ^ - alkyl) aminocarbonyl group at least one alkyl part by a methoxycarbonyl group or from position 2 by a di (C ₁ _ _3- alkyl) -amino group must be substituted,

one on the amide nitrogen atom by a C ₃ _ ₅ alkyl, cyclohexyl, phenyl, phenyl-C ^ alkyl or cyclohexyl-C ₁ . _2- alkyl group substituted aminocarbonyl or C ₁ , ₄ -alkylaminocarbonyl group, in each of which the phenyl part is substituted by a fluorine, chlorine or bromine atom, by a methyl, methoxy, C ₁ _ ₃ alkoxycarbonyl, cyano or nitro group can be or

a piperidinocarbonyl or morpholinocarbonyl group,

R _{3 is} a phenyl group,

R _{4 is} a phenyl group through

a methyl or ethyl group, each represented by a C - ^ - alkylamino, di (C -__ ₃ alkyl) amino, diethanolamino, N- (phenyl- C ₁ _ ₃ alkyl) -C ₁ _ ₃ alkylamino or piperidino group may be substituted, or by a C ₂ . ₄ alkylamino group, the amino group terminal in the 2-, 3- or 4-position by a di- (C ^ _j alkyl) and additionally the amine hydrogen atom by a C. ₂ ₅ -alkanoyl or C ₁ _ ₃ -alkylsulfonyl group is replaced, is substituted,

and R _{5 represents} a hydrogen atom,

their isomers and their salts.

The following may be mentioned as particularly preferred compounds:

(a) 3-Z- [1- (4-dimethylaminomethylphenylamino) -1-phenylmethylene] -5- (N-methyl-N-phenylcarbamoyl) -2-indolinone,

(b) 3-Z- [1- (4- (N-Benzyl-N-methylaminomethyl) phenylamino) -1-phenylmethylene] -5- (N-methyl-N-phenylcarbamoyl) -2 -indoline,

(c) 3-Z- [1- (3-dimethylaminomethylphenylamino) -1-phenylmethylene] -5- (N-methyl-N-benzylcarbamoyl) -2-indolinone,

(d) 3-Z- [1- (4-piperidinomethylphenylamino) -1-phenylmethylene] -5-piperidinocarbonyl-2-indolinone,

(e) 3-Z- [1- (4-piperidinomethylphenylamino) -1-phenylmethylene] -5- (N-methyl-N-benzylcarbamoyl) -2-indolinone,

(f) 3-Z- [1- (4-dimethylaminomethylphenylamino) -1-phenylmethylene] -5- (N-methyl-N-benzylcarbamoyl) -2-indolinone,

(g) 3-Z- (1- (4-dimethylaminomethylphenylamino) -1-phenylmethylene) -5- (cyclohexylmethylcarbamoyl) -2-indolinone, (h) 3-Z- (1- (4- (N-methylsulfonyl-N- (2-dimethylaminoethyl) amino) phenylamino) -1-phenylmethylene) -5-butylcarbamoyl-2-indolinone,

(i) 3-Z- (1- (4- (N-propionyl-N- (2-dimethylaminoethyl) amino) phenylamino) -1-phenylmethylene) -5-butylcarbamoyl) -2-indo- linon,

(j) 3-Z- (1- (4-dimethylaminomethylphenylamino) -1-phenylmethylene) -5- (3-chloro-benzyl-carbamoyl) -2-indolinone and

(k) 3-Z- (1- (4-dimethylaminomethylphenylamino) -1-phenylmethylene) -5- (n-butylcarbamoyl) -2-indolinone,

as well as their isomers 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, R ₂ and R ₃ are defined as mentioned at the outset and R _{6 is} a hydrogen atom or a protective group for the nitrogen atom of the lactam group, where R _{6 can} also represent a bond to a solid phase which may be formed via a spacer, and

Z _{x represents} a halogen atom, a hydroxyl, alkoxy or aralkoxy group, for example a 'chlorine or bromine atom, a methoxy, ethoxy or benzyloxy group, with an amine of the general formula

H - NA ^s (III),

R ₄ 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 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' -Dirnethoxyphenylamino-methyl) -phenoxy resin, where the binding is advantageously carried out via the amino group, or a p-benzyloxybenzyl alcohol resin, the binding advantageously via an intermediate member such as a 2, 5-Dimethoxy-4-hydroxy-benzyl derivative is considered.

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, one protective group used can be split off simultaneously as a result of transamidation.

If Z _x in a compound of the general formula II 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 Z _] _ in a compound of the general formula II denotes a hydroxyl, alkoxy or aralkoxy 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, methylamine, 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 performed.

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 which R _{2 represents} one of the aminocarbonyl groups mentioned at the outset:

Amidation of a compound of the general formula

in the

R- _L and R ₃ to R ₅ are defined as mentioned at the outset, or their reactive derivatives with an amine of the general formula

H - (R ₇ NR ₈ ) (V),

in the

R _{7 is} a hydrogen atom or

and R _{8 is} a C - ^ - alkyl group, at least one of the C - ^ - alkyl groups contained in the radicals R ₇ and R _{B being represented} by a carboxy group or from position 2 by a hydroxy-, C ₁ _ ₃ -alkoxy-, amino- , C - ^ - Alkyl- amino- or di- (C ^ alkyl) amino group can be substituted with the proviso that at least one C ^ alkyl group present in the above-mentioned groups by a carboxy group or from position 2 by an amino , C. ₃ -Alkylamino- or di- (C. ^ - alkyl) amino group is substituted, or

R _{7 is} a C ₃ .g-alkyl, C ₅ . _7- cycloalkyl, phenyl, phenyl-C ^ alkyl, C _s _ ₇ -cycloalkyl-C ₁ _ ₃ alkyl or naphthyl-C ₁ _ ₃ alkyl group, in each of which the phenyl part by fluorine, chlorine - or bromine atoms, mono- or di- substituted by C - ^ - alkyl or C - ^ - alkoxy groups, where the substituents can be the same or different, by three methoxy groups or by one trifluoromethyl, carboxy, C ₁ _ ₃ -alkoxycarbonyl-, cyano-, aminocarbonyl-, C - ^ - alkylaminocarbonyl-, di- (C - ^ - alkyl) -aminocarbonyl-, C ₃ . _7- cycloalkylaminocarbonyl-, N- (C 1-4 alkyl) -C ₃ . ₇ -cycloalkyl- aminocarbonyl, di- (C ₃ _ ₇ -cycloalkyl) aminocarbonyl or nitro group can be substituted, and R _{8 is} a hydrogen atom or a

the above mentioned C ₁ _ ₇ alkyl group additionally by a carboxy group or from position 2 by a hydroxy, C ₁ _ ₃ alkoxy, amino, C-. ₃ -Alkylamino- or di- (C ₁ _ ₃ -alkyl) -amino group may be substituted, or

R ₇ and R ₈ together with the nitrogen atom in between represent a 3- to 7-membered cycloalkyleneimino carbonyl group which is optionally substituted by a C _x _ ₃ alkyl group, a methylene group in a 6 or 7 membered cycloalkyleneimino group in the 4-position by an oxygen or sulfur atom, can be replaced by a sulfinyl or sulfonyl group or by an imino group which is optionally substituted by a C 1-4 alkyl, formyl or C 1-4 alkyl carbonyl group.

The amidation 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, carried out. Here, the amidation with an appropriate 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-dimethoxypropane, tetramethoxysilane, thionyl chloride, trimethylchlorosilane, phosphorus trichloride, phosphorus trichloride '-Dicyclohexylcarbodiimide, N, N' -dicyclohexyl-carbodiimide / N-hydroxysuccinimide, N, N '-dicyclohexylcarbodimide / l-hydroxy-benzotriazole, 2- (1H-benzotriazol-1-yl) -1,1,3, 3-tetramethyluronium tetrafluoroborate, 2- (1H-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-methylmorpholine at temperatures between 0 and 150 ° C, preferably at temperatures between 50 and 100 ° C carried out.

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 compound by means of acylation, 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 means of esterification or amidation, or

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

The subsequent hydrolysis is preferably carried out in an aqueous solvent, for example in water, isopropanol / water, tetrahydrofuran / water or dioxane / water, in the presence of an acid such as trifluoroacetic acid, hydrochloric acid or sulfuric acid or in the presence of an alkali base such as lithium hydroxide, sodium hydroxide or potassium hydroxide 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 from Hydrogen in the presence of Raney nickel, platinum or palladium / carbon, or in the presence of a metal hydride such as sodium borohydride, lithium borohydride or lithium aluminum hydride at temperatures between 0 and 100 ° C, preferably at temperatures between 20 and 80 ° C.

The subsequent acylation 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 , carried out. Here, the acylation with an appropriate acid is preferably carried out in the presence of a dehydrating agent, for example in the presence of isobutyl chloroformate, tetraethyl orthocarbonate, trimethyl orthoacetate, 2, 2-dimethoxypropane, tetra-methoxysilane, thionyl chloride, trimethylchlorosilane, phosphorus trichloride, phosphorus trichloride '-Dicyclohexylcarbodiimide, N, N' -dicyclohexylcarbodiimide / N-hydroxysuccinimide, N, N '-Di- cyclohexylcarbodiimide / 1-hydroxy-benzotriazole, 2 - (lH-benzotriazol-1-yl) -1,1,3, 3-tetramethyluronium tetrafluoroborate, 2- (1H-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-methylmorpholine or triethylamine, advantageously at temperatures between 0 and 150 ° C, preferably at temperatures between 0 and 100 ° C, and the acylation with egg a corresponding reactive compound such as its anhydride, Esters, imidazolides or halides 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.

The subsequent esterification or amidation is advantageously carried out by reacting a reactive corresponding carboxylic acid derivative with a corresponding 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.

In the reactions described above, any reactive groups present, such as carboxy, 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 carboxyl group

as a protective radical for an amino, alkylamino or imino group, the acetyl, trifluoroacetyl, benzoyl, ethoxycarbonyl, tert. Butoxycarbonyl-, Benzyloxycarbonyl -, Benzyl-, Methoxy- benzyl- or 2, -Dimethoxybenzylgruppe and for the amino group additionally the phthalyl group into consideration. The optional subsequent removal of a protective radical used takes place, for example, hydrolytically in an aqueous solvent, for example in water, isopropanol / water, tetrahydrofuran / water or dioxane / water, in the presence of an acid such as trifluoroacetic acid, hydrochloric acid or sulfuric acid or in the presence of an alkali 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 split 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 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.

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.

A tert-butyl or tert-butyloxycarbonyl radical is preferably cleaved off 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 methyl a in, 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 by methods known per se (see Allinger NL and Eliel EL in "Topics in Stereochemistry", Vol. 6, Wiley Interscience, 1971) and compounds of the general formula I with at least 2 asymmetric carbon atoms on the basis of 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 with the racemic compound, such as esters or amides, in particular acids and their activated derivatives or alcohols, and separating 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 an optically active alcohol, for example (+) - or (-) menthol and the optically active acyl radical in amides, 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, acetic acid, fumaric acid, succinic acid, lactic acid, citric acid, tartaric acid, maleic acid or methanesulfonic acid.

In addition, the new compounds of the formula I obtained in this way, if they contain a carboxy group, 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. Suitable bases here are, for example, sodium hydroxide, potassium hydroxide, cyclohexylamine, ethanolamine, diethanolamine and triethanolamine.

Some of the compounds of the general formulas I to V used as starting products are known from the literature or can be obtained by processes known from the literature or are described in the examples. For example, the compounds of the general formula IV are described in German patent application 198 24 922.5 of June 4, 1998, which corresponds to WO 99/62882.

As already mentioned at the beginning, the new compounds of the general formula I, in which R _{x 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, PDGFR, FGFR1 , EGFR, HER2, IGFIR and HGFR, and on complexes of CDK's (Cyclin Dependent Kinases) such as CDKl, CDK2, CDK3, CDK4, CDK6, CDK7, CDK8 and CDK9 with their specific cyclins (A, Bl, B2, C, Dl, D2, D3, E, F, Gl, G2, H, I and K) and on viral cyclin the proliferation of cultured human cells, in particular that of endothelial cells, for example in angiogenesis, but also on the proliferation of other cells, in particular tumor cells.

For example, the compounds listed in Table 1 were tested for their biological properties as follows:

TftHf. i

Tnh .b. r ng of Cyc.1. n /CDK-F.ri ym, act, vi tat in vitro

High Five ™ insect cells (BTI-TN-5B1-4), which were infected with a high titer of recombinant baculovirus, were used for the production of active human cyclin / CDK holoenzymes. By using a baculovirus vector that contained two promoters (polyhedrin enhancer promoter, P10 enhancer promoter), GST-tagged cyclins (eg Cyclin Dl or Cyclin D3) with the corresponding Hisg-tagged CDK subunit (eg for CDK4 or CDK6) expressed in the same cell. The active holoenzyme was isolated by affinity chromatography on glutathione-Sepharose. Recombinant GST-tagged pRB (aa 379-928) was produced in E. coli and purified by affinity chromatography on glutathione-Sepharose.

The substrates used for the kinase assays depended on the specific kinases. Histone Hl (Sigma) was used as a substrate for Cyclin E / CDK2, Cyclin A / CDK2, Cyclin B / CDK1 and for v-Cyclin / CDK6. GST-tagged pRB (aa 379-928) was used as a substrate for Cyclin D1 / CDK4, Cyclin D3 / CDK4, Cyclin D1 / CDK6 and for Cyclin D3 / CDK6.

Lysates of the insect cells infected with recombinant baculovirus or also recombinant kinases (obtained from the lysates by purification) were mixed with radioactive labeled ATP in the presence of a suitable substrate Concentrations of the inhibitor in a 1% DMSO solution (dimethyl sulfoxide) incubated at 30 ° C for 45 minutes. The substrate proteins with associated radioactivity were precipitated with 5% TCA (trichloroacetic acid) in hydrophobic PVDF multi-well microtiter plates (Millipore) or with 0.5% phosphoric acid solution on Whatman P81 filters. After adding scintillation fluid, the radioactivity was measured in a Wallace 1450 Microbeta liquid scintillation counter. Double measurements were carried out per concentration of the substance; IC5 _Q values for enzyme inhibition were calculated.

Test. 2

Inhibition of the profiling of cultured human tumor

Cells from the Leiomyosarcoma tumor line SK-UT-1B (obtained from the American Type Culture Collection (ATCC)) were in minimum essential medium with non-essential amino acids (Gibco), supplemented with sodium pyruvate (1 mmol), glutamine (2nd mmol) and 10% fetal bovine serum (Gibco) and harvested in the log growth phase. The SK-UT-IB cells were then introduced into Cytostar® multi-well plates (Amersham) with a density of 4000 cells per well and incubated overnight in an incubator. Different concentrations of the compounds (dissolved in DMSO; final concentration: <1%) were added to the cells. After 48 hours of incubation, ¹⁴ C-thymidine (Amersham) was added to each well and incubation was continued for 24 hours. The amount of

¹⁴ C-thymidine, which was incorporated into the tumor cells in the presence of the inhibitor and which represents the number of cells in the S phase, was measured in a Wallace 1450 Microbeta liquid scintillation counter. IC5 _Q values for the inhibition of proliferation (= inhibition of built-in ¹⁴ C-thymidine) were calculated - with correction for the background radiation. All measurements were carried out twice. Tf. pt. 3

Tπ vivo effects on tumor-bearing Naπ t.πiä spn

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

The following table contains the results of the in vitro test 2:

Because of their biological properties, the new compounds of general formula I, their isomers and their physiologically tolerable salts are suitable for the treatment of diseases which are characterized by excessive or abnormal cell proliferation. Such diseases include (without claim to completeness): viral infections (eg HIV and Kaposi's sarcoma); Inflammation and autoimmune diseases (eg colitis, arthritis, Alzheimer's disease, glomerulonephritis and wound healing); bacterial, fungal and / or parasitic infections; Leukemia, lymphoma and solid tumors; Skin diseases (eg psoriasis); Bone diseases; cardiovascular diseases (e.g. restenosis and hypertrophy). They are also useful as protection of proliferating cells (eg hair, intestinal, blood and progenitor cells) against DNA damage by radiation, UV treatment and / or cytostatic treatment.

The new compounds can also be used for the short-term or long-term treatment of the abovementioned diseases, if appropriate in combination with other "state-of-art" compounds such as other cytostatics.

The dosage required to achieve a corresponding effect is expediently 0.1 to 30 mg / kg, preferably 0.3 to 10 mg / kg for intravenous administration, and 0.1 to 100 mg / kg, preferably 0.3 to for oral administration 30 mg / kg, 1 to 4 times a day. For this purpose, the compounds of the formula I prepared according to the invention, optionally in combination with other active substances, together with one or more inert customary carriers and / or diluents, for example with corn starch, lactose, cane sugar, microcrystalline cellulose, magnesium stearate, polyvinylpyrrolidone, citric acid, Tartaric acid, water, water / ethanol, water / glycerin, water / sorbitol, water / polyethylene glycol, propylene glycol, cetylstearyl alcohol, carboxymethyl cellulose or fatty substances such as hard fat or their suitable mixtures, in conventional pharmaceutical preparations such as tablets, dragees, capsules, Incorporate powders, suspensions, suppositories or as solutions for injections or infusions. The following examples are intended to explain the invention in more detail:

At πpi 1 T

1-Acetyl -2-inr.o1 i non- -πarbonsäuremethyl eπter

10.5 g of 2-indolinone-5-carboxylic acid methyl ester (preparation analogous to Ogawa, Hidenori et al. In Chem. Pharm.Bull 36, 2253-2258 (1988)) are stirred in 30 ml of acetic anhydride at 140 ° C. for 4 hours. Then allowed to cool, poured onto ice water and suctioned off the precipitate. The product is washed again with water, then taken up in methylene chloride, dried over sodium sulfate and concentrated. Yield: 11 g (86% of theory), R _f value: 0.63 (silica gel, methylene chloride / methanol = 50: 1)

The following connections are made analogously:

(1) 1-Acetyl-2-indolinone-5-carboxylic acid ethyl ester

(2) 1-Acetyl-2-indolinone-6-carboxylic acid ethyl ester Prepared analogously to Example I from 2-indolinone-6-carboxylic acid ethyl ester (see also Langenbeck et al. In Justus Liebig Ann. Chem. 499, 201 and 208 (1932))

Example TT

l-acetyl-3- (1-ethoxy-l-butylmethylene) -2-indolinone- 5-carbon-

.qaurf.mpt-.hy1 este

11 g of methyl l-acetyl-2-indolinone-5-carboxylate are stirred in 110 ml of acetic anhydride and 30 ml of triethyl orthovalerate at 100 ° C. for 2 hours. The mixture is then evaporated, the residue washed with ether and suction filtered. Yield: 11.5 g (67% of theory),

R _f value: 0.55 (silica gel, methylene chloride / petroleum ether / ethyl acetate = 4: 5: 1) The following connections are made as in Example II:

(1) 1-Cetyl -3- (1-methoxy-methylene) -2-indolinone-5-carboxylic acid methyl ester

Made from methyl l-acetyl-2-indolinone-5-carboxylate and trimethyl orthoformate

(2) 1-Acetyl-3- (1-ethoxy-1-methylmethylene) -2-indolinone-5-carboxylic acid methyl ester

Made from 1-acetyl -2-indolinone-5-carboxylic acid methyl ester and orthoacetic acid triethyl ester

(3) 1-Acetyl-3- (1-ethoxy-1-ethylmethylene) -2-indolinone-5-carboxylic acid methyl ester

Made from l-acetyl-2-indolinone-5-carboxylic acid methyl ester and orthopropionic acid triethyl ester

(4) 1-Acetyl-3- (1-ethoxy-1-phenylmethylene) -2-indolinone-5-carboxylic acid ethyl ester

Made from l-acetyl-2-indolinone-5-carboxylic acid methyl ester and orthobenzoic acid triethyl ester

R _f value: 0.50 (silica gel, toluene / ethyl acetate = 10: 1)

(5) 1-Acetyl-3- (1-ethoxy-1-phenylmethylene) -2-indolinone-6-carboxylic acid ethyl ester

Made from ethyl l-acetyl-2-indolinone-6-carboxylate and triethyl orthobenzoate

Rei play TTT

4- (N-ethyl. Aminomethy]) nitrobenzene

6 g of 4-nitrobenzyl bromide are dissolved in 25 ml of ethanol, mixed with 25 ml of 10% ethanolic ethylamine solution and boiled under reflux for 2 hours. Then the solution is spun in, the residue taken up with methylene chloride and washed with dilute sodium hydroxide solution. Finally the organic phase is concentrated. Yield: 2.3 g (46% of theory),

R _f value: 0.20 (silica gel, methylene chloride / methanol = 9: 1)

The following compounds are prepared analogously to Example III:

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

4- (N-cyclohexylaminomethyl) nitrobenzene

4- (N-isopropylaminomethyl) nitrobenzene

4- (N-butylaminomethyl) nitrobenzene

4- (N-methoxycarbonylmethylaminomethyl) nitrobenzene

4- (N-benzylaminomethyl) nitrobenzene

4- (pyrrolidinomethyl) nitrobenzene.

4- (morpholino-methyl) nitrobenzene

4- (piperidino-methyl) nitrobenzene.

4- (hexamethyleneimino-methyl) nitrobenzene

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

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

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

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

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

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

- (Dimethylaminomethyl) nitrobenzene

- (Di-n-propylaminomethyl) nitrobenzene

- (4-tert-Butoxycarbonyl-piperazino-methyl) -nitrobenzene

- (Dimethylaminomethyl) nitrobenzene

- (2-Diethylamino-ethyl) nitrobenzene

- (2-Morpholino-ethyl) nitrobenzene

- (2-Pyrrolidino-ethyl) nitrobenzene

- (2-Piperidino-ethyl) nitrobenzene

- (N-Ethyl-N-benzylaminomethyl) nitrobenzene

4- (N-n-propyl-N-benzylaminomethyl) nitrobenzene

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

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

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

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

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

4- [N- (2,2,2-trifluoroethyl) -N-benzylaminomethyl] nitrobenzene

4- [N- (2,2,2-trifluoroethyl) -N- (4-chlorophenylmethyl) aminomethyl] nitrobenzene - (2, 6-Dimethyl-piperidino-methyl) nitrobenzene

- (Thiomorpholino-methyl) nitrobenzene

- (S-Oxido-thiomorpholino-methyl) -nitrobenzene

- (S, S-Dioxido-thiomorpholino-methyl) -nitrobenzene

- (Azetidino-methyl) nitrobenzene

- (2, 5-Dihydropyrrol-l-ylmethyl) nitrobenzene

4- (3, 6-Dihydro-2H-pyridin-l-ylmethyl) nitrobenzene

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

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

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

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

4- [N- (3, 4, 5-Trimethoxybenzyl) -N-methylaminomethyl] nitrobenzene

4- [N- (3, 4-Dimethoxy-benzyl) -N-ethylaminomethyl] nitrobenzene

4- [N- (3-chlorobenzyl) -N-methylaminomethyl] nitrobenzene

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

4- [N- (4-trifluoromethylbenzyl) -N-methylaminomethyl] nitrobenzene

4- (N-benzyl-N-isopropylaminomethyl) nitrobenzene - (N-Benzyl-N-tert. Butyl aminomethyl) nitrobenzene

- (Diisopropylaminomethyl) nitrobenzene

- (Di-n-propylaminomethyl) nitrobenzene

4- (diisobutylaminomethyl) nitrobenzene

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

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

4- (6, 7-Dimethoxy-l, 2,3, 4-tetrahydro-isoquinolin-2-yl-methyl) nitrobenzene

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

4- [N- (2-Hydroxyethyl) -N-benzylaminomethyl] nitrobenzene

4- [N- (1-ethylpentyl) -N- (pyridin-2-ylmethyl) aminomethyl] nitrobenzene

4- (N-phenethyl-N-methylaminomethyl) nitrobenzene

4- [N- (3,4-Dihydroxy-phenethyl) -N-methylaminomethyl] nitrobenzene

4- [N- (3, 4, 5-Trimethoxyphenethyl) -N-methylaminomethyl] nitrobenzene

4- [N- (3, 4-Dimethoxyphenethyl) -N-methylaminomethyl] nitrobenzene

4- [N- (4-nitro-phenethyl) -N-methylaminomethyl] nitrobenzene

4- (N-phenethyl-N-benzylaminomethyl) nitrobenzene 4- (N-phenethyl -N-cyclohexylaminomethyl) nitrobenzene

4- [N- (2- (pyridin-2-yl) ethyl) -N-methylaminomethyl] nitrobenzene

4- [N- (2- (pyridin-4-yl) ethyl) -N-methylaminomethyl] nitrobenzene

4- [N- (pyridin-4-ylmethyl) -N-methylaminomethyl] nitrobenzene

4- (dibenzyla inomethyl) nitrobenzene

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

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

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

4- [N- (Benzo (1,3) dioxol-5-ylmethyl) -N-methylaminomethyl] nitrobenzene

When playing] ΩL

4- (N-Fthyl-N-tert.butoxycarbonyl-amino-ethyl) -nitrobenzene 2.2 g of 4- (N-ethyl-aminomethyl) -nitrobenzene are dissolved in 50 ml of ethyl acetate and mixed with 2.6 g of di-tert. Butyl dicarbonate (Boc anhydride) stirred for 30 minutes at room temperature. The solution is then washed with water and concentrated. Yield: 3.4 g (97% of theory), R _f value: 0.90 (silica gel, methylene chloride / methanol = 9: 1)

The following compounds are prepared analogously to Example IV:

4- [N- (4-chlorophenylmethyl) -N-tert. Butoxycarbonylaminomethyl] nitrobenzene

4- (N-Cyclohexyl-N-tert. Butoxycarbonyl aminomethyl) nitrobenzene 4- (N-isopropyl-N-tert.butoxycarbonylaminomethyl) nitrobenzene

4- (N-butyl-N-tert. Butoxycarbonyl aminomethyl) nitrobenzene

4- (N-methoxycarbonylmethyl-N-tertbutoxycarbonylaminomethyl) nitrobenzene

4- (N-benzyl-N-tert. Butoxycarbonyl aminomethyl) nitrobenzene

4- (N-methyl-N-tert. Butoxycarbonyl aminomethyl) nitrobenzene

Example V

4- (N-Fthyl -N- er. Butoxyca bonyl -ami nomethyl. -Ani 1 in 6.4 g of 4- (N-ethyl-N-tert .butoxycarbonyl-aminomethyl) -nitrobenzene are dissolved in 60 ml of methanol and mixed with 1.5 g of Raney nickel are hydrogenated at room temperature and 3 bar, then the catalyst is filtered off and the solution is concentrated. Yield: 4.78 g of R _f value: 0.70 (silica gel, methylene chloride / methanol = 50: 1)

The following compounds are produced analogously to Example V:

4- [N- (4-chlorophenylmethyl) -N-tert. Butoxycarbonylaminomethyl) aniline

4- (N-Cyclohexyl-N-tert. Butoxycarbonyl aminomethyl) aniline

4- (N-isopropyl-N-tert. Butoxycarbonyl aminomethyl) aniline

4- (N-butyl-N-tert. Butoxycarbonyl aminomethyl) aniline

4- (N-methoxycarbonylmethyl-N-tert-butoxycarbonylaminomethyl) aniline

4- (N-Benzyl-N-tert. Butoxycarbonyl aminomethyl) aniline - (Pyrrolidino-methyl) aniline

- (Morpholino-methyl) aniline

- (Piperidino-methyl) aniline

- (Hexamethyleneimino-methyl) aniline

- (4-Hydroxy-piperidino-methyl) aniline

- (4-Methyl-piperidino-methyl) aniline

- (4-ethyl-piperidino-methyl) aniline

- (4-Isopropyl-piperidino-methyl) aniline

- (4-phenyl-piperidino-methyl) aniline

- (4-Benzyl-piperidino-methyl) aniline

- (4-Ethoxycarbonyl-piperidino-methyl) aniline

- (Dimethylaminomethyl) aniline

- (Di-n-propylaminomethyl) aniline

- (4-tert. Butoxycarbonyl-piperazino-methyl) -aniline

- (Dimethylaminomethyl) aniline

- (2-Diethylamino-ethyl) aniline

- (2-Morpholino-ethyl) aniline

- (2-Pyrrolidino-ethyl) aniline

- (2-piperidino-ethyl) aniline - (N-Ethyl-N-benzylaminomethyl) aniline

- (N-Propyl-N-benzylaminomethyl) aniline

- (N-Methyl-N- (4-chlorophenylmethyl) aminomethyl) aniline

- (N-Methyl-N- (4-bromophenylmethyl) aminomethyl) aniline

- (N-Methyl-N- (3-chlorophenylmethyl) aminomethyl) aniline

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

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

4- [N- (2,2, 2-trifluoroethyl) -N-benzylaminomethyl] aniline

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

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

4- (thiomorpholino-methyl) aniline

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

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

4- (azetidino-methyl) aniline

4- (2, 5-dihydropyrrol-1-ylmethyl) aniline

4- (3, 6-Dihydro-2H-pyridin-l-ylmethyl) aniline

4- (2-methoxycarbonyl-pyrrolidinomethyl) aniline

4- (3, 5-Dimethyl-piperidino-methyl) aniline - (4-phenyl-piperazino-methyl) aniline

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

- [N- (3,4,5-Trimethoxybenzyl) -N-methylaminomethyl] aniline

- [N- (3, 4-Dimethoxybenzyl) -N-ethylaminomethyl] aniline

- (N-Benzyl-N-ethylaminomethyl) aniline

- [N- (3-Chlorobenzyl) -N-methylaminomethyl] aniline

- [N- (2,6-dichlorobenzyl) -N-methylaminomethyl] aniline

- [N- (4-Trifluoromethylbenzyl) -N-methylaminomethyl) aniline

- (N-Benzyl-N-isopropylaminomethyl) aniline

- (N-Benzyl-N-tert. Butyl aminomethyl) aniline

- (Diisopropylaminomethyl) aniline

- (Di-n-propylaminomethyl) aniline

- (Diisobutylaminomethyl) aniline

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

4- (2, 3-dihydro-isoindol-2-ylmethyl) aniline

4- (6, 7-Dimethoxy-l, 2,3, 4-tetrahydro-isoquinolin-2-yl-methyl) aniline

4- (1,2,3, 4-tetrahydro-isoquinolin-2-ylmethyl) aniline

4- [N- (2-Hydroxyethyl) -N-benzylaminomethyl] aniline 4- [N- (1-ethylpentyl) -N- (pyridin-2-ylmethyl) aminomethyl] aniline

4- (N-phenethyl-N-methylaminomethyl) aniline

4- [N- (3,4-Dihydroxy-phenethyl) -N-methylaminomethyl) aniline

4- [N- (3, 4, 5-Trimethoxy-phenethyl) -N-methylaminomethyl] aniline

4- [N- (3,4-dimethoxyphenethyl) -N-methylaminomethyl) aniline

4- [N- (4-nitro-phenethyl) -N-methylaminomethyl) aniline

4- (N-phenethyl-N-benzylaminomethyl) aniline

4- (N-phenethyl-N-cyclohexylaminomethyl) aniline

4- [N- (2- (pyridin-2-yl) ethyl) -N-methylaminomethyl] aniline

4- [N- (2- (pyridin-4-yl) ethyl) -N-methylaminomethyl] aniline

4- [N- (pyridin-4-ylmethyl) -N-methylaminomethyl] aniline

4- (dibenzylaminomethyl) aniline

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

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

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

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

4- [N- (Benzo (1,3) dioxol-5-ylmethyl) -N-methylaminomethyl] aniline Rp j game VT

3-Z- [1- (4- (N-benzyl-N-methylaminomethyl) phenylamino) -1-methyl-methyl enl -2-inc_ol i non-S-πarbonπäuremethyl es pr-

8.0 g (28 mmol) of l-acetyl-3- (1-ethoxy-1-methylmethylene) -2-indolinone-5-carboxylic acid methyl ester are dissolved in 60 ml of dimethylformamide and mixed with 6.3 g (28 mmol) 4 - (N-Benzyl-N-methyl-aminomethyl) aniline stirred for 6 hours at 80 ° C. Then 30 ml of concentrated ammonia are added and the mixture is left to stand at 45 ° C. The solution is evaporated and the residue washed with ethanol and ether, then chromatographed on a small silica gel column with ethyl acetate / ethanol (9: 1). Yield: 8.6 g (70% of theory), melting point: 150-152 ° C ₂₇ H ₂₇ N ₃ 0 ₃ Mass spectrum: m / z = 442 (M) ⁺

The following compounds are prepared analogously to Example VI:

(1) 3-Z- [1- (4-piperidinomethylphenylamino) -1-methylmethylene] -2-indolinone-5-carboxylic acid methyl ester

C ₂₄ H ₂₇ N ₃ 0 ₃

Mass spectrum: m / z = 406 (M + H) ⁺

(2) 3-Z- [1- (4-bromophenylamino) -1-methylmethylene] -2-indolinonon-5-carboxylic acid methyl ester

C ₁₈ H ₁₅ BrN ₂ 0 ₃

Mass spectrum: m / z = 386/388 (M) ⁺

(3) 3-Z- [1- (4-chlorophenylamino) -1-methylmethylene] -2-indolinonon-5-carboxylic acid methyl ester

C _1B H ₁₅ C1N ₂ 0 ₃

Mass spectrum: m / z = 342/344 (M) ⁺

(4) 3-Z- [1- (4- (N-methyl-N-methylsulfonylamino) phenylamino) - 1-ethylmethylene] -2-indolinone-5-carboxylic acid methyl ester C ₂₀ H ₂₁ N ₃ O ₅ S Mass spectrum: m / z = 415 (M) ⁺

(5) 3-Z- [1- (4- (2,4,5,5-tetrahydro-benzo (d) azepine-3 -ylmethyl) phenylamino) -1-methylmethylene] -2-indolinone -5-methyl carbonate C ₂ -H ₂ -N ₃ 0 ₂

Mass spectrum: m / z = 467 (M) ⁺

(6) 3-Z- [1- (l-methyl-piperidin-4-yl-amino) -1-phenylmethylene] - 2-indolinone-5-carboxylic acid methyl ester R _f value: 0.20 (silica gel, methylene chloride / Methanol = 9: 1)

C ₂₃ H ₂₅ N ₃ 0 ₃

Mass spectrum: m / z = 391 (M) ⁺

(7) 3-Z- [1- (4-piperidinomethylphenylamino) -1-phenylmethylene] -2-indolinone-5-carboxylic acid methyl ester R _f value: 0.40

(Silica gel, methylene chloride / methanol = 9: 1)

C ₂₉ H ₂₉ N ₃ 0 ₃

Mass spectrum: m / z = 467 (M) ⁺

(8) 3-Z- [1- (4- (N-Phenylmethyl-N-methylaminomethyl) phenylamino) -1-phenylmethylene] -2-indolinone-5-carboxylic acid methyl ester

C ₃₂ H ₂₉ N ₃ 0 ₃

Mass spectrum: m / z = 503 (M) ⁺

(9) 3-Z- [1- (4-Dimethylaminomethylphenylamino) -1-phenylmethylene] -2-indolinone-5-carboxylic acid methyl ester C ₂₆ H ₂₅ N ₃ 0 ₃ mass spectrum: m / z = 427 (M) ⁺

(10) 3-Z- [1- (3-Dimethylaminomethylphenylamino) -1-phenylmethylene] -2 - indolinone-5-carboxylic acid methyl ester

C ₂₆ H ₂₅ N ₃ 0 ₃

Mass spectrum: m / z = 427 (M) ⁺

(11) 3-Z- [1- (4-chlorophenylamino) -1-phenylmethylene] -2-indoli- non-5-carboxylic acid methyl ester (12) 3-Z- (1-Phenylamino-1-phenylmethylene] -2-indolinone-5-carboxylic acid methyl ester

(13) 3-Z- [1- (4-Dimethylaminomethyl-phenylamino) -1-methyl-methylene] -2-indolinone-5-carboxylic acid methyl ester

(14) 3-Z- [1- (4-Dimethylaminomethylphenylamino) -1-butylmethylene] -2-indolinone-5-carboxylic acid methyl ester

(15) 3-Z- [1- (4- (2-Dimethylaminoethyl) phenylamino) -1-phenylmethylene] -2-indolinone-5-carboxylic acid methyl ester

(16) 3-Z- [(1- (l-methyl-piperidin-4-yl-amino) -1-phenylmethylene] -2-indolinone-5-carboxylic acid methyl ester

Yield: 11.9 g (97% of theory),

R _f value: 0.20 (silica gel, methylene chloride / methanol = 9: 1)

C ₂₃ H ₂₅ N ₃ 0 ₃

Mass spectrum: m / z = 391 (M) ⁺

(17) 3-Z- [1- (4- (Piperidinomethylphenylamino) -1-phenylmethylene] -2 - indolinone-6-carboxylic acid ethyl ester

R _f value: 0.50 (silica gel, methylene chloride / methanol = 100: 3)

C ₃₀ H ₃₁ N ₃ θ ₃

Mass spectrum: m / z = 481 (M) ⁺

(18) 3-Z- (1- (4- (N-Methylsulfonyl-N- (2-dimethylamino-ethyl) aminophenylamino) -1-phenylmethylene) -2-indolinone-5-carboxylic acid, ethyl ester

(19) 3-Z- (1- (4- (N-Propionyl-N- (2-dimethylaminoethyl) amino) phenylamino) -1-phenylmethylene) -2-indolinone-5-carboxylic acid methyl ester

(20) 3-Z- (1- (4- (N-tert-Butyloxycarbonyl-N-methylaminomethyl) phenylamino) -1-phenylmethylene) -2-indolinone-5-carbonate, ethyl ester (21) 3-Z- (1- (4- (N-tert-Butyloxycarbonyl-N-butylaminomethyl) phenylamino) -1-phenylmethylene) -2-indolinone-5-carboxylic acid ethyl ester

RPI game VTT

3-Z- [1- (4- (N-Benzyl-N-methylaminomethyl) phenylamino) -1-methyl-methyl enl -..- inriol i non-5-carboxylic acid

2.3 g (5 mmol) of 3-Z- [1- (4- (N-benzyl-N-methylaminomethyl) phenylamino) -1-methyl-methylene] -2-indolinone-5-carboxylic acid methyl ester are dissolved in 50 ml of methanol and 50 ml of dioxane dissolved and stirred with 25 ml of 1N sodium hydroxide solution at 70 ° C. for 1 hour. Then neutralized with 25 ml IN hydrochloric acid and concentrated to dryness. The residue is washed several times with water and dried.

Yield: 1.9 g (85% of theory), C ₂₆ H ₂₅ N ₃ 0 ₃ mass spectrum: m / z = 428 (M + H) ⁺

The following compounds are prepared analogously to Example VII:

(1) 3-Z- [1- (4-piperidinomethylphenylamino) -1-methylmethylene] -2-indolinone-5-carboxylic acid

C ₂₃ H ₂₅ N ₃ 0 ₃

Mass spectrum: m / z = 392 (M + H) ⁺

(2) 3-Z- [1- (4-bromophenylamino) -1-methyl-methylene] -2-indolinon-5-carboxylic acid

(3) 3-Z- [1- (4-chlorophenylamino) -1-methylmethylene] -2-indolinon-5-carboxylic acid

C ₁₇ H ₁₃ C1N ₂ 0 ₃

Mass spectrum: m / z = 327/329 (MH) ⁺

(4) 3-Z- [1- (4- (N-Methyl-N-methylsulfonylamino) phenylamino) - 1-methylrmethylene] -2-indolinone-5-carboxylic acid

C ₁₉ H ₁₉ N ₃ 0 ₅ p Mass spectrum: m / z = 401 (M) ⁺

(5) 3-Z- [1- (4- (2,3,4,5-tetrahydro-benzo (d) azepin-3-ylmethyl) phenylamino) -1-methyl-methylene] -2-indolinone -5-carboxylic acid C ₂₈ H ₂₇ N ₃ 0 ₃

Mass spectrum: m / z = 453 (M) ⁺

(6) 3-Z- [1- (l-methyl-piperidin-4-yl-amino) -1-phenylmethylene] - 2-indolinone-5-carboxylic acid

R _f value: 0.17 (silica gel, methylene chloride / methanol = 4: 1)

C ₂₂ H ₂₃ N ₃ 0 ₃

Mass spectrum: m / z = 377 (M) ⁺

(7) 3-Z- [1- (4-piperidinomethylphenylamino) -1-phenylmethylene] -2-indolinone-5-carboxylic acid

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

C ₂₈ H ₂₇ N ₃ 0 ₃

Mass spectrum: m / z = 453 (M) ⁺

(8) 3-Z- [1- (4- (N-Benzyl-N-methylaminomethyl) phenylamino) - 1-phenylmethylene] - 2-indole inone-5-carboxylic acid

C ₃₁ H ₂₇ N ₃ 0 ₃

Mass spectrum: m / z = 489 (M) ⁺

(9) 3-Z- [1- (4-Dimethylaminomethylphenylamino) -1-phenylmethylene] - 2-indole inone-5-carboxylic acid

C ₂₅ H ₂₃ N ₃ 0 ₃

Mass spectrum: m / z = 413 (M) ⁺

(10) 3-Z- [1- (3-Dimethylaminomethylphenylamino) -1-phenylmethylene] - 2-indole inone-5-carboxylic acid

C ₂₅ H ₂₃ N ₃ 0 ₃

Mass spectrum: m / z = 413 (M) ⁺

(11) 3-Z- [1- (4-chlorophenylamino) -1-phenylmethylene] -2-indolinonon-5-carboxylic acid (12) 3-Z- (1-Phenylamino-1-phenylmethylene] -2-indolinone-5-carboxylic acid

(13) 3-Z- [1- (4-Dimethylaminomethyl-phenylamino) -1-methyl-methylene] -2-indolinone-5-carboxylic acid

(14) 3-Z- [1- (-Dimethylaminomethylphenylamino) -1-butylmethylene] -2-indolineόn-5-carboxylic acid

(15) 3-Z- [1- (4- (2-Dimethylaminoethyl) phenylamino) -1-phenylmethylene] -2-indolinone-5-carboxylic acid

(16) 3-Z- [1- (l-methyl-piperidin-4-yl-amino) -1-phenylmethylene] -2-indolinone-5-carboxylic acid

R _f value: 0.17 (silica gel, methylene chloride / methanol = 4: 1)

C ₂₂ H ₂₃ N ₃ 0 ₃

Mass spectrum: m / z = 377 (M) ⁺

(17) 3-Z- [1- (-piperidinomethylphenylamino) -1-phenylmethylene] -2-indolinone-6-carboxylic acid

R _f value: 0.20 (silica gel, methylene chloride / methanol = 5: 2)

C ₂₈ H ₂₇ N ₃ 0 ₃

Mass spectrum: m / z = 453 (M) ⁺

(18) 3-Z- (1- (4- (N-Methylsulfonyl-N- (2-dimethylaminoethyl) amino) phenylamino) -1-phenylmethylene) -2-indolinone-5-carboxylic acid

(19) 3-Z- (1- (4- (N-Propionyl-N- (2-dimethylaminoethyl) amino) phenylamino) -1-phenylmethylene) -2-indolinone-5-carboxylic acid

(20) 3-Z- (1- (4- (N-tert-Butyloxycarbonyl-N-methylaminomethyl) phenylamino) -1-phenylmethylene) -2-indolinone-5-carboxylic acid

(21) 3-Z- (1- (4- (N-tert.Butyloxycarbonyl-N-butylaminomethyl) phenyl) amino-1-phenylmethylene) -2-indolinone-5-carboxylic acid Production of the end products:

Rei game 1

3-Z- [1- (4-piperidinomethylphenylamino) -1-phenylmethylene] -

5- (N-methyl. -N-benzyl-carbamoyl) - -in ol inon

0.3 g of 3 -Z- [1- (4-piperidinomethylphenylamino) -1-phenylmethylene] -2-indolinone-5-carboxylic acid are mixed with 1.2 g of N, N-diisopropylethylamine dissolved in 8 ml of dimethylformamide. Then 0.2 g of N-methyl-benzylamine, 0.4 g of O-benzotriazol-1-yl-N, N, N ', N' -tetramethyluronium tetrafluoroborate (TBTU) and 0.2 g of 1-hydroxy-1H- benzotriazole hydrate and stirred for 20 hours at room temperature. The mixture is then concentrated and the residue is suspended in water and extracted with methylene chloride. The organic phase is concentrated and chromatographed on a silica gel column with methylene chloride / ethanol (8: 2). Yield: 0.3 g (68% of theory),

R _f value: 0.70 (silica gel, methylene chloride / ethanol = 8: 2) C ₃₆ H ₃₆ N ₄ 0 ₂ mass spectrum: m / z = 557 (M + H) ⁺

The following compounds are produced analogously to Example 1:

(1) 3-Z- [1- (4-piperidinomethylphenylamino) -1-phenylmethylene] -5-piperidinocarbonyl-2-indolinone

Made from 3-Z- [1- (4-piperidinomethyl-phenylamino) -1-methyl-methylene] -2-indolinone-5-carboxylic acid and piperidine

C ₃₃ H ₃₆ N ₄ 0 ₂

Mass spectrum: m / z = 521 (M + H) ⁺

(2) 3-Z- [1- (4-Dimethylaminomethylphenylamino) -1-phenylmethylene] -5- (N-methyl-N-benzyl-carbamoyl) -2-indolinone Made from 3-Z- [1 - (4-dimethylaminomethyl-phenylamino) -

1-methyl-methylene] -2-indolinone-5-carboxylic acid and N-methyl-benzylamine C ₃₃ H ₃₂ N ₄ 0 ₂ mass spectrum: m / z = 516 (M) ⁺ (3) 3-Z- [1- (4- (N-benzyl-N-methylaminomethyl) phenylamino) -

1-phenylmethylene] -5- (N-benzyl-N-methyl-carbamoyl) -2-indolinone Made from 3-Z- [1- (4- (N-benzyl-N-methylaminomethyl) phenylamino) -1-phenylmethylene] -2-indolinone-5-carboxylic acid and N-methyl-benzylamine C ₃₉ H ₃₆ N ₄ 0 ₂ mass spectrum: m / z = 592 (M) ⁺

(4) 3-Z- [1- (4-Dimethylaminomethylphenylamino) -1-phenylmethylene] - 5-butylcarbamoyl-2-indolinone

Made from 3-Z- [1- (4-dimethylaminomethylphenylamino) -

1-methyl-methylene] -2-indolinone-5-carboxylic acid and butylamine

C ₂₉ H ₃₂ N ₄ 0 ₂

Mass spectrum: m / z: 469 (M + H) ⁺

(5) 3-Z- [1- (3-Dimethylaminomethylphenylamino) -1-phenylmethylene] -5- (N-methyl-N-benzylcarbamoyl) -2-indolinone Made from 3 -Z- [1 - (3-dimethylaminomethyl-phenylamino) -

1-methyl-methylene] -2-indolinone-5-carboxylic acid and N-methyl-benzylamine

(6) 3-Z- [1- (-Dimethylaminomethylphenylamino) -1-phenylmethylene] -5- (N-phenethylcarbamoyl) -2-indolinone

Made from 3-Z- [1- (4-dimethylaminomethylphenylamino) -

1-methyl-methylene] -2-indolinone-5-carboxylic acid and phenethylamine

C ₃₃ H ₃₂ N ₄ 0 ₂

Mass spectrum: m / z: 517 (M + H) ⁺

(7) 3-Z- [1- (4-Dimethylaminomethyl-phenylamino) -1-phenylmethylene] -5- (N-methyl-N-phenethyl-carbamoyl) -2-indolinone Made from 3 -Z- [1 - (4-dimethylaminomethyl-phenylamino) -

1-methyl-methylene] -2-indolinone-5-carboxylic acid and N-methyl-phenethylamine

C ₃₄ H ₃₄ N ₄ 0 ₂

Mass spectrum: m / z: 530 (M) ⁺ (8) 3-Z- [1- (4-Dimethylaminomethylphenylamino) -1-phenylmethylene] -5- (N-benzylcarbamoyl) -2-indolinone

Made from 3 -Z- [1- (4 -dimethylaminomethylphenylamino) -

1-methyl-methylene] -2-indolinone-5-carboxylic acid and benzylamine

C ₃₂ H ₃₀ N ₄ O ₂

R _f value: 0.29 (silica gel, methylene chloride / methanol = 9: 1)

(9) 3-Z- [1- (4-piperidinomethylphenylamino) -1-phenylmethylene] -5-morpholinocarbonyl-2-indolinone

Made from 3-Z- [1- (4-piperidinomethyl-phenylamino) -1-methyl-methylene] -2-indolinone-5-carboxylic acid and morpholine

(10) 3-Z- [1- (4-piperidinomethylphenylamino) -1-phenylmethylene] -6- (N-butylcarbamoyl) -2-indolinone

Made from 3-Z- [1- (4-piperidinomethylphenylamino) -1-phenylmethylene] -2-indolinone-6-carboxylic acid and butylamine.

C ₃₂ H ₃₆ N ₄ 0 ₂

Mass spectrum: m / z: 509 (M + H) ⁺

(11) 3-Z- [1- (4-piperidinomethylphenylamino) -1-phenylmethylene] -5- (N, N-dibutylcarbamoyl) -2-indolinone

Made from 3-Z- [1- (4-piperidinomethylphenylamino) -1-phenylmethylene] -2-indolinone-5-carboxylic acid and dibutylamine.

(12) 3-Z- [1- (4-piperidinomethylphenylamino) -1-phenylmethylene] -6-pyrrolidinocarbonyl-2-indolinone

Made from 3-Z- [1- (4-piperidinomethylphenylamino) -1-phenylmethylene] -2-indolinone-6-carboxylic acid and pyrrolidine

C ₃₂ H ₃₄ N ₄ 0 ₂

Mass spectrum: m / z = 506 (M) ⁺

(13) 3-Z- [1- (4-piperidinomethylphenylamino) -1-phenylmethylene] -6- (N-benzylcarbamoyl) -2-indolinone

Made from 3-Z- [1- (4-piperidinomethylphenylamino) -1-phenylmethylene] -2-indolinone-6-carboxylic acid and benzylamine

C ₃₅ H ₃₄ N ₄ 0 ₂

Mass spectrum: m / z = 543 (M + H) ⁺ (14) 3-Z- [1- (4-piperidinomethylphenylamino) -1-phenylmethylene] -6- (N-butyl-carbamoyl) -2-indolinone

Made from 3-Z- [1- (4-piperidinomethyl-phenylamino) -1-phenylmethylene) -2-indolinone-6-carboxylic acid and butylamine

C ₃₂ H ₃₆ N ₄ 0 ₂

Mass spectrum: m / z = 509 (M + H) ⁺

(15) 3-Z- [1- (4-piperidinomethylphenylamino) -1-phenylmethylene] -6- (N, N-dibutylcarbamoyl) -2-indolinone

Made from 3-Z- [1- (4-piperidinomethylphenylamino) -1-phenylmethylene] -2-indolinone-6-carboxylic acid and di-n-butylamine

C ₃₆ H ₄₄ N ₄ 0 ₂

Mass spectrum: m / z = 565 (M + H) ⁺

(16) 3-Z- [1- (4-piperidinomethyl-phenylamino) -1-phenylmethylene] -6- (N-benzyl-N-methyl-carbamoyl) -2-indolinone Made from 3-Z- [1 - (4-Piperidinomethyl-phenylamino) -1-phenylmethylene] -2-indolinone-6-carboxylic acid and N-methylbenzylamine C ₃₆ H ₃₆ N ₄ 0 ₂

Mass spectrum: m / z = 557 (M + H) ⁺

(17) 3-Z- [1- (4-piperidinomethylphenylamino) -1-phenylmethylene] -5- [N, N-di- (2-hydroxylethyl) carbamoyl] -2 -indolinone Made from 3 - Z- [1- (4-piperidinomethylphenylamino) -1-phenylmethylene] -2-indolinone-5-carboxylic acid and diethanolamine C ₃₂ H ₃₆ N ₄ 0 ₂

Mass spectrum: m / z = 540 (M) ⁺

(18) 3-Z- (1- (4-Dimethylaminomethylphenylamino) -1-phenylmethylene) -5- (N-methyl-N- (4-methoxyphenyl) carbamoyl) -2-indoline

Made from 3-Z- (1- (4-dimethylaminomethylphenylamino) -

1-phenylmethylene) -2-indolinone-5-carboxylic acid and N-methyl

4-methoxyaniline

C ₃₃ H ₃₂ N ₄ 0 ₃

Mass spectrum: m / z: 532 (M) ⁺ (19) 3-Z- (1- (4-Dimethylaminomethylphenylamino) -1-phenylmethylene) -5 -phenylcarbamoyl -2-indolinone

Made from 3-Z- (1- (4-dimethylaminomethylphenylamino) -

1-phenylmethylene) -2-indolinone-5-carboxylic acid and aniline

C ₃ .H ₂₈ N ₄ 0 ₂

Mass spectrum: m / z: 489 (M + H) ⁺

(20) 3-Z- (1- (4-Dimethylaminomethylphenylamino) -1-phenylmethylene) -5- (N-methyl-N- (2,4,5-trimethoxyphenyl) carbamoyl) -2-indolinone

Made from 3-Z- (1- (4-dimethylaminomethylphenylamino) -

1-phenylmethylene) -2-indolinone-5-carboxylic acid and N-methyl

3,4,5 -1 trimethoxybenzylamine

C ₃₆ H ₃₈ N ₄ 0

Mass spectrum: m / z: 607 (M + H) ⁺

(21) 3-Z- (1- (4-Dimethylaminomethylphenylamino) -1-phenylmethylene) -5- (N-methyl-N- (naphth-1-ylmethyl) carbamoyl) -2-indolinone

Made from 3-Z- (1- (4-dimethylaminomethylphenylamino) -

1-phenylmethylene) -2-indolinone-5-carboxylic acid and 1- (N-methylaminomethyl) naphthalene

C ₃₇ H ₃₄ N ₄ 0 ₂

Mass spectrum: m / z: 567 (M + H) ⁺

(22) 3-Z- (1- (4-Dimethylaminomethyl-phenylamino) -1-phenylmethylene) -5- (N-methyl-N-butyl-carbamoyl) -2-indolinone Made from 3-Z- (1 - (4-Dimethylaminomethyl-phenylamino) - 1-phenylmethylene) -2-indolinone-5-carboxylic acid and N-methyl-butylamine

C ₃₀ H ₃₄ N ₄ O ₂

Mass spectrum: m / z: 482 (M) ⁺ (23) 3-Z- (1- (4-Dimethylaminomethylphenylamino) -1-phenylmethylene) -5- (N-methyl-N-cyclohexyl-carbamoyl) -2-indolinone Made from 3-Z- (1 - (4-Dimethylaminomethyl-phenylamino) - 1-phenylmethylene) -2-indolinone-5-carboxylic acid and N-methylcyclohexylamine

C ₃₂ H ₃₆ N ₄ 0 ₂

Mass spectrum: m / z: 508 (M) ⁺

(24) 3-Z- (1- (4-Dimethylaminomethylphenylamino) -1-phenylmethylene) -5-cyclohexylcarbamoyl -2-indolinone

Made from 3-Z- (1- (4-dimethylaminomethylphenylamino) -1-phenylmethylene) -2-indolinone-5-carboxylic acid and cyclohexylamine

C ₃₁ H ₃₄ N ₄ 0 ₂

Mass spectrum: m / z: 494 (M) ⁺

(25) 3-Z- (1- (4-Dimethylaminomethylphenylamino) -1-phenylmethylene) - 5-pentylcarbamoyl-2 - indolinone

Made from 3-Z- (1- (4-dimethylaminomethylphenylamino) -

1-phenylmethylene) -2-indolinone-5-carboxylic acid and pentylamine

C ₃₀ H ₃₄ N ₄ O ₂

Mass spectrum: m / z: 482 (M) ⁺

(26) 3-Z- (1- (4-Dimethylaminomethylphenylamino) -1-phenylmethylene) - 5-hexylcarbamoyl-2-indolinone

Made from 3-Z- (1- (4-dimethylaminomethylphenylamino) -

1-phenylmethylene) -2-indolinone-5-carboxylic acid and hexylamine

C ₃₁ H ₃₆ N ₄ 0 ₂

Mass spectrum: m / z: 496 (M) ⁺

(27) 3-Z- (1-phenylamino-l-phenylmethylene) -5-butylcarbamoyl-2-indolinone

Made from 3-Z- (1-phenylamino-l-phenylmethylene) -2-indoline-5-carboxylic acid and butylamine

C ₂₆ H ₂₅ N ₃ 0 ₂

Mass spectrum: m / z: 412 (M + H) ⁺ (28) 3-Z- (1- (4-dimethylaminomethylphenylamino) -1-phenylmethylene) -5- (cyclohexylmethylcarbamoyl) -2-indolinone Made from 3-Z- (1- (4-dimethylaminomethyl) phenylamino) -

1-phenylmethylene) -2-indolinone-5-carboxylic acid and aminomethylcyclohexane

C ₃₂ H ₃₆ N ₄ 0 ₂

Mass spectrum: m / z: 509 (M + H) ⁺

(29) 3-Z- (1- (4-Dimethylaminomethylphenylamino) -1-phenylmethylene) -5 -heptylcarbamoyl -2 - indolinone

Made from 3-Z- (1- (4-dimethylaminomethylphenylamino) -

1-phenylmethylene) -2-indolinone-5-carboxylic acid and heptylamine

C ₃₂ H ₃₈ N ₄ 0

Mass spectrum: m / z: 511 (M + H) ⁺

(30) 3-Z- (1- (4-dimethylaminomethylphenylamino) -1-phenylmethylene) -5- (3-methylbutylcarbamoyl) -2 -indolinone Made from 3 -Z- (1- (4-dimethylaminomethyl- phenylamino) - 1-phenylmethylene) -2-indolinone-5-carboxylic acid and 3-methylbutylamine

C ₃₀ H ₃₄ N ₄ 0 ₂

R _f value: 0.25 (silica gel, methylene chloride / methanol = 4: 1)

(31) 3-Z- (1- (4-Dimethylaminomethylphenylamino) -1-phenylmethylene) -5-isobutylcarbamoyl-2-indolinone

Made from 3-Z- (1- (4-dimethylaminomethylphenylamino) -

1-phenylmethylene) -2-indolinone-5-carboxylic acid and isobutylamine

C ₂₉ H ₃₂ N ₄ 0 ₂

Mass spectrum: m / z: 469 (M + H) ⁺

(32) 3-Z- (1- (4-Dimethylaminomethylphenylamino) -1-phenylmethylene) -5-isopropylcarbamoyl-2-indolinone

Made from 3-Z- (1- (4-dimethylaminomethylphenylamino) -

1-phenylmethylene) -2-indolinone-5-carboxylic acid and isopropylamine

C _2B H _3O N ₄ 0 ₂

Mass spectrum: m / z: 453 (MH) ^' (33) 3-Z- (1- (4-dimethylaminomethylphenylamino) -1-phenylmethylene) -5- (3, 3-dimethylbutylcarbamoyl) -2 -indolinone Made from 3-Z- (1- (4 - Dimethylaminomethyl-phenylamino) - 1-phenylmethylene) -2-indolinone-5-carboxylic acid and 3,3-dimethylbutylamine

C ₃₁ H ₃₆ N ₄ 0 ₂

Mass spectrum: m / z: 497 (M + H) ⁺

(34) 3-Z- (1- (4-Dimethylaminomethyl-phenylamino) -1-phenylmethylene) -5- (N- (2 -methyl-1-methoxycarbonyl-propyl) -carbamoyl) - 2-indolinone

Made from 3-Z- (1- (4-dimethylaminomethylphenylamino) -

1-phenylmethylene) -2-indolinone-5-carboxylic acid and D, L-valine methyl ester

C ₃₁ H ₃₄ N ₄ 0 ₄

Mass spectrum: m / z: 525 (MH) ^"

(35) 3-Z- (1- (1-methyl-piperidin-4-ylamino-1-phenylmethylene) - 5-butyl carbamoyl - 2 - indolinone

Made from 3-Z- (1- (l-methyl-piperidin-4-ylamino-l-phenylmethylene) -2-indolinone-5-carboxylic acid and butylamine

C ₂₆ H ₃₂ N ₄ 0 ₂

Mass spectrum: m / z: 433 (M + H) ⁺

(36) 3-Z- (1- (4-dimethylaminomethylphenylamino) -1-phenylmethylene) -5- (N- (4-hydroxybutyl) carbamoyl) -2-indolinone Made from 3- Z- (1- (4-dimethylaminomethylphenylamino) -1phenylmethylene) -2-indolinone-5-carboxylic acid and 4-amino-1-butanol

C ₂₉ H ₃₂ N ₄ 0 ₃

Mass spectrum: m / z: 485 (M + H) ⁺ (37) 3-Z- (1- (4-Dimethylaminomethylphenylamino) -1-phenylmethylene) -5- (N- (3-methoxycarbonylpropyl) carbamoyl) -2-indolinone

Made from 3-Z- (1- (4-dimethylaminomethylphenylamino) -

1-phenylmethylene) -2-indolinone-5-carboxylic acid and 4-amino-butyric acid methyl ester

C ₃₀ H ₃₂ N ₄ O ₄

Mass spectrum: m / z: 513 (M + H) ⁺

(38) 3-Z- (1- (4-Dimethylaminomethylphenylamino) -1-phenylmethylene) -5- (4- (tert-butoxycarbonylamino) butylcarbamoyl) -2-indolinone

Made from 3-Z- (1- (4-dimethylaminomethyl-phenylamino) -1-phenylmethylene) -2-indolinone-5-carboxylic acid and N-tert. Butyloxycarbonyl-diaminobutane C ₃₄ H ₄₁ N _s 0 ₄ mass spectrum: m / z: 584 (M + H) ⁺

(39) 3-Z- (1- (4- (N-methylsulfonyl-N- (2-dimethylaminoethyl) amino) phenylamino) -1-phenylmethylene) -5-butylcarbamoyl-

2 -indolinone

Made from 3-Z- (1- (4- (N-methylsulfonyl-N- (2 -dimethylamino-no-ethyl) amino) phenylamino) -1-phenylmethylene) -2-indolinone-

5-carboxylic acid and butylamine

C ₃₁ H ₃₇ N ₅ 0 ₄ p

Mass spectrum: m / z: 576 (M + H) ⁺

(40) 3-Z- (1- (4- (N-Propionyl-N- (2-dimethylaminoethyl) amino) phenylamino) -1-phenylmethylene) -5-butylcarbamoyl-2-indolinone Made from 3 -Z- (1- (4- (N-propionyl-N- (2-dimethylaminoethyl) amino) phenylamino) -1-phenylmethylene) -2-indolinone-

5-carboxylic acid and butylamine

C ₃₃ H ₃₉ N ₅ 0 ₃

Mass spectrum: m / z: 554 (M + H) ⁺ (41) 3-Z- (1- (4-dimethylaminomethylphenylamino) -1-phenylmethylene) -5- (N- (1-amido-methyl) carbamoyl) -2-indolinone Made from 3-Z- (1- (4-Dimethylaminomethylphenylamino) -1-phenylmethylene) -2-indolinone-5-carboxylic acid and glycinamide C ₂₇ H ₂₇ N ₅ 0 ₃

Mass spectrum: m / z: 469 (M) ⁺

(42) 3-Z- (1- (4-piperidinomethylphenylamino) -1-phenylmethylene) - 6 -azetidinocarbamoyl-2 - indolinone

Made from 3-Z- (1- (4-piperidino-methyl-phenylamino) -

1-phenylmethylene) -2-indolinone-6-carboxylic acid and azetidine

C ₃₁ H ₃₂ N ₄ 0 ₂

Mass spectrum: m / z: 493 (M + H) ⁺

(43) 3-Z- (1- (4-piperidinomethyl-phenylamino) -1-phenylmethylene) -6-isopropylcarbamoyl-2-indolinone

Made from 3-Z- (1- (4-piperidino-methyl-phenylamino) -

1-phenylmethylene) -2-indolinone-6-carboxylic acid and isopropylamine

C ₃₁ H ₃₄ N ₄ 0 ₂

Mass spectrum: m / z: 494 (M) ⁺

(44) 3-Z- (1- (4- (N-tert-Butoxycarbonyl-N-butylaminomethyl) phenylamino) -1-phenylmethylene) -5-butylcarbamoyl-2-indolinone C ₃₆ H ₄₄ N ₄ 0 ₄

Mass spectrum: m / z: 595 (MH) ^"

(45) 3-Z- (1- (4- (N-tert.Butoxycarbonyl-N-butylaminomethyl) phenylamino) -1-phenylmethylene) -5- (N-methyl-N-phenylcarbamoyl) -2-indolinone

(46) 3-Z- (1- (4- (N-tert.Butoxycarbonyl-N-butylaminomethyl) phenylamino) -1-phenylmethylene) -5- (N-cyclohexylmethylcarbamoyl) -2-indolinone

(47) 3-Z- (1- (4- (N-tert.Butoxycarbonyl-N-butylaminomethyl) phenylamino) -1-phenylmethylene) -5- (N- (3-chlorobenzyl) carbamoyl) -2-indolinone (48) 3-Z- (1- (4- (N-tert.butoxycarbonyl-N-butylaminomethyl) phenylamino) -1-phenylmethylene) -5- (N-methyl-N-butyl-carb- amoyl) -2-indolinone

(49) 3-Z- (1- (4-diethanolaminomethylphenylamino) -1-phenylmethylene) - 5-butylcarbamoyl-2-indolinone

C ₃₁ H ₃₆ N ₄ 0 ₄

Mass spectrum: m / z: 529 (M + H) ⁺

(50) 3-Z- (1- (4-diethanolaminomethylphenylamino) -1-phenylmethylene) -5- (N-methyl-N-phenylcarbamoyl) -2-indolinone

(51) 3-Z- (1- (4-Diethanolaminomethyl-phenylamino) -1-phenylmethylene) -5- (N-cyclohexylmethyl-carbamoyl) -2 -indolinone C ₃₄ H ₄₀ N ₄ O ₄

Mass spectrum: m / z: 569 (M + H) ⁺

(52) 3-Z- (1- (4-diethanolaminomethylphenylamino) -1-phenylmethylene) -5- (N- (3-chlorobenzyl) carbamoyl) -2 -indolinone C ₃₄ H ₃₃ C1N ₄ 0 ₄

Mass spectrum: m / z: 597/599 (M + H) ⁺

(53) 3-Z- (1- (4-Diethanolaminomethyl-phenylamino) -1-phenylmethylene) -5- (N-methyl-N-butyl-carbamoyl) -2-indolinone C ₃₂ H ₃₈ N ₄ 0 ₄

Mass spectrum: m / z: 543 (M + H) ⁺

(54) 3-Z- (1- (4- (N-tert.butoxycarbonyl-N-butylaminomethyl) phenylamino) -1-phenylmethylene) -5-butylcarbamoyl-2-indolinone

(55) 3-Z- (1- (4- (N-tert-butoxycarbonyl-N-butylaminomethyl) phenylamino) -1-phenylmethylene) -5- (N-methyl-N-phenylcarbamoyl) -2-indolinone (56) 3-Z- (1- (4- (N-tert.butoxycarbonyl-N-butylaminomethyl) phenylamino) -1-phenylmethylene) -5- (N-cyclohexylmethyl-carbamoyl) -2 -indolinone

C ₃ -H ₄₈ N ₄ 0 ₄

Mass spectrum: m / z: 635 (MH) ^"

(57) 3-Z- (1- (4- (N-tert-butoxycarbonyl-N-butylaminomethyl) phenylamino) -1-phenylmethylene) -5- (N- (3-chlorobenzyl) carbamoyl) -2-indolinone

(58) 3-Z- (1- (4- (N-tert.butoxycarbonyl-N-butylaminomethyl) phenylamino) -1-phenylmethylene) -5- (N-methyl-N-butyl-carb- amoyl) -2-indolinone

(59) 3-Z- (1- (4- (N-tert-Butoxycarbonyl-N-methylaminomethyl) phenylamino) -1-phenylmethylene) -5-butylcarbamoyl-2-indolinone

(60) 3-Z- (1- (4- (N-tert.butoxycarbonyl-N-methylaminomethyl) phenylamino) -1-phenylmethylene) -5- (N-methyl-N-phenylcarbamoyl) -2-indolinone

(61) 3-Z- (1- (4- (N-tert-butoxycarbonyl-N-methylaminomethyl) phenylamino) -1-phenylmethylene) -5- (N-cyclohexylmethyl-carbamoyl) -2 -indolinone

(62) 3-Z- (1- (4- (N-tert.Butoxycarbonyl-N-methylaminomethyl) phenylamino) -1-phenylmethylene) -5- (N- (3-chlorobenzyl) carbamoyl) -2-indolinone

(63) 3-Z- (1- (4- (N-tert.Butoxycarbonyl-N-methylaminomethyl) phenylamino) -1-phenylmethylene) -5- (N-methyl-N-butyl-carb- amoyl) -2-indolinone

(64) 3-Z- (1- (4- (N-acetyl-N- (2-dimethylaminoethyl) amino) phenylamino) -1-phenylmethylene) -5-butylcarbamoyl-2-indolinone C ₃₂ H ₃₇ N ₅ 0 ₃

Mass spectrum: m / z = 540 (M + H) ⁺ (65) 3-Z- (1- (4-N- (N-acetyl-N- (2-dimethylaminoethyl) amino) phenylamino) -1-phenylmethylene) -5- (N-methyl-N -phenyl-carbamoyl) -2 -indolinone

C _3S H _3ε N ₅ 0 ₃

Mass spectrum: m / z = 572 (MH) ^"

(66) 3-Z- (1- (4- (N-acetyl-N- (2-dimethylaminoethyl) amino) phenylamino) -1 phenylmethylene) -5- (N-cyclohexylmethylcarbamoyl) -2-indolinone

C ₃₅ H ₄₁ N ₅ 0 ₃

Mass spectrum: m / z = 578 (M-H)

(67) 3-Z- (1- (4- (N-acetyl-N- (2-dimethylaminoethyl) amino) phenylamino) -1-phenylmethylene) -5- (N- (3-chlorobenzyl ) -carbamoyl) -2 -indolinone

(68) 3-Z- (1- (4- (N-acetyl-N- (2-dimethylamino-ethyl) amino) phenylamino) -1-phenylmethylene) -5- (N-methyl-N- butyl-carb-amoyl) -2-indolinone

C ₃₃ H ₃₉ N ₅ 0 ₃

Mass spectrum: m / z = 554 (M + H) ⁺

(69) 3-Z- (1- (4-Dimethylaminomethylphenylamino) -1-phenylmethylene) -5- (N- (3-bromobenzyl) carbamoyl) -2-indolinone C ₃₂ H ₂₉ BrN ₄ 0 ₂

Mass spectrum: m / z: 580/582 (M) ⁺

(70) 3-Z- (1- (4-dimethylaminomethyl phenylamino) -1-phenyl ethylene) -5- (N- (3-f luorbenzyl) carbamoyl) -2-indolinone C ₃₂ H ₂₉ FN ₄ 0 _2nd

Mass spectrum: m / z: 520 (M) ⁺

(71) 3-Z- (1- (4-Dimethylaminomethylphenylamino) -1-phenylmethylene) -5- (N- (3-methylbenzyl) carbamoyl) -2 -indolinone C ₃₃ H ₃₂ N ₄ 0 ₂

Mass spectrum: m / z: 517 (M + H) ⁺ (72) 3-Z- (1- (4-Dimethylaminomethylphenylamino) -1-phenylmethylene) -5- (N- (3 -cyanobenzyl) carbamoyl) -2-indolinone

(73) 3-Z- (1- (4-piperidinomethylphenylamino) -1-phenylmethylene) -5-butylcarbamoyl -2-indolinone

C ₃₂ H ₃₆ N ₄ 0 ₂

Mass spectrum: m / z: 508 (M + H) ⁺

(74) 3-Z- (1- (4-piperidinomethylphenylamino) -1-phenylmethylene) -5- (N-methyl-N-phenylcarbamoyl) -2-indolinone C ₃₅ H ₃₄ N ₄ 0 ₂

Mass spectrum: m / z: 542 (M) ⁺

(75) 3-Z- (1- (4-piperidinomethylphenylamino) -1-phenylmethylene) -5- (N-cyclohexylmethylcarbamoyl) -2 -indolinone C ₃₅ H ₄₀ N ₄ O ₂

Mass spectrum: m / z: 549 (M + H) ⁺

(76) 3-Z- (1- (4-piperidinomethylphenylamino) -1-phenylmethylene) -5- (N- (3-chlorobenzyl) carbamoyl) -2-indolinone C ₃₅ H ₃₃ C1N ₄ 0 ₂

Mass spectrum: m / z: 575/577 (MH) ^"

(77) 3-Z- (1- (4-piperidinomethylphenylamino) -1-phenylmethylene) -5- (N-methyl-N-butylcarbamoyl) -2-indolinone C ₃₃ H ₃₈ N ₄ 0 ₂

Mass spectrum: m / z: 523 (M + H) ⁺

(78) 3-Z- (1- (4- (N-methylsulfonyl-N- (2-dimethylaminoethyl) amino) phenylamino) -1-phenylmethylene) -5- (N-methyl-N- phenyl-carbamoyl) -2-indolinone

C ₃₄ H ₃₅ N ₅ 0 ₄ p

Mass spectrum: m / z = 610 (M + H ⁺ ) (79) 3-Z- (1- (4- (N-methylsulfonyl-N- (2-dimethylaminoethyl) amino) phenylamino) -1-phenylmethylene) -5- (N-cyclohexylmethylcarbamoyl) -2-indolinone

C ₃₄ H ₄₁ N ₅ 0 ₄ p

Mass spectrum: m / z = 614 (MH) ^"

(80) 3-Z- (1- (4- (N-Methylsulfonyl-N- (2-dimethylaminoethyl) amino) phenylamino) -1-phenylmethylene) -5- (N- (3-chlorobenzyl ) - carbamoyl) -2 -indolinone

C ₃₄ H ₃₄ C1N ₅ 0 ₄ p

Mass spectrum: m / z = 644/646 (M + H) ⁺

(81) 3-Z- (1- (4- (N-methylsulfonyl-N- (2-dimethylaminoethyl) amino) phenylamino) -1-phenylmethylene) -5- (N-methyl-N- butyl-carbamoyl) -2-indolinone

C ₃₂ H ₃₉ N ₅ 0 ₄ S

Mass spectrum: m / z = 590 (M + H) ⁺

(82) 3-Z- (1- (4-pyrrole idinomethylphenylamino) -1phenylmethylene) -5butylcarbamoyl-2-indolinone

C ₃₁ H ₃₄ N ₅ 0 ₂

Mass spectrum: m / z = 495 (M + H) ⁺

(83) 3-Z- (1- (4-pyrrole idinomethylphenylamino) -1-phenylmethylene) -5- (N-methyl-N-phenyl-carbamoyl) -2-indolinone

C ₃₄ H ₃₂ N ₄ 0 ₂

Mass spectrum: m / z = 528 (M ⁺ )

(84) 3-Z- (1- (4-pyrrolidinomethylphenylamino) -1-phenylmethylene) -5- (N-cyclohexylmethyl-carbamoyl) -2 -indolinone C ₃₄ H ₃₈ N ₄ 0 ₂ mass spectrum: m / z: 535 (M + H) ⁺

(85) 3-Z- (1- (4-pyrrole idinomethylphenylamino) -1-phenylmethylene) -5- (N- (3-chlorobenzyl) carbamoyl) -2-indolinone C ₃₄ H ₃ .C1N ₄ 0 ₂ mass spectrum: m / z = 563/565 (M + H) ⁺ (86) 3-Z- (1- (4-pyrrolidinomethylphenylamino) -1-phenylmethylene) -5- (N-methyl-N-butylcarbamoyl) -2-indolinone

C ₃₂ H ₃₆ N ₄ 0 ₂

Mass spectrum: m / z: 508 (M) ⁺

(87) 3-Z- (1- (4-pyrrolidinomethylphenylamino) -1-phenylmethylene) -5- (3-ethylbutylcarbamoyl) -2-indolinone

(88) 3-Z- (1- (4-Diethylaminomethylphenylamino) -1-phenylmethylene) -5-butylcarbamoyl-2-indolinone

Mass spectrum: m / z: 497 (M + H) ⁺

(89) 3-Z- (1- (4-Diethylaminomethylphenylamino) -1-phenylmethylene) -5- (N-methyl-N-phenylcarbamoyl) -2-indolinone

C ₃₄ H ₃₄ N ₄ 0 ₂

Mass spectrum: m / z: 531 (M + H) ⁺

(90) 3-Z- (1- (4-Diethylaminomethylphenylamino) -1-phenylmethylene) -5- (N-cyclohexylmethyl-carbamoyl) -2-indolinone

C ₃₄ H ₄₀ N ₄ O ₂

Mass spectrum: m / z: 537 (M + H) ⁺

(91) 3-Z- (1- (4-Diethylaminomethylphenylamino) -1-phenylmethylene) -5- (N- (3-chlorobenzyl) carbamoyl) -2 -indolinone C ₃₅ H ₃₅ C1N ₄ 0 ₂

Mass spectrum: m / z: 565/567 (M + H) ⁺

(92) 3-Z- (1- (4-Diethylaminomethylphenylamino) -1-phenylmethylene) -5- (N-methyl-N-butyl-carbamoyl) -2-indolinone

C ₃₂ H ₃₈ N ₄ 0 ₂

Mass spectrum: m / z: 511 (M + H) ⁺

(93) 3-Z- (1- (4-Diethylaminomethylphenylamino) -1-phenylmethylene) -5- (3-ethylbutylcarbamoyl) -2-indolinone (94) 3-Z- (1- (4-tert-butoxycarbonylaminomethylphenylamino) phenylmethylene) -5- (N-methyl-N-butylcarbamoyl) -2-indolinone

(95) 3-Z- (1- (4-tert-butoxycarbonylaminomethylphenylamino) phenylmethylene) -5-butylcarbamoyl-2-indolinone

(96) 3-Z- (1- (4-tert.butoxycarbonylmino-methylphenylamino) -

1-phenylmethylene) -5- (N-methyl-N-phenylcarbamoyl) -2-indolinone

(97) 3-Z- (1- (4-tert-Butoxycarbonylamino-methyl-phenylamino) - 1-phenylmethylene) -5- (N-cyclohexylmethyl-carbamoyl) -2-indolinone

(98) 3-Z- (1- (4-tert.butoxycarbonylaminomethylphenylamino) -

1-phenylmethylene) -5- (N- (3-chlorobenzyl) carbamoyl) -2-indolinone

(99) 3-Z- (1- (4-tert-Butoxycarbonylaminomethyl-phenylamino) - 1-phenylmethylene) -5- (3-methyl-butyl-carbamoyl) -2-indolinone

(100) 3-Z- (1- (4- (4-methyl-piperazinomethyl) phenylamino) -

1-phenylmethylene) -5- (N-methyl-N-butyl-carbamoyl) -2-indolinone

(101) 3-Z- (1- (4- (4-methylpiperazinomethyl) phenylamino) -1-phenylmethylene) -5-butylcarbamoyl-2-indolinone

(102) 3-Z- (1- (4- (4-methyl-piperazinomethyl) phenylamino) -

1-phenylmethylene) -5- (N-methyl-N-phenylcarbamoyl) -2-indolinone

(103) 3-Z- (1- (4- (4-methyl-piperazinomethyl) phenylamino) -

1-phenylmethylene) -5- (N-cyclohexylmethyl-carbamoyl) -2-indoline

(104) 3-Z- (1- (4- (4-methylpiperazinomethyl) phenylamino) -

1-phenylmethylene) -5- (N- (3-chlorobenzyl) carbamoyl) -2-indolinone

(105) 3-Z- (1- (4- (4-methylpiperazinomethyl) phenylamino) -

1-phenylmethylene) -5- (3-methylbutylcarbamoyl) -2-indolinone (106) 3-Z- (1- (4- (3-Dimethylamino-propionyl-N-methylamino) - phenylamino) -1-phenylmethylene) -5- (N-methyl-N-butyl-carbamoyl) -2-indolinone

(107) 3-Z- (1- (4- (3-Dimethylamino-propionyl-N-methylamino) phenylamino) -1-phenylmethylene) -5-butylcarbamoyl-2-indolinone C ₃₂ H ₃₇ N ₅ 0 ₃

Mass spectrum: m / z = 540 (M + H) ⁺

(108) 3-Z- (1- (4- (3-dimethylamino-propionyl -N-methylamino) - phenylamino) -1-phenylmethylene) -5- (N-methyl-N-phenylcarbamoyl) -2-indolinone

(109) 3-Z- (1- (4- (3-Dimethylamino-propionyl-N-methylamino) - phenylamino) -1-phenylmethylene) -5- (N-cyclohexylmethyl-carbamoyl) -2 -indolinone

(110) 3-Z- (1- (4- (3-dimethylamino-propionyl -N-methylamino) - phenylamino) -1-phenylmethylene) -5- (N- (3-chlorobenzyl) carbamoyl) -2-indolinone

(111) 3-Z- (1- (4- (3-Dimethylamino-propionyl-N-methylamino) - phenylamino) -1-phenylmethylene) -5- (3-methylbutylcarbamoyl) - 2 -indolinone

(112) 3-Z- (1- (4- (2-Diethylaminoethylcarbamoyl) phenylamino) -1-phenylmethylene) -5- (N-methyl-N-butylcarbamoyl) -2-indolinone

(113) 3-Z- (1- (4- (2-Diethylaminoethylcarbamoyl) phenylamino) 1-phenylmethylene) -5-butylcarbamoyl-2-indolinone

C ₃₃ H ₃₉ N ₅ 0 ₃

Mass spectrum: m / z = 554 (M + H) ⁺

(114) 3-Z- (1- (4- (2-Diethylaminoethylcarbamoyl) phenylamino) -1-phenylmethylene) -5- (N-methyl-N-phenylcarbamoyl) -2-indolinone (115) 3-Z- (1- (4- (2-Diethylaminoethylcarbamoyl) phenylamino) - 1-phenylmethylene) -5- (N-cyclohexylmethylcarbamoyl) -2-indolinone

(116) 3-Z- (1- (4- (2-diethylaminoethylcarbamoyl) phenylamino) -

1-phenylmethylene) -5- (N- (3-chlorobenzyl) carbamoyl) -2-indolinone

(117) 3-Z- (1- (4- (2-Diethylaminoethylcarbamoyl) phenylamino) - 1-phenylmethylene) -5- (3-methylbutylcarbamoyl) -2-indolinone

(118) 3-Z- (1- (4- (N-acetyl-N- (2-dimethylaminoethyl) amino) phenylamino) -1-phenylmethylene) -5- (3-methylbutyl- carbamoyl) - 2 -indolinone

C ₃₃ H ₃₉ N ₅ 0 ₃

Mass spectrum: m / z = 554 (M + H) ⁺

(119) 3-Z- (1- (4- (N-methylsulfonyl-N- (2-dimethylamino-ethyl) amino) phenylamino) -1-phenylmethylene) -5- (3-methylbutyl-carbamoyl) -2-indolinone

C ₃₂ H ₃₉ N ₅ 0 ₄ S

Mass spectrum: m / z = 588 (MH) ^"

Example 2.

3-Z- [1- (-Dimethylaminomethylphenylamino) -1-phenylmethylene] -

5- (N-methyl -N-phenylcarbamoyl -2-indolinone

0.5 g of 3-Z- [1- (4-dimethylaminomethylphenylamino) -1-phenylmethylene] -2-indolinone-5-carboxylic acid are added in portions in 10 ml of thionyl chloride cooled to 0 ° C. and then 40 Minutes stirred. The mixture is then concentrated and the residue is taken up in 30 ml of methylene chloride, 0.32 g of N-methylaniline is added and the mixture is boiled under reflux for 2 hours. The organic phase is then washed with aqueous dilute ammonia, dried with sodium sulfate and evaporated. The residue is finally chromatographed on a silica gel column using methylene chloride / ethanol (19: 1). Yield: 0.36 g (58% of theory), R _f value: 0.16 (silica gel, methylene chloride / ethanol = 9: 1)

C ₃₂ H ₃₀ N ₄ O ₂

Mass spectrum: m / z = 502 (M) ⁺

The following compounds are prepared analogously to Example 2:

(1) 3-Z- [1- (3-Dimethylaminomethylphenylamino) -1-phenylmethylene] -5- (N-methyl-N-phenyl-carbamoyl) -2-indolinone Made from 3 -Z- [1 - (3-dimethylaminomethyl-phenylamino) -

1-phenylmethylene] -2-indolinone-5-carboxylic acid and N-methylaniline

R _f value: 0.15 (silica gel, methylene chloride / ethanol = 9: 1)

C ₃₃ H ₃₂ N ₄ 0 ₂

Mass spectrum: m / z = 502 (M) ⁺

(2) 3-Z- [1- (4- (N-benzyl-N-methylaminomethyl) phenylamino) -

1-phenylmethylene] -5- (N-methyl-N-phenylcarbamoyl) -2-indolinone Made from 3-Z- [1- (4- (N-benzyl-N-methylaminomethyl) phenylamino) -1-phenylmethylene] -2-indolinone-5-carboxylic acid and N-methylaniline.

R _f value: 0.50 (silica gel, methylene chloride / ethanol = 9: 1) C ₃₈ H ₃₄ N ₄ 0 ₂ mass spectrum: m / z = 578 (M) ⁺

(3) 3-Z- [1- (4-Dimethylaminomethylphenylamino) -1-phenylmethylene] -5- (N-methyl-N- (4-chlorophenyl) carbamoyl) -2 -indolinone Made from 3-Z- [1- (4-dimethylaminomethylphenylamino) -

1-phenylmethylene] -2- indolinone- 5-carboxylic acid and 4-chloro

N-methyl aniline.

C ₃₂ H ₂₉ C1N ₄ 0 ₂

Mass spectrum: m / z: 536/538 (M) ⁺

(4) 3-Z- [1- (4-Dimethylaminomethylphenylamino) -1-phenylmethylene] -5- (N-methyl-N- (4-methoxyphenyl) carbamoyl) -2-indolinone Made from 3-Z- [1- (4-dimethylaminomethylphenylamino) -

1-phenylmethylene] -2-indolinone-5-carboxylic acid and 4-methoxy-N-methyl-aniline (5) 3-Z- [1- (4-Dimethylaminomethylphenylamino) -1-phenylmethylene] -5- (N-ethyl-N-phenyl-carbamoyl) -2-indolinone Made from 3-Z- [1 - (4-dimethylaminomethyl-phenylamino) -

1-phenylmethylene] -2-indolinone-5-carboxylic acid and N-ethyl-aniline

(6) 3-Z- [1- (4-Dimethylaminomethylphenylamino) -1-phenylmethylene] -5- (N-butyl -N-phenyl-carbamoyl) -2-indolinone Made from 3-Z- [1 - (4-dimethylaminomethyl-phenylamino) -

1-phenylmethylene] -2-indolinone-5-carboxylic acid and N-butyl aniline

C ₃₅ H ₃ -N ₄ 0 ₂

Mass spectrum: m / z: 544 (M) ⁺

(7) 3-Z- [1- (4-Dimethylaminomethylphenylamino) -1-phenylmethylene] -5- (N-methoxycarbonylmethyl-N-phenylcarbamoyl) -2-indolinone

Made from 3-Z- [1- (4-dimethylaminomethylphenylamino) -

1-phenylmethylene] -2-indolinone-5-carboxylic acid and N-phenylglycine methyl ester

C ₃₄ H ₃₂ N ₄ 0 ₄

Mass spectrum: m / z: 560 (M) ⁺

(8) 3-Z- [1- (4-Dimethylaminomethylphenylamino) -1-phenylmethylene] -5- (N-phenyl-N-ethylcarbamoyl) -2-indolinone Made from 3-Z- [1 - (4-dimethylaminomethyl-phenylamino) -

1-phenylmethylene] -2-indolinone-5-carboxylic acid and N-ethyl-aniline

(9) 3-Z- [1- (4-Dimethylaminomethylphenylamino) -1-phenylmethylene] -5- (N- (2-diethylaminoethyl) -N-phenylcarbamoyl) -2-indoline

Made from 3-Z- [1- (4-dimethylaminomethyl-phenylamino) -1-phenylmethylene] -2-indolinone-5-carboxylic acid and N, N-diethyl-N '-phenyl-ethylenediamine (10) 3-Z- [1- (4-Dimethylaminomethylphenylamino) -1-phenylmethylene] -5- (N-methyl-N- (4-methoxycarbonylphenyl) carbamoyl) -2-indolinone

Made from 3-Z- [1- (4-dimethylaminomethyl-phenylamino) -1-phenylmethylene] -2-indolinone-5-carboxylic acid and 4-methylamino-benzoic acid methyl

(11) 3-Z- [1- (4-Dimethylaminomethylphenylamino) -1-methylmethylene] -5- (N-methyl-N-phenylcarbamoyl) -2-indolinone Made from 3 -Z- [1 - (4-Dimethylaminomethyl-phenylamino) - 1-methyl-methylene] -2-indolinone-5-carboxylic acid and N-methyl-aniline

C ₂₇ H ₂₈ N ₄ 0 ₂

Mass spectrum: m / z: 440 (M) ⁺

(12) 3-Z- [1- (4-Dimethylaminomethylphenylamino) -1-butylmethylene] -5- (N-methyl-N-phenylcarbamoyl) -2-indolinone Made from 3-Z- [1 - (4-dimethylaminomethyl-phenylamino) -

1-butylmethylene] -2-indolinone-5-carboxylic acid and N-methylaniline

(13) 3-Z- [1- (4- (2-Dimethylaminoethyl) phenylamino) -1-butylmethylene] -5- (N-methyl-N-phenylcarbamoyl) -2 -indolinone Made from 3-Z- [1- (4- (2-Dimethylaminoethyl) phenylamino) -1-butylmethylene] -2-indolinone-5-carboxylic acid and N-methylaniline

(14) 3-Z- [1- (l-methyl-piperidin-4-yl-amino) -1-phenylmethylene] -5- (N-methyl-N-phenyl-carbamoyl) -2-indolinone Made from 3-Z- [1- (l-methyl-piperidin-4-yl-amino) -1-phenylmethylene] -2-indolinone-5-carboxylic acid and N-methyl-aniline

R _f value: 0.21 (silica gel, methylene chloride / methanol = 9: 1)

(15) 3-Z- [1- (4-chlorophenylamino) -1-phenylmethylene] -5- (N-methyl-N-phenylcarbamoyl) -2-indolinone

Made from 3-Z- [1- (4-chlorophenylamino) -1-phenylmethylene] -2-indolinone-5-carboxylic acid and and N-methyl-aniline (16) 3-Z- [1- (4-piperidinomethylphenylamino) -1-phenylmethylene] -5- (N-methyl-N-phenylcarbamoyl) -2-indolinone Made from 3 -Z- [1 - (4-Piperidinomethyl-phenylamino) -1-phenylmethylene] -2-indolinone-5-carboxylic acid and and N-methylaniline

(17) 3-Z- [1- (4-piperidinomethylphenylamino) -1-phenylmethylene] -6- (N-phenyl-N-ethylcarbamoyl) -2-indolinone Made from 3 -Z- [1 - (4-Piperidinomethyl-phenylamino) - 1-phenylmethylene] -2-indolinone-6-carboxylic acid and N-ethylaniline

(18) 3-Z- [1- (4-piperidinomethylphenylamino) -1-phenylmethylene] -6- (N-phenylcarbamoyl) -2 -indolinone

Made from 3 -Z- [1- (4-piperidinomethylphenylamino) -1-phenylmethylene] -2-indolinone-6-carboxylic acid and aniline

(19) 3-Z- [1- (4-Dimethylaminomethylphenylamino) -1-phenylmethylene] -5- (N-methyl-N- (4-bromophenyl) carbamoyl) -2-indolinone

(20) 3-Z- [1- (4-Dimethylaminomethylphenylamino) -1-phenylmethylene] -5- (N-methyl-N- (4-fluorophenyl) carbamoyl) -2-indolinone

(21) 3-Z- [1- (4-Dimethylaminomethylphenylamino) -1-phenylmethylene] -5- (N-methyl-N- (3-chlorophenyl) carbamoyl) -2-indolinone

(22) 3-Z- [1- (-Dimethylaminomethylphenylamino) -1-phenylmethylene] -5- (N-methyl-N- (2-chlorophenyl) carbamoyl) -2-indolinone

(23) 3-Z- [1- (4-Dimethylaminomethylphenylamino) -1-phenylmethylene] -5- (N-methyl-N- (4-methylphenyl) carbamoyl) -2-indolinone

(24) 3-Z- [1- (4-Dimethylaminomethylphenylamino) -1-phenylmethylene] -5- (N-methyl-N- (4-nitro-phenyl) carbamoyl) -2-indolinone

(25) 3-Z- [1- (4-Dimethylaminomethylphenylamino) -1-phenylmethylene] -5- (N-methyl-N- (4-cyano-phenyl) carbamoyl) -2-indolinone (26) 3-Z- (1- (4- (2-Dimethylaminoethyl) phenylamino) -1-phenylmethylene) -5- (N-methyl-N-phenylcarbamoyl) -2-indolinone Made from 3-Z- (1- (4- (2-Dimethylaminoethyl) phenylamino) -1-phenylmethylene) -2-indolinone-5-carboxylic acid and N-methyl-aniline

C ₃₃ H ₃₂ N ₄ 0 ₂

Mass spectrum: m / z: 517 (M + H) ⁺

(27) 3-Z- (1- (4-Dimethylaminomethylphenylamino) - 1-phenylmethylene) -5- (N- (4-chlorobenzyl) carbamoyl) -2-indolinone Made from 3-Z- (1- (4-Dimethylaminomethyl-phenylamino) -1-phenylmethylene) -2-indolinone-5-carboxylic acid and 4-chlorobenzylamine

C ₃₂ H ₂₉ C1N ₄ 0 ₂

Mass spectrum: m / z: 536/538 (M) ⁺

(28) 3-Z- (1- (4-Dimethylaminomethylphenylamino) -1-phenylmethylene) -5- (N- (3-chloro-benzyl) carbamoyl) -2-indolinone Made from 3-Z- (1- (4-dimethylaminomethyl-phenylamino) -1-phenylmethylene) -2-indolinone-5-carboxylic acid and 3-chlorobenzylamine

C ₃₂ H ₂₉ C1N ₄ 0 ₂

Mass spectrum: m / z: 536/538 (M) ⁺

(29) 3-Z- (1- (4-dimethylaminomethylphenylamino) -1-phenylmethylene) -5- (N- (2-chloro-benzyl) carbamoyl) -2 -indolinone Made from 3-Z- (1- (4-Dimethylaminomethyl-phenylamino) - 1-phenylmethylene) -2-indolinone-5-carboxylic acid and 2-chlorobenzylamine

C ₃₂ H ₂₉ C1N ₄ 0 ₂

Mass spectrum: m / z: 535/537 (MH) ^" Example 3.

3-Z- (1- (4-dimethylaminomethylphenylamino) -1-phenylmethylene) -

5- (N- (carboxyl methyl. -N-phenyl-carbamoyl -2-indole nnn

Made from 3-Z- (1- (4-dimethylaminomethylphenylamino) -

1-phenylmethylene) -5- (N- (methoxycarbonylmethyl) -N-phenyl-carbamoyl) -2 -indolinone by saponification with sodium hydroxide solution in

Dioxane.

C ₃₃ H ₃₀ N ₄ O ₄

Mass spectrum: m / z: 545 (MH) ^"

The following connection is established analogously to Example 3:

(1) 3-Z- (1- (4-Dimethylaminomethylphenylamino) -1-phenylmethylene) -5- (N- (3-hydroxycarbonylpropyl) carbamoyl) -2-indolinone

Made from 3-Z- (1- (4-dimethylaminomethylphenylamino) -

1-phenylmethylene) -5- (N- (3-methoxycarbonylpropyl) carbamoyl) -

2-indolinone

C ₂₉ H ₃₀ N ₄ O ₄

Mass spectrum: m / z: 497 (MH) ^"

In game 4

3-Z- (1- (4-dimethylaminomethylphenylamino) -1-phenylmethylene) -

5- (N- (4-aminobutylcarbamoyl) -2-indolinone

Made from 3-Z- (1- (4-dimethylaminomethyl-phenylamino) - 1-phenylmethylene) -5- (4- (N-tert .butyloxycarbonylamino-butyl) carbamoyl) -2-indolinone by splitting off the tert. Butyloxycarbonyl protecting group with trifluoroacetic acid in methylene chloride at room temperature. C ₂₉ H ₃₃ N ₅ 0 ₂ mass spectrum: m / z: 484 (M + H) ⁺ / Analogously to example 4, the following connections are made:

(1) 3-Z- (1- (4-Butylaminomethylphenylamino) -1-phenylmethylene) -5-butylcarbamoyl-2-indolinone

C ₃₆ H ₄₄ N ₄ 0 ₄

Mass spectrum: m / z: 595 (MH) ^"

(2) 3-Z- (1- (4-Butylaminomethylphenylamino) -1-phenylmethylene) -5- (N-methyl-N-phenylcarbamoyl) -2-indolinone

(3) 3-Z- (1- (4-butylaminomethylphenylamino) -1-phenylmethylene) -5- (N-cyclohexylmethylcarbamoyl) -2-indolinone C ₃₄ H ₄₀ N ₄ O ₂

Mass spectrum: m / z: 537 (M + H) ⁺

(4) 3-Z- (1- (4-butylaminomethylphenylamino) -1-phenylmethylene) -5- (N- (3-chlorobyl) carbamoyl) -2-indolinone

(5) 3-Z- (1- (4-Butylaminomethylphenylamino) -1-phenylmethylene) -5- (N-methyl-N-butylcarbamoyl) -2-indolinone

(6) 3-Z- (1- (4-methylaminomethylphenylamino) -1-phenylmethylene) -5-butylcarbamoyl-2-indolinone

(7) 3-Z- (1- (4-Methylaminomethylphenylamino) -1-phenylmethylene) -5- (N-methyl-N-phenylcarbamoyl) -2-indolinone

(8) 3-Z- (1- (4-Methylaminomethylphenylamino) -1-phenylmethylene) -5- (N-cyclohexylmethyl-carbamoyl) -2-indolinone

(9) 3-Z- (1- (4-Methylaminomethylphenylamino) -1-phenylmethylene) -5- (N- (3-chlorobyl) carbamoyl) -2-indolinone

(10) 3-Z- (1- (4-Methylaminomethylphenylamino) -1-phenylmethylene) -5- (N-methyl-N-butylcarbamoyl) -2-indolinone (11) 3-Z- (1- (4-Aminomethylphenylamino) -1-phenylmethylene) - - (N-methyl-N-butyl-carbamoyl) -2-indolinone

(12) 3-Z- (1- (4-aminomethylphenylamino) -1-phenylmethylene) - butylcarbamoyl -2 - indolinone

(13) 3-Z- (1- (4-aminomethylphenylamino) -1-phenylmethylene) - - (N-methyl-N-phenylcarbamoyl) -2-indolinone

(14) 3-Z- (1- (4-aminomethylphenylamino) -1-phenylmethylene) - 5- (N-cyclohexylmethylcarbamoyl) -2-indolinone

(15) 3-Z- (1- (4-aminomethylphenylamino) -1-phenylmethylene) - 5- (N- (3-chlorobenzyl) carbamoyl) -2-indolinone

(16) 3-Z- (1- (4-aminomethylphenylamino) -1-phenylmethylene) - 5- (3-methylbutylcarbamoyl) -2-indolinone

(17) 3-Z- (1- (4-aminomethylphenylamino) -1-phenylmethylene) - 5-butylcarbamoyl-2-indolinone

Example] 5.

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

Manufacturing:

Active ingredient and mannitol are dissolved in water. After filling, freeze-drying. The ready-to-use solution is dissolved with water for injections. Be i πpi el 6.

Dry mpu1 le with 35 mg active ingredient per 2 ml

Composition:

Active ingredient 35.0 mg

Mannitol 100.0 mg

Water for injections ad 2.0 ml

Manufacturing:

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

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

Example] T

Tablet with 50 mg Wi stnf

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

Manufacturing:

(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 8

Tablet with 350 mg W ksto f

Composition:

(1) Active ingredient 350.0 mg

(2) milk sugar 136.0 mg

(3) corn starch 80.0 mg

(4) polyvinyl pyrrolidone 30.0 mg

(5) Magnesium stearate 4.0 mg

600.0 mg

Manufacturing:

(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 facets on both sides and partial notch on one side. Tablet diameter: 12 mm.

Example 9

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

Manufacturing:

(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 3 hard gelatin capsules on a capsule filling machine.

At spi ei lü

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

Manufacturing:

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

This powder mixture is filled on a capsule filling machine into hard gelatin capsules Gr6Be 0.

Example 11

Suppositor n 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

Herstel hung:

The polyethylene glycol is melted together with polyethylene sorbitan monostearate. The milled active substance is homogeneously dispersed in the melt at 40 ° C. It gets to 38 ° C cooled and poured into weakly pre-cooled suppository molds.

Claims

claims

1. Substituted indolinones of the general formula

in the

X is an oxygen or sulfur atom,

R- _{L is} a hydrogen atom, a C - ^ - alkoxycarbonyl or C ₂ _ ₄ -alkanoyl group,

R _{2 is} one on the amide nitrogen atom by a

substituted aminocarbonyl or

in which one or both of the alkyl parts present in each case by a carboxy group or from position 2 by a hydroxy, C- _L .- _j alkoxy, amino, C ₁ _ ₃ alkylamino or di (C _1. ₃ - Alkyl) - amino group can be substituted, but in a C - ^ - alkylaminocarbonyl or di (C _x _ ₃ alkyl) aminocarbonyl group at least one alkyl part by a carboxy group or from position 2 by an amino, C ^ -, ₍₃ -Al- kyl C. ₁₎ amino group must be substituted alkylamino or di-

a -5-7 -Cycloal- on the amide with a C ₃ _ ₆ alkyl alkyl-, phenyl, phenyl - alkyl C ₁ _ _3, C _{_5-7} cycloalkyl-C ₁ _ ₃ alkyl- or naphthyl -C - ^ - alkyl group substituted aminocarbonyl or C ₁ . ₇ -alkylaminocarbonyl group, in each of which the phenyl part is mono- or disubstituted by fluorine, chlorine or bromine atoms, by C ₁ _ ₃ -alkyl or C _x - ₃ -alkoxy groups, the substituents tuenten can be the same or different, by three methoxy groups or by a trifluoromethyl, carboxy, C - ^ - alkoxycarbonyl, cyano, aminocarbonyl, C - ^ - alkylaminocarbonyl, di- (C - ^ - alkyl) -aminocarbonyl-, C ₃ _ ₇ -cycloalkylaminocarbonyl-, N- (C _1.3 -alkyl) -C ₃ _ ₇ -cycloalkylaminocarbonyl-, di- (C _3. ₇ -cycloalkyl) -aminocarbonyl or nitro group can be substituted, and the alkyl part of those mentioned above

nyl group can also be substituted by a carboxy group or from position 2 by a hydroxy, C _x _ ₃ alkoxy, amino, C ₁ _ ₃ alkyl amino or di (C ₁ _ ₃ alkyl) amino group can, or

a 3- to 7-membered cycloalkyleneiminocarbonyl group optionally substituted by a C ^ ₃ -alkyl group, a methylene group in a 6- or 7-membered cycloalkyleneimino group in the 4-position being represented by an oxygen or sulfur atom, by a sulfinyl or sulfonyl group or by a optionally by a C 1-4 alkyl, formyl or C ₁ . _3- alkyl-carbonyl-substituted imino group can be replaced,

R _{3 is} a hydrogen atom, a C _x . ₆ -Alkylgruppe or optionally by a fluorine, chlorine or bromine atom, by a C ₁ _ ₃ alkyl, hydroxy, C ₁ _ ₃ alkoxy, C _x _ ₃ alkylsulfenyl, C - ^ - alkylsulfinyl -, C ^ - _. -Alkylsulfonyl-, Phenylsulfenyl-, Phenylsulfinyl-, Phenylsulfonyl-, Amino-, C ₁ _ ₃ -Alkylamino-, Di- (C ^ -Alkyl) -amino-, C ₂ _ ₅ -Alkanoylamino- or N- (C ^ - Alkylamino) -C _2.5 alkanoylamino group substituted phenyl group,

R _{4 is} a C - ^ - alkyl group or a C ₅ - ₇ cycloalkyl group optionally substituted by a C - ^ - alkyl group, in which a methylene group in the 3 or 4 position based on the carbon atom of the R ₃ -C (R ₄ NR _S ) = group can be replaced by an imino group optionally substituted by a C - ^ - alkyl group,

a thiophenyl group optionally substituted by a fluorine, chlorine or bromine atom or by a C ₁ _ ₃ alkyl group, a phenyl or naphthyl group, the

by a fluorine, chlorine, bromine or iodine atom,

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

by a C ₂ . ₃ -alkoxy group, which can be substituted in the 2- or 3-position by a C ₁ _ ₃ -alkylamino, di- (C _x - ₃ -alkyl) -amino or 5- to 7-membered cycloalkyleneimino group, in each case additionally an alkyl part in the above-mentioned alkylamino and dialkylamino groups may be substituted by a phenyl group,

by a trifluoromethyl, amino, C _x . ₃ -Alkylamino-, di- (C _x . ₃ -alkyl) -amino-, C ₂ _ ₅ -alkanoylamino-, N- (C _x . ₃ -alkyl) - C ₂ _ ₅ -alkanoylamino-, C ₁ _ _s -Alkylsulfonylamino-, N- (C ₁ _ ₃ -alkyl) - C - ^ - alkylsulfonylamino-, phenylsulfonylamino-, N- (C ^ -alkyl) - phenylsulfonylamino-, aminosulfonyl-, C ^ -alkylaminosulfonyl- or di- (C _x _ ₃ -alkyl) -aminosulfonyl group, where in each case an alkyl part in the above-mentioned alkylamino and dialkylamino groups may additionally be substituted by a phenyl group,

by a C ₂ . ₄ -alkylamino group which is terminally substituted in the 2-, 3- or 4-position by a di- (C - ^ - alkyl) -amino group and in which the hydrogen amine atom is additionally substituted by a C _2.s -alkanoyl or C ^ - Alkylsulfonyl group can be replaced

by a carbonyl group, which is substituted by a hydroxy, C ₁ _ ₃ -alkoxy, amino, C - ^ - alkylamino or N- (C ^ _j -alkyl) - C _x .. ₃ -alkylamino group, in each case additionally an alkyl part in the above-mentioned groups by a carboxy, C ₁ _ ₃ -alkoxycarbonyl or phenyl group or in the ^' 2- or 3-position by a di- (C - ^ - alkyl) -amino-, pipera- zino-, N- (C _x _ ₃ -alkyl) -piperazino or 5- to 7-membered cycloalkyleneimino group can be substituted,

by a C _x . ₃ alkyl group, which is replaced by an amino, C ₁ . _7- alkylamino-, C ₅ . _7- Cycloalkylamino- or phenyl-C _x _ ₃ alkylamino group, each of which is additionally substituted on the amine nitrogen atom by a C _x _ ₃ alkyl group in which the hydrogen atoms are partially or completely replaced by fluorine atoms, by a C ₅ _ ₇ -Cycloalkyl-, C ₂ _ ₄ alkenyl or C _x _ ₄ alkyl group may be substituted, wherein

the above-mentioned C _x . ₄ -Alkylsubstituent in each case additionally by a cyano, carboxy, C ₁ _ ₃ alkoxycarbonyl, pyridyl, imidazolyl, benzo [1, 3] dioxol or phenyl group, the phenyl group by fluorine, chlorine or bromine atoms, can be mono-, di- or tri-substituted by methyl, methoxy, trifluoromethyl, cyano or nitro group and the substituents can be the same or different, or substituted in the 2-, 3- or 4-position by a hydroxy group can,

by a C ₁ _ ₃ alkyl group which is replaced by a hydroxy, carboxy, thiomorpholino, 1-oxothiomorpholino, 1,1-dioxothiomorpholino, piperazino, N- (C ₁ _ ₃ -alkyl) -piperazino- or N-phenyl-piperazino group, by a 5- to 7-membered cycloalkenyleneimino group or by a 4- to 7-membered cycloalkyleneimino group, the above-mentioned 5- to 7-membered cycloalkyleneimino groups being substituted by one or two C ₁ _ ₃ alkyl groups, by a C ₅ _ ₇ cycloalkyl or phenyl group, by a C - ^ - alkyl, C ₅ . ₇ cycloalkyl, phenyl, carboxy or C ₁ _ ₄ alkoxy-carbonyl group and may be substituted by a Hydroxygruppe- and an adjacent to the nitrogen atom of methylene group may be replaced by a carbonyl group in the above-mentioned Cycloalkyleniminogruppen, by a C ₁ _ ₃ -alkyl group which is substituted by a 5- to 7-membered cycloalkyleneimino group, the abovementioned 5- to 7-membered cycloalkyleneimino groups having 2 adjacent carbon atoms, optionally by fluorine, chlorine or bromine atoms, by Methyl or methoxy groups mono- or disubstituted phenyl group, where the substituents can be the same or different, or an oxazolo, imidazolo, optionally substituted by a fluorine, chlorine, bromine or iodine atom, by a methyl, methoxy or amino group. Thiazolo, pyridino, pyrazino or pyrimidino group is fused, or

by a di- (C ₂ _ ₄ -alkylamino) -C - ^ - alkyl group in which the C ₂ _ ₄ -alkyl parts are each substituted in the 2-, 3- or 4-position by a hydroxy group,

R _{5 represents} a hydrogen atom or a C - ^ - alkyl group, existing carboxy, amino or imino groups can be substituted by residues which can be split off in vivo,

their isomers and their salts.

2. Substituted indolinones of general formula I according to claim 1, in which

X is an oxygen atom,

R _{x is} a hydrogen atom,

R ₂ in position 5 or 6 substituted on the amide with a C- _{^ g} alkyl aminocarbonyl or C ₁ _ ₆ alkyl aminocarbonyl group in which one of the existing alkyl moieties by a carboxy group or from position 2 by an amino, C - _{^ 3} -Alkylamino- or di- (C - ^ - alkyl) amino group may be substituted, but in a C ^ - _j -alkylaminocarbonyl or di- (C -__ ₃ -alkyl) aminocarbonyl group by at least one alkyl part a carboxy or C-_. ₃ -alkoxycarbonyl group or from position 2 must be substituted by an amino, C ₁ _ ₃ -alkylamino or di- (C ₁ _ ₃ -alkyl) - amino group,

one on the amide nitrogen atom by a C ₃ . _6- alkyl-, C ₅ _ ₇ -cycloalkyl-, phenyl-, phenyl-C _x _ ₃ -alkyl, C ₅ _ ₇ -cycloalkyl-C ₁ _ ₃ -alkyl or naphthylmethyl group substituted aminocarbonyl or C ₁ . ₇ -Alkylaminocarbonylgruppe in which the phenyl part by three methoxy groups or by a fluorine, chlorine or bromine atom, by a C ^ alkyl, C - ^ - alkoxy, carboxy, C - ^ - alkoxycarbonyl, cyano or May be nitro group, and the alkyl part of C ₁ . ₆ -Alkylaminocarbonylgruppe additionally by a carboxy group or from position 2 by an amino, Ci- ₃ -alkylamino or di- (C -__ ₃ -alkyl) -amino group, or

a 6-membered cycloalkyleneiminocarbonyl group optionally substituted by a C 1-4 alkyl group, in which a thylene group in the 4-position by an oxygen or sulfur atom or by an optionally by a C _x . _3- alkyl group substituted imino group can be replaced,

R ₃ is a C ^ alkyl group or a group optionally substituted by a fluorine, chlorine or bromine atom, by a C ₁ _ ₃ alkyl, hydroxy or C _{^ j} alkoxy phenyl group,

R _{4 is} a C - ^ - alkyl group or a cyclopentyl or cyclohexyl group which is optionally substituted by a methyl group, where in the cyclopentyl and cyclohexyl group a methylene group in the 3 or 4 position based on the carbon atom of the R ₃ -C (R ₄ NR ₅ ) = Group can be replaced by an imino group optionally substituted by a methyl group,

a phenyl group that

by a fluorine, chlorine, bromine or iodine atom,

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

by a C ₂ _ ₃ alkoxy group which is substituted in the 2- or 3-position by a methylamino, dimethylamino or 5- to 7-membered cycloalkyleneimino group, in each case additionally a methyl group in the above-mentioned amino groups by a phenyl group can be substituted

by a trifluoromethyl, amino, C ₂ , ₅ -alkanoylamino, N- (C - ^ - alkyl) -C ₂ _ ₅ -alkanoylamino-, C ^ -alkylsulfonylamino-, N- (C- _^ - _j -alkyl ) -C - ^ - alkylsulfonylamino-, phenylsulfonylamino-, N- (C - ^ - alkyl) -phenylsulfonylamino- or aminosulfonyl group, each with an additional alkyl part in the above- mentioned alkylamino and dialkylamino groups can be substituted by a phenyl group,

by a C ₂ _ ₄ alkylamino group, amino group terminally substituted in the 2-, 3- or 4-position by a di- (. ₁ C ₃ alkyl) and additionally the amine hydrogen atom by a C ₂ _ ₅ - Alkanoyl or C _x _ ₅ alkylsulfonyl group can be replaced,

by a carbonyl group which is substituted by a hydroxy, C ₁ _ ₃ alkoxy, amino, C ₁ _ ₃ alkylamino or N- (C _x _ ₅ alkyl) - C ₁ _ ₃ alkylamino group, where each an alkyl part of the above-mentioned groups additionally by a carboxy, C _x _ ₃ alkoxycarbonyl or phenyl group or in the 2- or 3-position by a di- [C ₁ _ ₃ alkyl) amino, piperazino, N - (C - ^ - Alkyl) -piperazino or 5- to 7-membered cycloalkyleneimino group may be substituted,

by a C _x _ ₃ alkyl group which is replaced by an amino, C - ^ - alkylamino, C ₅ . _7- Cycloalkylamino- or phenyl-C ₁ _ ₃ -alkylamino group, each of which is additionally substituted on the amine nitrogen atom by a C - ^ - alkyl group in which the hydrogen atoms are partially or completely replaced by fluorine atoms, by a cyclohexyl, C ₂ . ₄ -Alkenyl or C - ^ - alkyl group may be substituted, wherein

the above-mentioned C - ^ - alkyl substituent each additionally by a cyano, carboxy, C ₁ _ ₃ alkoxycarbonyl, pyridyl, imidazolyl, benzo [1, 3] dioxole or phenyl group, the phenyl group being substituted by a fluorine , Chlorine or bromine atom, may be monosubstituted by a methyl, methoxy, cyano, trifluoromethyl or nitro group or may be di- or tri-substituted by fluorine, chlorine or bromine atoms, by methyl or methoxy groups and the substituents may be the same or different, or can be substituted in the 2-, 3- or 4-position by a hydroxy group, by a C _x _ ₃ alkyl group, which is replaced by a hydroxy, carboxy, thiomorpholino, 1-oxothiomorpholino, 1,1-dioxothiomorpholino, piperazino, N- (C - ^ - alkyl) - piperazino or N-phenyl-piperazino group, by a 5- to 7-membered cycloalkenyleneimino group or by a 4- to 7-membered cycloalkyleneimino group, the above-mentioned 5- to 7-membered cycloalkyleneimino groups being substituted by one or two C. ^ Alkyl groups, by a cyclohexyl or phenyl group, by a C ^ alkyl, cyclohexyl, phenyl, carboxy or C ₁ _ ₄ alkoxycarbonyl group and by a hydroxy group and can be substituted and in the above-mentioned cycloalkyleneimino groups methylene group adjacent to the nitrogen atom can be replaced by a carbonyl group,

by a C ₁ _ ₃ -alkyl group which is substituted by a 5- to 7-membered cycloalkyleneimino group, the abovementioned 5- to 7-membered cycloalkyleneimino groups having 2 adjacent carbon atoms, optionally by fluorine, chlorine or bromine atoms, by Methyl or methoxy groups mono- or disubstituted phenyl group, where the substituents can be the same or different, or a pyrazino or thiazole group optionally substituted by an amino group is fused on, or

by a di- (C ₂ _ ₄ alkylamino) -C - ^ - alkyl group in which the C ₂ . ₄ -alkyl parts are each substituted in the 2-, 3- or 4-position by a hydroxyl group,

may be substituted, it being additionally possible for the abovementioned monosubstituted phenyl groups to be substituted by a fluorine, chlorine or bromine atom, by a methyl, methoxy or nitro group,

a pyridyl group optionally substituted by a chlorine or bromine atom or by a methyl group, an oxazolyl, isoxazolyl, imidazolyl or thiazolyl group optionally substituted by a methyl group, to which a phenyl ring can be fused via 2 adjacent carbon atoms, and

R _{5 represents} a hydrogen atom a C - ^ - alkyl group,

their isomers and their salts.

3. Substituted indolinones of general formula I according to claim 1, in which R _x to R ₃ and R _{5 are} as defined above and

R ₄ represents a C- _{^ g} alkyl group or an optionally by a C - ^ - alkyl substituted C ₅ _ ₇ cycloalkyl group, wherein a methylene group in the 3- or 4-position relative to the carbon atom of the R ₃ -C (R ₄ NR ₅ ) = group can be replaced by an imino group optionally substituted by a C - ^ - alkyl group,

a phenyl or naphthyl group, the

by a fluorine, chlorine, bromine or iodine atom,

by a C ₁ _ ₃ -alkoxy-, amino-, C - ^ - alkylamino-, di- (C - ^ - alkyl) -amino-, C ₂ , ₅ -alkanoylamino-, N- (C _1. ₃ -Alkylamino) -C ₂ . ₅ -al- kanoylamino-, C - ^ - alkylsulfonylamino-, N- (C _x . ₃ alkyl) - C _x . _5- alkylsulfonylamino, phenylsulfonylamino or N- (C _1, _3- alkyl) -phenylsulfonylamino group,

by a C ₂ _ ₄ alkylamino group which is terminated in the 2-, 3- or 4-position by a di-

-amino group and in which the hydrogen amine atom is additionally substituted by a C ₂ . ₅ -alkanoyl or C - ^ - alkylsulfonyl group can be replaced, by a C - ^ - alkyl group, which by a C ..., - alkylamino, di- (C .. ₅ alkyl) amino, thiomorpholino, 1-oxothiomorpholino-, 1, 1 -Dioxo-thiomorpholino-, piperazino-, N- (C - ^ - alkyl) - piperazino-, N-phenyl -piperazino-, C ₅ . _7- Cycloalkenylenimino- or C ₄ _ ₇ -cycloalkyleneimino group can be substituted, wherein the above-mentioned C ₅ .-- cycloalkyleneimino groups by one or two C ^ alkyl groups, by a C ₅ _ ₇ cycloalkyl or phenyl group, by one C ₁ . ₃ alkyl, C ₅ _ ₇ cycloalkyl, phenyl, carboxy or C _x . ₄ -alkoxy-carbonyl group and can be substituted by a hydroxy group, or

by a di- -C (C ₂ H ₄ alkylamino.) - ^ - alkyl group in which the C substituted -Alkylteile _2.4 respectively in the 2-, 3- or 4-position by a hydroxy group,

can be substituted

means, their isomers and their salts.

4. Substituted indolinones of general formula I according to claim 1, in which

X is an oxygen atom,

R- _{L is} a hydrogen atom,

R ₂ in position 5 or 6 is an aminocarbonyl or C - ^ - alkylamino carbonyl group substituted on the amide nitrogen atom by a C 1-4 alkyl group, in which one of the existing alkyl parts by a carboxy or methoxycarbonyl group or from position 2 by a di- (C _x . ₃ alkyl) amino group can be substituted, but in a C - ^ - alkylaminocarbonyl or di (C _1, ₃ alkyl) aminocarbonyl group at least one alkyl part by a carboxy or methoxycarbonyl group or from position 2 by one Di- (C ₁ _ ₃ -alkyl) -amino group must be substituted, an aminocarbonyl or C _x substituted on the amide nitrogen atom by a C ₃ _ ₅ alkyl, cyclohexyl, phenyl, phenyl - C ₁ _ ₂ alkyl or cyclohexyl -C ₁ _ ₂ alkyl group. ₄ -Alkylaminocarbonylgruppe, in each of which the phenyl part by three methoxy groups or by a fluorine, chlorine or bromine atom, by a C ₁ _ ₃ alkyl, C _x.3 alkoxy, carboxy, C ₁ _ ₃ alkoxycarbonyl -, Cyano- or nitro group and the alkyl part of the C._ ₄ -alkylaminocarbonyl group may additionally be substituted by a carboxy or methoxycarbonyl group or from position 2 onwards by a di- (C _x _ ₃ -alkyl) -amino group, or

a 6-membered cycloalkyleneiminocarbonyl group optionally substituted by a C 1-4 alkyl group, in which a methylene group in the 4 position can be replaced by an oxygen atom,

R _{3 is} a C - ^ - alkyl group or a phenyl group optionally substituted by a fluorine, chlorine or bromine atom, by a C - ^ - alkyl or C - ^ - alkoxy group,

R _{4 is} a C - ^ - alkyl group or a cyclopentyl or cyclohexyl group optionally substituted by a methyl group, wherein in the cyclohexyl group a methylene group in the 4 position based on the carbon atom of the R ₃ -C (R ₄ NR _S ) = group by an optionally can be replaced by a methyl group-substituted imino group,

a phenyl group that

by a fluorine, chlorine, bromine or iodine atom,

by a methyl or ethyl group, each by a C _x _ ₃ alkylamino, di (C - ^ - alkyl) amino, diethanolamino, thiomorpholino, 1-oxothiomorpholino, 1, 1-dioxo -thiomorpholino, N-phenylpiperazino, 5- to 6-membered cycloalkenimino or 5- to 7-membered cycloalkyleneimino group may be substituted, the above-mentioned 5 to 7-membered cycloalkyleneimino groups can be substituted by one or two methyl groups, by a cyclohexyl or phenyl group, by a methyl, cyclohexyl or phenyl group and by a hydroxy group, or

by a C ₂ . ₄ -Alkylamino group which is terminally substituted in the 2-, 3- or 4-position by a di- (C ^ -alkyl) -amino group and in which the hydrogen amine atom is additionally replaced by a C _2.5 -alkanoyl or C - ^ - alkylsulfonyl group can be,

may be substituted, in addition the monosubstituted phenyl groups mentioned above may be substituted by a fluorine, chlorine or bromine atom, by a methyl, methoxy or nitro group, and

R _{5 represents} a hydrogen atom or a C ₁ _ ₄ alkyl group,

their isomers and their salts.

5. Substituted indolinones of general formula I according to claim 1, in which

X is an oxygen atom,

R _{x is} a hydrogen atom,

R ₂ in position 5 or 6 aminocarbonyl group substituted at the amide nitrogen atom by a C ^ alkyl group, aminocarbonyl or C ₁ _ ₄ alkyl, in which one of the existing alkyl moieties by a carboxy or methoxycarbonyl group or from position 2 by a di- ( C ₁ _ ₃ alkyl) amino group can be substituted, but in a C ₁ _ ₃ alkylaminocarbonyl or di (C _1.3 alkyl) aminocarbonyl group at least one alkyl part by a carboxy or methoxycarbonyl group or from position 2 by one Di (C 1-4 alkyl) amino group must be substituted,

one on the amide nitrogen atom by a C ₃ . _5- alkyl-, cyclohexyl-, phenyl-, phenyl-C _1.2 -alkyl- or cyclohexyl-C- _^ -.- alkyl group substituted aminocarbonyl or C - ^ - alkylaminocarbonyl group, in each of which the phenyl part by a fluorine, chlorine or bromine atom, by a C - ^ - alkyl, C ^ alkoxy, carboxy, C- _L .- _j alkoxycarbonyl, cyano or nitro group and the alkyl part of the C - ^ - alkylaminocarbonyl group additionally by a carboxy or Methoxycarbonylgruppe or from position 2 can be substituted by a di- (C - ^ - alkyl) amino group, or

a 6-membered cycloalkyleneiminocarbonyl group optionally substituted by a C 1-4 alkyl group, in which a methylene group in the 4-position can be replaced by an oxygen atom,

R _{3 is} a C _x _ ₅ alkyl group or a phenyl group optionally substituted by a fluorine, chlorine or bromine atom, by a C ₁ _ ₃ alkyl or C - ^ - alkoxy group, R _{4 is} a cyclohexyl group which is optionally substituted by a methyl group, in which a methylene group in the 4-position relative to the carbon atom of the R ₃ -C (R ₄ NR ₅ ) = group is replaced by an imino group which is optionally substituted by a methyl group,

a phenyl group that

by a fluorine, chlorine, bromine or iodine atom,

by a methyl or ethyl group, each by an amino, C ₁ _ ₃ -alkylamino, di- (C ₁ _ ₃ -alkyl) -amino-, diethanolamino-, N- (phenyl-C - ^ - alkyl) -C - ^ - alkylamino-, thiomorpholino-, 1-oxo-thiomorpholino-, 1, 1-dioxo-thiomorpholino-, N-phenyl-piperazino-, 5 to 6-membered cycloalkenylene imino or 5 to 7-membered cycloalkyleneimino group may be substituted, wherein the above-mentioned 5 to 7-membered cycloalkyleneimino groups may be substituted by one or two methyl groups, by a cyclohexyl or phenyl group, by a methyl, cyclohexyl or phenyl group and by a hydroxy group, or

by a C ₂ _ ₄ -alkylamino group which is terminally substituted in the 2-, 3- or 4-position by a di- (C ^ -, - alkyl) -amino group and in which the hydrogen amine atom is additionally substituted by a C ₂ _ ₅ - Alkanoyl or C - ^ - alkylsulfonyl group may be replaced, may be substituted,

and R _{5 represents} a hydrogen atom,

their isomers and their salts.

6. Substituted indolinones of general formula I according to claim 1, in which

X is an oxygen atom, R _{x is} a hydrogen atom,

R ₂ in position 5 or 6 is an aminocarbonyl or C _x _ ₄ alkyl aminocarbonyl group substituted on the amide nitrogen atom by a C _1.4 alkyl group, in which one of the alkyl parts present is represented by a methoxycarbonyl group or from position 2 by a di (Ci ₃ -Alkyl) -amino group can be substituted, but in a C _x _ ₃ -alkylaminocarbonyl or di- (C ₁ _ ₃ -alkyl) -aminocarbonyl group at least one alkyl part by a methoxycarbonyl group or from position 2 by a di- (C ^ -Alkyl) -amino group must be substituted,

an amine nitrogen atom substituted by a C ₃ _ ₅ -alkyl, cyclohexyl, phenyl, phenyl -C- _^ -.- alkyl or cyclohexyl-C ₁ _ ₂ -alkyl group, aminocarbonyl or C - ^ - alkylaminocarbonyl group, in which in each case the phenyl part can be substituted by a fluorine, chlorine or bromine atom, by a methyl, methoxy, C _x _ ₃ alkoxycarbonyl, cyano or nitro group, or

a piperidinocarbonyl or morpholinocarbonyl group,

R _{3 is} a phenyl group,

R _{4 is} a phenyl group through

a methyl or ethyl group, each represented by a Ci -, - lkylamino-, Di- (C _x . ₃ -alkyl) -amino-, Diethanolamino-, N- (phenyl-Ci.-.- alkyl) -C _x _ ₃ -alkylamino or piperidino group may be substituted, or

by a C ₂ . ₄ alkylamino group which is terminally substituted in the 2-, 3- or 4-position by a di- (C _x _ ₃ -alkyl) amino group and in which the hydrogen amine atom is additionally substituted by a C ₂ . ₅ -alkanoyl or C - ^ - alkylsulfonyl group is substituted, is substituted,

and R _{5 represents} a hydrogen atom, their isomers and their salts.

7. The following compounds of general formula I according to claim 1:

(b) 3-Z- [1- (4- (N-Benzyl-N-methylaminomethyl) phenylamino) -1-phenylmethylene] -5- (N-methyl-N-phenylcarbamoyl) -2 -indolinone,

(g) 3-Z- (1- (4-dimethylaminomethylphenylamino) -1-phenylmethylene) -5- (cyclohexylmethyl) carbamoyl-2-indolinone,

(h) 3-Z- (1- (4- (N-methylsulfonyl-N- (2-dimethylaminoethyl) amino) phenylamino) -1-phenylmethylene) -5-butylcarbamoyl) -2-indolinone,

(i) 3-Z- (1- (4- (N-propionyl-N- (2-dimethylaminoethyl) amino) phenylamino) -1-phenylmethylene) -5-butyl-carbamoyl) -2- indoline, (j) 3-Z- (1- (4-dimethylaminomethyl-phenylamino) -1-phenylmethylene) -5- (3-chloro-benzyl-carbamoyl) -2-indolinone and

their isomers and their salts.

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

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

10. Use of a compound according to at least one of claims 1 to 7 or a salt according to claim 8 for the manufacture of a medicament which is suitable for the treatment of excessive or abnormal cell proliferation.

11. A method for producing a medicament according to claim 9, characterized in that a compound according to at least one of claims 1 to 7 or a salt according to claim 8 is incorporated in one or more inert carriers and / or diluents in a non-chemical way.

12. A process for the preparation of the compounds according to claims 1 to 8, characterized in that

a. a compound of the general formula

in the

X, R ₂ and R _{3 are} as defined in claims 1 to 7 and

R _{6 is} a hydrogen atom or a protective group for the nitrogen atom of the lactam group, where R _{6 can} also represent a bond to a solid phase which may be formed via a spacer, and

Z _{x represents} a halogen atom, a hydroxyl, alkoxy or aralkoxy group,

with an amine of the general formula

in the

R ₄ and R _{5 are} as defined in claims 1 to 7, implemented and, if necessary, subsequently used

Protecting group for the nitrogen atom of the lactam group or a compound thus obtained is split off from a solid phase or

b. for the preparation of a compound of the general formula I which R _{2 represents} one of the aminocarbonyl groups mentioned at the outset in claims 1 to 7, a compound of the general formula

in the

R _x and R ₃ to R _{5 are defined} as mentioned in claims 1 to 7, or their reactive derivatives with an amine of the general formula

H - (R ₇ NR ₈ ) (V),

in the

R _{7 is} a hydrogen atom or a C ₁ _ ₆ alkyl group and R _{8 is} a C _x _ _s alkyl group, at least one of the C ^ alkyl groups contained in the radicals R ₇ and R ₈ being represented by a carboxy group or from position 2 by a hydroxy -, C ^ -alkoxy-, amino-, C ₁ . _3- alkylamino or di- (C - ^ - alkyl) -amino group can be substituted with the proviso that at least one C ₁ , ₃ -alkyl group present in the above-mentioned groups is substituted by a carboxy group or from position 2 by an amino , C ^ - _. -Alkylamino- or di- (C _x . ₃ alkyl) amino group is substituted, or

R _{7 is} a C ₃ . ₆ -alkyl-, C ₅ _ ₇ -cycloalkyl-, phenyl-, phenyl-C ₁ -alkyl-, C ₅ . _7- cycloalkyl-C ₁ . _3- alkyl- or naphthyl-C-_. ₃ -alkyl group, in each of which the phenyl part by fluorine, chlorine or bromine atoms, by C - ^ - alkyl or C - ^ - alkoxy groups mono- or di-substituted, where the substituents may be the same or different, by three methoxy groups or by a trifluoromethyl, carboxy, C ₁ . ₃ -alkoxycarbonyl-, cyano-, aminocarbonyl-, Ci- ₃ -alkylaminocarbonyl-, di- (C - ^ - alkyl) -aminocarbonyl-, C ₃ _ ₇ -cycloalkylaminocarbonyl-, N- (C -__ ₃ -alkyl) - C ₃ _ ₇ -cycloalkyl-aminocarbonyl, di- (C ₃ _ _7- cycloalkyl) aminocarbonyl or nitro group, and R _{8 may be} a hydrogen atom or a C ^ -, - alkyl group, the C - ^ - alkyl part the above mentioned C _x _ ₇ alkyl group additionally by a carboxy group or from position 2 by a hydroxy, C ₁ . ₃ -Alkoxy-, amino-, C _x - ₃ -alkylamino- or di- (C ₁ , ₃ -alkyl) -amino group may be substituted, or

R ₇ and R ₈ together with the intermediate nitrogen atom represent a 3- to 7-membered cycloalkyleneimocarbonyl group which is optionally substituted by a C _ ₃ -alkyl group, a methylene group in a 6 or 7-membered cycloalkyleneimino group in the 4-position by an oxygen or Sulfur atom, can be replaced by a sulfinyl or sulfonyl group or by an imino group optionally substituted by a C ₁ _ ₃ alkyl, formyl or C ₁ _ ₃ alkyl carbonyl group, mean, is amidated 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 compound by acylation 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 nitro group is converted into a corresponding amino compound by reduction or if necessary, a protective residue used during the reactions to protect reactive groups is split off or

a compound of the general formula I thus obtained is 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.