DE10054019A1 - New substituted indolinones, their production and their use as medicines - Google Patents

Abstract

The invention relates to substituted indolinones of the general formula I DOLLAR F1, their isomers, their salts, in particular their physiologically tolerable salts, in which R¶1¶, R¶2¶, R¶3¶, R¶4¶, R¶5¶, R ¶6¶ and X have the meaning given in claim 1, and methods for their preparation and their use. The new compounds are valuable inhibitors of cell proliferation, especially that of tumor cells, and inhibitors of protein kinases.

Description

The present invention relates to new substituted indolinones 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 _{1 represents} a hydrogen atom or a prodrug residue, have valuable pharmacological properties, in particular an inhibitory effect on the proliferation of cultured human tumor cells, but also on the proliferation of other cells, in particular those of endothelial cells, e.g. , B. in angiogenesis, on various kinases, especially on receptor tyrosine kinases (such as VEGFR2, EGFR, IGF1R,) not receptor tyrosine kinases (such as c-src), and serine / threonine kinases (such as cyclin-dependent kinases), and the other compounds of the general formula I above, in which R ₁ does not represent a hydrogen atom or a prodrug residue, are valuable intermediates for the preparation of the compounds mentioned above.

The present invention thus relates to the above compounds of the general formula I, wherein
X represents an oxygen or sulfur atom,
R _{1 represents} a hydrogen atom, a C _1-4 alkoxycarbonyl or C _2-4 alkanoyl group,
R ₂ for a C _1-6 alkyl group optionally substituted by one or more halogen atoms or a phenyl group or a C _2-6 alkenyl group optionally substituted by a phenyl group, in which the phenyl part in each case by a fluorine, chlorine, bromine or Iodine atom, which may be substituted by a C _1-3 alkyl or C _1-3 alkoxy group,
represents a phenyl group which can be mono- or disubstituted by fluorine, chlorine, bromine or iodine atoms, by C _1-3 -alkyl or C _1-3 -alkoxy groups, where the substituents can be identical or different,
represents a phenyl group substituted by a trifluoromethyl, carboxy, C _1-3 alkoxycarbonyl, aminocarbonyl, cyano, aminomethyl, nitro or amino group,
represents a C _4-6 alkyl, C _3-7 cycloalkyl, trimethylphenyl or naphthyl group,
represents a 5-membered heteroaromatic group which is optionally substituted by a C _1-3 alkyl group and which is in the heteroaromatic part
an imino group optionally substituted by a C _1-3 alkyl group, an oxygen or sulfur atom,
an imino group optionally substituted by a C _1-3 alkyl group and an oxygen, sulfur or nitrogen atom,
an imino group optionally substituted by a C _1-3 alkyl group and two nitrogen atoms, or
contains an oxygen or sulfur atom and two nitrogen atoms and to which a phenyl ring can be fused via two adjacent carbon atoms,
or represents a 6-membered heteroaromatic group which is optionally substituted by a C _1-3 alkyl group and which contains one or two heteroatoms in the heteroaromatic part and to which a phenyl ring can be fused via two adjacent carbon atoms,
R ₃ for a hydrogen atom or a C _1-6 alkyl group, for one optionally through a fluorine, chlorine or bromine atom, through a C _1-3 alkyl, hydroxy, C _1-3 alkoxy, C _{1 -3} -Alkylsulfenyl-, C _1-3 alkylsulphinyl, C _1-3 - kylamino- alkylsulfonyl, Phenylsulfenyl-, phenylsulfinyl, phenylsulfonyl, nitro, amino, C _1-3 -alkyl, di- (C _1-3- alkyl) -amino-, C _2-5 -alkanoylamino- or N- (C _1-3 -alkylamino) -C _2-5 -alkanoylamino group substituted phenyl group,
R _{4 represents} a phenyl or naphthyl group optionally substituted by R ₇ , which may additionally be substituted by a chlorine or bromine atom or a nitro group, represents a 5-membered heteroaromatic group which has an imino group, an oxygen or sulfur atom or one Imino group, contains an oxygen or sulfur atom and one or two nitrogen atoms, or
for 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 in which the abovementioned 5 - and 6-membered heteroaromatic groups can be fused to a phenyl ring via 2 adjacent carbon atoms, or
R ₅ and R ₆ each independently represent hydrogen atoms or C _1-3 alkyl groups, and
R _{7 represents} a fluorine, chlorine, bromine or iodine atom or a cyano group, represents a methoxy group or a C _2-3 alkoxy group which is in the 2- or 3-position by an amino, C _1-3 - Alkylamino-, di- (C _1-3 -alkyl) -amino- or 5- to 7-membered cycloalkyleneimino group can be substituted, wherein in each case an alkyl part in the above-mentioned alkylamino and dialkylamino groups can be substituted by a phenyl group,
for a trifluoromethyl, nitro, amino, C _1-3 alkylamino, di (C _1-3 alkyl) amino, C _2-5 alkanoylamino, N- (C _1-3 alkyl ) -C _2-5 -alkanoylamino-, C _1-5 -alkylsulfonylamino-, N- (C _1-3 -alkyl) -C _1-5 -alkylsulfonylamino-, phenylsulfonylamino-, N- (C _1-3 -alkyl) - phenylsulfonylamino, aminosulfonyl, C _1-3 alkylaminosulfonyl or di (C _1-3 alkyl) aminosulfonyl group, each additionally having an alkyl part in the aforementioned alkylamino and dialkylamino groups by a carboxy, C _{1- 3} -alkoxycarbonyl, aminocarbonyl, C _1-3 alkylaminocarbonyl, di (C _1-3 alkyl) aminocarbonyl, 2-dimethylaminoethylaminocarbonyl or N-methyl- (2-dimethylaminoethyl) aminocarbonyl group and can be substituted each additionally the alkyl part of the abovementioned alkanoylamino or alkysulfonylamino groups can be substituted by a phenyl, amino, C _1-3 alkylamino, di (C _1-3 alkyl) amino or a 4 to 7-membered cycloalkyleneimino group .
stands for a C _2-4 alkylamino group which is terminal in the 2-, 3- or 4-position by an amino, C _1-3 alkylamino, di (C _1-3 alkyl) amino, benzylamino -, N- (C _1-3 - Alkyl) -benzylamino-, C _2-5 -alkanoylamino or N- (C _1-3 -alkyl) -C _2-5 - alkanoylamino group and in which the amine hydrogen atom is additionally substituted a C _2-5 alkanoyl, benzoyl, C _1-3 alkylsulfonyl or phenylsulfonyl group can be replaced, the last-mentioned C _2-5 alkanoyl or C _1-5 alkylsulfonyl groups in the alkyl part being substituted by a phenyl group can represent a carbonyl group which is substituted by a hydroxy, C _1-3 alkoxy, amino, C _1-3 alkylamino, N- (C _1-5 alkyl) -C _1-3 alkylamino or C _5-7 - cycloalkyleneimino group is substituted,
represents a C _1-3 alkyl group which can be substituted by an amino, C _1-5 alkylamino, C _5-7 cycloalkylamino or phenylC _1-3 alkylamino group, each of which is additionally on the amine nitrogen atom a C _1-4 alkyl, C _5-7 cycloalkyl or C _2-4 alkenyl or C _1-4 alkyl group may be substituted, where
the aforementioned C _1-4 alkyl substituent each additionally by a cyano, carboxy, C _1-3 alkoxycarbonyl, C _2-4 alkanoyl, pyridyl, imidazolyl, benzo [1,3] dioxole or Phenyl group, where the phenyl group can be mono-, di- or tri-substituted by fluorine, chlorine or bromine atoms, by methyl, methoxy, trifluoromethyl, cyano or nitro groups and the substituents can be identical or different, or in 2- , 3- or 4-position can be substituted by a hydroxy group,
represents a C _1-3 alkyl group which is substituted by a hydroxy, carboxy, morpholino, thiomorpholino, 1-oxothiomorpholino, 1,1-dioxothiomorpholino, piperazino, N- (C _{1- 3-} alkyl) -piperazino or N-benzyl-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 which may be terminally substituted by an amino or C _2-4 alkanoylamino group, may be substituted by a C _5-7 cycloalkyl or phenyl group and by a hydroxy group and one in the above-mentioned cycloalkyleneimino groups methylene group adjacent to the nitrogen atom can be replaced by a carbonyl group,
represents a C _1-3 alkyl group which is substituted by a 5- to 7-membered cycloalkyleneimino group, where the above-mentioned 5- to 7-membered cycloalkyleneimino groups have 2 adjacent carbon atoms, optionally by fluorine, chlorine or bromine atoms, phenyl group mono- or disubstituted by methyl or methoxy groups, where the substituents may be the same or different, or an oxazolo or 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, whereby the above-mentioned monosubstituted phenyl groups can additionally be substituted by a fluorine, chlorine or bromine atom, by a methyl, methoxy or nitro group, or
represents an imidazolyl or 1H-C _1-3 alkylimidazolyl group.

If R _{1 represents} a hydrogen atom, the present invention also includes the tautomeric compounds of the formula I '

The invention furthermore relates to those compounds of the formula I in which R _{1 represents} a prodrug residue which can be removed.

The invention further relates to the pharmacologically active compounds medicines containing them, their use and processes for their manufacture.

Preferred compounds of the formula I are those in which the sulfonylamino radical of the formula R ₂ -SO ₂ NR ₆ - is linked to the 5-position of the indolinone group.

Preference is furthermore given to compounds of the formula I in which
R ₃ for an optionally by a fluorine, chlorine or bromine atom, by a C _1-3 alkyl, hydroxy, C _1-3 alkoxy, C _1-3 alkylsulfenyl, C _1-3 alkylsulfinyl -, C _1-3 alkylsulfonyl, phenylsulfenyl, phenylsulfinyl, phenylsulfonyl, nitro, amino, C _1-3 alkylamino, di (C _1-3 alkyl) amino, C _{2- 5} -alkanoylamino or N- (C _1-3 -alkylamino) -C _2-5 -alkanoylamino group substituted phenyl group, in particular for a possibly by a fluorine, chlorine, bromine or iodine atom, by a C _1-3 alkyl -, C _1-3 alkoxy, nitro or amino group substituted phenyl group.

In a further preferred embodiment, R _{2 represents} a C _1-4 alkyl group optionally substituted by one or more halogen atoms or a phenyl group, a C _3-5 cycloalkyl group or a C _2-4 alkenyl group optionally substituted by a phenyl group, in which the phenyl moiety can in each case be substituted by a fluorine, chlorine, bromine or iodine atom, by a C _1-3 alkyl or C _1-3 alkoxy group.

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

In addition to the alkoxycarbonyl and alkanoyl groups already mentioned above, there are residues which can be split off in vivo, such as an acyl group such as the benzoyl, pyridinoyl, pentanoyl or hexanoyl group, an allyloxycarbonyl group, a C _1-16 alkoxycarbonyl group such as the tert.-butyloxycarbonyl group. , Pentlyoxycarbonyl, hexyloxy carbonyl, octyloxycarbonyl, nonyloxycarbonyl, decyloxycarbonyl, undecyloxycarbonyl, dodecyloxycarbonyl or hexadecyloxycarbonyl group, a phenyl-C _1-6 -alkoxycarbonyl group such as the benzyloxycarbonyl, phenylethoxycarbonyl or _1-3- carbonyl group, a phenyl propyl group Alkylsulfonyl-C _2-4 alkoxycarbonyl, C _1-3 alkoxy-C _2-4 alkoxy-C _2-4 alkoxycarbonyl or R _c CO-O- (R _d CR _e ) -O-CO group , in the
R _{c is} a C _1-8 alkyl, C _5-7 cycloalkyl, phenyl or phenyl C _1-3 alkyl group,
R _{e is} a hydrogen atom, a C _1-3 alkyl, C _5-7 cycloalkyl or phenyl group and
R _{d is} a hydrogen atom or a C _1-3 alkyl group or an R _f CO-O- (R _g CR _h ) -O radical,
wherein
R _{f is} a C _1-8 alkyl, C _5-7 cycloalkyl, phenyl or phenyl C _1-3 alkyl group,
R _{g is} a hydrogen atom, a C _1-3 alkyl, C _5-7 cycloalkyl or phenyl group and
R _{h is} a hydrogen atom or a C _1-3 alkyl group
represent
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 the above general formula I are those in which
X represents an oxygen atom,
R _{1 represents} a hydrogen atom,
R _{2 represents} a C _1-3 alkyl group optionally substituted by one or more fluorine atoms or a phenyl group or a C _2-4 alkenyl group optionally substituted by a phenyl group,
represents a phenyl group substituted by fluorine, chlorine, bromine or iodine atoms, by C _1-3 - alkoxy mono- _1-3 alkyl or C or may be disubstituted, the substituents can be identical or different,
represents a phenyl group substituted by a trifluoromethyl, carboxy, C _1-3 alkoxycarbonyl, aminocarbonyl, cyano, aminomethyl, nitro or amino group,
represents a C _4-6 alkyl, C _3-7 cycloalkyl, trimethylphenyl or naphthyl group, or
represents a pyridinyl, quinolyl, isoquinolyl, oxazolyl, isoxazolyl, imidazolyl or 1- (C _1-3 alkyl) imidazolyl group which is optionally substituted by a C _1-3 alkyl group,
R _{3 represents} a hydrogen atom or a C _1-4 alkyl group, or
represents a phenyl group optionally substituted by a fluorine, chlorine, bromine or iodine atom, by a C _1-3 alkyl, C _1-3 alkoxy, nitro or amino group,
R _{4 represents} a phenyl group which may be substituted by R ₇ and which may additionally be substituted by a chlorine or nitro group,
R ₅ and R ₆ each represent a hydrogen atom, and
R _{7 represents} a fluorine, chlorine, bromine or iodine atom,
for a methoxy, nitro, cyano, carboxy, C _1-3 alkoxycarbonyl, aminocarbonyl, C _1-3 alkylaminocarbonyl, di (C _1-3 alkyl) aminocarbonyl, phenyl-C _1-3 - alkylaminocarbonyl, N- (phenyl-C _1-3 -alkyl) -C _1-3 -alkylaminocarbonyl or 5- to 7-membered cycloalkyleneimnocarbonyl group,
for a C _1-3 alkyl group which is substituted by a carboxy, C _1-3 alkoxycarbonyl, aminocarbonyl, C _1-3 alkylaminocarbonyl, di (C _1-3 alkyl) aminocarbonyl, phenyl C _1-3 -alkylaminocarbonyl-, N- (phenyl-C _1-3 -alkyl) -C _1-3 -alkylaminocarbonyl-, 5- to 7-membered cycoalkyleniminocarbonyl-, amino-, C _1-3 -alkylamino-, di - (C _1-3 alkyl) - amino, phenyl-C _1-3 alkylamino, N- (phenyl-C _1-3 alkyl) -C _1-3 alkylamino or 5- to 7-membered Cycoalkylenimino group stands,
wherein the 5- to 7-membered cycoalkyleneimino parts mentioned above can be substituted by one or two C _1-3 alkyl groups which can be terminally substituted by an amino or C _2-4 alkanoylamino group, and simultaneously in the above-mentioned 5- to 7-membered cycoalkyleneimino parts a methylene group in the 2-position can be replaced by a carbonyl group or in the above-mentioned 6- and 7-membered cycoalkyleneimino parts a methylene group in the 4-position can be replaced by an oxygen atom, by an imino, N- (C _{1- 3} -alkyl) -imino-, N- (phenyl-C _1-3 -alkyl) - imino or N- (C _1-5 -alkoxycarbonyl) -imino group can be replaced,
for an amino, C _1-3 alkylamino, phenylC _1-3 alkylamino, C _1-5 alkanoylamino, phenylC _1-4 alkanoylamino, C _1-5 alkoxycarbonylamino, phenyl -C _1-3 - alkoxycarbonylamino-, C _1-5 -alkylsulfonylamino-, phenyl-C _1-3 -alkylsulfonylamino- or phenylsulfonylamino group, in which the hydrogen atom of the amino group can be replaced by a C _1-3 -alkyl group, the C _1-3 alkyl part by a carboxy, C _1-3 alkoxycarbonyl, aminocarbonyl, C _1-3 alkylaminocarbonyl, di (C _1-3 alkyl) aminocarbonyl, phenyl C _1-3 - alkylaminocarbonyl, N- (phenyl-C _1-3 -alkyl) -C _1-3 -alkylaminocarbonyl-, 2-dimethylaminoethylaminocarbonyl-, N-methyl- (2-dimethylaminoethyl) - aminocarbonyl or C _4-6- cycoalkyleneimnocarbonyl group or from position 2 also by amino-, C _1-3 -alkylamino, di- (C _1-3 -alkyl) -amino-, phenyl-C _1-3 -alkylamino-, N- (phenyl-C _1-3 - alkyl) -C _1-3 -alkylamino-, C _2-5 -alkanoylamino-, N- (C _1-3 -alkyl) -C _2-5 - alkanoylamino-, C _1-5 -alkoxycarbonylamino- or N- (C _1-5 alkoxycarbonyl) C _1-3 alkylamino group can be substituted,
represents an imidazlyl or 1-C _1-3 alkylimidazolyl group.

Particularly preferred compounds of the general formula I are those in which
X is an oxygen atom,
R _{1 is} a hydrogen atom,
R _{2 is} a C _1-3 alkyl group optionally substituted by a phenyl group, a C _1-3 perfluoroalkyl group or a phenylvinyl group,
a phenyl group which can be substituted by a fluorine, chlorine, bromine or iodine atom, by a C _1-3 alkyl, C _1-3 alkoxy, nitro, amino, cyano or aminomethyl group,
a C _4-6 alkyl, C _3-7 cycloalkyl, trimethylphenyl or naphthyl group, a pyridinyl, quinolyl, isoquinolyl, oxazolyl, isoxazolyl, imidazolyl, optionally substituted by a C _1-3 alkyl group or 1- (C _1-3 alkyl) imidazolyl group,
R _{3 is} a phenyl group optionally substituted by a fluorine, chlorine, bromine or iodine atom, by a C _1-3 alkyl, C _1-3 alkoxy, nitro or amino group,
R _{4 is} a phenyl group which may be substituted by R ₇ and additionally by a chlorine atom or a nitro group, where
R _{7 is} a fluorine, chlorine, bromine or iodine atom, a methoxy, nitro, cyano, carboxy, methoxycarbonyl, aminocarbonyl, methylaminocarbonyl, dimethylaminocarbonyl, benzylaminocarbonyl, N-benzylmethylaminocarbonyl, pyrrolidinocarbonyl - or piperidinocarbonyl group, a methyl or ethyl group which is formed by a carboxy, methoxycarbonyl, aminocarbonyl, methylaminocarbonyl, dimethylaminocarbonyl, benzylaminocarbonyl, N-benzylmethylaminocarbonyl, pyrrolidinocarbonyl, piperidinocarbonyl, amino, C _{1- 4} -alkylamino-, di-C _1-4 -alkylamino-, benzylamino-, N-benzyl-C _1-4 -alkylamino-, C _2-4 -alkanoylamino-, NC _1-4 -alkyl-C _2-4 - alkanoylamino-, tert-butyloxycarbonylamino-, N-methyl-tert.butyloxycarbonylamino-, pyrrolidino-, piperidino-, 4- (3-aminopropyl) -piperidino-, 4- (3-acetylaminopropyl) -piperidino-, dimethylpiperidino-, 2- Oxopiperidino, piperazino, 4-methyl-piperazino, 4-benzyl piperazino, 4-tert-butoxycarbonyl-piperazino or morpholino group may be substituted, or
an amino, methylamino, ethylamino, C _1-3 alkanoylamino, phenylacetylamino, tert-butoxycarbonylamino, piperidinomethylcarbonylamino, C _1-4 alkylsulfonylamino, phenylmethylsulfonylamino or phenylsulfonylamino group in which the hydrogen atom is the amine group in which the hydrogen atom is can be replaced by a methyl, ethyl or propyl group, the methyl or ethyl part in each case by a carboxy, methoxycarbonyl, aminocarbonyl, methylaminocarbonyl, dimethylaminocarbonyl, 2-dimethylaminoethylaminocarbonyl or N-methyl (2-dimethylaminoethyl ) -aminocarbonyl group or the ethyl part also from position 2 by an amino, methylamino, dimethylamino, benzylalkylamino, N-benzyl methylamino, C _2-3 alkanoylamino, N-methyl-C _2-3 alkanoylamino, tert-butyloxycarbonylamino or N-methyl-tert.butyloxycarbonylamino group can be substituted,
an imidazolyl or 1-methylimidazolyl group,
R ₅ and R ₆ each represent a hydrogen atom,
mean; as well as their isomers and their salts.

Compounds of the formula I in which R _{4 is} a phenyl group substituted in the 3- or 4-position, in particular in the 4-position by R ₇ , are particularly preferred.

According to the invention, the new compounds are obtained, for example, as follows in the Principle of procedures known from the literature:

a. Implementation of a compound of the general formula

in the
X, R ₂ , R ₃ and R ₆ are defined as mentioned at the beginning and
R _{8 has} one of the meanings given for R ₁ or a protective group for the nitrogen atom of the lactam group, where R _{8 can} also represent a bond to a solid phase which may be formed via a spacer, and
Z _{1 is} a halogen atom, a hydroxy, alkoxy or aralkoxy group, e.g. B. a chlorine or bromine atom, a methoxy, ethoxy or benzyloxy group,
with an amine of the general formula

by doing
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 Acetyl, benzoyl, ethoxycarbonyl, tert.butyloxycarbonyl or benzyloxycarbonyl group and as a solid phase, a resin such as a 4- (2 ', 4'-dimethoxyphenylaminomethyl) phenoxy resin, where the binding is advantageously carried out via the amino group, or a p- Benzyloxybenzyl alcohol resin, the bond expediently via an intermediate member takes place as a 2,5-dimethoxy-4-hydroxy-benzyl derivative.  

The reaction is advantageously carried out in a solvent such as dimethylformamide, Toluene, acetonitrile, tetrahydrofuran, dimethyl sulfoxide, dichloromethane or their Mixtures optionally in the presence of an inert base such as triethylamine, N-ethyl diisopropylamine or sodium hydrogen carbonate at temperatures between 20 and 175 ° C carried out, a protective group used abge due to Umamidierung at the same time can be split.

If Z ₁ 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 ₁ 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 conveniently either hydrolytic in an aqueous or alcoholic Solvents, e.g. B. 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 transamidation 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 used Amines at temperatures between 0 and 100 ° C, preferably at temperatures between 10 and 50 ° C.

A solid phase used is preferably split off by means of Trifluoroacetic acid and water at temperatures between 0 and 35 ° C, preferably at Room temperature.  

b. Implementation of a compound of the general formula

in the
R ₁ and R ₃ to R ₆ are defined as mentioned at the outset, with a compound of the general formula

R ₂ -SO ₂ -OH (V),

in the
R ₂ is defined as mentioned at the beginning, or with its reactive derivatives.

The reaction is preferably carried out in a solvent such as dichloromethane, diethyl ether, Tetrahydrofuran, toluene, dioxane, acetonitrile, dimethyl sulfoxide or dimethylformamide optionally with a reactive derivative of a compound of general formula V such as its halide in the presence of an inorganic or a tertiary organic Base, preferably at temperatures between 0 ° C and the boiling point of solvents used, preferably at temperatures between 50 and 100 ° C, carried out.

With an appropriate sulfonic acid, the reaction is preferably carried out in the presence of a dehydrating agents, e.g. B. in the presence of isobutyl chloroformate, Orthocarbonic acid tetraethyl ester, orthoacetic acid trimethyl ester, 2,2-dimethoxypropane, Tetramethoxysilane, thionyl chloride, trimethylchlorosilane, phosphorus trichloride, Phosphorus pentoxide, N, N'-dicyclohexylcarbodiimide, N, N'-dicyclohexylcarbodiimide / N- Hydroxysuccinimide, N, N'-dicyclohexylcarbodiimide / 1-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 expediently at temperatures between 0 and 150 ° C, preferably at Temperatures between 0 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 dialkyl amino 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 general formula I which contains a carboxy group, this can be converted into an appropriate ester or aminocarbonyl compound by 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, or
a compound of general formula I which contains a cyano group, this can be converted into a corresponding aminomethyl compound by reduction.

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

The subsequent reductive alkylation is preferably carried out in a suitable Solvents such as methanol, methanol / water, methanol / water / ammonia, ethanol, Ether, tetrahydrofuran, dioxane or dimethylformamide, optionally with the addition of a Acid such as hydrochloric acid in the presence of catalytically excited hydrogen, e.g. B. from Hydrogen in the presence of Raney nickel, platinum or palladium / coal, or in Presence of a metal hydride such as sodium borohydride, sodium cyanoborohydride, Lithium borohydride or lithium aluminum hydride at temperatures between 0 and 100 ° C, preferably carried out 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 Boiling temperature of the solvent used. This is the acylation with an appropriate acid, preferably in the presence of a dehydrating agent By means of e.g. B. in the presence of isobutyl chloroformate, Orthocarbonic acid tetraethyl ester, orthoacetic acid trimethyl ester, 2,2-dimethoxypropane, tetra methoxysilane, thionyl chloride, trimethylchlorosilane, phosphorus trichloride, phosphorus pentoxide, N, N'-dicyclohexylcarbodiimide, N, N'-dicyclohexylcarbodiimide / N-hydroxysuccinimide, N, N'- Dicyclohexylcarbodiimide / 1-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 expediently at temperatures between 0 and 150 ° C, preferably at tempera tures between 0 and 100 ° C, and the acylation with an appropriate reactive Compound such as its anhydride, ester, imidazolide or halide, optionally in Presence of a tertiary organic base such as triethylamine, N-ethyldiisopropylamine or N-methyl-morpholine at temperatures between 0 and 150 ° C, preferably at Temperatures between 50 and 100 ° C carried out.  

The subsequent esterification or amidation is advantageously carried out by reaction a reactive corresponding carboxylic acid derivative with a corresponding one Alcohol or amine carried out as described above.

The subsequent reduction of a nitro group is preferably carried out hydrogenolytically, e.g. B. 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 of 3 up to 5 bar.

The subsequent reduction of a cyano group is preferably carried out hydrogenolytically, for. B. with hydrogen in the presence of a catalyst such as palladium / carbon or Raney nickel in a solvent such as methanolic ammonia, ethanolic ammonia, Ethyl acetate, dimethylformamide, dimethylformamide / acetone, dichloromethane or Glacial acetic acid, optionally with the addition of an acid such as hydrochloric acid or glacial acetic acid Temperatures between 0 and 50 ° C, but preferably at room temperature, and at a hydrogen pressure of 1 to 7 bar, but preferably of 3 to 5 bar

In the reactions described above, any reactive ones which may be present Groups such as carboxy, amino, alkylamino or imino groups during the reaction be protected by usual protective groups, which after the implementation again be split off.

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 2,4-dimethoxybenzyl group and additionally for the amino group Phthalyl group into consideration.

Any subsequent removal of a protective residue used is carried out for example hydrolytically in an aqueous solvent, e.g. B. 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 removed for example hydrogenolytically, e.g. B. with hydrogen in the presence of a catalyst such as Palladium / carbon in a solvent such as methanol, ethanol, ethyl acetate, Dimethylformamide, dimethylformamide / acetone or glacial acetic acid, optionally with addition 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, if necessary Use of a solvent such as methylene chloride, dioxane, ethyl acetate or ether.

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

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

For example, the compounds of general formula I obtained, which occur in racemates, according to methods known per se (see Allinger N.L. and Eliel E. L. in "Topics in Stereochemistry", Vol. 6, Wiley Interscience, 1971) in their optical Antipodes and compounds of general formula I with at least 2 asymmetrical Carbon atoms per se due to their physico-chemical differences known methods, e.g. B. by chromatography and / or fractional crystallization, in separate their diastereomers, which, if they occur in racemic form, then like can be separated into the enantiomers mentioned above.

The separation of enantiomers is preferably carried out by column separation on chiral phases or by recrystallization from an optically active solvent or by reaction with one, with the racemic compound salts or derivatives such. B. esters or amides forming optically active substance, in particular acids and their activated derivatives or Alcohols, and separating the mixture of diastereomeric salts or Derivatives, e.g. B. due to different solubilities, with the pure diastereomeric salts or derivatives the free antipodes by the action of suitable Funds can be released. Particularly common, optically active acids are e.g. B. 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 as an optically active acyl radical in amides, for example the (+) - or (-) - Mentyloxycarbonylrest into consideration.

Furthermore, the compounds of formula I obtained in their salts, especially for pharmaceutical use in their physiologically compatible salts with inorganic or organic acids. Examples of these are acids 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 into consideration.  

In addition, the new compounds of formula I obtained in this way, if one Contain carboxy group, if desired subsequently in their salts with inorganic or organic bases, especially for pharmaceutical use in their transfer physiologically acceptable salts. Here come as bases, for example Sodium hydroxide, potassium hydroxide, cyclohexylamine, ethanolamine, diethanolamine and Triethanolamine into consideration.

The compounds of general formulas II to V used as starting products are partially known from the literature or obtained by methods known from the literature or are described in the examples. For example, the connections of the general formula IV in German patent application 198 24 922.5 dated June 4, 1998 described.

As already mentioned at the beginning, the new compounds of the general formula I in which R _{1 represents} a hydrogen atom or a prodrug residue have valuable pharmacological properties, in particular an inhibitory effect on the proliferation of cultured human cells, in particular tumor cells, but also on the proliferation of others Cells, especially endothelial cells, e.g. B. in angiogenesis.

For example, the compounds listed in Table 1 are based on their biological Properties checked as follows:

Test 1 Inhibition of the proliferation of cultured human tumor cells

Cells from the Leiomyosarcoma tumor cell line SK-UT-1B or from the non-small cell lung tumor cell line NCI-H460 (obtained from American Type Culture Collection (ATCC)) were supplemented in minimum essential medium with non-essential amino acids (Gibco) cultivated with sodium pyruvate (1 mmol), glutamine (2 mmol) and 10% fetal bovine serum (Gibco) or RPMI1640 medium (Gibco) and 10% fetal bovine serum (Gibco) and harvested in the 10 g growth phase. The SK-UT-1B cells were then introduced into Cytostar® multi-well plates (Amersham) with a density of 4000 cells per well or 3000 cells per well for NCI-H460 cells and incubated overnight in an incubator. Different concentrations of the compounds (dissolved in DMSO; final concentration: 0.1%) 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 Wallac 1450 Microbeta liquid scintillation counter. IC ₅₀ 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.

Test 2 In vivo effects on tumor-bearing nude mice

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 injection or implantation, an 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 compound on tumor growth was determined as percent inhibition compared to a control group treated with placebo.

The following table contains the results of in vitro test 1 (++: <0.01 µM, +: 0.01-1.0 µM):

Because of their biological properties, the new compounds of general formula I, their isomers and their physiologically tolerable salts for Treatment of diseases caused by excessive or abnormal cell proliferation are characterized.

Such diseases include (without claim to completeness): viral infections (e.g. HIV and Kaposi's sarcoma); Inflammation and autoimmune diseases (e.g. colitis, Arthritis, Alzheimer's disease, glomerulonephritis and wound healing); bacterial, fungal and / or parasitic infections; Leukemia, lymphoma and solid tumors; Skin- Diseases (e.g. psoriasis); Bone diseases; cardiovascular diseases (e.g. Restenosis and hypertrophy).

The new compounds can be used for short or long-term treatment of the above Diseases mentioned may also be combined with other "state-of-the-art" Compounds like other cytostatics can be used.

The dosage required to achieve a corresponding effect is expediently with intravenous administration 0.1 to 30 mg / kg, preferably 0.3 to 10 mg / kg, and in the case of oral administration 0.1 to 100 mg / kg, preferably 0.3 to 30 mg / kg, in each case 1 to 4 × Every day. For this purpose, the compounds of the formula I prepared according to the invention, optionally in combination with other active substances, together with an or several inert customary carriers and / or diluents, e.g. B. with corn starch, Milk sugar, cane sugar, microcrystalline cellulose, magnesium stearate, polyvinylpyrro lidon, citric acid, tartaric acid, water, water / ethanol, water / glycerin, water / sorbitol, Water / polyethylene glycol, propylene glycol, cetyl stearyl alcohol, carboxymethyl cellulose or fatty substances such as hard fat or their suitable mixtures, in conventional  pharmaceutical preparations such as tablets, dragees, capsules, powders, suspensions, suppositories or incorporate as solutions for injections or infusions.

The following examples are intended to explain the invention in more detail without limiting it:  

used abbreviations

CDI: N, N'-carbonyldiimidazole
DMF: dimethylformamide
DMSO: dimethyl sulfoxide
TBTU: O- (benzotriazol-1-yl) -N, N, N'-N'-bis (tetramethylene) uronium hexafluorophosphate
THF: tetrahydrofuran

Preparation of the starting compounds Example I 4- [N-acetyl-N- (2-trifluoroacetylaminoethyl) amino] aniline a. 4- (2-t-butoxycarbonylamino-ethylamino) -nitrobenzene

4.2 g (29.7 mmol) of N-tert-butoxycarbonyl-ethylenediamine, 5.0 g (31.2 mmol) of 4-fluoro nitrobenzene and 7.0 g (50.6 mmol) of potassium carbonate are stirred in 25 ml of DMSO at 60 ° C. for 9 hours. After cooling, it is diluted with water and extracted with ethyl acetate. The combined organic extracts are dried and evaporated. The residue is stirred with petroleum ether, decanted off and evaporated again. The product is stirred with ether and suction filtered.
Yield: 3.2 g (38% of theory),
Melting point: 119 ° C
R _f value: 0.5 (silica gel; toluene / ethyl acetate = 7: 3)
C ₁₃ H ₁₉ N ₃ O ₄ (281.31)
Mass spectrum: (M - H) ^- = 280

b. 4- (2-trifluoroacetylamino-ethylamino) -nitrobenzene

1.5 g (5.3 mmol) of 4- (2-tert-butoxycarbonylamino-ethylamino) -nitrobenzene are stirred in 15 ml of trifluoroacetic acid for 3 hours at room temperature. Then 0.8 ml (5.7 mmol) of trifluoroacetic anhydride are added with ice cooling. The reaction is allowed to warm to room temperature overnight. It is then evaporated, diluted with water and made alkaline with sodium bicarbonate. The crude product is filtered off and purified by chromatography (silica gel; dichloromethane / methanol = 98: 2).
Yield: 1.2 g (81% of theory),
R _f value: 0.5 (silica gel; dichloromethane / methanol = 19: 1)
C ₁₀ H ₁₀ F ₃ N ₃ O ₃ (277.21)
Mass spectrum: (M - H) ^- = 276

c. 4- [N-acetyl-N- (2-trifluoroacetylamino-ethyl) -amino] -nitrobenzene

0.6 g (2.1 mmol) of 4- (2-trifluoroacetylamino-ethylamino) nitrobenzene are dissolved in 10 ml of glacial acetic acid and, after addition of 2 ml (21.2 mmol) of acetic anhydride, stirred for 5 hours at 80 ° C. and overnight at room temperature. The solvent is distilled off, the residue is made alkaline with sodium hydrogen carbonate and extracted with ethyl acetate. The combined organic extracts are dried and evaporated.
Yield: 0.7 g (97% of theory),
R _f value: 0.4 (silica gel; dichloromethane / methanol = 19: 1)
C ₁₂ H ₁₂ F ₃ N ₃ O ₄ (319.24)
Mass spectrum: (M - H) ^- = 318

d. 4- [N-acetyl-N- (2-trifluoroacetylamino-ethyl) -amino] aniline

0.7 g (2.1 mmol) of 4- [N-acetyl-N- (2-trifluoroacetylaminoethyl) amino] nitrobenzene are dissolved in 20 ml of methanol and, after addition of 100 mg of 10% palladium on activated carbon, hydrogenated with hydrogen for 3 hours , The catalyst is then filtered off and evaporated.
Yield: 0.6 g (91% of theory),
R _f value: 0.7 (silica gel; dichloromethane / methanol / ammonia = 9: 1: 0.1)
C ₁₂ H ₁₄ F ₃ N ₃ O ₂ (289.26)
Mass spectrum: (M - H) ^- = 288, (M + Na) ⁺ = 312

The following compounds were prepared analogously to Example I:

• 1. 4- [N- (2-Dimethylamino-ethyl) -N-acetylamino] aniline
  R _f value: 0.3 (silica gel; dichloromethane / methanol / ammonia = 9: 1: 0.1)
  C ₁₂ H ₁₉ N ₃ O (221.31)
  Mass spectrum: (M + H) ⁺ = 222
• 2. 4- [N- (2-acetylamino-ethyl) -N-acetylamino] aniline
  R _f value: 0.4 (silica gel; ethyl acetate / methanol = 8: 2)
  C ₁₂ H ₁₇ N ₃ O ₂ (235.28)
  Mass spectrum: (M + Na) ⁺ = 258, (M - H) ^- = 234
• 3. 4- [N- (2-Acetylamino-ethyl) -N-propionylamino] aniline
  R _f value: 0.4 (silica gel; ethyl acetate / methanol = 9: 1)
• 4. [N- (2-Propionylamino-ethyl) -N-propionyl-amino] aniline
  R _f value: 0.5 (silica gel; ethyl acetate / methanol = 9: 1)
• 5. 4- {N- [2- (N-acetyl-N-methylamino) ethyl] -N-propionylamino} aniline
  R _f value: 0.5 (silica gel; dichloromethane / methanol / ammonia = 19: 1: 0.1)
  C ₁₄ H ₂₁ N ₃ O ₂ (263.34)
  Mass spectrum: (M + Na) ⁺ = 286
• 6. 4- {N- [2- (N-acetyl-N-methylamino) ethyl] -N-acetylamino} aniline
  R _f value: 0.3 (silica gel; ethyl acetate / methanol = 9: 1)
  C ₁₃ H ₁₉ N ₃ O ₂ (249.31)
  Mass spectrum: (M - H) ^- = 248, (M + Na) ⁺ = 272
• 7. 4- (Dimethylaminocarbonylmethylamino) aniline
  R _f value: 0.6 (silica gel; dichloromethane / methanol / ammonia = 9: 1: 0.1)
  C ₁₀ H ₁₅ N ₃ O (193.25)
  Mass spectrum: (M + H) ⁺ = 194, (M + Na) ⁺ = 216
• 8. 4- (N-ethoxycarbonylmethyl-N-acetylamino) aniline
  R _f value: 0.5 (silica gel; dichloromethane / methanol / ammonia = 9: 1: 0.1)
  C ₁₂ H ₁₆ N ₂ O ₃ (236.27)
  Mass spectrum: (M - H) ^- = 235, (M + Na) ⁺ = 259
• 9. 4- [N- (3-Dimethylamino-propyl) -N-propionylamino] aniline
  R _f value: 0.2 (silica gel; dichloromethane / methanol / ammonia = 8.5: 1.5: 0.15)
  C ₁₄ H ₂₃ N ₃ O (249.36)
  Mass spectrum: (M - H) ^- = 248, (M + H) * = 250

Example II 4- [N- (2-benzyloxycarbonylamino-ethyl) -N-acetyl-amino) -aniline

450 mg (1.26 mmol) of 4- [N- (2-benzyloxycarbonylamino-ethyl) -N-acetylamino) nitrobenzene (prepared analogously to Example I) are dissolved in 20 ml of methanol and after addition of 100 mg of Lindlar catalyst for 2 hours hydrogenated with hydrogen. The catalyst is filtered off and the solution is evaporated.
Yield: 410 mg (99% of theory),
R _f value: 0.4 (silica gel; ethyl acetate / dichloromethane = 7: 3)
C ₁₈ H ₂₁ N ₃ O ₃ (327.38)
Mass spectrum: (M + Na) ⁺ = 350, (M - H) ^- = 326

The following compounds were prepared analogously to Example II:

• 1. 4- {N- [2- (N-benzyl-N-methylamino) ethyl] -N-acetylamino} aniline
  R _f value: 0.7 (silica gel; ethyl acetate / methanol / ammonia = 9: 1: 0.1)
  C ₁₈ H ₂₃ N ₃ O (297.40)
  Mass spectrum: (M + H) ⁺ = 298, (M - H) ^- = 296
• 2. 4- {N- [2- (N-benzyl-N-methylamino) ethyl] -N-propionylamino} aniline
  R _f value: 0.5 (silica gel; dichloromethane / methanol / ammonia = 9: 1: 0.1)
  C ₁₉ H ₂₅ N ₃ O (311.43)
  Mass spectrum: (M + H) ⁺ = 312

Example III 4- [N- (2-trifluoroacetylamino-ethyl) -N-methylsulphonyl-amino] -aniline a. 4- (N-ethoxycarbonylmethyl-N-methylsulphonyl-amino) -nitrobenzene

20 g (92.5 mmol) of 4- (methylsulfonylamino) nitroaniline are dissolved in 155 ml of DMSO and 11.7 (104 mmol) of potassium tert-butoxide are added while cooling with ice. After 1 hour, 13.5 ml (121 mmol) of ethyl bromoacetate are added. The mixture is stirred at room temperature for 18 hours and then poured into ice water. It is extracted with ethyl acetate. The organic phase is washed with water, dried and freed from the solvent in vacuo. The residue is triturated with petroleum ether.
Yield: 27.1 g (97% of theory),
Melting point: 73-75 ° C
R _f value: 0.8 (silica gel; dichloromethane / ethyl acetate = 9: 1)
C ₁₁ H ₁₄ N ₂ O ₆ S (302.31)
Mass spectrum: (M + Na) ⁺ = 325, (M - H) ^- = 301

b. 4- (N-carboxymethyl-N-methylsulfonyl-amino) -nitrobenzene

26.8 g (88.6 mmol) of 4- (N-ethoxycarbonylmethyl-N-methylsulfonylamino) nitrobenzene are suspended in 320 ml of ethanol and mixed with 268 ml of 1 N sodium hydroxide solution. The mixture is stirred for one hour at room temperature and then 268 ml of 1N hydrochloric acid are added. The precipitate is filtered off, washed with a little ethanol and ether, and dried in vacuo.
Yield: 21.9 g (90% of theory),
Melting point: 215-218 ° C
R _f value: 0.6 (silica gel; dichloromethane / methanol / glacial acetic acid = 9: 1: 0.1)
C ₉ H ₁₀ N ₂ O ₆ S (274.25)
Mass spectrum: (M - H) ^- = 273

c. 4- (N-aminocarbonylmethyl-N-methylsulphonyl-amino) -nitrobenzene

2.5 g (15.4 mmol) of CDI are added to a solution of 3 g (10.9 mmol) of 4- (N-carboxymethyl-N-methylsulfonylamino) nitrobenzene in 30 ml of DMF. It is stirred for one hour at room temperature. NH _{3 is then} introduced at 0 ° C. over a period of 10 min. After 2 hours of stirring at room temperature, 100 ml of water are added. It is extracted with ethyl acetate, the organic phase is washed with water, dried over magnesium sulfate and concentrated to dryness. The residue is stirred with water, suction filtered and washed with ether.
Yield: 2.3 g (78% of theory),
Melting point: 160 ° C
R _f value: 0.5 (silica gel; ethyl acetate / dichloromethane = 3: 2)

d. 4- [N- (2-aminoethyl) -N-methylsulphonyl-amino] -nitrobenzene

2.3 g (8.4 mmol) of 4- (N-aminocarbonylmethyl-N-methylsulfonylamino) nitrobenzene are refluxed in 35 ml (35 mmol) of borane-THF (1 M solution in THF) for 7 hours. Then 30 ml of 6N hydrochloric acid are added and the mixture is heated under reflux for a further 8 hours. The solvent is distilled off, the residue is mixed with water and extracted with ethyl acetate. The aqueous phase is made alkaline with potassium carbonate and extracted with dichloromethane. The organic phase is separated off, dried and evaporated.
Yield: 1.7 g (77% of theory),
R _f value: 0.5 (silica gel; dichloromethane / methanol ammonia = 9: 1: 0.1)
C ₉ H ₁₃ N ₃ O ₄ S (259.29)
Mass spectrum: (M + H) ⁺ = 260, (M - H) ^- = 258

e. 4- [N- (2-trifluoroacetylamino-ethyl) -N-methylsulphonyl-amino] -aniline

Prepared analogously to Example Ib by reacting 4- [N- (2-aminoethyl) -N-methylsulfonylamino] nitrobenzene with trifluoroacetic anhydride in trifluoroacetic acid and subsequent catalytic reduction analogously to Example Id with 10% palladium / carbon in methanol.
Yield: 76% of theory,
R _f value: 0.6 (silica gel; dichloromethane / methanol / ammonia = 9: 1: 0.1)

The following compounds were prepared analogously to Example III:

• 1. 4- (N-ethoxycarbonylmethyl-N-ethylsulfonylamino) aniline
  R _f value: 0.5 (silica gel; petroleum ether / ethyl acetate = 4: 6)
  Melting point: 78 ° C
  C ₁₂ H ₁₈ N ₂ O ₄ S (286.35)
  Mass spectrum: (M + Na) ⁺ = 309, (2M + Na) ⁺ = 593
• 2. 4- {N- [2- (N-acetyl-N-methylamino) ethyl] -N-methylsulfonylamino) aniline
  R _f value: 0.5 (silica gel; dichloromethane / methanol / ammonia = 19: 1: 0.1)
• 3. 4- [N- (2-acetylaminoethyl) -N-methylsulfonylamino] aniline
  R _f value: 0.5 (silica gel; dichloromethane / methanol / ammonia = 19: 1: 0.1)
  C ₁₁ H ₁₇ N ₃ O ₃ S (271.34)
  Mass spectrum: (M + H) ⁺ = 272, (M + Na) ⁺ = 294
• 4. 4- {N- [2- (N-acetyl-N-methylamino) ethyl] -N-ethylsulfonylamino} aniline
  R _f value: 0.5 (silica gel; dichloromethane / methanol / ammonia = 19: 1: 0.1)
  Melting point: 140 ° C
  C ₁₃ H ₂₁ N ₃ O ₃ S (299.39)
  Mass spectrum: M ⁺ = 299
• 5. 4- [N- (2-Acetylamino-ethyl) -N-ethylsulfonylamino) aniline
  R _f value: 0.4 (silica gel; dichloromethane / methanol / ammonia = 19: 1: 0.1)
  C ₁₂ H ₁₉ N ₃ O ₃ S (285.36)
  Mass spectrum: (M - H) ^- = 284, (M + Na) ⁺ = 308
• 6. 4- {N- [2- (N-methyl-N-trifluoroacetylamino) ethyl] -N-methylsulfonylamino} aniline
  R _f value: 0.5 (silica gel; dichloromethane / ethyl acetate = 9: 1)

Example IV 4- [N- (2-dimethylamino-ethyl) -N-phenylsulfonyl-amine-aniline a. N- (2-dimethylamino-ethyl) -phenylsulfonamide

2.8 g (30 mmol) of N, N-dimethylethylenediamine are placed in 100 ml of dichloromethane and 8.3 ml (60 mmol) of triethylamine. A solution of 3.9 ml (30 mmol) of benzenesulfonic acid chloride in 100 ml of dichloromethane is added dropwise with ice cooling and the mixture is stirred at room temperature overnight. Water is added and the mixture is extracted with dichloromethane. The organic phase is dried and evaporated.
Yield: 6.8 g (99% of theory),
R _f value: 0.4 (silica gel; dichloromethane / methanol / ammonia = 9: 1: 0.1)
C ₁₀ H ₁₆ N ₂ O ₂ S (228.23)
Mass spectrum: (M - H) ^- = 227, (M + H) ⁺ = 229

b. 4- [N- (2-dimethylamino-ethyl) -N-phenylsulfonyl-amino] -nitrobenzene

6.8 g (29.8 mmol) of N- (2-dimethylamino-ethyl) -phenylsulfonamide are dissolved in 100 ml of DMF and 1.3 g (30 mmol) of sodium hydride (55% in oil) are added. The mixture is stirred for one hour at room temperature. Then 4.2 g (29.8 mmol) of 4-fluoronitrobenzene are added and the mixture is stirred for a further 16 hours. After adding 300 ml of water, the mixture is extracted with ethyl acetate. The organic phase is washed with water, dried and evaporated. The residue is acidified with 1N hydrochloric acid and washed with ethyl acetate. The aqueous phase is then made basic again with sodium hydroxide solution and extracted with ethyl acetate. The organic phase is dried and evaporated.
Yield: 6.0 g (58% of theory),
R _f value: 0.4 (silica gel; dichloromethane / methanol / ammonia = 9: 1: 0.1)
C ₁₆ H ₁₉ N ₃ O ₄ S (349.41)
Mass spectrum: (M - H) ^- = 348, (M + H) ⁺ = 350

c. 4- [N- (2-dimethylaminoethyl) -N-phenylsulfonyl-amino] -aniline

Prepared analogously to Example Id by catalytic hydrogenation of 6 g (17.2 mmol) of 4- [N- (2-dimethylamino-ethyl) -N-phenylsulfonylamino] nitrobenzene.
Yield: 5.5 g (99% of theory),
R _f value: 0.5 (silica gel; dichloromethane / methanol / ammonia = 9: 1: 0.1)
C ₁₆ H ₂₁ N ₃ O ₂ S (319.43)
Mass spectrum: (M + H) ⁺ = 320

The following compounds were prepared analogously to Example IV:

• 1. 4- [N- (2-Dimethylamino-ethyl) -N-propylsulfonylamino] aniline
  R _f value: 0.4 (silica gel; dichloromethane / methanol / ammonia = 9: 1: 0.1)
  C ₁₃ H ₂₃ N ₃ O ₂ S (285.41)
  Mass spectrum: (M + H) ⁺ = 286, (M - H) ^- = 284
• 2. 4- [N- (2-Dimethylamino-ethyl) -N-butylsulfonylamino] aniline
  R _f value: 0.4 (silica gel; dichloromethane / methanol / ammonia = 9: 1: 0.1)
  C ₁₄ H ₂₅ N ₃ O ₂ S (299.43)
  Mass spectrum: (M + H) ⁺ = 300
• 3. 4- [N- (3-Dimethylamino-propyl) -N-methylsulfonylamino] aniline
  Melting point: 112-113 ° C
  R _f value: 0.4 (silica gel; dichloromethane / methanol / ammonia = 9: 1: 0.1)
  C ₁₂ H ₂₁ N ₃ O ₂ S (271.38)
  Mass spectrum: (M + H) ⁺ = 272, (M + Na) ⁺ = 294
• 4. 4- [N- (2-Dimethylamino-ethyl) -N-benzylsulfonylamino-aniline
  R _f value: 0.3 (silica gel; dichloromethane / methanol / ammonia = 9: 1: 0.1)
  C ₁₇ H ₂₃ N ₃ O ₂ S (333.46)
  Mass spectrum: (M + H) ⁺ = 334, (M + Na) ⁺ = 356
• 5. 3-Chloro-4- [N- (2-dimethylaminoethyl) -N-methylsulfonylamino] aniline
  Melting point: 145-148 ° C
  R _f value: 0.5 (silica gel; dichloromethane / ethanol / ammonia = 5: 1: 0.01)
  C ₁₁ H ₁₈ ClN ₃ O ₂ S (291.80)
  Mass spectrum: (M + H) ⁺ = 294, 292, (M - H) ^- = 292, 290
• 6. 3-Amino-4- [N- (2-dimethylaminoethyl) -N-methylsulfonylamino] aniline
  R _f value: 0.3 (silica gel; dichloromethane / methanol / ammonia = 9: 1: 0.1)
  C ₁₁ H ₂₀ N ₄ O ₂ S (272.37)
  Mass spectrum: (M + H) ⁺ = 273
• 7. 4- [N- (2-Dimethylamino-ethyl) -N-methylsulfonylamino] aniline
  R _f value: 0.3 (silica gel; dichloromethane / methanol / ammonia = 9: 1: 0.1)
  Melting point: 147-148 ° C
  C ₁₁ H ₁₉ N ₃ O ₂ S (257.36)
  Mass spectrum: (M + H) ⁺ = 258, (M + Na) ⁺ = 280

Example V 3- [N- (2-dimethylamino-ethyl) -N-methylsulphonyl-amino] -aniline a. 3- [N- (2-dimethylamino-ethyl) -N-methylsulphonyl-amino] -nitrobenzene

5 g (23.1 mmol) of 3-methylsulfonylamino-nitrobenzene are dissolved in 50 ml of DMSO, and 6.5 g (58 mmol) of potassium tert-butoxide are added with ice-cooling. The solution thus obtained is added dropwise to a solution of 5 g (34.7 mmol) of 2-chloro-N, N-dimethyl-ethylamine in 30 ml of DMSO. The mixture is stirred at room temperature for 2 hours and then heated to 100 ° C. for 6 hours. After cooling to room temperature, 400 ml of water are added. It is extracted with ethyl acetate. Water and 1 N hydrochloric acid are added to the combined organic phases until an acid reaction. The aqueous phase is washed with ethyl acetate. Then the aqueous phase is made alkaline with sodium carbonate and the product extracted with ethyl acetate. Drying the combined organic phases over magnesium sulfate and removing the solvent in vacuo provide the product as a red oil.
Yield: 2.07 g (31% of theory),
R _f value: 0.3 (silica gel; ethyl acetate / methanol = 4: 1)
C ₁₁ H ₁₇ N ₃ O ₄ S (287.34)
Mass spectrum: (M - H) ^- = 286, (M + H) ⁺ = 288

b. 3- [N- (2-dimethylamino-ethyl) -N-methylsulphonyl-amino] -aniline

Prepared analogously to Example 1d by catalytic hydrogenation of 1.9 g (6.8 mmol) of 3- [N- (2-dimethylaminoethyl) -N-methylsulfonylamino] nitrobenzene over palladium / carbon.
Yield: 1.8 g (99% of theory),
R _f value: 0.3 (silica gel; ethyl acetate / methanol / NH ₄ OH = 8: 2: 0.1)
C ₁₁ H ₁₉ N ₃ O ₂ S (257.36)
Mass spectrum: (M - H) ^- = 256, (M + H) ⁺ = 258

Example VI 4- (4-Benzylpiperazinomethyl) aniline a. 4- (4-tert.Butoxycarbonvl-piperazinomethyl) nitrobenzene

A mixture of 10.6 g (57 mmol) of N-tert-butoxycarbonyl-piperazine, 10.8 g (62.7 mmol) of 4-nitrobenzyl chloride, 23.8 ml (171 mmol) of triethylamine in 100 ml of dichloromethane is stirred at 70 ° C. for 12 hours. After dilution with water, the organic phase is separated off, dried and evaporated.
Yield: 19 g (99% of theory),
Melting point: 83-84 ° C
R _f value: 0.7 (silica gel; dichloromethane / methanol / ammonia = 9: 1: 0.1)
C ₁₆ H ₂₃ N ₃ O ₄ (321.38)
Mass spectrum: (M + H) ⁺ = 322, (M - H) ^- = 320

b. 4-piperazinomethyl-nitrobenzene dihydrochloride

6.4 g (20 mmol) of 4- (4-tert-butoxycarbonyl-piperazinomethyl) nitrobenzene are dissolved in 20 ml of dichloromethane and mixed with 40 ml of ethyl acetate / HCl. The reaction solution is diluted with ether.
Yield: 5.4 g (92% of theory),
Melting point: 257-258 ° C
R _f value: 0.3 (silica gel; dichloromethane / methanol / ammonia = 9: 1: 0.1)

c. 4- (4-Benzylpiperazinomethyl) nitrobenzene

The free base is produced from 1.5 g (5 mmol) of 4-piperazinomethyl-nitrobenzene dihydrochloride by dissolving in 25 ml of 1N sodium hydroxide solution, extracting with ethyl acetate and then removing the solvent in vacuo. The solid thus obtained is mixed with 2.5 ml of 2N acetic acid, 0.5 ml (5.5 mmol) of benzaldehyde and 50 ml of methanol and, after addition of 0.7 g (5 mmol) of sodium cyanoborohydride, stirred for 2 hours. Then an acidic pH is adjusted with 1 N hydrochloric acid and the reaction solution is washed with ether. The aqueous phase is then made basic with sodium hydroxide solution. The product is extracted with ether, the combined ether extracts are dried and the solvent is removed in vacuo.
Yield: 1.3 g (84% of theory),
R _f value: 0.6 (silica gel; dichloromethane / methanol / ammonia = 9: 1: 0.1)
C ₁₈ H ₂₁ N ₃ O ₂ (311.39)
Mass spectrum: (M + H) ⁺ = 312

d. 4- (4-Benzylpiperazinomethyl) aniline

Prepared analogously to Example Id by catalytic hydrogenation of 1.3 g (4.2 mmol) of 4- (4-benzylpiperazinomethyl) nitrobenzene over palladium / carbon.
Yield: 1.2 g (87% of theory),
Melting point: 88-89 ° C
C ₁₈ H ₂₃ N ₃ (281.4)
Mass spectrum: (M + H) ⁺ = 282

Example VII 4- (4-tert-butoxycarbonyl-piperazinomethyl) aniline a. 4- (4-tert.Butoxycarbonvl-piperazinomethyl) nitrobenzene

10.6 g (57 mmol) of N-tert-butoxycarbonyl-piperazine are dissolved in 100 ml of dichloromethane, and 10.7 g (63 mmol) of 4-nitrobenzyl chloride and 24 ml (171 mmol) of triethylamine are added. The mixture is heated to reflux for 12 hours. After cooling to room temperature, the reaction solution is washed several times with water. The organic phase is dried over magnesium sulfate and then evaporated to dryness.
Yield: 17 g (99%) of theory
Melting point: 83-84 ° C
R _f value: 0.7 (silica gel; dichloromethane / methanol / ammonia = 9: 1: 0.1)
C ₁₆ H ₂₃ N ₃ O ₄ (321.38)
Mass spectrum: (M + H) ⁺ = 322, (M - H) ^- = 320

b. 4- (4-tert-butoxycarbonyl-piperazinomethyl) aniline

Prepared analogously to Example Id by catalytic hydrogenation of 4- (4-tert-butoxycarbonylpiperazinomethyl) nitrobenzene with Raney nickel in ethyl acetate / methanol (1: 1).
Melting point: 106-107 ° C
R _f value: 0.6 (silica gel; dichloromethane / methanol / ammonia = 9: 1: 0.1)
C ₁₆ H ₂₅ N ₃ O ₂ (291.39)
Mass spectrum: (M + H) ⁺ = 292, (M + Na) ⁺ = 314

The following compounds were prepared analogously to Example VII:

• 1. 4- (pyrrolidin-1-yl-methyl) aniline
  R _f value: 0.2 (silica gel; dichloromethane / methanol / NH ₄ OH = 5: 1: 0.01)
  Melting point: 48-50 ° C
• 2. 4- (4-methylpiperazinomethyl) aniline
  Melting point: 94-95 ° C
  R _f value: 0.2 (silica gel; dichloromethane / methanol / ammonia = 9: 1: 0.1)
  C ₁₂ H ₁₉ N ₃ (205.31)
  Mass spectrum: (M + H) ⁺ = 206
• 3. 3- (Dimethylaminomethyl) aniline
  R _f value: 0.7 (silica gel; ethyl acetate)
  Melting point: 43-46 ° C
• 4. 4- (dimethylaminomethyl) aniline
  R _f value: 0.13 (silica gel; ethyl acetate / ethanol = 8: 2)
• 5. 4- (2-Dimethylamino-ethyl) aniline
  R _f value: 0.3 (silica gel; dichloromethane / methanol / ammonia = 19: 1: 0.1)
  Melting point: 40 ° C
  C ₁₀ H ₁₆ N ₂ (164.25)
  Mass spectrum: (M + H) ⁺ = 165
• 6. 4- (N-Benzyl-N-methylaminomethyl) aniline
  R _f value: 0.5 (silica gel; dichloromethane / methanol / ammonia = 10: 1: 0.01)
  Melting point: 48-50 ° C
  C ₁₅ H ₁₈ N ₂ (226.32)
  Mass spectrum: (M + H) ⁺ = 227
• 7. 4-piperidinomethyl aniline
  R _f value: 0.2 (silica gel; dichloromethane / methanol / ammonia = 9: 1: 0.1)
  Melting point: 88-89 ° C
• 8. 4- (2,6-dimethylpiperidinomethyl) aniline
  R _f value: 0.3 (silica gel; dichloromethane / methanol / ammonia = 5: 1: 0.01)
  Melting point: 112-115 ° C
• 9. 4- (N-ethyl-N-methylaminomethyl) aniline
  R _f value: 0.4 (silica gel; dichloromethane / methanol / ammonia = 10: 1: 0.1)
  C ₁₀ H ₁₆ N ₂ (164.25)
  Mass spectrum: (M + H) ⁺ = 165
• 10. 4- [4- (3-trifluoromethylcarbonylamino-propyl) piperidinomethyl] aniline
  R _f value: 0.4 (silica gel; dichloromethane / methanol / ammonia = 10: 1: 0.1)
  C ₁₇ H ₂₄ F ₃ N ₃ O (343.40)
  Mass spectrum: (M + H) ⁺ = 344
• 11. 4- (N-tert-butoxycarbonyl-N-propylaminomethyl) aniline
  C ₁₅ H _{247570 00070 552 001000280000000200012000285913745900040 0002010054019 00004 37451UB <N 2 O 2 (264.37)
  Mass spectrum: (M + Na) ⁺ = 287 12. 4- (N-tert-Butoxycarbonyl-N-butylaminomethyl) aniline
  R f value: 0.19 (silica gel; dichloromethane / methanol = 50: 1)
  C 16 H 26 N 2 O 2 (278.40)
  Mass spectrum: (M + Na) ⁺ = 301}
  • _{13. 4- (N-tert-Butoxycarbonyl-N-ethylaminomethyl) aniline
    Melting point: 85 ° C
    R f value: 0.3 (silica gel; dichloromethane / methanol / = 50: 1)
    C 14 H 22 N 2 O 2 (250.34)
    Mass spectrum: (M + Na) ⁺ = 273}
  _{Example VIII 4- (2-oxopiperidinomethyl) aniline 6.4 g (42 mmol) of 4-nitrobenzaldehyde are dissolved in 150 ml of methanol, and 4.9 g (42 mmol) of 5-aminovaleric acid and 1.8 g (29 mmol) of sodium cyanoborohydride are added. The mixture is stirred at room temperature for 18 hours and then 20 ml of conc. Hydrochloric acid. The solvent is removed in vacuo, the residue is taken up in water and extracted with dichloromethane. The residue obtained after evaporation is chromatographed on silica gel (dichloromethane / methanol, 4: 1). A mixture of 5- (4-nitrobenzylamino) pentanoic acid methyl ester and 4- (2-oxopiperidinomethyl) nitrobenzene is obtained, which is dissolved in 100 methanol and mixed with 50 ml of 1N sodium hydroxide solution. The mixture is stirred for one hour at room temperature, 50 ml of 1N hydrochloric acid are added and the reaction solution is concentrated to 100 ml. The aqueous phase thus obtained is extracted with dichloromethane. The combined organic phases are dried over sodium sulfate and evaporated to dryness. The residue is hydrogenated for 11 hours over Raney nickel in methanol in a hydrogen atmosphere of 3 bar, analogously to Example Id.
  Overall yield: 2.2 g (26% of theory),
  R f value: 0.63 (silica gel; dichloromethane / methanol = 9: 1) Example XIV 4- (N-Piperidinomethylcarbonyl-N-methyl-amino) -aniline a. 4- (N-Brommethylcarbonyl-N-methylamino) nitrobenzene 23.5 g (0.15 mol) of N-methyl-4-nitroaniline are dissolved in 400 ml of dioxane, and 22.2 g (0.3 mol) of lithium carbonate are added. Then 32.2 g (0.18 mol) of bromoacetyl bromide are added dropwise so that the internal temperature does not exceed 33 ° C. After stirring for 18 hours, the reaction solution is concentrated to 100 ml, mixed with 500 ml of water and stirred for 1 hour. The precipitate is filtered off, washed with water and dried. The crude product is stirred in 400 ml of ethyl acetate at 40 ° C. The undissolved material is then filtered off, the solution is evaporated and the solid residue is triturated with ether.
  Yield: 35 g (83% of theory),
  Melting point: 85-87 ° C b. 4- (N-Piperidinomethylcarbonyl-N-methylamino) nitrobenzene 5.4 g (20 mmol) of 4- (N-bromomethylcarbonyl-N-methyl-amino) -nitrobenzene are dissolved in 100 ml of acetone and mixed with 5.5 g (40 mmol) of potassium carbonate. 3 ml (30 mmol) of piperidine are slowly added dropwise and the mixture is stirred at room temperature for 18 hours. The reaction solution is filtered and the filtrate is evaporated to dryness. The residue is dissolved in ethyl acetate, washed with water, dried over magnesium sulfate and evaporated to dryness.
  Yield: 5.6 g (99% of theory). c. 4- (N-Piperidinomethylcarbonyl-N-methyl-amino) -aniline Prepared analogously to Example Id by catalytic hydrogenation of 4- (N-piperidinomethylcarbonyl-N-methylamino) nitrobenzene in methanol over palladium / carbon.
  Yield 4.95 g (99% of theory) Example X 4- (tert.Butoxycarbonvlaminomethyl) aniline 20 g (164 mmol) of 4-aminobenzylamine and 20.2 g (210 mmol) of triethylamine are dissolved in 100 ml of dioxane and 50 ml of water. 35.8 g (165 mmol) of di-tert-butyl dicarbonate dissolved in 60 ml of dioxane are added to this solution with ice cooling and the mixture is stirred at room temperature for 18 hours. The solvent is then distilled off in vacuo and the residue is distributed in ethyl acetate / water. The combined organic extracts are freed from the solvent in vacuo. The crude product is heated in 200 ml of petroleum ether, slowly cooled with vigorous stirring and the crystalline product is filtered off with suction.
  Yield: 34.8 g (96% of theory),
  Melting point: 77-78 ° C Example XI 4- (1H-imidazol-2-yl) aniline 7.2 g (50 mmol) of 2-phenylimidazole are concentrated in 100 ml. Dissolved sulfuric acid. While cooling with ice, 5.0 g (62 mmol) of ammonium nitrate are added in portions and the mixture is stirred for 2.5 hours. The reaction solution is then poured onto ice, with conc. Ammonia is made basic and the crystalline product is suctioned off. The nitro compound obtained in this way is catalytically hydrogenated in pallet / carbon analogously to Example Id in DMF.
  Yield: 24% of theory,
  R f value: 0.4 (silica gel; dichloromethane / methanol / ammonia = 9: 1: 0.1) Example XII Pyridine-2-sulfonic acid chloride 5.0 g (45 mmol) of pyridine-2-thiol are concentrated in 40 ml. Hydrochloric acid dissolved. Chlorine gas is introduced over a period of 2.5 hours with ice cooling. To destroy excess gas, a wash bottle with 1 N sodium thiosulfate solution is added. The reaction solution is then poured onto ice water and extracted with ether and dichloromethane. The organic phases are combined, dried and freed from the solvent in vacuo. The raw product is immediately implemented further.
  Yield: 8 g (100% of theory). Example XIII Pyridine-3-sulfonic acid chloride hydrochloride 1 g (6.3 mmol) of pyridine-3-sulfonic acid and 1.4 g (6.7 mmol) of phosphorus pentachloride are stirred at 150 ° C for 2 hours. After cooling, excess phosphorus pentachloride is removed in vacuo. The raw product is immediately implemented further.
  Yield: 1.2 g (91% of theory). Manufacture of end products example 1 (Z) -3- {1- [4- (N-acetyl-N- (2-aminoethyl) amino) phenylamino] -1-phenylmethylidene} -S- phenylsulfonylamino-2-indolinone a. 1-acetyl-2-indolinone}

  _{13.3 g (0.1 mol) of 2-indolinone and 30 ml of acetic anhydride are stirred at 170 ° C for 3 hours. After cooling, 150 ml of ice water are added, the crystalline product is filtered off with suction, washed with water and dried.
  Yield: 16.6 g (95% of theory),
  Melting point: 129-130 ° C.}

  _{b. 1-acetyl-5-nitro-2-indolinone}

  _{0.5 g (2.8 mmol) of 1-acetyl-2-indolinone are concentrated in 4 ml. Submitted sulfuric acid. At a temperature of -10 to -5 ° C, 0.3 g (3.4 mmol) of ammonium nitrate are added in portions. After 45 minutes, the mixture is poured onto ammonia / ice water, the crystalline precipitate is filtered off with suction, washed with water and dried. The crude product is recrystallized from 70 ml of cyclohexane.
  Yield: 0.2 g (32% of theory),
  Melting point: 150-157 ° C
  R f value: 0.7 (silica gel; cyclohexane / ethyl acetate = 4: 6)}

  _{c. 1-Acetyl-5-amino-2-indolinone}

  _{30.0 g (136 mmol) of 1-acetyl-5-nitro-2-indolinone are dissolved in a mixture of 650 ml of dichloromethane and 650 ml of methanol and, after addition of 5 g of 10% palladium on activated carbon, hydrogenated with hydrogen for 45 minutes. The catalyst is then filtered off and evaporated.
  Yield: 22.4 g (87% of theory),
  Melting point: 177 ° C
  R f value: 0.7 (silica gel; ethyl acetate)
  C 10 H 10 N 2 O 2 (190.20)
  Mass spectrum: (M - H) ^- = 189, (M + Na) ⁺ = 213}

  _{d. 1-acetyl-5-phenylsulfonylamino-2-indolinone}

  _{20.0 g (105 mmol) of 1-acetyl-5-amino-2-indolinone are placed in 200 ml of pyridine, 15.3 ml (120 mmol) of benzenesulfonic acid chloride are added while cooling with ice and the mixture is stirred for 2 hours. Then poured into 1.8 l of water and suction filtered. The crude product is stirred in acetone, suction filtered and dried.
  Yield: 30.5 g (88% of theory),
  Melting point: 245 ° C
  R f value: 0.5 (silica gel; dichloromethane / ethyl acetate = 9: 1)
  C 16 H 14 N 2 O 4 S (330.37)
  Mass spectrum: (M - H) ^- = 329, (M + Na) ⁺ = 353}

  _{e. 1-acetyl-3- (1-ethoxy-1-phenyl-methylidene) -5- (N-acetyl-N-phenylsulfonylamino) -2-indolinone}

  _{8.0 g (24.2 mmol) of 1-acetyl-5-phenylsulfonylamino-2-indolinone are dissolved in 150 ml of acetic anhydride and, after addition of 20 ml (88.1 mmol) of triethyl orthobenzoate, heated to reflux for 6 hours. The solvent is distilled off, the residue is triturated with ether, suction filtered and dried.
  Yield: 7.8 g (64% of theory),
  Melting point: 237 ° C
  R f value: 0.7 (silica gel; dichloromethane / ethyl acetate = 19: 1)
  C 27 H 24 N 2 O 6 S (504.57)
  Mass spectrum: M ⁺ = 504}

  _{f. (Z) -3- {1- [4- (N-Acetyl-N- (2-aminoethyl) amino) phenylaminol] -1-phenylmethylidene} -5-phenylsulfonylamino-2-indolinone}

  _{A mixture of 0.5 g (1 mmol) of 1-acetyl-3- (1-ethoxy-1-phenyl-methylidene) -5- (N-acetyl-N phenylsulfonyl-amino) -2-indolinone and 0.3 g (1.2 mmol) 4- [N-Acetyl-N- (2-trifluoroacetylamino-ethyl) -amino] aniline are stirred in 5 ml of DMF at 120 ° C. for 6 hours. After cooling to room temperature, 5 ml of methanol and 3 ml (6 mmol) of 2N sodium hydroxide solution are added, and the mixture is stirred for 30 minutes. The reaction mixture is diluted with 50 ml of water and the crystalline precipitate is filtered off with suction and dried. The residue is chromatographed on silica gel (dichloromethane / methanol / ammonia = 9: 1: 0.1).
  Yield: 0.3 g (49% of theory),
  Melting point: 216 ° C
  R f value: 0.3 (silica gel; dichloromethane / methanol / ammonia = 9: 1: 0.1)
  C 31 H 29 N 5 O 4 S (567.67)
  Mass spectrum: (M - H) ^- = 566, (M + H) ⁺ = 568}

  _{Examples 2 to 97}

  _{Analogously to Example 1, the compounds of the formula IA of Examples 2 to 97 listed in Table I are prepared using the intermediates prepared in Examples I to XIII.}

  _{Example 98 (Z) -3- [1- (4-piperidinomethylphenylamino) -1-phenylmethylidene] -5-methylsulfonylamino-2-indolinone a. 1-acetyl-3- (1-ethoxy-1-phenyl-methylidene) -5-nitro-2-indolinone}

  _{0.2 g (0.9 mmol) of 1-acetyl-5-nitro-2-indolinone and 0.6 g (2.7 mmol) of orthobenzoic acid triethyl ester are heated in 2 ml of acetic anhydride at 100 ° C for 1.5 hours. After cooling, ether is added and the precipitate which has separated out is filtered off with suction.
  Yield: 0.2 g (66% of theory),
  Melting point: 244-250 ° C
  R f value: 0.7 (silica gel; ethyl acetate / cyclohexane = 3: 2)}

  _{b. (Z) -1-acetyl-3- [1- (4-piperidinomethylphenylamino) -1-phenylmethylidene] -5-nitro-2-indolinone}

  _{3 g (8.5 mmol) of 1-acetyl-3- (1-ethoxy-1-phenyl-methylidene) -5-nitro-2-indolinone and 1.9 g (10 mmol) of 4-piperidinomethyl-aniline are mixed in 30 ml of DMF for 3.5 hours heated to 90 ° C. After cooling to room temperature, the reaction solution is poured onto ice water and extracted with ethyl acetate. The combined organic extracts are dried and evaporated. The residue is triturated with ether and suction filtered.
  Yield: 3.5 g (82% of theory),
  R f value: 0.6 (silica gel; dichloromethane / methanol / ammonia = 9: 1: 0.1)
  Melting point: 165 ° C}

  _{c. (Z) -1-acetyl-3- [1- (4-piperidinomethylphenylamino) -1-phenylmethylidene] -5-amino-2-indolinone}

  _{Prepared analogously to Example VIIb from (Z) -1-acetyl-3- [1- (4-piperidinomethyl-phenylamino) -1-phenyl-methylidene] -5-nitro-2-indolinone by catalytic reduction over Raney nickel in dichloromethane / Methanol (1: 1).
  Yield: 99% of theory,
  R f value: 0.5 (silica gel; dichloromethane / methanol / ammonia = 9: 1: 0.1)
  Melting point: 278-281 ° C
  C 29 H 30 N 4 O 2 (466.59)
  Mass spectrum: (M + H) ⁺ = 467}

  _{d. (Z) -3- [1- (4-piperidinomethylphenylamino) -1-phenylmethylidene] -5-methylsulfonylamino-2-indolinone}

  _{466 mg (1 mmol) (Z) -1-acetyl-3- [1- (4-piperidinomethyl-phenylamino) -1-phenyl methylidene] -5-amino-2-indolinone are suspended in 15 ml of pyridine, with 0.2 ml (2.3 mmol) of methanesulfonic acid chloride are added and the mixture is stirred for 1.5 hours. Then 6 ml of 1 N sodium hydroxide solution are added. After 1 hour, 1 ml of piperidine is added and the mixture is stirred overnight. The reaction solution is poured onto water and the precipitate which has separated out is filtered off with suction. The residue is stirred with ether, suction filtered and dried.
  Yield: 290 mg (58% of theory),
  R f value: 0.4 (silica gel; dichloromethane / methanol / ammonia = 9: 1: 0.1)
  Melting point: 266 ° C
  C 28 H 30 N 4 O 3 S (502.64)
  Mass spectrum: (M + H) ⁺ = 503
  Calculated:
  C 66.91; H 6.02; N 11.15
  Found:
  C 66.49; H 6.06; N 11.01}

  _{Examples 99 to 151}

  _{Analogously to Example 98, the compounds of the formula IB of Examples 99 to 151 listed in Table II are prepared using the intermediates prepared in Examples I to XIII. Hydrochlorides or dihydrochlorides are obtained according to the following general procedure: The starting compound is dissolved in dichloromethane and mixed with ether / HCl. The precipitate is filtered off and dried.}

  _{Example 152 (Z) -3- [1- (4-Ethoxycarbonylmethyl-phenylamino) -1-phenyl-methylidene] -5-phenylsulfonylamino-2-indolinone a. 3- (1-ethoxy-1-phenyl-methylidene) -5-phenylsulfonylamino-2-indolinone}

  _{To a solution of 4.0 g (8 mmol) of 1-acetyl-3- (1-ethoxy-1-phenyl-methylidene) -5- (N-acetyl-N-phenylsulfonylamino) -2-indolinone (Example 1e) in 8 ml of 4N sodium hydroxide solution are added to a mixture of 20 ml of dichloromethane and 20 ml of ethanol and the mixture is stirred at room temperature for 20 minutes. The mixture is then concentrated to about 10 ml and 150 ml of water are added. The pH is adjusted to 8-9 using 1 N hydrochloric acid. The precipitate is filtered off, washed with water, isopropanol and ether, then dried in vacuo.
  Yield: 6.6 g (82% of theory),
  Melting point: 292-294 ° C
  R f value: 0.4 (silica gel; dichloromethane / methanol / NH 4 OH = 9: 1: 0.1)
  C 23 H 20 N 2 O 4 S (420.49)
  Mass spectrum: (M + H) ⁺ = 421, (M - H) ^- = 419}

  _{b. (Z) -3- [1- (4-Ethoxycarbonylmethyl-phenylamino) -1-phenyl-methylidene] -5-phenylsulfonylamino-2-indolinone}

  _{0.84 g (2 mmol) of 3- (1-ethoxy-1-phenyl-methylidene) -5-phenylsulfonylamino-2-indolinone and 0.39 g (2.2 mmol) of 4-ethoxycarbonylmethyl-aniline are dissolved in 10 ml of DMF. The mixture is heated at 140 ° C. for 5 hours. Then water is added while cooling with ice and the mixture is stirred at room temperature for 1 hour. The precipitate is filtered off, washed with water, a little isopropanol and ether, then dried in vacuo.
  Yield: 0.95 g (86% of theory),
  Melting point: 248-249 ° C
  C 31 H 27 N 3 O 5 S (553.64)
  Mass spectrum: M ⁺ = 553, (M - H) ^- = 552}

  _{Example 153 (Z) -3- [1- (4-Carboxymetbylphenylamino) -1-phenylmethylidene] -5-phenylsulfonylamino-2-indolinone}

  _{720 mg (1.3 mmol) (Z) -3- [1- (4-ethoxycarbonylmethyl-phenylamino) -1-phenyl-methylidene] - 5-phenylsulfonylamino-2-indolinone are dissolved in a mixture of 20 ml of methanol and 20 ml of dichloromethane , 4 ml of 1 N sodium hydroxide solution are added and the mixture is stirred at room temperature for 18 hours and at 40 ° C. for a further hour. The reaction solution is concentrated to half the volume and the pH is adjusted to 4-5 with 1N hydrochloric acid. The precipitate is filtered off, washed with water, a little isopropanol and ether.
  Yield: 620 mg (91% of theory)
  Melting point: 305-306 ° C
  C 29 H 23 N 3 O 5 S (525.59)
  Mass spectrum: (M - H) ^- = 524}

  _{Example 154 (Z) -3- {1- [4- (Benzylaminocarbonylmethyl) phenylamino] -1-phenylmethylidene} -5-phenylsulfonylamino-2-indolinone}

  _{A solution of 315 mg (0.6 mmol) of (Z) -3- [1- (4-carboxymethylphenylamino) -1-phenyl methylidene] -5-phenylsulfonylamino-2-indolinone, 85 mg (0.8 mmol) of benzylamine, 212 mg (0.66 mmol) TBTU and 1 ml of N-ethyl-N, N-diisopropyl-amine in 5 ml of DMF is stirred for 3 hours at room temperature. Then add 50 ml of water. The precipitated yellow precipitate is filtered off, washed with water, a little isopropanol and ether, then dried in vacuo.
  Yield: 0.3 mg (81% of theory),
  Melting point: 219-220 ° C
  C 36 H 30 N 4 O 4 S (614.73)
  Mass spectrum: (M + Na) ⁺ = 637, (M - H) ^- = 613}

  _{Example 155 (Z) -3- {1- (4- (N- (Aminocarbonylmethyl) -N-methylsulfonylamino) phenylamino] -1-phenylmethylidene} -5-phenylsulfonylamino-2-indolinone}

  _{A solution of 250 mg (0.4 mmol) (Z) -3- [1- (4- (N-carboxymethyl-N-methylsulfonylamino) -phenylamino) -1-phenyl-methylidene] -5-phenylsulfonylamino-2-indolinone and 82 mg (0.4 mmol) CDI in 5 ml DMF is stirred at 50 ° C for 1 hour. 1 ml of condensed ammonia is added and the mixture is stirred at room temperature for 5 hours. Then add water. The yellow precipitate is filtered off, washed with water, a little isopropanol and ether, then dried in vacuo.
  Yield: 190 mg (76% of theory)
  Melting point: 216-217 ° C
  C 30 H 27 N 5 O 6 S 2 (617.71)
  Mass spectrum: (M + Na) ⁺ = 640, (M - H) ^- = 616}

  _{Examples 156 to 170}

  _{Analogously to Examples 152 to 155, the compounds of the formula IB of Examples 156 to 170 listed in Table III are prepared with the aid of the intermediates prepared in Examples I to XIII.}

  _{Examples 171 to 196}

  _{The compounds of the formula IR of Examples 171 to 196 listed in Table IV below are obtained from compounds of Examples 1 to 170 listed above by the following general working instructions A to E:}

  _{A: Elimination of tert-butoxycarbonyl}

  _{0.6 mmol of the starting compound are dissolved in 5 ml of dichloromethane. 10 ml of ethyl acetate / HCl are added and the mixture is stirred at room temperature for 2 hours. A basic pH is then set by adding sodium hydroxide solution. The organic phase is washed with water, dried over sodium sulfate and the solvent removed in vacuo. For the production of hydrochlorides, no sodium hydroxide solution is added. To produce hydrotrifluoroacetate, trifluoroacetic acid is added to the solution of the starting compound.}

  _{B: Elimination of benzyl}

  _{1.5 mmol of the starting compound are dissolved in 20 ml dichloromethane / methanol (1: 1). 100 mg of palladium / carbon (10%) and 1.5 ml of 1N hydrochloric acid are added, and the mixture is then hydrogenated in a hydrogen atmosphere at 50 psi. The catalyst is suctioned off and the filtrate is evaporated to dryness. The residue is chromatographed on silica gel (dichloromethane / methanol / NH 4 OH, 9: 1: 0.1).}

  _{C: Hydrogenation of cyano to CH 2 NH 2}

  _{0.5 mmol of the starting compound are dissolved in 20 ml of methanolic ammonia solution and Raney nickel is added. It is hydrogenated in a hydrogen atmosphere of 50 psi, then the catalyst is suctioned off and the solvent is removed in vacuo. The residue is chromatographed on silica gel (dichloromethane / methanol / NH 4 OH, 9: 1: 0.1).}

  _{D: Hydrogenation of nitro to amino}

  _{0.2 mmol of the starting compound are dissolved in 20 ml of ethyl acetate / methanol (1: 1). Then hydrogenation is carried out over Raney nickel analogous to working instruction C. The residue is optionally chromatographed on silica gel (dichloromethane / methanol / NH 4 OH, 9: 1: 0.1).}

  _{Example 197 (Z) -3- {1- [4- (N- (2-Dimethylaminoethyl) -N-methylsulfonylamino) phenylamino) -1- phenylmethylidene} -5- (N-methyl-N-phenylsulfonyl amino) -2-indolinone a. (Z) -1-acetyl-3- (1-ethoxy-1-phenylmethylidene) -5- (N-methyl-N-phenylsulfonylamino) -2-indolinone}

  _{10 g (20 mmol) of 1-acetyl-3- (1-ethoxy-1-phenyl-methylidene) -5- (N-acetyl-N-phenylsulfonylamino) -2-indolinone (Example 1e) are in 150 ml of DM50 dissolved and mixed with 2.2 g (20 mmol) of potassium tert-butoxide with stirring. After stirring for 15 minutes, 1.9 ml (31 mmol) of iodomethane are added. The mixture is stirred for 3 hours at room temperature. Then 2.2 g (20 mmol) of potassium tert-butoxide and 1 ml (16 mmol) of iodomethane are added again. The mixture is stirred at room temperature for 18 hours. Then water is added. The reaction mixture is extracted with ethyl acetate. The organic phase is washed with water, dried over magnesium sulfate and evaporated to dryness. The residue is chromatographed on silica gel (petroleum ether / dichloromethane, 7: 3).
  Yield: 2.7 g (28% of theory)
  R f value: 0.65 (silica gel; dichloromethane / petroleum ether = 8: 2)
  C 26 H 24 N 2 O 5 S (476.56)
  Mass spectrum: (M + Na) ⁺ = 499}

  _{b. (Z) -3- {1- [4- (N- (2-Dimethylaminoethyl) -N-methylsulfonylamino) phenylamino) -1- phenylmethylidene} -5- (N-methyl-N-phenylsulfonyl -indolinon -amino-2)}

  _{Prepared analogously to Example 1f from 350 mg (0.73 mmol) (Z) -1-acetyl-3- (1-ethoxy-1-phenyl methylidene) -5- (N-methyl-N-phenylsulfonylamino) -2-indolinone and 257 mg (1 mmol) of 4- [N- (2-dimethylaminoethyl) -N-methylsulfonylamino] aniline in DMF and subsequent treatment with sodium hydroxide solution.
  Yield: 380 mg (80% of theory)
  R f value: 0.5 (silica gel; dichloromethane / methanol / NH 4 OH = 9: 1: 0.1)
  C 33 H 35 N 5 O 5 S 2 (645.80)
  Mass spectrum: M ⁺ = 645
  Calculated:
  C 61.38; H 5.46; N 10.84
  Found:
  C 61.09; H 5.45; N 10.82}

  _{The following compounds of Examples 198 to 200 are prepared analogously to Example 197 with the aid of the intermediates prepared in Examples I to XIII:}

  _{Example 198 (Z) -3- {1- [4- (N- (2-Dimethylaminoethyl) -N-acetylamino) phenylamino) -1-phenyl methylidene} -5- (N-methyl-N-phenylsulfonyl- amino) -2-indolinone Melting point: 217 ° C
  R f value: 0.5 (silica gel; dichloromethane / methanol / NH 4 OH = 9: 1: 0.1)
  C 34 H 35 N 5 O 4 S (609.75)
  Mass spectrum: (M + H) ⁺ = 610
  Calculated:
  C 66.97; H 5.79; N 11.49
  Found:
  C 66.92; H 5.78; N 11.39 Example 199 (Z) -3- {1- [4- (N-methyl-N-piperidinomethylcarbonylamino) phenylamino) -1-phenylmethylidene} -5- (N-methyl-N-phenylsulfonylamino) -2-indolinone Melting point: 160 ° C
  R f value: 0.65 (silica gel; dichloromethane / methanol / NH 4 OH = 9: 1: 0.1)
  C 36 H 37 N 5 O 4 S (635.79)
  Mass spectrum: (M + H) ⁺ = 636 Example 200 (Z) -3- [1- (3-Dimethylaminomethylphenylamino) -1-phenylmethylidene] -5- (N-methyl-N-phenylsulfonylamino) -2-indolinone Melting point: 226 ° C
  R f value: 0.75 (silica gel; dichloromethane / methanol / NH 4 OH = 9: 1: 0.1)
  C 31 H 30 N 4 O 3 S (538.67)
  Mass spectrum: (M + H) ⁺ = 539 Analogous to the above examples, the following compounds can be obtained:}
  
  • _{1. (Z) -3- [1- (4-Dimethylaminomethylphenylamino) -1-phenylmethylidene] -5-methylsulfonylamino-2-indolinone}
  • _{2. (Z) -3- {1- [4- (2-Dimethylaminoethyl) phenylamino] -1-phenylmethylidene} -5-methylsulfonylamino-2-indolinone}
  • _{3. (Z) -3- [1- (4-Diethylaminomethyl-phenylamino) -1-phenyl-methylidene] -5-methylsulfonylamino-2-indolinone}
  • _{4. (Z) -3- [1- (4-Dipropylaminomethyl-phenylamino) -1-phenyl-methylidene] -5-methylsulfonylamino-2-indolinone}
  • _{5. (Z) -3- [1- (4-Hexamethyleneiminomethylphenylamino) -1-phenylmethylidene] -5-methylsulfonylamino-2-indolinone}
  • _{6. (Z) -3- {1- [4- (4-Methylpiperidinomethyl) phenylamino] -1-phenylmethylidene} -5-methylsulfonylamino-2-indolinone}
  • _{7. (Z) -3- [1- (4-morpholinomethyl-phenylamino) -1-phenyl-methylidene] -5-methylsulfonylamino-2-indolinone}
  • _{8. (Z) -3- {1- [4- (4-Methylpiperazinomethyl) phenylamino] -1-phenylmethylidene} -5-methylsulfonylamino-2-indolinone}
  • _{9. (Z) -3- [1- (4-piperazinomethylphenylamino) -1-phenylmethylidene] -5-methylsulfonylamino-2-indolinone}
  • _{10. (Z) -3- {1- [4- (2,6-Dimethylpiperidinomethyl) phenylamino] -1-phenylmethylidene} -5-methylsulfonylamino-2-indolinone}
  • _{11. (Z) -3- [1- (4-Diethylaminomethyl-phenylamino) -1-phenyl-methylidene] -5-ethylsulfonylamino-2-indolinone}
  • _{12. (Z) -3- [1- (4-Dipropylaminomethyl-phenylamino) -1-phenyl-methylidene] -5-ethylsulfonylamino-2-indolinone}
  • _{13. (Z) -3- [1- (4-Hexamethyleneiminomethylphenylamino) -1-phenylmethylidene] -5-ethylsulfonylamino-2-indolinone}
  • _{14. (Z) -3- {1- [4- (4-Methylpiperidinomethyl) phenylamino] -1-phenylmethylidene} -5-ethylsulfonylamino-2-indolinone}
  • _{15. (Z) -3- [1- (4-morpholinomethyl-phenylamino) -1-phenyl-methylidene] -5-ethylsulfonylamino-2-indolinone}
  • _{16. (Z) -3- {1- [4- (4-Methylpiperazinomethyl) phenylamino] -1-phenylmethylidene} -5-ethylsulfonylamino-2-indolinone}
  • _{17. (Z) -3- [1- (4-piperazinomethylphenylamino) -1-phenylmethylidene] -5-ethylsulfonylamino-2-indolinone}
  • _{18. (Z) -3- {1- [4- (2,6-Dimethylpiperidinomethyl) phenylamino] -1-phenylmethylidene} -5-ethylsulfonylamino-2-indolinone}
  • _{19. (Z) -3- [1- (4-Dimethylaminomethylphenylamino) -1-phenylmethylidene] -5-propylsulfonylamino-2-indolinone}
  • _{20. (Z) -3- [1- (4-Diethylaminomethylphenylamino) -1-phenylmethylidene] -5-propylsulfonylamino-2-indolinone}
  • _{21. (Z) -3- [1- (4-Dipropylaminomethylphenylamino) -1-phenylmethylidene] -5-propylsulfonylamino-2-indolinone}
  • _{22. (Z) -3- [1- (4-Hexamethyleneiminomethylphenylamino) -1-phenylmethylidene] -5-propylsulfonylamino-2-indolinone}
  • _{23. (Z) -3- {1- [4- (4-Methylpiperidinomethyl) phenylamino] -1-phenylmethylidene} -5-propylsulfonylamino-2-indolinone}
  • _{24. (Z) -3- [1- (4-Morpholinomethylphenylamino) -1-phenylmethylidene] -5-propylsulfonylamino-2-indolinone}
  • _{25. (Z) -3- {1- [4- (4-Methylpiperazinomethyl) phenylamino] -1-phenylmethylidene} -5-propylsulfonylamino-2-indolinone}
  • _{26. (Z) -3- [1- (4-piperazinomethylphenylamino) -1-phenylmethylidene] -5-propylsulfonylamino-2-indolinone}
  • _{27. (Z) -3- {1- [4- (2,6-Dimethylpiperidinomethyl) phenylamino] -1-phenylmethylidene} -5-propylsulfonylamino-2-indolinone}
  • _{28. (Z) -3- [1- (4-Dimethylaminomethylphenylamino) -1-phenylmethylidene] -5-cyclopropylsulfonylamino-2-indolinone}
  • _{29. (Z) -3- {1- [4- (2-Dimethylaminoethyl) phenylamino] -1-phenylmethylidene} -5-cyclopropylsulfonylamino-2-indolinone}
  • _{30. (Z) -3- [1- (4-Diethylaminomethyl-phenylamino) -1-phenyl-methylidene] -5-cyclopropylsulfonylamino-2-indolinone}
  • _{31. (Z) -3- [1- (4-Dipropylaminomethyl-phenylamino) -1-phenyl-methylidene] -5-cyclopropylsulfonylamino-2-indolinone}
  • _{32. (Z) -3- [1- (4-Hexamethyleneiminomethylphenylamino) -1-phenylmethylidene] -5-cyclopropylsulfonylamino-2-indolinone}
  • _{33. (Z) -3- {1- [4- (4-Methylpiperidinomethyl) phenylamino] -1-phenylmethylidene} -5-cyclopropylsulfonylamino-2-indolinone}
  • _{34. (Z) -3- [1- (4-Morpholinomethylphenylamino) -1-phenylmethylidene] -5-cyclopropylsulfonylamino-2-indolinone}
  • _{35. (Z) -3- {1- [4- (4-Methylpiperazinomethyl) phenylamino] -1-phenylmethylidene} -5-cyclopropylsulfonylamino-2-indolinone}
  • _{36. (Z) -3- [1- (4-piperazinomethylphenylamino) -1-phenylmethylidene] -5-cyclopropylsulfonylamino-2-indolinone}
  • _{37. (Z) -3- {1- [4- (2,6-Dimethylpiperidinomethyl) phenylamino] -1-phenylmethylidene} -5-cyclopropylsulfonylamino-2-indolinone}
  • _{38. (Z) -3- [1- (4-Dimethylaminomethyl-phenylamino) -1-phenyl-methylidene] -5-trifluoromethylsulfonylamino-2-indolinone}
  • _{39. (Z) -3- {1- [4- (2-Dimethylaminoethyl) phenylamino] -1-phenylmethylidene) -5-trifluoromethylsulfonylamino-2-indolinone}
  • _{40. (Z) -3- [1- (4-Diethylaminomethyl-phenylamino) -1-phenyl-methylidene] -5-trifluoromethylsulfonylamino-2-indolinone}
  • _{41. (Z) -3- [1- (4-Dipropylaminomethyl-phenylamino) -1-phenyl-methylidene] -5-trifluoromethylsulfonylamino-2-indolinone}
  • _{42. (Z) -3- {1- [4- (Pyrrolidin-1-yl) methylphenylamino] -1-phenylmethylidene} -5- trifluoromethylsulfonylamino-2-indolinone}
  • _{43. (Z) -3- [1- (4-Piperidinomethyl-phenylamino) -1-phenyl-methylidene] -5-trifluoromethylsulfonylamino-2-indolinone}
  • _{44. (Z) -3- [1- (4-Hexamethyleneiminomethyl-phenylamino) -1-phenyl-methylidene] -5-trifluoromethylsulfonylamino-2-indolinone}
  • _{45. (Z) -3- {1- [4- (4-Methylpiperidinomethyl) phenylamino] -1-phenylmethylidene} -5-trifluoromethylsulfonylamino-2-indolinone}
  • _{46. (Z) -3- [1- (4-Morpholinomethylphenylamino) -1-phenylmethylidene] -5-trifluoromethylsulfonylamino-2-indolinone}
  • _{47. (Z) -3- {1- [4- (4-Methylpiperazinomethyl) phenylamino] -1-phenylmethylidene} -5-trifluoromethylsulfonylamino-2-indolinone}
  • _{48. (Z) -3- [1- (4-Piperazinomethyl-phenylamino) -1-phenyl-methylidene] -5-trifluoromethylsulfonylamino-2-indolinone}
  • _{49. (Z) -3- {1- (4- (2,6-Dimethylpiperidinomethyl) phenylamino] -1-phenylmethylidene} -5-trifluoromethylsulfonylamino-2-indolinone}
  • _{50. (Z) -3- [1- (4-Dimethylaminomethylphenylamino) -1-phenylmethylidene] -5-isopropylsulfonylamino-2-indolinone}
  • _{51. (Z) -3- [1- (4-Diethylaminomethyl-phenylamino) -1-phenyl-methylidene] -5-isopropylsulfonylamino-2-indolinone}
  • _{52. (Z) -3- [1- (4-Dipropylaminomethyl-phenylamino) -1-phenyl-methylidene] -5-isopropylsulfonylamino-2-indolinone}
  • _{53. (Z) -3- {1- [4- (Pyrrolidin-1-yl) methylphenylamino] -1-phenylmethylidene} -5-isopropylsulfonylamino-2-indolinone}
  • _{54. (Z) -3- [1- (4-Hexamethyleneiminomethyl-phenylamino) -1-phenyl-methylidene] -5-isopropylsulfonylamino-2-indolinone}
  • _{55. (Z) -3- {1- [4- (4-Methylpiperidinomethyl) phenylamino] -1-phenylmethylidene} -5-isopropylsulfonylamino-2-indolinone}
  • _{56. (Z) -3- [1- (4-morpholinomethyl-phenylamino) -1-phenyl-methylidene] -5-isopropylsulfonylamino-2-indolinone}
  • _{57. (Z) -3- {1- [4- (4-Methylpiperazinomethyl) phenylamino] -1-phenylmethylidene} -5-isopropylsulfonylamino-2-indolinone}
  • _{58. (Z) -3- [1- (4-Piperazinomethylphenylamino) -1-phenylmethylidene] -5-isopropylsulfonylamino-2-indolinone}
  • _{59. (Z) -3- {1- [4- (2,6-Dimethylpiperidinomethyl) phenylamino] -1-phenylmethylidene} -5-isopropylsulfonylamino-2-indolinone}
  _{Example 201 Dry ampoule with 75 mg of active ingredient per 10 ml composition active substance 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. Example 202 Dry ampoule with 35 mg of active ingredient per 2 ml composition active substance 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 is carried out, and the solution is ready for use with water for injections. Example 203 Tablet with 50 mg of active ingredient composition (1) Active ingredient 50.0 mg (2) milk sugar 98.0 mg (3) corn starch 50.0 mg (4) polyvinyl pyrrolidone 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 204 Tablet with 350 mg of active ingredient 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 a facet on both sides and a partial notch on one side.
  Tablet diameter: 12 mm. Example 205 Capsules with 50 mg of active ingredient composition (1) Active ingredient 50.0 mg (2) Dried corn starch 58.0 mg (3) powdered milk sugar 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. Example 206 Capsules with 350 mg of active ingredient composition (1) Active ingredient 350.0 mg (2) Dried corn starch 46.0 mg (3) powdered milk sugar 30.0 mg (4) Magnesium stearate 4.0 mg 430.0 mg 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 0 hard gelatin capsules on a capsule filling machine. Example 207 Suppositories with 100 mg of active ingredient Contains 1 suppository active substance 100.0 mg Polyethylene glycol (MG 1500) 600.0 mg Polyethylene glycol (MG 6000) 460.0 mg polyethylene sorbitan monostearate 840.0 mg 2,000.0 mg manufacturing The polyethylene glycol is melted together with polyethylene sorbitan monostearate. The milled active substance is homogeneously dispersed in the melt at 40 ° C. It is cooled to 38 ° C and poured into weakly pre-cooled suppository molds.}

Claims (15)

1. Substituted indolinones of the general formula I
their isomers, their salts, in particular their physiologically tolerable salts,
wherein
X represents an oxygen or sulfur atom,
R _{1 represents} a hydrogen atom, a C _1-4 alkoxycarbonyl or C _2-4 alkanoyl group,
R ₂ for a C _1-6 alkyl group optionally substituted by one or more halogen atoms or a phenyl group or a C _2-6 alkenyl group optionally substituted by a phenyl group, in which the phenyl part in each case by a fluorine, chlorine, bromine or Iodine atom, which may be substituted by a C _1-3 alkyl or C _1-3 alkoxy group,
represents a phenyl group which can be mono- or disubstituted by fluorine, chlorine, bromine or iodine atoms, by C _1-3 -alkyl or C _1-3 -alkoxy groups, where the substituents can be identical or different,
represents a phenyl group substituted by a trifluoromethyl, carboxy, C _1-3 alkoxycarbonyl, aminocarbonyl, cyano, aminomethyl, nitro or amino group, represents a C _4-6 alkyl, C _3-7 - Cycloalkyl, trimethylphenyl or naphthyl group represents a 5-membered heteroaromatic group which is optionally substituted by a C _1-3 -alkyl group and which is in the heteroaromatic part
an imino group optionally substituted by a C _1-3 alkyl group, an oxygen or sulfur atom,
an imino group optionally substituted by a C _1-3 alkyl group and an oxygen, sulfur or nitrogen atom,
an imino group optionally substituted by a C _1-3 alkyl group and two nitrogen atoms, or
contains an oxygen or sulfur atom and two nitrogen atoms and to which a phenyl ring can be fused via two adjacent carbon atoms,
or represents a 6-membered heteroaromatic group which is optionally substituted by a C _1-3 alkyl group and which contains one or two heteroatoms in the heteroaromatic part and to which a phenyl ring can be fused via two adjacent carbon atoms,
R _{3 represents} a hydrogen atom or a C _1-6 alkyl group,
for one optionally by a fluorine, chlorine or bromine atom, by a C _1-3 alkyl, hydroxy, C _1-3 alkoxy, C _1-3 alkylsulfenyl, C _1-3 alkylsulfinyl, C _1-3 - alkylsulfonyl, phenylsulfenyl, phenylsulfinyl, phenylsulfonyl, nitro, amino, C _{1- 3} alkylamino, di (C _1-3 alkyl) amino, C _2-5 - Alkanoylamino- or N- (C _1-3 - alkylamino) -C _2-5 -alkanoylamino group substituted phenyl group,
R _{4 represents} a phenyl or naphthyl group optionally substituted by R ₇ , which may additionally be substituted by a chlorine or bromine atom or a nitro group, represents a 5-membered heteroaromatic group which has an imino group, an oxygen or sulfur atom or one Imino group, contains an oxygen or sulfur atom and one or two nitrogen atoms, or
for 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 in which the abovementioned 5 - and 6-membered heteroaromatic groups can be fused to a phenyl ring via 2 adjacent carbon atoms, or
R ₅ and R ₆ each independently represent hydrogen atoms or C _1-3 alkyl groups, and
R _{7 represents} a fluorine, chlorine, bromine or iodine atom or a cyano group, represents a methoxy group or a C _2-3 alkoxy group which is in the 2- or 3-position by an amino, C _1-3 - Alkylamino-, di- (C _1-3 -alkyl) -amino- or 5- to 7-membered cycloalkyleneimino group can be substituted, wherein in each case an alkyl part in the above-mentioned alkylamino and dialkylamino groups can be substituted by a phenyl group,
for a trifluoromethyl, nitro, amino, C _1-3 alkylamino, di (C _1-3 alkyl) amino, C _2-5 alkanoylamino, N- (C _1-3 alkyl ) -C _2-5 -alkanoylamino-, C _1-5 -alkylsulfonylamino-, N- (C _1-3 -alkyl) -C _1-5 -alkylsulfonylamino-, phenylsulfonylamino-, N- (C _1-3 -alkyl) - phenylsulfonylamino, aminosulfonyl, C _1-3 alkylaminosulfonyl or di (C _1-3 alkyl) aminosulfonyl group, each additionally having an alkyl part in the aforementioned alkylamino and dialkylamino groups by a carboxy, C _{1- 3} -alkoxycarbonyl, aminocarbonyl, C _1-3 alkylaminocarbonyl, di (C _1-3 alkyl) aminocarbonyl, 2-dimethylaminoethylaminocarbonyl or N-methyl- (2-dimethylaminoethyl) aminocarbonyl group and can be substituted each additionally the alkyl part of the abovementioned alkanoylamino or alkysulfonylamino groups can be substituted by a phenyl, amino, C _1-3 alkylamino, di (C _1-3 alkyl) amino or a 4 to 7-membered cycloalkyleneimino group .
represents a C _2-4 -alkylamino group which is terminated in the 2-, 3- or 4-position by an amino-, C _1-3 -alkylamino-, di- (C _1-3 -alkyl) -amino, benzylamino, N- (C _1-3 alkyl) - benzylamino, C _2-5 alkanoylamino or N- (C _1-3 alkyl) -C _2-5 alkanoylamino group is substituted and in which the amine hydrogen atom is additionally substituted by a C _2-5 - alkanoyl, benzoyl, C _1-5 alkylsulfonyl or phenylsulfonyl group can be replaced, it being possible for the latter C _2-5 alkanoyl or C _1-5 alkylsulfonyl groups in the alkyl part to be substituted by a phenyl group,
represents a carbonyl group which is substituted by a hydroxy, C _1-3 alkoxy, amino, C _1-3 alkylamino, N- (C _1-5 alkyl) -C _1-3 alkylamino or C _5-7 - cycloalkyleneimino group is substituted,
represents a C _1-3 alkyl group which can be substituted by an amino, C _1-5 alkylamino, C _5-7 cycloalkylamino or phenylC _1-3 alkylamino group, each of which is additionally on the amine nitrogen atom a C _1-4 alkyl, C _5-7 cycloalkyl or C _2-4 alkenyl or C _1-4 alkyl group may be substituted, where
the aforementioned C _1-4 alkyl substituent each additionally by a cyano, carboxy, C _1-3 alkoxycarbonyl, C _2-4 alkanoyl, pyridyl, imidazolyl, benzo [1,3] dioxole or Phenyl group, where the phenyl group can be mono-, di- or tri-substituted by fluorine, chlorine or bromine atoms, by methyl, methoxy, trifluoromethyl, cyano or nitro groups and the substituents can be identical or different, or in 2- , 3- or 4-position can be substituted by a hydroxy group,
represents a C _1-3 alkyl group which is substituted by a hydroxy, carboxy, morpholino, thiomorpholino, 1-oxothiomorpholino, 1,1-dioxothiomorpholino, piperazino, N- (C _{1- 3-} alkyl) -piperazino- or N-benzyl-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 which may be terminally substituted by an amino or C _2-4 alkanoylamino group, may be substituted by a C _5-7 cycloalkyl or phenyl group and by a hydroxy group and one in the above-mentioned cycloalkyleneimino groups methylene group adjacent to the nitrogen atom can be replaced by a carbonyl group,
represents a C _1-3 alkyl group which is substituted by a 5- to 7-membered cycloalkyleneimino group, where the above-mentioned 5- to 7-membered cycloalkyleneimino groups have 2 adjacent carbon atoms, optionally by fluorine, chlorine or bromine atoms, phenyl group mono- or disubstituted by methyl or methoxy groups, where the substituents may be the same or different, or an oxazolo or imidazolo optionally substituted by a fluorine, chlorine, bromine or iodine atom, by a methyl, methoxy or amino group -, Thiazolo-, Pyridino-, Pyrazino- or Pyrimidinognippe is fused, wherein the above-mentioned monosubstituted phenyl groups may additionally be substituted by a fluorine, chlorine or bromine atom, by a methyl, methoxy or nitro group, or
represents an imidazolyl or 1H-C _1-3 alkylimidazolyl group. 2. Compound of formula I according to claim 1, wherein the sulfonylamino radical of the formula R ₂ -SO ₂ NR ₆ - is linked to the 5-position of the indolinone group. 3. A compound of formula I according to claim 1 or 2, wherein R ₃ for a optionally by a fluorine, chlorine or bromine atom, by a C _1-3 alkyl, hydroxy, C _1-3 alkoxy, C _1-3 alkylsulfenyl, C _1-3 alkylsulfinyl, C _1-3 alkylsulfonyl, phenylsulfenyl, phenylsulfinyl, phenylsulfonyl, nitro, amino, C _1-3 alkylamino, di (C _1-3- alkyl) -amino-, C _2-5 -alkanoylamino- or N- (C _1-3 -alkylamino) -C _2-5 -alkanoylamino group substituted phenyl group. 4. A compound of formula I according to any one of claims 1 to 3, wherein R ₂ for a C _1-3 alkyl group optionally substituted by one or more halogen atoms or a phenyl group or a C _2-4 alkenyl group optionally substituted by a phenyl group, in which the phenyl part can each be substituted by a fluorine, chlorine, bromine or iodine atom, by a C _1-3 alkyl or C _1-3 alkoxy group. 5. A compound of formula I according to any one of claims 1 to 4, wherein
X represents an oxygen atom,
R _{1 represents} a hydrogen atom,
R _{2 represents} a C _1-3 alkyl group optionally substituted by one or more fluorine atoms or a phenyl group or a C _2-4 alkenyl group optionally substituted by a phenyl group,
represents a phenyl group substituted by fluorine, chlorine, bromine or iodine atoms, by C _1-3 - alkoxy mono- _1-3 alkyl or C or may be disubstituted, the substituents can be identical or different,
represents a phenyl group substituted by a trifluoromethyl, carboxy, C _1-3 alkoxycarbonyl, cyano, aminocarbonyl, aminomethyl, nitro or amino group,
represents a C _4-6 alkyl, C _3-7 cycloalkyl, trimethylphenyl or naphthyl group, or
represents a pyridinyl, quinolyl, isoquinolyl, oxazolyl, isoxazolyl, imidazolyl or 1- (C _1-3 alkyl) imidazolyl group optionally substituted by a C _1-3 alkyl group,
R _{3 represents} a hydrogen atom or a C _1-4 alkyl group, or
represents a phenyl group optionally substituted by a fluorine, chlorine, bromine or iodine atom, by a C _1-3 alkyl, C _1-3 alkoxy, nitro or amino group,
R _{4 represents} a phenyl group optionally substituted by R ₇ ,
R ₅ and R ₆ each represent a hydrogen atom, and
R _{7 represents} a fluorine, chlorine, bromine or iodine atom,
for a methoxy, nitro, cyano, carboxy, C _1-3 alkoxycarbonyl, aminocarbonyl, C _1-3 alkylaminocarbonyl, di (C _1-3 alkyl) aminocarbonyl, phenyl-C _1-3 - alkylaminocarbonyl, N- (phenyl-C _1-3 -alkyl) -C _1-3 -alkylaminocarbonyl or 5- to 7-membered cycloalkyleneimnocarbonyl group,
for a C _1-3 alkyl group which is substituted by a carboxy, C _1-3 alkoxycarbonyl, aminocarbonyl, C _1-3 alkylaminocarbonyl, di (C _1-3 alkyl) aminocarbonyl, phenyl C _1-3 - alkylaminocarbonyl-, N- (phenyl-C _1-3 -alkyl) -C _1-3 -alkylaminocarbonyl-, 5- to 7-membered cycoalkyleneiminocarbonyl-, amino-, C _1-3 -alkylamino-, di - (C _1-3 alkyl) amino, phenyl C _1-3 alkylamino, N- (phenyl C _1-3 alkyl) -C _1-3 alkylamino or 5- to 7-membered Cycoalkylenimino group stands,
wherein the above-mentioned 5- to 7-membered cycoalkyleneimino parts can be substituted by one or two C _1-3 alkyl groups and at the same time in the above-mentioned 5- to 7-membered cycoalkyleneimino parts a methylene group in the 2-position can be replaced by a carbonyl group or in the 6- and 7-membered cycoalkyleneimino parts mentioned above, a methylene group in the 4-position through an oxygen atom, through an imino, N- (C _1-3 -alkyl) -imino-, N- (phenyl-C _1-3 - alkyl) - imino or N- (C _1-5 -alkoxycarbonyl) -imino group can be replaced,
for an amino, C _1-3 alkylamino, phenylC _1-3 alkylamino, C _1-5 alkanoylamino, phenylC _1-4 alkanoylamino, C _1-5 alkoxycarbonylamino, phenyl -C _1-3 - alkoxycarbonylamino-, C _1-5 -alkylsulfonylamino-, phenyl-C _1-3 -alkylsulfonylamino- or phenylsulfonylamino group, in which the hydrogen atom of the amino group can be replaced by a C _1-3 -alkyl group, the C _1-3 -alkyl moiety by a carboxy, C _{1- 3} alkoxycarbonyl, aminocarbonyl, C _1-3 -alkylaminocarbonyl-, di- (C _1-3 alkyl) - aminocarbonyl, phenyl-C _1-3 -alkylaminocarbonyl-, N- (phenyl-C _1-3 -alkyl) -C _1-3 - alkylaminocarbonyl or C _4-6 -cycoalkyleneimnocarbonyl group or from position 2 also by amino-, C _1-3 -alkylamino-, di- (C _1-3 -alkyl) -amino-, phenyl-C _1-3 -alkylamino-, N- (phenyl-C _1-3 -alkyl) -C _1-3 -alkylamino-, C _2-5 -alkanoylamino- , N- (C _1-3 alkyl) -C _2-5 alkanoylamino, C _1-5 alkoxycarbonylamino or N- (C _1-5 alkoxycarbonyl) -C _1-3 alkylamino group. 6. A compound of formula I according to any one of claims 1 to 5, wherein
R _{2 represents} a C _1-3 alkyl group which is optionally substituted by a phenyl group, a C _1-3 perfluoroalkyl group or a phenylvinyl group,
represents a phenyl group which is represented by a fluorine, chlorine, bromine or iodine atom, by a C _1-3 -alkyl, C _1-3 -alkoxy, nitro, amino, cyano, caynomethyl or aminomethyl group can be substituted
represents a C _4-6 alkyl, C _3-7 cycloalkyl, trimethylphenyl or naphthyl group, or
represents a pyridinyl, quinolyl, isoquinolyl, oxazolyl, isoxazolyl, imidazolyl or 1- (C _1-3 alkyl) imidazolyl group optionally substituted by a C _1-3 alkyl group,
R _{3 represents} a phenyl group optionally substituted by a fluorine, chlorine, bromine or iodine atom, by a C _1-3 alkyl, C _1-3 alkoxy, nitro or amino group,
R ₄ for a phenyl group substituted by R ₇ , which is additionally substituted by a chlorine atom or
a nitro group can be substituted,
R _{7 represents} a fluorine, chlorine, bromine or iodine atom,
represents a methoxy, nitro, cyano, carboxy, methoxycarbonyl, aminocarbonyl, methylaminocarbonyl, dimethylaminocarbonyl, benzylaminocarbonyl, N-benzyl methylaminocarbonyl, pyrrolidinocarbonyl or piperidinocarbonyl group,
represents a methyl or ethyl group which is substituted by a carboxy, methoxycarbonyl, aminocarbonyl, methylaminocarbonyl, dimethylaminocarbonyl, benzylaminocarbonyl, N-benzylmethylaminocarbonyl, pyrrolidinocarbonyl, piperidinocarbonyl, amino, methylamino, dimethylamino , Benzylamino-, N-benzyl-methylamino-, C _2-4 - alkanoylamino-, N-methyl-C _2-4 -alkanoylamino-, tert.butyloxycarbonylamino-, N-methyl tert.butyloxycarbonylamino-, pyrrolidino-, piperidino-, Dimethylpiperidino, 2-oxo piperidino, piperazino, 4-methyl-piperazino, 4-benzyl-piperazino, 4-tert-butoxycarbonyl-piperazino or morpholino group may be substituted, or
represents an amino, methylamino, ethylamino, C _1-3 alkanoylamino, phenylacetylamino, tert.butoxycarbonylamino, C _1-4 alkylsulfonylamino, phenylmethylsulfonylamino or phenylsulfonylamino group in which the hydrogen atom of the amino group passes through a methyl or ethyl group can be replaced, the methyl or ethyl part in each case by a carboxy, methoxycarbonyl, aminocarbonyl, methylaminocarbonyl or dimethylaminocarbonyl group or the ethyl part also from position 2 by an amino, methylamino, dimethylamino, benzylalkylamino -, N-Benzyl-methylamino, C _2-3 - alkanoylamino, N-methyl-C _2-3 -alkanoylamino, tert-butyloxycarbonylamino or N-methyl-tert.butyloxycarbonylamino group can be substituted. 7. A compound of formula I according to any one of claims 1 to 6, wherein R _{4 represents} a phenyl group substituted in the 4-position by R ₇ . 8. Compound of formula IA
wherein R _{7 has} the meaning given in claims 1 to 7. 9. A compound of formula IA according to claim 8, wherein R _{7 is} selected from the group consisting of:
Hydrogen, (2,6-dimethylpiperidino) methyl, (N-ethylsulfonyl) -N- (2-dimethylaminoethyl) aminocarbonylmethyl) amino, N-ethylsulfonyl-N- (N- (2-dimethylaminoethyl) -N-methyl- amino-carbonylmethyl) -amino, 2-oxopiperidinomethyl, 4-benzyl-piperazino-methyl, 4-methylpiperazinomethyl, 4-tert-butoxycarbonyl-piperazinomethyl, acetylamino, acetylaminomethyl, amino, aminomethyl, benzylaminocarbonyl, benzylaminocarbonyl methyl, carboxy, carboxymethyl Cyano, dimethylaminocarbonylmethylamino, dimethylaminoethyl, dimethylaminomethyl, ethoxycarbonylmethyl, ethylsulfonylamino, formylamino, methoxycarbonyl, methylsulfonylamino, morpholinomethyl, N- (2- (N-acetyl-N-methyl-amino) -ethyl) -ethylsulfonylamino, N- Acetyl-N-methyl-amino) -ethyl) -methylsulfonylamino, N- (2- (N-acetyl-N-methyl-amino) -ethyl) -propionylamino, N- (2- (N-acetyl-N-methyl- amino) ethylamino, N- (2- (N-benzyl-N-methylamino) ethyl) propionylamino, N- (2-acetylaminoethyl) -N-acetylamino, N- (2- Acetylamino-ethyl) -N-ethylsulfonyl- am ino, N- (2-acetylamino-ethyl) -N-methylsulfonyl-amino, N- (2-acetylamino-ethyl) -N-propionyl-amino, N- (2-aminoethyl) -N-methylsulfonyl-amino, N- (2-dimethylamino-ethyl) - N-acetyl-amino, N- (2-dimethylamino-ethyl) -N-butylsulfonyl-amino, N- (2-dimethylamino ethyl) -N-methylsulfonyl-amino, N- (2- Dimethylamino-ethyl) -N-phenylsulfonyl-amino, N- (2-dimethylaminoethyl) -N-propylsulfonyl-amino, N- (2-methylamino-ethyl) -acetylamino, N- (2-methylamino-ethyl) -N-methylsulfonyl -amino, N- (2-methylamino-ethyl) -propionylamino, N- (2-propionylamino-ethyl) -N-propionyl-amino, N- (aminocarbonylmethyl) -N-methylsulfonylamino, N- (dimethylaminocarbonylmethyl) -N- (methylsulfonyl-amino, N- (dimethylaminoethyl) -N-methylsulfonyl-amino, N- (methylaminocarbonyl-methyl) -N-methylsulfonyl-amino, N- (piperidinomethylcarbonyl) -N-methyl-amino, N-acetyl-N- ( 2- (N-benzyl-N-methyl-amino) -ethylamino, N-acetyl-N- (2-benzyl-oxycarbonylamino-ethyl) - amino, N-carboxylmethyl-N-methylsulfonyl-amino, N-ethylsulfonyl-N- hydroxycarbonylmethyl-amino , N-methyl-N-acetyl-amino, N-methyl-N-ethylsulfonyl-amino, N-methyl-N-formyl-amino, N-methyl-N-methylsulfonyl-amino, N-methyl-N-propionyl amino, Piperazinomethyl, propionylamino, pyrrolidin-1-yl-methyl and tert-butoxycarbonylamino. 10. Compound of formula IB
wherein R ₂ and R _{7 have} the meanings given in claims 1 to 7. 11. A compound of formula IB according to claim 10, wherein R _{7 has} one of the meanings given in claim 7 and R _{2 is} selected from the group consisting of:
1-methyl-1H-imidazol-4-yl, 2-aminophenyl, 2-chlorophenyl, 2-cyanophenyl, 2-nitrophenyl, 2-phenylethene, 3-aminomethylphenyl, 3-aminophenyl, 3-chlorophenyl, 3-cyanophenyl, 3- Methoxyphenyl, 3-methylphenyl, 3-nitrophenyl, 4-aminophenyl, 4-chlorophenyl, 4-methoxyphenyl, 4-methylphenyl, 4-nitrophenyl, benzyl, quinolin-8-yl, cyclopropyl, ethyl, isopropyl, methyl, naphthalene-1- yl, naphthalin-2-yl, propyl, pyrid-2-yl, pyrid-3-yl, 3,5-dimethyl-isoxazol-4-yl and 2,4,6-trimethylphenyl 12. A compound of formula I selected from the group consisting of:
(Z) -3- {1- [4- (N- (2-Aminoethyl) -N-methylsulfonylamino) phenylamino] -1-phenylmethylidene} -5-phenylsulfonylamino-2-indolinone
(Z) -3- {1- [4- (N- (2-Dimethylaminoethyl) -N-phenylsulfonylamino) phenylamino) -1-phenylmethylidene} -5-phenylsulfonylamino-2-indolinone
(Z) -3- {1- [4- (4-Methylpiperazinomethyl) phenylamino] -1-phenylmethylidene} -5-phenylsulfonylamino-2-indolinone
(Z) -3- {1- [4- (pyrrolidin-1-ylmethyl) phenylamino] -1-phenylmethylidene} -5-phenylsulfonylamino-2-indolinone
(Z) -3- {1- [4- (N-methyl-N-acetylamino) phenylamino] -1-phenylmethylidene} -5-phenylsulfonylamino-2-indolinone
(Z) -3- (1-phenylamino-1-phenyl-methylidene) -5-phenylsulfonylamino-2-indolinone
(Z) -3- [1- (4-chloro-phenylamino) -1-phenyl-methylidene] -5-phenylsulfonylamino-2-indolinone
(Z) -3- {1- [4- (N- (2-Propionylaminoethyl) -N-propionylamino) phenylamino] -1-phenylmethylidene} -5-phenylsulfonylamino-2-indolinone
(Z) -3- [1- (4-Dimethylaminomethyl-phenylamino) -1-phenyl-methylidene] -5-phenylsulfonylamino-2-indole
(Z) -3- [1- (4- (N-Methyl-N-methylsulfonylamino) phenylamino) -1-phenylmethylidene] -5-phenylsulfonylamino-2-indolinone
(Z) -3- [1- (4- (N-Methyl-N-piperidinomethylcarbonylamino) phenylamino) -1-phenylmethylidene] -5-phenylsulfonylamino-2-indolinone
(Z) -3- {1- [4- (pyrrolidin-1-ylmethyl) phenylamino] -1-phenylmethylidene} -5-benzylsulfonylamino-2-indolinone
(Z) -3- {1- [4 - ((2,6-Dimethylpiperidino) methyl) phenylamino] -1-phenylmethylidene} -5- (3-nitrophenylsulfonylamino) -2-indolinone
(Z) -3- {1- [4-Dimethylaminomethylphenylamino] -1-phenylmethylidene} -5-ethylsulfonylamino-2-indolinone
(Z) -3- {1- [4- (N-Benzyl-N-methylaminomethyl) phenylamino] -1-phenylmethylidene} -5-ethylsulfonylamino-2-indolinone
(Z) -3- {1- [4- (2-Dimethylaminoethyl) phenylamino] -1-phenylmethylidene} -5-ethylsulfonylamino-2-indolinone
(Z) -3- {1- [4- (pyrrolidin-1-ylmethyl) phenylamino] -1-phenylmethylidene} -5- (pyridin-3 - ylsulfonylamino) -2-indolinone
(Z) -3- {1- [4- (pyrrolidin-1-ylcarbonyl) phenylamino] -1-phenylmethylidene} -5- (pyridin-3-ylsulfonylamino) -2-indolinone
(Z) -3- [1- (4-piperidinomethylphenylamino) -1-phenylmethylidene] -5-methylsulfonylamino-2-indolinone (Z) -3- {1- [4- (piperidinomethyl) phenylamino] - 1-phenyl-methylidene} -5-ethylsulfonylamino-2-indolinone
(Z) -3- {1- [4- (piperidinomethyl) phenylamino] -1-phenylmethylidene} -5-isopropylsulfonylamino-2-indolinone
(Z) -3- {1- [4- (piperidinomethyl) phenylamino] -1-phenylmethylidene} -5- (naphthalin-1-ylsulfonylamino) -2-indolinone
(Z) -3- {1- [4- (piperidinomethyl) phenylamino] -1-phenylmethylidene} -5- (3-nitrophenylsulfonylamino) -2-indolinone
(Z) -3- {1- [4- (piperidinomethyl) phenylamino] -1-phenylmethylidene} -5- (3,5-dimethylisoxazol-4-ylsulfonylamino) -2-indolinone
(Z) -3- {1- [4- (piperidinomethyl) phenylamino] -1-phenylmethylidene} -5-cyclopropylsulfonylamino-2-indolinone
(Z) -3- {1- [4- (piperidinomethyl) phenylamino] -1-phenylmethylidene} -5- (pyridin-3-ylphenylsulfonylamino) -2-indolinone
(Z) -3- {1- [4- (pyrrolidin-1-ylmethyl) phenylamino] -1-phenylmethylidene} -5-cyclopropylsulfonylamino-2-indolinone
(Z) -3- {1- [4- (pyrrolidin-1-ylmethyl) phenylamino] -1-phenylmethylidene} -5-propylsulfonylamino-2-indolinone
(Z) -3- {1- [4- (pyrrolidin-1-ylmethyl) phenylamino] -1-phenylmethylidene} -5-ethylsulfonylamino-2-indolinone
(Z) -3- (1- [4- (pyrrolidin-1-ylmethyl) phenylamino] -1-phenylmethylidene} -5-methylsulfonylamino-2-indolinone
(Z) -3- {1- [4- (Benzylaminocarbonyl) phenylamino] -1-phenyl-methylidene} -5-phenylsulfonylamino-2-indolinone
(Z) -3- {1- [4- (N-Dimethylaminocarbonylmethyl-N-acetylamino) phenylamino] -1-phenyl methylidene} -5-phenylsulfonylamino-2-indolinone
(Z) -3- [1- (4-piperidinomethylphenylamino) -1-phenylmethylidene] -5- (4-aminophenylsulfonylamino) -2-indolinone
(Z) -3- {1- [4- (N- (2-Dimethylaminoethyl) -N-methylsulfonylamino) phenylamino) -1-phenylmethylidene) -5- (N-methyl-N-phenylsulfonyl- amino) -2-indolinone 13. A process for the preparation of a compound of formulas I, IA or IB according to any one of claims 1 to 11, characterized in that

• a) a compound of the general formula
  in the
  X, R ₂ , R ₃ and R ₆ are defined as mentioned at the beginning and
  R _{8 has} one of the meanings given for R ₁ or a protective group for the nitrogen atom of the lactam group, where R _{8 can} also represent a bond to a solid phase which may be formed via a spacer, and
  Z _{1 is} a halogen atom, a hydroxy, alkoxy or aralkoxy group, e.g. B. a chlorine or bromine atom, a methoxy, ethoxy or benzyloxy group,
  reacted with an amine of the general formula III
  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; or
• b) a compound of the general formula
  in the
  R ₁ and R ₃ to R _& are defined as mentioned at the outset, with a compound of the general formula
  R ₂ -SO ₂ -OH (V),
  in the
  R ₂ is defined as mentioned at the outset, or is reacted with its reactive derivatives.

14. Pharmaceutical preparation containing a compound according to one of the Claims 1 to 11 and pharmaceutically acceptable carriers and / or excipients. 15. Use of a compound according to any one of claims 1 to 11 for the Manufacture of a medicament for the therapy and prevention of diseases which are characterized by excessive or abnormal cell proliferation.