SK18222000A3 - SUBSTITUTED INDOLINONES, THE PRODUCTION THEREOF AND THEIR USE ASì (54) MEDICAMENTS - Google Patents

Abstract

The invention relates to substituted indolinones of general formula (I) in which R1 to R5 and X are defined as in Claim No. 1, to the isomers thereof, and to their salts, especially to the physiologically compatible salts thereof, which exhibit valuable pharmacological characteristics, especially an inhibiting effect on different kinases and cyclin/CDK complexes, and on the proliferation of different tumor cells. The invention also relates to medicaments containing these compounds, to their use, and to a method for the production thereof.

Description

The invention relates to substituted indolinones, a process for their preparation, a pharmaceutical composition containing them and their use as a medicament.

BACKGROUND OF THE INVENTION

WO 96/40116 discloses indolinone compounds capable of modulating, regulating and / or inhibiting tyrosine kinase signal transduction. The compounds of this specification are useful for treating diseases associated with unregulated TKS transduction, including diseases associated with cell proliferation, such as cancer, atherosclerosis, arthritis and restenosis, and metabolic diseases such as diabetes.

WO 98/07695 discloses indolinone compounds capable of modulating, regulating and / or inhibiting protein kinase signal transduction. The compounds of this disclosure are useful for treating diseases associated with unregulated protein kinase signal transduction, including diseases associated with cell proliferation, such as cancer, atherosclerosis, arthritis and restenosis, and metabolic diseases, such as diabetes. Also disclosed is a process for the preparation of these compounds, as well as novel water-soluble indolinone compounds and a process for their preparation.

SUMMARY OF THE INVENTION

The present invention provides substituted indolinones of formula (I):

x

• · • · • ··· ·· • · • · • · • · • ·· • · • t • · • • · ·· ·· · · ···· · ·

their isomers, salts, in particular physiologically acceptable salts with valuable properties.

The compounds of formula I, wherein R ¹ is a hydrogen atom or a prodrug group have valuable pharmacological properties, particularly an inhibitory effect on various kinases, especially on complexes of CDKs (CDK1, CDK2, CDK3, CDK4, CDK6, CDK7, CDK8 and CDK9) with specific cyclins (A, B1, B2, C, D1, D2, D3, E, F, G1, G2, H, I and K) and viral cyclins (see L. Mengtao, J. Virology 71 (3), 1984-1991 (1997), and other compounds of formula I wherein R ¹ is not a hydrogen atom and is not a precursor residue, are valuable intermediates for the preparation of the above compounds.

Accordingly, the invention provides compounds of formula I, wherein the compounds wherein R ¹ is hydrogen or a precursor moiety have valuable pharmacological properties, medicaments containing pharmacologically active compounds, their uses and methods for their preparation.

In the above general formula

X is an oxygen or sulfur atom,

R ¹ is hydrogen, C 1-4 -alkoxycarbonyl or C 2-4 -alkanoyl, R ² is carboxy or C 1-4 -alkoxycarbonyl or aminocarbonyl optionally substituted with one or two C 1-3 -alkyl groups, wherein the substituents may be same or different,

R ³ is a hydrogen atom or a C 1-6 -alkyl group which, from position 2 with respect to the carbon atom of the group R ³ -C (R ⁴ NR ⁵ ) = may be substituted by a fluorine, chlorine or bromine atom, a hydroxy group, a C 1-3 -alkoxy group C1-3alkylsulfenyl; C1-3alkylsulfinyl; C1-3alkylsulfenyl; _3- alkylsulfonyl, phenylsulfenyl, phenylsulfinyl, phenylsulfonyl, amino, C 1-6 -alkylamino, di- (C _1-3 -alkyl) amino, C 2-5 -alkanoylamino or N - (C _1-3 -alkylamino) -C 2 5-alkanoylamino,

R ⁴ is hydrogen, C 1-6 -alkyl or C 5-7 -cycloalkyl optionally substituted with C 1-6 -alkyl; _{A 3-} alkyl group in which one methylene group at the 4-position relative to the carbon atom of the group R ³ -C (R ⁴ NR ⁵ ) = can be replaced by an imino group which is optionally substituted by C 1-6 alkyl; _{A 3-} alkyl group, a phenyl or naphthyl group which may be substituted by a fluorine, chlorine, bromine or iodine atom,

-3-methoxy optionally substituted with 1 to 3 fluorine atoms, C 2-3 -alkoxy which in the 2 or 3 position may be substituted by C 1-3 alkylamino, di- (C _1-3 -alkyl) amino or 5- to 7-membered cycloalkyleneimino, wherein the alkyl moiety in said alkylamino and dialkylamino groups may be additionally substituted with phenyl, trifluoromethyl, amino, C 1-3 -alkylamino, di- (C 1-3 -alkyl) amino, C 2-5 -alkanoylamino, N - (C _1-3 -) alkyl) -C2-5-alkanoylamino, C1-5-alkylsulfonylamino, N- (C1-3-alkyl) -C1-5-alkylsulfonylamino, phenylsulfonylamino, N- (C1-3-alkyl) -phenylsulfonylamino, aminosulfonyl, A C 1-3 -alkylaminosulfonyl group or a di- (C 1-3 alkyl) -aminosulfonyl group, wherein the alkyl moiety in said alkyl-amino and dialkylamino groups may be substituted by phenyl, carbonyl, which is substituted with hydroxy, C 1-3 -alkoxy, amino, C 1-3 -alkylamino or N - (C 1-5 -alkyl) -C _1-3 alkylamino, wherein the alkyl moiety in said groups may be additionally substituted with carboxy, C 1-3 -alkoxycarbonyl or phenyl or in the 2 or 3 position may be substituted by a di- (C 1-3 -alkyl) amino, piperazine, N - (C 1-3 -alkyl) -piperazine or 5-7 membered cycloalkyleneimino group,

Ci-3-alkyl group which is substituted by amino, Ci-7-alkylamino, -C-D-cycloalkylamino, C ₅ -7 -cycloalkyl-C-3-alkylamino, or phenyl-C-3-alkylamino group which may be on a carbon nitrogen of an amine additionally substituted with a C 1-3 -alkyl group in which the hydrogen atoms are partially or completely replaced by fluorine atoms, a C 5-7 -cycloalkyl group, a C 2-4 -alkenyl group or a C 1-4 -alkyl group, said C 1-4 alkyl substituent being optionally substituted cyano, carboxy, C 1-3 alkoxycarbonyl, pyridyl, imidazolyl, benzo [1,3] dioxole or phenyl, wherein the phenyl may be mono-, di- or trisubstituted by fluorine, chlorine or bromine atoms, methyl, methoxy, trifluoromethyl, cyano or nitro and the substituents may be the same or different, or in the 2, 3 or 4 position may be substituted hydroxy group, ·· ·· • ·

-4 ·· ··· 99 · 99

C 1-3 -alkyl, which may be substituted by hydroxy, carboxy, thiomorpholine, 1-oxido-thiomorpholine, 1,1-dioxidothiomorpholine, piperazine, N - (C 1-3 -alkyl) -piperazine or N- phenyl-piperazine, 5- to 7-membered cycloalkenyleneimino or 4- to 7-membered cycloalkyleneimino, wherein said 5- to 7-membered cycloalkyleneimino groups may be substituted with one or two C 1-3 alkyl, C 3-8 -cycloalkyl or phenyl groups, C 1-6 3-alkoxycarbonyl and hydroxy, and in said cycloalkyleneimino groups the methylene adjacent to the nitrogen atom may be replaced by a carbonyl group,

A C 1-3 alkyl group substituted with a 5- to 7-membered cycloalkyleneimino group, wherein said 5- to 7-membered cycloalkyleneimino group is fused via a 2 adjacent carbon atom with a phenyl group optionally mono or disubstituted with fluorine, chlorine or bromine atoms, methyl or methoxy groups, wherein the substituents may be the same or different, or an oxazole, imidazole, thiazole, pyridine, pyrazine or pyrimidine group optionally substituted with a fluorine, chlorine, bromine or iodine atom, methyl, methoxy or amino group, said monosubstituted phenyl groups may be additionally substituted by a fluorine, chlorine or bromine atom, a methyl group, a methoxy group or a nitro group,

A 5-membered heteroaromatic group containing an imino, oxygen or sulfur atom, or an imino, oxygen or sulfur atom and one or two nitrogen atoms, or

A 6-membered heteroaromatic group containing one, two or three nitrogen atoms, wherein said 5- and 6-membered heteroaromatic groups may be additionally substituted by a chlorine or bromine atom or a methyl group, or to said 5- and 6-membered heteroaromatic groups through 2 adjacent carbon atoms, the phenyl core may be fused, and

R ⁵ is a hydrogen atom or a C 1-3 -alkyl group.

• ·· • · · • ··· • e • · • · · · • · • ·· • • • · • • · · ··· ·· • · ·· • ···· • ·· • •

The carboxy, amino or imino groups present in the compound of formula (I) may be further substituted with in vivo cleavable residues.

In addition to the alkoxycarbonyl and alkanoyl groups mentioned above, in vivo leaving groups such as an acyl group such as a benzoyl group, a pyridinoyl group, a pentanoyl group or a hexanoyl group, an allyloxycarbonyl group, a C 1-6 -alkoxycarbonyl group such as a pentoxycarbonyl group, , octyloxycarbonyl, nonyloxycarbonyl, decyloxycarbonyl, undecyloxycarbonyl, dodecyloxycarbonyl or hexadecyloxycarbonyl, phenyl-C 1-6 -alkoxycarbonyl, such as benzyloxycarbonyl-alkoxy, phenylethoxycarbonyl, phenylethoxycarbonyl or phenylethoxycarbonyl , A C 1-3 -alkoxy-C 2-4 -alkoxy-C 2-4 -alkoxycarbonyl group or a R ^c CO-O- (R ^d CR ^e ) -OCO group in which

R ^c is C 1-6 -alkyl, C 5-6 -cycloalkyl, phenyl or phenyl-C 1-3 -alkyl,

R ^e is hydrogen, C _1-3 -alkyl, C 3-7 -cycloalkyl or phenyl and

R ^d is a hydrogen atom or a C 1-3 -alkyl group or a radical R ^c CO-O- (R ^d CR ^e ) -O-, wherein said ester residues may also be used in vivo as a carboxy-convertible group.

Preferred compounds of formula I are those in which:

X is an oxygen atom, R ¹ is a hydrogen atom, R ² is an aminocarbonyl group,

R ³ is a hydrogen atom or a C 1-4 alkyl group which, from position 2 with respect to the carbon atom of the group R ³ -C (R ⁴ NR ⁵ ) =, may be substituted by a chlorine or bromine atom or a phenylsulfonyl group,

R ⁴ is a hydrogen atom, a C 1-3 -alkyl group or a cyclopentyl or cyclohexyl group optionally substituted by a methyl group, wherein in the cyclopentyl and cyclohexyl methylene group in the 3 or 4 position relative to the carbon atom · ··· ··· · · · ·

-6R ³ -C (R ⁴ NR ⁵ ) = may be replaced by an imino group which may be optionally substituted by a methyl group, a phenyl group which may be substituted by a fluorine, chlorine, bromine or iodine atom, a methoxy group optionally substituted by 1 to 3 fluorine atoms .

C 2-3 alkoxy group in the 2 or 3 is substituted methylamino, dimethylamino or 5- to 7-membered cycloalkyleneimino group, wherein the methyl group of said amino group may additionally be substituted by phenyl, trifluoromethyl, amino, C _2, 5-alkanoylamino A / - (Ci-3 alkyl) _2-C, 5-alkanoylamino, C-alkylsulfonylamino, / V- (Ci-3 alkyl) C 5 alkylsulfonylamino, phenylsulfonylamino, A / - (Ci_3-alkyl) - phenylsulfonylamino or aminosulfonyl, wherein the alkyl portion of said alkylamino and dialkylamino groups may be substituted with phenyl, carbonyl which is substituted with hydroxy, C 1-3 -alkoxy, amino, C 1-3 -alkylamino or N - (C 1-5 -alkyl) ) -C 1-3 -alkylamino, wherein the alkyl portion of said groups may be additionally substituted by carboxy, C 1-3 -alkoxycarbonyl or phenyl or in the 2 or 3 position may be substituted by a di- (C _1-3 -alkyl) amino, piperazine, N - (C 1-3 -alkyl) -piperazine or 5- to 7-membered cycloalkyleneimino group,

C 1-3 -alkyl which is substituted with amino, C 1-7 -alkylamino, C 5-7 -cycloalkylamino, C 5-7 -cycloalkyl-C 1-3 -alkylamino or phenyl-C 1-3 -alkylamino which may be additionally present on the amine nitrogen atom Ci_3-substituted alkyl group wherein the hydrogen atoms are partially or fully substituted by fluorine, C 7-cycloalkyl, _C2-.4 alkenyl, or CM-alkyl, wherein said Cualkylový substituent may be additionally substituted by a cyano, carboxy, A C 1-3 -alkoxycarbonyl group, a pyridyl group, an imidazolyl group, a benzo [1,3] dioxole group or a phenyl group, wherein the phenyl group may be monosubstituted with a fluorine, chlorine atom or · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · ·

-Bromine, methyl, methoxy, cyano, trifluoromethyl or nitro, or it may be di- or trisubstituted by fluorine, chlorine or bromine atoms, methyl or methoxy groups and the substituents may be the same or different, or in the 2, 3 or 4 position may be substituted by hydroxy,

C 1-3 -alkyl, which may be substituted by hydroxy, carboxy, thiomorpholine, 1-oxido-thiomorpholine, 1,1-dioxido-thiomorpholine, piperazine, N - (C 1-3 -alkyl) piperazine or N - phenyl-piperazine, 5- to 7-membered cycloalkenyleneimino or 4- to 7-membered cycloalkyleneimino, wherein said 5- to 7-membered cycloalkyleneimino groups may be substituted by one or two C 1-3 -alkyl groups, cyclohexyl or phenyl, C 1-3 alkyl, cyclohexyl, phenyl, carboxy or C 1-4 -alkoxycarbonyl and hydroxy and in said cycloalkyleneimino groups the methylene adjacent to the nitrogen atom may be replaced by a carbonyl group,

A C 1-3 -alkyl group which is substituted by a 5- to 7-membered cycloalkyleneimino group, wherein said 5- to 7-membered cycloalkyleneimino group is fused via a 2 adjacent carbon atom with a phenyl group optionally mono- or disubstituted with fluorine, chlorine or bromine atoms with methyl or a fused pyrazine or thiazole group optionally substituted with an amino group, said monosubstituted phenyl groups may be additionally substituted with a fluorine, chlorine or bromine atom, a methyl group, a methoxy group or a nitro group optionally substituted by a pyridyl group a chlorine or bromine atom or a methyl group, an oxazolyl group, an isoxazolyl group, an imidazolyl group or a thiazolyl group optionally substituted by a methyl group and can be fused through it via 2 adjacent carbon atoms and R ⁵ is hydrogen or C 1-6 alkyl. _3- alkyl,

• ·· ·· · • ··· ·· • · • · • · • · • ·· • · • · • · • · · ··· ·· • · · · • ·· ·· • · ·· • · ·

in particular, those compounds of formula I in which R ¹ to R ³ and R ⁵ are as defined above and

R ⁴ is a hydrogen atom, a C 1-6 alkyl group or a C 5-6 cycloalkyl group optionally substituted with a C 1-3 alkyl group wherein the methylene group at the 3 and 4 positions relative to the carbon atom of the R ³ -C (R ⁴ NR ⁵ ) group = can be replaced by an imino group which is optionally substituted by a C 1-3 alkyl group, a phenyl or a naphthyl group which can be substituted by a fluorine, chlorine, bromine or iodine atom, C 1-6 -alkyl; _3- alkoxy, amino, C 1-6 alkyl; ₃ alkylamino, di (Ci.3 alkyl) amino, C _2, 5-alkanoylamino, / N (C ₃ alkylamino) -) - C ₂ 5-alkanoylamino, C-alkylsulfonylamino, N- (C 1-6 alkyl) -C _1-5 -alkylsulfonylamino, phenylsulfonylamino or N - (C _1-3 alkyl) -phenylsulfonylamino or C 1-3 -alkyl, which may be substituted with C _1-5 -alkylamino, di- (C _1-5 -alkyl) ) -amino, thiomorpholino, 1-oxido-thiomorpholino, 1,1-dioxide-thiomorpholino, piperazino, / V- (Ci. ₃ alkyl) piperazino group, a / V-phenyl piperazine group, a C ₅ .7 -cykloalkenyléniminoskupinou or C4-7-cycloalkyleneimino group, wherein the _C-5 .7 cycloalkyleneimino groups may be substituted by one or two Ci-3-alkyl, C5-7-cycloalkyl or phenyl, C. _3- alkyl, C 5,7 -cycloalkyl, phenyl, carboxy or C 1-4 -alkoxycarbonyl and hydroxy, their isomers and salts.

Particularly preferred are those compounds of formula I wherein R ¹ to R ⁵ are as defined above and R ² is in the 5-position, especially those compounds in which

X is an oxygen atom,

R ¹ is a hydrogen atom,

R ² at the 5-position is an aminocarbonyl group,

R ³ is a hydrogen atom or a C 1-4 alkyl group which in the terminal position may be substituted by a chlorine or bromine atom or a phenylsulphonyl group,

R ⁴ is a hydrogen atom, a C 1-3 -alkyl group or a cyclopentyl or cyclohexyl group optionally substituted with a methyl group, wherein in the cyclohexyl

• · • · • ··· ·· ·· • · · · • · · ·· • · • · · · ·· ·· ·· ···· · · • ·

a methylene group in the 4-position relative to the carbon atom of the group R ³ C (R ⁴ NR ⁵ ) = may be replaced by an optionally substituted methyl group, a phenyl group which may be substituted by a fluorine, chlorine, bromine or iodine atom, methyl or ethyl , which may be substituted by C 1-3 -alkylamino, di- (C 1-3 -alkyl) amino, thiomorpholine, 1-oxidothiomorpholine, 1,1-dioxido-thiomorpholine, N-phenylpiperazine, 5- to 6 a membered cycloalkenyleneimino group or a 5- to 7-membered cycloalkyleneimino group, wherein said 5- to 7-membered cycloalkyleneimino groups may be substituted by one or two methyl, cyclohexyl or phenyl, methyl, cyclohexyl or phenyl or hydroxy groups, or methyl and hydroxy, or an ethyl group which is substituted by a phenyl group substituted in the 4-position, a 5- to 7-membered cycloalkyleneimino group, wherein said cycloalkyleneimino group is fused via a 2 adjacent carbon atom with a phenyl, methyl or ethyl group substituted with amino, methylamino or ethylamino group which are additionally substituted on the benzyl amine nitrogen atom the phenyl part of said groups may be monosubstituted by fluorine, chlorine or bromine, methyl, methoxy, cyano, trifluoromethyl or nitro, or di- or trisubstituted by fluorine, chlorine or bromine atoms, methyl or methoxy groups and the substituents may be the same or different, wherein said monosubstituted phenyl groups may be additionally substituted by fluorine, chlorine or bromine atoms, methyl, methoxy or nitro, and

R ⁵ is a hydrogen atom or a C 1-6 alkyl group, isomers and salts thereof.

Particularly preferred are those compounds of formula I in which

X is an oxygen atom, • · · · φ · φ · φ ·

R ¹ is a hydrogen atom,

R ² at the 5-position is an aminocarbonyl group,

R ³ is H or C ₄ -alkyl,

R ⁴ is a phenyl group which may be substituted by a fluorine, chlorine, bromine or iodine atom, a methyl or ethyl group which may be substituted by a C 1-3 -alkylamino group, a di- (C 1-3 -alkyl) amino group, a thiomorpholine group, -oxidothiomorpholine, 1,1-dioxido-thiomorpholine, N-phenylpiperazine, 5- to 6-membered cycloalkenyleneimino or 5- to 7-membered cycloalkyleneimino, wherein said 5- to 7-membered cycloalkyleneimino may be substituted with one or two methyl, cyclohexyl or phenyl, methyl, cyclohexyl or phenyl and hydroxy, or methyl or ethyl substituted by a phenyl substituted in the 4-position with a 5- to 7-membered cycloalkyleneimino group, wherein at said cycloalkyleneimino groups there are over 2 adjacent carbon atoms additionally condensed f an aryl, methyl or ethyl group substituted with an amino, methylamino or ethylamino group which is additionally substituted on the amine nitrogen atom by a benzyl group and in the phenyl moiety may be monosubstituted by a fluorine, chlorine or bromine atom, a methyl group, a methoxy group, a cyano group, a cyano group or nitro, disubstituted by methyl or methoxy, or trisubstituted by methyl or methoxy, and the substituents may be the same or different, said monosubstituted phenyl groups being substituted by a fluorine, chlorine or bromine atom, methyl, methoxy or nitro, and

R ⁵ is a hydrogen atom or a C 1-4 -alkyl group, their isomers and salts thereof.

Particularly preferred compounds are, for example, the following compounds:

··················

-11- (a) 3-Z- [1- (4-Piperidinomethylphenylamino) -1-methyl-methylene] -5-amido-2-indolinone, ( b) 3-Z- [1- (4-Bromo-phenylamino) -1-methyl-methylene] -5-amido-2-indolinone, (c) 3-Z- [1- (4-Piperidinomethyl-phenylamino) -1-butyl- (d) 3-Z- [1- (4-Chloro-phenylamino) -1-methyl-methylene] -5-amido-2-indolinone, (e) 3-Z- (methylene) -5-amido-2-indolinone; 1-Phenylaminomethylene) -5-amido-2-indolinone, (f) 3-Z- [1- (4- (N-Benzyl- N -methyl-aminomethyl) -phenylamino) -1-methyl-methylene] - 5-amido-2-indolinone, (g) 3-Z- [1- (4 - (N - (4-Chlorobenzyl) -aminomethyl) -phenylamino) -1-methyl-methylene] -5-amido-2-indolinone, (h 13-Z- [1- (4- (N-Benzyl- N -ethyl-aminomethyl) -phenylamino) -1-methyl-methylene] -5-amido-2-indolinone, (i) 3-Z- [1] - (4- (N -Benzylaminomethyl) phenylamino) -1-methylmethylene] -5-amido-2-indolinone, (j) 3-Z- [1- (4- (N-Benzyl - N) -methyl) (aminomethyl) -phenylamino) -methylene] -5-amido-2-indolinone, (k) 3-Z- [1- (4- (2,3,4,5-Tetrahydro-benzo (c)) azepin-3-yl) (methyl) -phenylamino) -1-methylmethylene] -5-amido-2-indolinone, (1) 3-Z- [1- (4-Piperidinomethyl-3-nitro-phenylamino) -1-methyl-methylene] -5-amido-2-indolinone, and (m) 3-Z- [1- (4-Methyl-3-nitro-phenylamino)] -1-methyl-methylene] -5-amido-2-indolinone, as well as their isomers and salts.

The compounds of the invention can be prepared, for example, by the following methods, essentially known in the literature.

a. To the compound of formula II

R ³

in which

·· • ··· • · • · • · · · • · • · · • · · • · • · • · • • · • ·· • · ···· ·· ·

X and R ³ are as defined above,

R ² is defined as R ² above,

R ⁶ is a hydrogen atom or a protecting group for a nitrogen atom in a lactam group, one of which R ² or R ⁶ may optionally also represent a bond formed through a spacer to a solid phase, and the other of R ² or R ⁶ has the meanings given above, and Z ¹ is a halogen atom, a hydroxy-, alkoxy- or aralkoxy group, for example a chlorine or bromine atom, a methoxy-, ethoxy- or benzyloxy group, is treated with an amine of the formula III

R ⁵ /

H-N (III) \

R ⁴ in which

R ⁴ and R ⁵ are as defined above, followed, if necessary, by cleavage of the nitrogen protecting group used in the lactam group or from the solid phase.

As the nitrogen protecting group in the lactam group, there may be, for example, acetyl, benzoyl, ethoxycarbonyl, tert-butyloxycarbonyl or benzyloxycarbonyl, and as the solid phase a resin such as 4- (2 ', 4 ^, -dimethoxyphenylaminomethyl) -phenoxy a resin, wherein the bond is preferably via an amino group, or a p-benzyloxybenzyl alcohol resin, wherein the bond is preferably via an intermediate, such as a 2,5-dimethoxy-4-hydroxybenzyl derivative.

The reaction is preferably carried out in a solvent such as dimethylformamide, toluene, acetonitrile, tetrahydrofuran, dimethylsulfoxide, methylene chloride or mixtures thereof, optionally in the presence of an inert base such as triethylamine, N-ethyldiisopropylamine or sodium bicarbonate at a temperature between 20 and 175 ° C. the protective group used can also be cleaved off as a result of the amidization.

When Z ¹ is a halogen atom in the compound of formula (II), the reaction is preferably carried out in the presence of an inert base at a temperature between 20 and 120 ° C.

• ·· • · • ··· • · · · · • · • · • · · · · • · • • · · · • · • · • · · · ·· ·· · · ···· · · · ·

When Z ¹ in the compound of formula II is hydroxy, alkoxy or aralkoxy, the reaction is preferably carried out at a temperature between 20 and 200 ° C.

The optional desired subsequent cleavage of the protecting group used is preferably carried out either hydrolytically in an aqueous or alcoholic solvent, for example in methanol / water, ethanol / water, isopropanol / water, tetrahydrofuran / water, dioxane / water, dimethylformamide / water, methanol or ethanol in the presence of alkaline. a base such as lithium hydroxide, sodium hydroxide or potassium hydroxide at a temperature between 0 and 100 ° C, preferably at a temperature between 10 and 50 ° C, or preferably by amidization with an organic base such as ammonia, methylamine, butylamine, dimethylamine or piperidine; a solvent such as methanol, ethanol, dimethylformamide and mixtures thereof, or in excess of the amine used at temperatures between 0 and 100 ° C, preferably at temperatures between 10 and 50 ° C.

The cleavage of the solid phase used is preferably carried out with trifluoroacetic acid and water at a temperature between 0 and 35 ° C, preferably at room temperature.

b. For a compound of formula I, wherein R ² represents one of the abovementioned aminocarbonyl groups is carried amidization of IV

(IV) in which

R ¹ and R ³ to R ⁵ have been defined above, or a reactive derivative thereof with an amine of the general formula

H - (R ⁷ NR ⁸ ) (V) ·· ··

-14 in which

R ⁷ and R ⁸ , which may be the same or different, represent hydrogen atoms or C 1-3 alkyl groups.

The amidization is preferably carried out in a solvent such as methylene chloride, diethyl ether, tetrahydrofuran, toluene, dioxane, acetonitrile, dimethylsulfoxide or dimethylformamide, optionally in the presence of an inorganic or tertiary organic base, preferably at temperatures between 20 ° C and the boiling point of the solvent used. The amidization is carried out with the corresponding acid, preferably in the presence of a dehydrating agent, for example in the presence of isobutyl chloroformate, tetraethyl carbonate, trimethyl orthoacetate, 2,2-dimethoxypropane, tetramethoxysilane, thionyl chloride, trimethylchloride, trimethylchloride, N, N-dicyclohexylcarbodiimide, N, Ndicyclohexylcarbodiimide, N-hydroxysuccinimide, N, N'-dicyclohexylcarbodiimide, 1-hydroxybenzotriazole, 2- (1H-benzotriazol-1-yl) -1,1,3,3-tetramethylboron 2- (1H-benzotriazol-1-yl) -1,1,3,3-tetramethyluronium tetrafluoroborate / 1-hydroxybenzotriazole, Λ /, Λ / - carbonyldiimidazole or triphenylphosphine / carbon tetrachloride, and optionally with the addition of a base such as e.g. pyridine, 4-dimethylaminopyridine, N-methylmorpholine or triethylamine, suitably at temperatures between 0 and 150 ° C, preferably at temperatures between 0 and 100 ° C, and acylation with a corresponding reactive compound such as an anhydride, ester, imidazolide or halide, optionally in the presence of a tertiary organic base such as triethylamine, Nethyldiisopropylamine or N-methylmorpholine at temperatures between 0 and 150 ° C, preferably between 50 and 100 ° C.

If a compound of the formula I according to the invention which contains an alkoxycarbonyl group is obtained, it can be converted by hydrolysis to the corresponding carboxy compound, or if a compound of the formula I containing an amino or alkylamino group is obtained, then by alkylation or reductive alkylation can be converted to the corresponding alkylamino - or a dialkylamino compound, or if a compound of formula I containing an amino or alkylamino group is obtained, then it can be converted by acylation to the corresponding acyl compound, or · · ·

When a compound of formula (I) containing a carboxy group is obtained, it can be converted by esterification or amidization to the corresponding ester or aminocarbonyl compound, or, if a compound of formula (I) containing a nitro group is obtained, then converted to the corresponding amino compound.

The subsequent hydrolysis is preferably carried out in an aqueous solvent, for example 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 alkaline 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.

Subsequent reductive alkylations are preferably carried out in a suitable solvent such as methanol, methanol / water, methanol / water / ammonia, ethanol, ether, tetrahydrofuran, dioxane or dimethylformamide optionally with the addition of an acid such as hydrochloric acid in the presence of catalytic excited hydrogen, e.g. in the presence of Raney nickel, platinum or palladium / coal, or in the presence of a metal hydride such as sodium boron hydride, lithium boron hydride or lithium aluminum hydride at temperatures between 0 and 100 ° C, preferably between 20 and 80 ° C.

Subsequent alkylation is carried out with a alkylating agent such as an alkyl halide or dialkyl sulfate, such as methyl iodide, dimethyl sulfate or propyl bromide, preferably in a solvent such as methanol, ethanol, methylene chloride, tetrahydrofuran, toluene, dioxane, dimethylsulfoxide or dimethylformamide in an optional bases such as triethylamine, N-ethyldiisopropylamine or dimethylaminopyridine, preferably at temperatures between 20 ° C and the boiling point of the solvent used.

The subsequent acylation is preferably carried out in a solvent such as methylene chloride, diethyl ether, tetrahydrofuran, toluene, dioxane, acetonitrile, dimethylsulfoxide or dimethylformamide optionally in the presence of an inorganic or tertiary organic base, preferably at temperatures between 20 ° C and the boiling point of the solvent used. The acylation is carried out with the corresponding acid, preferably in the presence of a dehydrating agent, for example in the presence of isobutyl ester.

-16-chloroformic acid, tetraethyl carbonate, trimethyl orthoacetate, 2,2-dimethoxypropane, tetramethoxysilane, thionyl chloride, trimethylchlorosilane, phosphorus trichloride, phosphorus pentoxide, (N, N -dicyclohexylcarbodiimide, N) - (cyclohexylcarbodiimide), _1- hydroxy-dicyclohexylcarbodiimide / 1-hydroxybenzotriazole, 2- (1H-benzotriazol-1-yl) -1,1,3,3-tetramethyluronium tetrafluoroborohydride, 2- (1H-benzotriazol-1-yl) hydroxysuccinimide -1,1,3,3-tetramethyluronium tetrafluoroborate / 1-hydroxybenzotriazole, N, N -carbonyldiimidazole or triphenylphosphine / carbon tetrachloride, and optionally with the addition of a base such as pyridine, 4-dimethylaminopyridine, N-methylmorpholine or triethylamine , suitably at temperatures between 0 and 150 ° C, preferably at temperatures between 0 and 100 ° C, and acylation with the corresponding reactive compound such as anhydride, ester, imidazolide or halide, optionally in the presence of a tertiary organic base such as is, for example, triethylamine, N-methyldiisopropylamine or N-methylmorpholine at temperatures between 0 and 150 ° C, preferably at temperatures between 50 and 100 ° C.

Subsequent esterification or amidization is conveniently carried out by reacting a reactive corresponding carboxylic acid derivative with the corresponding alcohol or amine as described above.

The subsequent reduction of the nitro group is preferably carried out hydrogenolytically, for example with hydrogen in the presence of a catalyst such as palladium / charcoal or Raney nickel in a solvent such as methanol, ethanol, ethyl acetate, dimethylformamide, dimethylformamide / acetone, or glacial acetic acid optionally. such as hydrochloric acid or acetic acid at temperatures between 0 and 50 ° C, preferably at room temperature, and at a hydrogen pressure of 100 to 700 kPa (1 to 7 bar), preferably at a pressure of 300 to 500 kPa (3 to 5 bar) ).

In the reactions described above, optionally reactive groups present, such as, for example, carboxy, amino, alkylamino or imino, can be protected during the reaction by conventional protecting groups which are cleaved again after the reaction.

Suitable protective groups for the carboxyl group include, for example, trimethylsilyl, methyl, ethyl, tert-butyl, benzyl or tetrahydropyranyl, and, for example, trimethylsilyl, methyl, ethyl, tert-butyl, benzyl or tetrahydropyranyl; · · · · · ^{9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9}

-17 as an amino, alkylamino or imino protecting group, an acetyl, trifluoroacetyl, benzoyl, ethoxycarbonyl, tert-butoxycarbonyl, benzyloxycarbonyl, benzyl, methoxybenzyl or 2,4-dimethoxybenzyl group may also be used; phthalyl group.

Optionally, the subsequent cleavage of the protective moiety used is carried out, for example, hydrolytically in an aqueous solvent, for example water, isopropanol / water, tetrahydrofuran / water or dioxane / water, in the presence of an acid such as trifluoroacetic acid, hydrochloric acid or sulfuric acid or alkaline base. such as lithium hydroxide, sodium hydroxide or potassium hydroxide at a temperature between 0 and 100 ° C, but preferably at a temperature between 10 and 50 ° C.

The cleavage of the benzyl, methoxybenzyl or benzyloxycarbonyl radical is carried out, for example, hydrogenolytically, for example 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. such as hydrochloric acid or glacial acetic acid at a temperature between 0 and 50 ° C, preferably at room temperature, and at a hydrogen pressure of 100 to 700 kPa (1 to 7 bar), preferably at a pressure of 300 to 500 kPa (3 to 5 bars).

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

The cleavage of the 2,4-dimethoxybenzyl residue is preferably carried out in trifluoroacetic acid in the presence of anisole.

The cleavage of the tert-butyl or tert-butyloxycarbonyl radical is preferably carried out by exposure to an acid such as trifluoroacetic acid or hydrochloric acid optionally using a solvent such as methylene chloride, dioxane, acetic acid ester or ether.

The cleavage of the phthalyl residue is preferably carried out in the presence of hydrazine or a primary amine such as methylamine, ethylamine or n-18-butylamine in a solvent such as methanol, ethanol, isopropanol, toluene / water or dioxane at a temperature between 20 and 50 ° C.

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

Thus, for example, the compounds of the formula I obtained in racemates can be separated according to known methods (see Allinger NL and Eliel EL, " Topics in Stereochemistry ", Vol. 6, Wiley Interscience, 1971) into their optical antipodes and compounds of of the formula I with at least 2 asymmetric carbon atoms, by virtue of their physicochemical differences according to known methods, for example by chromatography and / or fractional crystallization, to diastereomers which, if present in racemic form, can subsequently be separated into enantiomers according to said process.

The separation of the enantiomers is preferably carried out by column chromatography on chiral phases or by crystallization from an optically active solvent, or by reaction with an optically active substance which forms salts or derivatives with the racemic compound such as esters or amides, in particular acids and their activated derivatives or alcohols, and separating the mixture of diastereomeric salts or derivatives thus obtained, for example because of different solubilities, whereby free antipodes can be liberated from the pure diastereomeric salts or derivatives by treatment with suitable agents. Particularly preferred optically active acids are, for example, the D- and L-forms of tartaric acid, dibenzoyltartaric acid, di-otolyltartaric acid, malic acid, mandelic acid, camphorsulfonic acid, glutamic acid, N-acetylglutamic acid, aspartic acid, N-acetylaspartic acid. or quinic acid. An optically active alcohol is, for example, (+) - or (-) - menthol and an optically active acyl radical in amides is, for example, the (+) - or (-) - mentyloxycarbonyl radical.

The compounds of the formula I obtained can be converted into their salts, especially in the case of pharmaceutical use, into physiologically acceptable salts with inorganic or organic acids. Suitable acids for this purpose are hydrochloric acid, hydrobromic acid, sulfuric acid, acid.

-Phosphoric acid, fumaric acid, succinic acid, lactic acid, citric acid, tartaric acid, maleic acid or methanesulfonic acid.

In addition, the novel compounds of the formula I thus obtained, if they contain a carboxy group, can be subsequently converted, if necessary, with inorganic or organic bases into their salts, especially in the case of pharmaceutical use, into physiologically acceptable salts. Suitable bases are, for example, sodium hydroxide, potassium hydroxide, cyclohexylamine, ethanolamine, diethanolamine and triethanolamine.

The compounds of the formulas I to V used as starting products are partly known from the literature or can be obtained according to methods known in the literature or are described in the examples.

Already mentioned above, the novel compounds of formula I, wherein R ¹ is a hydrogen atom or a prodrug group have valuable pharmacological properties, in particular they have an inhibitory effect on different kinases and cyclin / CDK complexes, on the proliferation of cultivated human tumor cells, and after oral administration for tumor growth in nude mice infected with human tumor cells.

For example, the compounds listed in Table 1 were tested for the following biological properties.

Test 1

Inhibition of cyclin / CDK enzyme and cyclin / CDK activity in vitro

High Five ™ insect cells (BTI-TN-5B1-4) that were infected with recombinant baculovirus at high titers were used to produce active human cyclin / CDK holoenzymes. Using a baculovirus vector containing two promoters (polyhedrin enhancer promoter, P10-enhancer promoter), GST-labeled cyclins (e.g., cyclin D1 or cyclin D3) were expressed with the corresponding His6-labeled CDK subunit (e.g., for CDK4 or CDK6) in the same cell. The active holoenzyme was isolated by affinity chromatography on glutathione-sepharose. Recombinant GST-labeled pRB (aa 379-928) was produced in E. coli and purified by glutathione-sepharose affinity chromatography.

• ··················································· ·· ···· ·· ·

The substrates used for kinase assays were dependent on specific kinases. Histone H1 (Sigma) was used as a substrate for cyclin E / CDK2, cyclin A / CDK2, cyclin B / CDK1 and v-cyclin / CDK6. GST-labeled pRB (aa 379-928) was used as a substrate for cyclin D1 / CDK4, cyclin D3 / CDK4, cyclin D1 / CDK6, and cyclin D3 / CDK6.

Insect cell lysates infected with recombinant baculovirus or even recombinant kinases (obtained from lysates by purification) were incubated with radiolabeled ATP for 45 minutes in the presence of a suitable substrate with various inhibitor concentrations in 1% dimethylsulfoxide (DMSO) at 30 ° C. Substrate proteins with associated radioactivity were precipitated with 5% trichloroacetic acid (TCA) in hydrophobic multi-well PVDF microtiter plates (Millipore) or 5% phosphoric acid solution on Whatman P81 filters. After the scintillation fluid was added, the radioactivity was measured by a Wallace 1450 Microbeta liquid scintillation counter. Two measurements were made for each substance concentration; IC50 values were calculated for enzyme inhibition ·

Test 2

Inhibition of proliferation of cultured human tumor cells

Leiomyosarcoma-derived SK-UT-1B cell line (obtained from the American Type Culture Collection (ATCC)) was cultured in minimal essential medium with non-essential amino acids (Gibco) supplemented with sodium pyruvate (1 mmol), glutamine (2 mmol) and 10 min. % fetal bovine serum (Gibco) and obtained in logarithmic growth phase. Thereafter, SK-UT-1B cells were plated onto Cytostar® multwell plates (Amersham) at a density of 4000 cells per well, and the plates were cultured overnight in an incubator. Different concentrations of compounds (dissolved in DMSO; final concentration less than 1%) were added to the cells. After 48 hours of incubation, ¹⁴ C thymidine (Amersham) was added to each well, and the plates were incubated for an additional 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 of growth was measured in a liquid scintillation counter. · · · · ··· ··· · · ··· ·· ·· ···· ·· ···

-21 Wallace 1450 Microbeta. IC 50 values for inhibition of proliferation (inhibition of embedded ¹⁴ C thymidine) were corrected after background radiation subtraction.

All measurements were made in duplicate.

Test 3

In vivo effects on tumors in nude mice

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

The following table shows the results obtained from in vitro test 2.

Compound (Example #) Inhibition of SK-UT-1B cell proliferation IC50 [μΜ] 1 (11) 0,032 1 (8) 0,060 1 (26) 0,036 1 (3) 0,040 KD 0,100 1 (96) 0,005 1 (91) 0,010 1 (95) 0,008 1 (51) 0,013 1 (105) 0,019 1 (110) 0,020 1 (117) 0,020 Κ71) 0,030

• ································· ··· ··· · · ··· ·· ·· ···· ·· ·

Because of their biological properties, the novel compounds of formula I, their isomers and their physiologically acceptable salts are useful in the treatment of diseases characterized by excessive or inadequate cell proliferation.

Such diseases include, but are not limited to: viral diseases (e.g., HIV and Kaposi's sarcoma); inflammatory and autoimmune diseases (e.g., colitis, arthritis, Alzheimer's disease, glomerulonephritis and wound healing); bacterial, fungal and / or parasitic infections; leukemias, lymphomas and solid tumors; skin diseases (e.g. psoriasis); bone diseases; cardiovascular diseases (e.g. restenosis and hypertrophy). Further, they are useful for protecting proliferating cells (e.g., hair, intestine, blood and progenitor cells) from DNA damage due to exposure to radiation, UV light and / or cytostatic treatment.

These novel compounds can be used for the short or long term treatment of the aforementioned diseases, optionally also in combination with other similar compounds, such as other cytostatics.

The dose required to achieve a corresponding effect is preferably 0.1 to 30 mg / kg, preferably 0.3 to 10 mg / kg, and 0.1 to 100 mg / kg, preferably 0.3 to 30 mg, for intravenous administration. / kg, always 1 to 4 times a day. For this purpose, the compounds of the formula I prepared according to the invention, optionally in combination with other active substances, are mixed together with one or more inert customary carriers and / or diluents, for example, corn starch, milk sugar, cane sugar, microcrystalline cellulose, magnesium stearate. , polyvinylpyrrolidone, citric acid, tartaric acid, water, water / ethanol, water / glycerin, water / sorbitol, water / polyethylene glycol, propylene glycol, cetyl stearyl alcohol, carboxymethylcellulose or fat-containing substances such as petrolatum, or suitable mixtures thereof, such as tablets, dragees, capsules, powders, suspensions, suppositories or solutions for injection or infusion.

The following examples are intended to illustrate the invention in more detail.

23 Examples

Preparation 1

1-Acetyl-2-indolinone-5-carboxylic acid methyl ester

10.5 g of 2-indolinone-5-carboxylic acid methyl ester (prepared according to Ogawa, Hidenori et al. In Chem. Pharm. Bull. 36, 2253-2258 (1988)) is stirred for 4 hours in 30 ml of acetic anhydride at 140 ° C. . It is then allowed to cool, ice water is added and the precipitate is filtered off with suction. The product was washed once more with water, then stirred in methylene chloride, dried over sodium sulfate and concentrated. Yield: 11 g (86% of theory),

Rf value: 0.63 (silica gel), methylene chloride / methanol = 50: 1)

Preparation 2

1-Acetyl-3- (1-ethoxy-1-butyl-methylene) -2-indolinone-5-carboxylic acid methyl ester 1-acetyl-2-indolinone-5-carboxylic acid methyl ester was stirred for 2 hours in 110 ml acetic anhydride and 30 ml of triethyl orthovaleric acid ester at 100 ° C. It is then concentrated, the residue is washed with ether and filtered off with suction.

Yield: 11.5 g (67% of theory)

Rf value: 0.55 (silica gel, methylene chloride / petroleum ether / acetic acid ester = 4: 5: 1)

The following compounds were prepared analogously to Preparation 2:

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

Prepared from 1-acetyl-2-indolinone-5-carboxylic acid methyl ester and trimethyl orthoformate.

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

Prepared from 1-acetyl-2-indolinone-5-carboxylic acid methyl ester and triethyl orthoacetate.

• ·· • · • ··· · · · · • · • • · • • • • • • • • • · · • • • • • ·· ·· · · ···· · ·

(3) 1-Acetyl-3- (1-ethoxy-1-ethylmethylene) -2-indolinone-5-carboxylic acid methyl ester Prepare 1-acetyl-2-indolinone-5-carboxylic acid methyl ester and orthopropionic acid ethyl ester.

Preparation

28.0 g of Rink resin (MBHA resin, Novobiochem) is swollen in 330 ml of dimethylformamide. 330 ml of 30% piperidine in dimethylformamide is then added and shaken for 7 minutes to cleave the 9H-fluoren-9-ylmethoxycarbonyl group. 10.5 g of 2-indolinone-5-carboxylic acid (prepared according to Ogawa, Hidenori et al., Chem. Pharm. Bull. 36, 2253-2258 (1988)), 5.6 g of hydroxybenzotriazole, 13, 3 g of O- (benzotriazol-1-yl) -N, N, N, N, N-tetramethyluronium tetrafluoroborate and 5.7 ml of N-ethyl diisopropylamine in 300 ml of dimethylformamide are shaken for 1 hour. The solution is filtered off with suction and the resin is washed five times with 300 ml of dimethylformamide and three times with 300 ml of methylene chloride. The resin is dried by bubbling nitrogen.

Preparation 4

0.4 g of the coated resin prepared according to Preparation 3 was stirred for 1 hour at 90 ° C with 2.5 ml of acetic anhydride. Then 2.5 ml of trimethyl orthovaleric acid ester is added and shaken for a further 3 hours at 110 ° C. The resin is aspirated and washed with dimethylformamide, methanol and finally methylene chloride.

Yield: 0.6 g wet resin

The following coated resins are prepared analogously to Preparation 4:

(1) Resin coated with 3-Z- (1-ethoxy-methylene) -5-amido-2-indolinone by reacting the product of Preparation 1 with triethyl orthoformate (2) Resin coated with 3-Z- (1-methoxy-1-methylmethylene) ) -5-amido-2-indolinone by reacting the product of Preparation 1 with trimethyl orthoacetate (3) Resin coated with 3-Z- (1-methoxy-1-ethyl-methylene) -5-amido-2-indolinone by reacting the product of Preparation 1 with trimethyl orthopropionate

-25 • ·· ·· ·· ·· ·

9 9 9 9 9 9 99

999 9 9 9 9 9 9

9 9 9 9 9

999 99 99 9999 99 999 (4) 3-Z- (1-methoxy-1-propylmethylene) -5-amido-2-indolinone coated resin by reacting the product of Preparation 1 with ortho-butyric acid trimethyl ester (5) 3-Z- coated resin (1-methoxy-1-ethenylmethylene) -5-amido-2-indolinone by reacting the product of Preparation 1 with 3,3,3-triethoxyprop-1-ene (6) Resin coated with 3-Z- [1-methoxy-1- (3-bromopropyl) methylene] -5-amido-2-indolinone by reacting the product of Preparation 1 with 4-bromo-orthobutyric acid trimethyl ester (7) 3-Z- [1-methoxy-1- (2-phenylsulfonylethyl) methylene coated resin ] -5-amido-2-indolinone by reacting the product of Preparation 1 with 3-phenylsulfonyl-propionic acid triethyl ester

Preparation

4- (N-Ethyl-aminomethyl) -nitrobenzene 4-nitrobenzyl bromide g was dissolved in 25 ml of ethanol, treated with 25 ml of a 10% ethanol solution of ethylamine and heated at reflux for 2 hours. The solution is then concentrated, the residue is triturated with methylene chloride and washed with dilute sodium hydroxide solution. The organic phase is finally concentrated.

Yield: 2.3 g (46% of theory)

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

The following compounds are prepared analogously to Preparation 5:

4 - [N - (4-chlorophenyl-methyl) -aminomethyl] -nitrobenzene 4- (N-cyclohexyl-aminomethyl) -nitrobenzene 4- (N-isopropyl-aminomethyl) -nitrobenzene 4- (N-butyl- aminomethyl) -nitrobenzene 4- (N-methoxycarbonylmethyl-aminomethyl) -nitrobenzene 4- (N -benzyl-aminomethyl) -nitrobenzene 4- (pyrrolidin-methyl) -nitrobenzene 4- (morpholine-methyl) -nitrobenzene

4- (peperidin-methyl) -nitrobenzene 4- (hexamethylenimino-methyl) -nitrobenzene

-264- (4-hydroxy-peperidin-methyl) -nitrobenzene 4- (4-methyl-peperidin-methyl) -nitrobenzene 4- (4-ethyl-peperidin-methyl) -nitrobenzene 4- (4-isopropyl-peperidin) -methyl) -nitrobenzene 4- (4-phenyl-peperidin-methyl) -nitrobenzene 4- (4-benzyl-peperidin-methyl) -nitrobenzene 4- (4-ethoxycarbonyl-peperidin-methyl) -nitrobenzene 4- (dimethylamino-methyl) 4- (di-n-propylamino-methyl) -nitrobenzene 4- (4-tert-butoxycarbonyl-piperazinomethyl) -nitrobenzene

3- (dimethylamino-methyl) -nitrobenzene

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

4- (2-pyrrolidin-ethyl) -nitrobenzene 4- (2-peperidin-ethyl) -nitrobenzene 4- (N-ethyl-N-benzyl-aminomethyl) -nitrobenzene 4- (N-n-propyl-) N-benzyl-aminomethyl) -nitrobenzene 4- [N -methyl- N - (4-chlorophenylmethyl) -aminomethyl] -nitrobenzene 4- [N -methyl- N - (4-bromophenylmethyl) -aminomethyl] -nitrobenzene 4- [N-methyl-N- (3-chlorophenylmethyl) aminomethyl] nitrobenzene 4- [N-methyl-N- (3,4-dimethoxyphenylmethyl) aminomethyl] nitrobenzene 4- [N-methyl - N - (4-methoxyphenylmethyl) aminomethyl] nitrobenzene 4 - [N - (2,2 _L 2-trifluoroethyl) - N -benzylaminomethyl] nitrobenzene 4 - [N - (2,2 _L) 2-Trifluoroethyl) - N - (4-chlorophenylmethyl) aminomethyl] -nitiobenzene 4- (2,6-dimethyl-peperidine-methyl) -nitrobenzene

4- (thiomorpholine-methyl) -nitrobenzene 4- (S-oxido-thiomorpholine-methyl) -nitrobenzene 4- (S, S-dioxido-thiomorpholine-methyl) -nitrobenzene 4- (azetidine-methyl) -nitrobenzene 4- (2 5-Dihydroxypyrol-1-yl-methyl) -nitrobenzene 4- (3,6-dihydro-2H-pyridin-1-ylmethyl) -nitrobenzene 4- (2-methoxycarbonyl-pyrrolidin-methyl) -nitrobenzene

• ·· · · · · ·· · • · · • • • · • • • · • ··· • • • • • • · · · · ··· • · · • • ··· * • ·· • • ·

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

4- (4-phenyl-piperazinyl-methyl) -nitrobenzene 4- (4-phenyl-4-hydroxy-peperidin-methyl) -nitrobenzene 4- [N - (3,4,5-trimethoxy-benzyl) - N -] -methyl-aminomethyl] -nitrobenzene 4- [N- (3,4-dimethoxy-benzyl) - N -ethyl-aminomethyl] -nitrobenzene 4- [N- (3-chlorobenzyl) - N -methyl) -aminomethyl] -nitrobenzene 4- [N- (2,6-dichlorobenzyl) -N-methyl-aminomethyl] -nitrobenzene 4- [N- (4-trifluoromethylbenzyl) -N-methyl-aminomethyl] nitrobenzene 4- (N-benzyl) N- (N-isopropyl-aminomethyl) -nitrobenzene 4- (N-benzyl- N-tert-butyl-aminomethyl) -nitrobenzene 4- (diisopropylamino-methyl) -nitrobenzene 4- (di-n-propylamino-methyl) - nitrobenzene 4- (diisobutylamino-methyl) -nitrobenzene

4- (2,3,4,5-tetrahydro-benzo (d) azepin-3-yl-methyl) -nitrobenzene 4- (2,3-dihydro-isoindol-2-ylmethyl) -nitrobenzene 4- (6 7-Dimethoxy-1,2,3,4-tetrahydro-isoquinolin-2-ylmethyl) -nitrobenzene 4- (1,2,3,4-tetrahydro-isoquinolin-2-ylmethyl) -nitrobenzene 4- N - (2-hydroxyethyl) - N -benzyl-aminomethyl] nitrobenzene 4- [N- (1-ethylpentyl) - N - (pyridin-2-ylmethyl) aminomethyl] nitrobenzene 4 - (N-Phenethyl-N-methyl-aminomethyl) -nitrobenzene 4 - [N - (3,4-dihydroxy-phenethyl) - N -methyl-aminomethyl] -nitrobenzene 4 - [N - (3,4) 5-trimethoxy-phenethyl) - N -methyl-aminomethyl] -nitrobenzene 4- [N - (3,4-dimethoxy-phenethyl) - N -methyl-aminomethyl] -nitrobenzene 4- [N] - (4 -nitro-phenethyl) - N -methyl-aminomethyl] -nitrobenzene 4- (N-phenethyl- N -benzyl-aminomethyl) -nitrobenzene 4- (N-phenethyl-N -cyclohexyl-aminomethyl) -nitrobenzene 4- N- (2- (pyridin-2-yl) ethyl) -N-methyl-aminomethyl-nitrobenzene 4- [N- (2- (pyridin-4-yl) ethyl) -N-methyl-aminomethyl 4- [N- (pyridin-4-yl-methyl) -N-methyl-aminomethyl] -nitrobenzene 4- (dibenzylamino-methyl) -nitrobenzene] -nitrobenzene

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

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

• ·· ·· 99 99 9 ·· · · · 9 99 9 9 9 9 9 • · · · · · 9 9 9 9 9 9 999 99 99 9999 99 999

4- (N-benzyl- N -allyl-aminomethyl) nitrobenzene 4- [N - (benzo (1,3) dioxol-5-ylmethyl) - N -methyl-aminomethyl] nitrobenzene 4- (7-chloro-2,3,4,5-tetrahydro-benzo (d) azepin-3-ylmethyl) -nitrobenzene 4- (7,8-dichloro-2,3,4,5-tetrahydro-benzo ( d) Azepin-3-yl-methyl-nitrobenzene 4- (7-methoxy-2,3,4,5-tetrahydro-benzo (d) azepin-3-yl-methyl) -nitrobenzene 4- (7-methyl- 2,3 _L 4 ₁ 5-tetrahydro-benzo (d) azepin-3-ylmethyl) -nitrobenzene 4- (7,8-dimethoxy-2,3,4,5-tetrahydro-benzo (d) azepin-3) -yl-methyl) -nitrobenzene 4- (6,7-dichloro- _1,2,3,4 -tetrahydro-isoquinolin-2-ylmethyl) -nitrobenzene 4- (6,7-dimethyl-1,2,3) , 4-tetrahydro-isoquinolin-2-yl-methyl) nitrobenzene 4- _{(6-chloro-1-I,} 2,3,4-tetrahydro-isoquinolin-2-yl-methyl) nitrobenzene 4- (7-chloro-1 2,3,4-tetrahydro-isoquinolin-2-yl-methyl) -nitrobenzene 4- (6-methoxy-1,2,3,4-tetrahydro-isoquinolin-2-yl-methyl) -nitrobenzene 4- (7 -methoxy-1,2,3,4-tetrahydro-isoquinolin-2-yl-methyl) -nitrobenzene 4- (2,3,4,5-tetrahydro-azepino (4,5-b) pyrazin-3-yl) -methyl) -nitrobenzene 4- (7-amino-2,3,4), 5-Tetrahydro-azepino (4,5-b) pyrazin-3-ylmethyl-nitrobenzene 4- (2-amino-5,6,7,8-tetrahydro-azepino (4,5-d) thiazol-6- yl-methyl) -nitrobenzene 4- (5,6,7,8-tetrahydro-azepino (4,5-d-thiazol-6-ylmethyl) -nitrobenzene

Preparation 6

4 (A / -ethyl- / V-t-butoxycarbonyl-aminomethyl) -nitrobenzene

2.2 g of 4- (N-ethyl-aminomethyl) nitrobenzene was dissolved in 50 ml of the acid ester and stirred at room temperature for 30 minutes in the presence of 2.6 g of di-tert-butyl dicarbonate. The solution was washed with water and concentrated.

Yield: 3.4 g (97% of theory)

Rf value: 0.90 (silica gel, methylene chloride / methanol = 9: 1)

The following compounds are prepared analogously to Preparation 6:

4- [N- (4-chlorophenylmethyl) -N- tert -butoxycarbonyl-aminomethyl] nitrobenzene 4- (N-cyclohexyl- N-tert-butoxycarbonyl-aminomethyl) nitrobenzene 4- (N-isopropyl- (N-tert-butoxycarbonyl-aminomethyl) -nitrobenzene · ··· ··· ··· ··· ··· ··· ···· ·· ·

-294 - (N-Butyl- N-tert-butoxycarbonyl-aminomethyl) -nitrobenzene 4- (N-methoxycarbonylmethyl- N-tert-butoxycarbonyl-aminomethyl) -nitiobenzene 4- (N-benzyl- N -tert) -butoxycarbonyl-aminomethyl) -nitrobenzene 4- (N-ethyl-N-tert-butoxycarbonyl-aminomethyl) -nitrobenzene

Preparation 7

4 - (/ V-ethyl- / V-t-butoxycarbonyl-aminomethyl) -aniline

6.4 g of 4- (N-ethyl-N-tert-butoxycarbonyl-aminomethyl) nitrobenzene are dissolved in ml of methanol and hydrogenated with 1.5 g of Raney nickel at room temperature and bar pressure. The catalyst was filtered off and the solution was concentrated.

Yield: 4.78 g

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

The following compounds are prepared analogously to Preparation 7:

4 - [N - (- chlorophenylmethyl) - N - tert -butoxycarbonyl-aminomethyl] -aniline 4- (N -cyclohexyl- N - tert -butoxycarbonyl-aminomethyl) -aniline 4 - (N -isopropyl- N - tert -butoxycarbonyl-aminomethyl) -aniline 4- (N -butyl- N - tert -butoxycarbonyl-aminomethyl) -aniline 4- (N -methoxycarbonylmethyl-N-tert-butoxycarbonyl-aminomethyl) -aniline 4 - (/ V-benzyl- / V-t-butoxycarbonyl-aminomethyl) -aniline

4- (pyrrolidin-methyl) -aniline

4- (morpholino-methyl) -aniline

4- (peperidín-methyl) -aniline

4- (hexamethyleneimino-methyl) -aniline

4- (4-hydroxy-peperidín-methyl) -aniline

4- (4-methyl-peperidín-methyl) -aniline

4- (4-Ethyl-peperidin-methyl) -aniline

4- (4-isopropyl-peperidin-methyl) -aniline 4- (4-phenyl-peperidin-methyl) -aniline 4- (4-benzyl-peperidin-methyl) -aniline • ·· ·· ·· ·· ·· · ···· · · · · ··· · · · · ·

-304- (4-ethoxycarbonyl-peperidin-methyl) -aniline 4- (dimethylamino-methyl) -aniline 4- (di-n-propylamino-methyl) -aniline 4- (4-tert-butoxycarbonyl-piperazinomethyl) - aniline

3- (dimethylamino-methyl) -aniline

4- (2-diethylamino-ethyl) -aniline 4- (2-morpholin-ethyl) -aniline 4- (2-pyrrolidin-ethyl) -aniline 4- (2-peperidin-ethyl) -aniline 4- (N -) ethyl N- (N-benzylaminomethyl) -aniline 4- (N-propyl-N-benzyl-aminomethyl) -aniline 4 - (N-methyl-N- (4-chlorophenylmethyl) aminomethyl) - 4- (N-methyl-N- (4-bromophenylmethyl) aminomethyl) aniline 4- (N-methyl- N - (3-chlorophenylmethyl) aminomethyl) aniline 4- (N-methyl-N) - (3,4-Dimethoxyphenylmethyl) aminomethyl) aniline 4- (N-methyl- N - (4-methoxyphenylmethyl) aminomethyl) aniline 4- [N- (2,2 ₁ 2-trifluoroethyl) -] - N-benzyl-aminomethyl] -aniline 4- [N- (2,2,2-trifluoroethyl) - N - (4-chlorophenylmethyl) -aminomethyl] -aniline 4- (2,6-dimethyl-peperidin-methyl) - aniline

4- (S, S-dioxido-thiomorpholine-methyl) -aniline 4- (S-oxido-thiomorpholine-methyl) -aniline 4- (S-oxido-thiomorpholine-methyl) -aniline 4- (azetidin-n-methyl) -aniline 4- (2,5-Dihydropyrrol-1-yl-methyl) -aniline 4- (3,6-dihydro-2H-pyridin-1-ylmethyl) -aniline 4- (2-methoxycarbonyl-pyrrolidine-) methyl) -aniline 4- (3 ₁ 5-dimethyl-peperidín methyl) -aniline 4- (4-phenyl-piperazino-methyl) -aniline 4- (4-phenyl-4-hydroxy-peperidín-methyl) -aniline 4 - [N- (3,4,5-trimethoxybenzyl) - N -methyl-aminomethyl] -aniline 4 - [N - (3,4-dimethoxybenzyl) - N -ethyl-aminomethyl] -aniline 4- ( N-benzyl- N -ethyl-aminomethyl] -aniline · · · · · t · · ·

-31 4 - [N - (3-chlorobenzyl) - N -methyl-aminomethyl] -aniline 4 - [N - (2,6-dichlorobenzyl) -N-methyl-aminomethyl] -aniline 4 - [N - (4-Trifluoromethylbenzyl) -N-methyl-aminomethyl] -aniline 4- (N-benzyl- N -isopropyl-aminomethyl) -aniline 4- (N-benzyl-N-tert-butyl-aminomethyl) -aniline 4 - (diisopropylamino-methyl) -aniline 4- (di-n-propylamino-methyl) -aniline 4- (diisobutylamino-methyl) -aniline

4- (2,3,4,5-tetrahydro-benzo (d) azepin-3-ylmethyl) -aniline 4- (2,3-dihydro-isoindol-2-ylmethyl) -aniline 4- (6 7-Dimethoxy-1,2,3,4-tetrahydro-isoquinolin-2-yl-methyl) -aniline 4- (1,2,3,4-tetrahydro-isoquinolin-2-yl-methyl) -aniline 4- N- (2-hydroxyethyl) - N -benzyl-aminomethyl] -aniline 4- [N- (1-ethyl-pentyl) -N- (pyridin-2-ylmethyl) -aminomethyl] -aniline 4- (N-Phenethyl- N -methyl-aminomethyl) -aniline 4- [N - (3,4-dihydroxy-phenethyl) - N -methyl-aminomethyl) -aniline 4- [N - (3,4, 5-trimethoxy-phenethyl) -N-methyl-aminoniethyl] -aniline 4- [N- (3,4-dimethoxy-phenethyl) - N -methyl-aminomethyl) -aniline 4- [N- (4-nitro-phenethyl) N- (N-methyl-aminomethyl) -aniline 4 - [(N-phenethyl) - N -benzyl-aminomethyl) -aniline 4- (N-phenethyl) -N-cyclohexyl-aminomethyl) -aniline 4 - [/ N- (2- (pyridin-2-yl) -ethyl) - N -methyl-aminomethyl) aniline 4- [N- (2- (pyridin-4-yl) -ethyl) - N -methyl-aminomethyl Aniline 4- [N- (pyridin-4-ylmethyl) -N-methyl-aminomethyl] -aniline 4- (dibenzylamino-methyl) -aniline 4 - [N - (4-nitro-benzyl) -A N-propyl-aminomethyl) -aniline 4- [N-benzyl- N - (3-cyano-propyl) -amino 4- (N-benzyl- N -allyl-aminomethyl) -aniline 4- [N -benzyl-N- (2,2,2-trifluoroethyl) -aminomethyl] -aniline 4- [N- (benzo (1,3) dioxol-5-yl-methyl) - N -methyl-aminomethyl] -aniline 4- (7-chloro-2,3,4,5-tetrahydro-benzo (d) azepine-3- yl-methyl-aniline 4- (7,8-dichloro-2,3,4,5-tetrahydro-benzo (d) azepin-3-yl-methyl-aniline) · · · · · · · · · · · ·

-324- (7-Methoxy-2,3,4,5-tetrahydro-benzo (cl) azepin-3-ylmethyl) -aniline 4- (7-methyl-2,3,4,5-tetrahydro-benzo (d) Azepin-3-ylmethyl) -aniline 4- (7,8-dimethoxy-2,3,4,5-tetrahydro-benzo (d) azepin-3-ylmethyl) -aniline 4- (6) , 7-dichloro-1,2,3,4-tetrahydro-isoquinolin-2-yl-methyl) -aniline 4- _{(6,7-dimethyl-1-I,} 2,3,4-tetrahydro-isoquinolin-2-yl methyl) -aniline 4- (6-chloro-1 _l 2,3,4-tetrahydro-isoquinolin-2-yl-methyl) -aniline 4- (7-chloro-1 _l 2,3,4-tetrahydro-isoquinoline 2-yl-methyl) -aniline 4- (6-methoxy-1,2,3,4-tetrahydro-isoquinolin-2-yl-methyl) -aniline 4- _{(7-methoxy-1-I,} 2,3,4- tetrahydro-isoquinolin-2-yl-methyl) -aniline 4- (2,3,4,5-tetrahydro-azepino (4,5-b) pyrazin-3-ylmethyl) -aniline 4- (7-amino- 2,3,4,5-tetrahydro-azepino (4,5-b) pyrazin-3-ylmethyl) -aniline 4- (2-amino-5,6,7,8-tetrahydro-azepino (4,5) (d) thiazol-6-ylmethyl) -aniline 4- (5,6,7,8-tetrahydro-azepino (4,5-d) thiazol-6-ylmethyl) -aniline.

Preparation of end products

Example 1

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

600 mg of the resin obtained in Preparation 4 was suspended in 3 ml of DMF and shaken for 10 hours with 0.4 g of aniline at 70 ^e C. It is filtered and the resin was washed several times with methylene chloride, methanol and dimethylformamide. Then 3 ml of methanolic ammonia are added for 2 hours to cleave off the acetyl group. Finally, after further washing with dimethylformamide and methylene chloride, 4 ml of 10% trifluoroacetic acid in methylene chloride are added over 90 minutes, the resin is separated and the solution is concentrated. The residue was stirred with a small amount of 1N sodium hydroxide solution and extracted with a small amount of methylenechoride. The organic phase is dried over sodium sulphate and concentrated.

Yield: 37 mg

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

C20H21N3O2

Mass Spectrum: m / z = 335 (M *) · · · · · · · 335 · · ·

-33 ··· · · ··· ··· ai ·· ···· ·· ···

The following compounds were prepared analogously to Example 1:

(1) 3-Z- (1-Phenylamino-methylene) -5-amido-2-indolinone

It is prepared from the resin prepared according to Preparation 4 (1) and aniline.

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

C16H13N3O2

Mass spectrum: m / z = 279 (M ⁺ ) (2) 3-Z- [1- (4-Methyl-phenylamino) -1-methyl-methylene] -5-amido-2-indolinone

It is prepared from the resin prepared according to Preparation 4 (2) and 4-methylaniline.

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

C18H17N3O2

Mass Spectrum: m / z = 307 (M ⁺ ) (3) 3-Z- [1- (4-Chloro-phenylamino) -1-methyl-methylene] -5-amido-2-indolinone

It is prepared from the resin prepared according to Preparation 4 (2) and 4-chloroaniline.

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

C17H14CIN3O2

Mass Spectrum: m / z = 327/329 (M ⁺ ) (4) 3- Z- [1- (4-Ethyl-phenylamino) -1-methyl-methylene] -5-amido-2-indolinone

It is prepared from the resin prepared according to Preparation 4 (2) and 4-ethylaniline.

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

C19H19N3O2

Mass spectrum: m / z = 321 (M ⁺ ) (S) 3-Z- [1- (4-Methoxy-phenylamino) -1-methyl-methylene] -5-amido-2-indolinone

It is prepared from the resin prepared according to Preparation 4 (2) and 4-methoxyaniline.

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

C1BH17N3O3

Mass Spectrum: m / z = 323 (M < ^{+ >} )

-34 · · 34 34 34 34 34 34 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9

999 99 99 9999 99 ··· (6) 3-Ζ- [1- (4-Iodo-phenylamino) -1-methyl-methylene] -5-amido-2-indolinone

It is prepared from the resin prepared according to Preparation 4 (2) and 4-Iodoaniline.

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

C17H14IN3O2

Mass Spectrum: m / z = 419 (M ⁺ ) (7) 3-Z- [1- (4-Fluoro-phenylamino) -1-methyl-methylene] -5-amido-2-indolinone

It is prepared from the resin prepared according to Preparation 4 (2) and 4-fluoroaniline.

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

C ₁₇ H ₁₄ FN ₃ O ₂

Mass Spectrum: m / z = 311 (M < ^{+ >} ) (8) 3-Z- [1- (4-Bromo-phenylamino) -1-methyl-methylene) -5-amido-2-indolinone

It is prepared from the resin prepared according to Preparation 4 (2) and 4-bromoaniline.

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

C 17 H ₁₄ BrN ₃ O 2

Mass Spectrum: m / z = 371/373 (M ⁺ ) (9) 3-Z- (1-Phenylamino-1-methylmethylene) -5-amido-2-indolinone

It is prepared from the resin prepared according to Preparation 4 (2) and aniline.

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

C17H15N3O2

Mass Spectrum: m / z = 293 (M ⁺ ) (10) 3-Z- (1-Amino-1-methylmethylene) -5-amido-2-indolinone

It is prepared from the resin prepared according to Preparation 4 (2) and ammonia.

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

C11H11N3O2

Mass Spectrum: m / z = 217 (M < ^{+ >} ) ············

-35φ · (11) 3-Z- [1- (4-Piperidinomethyl-phenylamino) -1-methyl-methylene] -5-amido -2-indolinone Prepared from the resin prepared according to Preparation 4 (2) and 4- (peperidine-methyl) -aniline. _Rf value: 0.31 (silica gel, methylene chloride / methanol = 9: 1)

C23H26N4O2

Mass spectrum: m / z = 390 (III ') (12) 3-Z- [1- (4-Pyrrolidinomethyl-phenylamino) -1-methyl-methylene) -5-amido-2-indolinone Prepared from the resin prepared according to preparation 4 (2) and 4- (pyrrolidine-methyl) -aniline. Rf value: 0.20 (silica gel, methylene chloride / methanol = 4: 1)

C22H24N4O2

Mass spectrum: m / z = 376 (M ⁺ ) (13) 3-Z- [1- (4-Dipropylaminomethylphenylamino) -1-methylmethylene] -5-amido-2-indolinone Prepared from the resin prepared according to Preparation 2 (2) and 4- (di-n-propylaminomethyl) aniline.

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

C24H30N4O2

Mass Spectrum: m / z = 406 (M < ^{+ >} ) (14) 3-Z- [1- [4- (2-Piperidin-ethyl) -phenylamino] -1-methyl-methylene) -5-amido-2-indolinone Prepared by from the resin prepared according to Preparation 4 (2) and 4- (2-peperidine-ethyl) -aniline. Rf value: 0.38 (silica gel, methylene chloride / methanol = 4: 1)

C24H28N4O2

Mass spectrum: m / z = 404 (M ⁺ ) (15) 3-Z- [1- [4- (2-Diethylaminoethyl) phenylamino] -1-methylmethylene) -5-amido-2-indolinone Prepared from a resin prepared according to Preparation 4 (2) and 4- (2-diethylaminoethyl) aniline.

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

C23H28N4O2

Mass Spectrum: m / z = 393 (M < ^{+ >} )

-36 • ·····························

999 99 J (16) 3-Z- [1- (4-Hexamethyleniminomethylphenylamino) -1-methylmethylene) -5- amido-2-indolinone

It is prepared from the resin prepared according to Preparation 4 (2) and 4- (hexamethyleneiminomethyl) -aniline.

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

C24H28N4O2

Mass Spectrum: m / z = 404 (M ⁺ ) (17) 3-Z- [1- [4- (N-Methyl- N -methanesulfonylamino) phenylamino] -1-methylmethylene] -5-amido-2- indolinone

It is prepared from the resin prepared according to Preparation 4 (2) and 4- (N-methyl- N -methanesulfonylamino) -aniline.

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

C19H20N4O4S

Mass spectrum: m / z = 400 (M ⁺ ) (18) 3-Z- [1- (4-Methanesulfonylaminophenylamino) -1-methylmethylene) -5-amido-2-indolinone Prepared from the resin prepared according to Preparation 4 (2) and 4- (methanesulfonylamino) aniline.

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

C18H18N4O4S

Mass spectrum: m / z = 386 (M ⁺ ) (19) 3-Z- [1- (4-Bromo-phenylamino) -1-ethyl-methylene) -5-amido-2-indolinone Prepared from the resin prepared according to Preparation 4 (3) and 4-bromoaniline.

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

Ci8Hi6BrN3O ₂

Mass spectrum: m / z = 385/387 (M + / M + 2 ⁺ ) (20) 3-Z- [1- (4-Piperidinomethyl-phenylamino) -1-ethyl-methylene] -5-amido-2- indolinone Prepared from the resin prepared according to Preparation 4 (3) and 4- (peperidine-methyl) -aniline. Rf value: 0.42 (silica gel, methylene chloride / methanol = 4: 1)

• ·· ·· 9 • ··· • · • · • · • · • · • ·· • · • · • · • · · «·· ·· • · • · • ···· • · · · · ·

C24H28N4O2

Mass Spectrum: m / z = 404 (M ⁺ ) (21) 3-Z- [1- (4-Piperidinomethyl-phenylamino) -1-propylmethylene] -5-amido-2-indolinone Prepared from a resin prepared according to of preparation 4 (4) and 4- (peperidine-methyl) -aniline. Rf value: 0.49 (silica gel, methylene chloride / methanol = 4: 1)

C25H30N4O2

Mass Spectrum: m / z = 418 (M < ^{+ >} ) (22) 3-Z- [1- (4-Bromo-phenylamino) -1-propyl-methylene] -5-amido-2-indolinone

It is prepared from the resin prepared according to Preparation 4 (4) and 4-bromoaniline.

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

CigHi8BrN3O2

Mass Spectrum: m / z = 399/401 (M ⁺ / M + 2 ⁺ ) (23) 3-Z - [(4-Bromo-phenylamino) -methylene] -5-amido-2-indolinone

It is prepared from the resin prepared according to Preparation 4 (1) and 4-bromoaniline.

^ ^ Of whose BRNS

Mass Spectrum: m / z = 357/359 (M ⁺ / M + 2 ⁺ ) (24) 3-Z - [(4-Piperidinomethyl-phenylamino) -methylene] -5-amido-2-indolinone

It is prepared from the resin prepared according to Preparation 4 (1) and 4- (peperidine-methyl) -aniline. C22H24N4O2

Mass Spectrum: m / z = 376 (M ⁺ ) (25) 3-Z- [1- (4-Bromo-phenylamino) -1-butyl-methylene] -5-amido-2-indolinone Prepared from the resin prepared according to Preparation 4 and 4-bromoaniline. _Rf value: 0.53 (silica gel, methylene chloride / methanol = 9: 1) ₂ 0 ₂ οΗ οΒγΝ ₃ 02

Mass Spectrum: m / z = 413/415 (M ⁺ / M + 2 ⁺ ) (26) 3-Z- [1- (4-Piperidinomethyl-phenylamino) -1-butyl-methylene] -5-amido-2- indolinone Prepared from the resin prepared according to Preparation 4 and 4- (peperidine-methyl) -aniline. Rf value: 0.48 (silica gel, methylene chloride / methanol = 4: 1)

C26H32N4O2

Mass Spectrum: m / z = 432 (M < ^{+ >} ) (27) 3-Z- [1- (4-Piperidinomethyl-phenylamino) -1-ethylene-methylene] -5-amido-2-indolinone Prepared from a resin prepared according to of preparation 4 (5) and 4- (peperidine-methyl) -aniline.

(28) 3-Z- [1- (4-Piperidinomethylphenylamino) -1- (3-bromopropyl) methylene] -5-amido-2-indolinone

It is prepared from the resin prepared according to Preparation 4 (6) and 4- (peperidine-methyl) -aniline.

(29) 3-Z- [1- (4-Piperidinomethyl-phenylamino) -1- (2-phenylsulfonylethyl) methylene] -5-amido-

2-indolinone

It is prepared from the resin prepared according to Preparation 4 (7) and 4- (peperidine-methyl) -aniline.

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

It is prepared from the resin prepared according to Preparation 4 (2) and 4- (2,6-dimethylpeperidinomethyl) -aniline.

(31) 3-Z- [1- (4-Thiomorpholinomethyl-phenylamino) -1-methyl-methylene] -5-amido-2-indolinone Prepared from the resin prepared according to Preparation 4 (2) and 4- (thiomorpholine-methyl) ) aniline.

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

C22H24N4O2S

Mass Spectrum: m / z = 408 (M < ^{+ >} ) (32) 3-Z- [1 - [(4-Thiomorpholine-S-oxide-methyl) -phenylamino] -1-methyl-methylene] -5-amido-2 - indolinone

• ·· • · • ··· ·· • · • 9 · · • · • ·· 9 9 9 9 9 • · · · · · ·· ·· 99 99

It is prepared from the resin prepared according to Preparation 4 (2) and 4- (thiomorpholine-S-oxidmethyl) -aniline.

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

C22H24N4O3S

Mass spectrum: m / z = 425 (M + H +) (33) 3-Z- [1- (4-Thiomorpholine-S, S-dioxide-methyl) -phenylamino] -1-methyl-methylene] -5- amido2-indolinone

It is prepared from the resin prepared according to Preparation 4 (2) and 4- (thiomorpholine-S, S-dioxidomethyl) -aniline.

(34) 3-Z- [1- (4-Azetidinomethyl-phenylamino) -1-methyl-methylene] -5-amido-2-indolinone Prepared from the resin prepared according to Preparation 4 (2) and 4- (azetidinomethyl) ) aniline.

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

It is prepared from the resin prepared according to Preparation 4 (2) and 4- (2,5-dihydropyrrol-1-ylmethyl) -aniline.

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

C22H22N4O2

Mass Spectrum: m / z = 375 (M + H +) (36) 3-Z- [1- [4- (3,6-Dihydro-2H-pyridin-1-ylmethyl) -phenylamino] -1- methyl-methylene] -5amido-2-indolinone

It is prepared from the resin prepared according to Preparation 4 (2) and 4- (3,6-dihydro-2H-pyridine-

1-yl-methyl) -aniline.

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

C23H24N4O2

Mass Spectrum: m / z = 389 (M + H +) (37) 3-Z- [1- [4- (2-Ethoxycarbonylpyrrolidinomethyl) phenylamino] -1-methylmethylene] -5-amido-

2- indolinone

-40 ·· ·· ·· ·· ·

9 · · · · ···

999 9 9 9 9 9 9

9 9 9 9 9

99,999 99,999

It is prepared from the resin prepared according to Preparation 4 (2) and 4- (2-ethoxycarbonylpyrrolidin-methyl) -aniline.

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

C24H26N4O4

Mass Spectrum: m / z = 435 (M + H ⁺ ) (38) 3-Z- [1- [4- (3,5-Dimethyl-piperidin-methyl) -phenylamino] -1-methyl-methylene] -5 amido

2-indolinone

It is prepared from the resin prepared according to Preparation 4 (2) and 4- (3,5-dimethyl-peperidinomethyl) -aniline.

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

C25H30N4O2

Mass spectrum: m / z = 418 (M +) (39) 3-Z- [1- [4- (4-Phenyl-piperazinomethyl) -phenylamino] -1-methyl-methylene] -5-amido-2-indolinone -trifluoroacetate

It is prepared from the resin prepared according to Preparation 4 (2) and 4- (4-phenyl-piperazinomethyl) -aniline.

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

C28H29N5O2

Mass Spectrum: m / z = 468 (M + H +) (40) 3-Z- [1- [4- (4-Phenyl-4-hydroxy-peperidine-methyl) -phenylamino] -1-methyl-methylene] -5-amido-2-indolinone trifluoroacetate

It is prepared from the resin prepared according to Preparation 4 (2) and 4- (4-phenyl-4-hydroxypeperidine-methyl) -aniline.

C29H30N4O3

Mass Spectrum: m / z = 483 (M + H +) (41) 3-Z- [1- (3-Methoxy-phenylamino) -1-methyl-methylene] -5-amido-2-indolinone

It is prepared from the resin prepared according to Preparation 4 (2) and 3-methoxy-aniline.

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

• ·· ·· · • ··· • · • • • · · • · • ·· • · • · t • · • • • · · · · · · · · · · · • · • • ···· • · ·· • ···

-41 C18H17N3O3

Mass Spectrum: m / z = 323 (M < ^{+ >} ) (42) 3-Z- [1- (3-Ethoxycarbonyl-phenylamino) -1-methyl-methylene] -5-amido-2-indolinone. of Preparation 4 (2) and 3-aminobenzoic acid ethyl ester.

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

C20H19N3O4

Mass Spectrum: m / z = 365 (M < ^{+ >} ) (43) 3-Z- [1- (4-Dimethylaminomethyl-phenylamino) -1-methylmethylene] -5-amido-2-indolinone trifluoroacetate

It is prepared from the resin prepared according to Preparation 4 (2) and 4-dimethylaminomethylaniline.

C20H22N4O2

Mass Spectrum: m / z = 351 (M + H ⁺ ) (44) 3- Z- [1- [4- (4-Cyclohexyl-peperidin-methyl) -phenylamino] -1-methyl-methylene] -5-amido 2 -indolinón

It is prepared from the resin prepared according to Preparation 4 (2) and 4- (4-cyclohexyl-peperidinomethyl) -aniline.

(45) 3-Z- [1- (4-Morpholin-phenylamino) -1-methyl-methylene] -5-amido-2-indolinone Prepared from the resin prepared according to Preparation 4 (2) and 4-Morpholine-aniline. C21H22N4O3

Mass Spectrum: m / z = 378 (M ⁺ ) (46) 3- Z - [1- (N-Methyl-piperidin-4-yl-amino) -1-methyl-methylene] -5-amido-2- indolinone Prepared from the resin prepared according to Preparation 4 (2) and 4-amino-N-methylpiperidine.

C17H22N4O2

Mass Spectrum: m / z = 314 (M < ^{+ >} )

• ·· • · • ··· ·· ·· • · · · • · · ·· · • · ·· • · · ·· ·· ·· ···· ·· ··

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

It is prepared from the resin prepared according to Preparation 4 (2) and 4-methyl-cyclohexylamine. C18H23N3O2

Mass Spectrum: m / z = 313 (M < ^{+ >} ) (48) 3-Z- (1-Cyclopentylamino-1-methylmethylene) -5-amido-2-indolinone

It is prepared from the resin prepared according to Preparation 4 (2) and cyclopentylamine.

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

C16H19N3O2

Mass Spectrum: m / z = 285 (M < ^{+ >} ) (49) 3-Z- (1-isopropylamino-1-methylmethylene) -5-amido-2-indolinone

It is prepared from the resin prepared according to Preparation 4 (2) and isopropylamine.

Rf value: 0.40 (silica gel, methylene chloride / methanol = 9: 1) C14H17N3O2

Mass Spectrum: m / z = 259 (M ⁺ ) (50) 3- Z- [1- (4-Ethoxycarbonylmethylaminomethylphenylamino) -1-methylmethylene] -5-amido-2-indolinone

It is prepared from the resin prepared according to Preparation 4 (2) and 4- (ethoxycarbonylmethyl- tert -butyloxycarbonyl-aminomethyl) -aniline.

C21H22N4O4

Mass Spectrum: m / z = 394 (M ⁺ ) (51) 3-Z- [1- (4-Benzylaminomethyl-phenylamino) -1-methyl-methylene] -5-amido-2-indolinone Prepared from a resin prepared according to of Preparation 4 (2) and 3- (N-benzyl- N -t-tert-butyloxycarbonylaminomethyl) -aniline.

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

C25H24N4O2

Mass Spectrum: m / z = 412 (M < ^{+ >} )

• ·· ·· · • «·· • · • · · · • · • · · • · · · • • • · · • · • • • ··· ·· · · ···· • ft • ·

(52) 3- Ζ- [1- (4-Butylaminomethyl-phenylamino) -1-methyl-methylene] -5-amido-2-indolinone trifluoroacetate

It is prepared from the resin prepared according to Preparation 4 (2) and 4- (N-butyl- N - tert -butyloxycarbonyl-aminomethyl) -aniline.

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

C22H26N4O2

Mass Spectrum: m / z = 378 (M < ^{+ >} ) (53) 3-Z- [1- (4-Ethylaminomethyl-phenylamino) -1-methyl-methylene] -5-amido-2-indolinone trifluoroacetate

It is prepared from the resin prepared according to Preparation 4 (2) and 4- (N-ethyl- N - tert -butyloxycarbonyl-aminomethyl) -aniline.

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

C20H22N4O2

Mass Spectrum: m / z = 351 (M + H ⁺ ) (54) 3- Z- [1- (4-Cyclohexylaminomethylphenylamino) -1-methylmethylene] -5-amido-2-indolinone trifluoroacetate

It is prepared from the resin prepared according to Preparation 4 (2) and 4- [cyclohexyl- (N-tert-butyloxycarbonyl-aminomethyl) -aniline.

C24H28N4O2

Mass Spectrum: m / z = 405 (M + H ⁺ ) (55) 3- Z- [1- (4-isopropylaminomethylphenylamino) -1-methylmethylene] -5-amido-2-indolinone trifluoroacetate

It is prepared from the resin prepared according to Preparation 4 (2) and 4- (N-Isopropyl- N-tert-butyloxycarbonyl-aminomethyl) -aniline.

C21H24N4O2

Mass spectrum: m / z = 365 (M + H ⁺ ) (56) 3- Z- [1- (4-Trifluoromethoxy-phenylamino) -1-methyl-methylene] -5-amido-2-indolinone Prepared from a resin prepared according to Preparation 4 (2) and 4-trifluoromethoxy-aniline.

• 00 • · • ··· • 0 0 0 0 t 0 0 0 0 00 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 • 0 0000 00 00

C18H14F3N3O3

Mass spectrum: m / z = 377 (M ⁺ ) (57) 3-Z- [1- (4-Difluoromethoxy-phenylamino) -1-methyl-methylene] -5-amido-2-indolinone Prepared from the resin prepared according to of preparation 4 (2) and 4-difluoromethoxy-aniline. Rf value: 0.5 (silica gel, methylene chloride / methanol = 9: 1) • C18H15F2N3O3

Mass Spectrum: m / z = 359 (M + H ⁺ ) (58) 3- Z- [1- (4-Bromo-3-chloro-phenylamino) -1-methyl-methylene] -5-amido-2-indolinone It is prepared from the resin prepared according to Preparation 4 (2) and 4-bromo-3-chloroaniline. Ci7Hi3BrCIN3O2

Mass Spectrum: m / z = 405/407/409 (M ⁺ / M + 2 ⁺ / M + 4 ⁺ ) (59) 3- Z- [1- (4-Trifluoromethyl-3-bromophenylamino) -1-methylmethylene 5-Amino-2-indolinone Prepared from the resin prepared according to Preparation 4 (2) and 4-Trifluoromethyl-3-bromoaniline.

CieHi3BrF3N3O2

Mass Spectrum: m / z = 439/441 (M ⁺ / M + 2 ⁺ ) (60) 3- Z- [1- (4-Chloro-phenylamino) -methylene] -5-amido-2-indolinone

It is prepared from the resin prepared according to Preparation 4 (1) and 4-chloroaniline.

• C16H12CIN3O2

Mass spectrum: m / z = 312/314 (M < ^{+ >} ) t

(61) 3-Z- [1- (3-Bromo-phenylamino) -1-methyl-methylene] -5-amido-2-indolinone Prepared from the resin prepared according to Preparation 4 (2) and 3-bromoaniline. C-i7Hi4BrN3O2

Mass Spectrum: m / z = 371/373 (M ⁺ ) (62) 3- Z- [1- (3-Chloro-phenylamino) -1-methyl-methylene] -5-amido-2-indolinone

It is prepared from the resin prepared according to Preparation 4 (2) and 3-chloroaniline.

• ·· · · · · ·· · ·· · • · • · • • • · • ··· • · • • • • · · • · • • • ··· ·· · · ···· · · • ·

-45C17H14CIN3O2

Mass Spectrum: m / z = 327/329 (M < ^{+ >} ) (63) 3-Z- [1- (2-Chloro-phenylamino) -1-methyl-methylene] -5-amido-2-indolinone

It is prepared from the resin prepared according to Preparation 4 (2) and 2-chloroaniline. C17H14CIN3O2

Mass spectrum: m / z = 327/329 (M ⁺ ) (64) 3- Z- [1- (4-Bromo-3-methyl-phenylamino) -1-methyl-methylene] -5-amido-2-indolinone It is prepared from the resin prepared according to Preparation 4 (2) and 4-bromo-3-methyl-aniline. Rf value: 0.60 (silica gel, methylene chloride / methanol = 9: 1)

CieHi6BrN3O2

Mass Spectrum: m / z = 385/387 (M ⁺ ) (65) 3- Z- [1- (4-Bromo-3-methoxy-phenylamino) -1-methyl-methylene] -5-amido-2-indolinone It is prepared from the resin prepared according to Preparation 4 (2) and 4-bromo-3-methoxy-aniline. Rf value: 0.60 (silica gel, methylene chloride / methanol = 9: 1)

Ci8Hi6BrN3O3

Mass Spectrum: m / z = 401/403 (M ⁺ ) (66) 3- Z- [1- (4-Fluoro-3-nitro-phenylamino) -1-methyl-methylene] -5-amido-2-indolinone It is prepared from the resin prepared according to Preparation 4 (2) and 4-fluoro-3-nitroaniline. Rf value: 0.40 (silica gel, methylene chloride / methanol = 9: 1)

Ci7H ₁₃ FN ₄ O4

Mass Spectrum: m / z = 356 (M +) (67) 3-Z- [1- (4-Bromo-3-nitro-phenylamino) -1-methyl-methylene] -5-amido-2-indolinone Prepared from a resin prepared according to Preparation 4 (2) and 4-bromo-3-nitroaniline. Rf value: 0.50 (silica gel, methylene chloride / methanol = 9: 1)

Ci7H-i3BrN4O4

Mass Spectrum: m / z = 416/418 (M ⁺ )

• ·· • · • ··· · · • · • · · · • · • · · • · • • • • • · · • · • • • ·· ·· · · ···· · · • ·

(68) 3-Z- [1- (4-Ethyl-3-nitro-phenylamino) -1-methyl-methylene] -5-amido-2-indolinone Prepared from the resin prepared according to Preparation 4 (2) and 4- ethyl-3-nitro-aniline. Rf value: 0.70 (silica gel, methylene chloride / methanol = 9: 1)

C19H18N4O4

Mass Spectrum: m / z = 366 (M < ^{+ >} ) (69) 3-Z- [1- (4-Chloro-3-nitro-phenylamino) -1-methyl-methylene] -5-amido-2-indolinone

It is prepared from the resin prepared according to Preparation 4 (2) and 4-chloro-3-nitroaniline. C17H13CIN4O4

Mass Spectrum: m / z = 371/373 (M ⁺ ) (70) 3- Z- [1- (3-Nitro-phenylamino) -1-methyl-methylene] -5-amido-2-indolinone

It is prepared from the resin prepared according to Preparation 4 (2) and 3-nitroaniline. C17H14N4O4

Mass spectrum: m / z = 338 (M + H +) (71) 3- Z- [1- (4-Methyl-3-nitro-phenylamino) -1-methyl-methylene] -5-amido-2-indolinone

It is prepared from the resin prepared according to Preparation 4 (2) and 4-methyl-3-nitroaniline.

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

C18H16N4O4

Mass Spectrum: m / z = 352 (M +) (72) 3-Z- [1- (4-Bromo-3-methoxycarbonylphenylamino) -1-methylmethylene] -5-amido-2-indolinone

It is prepared from the resin prepared according to Preparation 4 (2) and 2-bromo-5-amino-benzoic acid methyl ester.

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

CigHi6BrN3O4

Mass Spectrum: m / z = 429/431 (M + H +) (73) 3-Z- [1- (4-Carbamoyl-phenylamino) -1-methyl-methylene] -5-amido-2-indolinone Prepared from the resin prepared according to Preparation 4 (2) and 4-aminobenzamide.

-47 • ····································· ··· ·· ···

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

C18H16N4O3

Mass Spectrum: m / z = 336 (M < ^{+ >} ) (74) 3-Z- [1- (4-Piperidinocarbonyl) -phenylamino) -1-methylmethylene] -5-amido-2-indolinone Prepared from a resin prepared by according to Preparation 4 (2) and 1- (4-aminobenzoyl) piperidine.

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

C23H24N4O3

Mass Spectrum: m / z = 404 (M ⁺ ) (75) 3- Z- [1- (4- (2- (Diethylamino) ethylcarbamoyl) phenylamino) -1-methylmethylene] -5-amido-2-indolinone trifluoroacetate

It is prepared from the resin prepared according to Preparation 4 (2) and 4-amino- N - [2- (diethylamino) ethyl] benzamide.

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

C24H29N5O3

Mass spectrum: m / z = 436 (M + H ⁺ ) (76) 3- Z- [1- (4-Trifluoromethyl-phenylamino) -1-methyl-methylene] -5-amido-2-indolinone Prepared from a resin prepared according to Preparation 4 (2) and 4-trifluoromethyl-aniline. C18H14F3N3O2

Mass spectrum: m / z = 361 (M ⁺ ) (77) 3-Z- [1- (3-Hydroxymethyl-phenylamino) -1-methyl-methylene] -5-amido-2-indolinone Prepared from a resin prepared according to of Preparation 4 (2) and 3-aminobenzyl alcohol. C18H17N3O3

Mass spectrum: m / z = 323 (M ⁺ ) (78) 3- Z- [1- (4-Hydroxycarbonyl-phenylamino) -1-methyl-methylene] -5-amido-2-indolinone Prepared from a resin prepared according to of preparation 4 (2) and 4-aminobenzoic acid. Rf value: 0.20 (silica gel, methylene chloride / methanol = 4: 1)

• ·· · · · · ·· · ·· · • ··· • • • • • · • • · • · • · • · · ··· ·· • ·· • • ···· • · · · · ·

C18H15N3O4

Mass Spectrum: m / z = 336 (MH ⁺ ) (79) 3-Z- [1- (4-Ethoxycarbonylmethyl-3-nitro-phenylamino) -1-methyl-methylene] -5-amido-2-indolinone

It is prepared from the resin prepared according to Preparation 4 (2) and 4-amino-2-nitro-phenylacetic acid ethyl ester.

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

C21H20N4O6

Mass Spectrum: m / z = 424 (M +) (80) 3-Z- [1- (3-Methoxycarbonyl-4-methylphenylamino) -1-methylmethylene] -5-amido-2-indolinone

It is prepared from the resin prepared according to Preparation 4 (2) and 3-amino-6-methyl-benzoic acid methyl ester.

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

C20H19N3O4

Mass Spectrum: m / z = 365 (M ⁺ ) (81) 3- Z - [1- (3-Diethylcarbamoyl-4-methylphenylamino) -1-methylmethylene] -5-amido-2-indolinone

It is prepared from the resin prepared according to Preparation 4 (2) and 3-amino-6-methyl-benzoic acid diethylamide.

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

C23H26N4O3

Mass Spectrum: m / z = 406 (M ⁺ ) (82) 3- Z- [1- (3-Ethylcarbamoyl-4-methylphenylamino) -1-methylmethylene] -5-amido-2-indolinone

It is prepared from the resin prepared according to Preparation 4 (2) and 3-amino-6-methyl-benzoic acid ethylamide.

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

• ·· • · • e ·· ·· • · • · · · • · • · · • · • • • • • e · • · • • • • · ·· · · ···· · · • ·

-49C21H22N4O3

Mass spectrum: m / z = 378 (M ⁺ ) (83) 3- Z- [1- (3-Sulfamoyl-4-methyl-phenylamino) -1-methyl-methylene] -5-amido-2-indolinone Prepared from the resin prepared according to Preparation 4 (2) and 3-amino-6-methylphenylsulfonic acid amide.

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

C18H18N4O4S

Mass Spectrum: m / z = 386 (M < ^{+ >} ) (84) 3-Z- [1- (3-Acetylamino-4-methylphenylamino) -1-methylmethylene] -5-amido-2-indolinone Prepared from a resin prepared according to of preparation 4 (2) and 4-amino-2-acetylaminotoluol.

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

C20H20N4O3

Mass Spectrum: m / z = 364 (M < ^{+ >} ) (85) 3-Z- [1- (4- (2-Dimethylaminoethoxy) phenylamino) -1-methylmethylene] -5-amido-2-indolinone trifluoroacetate

It is prepared from the resin prepared according to Preparation 4 (2) and 4- (2-dimethylaminoethoxy) aniline.

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

C21H24N4O3

Mass Spectrum: m / z = 380 (M +) (86) 3-Z- [1- (4- (2-Peperidinethoxy) phenylamino) -1-methylmethylene] -5-amido-2-indolinone trifluoroacetate

It is prepared from the resin prepared according to Preparation 4 (2) and 4- (2-peperidine-ethoxy) aniline.

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

C24H28N4O3

Mass Spectrum: m / z = 420 (M < ^{+ >} )

9 99 9 9 9 999 99 99 • · • ·· • · • · • · 9 9 9 9 99 99 9 9 ····  · • ·

(87) 3- Ζ- [1- (4- (3-Dimethylamino-propoxy) -phenylamino) -1-methyl-methylene] -5-amido-2-indolinone trifluoroacetate

It is prepared from the resin prepared according to Preparation 4 (2) and 4- (3-dimethylaminopropoxy) -aniline.

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

C22H26N4O3

Mass Spectrum: m / z = 394 (M < ^{+ >} ) (88) 3-Z- [1- (4- (3-Piperidinepropoxy) phenylamino) -1-methylmethylene] -5-amido-2-indolinone trifluoroacetate

It is prepared from the resin prepared according to Preparation 4 (2) and 4- (3-peperidine-propoxy) aniline.

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

C25H30N4O3

Mass Spectrum: m / z = 434 (M < ^{+ >} ) (89) 3-Z- [1- (4- (3- (N-benzyl- N -methylamino) propoxy) phenylamino) -1-methyl- methylene] -5-amido-2-indolinone-trifluoroacetate

It is prepared from the resin prepared according to Preparation 4 (2) and 4- [3- (N-benzyl- N -methylamino) -propoxy] -aniline.

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

C28H30N4O3

Mass Spectrum: m / z = 470 (M ⁺ ) (90) 3-Z- [1- (4- (N-Benzyl-aminomethyl) -phenylamino) -methylene] -5-amido-2-indolinone trifluoroacetate

It is prepared from the resin prepared according to Preparation 4 (1) and 4- (N-benzyl- N - tert -butoxycarbonyl-aminomethyl) aniline.

C24H22N4O2

Mass Spectrum: m / z = 399 (M + H < ^{+ >} )

• ·· ·· · • ··· · · • · • · · · • · • ·· • · • · • • · · ··· ·· • · ·· • ···· • · ·· •

(91) 3-Z- [1- (4 - ([7- (4-Chlorobenzyl) aminomethyl) phenylamino) -1-methylmethylene] -5-amido-2-indolinone trifluoroacetate

It is prepared from the resin prepared according to Preparation 4 (2) and 4 - [[7- (4-chlorobenzyl- [7-tert-butoxycarbonylaminomethyl) aniline]].

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

C25H23CIN4O2

Mass Spectrum: m / z = 446/448 (M < ^{+ >} ) (92) 3-Z- [1- (4 - ([7- (3,4,5-Trimethoxybenzyl) - N -methyl-aminomethyl) -phenylamino]] -1-methylmethylene] -5-amido-2-indolinone trifluoroacetate

It is prepared from the resin prepared according to Preparation 4 (2) and 4 - (β - ((3,4,5-trimethoxybenzyl) - β-methylaminomethyl) -aniline.

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

C29H32N4O5

Mass Spectrum: m / z = 516 (M < ^{+ >} ) (93) 3-Z- [1- (4 - ([7- (3,4-Dimethoxy-benzyl) - (7-methyl-aminomethyl) -phenylamino)] - 1-methylmethylene] -5-amido-2-indolinone trifluoroacetate

It is prepared from the resin prepared according to Preparation 4 (2) and 4 - [[7- (3,4-dimethoxybenzyl) N-methylaminomethyl] aniline.

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

C28H30N4O4

Mass Spectrum: m / z = 486 (M < ^{+ >} ) (94) 3-Z- [1- (4 - ([7- (3,4-Dimethoxybenzyl) - [7-ethylaminomethyl) phenylamino) -1-methylmethylene]] ] -5-amido-2-indolinone-trifluoroacetate

It is prepared from the resin prepared according to Preparation 4 (2) and 4 - ([7- (3,4-dimethoxy-benzyl)] - 7-ethyl-aminomethyl] -aniline.

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

C29H32N4O4

Mass Spectrum: m / z = 500 (M < ^{+ >} ) • (95) 3-Ζ- [1 - (4- (N -Benzyl-N-ethyl-aminomethyl) -phenylamino) -1-methyl-methylene] -5-amido-2-indolinone trifluoroacetate

It is prepared from the resin prepared according to Preparation 4 (2) and 4- (N-benzyl-N-ethylaminomethyl) -aniline.

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

C27H28N4O2

Mass Spectrum: m / z = 440 (M < ^{+ >} ) (96) 3-Z- [1- (4- (N-Benzyl-N-methylaminomethyl) phenylamino) -1-methylmethylene] -5-amido-2-indolinone- trifluoroacetate

It is prepared from the resin prepared according to Preparation 4 (2) and 4- (N-benzyl- N -methylaminomethyl) -aniline.

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

C26H26N4O2

Mass Spectrum: m / z = 426 (M < ^{+ >} ) (97) 3-Z- [1- (4- (N-Benzyl- N -methyl-aminomethyl) -phenylamino) -1-ethyl-methylene] -5 -amido2-indolinone-trifluoroacetate

It is prepared from the resin prepared according to Preparation 4 (3) and 4- (N-benzyl- N -methylaminomethyl) -aniline.

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

C27H28N4O2

Mass spectrum: m / z = 440 (M ⁺ ) (98) 3- Z - [1- (4- (N-Benzyl- N -methylaminomethyl) phenylamino) -1-propylmethylene] -5-amido-2-indolinone- trifluoroacetate

It is prepared from the resin prepared according to Preparation 4 (4) and 4- (N-benzyl- N -methylamino-methyl) -aniline.

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

C28H30N4O2

Mass Spectrum: m / z = 454 (M < ^{+ >} ) (99) 3-Z- [1- (4 - (/ N- (4-Chlorobenzyl) - N -methylaminomethyl) phenylamino) -1-methylmethylene] 5-amido-2-indolinone trifluoroacetate

It is prepared from the resin prepared according to Preparation 4 (2) and 4- [N - (4-chlorobenzyl) - N -methyl-aminomethyl) -aniline.

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

C26H25N4O2

Mass Spectrum: m / z = 460/462 (M ⁺ ) (100) 3- Z - [1- (4- (N - (3-Chlorobenzyl) - N -methylaminomethyl) phenylamino) -1-methyl- methylene] -5-amido-2-indolinone-trifluoroacetate

It is prepared from the resin prepared according to Preparation 4 (2) and 4- [N- (3-chlorobenzyl) -1H-methylaminomethyl] aniline.

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

C26H25CIN4O2

Mass Spectrum: m / z = 460/462 (M ⁺ ) (101) 3- Z - [1- (4 - ([7- (2,6-Dichlorobenzyl) - N -methylaminomethyl) phenylamino] - 1-methylmethylene] -5-amido-2-indolinone trifluoroacetate

It is prepared from the resin prepared according to Preparation 4 (2) and 4 - ([7- (2,6-dichlorobenzyl) - [7-methylaminomethyl) aniline].

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

C26H24CI2N4O2

Mass Spectrum: m / z = 494/496/498 (M + 2 ⁺ / M + 4 ⁺ ) (102) 3-Z- [1- (4 - ([7- (4-Trifluoromethylbenzyl)] - / 7-methyl) aminomethyl-phenylamino) -1-methylmethylene] -5-amido-2-indolinone-trifluoroacetate

It is prepared from the resin prepared according to Preparation 4 (2) and 4 - [[7- (4-Trifluoromethylbenzyl) -N-methyl-aminomethyl] aniline.

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

C27H25F3N4O2

Mass Spectrum: m / z = 494 (M < ^{+ >} ) (103) 3-Z- [1- (4- (N-Benzyl- N -isopropyl-aminomethyl) -phenylamino) -1-methyl-methylene] -5-amido 2-indolinone-trifluoroacetate

It is prepared from the resin prepared according to Preparation 4 (2) and 4- (N-benzyl-N-isopropylaminomethyl) -aniline.

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

C28H30N4O2

Mass Spectrum: m / z = 454 (M ⁺ ) (104) 3- [1- (4- (N-Benzyl- N - tert -butyl-aminomethyl) -phenylamino) -1-methyl-methylene] - 5 amido-2-indolinón-trifluóracetát

It is prepared from the resin prepared according to Preparation 4 (2) and 4- (N-benzyl- N -t-butylaminomethyl) -aniline.

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

C29H32N4O2

Mass spectrum: m / z = 468 (M ⁺ ) (105) 3- Z - [1- (4- (N-Benzyl- N -methyl-aminomethyl) -phenylamino) -methylene] -5-amido-2-indolinone -trifluoroacetate

It is prepared from the resin prepared according to Preparation 4 (1) and 4- (N-benzyl- N -methylaminomethyl) -aniline.

C25H24N4O2

Mass Spectrum: m / z = 413 (M + H ⁺ ) (106) 3-Z- [1- (4- (N-Benzyl- N -ethylaminomethyl) phenylamino) -1-methylmethylene] -5- amido2-indolinone-trifluoroacetate

It is prepared from the resin prepared according to Preparation 4 (1) and 4- (N-benzyl- N -ethylaminomethyl) -aniline.

C26H26N4O2

Mass Spectrum: m / z = 427 (M + H ⁺ ) (107) 3- Z- [1- (4- (Diisopropylamino-methyl) -phenylamino) -1-methyl-methylene] -5-amido-2-indolinone trifluoroacetate • ······························

It is prepared from the resin prepared according to Preparation 4 (2) and 4- (Diisopropylaminomethyl) aniline.

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

C24H30N4O2

Mass Spectrum: m / z = 406 (M < ^{+ >} ) (108) 3-Z- [1- (4- (Di-n-propylamino-methyl) -phenylamino) -methylene] -5-amido-2-indolinone trifluoroacetate

It is prepared from the resin prepared according to Preparation 4 (2) and 4- (Di-n-propylamino-methyl) aniline.

C23H28N4O2

Mass spectrum: m / z = 393 (M + H ⁺ ) (109) 3- Z- [1- (4- (Diisobutylamino-methyl) -phenylamino) -1-methyl-methylene] -5-amido-2-indolinone trifluoroacetate

It is prepared from the resin prepared according to Preparation 4 (2) and 4- (diisobutylaminomethyl) aniline.

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

C26H34N4O2

Mass Spectrum: m / z = 434 (M < ^{+ >} ) (110) 3-Z- [1- (4- (2,3,4,5-Tetrahydro-benzo (d) azepin-3-ylmethyl) -phenylamino) ) -1-methylmethylene] -5-amido-2-indolinone-trifluoroacetate

It is prepared from the resin prepared according to Preparation 4 (2) and 4- (2,3,4,5-tetrahydrobenzo (d) azepin-3-ylmethyl) -aniline.

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

C28H28N4O2

Mass Spectrum: m / z = 452 (M ⁺ ) (111) 3-Z- [1- (4- (1,3-Dihydroisoindol-2-ylmethylphenylamino) -1-methylmethylene] -5-amido-2-indolinone- Trifluoroacetate • ·································· · ···

It is prepared from the resin prepared according to Preparation 4 (2) and 4- (1,3-dihydro-isoindol-2-ylmethyl) -aniline.

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

C26H24N4O2

Mass Spectrum: m / z = 425 (M + H ⁺ ) (112) 3-Z- [1- (4- (6,7-Dimethoxy-1,2,3,4-tetrahydro-isoquinolin-2-yl) - methyl) phenylamino) -

1-methyl-methylene] -5-amido-2-indolinone-trifluoroacetate

It is prepared from the resin prepared according to Preparation 4 (2) and 4- (6,7-dimethoxy-1,2,3,4-tetrahydro-isoquinolin-2-ylmethyl) -aniline.

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

C29H30N4O4

Mass Spectrum: m / z = 499 (M + H ⁺ ) (113) 3-Z- [1- (4- (1,2,3,4-Tetrahydro-isoquinolin-2-ylmethyl) -phenylamino) - 1-methyl-methylene] -5-amido-2-indolinone trifluoroacetate

It is prepared from the resin prepared according to Preparation 4 (2) and 4- (1,2,3,4-tetrahydroisoquinolin-2-ylmethyl) -aniline.

(114) 3-N- [1- (4- (N - (Ethoxycarbonylmethyl) - N -benzylaminomethyl) phenylamino) -1-methylmethylene] -5-amido-2-indolinone trifluoroacetate

It is prepared from the resin prepared according to Preparation 4 (2) and 4- (N - (ethoxycarbonylmethyl) N -benzyl-aminomethyl) -aniline.

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

C29H30N4O4

Mass Spectrum: m / z = 498 (M ⁺ ) (115) 3- Z - [1- (4- (N - (2-Hydroxyethyl) - N -benzylaminomethyl) phenylamino) -1-methylmethylene] -5-amido-2-indolinone-trifluoroacetate

It is prepared from the resin prepared according to Preparation 4 (2) and 4- [N- (2-hydroxyethyl) - N -benzyl-aminomethyl) -aniline.

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

C27H28N4O3

Mass Spectrum: m / z = 456 (M ⁺ ) (116) 3- Z - [1- (4 - ([7- (1-Ethyl-pentyl) -N] - (pyridin-2-ylmethyl) - aminomethyl-phenylamino) -1-methyl-methylene] -5-amido-2-indolinone trifluoroacetate

It is prepared from the resin prepared according to Preparation 4 (2) and 4 - ([7- (1-ethyl-pentyl) - [7 (pyridin-2-ylmethyl) -aminomethyl] -aniline.

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

C31H37N5O2

Mass Spectrum: m / z = 511 (M < ^{+ >} ) (117) 3-Z- [1- (4- (Peperidin-methyl) -3-nitro-phenylamino) -1-methyl-methylene] -5-amido-2-indolinone

It is prepared from the resin prepared according to Preparation 4 (2) and 4- (peperidine-methyl) -3-nitroaniline.

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

C23H25N5O4

Mass Spectrum: m / z = 436 (M + H ⁺ ) (118) 3-Z- [1- (4 - ((7-Phenethyl- / 7-methyl-aminomethyl) phenylamino) -1-methyl-methylene] -5amido-2-indolinone-trifluoroacetate

It is prepared from the resin prepared according to Preparation 4 (2) and 4- (N-phenethyl- [7-methylaminomethyl] aniline).

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

C27H28N4O2

Mass Spectrum: m / z = 441 (M + H ⁺ ) (119) 3-Z- [1- (4 - ((7-Phenethyl- / 7-ethylaminomethyl) phenylamino) -1-methylmethylene] -5-amido-2- indolinone (120) 3-N- [1- (4 - ([7- (3,4-Dihydroxy-phenethyl) - [7-methylaminomethyl) phenylamino) -1-methylmethylene] -5-amido-2-indolinone]

• ·· • · • ··· ·· • · • · • e • · • ·· • · • · • · ·· ·· · · ···· · · · ·

(121) 3- [4- (1- (4 - ([7- (3,4,5-trimethoxy-phenethyl) - [7-methyl-aminomethyl) -phenylamino) -1-methyl-methylene] -5-amido] -2-indolinone (122) 3- [1- (4 - ([7- (3,4-Dimethoxyphenethyl) - [7-methyl-aminomethyl) phenylamino) -1-methylmethylene] -5-amido] -2-indolinone (123) 3-Z- [1- (4 - ([7- (4-Nitro-phenethyl) - [7-methyl-aminomethyl) -phenylamino) -1-methylmethylene] -5-amido-2] -indolinone (124) 3-Z- [1- (4 - ((7-Phenethyl- [7-benzylaminomethyl) phenylamino) -1-methylmethylene] -5-amido-2-indolinone)

C33H32N4O2

Mass Spectrum: m / z = 517 (M + H < ^{+ >} )

Rf value: 0.43 (silica gel, methylene chloride / methanol = 9: 1) (125) 3-Z- [1- (4 - (/ 7-Phenethyl- / 7-cyclohexyl-aminomethyl) -phenylamino) -1-methyl -methylene] 5-amido-2-indolinone (126) 3-Z- [1- (4 - ([7- (4-Nitro-phenethyl) - [7-isopropyl-aminomethyl) -phenylamino) -1-methylmethylene]] -5-amido-2-indolinone (127) 3-Z- [1- (4 - ([7- (2- (Pyridin-2-yl) ethyl) - [7-methyl-aminomethyl) phenylamino]] - 1-methylmethylene] -5-amido-2-indolinone

C26H27N5O2

Mass Spectrum: m / z = 441 (M < ^{+ >} )

Rf value: 0.51 (silica gel, methylene chloride / methanol = 4: 1) (128) 3-Z- [1- (4 - ([7- (2-Pyridin-4-yl) ethyl)] - [7-] methyl-aminomethyl-phenylamino) -1-methylmethylene] -5-amido-2-indolinone (129) 3-Z- [1- (4 - ([7- (Pyridin-2-ylmethyl)] - [7-] methyl) aminomethyl) phenylamino) -1-methylmethylene] -5-amido-2-indolinone

• ·· • · • ··· • · • · • · · · • · • • · · · · · · · · • · · • · · · · · ···· ·· · ·

(130) 3-N- [1- (4 - (N - (Pyridin-3-ylmethyl) - N -methyl-aminomethyl) -phenylamino) -1-methylmethylene] -5-amido-2-indolinone (131) 3-Z- [1- (4- (N - (Pyridin-4-ylmethyl) -N-methyl-aminomethyl) -phenylamino) -1-methylmethylene] -5-amido-2-indolinone ( 132) 3-Z- [1- (4- (Dibenzylamino-methyl) -phenylamino) -1-methyl-methylene] -5-amido-2-indolinone

C32H30N4O2

Mass Spectrum: m / z = 503 (M + H < ^{+ >} )

Rf value 0.47 (silica gel, methylene chloride / methanol = 9: 1) (133) 3-Z- [1- (4- (N - (4-nitrobenzyl) - N -propylaminomethyl) phenylamino) -1-methyl -methylene] -5-amido-2-indolinone (134) 3-Z- [1- (4 - (N-Benzyl-N- (3-cyano-propyl) -aminomethyl) -phenylamino) -1-methyl-methylene -5-amido-2-indolinone (135) 3- Z - [1- (4- (N-Benzyl-N -alyl-aminomethyl) -phenylamino) -1-methyl-methylene] -5-amido-2- indolinone

C28H26N4O2

Mass Spectrum: m / z = 451 (M + H < ^{+ >} )

Rf value 0.53 (silica gel, methylene chloride / methanol = 9: 1) (136) 3-Z- [1- (4- (imidazol-1-ylmethyl) phenylamino) -1-methylmethylene] -5-amido- 2-indolinone

C21H20N6O2

Mass Spectrum: m / z = 389 (M + H < ^{+ >} )

Rf value 0.20 (silica gel, methylene chloride / methanol = 4: 1) (137) 3-Z- [1- (4- (imidazol-2-yl-amino-methyl) -phenylamino) -1-methyl-methylene] 5-amido2-indolinone

-60 · · 60 60 60 60 60 60 60 60 60 60 60 60 60 60 60 60 60 60 60 60 60 60 (138) 3-Z- [1- (4 - (N-Benzylamino) - (2,2,2-trifluoroethyl) -amino-methyl) -phenylamino) -1-methyl-methylene] -5-amido-2-indolinone (139) 3- [1- (4 - (N-Benzo (1,3) dioxol-5-ylmethyl) -N-methyl-aminomethyl) -phenylamino) - 1-methyl-methylene] -5-amido-2-indolinone

C27H26N4O4

Mass Spectrum: m / z = 470 (M + H < ^{+ >} )

Rf value: 0.50 (silica gel, methylene chloride / methanol = 9: 1) (140) 3-Z- [1- (4- (7-Chloro-2,3,4,5-tetrahydro-benzo (d) azepine)) 3-yl-methyl) phenylamino) -

1-Methyl-methylene] -5-amido-2-indolinone (141) 3-Z- [1- (4- (7,8-Dichloro-2,3,4,5-tetrahydrobenzo (c)) azepine-3) -ylmethyl) phenylamino) -1-methyl-methylene] -5-amido-2-indolinone (142) 3-Z- [1- (4- (7-Bromo-2,3,4,5-tetrahydro-benzo) ( d) azepin-3-yl-methyl) phenylamino) -

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

1-Methyl-methylene] -5-amido-2-indolinone (144) 3-Z- [1- (4- (7-Methoxy-2,3,4,5-tetrahydro-benzo (d) azepine-3-)) yl-methyl) -phenylamino) -1-methyl-methylene] -5-amido-2-indolinone (145) 3-Z- [1- (4- (7-Methyl-2,3,4,5-tetrahydro- benzo (c) azepin-3-yl-methyl) -phenylamino) 1-methyl-methylene] -5-amido-2-indolinone (146) 3-Z- [1- (4- (7,8-Dimethoxy- 2,3,4,5-tetrahydrobenzo (d) azepin-3-ylmethyl) phenylamino) -1-methylmethylene] -5-amido-2-indolinone (147) 3-Z- [1- (4- (6,7-Dichloro-2,3,4,5-tetrahydro-isoquinolin-2-ylmethyl) -phenylamino) -1-methyl-methylene] -5-amido-2-indolinone • ·· ·· ·· ·· ··· ······· (148) 3-Z- [1] - (4- (6,7-Dimethyl-1,2,3,4-tetrahydro-isoquinolin-2-ylmethyl) -phenylamino) -1-methyl-methylene] -5-amido-2-indolinone (149) 3-Z- [1- (4- (6,7-Difluoro-1,2,3,4-tetrahydro-isoquinolin-2-ylmethyl) -phenylamino) -1-methyl-methylene] -5-amido- 2-indolinone

C27H26N4O2

Mass Spectrum: m / z = 439 (M + H < ^{+ >} )

Rf value 0.43 (silica gel, methylene chloride / methanol = 9: 1) (150) 3-Z- [1- (4- (6-Chloro-1,2,3,4-tetrahydroisoquinolin-2-ylmethyl) phenylamino) -1-methyl-methylene] -5-amido-2-indolinone (151) 3- Z- [1- (4- (7-Chloro-1,2,3,4-tetrahydro-isoquinolin-2-yl) -methyl) (phenylamino) -1-methyl-methylene] -5-amido-2-indolinone (152) 3-Z- [1- (4- (6-Methoxy-1,2,3,4-tetrahydro-isoquinolin-2)) -yl-methyl) -phenylamino) -1-methyl-methylene] -5-amido-2-indolinone (153) 3-Z- [1- (4- (7-Methoxy-1,2,3,4-tetrahydro) (isoquinolin-2-yl-methyl) -phenylamino) -1-methyl-methylene] -5-amido-2-indolinone (154) 3-Z- [1- (4- (2,3,4,5-Tetrahydro) -azepino (4,5-b) pyrazin-3-yl-methyl) -phenylamino) -1-methyl-methylene] -5-amido-2-indolinone (155) 3-Z- [1- (4- (7) -Amino-2,3,4,5-tetrahydroazepino (4,5-b) pyrazin-3-ylmethyl) -phenylamino) -1-methyl-methylene] -5-amido-2-indolinone (156) 3-Z- [1- (4- (2-amino-5,6,7,8-tetrahydro-azepino (4,5-d) thiazol-6-ylmethyl) -phenylamino) -1-methyl -methylene] -5-amido-2-indolinone (157) 3- Z- [1- (4- (5,6,7,8-Tetrahydro-azepino (4,5-d) thiazol-6-ylmethyl)) ) Phenylamino) -1-methyl-methylene] -5-amido-2-indolinone

• ·· • · • · • · • · • • • · • • • ··· • • • • • • · · • • • • • • · ·· · · ···· · ·

(158) 3-Z- [1- (Pyridin-3-yl-amino) -1-methyl) -methylene] -5-amido-2-indolinone (159) 3-Z- [1- (Thiazol-2- yl-amino) -1-methyl-methylene] -5-amido-2-indolinone (160) 3-Z- [1- (Benzimidazol-2-ylamino) -1-methyl] methylene] -5- amido-2-indolinone (161) 3- [1- (5-Methyl-isoxazol-3-ylamino) -1-methyl) -methylene] -5-amido-2-indolinone (162) 3-Z - [1- (Imidazol-2-yl-amino) -1-methyl) -methylene] -5-amido-2-indolinone (163) 3- Z- [1- (5-Methyl-pyridin-2-yl) - amino) -1-methyl-methylene] -5-amido-2-indolinone (164) 3- [1- (5-Bromo-pyridin-2-yl-amino) -1-methyl) -methylene] - 5-Amido-2-indolinone (165) 3- [1- (2-Chloro-pyridin-5-ylamino) -1-methyl) -methylene] -5-amido-2-indolinone (166) 3 -Z- [1- (4- (N-Butyl- N -methyl-aminomethyl) -phenylamino) -1-methyl) -methylene] -5-amido-2-indolinone

C23H28N4O2

Mass Spectrum: m / z = 392 (M < ^{+ >} ) (167) 3-Z- [1- (4- (N-isobutyl-aminomethyl) -phenylamino) -1-methyl) -methylene] -5-amido-2 - indolinone

C22H26N4O2

Mass Spectrum: m / z = 378 (M < ^{+ >} ) (168) 3-Z- [1- (4- (N-Cyclohexylmethyl-aminomethyl) -phenylamino) -1-methyl-methylene] -5-amido-2-indolinone

C25H30N4O2

Mass spectrum: m / z = 418

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

Example 2 3-Z- [1- (4-Diethylcarbamoyl-phenylamino) -1-methyl-methylene] -5-amino-2-indolinone g of the resin prepared according to Preparation 4b is reacted in analogy to Example 1 with 2 g of 4-aminobenzoic acid ethyl ester in dimethylformamide at 110 ° C. The wet swollen resin is suspended in 15 ml of dioxane and 15 ml of methanol and stirred with 12 ml of 1N sodium hydroxide solution for 40 hours. It is then neutralized with dilute hydrochloric acid and washed with methylene chloride, methanol and dimethylformamide. 300 mg of the resin are suspended in 3 ml of dimethylformamide and allowed to stand for 40 hours with 0.2 ml of diethylamine, 0.5 g of TBTU (O-benzotriazol-1-yl- N, N, N-tetramethyluronium) tetrafluoroborate and 0.8 ml of N-ethyl-diisopropylamine at room temperature. Finally, the product is cleaved from the resin as described in Example 1.

Yield: 61 mg

Rf value: 0.30 (silica gel, methylene chloride / methanol = 9: 1) C22H24N4O3

Mass Spectrum: m / z = 392 (M < ^{+ >} )

The following compounds were prepared analogously to Example 2:

(1) 3-Z- [1- (4-Benzylcarbamoyl-phenylamino) -1-phenyl-methylene] -5-amido-2-indolinone Prepared in analogy to Example 2 with benzylamine

Rf value: 0.30 (silica gel, methylene chloride / methanol = 9: 1) C25H22N4O3

Mass Spectrum: m / z = 426 (M ⁺ ) (2) 3-Z- [1- (4- (N-Methoxycarbonylmethylcarbamoyl) -phenylamino) -1-phenylmethylene] -5-amido-2-indolinone

Analogously to Example 2, it is prepared with glycine ethyl ester

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

C21H20N4O5

Mass Spectrum: m / z = 408 (M < ^{+ >} ) • (3) 3-Ζ- [1- - ( 4-Dimethylcarbamoyl-phenylamino) -1-phenyl-methylene] -5-amido-2-indolinone Prepared in analogy to Example 2 with dimethylamine

Rf value: 0.40 (silica gel, methylene chloride / methanol = 9: 1) C20H20N4O3

Mass Spectrum: m / z = 364 (M < ^{+ >} ) (4) 3-Z- [1- (4 - (N - (2-Piperidinomethyl) carbamoyl) phenylamino) -1-methylmethylene] -5-amido-2-indolinone -trifluoroacetate

Analogously to Example 2, it is prepared with 1- (2-amino-ethyl) -piperidine

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

C25H29N5O3

Mass Spectrum: m / z = 448 (M + H ⁺ ) (S) 3-Z- [1- (4- (N -Methyl-piperazinocarbamoyl) -phenylamino) -1-phenyl-methylene] -5- amido2-indolinone-trifluoroacetate

Analogously to Example 2, it is prepared with N-methylpiperazine

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

C23H25N5O3

Mass Spectrum: m / z = 419 (M ⁺ ) (6) 3-Z- [1- (4- (N-Diethylamino-ethyl) - N -methyl-carbamoyl) -phenylamino) -1-phenyl-methylene] amido-2-indolinone-trifluoroacetate

Analogously to Example 2, it is prepared with N, N -diethyl- N -methyl-ethylenediamine

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

C25H31N5O3

Mass spectrum: m / z = 449 (M ⁺ ) (7) 3-Z- [1- (4-Butylcarbamoyl-phenylamino) -1-phenyl-methylene] -5-amido-2-indolinone Prepared in analogy to Example 2 with butylamine

Rf value: 0.80 (silica gel, methylene chloride / methanol = 4: 1)

C22H24N4O3

Mass Spectrum: m / z = 392 (M < ^{+ >} )

99 99 99 99

9 9 9 9 9

9999 98 9 99

Example 3 3-N- [1- (4- (N-Methyl-N-benzoyl-amino) -phenylamino) -1-methyl-methylene] -5-amido-2-indolinone

Analogously to Example 1, 4.5 g of the resin prepared according to Preparation 4b was converted with 3.4 g of 4- (9H-fluoren-9-ylmethoxycarbonyl) methylamino) aniline in dimethylformamide. Subsequently, the 9H-fluoren-9-ylmethoxycarbonyl group is cleaved by treatment with 40 ml of 30% piperidine in dimethylformamide and the resin is washed several times. 400 mg of the resin is suspended in 4 ml of dimethylformamide and 0.3 ml of triethylamine and converted for one hour at room temperature with 0.3 ml of benzoyl chloride. Finally, the product is cleaved from the resin with trifluoroacetic acid as described in Example 1.

Yield: 25 mg Rf value: 0.51 (silica gel, methylene chloride / methanol = 9: 1) C30H24N4O3

Mass Spectrum: m / z = 426 (M < ^{+ >} )

The following compounds are prepared analogously to Example 3:

(1) 3-Z- [1- (4 - (N-Methyl-N-propionyl-amino) -phenylamino) -1-methyl-methylene] -5-amido-2-indolinone

Analogously to Example 3, it is prepared with propionic acid chloride Rf value: 0.52 (silica gel, methylene chloride / methanol = 9: 1)

C21H22N4O3

Mass Spectrum: m / z = 378 (M +) (2) 3-Z- [1- (4 - (N-Methyl-N-butyryl-amino) -phenylamino) -1-methyl-methylene] -5- amide 2indolinón

Analogously to Example 3, it is prepared with butyric acid chloride

Rf value: 0.28 (silica gel, methylene chloride / methanol = 9: 1) C22H24N4O3

Mass Spectrum: m / z = 392 (M ^{@ +} ) (3) 3-Z- [1- (4- (N-Methyl-N-ethanesulfonyl-amino) -phenylamino) -1-methyl-methylene] -5-amido-

2-indolinone

Analogously to Example 3, it is prepared with ethanesulfonic acid chloride

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

C20H22N4O4S

Mass Spectrum: m / z = 413 (MH ⁺ ) (4) 3-Z- [1- (4- (N -Methyl-N-propanesulfonylamino) phenylamino) -1-methylmethylene] -5-amido-2-indolinone

Analogously to Example 3, it is prepared with propanesulfonic acid chloride

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

C21H24N4O4S

Mass Spectrum: m / z = 451 (M + Na ⁺ ) (S) 3-Z- [1- (4- (N-Methyl- N -phenylsulfonylamino) -phenylamino-1-methyl-methylene] -5- amido-

2-indolinone

Analogously to Example 3, it is prepared with phenylsulfonic acid chloride

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

C24H22N4O4S

Mass Spectrum: m / z = 462 (M ⁺ ) (6) 3-Z- [1- (4- (N-Methyl- N -acetylamino) phenylamino) -1-methylmethylene] -5-amido-2- indolinone

Analogously to Example 3, it is prepared with acetyl chloride

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

C20H20N4O3

Mass Spectrum: m / z = 364 (M ⁺ ) (7) 3-Z- [1- (4- (N-Methyl- N -phenylmethylsulfonyl-amino) -phenylamino) -1-methyl-methylene] -5-amido -2-indolinone

Analogously to Example 3, it is prepared with phenylmethanesulfonic acid chloride Rf value: 0.43 (silica gel, methylene chloride / methanol = 9: 1). ·

-67 • ····································

C25H24N4O4S

Mass Spectrum: m / z = 475 (MH < ^{+ >} )

Example 4

3-Z- [1- (4- (N-Benzyl- N -methyl-aminomethyl) -phenylamino) -1-methylmethylene] -2-indolinone-5-carboxylic acid methyl ester

8.0 g (28 mmol) of 1-acetyl-3- (1-ethoxy-1-methyl-methylene) -2-indolinone-5-carboxylic acid methyl ester are dissolved in 60 ml of dimethylformamide and stirred for 6 hours at 80 ° C with 6 3 g (28 mmol) of 4- (N-benzyl-N-methyl-aminomethyl) -aniline. Concentrated ammonia (30 ml) was added and allowed to stand at 45 ° C for 2 hours. The solution was evaporated and the residue was washed with ethanol and ether and chromatographed through a small silica gel column with ethyl acetate / ethanol (9: 1).

Yield: 8.6 g (70% of theory)

Melting point: 150-152 ° C

C27H27N3O3

Mass Spectrum: m / z = 442 (M < ^{+ >} )

The following compounds are prepared analogously to Example 4:

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

C24H27N3O3 Mass Spectrum: m / z = 406 (M + H +) (2) 3-Z- [1- (4-Bromo-phenylamino) -1-methyl-methylene] -2-indolinone-5-carboxylic acid methyl ester

Mass Spectrum: m / z = 386/388 (M +) (3) 3-Z- [1- (4-Chloro-phenylamino) -1-methyl-methylene] -2-indolinone-5-carboxylic acid methyl ester · · ··························

C18H15CIN2O3

Mass Spectrum: m / z = 342/344 (M +) (4) 3-Z- [1- (4- (N-Methyl-N-methylsulfonyl-amino) -phenylamino) -1-ethyl-methylene] methyl ester] -2-indolinone-5-carboxylate

C20H21N3O5S

Mass spectrum: m / z = 415 (M +) (5) 3-Z- [1- (4- (2,3,4,5-tetrahydro-benzo (d) azepin-3-ylmethyl) -methyl) -methyl ester phenylamino) -1-methyl-methylene] -2-indolinone-5-carboxylate

C29H29N3O2

Mass Spectrum: m / z = 467 (M < ^{+ >} )

Example 5

3-Z- [1- (4- (N-benzyl- N -methyl-aminomethyl) -phenylamino) -1-methyl-methylene] -2indolinone-5-carboxylic acid

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

Yield: 1.9 g (85% of theory) of C 26 H 25 N 3 O 3

Mass Spectrum: m / z = 428 (M + H < ^{+ >} )

The following compounds were prepared analogously to Example 5:

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

C23H25N3O3

Mass Spectrum: m / z = 392 (M + H +)

• ·· • · • ··· ·· • · • · · · • · • • · · • · ·· • · · ·· ·· · · ···· ·· ··

(2) 3-Z- [1- (4-bromo-phenylamino) -1-methyl-methylene] -2-indolinone-5-carboxylic acid (3) 3-Z- [1- (4-chloro-phenylamino) -acetic acid ) -1-methyl-methylene] -2-indolinone-5-carboxylic acid C17H13CIN2O3

Mass Spectrum: m / z = 327/329 (MH ⁺ ) (4) 3-Z- [1- (4- (N-methyl- N -methylsulfonylamino) phenylamino) -1-methylmethylene] -

2-indolinone-5-carboxylic acid

C19H19N3O5S

Mass Spectrum: m / z = 401 (M ⁺ ) (5) 3-Z- [1- (4- (2,3,4,5-tetrahydro-benzo (d) azepin-3-yl-methyl)) - phenylamino) -1-methylmethylene] -2-indolinone-5-carboxylic acid

C28H27N3O3

Mass Spectrum: m / z = 453 (M < ^{+ >} )

Example 6

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

0.3 g of 3-Z- [1- (4- (N-benzyl-N-methyl-aminomethyl) -phenylamino) -1-methylmethylene] -2-indolinone-2-indolinone-5-carboxylic acid Dissolve 1.2 g of N-ethyldiisopropylethylamine in 8 ml of dimethylformamide. 0.1 g of diethylamine and 0.4 g of TBTU (O-benzotriazol-1-yl-N, N, N, N ', N-tetramethyluronium tetrafluoroborate) were added and stirred at room temperature for 20 hours. It is then concentrated and the residue is suspended in water and extracted with methylene chloride. The organic phase is concentrated and chromatographed with methylene chloride / ethanol (19: 1) over a silica gel column.

Yield: 0.2 g (68% of theory)

Rf value: 0.36 (silica gel, methylene chloride / ethanol = 19: 1)

C30H34N4O2

Mass Spectrum: m / z = 482 (M < ^{+ >} )

• ·· • · · · · · • · • • • · • • • · • ··· • • • • • • · · • • • • • ·· ·· · · ···· · · · ·

The following compounds were prepared analogously to Example 6:

(1) 3-N- [1- (4- (Peperidin-methyl) -phenylamino) -1-methyl-methylene] -2-indolinone-5-diethylcarbamoyl-2-indolinone

It is prepared from the compound prepared according to Example 5 (1) and diethylamine.

C27H34N4O2

Mass Spectrum: m / z = 446 (M < ^{+ >} ) (2) 3-Z- [1- (4- (N-Methyl- N -methylsulfonylamino) phenylamino) -1-methylmethylene] -2-indolinone-5- diethylcarbamoyl-2-indolinone

It is prepared from the compound prepared according to Example 5 (4) and diethylamine.

C23H28N4O4S

Mass Spectrum: m / z = 457 (M + H ⁺ ) (3) 3-Z- [1- (4- (2,3,4,5-tetrahydro-benzo (d) azepin-3-ylmethyl) - phenylamino) -1-methylmethylene] -5-diethylcarbamoyl-2-indolinone (4) 3-Z- [1- (4- (2,3,4,5-tetrahydro-benzo (c)) azepin-3-yl- methyl-phenylamino) -1-methyl-methylene] -5-dimethylcarbamoyl-2-indolinone (S) 3-Z- [1- (4- (N-phenylmethyl-N-methylamino-methyl) -phenylamino) -1 -methyl-methylene] -5-methylcarbamoyl-2-indolinone (6) 3-Z- [1- (4- (N-phenylmethyl- N -methylamino-methyl) -phenylamino) -1-methyl-methylene] - 5-Dimethylcarbamoyl-2-indolinone (7) 3-Z- [1- (4- (N-phenylmethyl- N -methylamino-methyl) -phenylamino) -1-methylmethylene] -5-diethylcarbamoyl-2-indolinone (8) 3-Z- [1- (4- (N-phenylmethyl-N-methylamino-methyl) -phenylamino) -1-methyl-methylene] -5-propylcarbamoyl-2-indolinone

• ·· · · • e · · • · • • • · • • • · • ··· • • • • • • · · • • • • • • · ·· · · ···· · · · ·

(9) 3-Z- [1- (4- (N-phenylmethyl- N -methylamino-methyl) -phenylamino) -1-methyl-methylene] -5-dipropylcarbamoyl-2-indolinone (10) 3-Z- [ 1- (4- (Dimethylaminomethyl) phenylamino) -1-methylmethylene] -5-methylcarbamoyl-2-indolinone (11) 3-Z- [1- (4- (Dimethylaminomethyl) phenylamino) -1-methylmethylene] -5-dimethylcarbamoyl2 (12) 3-Z- [1- (4- (dimethylaminomethyl) phenylamino) -1-methylmethylene] -5-diethylcarbamoyl-indolinone (13) 3-Z- [1- (4- (dimethylaminomethyl) phenylamino) -1-methylmethylene] -5-propylcarbamoyl-2-indolinone (14) 3-Z- [1- (4- (Dimethylaminomethyl) phenylamino) -1-methylmethylene] -5-dipropylcarbamoyl-2-indolinone (15) 3-Z- [1- (3- (Dimethylaminomethyl) phenylamino) -1-methylmethylene] -5-methylcarbamoyl-2-indolinone (16) 3-Z- [1- (3- (Dimethylaminomethyl) phenylamino) -1-methylmethylene] -5- dimethylcarbnoyl-2-indolinone (17) 3-Z- [1- (3- (dimethylaminomethyl) phenylamino) -1-methylmethylene] -5-diethylcarbamoyl-indolinone (18) 3-Z- [1- (3- (dimethylaminomethyl)) phenylamino) -1-methyl-methylene] -5-propylcarbamoyl-2-indolinone (19) 3-Z- [1- (3- (Dimethylaminomethyl) yl) phenylamino) -1-methylmethylene] -5-dipropylcarbamoyl-2-indolinone • ·· ·· φφ φφ

ΦΦΦ φφφφ ΦΦΦ φ ΦΦΦ φ φ ΦΦΦ

ΦΦΦ ΦΦΦ ΦΦΦ

(20) 3-Z- [1- (4-Chloro-phenylamino) -1-methyl-methylene] -5-methylcarbamoyl-2-indolinone (21) 3-Ζ- [1- (4) -Chloro-phenylamino) -1-methyl-methylene] -5-dimethylcarbamoyl-2-indolinone (22) 3-Z- [1- (4-Chloro-phenylamino) -1-methyl-methylene] -5-diethylcarbamoyl-2 (23) 3-Z- [1- (4-Chloro-phenylamino) -1-methyl-methylene] -5-propylcarbamoyl-2-indolinone (24) 3-Z- [1- (4-Chloro-phenylamino) -indolinone] -1-methyl-methylene] -5-dipropylcarbamoyl-2-indolinone (2S) 3-Z- (1-Phenylamino-1-methyl-methylene) -5-methylcarbamoyl-2-indolinone (26) 3-Z- ( 1-Phenylamino-1-methyl-methylene) -5-dimethylcarbamoyl-2-indolinone (2 S) 3-Z- (1-Phenylamino-1-methyl-methylene) -5-diethylcarbamoyl-2-indolinone

Example 7 3-Z- [1- (4-Methyl-3-amino-phenylamino) -1-methyl-methylene) -5-amido-2-indolinone

130 mg of 3-Z- [1- (4-Methyl-3-nitrophenylamino) -1-methylmethylene) -5-amido-2-indolinone are dissolved in 9 ml of methanol and hydrogenated with 50 mg of Raney nickel at room temperature and pressure. hydrogen 3 bar. The catalyst was filtered off and the solution was concentrated.

Yield: 97 mg (70% of theory) Rf value 0.60 (silica gel, methylene chloride / ethanol = 4: 1) C18H18N4O2

Mass Spectrum: m / z = 322 (M < ^{+ >} )

The following compounds were prepared analogously to Example 7:

(1) 3-Z- [1- (4- (Peperidin-methyl) -3-amino-phenylamino) -1-methyl-methylene) -5-amido-2-indolinone

• ·· • · • ··· ·· ·· • · · · • · · ·· · • · ·· • · · ·· ·· ·· ···· ·· ··

Prepared from 3-Z- [1- (4- (peperidin-methyl) -3-nitro-phenylamino) -1-methyl-methylene) -5-amido-2-indolinone

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

C23H27N5O2

Mass Spectrum: m / z = 406 (M + H < ^{+ >} )

Example 8

Dry ampoules of 75 mg of active substance per 10 ml

Ingredients:

Active substance 75.0 mg mannitol 50.0 mg Water for injections ad 10.0 ml

Preparation:

The active substance and mannitol are dissolved in water. After filling, it is lyophilized. Dissolve before use with water for injections.

Example 9

Dry ampoules with 35 mg of active substance per 2 ml

Ingredients:

Active substance 35.0 mg mannitol 100.0 mg Water for injections ad 2.0 ml

Preparation:

The active substance and mannitol are dissolved in water. After filling, it is lyophilized. Dissolve before use with water for injections.

-74Example 10

Tablets containing 50 mg of the active substance

Ingredients:

(1) Active substance 50.0 mg (2) Milk sugar 98.0 mg (3) Corn starch 50.0 mg (4) Polyvinylpyrrolidone 15.0 mg (5) Magnesium stearate 2.0 mg 215.0 mg

Preparation:

(1), (2) and (3) are mixed and granulated with an aqueous solution (4). The dry granulate is admixed with (5). From this mixture, tablets are compressed flat on both sides, with double faced facets and a slit on one side. The diameter of the tablets is 9 mm.

Example 11 Tablets of 350 mg of active ingredient

Ingredients:

(1) Active substance (2) Milk sugar (3) Corn starch (4) Polyvinylpyrrolidone (5) Magnesium stearate 350.0 mg 136.0 mg 80.0 mg 30.0 mg 4.0 mg 600.0 mg

Preparation:

(1), (2) and (3) are mixed and granulated with an aqueous solution. The dried granulate is admixed with (5). From this mixture, tablets are compressed to form tablets

• ·· • · • ··· · «• · • · · · • · • ·· · e · ·· • · · ·· ·· · · ···· ·· ··

flat on both sides, with double-faced facets and one-sided slit.

Tablet diameter: 12 mm.

Example 12

Capsules containing 50 mg of the active substance

Ingredients:

(1) Active substance (2) Dried corn starch (3) Powdered milk sugar (4) Magnesium stearate

50.0 mg

58.0 mg

50.0 mg

2.0 mg

160.0 mg

Preparation:

(1) is rubbed with (3). This mixture is added with vigorous stirring to the mixture consisting of (2) and (4).

This powder mixture is filled into a size 3 hard gelatin capsule using a capsule filling machine.

Example 13

Capsules with 350 mg of the active substance

Ingredients:

(1) Active substance

350,0 mg (2) Dried corn starch

46,0 mg (3) Milk sugar powder

30,0 mg (4) Magnesium stearate

4.0 mg

430.0 mg

• ·· · · · · · · • · • • • · • · e • ··· • • • 9 · • · · • • • • · ·· ·· · · ···· ·· ·

Preparation (1) is rubbed with (3). This mixture is added with vigorous stirring to the mixture consisting of (2) and (4).

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

Example 14

Suppositories with 100 mg of the active ingredient suppository contains:

Active substance

Polyethylene glycol (MW 1500)

Polyethylene glycol (MW 6000)

polyethylene glycol monostearate

100.0 mg

600.0 mg

460.0 mg

840.0 mg

000.0 mg

Preparation:

The polyethylene glycol is melted together with the polyethylene glycol monostearate. At 40 ° C the milled active substance is uniformly distributed in the melt. Cool to 38 ° C and pour into pre-cooled suppository molds.

Claims (13)

Substituted indolinones of general formula I (i) in which X is an oxygen or sulfur atom, R ¹ is hydrogen, C 1-4 -alkoxycarbonyl or C 2-4 -alkanoyl, R ² is carboxy or C 1-4 -alkoxycarbonyl or aminocarbonyl optionally substituted with one or two C 1-3 -alkyl groups, wherein the substituents may be same or different, R ³ is a hydrogen atom or a C 1-6 alkyl group which, from position 2 with respect to the carbon atom of the R ³ -C (R ⁴ NR ⁵ ) = group, may be substituted by a fluorine, chlorine or bromine atom, a hydroxy group, a C 1-3 alkoxy group , C 1-3 -alkylsulfenyl, C 1-3 alkylsulfinyl, C 1-3 -alkylsulfonyl, phenylsulfenyl, phenylsulfinyl, phenylsulfonyl, amino, C 1-3 -alkylamino, di- (C 1-3 -alkyl) amino, C2 -5-alkanoylamino or N- (C 1-3 -alkylamino) -C 2-5 -alkanoylamino, R ⁴ is hydrogen, C 1-6 -alkyl or C 5-6 -cycloalkyl optionally substituted with C 1-6 -alkyl; _{A 3-} alkyl group in which one methylene group in the 3 or 4 position relative to the carbon atom of the group R ³ -C (R ⁴ NR ⁵ ) = can be replaced by an imino group optionally substituted by C 1-3 alkyl, phenyl or naphthyl a group which may be substituted by a fluorine, chlorine, bromine or iodine atom, a methoxy group optionally substituted by 1 to 3 fluorine atoms, -78C ₂ -3-alkoxy which in position 2 or 3 may be substituted by C 1-3 -alkylamino, di- (C 1-3 -alkyl) amino or 5- to 7-membered cycloalkyleneimino, the alkyl moiety in said alkylamino and dialkylamino may be additionally substituted with phenyl, trifluoromethyl, amino, C 1-3 -alkylamino, di- (C 1-3 -alkyl) amino, C 2-5 -alkanoylamino, N - (C _1-3 -alkyl) -C 2-5 -alkanoylaminoskupinou, C 5 alkylsulfonylamino, A / - (Cl. ₃ alkyl) -C. _5- alkylsulfonylamino, phenylsulfonylamino, N - (C _1-3 -alkyl) -phenylsulfonylamino, aminosulfonyl, C 1-6 -alkylsulfonylamino; _{A 3-} alkylaminosulfonyl group or a di- (C _1-3 alkyl) -aminosulfonyl group, wherein the alkyl moiety in said alkylamino and dialkylamino groups may be substituted with a phenyl group, a carbonyl group which is substituted with a hydroxy group, C 1-6 alkyl; _3- alkoxy, amino, C 1-6 alkyl; _3- alkylamino or N - (C _1-5 -alkyl) -C _1-3 -alkylamino, wherein the alkyl moiety in said groups may be additionally substituted with carboxy, C 1-6 -alkylamino; _3- alkoxycarbonyl or phenyl, or in the 2 or 3 position, may be substituted by a di- (C _1-3 -alkyl) amino, piperazine, N - (C _1-3 -alkyl) -piperazine or 5-7 membered cycloalkyleneimino group . Ci. _{A 3-} alkyl group which is substituted with an amino group, C 1-6 alkyl; _7- alkylamino, C 5-7 -cycloalkylamino, C 5-7 -cycloalkyl-C 1-6 -alkylamino; _3- alkylamino or phenyl-C _1-3 -alkylamino, which may be additionally substituted on the amine nitrogen atom by C 1-6 -alkylamino; _{A 3-} alkyl group in which the hydrogen atoms are partially or fully replaced by fluorine atoms, a C 5,7 -cycloalkyl group, a C 2-4 -alkenyl group or a C 1-4 alkyl group, wherein said C 1-4 alkyl substituent may be substituted by cyano, carboxy , Ci. _3- alkoxycarbonyl, pyridyl, imidazolyl, benzo [1,3] dioxol or phenyl, wherein the phenyl may be mono-, di- or trisubstituted by fluorine, chlorine or bromine atoms, methyl, methoxy, trifluoromethyl, cyano or the nitro group and the substituents may be the same or different, or in the 2, 3 or 4 position may be substituted by a hydroxy group, -79 ··· ··· ··· ··· ·· ·· ···· ·· ··· C 1-3 -alkyl, which may be substituted by hydroxy, carboxy, thiomorpholine, 1-oxido-thiomorpholine, 1,1-dioxido-thiomorpholine, piperazine, N - (C 1-3 -alkyl) piperazine or N - phenyl-piperazine, 5- to 7-membered cycloalkenyleneimino or 4- to 7-membered cycloalkyleneimino, wherein said 5- to 7-membered cycloalkyleneimino groups may be substituted by one or two C 1-3 -alkyl, C 3-8 -cycloalkyl or phenyl groups, A C 1-3 -alkoxycarbonyl and hydroxy group, and in the cycloalkyleneimino groups mentioned, the methylene group adjacent to the nitrogen atom may be replaced by a carbonyl group, A C 1-3 alkyl group substituted with a 5- to 7-membered cycloalkyleneimino group, wherein said 5- to 7-membered cycloalkyleneimino group is fused via a 2 adjacent carbon atom with a phenyl group optionally mono or disubstituted with fluorine, chlorine or bromine atoms, methyl or methoxy groups, wherein the substituents may be the same or different, or an oxazole, imidazole, thiazole, pyridine, pyrazine or pyrimidine group optionally substituted with a fluorine, chlorine, bromine or iodine atom, methyl, methoxy or amino group, said monosubstituted phenyl groups may be additionally substituted by a fluorine, chlorine or bromine atom, a methyl group, a methoxy group or a nitro group, A 5-membered heteroaromatic group containing an imino, oxygen or sulfur atom, or an imino, oxygen or sulfur atom and one or two nitrogen atoms, or A 6-membered heteroaromatic group containing one, two or three nitrogen atoms, wherein said 5- and 6-membered heteroaromatic groups may be additionally substituted by a chlorine or bromine atom or a methyl group, or to said 5- and 6-membered heteroaromatic groups through 2 adjacent carbon atoms, the phenyl core may be fused, and R ⁵ is a hydrogen atom or a C 1-3 -alkyl group, Wherein the carboxy, amino or imino groups present may be substituted with in vivo cleavable residues, their isomers and salts thereof. Substituted indolinones of general formula I according to claim 1, in which X is an oxygen atom, R ¹ is a hydrogen atom, R ² is aminocarbonyl, R ³ is a hydrogen atom or a C 1-4 -alkyl group which, from position 2 with respect to the carbon atom of the group R ³ -C (R ⁴ NR ⁵ ) =, may be substituted by a chlorine or bromine atom or by a phenylsulfonyl group, R ⁴ is a hydrogen atom, a C 1-3 alkyl group or a cyclopentyl or cyclohexyl group optionally substituted by a methyl group, wherein in the cyclopentyl and cyclohexyl methylene group at the 3 or 4 position relative to the carbon atom of the R ³ -C (R ⁴ NR ⁵ ) = it may be replaced by an imino group which may be optionally substituted by a methyl group, a phenyl group which may be substituted by a fluorine, chlorine, bromine or iodine atom, a methoxy group optionally substituted by 1 to 3 fluorine atoms, A C 2-3 alkoxy group which is substituted in the 2 or 3 position by methylamino, dimethylamino or 5- to 7-membered cycloalkyleneimino, wherein the methyl in said amino groups may be additionally substituted by phenyl, trifluoromethyl, amino, C2-5-alkanoylamino, / V- (Ci-3 alkyl) _2-C, 5-alkanoylamino, C. _5- alkylsulfonylamino, N - (C 1-3 -alkyl) C 1-5 -alkylsulfonylamino, phenylsulfonylamino, N - (C 1-3 -alkyl) -phenylsulfonylamino or aminosulfonyl, wherein the alkyl portion of said alkylamino and dialkylamino groups may be substituted by phenyl, a carbonyl group which is substituted with a hydroxy group, C 1-6 alkyl; _3- alkoxy, amino, C 1-6 alkyl; ₃ alkylamino and A / - (C ₁ _ ₅ alkyl) -C 3 alkylamino, the alkyl portion of said groups may be substituted by a • · · · · · · · · · · · ··· ··· • · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · -81 additionally carboxy, C 1-3 -alkoxycarbonyl or phenyl or in the 2 or 3 position may be substituted by di- (C 1-3 -alkyl) amino, piperazine, N - (C 1-3 -alkyl) -piperazine or a 5- to 7-membered cycloalkyleneimino group, Ci-3-alkyl group which is substituted by amino, Ci-7-alkylamino, C ₅ 7-cycloalkylamino, C ₅ -7 -cycloalkyl-C-3-alkylamino, or phenyl-C ^ alkylamino, which may be on a carbon an amine nitrogen additionally substituted with a C 1-3 alkyl group in which the hydrogen atoms are partially or totally replaced by fluorine atoms, a C 3-7 cycloalkyl group, a C 2-4 alkenyl group or a C 1-4 alkyl group, said C 1-4 alkyl substituent it may be additionally substituted with cyano, carboxy, C 1-3 -alkoxycarbonyl, pyridyl, imidazolyl, benzo [1,3] dioxole or phenyl, wherein the phenyl may be monosubstituted with fluorine, chlorine or bromine, methyl, methoxy , cyano, trifluoromethyl or nitro, or may be di- or trisubstituted by fluorine, chlorine or bromine atoms, methyl the upins or methoxy groups and the substituents may be the same or different, or in the 2, 3 or 4 position may be substituted by a hydroxy group, C 1-3 -alkyl, which may be substituted by hydroxy, carboxy, thiomorpholine, 1-oxido-thiomorpholine, 1,1-dioxidothiomorpholine, piperazine, N - (C 1-3 -alkyl) -piperazine or N, -phenyl-piperazine, 5- to 7-membered cycloalkenyleneimino or 4- to 7-membered cycloalkyleneimino, wherein said 5- to 7-membered cycloalkyleneimino group may be substituted by one or two C 1-3 alkyl, cyclohexyl or phenyl, C 1-3 -alkyl a cyclohexyl group, a phenyl group, a carboxy group or a C 1-4 -alkoxycarbonyl group and a hydroxy group, and in said cycloalkyleneimino groups the methylene adjacent to the nitrogen atom may be replaced by a carbonyl group, A C 1-3 -alkyl group which is substituted by a 5- to 7-membered cycloalkyleneimino group, wherein on said 5- to 7-membered cycloalkyleneimino group there are over 2 • ··· · · · · · Adjacent carbon atoms a fused phenyl group optionally mono- or disubstituted with fluorine, chlorine or bromine atoms, methyl or methoxy groups, wherein the substituents may be the same or different, or the fused pyrazine or thiazole group is optionally substituted with an amino group, said monosubstituted groups additionally substituted by fluorine, chlorine or bromine, methyl, methoxy or nitro, pyridyl optionally substituted by chlorine or bromine or methyl, oxazolyl, isoxazolyl, imidazolyl or thiazolyl optionally substituted by methyl and via carbon with 2 carbon atoms be condensed with a phenyl core, and R ⁵ is hydrogen or C 1-6 alkyl; _3- alkyl, isomers and salts thereof. Substituted indolinones of formula I according to claim 1 or 2, wherein R ² is in the 5-position, their isomers and salts. The substituted indolinones of formula I according to claim 1, wherein: X is an oxygen atom, R ¹ is a hydrogen atom, R ² at the 5-position is an aminocarbonyl group, R ³ is a hydrogen atom or a C 1-4 -alkyl group which in the terminal position may be substituted by a chlorine or bromine atom or by a phenylsulphonyl group, R ⁴ is hydrogen, C 1-6. _{A 3-} alkyl or cyclopentyl or cyclohexyl group optionally substituted by a methyl group, wherein in the cyclohexyl group the methylene group at the 4-position relative to the carbon atom of the R ³ C (R ⁴ NR ⁵ ) = can be replaced by an optionally substituted methyl group; which may be substituted • ················· -83 · fluorine, chlorine, bromine or iodine, methyl or ethyl, which may be substituted with a C 1-3 -alkylamino group, di - (C 1-3 -alkyl) amino, thiomorpholine, 1-oxidothiomorpholine, 1,1-dioxido-thiomorpholine, N-phenylpiperazine, 5- to 6-membered cycloalkenyleneimino or 5- to 6-membered cycloalkenyleneimino A 7-membered cycloalkyleneimino group, wherein said 5- to 7-membered cycloalkyleneimino groups may be substituted by one or two methyl, cyclohexyl or phenyl, methyl, cyclohexyl or phenyl and hydroxy, or methyl or ethyl groups substituted with phenyl substituted at the 4- position by a 5- to 7-membered cycloalkyleneimino group, wherein said cycloalkyleneimino group is fused via a 2 adjacent carbon atom with a phenyl, methyl or ethyl group substituted with an amino, methylamino or ethylamino group which are additionally substituted on the benzine nitrogen atom or a phenylethyl group, wherein the phenyl part of said groups may be monosubstituted by a fluorine, chlorine or bromine atom, a methyl group, a methoxy group, a cyano group, or a trifluoromethyl group or a lower one trio, or di- or trisubstituted by fluorine, chlorine or bromine atoms, methyl or methoxy groups and substituents may be the same or different, said monosubstituted phenyl groups being additionally substituted by fluorine, chlorine or bromine atoms, methyl, methoxy or nitro, and R ⁵ is a hydrogen atom or a C 1-4 alkyl group, isomers and salts thereof. The substituted indolinones of formula I according to claim 1, wherein: X is an oxygen atom, R ¹ is a hydrogen atom, R ² at the 5-position is an aminocarbonyl group, R ³ is a hydrogen atom or a C 1-4 -alkyl group, and -84R ⁴ is a phenyl group which may be substituted by a fluorine, chlorine, bromine or iodine atom, a methyl or ethyl group which may be substituted by a C 1-3 -alkylamino group, a di- (C 1-3 -alkyl) amino group, a thiomorpholine group, 1-oxidothiomorpholine, 1,1-dioxido-thiomorpholine, N-phenylpiperazine, 5- to 6-membered cycloalkenyleneimino or 5- to 7-membered cycloalkyleneimino, wherein said 5- to 7-membered cycloalkyleneimino group may be substituted once or two methyl groups, a cyclohexyl group or a phenyl group, a methyl group, a cyclohexyl group or a phenyl group and a hydroxy group, or a methyl or ethyl group which is substituted by a phenyl group substituted at the 4-position with a 5- to 7-membered cycloalkyleneimino group 2 adjacent carbon atoms additionally condensed phenyl, methyl or ethyl substituted with amino, methylamino or ethylamino, which is additionally substituted on the amine nitrogen with benzyl and in the phenyl moiety can be monosubstituted with fluorine, chlorine or bromine, methyl, methoxy, cyano, cyano, cyano or nitro, disubstituted with methyl or methoxy, or trisubstituted with methyl or methoxy and the substituents may be the same or different, said monosubstituted phenyl groups being substituted by a fluorine, chlorine or bromine atom, methyl, methoxy or nitro, and R ⁵ is a hydrogen atom or a C 1-6 alkyl group, isomers and salts thereof. 6. A compound according to claim 1 selected from the group consisting of: (a) 3-Z- [1- (4-Piperidinomethyl-phenylamino) -1-methyl-methylene] -5-amido-2-indolinone, (b) 3-Z- [1- (4-Bromo-phenylamino)] -1-methyl-methylene] -5-amido-2-indolinone, 9 (c) 3-Z - [1- (4-Piperidinomethyl-phenylamino) -1-butyl-methylene] -5-amido-2-indolinone, (d) 3-Z- [1- (4-Chloro-phenylamino) -1-methyl-methylene -5-amido-2-indolinone, (e) 3-Z- (1-Phenylamino-methylene) -5-amido-2-indolinone, (f) 3-Z- [1- (4 - (N -) - Benzyl- (N-methyl-aminomethyl) -phenylamino) -1-methyl-methylene] -5-amido- 2-indolinone, (g) 3-Z- [1- (4- (N - (4-Chlorobenzyl) aminomethyl) phenylamino) -1-methylmethylene] -5-amido- 2-indolinone, (h) 3-Z- [1- (4 - (N-Benzyl- N -ethyl-aminomethyl) -phenylamino) -1-methyl-methylene] -5-amido-2-indolinone, (i) 3-Z- [1- (4- (N-Benzylaminomethyl) phenylamino) -1-methylmethylene] -5-amido-2-indolinone, (j) 3-Z- [1- (4 - (N-Benzyl) (N-methylaminomethyl) phenylamino) methylene] -5-amido-2-indolinone, (k) 3-Z- [1- (4- (2,3,4,5-Tetrahydro-benzo (d) azepi)] (3-ylmethyl) -phenylamino) -1-methylmethylene] -5-amido-2-indolinone, (1) 3-Z- [1- (4-Piperidinomethyl-3-nitro-phenylamino) -1-methyl- methylene] -5-amido-2-indolinone, and (m) 3-Z- [1- (4-Methyl-3-nitro-phenylamino) -1-methyl-methylene] -5-amido-2-indolinone, as well as their isomers and salts. 7. A compound according to claim 1 which is 3- Z- [1- (4- (N-Benzyl-N-methyl-aminomethyl) -phenylamino) -1-methyl-methylene] -5-amido-2-indolinone and its salts. 3. A compound according to claim 1 which is 3-Z- [1- (4- (2,3,4,5-tetrahydrobenzo (d) azepin-3-ylmethyl) phenylamino) -1-methylmethylene]. amido-2-indolinone and its salts. Physiologically acceptable salts of substituted indolinones of the general formula I according to claims 1 to 8. A process for the preparation of substituted indolinones according to claims 1 to 9, characterized in that • ·· • · • ··· · · • · • · · · • · • ·· · • · ·· • · · • · · · · · ···· ·· ·· a. To a compound of formula II wherein: X and R ³ are as defined in claims 1 to 8, R ² has the meanings as R ² defined in claims 1 to 8, R ⁶ is a hydrogen atom or a protecting group for a nitrogen atom in a lactam group, one of which R ² or R ⁶ may optionally also represent a bond formed through a spacer to a solid phase, and the other of R ² or R ⁶ has the meanings given above, and Z ¹ is a halogen atom, a hydroxy-, alkoxy- or aralkoxy group, for example a chlorine or bromine atom, a methoxy-, ethoxy- or benzyloxy group, is treated with an amine of the formula III R ⁵ / H-N (III) \ . R ⁴ «in which R ⁴ and R ⁵ are as defined in claims 1 to 8, followed, if necessary, by cleavage of the nitrogen protecting group used in the lactam group or from the solid phase, or b. For a compound of formula I, wherein R ² is one of the aminocarbonyl groups defined in claims 1 to 8, the compound of formula IV • ·· ·· ·· ·· · • · • · · · • · ·· • ··· • e • • · · ·· ·· · · ···· ·· ·· (iv) in which: R ¹ and R ³ to R ⁵ are as defined in claims 1 to 6, or their reactive derivatives amidate with an amine of formula V H - (R ⁷ NR ⁸ ) (V) wherein R ⁷ and R ⁸ , which may be the same or different, are hydrogen atoms or C 1-3 alkyl groups, the compound of formula I containing alkoxycarbonyl thus obtained is then hydrolytically converted to the corresponding carboxy compound or the compound thus obtained of formula I which contains an amino or alkylamino group is converted by the alkylation or reductive alkylation to the corresponding alkylamino or dialkylamino compound, or the compound of the formula I which contains an amino or alkylamino group thus obtained is converted by acylation to the corresponding acyl or I which contains a carboxy group is converted by esterification or amidization to the corresponding ester or aminocarbonyl compound or the compound of formula I thus obtained which contains is converted to the corresponding amino compound, or, by reduction, to the corresponding amino compound, or If necessary, the protecting group used to protect the reactive groups during the reactions is cleaved, or the compound of formula I thus obtained is separated into stereoisomers, or the compound of formula I thus obtained is inorganic or organic acid. or by converting it into its salts, especially in the case of pharmaceutical use, into physiologically acceptable salts. Pharmaceutical composition, characterized in that it comprises a substituted inolinone according to at least one of claims 1 to 8, or a physiologically acceptable salt thereof according to claim 9 and optionally one or more inert carriers and / or diluents. A process for the preparation of a pharmaceutical composition according to claim 11, characterized in that the substituted indolinones according to at least one of claims 1 to 8, or a physiologically acceptable salt thereof according to claim 9, are mixed with one or more inert carriers and / or diluents. Use of substituted indolinones according to at least one of claims 1 to 8 or their physiologically acceptable salts according to claim 9 for the preparation of a medicament for the treatment of excessive or anomalous cell division.