SK283824B6 - Substituted indolinones, method for their production, pharmaceutical composition containing them and use thereof - Google Patents

Abstract

The invention relates to substituted indolinones of general formula (I), wherein R1 to R5 and X have the meanings given in claim 1, to their isomers and to their salts, especially their physiologically compatible salts. The inventive compounds have valuable pharmacological properties, especially an inhibitory effect on various kinases and cycline/CDK complexes, and on the proliferation of various tumour cells. The invention also relates to medicaments containing these compounds, to their use and to methods for producing them.

Description

Technical field

The invention relates to novel substituted indolinones of the general formula (I) which have an inhibitory effect on kinases and cyclin / CDK complexes.

BACKGROUND OF THE INVENTION

International patent applications WO 96/40116, WO 96/22976 and WO 99/15500 disclose indolinone derivatives having kinase inhibitory activity. These documents do not disclose compounds with an aryl-methylene group.

SUMMARY OF THE INVENTION

The present invention provides substituted indolinones of formula (I)

Their isomers and salts, in particular their physiologically acceptable salts, which have valuable properties.

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

The present invention relates to those compounds of formula (I), the compounds wherein R ¹ is a hydrogen atom or a prodrug group have valuable pharmacological properties, to pharmaceutical compositions containing pharmacologically active compounds, their use and processes for their preparation.

In the above general formula (I)

X is an oxygen or sulfur atom,

R ¹ is hydrogen, C _1-4 -alkoxycarbonyl or C ₂ . _4- alkanoyl group,

R ² is carboxy-, C 1-6 _{A 4} -alkoxycarbonyl or aminocarbonyl group in which the amino group may be substituted by one or two C 1-6 -carbonyl groups; _{The 3-} alkyl groups and substituents may be the same or different,

R ³ is a phenyl or naphthyl group which may be substituted by one to five substituents selected from the group consisting of fluorine, chlorine or bromine atoms, C 1-6 -alkyl, C 1-6 -alkyl; _3- alkoxy-, cyano-, trifluoromethyl-, nitro-, amino-, C 1-6 -alkylamino-, di-C 1-6 -alkylamino-, C _{2 -} . . _4-alkanoyl amino, / V- (C _M alkyl) -C _{second 4} alkanoylamino-, C1-4alkylamino; _3- alkylsulfonylamino-, amino-C _{1 -} . _3- alkyl, C]. _3- alkylamino-C 1-6 -alkyl. di- (C _1-3 -alkyl) -amino-C 1-6 alkyl; ₃ alkyl, N (C ₂ _ ₄ alkanoyl) amino-C. ₃ alkyl and / or N (C _{2nd 4} alkanoyl) C | _3- alkylamino-C ₃ -alkyl, and the substituents may be the same or different,

R ⁴ is H or C alkyl group, and _W

R ⁵ is a hydrogen atom,

C 1-6 -alkyl optionally substituted by phenyl, carboxy- or C 1-6 -alkyl; ₃ -alkoxycarbonyl, C ₃ . ₇ -cycloalkyl optionally substituted with C _B3 -alkyl, indanyl optionally substituted with C |. _3- alkyl,

A 5-membered heteroaryl group that contains an imino group optionally substituted with C 1-6. _{A 3-} alkyl group, an oxygen or sulfur atom, or an amino group optionally substituted with a C 1-6 alkyl group; _{A 3-} alkyl group and an oxygen, sulfur or nitrogen atom or two nitrogen atoms, or a 6-membered heteroaryl group containing 1 to 3 nitrogen atoms, through two adjacent carbon or nitrogen atoms and the adjacent imino group of said 5- and 6- a 1,3-butadienylene bridge may be attached to the membered heteroaryl group and the carbon core of said mono- and bicyclic rings may be mono- or disubstituted with chlorine, bromine or iodine atoms, a C _1-5 -alkyl or cyano group and the substituents may be the same or different, pyrrolidinyl or a piperidinyl group attached via a carbon atom which may be substituted on the nitrogen atom by a C 1-4 alkyl group, a phenyl group optionally disubstituted by fluorine, chlorine, bromine or iodine atoms, C 1-6 alkyl; _5- alkyl, C 1-6 alkyl. ₃ -alkoxy, carboxy, C _b3 -alkoxykarbonylovou-, sulfonylovou- amino, nitro or cyano groups, wherein the substituents may be the same or different, phenyl, pyridyl, pyrimidyl or thienyl, which is substituted by trifluoromethoxy, fluorine, chlorine, , bromine or iodine,

C |. _3- alkoxy, which in position 2 or 3 may be substituted with amino-, C 1-6 -alkoxy; _3- alkylamino, di- (C). _(3- alkyl) -amino-, phenyl, C1-6alkyl; ₃ -alkylamino, N- (C _a -alkyl) phenyl-C ,. . _{A 3-} alkylamino-, pyrrolidine or piperidine group, a phenyl-C 1-6 -alkylamino-C 1-6 -alkylamino-C 1-6 -alkyl group which in the phenyl core may be mono- or disubstituted with trifluoromethyl, fluorine, chlorine, bromine or iodine atoms, or alkyl. ₃ -alkoxy groups, wherein the substituents may be the same or different, and the additional nitrogen atom of the amine C _H -alkyl, wherein the hydrogen atoms may be replaced by the position of two completely or partially by fluorine atoms,

C |. _5- alkyl, phenyl, imidazolyl, C ₃ . ₇ -cycloalkyl, C ₁ _, - _alkoxy-C! . _(Alkoxy-. CJJ-phenyl-alkoxy, carboxy-C ₃ -alkyl, _{C1. 3 -alkoxycarbonyl-C1. 3} -alkyl, carboxy, Cu-alkoxycarbonyl, aminocarbonyl, C _N -alkylamino-carbonyl, di - (C |. ₃ alkyl) -aminokarbonylovou, phenyl-C |. -alkylaminokarbonylovou _3, N- _{(C1. 3} alkyl) phenyl-C ₃ -alkylaminokarbonylovou, piperazinecarbonyl, ^A, - (C |. ₃ - alkyl) -piperazínkarbonylovou, nitro, amino, C. ₃ -alkylamino, di-JCU-alkylj-amino, pyrrolidino, piperidino, morpholino, _{C2. 4} -alkanoylamino-, /V-(C[.·; -alkyl) -C _{second 4} -alkanoylamino-, benzoylamino or 1V- (C |. ₃ -alkyl) - benzoylamino, / N _{(C1. 3} alkyl) -C _second -alkanoylaminoskupinou _4, which is alkyl substituted with carboxy or C additionally _{L 3} alkoxycarbonyl group, a Cu-alkylaminocarbonyl or di- (C |. ₃ alkyl) -aminokarbonylovou group wherein the alkyl moiety is additionally substituted by di (C |. ₃ alkyl) - amino, or IV-C 1-6 -alkyl-C 1-6 -alkylsulfonylamino- or N - (C _1-3 -a); (alkyl) -phenylsulfonylamino-group in which the alkyl moiety may be additionally substituted by cyano-, carboxy-, C1-6-alkylsulfonylamino-, C1-6alkyl-, C1-6alkynyl-, C1-6alkynyl-, C1-6alkynyl-, C1-6alkylamino- ₃

-alkoxycarbonyl, C 1-4 -alkylamino-, di- (C _1-4 -alkyl) -amino-, amino-carbonyl, C 1-4 -alkyloxy- ₃ -alkylaminokarbonylovou, di- _{(C1. 3} alkyl) -aminokarbonylovou, piperidinocarbonyl or 2- [di- (C |. ₃ -alkylamino)] ethylaminocarbonyl, phenyl or thienyl, substituted C]. _{A 3-} alkyl group in which the alkyl moiety is substituted with hydroxy, C _1-3 -alkoxy-, carboxy-, C _1-3 -alkoxycarbonyl, amino-, C 1-6 -alkylamino-, di-C 1-6 -alkylamino-C ₂ . ₄ -alkanoylamino-, TV- _{(Art. 3} alkyl) _{-C2. 4-} alkanoylamino-, pyrrolidine, dehydropyrrolidine, piperidine, dehydropiperidine, 3-hydroxypiperidine, 4-hydroxypiperidine, hexamethyleneimino-, morpholine, thiomorpholine, piperazine, 4- (C _1-6 -alkyl, 4-piperazine, 4-phenyl, 4-phenyl, 4-phenyl, 4-phenyl, 4-phenyl, 4-phenyl) - (C _{2nd 4} alkanoyl) -piperazine, 4-benzoyl-piperazino or imidazolyl group wherein said saturated cykloalkyléniminokruhy, C] _ ₅ -alkylamino or di-t C ^ -alkylj-amino groups may be additionally substituted with one or two Cj_ ₅ alkyl groups, one _C3-.7 cycloalkyl, hydroxy, C |. _3- alkoxy-, carboxy-, C1-8; _3- alkoxycarbonyl, aminocarbonyl; ₃ -alkylaminokarbonylovou or di- (C _h _ ₃ alkyl) -aminokarbonylovou group, an phenyl-C _U3 alkyl or phenyl group which the phenyl nucleus may additionally be mono- or disubstituted by fluorine, chlorine, bromine, iodine, C ]. _{The 3-} alkyl or cyano groups, wherein the substituents may be the same or different, or the methylene adjacent to the nitrogen in said cycloalkyleneiminocycles may be replaced by a carbonyl or sulfonyl group, and said monosubstituted phenyl groups may be additionally substituted by fluorine, chlorine or bromine, methyl, amino, C ^ -alkvIamino- or di- (Cj_ ₃ -alkyl) amino, or one of the said unsubstituted cykloalkyléniminokruhoch may be through two adjacent carbon atoms fused phenyl ring optionally substituted by one or two C ₁ _ ₃ -alkoxy groups.

In addition, the carboxyl groups mentioned in the definition of said residues may be replaced by a group which can be converted into a carboxy group in vivo, and the amino and imino groups mentioned in the definition of said residues may additionally be substituted by a residue which is cleavable in vivo.

In addition, the saturated alkyl and alkoxy moieties mentioned in the definition that contain more than two carbon atoms also include their branched isomers such as isopropyl, tert-butyl, isobutyl, and the like.

Preferred compounds of formula (1) are those in which:

X is an oxygen or sulfur atom;

R ¹ is hydrogen, C 1-6. ₄ -alkoxy-carbonyl or C _{2nd 4-} alkanoyl group,

R ² is a carboxy-, C 1-6 -alkoxycarbonyl or aminocarbonyl group in which the amino group may be substituted by one or two C ₃ -alkyl groups and the substituents may be the same or different,

R ³ is a phenyl or naphthyl group which may be substituted with one to five substituents selected from the group consisting of fluorine, chlorine or bromine atoms, C 1-6 alkyl; _3- alkyl, Ci. _3- alkoxy-, cyano-, trifluoromethyl-, nitro-, amino-, C1-6alkoxy; ₃ -alkylamino, di- (C _{first 3} alkyl) amino, C _{2nd 4-} alkanoyl-amino-, N - (C _1-3 -alkyl) -C ₂ - alkanoylamino-, C 1-6 -alkanoylamino- ₃ alkylsulfonylamino-, amino-C 1-6 alkylsulfonylamino- _3- alkyl, C 1-6 alkyl. ₃ -alkylamino-C ^ alkyl, di- _{(C1. 3} alkyl) _{amino-C. 3} alkyl, N (C _{2nd 4} alkanoyl) amino-C _{first 3} alkyl or N _{(C2. 4} -alkane oyl) -C. _3- alkylamino-Ci. _{The 3-} alkyl group and the substituents may be the same or different,

R ⁴ is hydrogen or C 1-6. _{A 3-} alkyl group and a

R ⁵ is a hydrogen atom,

_C, _5-alkyl optionally substituted by phenyl, carboxy or C. ₃ -alkoxycarbonyl, C ₃ . _7- cycloalkyl optionally substituted with C _1-3 -alkyl, indanyl optionally substituted with C _1-3 . _3- alkyl,

A 5-membered heteroaryl group that contains an imino group optionally substituted with C 1-6 alkyl; _{A 3-} alkyl group, an oxygen or sulfur atom, or an amino group optionally substituted with C 1. _{A 3-} alkyl group and an oxygen, sulfur or nitrogen atom or two nitrogen atoms, or a 6-membered heteroaryl group containing 1 to 3 nitrogen atoms, through two adjacent carbon or nitrogen atoms and the adjacent imino group of said 5- and 6- a 1,3-butadienylene bridge may be attached to the membered heteroaryl group, and the carbon core of said mono- and bicyclic rings may be mono- or disubstituted by chlorine, bromine or iodine atoms, C 1-6. _{The 5-} alkyl or cyano group and the substituents may be the same or different, the pyrrolidinyl or piperidinyl group attached via a carbon atom, which on the nitrogen atom may be substituted by C 1-6 -alkyl. ₃ -alkyl, phenyl optionally disubstituted by fluorine, chlorine, bromine, iodine, C _{first 5-} alkyl, C 1-4 -alkoxy-, carboxy-, C 1-4 -alkyl- _3- alkoxycarbonyl, aminosulfonyl, nitro or cyano, wherein the substituents may be the same or different, a phenyl, pyridyl, pyrimidyl or thienyl group which is substituted by C ₃ . ₇ -cycloalkyl, Ci. _3- alkoxy-, phenyl-C 1-6 alkyl; _3- alkoxy-, carboxy-C ₁ . _3- alkyl, C ,. _3- alkoxycarbonyl-C 1. ₃ -alkyl, carboxy, C ^ -alkoxykarbonvlovou, aminocarbonyl, C _{l. 3} alkylaminocarbonyl, di _{(first 3} alkyl) -aminokarbonylovou, nitro, amino, C _{L 3} -alkylamino, di- ₍₃ Cj_ alkyl) amino, C _{2nd 4-alkanoyl-amino,} N- (C _{first 3} -alkyl) -C _{second 4-} alkanoylamino- or N '- (C _1-3 -alkyl) -C ₃ . _4- alkanoylamino, C ₁ . _{A 3-} alkylamino-carbonyl group in which the alkyl moiety is additionally substituted with a di- (C _1-3 -alkyl) amino group, or N-C 1-6 -alkyl-C). A _3- alkylsulfonylamino group in which the alkyl moiety may be additionally substituted with cyano-, carboxy-, C 1-6 alkyl; _{3 alkoxycarbonyl,} C. _3- alkylamino-di- (C _1-3 -alkyl) -amino, phenyl or thienyl substituted with C 1-6 -alkyl, wherein the alkyl moiety is substituted with hydroxy-, C 1 -alkyl. ₃ -alkoxy, carboxy, C _{first 3} -alkoxy-carbonyl, amino, C _{first 5-} alkylamino-, N - (C _1-5 -alk) -amino-, C ₂ . ₄ -alkanoylamino-, and ^L - _{(Art. 3} alkyl) _{-C2. 4} -alkanoylamino-, pyrrolidino, piperidino, hexamethyleneimino, morpholino, piperazino, 4- (C _{first 3} -alkyl) -piperazine, 4- (C _2nd -alkanoylj _{4-piperazine,} 4-benzoyl-piperazino or imidazolyl group, wherein the cykloalkyléniminokruhy, C-5-alkylamino or di- (C. _5-alkyl) - amino groups may additionally be substituted by C _V5 -alkyk:> acid, _{C3. 7} -cycloalkyl, hydroxy, C |. ₃ -alkoxy- , carboxy, C _{i.. 3} -alkoxycarbonyl, aminocarbonyl, C ₃ -alkylaminokarbonylovou or di-C |. ₃ alkyl) -aminokarbonylovou group, a phenyl-C |. _{A 3-} alkyl or phenyl group, which in the phenyl ring may optionally be mono or disubstituted by fluorine, chlorine, bromine or iodine atoms, Cj. _{The 3-} alkyl or cyano group, wherein the substituents may be the same or different, or the methyl group adjacent to the nitrogen atom in said cycloalkylene imino rings may be replaced by a carbonyl or sulfonyl group, and said monosubstituted phenyl groups may be additionally substituted by fluorine, chlorine or bromine or a methyl group, especially those compounds of formula (1) in which X is an oxygen atom,

R ¹ is hydrogen, C _1-4 alkoxycarbonyl,

R ² is a carboxy-, C 1 -alkoxy-carbonyl or aminocarbonyl group in which the amino moiety may be substituted by one or two C _1-3 -alkyl groups and the substituents may be the same or different,

R ³ is a phenyl group optionally substituted by a fluorine, chlorine or bromine atom, a methyl, cyano, or aminomethyl group,

R ⁴ is a hydrogen atom or a methyl group; and

R ⁵ is a hydrogen atom,

C 1-6 -alkyl optionally substituted by carboxy- or C 1-6 -alkyl; ₃ -alkoxycarbonyl or benzyl,

C ₃ . _{A 7-} cycloalkyl group optionally substituted by a methyl, indanyl, pyridyl, oxazolyl, thiazolyl or imidazolyl group optionally substituted by a methyl group on which two adjacent carbon atoms can be additionally fused with a phenyl core, a methylphenyl group optionally substituted with methoxy or fluorine, chlorine, chlorine -, carboxy-, C ₁ . _{A 3-} alkyloxycarbonyl, nitro- or aminosulfonyl group, or a dimethoxyphenyl group, a pyrrolidinyl or piperidinyl group attached via a carbon atom which is substituted on the nitrogen atom by a C 1-6 atom. _3- alkyl, phenyl, which is substituted with trifluoromethoxy, fluoro, chloro, bromo or iodo,

Ci. _3- alkoxy, which may be substituted at the 2 or 3 position with amino, C 1-6 -alkylamino-, di- (C _1-3 -alkyl) -amino-, phenyl-C 1-6 -alkylamino-, N'-C 1-6 -alkylamino- -alkyl-phenyl-C 1-6 -alkylamino-, pyrrolidine or piperidine, phenyl-C 1-6 -alkylamino-C 1-6 -alkyl which may be substituted in the phenyl ring by a fluorine, chlorine, bromine or iodine atom; _{The 5-} alkyl, C _{1 (} -alkoxy- or trifluoromethyl group) and additionally at the amine nitrogen atom may be substituted by a C _1-3 -alkyl group in which the hydrogen atoms from the 2-position can be replaced in whole or in part by fluorine atoms,

C |. ₅ -alkyl, phenyl, imidazolyl, _{Cl 7} -cycloalkyl, C ^ -alkoxy-Cu-alkoxy, phenyl-Cj-alkoxy, carboxy-C-j alkyl, C) J-alkoxycarbonyl-C ^ -alkyl, carboxy-, C _1-3 -alkoxycarbonyl, aminocarbonyl, C _1-3 . _3- alkylamino-carbonyl, di- (C 1-3 -alkyl) -aminol-arbonyl, phenyl-C 1-6 -alkylamino-carbonyl; ₃ -alkylaminokarbonylovou, cis- (C _[R _-alkylj phenylmercuric alkylaminocarbonyl, piperazinecarbonyl, N - (C |. ₃ alkyl) -piperazinkarbonylovou, nitro, amino, C [. ₃ alkylamino-, di- _{(C1. 3} alkyl) amino, pyrrolidino, piperidino, morpholino, C 2-4 alkanoylamino, A-jCi.j -alkyl is C ^ -alkanoylamino-, benzoylamino or y- (C |. _3- alkyl) -benzoylamino,

N - (C 1 - ₍ alkyl) -C _1-4 -alkanoylamino, which is additionally substituted in the alkyl moiety by carboxy- or C 1-6 -alkoxycarbonyl,

Ci. _3- alkylaminocarbonyl or di-C 1-6 alkyl-aminocarbonyl, in which the alkyl moiety is additionally substituted with di-C 1-6 -alkyl-amino, or X- (C _1-3 -alkyl) -C 1-6 -alkyl. _3- alkylsulfonylamino- or N '- (C 1-6 -alkyl) -phenylsulfonylamino- group in which the alkyl moiety may be additionally substituted by cyano-, carboxy-, C 1-6 -alkylsulfonylamino-; ₃

alkoxycarbonyl, C _{first 3} -alkylamino, di- _{(C1. 3} alkyl) amino, aminocarbonyl, C. _3- alkylaminocarbonyl, di- (C _1-3 -alkyl) -aminocarbonyl, piperidinecarbonyl or 2-di-C 1-6 -alkylamino-1-ethylaminocarbonyl, a phenyl group optionally substituted with C 1-6 alkyl; _{A 3-} alkyl group in which the alkyl moiety is substituted with hydroxy-, C 1-6 -alkyl; _(-Alkoxy, carboxy, C |. ₃ -alkoxy-carbonyl, amino, _C, -alkyl) amir> o, di-fC ^ -alkylj-amino, C ₂₇ -alkanoylamino-, N- ( C _{first and} alkyl) - C _{2nd 4-} alkanoylamino-, pyrrolidine, dehydropyrrolidine, piperidine, dehydropiperidine, 3-hydroxypiperidine, 4-hydroxypiperidine, hexamethyleneimino-, morpholine, thiomorpholine, piperazine, 4- (C _1-3 -alkyl) -piperazine, 4-phenyl-piperazine, - (C _2-4 -alkanoyl) -piperazine, 4-benzoyl-piperazine or imidazolyl, wherein said saturated cycloalkyleneimino rings, C _1-5 -alkylamino- or di-C 1-4 -alkyl-amino groups may be additionally substituted with one or two C 1-6 -alkylamino groups. _5- alkyl groups, once C ₃ . ₇ -cycloalkyl, hydroxy-, C1-7. _3- alkoxy-, carboxy-, C1-6alkyl- _3- alkoxycarbonyl, aminocarbonyl; _3- alkylaminocarbonyl or di- (C _1-3 -alkyl) aminocarbonyl, one phenyl-C 1-6 -alkyl or phenyl group, which in the phenyl core may additionally be mono- or disubstituted by fluorine, chlorine, bromine or iodine atoms; _{The 3-} alkyl or cyano groups, wherein the substituents may be the same or different, or the methylene group adjacent to the nitrogen atom in said cycloalkyleneiminocycles may be replaced by a carbonyl or sulfonyl group, and said monosubstituted phenyl groups may additionally be substituted by fluorine, chlorine or bromine, -, C _1-3 -alkylamino- or di- (C _1-3 -alkyl) -amino, or on one of said unsubstituted cycloalkyleneimino rings, the fused phenyl ring optionally substituted by one or two C 1 -alkoxy groups via two adjacent carbon atoms may be substituted, isomers and their salts.

Particularly preferred compounds of formula (I) are those in which:

X is an oxygen atom, R ¹ is a hydrogen atom,

R * is carboxy-. C, _{4-alkoxy-carbonyl} or aminocarbonyl group wherein the amino moiety may be substituted by one or two C alkyl groups and _b3 may be the same or different,

R ³ is a phenyl group optionally substituted with a methyl group,

R ⁴ is a hydrogen atom or a methyl group; and

R ⁵ is a hydrogen atom,

C _{I. 3-} alkyl, benzyl or methyl or ethyl substituted by carboxy- or C 1-6 -alkyl; ₃ -alkoxycarbonyl,

C ₃ . _7- cycloalkyl optionally substituted by methyl, indanyl, pyridyl, oxazolyl, thiazolyl or imidazolyl optionally substituted by methyl, on which two adjacent carbon atoms can be additionally fused to a phenyl core, methylphenyl optionally substituted by methoxy, fluorine, chlorine, chlorine -, carboxy-, C 1-6 -alkyloxycarbonyl, nitro- or aminosulfonyl, or dimethoxyphenyl,

A 3-pyrrolidinyl or 4-piperidinyl group which is substituted on the nitrogen atom by a C 1-6 -alkyl group, a phenyl group which is substituted by a trifluoromethoxy, benzyloxy, cyano or nitro group, a fluorine, chlorine or bromine atom; _{The 3-} alkoxy group, wherein the ethoxy and n-propoxy group may be end-substituted with dimethylamino, diethylamino, N-ethyl-methylamino, N-benzyl-methylamino or piperidine, phenyl-C _1-3 -alkylamino-C | The alkyl group, which in the phenyl ring may be substituted by a fluorine, chlorine, bromine or iodine atom, a methyl, methoxy or trifluoromethyl group, and in addition and by an amino nitrogen atom, may be substituted by a C1-6 -alkyl. _5- alkyl- or 2,2,2-trifluoroethyl;

C ^ -alkyl, phenyl, imidazolyl, cyclohexyl, methoxymethyl, carboxymethyl, C _{first 3} -alkoxycarbonyl-methyl, carboxy, C _{first 3} -alkoxycarbonyl, aminocarbonyl, C. ₃ -alkylaminokarbonylovou, di- (Cl _ ₃ alkyl) -aminokarbonylovou, phenyl-C i .3-alkylaminocarbonyl, N-alkyli ICIJ-phenyl-Qj-alkylaminocarbonyl, piperazinecarbonyl, N-FCU-alkyli-piperazinecarbonyl, amino- , C |. _3- alkylamino-, di- (C _1-3 -alkyl) -amino-, pyrrolidine, piperidine, morpholine, C ₂ . ₄ -alkanoylamino-, 7V- (C | .j-alkyl) -C _{second 4-} alkanoylamino-, benzoylamino- or N - (C _1-3 -alkyl) -benzoylamino, N '- (C _1-3 -alkyl) -C ₂ . -Alkanoylaminoskupinou _4, which is additionally substituted by alkyl or carboxy-C _1T alkoxycarbonyl group,

A C 1-3 -alkylaminocarbonyl or di- (C 1-6 -alkyl) -aminocarbonyl group in which the alkyl moiety is additionally substituted by a di- (C _1-3 -alkyl) -amino group, or a N-C 1-6 -alkyl-C 1-6 -alkylsulfonylamino- or an N- (C _1-3 -alkyl) -phenylsulfonylamino-group in which the alkyl moiety may be additionally substituted by cyano-, carboxy-, C _1-3 -alkoxycarbonyl, C 1-4 -alkylamino-, di- (C _1-3 -alkyl) ) -amino-, aminocarbonyl, C 1-4 -alkylaminocarbonyl, di- (C 1-6 -alkyl) aminocarbonyl, piperidinecarbonyl or 2- [di- (C 1-6 -alkylamino)] - ethylaminocarbonyl, phenyl optionally substituted C1-6. ₃ -alkyl, wherein the alkyl moiety is substituted by hydroxy, C ^ -alkoxy, carboxy, C ^ alkoxy-carbonyl, amino, C |, 5-alkylamino, di- (C _{first 5} alkyl ) amino, C _{2nd 4} -alkanoylamino-, N-fC _{l 3} alkyl) - C _{2nd 4-} alkanoylamino-, pyrrolidine, dehydropyrrolidine, piperidine, dehydropiperidine, 4-hydroxypiperidine, hexamethyleneimino-, morpholine, thiomorpholine, piperazine, 4- (C _1-3 -alkyl) -piperazine, 4-phenyl-piperazine, 4- (C ₂₎ The _4- alkanoyl) -piperazine, 4-benzoyl-piperazine or imidazolyl group, wherein said saturated cycloalkyleneimino rings, may be additionally substituted by a phenyl group or one or two methyl groups, indicated by C 1-6 alkyl. ₅ -alkylamino and di- _{(C1. 5} alkyl) amino can additionally be substituted by one or two C |. _3- alkyl groups, one cyclohexyl, hydroxy-, C 1-6 -alkoxy-, carboxy-, C 1-6 -alkyl-; _3- alkoxycarbonyl, aminocarbonyl, C 1-6 -alkylaminocarbonyl or di- (C _1-3 -alkyl) aminocarbonyl, phenyl-C 1-6 -alkyloxycarbonyl; _{A 3-} alkyl or phenyl group which in the phenyl ring may be optionally substituted by a fluorine, chlorine, bromine or iodine atom, a methyl or cyano group, or a methyl group adjacent to a nitrogen atom in said cycloalkyleneimino rings may be replaced by a carbonyl or sulfonyl group and the groups may be additionally substituted by a fluorine, chlorine or bromine atom, methyl, amino-, C1-6-alkyl. _{The 3-} alkylamino- or di-C 1-6 -alkyl-amino group, or on one of said unsubstituted cycloalkyleneimino rings, the fused phenyl core may optionally be substituted by one or two C 1 through two adjacent carbon atoms. _3- alkoxy groups, their isomers and their salts.

Particularly preferred compounds of formula (I) are those in which:

X is an oxygen atom,

R ¹ is a hydrogen atom,

R ² is a carboxy- or aminocarbonyl group in which the amino moiety may be substituted with one or two C 1-6 moieties. _{The 3-} alkyl groups and substituents may be the same or different,

R ³ is a phenyl group optionally substituted with a methyl group,

R ⁴ is a hydrogen atom and R ⁵ is a hydrogen atom, a 3-pyrrolidinyl or 4-piperidinyl group which is substituted on the nitrogen atom by C 1-6. _{A 3-} alkyl group, a phenyl group which is substituted with a C 1-6 alkyl group; _{The 3-} alkoxy group, wherein the ethoxy and n-propoxy group may be end-substituted with dimethylamino-, diethylamino-, N'-ethyl-methylamino-, N -benzylmethylamino- or piperidine, phenyl-C 1-6 -alkyloxy; _{The 3-} alkylamino-C _1-3 -alkyl group, which in the phenyl ring may be substituted by a fluorine, chlorine, bromine or iodine atom, a methyl, methoxy or trifluoromethyl group, and in addition and by an amino nitrogen atom, may be substituted by C ₁ . _5- alkyl- or 2,2,2-trifluoroethyl, phenyl optionally substituted with C 1-6 alkyl; _{A 3-} alkyl group in which the alkyl moiety is substituted with hydroxy-, C 1-6 -alkyl; _3- alkoxy-, carboxy-, C 1-6 alkyl; _3- alkoxycarbonyl, amino-, C ₁ . _5- alkylamino-, di- (C _1-5 -alkyl) -amino-, C ₂ . _4- alkanoylamino-, N- (C 1-6 -alkyl) - C ₂ . ₄ -alkanoylamino-, pyrrolidino, dehydropyrolidínovou, piperidine, dehydropiperidínovou, 4-hydroxypiperidino, hexametylénimino-, morpholino, thiomorpholino, piperazino, 4- (C _{i. 3-alkyl)} -piperazine, 4-phenyl-piperazine, 4- (C ₂ The _4- alkanoyl) -piperazine, 4-benzoyl-piperazine or imidazolyl group, wherein said saturated cycloalkyleneimino rings, may be additionally substituted with a phenyl group or one or two methyl groups, indicated by C 1-6. _{The 5-} alkylamino- and di- (C _1-5 -alkyl) amino groups may be additionally substituted with one or two C 1-6 -alkylamino groups. _3- alkyl groups, one cyclohexyl, hydroxy-, C 1-6 -alkyl; _3- alkoxy, carboxy-, C _1-3 -alkoxycarbonyl, aminocarbonyl, C 1-4 -alkylaminocarbonyl or di- (C 1-3 -alkyl) aminocarbonyl, one phenylC _1-3 -alkyl or phenyl group, which in the phenyl core may be optionally substituted by a fluorine, chlorine, bromine or iodine atom, a methyl or cyano group, or a methyl group adjacent to a nitrogen atom in said cycloalkyleneiminocycles may be replaced by a carbonyl or sulfonyl group, and said monosubstituted phenyl groups may additionally be substituted by fluorine or chlorine , amino-, C1-8. _{The 3-} alkylamino- or di-C 1-6 -alkyl-amino group, or on one of said unsubstituted cycloalkyleneimino rings, the fused phenyl core may be optionally substituted by one or two C 1 through two adjacent carbon atoms. _3- alkoxy groups, their isomers and their salts.

Especially preferred are the compounds in which R ² is in the 5-position, especially the following compounds:

(a) 3 Z- [1- (4-Aminomethyl-phenylamino) -1-phenyl-methylene] -5-amido-2-indolinone, (b) 3-Z- [1- (1-Phenylamino) - 1-phenyl-methylene] -5-amido-2-indolinone, (c) 3-Z- [1- (4-bromo-phenylamino) -1-phenyl-methylene] -5-amido-2-indolinone, (d) 13-Z- [1- (4-dimethylamino-methyl) -phenylamino) -1-phenyl-methylene] -5-amido-2-indolinone, (e) 3-Z- [1- (4-pyrrolidinomethyl-phenylamino)] -1-phenyl-methylene] -5-amido-2-indolinone, (f) 3-Z- [1- (4-piperidinomethyl-phenylamino) -1-phenyl-methylene] -5-amido-2-indolinone, ( (g) 3-Z- [1- (4-hexamethyleneiminomethyl-phenylamino) -1-phenyl-methylene] -5-amido-2-indolinone, (h) 3-Z- [1- (4-benzyl-piperidine) - methyl) -phenylamino) -1-phenyl-methylene] -5-amido-2-indolinone, (R) 3-Z- [1- (4- (N-butyl-aminomethyl) -phenylamino) -1-phenyl-methylene ] -5-amido-2-indolinone,

Q) 3-Z- [1- [4- (N - (phenyl-methyl) -aminomethyl) -phenylamino] -1-phenyl-methylene] -5-amido-2-indolinone, (k) 3-Z- [1- (4- (N-methyl-N-benzyl-amino-methyl) -phenylamino) -1-phenyl-methylene] -5-amido-2-indolinone, (1) 3-Z- [1- (4-piperidine- methyl-phenylamino) -1-phenyl-methylene] -5-dimethylcarbamoyl-2-indolinone, (m) 3-Z- [1- (4-piperidin-methyl-phenylamino) -1-phenyl-methylene] -5-diethylcarbamoyl -2-indolinone, (n) 3-Z- [1- (4- (3-diethylamino-propoxy) -phenylamino) -1-phenyl-methylene] -5-amido-2-indolinone, and salts thereof.

The invention also provides methods for preparing (essentially known from the literature) compounds of the invention, including:

a) reaction of a compound of formula (II)

R ³

in which

X, R ² and R ³ are as defined above,

R ⁶ is a hydrogen atom, a protecting group for a nitrogen atom of a lactam group or a solid phase bond; and

Z ¹ is halogen, hydroxy, alkoxy or aralkoxy, for example chlorine or bromine, methoxy, ethoxy or benzyloxy, with an amine of formula (III)

(III) in which

R ⁴ and R ⁵ were as previously defined and, if necessary, the used protective groups of the nitrogen atom of the lactam group were subsequently cleaved, or the obtained compound was cleaved from the solid phase.

The nitrogen protecting group of the lactam group may be, for example, acetyl, benzoyl, ethoxycarbonyl, tert-butylcarbonyl or benzyloxycarbonyl, and the solid phase may be a Rink or Sieber resin.

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, Λ'-ethyl-diisopropylanine or sodium bicarbonate at 20 ° C. up to 175 ° C, whereby one protecting group can be cleaved simultaneously as a result of amidization.

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

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

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

The cleavage of the solid phase used is preferably carried out with trifluoroacetic acid and water in the presence of a dialkyl sulfide such as dimethyl sulfide at a temperature between 0 to 35 ° C, preferably at room temperature.

b) Compounds of formula (I) which contain an aminomethyl group and X is an oxygen atom are prepared by: reduction of a compound of formula (IV)

(iv) in which:

R ¹ to R ⁴ have been identified previously, and

R ⁷ is as previously defined R ^3, with R ⁵ containing cyano.

The reduction is preferably carried out by catalytic hydration with hydrogen in the presence of a catalyst such as palladium / carbon or platinum in a solvent such as methanol, ethanol, ethyl acetate, dimethylformamide, dimethylformamide / acetone or glacial acetic acid, optionally with acid addition. such as hydrochloric acid at temperatures between 0 DEG and 50 DEG C., but preferably at room temperature and at a hydrogen pressure of 10 ² to 7.10 ² kPa (1-7 bar), but preferably at 3.10 ² to 5.10 ² kPa (3 to 5 bar).

If a compound of formula (I) containing an alkoxycarbonyl group is obtained according to the invention, then it can be converted by hydrolysis to the corresponding carboxy compound, or a compound of formula (I) containing an amino or alkylamino group, then converted by alkylation or reducing alkylation to the corresponding alkylamino- or dialkylamino compound, or a compound of formula (I) containing an amino or alkylamino group, may then be converted by acylation to the corresponding acyl compound, or a compound of formula (I) containing a carboxy group, then convertible esterification or amidization to the corresponding ester or aminocarbonyl compound.

The subsequent hydrolysis is preferably carried out in an aqueous solvent such as 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 for example lithium hydroxide, sodium hydroxide or potassium hydroxide at a temperature between 0 to 100 ° C, preferably at a temperature between 10 to 50 ° C.

Subsequent reductive alkylation is preferably carried out in a suitable solvent such as methanol, methanol / water, methanol / water / ammonia, ethanol, ether, tetrahydrofuran, dioxane or dimethylformamide optionally with the addition of an acid such as hydrochloric acid in the presence of catalytically active hydrogen, for example hydrogen in the presence of Raney nickel, platinum or palladium / coal, or in the presence of a metal hydride such as sodium borohydride, lithium boron hydride or lithium aluminum hydride at a temperature between 0 to 100 ° C, preferably at a temperature between 20 to 80 ° C.

Subsequent alkylation is carried out with an alkylating agent such as an alkyl halide or dialkyl sulfate, for example methyl iodide, dimethyl sulfate or propyl bromide, suitably in a solvent such as methanol, ethanol, methylene chloride, tetrahydrofuran, toluene, dioxane, dimethylsulfoxide or dimethylformamide, optionally an inorganic or tertiary organic base such as triethylamine, Λ'-ethyl-diisopropylamine or dimethylaminopyridine, preferably at a temperature between 20 ° C and the boiling point of the solvent used.

Subsequent acylation is 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 a temperature 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 chloroformate, tetraethyl carbonate, trimethyl orthoacetic acid, 2,2-dimethoxypropane, tetramethoxysilane, thionyl chloride, trimethylchloride, trimethylchloride N, N'-dicyclohexylcarbodiimide, N, N'-dicyclohexylcarbodiimide, N-N-hydroxysuccinimide, N, N'-dicyclohexylcarbodiimide / 1-hydroxybenzotriazole, 2- (1H-benzotriazol-1-yl) -1, 1,3,3-tetramethyluronium tetrafluoroborate, 2- (1H-benzotriazol-1-yl) -1,1,3,3-tetramethyluronium tetrafluoroborate / 1-hydroxybenzotriazole, N, N-carbonyldiimidazole or triphenylphosphine n-carbon tetrachloride, and optionally with the addition of a base such as pyridine, 4-dimethylaminopyridine, Λ'-methylmorpholine or triethylamine, suitably at a temperature between 0 to 150 ° C, preferably at a temperature between 0 to 100 ° C, and acylation with a corresponding reactive compound such as their anhydride, ester, imidazolide or halide optionally in the presence of a tertiary organic base such as triethylamine, N-ethyl-diisopropylamine or N-methyl-morpholine at a temperature between 0 to 150 ° C, preferably at a temperature between 50 and 100 ° C.

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

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

The protecting group for the carboxyl group may be trimethylsilyl, methyl, ethyl, tert-butyl, benzyl or tetrahydropyranyl, and the protecting group for the amino, alkylamino or imino group may be acetyl, trifluoroacetyl, benzoyl, ethoxycarbonyl, / erobutoxycarbonyl, benzobutoxycarbonyl, benzobutoxycarbonyl, benzyl, methoxybenzyl or 2,4-dimethoxybenzyl and, for the amino group, additionally phthalyl.

The optional subsequent cleavage of the protecting group used is carried out, for example, hydrolytically in an aqueous solvent such as water, isopropanol / water, tetrahydrofuran / water or dioxane / water, in the presence of an acid such as trifluoroacetic acid, hydrochloric acid or sulfuric acid, or an alkali base such as lithium hydroxide, sodium hydroxide or potassium hydroxide at a temperature between 0 to 100 ° C, preferably at a temperature between 10 to 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. optionally with the addition of an acid such as hydrochloric or glacial acetic acid at temperatures between 0 DEG and 50 DEG C., but preferably at room temperature and at a hydrogen pressure of 10 ² to 7.10 ² kPa (1-7 bar), but preferably at 3:10 ² to 5.10 ² kPa (3 to 5 bar).

The cleavage of the methoxybenzyl group may 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 to 50 ° C, preferably at room temperature.

However, 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 residue is preferably carried out by exposure to an acid such as trifluoroacetic acid or hydrochloric acid 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 a hydrazine or a primary amine such as methylamine, ethylamine or n-butylamine in a solvent such as methanol, ethanol, isopropanol, toluene / water or dioxane at a temperature between 20-50 ° C.

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

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

The resolution of the enantiomers is preferably carried out by column separation into 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, especially acids and their activated derivatives or alcohols, and separating the mixture of diastereomeric salts or derivatives thus obtained, for example on the basis of different solubilities, wherein free antipodes can be released from the pure diastereomeric salts or derivatives by treatment with suitable agents. Particularly useful optically active acids are, for example, the D- and L-forms of tartaric acid, dibenzoyltartaric acid, di-o-tolyltartaric acid, malic acid, mandelic acid, camphorsulfonic acid, glutamic acid, Λ'-acetylglutamic acid, aspartic acid, acids. N-acetyl aspartic or quinic acid. The optically active alcohol may be, for example, (+) or (-) - menthol, and the optically active acyl residue in the amides may be, for example, a (+) or (-) - mentyloxycarbonyl radical.

In addition, the compounds of formula (I) obtained can be converted into their salts, especially for pharmaceutical use, into their pharmaceutically acceptable salts with inorganic or organic acids. The acids may be, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, fumaric acid, succinic acid, lactic acid, citric acid, tartaric acid, maleic acid or methanesulfonic acid.

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

The compounds used as starting products of formulas (I) to (VII) are partially known from the literature, or are obtained by methods known from the literature, or will be described in the examples.

As indicated at the outset, the novel compounds of formula (I), wherein R ¹ is hydrogen or a prodrug group have valuable pharmacological properties, particularly inhibitory effects on various kinases and cyclin / CDK complexes, on the proliferation of cultivated human tumor cells, and also after oral administration for tumor growth in nude mice previously infected with human tumor cells.

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

Test 1

Inhibition of the enzyme cyclin / CDK, in vitro activity

High Five ™ insect cells (BTI-TN-5B1-4) infected with high titer recombinant baculovirus were used to produce active human cyclin / CDK holoenzymes. Using a baculovirus vector containing two promoters (a polyhedrin promoter, a P10 promoter), GST-labeled cyclins (e.g., cyclin D1 or cyclin D3) were expressed in the same cell with the corresponding His ₆ -labeled CDK subunit (e.g., for CDK4 or CDK6). The active holoenzyme was isolated by glutathione / Sepharose affinity chromatography. 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.

Lysates with recombinant baculovirus-infected insect cells or even recombinant kinases (obtained from lysate purification) were incubated for 45 minutes at 30 ° C together with radiolabeled ATP in the presence of a suitable substrate at various inhibitor concentrations in 1% DMSO (dimethylsulfoxide). Substrate proteins with associated radioactivity were precipitated with 5% TCA (trichloroacetic acid) in hydrophobic PVDF multiwell microtiter plates (Millipore) or with a 0.5% phosphoric acid solution on Whatman P81 filters. After addition of the scintillation solution, radioactivity was measured in a 1450 Microbeta liquid scintillation counter from Wallace. Two measurements were performed for each substance concentration; for enzyme inhibition was calculated the IC _50th

Test 2

Inhibition of proliferation of cultured human tumor cells

Leiomyosarcoma-derived tumor cell line SK-UT-1B (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% fetal bovine serum (Gibco) and harvested in logarithmic growth phase, then SK-UT-1B cells were plated in Cytostar® type multi-well plates (Amersham) at 4000 cells per well and incubated overnight in an incubator. were added various concentrations of compounds (dissolved in DMSO; final concentration <1%). After 48 h of incubation, each well was added ¹⁴ C-thymidine (Amersham), and the plate was incubated for additional 24 hours. the amount of ¹⁴ C-thymidine to the the presence of inhibitor incorporated into the tumor cells and means the number of cells in the S-phase was measured in a 1450 Microbeta liquid scintillation counter from Wallace. notes 1C ₅₀ for inhibition of proliferation (= inhibition of incorporated ¹⁴ C-thymidine) corrected for background background radiation. All measurements were performed in duplicate.

Test 3

In vivo effects on nude tumor-bearing mice

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

The following table shows the results of Test 2 in vitro.

Compound (Example #) Inhibition of SK-UT-1B 1C _5O cell proliferation [μΜ] 4 (2) 0.17 4 (14) 0.18 4 (62) 0.05 4 (53) 0.01 4 (54) 0.03 4 (60) 0.03 4 (120) 0.04 4 (122) 0.04 4 (94) 0.03 3 (3) 0.01 3 (7) 0.01 4 (129) 0.04

Because of their biological properties, the novel compounds of formula (I), their isomers and their physiologically acceptable salts are suitable for the treatment of diseases characterized by excessive or anomalous cell proliferation.

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

The novel compounds can be used for the short or long term treatment of said diseases and optionally also in combination with other standard compounds, such as other cytostatics.

To achieve a corresponding effect, the desired dosage is suitably 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, 1 to 4 times a day. For this purpose, the compounds of formula (I) prepared according to the invention, optionally in combination with other active ingredients, together with one or more inert conventional carriers and / or diluents, such as 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 fatty substances such as fat or suitable mixtures thereof may be incorporated into conventional galenic preparations such as tablets, dragees, capsules, powders, suspensions, suppositories or solutions for injection or infusion.

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

DETAILED DESCRIPTION OF THE INVENTION

Preparation 1

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

10.5 g of 2-indolinone-5-carboxylic acid methyl ester (prepared analogously to Ogaw et al., Chem. Pharm. Bull 36, 2253-2258 (1988)) is stirred in 30 ml of acetic anhydride for 4 hours at 140 ° C. The cold 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 collected in methylene chloride, dried over sodium sulfate and concentrated. Yield: 11 g (86% of theory)

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

Preparation 2

1-Acetyl-3- (1-ethoxy-1-phenyl-methylene) -2-indolinone-5-carboxylic acid methyl ester 1-acetyl-2-indolinone-5-carboxylic acid methyl ester is stirred in 110 ml acetic anhydride and 30 ml of triethyl orthobenzoic acid at 100 ° C for 2 hours. The mixture is evaporated, the residue is washed with ether and filtered off with suction. Yield: 11.5 g (67% of theory) Rf: 0.55 (silica gel; methylene chloride / petroleum ether / acetic acid ester = 4: 5: 1)

Preparation 3

28.0 g of Rink resin (MBHA resin, Novobiochem) was swelled in 330 ml of dimethylformamide. Then 330 ml of 30% piperidine in dimethylformamide is added and shaken for 7 minutes to cleave the FMOC protecting group. The resin is then washed several times with dimethylformamide. 7.3 g of 2-indolinone-5-carboxylic acid, 5.6 g of hydroxybenzotriazole, 13.3 g of O- (benzotriazol-1-yl-A'.A '', N ', N' -tetramethyl 1-) are added. of uronium tetrafluoroborate and 5.7 ml of N-ethyl-diisopropylamine in 300 ml of dimethylformamide and 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.

Yield: 28 g filled resin

PREPARATION 4 g of the resin prepared according to preparation 3 are stirred for 1 hour at 80 DEG C. with 15 ml of acetic anhydride. 15 ml of triethyl orthobenzoate are then added and the mixture is shaken for a further 3 hours at 110 ° C. The resin is then filtered off with suction and washed with dimethylformamide, methanol and finally methylene chloride.

Yield: 7 g wet resin

Preparation

4- (Ethylamino-methyl) -nitrobenzene nitrobenzyl bromide g was dissolved in 25 ml of ethanol, treated with 25 ml of a 10% solution of ethylamine in ethanol and heated at reflux for 2 hours. Then the solution is evaporated, the residue is taken up in methylene chloride and washed with dilute sodium hydroxide solution. Finally, the organic phase is concentrated.

Yield: 2.3 g (46% of theory)

_Rf: 0.2 (silica gel, methylene chloride / methanol = 9: 1)

Similarly prepared are: 4- [N- (4-chlorophenyl-methyl) -amino-methyl] -nitrobenzene, 4- (N-cyclohexyl-amino-methyl) -nitrobenzene, 4- (N-isopropyl-amino-methyl) - nitrobenzene, 4- (N-butyl-amino-methyl) -nitrobenzene, 4- (N-methoxycarbonyl-methyl-aminomethyl) -nitrobenzene, 4- (N - (phenyl-methyl) -amino-methyl) - nitrobenzene, 4- (pyrrolidin-methyl) -nitrobenzene, 4- (morpholin-methyl) -nitrobenzene, 4- (piperidin-methyl) -nitrobenzene, 4- (hexamethylenimino) -nitrobenzene, 4- (4-hydroxy-piperidin-methyl) -nitrobenzene, 4- (4-methyl-piperidin-methyl) -nitrobenzene, 4- (4-ethyl-piperidin-methyl) -nitrobenzene,

4- (4-Isopropyl-piperidin-methyl) nitrobenzene.

4- (4-phenyl-piperidin-ylmethyl) nitrobenzene.

4- (4-benzyl-piperidin-methyl) nitrobenzene.

4- (4-ethoxycarbonyl-piperidino-methyl) -nitrobenzene.

4- (Dimethylamino-methyl) nitrobenzene.

4- (dipropylamino-methyl) nitrobenzene.

4- (4-tert-butyloxycarbonyl-piperazine-methyl) nitrobenzene.

3- (dimethylamino-methyl) -nitrobenzene

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

4- (2-morpholinyl-ethyl) nitrobenzene.

4- (2-pyrrolidinyl-ethyl) nitrobenzene.

4- (2-piperidinyl-ethyl) nitrobenzyl,

4- ^{(N-ethyl-I 's-benzyl-amino-methyl)} nitrobenzene.

4- (N ^, -propyl-N ^, -benzyl-amino-methyl) -nitrobenzene,

4 - [. N-methyl-N - (4-chlorophenyl methyl) amino-methyl]) - nitrobenzene,

4- [N-methyl-N- (4-bromophenyl-methyl) amino-methyl] nitrobenzene.

4 - [/ V-methyl- / V- (3-chlorophenylmethyl) amino-methyl] nitrobenzene.

4 - [. V-methyl- / V- (3,4-dimethoxyphenylmethyl) amino-methyl] nitrobenzene.

4- [N-methyl-N - (4-metoxyfenylmctyl) -methyl-amino] nitrobenzene.

4- [7V-2,2,2-trifluoro -. '-N- (phenylmethyl) amino-methyl | nitrobenzene,

4 - [/ ^{V-2,2,2-trifluoroethyl-A,} - (4-chlorophenyl methyl) amino-methyl] nitrobenzene.

Preparation 6 4- (N-Ethyl- N - tert -butoxycarbonyl-amino-methyl) -nitrobenzene

2.2 g of 4- (ethylamino-methyl) -nitrobenzene are dissolved in 50 ml of acetic acid ester and stirred with 2.6 g of tert-butyl dicarbonate for 30 minutes at room temperature. The solution was washed with water and concentrated. Yield: 3.4 g Rg 0.9 (silica gel; methylene chloride / methanol = 9: 1)

Similarly prepared:

4- [7V- (4-chloro-phenyl-methyl) - / V- / t-butoxycarbonylamino-methyl) nitrobenzene.

4 (A-cyclohexyl-N- / t-butoxycarbonyl-methyl-amino) nitrobenzene,

4- (N-isopropyl-N-tert-butoxycarbonyl-methyl-amino) nitrobenzene,

4- (N-butyl-N-a-tert-butoxycarbonyl-methyl-amino) nitrobenzene,

4- (N'-methoxycarbonyl-methyl-N-tert-butoxycarbonyl-amino-methyl) -nitrobenzene; 4- (N - (phenylmethyl) - N-tert-butoxycarbonyl-amino-methyl) -nitrobenzene.

Preparation of Ί 4- (N-ethyl- N -t-butoxycarbonyl-amino-methyl) -aniline

6.4 g of 4- (N-ethyl- N - tert -butoxycarbonyl-amino-methyl) -nitrobenzene are dissolved in 60 ml of methanol and hydrated with 1.5 g of Raney nickel for 3 hours at room temperature. The catalyst was then filtered off and the solution was concentrated. Yield: 4.78 g _Rf: 0.7 (silica gel; methylene chloride / methanol 50: 1)

Similarly prepared:

4- [N- (4-chloro-phenyl-methyl) -N-tert-butoxycarbonyl-amino-METHYL-aniline,

4- (N-cyclohexyl-N-tert-butoxycarbonyl-methyl-amino) -aniline,

4- (TV-isopropyl-A ^I -tert-butoxycarbonyl-methyl-amino) -aniline,

4- (N -butyl- N- tert -butoxycarbonyl-amino-methyl) -aniline, 4- (N-methoxycarbonyl-methyl-N-tert-butoxycarbonyl-amino-methyl) -aniline, 4- (N- (phenylmethyl) -N- / t-butoxycarbonyl-methyl-amino) -aniline,

4- (pyrrolidin-methyl) -aniline,

4- (morpholino-methyl) -aniline,

4- (piperidin-methyl) -aniline, 4- (hexamethylenimino-methyl) -aniline, 4- (4-hydroxy-piperidin-methyl) -aniline, 4- (4-methyl-piperidin-methyl) -aniline, 4- (4-ethyl-piperidin-methyl) -aniline, 4- (4-isopropyl-piperidin-methyl) -aniline, 4- (4-phenyl-piperidin-methyl) -aniline, 4- (4-benzyl-piperidin-methyl) Aniline, 4- (4-ethoxycarbonyl-piperidin-methyl) -aniline, 4- (2-morpholinyl-ethyl) -aniline, 4- (2-pyrrolidnyl-ethyl) -aniline, 4- (2-piperidinyl-ethyl) -aniline, 4 - (, N-ethyl-N'-benzyl-amino-methyl) -aniline, N-N-propyl-N-benzyl-amino-methyl-aniline, 4- N, N-methyl-A - (4-Chloro-phenylmethyl) -amino-methyl] -aniline, 4- [N -methyl-N- (4-bromophenylmethyl) -amino-methyl] -aniline, 4- [N-methyl-N- (3-chlorophenylmethyl)] methyl-amino] -aniline, 4- ^[N-methyl-In - (3,4-dimethoxyphenylmethyl) amino-methyl] aniline,

4 - [. V-mctyl- / N- (4-metoxyfcnylmetyi) amino-methyl [| -anilíti. 4- [ _N -2,2,2-Tritluoro-ethyl- N - (phenylethyl) -amino-methyl] -aniline. 4- [2,2,2-trifluoro-N- (4-chlorophenylmethyl) amino-aniline methyliodide.

Preparation of end products

Example 1

3-Z- [1- (1-Methyl-piperidin-4-yl-amino) -1-phenyl-methylene] -2-indolinone-5-carboxylic acid methyl ester

11.5 g of methyl 1-acetyl-3- (1-ethoxy-1-phenylmethylene) -2-indolinone-5-carboxylic acid methyl ester are dissolved in 115 ml of methylene chloride and stirred with 10.8 g of 4-amino-V. -methylpiperidine for 5 hours at room temperature. Then 20 ml of methanolic ammonia are added and allowed to stand overnight. The solution was evaporated and the residue was washed with ether. Yield: 11.9 g (97% of theory) _Rf: 0.20 (silica gel; methylene chloride / methanol = 9: 1) C ₂₃ H ₂₅ N ₃ O ₃

Mass spectrum; m / z = 391 (M &lt; ^{+ &gt;} )

Analogously prepare:

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

_Rf: 0.4 (silica gel, methylene chloride / methanol = 9: 1) C ₃₉ H _2u N> 0-,

Mass Spectrum: m / z = 467 (M ⁺ ) (2) 3-Z- [1- (4- (N-Phenylmethyl- N -methylamino-methyl) -phenylamino) -1-phenyl-methylene acid methyl ester ] -2-indolinone-5-carboxylate

C ₃₂ H ₂₉ N ₃ O ₃

Mass spectrum: m / z = 503 (M ⁺ ) (3) 3-Z- [1- (4- (dimethylamino-methyl) -phenylamino) -1-phenyl-methylene] -2-indolinone-5-carboxylic acid methyl ester C ₂₆ 1 I ₂₅ N ₃ O ₃

Mass spectrum: m / z = 427 (M ⁺ ) (4) 3-Z- [1- (3- (Dimethylamino-methyl) -phenylamino) -1-phenyl-methylene] -2-indolinone-5-carboxylic acid methyl ester C ₂₆ H ₂₅ N ₃ O ₃

Mass Spectrum: m / z = 427 (M ⁺ ) (5) 3-Z- [1- (4-Chloro-phenylamino) -1-phenyl-methylene] -2-indolinone-5-carboxylic acid methyl ester (6) Methyl ester 3-Z- (1-phenylamino-12-phenyl-methylene) -2-indolinone-5-carboxylic acid

Example 2

3-Z- [1- (1-Methyl-piperidin-4-yl-amino) -1-phenyl-methylene] -2-indolinone-5-carboxylic acid

11.9 g of 3-Z- [1- (1-methyl-piperidin-4-ylamino) -1-phenyl-1-methylene] -2-indolinone-5-carboxylic acid methyl ester was heated to reflux 4. hours in 300 ml of methanol and 150 ml of 1 N sodium hydroxide solution. It is then neutralized with 150 ml of 1 N hydrochloric acid and concentrated to dryness. The residue was washed several times with water and dried. Yield: 86% of theory _Rf: 0.17 (silica gel; methylene chloride / methanol = 4: 1) C ₂₂ H ₂₃ N ₃ O ₃

Mass Spectrum: m / z = 377 (M &lt; ^{+ &gt;} )

Analogously prepare:

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

Rf: 0.15 (silica gel; methylene chloride / methanol = 9: 1) C28H ₂ 7 N ₃ O ₃

Mass spectrum: m / z = 453 (M ⁺ ) (2) 3-Z- [1- (4- (N-Phenylmethyl-N-methylamino-methyl) -phenylamino) -1-phenyl-methylene) - 2-indolinone-5-carboxylic acid

C ₃₂ H ₂₇ N ₃ O ₃ Mass spectrum: m / z = 489 (M ⁺ ) (3) 3-Z- [1- (4- (dimethylamino-methyl) -phenylamino) -1-phenyl-methylene] -2- indolinone-5-carboxylic acid

C ₂₅ H ₂₃ N ₃ O ₃

MS: m / z = 413 (M @ +) (4) 3-Z- [l- (3- (dimethylamino-methyl) phenylamino) -1-phenyl-methylene) -2-indolinone-5-carboxylic acid _C2 5H ₂₃ N ₃ O ₃

Mass spectrum: m / z = 413 (M ⁺ ) (5) 3-Z- [1- (4-chloro-phenylamino) -1-phenyl-methylene] -2-indolinone-5-carboxylic acid (6) 3- Z- [l-phenylamino-l-phenyl-methylene) -2-indoliηόη-5-carboxylic acid

Example 3

3-Z- [1- (1-methyl-piperidin-4-yl-amino) -1-phenyl-methylene] -5-dimethylcarbamoyl-indole-3-z- [1- (1- methyl-piperidin-4-yl-amino) -1-phenyl-methylene] -2-indolin-5-carboxylic acid was heated to reflux with 5 ml of thionyl chloride for 2 hours. It is then evaporated and the residue is washed with ether. 0.5 g of this acid chloride is taken up in 5 ml of methylene chloride without further purification and mixed with 0.5 ml of dimethylamine in 5 ml of methylene chloride and stirred overnight at room temperature. The product is chromatographed over a column of silica gel and methylene chloride / methanol / ammonia (4: 1: 0.1). Yield: 50% of theory

_Rf: 0.14 (silica gel; methylene chloride / methanol = 9: 1) C ₂₄ H ₂₈ N ₄ O ₂

Mass Spectrum: m / z = 404 (M &lt; ^{+ &gt;} )

The following compounds are prepared analogously:

(1) 3-Z- [1- (1-methyl-piperidin-4-yl-amino) -1-phenyl-1-methyl-ene-5-methylcarbamoyl-2-indolinone

Yield: 49% of theory

Rf: 0.19 (silica gel; methylene chloride / methanol = 4: 1) C ₂₃ H ₂₆ N ₄ 0 ₂

Mass spectrum: m / z = 390 (M ⁺ ) (2) 3-Z- [1- (1-methyl-piperidin-4-yl-amino) -1-phenyl-methylene} -5-carbamoyl-2-indolinone

Yield: 58% of theory

Rf: 0.15 (silica gel; methylene chloride / methanol = 4: 1) C ₂₂ H ₂₄ N ₄ O ₂

Mass Spectrum: m / z = 376 (M &lt; ^{+ &gt;} ) (3) 3-Z- [1- (4-piperidinomethyl-phenylamino) -1-phenyl-methylene] -5-dimethylcarbamoyl-2-indolinone

Prepared from 3-Z- [1- (4-piperidin-methyl-phenylamino) -1-phenyl-methylene] -2-indolinone-5-carboxylic acid or with 0.64 g of Z- [1- (4- piperidine-methyl-phenylamino) -1-phenyl-methylene] -2-indolinone-5-carboxylic acid, 0.34 g of dimethylamine hydrochloride, 0.9 g of O-benzotriazol-1-yl-; N, N'-tetramethyluronium; -tetrafluoroborate, 0.4 g of 1-hydroxy-1 H -benzotriazole and 2.9 g of diisopropylethylamine are stirred in 20 ml of dimethylformamide for 20 hours at room temperature. It is then concentrated and the residue is suspended in water. The precipitate is filtered off with suction.

Yield: 600 mg (88% of theory) _Rf: 0.2 (silica gel, methylene chloride / ethanol = 9: 1) C ₃₀ H ₃₂ N ₄ O ₂

Mass Spectrum: m / z = 481 (M + H) ⁺ (4) 3- Z- [1- (4-piperidin-methyl-phenylamino) -1-phenyl-methylene] -5-methylcarbamoyl-2-indolinone

Prepared from 3-Z- [1- (4-piperidin-methyl-phenylamino) -1-phenyl-methylene] -2-indolinone-5-carboxylic acid and methylamine in analogy to Example 3 (3).

Rf: 0.2 (silica gel, methylene chloride / ethanol = 9: 1) C ₂₉ H ₃₀ N ₄ O ₂

Mass Spectrum: m / z = 467 (M + H) ⁺ (S) 3-Z- [1- (4-piperidin-methyl-phenylamino) -1-phenyl-methylene] -5-methylethylcarbamoyl-2-indolinone

Prepared from 3-Z- [1- (4-piperidin-methyl-phenylamino) -1-phenyl-methylene] -2-indolinone-5-carboxylic acid and methyl-ethylamine in analogy to Example 3 (3).

Rf: 0.55 (silica gel; methylene chloride / ethanol = 9: 1) C ₃₁ H ₃₄ N ₄ O ₂

Mass Spectrum: m / z = 495 (M + H) ⁺ (6) 3- Z- [1- (4-piperidin-methyl-phenylamino) -1-phenyl-methylene] -5-propylcarbamoyl-2-indolinone

Prepared from 3-Z- [1- (4-piperidin-methyl-phenylamino) -1-phenyl-methylene] -2-indolinone-5-carboxylic acid and propylamine in analogy to Example 3 (3).

Rf: 0.31 (silica gel; methylene chloride / ethanol = 9: 1) C ₃ H ₃₄ N ₄ O ₂

Mass spectrum: m / z = 495 (M + H + (7) 3-Z- [1- (4-piperidin-methyl-phenylamino) -1-phenyl-1-methylene] -5-diethylcarbamoyl-2-indolinone

Prepared from 3-Z- [1- (4-piperidin-methyl-phenylamino) -1-phenyl-methylene] -2-indolinone-5-carboxylic acid and diethylamine in analogy to Example 3 (3).

R _f : 0.55 (silica gel; methylene chloride / ethanol = 9: 1) C, ₂ H, ₆ N ₄ O ₂

Mass Spectrum: m / z = 509 (M + H) ⁺ (8) 3-Z- [1- (4- (N-phenylmethyl-N, methyl-aminomethyl) -phenylamino] -1-phenyl-methylene] -5-methylcarbamoyl-2-indolinone (9) 3-Z- [1- (4- (N-phenylmethyl-N'-methyl-aminomethyl-1-phenylamino) -1-phenylmethylene] -5-dimethylcarbamoyl-2- indolinone (10) 3-Z [1- (4- (1H-phenylmethyl-N-methyl-aminomethyl) -phenylamino) -1-phenyl-methylene] -5-diethylcarbamoyl-2-indolinone (11) 3-Z- [1- (4- (N-Phenylmethyl-N-methyl-aminomethyl) -phenylamino) -1-phenyl-methylene] -5-propylcarbamoyl-2-indolinone (12) 3-Z- [1- (4- (N-Phenylmethyl-N'-methyl-aminomethyl) -phenylamino) -1-phenyl-methylene] -5-dipropylcarbamoyl-2-indolinone (13) 3- Z- [1- (4- (dimethylamino-methyl) - phenylamino) -1-phenyl-methylene] -5-methylcarbamoyl-2-indolinone (14) 3-Z- [1- (4- (dimethylamino-methyl) -phenylamino) -1-phenylmethylene] -5-dimethylcarbamoyl-2- indolinone (15) 3-Z- [1- (4- (dimethylamino-methyl) -phenylamino) -1-phenylmethylene] -5-diethylcarbamoyl-2-indolinone (16) 3-Z- [1- (4- (dimethylamino) (methyl) -phenylamino) -1-phenylmethylene] -5-propylcarbamoyl-2-indolinone 7) 3-Z- [1- (4- (dimethylamino-methyl) -phenylamino) -1-phenylmethylene] -5-dipropylcarbamoyl-2-indolinone (18) 3-Z- [1- (3- (dimethylamino-methyl) (1-Phenylamino) -1-phenylmethylene] -5-methylcarbamoyl-2-indolinone (19) 3-Z- [1- (3- (dimethylamino-methyl) -phenylamino) -1-phenylmethylene] -5-dimethylcarbamoyl-2- indolinone (20) 3-Z- [1- (3- (dimethylamino-methyl) -phenylamino) -1-phenylmethylene] -5-diethylcarbamoyl-2-indolinone (21) 3-Z- [1- (3- (dimethylamino) (methyl) -phenylamino) -1-phenylmethylene] -5-propylcarbamoyl-2-indolinone (2 S) 3-Z- [1- (3- (dimethylaminomethyl) phenylamino) -1-phenylmethylene] -5-dipropylcarbamoyl- 2-indolinone (2 S) 3-Z- [1- (4-chloro-phenylamino) -1-phenyl-methylene] -5-methylcarbamoyl-2-indolinone (24) 3-Z- [1- (4-chloro- phenylamino) -1-phenyl-methylene] -5-dimethylcarbamoyl-2-indolinone (2S) 3-Z- [1- (4-chloro-phenylamino) -1-phenyl-methylene] -5-diethylcarbamoyl-2-indolinone ( 26) 3-Z- [1- (4-chloro-phenylamino) -1-phenyl-methylene] -5-propylcarbamoyl-2-indolinone (27) 3-Z- [1- (4-chloro-phenylamino) -1] phenyl-methylene] -5-dipropylcarbamoyl-2-indole (28) 3-Z- (1-phenylamino-1-phenyl-methylene) -5-methylcarbamoyl-2-indolinone (29) 3-Z- (1-phenylamino-1-phenyl-methylene) -5-dimethylcarbamoyl- 2-indolinone (3 S) 3-Z- (1-phenylamino-1-phenylmethylene) -5-diethylcarbamoyl-2-indolinone (31) 3-Z- (1-phenylamino-1-phenylmethylene) -5- propylcarbamoyl-2-indolinone (32) 3-Z- (1-phenylamino-1-phenylmethylene) -5-dipropylcarbamoyl-2-indolinone

Example 4

3-Z- [1- (4-Amino-phenylamino) -1-phenyl-methylene] -5-amido-2-indolinone

800 mg of the resin prepared according to Example IV are suspended in 4 ml of methylene chloride and shaken with 0.8 g of 1,4-phenylenediamine for 16 hours at room temperature. Filter and wash the resin several times with methylene chloride, methanol and dimethylformamide. Then 3 ml of methanolic ammonia are added for 2 hours to remove the acetyl group. Finally, after further washing, 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 collected in a small volume of 1 N sodium hydroxide solution and extracted with methylene chloride. The organic phase is dried over sodium sulphate and evaporated.

Yield: 45 mg (30% of theory in all steps)

_Rf: 0,26 (silica gel, methylene chloride / methanol = 9: 1) C ₂₂ H ₁₈ N ₄ O ₂

Mass Spectrum: m / z = 370 (M &lt; ^{+ &gt;} )

The following compounds are prepared analogously:

(1) 3-Z- [1- (3-amino-phenylamino) -1-phenyl-1-methylene] -5-amido-2-indolinone

Yield: 24% of theory

_Rf: 0.44 (silica gel: methylene chloride / methanol = 9: 1) C ₂₂ H _{1 S} N ₄ O ₂

Mass Spectrum: m / z = 370 (M ⁺ ) (2) 3-Z- (1-phenylamino-1-phenylmethylene) -5-amido-2-indolinone

Yield: 27% of theory

_Rf: 0.53 (silica gel; methylene chloride / methanol = 9: 1)

C ₂₂ H ₁₇ N ₃ O ₂

Mass Spectrum: m / z = 355 (M &lt; ^{+ &gt;} ) (3) 3-Z- [1- (4-acetylamino-phenylamino) -1-phenyl-methylene] -5-

amido-2-indolinone

Yield: 28% of theory

_Rf: 0.35 (silica gel; methylene chloride / methanol 9: 1) C ₂₄ H ₂₀ N ₄ O ₃

Mass Spectrum: m / z = 412 (M ⁺ ) (4) 3-Z- [1- (4-acetyl- N -methyl-amino-phenylamino) -1-phenyl-methylene] -5-amido-2- indolinone

Yield: 15% of theory

R 0.36 (silica gel: methylene chloride / methanol = 9: 1) C 5 H ₂₂ N ₂ O _{4 3}

Mass Spectrum: m / z = 426 (M &lt; ^{+ &gt;} ) (S) 3-Z- [1- (4- (2-Amino-ethyl) -phenylamino) -1-phenyl-methylene] -5-amido-2-indolinone

Yield: 30% of theory

Rf · 0.04 (silica gel; methylene chloride / methanol = 9: 1) C ₂₄ H ₂₂ N ₄ O ₂

Mass Spectrum: m / z = 398 (M ⁺ ) (6) 3-Z- [1- (4-methoxy-phenylamino) -1-phenyl-methylene] -5-amido-2-indolinone

Yield: 32% of theory

Rg 0.48 (silica gel; methylene chloride / methanol = 9: 1)

C ₂₃ H ₁₉ N ₃ O ₃

Mass Spectrum: m / z = 385 (M ⁺ ) (7) 3- Z- [1- (4-Biphenylamino) -1-phenyl-methylene] -5-amido-2-indolinone

Yield: 22% of theory

_Rf: 0.51 (silica gel; methylene chloride / methanol = 9: 1) C ₂₈ H ₂₁ N ₃ O ₂

Mass Spectrum: m / z = 431 (M ⁺ ) (8) 3- Z- [1- (3-pyridylamino) -1-phenylmethylene] -5-amido-2-indolinone

Yield: 35% of theory

_Rf: 0.41 (silica gel; methylene chloride / methanol = 9: 1) C ₂₁ H _I6 N ₄ O ₂

Mass Spectrum: m / z = 356 (M &lt; ^{+ &gt;} ) (9) 3-Z- [1- (4-dimethylamino-phenylamino) -1-phenyl-methylene] -5-amido-2-indolinone

Yield: 19% of theory

_Rf: 0.49 (silica gel; methylene chloride / methanol = 9: 1)

C24H22N4O2

Mass spectrum: m / z = 398 (M +) (10) 3-Z-11- (4-morpholino-phenylamino) -1-phenyl-methylene] -5-

amido-2-indolinone

Yield: 42% of theory

Rf 0.48 (silica gel; methylene chloride / methanol = 9: 1)

C26H24N4O3

Mass Spectrum: m / z = 440 (M ⁺ ) (11) 3-Z- [1- (4- tert -butyl-phenylamino) -1-phenyl-methylene] -5-

amido-2-indolinone

Yield: 32% of theory

_Rf: 0.48 (silica gel; methylene chloride / methanol 9: 1)

C ₂₆ H ₂₅ N ₃ O ₂

Mass Spectrum: m / z = 411 (M &lt; ^{+ &gt;} ) (12) 3-Z- [1- (2-Amino-phenylamino) -1-phenylmethylene] -5-amido-2-indolinone

Yield: 28% of theory

_Rf: 0.52 (silica gel; methylene chloride / methanol = 9: 1)

C ₂₂ H ₁₈ N ₄ O ₂

Mass Spectrum: m / z = 370 (M ⁺ ) (13) 3-Z- [1- (4-benzyloxy-phenylamino) -1-phenyl-methylene] -5-

amido-2-indolinone

Yield: 40% of theory

_Rf: 0.4 (silica gel, methylene chloride / methanol = 9: 1)

C ₂ 9 H ₂₃ N ₃ O ₃

Mass Spectrum: m / z = 461 (M ⁺ ) (14) 3-Z- [1- (4-bromo-phenylamino) -1-phenyl-methylene] -5-amido-2-indolinone

Yield: 35% of theory

_Rf: 0.46 (silica gel; methylene chloride / methanol = 9: 1)

C ₂₂ H ₁₆ BrN ₃ O ₂

Mass Spectrum: m / z = 433/435 (M ⁺ ) (15) 3-Z- [1- (4-methoxycarbonyl-phenylamino) -1-phenyl-methylene] -5-amido-2-indolinone

Yield: 34% of theory

F. 0.36 (silica gel: methylene chloride / methanol = 9: 1)

C24H19N3O4

Mass Spectrum: m / z = 413 (M ⁺ ) (16) 3- Z- [1- (3-amido-phenylamino) -1-phenyl-methylene] -5-amido-2-indolinone

Yield: 32% of theory

_Rf: 0.32 (silica gel; methylene chloride / methanol = 9: 1)

C ₂₃ H ₁₈ N ₄ O ₃

Mass Spectrum: m / z = 398 (M ⁺ ) (17) 3- Z- [1- (3-methyl-phenylamino) -1-phenyl-methylene] -5-amido-2-indolinone

Yield: 12% of theory

_Rf: 0.5 (silica gel, methylene chloride / methanol = 9: 1) C ₂₃ H | ₉ n ₃ o ₂ +

Mass Spectrum: m / z = 369 (M &lt; ^{+ &gt;} ) (18) 3-Z- [1- (2-methyl-phenylamino) -1-phenyl-methylene] -5-amido-2-indolinone

Yield: 21% of theory

_Rf: 0.5 (silica gel, methylene chloride / methanol = 9: 1)

C _{2 J} H ₁₉ N ₃ O ₂

Mass Spectrum: m / z = 369 (M &lt; ^{+ &gt;} ) (19) 3-Z- [1- (3-methoxy-phenylamino) -1-phenyl-methylene] -5-amido-2-indolinone

_Rf: 0.49 (silica gel; methylene chloride / methanol = 9: 1) C ₂₃ H ₁₉ N ₃ O ₃

Mass Spectrum: m / z = 385 (M ⁺ ) (20) 3-Z- [1- (3-ethoxycarbonyl-phenylamino) -1-phenyl-methylene] -5-amido-2-indolinone

_Rf: 0.48 (silica gel; methylene chloride / methanol = 9: 1)

C ₂₅ H ₂₁ N ₃ O ₄

Mass Spectrum: m / z = 427 (M &lt; ^{+ &gt;} ) (21) 3-Z- [1- (3-nitro-phenylamino) -1-phenyl-methylene] -5-amido-2-indolinone

Yield: 32% of theory

_Rf: 0.56 (silica gel; methylene chloride / methanol = 9: 1)

C ₂₂ H ₁ N ₄ O ₄

Mass Spectrum: m / z = 400 (M &lt; ^{+ &gt;} ) (22) 3-Z- [1- (4-amido-phenylamino) -1-phenyl-methylene] -5-amido-2-indolinone

Yield: 26% of theory

_Rf: 0.47 (silica gel; methylene chloride / methanol = 9: 1)

C ₂₃ H ₁₈ N ₄ O ₃

Mass Spectrum: m / z = 398 (M &lt; ^{+ &gt;} ) (23) 3-Z- [1- (4-pyridylamino) -1-phenylmethylene] -5-amido-2-indolinone

Yield: 15% of theory

_Rf: 0.42 (silica gel; methylene chloride / methanol = 9: 1)

C ₂₁ H ₁₆ N ₄ O ₂

Mass Spectrum: m / z = 356 (M &apos;) (24) 3-Z- [1- (4-methyl-phenylamino) -1-phenyl-methylene] -5-amido-2-indolinone

Yield: 45% of theoretical

Rf: 0.54 (silica gel; methylene chloride / methanol = 9: 1)

C ₂₃ H ₁₉ N ₃ O ₂

Mass Spectrum: m / z = 369 (M &lt; ^{+ &gt;} ) (25) 3-Z- [1- (4-ethoxy-phenylamino) -1-phenyl-methylene] -5-amido-2-indolinone

Yield: 40% of theory

_Rf: 0.51 (silica gel; methylene chloride / methanol = 9: 1)

C ₂₄ H ₃ N ₃ O ₃

Mass spectrum: m / z = 399 (M +) (26) 3-Z- [1- (3-bromo-phenylamino) -1-phenyl-methylene] -5-amido-2-indolinone

yield; 41% of theoretical value '

_Rf: 0.53 (silica gel; methylene chloride / methanol = 9: 1)

C ₂₂ H ₁₆ BrN ₃ O ₂

Mass spectrum: m / z = 433/435 (M ⁺ ) (2 S) 3-Z- [1- (4-chloro-phenylamino) -1-phenyl-methylene] -5-amido-2-indolinone

Yield: 50% of theory

_Rf: 0.49 (silica gel; methylene chloride / methanol = 9: 1)

C ₂₂ H, ₆ C 1 N ₃ O ₂

Mass Spectrum: m / z = 389/391 (M ⁺ ) (28) 3- Z- [1- (4-isopropyl-phenylamino) -1-phenyl-methylene] -5-amido-2-indolinone

Yield: 48% of theory

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

C ₂₅ H ₂₃ N ₃ O ₂

Mass Spectrum: m / z = 397 (M ⁺ ) (29) 3- Z- [1- (2-fluorenylamino) -1-phenylmethylene] -5-amido-2-indolinone

Yield: 43% of theory

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

C29H21N3O2

Mass spectrum: m / z = 443 (M +) (30) 3-Z- [1- (4- (2-hydroxyethyl) phenylamino) -1-phenylmethylene] -5-amido-2-indolinone

Yield: 22% of theory

_Rf: 0.37 (silica gel; methylene chloride / methanol = 9: 1)

C ₂₄ H ₂₁ N ₃ O ₃

Mass Spectrum: m / z = 398 (M-H) (31) 3-Z- [1- (4- (4-imidazolyl) phenylamino) -1-phenylmethylene] -5-amido-2-indolinone

Yield: 23% of theory

_Rf: 0.5 (silica gel, methylene chloride / methanol = 9: 1)

C ₂₅ H ₁₉ N ₅ O ₂

Mass Spectrum: m / z = 421 (M &lt; ^{+ &gt;} ) (32) 3-Z- [1- (4-ethoxycarbonylmethyl-phenylamino) -1-phenyl-methylene] -5-amido-2-indolinone

C ₂₆ H ₂₃ N ₃ O ₄

Mass Spectrum: m / z = 442 (M + H) ⁺ (33) 3- Z- [1- (4-bromo-3-methyl-phenylamino) -1-phenyl-methylene] -5-amido-2-indolinone

C ₂₃ H ₁₈ BrN ₃ O ₂

Mass Spectrum: m / z = 447/449 (M ⁺ ) (34) 3- Z- [1- (4-cyclohexyl-phenylamino) -1-phenyl-methylene] -5-amido-2-indolinone

C ₂₈ H ₂₇ N ₃ O ₂

Mass Spectrum: m / z = 437 (M ⁺ ) (35) 3- Z- [1- (4-bromo-2-methyl-phenylamino) -1-phenyl-methylene] -5-amido-2-indolinone

C ₂₃ H ₁₈ BrN ₃ O ₂

Mass Spectrum: m / z = 447/449 (M &lt; ^{+ &gt;} ) (36) 3-Z- [1-amino-1-phenylmethylene] -5-amido-2-indolinone

_Rf: 0.3 (silica gel, methylene chloride / methanol = 9: 1) C16H13N3O2

Mass Spectrum: m / z = 279 (M ⁺ ) (37) 3-Z- [1-cyclohexylamino-1-phenyl-methylene] -5-amido-2-indolinone

Rf 0.55 (silica gel; methylene chloride / methanol = 9: 1) C ₂₂ H ₂₃ N ₃ O ₂

Mass Spectrum: m / z = 361 (M &lt; ^{+ &gt;} ) (38) 3-Z- [1-cyclopentylamino-1-phenylmethylene] -5-amido-2-indolinone

_Rf: 0.53 (silica gel; methylene chloride / methanol = 9: 1)

C ₂₁ H ₂₁ N ₃ O ₂

Mass Spectrum: m / z = 347 (M &lt; ^{+ &gt;} ) (39) 3-Z- [1-methylamino-1-phenylmethylene] -5-amido-2-indolinone

Rf 0.5 (silica gel; methylene chloride / methanol = 9: 1)

_{I7 I5} C H N ₃ O,

Mass Spectrum: m / z = 293 (M &lt; ^{+ &gt;} ) (40) 3-Z- [1-ethylamino-1-phenylmethylene] -5-amido-2-indolinone

_Rf: 0.52 (silica gel; methylene chloride / methanol = 9: 1)

C _{18 H] 3} O ₇ N ₂

Mass Spectrum: m / z = 307 (M ⁺ ) (41) 3-Z- [1-isopropylamino-1-phenylmethylene] -5-amido-2-indolinone

_Rf: 0.44 (silica gel; methylene chloride / methanol = 9: 1)

C, H ₉ N ₃ O _{I9 2}

Mass Spectrum: m / z = 321 (M &lt; ^{+ &gt;} ) (42) 3-Z- [1-dimethylamino-1-phenylmethylene] -5-amido-2-indolinone

Rf: 0.39 (silica gel; methylene chloride / methanol = 9: 1)

C ₈ H 11 ₇ N ₃ O ₂

Mass Spectrum: m / z = 307 (M &lt; ^{+ &gt;} ) (43) 3-Z- [1-cyclopropylamino-1-phenyl-methylene] -5-amido-2-indolinone

Rf 0.47 (silica gel; methylene chloride / methanol = 9: 1)

C ₉ H ₇ N ₃ O ₂

Mass Spectrum: m / z = 319 (M &lt; ^{+ &gt;} ) (44) 3-Z- [1-cycloheptylamino-1-phenylmethylene] -5-amido-2-indolinone

_{R f:} 0.58 (silica gel; methylene chloride / methanol = 9: 1)

C ₂ H 25 N ₃ O ₂

Mass Spectrum: m / z = 375 (M &lt; ^{+ &gt;} ) (45) 3-Z- [1-cyclobutylamino-1-phenylmethylene] -5-amido-2-indolinone

_Rf: 0.49 (silica gel; methylene chloride / methanol = 9: 1)

C ₂₀ H ₃ N ₃ O ₂

Mass Spectrum: m / z = 333 (M ⁺ ) (46) 3- Z- [1- (4-methylcyclohexylamino) -1-phenylmethylene] -5-amido-2-indolinone

_Rf: 0.67 (silica gel; methylene chloride / methanol = 9: 1)

C ₂₃ H ₂₅ N ₃ O ₂

Mass Spectrum: m / z = 375 (M ⁺ ) (47) 3- Z - [1- (1- (R, S) -indanylamino) -1-phenyl-methylene] -5-amido-2-indolinone

_Rf: 0.59 (silica gel; methylene chloride / methanol = 9: 1)

C ₂₅ H ₂ N ₃ O ₂

Mass Spectrum: m / z = 395 (M &lt; ^{+ &gt;} ) (48) 3-Z- [1- (methoxycarbonylmethylamino) -1-phenylmethylene] -5-amido-2-indolinone

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

C ₁₉ H | ₇ N ₃ O ₄

Mass spectrum: m / z = 351 (M +) (49) 3-Z- [1 - ((2-methoxycarbonyl-ethyl) -amino) -1-phenyl-methylene] -5-amido-2-indolinone

_Rf: 0.45 (silica gel; methylene chloride / methanol = 9: 1)

C ₂ oH | ₉ N ₃ 0 ₄

Mass Spectrum: m / z = 365 (M &lt; ^{+ &gt;} ) (50) 3-Z- [1- (4-Aminomethyl-phenylamino) -1-phenyl-methylene] -

-5-amido-2-indolinone

Yield: 32% of theory

_Rf: 0.46 (silica gel; methylene chloride / methanol = 9: 1)

C ₂₃ H ₂₀ N ₄ O ₂

Mass Spectrum: m / z = 384 (M ⁺ ) (51) 3-Z- [1- (4-pyrrolidinomethyl-phenylamino) -1-phenyl-methylene] -

-5-amido-2-indolinone

Yield: 60% of theory

_Rf: 0.07 (silica gel; methylene chloride / methanol = 9: 1)

C27H26N4O2

Mass Spectrum: m / z = 438 (M +) (52) 3- Z- [1- (4-Morpholinomethyl-phenylamino) -1-phenyl-methylene] -5-

amido-2-indolinone

Yield: 65% of theory

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

C27H26N4O3

Mass Spectrum: m / z = 454 (M &lt; ^{+ &gt;} ) (53) 3-Z- [1- (4-piperidinomethyl-phenylamino) -1-phenyl-methylene] -

-5-amido-2-indolinone

Yield: 60% of theory

Rf: 0.08 (silica gel; methylene chloride / methanol = 9: 1)

C ₂ sH ₂₈ N ₄ O ₂

Mass Spectrum: m / z = 452 (M ⁺ ) (54) 3- Z- [1- (4-Hexamethyleneiminomethyl-phenylamino) -1-phenyl-methylene] -5-amido-2-indolinone trifluoroacetate

C29H30N4O2

Mass Spectrum: m / z = 466 (M &lt; ^{+ &gt;} ) (55) 3-Z- [1- (4- (4-Hydroxy-piperidinomethyl) -phenylamino) -1-phenyl-methylene] -5-amido-2-indolinone

C28H28N4O3

Mass Spectrum: m / z = 468 (M ⁺ ) (56) 3- Z- [1- (4- (4-methylpiperidinomethyl) phenylamino) -1-phenylmethylene] -5-amido-2-indolinone

C29H30N4O2

Mass spectrum: m / z = 466 (M ² ) (57) 3-Z- [1- (4- (4-ethyl-piperidinomethyl) -phenylamino) -1-phenyl-

-methylene] -5-amido-2-indolinone

C ₃₀ H ₃₂ N ₄ O ₂

Mass Spectrum: m / z = 480 (M &^lt; + & gt ^; ) (58) 3-Z- [1- (4- (4-isopropyl-piperidinomethyl) -phenylamino) -1-

phenyl-mctylén] -5-amido-2-indolinone

C ₃₁ H ₃₄ N ₄ O ₂

Mass Spectrum: m / z = 494 (M &lt; ^{+ &gt;} ) (59) 3- Z- [1- (4- (4-phenyl-piperidinomethyl-nitro-phenylamino) -1] -

phenyl-methylene] -5-amido-2-indolinone

C ₃₄ H ₃₂ N ₄ O ₂

Mass Spectrum: m / z = 528 (M ⁺ ) (60) 3- Z- [1- (4- (4-Benzyl-piperidinomethyl) -phenylamino) -1-phenyl-methylene] -5-amido-2-indolinone

Ο _{3 5} Η ₃₄ Ν ₄ Ο ₂

Mass Spectrum: m / z = 542 (M ⁺ ) (61) 3- Z- [1- (4- (4-ethoxycarbonyl-piperidinomethyl) -phenylamino) -1-phenyl-methylene] -5-amido-2-indolinone

C ₃₁ H ₃₂ N ₄ O ₄

Mass Spectrum: m / z = 524 (M &lt; ^{+ &gt;} ) (62) 3-Z- [1- (4-dimethylaminomethyl-phenylamino) -1-phenyl-methylene] -5-amido-2-indolinone

C ₂₅ H ₂₄ N ₄ O ₂

Mass Spectrum: m / z = 412 (M &lt; ^{+ &gt;} ) (63) 3-Z- [1- (4-dipropylaminomethyl-phenylamino) -1-phenyl-

methylene] -5-amido-2-indolinone

C29H3 ₂ N ₄ O ₂

Mass Spectrum: m / z = 468 (M &lt; ^{+ &gt;} ) (64) 3-Z- [1- (4-piperazinylmethyl-phenylamino) -1-phenylmethylene] -5-amido-2-indolinone

C ₂ 7H ₂ 7N ₅ O ₂

Mass Spectrum: m / z = 453 (M ⁺ ) (65) 3- Z- [1- (3-dimethylaminomethyl-phenylamino) -1-phenyl-methylene] -5-amido-2-indolinone

C ₂ 5H ₂ N ₄ O ₂

Mass Spectrum: m / z = 412 (M ⁺ ) (66) 3- Z- [1- (4- (2-diethylamino-ethyl) -phenylamino) -1-phenyl-methylene] -5-amido-2-indolinone

C ₂₈ H _{3 N 4} 0 ₂

Mass spectrum: m / z = 454 (M ⁺ ) (67) 3 -Z- [1- (4- (2-morpholin-ethyl) -phenylamino) -1-phenyl-1-methylene] -5-amido-2- indolinone

C ₂₈ H ₁₈ N ₄ O ₃

Mass Spectrum: m / z = 468 (M ⁺ ) (68) 3- Z- [1- (4- (2-pyrrolidinyl-ethyl) -phenylamino) -1-phenyl-methylene] -5-amido-2-indolinone c ₂₈ H ₂₈ N ₄ o ₂

Mass Spectrum: m / z = 452 (M ⁺ ) (69) 3- Z- [1- (4- (2-piperidinyl-ethyl) -phenylamino) -1-phenylmethylene] -5-amido-2-indolinone

C ₂₉ H ₃₀ N ₄ O ₂

Mass Spectrum: m / z = 466 (M &lt; ^{+ &gt;} ) (70) 3-Z- [1- (2-thiazolylamino) -1-phenyl-methylene] -5-amido-2-indolinone

Yield: 30% of theory

_Rf: 0.48 (silica gel; methylene chloride / methanol = 9: 1)

C ₁₉ H ₁₄ N ₄ O ₂ S

Mass Spectrum: m / z = 362 (M &lt; ^{+ &gt;} ) (71) 3-Z- [1- (benzimidazol-2-ylamino) -1-phenyl-methylene] -5-

amido-2-indolinone

Yield: 29% of theory

_Rf: 0.44 (silica gel; methylene chloride / methanol = 9: 1)

C ₂₃ H ₁₇ N ₅ O ₂

Mass Spectrum: m / z = 395 (M &lt; ^{+ &gt;} ) (72) 3-Z- [1- (5-methyl-isoxazol-3-yl-amino) -1-phenyl-methylene] -5-amido-2-indolinone

Yield: 39% of theory

_Rf: 0.43 (silica gel; methylene chloride / methanol = 9: 1)

C ₂ H ₁₈ N ₄ O ₃

Mass Spectrum: m / z = 374 (M &lt; ^{+ &gt;} ) (73) 3-Z- [1-benzylamino-1-phenyl-methylene] -5-amido-2-indolinone

_Rf: 0.63 (silica gel; methylene chloride / methanol = 9: 1)

C ₂₃ H ₁₉ N ₃ O ₂

Mass Spectrum: m / z = 369 (M &lt; ^{+ &gt;} ) (74) 3-Z- [1- (4- (1-imidazolylmethyl) phenylamino) -1-phenylmethylene] -5-amido-2-indolinone

_Rf: 0.45 (silica gel; methylene chloride / methanol = 9: 1)

C ₂₆ H ₂₂ N ₅ O ₂

Mass Spectrum: m / z = 436 (M &lt; ^{+ &gt;} ) (75) 3-Z- [1- (4 - ((2-diethylamino-ethyl) -aminocarbonyl) -phenylamino) -1-phenyl-methylene] -5-amido 2-indolinone-trifluoroacetate

Yield: 27% of theory

_Rf: 0.05 (silica gel; methylene chloride / methanol = 9: 1)

C29H31N5O3

Mass Spectrum: m / z = 497 (M ⁺ ) (76) 3- Z- [1- (4-acetylaminomethyl-phenylamino) -1-phenyl-methylene] -5-amido-2-indolinone

Rf · 0.4 (silica gel; methylene chloride / methanol = 9: 1)

C25H22N ₄ O ₃

Mass Spectrum: m / z = 426 (M) (77) 3 -Z- [1- (4 - ((2-dimethylaminoctyl) -; N -methanesulfonyl-amino) -phenylamino) -1-phenyl-methylene] -5 amido-2-indolinone

Rf: 0.1 (silica gel; methylene chloride / methanol = 9: 1)

C ₂₇ H _m N ₅ O ₄ N

Mass Spectrum: m / z = 519 (M &lt; ^{+ &gt;} ) (78) 3-Z- [1- (4- (N, N-ethoxycarbonylmethyl) -, N -methanesulfonyl-amino) -phenylamino] -1-phenyl- methylene] -5-amido-2-indolinone

Rf: 0.57 (silica gel; methylene chloride / methanol = 9: 1)

C ₂₇ H ₂₆ N ₄ O ₆

Mass spectrum: m / z = 534 (M ⁺ ) (79) 3- Z - [1- (4- (N - (cyanomethyl) - N -methanesulfonyl-amino) -phenylamino) -1-phenyl-methylene] - 5-amido-2-indolinone

_Rf: 0.49 (silica gel; methylene chloride / methanol = 9: 1) C ₂₅ H ₂₁ N ₅ O ₄ S

Mass Spectrum: m / z = 487 (M &lt; ^{+ &gt;} ) (80) 3-Z- [1- (4- (N-methyl-N-methanesulfonyl-amino) -phenylamino) -1-phenyl-methylene] -5-amido -2-indolinone

Rf 0.46 (silica gel; methylene chloride / methanol = 9: 1) C ₂₄ H ₂₂ N ₄ O ₄ S

Mass spectrum: m / z = 462 (M ⁺ ) (81) 3- Z- [1- (4- (2-oxo-pyrrolidin-1-ylmethyl) -phenylamino) -1-phenyl-methylene] -5 amido-2-indolinone

C ₂₇ H ₂₄ N ₄ O ₃

Mass Spectrum: m / z = 452 (M &lt; ^{+ &gt;} ) (82) 3-Z- [1- (4- (2-oxo-piperidin-1-ylmethyl-phenylamino) -1-phenyl-methylene] -5- amido-2-indolinone

C ₂₈ H ₂₆ N ₄ O ₃

Mass Spectrum: m / z = 466 (M &lt; ^{+ &gt;} ) (83) 3-Z- [1- (4- (4-cyclohexyl-piperidin-methyl) -phenylamino) -1-phenyl-methylone] -5-amido-2 -indolinone trifluoroacetate C ₃₄ H ₃₈ N ₄ O ₂

Mass Spectrum: m / z = 534 (M &^lt; + & gt ^; ) (84) 3-Z- [1- (4- (2,6-dimethyl-piperidin-methyl) -phenylamino) -1-phenyl-methylene] -5-amido -2-indolinone trifluoroacetate Ε ₃ θΗ ₃₂ Ν ₄ 0 ₂

Mass spectrum: m / z = 480 [mu] M (85) 3- [1- (4- (4-phenyl-4-hydroxy-piperidin-methyl) -phenylamino) -1-phenyl-methylene] -5- amido-2-indolinone-trifluoroacetate

C ₃₄ H ₃₂ N ₄ O ₃

Mass Spectrum: m / z = 545 (M &lt; ^{+ &gt;} )

Rf: 0.66 (silica gel; methylene chloride / methanol = 4: 1) (86) 3- Z- [1- (4- (2-methoxycarbonyl-pyrrolidin-methyl) -phenylamino) -1-phenyl-methylene] -5 amido-2-indolinone-trifluoroacetate

C ₂₉ H ₂₈ N ₄ O ₄

Mass spectrum: m / z = 497 (M + H) &lt; ⁺ &gt; ^.

Rf: 0.65 (silica gel; methylene chloride / methanol = 4: 1) (87) 3-Z- [1- (4- (1-oxo-thiomorpholin-4-ylmethyl) -phenylamino) -1-phenyl-methylene] -5-amido-2-indolinone trifluoroacetate C ₂₇ H ₂₆ N ₄ O ₃ S

Mass Spectrum: m / z = 487 (M + H) &lt; + &gt;

Ry. 0.68 (silica gel; methylene chloride / methanol = 4: 1) (88) 3- Z- [1- (4- (3,6-dihydro-2H-pyridin-1-ylmethyl) -phenylamino) -1-phenyl- methylene] -5-amido-2-indolinone trinuoroacetate C _{2 S} H ₃₆ N ₄ O ₂

Mass Spectrum: m / z = 451 (M + H) ⁺ (89) 3- Z- [1- (4- (2,5-dihydro-pyrrol-1-ylmethyl) -phenylamino) -

1-Phenylmethylene] -5-amido-2-indolinone trifluoroacetate

C ₂₇ H ₂₄ N ₄ O ₂

Mass spectrum: m / z = 437 (M + H) &lt; ⁺ &gt; ^.

Rf: 0.49 (silica gel; methylene chloride / methanol = 4: 1) (90) 3-Z- [1- (4- (thiomorpholin-4-ylmethyl) phenylamino) -1-phenylmethylene] -5-amido 2-indolinone-trifluoroacetate

C ₂₇ H ₂₅ N ₄ O ₂ S

Mass spectrum: m / z = 471 (M + H) &lt; ⁺ &gt; ^.

_Rf: 0.78 (silica gel; methylene chloride / methanol = 4: 1) (91) 3-Z- [l- (4- (4- (6,7-dimethoxy-tetrahydroisoquinolin-2-ylmethyl) phenylamino) - l-phenyl-methylene] -5-amido-2-indolinone-trifluoroacetate

C ₃₄ H ₃₂ N ₄ O ₄

Mass spectrum: m / z = 561 (M + H) &lt; ⁺ &gt; ^.

Rf: 0.8 (silica gel; methylene chloride / methanol = 4: 1) (92) 3- Z- [1- (4- (4-phenyl-piperazin-1-ylmethyl)) - phenylamino) -

1-Phenylmethylene] -5-amido-2-indolinone trifluoroacetate

C _{33 I 31} N ₅ O ₂

Mass spectrum: m / z = 530 (M + H) &lt; ⁺ &gt; ^.

_Rf: 0.78 (silica gel; methylene chloride / methanol = 4: 1) (93) 3-Z- [1- (4- (3,5-dimethyl-piperidino-methyl) phenylamino) -

1-Phenyl-methylene] -5-anido-2-indolinone trifluoroacetate

C ₃₀ H ₃₂ N ₄ O ₂

Mass Spectrum: m / z = 480 (M &lt; ^{+ &gt;} )

Ry 0.54 (silica gel; methylene chloride / methanol = 4: 1) (94) 3- Z- [1- (4- (N-methyl-2H-benzylamino-methyl) -phenylamino) -1-phenyl-methylene -5-amido-2-indolinone trifluoroacetate C ₃ H ₂₉ N ₄ O ₄

Mass Spectrum: m / z = 488 (M &lt; ^{+ &gt;} ) (95) 3-Z- [1- (3,4-dimethoxy-phenylamino) -1-phenyl-methylene] -5-amido-2-indolinone

C ₂₄ H ₂₂ N ₃ O ₄

Mass Spectrum: m / z = 415 (M &lt; ^{+ &gt;} )

_Rf: 0.5 (silica gel, methylene chloride / methanol = 9: 1) (96) 3-Z- [1 - (4-triflulórmetoxy-phenylamino) -1-phenyl-methylene] -

-5-amido-2-indolinone

C ₂₃ H, ₆ F ₃ N ₃ O ₃

Mass Spectrum: m / z = 439 (M &lt; ^{+ &gt;} )

_Rf: 0.5 (silica gel, methylene chloride / methanol = 9: 1) (97) 3-Z- [l- (3-ctoxykarbonyl-phenylamino) -l-phenyl-methylene] -5-amido-2-indolinone

C ₂₅ H ₂₁ N ₃ O ₄

Mass Spectrum: m / z = 427 (M &lt; ^{+ &gt;} )

F. 0.52 (silica gel; methylene chloride / methanol = 9: 1) (98) 3- Z- [1- (3-carboxy-phenylamino) -1-phenyl-methylene | -5-amido-2-indolinone

C23H17N3O4

Mass Spectrum: m / z = 399 (M &lt; ^{+ &gt;} )

_Rf: 0.14 (silica gel; methylene chloride / methanol = 9: 1) (99) 3-Z- \ 1 - (3 -dietylkarbamoyl-phenylamino) -1-phenyl-methylene] -5-amido-2-indolinone

C ₂₇ H ₂ N, N ₄ O,

MS: m / z = 454 (M ⁴⁾

Rf: 0.48 (silica gel; methylene chloride / methanol = 9: 1) (100) 3-Z- [1- (3-ethylcarbamoyl-phenylamino) -1-phenyl-methylene] -5-amido-2-indolinone

C ₂₅ H ₂₂ N ₄ O ₃

Mass Spectrum: m / z = 426 (M &lt; ^{+ &gt;} )

_Rf: 0.42 (silica gel; methylene chloride / methanol = 9: 1) (101) 3-Z- [l- (3-trifluoromethoxy-phenylamino) -l-phenyl-methylene] -5-amido-2-indolinone

C ^ FjNjOj

Mass Spectrum: m / z = 439 (M &lt; ^{+ &gt;} )

Ry 0.5 (silica gel; methylene chloride / methanol = 9: 1) (102) 3-Z- [1- (3-ethoxy-phenylamino) -1-phenyl-methylene] -5-amido-2-indolinone

C ₂₄ H ₂₁ N ₃ O ₃

Mass Spectrum: m / z = 399 (M &lt; ^{+ &gt;} )

_Rf: 0.49 (silica gel; methylene chloride / methanol = 9: 1) (103) 3-Z- [l - (4-mctoxymctyl-phenylamino) -l-phenyl-methylene] -5-

amido-2-indolinone

C ₂₄ H ₂ N ₃ O ₃

Mass Spectrum: m / z = 399 (M &lt; ^{+ &gt;} )

_Rf: 0.4 (silica gel, methylene chloride / methanol = 4: 1) (104) 3-Z- [1 - (4-ethyl-phenylamino) -1-phenyl-methylene] -5-amido-2-indolinone

C ₂₄ H ₂₁ N ₃ O ₂

Mass Spectrum: m / z = 383 (M &lt; ^{+ &gt;} )

_Rf: 0.52 (silica gel; methylene chloride / methanol = 4: 1) (105) 3-Z- [l- (4-methyl-3-nitro-phenylamino) -l-phenyl-mctylén] -5-

amido-2-indolinone

C ₂₃ H ₁₈ N ₄ O ₄ +

Mass Spectrum: m / z = 414 (M ⁺ ) (106) 3- Z- [1- (4-methyl-3-methoxy-phenylamino) -1-phenyl-methylene] -5-amido-2-indolinone

C ₂₄ H ₂₎ N ₃ O ₃

Mass Spectrum: m / z = 399 (M &lt; ^{+ &gt;} ) (107) 3-Z- [1- (4- (4-aminophenylmethyl) -phenylamino) -1-phenyl-

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

C ₂₉ H ₂₄ N ₄ O ₂

Mass spectrum: m / z = 460 (M ⁺ ) (108) 3- Z- [1- (4-methoxycarbonyl-3-methyl-phenylamino) -1-phenyl-methylene] -5-amido-2-indolinone

C ₅ H ₂ N ₃ O ₄

Mass Spectrum: m / z = 427 (M &lt; ^{+ &gt;} )

Rf: 0.56 (silica gel; methylene chloride / methanol = 4: 1) (109) 3-Z- [1- (4-cyanophenylamino) -1-phenylmethylene] -5-amido-2-indolinone c ₂₃ h ₁₆ n ₄ 0 ₂

Mass Spectrum: m / z = 380 (M &lt; + &gt;)

Rf 0.65 (silica gel; methylene chloride / methanol = 9: 1) (110) 3- Z- [1- (5-methyl-pyridin-2-ylamino) -1-phenyl-methylene] -5-amido- 2-indolinone

_Rf: 0.6 (silica gel, methylene chloride / methanol = 9: 1) C ₂₂ H18N ₂ O ₄

Mass Spectrum: m / z = 370 (M ⁺ ) (111) 3-Z [1- (5-bromo-pyridin-2-yl-amino) -1-phenyl-methylene] -5-amido-2-indolinone

_Rf: 0.65 (silica gel; methylene chloride / methanol = 9: 1)

C ₂ H ₁₅ BrN ₄ O ₂

Mass Spectrum: m / z = 434/436 (M + ⁴ ) (112) 3- Z- [1- (2-chloro-pyridin-5-yl-amino) -1-phenyl-methylene] -5-amido-2 -indolinón

_Rf: 0.49 (silica gel; methylene chloride / methanol = 9: 1) C ₂₁ H _I5 C1N ₄ O ₂

Mass spectrum: m / z = 390/392 (M ⁺ ) (113) 3- Z- [1- (3-cyanophenylamino) -1-phenyl-methylene] -5-amido-2-indolinone

C2íH | 6 N ₄ O ₂

Mass Spectrum: m / z = 380 (M &lt; ^{+ &gt;} )

Rf: 0.57 (silica gel; methylene chloride / methanol = 9: 1) (114) 3-Z- [1- (4- (N ^' -phenylamino-methyl) -phenylamino) -1-phenyl-methylene] - 5-amido-2-indolinone

C ₂₉ H ₂₄ N ₄ O2

Mass Spectrum: m / z = 460 (M &lt; ^{+ &gt;} )

_Rf: 0.74 (silica gel; methylene chloride / methanol = 9: 1) (115) 3-Z- [1 - (4- (FV-methyl- / V-phenyl-aminomethyl-phenylamino) -l-phenyl-methylene ] -5-amido-2-indolinone

C ₃ O ₂₆ N ₄ 0 ₂

Mass Spectrum: m / z = 474 (M &lt; ^{+ &gt;} )

Ry 0.75 (silica gel; methylene chloride / methanol = 9: 1) (116) 3- Z- [1- (4- (N-ethyl-aminomethyl) -phenylamino) -1-phenyl-methylene] -5-amido- 2-indolinone-trifluoroacetate

C ₂₅ H, ₄ N ₄ O ₂

Mass Spectrum: m / z = 412 (M ⁺ ) (117) 3- Z- [1- (4-N- (4-chlorophenylmethyl) aminomethyl) phenylamino) -1-phenylmethylene] -5- amido-2-indolinone-trifluoroacetate

C ₃₀ H ₂₅ ClN ₄ O ₂

Mass Spectrum: m / z = 508/510 (M ⁺ ) (118) 3- Z- [1- (4- (N-cyclohexyl-aminomethyl) -phenylamino) -1-phenyl-methylene] -5-amido-2 -indolinone trifluoroacetate C _m H ₃₀ N ₄ O ₂

Mass Spectrum: m / z = 466 (M &lt; ^{+ &gt;} ) (119) 3-Z- [1- (4- (N-isopropyl-aminomethyl) -phenylamino) -1-phenyl-methylene] -5-amido-2- indolinone-trifluoroacetate ₂ C 6 H ₂₆ N ₄ O ₂

MS: m / z = 426 (M +) (120) 3-Z- [l - (4- ^{(f-butyl-aminomethyl)} phenylamino) -l-phenyl-methylene] -5-amido-2- indolinone

C ₂₇ H ₂₈ N ₄ O ₂

Mass Spectrum: m / z = 440 (M ⁺ ) (121) 3- Z- [1- (4- (N'-methoxycarbonyl-methylamino-methyl) -phenylamino) -1-phenyl-methylene] -5-amido- 2-indolinone-trifluoroacetate

C26H24N4O4

Mass Spectrum: m / z = 456 (M &lt; ^{+ &gt;} ) (122) 3- [1- (4- (N- (phenylmethyl) aminomethyl) phenylamino) -1-phenyl-melylene] -5- amido-2-indolinone-trifluoroacetate ₃ oH C 6 N ₄ 0 _{2 2}

Mass Spectrum: m / z = 464 (M &lt; ^{+ &gt;} ) (123) 3- [1- [4- (N &apos; -acetyl-N &apos; -ethoxycarbonylmethyl-amino) -phenylamino) -1-phenylmethylene] -5- amido-2-indolinone CÄNÄ

Mass Spectrum: m / z = 498 (M &lt; ^{+ &gt;} ) (124) 3-Z- [1- (4-methyl-3-sulfamoyl-phenylamino) -1-phenyl-methenyl] -5-amido-2-indolinone

C ₂₃ H ₂₀ N ₄ O ₄ S

Mass spectrum: m / z = 448 (M ⁺ ) (125) 3- [1- (4- (N-methanesulfonyl-N- (methylcarbamoylmethyl) amino) -phenylamino) -1-phenyl-methylene] - 5-amido-2-indolinone

C ₂₆ H ₂₅ N, O ₅ S

Mass Spectrum: m / z = 519 (M &lt; ^{+ &gt;} ) (126) 3-Z- [1- (4- (N-methanesulfonyl-N &apos;-( piperidine-carbonylmethyl) amino) phenylamino) -1-phenyl methylene] -5-amido-2-indolinone

C ₃ o ₃₁ N ₅ 0 ₅ S

Mass Spectrum: m / z = 573 (M &lt; ^{+ &gt;} ) (127) 3- [1- (4-carboxy-phenylamino) -1-phenyl-methylene] -5-amido-2-indolinone

C ₂₃ H ₁₇ N ₃ O ₄

MS: m / z = 398 (MH ⁴⁾ (128) 3-Z- [l- (4-carboxy-3-methyl-phenylamino) -l-phenyl-methylene] -5-amido-2-indolinone

C ₂₄ H; ₉ N ₃ O ₄

Mass Spectrum: m / z = 412 (MH ⁺ ) (129) 3- Z- [1- (4- (3-diethylamino-propoxy) -phenylamino) -1-phenyl-methylene] -5-amido-2-indolinone -trifluoroacetate c ₂₉ h ₃₂ n ₄ o ₃

Mass Spectrum: m / z = 484 (M &lt; ^{+ &gt;} ) (130) 3 -Z- [1- (4- (2-piperidine-ethoxy) -phenylamino) -1-phenyl-1-methylene] -5-amido-2- indolinone-trifluoroacetate

C ₂₉ Hj |) N ₄ 0j

Mass Spectrum: m / z = 483 (M + H) ⁺ (131) 3- Z- [1- (4- (3-piperidine-propoxy) -phenylamino) -1-phenyl-methylene] -5-amido-2 -indolinone trifluoroacetate C ₃ H ₃₂ N ₄ 0 ₃

Mass Spectrum: m / z = 496 (M &lt; ^{+ &gt;} ) (132) 3-Z- [1- (4- (3-dimethylamino-propoxy) -phenylamino) -1-phenyl-methylene] -5-amido-2-indolinone -trifluoroacetate C ₂₇ H ₂₈ N ₄ O ₃

MS: m / z = 457 (M + H) ⁴ (133) 3-Z- [1 - (4- (3 / ^{V-methyl-d-benzylamino-propoxy)} phenylamino) -l-phenyl- methylene] -5-amido-2-indolinone-trifluoroacetate

C ₃₃ H ₃₂ N ₄ O ₃

Mass Spectrum: m / z = 533 (M + H) ⁺ (134) 3- [1- (4- (2-dimethylamino-ethoxy) -phenylamino) -1-phenyl-methylene] -5-amido-2 -indolinone trifluoroacetate ^ 26 ^ 1 ₂₉ Ν ₄ Ο ₃

Mass Spectrum: m / z = 443 (M + H) ⁺ (135) 3- Z- [1- (4- (N-ethyl-N-benzyl-aminomethyl) -phenylamino) -1-phenyl-methylene] - 5-amido-2-indolinone (136) 3- [1- (4- (N'-propyl-N-benzyl-aminomethyl) -phenylamino) -1-phenyl-methylene] -5-amido-2 -indolinón (137) 3-Z- [l- (4- ^(N-methyl-N- (4-chloro-phenyl-methyl) aminomethyl) phenylamino) -l-phenyl-methylene] -5-amido-2- indolinone (138) 3-Z- [1- (4- (N-methyl- N - (4-bromophenyl-methyl) -amino-methyl) -phenylamino) -1-phenyl-methylene] -5-amido-2 -indolinone (139) 3-Z- [1- (4- (N'-methyl-N '- (3-chlorothenyl-methyl) -amino-methyl) -phenylamino) -1-phenyl-methylene] -5- amido-2-indolinone (140) 3-Z- [1- (4- (N'-methyl-M (3,4-dimethoxyphenyl-triethyl) -amino-methyl) -phenylamino) -1-phenyl-methylene] - 5-Amido-2-indolinone (141) 3- [1- (4- (N'-methyl- N - (4-methoxyphenyl-methyl) amino-methyl) -phenylamino) -1-phenyl-methylene] -5-amido-2-indolinone (142) 3- [1- (4 - (N-trifluoroethyl-N- (phenylmethyl) amino-methyl) -phenylamino) -1-phenylmethylene] - 5-Amido-2-indolinone (143) 3- [1- (4 - (N-trifluoroethyl) -N- (4-chlorophenyl) -amino] ethyl) aminomethyl) phenylamino) -l-phenyl-mctylén] -5-amido-2-indoljnón

Example 5 3-Z- [1- (4- (4-acetyl-piperazinylmethyl) -phenylamino) -1-phenylmethylene] -5-amido-2-indolinone mg 3-Z- [1- (4- (piperazinylmethyl) - phenylamino) -1-phenyl-methylene] -5-amido-2-indolinone and 0.02 g of triethylamine are dissolved in 10 ml of methylene chloride and treated with 5 mg of acetyl chloride and the solution is stirred at room temperature for 16 hours. It is then washed with water and the organic phase is evaporated. Yield: 15 mg (68% of theory) C ₂₉ H ₂₉ N ₅ O ₃ Mass spectrum: m / z = 495 (M ⁺ )

The following compound was prepared analogously:

(1) 3-Z- [1- (4- (4-Benzoyl-piperazinylmethyl) -phenylamino) -1-phenyl-methylene] -5-amido-2-indolinone

Prepared from 3-Z- [1- (4- (piperazinyl-methyl-phenylamino) -1-phenyl-ethylene] -5-amido-2-indolinone and benzoyl chloride in yield: 91% of theory

C ₃₄ H ₃₁ N ₅ O ₃

Mass Spectrum: m / z = 557 (M &lt; ^{+ &gt;} )

Example 6 3-Z- [1- (4-diethylcarbamoyl-phenylamino-1-phenyl-methylene) -5-ainido-2-indolinone g of the resin from Step IV is mixed with ethyl 4-aminobenzoate in analogy to Step IV. The resin is suspended in 30 ml of dioxane and 30 ml of methanol and stirred for 40 hours with 25 ml of 1 N sodium hydroxide solution, neutralized with dilute hydrochloric acid and washed with methylene chloride, methanol and dimethylformamide. to stand for 60 hours at room temperature with 0.2 ml of diethylamine, 0.5 g of O- (benzotriazol-1-yl) - N, N, N ', N' - tetramethyluronium tetrafluoroborate and 0.8 ml of ethyldiisopropylamine Finally, the product is cleaved with the resin according to the example

4th

Yield: 29 mg

_Rf: 0.46 (silica gel; methylene chloride / methanol = 9: 1) C27H26N4O3

Mass Spectrum: m / z = 454 (M &lt; ^{+ &gt;} )

Analogously prepare:

(1) 3-Z- [1- (4- (piperidinecarbonyl) -phenylamino) -1-phenyl-methylene] -5-amido-2-indolinone

_Rf: 0.43 (silica gel; methylene chloride / methanol = 9: 1) C28H26N4O3

Mass Spectrum: m / z = 466 (M &lt; ^{+ &gt;} ) (2) 3-Z- [1- (4- (4-methylpiperazinecarbonyl) -phenylamino) -1-phenylmethylene] -5-amido-2-indolinone trifluoroacetate

R f 0.84 (silica gel; methylene chloride / methanol = 4: 1) C H ₂₇ N _{2 S;} ABOUT,

Mass spectrum: m / z = 481 (M ⁺ ) (3) 3-Z- [1- (4- (N - (2-dimethylamino-ethyl) -N-methyl-carbamoyl) -phenylamino) -1-phenyl- methylene] -5-amido-2-indolinone-trifluoroacetate of

_Rf: 0.25 (silica gel; methylene chloride / methanol = 9: 1) CjgHjsNjOj

Mass Spectrum: m / z = 484 (M + H) ⁺ (4) 3- Z- [1- (4- (N-methoxycarbonylmethylcarbamoyl) phenylamino) -1-phenylmethylene] -5-amido-2 -indolinón

_Rf: 0.4 (silica gel, methylene chloride / methanol = 9: 1) C _f H ₂₂ N ₄ O5

Mass spectrum: m / z = 470 (M ⁺ ) (S) 3 -Z- [1- (4-benzylcarbamoyl-phenylamino) -1-phenyl-1-methylene J -5-amido-2-indolinone

_Rf: 0.48 (silica gel; methylene chloride / methanol = 9: 1) C ₃₀ H ₂₄ N4O ₃

Mass Spectrum: m / z = 488 (M &lt; ^{+ &gt;} )

Example 7

3-Z- [1- (4- (N-methyl-benzoylamino) -phenylamino) -1-phenyl-methylene-5-amido-2-indolinone

4.5 g of the resin from Step IV was treated analogously to Example 4 with 3.4 g of 4- (9H-fluoren-9-ylmethoxycarbonyl) -methyl-amino) -ariline in dimethylformamide. Subsequently, the 9H-fluorene protecting group is cleaved with 4 ml of 30% piperidine in dimethylformamide and the resin is washed several times. Then 400 mg of the resin is suspended in 4 ml of dimethylformamide and 0.3 ml of triethylamine and stirred with 0.3 ml of benzoyl chloride for 1 hour at room temperature. Finally, the product is cleaved with the resin of Example 4.

Yield: 33 mg

R _f : 0.45 (silica gel; methylene chloride / methanol = 9: 1) C ₃ H ₂₄ N ₄ 0 ₃

Mass Spectrum: m / z = 488 (M &lt; ^{+ &gt;} )

Analogously prepare:

(1) 3-Z- [1- (4- (N-methyl-propionylamino) -phenylamino) -1-phenyl-methylene-5-amido-2-indolinone

Rf 0.42 (silica gel; methylene chloride / methanol = 9: 1) C ₆ H ₂₄ N ₄ O ₃

Mass spectrum: m / z = 440 (M +) (2) 3 -Z- [1- (4- (N-methyl-butyrylamino) -phenylamino) -1-phenyl-methylene-5-amido-2-indolinone

_Rf: 0.44 (silica gel; methylene chloride / methanol = 9: 1)

C ₂₇ H ₂₆ N ₄ O ₃

MS: m / z = 453 (MH ⁺⁾ (3) 3-Z- [l- (4- ^{(N-ethyl-sulfonylamino-methyl)} phenylamino) -1-phenyl-methylene-5-amido-2-indolinone

Rf 0.42 (silica gel; methylene chloride / methanol = 9: 1) C ₂₅ H ₂₄ N ₄ O ₄ S

Mass Spectrum: m / z = 475 (MH ⁺ ) (4) 3-Z- [1- (4- (N-methyl-propylsulfonylamino) -phenylamino) -1-phenyl-methylene-5-amido-2-indolinone

_Rf: 0.44 (silica gel; methylene chloride / methanol = 9: 1) ₂ ^ 25 H 6 N ₄ O ₄ S

Mass spectrum: m / z = 491 (M + H) ⁺ (S) 3 -Z- [1- (4- (N-methyl-phenylsulfonylamino) -phenylamino) -1-phenyl-methylene-5-amido-2 -indolinón

Rf 0.53 (silica gel; methylene chloride / methanol = 9: 1) C ₂₉ H ₂₄ N ₄ O ₄ S

Mass Spectrum: m / z = 524 (M &lt; ^{+ &gt;} )

Example 8

Dry ampoule with 75 mg of active substance per 10 ml

Ingredients: active substance mannitol water for injections

Preparation:

The active substance and mannitol are dissolved in water. After filling, it is lyophilized. The ready-to-use solution is prepared with water for injections before use.

Example 9

Dry ampoule with 35 mg of active substance per 2 ml

Ingredients: active substance mannitol water for injections

Preparation:

The active substance and mannitol are dissolved in water. After filling, it is lyophilized. The ready-to-use solution is prepared with water for injections before use.

75.0 mg

50.0 mg to 10.0 ml

35.0 mg 100.0 mg to 2.0 ml

Example 10

Tablet with 50 mg of the active substance

Ingredients:

Active Substance 50.0 mg Milk Sugar 98.0 mg Corn Starch 50.0 mg Polyvinylpyrrolidone 15.0 mg Magnesium stearate 2.0 m and 215.0 mg

Preparation:

(1), (2) and (3) are mixed and granulated with an aqueous solution (4). The dried granulate is admixed with (5). From this mixture, tablets are compressed flat, with veneers on both sides and with a dividing groove on one side.

Tablet diameter: 9 mm

Example 11

Tablet with 350 mg of the active substance

Ingredients:

Active Substance 350 mg milk sugar 136.0mg corn starch 80.0mg polyvinylpyrrolidone 30.0mg magnesium stearate 4.0mg

600.0 mg

Preparation:

(1), (2) and (3) are mixed and granulated with an aqueous solution (4). The dried granulate is admixed with (5). From this mixture, tablets are compressed flat, with veneers on both sides and with a dividing groove on one side.

Tablet diameter: 12 mm

Example 12

Capsules containing 50 mg of the active substance

Ingredients:

active substance 50.0 mg dried corn starch 58.0 mg powdered milk sugar 50.0 mg magnesium stearate 2.0 mg

160.0 mg

Preparation:

(1) is mixed with (3). This mixture is added vigorously to the mixture consisting of (2) and (4).

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

Example 13

Capsules with 350 mg of the active substance

Ingredients:

Active substance 350.0 mg dried corn starch 46.0 mg powdered milk sugar 30.0 mg magnesium stearate 4.0 mg

430.0 mg

Preparation:

(1) is mixed with (3). This mixture is added vigorously to the mixture consisting of (2) and (4).

This powder blend is filled into hard gelatin size 0 capsules using a capsule filling machine.

Example 14

Caps of 100 mg of active substance

1 cap contains: active substance 100.0 mg polyethylene glycol (MW 1500) 600.0 mg polyethylene glycol (MW 6000) 460.0 mg polyetylénsorbitanmonostearan 840.0 mg 2000.0 mg

Preparation:

The polyethylene glycol melts together with the polyethylene sorbitan monostearate. At 40 ° C, the milled active substance is uniformly distributed in the melt. Cool to 38 ° C and pour into pre-chilled capsule molds.

Claims (10)

Substituted indolinones of general formula (I) in which X is an oxygen or sulfur atom, R ¹ is hydrogen, C ₁ . ₄ -alkoxy-carbonyl or C _{2nd 4-} alkanoyl group, R ² is carboxy-, C 1-6. _{A 4} -alkoxycarbonyl or aminocarbonyl group in which the amino group may be substituted by one or two C 1-6 -alkyl groups and the substituents may be the same or different, R ³ is a phenyl or naphthyl group which may be substituted by one to five substituents selected from the group consisting of fluorine, chlorine or bromine atoms, C 1-6 alkyl, C 1-6 alkoxy, cyano, trifluoromethyl, nitro, amino-, C1-8. _3- alkylamino-, di- (C _1-3 -alkyl) -amino-, C ₂ . . _{4-alkanoyl-amino,} N - (C _{l. 3-alkyl) -C2. 4} -alkanol-ylamino-, N- (CII-Ck ^ alkyli -alkanovlamino-. C |. ₃ of alkyl sulfonyl) amino, amino-C,., - alkyl, _{C1. 3} -alkylamino-C _{first 3-} alkyl, di- (C 1-6 -alkyl) amino-C 1-6 alkyl; ₃ alkyl, / N (C _{2nd 4} alkanoyl) amino-C |. A 3-alkyl or N, -C 1-6 -alkanoyl-C 1-6 alkylamino-C 1-6 alkyl group, and the substituents may be the same or different; R ⁴ is H or C _{i. A 3-} alkyl group and a R ⁵ is a hydrogen atom, C |. _{A 5-} alkyl group optionally substituted by a phenyl, carboxy- or C ₁₃ -alkoxy-carbonyl group, C _3-7 -cycloalkyl optionally substituted with C 1-7. _3- alkyl, indanyl optionally substituted with C 1-6 alkyl; _3- alkyl, A 5-membered heteroaryl group that contains an imino group optionally substituted with C 1-6 alkyl; _{A 3-} alkyl group, an oxygen or sulfur atom, or an imino group optionally substituted by a C 1-6 -alkyl group and an oxygen, sulfur or nitrogen atom or two nitrogen atoms, or a 6-membered heteroaryl group containing 1 to 3 nitrogen atoms through two adjacent atoms carbon atom or a nitrogen atom and an adjacent imino group of said 5-and 6-membered heteroaryl group can be attached a 1,3-butadienylene bridge, and said carbon core of mono- and bicyclic rings may be mono or disubstituovanc Cl, Br, I, C _b5 - the alkyl or cyano group and the substituents may be the same or different, the pyrrolidinyl or piperidinyl group attached via a carbon atom, which may be substituted on the nitrogen atom by C 1-6. ₍ -alkyl), a phenyl group optionally disubstituted by fluorine, chlorine, bromine or iodine atoms, C 1-4 -alkyl, C 1 -alkoxy, carboxy, C 1 -alkoxycarbonyl, aminosulfonyl, nitro or cyano, wherein the substituents may be the same or different, phenyl, pyridyl, pyrimidyl or thienyl which is substituted by trifluoromethoxy, fluorine, chlorine, bromine or iodine, C |. _{A 3-} alkoxy group which at the 2- or 3-position may be substituted by amino-, C1-C3-alkoxy; _3- alkylamino, di- (C _1-3 -alkyl) -amino-, phenyl, C _1-3 -alkylamino-, N - (C _1-3 -alkyl) -phenyl- C 1-6 -alkylamino-, pyrrolidine or piperidine group, a _{phenyl-C 3} _ s alkylamino-C |. ₃ -alkylamino-C ₁ _ _i -alkyl, in which the phenyl ring may be mono- or disubstituovariá by trifluoromethyl, fluorine, chlorine, bromine, iodine, C ^ j alkyl or C |. _3- alkoxy, wherein the substituents may be the same or different, and additionally Cj on the amine nitrogen atom. _{A 3-} alkyl group in which the hydrogen atoms can be replaced in whole or in part by fluorine atoms from the 2-position, C | _5-alkyl, phenyl, imidazolyl, C _{3. 7-} cycloalkyl, C 1-3 -alkoxy-C _1-3 -alkoxy-, phenyl-C 1-6 -cycloalkyl; _3- Alkoxy-, carboxy-C1-4 -alkyl. _3- alkyl, C 1-6 -alkoxycarbonyl-C 1-6 -alkyl, carboxy, C ₁₃ -alkoxycarbonyl, aminocarbonyl, C 1-6 -alkyloxycarbonyl, C 1-6 -alkoxycarbonyl, _3- alkylamino-carbonyl, di- (C _1-3 -alkyl) aminocarbonyl, phenyl-C 1-6 -alkylamino-carbonyl; _3- alkylaminocarbonyl, N - (C _1-3 -alkyl) -phenyl-C 1-6 -alkylaminocarbonyl; _3- alkylaminocarbonyl, piperazinecarbonyl, N-C 1-6 -alkyl-piperazinecarbonyl, nitro-, amino-, C _1-3 -alkylamino-, di- (C 1-6 -alkyl) -amino-, pyrrolidine, piperidine, morpholine, C ₂ . ₄ -alkanoylamino-, N'-C 1'-alkyl-C 1'-alkanoylamino-, benzoylamino- or N-C'- _3- alkyl) -benzoylamino, N'-C'-alkyl-C 1'-alkanoylamino, which in the alkyl moiety is additionally substituted by carboxy- or C 1 -alkoxycarbonyl, C 1-6 -alkoxycarbonyl; ₃ -alkylaminokarbonylovou or di- (C _{l. 3-alkyl)} -aminokarbonylovou group, wherein the alkyl moiety is additionally substituted by di (C |. ₃ alkyl) amino, or N- (Ci. ₃ alkyl) -C . _3- alkylsulfonylamino- or N - (C _1-3 -alkyl) -phenylsulfonylamino, in which the alkyl moiety may be additionally substituted with cyano-, carboxy-, C ₁₃ -alkoxycarbonyl, C 1-6 -alkyloxycarbonyl; _3- alkylamino-, di- (C _1-3 -alkyl) -amino-, aminocarbonyl, C _1-3 -alkylaminocarbonyl, di (C _1-3 -alkyl) -aminocarbonyl, piperidinecarbonyl or 2- [di- (C _{1-3 )} - alkylamino)] - ethylaminocarbonyl, phenyl or thienyl which is substituted by C 1-6 alkyl. . _{A 3-} alkyl group in which the alkyl moiety is substituted by hydroxy-, C 1 -alkoxy-, carboxy-, C 1 -alkoxy-carbonyl, amino-, C 1-6 -alkylamino-, di- (C _1-5 -alkyl) -amino-, C ₂₄ -alkanoylamino-. .'V- (C ₁₃ alkyl) C ₂ _ ₄ -alkanoylamino-, pyrrolidino, dehydropyrolidínovou, piperidine, dehydropiperidínovou, 3-hydroxypiperidino, 4-hydroxypiperidine, hexametylénimino-, morpholino, thiomorpholino, piperazino, 4- (C _{1st 3-alkyl)} -piperazine, 4-phenyl-piperazine, 4- _{(C2. 4} alkanoyl) -piperazine, 4-benzoyl-piperazino or imidazolyl group wherein said saturated cykloalkyléniminokruhy, C. _{The 5-} alkylamino- or di- (C _1-5 -alkyl) amino groups may be additionally substituted with one or two C 1-6 -alkyls. _5- alkyl groups, once C ₃ . ₇ -cycloalkyl, hydroxy-, C 1-6 -cycloalkyl. _3- alkoxy-, carboxy-, Cj. _3- alkoxycarbonyl, aminocarbonyl, C _1-3 -alkylaminocarbonyl or di- (C _1-3 -alkyl) aminocarbonyl, one phenyl-C 1-4 -alkyl or phenyl group which may additionally be mono- or disubstituted by fluorine atoms in the phenyl core, chlorine, bromine or iodine, C _1-3 -alkyl or cyano, wherein the substituents may be the same or different, or the methylene group adjacent to the nitrogen atom in said cycloalkyleneiminocycles may be replaced by a carbonyl or sulfonyl group, and said monosubstituted phenyl groups may be additionally substituted fluorine, chlorine or bromine, methyl, amino-, C _1-3 -alkylamino- or di- (C _1-3 -alkyl) amino, or at one of said unsubstituted cycloalkyleneiminocycles, the phenyl core may optionally be fused via two adjacent carbon atoms substituted by one or two C _{first 3} -alkoxy groups, wherein the carboxy in addition, the amino and imino groups mentioned in the definition of said residues may be substituted by a residue which is cleavable in vivo, 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 hydrogen, C 1-4 -alkoxycarbonyl, R ² is carboxy-, C 1-6. _{A 4-} alkoxycarbonyl or aminocarbonyl group in which the amino moiety may be substituted with one or two C 1-6 -alkoxycarbonyl groups; _{The 3-} alkyl groups and substituents may be the same or different, R ³ is a phenyl group optionally substituted by a fluorine, chlorine or bromine atom, a methyl, cyano, or aminomethyl group, R ⁴ is a hydrogen atom or a methyl group; and R ⁵ is a hydrogen atom, C 1-6 -alkyl optionally substituted by carboxy- or C 1-6 -alkyl. ₃ -alkoxycarbonyl or benzyl, C ₃ . _7- cycloalkyl optionally substituted by methyl, indanyl, pyridyl, oxazolyl, thiazolyl or imidazolyl optionally substituted by methyl, on which two adjacent carbon atoms can be additionally fused to a phenyl core, methylphenyl optionally substituted by methoxy, fluorine, chlorine, chlorine -, carboxy-, C1-8. _{A 3-} alkyloxycarbonyl, nitro or aminosulfonyl group, or a dimethoxyphenyl group, a pyrrolidinyl or piperidinyl group attached via a carbon atom which is substituted on the nitrogen atom by a C _1-3 -alkyl group, a phenyl group which is substituted by a trifluoromethoxy group, a fluorine, chlorine, bromine or iodine, C | .j-alkoxy group in the 2 or 3 may be substituted with amino, C _{i. 3-} alkylamino-, di- (C _1-3 -alkyl) -amino-, phenyl-C 1-6 -alkyl; _3- alkylamino-, N, N-N, N-alkyl-phenyl-N, N-alkylamino, pyrrolidine or piperidine, phenyl-C 1 -alkylamino-N, -alkyl which may be substituted in the phenyl ring by a fluorine atom, chlorine, bromine or iodine; _{The 5-} alkyl, C _1-3 -alkoxy or trifluoromethyl group and additionally at the amine nitrogen atom may be substituted by C ₃ . _{A 3-} alkyloxy group in which the hydrogen atoms from the 2-position can be replaced, in whole or in part, by fluorine atoms, C 1-8 -alkyl, phenyl, imidazolyl, C _{3 -} . ₇ -cycloalkyl, C _1-3 -alkoxy-C 1-6 -cycloalkyl. _3- alkoxy-, phenyl-C ₃ -alkoxy-, carboxy-C ₁ . _3- alkyl, C ₁ . ₃ -alkoxycarbonyl-C _{first 3-} alkyl, carboxy-, C 1-6 -alkyl. _3- alkoxycarbonyl, aminocarbonyl; _3- alkylamino-carbonyl, di- (C _1-3 -alkyl) aminocarbonyl, phenyl-C 1-6 -alkylamino-carbonyl; _3- alkylaminocarbonyl, N - (C _1-3 -alkyl) -phenyl-C 1-6 alkyl; _3- alkylaminocarbonyl, piperazinecarbonyl, N - (C 1-6 -alkyl) -piperazinecarbonyl, nitro-, amino-, C _1-3 -alkylamino-, di- (C 1-6 -alkyl) -amino-, pyrrolidine, piperidine, morpholine, C ₂ . ₄ -alkanoylamino-, N - (C _1-3 -alkyl) -C ₂ . _4- alkanoylamino-, benzoylamino- or N - (C _1-3 -alkyl) -benzoylamino, N - (C _1-3 -alkyl) -C ₂ . -Alkanoylaminoskupinou _4, which is additionally substituted by alkyl or carboxy-C _b3 alkoxycarbonyl group, C |. ₃ -alkylaminokarbonylovou or di- (C _i. -Alkylj _{3-aminocarbonyl,} wherein the alkyl moiety is additionally substituted by di _(C, alkyl) amino, or, "in-fc |., - alkyl) C | . _3- alkyisulfonylamino- or N'-fcy1-alkyl) -phenylsulfonylamino group in which the alkyl moiety may be additionally substituted by cyano-, carboxy-, C 1-6 -alkoxycarbonyl, C ₃ -alkylamino-, di- (C _1-3 -alkyl) -amino-, amino-carbonyl, C 1. ₃ -alkylaminokarbonylovou, di- (C 3-alkyl _b) -aminokarbonylovou, piperidinocarbonyl or 2- [di- (C |. ₃ alkylamino)] - ethylaminocarbonyl group, a phenyl group optionally substituted with C ₃ -alkyl, wherein the alkyl portion substituted by hydroxy, C _{l 3} -alkoxy, carboxy, C |. _3- alkoxy-carbonyl, amino-, C 1-5 -alkylamino-, diTC. _5-alkyl) amino, C _{2nd 4-} alkanoylamino-, N- (C _1-3 -alkyl) - C ₂ . ₄ -alkanoylamino-, pyrrolidino, dehydropyrolidínovou, piperidine, dehydropiperidínovou, 3-hydroxypiperidine, 4-hydroxypiperidine, hexametylénimino-, morpholino, thiomorpholino, piperazino, 4- (C _{first 3} -alkyl) -piperazine, 4-phenyl-piperazine, 4 - _{(C2. 4} alkanoyl) -piperazine, 4-benzoyl-piperazino or imidazolyl group wherein said saturated cykloalkyléniminokruhy C |. ₅ -alkylamino or di (C _{first 5} -alkyl) amino may be additionally substituted with one or two Qj-alkyl groups, one C _{3. 7} -cycloalkyl, hydroxy-, C 1-6 -cycloalkyl; ₃ -alkoxy, carboxy, Cu-alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl or wire-di (C _{p. 3} alkyl) -aminokarbonylovou group, an tcnyl-C | ₃ alkyl or phenyl group which the phenyl nucleus may additionally be mono- or disubstituted by fluorine, chlorine, bromine, iodine, C _b3 -alkyl or cyano groups, wherein the substituents may be identical or different, or a methylene group adjacent to the nitrogen atom in said cykloalkyléniminokruhoch may be replaced by a carbonyl or sulfonyl group, and the abovementioned monosubstituted phenyl groups may additionally be substituted by F, Cl, Br, methyl, amino, C _b3 -alkylamino or di- (C |. ₃ alkyl) amino, or on one of said unsubstituted cycloalkyleneimino rings, the fused phenyl ring optionally substituted by one or two C 1-6 -alkoxy groups, their isomers and salts thereof may be fused via two adjacent carbon atoms. 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 carboxy-, C ₁ . _{A 4} -alkoxycarbonyl or aminocarbonyl group in which the amino moiety may be substituted with one or two C 1-6 -alkoxycarbonyl groups; _{The 3-} alkyl groups and substituents may be the same or different, R ³ is a phenyl group optionally substituted with a methyl group, R ⁴ is a hydrogen atom or a methyl group; and R ⁵ is a hydrogen atom, C ₁ . _{A 3-} alkyl group, a benzyl group or a methyl or ethyl group substituted with a carboxy- or C 1-6 -alkyl group; ₃ -alkoxycarbonyl, C ₃ . _7- cycloalkyl optionally substituted by methyl, indanyl, pyridyl, oxazolyl, thiazolyl or imidazolyl optionally substituted by methyl, on which two adjacent carbon atoms can be additionally fused to a phenyl core, methylphenyl optionally substituted by methoxy, fluorine, chlorine, chlorine -, carboxy-, C1-8. _3- alkyloxycarbonyl, nitro- or aminosulfonyl, or dimethoxyphenyl, A 3-pyrrolidinyl or 4-piperidinyl group which is substituted on the nitrogen atom by C 1-6. _{A 3-} alkyl group, a phenyl group which is substituted with trifluoromethoxy, benzyloxy, cyano or nitro, a fluorine, chlorine or bromine atom, C ₁ . _J- alkoxy, wherein the ethoxy and n-propoxy group may be end-substituted with dimethylamino-, diethylamino-, Λ-ethyl-methylamino-, N -benzyl-methyl-amino- or piperidine, phenyl-C 1-6 -alkylamino-C 1 - a j-alkyl group which in the phenyl ring may be substituted by a fluorine, chlorine, bromine or iodine atom, a methyl, methoxy or trifluoromethyl group and, in addition to the nitrogen atom of the amino group, may be substituted by a C 1-6 alkyl group. _5- alkyl- or 2,2,2-trifluoroethyl; C ₁₄ -alkyl, phenyl, imidazolyl, cyclohexyl, methoxymethyl, carboxymethyl, C ₁₄ -alkoxycarbonylmethyl, carboxy-, C _1-4 -alkyl. _3- alkoxy-carbonyl, aminocarbonyl, C 1-6 -alkylaminocarbonyl, di- (C _1-3 -alkyl) aminocarbonyl, phenyl-C 1-6 -alkylaminocarbonyl; ₃ -alkylaminokarbonylovou, N-JCU -alkyl is phenyl-C ^ -alkylaminokarbonylovou, piperazinecarbonyl, N - (C> alkyl) -piperazínkarbonylovou, amino, C _b3 alkylamino-, di (C]. ₃ alkyl 1-amino, pyrrolidine, piperidine, morpholine, C ₂₄ -alkanoylamino-, N '- (C _1-3 -alkyl) -C ₂ . ₄ -alkanoylamino-, benzoylamino or ^ - (C ^ -alkyl is a-benzoylamino, N - (C _{first 3} -alkyl) -C _second -alkanoylaminoskupinou _4, which is additionally substituted by alkyl or carboxy-C _H alkyloxycarbonyl, C |. ₃ -alkylaminokarbonylovou or di- (C | _ _{3-alkyl-aminocarbonyl,} where the alkyl moiety is additionally substituted by di (C |. _3-a) alkyl) amino, or, N- (C | _, - alkyl) -C _t _ ₃ -alkylsulfonylamino- or N- (Cl. ₃ alkyl) -phenylsulphonylamino-group in which the alkyl moiety may additionally be substituted by cyano, carboxy, C |. ₃ - alkoxycarbonyl, Ci.-alkylannno-, di (C _b3 alkyl) amino, aminocarbonyl, C ^ -alkylaminokarbonylovou, di- (C _b3-alkyl) -aminocarbonyl-nominal, piperidinocarbonyl or 2- [di- (C _B3 -alkylamino)] - ethylaminocarbonyl, a phenyl group optionally substituted with a C _1-3 -alkyl group in which the alkyl moiety is substituted with hydroxy-, C 1 -alkoxy-, carboxy-, C _1-3 -alkoxy-carbonylo vou, amino-, C _1-5 -alkylamino-, di-C 1-6 -alkyl-amino-, C _{2 -} . _4- alkanoylamino-, N-Cl; _3-alkyl) - C _{2nd 4-} alkanoylamino-, pyrrolidine, dehydropyrrolidine, piperidine, dehydropiperidine, 4-hydroxypiperidine, hexamethyleneimino-, morpholine, thiomorpholine, piperazine, 4- (C _1-3 -alkyl) -piperazine, 4-phenyl-piperazine, 4- (C ₂ -piperazine ₎ The _4- alkanoyl) -piperazine, 4-benzoyl-piperazine or imidazolyl group, wherein said saturated cycloalkyleneimino rings, may be additionally substituted with a phenyl group or one or two methyl groups, indicated by C 1-6. ₅ -alkylamino and di- (C 5 _b alkyl) amino can additionally be substituted by one or two C _3. j-alkyl groups, one cyclohexyl, hydroxy-, C _1-3 -alkoxy-, carboxy-, C 1-6 -alkoxycarbonyl, aminocarbonyl, C 1-6 -alkylaminocarbonyl or di- (C _1-3 -alkyl) aminocarbonyl, one phenyl-C _1-3 -alkyl- or phenyl group, which in phenyl the nucleus may be optionally substituted by a fluorine, chlorine, bromine or iodine atom, a methyl or cyano group, or a methyl group adjacent to a nitrogen atom in said cycloalkyleneimino rings may be replaced by a carbonyl or sulfonyl group, and said monosubstituted phenyl groups may be additionally substituted by a fluorine atom bromine, methyl, amino, C 1-6. _{The 3-} alkylamino- or di-C 1-6 -alkyl-amino group, or on one of said unsubstituted cycloalkyleneimino rings, may be fused via a two adjacent carbon atoms to the phenyl ring optionally substituted by one or two C _1-3 -alkoxy groups, 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 a carboxy or aminocarbonyl group wherein the amino moiety may be substituted by one or two C _p .j-alkyl groups and the substituents may be the same or different, R ³ is a phenyl group optionally substituted with a methyl group, R ⁴ is hydrogen and R ⁵ is a hydrogen atom, A 3-pyrrolidinyl or 4-piperidinyl group which is substituted on the nitrogen atom by a C 1-6 alkyl group; _{A 3-} alkyl group, a phenyl group which is substituted by C 1-6 alkyl; _3- alkoxy, wherein the ethoxy and n-propoxy groups may be terminally substituted by dimethylamino-, diethylamino-, N -ethyl-methylamino-, N -benzyl-methylamino- or piperidine, phenyl-C 1-4 -alkylamino-C 1-6 -alkyl a group which in the phenyl ring may be substituted by a fluorine, chlorine, bromine or iodine atom, a methyl, methoxy or trifluoromethyl group and, in addition to the nitrogen atom of the amino group, may be substituted by a C _1-5 -alkyl- or 2,2,2-trifluoroethyl group , a phenyl group optionally substituted by C 1-6. ₃ -alkyl, wherein the alkyl moiety is substituted by hydroxy, C ₃ -alkoxy, carboxy, Cu-alkoxycarbonyl, amino, C _{first 5} -alkylamino-, di - ( _{"C]. 5-alkyl)} amino, _{C2. 4-} alkanoylamino-, N- (C _1-3 -alkyl) - C ₂ . ₄ -alkanoylamino-, pyrrolidino, dehydropyrolidínovou, piperidine, dehydropiperidínovou, 4-hydroxypiperidine, hexametylénimino-, morpholino, thiomorpholino, piperazino, 4- (C _{first 3} -alkyl) -piperazine, 4-phenyl-piperazine, 4- (C ₂ . ₄ alkanoyl) -piperazine, 4-benzoyl-piperazino or imidazolyl group wherein said saturated cykloalkyléniminokruhy, may additionally be substituted by phenyl or by one or two methyl groups, said _{C1. The 1-} alkylamino- and di-C 1-6 -alkyl-amino groups may be additionally substituted with one or two C 1-6 -alkyls. . _3- alkyl groups, one cyclohexyl, hydroxy-, C 1-6 -alkyl; _3- alkoxy-, carboxy-, C 1-6 alkyl; _3- alkoxycarbonyl, aminocarbonyl, C _1-3 -alkylaminocarbonyl or di- (C ₁₃ -alkyl) aminocarbonyl, one phenyl-C 1-4 -alkyl or phenyl group, which in the phenyl ring may be optionally substituted by a fluorine, chlorine, bromine or iodine atom, a methyl or cyano group, or a methyl group adjacent to a nitrogen atom in said cycloalkyleneimino rings may be replaced by a carbonyl or sulfonyl group, and said monosubstituted phenyl groups may be additionally substituted by a fluorine, chlorine or bromine atom, methyl, amino-, C 1-4 -alkylamino- or di The C 1-6 alkyl-amino group or one of the above unsubstituted cycloalkylene imino rings may be fused via a two adjacent carbon atoms optionally substituted with one or two C _1-3 -alkoxy groups, their isomers and salts thereof. Substituted indolinones of formula (I) according to one of claims 1 to 4, wherein the residue R ² is in the 5-position. Substituted indolinones of formula (I) according to claim 1 selected from: 3-Z- [1- (4-Aminomethyl-phenylamino) -1-phenyl-methylene] -5-amido-2-indolinone, 3-Z- [l- (l-phenylamino) -l-phenyl-methylene] -5-amido-2-indolinone, 3-Z- [l- (4-bromo-phenylamino) -l-phenyl-methylene] -5-amido-2-indolinone, 3-Z- [1- (4-dimethylamino-methyl) -phenylamino) -1-phenyl-methylene] -5-amido-2-indolinone, 3-Z- [l- (4-pyrrolidinomethyl-phenylamino) -l-phenyl-methylene] -5-amido-2-indolinone, 3-Z- [1- (4-piperidinomethyl-phenylamino) -1-phenyl-methylene] -5-amido-2-indolinone, 3-Z- [1- (4-hexamethyleniminomethyl-phenylamino) -1-phenyl-methylene] ] -5-amido-2-indolinone, 3-Z- [1- (4-Benzyl-piperidin) -methyl) -phenylamino) -1-phenyl-methylene] -5-amido-2-indolinone, 3-Z- [1- (4- (N-butyl-aminomethyl) -phenylamino) -1-phenyl-methylene] -5-amido-2-indolinone, 3-Z- [l- (4- (N- (phenyl-methyl) aminomethyl) phenylamino) -l-phenyl-methylene] -5-amido-2-indolinone, 3-Z- [1- (4- (N-methyl-N-benzyl-amino-methyl) -phenylamino) -1-phenyl-methylene] -5-amido-2-indolinone, 3-Z- [l- (piperidin-4-methyl-phenylamino) -l-phenyl-melylén] -5-dimethylcarbamoyl-2-indolinone, 3-Z- [l- (piperidin-4-methyl-phenylamino) -l-phenyl-methylene] -5-diethylcarbamoyl-2-indolinone, 3-Z- [1- (4- (3-diethylamino-propoxy) -phenylamino) -1-phenyl-methylene] -5-amido-2-indolinone, and salts thereof. Physiologically acceptable salts of the compounds according to claims 1 to 6. A process for the preparation of compounds according to claims 1 to 7, characterized in that it comprises the following steps: (a) a compound of formula (II) wherein: X, R ² and R ³ are as defined in claims 1 to 6, R ⁶ is a hydrogen atom, a protecting group for a nitrogen atom of a lactam group or a solid phase bond; and Z ¹ is a halogen atom, a hydroxy-, alkoxy- or aralkoxy group, reacts with an amine of formula (III) in which: R ⁴ and R ⁵ are as defined in claims 1 to 6 and, if necessary, the nitrogen protecting group of the lactam group used is subsequently cleaved or the resulting compound is cleaved from the solid phase, or (b) for the preparation of a compound of formula (I) which contains an aminomethyl group and X is an oxygen atom, a compound of formula (IV) is reduced R ¹ where R ¹ to R ⁴ have been defined as in claims 1 to 6 and R ⁷ is as defined for R ⁵ in claims 1 to 6, wherein R ⁵ contains a cyano group and, if desired, a compound of formula (I) which contains an alkoxycarbonyl group is subsequently hydrolytically converted to the corresponding carboxy compound or prepared in this way a compound of formula (I) containing an amino or alkylamino group is converted by the alkylation or reductive alkylation to the corresponding alkylamino- or dialkylamino compound, or a compound of formula (I) containing an amino- or alkylamino group prepared in this way is converted by acylation to the corresponding an acyl compound or a compound of formula (I) containing a carboxy group prepared in this way is converted by esterification or amidization to the corresponding ester or aminocarbonyl compound or, if necessary, a protective residue is used during the reaction to protect the reactive groups, or if necessary, the compound of formula (I) thus prepared is subsequently resolved into stereoisomers, or the compound of formula (I) thus prepared is converted into salts, especially for pharmaceutical use, to physiologically acceptable salts with an inorganic or organic acid or base. A pharmaceutical composition comprising a substituted indolinone according to any one of claims 1 to 6 or a salt according to claim 7 optionally with one or more inert carriers and / or diluents. Use of substituted indolinones according to one of claims 1 to 6 or a salt thereof according to claim 7 for the preparation of a medicament for the treatment of extensive or anomalous cell proliferation.