BG64443B1 - Substituted indolinones having an inhibiting effect on kinases and cycline/cdk complexes - Google Patents

Abstract

The invention relates to substituted indolinones of general formula 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

(54) INSTALLINONS SUBSTITUTED WITH INHIBITING EFFECT ON KINASES AND CYCLINE / JAPANESE COMPLEXES

Technical field

The present invention relates to substituted indolinones of the general formula

their isomers, salts, in particular physiologically acceptable salts, which exhibit valuable properties.

The above compounds of general formula (I), in which R 1 represents a hydrogen atom or a prodrug moiety, exhibit valuable pharmacological properties, in particular inhibitory effects on various kinases, especially on CDK complexes (CDK1, CDK.2, CDK3, CDK4, CDK6, CDK7, CDK8 and CDK9) with their specific cyclins (A, Bl, B2, C, DI, D2, D3, E, F, Gl, G2, Η, I and K) and viral cyclin (see L. Mengtao in J. Virology 71 (3k 19841991 (1997)), and the other compounds of general formula (I) in which R1 is not hydrogen and is not a prodrug is a valuable intermediate for the preparation of the aforementioned compounds.

SUMMARY OF THE INVENTION

It is an object of the present invention to provide the above compounds of general formula (I) wherein the compounds wherein R1 represents a hydrogen atom or a prodrug exhibit valuable pharmacological properties, a medicament containing pharmacologically valuable compounds, their use and a method for their preparation.

In the above general formula (I)

X denotes an oxygen or sulfur atom,

Ri represents hydrogen or C b ₄ alkoxycarbonyl or C ₂ -4 alkanoyl group,

R ₂ is carboxy, C1 & apos ₄ -alkoxycarbonyl or aminocarbonyl group wherein the amino moiety may be substituted with one or two C _yz alkyl groups, the substituents can be identical or different,

R ₃ represents a phenyl or naphthyl group which is substituted by a fluorine, chlorine or bromine atom, a Ci_ ₃ alkyl, C _yz alkoxy, cyano, trifluoromethyl, nitro, amino, C _yz alkylamino, di- (C ₃ alkyl) amino, C ₂ . ₄ alkanoylamino, N- (C _1-3 alkyl) -C ₂ . ₄ alkanoylamino, NC _b3 alkyl) -C ₂ . ₄ alkanoylamino, Ci_ ₃ alkylsulfonylamino, amino-C1 & apos ₃ alkyl, C _yz alkylamino-C1 & apos ₃ alkyl, di- (C1. ₃ alkyl) amino-Cb ₃ alkyl, N- (C _{2. 4} alkanoyl) amino-C ₁ .z alkyl or N- (C ₂ -4 -alkanoyl) -C _yz alkylamino-C1. ₃ alkyl group, the substituents may be the same or different,

R ₄ represents a hydrogen atom or a C _1-3 alkyl group and R ₅ represents a hydrogen atom,

A C _1-5 alkyl group optionally substituted by a phenyl, carboxy or C 1-6 alkoxycarbonyl group,

C3-7 cycloalkyl optionally substituted with C _b h alkyl group, indanyl group, optionally substituted with Cl alkyl group,

A 5-atom heteroaryl group containing an imino group optionally substituted with a C1-3 alkyl group, an oxygen or sulfur atom, or an imino group optionally substituted with a C1.3 alkyl group and an oxygen, sulfur or nitrogen atom or two nitrogen atoms, or 6 -atomic heteroaryl group containing 1-3 nitrogen atoms, wherein through two adjacent carbon atoms or through one carbon atom and one adjacent imino group, the above 5-atom and 6-atom heteroaryl groups may further form a 1,3-butadienylene bridge and the carbon chain of the above mono- and itsiklichni rings may be mono or disubstituted by fluorine, chlorine, bromine or iodine atom, a Ci. _{The 5} alkyl or cyano group and the substituents may be the same or different, linked by the carbon atom a pyrrolidinyl or piperidinyl group, each of which may be substituted by a C 1-3 alkyl group at the nitrogen atom, a phenyl group optionally disubstituted by fluorine, chlorine, bromine or iodine atom, a Ci_ ₅ alkyl, Ci_ ₃ alkoxy, carboxy, Ci_ ₃ alkoxycarbonyl, aminosulfonyl, nitro or cyano group, the substituents may be the same or different, a phenyl, pyridyl, pyrimidyl or thienyl group each of which may b December substituted by a trifluoromethoxy group, a fluorine, chlorine, bromine or iodine atom, a Ci alkoxy group which in the 2-or 3-position may be substituted with amino, C ^ h alkylamino, di- (C1 & apos ₃ alkyl) amino , phenyl-C h alkylamino, N- (Ci_ ₃ alkyl) phenyl-C1 & apos ₃ -alkylamino, pyrrolidino or piperidino, phenyl-CF alkylamino-Ci alkyl group which may be mono- or disubstituted in the phenyl nucleus by a trifluoromethyl group , with a fluorine, chlorine, bromine or iodine atom, with C1. ₅ alkyl or Ci. ₃ alkoxy group, the substituents may be the same or different, and additionally, the amino nitrogen atom with a C _1-3 alkyl group, in which the hydrogen atoms in the second place may be completely or partially substituted by fluorine atoms, with C 1. ₅ alkyl, phenyl, imidazolyl,

C3-7 cycloalkyl, lower alkoxy-lower alkoxy, phenyl-lower alkoxy, carboxy-Ci alkyl, C _b h alkoxycarbonyl-Cl h alkyl, carboxy, C1-s alkoxycarbonyl, aminocarbonyl, Ci_ ₃ alkylaminocarbonyl, di- (C 1-3 alkyl) aminocarbonyl, phenylC 1-3 alkylaminocarbonyl, N- (C _1-3 alkyl) phenyl-C 3-3 alkylaminocarbonyl, piperazinecarbonyl, N- (C _1-3 alkyl) piperazinecarbonyl, nitro, 3-amino, C _1-3 amino, C _1-3 alkyl, C _1-3 alkyl (C 1-3 alkyl) amino, pyrrolidino, piperidino, morpholino, C ₂ . ₄ alkanoylamino, N- (C _1-3 alkyl) -C ₂ . ₄ alkanoylamino, benzoylamino or N- (Ci_3 alkyl) benzoilaminogrupa, c N- (Ci_ ₃ alkyl) -C ₂ -4 alkanoilaminogrupa, which alkyl moiety is further substituted with carboxy or Ci_ ₃ alkoxycarbonyl group, a Ci alkylaminocarbonyl or di- ( A C _1-3 alkyl) aminocarbonyl group in which the alkyl moiety is further substituted by a di- (C _1-3 alkyl) amino group or by N- (C _1-3 alkyl) -C 1. ₃ alkylsulfonylamino or N (C1. ₃ alkyl) fenilsulfonilaminogrupa in which the alkyl moiety may additionally be substituted by cyano, carboxy, C _yz alkoxycarbonyl, _yz alkylamino, di- (C1 & apos ₃ alkyl) amino, aminocarbonyl, Ci_ ₃ alkylaminocarbonyl, di - (C _1-3 alkyl) aminocarbonyl, piperidinocarbonyl, or 2- [di (C _1-3 alkylamino)] ethylaminocarbonyl group, phenyl or thienyl group substituted with C 1. ₃ alkyl group, the alkyl moiety being substituted by hydroxy, C 1-3 alkoxy, carboxy, C _1-3 alkoxycarbonyl, amino, C 1-5 alkylamino, di- (C _1-5 alkyl) amino, C ₂ . ₄ alkanoylamino, N- (C 1-3 alkyl) -C ₂ . ₄ alkanoylamino, pyrrolidino, dehidropirolidino, piperidino, dehidropiperidino, 3-hydroxypiperidino, 4hydroxypiperidin, hexamethyleneimino, morpholino, thiomorpholino, piperazino, 4- (0 ^ 3 alkyl) piperazino, 4fenilpiperazino, 4- (C _{2. 4} alkanoyl) piperazino or 4benzoilpiperazino an imidazolyl group, wherein the above saturated cycloalkyleneimino _ring , C _1-5 alkylamino or di- (C _1-5 alkyl) amino groups may be further substituted by one or two C _1-5 alkyl groups, with C 3-7 cycloalkyl, hydroxy, C 1-3. ₃ alkoxy, carboxy, Ci. ₃ alkoxycarbonyl, aminocarbonyl, Ci_ ₃ alkylaminocarbonyl or di (C1. ₃ alkylaminocarbonyl, phenyl-C1 & apos ₃ alkyl or a phenyl group optionally mono- or disubstituted in the phenyl nucleus by a fluorine, chlorine, bromine or iodine atom, by a C _yz alkyl or cyano group, the substituents may be the same or different, or one of the nitrogen-adjacent methylene groups in the above cycloalkylene ring may be substituted by a carbonyl or sulfonyl group, and the above monosubstituted phenyl groups may be optionally substituted enes with fluorine, chlorine, bromine or iodine atom, methyl, amino, Ci. ₃ alkylamino or di (C ₃ alkyl) amino group, or the above unsubstituted tsikloalkilennminoprasten may be annelated by two adjacent carbon atoms to a phenyl ring, optionally substituted with one or two Ci_ ₃ alkoxy groups.

The above moieties which, by definition, denote a carboxy group may also be substituted by a group which in vivo is converted to a carboxy group, as well as the above moieties which by definition denote an amino and an amino group, may also be substituted by an in vivo leaving moiety.

In addition, the definition of the above saturated alkyl and alkoxy moieties having more than 2 carbon atoms also includes their branched isomer such as isopropyl, t-butyl, isobutyl and the like.

Preferred compounds of formula (I) are those in which X represents an oxygen or sulfur atom,

R 1 represents a hydrogen atom, C 1. ₄ alkoxycarbonyl or C ₂ . ₄ alkanoyl group,

R ₂ denotes a carboxy, C _1-4 alkoxycarbonyl or aminocarbonyl group which in 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 represents a phenyl or naphthyl group which may be substituted by a fluorine, chlorine or bromine atom, by a C _yz alkyl, Ci_ ₃ alkoxy, cyano, trifluoromethyl, nitro, amino, C _yz alkylamino, di- (C1 & apos ₃ alkyl) amino , C ₂ . ₄ alkanoylamino, N- ( _C3-3 alkyl) -C ₂ . ₄ alkanoylamino, N- (Cb ₃ alkyl) -C ₂ . ₄ alkanoylamino, Cj. ₃ alkylsulfonylamino, amino-C _1-3 alkyl, Ci. ₃ -alkylamino-C _yz alkyl, di- (C1 & apos ₃ alkyl) amino-C1 & apos ₃ alkyl, N- (C _{2. 4} alkanoyl) amino, C] _ ₃ alkyl or N- (C _{2. 4} alkanoyl) -Sy ₃ alkylamino -C1. ₃ alkyl group, and the substituents may be the same or different,

R ₄ represents hydrogen or a C _1-3 alkyl group and

R ₅ represents hydrogen,

With _b5 alkyl group optionally substituted by a phenyl, carboxy or Cb ₃ alkoxycarbonyl group,

C ₃ _ ₇ cycloalkyl group optionally substituted by Ci_ ₃ alkyl group, indanyl group optionally substituted by a _yz alkyl group, a five-membered heteroaryl group contains an imino group optionally substituted by a C _yz alkyl group oxygen or sulfur atom , or an amino group substituted with a C _1-3 alkyl group and an oxygen, sulfur and nitrogen atom or two nitrogen atoms, or a six-atom heteroaryl group containing 1 to 3 nitrogen atoms, through two adjacent carbon atoms, or through one carbon atom and one adjacent one imino group, horn they 5atomni and 6-membered heteroaryl groups additionally can form 1,3-butadienilenov bridge and the carbon chain of the above mono- and bicyclic rings may optionally be mono- or disubstituted by fluorine, chlorine, bromine or iodine atom, with Cb ₅ alkyl, or a cyano group, linked through a carbon atom a pyrrolidinyl or piperidinyl group, each of which may be substituted with S1_z alkyl group, a phenyl group disubstituted by fluorine, chlorine, bromine or iodine atom, by a C _b5 alkyl or cyano group, the substituents may be the same or once PERSONAL, phenyl, pilidilova, pyrimidyl or thienyl group each of which may be substituted by a C 3-7 cycloalkyl group, C _b h alkoxy, phenyl-C1. ₃ alkoxy, carboxy-Cl h alkyl, C _b h alkoxycarbonyl-C1 & apos ₃ alkyl, carboxy, C h alkoxycarbonyl, aminocarbonyl, C1 & apos ₃ alkylaminocarbonyl, di-SSyz alkylaminocarbonyl, nitro, amino, Ci_ ₃ alkylamino, di (Ci alkyl ) amino, _2, 4 alkanoylamino, N- (Ci. ₃ alkyl) -C _{2. 4} alkanoylamino or N- (C _1-3 alkyl) -C ₂ . _{A 4} alkanoylamino group, with a C 1-3 alkylaminocarbonyl or di- (C _1-3 alkyl) aminocarbonyl group, which is further substituted in the alkyl portion with a di- (C _1-3 alkyl) amino group, or with N- (C _1-3 alkyl) -C ₃ alkyl alkylsulfonylamino sulfonylamino sulfonylamino; the alkyl moiety may additionally be substituted by cyano, carboxy, C _3-3 alkoxycarbonyl, C _1-3 alkylamino, di- (C _1-3 alkyl) amino, phenyl or thienyl group substituted by a C _1-3 alkyl group, the alkyl moiety being substituted by hydroxy , S1_z alkoxy, carboxy, C _b h alkoxycarbonyl, amino, C1-5 alkylamino, di- (C1. ₅ lkil) amino, C _{2. 4} alkanoylamino, N- (C 3-3 alkyl) -C ₂ . ₄ alkanoylamino, pyrrolidino, piperidino, hexamethyleneimino, morpholino, piperazino, 4- (Ci_ ₃ alkyl) piperazino, 4- (C _{2. 4} alkanoyl) piperazino, 4-benzoylpiperazin or imidazolyl group, wherein the above saturated cycloalkyleneimino, C _b5 alkylamino or di- (C1 & apos ₅ alkyl) amino groups may be further substituted with one or two C 1-5 alkyl groups, C _{3. 7} cycloalkyl, hydroxy, C _yz alkoxy, carboxy, C _yz alkoxycarbonyl, aminocarbonyl, C _yz alkylaminocarbonyl or di (C}. ₃ alkyl) aminocarbonyl, a phenyl group, optionally mono- or disubstituted in the phenyl nucleus by a fluorine, chlorine , bromine or iodine atom, with Ci. ₃ alkyl or cyano group, the substituents may be the same or different, or one of the nitrogen-adjacent methylene groups in the above cycloalkyleneimine ring may be substituted by a carbonyl or sulfonyl group, and the above monosubstituted phenyl groups may be further substituted by fluorine, or a bromine atom or a methyl group, especially those compounds of formula (I) in which

X stands for oxygen,

R 1 represents a hydrogen atom or C 1. ₄ alkoxycarbonyl group,

R ₂ is carboxy, Ci_ ₄ alkoxycarbonyl group or an aminocarbonyl group wherein the amino moiety is substituted with one or two C _yz alkyl groups and the substituents may be identical or different,

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

R ₄ represents a hydrogen atom or a methyl group and

R ₅ represents a hydrogen atom,

Ci_5 alkyl group or a benzyl group optionally substituted with carboxy or Ci_ ₃ alkoxycarbonyl group,

C ₃ . _{7 a} cycloalkyl group optionally substituted by a methyl group, indanyl, pyridyl, oxazolyl, thiazolyl or imidazolyl group optionally substituted by a methyl group, each of which, through two adjacent carbon atoms, may be fused to a phenyl ring, methylphenyl or methylphenyl group optionally substituted by a fluorine, chlorine or bromine atom with methoxy, carboxy, Ci. ₃ alkyloxycarbonyl, nitro or aminosulfonyl group bonded via a carbon atom to pyrrolidinyl or piperidinyl groups which at the nitrogen atom are replaced by a C _3-3 alkyl group, a phenyl group which is substituted by a trifluoromethoxy group, by fluorine, chlorine, bromoene, bromoene, bromoene with a C _1-3 alkoxy group which may be substituted at the 2 or 3 position by an amino, C _1-3 alkylamino, di- (C). ₃ alkyl) amino, phenyl-C _1-3 alkylamino, N- (C _1-3 alkyl) -phenyl-C _1-3 alkylamino, pyrrolidino or piperidino group, with a phenyl-C ₃ alkylamino-C ₃ alkyl group which at the phenyl nucleus may be substituted by fluorine, chlorine, bromine or iodine atom, a Ci_ ₅ alkyl or Ci. ₃ alkoxy group or trifluoromethyl group, and further, the amino nitrogen with C1 & apos ₃ alkyl group in which the hydrogen atom of the second site may be fully or partially substituted by fluorine atom, a C1-5 alkyl, phenyl, imidazolyl,

C ₃ . ₇ cycloalkyl, _C3-3 alkoxy-C1. ₃ alkoxy, phenyl-C1 & apos ₃ alkoxy, carboxy-C1. ₃ alkyl, C _yz alkoxycarbonyl-C1. ₃ alkyl, carboxy, C _yz alkoxycarbonyl, aminocarbonyl, C ₃ alkylaminocarbonyl, di- (C1. ₃ alkylaminocarbonyl, fenilS1. ₃ alkylaminocarbonyl, N- (Ci. ₃ alkyl) fenilS1. ₃ alkylaminocarbonyl, piperazinokarbonilna, N- (Ci_ ₃ alkyl) piperazinokarbonilna, nitro, amino, Ci. ₃ alkylamino, di (C1 & apos ₃ alkyl) amino, pyrrolidino, piperidino, morpholino, C _{2. 4} alkanoylamino, N- (Ci. ₃ alkyl) -C _{2. 4} alkanoylamino, benzoylamino or N- (Ci. ₃ alkyl) benzoilaminogrupa with N- (Ci_ ₃ alkyl) -C _{2. 4} alkanoilaminogrupa, which alkyl moiety is further substituted by carboxy or alkoxy _yz an iCarbonyl group, with a C _1-3 alkylaminocarbonyl or di- (C _1-3 alkylaminocarbonyl group, in which the alkyl moiety is further substituted with a di- (C _1-3 alkyl) amino group or with N- (C _1-3 alkyl) -C 1-10 ₃ alkylsulfonylamino or N (C1. ₃ alkyl) fenilsulfonilaminogrupa in which the alkyl moiety may additionally be substituted by cyano, carboxy, C ₃ alkoxycarbonyl, Ci. ₃ alkylamino, di- (C1. ₃ alkyl) amino, aminocarbonyl, alkylaminocarbonyl C _yz , di- (C _1-3 alkyl) aminocarbonyl, piperidinocarbonyl, or 2- [di (C _1-3 alkylamino)] ethylaminocarbonyl group, phenyl group and optionally substituted with Ci_ ₃ alkyl group in which the alkyl moiety is substituted by hydroxy, C _yz alkoxy, carboxy, C _yz alkoxycarbonyl, amino, C ₅ alkylamino, di- (C ₅₎ amino, C _{2. 4} alkanoylamino, N- (C _1-3 alkyl) C ₂ . ₄ alkanoylamino, pyrrolidino, dehidropirolidino, piperidino, dehidropiperidino, 3-hydroxypiperidino, 412 hydroxypiperidino, hexamethyleneimino, morpholino, thiomorpholino, piperazino, 4- (Ci_ ₃ alkyl) piperazino, 4fenilpiperazino, 4- (C ₂ -4 alkanoyl) piperazino or 4benzoilpiperazino imidazolyl group, wherein the above saturated cycloalkyleneimino, C1-5 alkylamino or di- (C1. ₅ alkyl) amino groups may be further substituted with one or two C _b5 alkyl groups, with C _{3. 7} cycloalkyl, hydroxy, C _1-3 alkoxy, carboxy, C 1. ₃ alkoxycarbonyl, aminocarbonyl, C _1-3 alkylaminocarbonyl or di- (C _1-3 alkyl) aminocarbonyl group, with a phenyl-C _1-3 alkyl or phenyl group, optionally mono- or disubstituted in the phenyl nucleus with fluorine, chlorine, bromine with Ci_ ₃ alkyl or cyano group, the substituents may be the same or different, or one of the neighboring nitrogen atom to methylene groups in the above cycloalkyleneimino may be substituted with a carbonyl or sulfonyl group, and the above monosubstituted phenyl groups may additionally be amesteni with fluorine, chlorine, bromine or iodine atom, methyl, amino, C _yz alkylamino or di- (C1 & apos ₃ alkyl) amino group, or the above unsubstituted cycloalkyleneimino may be annelated via two adjacent carbon atoms to a phenyl praset, optionally substituted with one or two C _yz alkoxy, isomers thereof and salts thereof.

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

X stands for oxygen,

R 1 represents a hydrogen atom,

R ₂ denotes a carboxy, C _1-4 alkoxycarbonyl or aminocarbonyl group in which the amino moiety may be mono or substituted with a C _1-3 alkyl group and the substituents may be the same or different,

R ₃ means a phenyl group optionally substituted by a methyl group,

R ₄ represents a hydrogen atom or a methyl group and

R ₅ represents a hydrogen atom,

Ci_ ₃ alkyl or benzyl, substituted with carboxy or C ^ alkoxycarbonyl group, a methyl or ethyl group,

_C3 _7 cycloalkyl group substituted by a methyl group, an indanyl, pyridyl, oxazolyl, thiazolyl or imidazolyl group optionally substituted with a methyl group in which further through two adjacent carbon atoms may be fused phenyl ring, methylphenyl or dimethoxyphenyl group, optionally substituted by a fluorine, chlorine or bromine atom with methoxy, carboxy, Ci. ₃ alkyloxycarbonyl, nitro or aminosulfonyl group,

A 3-pyrrolidinyl group or a 4-piperidinyl group which, at the nitrogen atom, may be substituted by a C _3-3 alkyl group, a phenyl group which may be substituted by trifluoromethoxy, benzyloxy, cyano or nitro, by a fluorine, chlorine or bromine atom, with A C _1-3 alkoxy group, wherein the ethoxy and normpropoxy groups may be substituted by a dimethylamino, diethylamino, N-ethylmethylamino, N-benzylmethylamino or piperidino group, with a phenyl-C 1-3 alkylamino-C 3 alkyl group which may be substituted in the phenyl ring, chlorine, bromine or an iodine atom, with a methyl, methoxy or trifluoromethyl group and optionally at the amino nitrogen atom with a C 1-5 alkyl or 2,2,2-trifluoroethyl group, with a C 1-4 alkyl, phenyl, imidazolyl, cyclohexyl, methoxymethyl, carboxymethyl, C _1-3 alkoxy, carboxymethyl, C 1-3 alkoxycarbonyl zalkoksikarbonilna, aminocarbonyl, Ci_ ₃ alkylaminocarbonyl, di- (C1. ₃ alkyl) aminocarbonyl, phenyl-C]. ₃ alkylaminocarbonyl, N- (C _1-3 alkyl) phenyl-C ₁ . ₃ alkylaminocarbonyl, piperazinocarbonyl, N- (C _1-3 alkyl) piperazinecarbonyl, amino, C 1-3 alkylamino, di- (C _1-3 alkyl) amino, pyrrolidium, piperidine, morpholine, C ₂ . ₄ alkanoylamino, N- (Ci- ₃ alkyl) C ₂ .4 alkanoylamino, benzoylamino or N- (Cx.3 alkyl) benzoilaminogrupa with N- (Ci- ₃ alkyl) -C _{2. A 4} alkanoylamino group, which in the alkyl moiety is further substituted by a carboxy or C _1-3 alkoxycarbonyl group, with a C 1-3 alkylaminocarbonyl or di- (C _1-3 alkylaminocarbonyl group, the alkyl portion of which is further substituted by di- (C _1-3 alkyl) or amino or C _1-3 alkyl or amino; N- (C 1-3 alkyl) -C 1-3 alkylsulfonylamino or N (C 1-3 alkyl) phenylsulfonylamino group, in which the alkyl moiety may be further substituted by cyano, carboxy, C _1-3 alkoxycarbonyl, C _1-3 alkylamino, di- (C _1-3 alkynyl) di (C1-3alkyl) amino. , C 1-3 alkylaminocarbonyl, di- (C _1-3 alkylaminocarbonyl CO-, piperidinocarbonyl or 2- [di- (C1. ₃ alkylamino)] etilaminokarbonilna group, a phenyl group optionally substituted by _d _ ₃ alkyl in which the alkyl group may be substituted by hydroxy, Ci_ ₃ alkoxy, carboxy, Sh_ ₃ alkoxycarbonyl, amino, C1-5 alkylamino, di- (C1 & apos ₅ alkyl) amino, C ₂ -4 alkanoylamino, N- (Ci_ ₃ alkyl) -C ₂ .4 alkanoylamino, pyrrolidino, dehidropirolidino, piperidino, dehidropiperidino, 4hydroxypiperidin, hexamethyleneimino, morpholino, thiomorpholino, piperazino, 4- (C _yz alkyl) piperazino, 4fenilpiperazino, 4- (C _{2. 4} alkanoyl) piperazino, 4benzoylpiperazino or imidazolyl group, wherein the above saturated cycloalkyleneimino ring may be further substituted by a phenyl group or by one or two methyl groups, the above C 1-5 alkylamino or di (C _1-5 alkyl) amino groups may additionally be substituted with one or two C1 & apos ₃ alkyl groups, cyclohexyl, hydroxy, C ₃ alkoxy, carboxy, C _yz alkoxycarbonyl, aminocarbonyl, C _yz alkylaminocarbonyl or di (C1. ₃ alkyl) aminocarbonyl, phenyl-Cb ₃ alkyl or phenyl group , optionally for ester in the phenyl nucleus with a fluorine, chlorine, bromine or iodine atom, with a methyl or cyano group, one of the nitrogen-adjacent methylene groups in the above cycloalkyleneimine ring may be substituted by a carbonyl or sulfonyl group, and the above monosubstituted phenyl groups may be substituted phenyl a fluorine, chlorine, bromine or iodine atom, methyl, amino, C1 & apos ₃ alkylamino or di (C _yz alkyl) amino group, or

the above unsubstituted cycloalkyleneimine ring may be co-condensed through two adjacent carbon atoms with a phenyl ring, optionally substituted by one or two Ci. ₃ alkoxyl groups;

their isomers and their salts.

Most preferred compounds of formula (I) are those wherein

X stands for oxygen,

R 1 represents a hydrogen atom,

R ₂ means a carboxy 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 means a phenyl group optionally substituted by a methyl group,

R ₄ represents a hydrogen atom and

Rs means a hydrogen atom,

A 3-pyrrolidinyl or 4-piperidinyl group which at the nitrogen atom is substituted by a C _1-3 alkyl group, a phenyl group which may be substituted by C 1-3. ₃ alkoxy group, wherein the ethoxy and normpropoksigrupata may be substituted with dimethylamino, diethylamino, N-ethylmethylamino, N-benzylmethylamino or piperidino, phenyl-C1 & apos ₃ alkylamino-C1 & apos ₃ alkyl group in the phenyl ring may be substituted with fluorine, chlorine, bromine or iodine atom, with a methyl, methoxy or trifluoromethyl group and can be further substituted at the amino nitrogen by Cj. _{A 3} alkyl or 2,2,2trifluoroethyl group, a phenyl group optionally substituted by Cj. ₃ alkyl group in which the alkyl group is substituted by hydroxy, C 1-3 alkoxy, carboxy, C _1-3 alkoxycarbonyl, amino, C _1-5 alkylamino, di- (C _1-5 alkyl) amino, C ₂ . ₄ alkanoylamino, N- (C _1-3 alkyl) -C ₂ . ₄ alkanoylamino, pyrrolidino, dehidropirolidino, piperidino, dehidropiperidino, 4-hydroxypiperidino, hexamethyleneimino, morpholino, thiomorpholino, piperazino, 4 (C 1_z alkyl) piperazino, 4-phenylpiperazino, 4- (C _{2. 4} alkanoyl) piperazino, 4-benzoylpiperazin or an imidazolyl group, wherein the above saturated cycloalkyleneimino ring may additionally be substituted by a phenyl group or by one or two methyl groups, the above C 1-5 alkylamino or di- (C _1-5 alkyl) amino groups may additionally be substituted by one or two C 1-6 alkyl groups , with cycloch eksilova, hydroxy, Ci_ ₃ alkoxy, carboxy, Ci alkoxycarbonyl, aminocarbonyl, Ci_ ₃ alkylaminocarbonyl or di (C _b h alkylaminocarbonyl group, a phenyl-Ci alkyl or a phenyl group optionally substituted in the phenyl nucleus by a fluorine, chlorine, bromine or an iodine atom, with a methyl or cyano group, one of the nitrogen-adjacent methylene groups in the above cycloalkyleneimine ring may be substituted with a carbonyl or sulfonyl group, and the above monosubstituted phenyl groups may be further substituted with fluorine, chlorine, Ommen or iodine atom, methyl, amino, Ci alkylamino or di- (C1 & apos ₃ alkyl) amino group, or the above unsubstituted cycloalkyleneimino may be annelated via two adjacent carbon atoms to a phenyl ring, optionally substituted with one or two C _ILI alkoxy, their isomers and their salts.

Particularly preferred are the aforementioned compounds wherein the residue R ₂ is in the 5th position, in particular the following compounds:

(a) 3-7- [1- (4-Aminomethyl-phenylamino) -1-phenylmethylene] -5-amido-2-indolinone, (b) 3- {1- [1-Phenylamino) -1-phenylmethylene] -5-amido- 2-indolinone, (c) 3-7- [1- (4-Bromophenylamino) -1-phenylmethylene] -5amido-2-indolinone, (d) 3-2- [1- (4-Dimethylaminomethyl) phenylamino-1-phenylmethylene] -5 -amido-2-indolinone, (e) 3-N- [1- (4-Pyrrolidinomethyl-phenylamino) -1-phenylmethylene] -5-amido-2-indolinone, (f) 3-7- [1- (4 -Piperidinomethyl-phenylamino) -1-phenylmethylene] -5-amido-2-indolinone, (g) 3-Z- [1- (4-Hexamethyleneiminomethyl-phenylamino) -1-phenylmethylene] -5-amido-2-indolinone, ( h) 3- [1- (4- (4-Benzylpiperidino) methylphenylamino) -

1-phenyl methylene] -5-amido-2-indolinone, (i) 3-Z- [1- (4- (N-butylaminomethyl) phenylamino) -1phenylmethylene] -5-amido-2-indolinone, (j) 3- N - [1- (4- (N- (Phenylmethyl) aminomethyl) phenylamino) -1-phenylmethylene) -5-amido-2-indolinone, (k) 3 - [1- (4- (M-Methyl) -N- [benzylaminomethyl) -phenylamino) -1-phenylmethylene] -5-amido-2-indolinone, (1) 3 '- [1- (4-Piperidinomethyl-phenylamino) -1-phenylmethylene] -5-dimethylcarbamoyl-2-indolinone , (m) 3-7- [1- (4-Piperidinomethyl-phenylamino) -1-phenylmethylene] -5-diethylcarbamoyl-2-indolinone, (η) 3-7- [1- (4- (3-Diethylaminopropoxy) -phenylamino] ) -1-phenylmethylene] -5-amido-2-indolinone, and salts thereof.

According to the invention, the new compounds are prepared, for example, according to the following generally known methods in the literature:

a) reacting a compound of the general formula

(N) in which

X, R ₂ and R ₃ have the above meanings,

R ₆ represents a hydrogen atom, a nitrogen atom protecting group on the lactam group or a solid phase bond, and

Z1 means a halogen atom, a hydroxy, alkoxy or aralkoxy group, for example a chlorine or bromine atom, methoxy, ethoxy or benzyloxy group, with an amine of the general formula (III) in which

R ₄ and R ₅ have the above meanings and, if necessary, subsequent cleavage of the protecting group used for the nitrogen atom of the lactam group or the solid phase.

The acetyl, benzoyl, ethoxycarbonyl, tert-butyloxycarbonyl or benzyloxycarbonyl groups are considered as the protecting group for the nitrogen atom of the lactam group and the Rink or Sieber resin is meant as a solid.

The reaction is conveniently carried out in a solvent such as dimethylformamide, toluene, acetonitrile, tetrahydrofuran, dimethylsulfoxide, methylene chloride or mixtures thereof, optionally in the presence of an inert base such as triethylamine, N-ethyldiisopropylamine, or sodium hydrocarbonate, or sodium hydrogenate, a protecting group as a result of this reamidation can be separated simultaneously.

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

When Z 1 represents a hydroxy, alkoxy or aralkoxy group in one compound, then the reaction is preferably carried out at a temperature between 20 and 200 ° C.

If necessary, subsequent cleavage of a protecting group used is suitably carried out either hydrolytically in an aqueous or alcoholic solvent, for example methanol / water, ethanol / water, isopropanol / water, tetrahydrofuran / water, dioxane / water, dimethylformamide / water, methanol or ethanol in the presence of an alkaline base such as lithium hydroxide, sodium hydroxide or potassium hydroxide at temperatures between 0 and 100 ° C, preferably at temperatures between 10 and 50 ° C, or advantageously by reamidation with a primary or secondary organic base such as a moniker, methylamine, butylamine, dimethylamine or piperidine in a solvent such as methanol, ethanol, dimethylformamide and mixtures thereof in excess of the above amines at temperatures between 0 and 100 ° C, preferably at temperatures between 10 and 50 ° C.

The separation of the solid used is preferably carried out using trifluoroacetic acid and water in the presence of dialkyl sulfide such as dimethyl sulfide at temperatures between 0 and 35 ° C, preferably at room temperature.

B) To prepare a compound of general formula (I) which contains an aminoethyl group and X represents an oxygen atom:

a compound of the general formula is reduced

(Iv) in which

Ri to R ₄ have the above meanings, and

R ₇ has the meanings given to R ₅ initially, with the consideration that R ₅ contains a cyano group.

The reduction is preferably carried out by catalytic hydrogenation with hydrogen in the presence of catalysts such as palladium / charcoal or platinum in a solvent such as methanol, ethanol, acetic acid ethyl ester, dimethylformamide, dimethylformamide / acetone or glacial acetic acid, with the addition of acid as acid. at a temperature between 0 and 50 ° C, preferably at room temperature and under hydrogen pressure of 1 to 7 bar, preferably 3 to 5 bar.

When a compound of the invention of general formula (I) containing an alkoxycarbonyl group is obtained, it can be converted to the corresponding carboxy compound by hydrolysis, or a compound of general formula (I) containing an amino or alkylamino group may be converted to the corresponding a alkylamino or dialkylamino compound by reductive alkylation, or a compound of general formula (I) containing an amino or alkylamino group, can be converted to the corresponding acyl compound by acylation, or a compound of general formula (I), k which contains a carboxy group, can be converted to the corresponding ester or aminocarbonyl compound by esterification or amidation.

Subsequent hydrolysis is preferably carried out in an aqueous solvent, for example in water, isopropanol / water, tetrahydrofuran / water or dioxane / water, in the presence of an acid such as trifluoroacetic acid, hydrochloric acid or sulfuric acid, or in the presence of an alkaline base such as lithium hydroxide. sodium hydroxide or potassium hydroxide at temperatures between 0 and 100 ° C, preferably at temperatures between 10 and 50 ° C.

Subsequent reductive alkylation is preferably carried out in a suitable solvent such as methanol, methanol / water, methanol / water / ammonia, ethanol, ether, tetrahydrofuran, dioxane or dimethylformamide, optionally when acid is added as hydrochloric acid in the presence of catalytically activated hydrogen, for example in the presence of Raneykelel, platinum or palladium / carbon, or in the presence of metal hydrides such as sodium borohydride, lithium borohydride or lithium aluminum hydride, at a temperature between 0 and 100 ° C, preferably at temperatures between 20 and 80 ° C.

Subsequent alkylation is carried out with an alkylating agent such as alkyl halide or dialkyl sulfate such as methyl iodide, dimethyl sulfate or propyl bromide, preferably in a solvent such as methanol, ethanol, methylene chloride, tetrahydrofuran, toluene, dioxomorphine, such as triethylamine, Nethyldiisopropylamine or dimethylaminopyridine, preferably at a temperature between 20 ° C and the reflux temperature of the solvent used.

Subsequent acylation is preferably carried out in a solvent such as methylene chloride, diethyl ether, tetrahydrofuran, toluene, dioxane, acetonitrile, dimethylsulfoxide or dimethylformamide, optionally in the presence of an inorganic or tertiary organic base, preferably at a temperature between 20 ° C and at a temperature between 20 ° C and at a temperature between 20 ° C. of the solvent used. The acylation with the corresponding acid is preferably carried out in the presence of an anhydrous agent, for example in the presence of isobutyl ester of chloroformic acid, trimethyl orthocarbonic acid ester, 2,2-dimethoxypropane, tetramethoxysilane, thionyl chloride, trimethylchlorosilane, phosphorylphosphoryl, phosphoryltrichloride, '-dicyclohexylcarbodiimide, Ν, Ν'cyclohexylcarbodiimide L-hydroxysuccinimide, Ν, дици'dicyclohexylcarbodiimide / 1-hydroxybenzotriazole, 2- (1H-benzotriazol-1-yl) -1,1,3,3-tetramethyl,

2- (1H-benzotriazol-1-yl) -1,1,3,3-tetramethyluronium tetrafluoroborate / 1-hydroxy-benztriazole, Ν, кар'carbonyldiimidazole or triphenylphosphine / tetrachlorohydrocarbon and optionally when added on a base such as pyridorine 4-dimethylaminopyridine, N-methylmorpholine or triethylamine, suitably at temperatures between 0 and 100 ° C, and acylation with a corresponding reactive compound such as its anhydride, ester, imidazolid or halide, in the presence of a tertiary organic base such as triethylaminopropylamino, pyrimidine; -methylmorpholine at temperatures between 0 and 1 50 ° C, preferably at temperatures between 50 and 100 ° C.

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

In the above reaction, the available reactive groups such as carboxy, amino, alklamino or imino groups can optionally be protected by reacting with the usual protecting groups, which are cleaved after the reaction.

For example, as a protective residue for a carboxy group, trimethylsilyl, methyl, ethyl, tertbutyl, benzyl or tetrahydropyranyl groups are meant, and acetyl, trifluoroacetyl, benzoyl, ethnoxycarboxyl, ethnoxycarbonyloxycarbonyloxycarbonyloxycarbonyl a benzyl, methoxybenzyl or 2,4 dimethoxybenzyl group, and further to an amino group, a phthalyl group is meant.

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

The cleavage of a benzyl, methoxybenzoyl or benzyloxycarbonyl residue is carried out, for example, by hydrogenolysis, for example with hydrogen in the presence of catalysts such as palladium / carbon in a solvent such as methanol, ethanol, ethyl acetate, dimethylformamide, dimethylformamide / acetone, or glacial acetic acid. acid or glacial acetic acid at temperatures between ° C and 50 ° C, preferably at room temperature, and at a hydrogen pressure of 1 to 7 bar, preferably 3 to 5 bar.

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

The cleavage of the 2,4-dimethoxybenzyl residue can be 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 treatment with an acid such as trifluoroacetic acid or hydrochloric acid, optionally using a solvent such as methylene chloride, dioxane, ethyl acetate or ether.

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

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

Thus, the compounds of general formula (I), which are present as racemates, can be separated by known methods (see Allinger NL and Eliel EL in Topics in Stereochemistry, Vol. 6, Wiley Interscience, 1971) optical antipodes, and compounds of general formula (I) with at least 2 asymmetric carbon atoms, are separated on the basis of their physicochemical properties by known methods, for example by chromatography and / or fractional crystallization of their diastereomers, which although are formed in racemic form, then as mentioned above can be sectioned enantiomers.

Separation of the enantiomers is preferably carried out by column separation on chiral phases or by recrystallization from an optically active solvent or by reaction with an optically active substance which forms with the racemic compound a salt or derivative such as an ester or amide, in particular acids and their activated derivatives or alcohols and separation of the mixtures thus obtained into diastereomeric salts or derivatives, for example on the basis of their different solubilities, whereby from pure diastereomeric salts or derivatives can be released free antipodes by action with a suitable agent. Particularly used optically active acids are the D- and L-forms of tartaric acid, dibenzoyltartaric acid, di-o-tolyltartaric acid, malic acid, almond acid, camphorsulfonic acid, glutamic acid, N-acetylglutamic acid, aspartic acid, N-aspartic acid, N-aspartic acid or quinic acid. Optically active alcohol means, for example, (+) - or (-) - menthol and optically active acyl residue in amides, for example (+) - or - (-) - menthyloxycarbonyl residue

The compounds of formula (I) further prepared may be converted into their salts, especially for pharmaceutical use, into their physiologically acceptable salts with inorganic or organic acids. Salts include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, fumaric acid, succinic acid, lactic acid, citric acid, tartaric acid, maleic acid, or methanesulfonic acid.

In addition, the new compounds of formula (I) thus obtained may, if they contain a carboxy group, be subsequently optionally converted into their salts with inorganic or organic bases, especially for pharmaceutical use, into their physiologically tolerated salts. Basics include, for example, sodium hydroxide, potassium hydroxide, cyclohexylamine, ethanolamine, diethanolamine and triethanolamine.

Compounds of general formula (I) to (III) used as starting materials are partly known in the literature or can be prepared by methods known in the literature or described in the examples.

As mentioned in the beginning, the new compounds of formula (I) in which R1 represents a hydrogen atom or a prodrug residue exhibit valuable pharmacological properties, especially inhibitory effects on various kinases and cyclin / CPK complexes, on the proliferation of cultured human cells tumors, as well as after oral administration to tumor growth in nude mice that were 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 cyclin / CPK enzyme activity in vitro

High Five ™ insect cells (BTI-TN-5B1-4), which are infected with the high titer of recombinant Baculovirus, are used to produce active human cyclin / CDK holoenzymes. Using a Baculovirus vector that contains two promoters (a polyhedrin enhancer promoter, a P-10 enhancer promoter), GST-labeled cyclins (e.g., cyclin Di or cyclin D ₃ ) are expressed in the same cells with the corresponding β4-labeled CDK subunit (e.g. for CDK4 or

CDK6). The active holoenzyme was isolated by glutathione-Sepharose affinity chromatography. The recombinant GST-labeled pRB (aa 379-928) is produced in E. coli and purified by affinity chromatography on gruation-sepharose.

The substrates used for kinase assays are derived from specific kinases. Histone H1 (Sigma) is used as a substrate for cyclin E / CDK2, cyclin A / CDK2, cyclin B / CDK1, and for γ-cyclin / CDKb. GST-labeled pRB (aa 379-928) is used as a substrate for cyclin D1 / CDK4, cyclin D3 / CDK4, cyclin D1 / CDK6 and for cyclin D3 / CDK6.

Lysates of recombinant Baculovirus-infected insect cells or also of recombinant kinases (obtained from the lysates by purification) are incubated together with radiolabeled ATP in the presence of a suitable substrate with different concentrations of the inhibitor in 1% DMSO (dimethyl) dimethylsulfoxide solution for 45 min at 30 ° C. The substrate proteins with associated radioactivity were precipitated with 5% TCA (trichloroacetic acid) in hydrophobic PVDF multi-well microtiter plates (Milipore) or with 0.5% phosphoric acid solution of Watman P81 filters. After the addition of scintillation fluid, the radioactivity was measured in a Wallace 1450 Microbeta liquid scintillation counter. For each concentration of the substance, double measurements are made; The IC ₅₀ values for enzyme inhibition are calculated.

Test 2

Inhibition of proliferation of cultured human tumor cells

Cells from the leiomyosarcoma tumor cell line SK-UT-1B (obtained from the American Type Culture Collection (ATCC) were cultured in Minimum Essential Medium with non-essential amino acids (Gibco) supplemented with sodium pyruvate (1 mMol), glutamine (2 mMol ) and 10% bovine germ serum and collected in the log growth phase, then SK-UT-1B cells were transferred to Cytostar® multi-well plates (Amersham) at a density of 4000 cells per well and incubated overnight. cells were added different concentrations of the compounds (dissolved in DMSO; final concentration: <1%). After 48 h incubation, added was added to each well ¹⁴ C-thymidine (Amersham) and incubated for an additional 24 h. The amount of ¹⁴ Stimidine that was incorporated in the presence of the inhibitor in the tumor cells and represented the number of cells in the S-phase was measured in a Wallace 1450 Microbeta liquid scintillation counter. Calculate IC ₅₀ values for proliferation inhibition (= inhibition of incorporated ¹⁴ C-thymidine) by correction for background radiation. All measurements are performed twice.

Test 3

In vivo effects in tumor-infected nude mice

10 ^b cells [SK-UT-1B, or non-small cell lung tumor NCI-H460 (obtained from ATCC)] in a volume of 0.1 ml were injected subcutaneously into male and / or female nude mice (NMRI nu / nu; 25-35 g N = 10-20); alternatively small pieces of SK-UT1B- or MC1-H460-cell clusters are implanted subcutaneously. One to three weeks after injection, the kinase inhibitor is administered daily for 2 to 4 weeks, orally (via a throat probe).

Tumor size is measured three times a week with a digital caliper. The effect of the kinase inhibitor was determined by tumor growth as a percentage of inhibition compared to a placebo-treated control group.

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

Compound (Example #) Inhibition of proliferation of SK.UT-1B 1C ₅₀ [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

Based on their biological properties, the novel compounds of general formula (I), their isomers and their physiologically tolerated salts are suitable for the treatment of diseases characterized by excessive or abnormal cell proliferation.

Such diseases include (without claim to completeness): viral infections (eg HIV and Kaposi's sarcoma); inflammatory and autoimmune disorders (eg, colitis, arthritis, Alzheimer's disease, glomerulonephritis and wound healing); leukemia, lymphoma and solid tumors; skin diseases (eg psoriasis); joint diseases; cardiovascular disease (eg restenosis and hypertrophy). They are also useful as protection against proliferating cells (eg hair cells, small intestines, blood and Progenitor cells), against DNA damage from radiation, from UV treatment and / or cytostatic treatment.

The novel compounds may be used for the short or long-term treatment of the aforementioned diseases, also optionally in combination with other state-of-art compounds such as other cytostatics.

The dosage required to achieve this action is appropriate for intravenous administration of 0.1 to 30 mg / kg, preferably 0.3 to 10 mg / kg for oral administration of 0.1 to 100 mg / kg, preferably 0, 3 to 30 mg / kg, 1 to 4 times daily, respectively. For this purpose, the compounds of formula (I) obtained according to the invention may optionally be mixed in combination with other active substances together with one or more inert, conventional carriers and / or diluents, e.g. with corn starch, milk sugar, cane sugar, microcrystalline cellulose, magnesium stearate, polyvinylpyrrolidone, citric acid, tartaric acid, water, water / ethanol, water / glycerol, water / sorbitol, water / polyethylene glycol, propylene glycol, cetylcellularlylcarbonylcarbonyl substances such as solid fat or mixtures thereof, suitable for processing into conventional herbal preparations such as tablets, dragees, capsules, powders, suspensions, suppositories or as solutions for injection or infusion.

Examples of carrying out the invention

The following examples illustrate the invention in greater detail.

Example I

Methyl 1-acetyl-2-indolinone-5-carboxylate

10.5 g of methyl 2-indolinone-5-carboxylate (prepared analogously to Ogawa et al., Chem. Pharm. Bull., 36, 2253-2258 (30, 2253-2258) was stirred in 30 ml of acetanhydride for 4 hours at 140 ° C. 1988)). It is then allowed to cool, poured into ice water and the precipitate is filtered off with a Noch filter. The product was washed once more with water, then stirred in methylene chloride, dried over sodium sulfate and concentrated.

Yield: 11 g (86% of theory).

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

Example II

Methyl 1-acetyl-3- (1-ethoxy-1-phenyl methyl ene) -2-indolinone-5-carboxylate

11 g of methyl 1-acetyl-2-indolinone-5-carboxylate were stirred in 110 ml of acetanhydride and 30 ml of triethyl orthobenzoate for 2 h at 100 ° C. It is then evaporated on a rotary evaporator, the residue is washed with ether and filtered on a Noch filter.

Yield: 11.5 g (67% of theory).

Rf value: 0.55 (silica gel, methylene chloride / petroleum ether / ethyl acetate = 4: 5: 1).

Example III

28.0 g of Rink resin (MBHA-Harz, Firm Novobiochim) was swollen in 330 ml of dimethylformamide. 330 ml of 30% piperidine in dimethylformamide are then added and shaken for 7 minutes to allow the FMOC-protecting group to cleave. The resin was then washed several times with dimethylformamide. 7.3 g of 2-indolinone-5carboxylic acid, 5.6 g of hydroxybenzotriazole, 13.3 g of O (benzotriazol-1-yl) -N, N, N ', LH-tetramethyluronium tetrafluoroborate and 5.7 ml are then added. N-Util-diisopropylamine in 300 ml of dimethylformamide and shaken for 1 hour. The solution was filtered off with a filter and the resin was washed 5 times with 300 ml of dimethylformamide and three times with 300 ml of methylene chloride. For drying, purge nitrogen through the resin.

Yield: 28 g of loaded resin.

Example IV

With 15 ml of acetanhydride at 80 ° C, 5 g of the resin obtained according to Example III was stirred for 1 h. Then, 15 ml of triethyl orthobenzoate was added and shaken for another 3 hours at 110 ° C. The resin was then filtered off with a Noch filter and washed with dimethylformamide, methanol and finally with methylene chloride.

Yield: 7 g wet resin.

Example V

4- (Ethylaminomethyl) nitrobenzene

Dissolve 6 g of 4-nitrobenzyl bromide in 25 ml of ethanol, mix with 25 ml of a 10% ethanol solution of ethylamine and reflux for 2 h. The solution was then evaporated on a rotary evaporator, the residue was stirred in methylene chloride and washed with dilute sodium hydroxide. Finally, the organic phase was concentrated.

Yield: 2.3 g (46% of theory).

Rf value: 0.2 (silica gel; methylene chloride / methanol = 9: 1).

In the same way:

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

4- (M-Cyclohexylaminomethyl) nitrobenzene

4- (N-Isopropylaminomethyl) nitrobenzene

4- (N-Butylaminomethyl) nitrobenzene

4- (N-Methoxycarbonylmethylaminomethyl) nitrobenzene

4- (N- (Phenylmethyl) aminomethyl) nitrobenzene

4- (Pyrrolidinomethyl) nitrobenzene

4- (Morpholinomethyl) nitrobenzene

4- (Piperidinomethyl) nitrobenzene

4- (Hexamethyleneimino) nitrobenzene

4- (4-Hydroxypiperidinomethyl) nitrobenzene

4- (4-Methylpiperidinomethyl) nitrobenzene

4- (4-Ethylpiperidinomethyl) nitrobenzene

4- (4-Isopropylpiperidinomethyl) nitrobenzene

4- (4-Phenylpiperidinomethyl) nitrobenzene

4- (4-Benzylpiperidinomethyl) nitrobenzene

4- (4-Ethoxycarbonylpiperidinomethyl) nitrobenzene

4- (Dimethylaminomethyl) nitrobenzene

4- (Dipropylaminomethyl) nitrobenzene

4- (4-tert-Butoxycarbonylpiperazinomethyl) nitrobenzene

3- (Dimethylaminomethyl) nitrobenzene

4- (Diethylaminoethyl) nitrobenzene

4- (2-Morpholinylethyl) nitrobenzene

4- (2-Pyrrolidinylethyl) nitrobenzene

4- (2-Piperidinylethyl) nitrobenzene

4- (N-Ethyl-N-benzylaminomethyl) nitrobenzene

4- (N-Propyl-N-benzylaminomethyl) nitrobenzene

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

4- [N-Methyl-L1- (4-bromophenyl methyl) aminomethyl] nitrobenzene

4- [N-Methyl-L1- (3-chlorophenylmethyl) aminomethyl] nitrobenzene

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

4- [1-Methyl-N- (4-methoxyphenylmethyl) aminomethyl] nitrobenzene

4- [N-2,2,2-Trifluoroethyl-N- (phenylmethyl) aminomethyl] nitrobenzene

4- [L1-2,2,2-Trifluoroethyl-N- (4-chlorophenylmethyl) aminomethyl] nitrobenzene.

Example VI

4- (N-Ethyl-N-tert-butoxycarbonylaminomethyl) nitrobenzene

Dissolve 2.2 g of 4 (ethylaminomethyl) nitrobenzene in 50 ml of ethyl acetate and stir with 2.6 g of di-tert-butyl dicarbonate for 30 minutes at room temperature. The solution was then washed with water and evaporated.

Yield: 3.4 g.

Rf value 0.9 (silica gel, methylene chloride / methanol =

9: 1).

- 37 Similarly,

4- [N- (4-Chlorophenylmethyl) -N-tert-butoxycarbonylaminomethyl] nitrobenzene

4- (N-Cyclohexyl-N-tert-butoxycarbonylaminomethyl) nitrobenzene

4- (N-Isopropyl-N-tert-butoxycarbonylaminomethyl) nitrobenzene

4- (L1-Butyl-N-tert-butoxycarbonylaminomethyl) nitrobenzene

4- (N-Methoxycarbonylmethyl-N-tert-butoxycarbonylaminomethyl) nitrobenzene

4- [N- (Phenylmethyl) -L-tert-butoxycarbonylaminomethyl) nitrobenzene.

Example VII

4- (N-Ethyl-N-tert-butoxycarbonylaminomethyl) aniline Dissolve 6.4 g of 4- (N-βτΗΠ-Ν-τρβτ-butoxycarbonylaminomethyl) nitrobenzene in 60 ml of methanol and hydrogenate with 1.5 g of Raneylicel at room temperature and 3 bar. The catalyst was then filtered and the solution was evaporated.

Yield: 4.78 g.

Rf value: 0.7 (silica gel, methylene chloride / methanol 50: 1).

Similarly, we obtain:

4- [N- (4-chlorophenyl) -N-tertbutoxycarbonylaminomethyl] aniline

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

4- (N-Isopropyl -? - tert-butoxycarbonylaminomethyl) aniline

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

4- (b1-Methoxycarbonylmethyl-L1-tert-butoxycarbonylaminomethyl) aniline

4- [N- (Phenylmethyl) -N-tert-butoxycarbonylamino methyl] aniline

4- (Pyrrolidinomethyl) aniline

4- (Morpholinomethyl) aniline

4- (Piperidinomethyl) aniline

4- (Hexamethyleneiminomethyl) aniline

4- (4-Hydroxypiperidinomethyl) aniline

4- (4-Methylpiperidinomethyl) aniline

4- (4-Ethylpiperidinomethyl) aniline

4- (4-Isopropylpiperidinomethyl) aniline

4- (4-Phenylpiperidinomethyl) aniline

4- (4-Benzylpiperidinomethyl) aniline

4- (4-Ethoxycarbonylpiperidinomethyl) aniline

4- (2-Morpholinylethyl) aniline

4- (2-Pyrrolidinylethyl) aniline

4- (2-Piperidinylethyl) aniline

4- (N-Ethyl-N-benzylaminomethyl) aniline

4- (N-Propyl-N-benzylaminomethyl) aniline

4- [N-Methyl-1 N- (4-chlorophenylmethyl) aminomethyl] aniline

4- [N-Methyl-L1- (4-bromophenylmethyl) aminomethyl] aniline

4- [N-Methyl-N- (3-chlorophenylmethyl) aminomethyl] aniline

9: 1).

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

4- [N-Methyl-N- (4-methoxyphenylmethyl) aminomethyl] aniline

4- [N-2,2,2-Trifluoroethyl-N- (phenyl methyl) aminomethyl] aniline

4-P'1-2,2,2-Trifluoroethyl-N- (4-chlorophenylmethyl) aminomethyl] aniline.

Getting the finished products

Example 1

3-7- [1- (1-Methyl-piperidin-4-ylamino) -1-phenylmethylene] -2-indolinone-5-carboxylate methyl

Dissolve 11.5 g of methyl 1-acetyl-3- (1-ethoxy-1-phenylmethylene) -2-indolinone-5-carboxylate in 115 ml of methylene chloride and stir with 10.8 g of 4-amino-N-methylpiperidine for 5 h. Then 20 ml of methanol ammonia was added and left to stand overnight. The solution was evaporated and the residue was washed with ether.

Yield: 11.9 g (97% of theory).

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

C23H25N3O3

Mass Spectrum: m / z = 391 (M ⁺ ).

In the same way:

(1) Methyl 3- [1- (4- (piperidinomethyl) phenylamino) -

1-Phenylmethylene] -2-indolinone-5-carboxylate

Rf value: 0.4 (silica gel, methylene chloride / methanol =

C29H29N3O3

Mass Spectrum: m / z = 467 (M ⁺ ).

(2) Methyl 3-7- [1- (4- (N-phenylmethyl) -Methylaminomethyl) phenylamino) -1-phenylmethylene] -2-indolinone-5carboxylate

C ₃₂ H ₂₉ N ₃ O ₃

Mass Spectrum: m / z = 503 (M ⁺ ).

(3) Methyl 3-7- [1- (4- (dimethylaminomethyl) phenylamino) -1-phenylmethylene] -2-indolinone-5-carboxylate

C ₂ $ H ₂ 5N ₃ O ₃

Mass Spectrum: m / z = 427 (M ⁺ ).

(4) Methyl 3-7- [1- (3- (dimethylaminomethyl) phenyl amino) -1-phenyl methyl] -2-yn to linone-5-carboxylic acid

C ₂₆ H ₂₅ N ₃ O ₃

Mass Spectrum: m / z = 427 (M ⁺ ).

(5) Methyl 3-7- [1- (4-chlorophenylamino) -1phenylmethylene] -2-indolinone-5-carboxylate (6) Methyl 3-7- (1- (phenylamino-1-phenylmethylene) -2indolinone-5- carboxylate

Example 2

3-Z- [1- (1-Methylpiperidin-4-ylamino) -1 phenylmethylene] -2-indolinone-5-carboxylic acid

In 300 ml of methanol and 150 ml of 1N sodium hydroxide, 11.9 g of methyl 3-2- [1- (1-methylpiperidinyl-4-ylamino) -1-phenylmethylene] -2-indolinone- 5-carboxylate. It was then neutralized with 150 ml of 1N hydrochloric acid and concentrated to dryness. The residue was washed repeatedly with water and dried.

Yield: 86% of theory.

Rf value: 0.17 (silica gel, methylene chloride / methanol = 4: 1).

C22H23N3O3

Mass Spectrum: m / z = 377 (M ⁺ ).

Similarly, we obtain:

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

Rf value: 0.15 (silica gel, methylene chloride / methanol = 4: 1).

C28H27N3O3

Mass Spectrum: m / z = 453 (M ⁺ ).

(2) 3-7- [1- (4- (1H-Phenylmethyl-N-methylaminomethyl) phenylamino) -1-phenylmethylene] -2-indolinone-5-carboxylic acid

Rf value: 0.17 (silica gel, methylene chloride / methanol = 4: 1).

C31H27N3O3

Mass Spectrum: m / z = 489 (M ⁺ ).

(3) 3-2- [1- (4- (Dimethylaminomethyl) phenylamino) -1phenylmethylene] -2-indolinone-5-carboxylic acid

C25H23N3O3

Mass Spectrum: m / z = 413 (M ⁺ ).

(4) 3- [1- (3- (Dimethylaminomethyl) phenylamino) -1-phenylmethylene] -2-indolinone-5-carboxylic acid

C25H23N3O3

Mass Spectrum: m / z = 413 (M ⁺ ).

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

5-carboxylic acid.

Example 3

3-7- [1- (1-Methylpiperidin-4-ylamino) -1phenylmethylene] -5-dimethylcarbamoyl-2-indolinone

2 g of 3-7- [1- (1-methylpiperidin-4-ylamino) -1-phenylmethylene] -2-indolinone-5-carboxylic acid was heated with reflux for 5 hours with 5 ml of thionyl chloride. It was then evaporated on a rotary evaporator and the residue was washed with ether. Without further purification, 5 g of this acid chloride was stirred in 5 ml of methylene chloride and mixed with 0a5 ml of dimethylamine and 5 ml of methylene chloride and stirred at room temperature overnight. The product was chromatographed on a silica gel column with methylene chloride / methanol / ammonia (4: 1: 0.1).

Yield: 50% of theory.

Rf value: 0.14 (silica gel: methylene chloride / methanol = 9: 1).

C24H28N4O2

Mass Spectrum: m / z = 404 (M ⁺ ).

The following compounds are similarly prepared:

(1) 3-7- [1- (1-Methylpiperidin-4-ylamino) -1phenylmethylene] -5-methylcarbamoyl-2-indolinone

Yield: 49% of theory.

Rf value: 0.19 (silica gel: methylene chloride / methanol = 4: 1).

C23H26N4O2

Mass spectrum: m / z = 390 (M ⁺ ).

(2) 3-Z- [1- (1-Methylpiperidin-4-ylamino) -1phenylmethylene] -5-carbamoyl-2-indolinone

Yield: 58% of theory.

Rf value: 0.15 (silica gel: methylene chloride / methanol = 4: 1).

C22H24N4O2

Mass Spectrum: m / z = 376 (M ⁺ ).

(3) 3-Z- [1- (4-Piperidinomethylphenylamino) -1 phenylmethylene] -5-dimethylcarbamoyl-2-indolinone

Obtained from 3- [1- (4-piperidinomethylphenylamino) -1-phenylmethylene] -2-indolinone-5-carboxylic acid and dimethylamine, or 0.64 g of Z- [0034] is stirred at room temperature for 20 hours. 1- (4-piperidinomethylphenyl amino) -1-phenyl methylene] -2-indolinone-5carboxylic acid, 0.34 g dimethylaminohydrochloride, 0.9 g Obenzotriazol-1-yl-M, M, M ', LH-tetramethyluronium tetrafluoroborate) , 4 g of 1-hydroxy-1H-benztriazole and 2.9 g of diisopropylethylamine in 20 ml of dimethylformamide. It was then concentrated and the residue was suspended in water. The precipitate was filtered off with a Noch filter.

Yield: 600 mg (88% of theory).

Rf value: 0.2 (silica gel: methylene chloride / ethanol = 9: 1).

C30H32N4O2

Mass Spectrum: m / z = 481 (M + H) ⁺ .

(4) 3-N- [1- (4-Piperidinomethylphenylamino) -1phenylmethylene] -5-methylcarbamoyl-2-indolinone

Prepared from 3 - [1- (4-piperidinomethylphenylamino) -1-phenylmethylene] -2-indolinone-5-carboxylic acid and methylamine in analogy to Example 3 (3).

Rf value: 0.2 (silica gel: methylene chloride / ethanol = 9: 1).

C29H30N4O2

Mass Spectrum: m / z = 467 (M + H) ⁺ .

(5) 3-Z- [1- (4-Piperidinomethylphenylamino) -1phenylmethylene] -5-methylethylcarbamoyl-2-indolinone

Obtained from 3 - [1- (4-piperidinomethylphenylamino) -1-phenyl methylene] -2-indolinone-5-carboxylic acid and methylethylamine in analogy to Example 3 (3).

Rf value: 0.55 (silica gel: methylene chloride / ethanol = 9: 1).

C31H34N4O2

Mass Spectrum: m / z = 495 (M + H) ⁺ .

(6) 3-7- [1- (4-Piperidinomethylphenylamino) -1phenylmethylene] -5-propylcarbamoyl-2-indolinone

Prepared from 3-N- [1- (4-piperidinomethylphenylamino) -1-phenylmethylene] -2-indolinone-5-carboxylic acid and propylamine in analogy to Example 3 (3).

Rf value: 0.31 (silica gel: methylene chloride / ethanol = 9: 1).

C31H34N4O2

Mass Spectrum: m / z = 495 (M + H) ⁺ .

(7) 3-Z- [1- (4-Piperidinomethylphenylamino) -1phenylmethylene] -5-diethylcarbamoyl-2-indolinone

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

Rf value: 0.55 (silica gel: methylene chloride / ethanol =

9: 1).

C32H36N4O2

Mass Spectrum: m / z = 509 (M + H) ⁺ .

(S) 3- N - [1- (4- (N-Phenylmethyl-N-methylaminomethyl) -phenyl amino) -1-phenylmethylene] -5-methylcarbamoyl-2-indolinone (9) 3-Z- [1- (4) - (N-Phenylmethyl-N-methylaminomethyl) phenylamino) -1-phenylmethylene] -5-dimethylcarbamoyl-2-indolinone (10) 3 N - [1- (4- (N-Phenylmethyl-N-methylaminomethyl) -phenylamino) - 1-Phenylmethylene] -5-diethylcarbamoyl-2-indolinone (11) 3-2- [1- (4- (N-Phenylmethyl-N-methylaminomethyl) -phenylamino) -1-phenylmethylene] -5-propylcarbamoyl-2-indolinone (12) 3-Z- [1- (4- (N-Phenylmethyl-N-methylaminomethyl) phenylamino) -1-phenylmethylene] -5-dipropylcarbamoyl-2-indolinone (13) 3-N- [1- (4- (Dimethylaminomethyl) phenylamino) -1phenylmethyl n] -5-methylcarbamoyl-2-indolinone (14) 3-Z- [1- (4- (Dimethylaminomethyl) phenylamino) -1-phenylmethylene] -5-dimethylcarbamoyl-2-indolinone (15) 3 '- [1- (4- (Dimethylaminomethyl) phenylamino) -1-phenylmethylene] -5-diethylcarbamoyl-2-indolinone (16) 3-N- [1- (4- (Dimethylaminomethyl) phenylamino) -1-phenylmethylene] -5-propylcarbamoyl-2 -indolinone (17) 3- (1- (4- (Dimethylaminomethyl) phenylamino) -1-phenylmethylene) -5-dipropylcarbamoyl-2-indolinone (18) 3-Z- [1- (3- (Dimethylaminomethyl) phenylamino) ) -1-phenylmethylene] -5-methylcarbamoyl-2-indolinone (19) 3-Z- [1- (3- (Dimethylaminomethyl) phenylamino) -1-phenylmethylene] -5-dimethylcarbamoyl-2-indole (20) 3- (1- (3- (Dimethylaminomethyl) phenylamino) -1-phenylmethylene) -5-diethylcarbamoyl-2-indolinone (21) 3 '- [1- (3- (Dimethylaminomethyl) phenylamino) - 1-phenylmethylene] -5-propylcarbamoyl-2-indolinone (22) 3-Z- [1- (3- (D-methylaminomethyl) phenylamino) -1-phenylmethylene] -5-dipropylcarbamoyl-2-indolinone (23) 3 '- [1- (4-Chlorophenylamino) -1-phenylmethylene] -5methylcarbamoyl-2-indolinone (24) 3 N - [1- (4-Chlorophenylamino) -1-phenylmethylene] -5 dimethylcarbamoyl-2-indolinone (25) 3-d- [1 - (4-Chlorophenylamino) -1-phenylmethylene] -5-diethylcarbamoyl-2-indolinone (26) 3 N - [1- (4-Chlorophenylamino) -1-phenylmethylene] -5-propylcarbamoyl-2-indolinone (27) 3- N- [1- (4-Chlorophenylamino) -1-phenylmethylene] -5-dipropylcarbamoyl-2-indolinone (2S) 3-Z- (1-Phenylamino-1-phenylmethylene) -5methylcarbamoyl-2-indolinone (29) 3-N- (1-Phenylamino-1-phenylmethylene) -5-dimethylcarbamoyl-2-indolinone (30) 3-N- (1-Phenylamino-1-phenylmethylene) -5-diethylcarbamoyl-2-indolinone (31) 3-N- (1 -Phenylamino-1-phenylmethylene] -5-propylcarbamoyl-2-indolinone (32) 3-N- (1-Phenylamino-1-phenylmethylene) -5-dipropylcarbamoyl-2-indolinone

Example 4

3- [1- (4-Aminophenylamino) -1-phenylmethylene] -5-amido-

2-indolinone

Suspend 800 mg of the resin obtained according to Example IV in 4 ml of methylene chloride and shake 0.8 g of 1.447

9: 1).

phenylenediamine at room temperature for 16 h. Filter and wash the resin several times with methylene chloride, methanol and dimethylformamide. Subsequently, 3 ml of methanol ammonia was added over 2 hours to remove the acetylone group. Finally, after further washing with 4 ml of 10% trifluoroacetic acid in methylene chloride over a period of 90 minutes, the resin was separated and the solution concentrated. The residue was stirred with a little 1N sodium hydroxide and extracted with methylene chloride. The organic phase was dried over sodium sulfate and evaporated on a rotary evaporator.

Yield: 45 mg (30% of theory over all steps). Rf value: 0.26 (silica gel; methylene chloride / methanol = 9: 1).

C22H18N4O2

Mass Spectrum: m / z = 370 (M ⁺ ).

The following compounds are similarly prepared:

(1) 3-7- [1- (3-Aminophenylamino) -1-phenylmethylene] -5amido-2-indolinone

Yield: 24% of theory.

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

C22H18N4O2

Mass Spectrum: m / z = 370 (M ⁺ ).

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

Yield: 27% of theory.

Rf value: 0.53 (silica gel; methylene chloride / methanol =

C22H17N3O2

Mass Spectrum: m / z = 355 (M ⁺ ).

(3) 3-Z- [1- (4-Acetylaminophenylamino) -1phenylmethylene] -5-amido-2-indolinone

Yield: 28% of theory.

Rf value: 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- [1- (4-Acetyl-N-methylaminophenylamino) -1phenylmethylene] -5-amido-2-indolinone

Yield: 15% of theory.

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

C ₂ 5H ₂₂ N ₄ O ₃

Mass Spectrum: m / z = 426 (M ⁺ ).

(5) 3-Z- [1- (4- (2-Aminoethyl) phenylamino) -1phenylmethylene] -5-amido-2-indolinone

Yield: 30% of theory.

Rf value: 0.04 (silica gel; methylene chloride / methanol = 9: 1).

C ₂₄ H ₂₂ N ₄ O ₂

Mass Spectrum: m / z = 398 (M ⁺ ).

(6) N- [1- (4-Methoxyphenylamino) -1-phenylmethylene] -5amido-2-indolinone

Yield: 32% of theory.

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

C ₂₃ H ₁₉ N ₃ O ₃

Mass Spectrum: m / z = 385 (M ⁺ ).

(7) 3-2- [1- (4-Biphenylamino) -1-phenylmethylene] -5-amido-

2-indolinone

Yield: 22% of theory.

Rf value: 0.51 (silica gel; methylene chloride / methanol =

9: 1).

C28H21N3O2

Mass Spectrum: m / z = 431 (M ⁺ ).

(S) 3- [1- (3-Pyridylamino) -1-phenylmethylene] -5-amido-

2-indolinone

Yield: 35% of theory.

Rf value: 0.41 (silica gel; methylene chloride / methanol = 9: 1).

C21Hi6N ₄ C> 2

Mass Spectrum: m / z = 356 (M ⁺ ).

(9) 3-Z- [1- (4-Dimethylaminophenylamino) -1-phenylmethylene] -5-amido-2-indolinone

Yield: 19% of theory.

Rf value: 0.49 (silica gel; methylene chloride / methanol =

9: 1).

C24H22N4O2

Mass Spectrum: m / z = 398 (M ⁺ ).

(10) N - [1 ~ (4-Morpholinophenylamino) -1-phenylmethylene] -5-amido-2-indolinone

Yield: 42% of theory.

Rf value: 0.48 (silica gel; methylene chloride / methanol =

9: 1).

C26H24N4O3

Mass Spectrum: m / z = 440 (M ⁺ ).

(11) 3-Z- [1- (4-tert-Butylphenylamino) -1 phenylmethylene] -5-amido-2-indolinone

Yield: 32% of theory.

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

C26H25N3O2

Mass Spectrum: m / z = 411 (M ⁺ ).

(12) 3- [1- (2-Aminophenylamino) -1-phenylmethylene] -5amido-2-indolinone

Yield: 28% of theory.

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

C22H18N4O2

Mass Spectrum: m / z = 370 (M ⁺ ).

(13) 3- N - [1- (4-Benzyloxyphenylamino) -1phenylmethylene] -5-amido-2-indolinone

Yield: 40% of theory.

Rf value: 0.4 (silica gel; methylene chloride / methanol = • 9: 1).

C29H23N3O3

Mass Spectrum: m / z = 461 (M ⁺ ).

(14) 3-Z- [1- (4-Bromophenylamino) -1-phenylmethylene] -5amido-2-indolinone

Yield: 35% of theory.

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

Cr2H2r2R2O2

Mass Spectrum: m / z = 433/435 (M ⁺ ).

(15) 3-Z- [1- (4-Methoxycarbonylphenylamino) -1 phenylmethylene] -5-amido-2-indolinone

Yield: 34% of theory.

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

C24H19N3O4

Mass spectrum: m / z = 413 (M ⁺ ).

(16) 3-Z- [1- (3-Amidophenylamino) -1-phenylmethylene] -5amido-2-indolinone

Yield: 32% of theory.

Rf value: 0.32 (silica gel; methylene chloride / methanol = 9: 1).

C23H18N4O3

Mass spectrum: m / z = 398 (M ⁺ ).

(17) 3-N- [1- (3-Methylphenylamino) -1-phenylmethylene] -5amido-2-indolinone

Yield: 12% of theory.

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

C23H19N3O2

Mass spectrum: m / z = 369 (M ⁺ ).

(18) 3-Z-flu- (2-Methylphenylamino) -1-phenylmethylene] -5amido-2-indolinone

Yield: 21% of theory.

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

C23H19N3O2

Mass spectrum: m / z = 369 (M ⁺ ).

(19) 3-2- [1- (3-Methoxyphenylamino) -1-phenylmethylene] -5amido-2-indolinone

Rf value: 0.49 (silica gel; methylene chloride / methanol = 9: 1).

C23H19N3O3

Mass Spectrum: m / z = 385 (M ⁺ ).

(20) 3-Z- [1- (3-Ethoxycarbonylphenylamino) -1phenylmethylene] -5-amido-2-indolinone

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

C ₂₅ H ₂₁ N ₃ O ₄

Mass Spectrum: m / z = 427 (M ⁺ ).

(21) 3-2- [1- (3-Nitrophenylamino) -1-phenylmethylene] -5amido-2-indolinone

Yield: 32% of theory.

Rf value: 0.56 (silica gel; methylene chloride / methanol = 9: 1).

C22H16N4O4

Mass Spectrum: m / z = 400 (M ⁺ ).

(22) 3-2- [1- (4-Amidophenylamino) -1-phenylmethylene] -5amido-2-indolinone

Yield: 26% of theory.

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

C23H18N4O3

Mass Spectrum: m / z = 398 (M ⁺ ).

(23) 3- N - [1- (4-Pyridylamino) -1-phenylmethylene] -5-amido-2-indolinone

Yield: 15% of theory.

Rf value: 0.42 (silica gel; methylene chloride / methanol =

9: 1).

C21H16N4O2

Mass Spectrum: m / z = 356 (M ⁺ ).

(24) 3-7- [1- (4-Methylphenylamino) -1-phenylmethylene] -5amido-2-indolinone

Yield: 45% of theory.

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

C23H19N3O2

Mass Spectrum: m / z = 369 (M ⁺ ).

(25) 3-2- [1- (4-Ethoxyphenylamino) -1-phenylmethylene] -5amido-2-indolinone

Yield: 40% of theory.

Rf value: 0.51 (silica gel; methylene chloride / methanol = 9: 1).

C24H21N3O3

Mass Spectrum: m / z = 399 (M ⁺ ).

(26) N- [1- (3-Bromophenylamino) -1-phenylmethylene] -5amido-2-indolinone

Yield: 41% of theory.

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

^ 22Η16ΒγΝ ₃ Ο2

Mass Spectrum: m / z = 433/435 (M ⁺ ).

(27) 3-7- [1- (4-Chlorophenylamino) -1-phenylmethylene] -5amido-2-indolinone

Yield: 50% of theory.

Rf value: 0.49 (silica gel; methylene chloride / methanol =

9: 1).

C22H16CIN3O2

Mass Spectrum: m / z = 389/391 (M ⁺ ).

(28) 3- [1- (4-Isopropylphenylamino) -1-phenylmethylene] -

5-Amido-2-indolinone

Yield: 48% of theory.

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

C25H23N3O2

Mass Spectrum: m / z = 397 (M ⁺ ).

(29) 3- [1- (2-Fluorenylamino) -1-phenylmethylene] -5amido-2-indolinone

Yield: 43% of theory.

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

C29H21N3O2

Mass Spectrum: m / z = 443 (M ⁺ ).

(30) 3-2- [1- (4- (2-Hydroxyethyl) phenylamino) -1phenylmethylene] -5-amido-2-indolinone

Yield: 22% of theory.

Rf value: 0.37 (silica gel; methylene chloride / methanol = 9: 1).

C24H21N3O3

Mass Spectrum: m / z = 398 (MH).

(31) 3-N- [1- (4- (4-Imidazolyl) phenylamino) -1-phenylmethylene] -5-amido-2-indolinone

Yield: 23% of theory.

Rf value: 0.5 (silica gel; methyl enchloride / methanol =

9: 1).

C25H19N5O2

Mass Spectrum: m / z = 421 (M ⁺ ).

(32) 3-7- [1- (4-Ethoxycarbonylmethylphenylamino) -1phenylmethylene] -5-amido-2-indolinone

C ₂ 6H ₂₃ N ₃ O ₄

Mass Spectrum: m / z = 442 (M + H) ⁺ .

(33) N- [1- (4-Bromo-3-methylphenylamino) -1-phenylmethylene] -5-amido-2-indolinone

C ₂ 3Hi8BrN ₃ O ₂

Mass Spectrum: m / z = 447/449 (M ⁺ ).

(34) 3-Z- [1- (4-Cyclohexylphenylamino) -1-phenylmethylene] -5-amido-2-indolinone

C ₂ 8H ₂ 7N ₃ O ₂

Mass Spectrum: m / z = 437 (M ⁺ ).

(35) 3-N- [1- (4-Bromo-2-methylphenylamino) -1-phenylmethylene] -5-amido-2-indolinone

C ₂ 3Hi ₈ BrN ₃ O ₂

Mass Spectrum: m / z = 447/449 (M ⁺ ).

(36) 3- [1- [Amino-1-phenylmethylene] -5-amido-2-indolinone]

Rf value: 0.3 (silica gel; methylene chloride / methanol =

9: 1).

C ₁₆ H ₁₃ N ₃ O ₂

Mass Spectrum: m / z = 279 (M ⁺ ).

(37) 3-7- [1-Cyclohexylamino-1-phenylmethylene] -5-amido-2-indolinone

Rf value: 0.55 (silica gel; methylene chloride / methanol =

9: 1).

C22H23N3O2

Mass Spectrum: m / z = 361 (M ⁺ ).

(38) 3-7- [1-Cyclopentylamino-1-phenylmethylene] -5amido-2-indolinone

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

C21H21N3O2

Mass Spectrum: m / z = 347 (M ⁺ ).

(39) 3-7- [1-Methylamino-1-phenylmethylene] -5-amido-2-indolinone

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

C17H15N3O2

Mass Spectrum: m / z = 293 (M ⁺ ).

(40) 3-7- [1-Ethylamino-1-phenylmethylene] -5-amido-2-indolinone

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

C ^H ^NзOг

Mass Spectrum: m / z = 307 (M ⁺ ).

(41) 3-Z- [1-Isopropylamino-1-phenylmethylene] -5-amido2-indolinone

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

C19H19N3O2

Mass Spectrum: m / z = 321 (M ⁺ ).

(42) 3-D- [1-Dimethylamino-1-phenylmethylene] -5-amido-2-indolinone

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

C18H17N3O2

Mass Spectrum: m / z = 307 (M ⁺ ).

(43) 3-N- [1-Cyclopropylamino-1-phenylmethylene] -5-amido-2-indolinone

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

C19H17N3O2

Mass Spectrum: m / z = 319 (M ⁺ ).

(44) 3-7- [1-Cycloheptylamino-1-phenylmethylene] -5-amido-2-indolinone

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

C23H25N3O2

Mass Spectrum: m / z = 375 (M ⁺ ).

(45) 3-N- [1-Cyclobutylamino-1-phenylmethylene] -5-amido-2-indolinone

Rf value: 0.49 (silica gel; methylene chloride / methanol = 9: 1).

C20H19N3O2

Mass Spectrum: m / z = 333 (M ⁺ ).

(46) 3-Z- [1- (4-Methylcyclohexylamino) -1phenylmethylene] -5-amido-2-indolinone

Rf value: 0.67 (silica gel; methylene chloride / methanol =

9: 1).

C23H25N3O2

Mass Spectrum: m / z = 375 (M ⁺ ).

(47) 3-2- [1- (1- (R> 8) -Indanylamino-1-phenylmethylene] -5amido-2-indolinone

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

C25H21N3O2

Mass Spectrum: m / z = 395 (M ⁺ ).

(48) 3-2- [1- (Methoxycarbonylmethylamino) -1phenylmethylene] -5-amido-2-indolinone

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

C19H17N3O4

Mass Spectrum: m / z = 351 (M ⁺ ).

(49) 3-2- [1 - ((2-Methoxycarbonylethyl) amino) -1phenylmethylene] -5-amido-2-indolinone

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

C20H19N3O4

Mass Spectrum: m / z = 365 (M ⁺ ).

(50) 3-7- [1- (4-Aminomethylphenylamino-1-phenylmethylene] -5-amido-2-indolinone

Yield: 32% of theory.

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

C23H20N4O2

Mass Spectrum: m / z = 384 (M ⁺ ).

(51) 3-7- [1- (4-Pyrrolidinomethylphenylamino-1-phenylmethylene] -5-amido-2-indolinone

Yield 60% of theory.

Rf value: 0.07 (silica gel; methylene chloride / methanol = 9: 1).

C27H26N4O2

Mass Spectrum: m / z = 438 (M ⁺ ).

(52) N- [1- (4-Morpholinomethylphenylamino-1phenylmethylene) -5-amido-2-indolinone

Yield: 65% of theory

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

C27H26N4O3

Mass spectrum: m / z = 454 (M ⁺ ).

(53) 3-N- [1- (4-Piperidinomethylphenylamino) -1phenylmethylene] -5-amido-2-indolinone

Yield: 60% of theory

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

C28H28N4O2

Mass Spectrum: m / z = 452 (M ⁺ ).

(54) 3-Z- [1- (4-Hexamethylenediaminophenylamino-1phenylmethylene) -5-amido-2-indolinone

C29H30N4O2

Mass Spectrum: m / z = 466 (M ⁺ ).

(55) N - [1- (4- (4-Hydroxypiperidinomethyl) phenylamino) -1-phenylmethylene] -5-amido-2-indolinone

C28H28N4O3

Mass Spectrum: m / z = 468 (M ⁺ ).

(56) 3- [1- (4- (4-Methylpiperidinomethyl) phenylamino) -

-phenylmethylene] -5-amido-2-indolinone

C29H30N4O2

Mass Spectrum: m / z = 466 (M ⁺ ).

(57) 3-N- [1- (4- (4-Ethylpiperidinomethyl) phenylamino) -1phenylmethylene] -5-amido-2-indolinone

C30H32N4O2

Mass Spectrum: m / z = 480 (M ⁺ ).

(58) 3 - [1- (4- (4-Isopropylpiperidinomethyl) phenylamino) -1-phenylmethylene] -5-amido-2-indolinone

C31H34N4O2

Mass Spectrum: m / z = 494 (M ⁺ ).

(59) 3-Z- [1- (4- (4-Phenylpiperidinomethyl) phenylamino) -

1-phenylmethylene] -5-amido-2-indolinone

C34H32N4O2

Mass Spectrum: m / z = 528 (M ⁺ ).

(60) 3-Z- [1- (4- (4-Benzylpiperidinomethyl) phenylamino) -1-phenylmethylene] -5-amido-2-indolinone

C35H34N4O2

Mass Spectrum: m / z = 542 (M ⁺ ).

(61) 3- N - [1- (4- (4-Ethoxycarbonylpiperidinomethyl) phenylamino) -1-phenylmethylene] -5-amido-2-indolinone

C31H32N4O4

Mass Spectrum: m / z = 524 (M ⁺ ).

(62) 3- N - [1- (4-Dimethylaminomethylphenylamino) -1phenylmethylene] -5-amido-2-indolinone

C25H24N4O2

Mass Spectrum: m / z = 412 (M ⁺ ).

(63) 3-Z- [1- (4-Dipropylaminomethylphenylamino) -1 phenylmethylene] -5-amido-2-indolinone

C29H32N4O2

Mass Spectrum: m / z = 468 (M ⁺ ).

(64) 3 N - [1- (4-Piperazinylmethylphenylamino-1-phenylmethylene] -5-amido-2-indolinone

C27H27N5O2

Mass Spectrum: m / z = 453 (M ⁺ ).

(65) 3-Z- [1- (3-D methyl aminomethylphenylamino) -1phenylmethylene] -5-amido-2-indolinone

C2 ₅ H ₂₄ N ₄ O ₂

Mass Spectrum: m / z = 412 (M ⁺ ).

(66) 3- [1- (4- (2-Diethylaminoethyl) phenylamino) -1-phenylmethylene] -5-amido-2-indolinone

0 ₂ βΗ ₃ οΝ ₄ 0 ₂

Mass spectrum: m / z = 454 (M ⁺ ).

(67) 3- [1- (4- (2-Morpholinoethyl) phenylamino) -1phenylmethylene] -5-amido-2-indolinone

C ₂₈ H ₂₈ N ₄ O ₃

Mass Spectrum: m / z = 468 (M ⁺ ).

(68) 3-Z- [1- (4- (2-Pyrrolidinylethyl) phenylamino) -1phenylmethylene] -5-amido-2-indolinone

C ₂ 8H ₂₈ N ₄ O ₂

Mass Spectrum: m / z = 452 (M ⁺ ).

(69) 3- [1- (4- (2-Piperidinylethyl) phenylamino) -1-phenylmethylene] -5-amido-2-indolinone

C ₂₉ H ₃₀ N ₄ O ₂

Mass Spectrum: m / z = 466 (M ⁺ ).

(70) 3 N - [1- (2-Thiazolylamino) -1-phenylmethylene] -5amido-2-indolinone

Yield: 30% of theory.

Rf value: 0.48 (silica gel; methylene chloride / methanol =

9: 1).

C19H14N4O2S

Mass Spectrum: m / z = 362 (M ⁺ ).

(71) 3-Z- [1- (Benzimidazol-2-ylamino) -1-phenylmethylene] -5-amido-2-indolinone

Yield: 29% of theory.

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

C23H17N5O2

Mass Spectrum: m / z = 395 (M ⁺ ).

(72) 3-7- [1- (5-Methylisoxazol-3-ylamino) -1phenylmethylene] -5-amido-2-indolinone

Yield: 39% of theory.

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

C21H18N4O3

Mass Spectrum: m / z = 374 (M ⁺ ).

(73) 3-Z- [1-Benzylamino-1-phenylmethylene] -5-amido-2-indolinone

Rf value: 0.63 (silica gel; methylene chloride / methanol = 9: 1).

C23H19N3O2

Mass Spectrum: m / z = 369 (M ⁺ ).

(74) 3-Z- [1- (4- (1-Imidazolylmethyl) phenylamino) -1 phenylmethylene] -5-amido-2-indolinone

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

C26H21N5O2

Mass Spectrum: m / z = 436 (M + H) ⁺ .

(75) 3-2- [1- (4 - ((2-Diethylaminoethyl) 63 aminocarbonyl) phenylamino) -1-phenylmethylene] -5-amido-2-indolinone-trifluoroacetate

Yield: 27% of theory.

Rf value: 0.05 (silica gel; methylene chloride / methanol =

9: 1).

C ₂₉ H ₃₁ N ₅ O ₃

Mass spectrum: m / z = 497 (M ⁺ ).

(76) 3-Z- [1- (4-Acetylaminomethylphenylamino) -1 phenylmethylene] -5-amido-2-indolinone

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

Mass spectrum: m / z = 426 (M ⁺ ).

(77) 3 - [1- (4 - ((2-Dimethylaminoethyl) -methanesulfonylamino) phenylamino) -1-phenylmethylene] -5-amido-2-indolinone

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

C27H29N5O4S

Mass spectrum: m / z = 519 (M ⁺ ).

(78) 3-Z- [1- (4- (N- (ETHOCHCHAPHOHHMeTHN) -Nmethanesulfonylamino) phenylamino) -1-phenylmethylene] -5-amido-2-indolinone

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

C27H26N4O6

Mass spectrum: m / z = 534 (M ⁺ ).

(79) 3- [1- (4- (N- (Cyanomethyl) -N-methanesulfonylamino) phenylamino) -1-phenylmethylene] -5-amido-2-indolinone)

Rf value: 0.49 (silica gel; methylene chloride / methanol = 9: 1).

C ₂₅ H _{2 and} N ₅ O _{4 S}

Mass Spectrum: m / z = 487 (M ⁺ ).

(80) 3- [1- (4- (N-Methyl-L-methanesulfonylamino) phenylamino) -1-phenylmethylene] -5-amido-2-indolinone

Rf value: 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-phenylmethylene] -5-amido-2-indolinone

C ^ Nm ^ Oz

Mass Spectrum: m / z = 452 (M ⁺ ).

(82) 3- [1- (4- (2-Oxo-piperidino-1-ylmethyl) phenylamino) -1-phenylmethylene] -5-amido-2-indolinone

C ₂₈ H ₂₆ N ₄ O ₃

Mass Spectrum: m / z = 466 (M ⁺ ).

(83) 3- [1- (4- (4-Cyclohexylpiperidinomethyl) phenylamino) -1-phenylmethylene] -5-amido-2-indolinone trifluoroacetate

C34H3gN ₄ O ₂

Mass Spectrum: m / z = 534 (M ⁺ ).

(84) 3-Z- [1- (4- (2,6-Dimethylpiperidinomethyl) phenylamino) -1-phenylmethylene] -5-amido-2-indolinone trifluoroacetate

C30H32N4O2

Mass Spectrum: m / z = 480 (M ⁺ ).

(85) 3 N - [1- (4- (4-Phenyl-4-hydroxypiperidinomethyl) phenylamino) -1-phenylmethylene] -5-amido-2-indolinone trifluoroacetate

C34H32N4O3

Mass Spectrum: m / z = 545 (M ⁺ ).

Rf value: 0.66 (silica gel, methylene chloride / methanol = 4: 1).

(86) 3-N- [1- (4- (2-Methoxycarbonylpyrrolidinomethyl) phenylamino) -1-phenylmethylene] -5-amido-2-indolinone trifluoroacetate

C29H28N4O4

Mass Spectrum: m / z = 497 (M + H) ⁺ .

Rf value: 0.65 (silica gel, methylene chloride / methanol = 4: 1).

(87) 3-Z- [1- (4- (1-Oxo-thiomorpholin-4-ylmethyl) phenylamino) -1-phenylmethylene] -5-amido-2-indolinone trifluoroacetate

C27H26N4O3S

Mass Spectrum: m / z = 487 (M + H) ⁺ .

Rf value: 0.68 (silica gel, methylene chloride / methanol = 4: 1).

(88) 3-Z- [1- (4- (3,6-Dihydro-2H-pyridin-1-ylmethyl) phenylamino) -1-phenylmethylene] -5-amido-2-indolinone trifluoroacetate

C28H26N4O2

Mass Spectrum: m / z = 451 (M + H) ⁺ .

(89) 3-Z- [1- (4- (2,5-Dihydropyrrol-1-ylmethyl) -phenylamino) -1-phenylmethylene] -5-amido-2-indolinone trifluoroacetate

C27H24N4O2

Mass Spectrum: m / z = 437 (M + H) ⁺ .

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

(90) 3- [1- (4- (Thiomorpholin-4-ylmethyl) phenylamino) -1phenylmethylene] -5-amido-2-indolinone-trifluoroacetate

C27H26N4O2S

Mass Spectrum: m / z = 471 (M + H) ⁺ .

Rf value: 0.78 (silica gel, methylene chloride / methanol = 4: 1).

(91) 3-Z- [1- (4- (6,7-Dimethoxytetrahydroisoquinolin-2ylmethyl) phenylamino) -1-phenylmethylene] -5-amido-2-indolinone trifluoroacetate

C34H32N4O4

Mass Spectrum: m / z = 561 (M + H) ⁺ .

Rf value: 0.8 (silica gel, methylene chloride / methanol = 4: 1).

(92) 3- [1- (4- (4-Phenylpiperazin-1-ylmethyl) phenylamino) -1-phenylmethylene] -5-amido-2-indolinone trifluoroacetate

C33H31N5O2

Mass Spectrum: m / z = 530 (M + H) ⁺ .

Rf value: 0.78 (silica gel, methylene chloride / methanol = 4: 1).

(93) 3-Z- [1- (4- (3,5-Dimethylpiperidinomethyl) phenylamino) -1-phenylmethylene] -5-amido-2-indolinone trifluoroacetate

C30H32N4O2

Mass Spectrum: m / z = 480 (M) ⁺ .

Rf value: 0.54 (silica gel, methylene chloride / methanol = 4: 1).

(94) 3-7- [1- (4- (N-Methyl-L [-benzylaminomethyl) phenylamino) -1-phenylmethylene] -5-amido-2-indolinone trifluoroacetate θ31Η29Ν ₄ Ο ₄

Mass Spectrum: m / z = 488 (M) ⁺ .

(95) 3- [1- (3,4-Dimethoxyphenylamino) -1-phenylmethylene] -5-amido-2-indolinone

C2 ₄ H21 NjO ₄

Mass Spectrum: m / z = 415 (M) ⁺ .

Rf value: 0.5 (silica gel, methylene chloride / methanol = 9: 1).

(96) 3-N- [1- (4-Trifluoromethoxyphenylamino) -1phenylmethylene] -5-amido-2-indolinone

C23H16F3N3O3

Mass Spectrum: m / z = 439 (M) ⁺ .

Rf value: 0.5 (silica gel, methylene chloride / methanol = 9: 1).

(97) N- [1- (3-Ethoxycarbonylphenylamino) -1phenylmethylene] -5-amido-2-indolinone

C25H21O3 ₄

Mass Spectrum: m / z = 427 (M) ⁺ .

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

(98) 3 N - [1- (3-Carboxyphenylamino) -1-phenyl methyl ene] -

5-Amido-2-indolinone

C ₂ 3Hi ₇ N ₃ O ₄

Mass Spectrum: m / z = 399 (M) ⁺ .

Rf value: 0.14 (silica gel, methylene chloride / methanol = 9: 1).

(99) 3-2- [1- (3-Diethylcarbamoylphenylamino) -1phenylmethylene] -5-amido-2-indolinone

C27H26N4O3

Mass Spectrum: m / z = 454 (M) ⁺ .

Rf value: 0.48 (silica gel, methylene chloride / methanol = 9: 1).

(100) 3-Z- [1- (3-Ethylcarbamoylphenylamino) -1phenylmethylene] -5-amido-2-indolinone

C25H22N4O3

Mass Spectrum: m / z = 426 (M) ⁺ .

Rf value: 0.42 (silica gel, methylene chloride / methanol = 9: 1).

(101) 3-Z- [1- (3-T Rfluoromethoxyphenylamino) -1 phenylmethylene] -5-amido-2-indolinone

C23H16F3N3O3

Mass Spectrum: m / z = 439 (M) ⁺ .

Rf value: 0.5 (silica gel, methylene chloride / methanol = 9: 1).

(102) 3- [1- (3-Ethoxyphenylamino) -1-phenylmethylene] -5amido-2-indolinone

C24H21N3O3

Mass Spectrum: m / z = 399 (M) ⁺ .

Rf value: 0.49 (silica gel, methylene chloride / methanol = 9: 1).

(103) 3-2- [1- (4-Methoxymethylphenylamino) -1phenylmethylene] -5-amido-2-indolinone

C24H21N3O3

Mass Spectrum: m / z = 399 (M) ⁺ .

Rf value: 0.4 (silica gel, methylene chloride / methanol = 4: 1).

(104) 3 N - [1- (4-Ethylphenylamino) -1-phenylmethylene] -5amido-2-indolinone

C24H21N3O2

Mass Spectrum: m / z = 383 (M) ⁺ .

Rf value: 0.52 (silica gel, methylene chloride / methanol = 4: 1).

(105) 3-Z- [1- (4-Methyl-3-nitrophenylamino) -1-phenylmethylene] -5-amido-2-indolinone

C23H18N4O4

Mass Spectrum: m / z = 414 (M) ⁺ .

(106) N- [1- (4-Methyl-3-methoxyphenylamino) -1phenylmethylene] -5-amido-2-indolinone

C24H21N3O3

Mass Spectrum: m / z = 399 (M) ⁺ .

(107) 3-Z- [1- (4-Aminophenylmethyl) phenylamino) -1 phenylmethylene] -5-amido-2-indolinone-trifluoroacetate

C29H24N4O2

Mass Spectrum: m / z = 460 (M) ⁺ .

(108) 3 N - [1- (4-Methoxycarbonyl-3-methyl-phenylamino) -

1-phenylmethylene] -5-amido-2-indolinone

C25H21N3O4

Mass Spectrum: m / z = 427 (M) ⁺ .

Rf value: 0.56 (silica gel, methylene chloride / methanol = 4: 1).

(109) 3-Z- [1- (4-Cyanophenylamino) -1-phenylmethylene] -5amido-2-indolinone

- 70 C23H16N4O2

Mass Spectrum: m / z = 380 (M) ⁺ .

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

(110) N- [1- (5-Methylpyridin-2-ylamino) -1phenylmethylene] -5-amido-2-indolinone

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

C22H18N4O2

Mass Spectrum: m / z = 370 (M) ⁺ .

(111) 3-Z- [1- (5-Bromopyridin-2-ylamino) -1-phenylmethylene] -5-amido-2-indolinone

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

^ 21Η15ΒγΝ4Ο2

Mass Spectrum: m / z = 434/436 (M) ⁺ .

(112) 3-Z- [1- (2-Chloropyridin-2-ylamino) -1phenylmethylene] -5-amido-2-indolinone

Rf value: 0.49 (silica gel, methylene chloride / methanol = 9: 1).

C2iH ₁₅ ClN ₄ O ₂

Mass Spectrum: m / z = 390/392 (M) ⁺ .

(113) N- [1- (3-Canophenylamino) -1-phenylmethylene] -5amido-2-indolinone

Rf value: 0.57 (silica gel, methylene chloride / methanol = 9: 1).

C23H16N4O2

Mass Spectrum: m / z = 380 (M) ⁺ .

(114) 3-Z- [1- (4- (N-Phenylaminomethyl) phenylamino) -1-phenylmethylene] -5-amido-2-indolinone

Rf value: 0.74 (silica gel, methylene chloride / methanol = 9: 1).

C29H24N4O2

Mass Spectrum: m / z = 460 (M) ⁺ .

(115) N - [1- (N-Methyl-N-phenylaminomethyl) phenylamino-1-phenyl methylene] -5-amido-2-indolinone

Rf value: 0.75 (silica gel, methylene chloride / methanol = 9: 1).

C30H26N4O2

Mass Spectrum: m / z = 474 (M) ⁺ .

(116) 3- [1- (N-Ethylaminomethyl) phenylamino) -1-phenylmethylene] -5-amido-2-indolinone

C25H24N4O2

Mass Spectrum: m / z = 412 (M) ⁺ .

(117) 3- [1- (4-Chlorophenylmethyl) aminomethyl) phenylamino) -1-phenylmethylene] -5-amido-2-indolinone

C30H25CIN4O2

Mass Spectrum: m / z = 508/510 (M) ⁺ .

(118) 3- [1- (4- (N-Cyclohexylaminomethyl) phenylamino) -1-phenylmethylene] -5-amido-2-indolinone trifluoroacetate

C29H30N4O2

Mass Spectrum: m / z = 466 (M) ⁺ .

(119) N - [1- (4- (N-Isopropylaminomethyl) phenylamino) -1-phenylmethylene] -5-amido-2-indolinone trifluoroacetate

C26H26N4O2

Mass Spectrum: m / z = 426 (M) ⁺ .

(120) 3-7- [1 ~ (4- (N-Butylaminomethyl) phenylamino) -1phenylmethylene] -5-amido-2-indolinone-trifluoroacetate

C27H28N4O2

Mass Spectrum: m / z = 440 (M) ⁺ .

(121) 3-Z- [1- (4- (N-Methoxycarbonylmethylaminomethyl) phenylamino) -1-phenylmethylene] -5-amido-2-indolinone trifluoroacetate

C26H24N4O4

Mass Spectrum: m / z = 456 (M) ⁺ .

(122) 3- [1- (4- (N-Phenylmethyl) aminomethyl) phenylamino) -1-phenylmethylene] -5-amido-2-indolinone trifluoroacetate

C30H26N4O2

Mass Spectrum: m / z = 464 (M) ⁺ .

(123) 3- [1- (4- (N-Acetyl-N-ethoxycarbonylmethylamino) phenylamino) -1-phenylmethylene] -5-amido-2-indolinone

C28H26N4O5

Mass Spectrum: m / z = 498 (M) ⁺ .

(124) N - [1- (4-Methyl-3-sulfamoylphenylamino) -1-phenylmethylene] -5-amido-2-indolinone

C23H20N4O4S

Mass Spectrum: m / z = 448 (M) ⁺ .

(125) 3-Z- [1- (4- (N-Methanesulfonyl-N (methylcarbamoylmethyl) amino) phenylamino) -1-phenylmethylene] -5amido-2-indolinone

C26H25N5O5S

Mass Spectrum: m / z = 519 (M) ⁺ .

(126) 3 N - [1- (4- (N-Methanesulfonyl-1 N- (piperidinecarbonyl methyl) amino) phenylamino) -1-phenyl methyl] 5-amido-2-indolinone

C ₃₀ H ₃₁ N ₅ O ₅ S

Mass Spectrum: m / z = 573 (M) ⁺ .

(127) 3- [1- (4-Carboxyphenylamino) -1-phenylmethylene] 5-amido-2-indolinone

C2 ₃ H17N ₃ O ₄

Mass Spectrum: m / z = 398 (MH ⁺ ).

(128) 3-Z- [1- (4-Carboxy-3-methylphenylamino) -1 phenylmethylene] -5-amido-2-indolinone

C24Hi9N ₃ O4

Mass Spectrum: m / z = 412 (MH ⁺ ).

(129) 3-Z- [1- (4- (3-Diethylaminopropoxy) phenylamino) -

1-phenylmethylene] -5-amido-2-indolinone-trifluoroacetate ^ 29Η ₃ 2Ν ₄ Ο ₃

Mass Spectrum: m / z = 484 (M) ⁺ .

(130) 3-Z- [1- (4- (2-Piperidinoethoxy) phenylamino) -1-phenylmethylene] -5-amido-2-indolinone-trifluoroacetate

C29H ₃ oN40 ₃

Mass Spectrum: m / z = 483 (M + H) ⁺ .

(131) 3- [1- (4- (3-Piperidinopropoxy) phenylamino) -1phenylmethylene] -5-amido-2-indolinone-trifluoroacetate

C ₃ qH ₃₂ N ₄ O ₃

Mass Spectrum: m / z = 496 (M) ⁺ .

(132) 3- [1- (4- (3-Dimethylaminopropoxy) phenylamino) -1-phenylmethylene] -5-amido-2-indolinone trifluoroacetate θ27Η2δΝ4θ ₃

Mass Spectrum: m / z = 457 (M + H) ⁺ .

(133) 3-Z- [1- (4- (3-N-Methyl-N-benzylaminopropoxy) phenylamino) -1-phenylmethylene] -5-amido-2-indolinone trifluoroacetate

C33H32N4O3

Mass Spectrum: m / z = 533 (M + H) ⁺ .

(134) 3-Z- [1- (4- (2-Dimethylaminoethoxy) -phenylamino) -

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

C2 _b H _2b H ₄ Oz

Mass Spectrum: m / z = 443 (M + H) ⁺ .

(135) 3-Z- [1- (4- (N-Ethyl-1-benzylaminomethyl) -phenylamino) -1-phenylmethylene] -5-amido-2-indolinone (136) 3-d- [1- (4 - (M-Propyl-N-benzylaminomethyl) phenylamino) -1-phenylmethylene] -5-amido-2-indolinone (137) 3-Ζ- [1- (4- (Μ-ΜβτΗΗ-Ν- (4-χποροφβΗΗΠΜβτππ)) aminomethyl) phenylamino) -1-phenylmethylene] -5-amido-2-indolinone (138) 3- [1- (4- (N-Methyl-N- (4-bromophenylmethyl) aminomethyl) phenylamino) -1-phenylmethylene] ] -5-Amido-2-indolinone (139) 3-Z- [1- (4- (Ν-Methyl-N- (3-chlorophenylmethyl) -aminomethyl) phenylamino) -1-phenylmethylene] -5-amido-2 -indolinone (140) 3-N- [1- (4- (N-ββπππ-N- (3,4-Δβοια-phenylmethyl) aminomethyl) phenylamino) -1-phenylmethylene] -5-amido

2- indolinone (141) 3- (1- (4- (N-Methyl-N- (4-methoxyphenylmethyl) aminomethyl) phenylamino) -1-phenylmethylene) -5-amido-2-indolinone (142) 3- N- [1- (4- (N-Trifluoroethyl-N- (phenyl methyl) -aminomethyl) phenylamino) -1-phenylmethylene) -5-amido-2-indolinone (143) 3-N- [1- (4 - (Ν-πρπφπγοροβτΗΗ-Ν- (4-chlorophenylmethyl) -aminomethyl) phenylamino) -1-phenylmethylene] -5amido-2-indolinone.

Example 5

3- [1- (4- (4-Acetylpiperazinylmethyl) phenylamino) -1phenylmethylene] -5-amido-2-indolinone

25 mg of 3-N- [1- (4 (Perazinyl methyl) phenyl amino) -1-phenyl methyl ene] -5-amide o-2indolinone and 0.02 g of triethylamine are dissolved in 10 ml of methylene chloride and mixed with 5 mg acetyl chloride and the solution was stirred for 16 h at room temperature. It is then washed with water and the organic phase is evaporated on a rotary evaporator.

Yield: 15 mg (68% of theory)

C29H29N 5Ο3

Mass Spectrum: m / z = 495 (M ⁺ ).

The following compounds are similarly prepared:

(1) 3-Z- [1- (4- (4-Benzoyl piperazinyl methyl) phenylamino) -1-phenylmethylene] -5-amido-2-indolinone

Obtained from 3 - [1- (4- (Perazinylmethylphenylamino) -1-phenylmethylene] -5-amido-2-indolinone and benzoyl chloride).

Yield: 91% of theory

C34H31N5O3

Mass Spectrum: m / z = 557 (M ⁺ ).

Example 6

-Z- [1- (4-Dethylcarbamoyl phenylamino) -1phenylmethylene] -5-amido-2-indolinone g resin from step IV was reacted analogously to example 4 with ethyl 4-aminobenzoate. The wet loaded resin was suspended in 30 ml of dioxane and 30 ml of methanol and stirred for 40 h with 1N sodium hydroxide. It is then neutralized with dilute hydrochloric acid and washed with methylene chloride, methanol and dimethylformamide. Then 300 mg of the resin was suspended in 3 ml of dimethylformamide and allowed to stand at room temperature for 60 h with 0.2 ml of diethylamine, 0.5 g of O- (6eH3OTpHa3on-1-Hn) -N, N. N ', N-tetramethyluronium tetrafluoroborate and 0.8 ml of ethyldiisopropylamine. Finally, the product was cleaved from the resin as described in Example 4.

Yield: 29 mg.

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

C27H26N4O3

Mass spectrum: m / z = 454 (M ⁺ ). Similarly, we obtain:

(1) 3-Z- [1- (4- (Piperidinocarbonyl) phenylamino) -1 phenylmethylene] -5-amido-2-indolinone

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

C28H26N4O3

Mass Spectrum: m / z = 466 (M ⁺ ).

(2) 3-Z- [1- (4- (4-Methylpiperazinocarbonyl) phenylamino) -1-phenylmethylene] -5-amido-2-indolinone

Rf value: 0.84 (silica gel, methylene chloride / methanol = 4: 1)

C28H27N5O3

Mass Spectrum: m / z = 481 (M ⁺ ).

(3) 3-Z- [1- (4- (N- (2-D imethylaminoethyl) -L-methylcarbamoyl) phenylamino) -1-phenylmethylene] -5-amido-2-indolinone-trifluoroacetate

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

C28H29N5O3

Mass Spectrum: m / z = 484 (M ⁺ ).

(4) 3-Z- [1- (4- (N-Methoxycarbonylmethylcarbamoyl) phenylamino) -1-phenylmethylene] -5-amido-2-indolinone

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

C26H22N4O5

Mass Spectrum: m / z = 470 (M ⁺ ).

(5) 3-Z- [1- (4-Benzylcarbamoyl) phenylamino) -1phenylmethylene] -5-amido-2-indolinone

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

C30H24N4O3

Mass Spectrum: m / z = 488 (M ⁺ ).

Example 7

-Z- [1- (4- (N-Methylbenzoylamino) phenylamino) -1-phenylmethylene] -5-amido-2-indolinone g resin from step IV is reacted analogously to Example 4 with 3.4 g of 4- (9H-fluorene- 9-ylmethoxycarbonyl) methylamino) aniline in dimethylformamide. The 9H-fluoro-protecting group was then cleaved with 4 ml of 30% piperidine in dimethylformamide and the resin was washed several times. The 400 mg of resin was then suspended in 4 ml of dimethylformamide and 0.3 ml of triethylamine and allowed to stand for one hour at room temperature with 0.3 ml of benzoyl chloride. Finally, the product was cleaved from the resin as described in Example 4.

Yield: 33 mg

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

C30H24N4O3

Mass spectrum: m / z = 488 (M ⁺ ).

Similarly, we obtain:

(1) 3-Z- [1- (4- (N-Methylpropylamino) phenylamino) -1-phenylmethylene] -5-amido-2-indolinone

Rf value: 0.42 (silica gel, methylene chloride / methanol = 9: 1)

C26H24N4O3

Mass spectrum: m / z = 440 (M ⁺ ).

(2) 3- [1- (4- (N-Methylbutylamino) phenylamino) -1phenylmethylene] -5-amido-2-indolinone

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

C27H26N4O3

Mass spectrum: m / z = 453 (MH ⁺ ).

(3) N - [1- (4- (N-Methylethylsulfonylamino) phenylamino) -1-phenylmethylene] -5-amido-2-indolinone

Rf value: 0.42 (silica gel, methylene chloride / methanol = 9: 1)

C25H24N4O4S

Mass spectrum: m / z = 475 (MH ⁺ ).

(4) 3-Z- [1- (4- (N-Propylsulfonylamino) phenylamino) -1phenylmethylene] -5-amido-2-indolinone

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

9: 1)

C ₂₅ H ₂₆ N ₄ O ₄ S

Mass Spectrum: m / z = 491 (M + H) ⁺ .

(5) 3-7- [1- (4- (B1-Methylphenylsulfonylamino) phenylamino) -1-phenylmethylene] -5-amido-2-indolinone

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

9: 1)

C29H24N4O4S

Mass Spectrum: m / z = 524 (M ⁺ ).

Example 8

Dry ampoules with 75 mg of active substance per 10 ml

Composition:

Active substance 75,0 mg Mannitol 50,0 mg Water for injection purposes to 10.0 ml

Receive:

The active substance and mannitol are dissolved in water. After filtration, it was freeze-dried. The reconstitution for ready-to-use solution is made with water for injection.

Example 9

Dry ampoules with 35 mg of active substance per 2 ml

Composition:

Active substance 35,0 mg Mannitol 100,0 mg Water for injection purposes up to 2.0 ml

Receive:

The active substance and mannitol are dissolved in water. After filtration, it was freeze-dried. The reconstitution for ready-to-use solution is made with water for injection.

Example 10

Tablets with 50 mg of active substance

Composition:

(1) Active substance 50,0 mg (2) Lactose 98.0 mg (3) Corn starch 50,0 mg (4) Polyvinylpyrrolidone 15.0 mg (5) Magnesium stearate 2 * 0 mg 215,0 mg

Receive:

(1), (2) and (3) are mixed and granulated with an aqueous solution of (4). The dry granulate is mixed with (5). From this mixture, flat tablets on both sides are pressed with a beveled edge on both sides and a dividing line on one side. Tablet diameter: 9 mm.

Example 11

Tablets with 350 mg of active substance

Composition:

(1) Active substance 350,0 mg (2) Lactose 136.0 mg (3) Corn starch1 80,0 mg (4) Polyvinylpyrrolidone 30.0 mg (5) Magnesium stearate 4.0 mg 600,0 mg

Receive:

(1), (2) and (3) are mixed and granulated with an aqueous solution of (4). The dry granulate is mixed with (5). From this mixture are compressed tablets flat on both sides with a beveled edge on both sides and a dividing line on one side. Tablet diameter: 12 mm.

Example 12

50 mg capsules of active substance

Composition:

(1) Active substance 50,0 mg (2) Dry corn starch 58,0 mg (3) Lactose 50,0 mg (4) Magnesium stearate 2.0 160.0 mg

Receive:

(1) and (3) are ground. The crushed mixture is added to the mixture of (2) and (4) with vigorous stirring.

This powder mixture is filled into solid, capsule size 3 gelatin capsules on a capsule filling machine.

Example 13

Capsules with 350 mg of active substance

Composition: (1) Active substance 350,0 mg (2) Dry corn starch 46,0 mg (3) Lactose 30.0 mg (4) Magnesium stearate 4.0 - 430,0 mg

Receive:

(1) and (3) are ground. The crushed mixture adheres to the mixture of (2) and (4) with vigorous mixing.

This powder mixture is filled into solid, gelatin capsules size 0 of a capsule filling machine.

Example 14

Suppositories with 100 mg of active substance Suppository contains:

Active substance

Polyethylene glycol (M.G.1500)

Polyethylene glycol (M.G.6000)

Polyethylenesulfonate

100,0 mg

600,0 mg

460,0 mg

840.0 mg

000,0 mg

Receive:

The polyethylene glycol is fused with the polyethylene sorbitan monostearate. At 40 ° C, the homogeneously milled active substance was dispersed in the melt. Cool to 38 ° C and pour into pre-cooled suppository molds.

Claims (11)

Patent Claims 1. Substituted indolinones of the general formula wherein X stands for oxygen or sulfur atom, Ri represents hydrogen or Ci_ ₄ alkoxycarbonyl or C ₂ -4 alkanoyl group, R ₂ represents carboxy, Cl. ₄ -alkoxycarbonyl or aminokarbonnlna group in which the amino moiety may be substituted with one or two Ci_ ₃ alkyl groups, the substituents can be identical or different, R ₃ means a phenyl or naphthyl group which is substituted by a fluorine, chlorine or bromine atom, with a C _1-3 alkyl, C _3-3 alkoxy, cyano, trifluoromethyl, nitro, amino, C _1-3 alkylamino, di- (C _1-3 alkyl) amino, C ₂ . ₄ alkanoylamino, N- (C _1-3 alkyl) -C ₂ alkanoylamino, N- (C _1-3 alkyl) -C ₂ . ₄ alkanoylamino, Ci alkylsulfonylamino, amino-C ^ h alkyl, C _yz alkylamino-Ci alkyl, di- (C1 & apos ₃ alkyl) amino-C1 & apos ₃ alkyl, N- (C _{2. 4} alkanoyl) amino, C1 & apos ₃ alkyl or N- (C _{2. 4} alkanoyl) -Sy ₃ alkylamino-Sh.z alkyl group, the substituents may be identical or different, R ₄ represents a hydrogen atom or C 1. ₃ alkyl group and R ₅ represents a hydrogen atom, Ci.5 alkyl group optionally substituted by a phenyl, carboxy or Ci_ ₃ alkoxycarbonyl group, C ₃ _ ₇ cycloalkyl group optionally substituted by a Ci alkyl group, indanyl group, optionally substituted with Ci_ ₃ alkyl group, A 5-atom heteroaryl group containing an imino group optionally substituted by a C _1-3 alkyl group, an oxygen or sulfur atom, or an imino group optionally substituted by a C _1-3 alkyl group and an oxygen, sulfur or nitrogen atom or two nitrogen atoms or a 6-atom a heteroaryl group containing 1-3 nitrogen atoms, wherein, through two adjacent carbon atoms or through one carbon atom and one adjacent imino group, the above 5-atom and 6-atom heteroaryl groups may further form a 1,3-butadienylene bridge and the carbon chain of the above mono- bicyclic rings may optionally be mono- or disubstituted by fluorine, chlorine, bromine or iodine atom, a Ci_ ₅ alkyl or cyano group, the substituents may be the same or different, linked through a carbon atom a pyrrolidinyl or piperidinyl group, each of which may be substituted with C1. ₃ alkyl group on the nitrogen atom, a phenyl group optionally disubstituted by fluorine, chlorine, bromine or iodine atom, with Cb ₅ alkyl, Ci_ ₃ alkoxy, carboxy, Ci. ₃ alkoxycarbonyl, aminosulfonyl, nitro or cyano group, the substituents being the same or different, a phenyl, pyridyl, pyrimidyl or thienyl group, each of which may be substituted by a trifluoromethoxy group, with a fluorine, chlorine, bromine or iodine atom, an alkoxy group which may be substituted in the 2nd or 3rd position by amino, C 1-3 alkylamino, di- (C _1-3 alkyl) amino, phenyl-C 3 alkylamino, L 1 - (C 3 alkyl) -phenyl-C 3 alkylamino, pyrrolidino or a piperidine group having a phenyl-C3 alkylamino-C3 alkyl group which may be mono- is disubstituted at the phenyl nucleus with a trifluoromethyl group, with a fluorine, chlorine, bromine or iodine atom, with a C1-3 alkyl or C3-3 alkoxy group, the substituents may be the same or different, and additionally, the amino nitrogen atom with the C1-3 alkyl group in which the hydrogen the second atoms may be completely or partially substituted by fluorine atoms, by C1-5 alkyl, phenyl, imidazolyl, _C3 _7 cycloalkyl, C1-3 alkoxy-Ci alkoxy, fenilSyz alkoxy, carboxy-Ci alkyl, Ci alkoxycarbonyl-C1-3 alkyl, carboxy, Ci alkoxycarbonyl, aminocarbonyl, Ci alkylaminocarbonyl, di- (Ci alkylaminocarbonyl, fenilSyz alkylaminocarbonyl, and - (Ci alkyl) phenyl-Ci alkylaminocarbonyl, piperazinokarbonilna, Y1- (Ci alkyl) piperazinokarbonilna, nitro, amino, Ci alkylamino, di (Ci alkyl) amino, pyrrolidino, piperidino, morpholino, C _{2. 4} alkanoylamino, Y1- (Ci alkyl) -C _{2. 4} alkanoylamino, benzoylamino or N- (Cb3 alkyl) benzoilaminogrupa with N- ( Ci_3 alkyl) -C _{2. 4} alkanoilaminogrupa, which alkyl moiety is further substituted with carboxy or Ci alkoxycarbonyl group, a Ci alkylaminocarbonyl or di- (Ci alkylaminocarbonyl group in which the alkyl moiety is additionally substituted by a di- (C1 & apos ₃ alkyl) amino, or N- (Ci_3 alkyl) -C1. ₃ alkylsulfonylamino or N (S1_z alkyl) fenilsulfonilaminogrupa in which the alkyl moiety may additionally be substituted by cyano, carboxy, C _b h alkoxycarbonyl, Cj. ₃ alkylamino, di- (C _1-3 alkyl) amino, aminocarbonyl, C _3-3 alkylaminocarbonyl, di- (C 1-3 alkyl) aminocarbonyl, piperidinecarbonyl, or 2- [di (C _1-3 alkylamino)] ethylaminocarbonyl group, phenyl or thienyl, phenyl or thienyl, phenyl or thienyl; with a C _1-3 alkyl group, the alkyl moiety being substituted by hydroxy, C 1-3 alkoxy, carboxy, C 1-3. ₃ alkoxycarbonyl, amino, C _1-3 alkylamino, di- (C _1-5 alkyl) amino, C ₂ . ₄ alkanoylamino, N- (C _1-3 alkyl) -C ₂ . ₄ alkanoylamino, pyrrolidino, dehidropirolidino, piperidino, dehidropiperidino, 3-hydroxy pi peri dino, 4hydroxypiperidin, hexamethyleneimino, morpholino, thiomorpholino, piperazino, 4- (Ci_ ₃ alkyl) piperazino, 4fenilpiperazino, 4- (C _{2. 4} alkanoyl) piperazino, A 4-benzoylpiperazino or imidazolyl group, wherein the above saturated cycloalkyliminone, C _1-5 alkylamino or di- (C _1-5 alkyl) amino groups may be further substituted by one or two C _t . ₅ alkyl groups, by a _C3 _7 cycloalkyl, hydroxy, Ci. ₃ alkoxy, carboxy, C _1-3 alkoxycarbonyl, aminocarbonyl, C 1-3. ₃ alkylaminocarbonyl or di- (S1_z alkylaminocarbonyl, phenyl-C1 & apos ₃ alkyl or a phenyl group optionally mono- or disubstituted in the phenyl nucleus by a fluorine, chlorine, bromine or iodine atom, by a C _b h alkyl or cyano group, the substituents may be identical or different, or one of the nitrogen-adjacent methylene groups in the above cycloalkyleneimine ring may be substituted by a carbonyl or sulfonyl group, and the above monosubstituted phenyl groups may be further substituted by fluorine, chlorine, bromine or iodine a Volume, methyl, amino, Ci alkylamino or di- _(yz alkyl) amino group, or the above unsubstituted cycloalkyleneimino may be annelated by two adjacent carbon atoms to a phenyl ring, optionally substituted with one or two C _yz alkoxy groups, wherein the above residues which by definition denote a carboxy group may further be substituted by a group which in vivo is converted to a carboxy group, as well as the above residues which by definition mean amino and amino group may also be substituted by an in vivo leaving residue, their iz eras and salts thereof. Substituted indolinones of the general formula (I) according to claim 1, wherein the formula X stands for oxygen, R 1 represents a hydrogen atom or a C _1-4 alkoxycarbonyl group, R ₂ represents carboxy, C 1. ₄ alkoxycarbonyl group or aminocarbonyl group in which the amino moiety is substituted by one or two Ci. ₃ alkyl groups, and the substituents may be the same or different, R ₃ means a phenyl group optionally substituted by a fluorine, chlorine or bromine atom with a methyl, cyano or aminomethyl group, R ₄ represents a hydrogen atom or a methyl group and Rs means a hydrogen atom, With _b5 alkyl group or a benzyl group optionally substituted with carboxy or Ci_ ₃ alkoxycarbonyl group, _C3 _7 cycloalkyl group optionally substituted by a methyl group, an indanyl, pyridyl, oxazolyl, thiazolyl or imidazolyl group optionally substituted by a methyl group, each of which through two adjacent carbon atoms may be fused to a phenyl ring, methylphenyl or dimethoxyphenyl group optionally substituted by fluorine, chlorine or bromine atom with methoxy, carboxy, Ci. ₃ alkyloxycarbonyl, nitro, or aminosulfonyl group bonded through a carbon atom a pyrrolidinyl or piperidinyl groups on the nitrogen atom are substituted by Ci_ ₃ alkyl group, phenyl group which is substituted by a trifluoromethoxy group, a fluorine, chlorine, bromine or iodine atom, with Ci. _{A 3} alkoxy group which may be substituted at the 2 or 3 position by amino, C _1-3 alkylamino, di- (C _1-3 alkyl) amino, phenyl-C _3-3 alkylamino, N- (C _1-3 alkyl) phenyl-C 1 . ₃ -alkylamino, pyrrolidino or piperidino, phenyl-C1 & apos ₃ alkylamino-Cb ₃ alkyl group on the phenyl ring may be substituted by a fluorine, chlorine, bromine or iodine atom, a Ci_ ₅ alkyl or Ci_ ₃ alkoxy group or trifluoromethyl group, and further, the amino nitrogen by a C _yz alkyl group in which the hydrogen atom of the second site may be fully or partially substituted by fluorine atom, a C1-5 alkyl, phenyl, imidazolyl, C 3-7 cycloalkyl, C 1-3 alkoxy-lower alkoxy, phenyl-lower alkoxy, carboxy-Ci alkyl, C _b h alkoxycarbonyl-Ci_ ₃ alkyl, carboxy, C1-3 alkoxycarbonyl, aminocarbonyl, C 1-3 alkylaminocarbonyl, di- (C _1-3 alkyl) aminocarbonyl, phenyl C 1-3 alkylaminocarbonyl, N- (C _1-3 alkyl) phenyl C _1-3 alkylaminocarbonyl, piperazinocarbonyl, N- (C _1-3 alkyl) piperazinecarbonyl, nitro, amino) C _1-3 alkylamino, C _1-3 alkylamino, C _1-3 alkylamino, C _1-3 alkylamino, C _1-3 alkylamino, C _1-3 alkylamino, C _1-3 alkylamino, C _1-3 alkylamino, C 1-3 alkylamino amino, pyrrolidino, piperidino, morpholino, C ₂ .4 alkanoylamino, N- (Ci. ₃ alkyl) -C _{2. 4} alkanoylamino, benzoylamino or N- (Cb3 alkyl) benzoilaminogrupa with N- (Ci_ ₃ alkyl) -C ₂ _4 alkanoilaminogrupa which the alkyl moiety is further substituted with carboxy or C h an alkoxycarbonyl group, a Ci-h alkylaminocarbonyl or di - (C ₃ alkylaminocarbonyl group in which the alkyl moiety is additionally substituted by a di- (C1 & apos ₃ alkyl) amino, or N- (Ci. ₃ alkyl) -C1. ₃ alkylsulfonylamino or N (Ci alkyl) fenilsulfonilaminogrupa in which the alkyl part can additionally be substituted by cyano, carboxy, Ci_ ₃ alkoxycarbonyl, C 1-3 alkylamino, di- (C1 & apos _3a alkyl) amino, aminocarbonyl, C ₃ alkylaminocarbonyl, di- (C1. ₃ alkyl) aminocarbonyl, piperidinocarbonyl or 2- [di- (C1. ₃ alkylamino)] etilaminokarbonilna group, a phenyl group optionally substituted by Ci_ ₃ alkyl group, wherein the alkyl moiety is substituted by hydroxy, C1-s alkoxy, carboxy, Ci alkoxycarbonyl, amino, Ci. ₅ alkylamino, di- (C1. ₅₎ amino, C _{2. 4} alkanoylamino, N- (Ci_3 alkyl) 90 _C2 -4 alkanoylamino, pyrrolidino, dehidropirolidino, piperidino, dehidropiperidino, 3-hydroxypiperidino, 4hydroxypiperidin, hexamethyleneimino, morpholino, thiomorpholino, piperazino, 4- (C1. ₃ alkyl) piperazino, 4fenilpiperazino, 4- _(C2 -C4 alkanoyl) piperazino, 4benzoilpiperazino or imidazolyl group, wherein the above saturated cycloalkyleneimino, C _b5 alkylamino or di- (C !. ₅ alkyl) amino groups may be further substituted with one or two Ci_ ₅ alkyl groups, by a _C3 _7 cycloalkyl, hydroxy, C _b h alkoxy, carboxy, Ci_ ₃ alkoxycarbonyl, minokarbonilna, CF alkylaminocarbonyl or di- (S1_z alkyl) aminocarbonyl group, a phenyl-C h an alkyl or phenyl group optionally mono- or disubstituted in the phenyl nucleus by a fluorine, chlorine, bromine or iodine atom, by a C _b h alkyl or a cyano group, the substituents may be the same or different, or one of the nitrogen-adjacent methylene groups in the above cycloalkyleneimine ring may be substituted by a carbonyl or sulfonyl group, and the above monosubstituted phenyl groups may be further substituted by fluorine, a chlorine, bromine or iodine atom, methyl, amino, C 1-3 alkylamino or di (C 1-3 alkyl) amino group, or the above unsubstituted cycloalkyleneimine ring may be co-condensed through two adjacent carbon atoms with a phenyl moiety, optionally substituted by one or two C ₁ -C 6 substituted carbon atoms. alkoxy groups, their isomers and their salts. Substituted indolinones of the general formula (I) according to claim 1, wherein the formula X stands for oxygen, R 1 represents a hydrogen atom, R ₂ denotes a carboxy, C _1-4 alkoxycarbonyl or aminocarbonyl group in which the amino moiety may be mono or substituted with a C _1-3 alkyl group and the substituents may be the same or different, R ₃ means a phenyl group optionally substituted by a methyl group, R ₄ represents a hydrogen atom or a methyl group and R ₅ represents a hydrogen atom, C1 & apos ₃ alkyl or benzyl, substituted with carboxy or C]. ₃ alkoxycarbonyl group, methyl or ethyl group, _C3 _7 cycloalkyl group substituted by a methyl group, an indanyl, pyridyl, oxazolyl, thiazolyl or imidazolyl group optionally substituted with a methyl group in which further through two adjacent carbon atoms may be fused phenyl ring, methylphenyl or dimethoxyphenyl group, optionally substituted by a fluorine, chlorine or bromine atom or by a methoxy, carboxy, C _yz alkyloxycarbonyl, nitro, or aminosulfonyl group, A 3-pyrrolidinyl group or a 4-piperidinyl group which, at the nitrogen atom, may be substituted by C1. ₃ alkyl group, a phenyl group which may be substituted by trifluoromethoxy, benzyloxy, cyano or nitro, with a fluorine, chlorine or bromine atom, with a C 1-3 alkoxy group, wherein the ethoxy and normpropoxy groups may be substituted by dimethylamino, diethylamino, N-ethylmethylamino, N-benzylmethylamino or piperidino group, with a phenyl-C3 alkylamino-C3 alkyl group which in the phenyl ring may be replaced by a fluorine, chlorine, bromine or iodine atom, with a methyl, methoxy or trifluoromethyl group and additionally with an amino group and an azotamide group with C1_5 lkilova or 2,2,2-trifluoroethyl group, a C1 & apos ₄ alkyl, phenyl, imidazolyl, cyclohexyl, methoxymethyl, carboxymethyl, C ₃ alkoksikarbonilmetilova, carboxy, C1. ₃ alkoxycarbonyl, aminocarbonyl, Ci_ ₃ alkylaminocarbonyl, di- (C1. ₃ alkyl) aminocarbonyl, phenyl-C h alkylaminocarbonyl, N- (Ci- ₃ alkyl) phenyl-C1. ₃ alkylaminocarbonyl, piperazinokarbonilna, N- (Ci_ ₃ alkyl) piperazinokarbonilna, amino, S1_z alkylamino, di- (C1 & apos ₃ alkyl) amino, pyrrolidino, piperidino, morpholino, C ₂ -4 alkanoylamino, N- (Ci_ ₃ alkyl) C _2. 4 alkanoylamino, benzoylamino or N- (C _1-3 alkyl) benzoylamino group, with N- (C _1-3 alkyl) -C ₂ . ₄ alkanoylamino group, which in the alkyl moiety is further substituted by a carboxy or C _1-3 alkoxycarbonyl group, with a C _1-3 alkylaminocarbonyl or di- (C _1-3 alkylaminocarbonyl group, the alkyl portion of which is further substituted by di- (C _1-3 alkyl) or with N- (Ci_ ₃ alkyl) -Syz alkylsulfonylamino or N (Ci. ₃ alkyl) fenilsulfonilaminogrupa in which the alkyl moiety may additionally be substituted by cyano, carboxy, Ci _"3 alkoxycarbonyl, Ci. ₃ alkylamino, di- (C1 & apos ₃ alkyl) amino, aminocarbonyl, Ci. ₃ alkylaminocarbonyl, di- (C1 & apos ₃ alkylaminocarbonyl onyl, piperidinocarbonyl or 2- [di- (C1. ₃ alkylamino)] etilaminokarbonilna group, a phenyl group optionally substituted by Ci_ ₃ alkyl group in which the alkyl group may be substituted with hydroxy, Cj. ₃ alkoxy, carboxy, C _yz alkoxycarbonyl, amino, C1-5 alkylamino, di- (C !. ₅ alkyl) amino, C ₂ _ ₄ alkanoylamino, N- (Ci. ₃ alkyl) -C ₂ -4 alkanoylamino, pyrrolidino, dehidropirolidino, piperidino, dehidropiperidino, 4hydroxypiperidin, hexamethyleneimino, morpholino, thiomorpholino, piperazino, 4- (C _1-3 alkyl) piperazino, 4 phenylpiperazino, 4- (C ₂ . ₄ alkanoyl) piperazino, 4benzoylpiperazino or imidazolyl group, wherein the above saturated cycloalkenyl ring may be further substituted by a phenyl group or. with one or two methyl groups, the above C 1-5 -alkylamino or di- (C1. ₅ alkyl) amino groups may be further substituted with one or two C1 & apos ₃ alkyl groups, cyclohexyl, hydroxy, _yz alkoxy, carboxy, C1 & apos ₃ alkoxycarbonyl, aminocarbonyl , A C _1-3 alkylaminocarbonyl or di- (C _1-3 alkyl) aminocarbonyl group, a phenyl-C _1-3 alkyl or phenyl group optionally substituted in the phenyl nucleus by a fluorine, chlorine, bromine or iodine atom, with a methyl or cyano group, one of its neighbors of the nitrogen atom of the methylene groups in the above cycloalkyleneimine the tan may be substituted by a carbonyl or sulfonyl group, and the above monosubstituted phenyl groups may be further substituted by a fluorine, chlorine, bromine or iodine atom, methyl, amino, C1-3 alkylamino or di- (C1-3 alkyl) amino, or the above unsubstituted cycloalkyl may be co-condensed through two adjacent carbon atoms with a phenyl ring, optionally substituted by one or two C3-3 alkoxy groups, their isomers and their salts. Substituted indolinones of the general formula (I) according to claim 1, wherein the formula X stands for oxygen, R 1 represents a hydrogen atom, R ₂ means a carboxy 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 means a phenyl group optionally substituted by a methyl group, R ₄ represents a hydrogen atom and R ₅ represents a hydrogen atom, A 3-pyrrolidinyl or 4-piperidinyl group which at the nitrogen atom is substituted by a C 1-3 alkyl group, a phenyl group which may be substituted by a C 1-3 alkoxy group, wherein the ethoxy and normpropoxy groups may be substituted by dimethylamino, diethylamino, N-ethylmethylamino, N-ethylmethylamino N-benzylmethylamino or piperidino group, with a phenyl-C3 alkylamino-C3 alkyl group which in the phenyl nucleus may be substituted by a fluorine, chlorine, bromine or iodine atom, by a methyl, methoxy or trifluoromethyl group and may be further substituted at the amino group ity atom by C _t _ ₃ alkyl or 2,2,2trifluoroetilova group, a phenyl group, optionally substituted with Ci_ ₃ alkyl group in which the alkyl group is substituted by hydroxy, C1. ₃ alkoxy, carboxy, Ci. ₃ alkoxycarbonyl, amino, Ci_ ₅ alkylamino, di- (Sy5 alkyl) amino, C ₂ .4 alkanoylamino, Ν- (Οχ. ₃ alkyl) -C ₂ _4 alkanoylamino, pyrrolidino, dehidropirolidino, piperidino, dehidropiperidino, 4-hydroxypiperidino, hexamethyleneimino , morpholino, thiomorpholino, piperazino, 4 (C1 & apos ₃ alkyl) piperazino, 4-phenylpiperazino, 4- (C _{2. 4} alkanoyl) piperazino, 4-benzoylpiperazin or imidazolyl group, wherein the above saturated cycloalkyleneimino further may be substituted with a phenyl group or with one or two methyl groups, the above C _1-5 alkylamino or di- (C _1-5 a lkil) amino groups may be further substituted with one or two C1 & apos ₃ alkyl groups, cyclohexyl, hydroxy, Ci_ ₃ alkoxy, carboxy, C _yz alkoxycarbonyl, aminocarbonyl, Ci_ ₃ alkylaminocarbonyl or di (C _yz alkyl) aminocarbonyl group, a phenyl- C _1-3 alkyl or phenyl group optionally substituted in the phenyl nucleus by a fluorine, chlorine, bromine or iodine atom with a methyl or cyano group, one of the nitrogen atom adjacent methylene groups in the above cycloalkyleneimine ring may be substituted by a carbonyl or sulphonyl group; upper monosubstituted phenyl groups may additionally be substituted by a fluorine, chlorine, bromine or iodine atom, methyl, amino, C1. _{The 3} alkylamino or di- (C _1-3 alkyl) amino group, or the above unsubstituted cycloalkyleneimino ring, may be condensed through two adjacent carbon atoms with a phenyl ring, optionally substituted by one or two C _1-3 alkoxy groups, their isomers and their salts. Substituted indolinones of general formula (I) according to at least one of claims 1 to 4, characterized in that the residue R ₂ is in the 5th position. Substituted indolinones of the general formula (I) according to claim 1: (a) 3-7- [1- (4-Aminomethylphenylamino) -1phenylmethylene] -5-amido-2-indolinone, (b) 3-Z- [1-Phenylamino) -1-phenylmethylene] -5-amido-2indolinone , (c) 3- [1- (4-Bromophenylamino) -1-phenylmethylene] -5amido-2-indolinone, (d) 3- [1- (4-Dimethylaminomethyl) phenylamino-1-phenylmethylene] -5- amido-2-indolinone, / k 0 V (e) 3-d- [1- (4-Pyrrolidinomethylphenylamino) -1phenylmethylene] -5-amido-2-indolinone, (f) 3 N - [1- (4-Piperidinomethylphenylamino) ) -1-phenylmethylene] -5-amido-2-indolinone, (g) 3-g- [1- (4-Hexamethyleneiminomethylphenylamino) -1phenylmethylene] -5-amido-2-indolinone, (h) 3-g- [1- (4- (4-Benzylpiperidinomethyl) phenylamino) 1-phenylmethylene] -5-amido-2-indole inone, (i) 3- N - [1- (4- (N-Butylaminomethyl) phenylamino) -1phenylmethylene] -5-amido-2-indolinone, (j) 3-2- [1- (4- (N- (Phenylmethyl) aminomethyl) phenylamino) -1-phenylmethylene] -5-amido-2-indolinone, (k) 3-Z- [1- (4- (N-Methyl-N-benzylaminomethyl) phenylamino) -1-phenylmethylene] -5-Amido-2-indolinone, (1) 3 '- [1- (4-Piperidinomethylphenylamino) -1phenylmethylene] -5-dimethylcarbamoyl-2-indolinone, (m) 3' - [1- (4-Piperidinomethylphenylamino) - 1phenylmethylene] -5-diethylcarbamoyl-2-indolinone, (n) 3-d- [1- (4- (3-Diethylaminopropoxy) phenylamino) -1phenylmethylene] -5-amido-2-indolinone, and salts thereof. 7. Physiologically acceptable salts of the compounds of claims 1 to 6. A medicament comprising a compound according to at least one of claims 1 to 6 or a salt according to claim 7, together with optionally one or more inert carriers and / or diluents. Use of a compound according to at least one of claims 1 to 6 or a salt according to claim 7, for the preparation of a medicament which is suitable for the treatment of excessive or abnormal cell proliferation. A method for the preparation of a medicament according to claim 8, characterized in that the compound according to at least one of claims 1 to 6 or the salt according to claim 7 is treated in a non-chemical manner with one or more carriers and / or diluents . A process for the preparation of compounds according to claims 1 to 7, characterized in that (a) a compound of general formula (Π) in which X, R ₂ and R ₃ have the meanings given in claims 1 to 6, R ₆ represents a hydrogen atom, a lactam group nitrogen atom protecting group or a solid phase bond, and Z1 denotes a halogen atom, hydroxy, alkoxy or aralkoxy group, reacted with an amine of the general formula wherein R ₄ and R ₅ have the meanings given in claims 1 to 6 and, if necessary, the protecting group used for the nitrogen atom of the lactam group or the solid phase is then cleaved off, B) for the preparation of a compound of general formula (I) which contains an aminoethyl group and X represents an oxygen atom, a compound of general formula wherein R 1 to R ₄ have the meanings given in claims 1 to 6, and R ₇ has the meanings given to R ₅ at the outset, with the consideration that R ₅ contains a cyano group, optionally reduced so the compound of general formula (I) containing an alkoxycarbonyl group is converted to the corresponding carboxy compound by hydrolysis, or so the resultant compound of general formula (I) containing an amino or alkylamino group is converted to the corresponding alkylamino or dialkylamino compound by reductive alkylation, or the resulting compound of general formula (I) containing an amino or alkylamino group is e.g. is returned to the corresponding acyl compound by acylation, or the carboxy group compound of formula (I) thus obtained is converted to the corresponding ester or aminocarbonyl compound by esterification or amidation, or, if necessary, used during the reaction to protect the reactive groups the protective residue cleaves, or 100, if desired, the compound of formula (I) thus obtained is then separated into its stereoisomers, or the compound of formula (I) thus obtained is converted into its salts, in particular for pharmaceutically acceptable salts of inorganic or organic salts. acids or bases.