EP1224169A2 - Production of 5-substituted indolinones and use thereof as medicaments - Google Patents

Abstract

The invention relates to 5-substituted indolinones of general formula (I), where R<1> to R<5> and X are as defined in claim 1, the isomers and salts thereof, in particular, the physiologically acceptable salts, which exhibit valuable pharmacological properties. Said properties, in particular, include an inhibitory effect on various kinases and cyclin/CDK complexes, receptor thyrosine kinases and on the proliferation of tumour cells. The invention further relates to medicaments containing these compounds, use and methods for production thereof.

Description

 Indolinones substituted in the 5-position, their preparation and their use as medicaments

The present invention relates to new 5-substituted indolinones of the general formula

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

The above compounds of general formula I, in which R _{x represents} a hydrogen atom or a prodrug residue, have valuable pharmacological properties, in particular an inhibitory effect on various kinases, especially on complexes of CDK's (CDK1, CDK2, CDK3, CDK4, CDK5, CDK6, CDK7, CDK8 and CDK9) with their specific cyclins (A, BI, B2, C, Dl, D2, D3, E, F, Gl, G2, H, I and K) and on viral cyclin (see L. Mengtao in J. Virology 21 (3), 1984-1991 (1997))

Receptor tyrosine kinases such as VEGFR2, PDGFRα, PDGFRß, FGFR1, FGFR3, EGFR, HER2, IGF1R and HGFR and on the proliferation of cells, in particular tumor cells.

The remaining compounds of the general formula I above, in which R _{x represents} no hydrogen atom and no prodrug residue, represent valuable intermediates for the preparation of the compounds mentioned above. The present invention thus relates to the above compounds of the general formula I, where the compounds in which R _{x represents} a hydrogen atom or a prodrug residue have valuable pharmacological properties, the medicaments containing the pharmacologically active compounds, their use and process for their preparation.

In the above general formula I mean

X is an oxygen or sulfur atom,

R _{x is} a hydrogen atom or a prodrug residue such as a C 1-4 alkoxycarbonyl or C ₂ . ₄ -alkanoyl group,

R _{2 is} hydroxy, C - ^ - alkoxy, aryloxy, phenyl-C ^ alkoxy, cyano, (HO) ₂ PO-, (HO) (C ^ -alkoxy) PO-, (HO) ( Aryloxy) PO-, (HO) (benzyloxy) PO-, (C ^ alkoxy) ₂ PO-, (aryloxy) ₂ PO-, (benzyloxy) ₂ PO-, (C ^ alkylene dioxy) PO-, H (C ^ alkoxy) PO-, H (aryloxy) PO-, H (benzyloxy) PO-, mercapto, C ^ alkylmercapto, arylmercapto, phenyl-C ^ alkylmercapto, C ^ alkylsulfinyl, arylsulfinyl -, phenyl-C ^ -alkylsulfinyl-, C ^ -alkylsulfonyl-, arylsulfonyl-, phenyl-C ^ -alkylsulfonyl-, sulfo-, C - ^ - alk-oxysulfonyl-, aryloxysulfonyl-, phenyl-C ^ -alkoxysulfonyl-, Aminosulfonyl-, C ^ -alkylaminosulfonyl-, arylaminosulfonyl-, heteroarylaminosulfonyl-, phenyl-C ^ -alkylaminosulfonyl-, di- (C - ^ - alkyl) -aminosulfonyl-, di- (aryl) -aminosulfonyl-, di- (phenyl- C ^ alkyl) -aminosulfonyl-, N- (C ^ alkyl) -arylaminosulfonyl-, N- (C ^ alkyl) -heteroarylaminosulfonyl-, N- (Ci. _j -alkyl) -phenyl-C _{j ^. j} -alkylaminosulfonyl or a 4- to 7-membered cycloalkyleneiminosulfonyl group,

R _{3 is} a hydrogen atom, a C ^ _j alkyl, C ₃ . _7- cycloalkyl, trifluoromethyl or heteroaryl group, a phenyl or naphthyl group, one by a fluorine, chlorine, bromine or iodine atom, by a trifluoromethyl, C 1-4 alkyl or C - ^ - alkoxy group mono- or disubstituted phenyl or naphthyl group, in the case of disubstitution the substituents can be the same or different and the abovementioned unsubstituted, mono- and disubstituted phenyl and naphthyl groups additionally

by a hydroxy, hydroxy-C 1-4 alkyl or C 1-4 alkoxy C _1-3 alkyl group,

by a cyano, cyano-C ^ alkyl, cyano-C ₂ . _3- alkenyl, cyano-C ₂ . ₃ -alkynyl-, carboxy-, carboxy-C - ^ - _j -alkyl-, carboxy- C ₂ _ ₃ -alkenyl-, carboxy-C ₂ . ₃ -alkynyl-, C ^ - _j -alkoxycarbonyl-, C ^ -alkoxycarbonyl-C ^ - _j -alkyl-, C ^ -alkoxycarbonyl-C ^ - _j -alkenyl- or C ₁ . ₃ -alkoxycarbonyl-C ₂ . _3- alkynyl group,

by a C 1-4 alkylcarbonyl-, C ₁ _ ₃ -alkylcarbonyl-C ₁ _ ₃ -alkyl-, C _1.3 -alkylcarbonyl-C ₂ . _3- alkenyl or C ^ -alkylcarbonyl-C ₂ _ ₃ -alkynyl group,

by an aminocarbonyl-, aminocarbonyl-C ^ -alky! -, aminocarbonyl -C _2.3 -alkenyl-, aminocarbonyl -C ₂ _ ₃ -alkynyl-, C ^ - _1- kylaminocarbonyl-, C ₁ . _3- alkylaminocarbonyl-C ₁ . _3- alkyl-, C _1.3 -alkylaminocarbonyl-C ₂ . ₃ -alkenyl-, C ^. _j -Alkylaminocarbon-C ₂ . _3- alkynyl, di- (C _{1, 3} -alkyl) -aminocarbonyl-, di- (C ^ -alkyl) -aminocarbonyl-C ^ - _j -alkyl-, di- (C ^ -alkyl) - aminocarbonyl-C ₂ _ ₃ -alkenyl- or di- (C ^ -alkyl) -aminocarbonyl -C ₂ _ ₃ -alkynyl group,

by a nitro, nitro-C ^ alkyl, nitro-C ₂ . _3- alkenyl or nitro-C ₂ . _3- alkynyl group,

by an amino, C _1-3 alkylamino, di -amino-, amino-C ₁ . ₃ -alkyl-, C ₁ . ₃ -alkylamino-C ₁ _ ₃ -alkyl- or di- (C ^ -alkyl) -amino-C _1.3 -alkyl group, by a C ₁ . ₃ -alkylcarbonylamino-, C ₁ . ₃ -alkylcarbonylamino- C ₁ . ₃ -alkyl-, N- or N- (C ^ alkyl) -C - ^ - j-alkylcarbonylamino-C ^ alkyl group,

by a C 1-4 alkyl, N- (C 1-4 alkyl) -C ₁ . _3- alkylsulfonylamino or N- (C 1-4 alkyl) -C ₁ . _3- alkylsulfonylamino-C ₁ . ₃ -alkyl group,

by a C ^ - _j -alkylaminosulfonyl-, C ^ -alkylaminosulfonyl- N- (C _{1, 3-} alkyl) -C ^ -alkylaminosulfonyl-C - ^ - alkyl group,

by a Cycloalkylenimino-, Cycloalkyleniminocarbonyl-, Cycloalkyleniminosulfonyl-, Cycloalkylenimino-C ₁ _ ₃ -alkyl-, Cycloalkyleniminocarbonyl-C _j ^ -alkyl- or Cycloalkylen-iminosulfonyl-C _{j ^} . _j -alkyl group with 4 to 7 ring members each, the methylene group in position 4 in a 6 or 7-membered cycloalkyleneimino group being represented by an oxygen or sulfur atom, by a sulfinyl, sulfonyl, -NH or -N (C ^ - _j -Alkyl) group can be replaced,

or ₃ alkyl group may be substituted by a heteroaryl or heteroaryl-C ₁ _,

R _{4 is} a phenyl group,

one by a fluorine, chlorine, bromine or iodine atom, by a cyano, nitro, C 1-4 alkyl or trifluoromethyl group, by one optionally substituted by 1 to 3 fluorine atoms amino-C ₂ . ₃ -alkoxy-, di- (C ^ - _j -alkyl) -amino-C ₂ . ₃ -alkoxy- or benzylamino-C ₂ . ₃ -alkoxy group, substituted by a cycloalkyleneimino-C ₂ _ ₃ -alkoxy group with 4 to 7 ring members, by a C ^ -alkylmercapto, carboxy, C ^ - _j -alkoxycarbonyl, tetrazolyl or heteroaryl group phenyl, one by a 4- to 7-membered cycloalkyleneimino group in which

a methylene group linked to the imino group can be replaced by a carbonyl or sulfonyl group or

the cycloalkylene part can be condensed with a phenyl ring or

one or two hydrogen atoms each case by a C ^ - _j -Al- kylgruppe may be replaced and / or

each the methylene group in position 4 of a 6- or 7-membered cycloalkyleneimino group by a carboxy, C- _L . _j -alkoxycarbonyl-, aminocarbonyl-, C ^ -alkylaminocarbonyl-, di- (C ^ - _j -alkyl) -aminocarbonyl-, phenyl-C ^ -alkyl- amino- or N- (C - ^ - _j -alkyl ) -phenyl-C ^ - _j -alkylamino group substituted or

by an oxygen or sulfur atom, by a sulfinyl, sulfonyl, -NH-, -N (C ^ alkyl) -, -N (phenyl) -, -N (C ^ alkylcarbonyl) - or -N (benzoyl) group can be replaced,

substituted phenyl group,

a C _j ^ alkylphenyl group in the alkyl part

by an amino, C 1-4 alkylamino, di- (C 1-4 alkyl) amino, N- (phenyl-C _{1, 4-} alkyl) -C ₁ . ₄ -alkylamino-, ω-hydroxy-C ₂ . ₄ -alkyl- amino-, di- (ω-hydroxy-C ₂ _ ₄ -alkyl) -amino- or C ₃ . _7- cycloalkylamino group,

by a 4- to 7-membered cycloalkyleneimino group in which a methylene group linked to the imino group can be replaced by a carbonyl or sulfonyl group or

the cycloalkylene part with a phenyl group or with an oxazolo, imidazolo, thiazolo, optionally substituted by a fluorine, chlorine, bromine or iodine atom, by a nitro, C ^ alkyl, C ^ - _j alkoxy or amino group, Pyridino, pyrazino or pyrimidino group can be condensed or

one or two hydrogen atoms each through a C- _L .- _j alkyl, C _s . _7- cycloalkyl or phenyl group can be replaced or / and

each the methylene group in position 4 of a 6- or 7-membered cycloalkyleneimino group by a hydroxy, carboxy, C - ^ - alkoxycarbonyl, aminocarbonyl, C ^ - _j -alkylaminocarbonyl-, di- (C _{1. 3} - alkyl) -aminocarbonyl-, phenyl -C ^ alkylamino or N- (C ^ alkyl) phenyl-C ^ alkylamino group substituted or

by an oxygen or sulfur atom, by a sulphinyl, sulphonyl, -NH-, -N (C _{1 3} alkyl.) -, -N (phenyl) -, -N (C ^ alkyl-carbonyl) - or -N (benzoyl) group can be replaced,

by a 5- to 7-membered cycloalkenyleneimino group in which the double bond is isolated from the nitrogen atom, by a phenylamino, N- -phenylamino-, phenyl -C ^ - _j -alkylamino-, N- (C ^ alkyl) -phenyl-C ₁ . ₃ -alkylamino or di- (phenyl-C ^ -alkyl) -amino group,

by a hydroxy, C ^ alkoxy, tetrazolyl, carboxy, , Aminocarbonyl, C ₁ . ₃ -Alkylaminocarbonyl-, di- (C ^ -alkyl) -aminocarbonyl-, C ₁ . _3- alkylcarbonylamino or N- (C ^ alkyl) -C ^ alkylcarbonylamino group or is substituted by a 4- to 7-membered cycloalkyleneiminocarbonyl group,

one by the group of formula

-N ⁽ R _a ⁾ -CO- (CH ₂ ⁾ _n -Rb (II),

substituted phenyl group in which

R _{a is} a hydrogen atom or a C ₁ . ₃ -alkyl group,

n one of the numbers 0, 1, 2 or 3 and

R _{b is} an amino, C - ^ - alkylamino, phenylamino, N- (C - ^ - alkyl) phenylamino, benzylamino, N- (C _{1, 4} alkyl) benzylamino or di (C - ^ - alkyl) amino group, a 4- to 7-membered cycloalkyleneimino group, the methylene group in position 4 of a 6- or 7-membered cycloalkyleneimino group being represented by an oxygen or sulfur atom, by a sulfinyl, sulfonyl, NH-, -N (C ^ -alkyl) -, -N (phenyl) -, -N (C _{1, 3-} alkyl-carbonyl) - or -N (benzoyl) - group can be replaced, or, if n one which represents numbers 1, 2 or 3, also denote a hydrogen atom,

or one through the group of formula

-N (R _C ) - (CH ₂ ) _m - (C0) _o -R _d (III),

substituted phenyl group in which

R _{c is} a hydrogen atom, a C ^ alkyl group, a C ^ - _j alkylcarbonyl, arylcarbonyl, phenyl-C ^ alkylcarbonyl, C ^ alkylsulfonyl, arylsulfonyl or phenyl-C ^ alky1sulfonyl group .

m one of the numbers 1, 2, 3 or 4, o one of the numbers 0 or 1 and

R _{d is} an amino, C ^ alkylamino, phenylamino, N- (C ^ alkyl) phenylamino, benzylamino, N- (C - ^ - alkyl) benzylamino or di (C- ^ alkyl) amino group, a 4- to 7-membered cycloalkyleneimino group, where the cycloalkylene part can be condensed with a phenyl ring or the methylene group in position 4 of a 6- or 7-membered cycloalkyleneimino group by an oxygen or sulfur atom, by a sulfinyl -, sulphonyl, -NH-, -N (. C ₁ -A1- ₃ alkyl) -, -N (phenyl) -, -N (C _{1 3} alkyl-carbonyl.) - or -N (as benzoyl ) - Group can be replaced, a C ₁ . ₃ alkoxy group or a 1-position optionally by a C ^ pe -Alkylgrup- substituted di (C _{1. 4} alkyl) amino-C _{j ^. j} denotes alkylamino group,

or, if R _{3 is} not the meaning of a hydrogen atom, one C ₃ . _7- cycloalkyl or trifluoromethyl group, also has an arylsulfonylaminophenyl or N- (C _{1, 3-} alkyl) arylsulfonylaminophenyl group,

where all the single-bonded or fused-on phenyl groups contained in the radicals mentioned under R ₄ by fluorine, chlorine, bromine or iodine atoms, by C ^ -alkyl, trifluoromethyl, C _{j ^} . _j -alkoxy, carboxy, C _1-3 -alkoxycarbonyl, aminosulfonyl, nitro or cyano groups can be mono- or disubstituted, where the substituents can be the same or different, or two adjacent hydrogen atoms of the phenyl groups by a methylenedioxy group can be replaced,

and

R _{5 is} a hydrogen atom or a C 1-4 alkyl group, an existing carboxy, amino or imino group can additionally be substituted by a residue which can be split off in vivo and can thus be present in the form of a prodrug residue,

and under a residue which can be split off from an imino or amino group in vivo, for example a hydroxyl group, an acyl group such as the benzoyl or pyridinoyl group or a C- _L .- _L g-alkanoyl group such as the formyl, acetyl, propionyl, Bu- tanoyl, pentanoyl or hexanoyl group, an allyloxycarbonyl group, a such as the methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, tert. Butoxycarbonyl, pentoxycarbonyl, hexyloxycarbonyl, octyloxycarbonyl, nonyloxycarbonyl, decyloxycarbonyl, undecyloxycarbonyl, dodecyloxycarbonyl or hexadecyloxycarbonyl group, a nyl group such as the benzyloxycarbonyl, phenylethoxycarbonyl or phenylpropoxycarbonyl group, a C 1-4 alkylsulfonyl C ₂ . ₄ -alkoxycarbonyl-, C _1-3 -alkoxy-C ₂ . ₄ -alkoxy-C ₂ . ₄ -alkoxycarbonyl or R _e CO-0- (R _f CR _g ) -O-CO group, in which

R _{e is} C ^ _a alkyl, C ₅ . _7- cycloalkyl, phenyl or phenyl - C 1-4 alkyl group,

R _{f is} a hydrogen atom, a C ^ alkyl, C _s . _7- cycloalkyl or phenyl group and

R _{g is} a hydrogen atom, a C ^ - _j alkyl or

R _{e represents} CO-0- (R _f CR _g ) -O group in which R _e to R _g are defined as mentioned above,

where the phthalimido group is additionally to be understood for an amino group, the ester radicals mentioned above also being able to be used as a group which can be converted into a carboxy group in vivo,

furthermore, the term an aryl group means one optionally by a fluorine, chlorine or bromine atom, by a Trifluoromethyl, C ₁ . _3- alkyl, C 1-4 alkoxy or nitro group mono- or disubstituted phenyl or naphthyl group and

a heteroaryl group means a monocyclic 5- or 6-membered heteroaryl group which is optionally substituted by a C 1-4 alkyl group, the 6-membered heteroaryl group having one, two or three nitrogen atoms and the 5-membered heteroaryl group one optionally having a C _{1- 3} alkyl group substituted imino group, an oxygen or sulfur atom or an imino group optionally substituted by a C 1-4 alkyl group and an oxygen or sulfur atom or one or two nitrogen atoms, and also to the monocyclic heterocyclic groups mentioned above a phenyl ring may be fused on via two adjacent carbon atoms.

Furthermore, the definition of the above-mentioned saturated alkyl and alkoxy parts which contain more than 2 carbon atoms also include their branched isomers such as the isopropyl, tert-butyl, isobutyl group, etc., unless stated otherwise.

Preferred compounds of the above general formula I are those in which

X is an oxygen atom,

R _{x is} a hydrogen atom, a C ₁ _ ₄ alkoxycarbonyl or C ₂ . ₄ -alkanoyl group,

R _{2 is} a C ^ - _j alkoxy, C ^ - _j alkyl mercapto, C ^ alkyl sulfinyl, C _1-3 alkyl sulfonyl, cyano, (C _1-4 alkoxy) ₂ P0, (C ^ -Alkylene-dioxy) PO-, aminosulfonyl-, C ₁ . ₄ alkylaminosulfonyl, di- (C _x "-. Alkyl) -aminosulfonyl-, phenylaminosulphonyl, N- (C ^ alkyl) -Phe- nylaminosulfonyl-, Pyridylaminosulfonyl- or N- (C _{1 3} alkyl.) - pyridylaminosulfonyl group, the phenyl radicals contained in the groups mentioned being replaced by fluorine, chlorine or bromine atoms, by C ^ alkyl, trifluoromethyl, C ₁ . ₃ -alkoxy, carboxy, C ^ -alkoxycarbonyl, aminosulfonyl, nitro or cyano groups can be mono- or disubstituted, where the substituents can be the same or different,

R _{3 is} a phenyl or naphthyl group,

one by a fluorine, chlorine, bromine or iodine atom, by a C 1-4 alkyl, trifluoromethyl, hydroxy, C ₁ . ₃ -alkoxy-, nitro-, cyano-, amino-, C _j ^ -alkylamino-, di- (C ^ -alkyl) -amino-, C - ^ - alkylcarbonylamino-, N- (C ^ -alkyl) -C ^ alkylcarbonylamino, C ^ alkylcarbonyl, carboxy, C ₁ . _3- alkoxycarbonyl, aminocarbonyl, C- _L ^ -alkylaminocarbonyl or di- (C _1-3 alkyl) aminocarbonyl group substituted phenyl or naphthyl group,

R _{4 is} a phenyl group,

one by a fluorine, chlorine, bromine or iodine atom, by a cyano, nitro, C ₁ . _3- alkyl-, trifluoromethyl-, C ^ -alkoxy-, di- (C ^ -alkyl) -amino-C ₁ _ ₃ -alkoxy-, C ^ -alkylmercapto-, carboxy-, 0 ^ ₃ -alkoxycarbonyl-, pyrrolyl -, furanyl, thienyl, oxazolyl, thiazolyl, imidazolyl, pyridinyl or pyrimidinyl group substituted phenyl group,

one by a 5- to 7-membered cycloalkyleneimino group in which

a methylene group linked to the imino group can be replaced by a carbonyl or sulfonyl group or

the cycloalkylene part can be condensed with a phenyl ring or

one or two hydrogen atoms can each be replaced by a C 1-4 alkyl group or / and in each case the methylene group in position 4 bonyl- or a 6- or 7-membered cycloalkyleneimino group by a carboxy, C ^ alkoxycarbonyl, aminocarbonyl, C ^ -Alkylaminocar- aminocarbonyl group substituted di (alkyl C _{1. 3,)} or

can be replaced by an oxygen or sulfur atom, by a sulfonyl, sulfonyl, -NH or -N (C _{1, 3} -alkyl) group,

substituted phenyl group,

a C ₁ . _4- n-alkylphenyl group, which is terminal in the alkyl part

by an amino, C ^ alkylamino, di (C - ^ - alkyl) amino, N - (phenyl-C ^ ₂ alkyl) -C ₁ . ₄ -alkylamino-, 2 -hydroxyethy1-amino-, di- (2-hydroxyethyl) -amino or C _5-6 -cycloalkyl-amino group,

by a 5- to 7-membered cycloalkyleneimino group in which

one or two hydrogen atoms each through a C ₁ . ₃ alkyl group can be replaced or

the methylene group in the 4-position of a piperidino group by a carboxy, C ^ - _j alkoxycarbonyl, aminocarbonyl, C _j ^ alkylaminocarbonyl or di- (C _{1 3} alkyl.) aminocarbonyl group substituted or

the cycloalkylene with a phenyl group or an optionally by a fluorine, chlorine or bromine atom, by a C ^ - alkyl or C _{j. 1 3} -alkoxy group substituted imidazolo or pyridino group can be condensed or can be replaced by an oxygen or sulfur atom, by a sulfinyl, sulfonyl, -NH or -N (C _1-3 -alkyl) group,

by a 3-pyrrolin-l-yl or 3,4-dehydropiperidino group, by a phenylamino, N- (C 1-4 alkyl) -phenylamino, phenyl-C ₁ . ₃ -alkylamino-, N- (C ^ -alkyl) -phenyl -C - ^ - alkylamino or di- (phenyl-C ^ -alkyl) -amino group,

by an aminocarbonyl, C ^ alkylaminocarbonyl,

Di- (C ₁ _ ₃ -alkyl) -aminocarbonyl-, C ^ - _j -alkylcarbonylamino- or

N- (C - ^ - _j alkyl) -C ^ alkylcarbonylamino group is substituted,

one by the group of formula

-N ⁽ R _a ⁾ -CO- ⁽ CH ₂ ⁾ _n -Rb ⁽ II ⁾ ,

substituted phenyl group in which

R _{a is} a hydrogen atom or a C ^ alkyl group,

n one of the numbers 0, 1 or 2 and

R _{b is} an amino, C _1-4 alkylamino, di (C ^ alkyl) amino, phenylamino or benzylamino group or a 5- to 6-membered cycloalkyleneimino group, the methylene group in position 4 of the piperidino group being replaced by a Oxygen or sulfur atom, can be replaced by a sulfinyl, sulfonyl, -NH or -N (C ^ alkyl) group, or, if n represents the number 1 or 2, also represent a hydrogen atom,

or one through the group of formula

-N (R _c ) - (CH ₂ ) _m - (C0) _o -R _d (III), substituted phenyl group in which

R _{c is} a hydrogen atom, a C _1-3 alkyl, C ^ - _j alkylcarbonyl or C ₁ _ ₃ alkylsulfonyl group,

m one of the numbers 1, 2 or 3,

o mean one of the numbers 0 or 1 and

R _{d is} an amino, C 1-4 alkylamino, di (C 1-4 alkyl) amino, phenylamino or benzylamino group or a 5- to 6-membered cycloalkyleneimino group, the methylene group in position 4 of the piperidino group being replaced by an oxygen or sulfur atom, can be replaced by a sulfinyl, sulfonyl, -NH or -N [C _ ₃ -alkyl) group, a di- (C ^ -alkyl) optionally substituted in the 1-position by a C ^ -alkyl group ) -amino-C ^ - _j -alkylamino group or, if n represents the number 1 or 2, also denote a hydrogen atom,

or a phenylsulfonylaminophenyl or

N- (C 1-4 alkyl) phenylsulfonylaminophenyl group,

where all the single-bonded or fused phenyl groups contained in the radicals mentioned under R ₄ by fluorine, chlorine or bromine atoms, by C 1-4 alkyl, trifluoromethyl, C ₁ . ₃ -alkoxy-, carboxy-, C ^ -alkoxycarbonyl, aminosulfonyl, nitro or cyano groups can be mono- or disubstituted, where the substituents can be the same or different, or two adjacent hydrogen atoms of the phenyl groups can be replaced by a methylenedioxy group can, and

R _{5 represents} a hydrogen atom or a methyl group,

their isomers and their salts. Particularly preferred compounds of the general formula I above are those in which

X is an oxygen atom,

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

R _{2 is} a C ₁ . ₃ alkoxy, C ^ alkylmercapto, C - ^ - (. C _{1 4} alkoxy) alkylsulfinyl, C- ^ _j alkylsulfonyl, cyano, ₂ P0, aminosulfonyl, C ^ alkylaminosulfonyl, di- (C _{1 4} alkyl.) -aminosulfonyl-, Phe nylaminosulfonyl-, N- (C - ^ - alkyl) -phenylaminosulfonyl-, 3-pyridine dylaminosulfonyl- or N- (C _{1 3} alkyl.) - 3-pyridylaminosulfonyl group, the phenyl radicals contained in the groups mentioned being replaced by a fluorine, chlorine or bromine atom, a C ₁ . ₃ -alkyl-, trifluoromethyl-, C ₁ . ₃ -alkoxy, nitro or cyano group can be substituted,

R _{3 is} a phenyl or naphthyl group, but especially the phenyl group,

R _{4 is} a phenyl group,

one by a fluorine, chlorine, bromine or iodine atom, by a cyano, nitro, C ^ alkyl, trifluoromethyl, C ^ alkoxy, di (C ^ alkyl) amino C ^ - _j -alkoxy-, C ^ -alkylmercapto, carboxy, C ^ -alkoxycarbonyl, pyridinyl or imidazolyl group substituted phenyl group,

a phenyl group substituted by a pyrrolidino, piperidino, 2, 6-dimethylpiperidino, 3, 5-dimethylpiperidino or azepino group, where

the methylene group in position 4 of the piperidino group by a carboxy, C ^ _j -alkoxycarbonyl, aminocarbonyl, C ₁ . ₃ -Alkylaminocarbonyl- or di- (C ^ alkyl) aminocarbonyl group substituted or can be replaced by an oxygen or sulfur atom, by a sulfonyl, sulfonyl, -NH or -N (C ^ -alkyl) group,

a those in the alkyl part terminal

by an amino, C 1-4 alkylamino or di- (C 1-4 alkyl) amino group,

by an N- (phenylmethyl) -C ^ alkylamino group which is monosubstituted in the phenyl part by a fluorine, chlorine or bromine atom, a C ^ alkyl, C ^ - _j alkoxy, trifluoromethyl or cyano group or can be disubstituted by two C 1-4 alkyl or C 1-4 alkoxy groups,

by a 2-hydroxyethylamino, di (2-hydroxyethyl) amino, cyclopentylamino or cyclohexylamino group,

by a pyrrolidino, piperidino, 2, 6-dimethyl-piperidino, 3, 5-dimethyl-piperidino or cyclohexyleneimino group, where

the methylene group in position 4 of the piperidino group by a carboxy, C ^ alkoxycarbonyl, aminocarbonyl, C- _{L. j} -Alkylaminocarbonyl- or di- (C ^ -alkyl) -aminocarbonyl group substituted or

can be replaced by an oxygen or sulfur atom, by a sulfinyl, sulfonyl, -NH or -N (C ^ -alkyl) group,

or the cycloalkylene part can be condensed with a phenyl group,

by a 3-pyrrolin-1-yl or 3,4-dehydropiperidino group, by a phenylamino, N- (C 1-4 alkyl) phenylamino, Phenyl -C ₁ . ₃ -alkylamino-, N- (C ^ -alkyl) -phenyl-C ^ -alkyl-amino- or di- (phenyl-C ^., - alkyl) -amino group,

by an aminocarbonyl, C ^ alkylaminocarbonyl,

Di- (C _x _ ₃ alkyl) aminocarbonyl, C ^ alkylcarbonylamino or

N- is substituted,

one by the group of formula

-N (R _a ) -CO- (CH ₂ ) _n -R _b (II),

substituted phenyl group in which

R _{a is} a C ^ alkyl group,

n one of the numbers 0, 1 or 2 and

R _{b is} an amino, C _1-4 alkylamino, di (C _1-4 alkyl) amino, pyrrolidino or piperidino group, the methylene group in position 4 of the piperidino group being represented by an oxygen or sulfur atom, by a sulfinyl , Sulfonyl, -NH or -N (C _x . ₃ -alkyl) group can be replaced, mean

or one through the group of formula

-N (R _C ) - (CH ₂ ) _m - (C0) _o -R _d (III),

substituted phenyl group in which

R _{c is} a C ₁ . _3- alkylcarbonyl or C _1-3 -alkylsulfonyl group,

m one of the numbers 1, 2 or 3,

o mean one of the numbers 0 or 1 and R _{d is} an amino, C ₁ . ₃ alkylamino, di (C _{1. 4,} alkyl) amino, pyrrolidino or piperidino group wherein the methylene group in position 4 of the piperidino group by an oxygen or sulfur atom, by a sulphinyl, sulphonyl, -NH- or ₍₃ alkyl C. ₁₎ may be replaced -N group or in the 1-position is optionally substituted by a C - ^ - substituted alkyl group, di- (C ^ _j alkyl) amino-C ^ alkylamino group,

or a phenylsulfonylaminophenyl or N- (C _1-3 alkyl) phenylsulfonylaminophenyl group,

where all the single-bonded or fused-on phenyl groups contained in the radicals mentioned under R _{4 are} replaced by a fluorine, chlorine or bromine atom, by a methyl, trifluoromethyl, methoxy, carboxy, methoxycarbonyl, ethoxycarbonyl, aminosulfonyl, Nitro or cyano group can be substituted or two neighboring hydrogen atoms of the phenyl groups can be replaced by methoxy groups or by a methylenedioxy group, and

R _{5 represents} a hydrogen atom,

their isomers and their salts.

The following may be mentioned as particularly preferred compounds:

(a) 3-Z- [1- (4- (piperidin-1-ylmethyl) anilino) -1-phenylmethylene] -5-methylsulfinyl-2-indolinone,

(b) 3-Z- [1- (4- (piperidin-1-ylmethyl) anilino) -1-phenylmethylene] -5-methylsulfonyl -2 - indolinone,

(c) 3-Z- [1- (4- (Piperidin-1-ylmethyl) anilino) -1-phenylmethylene] -5- (N-methyl-N-phenylaminosulfonyl) -2 -indolinon, (d) 3-Z- [1- (4- (Piperidin-1-ylmethyl) anilino) -1-phenylmethylene] -5- (N-butyl-N-methylaminosulfonyl) -2-indolinone .

(e) 3-Z- [1- (4- (piperidin-1-ylmethyl) anilino) -1-phenylmethylene] -5- (phenylaminosulfonyl) -2-indolinone,

(f) 3-Z- [1- (4- (piperidin-1-ylmethyl) anilino) -1-phenylmethylene] -5-diethoxyphosphoryl-2 - indolinone,

(g) 3-Z- [1- (4- ((N-benzyl-N-methylamino) methyl) anilino) -1-phenylmethylene] -5-diethoxyphosphoryl-2-indolinone,

(h) 3-Z- [1- (4- (N- (2-Dimethylamino-ethyl) -N-methylsulfonylamino) anilino) -1-phenylmethylene] -5-diethoxyphosphoryl-2-indoli - non,

(i) 3-Z- [1- (4- (N- (dimethylaminocarbonyl-methyl) -N-methylsulfonylamino) anilino) -1-phenylmethylene] -5-diethoxyphosphoryl - 2 -indolinone,

(j) 3-Z- [1- (4- (N-dimethylaminomethylcarbonyl-N-methylamino) anilino) -1-phenylmethylene] -5-diethoxyphosphoryl-2-indolinone,

(k) 3-Z- [1- (4- (2-dimethylaminoethyl) anilino) -1-phenylmethylene] -5- (phenylaminosulfonyl) -2-indolinone,

(1) 3-Z- [1- (4- (dimethylamino-methyl) anilino) -1-phenylmethylene] -5- (phenylaminosulfonyl) -2-indolinone,

(m) 3-Z- [1- (4- (N-methylacetylamino) anilino) -1-phenylmethylene] -5- (phenylaminosulfonyl) -2-indolinone and

(n) 3-Z- [1- (4- (N-Methylpiperazin-1-yl) anilino) -1-phenylmethylene] -5- (phenylaminosulfonyl) -2-indolinone

as well as their isomers and their salts. According to the invention, the new compounds are obtained, for example, by the following processes which are known in principle from the literature:

a. Implementation of a compound of the general formula

in the

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

Z _{1 represents} a halogen atom, a hydroxyl, alkoxy or aryloxy group, for example a chlorine or bromine atom, a methoxy, ethoxy or benzyloxy group,

with an amine of the general formula

in the

R ₄ and R _s are defined as mentioned at the beginning, and if necessary subsequent cleavage of a protective group used for the nitrogen atom of the lactam group or from a solid phase. A protective group for the nitrogen atom of the lactam group is, for example, an acetyl, benzoyl, ethoxycarbonyl, tert. - Butyloxycarbonyl or benzyloxycarbonyl group and

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

The reaction is advantageously carried out in a solvent such as dimethylformamide, toluene, acetonitrile, tetrahydrofuran, dimethyl sulfoxide, methylene chloride or mixtures thereof, optionally in the presence of an inert base such as triethylamine, N-ethyl-diisopropylamine or sodium hydrogen carbonate at temperatures between 20 and 175 ° C, one protective group used can be split off simultaneously as a result of transamidation.

If Z ₁ in a compound of the general formula II denotes a halogen atom, the reaction is preferably carried out in the presence of an inert base at temperatures between 20 and 120 ° C.

Z _] _ means in a compound of the general formula II

Hydroxy, alkoxy or aryloxy group, then the reaction is preferably carried out at temperatures between 20 and 200 ° C.

The subsequent splitting off of a protective group which may be required is expediently carried out either hydrolytically in an aqueous or alcoholic solvent, for example in methanol / water, ethanol / water, isopropanol / water, tetrahydrofuran / water, dioxane / water, dirnethylformamide / water, methanol or ethanol Presence of an alkali base such as lithium hydroxide, sodium hydroxide or potassium hydroxide Temperatures between 0 and 100 ° C, preferably at temperatures between 10 and 50 ° C,

or advantageously by transamidation with an organic base such as ammonia, butylamine, dimethylamine or piperidine in a solvent such as methanol, ethanol, dimethylformamide and mixtures thereof or in an excess of the amine used at temperatures between 0 and 100 ° C., preferably at Temperatures between 10 and 50 ° C, carried out.

A solid phase used is preferably cleaved off using trifluoroacetic acid and water at temperatures between 0 and 35 ° C., preferably at room temperature.

b. For the preparation of a compound of the general formula I in which R _{2 represents} one of the substituted sulfinyl or sulfonyl groups mentioned at the outset:

Oxidation of a compound of the general formula

in the

R ₁ and R ₃ to R ₅ are defined as mentioned at the outset and

R represents one of the substituted mercapto or sulfinyl groups mentioned at the outset for R ₂

The oxidation is preferably carried out in a solvent or solvent mixture, for example in water, water / pyridine, acetone, methylene chloride, acetic acid, acetic acid / acetic anhydride, dilute sulfuric acid or trifluoroacetic acid, depending on the oxidizing agent used advantageously carried out at temperatures between -80 and 100 ° C.

To prepare a corresponding sulfinyl compound of general formula I, the oxidation is conveniently carried out with one equivalent of the oxidizing agent used, e.g. with hydrogen peroxide in glacial acetic acid, trifluoroacetic acid or formic acid at 0 to 20 ° C or in acetone at 0 to 60 ° C, with a peracid such as performic acid in glacial acetic acid or trifluoroacetic acid at 0 to 50 ° C or with m-chloroperbenzoic acid in methylene chloride, chloroform or dioxane at -20 to 80 ° C, with sodium metaperiodate in aqueous methanol or ethanol at -15 to 25 ° C, with bromine in glacial acetic acid or aqueous acetic acid, optionally in the presence of a weak base such as sodium acetate, with N-bromosuccinimide in ethanol, with tert , - Butyl hypochlorite in methanol at -80 to -30 ° C, with iodobenzo dichloride in aqueous pyridine at 0 to 50 ° C, with nitric acid in glacial acetic acid at 0 to 20 ° C, with chromic acid in glacial acetic acid or in acetone at 0 to 20 ° C and with sulfuryl chloride in methylene chloride at -70 ° C, the thioether-chlorine complex obtained is expediently hydrolyzed with aqueous ethanol.

To prepare a sulfonyl compound of the general formula I, the oxidation is advantageously carried out with a corresponding sulfinyl compound using one or more equivalents of the oxidizing agent used or, starting from a corresponding mercapto compound, advantageously with two or more equivalents of the oxidizing agent used, for example with hydrogen peroxide in glacial acetic acid / acetane hydride, trifluoroacetic acid or in formic acid at 20 to 100 ° C or in acetone at 0 to 60 ° C, with a peracid such as performic acid or m-chloroperbenzoic acid in glacial acetic acid, trifluoroacetic acid, methylene chloride or chloroform at temperatures between 0 and 60 ° C, with nitric acid in glacial acetic acid at 0 to 20 ° C, with chromic acid, sodium periodate or potassium perma- ganate in acetic acid, water / sulfuric acid or in acetone at 0 to 20 ° C.

If, according to the invention, a compound of the general formula I is obtained which contains an alkoxycarbonyl group, this can be converted into a corresponding carboxy compound by means of hydrolysis, or

a compound of the general formula I which contains an amino or alkylamino group, this can be converted into a corresponding alkylamino, dialkylamino or pyrrolidino compound by means of alkylation or reductive alkylation, or

a compound of the general formula I which contains an amino or alkylamino group, this can be converted into a corresponding acyl compound by means of acylation, or

a compound of the general formula I which contains a carboxy group, this can be converted into a corresponding ester or aminocarbonyl compound by esterification or amidation, or

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

The subsequent hydrolysis is preferably carried out in an aqueous solvent, for example in water, methanol / water, ethanol / 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 one Alkali base such as lithium hydroxide, sodium hydroxide or potassium hydroxide at temperatures between 0 and 100 ° C, preferably at temperatures between 10 and 50 ° C. The subsequent reductive alkylation is preferably carried out in a suitable solvent such as methanol, methanol / water, methanol / water / ammonia, ethanol, ether, tetrahydrofuran, dioxane or dimethylformamide, optionally with the addition of an acid such as hydrochloric acid in the presence of catalytically excited hydrogen, for example from Hydrogen in the presence of Raney nickel, platinum or palladium / carbon, or in the presence of a metal hydride such as sodium borohydride, lithium borohydride, sodium cyanoborohydride or lithium aluminum hydride at temperatures between 0 and 100 ° C, preferably at temperatures between 20 and 80 ° C.

The subsequent acylation is preferably carried out in a solvent such as methylene chloride, diethyl ether, tetrahydrofuran, toluene, dioxane, acetonitrile, dimethyl sulfoxide or diethylformamide, if appropriate in the presence of an inorganic or a tertiary organic base, preferably at temperatures between 20 ° C. and the boiling point of the solvent used. Here, the acylation with an appropriate acid is preferably carried out in the presence of a dehydrating agent, for example in the presence of isobutyl chloroformate, tetraethyl orthocarbonate, trimethyl orthoacetate, 2, 2-dimethoxypropane, tetra-methoxysilane, thionyl chloride, trimethylchlorosilane, phosphorus trichloride, phosphorus trichloride, phosphorus trichloride, phosphorus Dicyclohexylcarbodiimide, N, N '-dicyclohexylcarbodiimide / N-hydroxysuccinimide, N, N' -dicyclohexylcarbodiimide / l-hydroxy-benzotriazole, 2- (1H-benzotriazol-1-yl) -1,1,3, 3- tetramethyluronium tetrafluoroborate, 2- (1H-benzotriazol-1-yl) -1,1,3, 3-tetramethyluronium tetraffluoroborate / l-hydroxy-benzotriazole, N, N '-carbonyldiimidazole or triphenylphosphine / carbon tetrachloride, and optionally with the addition of one Base such as pyridine, 4-dimethylamino-pyridine, N-methylmorpholine or triethylamine advantageously at temperatures between 0 and 150 ° C, preferably at temperatures between 0 and 100 ° C, and the acylation with a corresponding reactive compound such as its anhydride, ester, imidazolide or halide, optionally in the presence a tertiary organic base such as triethylamine, N-ethyl-di-isopropylamine, N-methyl-morpholine or pyridine at temperatures between 0 and 150 ° C, preferably at temperatures between 50 and 100 ° C.

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

The subsequent reduction of a nitro group is preferably carried out hydrogenolytically, e.g. with hydrogen in the presence of a catalyst such as palladium / carbon or Raney nickel in a solvent such as methanol, ethanol, ethyl acetate, dimethylformamide, dimethylformamide / acetone or glacial acetic acid, optionally with the addition of an acid such as hydrochloric acid or glacial acetic acid at temperatures between 0 and 50 ° C. , but preferably at room temperature, and at a hydrogen pressure of 1 to 7 bar, but preferably from 3 to 5 bar.

In the reactions described above, any reactive groups present, such as carboxy, aminosulfonyl, amino, alkylamino or imino groups, can be protected during the reaction by customary protective groups which are split off again after the reaction.

For example, the trimethylsilyl, methyl, ethyl, tert-butyl, benzyl or tetrahydropyranyl group and comes as a protective radical for a carboxyl group

as a protective radical for an amino, alkylamino or imino group, the acetyl, trifluoroacetyl, benzoyl, ethoxycarbonyl, tert. Butoxycarbonyl-, Benzyloxycarbonyl-, Benzyl-, Methoxy- benzyl- or 2, 4-Dimethoxybenzylgruppe and for the amino group additionally the phthalyl group into consideration. The optional subsequent removal of a protective radical used takes place, for example, hydrolytically in an aqueous solvent, for example in water, isopropanol / water, tetrahydrofuran / water or dioxane / water, in the presence of an acid such as trifluoroacetic acid, hydrochloric acid or sulfuric acid or in the presence of an alkali base such as lithium hydroxide , Sodium hydroxide or potassium hydroxide at temperatures between 0 and 100 ° C, preferably at temperatures between 10 and 50 ° C.

However, a benzyl, methoxybenzyl or benzyloxycarbonyl radical is split off, for example by hydrogenolysis, e.g. with hydrogen in the presence of a catalyst such as palladium / carbon in a solvent such as methanol, ethanol, ethyl acetate, dimethylformamide, dimethylformamide / acetone or glacial acetic acid, optionally with the addition of an acid such as hydrochloric acid or glacial acetic acid at temperatures between 0 and 50 ° C., but preferably at Room temperature, and at a hydrogen pressure of 1 to 7 bar, but preferably from 3 to 5 bar.

A methoxybenzyl group can also be split off in the presence of an oxidizing agent such as cerium (IV) ammonium nitrate in a solvent such as methylene chloride, acetonitrile or acetonitrile / water at temperatures between 0 and 50 ° C., but preferably at room temperature.

However, a 2,4-dimethoxybenzyl radical is preferably cleaved in trifluoroacetic acid in the presence of anisole.

A tert-butyl or tert-butyloxycarbonyl radical is preferably cleaved off by treatment with an acid such as trifluoroacetic acid or hydrochloric acid, optionally using a solvent such as methylene chloride, dioxane, ethyl acetate or ether.

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

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

For example, the compounds of general formula I obtained which occur in racemates can be converted into their optical antipodes and by known methods (see Allinger NL and Eliel EL in "Topics in Stereochemistry", Vol. 6, Wiley Interscience, 1971) Compounds of the general formula I with at least 2 asymmetric carbon atoms on the basis of their physico-chemical differences according to methods known per se, for example by chromatography and / or fractional crystallization, into their diastereomers, which, if they occur in racemic form, can then be separated into the enantiomers as mentioned above.

The enantiomers are separated preferably by column separation on chiral phases or by recrystallization from an optically active solvent or by reaction with an optically active substance which forms salts or derivatives, such as esters or amides, for example esters or amides, in particular acids and their activated derivatives or alcohols, and Separating the mixture of diastereomeric salts or derivatives obtained in this way, for example on the basis of different solubilities, it being possible for the free antipodes to be released from the pure diastereomeric salts or derivatives by the action of suitable agents. Particularly common, optically active acids are, for example, the D and L forms of tartaric acid, dibenzoyl tartaric acid, di-o-tolyltartaric acid, malic acid, mandelic acid, camphorsulfonic acid, glutamic acid, N-acetylglutamic acid, aspartic acid, N-acetyl-aspartic acid or quinic acid. As an optically active alcohol, for example (+) - or (-) menthol and the optically active acyl radical in amides, for example the (+) - or (-) menthyloxycarbonyl radical.

Furthermore, the compounds of the formula I obtained can be converted into their salts, in particular for pharmaceutical use into their physiologically tolerable salts with inorganic or organic acids. Suitable acids for this are, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, fumaric acid, succinic acid, lactic acid, citric acid, tartaric acid, maleic acid or methanesulfonic acid.

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

Some of the compounds of the general formulas IV to VI used as starting products are known from the literature or can be obtained by processes known from the literature or can be obtained by the processes described above and in the examples. For example, the compounds of general formula VI are described in German patent application 198 24 922.5.

As already mentioned at the beginning, the new compounds of the general formula I in which R _{1 represents} a hydrogen atom or a prodrug residue have valuable pharmacological properties, in particular inhibitory effects on various kinases and cyclin / CDK complexes, on the proliferation of cultured human tumor Cells as well as after oral Given for the growth of tumors in nude mice infected with human tumor cells.

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

Inhihie-ning of Cyclin / CnK-F.nzym, -Ak i vi tat in vitro

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

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

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

Test 2

Inhibition of the profiling of cultured human tumor-1 PTI

Cells of the Leiomyosarcoma tumor cell line SK-UT-1B (obtained from the American Type Culture Collection (ATCC)) were in minimum essential medium with non-essential amino acids (Gibco), supplemented with sodium pyruvate (1 mmol), glutamine (2nd mmol) and 10% fetal bovine serum (Gibco) and harvested in the log growth phase. Then the SK

UT-IB cells were placed in Cytostar® multi-well plates (Amersham) with a density of 4000 cells per well and incubated overnight in an incubator. Different concentrations of the compounds (dissolved in DMSO; final concentration: <1%) were added to the cells. After 48 hours of incubation, ¹⁴ C-thymidine (Amersham) was added to each well and incubation was continued for 24 hours. The amount of

³ - ^4, which has been incorporated in the presence of the inhibitor in the tumor cells C-thymidine and represents the number of cells in the S phase was measured in a Wallace 1450 Microbeta Liquid Scintillation Counter measured. IC50 values for the inhibition of proliferation (= inhibition of built-in ¹⁴ C-thymidine) were calculated - with correction for the background radiation. All measurements were carried out twice. Table 1 below contains the results of in vitro test 2:

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

Such diseases include (without claim to completeness): viral infections (eg HIV and Kaposi's sarcoma); Inflammation and autoimmune diseases (eg colitis, arthritis, Alzheimer's disease, glomerulonephritis and wound healing); bacterial, fungal and / or parasitic infections; Leukemia, lymphoma and solid tumors; Skin diseases (eg psoriasis); Bone diseases; cardiovascular diseases (e.g. restenosis and hypertrophy). They are also useful for protecting proliferating cells (e.g. hair, intestine) tinal, blood and progenitor cells) against DNA damage from radiation, UV treatment and / or cytostatic treatment.

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

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

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

Preparation of the starting compounds:

Used abbreviations:

TBTU = O- (benzotriazol-1-yl) -N, N, N ', N' -bis (tetramethylene) uronium hexafluorophosphate HOBt = 1-hydroxy-1H-benzotriazole

Example i A

(5-Methylmer apto-2-i-tro-phenyl) -essi gsän- rt. Butyl ps he 6.4 g of potassium tert-butoxide are placed in 120 ml of dimethylformamide and at 5 ° C a mixture of 4.1 g of 4-methyl mercapto-nitrobenzene and 3.8 g of tert-butyl 2-chloroacetic acid in 20 ml of dimethylformamide were quickly added dropwise. The resulting solution is stirred for 8 minutes and then poured onto a mixture

1.6 1 ice-cold water and 100 ml of concentrated hydrochloric acid are poured. The solution is extracted five times with 150 ml of methylene chloride, the combined organic phases are washed twice with 200 ml of water, dried over sodium sulfate and evaporated. The residue is purified on a silica gel column using methylene chloride / cyclohexane (7: 3) as the eluent. Yield: 2.7 g (39% of theory),

R _f value: 0.45 (silica gel, methylene chloride / cyclohexane = 7: 3)

C ₁₃ H ₁₇ N0 ₄ S

Mass spectrum: m / z = 283 [M ⁺ ]

At spi ei B

5 -Methyl merrapto -? - i nrinl inon

2.7 g (5-methylmercapto-2-nitro-phenyl) acetic acid tert-butyl ester are dissolved in 10.4 ml glacial acetic acid and 3.7 ml concentrated hydrochloric acid and 3.7 g tin-II-chloride dihydrate are added. The mixture is stirred at 110 ° C. for 5 hours. After cooling, the solvent is drawn off, the residue is mixed with 100 ml of ice water and made basic with sodium hydroxide solution. The aqueous phase is extracted with methylene chloride and the organic phase is dried over sodium sulfate. After the solvent has been stripped off, the residue is recrystallized from petroleum ether. Yield: 2.3 g (61% of theory), R _f value: 0.12 (silica gel, methylene chloride) C ₉ H ₉ NOS melting point: 112-114 ° C

Example C

5-Di e hoxyphosphoryl -2- i ndoli non

3.0 g of 5-bromo-2-indolinone (produced according to J. Med. Chem. L, 2588 (1998)), 3.6 ml of diethyl phosphite and 3.9 ml of triethylamine are dissolved in 20 ml of absolute toluene. Then 0.8 g of tetrakistriphenylphosphine palladium (0) is added and the mixture is stirred at 90 ° C. for 30 hours. After 20 hours, a further 10 ml of absolute toluene, 3.0 ml of diethyl phosphite, 3.0 ml of triethylamine and 0.7 g of tetrakistriphenylphosphine palladium (0) are added. When the reaction time has ended, the mixture is filtered through kieselguhr and the filtrate is evaporated. The residue is purified on a silica gel column with ethyl acetate, then with ethyl acetate / ethanol (10: 1). The product is recrystallized from ether and dried in vacuo at 100 ° C. Yield: 2.3 g (61% of theory),

R _f value: 0.4 (silica gel, ethyl acetate / ethanol = 10: 1) C ₁₂ H ₁₆ N0 ₄ P ESI mass spectrum: m / z = 268 [MH ^~ ]

At game D

5-Ohlnrosul fonyl -2 -indol ion

10.0 g of 2-indolinone are added to 25.0 ml of chlorosulfonic acid at -10 ° C to 0 ° C in small portions. The mixture will Stirred at room temperature overnight, poured onto 600 ml of ice water (violent reaction) and stirred for 1 hour. The resulting white precipitate is filtered off, washed well with water and dried at 70 ° C for 3 hours. Yield: 14.3 g (82% of theory),

R _f value: 0.48 (silica gel, methylene chloride / methanol = 9: 1) C ₈ H ₆ C1N0 ₃ S ESI mass spectrum: m / z = 230/232 [MH ^~ ]

Example F, -Αminns l onyl -2-in olinon

2.0 g of 5-chlorosulfonyl-2-indolinone are suspended in 40 ml of methylene chloride, mixed with 10 ml of aqueous ammonia and stirred at room temperature for 3 hours. The resulting precipitate is filtered off and washed with ether. Yield: 1.0 g (55% of theory),

R _f value: 0.14 (silica gel, methylene chloride / methanol = 9: 1) C ₈ H ₈ N ₂ 0 ₃ S ESI mass spectrum: m / z = 211 [MH ^~ ]

The following compounds are produced analogously to Example E:

5 -phenylaminosulfonyl-2-indolinone

Made from 5-chlorosulfonyl-2-indolinone and aniline

5- (N-methyl-N-phenyl-aminosulfonyl) -2-indolinone Made from 5-chlorosulfonyl-2-indolinone and N-methyl-aniline

5- (N-Butyl-N-methyl-aminosulfonyl) -2-indolinone Made from 5-chlorosulfonyl-2-indolinone and N-methyl-butylamine

5- (3-pyridylaminosulfonyl) -2-indolinone Made from 5-chlorosulfonyl-2-indolinone and 3-aminopyridine 5- (3-nitrophenyl-aminosulfonyl) -2-indolinone Made from 5-chlorosulfonyl-2-indolinone and 3-aminonitrotoluene

Example E

1-acetyl - methyl mercapto-2 indole

0.7 g of 5-methylmercapto-2-indolinone are dissolved in 10.4 ml of glacial acetic acid and 3.7 ml of concentrated hydrochloric acid. 5.0 ml of acetic anhydride are added to this solution and the mixture is stirred at 110 ° C. for 5 hours. The solvent is removed, the residue is mixed with 100 ml of ice water and made alkaline with sodium hydroxide solution. The aqueous phase is extracted with methylene chloride and the organic phase is dried over sodium sulfate. After the solvent has been stripped off, the residue is recrystallized from petroleum ether. Yield: 0.6 g (69% of theory), R _f value: 0.12 (silica gel, methylene chloride) C ^ H ^ NO.S melting point: 112-114 ° C

At game G

l-acetyl-3- (1-ethoxy-l-phenylmethylene) -5-methylmercapto-2-indolinone

0.6 g of l-acetyl-5-methylmercapto-2-indolinone and 3.0 ml of ortho-benzoic acid triethyl ester are added in 10 ml of acetic anhydride

Stirred at 100 ° C for 2 hours. After this time there will be more

10 ml of acetic anhydride and 3 ml of orthoester are added and the mixture is heated for 4 hours with stirring. The solvent is removed and the

Purified residue on a silica gel column with methylene chloride / cyclohexane (8: 2).

Yield: 0.8 g (78% of theory),

R _f value: 0.33 (silica gel, methylene chloride / cyclohexane = 8: 2)

C ₂₀ H ₁₉ NO ₃ S

Mass spectrum: m / z = 353 [M ⁺ ] Example H

1-acetyl -3- (1-ethoxy-1-phenylmethylene) -5-methoxy-2-indolone on 1.1 g 5-methoxy-2-indolinone (manufactured according to Quallich, GJ; Morrissey, PM; Synthesis 1 93, 51), 4.6 ml of triethyl orthobenzoate and 11 ml of acetic anhydride are stirred at 100 ° C. for 20 hours. The solvent is removed and the residue is separated on a silica gel column using petroleum ether / methylene chloride / ethyl acetate (5: 4: 1). Yield: 0.7 g (29% of theory), R _f value: 0.6 (silica gel, petroleum ether / methylene chloride / ethyl acetate

= 5: 4: 1) C ₂₀ H ₁₉ NO ₄ mass spectrum: m / z = 337 [M ⁺ ]

The following compounds are prepared analogously to Example H:

(1) 1-Acetyl-3- (1-ethoxy-1-phenylmethylene) -5-diethoxyphosphoryl-2-indolinone

Made from 5-diethoxyphosphoryl-2-indolinone, orthobenzoic acid triethyl ester and acetic anhydride

(2) 1-Acetyl-3- (1-ethoxy-1-phenylmethylene) -5-cyano-2-indoline

Made from 5-cyano-2-indolinone (according to Tetrahedron Lett. 2 &, 4027 (1987), orthobenzoic acid triethyl ester and acetic anhydride

(3) 1-Acetyl-3- (1-ethoxy-1-phenylmethylene) -5- (N-acetylaminosulfonyl) -2-indolinone

Made from 5-aminosulfonyl-2-indolinone, triethyl orthobenzoate and acetic anhydride

(4) 1-Acetyl-3- (1-ethoxy-1-phenylmethylene) -5-phenylaminosulfonyl -2-indolinone Made from 5-phenylaminosulfonyl-2-indolinone, triethyl orthobenzoate and acetic anhydride

(5) 1-Acetyl-3- (1-ethoxy-1-phenylmethylene) -5- (N -methyl-N-phenyl-aminosulfonyl) -2 -indolinone

Made from 5- (N-methyl-N-phenylaminosulfonyl) -2-indolinone, triethyl orthobenzoate and acetic anhydride

(6) 1-Acetyl-3- (1-ethoxy-1-phenylmethylene) -5- (N-butyl-N-methyl-aminosulfonyl) -2-indolinone

Made from 5- (N-butyl-N-methyl-aminosulfonyl) -2-indolinone, triethyl orthobenzoate and acetic anhydride

(7) 1-Acetyl-3- (1-ethoxy-1-phenylmethylene) -5- (3-pyridylaminosulfonyl) -2 -indolinone

Made from 5- (3-pyridyl-aminosulfonyl) -2-indolinone, triethyl orthobenzoate and acetic anhydride

(8) 1-Acetyl-3- (1-ethoxy-1-phenylmethylene) -5- (3-pyridylaminosulfonyl) -2-indolinone

Made from 5- (3-nitrophenyl-aminosulfonyl) -2-indolinone, triethyl orthobenzoate and acetic anhydride

(9) 1-Acetyl-3- (1-ethoxy-1-methylmethylene) -5-cyano-2-indoline

Made from 5-cyano-2-indolinone. (according to Tetrahedron Lett. 2h., 4027 (1987), orthoacetic acid triethyl ester and acetic anhydride

example 1

N- f 2 -Di methyl amino-ethyl -N-methyls l fonyl -4-ni troani 1 in 38.9 g N-methylsulfonyl-4-nitroaniline are dissolved in 2.0 1 acetone, 51.9 g l-chloro-2-dimethylamino-ethane , 77.4 g of potassium carbonate and 5.0 g of sodium iodide were added and the mixture was stirred for a total of 4 days at 50 ° C., after 12 hours a further 25.9 g of l-chloro-2-dimethylamino-ethane, 49.8 g of potassium carbonate and 5.0 g of sodium iodide in 500 ml Acetone and after 36 hours a further 26.0 g of l-chloro-2-dimethylaminoethane, 50.0 g of potassium carbonate and 5.0 g of sodium iodide in 100 ml of acetone are added. After this time, the mixture is filtered and the filtrate is concentrated. The residue is stirred with ether, suction filtered and dried at 40 ° C. Yield: 25.3 g (49% of theory), R _f value: 0.5 (silica gel, methylene chloride / methanol / ammonia =

9: 1: 0.1) C ^ H ^ OS ESI mass spectrum: m / z = 288 [M + H ⁺ ]

The following connection is produced analogously to Example I:

(1) N-carboxymethyl-N-methylsulfonyl-4-nitroaniline

At game el J_

N- (Di methylcarba oy -methyl) -N-methyl snl f nyl -4-ni roani 1 in 7.0 g N-carboxymethyl-N-methylsulfonyl-4-nitroaniline, 2.5 g dimethylamine hydrochloride, 8.1 g TBTU and 3.9 g HOBT are in 125 ml of dimethylformamide dissolved and 17.6 ml of N-ethyl-diisopropylamine added at 0 ° C. The mixture is stirred for 4 hours at room temperature, diluted with 1 l of water and the precipitate which has separated out is filtered off with suction. After washing with water, ethanol and ether, the residue is dried at 70 ° C in a vacuum.

Yield: 5.3 g (69% of theory),

R _f value: 0.40 (silica gel, methylene chloride / methanol = 9: 1) C ₁₁ H ₁₅ N ₃ 0 ₅ S ESI mass spectrum: m / z = 300 [MH ^~ ]

At spi ei K

N- (dimethylamomethyl-carbonyl) -N-methyl-4-nitro-ani 1 in 1.8 g of dimethylamine hydrochloride and 5.5 g of potassium carbonate are placed in 80 ml of acetone and 4.2 g of N- (2-bromomethylcarbonyl) - N- methyl-4-nitroaniline (manufactured according to Chem. Ber. 11, 2430 (1986)) added in three portions at room temperature. The mixture is stirred for 12 hours at room temperature. After this time the mixture is filtered and the filtrate is concentrated. The residue is dissolved in ethyl acetate, washed twice with water, dried over sodium sulfate and finally evaporated.

Yield: 2.8 g (79% of theory),

R _f value: 0.5 (silica gel, ethyl acetate / methanol = 7: 3) melting point: 121-122 ° C

Example T

4- (Pipeτ-i in-1 -yl-methyl) -ni robenzol

40.0 g of 4-nitrobenzyl bromide are dissolved in 500 ml of methylene chloride, 51.5 ml of triethylamine are added and 18.3 ml of piperidine are carefully added dropwise. After the exothermic reaction has ended, the mixture is heated under reflux for a further 30 minutes. After cooling, it is washed with water and the organic phase is dried over sodium sulfate. Finally the organic phase is concentrated.

Yield: 36.3 g (89% of theory),

R _f value: 0.6 (silica gel, methylene chloride / methanol = 9: 1) C ₁₂ H ₁₆ N ₂ 0 ₂ mass spectrum: m / z = 221 [M ⁺ ]

The following compounds are produced analogously to Example L:

(1) 4- [(N-Benzyl-N-methylamino) methyl] nitrobenzene

(2) 3- (Dimethylaminomethyl) nitrobenzene

(3) 4- (dimethylaminomethyl) nitrobenzene

(4) 4- (2-Dimethylamino-ethyl) nitrobenzene

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

4- (4-methyl-pi pera n-1-yl) -ni trobenzene

31.5 g of 4-chloro-1-nitrobenzene and 44.4 ml of 1-methylpiperazine are combined and stirred at 90 ° C for 18 hours. The solution is then poured onto ice water and the precipitate which has separated out is filtered off with suction, washed with water and recrystallized from ethanol / water 1: 1. The residue is dried in vacuo at 75 ° C. Yield: 44.0 g (99% of theory), Rf value: 0.5 (silica gel, methylene chloride / methanol = 10: 1)

Melting point: 108-112 ° C

The following connection is established analogously to example M:

(1) 4- (morpholin-4-yl) nitrobenzene

Example N

4- (Pi eri i -1 -yl -methyl -ani 1 in

37.0 g of 4- (piperidin-1-yl-methyl) nitrobenzene are added in 300 ml

Methanol dissolved, 8.0 g of Raney nickel added and for 1 hour

Hydrogenated for 25 minutes with 3 bar of hydrogen at room temperature.

The catalyst is filtered off and the filtrate is evaporated.

Yield: 24.0 g (75% of theory),

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

C ₁₂ H ₁₈ N ₂

ESI mass spectrum: m / z = 191 [M + H ⁺ ]

The following compounds are produced analogously to Example M:

(1) 4- [(N-Benzyl-N-methylamino) methyl] aniline

(2) N- (2-Dimethylaminoethyl) -N-methylsulfonyl-p-phenylene diamine (3) 3- (dimethylaminomethyl) aniline

(4) 4- (dimethylaminomethyl) aniline

(5) N- (Dimethylaminomethylcarbonyl) -N-methyl-p-phenylenediamine

(6) N- (Dirnethylcarbamoyl-methyl) -N-methylsulfonyl-p-phenylene diamine

(7) 4- (2-Dimethylaminoethyl) aniline

(8) 4- (2,3,4,5-Tetrahydro-benzo (d) azepin-3-yl) methyl] aniline

(9) 4- (4-Methylpiperazin-l-yl) aniline

(10) 4- (morpholin-4-yl) aniline

Example O

3-Z- [1- (4- (dimethylaminomethyl) anilino) -1-phenylmethylene] -

5- (N-acetylamino nosnl onyl -2-indol ion non

780 mg of l-acetyl-3- (1-ethoxy-l-phenylmethylene) -5- (N-acetylaminosulfonyl) -2-indolinone are dissolved in 6.0 ml of dimethylformamide and 300 mg of 4- (dimethylaminomethyl) aniline are added , The mixture is stirred at 110 ° C for 4 hours. After cooling, the solvent is stripped off and the residue is dissolved in 20 ml of methanol and 20 ml of dichloromethane. 5.0 ml of concentrated ammonia are added to this mixture and the mixture is stirred at room temperature for 1 hour. After the solvent has been stripped off, the residue is purified on a silica gel column using methylene chloride / methanol (4: 1). Yield: 150 mg (18% of theory),

R _f value: 0.29 (silica gel, methylene chloride / methanol = 9: 1) C ₂₆ H ₂₆ N ₄ 0 ₄ S mass spectrum: m / z = 490 [M ⁺ ] Making the end connections:

example 1

3-Z- [1- (4- (piperidin-1-ylmethyl) anilino) -1-phenylmethylene] -

5-methoxy-2 - indole in non

0.3 g of l-acetyl-3- (1-ethoxy-l-phenylmethylene) -5-methylmercapto-2-indolinone and 0.3 g of 4- (piperidin-1-ylmethyl) aniline are dissolved in 3.0 ml of dimethylformamide dissolved and stirred at 110 ° C for 2 hours. After cooling, 1.0 ml of piperidine is added and the mixture is stirred at room temperature for 3 hours, water is added and the precipitate which has separated out is filtered off with suction. The precipitate is washed with water, isopropanol and ether and dried in vacuo at 100 ° C. Yield: 200 mg (44% of theory), R _f value: 0.5 (silica gel, methylene chloride / methanol = 5: 1)

Mass spectrum: m / z = 439 [M ⁺ ]

The following compounds are prepared analogously to Example 1:

(1) 3-Z- [1- (4-methoxy-anilino) -1-phenylmethylene] -5-methoxy-2-indolinone

Made from l-acetyl-3- (1-ethoxy-1-phenylmethylene) -5 - methoxy-2-indolinone and p-anisidine

R _f value: 0.2 (silica gel, toluene / ethyl acetate = 5: 1)

C ₂₃ H ₂₀ N ₂ O ₃

Mass spectrum: m / z = 372 [M ⁺ ]

(2) 3-Z- [1- (4- (piperidin-1-ylmethyl) anilino) -1-phenylmethylene] -5-methylmercapto-2-indolinone

Made from l-acetyl-3- (1-ethoxy-l-phenylmethylene) -5-methylmercapto-2-indolinone and 4- (piperidin-1-ylmethyl) aniline

R _f value: 0.27 (silica gel, methylene chloride / ethanol = 9: 1)

C ₂₈ H ₂₉ N ₃ OS

ESI mass spectrum: m / z = 456 [M + H ⁺ ] (3) 3-Z- [1- (4- (piperidin-1-ylmethyl) anilino) -1-phenylmethylene) -5-diethoxyphosphoryl-2-indolinone

Made from l-acetyl-3- (1-ethoxy-l-phenylmethylene) -5-diethoxyphosphoryl-2-indolinone and 4- (piperidin-1-ylmethyl) aniline

R _f value: 0.7 (aluminum oxide, ethyl acetate / ethanol = 10: 1)

C ₃₁ H ₃₆ N ₃ 0 ₄ P

Mass spectrum: m / z = 545 [M ⁺ ]

(4) 3-Z- [1- (4- ((N-Benzyl-N-methylamino) methyl) anilino) - 1-phenylmethylene] -5-diethoxyphosphoryl-2-indolinone Made from l- Acetyl-3- (1-ethoxy-1-phenylmethylene) -5-diethoxyphosphoryl-2-indolinone and 4- [(N-benzyl-N-methylamino) methyl] aniline

R _f value: 0.5 (silica gel, methylene chloride / ethanol = 10: 1)

C ₃₄ H ₃₆ N ₃ 0 ₄ P

Mass spectrum: m / z = 581 [M ⁺ ]

(5) 3-Z- [1- (3- (Dimethylaminomethyl) anilino) -1-phenylmethylene) -5-diethoxyphosphoryl-2-indolinone

Made from l-acetyl-3- (1-ethoxy-l-phenylmethylene) -5-diethoxyphosphoryl-2-indolinone and 3- (dimethylaminomethyl) aniline

R _f value: 0.6 (silica gel, methylene chloride / ethanol / ammonia =

5: 1: 0.01) C ₂₈ H ₃₂ N ₃ 0 ₄ P mass spectrum: m / z = 505 [M ⁺ ]

(6) 3-Z- [1- (4-chloroanilino) -1-phenylmethylene] -5-diethoxyphosphoryl-2-indolinone

Made from l-acetyl-3- (1-ethoxy-l-phenylmethylene) -5-diethoxyphosphoryl-2-indolinone and 4-chloroaniline

R _f value: 0.6 (silica gel, methylene chloride / ethanol = 10: 1)

C ₂₅ H ₂₄ C1N ₂ 0 ₄ P

ESI mass spectrum: m / z = 505/507 [M + Na ⁺ ] (7) 3-Z- [1- (4- (N- (2-Dimethylaminoethyl) -N-methylsulfonylamino) anilino) -1-phenylmethylene] -5-diethoxyphosphoryl -2-indoli - non

Made from l-acetyl-3- (1-ethoxy-l-phenylmethylene) -5- diethoxyphosphoryl-2-indolinone and N- (2-dimethylamino-ethyl) -

N-methylsulfonyl-p-phenylenediamine

R _£ value: 0.4 (silica gel, methylene chloride / ethanol = 5: 1)

C ₃₀ H ₃₇ N ₄ O ₆ PS

Mass spectrum: m / z = 612 [M ⁺ ]

(8) 3-Z- [1- (4- (N- (Dirnethylaminocarbonyl-methyl) -N-methylsulfonylamino) anilino) -1-phenylmethylene] -5-diethoxyphosphoryl-2-indolinone

Made from l-acetyl-3- (1-ethoxy-l-phenylmethylene) -5-diethoxyphosphoryl-2-indolinone and N- (dimethylcarbamoylmethyl) -N-methylsulfonyl-p-phenylenediamine

R _f value: 0.6 (silica gel, ethyl acetate / ethanol = 5: 1)

C ₃₀ H ₃₅ N ₄ O ₇ PS

Mass spectrum: m / z = 626 [M ⁺ ]

(9) 3-Z- [1- (4- (N-Dimethylaminomethylcarbonyl-N-methylamino) anilino) -1-phenylmethylene] -5 -diethoxyphosphoryl -2 -indolinone Made from l-acetyl-3- (1-ethoxy-l-phenylmethylene) -5-diethoxyphosphoryl-2-indolinone and N- (dimethylaminomethylcarbonyl) -N-methyl-p-phenylenediamine

R _f value: 0.6 (aluminum oxide, methylene chloride / ethanol = 10: 1)

C ₃₀ H ₃₅ N ₄ O ₅ P

Mass spectrum: m / z = 562 [M ⁺ ]

(10) 3-Z- [1- (4- (piperidin-1-ylmethyl) anilino) -1-phenylmethylene) -5-cyano-2-indolinone

Made from l-acetyl-3- (1-ethoxy-l-phenylmethylene) -5-cyano-2-indolinone and 4- (piperidin-1-ylmethyl) aniline

R _f value: 0.3 (silica gel, methylene chloride / methanol 9: 1)

C ₂₈ H ₂₆ N ₄ 0

Mass spectrum: m / z = 434 [M ⁺ ] (11) 3-Z- [1- (4- (Piperidin-1-ylmethyl) anilino) -1-phenylmethylene] -5- (phenylaminosulfonyl) -2-indolinone

Made from l-acetyl-3- (1-ethoxy-l-phenylmethylene) -5-phenylaminosulfonyl-2-indolinone and 4- (piperidin-1-ylmethyl) aniline

R _f value: 0.17 (silica gel, methylene chloride / methanol = 9: 1)

C ₃₃ H ₃₂ N ₄ 0 ₃ S

ESI mass spectrum: m / z = 563 [MH ^~ ]

(12) 3-Z- [1- (4- (Piperidin-1-ylmethyl) anilino) -1-phenylmethylene] -5- (N-methyl -N-phenylaminosulfonyl) -2 -indolinone Made from l-acetyl-3- (1-ethoxy-l-phenylmethylene) -

5- (N-methyl-N-phenylaminosulfonyl) -2-indolinone and

4- (piperidin-1-yl-methyl) aniline

R _f value: 0.22 (silica gel, methylene chloride / methanol = 9: 1)

C ₃₄ H ₃₄ N ₄ 0 ₃ p

ESI mass spectrum: m / z = 577 [MH ^~ ]

(13) 3-Z- [1- (4- (piperidin-1-ylmethyl) anilino) -1-phenylmethylene] -5- (N-butyl-N-methylaminosulfonyl) -2 -indolinone Made from l-acetyl-3- (1-ethoxy-l-phenylmethylene) -

5- (N-butyl-N-methyl-aminosulfonyl) -2-indolinone and 4- (piperidin-l-yl-methyl) aniline

R _f value: 0.19 (silica gel, methylene chloride / methanol = 9: 1)

C ₃₂ H ₃₈ N ₄ 0 ₃ S

ESI mass spectrum: m / z = 557 [MH ^~ ]

(14) 3-Z- [1- (4- (2-Dimethylaminoethyl) anilino) -1-phenylmethylene] -5- (phenylaminosulfonyl) -2-indolinone

Made from l-acetyl-3- (1-ethoxy-l-phenylmethylene) -5-phenylaminosulfonyl-2-indolinone and 4- (2-dimethylamino-ethyl) aniline

R _f value: 0.17 (silica gel, methylene chloride / methanol = 9: 1)

C ₃₁ H ₃₀ N ₄ O ₃ S

ESI mass spectrum: m / z = 537 [MH ^~ ] (15) 3 - Z- [1- (4 - (Dimethylamino-methyl) -anilino) - 1-phenyl-methylene] - 5 - (phenyl-aminosulfonyl) - 2-indolinone

Made from l-acetyl -3 - (1-ethoxy-l-phenylmethylene) -5 -phe - nylaminosulfonyl -2 - indolinone and 4 - (dimethylamino-methyl) - aniline

R _f value: 0.18 (silica gel, methylene chloride / methanol = 9: 1)

C ₃₀ H ₂₈ N ₄ O ₃ S

ESI mass spectrum: m / z = 523 [MH ^" ]

(16) 3-Z- [1- ((1-Methylpiperidin-4-yl) amino) -1-phenylmethylene] -5- (phenylaminosulfonyl) -2-indolinone

Made from 1-acetyl -3 - (1-ethoxy-1-phenylmethylene) -5-phenylaminosulfonyl-2-indolinone and 4-amino-methyl-piperidine R _f value: 0.20 (silica gel, methylene chloride / methanol = 9: 1)

ESI mass spectrum: m / z = 487 [MH ^" ]

(17) 3-Z- (1-anilino-1-phenylmethylene) -5- (phenylaminosulfonyl) -2-indolinone

Made from l-acetyl-3- (1-ethoxy-l-phenylmethylene) -5-phenylaminosulfonyl-2-indolinone and aniline

R _f value: 0.66 (silica gel, methylene chloride / methanol = 9: 1)

C ₂₇ H ₂₁ N ₃ 0 ₃ S

Mass spectrum: m / z = 467 [M ⁺ ]

(18) 3-Z- [1- (4-Acetylamino-anilino) -1-phenylmethylene] -5- (phenylaminosulfonyl) -2-indolinone

Made from l-acetyl-3- (1-ethoxy-l-phenylmethylene) -5-phenylaminosulfonyl-2-indolinone and 4-aminoacetanilide

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

C ₂₉ H ₂₄ N ₄ 0 ₄ S

Mass spectrum: m / z = 524 [M ⁺ ]

(19) 3-Z- [1- (3-Dimethylaminomethyl-anilino) -1-phenylmethylene] -5- (phenylaminosulfonyl) -2-indolinone Made from l -acetyl - 3 - (1 - ethoxy-l-phenylmethylene) - 5 -phe - nylaminosulfonyl - 2 - indole inon and 3 - (dimethylamino-methyl) - anil in

R _f value: 0.32 (silica gel, methylene chloride / methanol = 9: 1)

C ₃₀ H ₂₈ N ₄ O ₃ S

Mass spectrum: m / z = 524 [M ⁺ ]

(20) 3-Z- [1- (4- (N-Benzyl-N-methylamino) methyl) anilino) -1-phenylmethylene] -5- (phenylaminosulfonyl) -2-indolinone from l-acetyl-3- (1-ethoxy-l-phenylmethylene) -5-phenylaminosulfonyl-2-indolinone and 4- [(N-benzyl-N-methylamino) methyl] aniline

R _£ value: 0.63 (silica gel, methylene chloride / methanol = 9: 1)

C ₃₆ H ₃₂ N ₄ 0 ₃ S

ESI mass spectrum: m / z = 601 [M + H ⁺ ]

(21) 3-Z- (1- (4- (2,3,4,5-tetrahydro-benzo (d) azepin-3-yl) methyl) anilino) -1-phenylmethylene] -5- (phenylaminosulfonyl) -2-indolinone

Made from l-acetyl-3- (1-ethoxy-l-phenylmethylene) -5-phenylaminosulfonyl-2-indolinone and 4- (2, 3, 4, 5-tetrahydrobenzo (d) azepine-3 -yl) -methyl] -aniline

R _f value: 0.63 (silica gel, methylene chloride / methanol = 9: 1)

C ₃₈ H ₄ N ₄ 0 ₃ S

ESI mass spectrum: m / z = 626 [M ⁺ ]

^" (22) 3-Z- [1- (4- (N-methylacetylamino) anilino) -1-phenylmethylene] -5- (phenylaminosulfonyl) -2-indolinone

Made from 1-acetyl -3 - (1-ethoxy-l-phenylmethylene) -5-phenylaminosulfonyl-2-indolinone and 4-amino-N-methyl-acetanilide

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

C ₃₀ H ₂₆ N ₄ O ₄ S

Mass spectrum: m / z = 538 [M ⁺ ]

(23) 3-Z- [1- (4- (N-Methylpiperazin-1-yl) anilino) -1-phenylmethylene] -5- (phenylaminosulfonyl) -2-indolinone Made from l-acetyl-3- (1-ethoxy-l-phenylmethylene) -5-phenylaminosulfonyl -2-indolinone and 4- (N-methylpiperazin-1-yl) aniline

R _f value: 0.18 (silica gel, methylene chloride / methanol = 9: 1)

C ₃₂ H ₃₁ N ₅ 0 ₃ S

Mass spectrum: m / z = 565 [M ⁺ ]

(24) 3-Z- [1- (4- (Morpholin-4-yl) anilino) -1-phenylmethylene] -5- (phenylaminosulfonyl) -2-indolinone

Made from l-acetyl-3- (1-ethoxy-l-phenylmethylene) -5-phenylaminosulfonyl-2-indolinone and 4-morpholin-4-yl-aniline

R _f value: 0.61 (silica gel, methylene chloride / methanol = 9: 1)

C ₃₁ H ₂₈ N ₄ 0 ₄ S

ESI mass spectrum: m / z = 551 [MH ^" ]

(25) 3-Z- [1- (4-toluenesulfonylamino-anilino) -1-phenylmethylene] -5- (phenyl-aminosulfonyl) -2-indolinone

Made from l-acetyl-3- (1-ethoxy-l-phenylmethylene) -5-phenylaminosulfonyl -2-indolinone and N- (4-aminophenyl) toluenesulfonic acid amide

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

C ₃₄ H ₂₈ N ₄ 0 ₅ S ₂

Mass spectrum: m / z = 636 [M ⁺ ]

(26) 3-Z- [1- (4- (Dimethylamino-methyl) anilino) -1-phenylmethylene] -5- (3-pyridylaminosulfonyl) -2-indolinone Made from l-acetyl- 3- (1-ethoxy-l-phenylmethylene) -5- (3-pyridylaminosulfonyl) -2-indolinone and 4- (dimethylaminomethyl) aniline

R _f value: 0.28 (silica gel, methylene chloride / methanol = 9: 1)

C ₂₉ H ₂₇ N ₅ 0 ₃ p

ESI mass spectrum: m / z = 524 [MH ^" ]

(27) 3-Z- [1- (4- (Dimethylamino-methyl) anilino) -1-phenylmethylene] -5- (3-nitrophenylaminosulfonyl) -2-indolinone Made from l-acetyl-3- (1-ethoxy-l-phenylmethylene) -5- (3-nitrophenylaminosulfonyl) -2-indolinone and 4- (dimethylaminomethyl) aniline

R _f value: 0.25 (silica gel, methylene chloride / methanol = 9: 1) C ₃₀ H ₂₇ N ₅ O ₅ S ESI mass spectrum: m / z = 568 [MH ^" ]

(28) 3-Z- [1- (4- (piperidin-1-ylmethyl) anilino) -1-methylmethylene) -5-cyano-2-indolinone

Made from l-acetyl-3 - (1-ethoxy-l-methylmethylene) -5-cyano-2-indolinone and 4- (piperidin-1-ylmethyl) aniline

R _f value: 0.77 (silica gel, methylene chloride / methanol 8: 2)

C ₂₃ H ₂₄ N ₄ 0

Mass spectrum: m / z = 373 [M + H ^" ]

(29) 3-Z- [1- (4- (piperidin-1-ylmethyl) anilino) -1-phenylmethylene] -5- (3-pyridylaminosulfonyl) -2-indolinone Manufactured from l-acetyl-3- (1-ethoxy-l-phenylmethylene) -5- (3-pyridylaminosulfonyl) -2-indolinone and 4- (piperidin-1-ylmethyl) aniline

R _f value: 0.12 (silica gel, methylene chloride / methanol = 9: 1)

C ₃₂ H ₃₁ N ₅ 0 ₃ S

ESI mass spectrum: m / z = 564 [MH ^" ]

(30) 3-Z- [1- (4- (2,3,4,5-tetrahydro-benz [d] azepin-3-yl-methyl) anilino) -1-phenylmethylene] -5-cyano- 2-indolinone Made from l-acetyl-3- (1-ethoxy-l-phenylmethylene) -5-cy-ano-2-indolinone and 4- (2, 3, 4, 5-tetrahydro-benz [d] azepin-3-ylmethyl) aniline

R _f value: 0.4 (silica gel, methylene chloride / methanol / ammonia

9: 1: 0.1)

C ₃₃ H ₂₈ N ₄ 0

Mass spectrum: m / z = 495 [MH ^" ]

(31) 3 - Z- [1- (4 - (Dimethylamino-methyl) -anilino) - 1-phenyl-methylene] - 5 -cyano-2-indolinone Made from l-acetyl-3- (1-ethoxy-l-phenylmethylene) -5-cyano-2-indolinone and 4- (dimethylamino-methyl) aniline

R _f value: 0.3 (silica gel, methylene chloride / methanol / ammonia

9: 1: 0.1)

C ₂₅ H ₂₂ N ₄ 0

Mass spectrum: m / z = 395 [M + H ⁺ ]

In game 2.

3-Z- [1- (4- (Dimethylaminomethyl) anilino) -1-phenylmethylene] -

5-aminosnl for nyl-2-indole inone

100 mg of 3-Z- [1- (4- (dimethylaminomethyl) anilino) -1-phenylmethylene] -5- (N-acetylaminosulfonyl) -2-indolinone are dissolved in 10 ml of ethanol and 5.0 ml Added in hydrochloric acid. The mixture is stirred for two weeks at room temperature. After this time, 5.0 ml IN sodium hydroxide solution are added and the solution is concentrated. The residue is taken up in a little methylene chloride and methanol and filtered. The filtrate is concentrated and purified on a silica gel column with ethyl acetate / cyclohexane / methanol (2: 2: 6).

Yield: 39 mg (33% of theory), R _f value: 0.19 (silica gel, ethyl acetate / cyclohexane / methanol =

2: 2: 6) C ₂₄ H ₂₄ N ₄ 0 ₃ S mass spectrum: m / z = 448 [M ⁺ ]

Example 3

3-Z- [1- (4- (piperidin-1-ylmethyl) anilino) -1-phenylmethylene] -

5-methyl snl inyl -2-indole inone

200 mg of 3 -Z- [1- (4- (piperidin-1-ylmethyl) anilino) -1-phenylmethylene] -5-methylmercapto-2-indolinone are dissolved in 2.0 ml of glacial acetic acid and 330 mg Hydrogen peroxide (35%) added in 20 ml glacial acetic acid. The mixture is stirred for 5 hours at room temperature. After this time, the solvent is stripped off, neutralized with dilute ammonia solution and dried over sodium sulfate. The residue is purified on a silica gel column with methylene chloride / ethanol (9: 1). Yield: 0.2 g (87% of theory),

R _f value: 0.25 (silica gel, methylene chloride / ethanol = 9: 1)

C ₂₈ H ₂₉ N ₃ 0 ₂ S

ESI mass spectrum: m / z = 472 [M + H ⁺ ]

The following connection is established analogously to Example 3:

(1) 3-Z- [1- (4- (Piperidin-1-ylmethyl) anilino) -1-phenylmethylene] -5-methylsulfonyl -2-indolinone

Made from 3 -Z- [1- (4- (piperidin-1-ylmethyl) anilino) -

1-phenylmethylene] -5-methylsulfinyl-2-indolinone and

Hydrogen peroxide (35%)

R _f value: 0.19 (silica gel, methylene chloride / ethanol = 9: 1)

C ₂₈ H ₂₉ N ₃ 0 ₃ S

Mass spectrum: m / z = 487 [M ⁺ ]

The following compounds can be prepared analogously to the examples above:

(1) 3-Z- (1-anilino-1-phenylmethylene) -5-diethoxyphosphoryl-2-indolinone

(2) 3-Z- [1- (4-nitro-anilino) -1-phenylmethylene] -5-diethoxyphosphoryl-2-indolinone

(3) 3-Z- [1- (4-ethoxycarbonylanilino) -1-phenylmethylene] -5-diethoxyphosphoryl-2-indolinone

(4) 3-Z- [1- (4-carboxy-anilino) -1-phenylmethylene] -5-diethoxyphosphoryl-2-indolinone

(5) 3-Z- [1- (4-fluoro-anilino) -1-phenylmethylene] -5-diethoxyphosphoryl-2-indolinone

(6) 3-Z- [1- (4-bromoanilino) -1-phenylmethylene] -5-diethoxyphosphoryl-2-indolinone (7) 3-Z- [1- (4-iodo-anilino) -1-phenylmethylene] -5-diethoxyphosphoryl -2-indolinone

(8) 3-Z- [1- (4-cyanoanilino) -1-phenylmethylene] -5-diethoxyphosphoryl-2-indolinone

(9) 3-Z- [1- (4-methoxy-anilino) -1-phenylmethylene] -5-diethoxyphosphoryl-2-indolinone

(10) 3-Z- [1- (4-ethoxy-anilino) -1-phenylmethylene] -5-diethoxyphosphoryl-2-indolinone

(11) 3-Z- [1- (4-Trifluoromethyl-anilino) -1-phenylmethylene] -5-diethoxyphosphoryl-2-indolinone

(12) 3-Z- [1- (4-Methylanilino) -1-phenylmethylene] -5-diethoxyphosphoryl-2-indolinone

(13) 3-Z- [1- (4-Methylmercapto-anilino) -1-phenylmethylene] - 5-diethoxyphosphoryl-2-indolinone

(14) 3-Z- [1- (4-aminomethyl anilino) -1-phenylmethylene] -5-diethoxyphosphoryl-2-indolinone

(15) 3-Z- [1- (4-Methylaminomethyl-anilino) -1-phenylmethylene] - 5-diethoxyphosphoryl-2-indolinone

(16) 3-Z- [1- (4-isopropylaminomethyl anilino) -1-phenylmethylene] -5-diethoxyphosphoryl-2-indolinone

(17) 3-Z- [1- (4-phenylaminomethyl-anilino) -1-phenylmethylene] - 5-diethoxyphosphoryl -2-indolinone

(18) 3-Z- [1- (4-Ethylaminomethylanilino) -1-phenylmethylene] -5-diethoxyphosphoryl-2-indolinone (19) 3-Z- [1- (4-Propylaminomethyl-anilino) -1-phenylmethylene] -5-diethoxyphosphoryl-2-indolinone

(20) 3-Z- [1- (4-butylaminomethylanilino) -1-phenylmethylene] -5-diethoxyphosphoryl-2-indolinone

(21) 3-Z- [1- (4-isobutylaminomethyl-anilino) -1-phenylmethylene] -5 -diethoxyphosphoryl-2-indolinone

(22) 3-Z- [1- (4-Cyclohexylaminomethylanilino) -1-phenylmethylene] -5 -diethoxyphosphoryl-2-indolinone

(23) 3-Z- [1- (4-Benzylaminomethyl-anilino) -1-phenylmethylene] -5-diethoxyphosphoryl-2-indolinone

(24) 3-Z- [1- (4-Dimethylaminomethyl-anilino) -1-phenylmethylene] -5-diethoxyphosphoryl -2-indolinone

(25) 3-Z- [1- (4- ((N-Ethyl-N-methylamino) methyl) anilino) 1-phenylmethylene] -5-diethoxyphosphoryl-2-indolinone

(26) 3-Z- [1- (4 -Diethylaminomethylanilino) -1-phenylmethylene] 5 -diethoxyphosphoryl-2-indolinone

(27) 3-Z- [1- (4- ((N-Methyl-N-propylamino) methyl) anilino) -1-phenylmethylene] -5-diethoxyphosphoryl-2-indolinone

(28) 3-Z- [1- (4- ((N-Isopropyl-N-methylamino) methyl) anilino) 1-phenylmethylene] -5-diethoxyphosphoryl -2-indolinone

(29) 3-Z- [1- (4- ((N-Ethyl-N-propylamino) methyl) anilino) -1-phenylmethylene] -5-diethoxyphosphoryl -2-indolinone

(30) 3-Z- [1- (4- ((N-Ethyl-N-isopropylamino) methyl) anilino) - 1-phenylmethylene] - 5 -diethoxyphosphoryl -2-indolinone (31) 3-Z- [1- (4-Dipropylaminomethyl-anilino) -1-phenylmethylene] -5-diethoxyphosphoryl-2-indolinone

(32) 3-Z- [1- (4-diisopropylaminomethyl) anilino) -1-phenylmethylene] -5-diethoxyphosphoryl-2-indolinone

(33) 3-Z- [1- (4- ((N-Benzyl-N-ethylamino) methyl) anilino) -1-phenylmethylene] -5-diethoxyphosphoryl-2-indolinone

(34) 3-Z- [1- (4-Dibenzylaminomethyl-anilino) -1-phenylmethylene] -5-diethoxyphosphoryl-2-indolinone

(35) 3-Z- [1- (4- (Pyrrolidin-1-ylmethyl) anilino) -1-phenylmethylene] -5-diethoxyphosphoryl-2-indolinone

(36) 3-Z- [1- (4- (3,6-Dihydro-2H-pyridin-l-ylmethyl) anilino) -1-phenylmethylene] -5-diethoxyphosphoryl-2-indolinone

(37) 3-Z- [1- (4- (2,6-Dirnethyl-piperidin-1-ylmethyl) anilino) -1-phenylmethylene] -5-diethoxyphosphoryl-2-indolinone

(38) 3-Z- [1- (4- (3,5-Dimethylpiperidin-1-ylmethyl) anilino) - 1-phenylmethylene] -5-diethoxyphosphoryl -2 - indolinone

(39) 3-Z- [1- (4- (azepan-1-ylmethyl) anilino) -1-phenylmethylene] -5-diethoxyphosphoryl-2-indolinone

(40) 3-Z- [1- (4- (piperazin-1-ylmethyl) anilino) -1-phenylmethylene] -5-diethoxyphosphoryl-2-indolinone

(41) 3-Z- [1- (4- (morpholin-4-ylmethyl) anilino) -1-phenylmethylene] -5-diethoxyphosphoryl -2-indolinone

(42) 3-Z- [1- (4- (Thiomorpholin-4-ylmethyl) anilino) -1-phenylmethylene] -5-diethoxyphosphoryl-2-indolinone (43) 3-Z- [1- (4- (l-oxothiomorpholin-4-ylmethyl) anilino) -1-phenylmethylene] -5-diethoxyphosphoryl-2-indolinone

(44) 3-Z- [1- (4- (acetylamino-methyl) anilino) -1-phenylmethylene] -5-diethoxyphosphoryl-2-indolinone

(45) 3-Z- [1- (4- (2-Aminoethyl) anilino) -1-phenylmethylene] -5-diethoxyphosphoryl-2-indolinone

(46) 3-Z- [1- (4- (2-Methylaminoethyl) anilino) -1-phenylmethylene] -5 -diethoxyphosphoryl-2-indolinone

(47) 3-Z- [1- (4- (2-Ethylaminoethyl) anilino) -1-phenylmethylene] -5-diethoxyphosphoryl-2-indolinone

(48) 3-Z- [1- (4- (2-Dimethylaminoethyl) anilino) -1-phenylmethylene] -5-diethoxyphosphoryl-2-indolinone

(49) 3-Z- [1- (4- (2-Diethylaminoethyl) anilino) -1-phenylmethylene] -5-diethoxyphosphoryl-2-indolinone

(50) 3-Z- [1- (4- (2-Piperidin-1-yl-ethyl) anilino) -1-phenylmethylene] -5-diethoxyphosphoryl-2-indolinone

(51) 3-Z- [1- (4- (2- (4-Ethoxycarbonylpiperidin-1-yl) ethyl) anilino) -1-phenylmethylene] -5-diethoxyphosphoryl-2-indolinone

(52) 3-Z- [1- (4- (2- (4-Carboxypiperidin-l-yl) ethyl) anilino) -1-phenylmethylene] -5-diethoxyphosphoryl -2-indolinone

(53) 3-Z- [1- (4- (2- (4-Dimethylcarbamoylpiperidin-l-yl) ethyl) anilino) -1-phenylmethylene] -5-diethoxyphosphoryl-2-indolinone

(54) 3-Z- [1- (4- (2-Acetylaminoethyl) anilino) -1-phenylmethylene] -5-diethoxyphosphoryl-2-indolinone (55) 3-Z- [1- (4- (3-aminopropyl) anilino) -1-phenylmethylene] -5-diethoxyphosphoryl-2-indolinone

(56) 3-Z- [1- (4- (3-Dimethylamino-propyl) anilino) -1-phenylmethylene] -5-diethoxyphosphoryl-2-indolinone

(57) 3-Z- [1- (4- (N-aminomethylcarbonyl-N-methylamino) anilino) -1-phenylmethylene] -5-diethoxyphosphoryl-2-indolinone

(58) 3-Z- [1- (4- (N-methylaminomethylcarbonyl-N-methylamino) anilino) -1-phenylmethylene] -5-diethoxyphosphoryl-2-indolinone

(59) 3-Z- [1- (4- (N-ethylaminomethylcarbonyl-N-methylamino) anilino) -1-phenylmethylene] -5-diethoxyphosphoryl-2-indolinone

(60) 3-Z- [1- (4- (N-Diethylaminomethylcarbonyl-N-methylamino) anilino) -1-phenylmethylene] -5-diethoxyphosphoryl-2-indolinone

(61) 3-Z- [1- (4- (N- (Piperidin-1-ylmethylcarbonyl) -N-methylamino) anilino) -1-phenylmethylene] -5-diethoxyphosphoryl-2-indolinone

(62) 3-Z- [1- (4- (N- (Morpholin-4-ylmethylcarbonyl) -N-methylamino) anilino) -1-phenylmethylene] -5-diethoxyphosphoryl-2-indolinone

^" (63) 3-Z- [1- (4- (N- (Piperazin-1-yl-methylcarbonyl) -N-methylamino) anilino) -1-phenylmethylene] -5 -diethoxyphosphoryl -2- indolinone

(64) 3-Z- [1- (4- (N- (2-Aminoethylcarbonyl) -N-methylamino) anilino) -1-phenylmethylene] -5-diethoxyphosphoryl-2-indolinone

(65) 3-Z- [1- (4- (N- (2-Methylaminoethylcarbonyl) -N-methylamino) anilino) -1-phenylmethylene] -5-diethoxyphosphoryl-2-indolinone (66) 3-Z- [1- (4- (N- (2-Diethylaminoethylcarbonyl) -N-methylamino) anilino) -1-phenylmethylene] -5-diethoxyphosphoryl-2-indolinone

(67) 3-Z- [1- (4- (N-Acetyl-N- (2-aminoethyl) amino) anilino) -1-phenylmethylene] -5-diethoxyphosphoryl-2-indolinone

(68) 3-Z- [1- (4- (N-Acetyl-N- (2 -methylaminoethyl) amino) anilino) -1-phenylmethylene] -5-diethoxyphosphoryl-2-indolinone

(69) 3-Z- [1- (4- (N-Acetyl-N- (2-dimethylaminoethyl) amino) anilino) -1-phenylmethylene] -5-diethoxyphosphoryl-2-indolinone

(70) 3-Z- [1- (4- (N-acetyl-N- (3-aminopropyl) amino) anilino) -1-phenylmethylene] -5-diethoxyphosphoryl-2-indolinone

(71) 3-Z- [1- (4- (N-Acetyl-N- (3-dimethylamino-propyl) -amino) anilino) -1-phenylmethylene] -5-diethoxyphosphoryl-2-indolinone

(72) 3-Z- [1- (4- (N-Acetyl-N- (3-methylamino-propyl) amino) anilino) -1-phenylmethylene] -5-diethoxyphosphoryl-2-indolinone

(73) 3-Z- [1- (4- (N-acetyl-N- (2-piperidin-1-yl-ethyl) amino) anilino) -1-phenylmethylene] -5-diethoxyphosphoryl-2 - indolinone

(74) 3-Z- [1- (4- (N-Acetyl-N-carbamoylmethylamino) anilino) - ϊ-phenylmethylene] -5-diethoxyphosphoryl-2-indolinone

(75) 3-Z- [1- (4- (N-Acetyl-N-dimethylcarbamoylmethylamino) anilino) -1-phenylmethylene] -5-diethoxyphosphoryl -2-indolinone

(76) 3-Z- [1- (4- (N-acetyl-N- (piperidin-1-yl-carbonylmethyl) amino) anilino) -1-phenylmethylene] -5-diethoxyphosphoryl-2-indolinone

(77) 3-Z- [1- (4- (N-methyl-N-carbamoylamino) anilino) -1-phenylmethylene] -5-diethoxyphosphoryl -2-indolinone (78) 3-Z- [1- (4- (N-methyl-N-methylcarbamoylamino) anilino) -1-phenylmethylene] -5-diethoxyphosphoryl-2-indolinone

(79) 3-Z- [1- (4- (N-methyl-N-dimethylcarbamoylamino) anilino) -1-phenylmethylene] -5-diethoxyphosphoryl-2-indolinone

(80) 3-Z- [1- (4- (N-Methyl-N- (piperidin-1-ylcarbonyl) amino) anilino) -1-phenylmethylene] -5-diethoxyphosphoryl-2-indolinone

(81) 3-Z- [1- (4- (N- (2-Aminoethyl) -N-methylsulfonylamino) anilino) -1-phenylmethylene] -5-diethoxyphosphoryl-2-indolinone

(82) 3-Z- [1- (4- (N- (2-Methylamino-ethyl) -N-methylsulfonylamino) anilino) -1-phenylmethylene] -5-diethoxyphosphoryl-2-indolinone

(83) 3-Z- [1- (4- (N- (2-Ethylaminoethyl) -N-methylsulfonylamino) anilino) -1-phenylmethylene] -5-diethoxyphosphoryl-2-indolinone

(84) 3-Z- [1- (4- (N- (2-Diethylamino-ethyl) -N-methylsulfonylamino) anilino) -1-phenylmethylene] -5-diethoxyphosphoryl-2-indolinone

(85) 3-Z- [1- (4- (N- (2-Pyrrolidin-1-yl-ethyl) -N-methylsulfonylamino) anilino) -1-phenylmethylene] -5-diethoxyphosphoryl-2-indolinone

(86) 3-Z- [1- (4- (N- (2-Piperidin-1-yl-ethyl) -N-methylsulfonylamino) anilino) -1-phenylmethylene] -5-diethoxyphosphoryl-2-indolinone

(87) 3-Z- [1- (4- (N- (2-Piperazin-l-yl-ethyl) -N-methylsulfonylamino) anilino) -1-phenylmethylene] -5-diethoxyphosphoryl-2-indolinone (88) 3-Z- [1- (4- (N- (2-Morpholin-4-yl-ethyl) -N-methylsulfonylamino) anilino) -1-phenylmethylene] -5-diethoxyphosphoryl-2-in - dolinon

(89) 3-Z- [1- (4- (N-Carbamoylmethyl-N-methylsulfonylamino) anilino) -1-phenylmethylene] -5-diethoxyphosphoryl-2-indolinone

(90) 3-Z- [1- (4- (N-Methylcarbamoylmethyl-N-methylsulfonylamino) anilino) -1-phenylmethylene] -5-diethoxyphosphoryl-2-indolinone

(91) 3-Z- [1- (4- (N-Ethylcarbamoylmethyl-N-methylsulfonylamino) anilino) -1-phenylmethylene] -5-diethoxyphosphoryl-2-indolinone

(92) 3-Z- [1- (4- (N- ((2-Dimethylaminoethyl) carbamoylmethyl) N-methylsulfonylamino) anilino) -1-phenylmethylene] -5-diethoxyphosphoryl -2 -indolinon

(93) 3-Z- [1- (4- (N- (N- (2-Dimethylaminoethyl) -N-methyl-carbamoylmethyl) -N-methylsulfonylamino) anilino) -1-phenyl- methylene] -5-diethoxyphosphoryl-2-indolinone

(94) 3-Z- [1- (4- (N-Diethylcarbamoylmethyl-N-methylsulfonylamino) anilino) -1-phenylmethylene] -5-diethoxyphosphoryl-2-indolinone

(95) 3-Z- [1- (4- (N- (Pyrrolidin-1-ylcarbonylmethyl) -N-methylsulfonylamino) anilino) -1-phenylmethylene] -5-diethoxyphosphoryl-2-indolinone

(96) 3-Z- [1- (4- (N- (Piperidin-1-ylcarbonylmethyl) -N-methylsulfonylamino) anilino) -1-phenylmethylene] -5 -diethoxyphosphoryl- 2 -indolinon (97) 3-Z- [1- (4- (N- (Piperazin-1-ylcarbonylmethyl) -N-methylsulfonylamino) anilino) -1-phenylmethylene] -5-diethoxyphosphoryl- 2 -indolinon

(98) 3-Z- [1- (4- (N- (Morpholin-4-ylcarbonylmethyl) -N-methylsulfonylamino) anilino) -1-phenylmethylene] -5 -diethoxyphosphoryl- 2 -indolinon

(99) 3-Z- [1- (4- (2-Dimethylaminoethoxy) anilino) -1-phenylmethylene] -5-diethoxyphosphoryl-2-indolinone

(100) 3-Z- [1- (4- (3-Dimethylamino-propoxy) anilino) -1-phenylmethylene] -5-diethoxyphosphoryl-2-indolinone

(101) 3-Z- [1- (4-carbamoylmethyl anilino) -1-phenylmethylene] -5-diethoxyphosphoryl-2-indolinone

(102) 3-Z- [1- (4- (2-Carbamoyl-ethyl) -anilino) -1-phenylmethylene] -5-diethoxyphosphoryl-2-indolinone

(103) 3-Z- [1- (4- (1H-Imidazol-4-yl) anilino) -1-phenylmethylene] -5-diethoxyphosphoryl-2-indolinone

(104) 3-Z- [1- (4- (pyridin-2-yl) anilino) -1-phenylmethylene] - 5-diethoxyphosphoryl-2-indolinone

^" (105) 3-Z- [1- (4- (pyridin-3-yl) anilino) -1-phenylmethylene] -5-diethoxyphosphoryl-2-indolinone

(106) 3-Z- [1- (4- (pyridin-4-yl) anilino) -1-phenylmethylene] -5-diethoxyphosphoryl -2-indolinone

(107) 3-Z- (1-anilino-1-phenylmethylene) -5- (phenylaminosulfonyl) -2-indolinone

(108) 3-Z- [1- (4-nitro-anilino) -1-phenylmethylene] -5- (phenylaminosulfonyl) -2-indolinone (109) 3-Z- [1- (4-Ethoxycarbonylanilino) -1-phenylmethylene] - 5- (phenylaminosulfonyl) -2 -indolinone

(110) 3-Z- [1- (4-carboxy-anilino) -1-phenylmethylene] -5- (phenylaminosulfonyl) -2-indolinone

(111) 3-Z- [1- (4-fluoro-anilino) -1-phenylmethylene] -5- (phenylaminosulfonyl) -2-indolinone

(112) 3-Z- [1- (4-chloro-anilino) -1-phenylmethylene] -5- (phenylaminosulfonyl) -2-indolinone

(113) 3-Z- [1- (4-bromoanilino) -1-phenylmethylene] -5- (phenylaminosulfonyl) -2-indolinone

(114) 3-Z- [1- (4-iodo-anilino) -1-phenylmethylene] -5- (phenylaminosulfonyl) -2-indolinone

(115) 3-Z- [1- (4-cyanoanilino) -1-phenylmethylene] -5- (phenylaminosulfonyl) -2-indolinone

(116) 3-Z- [1- (4-methoxy-anilino) -1-phenylmethylene] -5- (phenylaminosulfonyl) -2-indolinone

(117) 3-Z- [1- (4-ethoxy-anilino) -1-phenylmethylene] -5- (phenylaminosulfonyl) -2-indolinone

(118) 3-Z- [1- (4-Trifluoromethyl-anilino) -1-phenylmethylene] - 5- (phenylaminosulfonyl) -2-indolinone

(119) 3-Z- [1- (4-methylanilino) -1-phenylmethylene] -5- (phenylaminosulfonyl) -2-indolinone

(120) 3-Z- [1- (4-Methylmercapto-anilino) -1-phenylmethylene] - 5- (phenylaminosulfonyl) -2-indolinone (121) 3-Z- [1- (4-aminomethylanilino) -1-phenylmethylene] - 5- (phenylaminosulfonyl) -2-indolinone

(122) 3-Z- [1- (4-Methylaminomethyl) anilino) -1-phenylmethylene] -5- (phenylaminosulfonyl) -2-indolinone

(123) 3-Z- [1- (4-isopropylaminomethyl anilino) -1-phenylmethylene] -5- (phenylaminosulfonyl) -2-indolinone

(124) 3-Z- [1- (4-phenylaminomethyl-anilino) -1-phenylmethylene] - 5- (phenylaminosulfonyl) -2-indolinone

(125) 3-Z- [1- (4-ethylaminomethyl anilino) -1-phenylmethylene] - 5- (phenylaminosulfonyl) -2-indolinone

(126) 3-Z- [1- (4-Propylaminomethyl-anilino) -1-phenylmethylene] - 5- (phenylaminosulfonyl) -2-indolinone

(127) 3-Z- [1- (4-butylaminomethyl anilino) -1-phenylmethylene] - 5- (phenylaminosulfonyl) -2-indolinone

(128) 3-Z- [1- (4-isobutylaminomethyl anilino) -1-phenylmethylene] -5- (phenylaminosulfonyl) -2-indolinone

(129) 3-Z- [1- (4-Cyclohexylaminomethyl-anilino) -1-phenylmethylene] -5- (phenylaminosulfonyl) -2-indolinone

(130) 3-Z- [1- (4-Benzylaminomethyl-anilino) -1-phenylmethylene] - 5- (phenylaminosulfonyl) -2-indolinone

(132) 3-Z- [1- (3-Dimethylaminomethylanilino) -1-phenylmethylene] -5- (phenylaminosulfonyl) -2-indolinone

(133) 3-Z- [1- (4- ((N-Ethyl-N-methylamino) methyl) anilino) -1-phenylmethylene] -5- (phenylaminosulfonyl) -2-indolinone (134) 3-Z- [1- (4-Diethylaminomethyl anilino) -1-phenylmethylene] -5- (phenylaminosulfonyl) -2-indolinone

(135) 3-Z- [1- (4- ((N-Methyl-N-propylamino) methyl) anilino) -1-phenylmethylene] -5- (phenylaminosulfonyl) -2-indolinone

(136) 3-Z- [1- (4- ((N-Isopropyl-N-methylamino) methyl) anilino) -1-phenylmethylene] -5- (phenylaminosulfonyl) -2-indolinone

(137) 3-Z- [1- (4- ((N-Ethyl-N-propylamino) methyl) anilino) -1-phenylmethylene] -5- (phenylaminosulfonyl) -2-indolinone

(138) 3-Z- [1- (4- ((N-Ethyl-N-isopropylamino) methyl) anilino) 1-phenylmethylene] -5- (phenylaminosulfonyl) -2-indolinone

(139) 3-Z- [1- (4-Dipropylaminomethyl-anilino) -1-phenylmethylene] -5- (phenylaminosulfonyl) -2-indolinone

(140) 3-Z- [1- (4-diisopropylaminomethyl anilino) -1-phenylmethylene] -5- (phenylaminosulfonyl) -2-indolinone

(141) 3-Z- [1- (4- ((N-Benzyl-N-methylamino) methyl) anilino) -1-phenylmethylene] -5- (phenylaminosulfonyl) -2-indolinone

(142) 3-Z- [1- (4- ((N-Benzyl-N-ethylamino) methyl) anilino) -1-phenylmethylene] -5- (phenylaminosulfonyl) -2-indolinone

(143) 3-Z- [1- (4-Dibenzylaminomethyl-anilino) -1-phenylmethylene] -5- (phenylaminosulfonyl) -2-indolinone

(144) 3-Z- [1- (4- (pyrrolidin-1-ylmethyl) anilino) -1-phenylmethylene] -5- (phenylaminosulfonyl) -2-indolinone

(145) 3-Z- [1- (4- (3,6-dihydro-2H-pyridin-l-ylmethyl) anilino) 1-phenylmethylene] -5- (phenylaminosulfonyl) -2- indolinone (146) 3-Z- [1- (4- (2,6-Dimethylpiperidin-1-ylmethyl) anilino) -1-phenylmethylene] -5- (phenylaminosulfonyl) -2-indolinone

(147) 3-Z- [1- (4- (3,5-Dimethylpiperidin-1-ylmethyl) anilino) -1-phenylmethylene] -5- (phenylaminosulfonyl) -2-indolinone

(148) 3-Z- [1- (4- (azepan-1-ylmethyl) anilino) -1-phenylmethylene] -5- (phenylaminosulfonyl) -2-indolinone

(149) 3-Z- [1- (4- (Piperazin-1-ylmethyl) anilino) -1-phenylmethylene] -5- (phenylaminosulfonyl) -2-indolinone

(150) 3-Z- [1- (4- (Morpholin-4-ylmethyl) anilino) -1-phenylmethylene] -5- (phenylaminosulfonyl) -2-indolinone

(151) 3-Z- [1- (4- (Thiomorpholin-4-ylmethyl) anilino) -1-phenylmethylene] -5- (phenylaminosulfonyl) -2-indolinone

(152) 3-Z- [1- (4- (l-oxothiomorpholin-4-ylmethyl) anilino) -1-phenylmethylene] -5- (phenylaminosulfonyl) -2-indolinone

(153) 3-Z- [1- (4-Acetylaminomethylanilino) -1-phenylmethylene] - 5- (phenylaminosulfonyl) -2-indolinone

(154) 3-Z- [1- (4- (2-Aminoethyl) anilino) -1-phenylmethylene] - 5- (phenylaminosulfonyl) -2-indolinone

(155) 3-Z- [1- (4- (2-Methylaminoethyl) anilino) -1-phenylmethylene] -5- (phenylaminosulfonyl) -2-indolinone

(156) 3-Z- [1- (4- (2-Ethylaminoethyl) anilino) -1-phenylmethylene] -5- (phenylaminosulfonyl) -2-indolinone

(157) 3-Z- [1- (4- (2-Diethylaminoethyl) anilino) -1-phenylmethylene] -5- (phenylaminosulfonyl) -2-indolinone (158) 3-Z- [1- (4- (2-Piperidin-1-yl-ethyl) anilino) -1-phenylmethylene] -5- (phenylaminosulfonyl) -2-indolinone

(159) 3-Z- [1- (4- (2- (4-Ethoxycarbonylpiperidin-l-yl) ethyl) anilino) -1-phenylmethylene] -5- (phenylaminosulfonyl) -2 -indolinone

(160) 3-Z- [1- (4- (2- (4-Carboxy-piperidin-l-yl) ethyl) anilino) -1-phenylmethylene] -5- (phenylaminosulfonyl) -2 -indolinon

(161) 3-Z- [1- (4- (2- (4-Dimethylcarbamoylpiperidin-1-yl) ethyl) anilino) -1-phenylmethylene] -5- (phenylaminosulfonyl) -2 -indolinon

(162) 3-Z- [1- (4- (2-Acetylaminoethyl) anilino) -1-phenylmethyl] 5- (phenylaminosulfonyl) -2-indolinone

(163) 3-Z- [1- (4- (3-aminopropyl) anilino) -1-phenylmethylene] - 5- (phenylaminosulfonyl) -2-indolinone

(164) 3-Z- [1- (4- (3-Dimethylamino-propyl) anilino) -1-phenylmethylene] -5- (phenylaminosulfonyl) -2-indolinone

(165) 3-Z- [1- (4- (N-aminomethylcarbonyl-N-methylamino) anilino) -1-phenylmethylene] -5- (phenylaminosulfonyl) -2-indolinone

^" (166) 3-Z- [1- (4- (N-methylaminomethylcarbonyl-N-methylamino) anilino) -1-phenylmethylene] -5- (phenylaminosulfonyl) -2-indolinone

(167) 3-Z- [1- (4- (N-Dimethylaminomethylcarbonyl-N-methylamino) anilino) -1-phenylmethylene] -5- (phenylaminosulfonyl) -2-indolinone

(168) 3-Z- [1- (4- (N-ethylaminomethylcarbonyl-N-methylamino) anilino) -1-phenylmethylene] -5- (phenylaminosulfonyl) -2-indolinone (169) 3-Z- [1- (4- (N-Diethylaminomethylcarbonyl-N-methylamino) anilino) -1-phenylmethylene] -5- (phenylaminosulfonyl) -2-indolinone

(170) 3-Z- [1- (4- (N- (piperidin-1-ylmethylcarbonyl) -N-methylamino) anilino) -1-phenylmethylene] -5- (phenylaminosulfonyl) - 2-indolinone

(171) 3-Z- [1- (4- (N- (Morpholin-4-ylmethylcarbonyl) -N-methylamino) anilino) -1-phenylmethylene] -5- (phenylaminosulfonyl) -2-indolinone

(172) 3-Z- [1- (4- (N- (Piperazin-1-ylmethylcarbonyl) -N-methylamino) anilino) -1-phenylmethylene] -5- (phenylaminosulfonyl) -2-indolinone

(173) 3-Z- [1- (4- (N- (2-Aminoethylcarbonyl) -N-methylamino) anilino) -1-phenylmethylene] -5- (phenylaminosulfonyl) -2 -indolinone

(174) 3-Z- [1- (4- (N- (2-Methylaminoethylcarbonyl) -N-methylamino) anilino) -1-phenylmethylene] -5- (phenylaminosulfonyl) -2 -indolinone

(175) 3-Z- [1- (4- (N- (2-Diethylaminoethylcarbonyl) -N-methylamino) anilino) -1-phenylmethylene] -5- (phenylaminosulfonyl) -2 -indolinon

(176) 3-Z- [1- (4- (N-Acetyl-N- (2-aminoethyl) amino) anilino) -1-phenylmethylene] -5- (phenylaminosulfonyl) -2-indolinone

(177) 3-Z- [1- (4- (N-acetyl-N- (2-methylaminoethyl) amino) anilino) -1-phenylmethylene] -5- (phenylaminosulfonyl) -2 -indolinon

(178) 3-Z- [1- (4- (N-Acetyl-N- (2-dimethylaminoethyl) amino) anilino) -1-phenylmethylene] -5- (phenylaminosulfonyl) -2-indolinone (179) 3-Z- [1- (4- (N-acetyl-N- (3-aminopropyl) amino) anilino) - 1-phenylmethylene] -5- (phenylaminosulfonyl) -2 -indolinon

(180) 3-Z- [1- (4- (N-acetyl-N- (3-dimethylaminopropyl) amino) anilino) -1-phenylmethylene] -5- (phenylaminosulfonyl) -2 -indolinone

(181) 3-Z- [1- (4- (N-Acetyl-N- (3 -methylamino-propyl) amino) anilino) -1-phenylmethylene] -5- (phenylaminosulfonyl) -2 -indolinon

(182) 3-Z- [1- (4- (N-acetyl-N- (2-piperidin-1-yl-ethyl) amino) - anilino) -1-phenylmethylene] -5- (phenyl- aminosulfonyl) -2-indolinone

(183) 3-Z- [1- (4- (N-Acetyl-N- (carbamoylmethyl) amino) anilino) -1-phenylmethylene] -5- (phenylaminosulfonyl) -2-indolinone

(184) 3-Z- [1- (4- (N-Acetyl-N-dimethylcarbamoylmethylamino) anilino) -1-phenylmethylene] -5- (phenylaminosulfonyl) -2-indolinone

(185) 3-Z- [1- (4- (N-Ethylcarbonyl-N-dimethylcarbamoylmethylamino) anilino) -1-phenylmethylene] -5- (phenylaminosulfonyl) -2-indolinone

^" (186) 3-Z- [1- (4- (N-acetyl-N- (piperidin-1-ylcarbonylmethyl) amino) anilino) -1-phenylmethylene] -5- (phenylaminosulfonyl ) - 2 -indolinone

(187) 3-Z- [1- (4- (N-methyl-N-carbamoylamino) anilino) -1-phenylmethylene] -5- (phenylaminosulfonyl) -2-indolinone

(188) 3-Z- [1- (4- (N-methyl-N-methylcarbamoylamino) anilino) -1-phenylmethylene] -5- (phenylaminosulfonyl) -2-indolinone (189) 3-Z- [1- (4- (N-Methyl-N-dimethylcarbamoylamino) anilino) -1-phenylmethylene] -5- (phenylaminosulfonyl) -2-indolinone

(190) 3-Z- [1- (4- (N-methyl-N- (piperidin-1-ylcarbonyl) amino) anilino) -1-phenylmethylene] -5- (phenylaminosulfonyl) -2-indoline

(191) 3-Z- [1- (4- (N- (2-Aminoethyl) -N-methylsulfonylamino) anilino) -1-phenylmethylene] -5- (phenylaminosulfonyl) -2-indolinone

(192) 3-Z- [1- (4- (N- (2-Methylamino-ethyl) -N-methylsulfonylamino) anilino) -1-phenylmethylene] -5- (phenylaminosulfonyl) -2 -indolinone

(193) 3-Z- [1- (4- (N- (2-Ethylaminoethyl) -N-methylsulfonylamino) anilino) -1-phenylmethylene] -5- (phenylaminosulfonyl) -2-indolinone

(194) 3-Z- [1- (4- (N- (2-Dimethylamino-ethyl) -N-methylsulfonylamino) anilino) -1-phenylmethylene] -5- (phenylaminosulfonyl) -2-indolinone

(195) 3-Z- [1- (4- (N- (2-Diethylamino-ethyl) -N-methylsulfonylamino) anilino) -1-phenylmethylene] -5- (phenylaminosulfonyl) -2-indolinone

^" (196) 3-Z- [1- (4- (N- (2-Pyrrolidin-1-yl-ethyl) -N-methylsulfonylamino) anilino) -1-phenylmethylene] -5- (phenylaminosulfonyl ) - 2 -indolinone

(197) 3-Z- [1- (4- (N- (2-Piperidin-1-yl-ethyl) -N-methylsulfonylamino) anilino) -1-phenylmethylene] -5- (phenylaminosulfonyl) -2-indolinone

(198) 3-Z- [1- (4- (N- (2-Piperazin-l-yl-ethyl) -N-methylsulfonylamino) anilino) -1-phenylmethylene] -5- (phenylaminosulfonyl) -2-indolinone (199) 3-Z- [1- (4- (N- (2-Morpholin-4-yl-ethyl) -N-methylsulfonylamino) anilino) -1-phenylmethylene] -5- (phenylaminosulfonyl) -2-indolinone

(200) 3-Z- [1- (4- (N-carbamoylmethyl-N-methylsulfonylamino) anilino) -1-phenylmethylene] -5- (phenylaminosulfonyl) -2-indolinone

(201) 3-Z- [1- (4- (N-methylcarbamoylmethyl-N-methylsulfonylamino) anilino) -1-phenylmethylene] -5- (phenylaminosulfonyl) -2-indolinone

(202) 3-Z- [1- (4- (N-ethylcarbamoylmethyl-N-methylsulfonylamino) anilino) -1-phenylmethylene] -5- (phenylaminosulfonyl) -2-indolinone

(203) 3-Z- [1- (4- (N- ((2-Dimethylaminoethyl) carbamoylmethyl) N-methylsulfonylamino) anilino) -1-phenylmethylene] -5- (phenyl- aminosulfonyl) -2-indolinone

(204) 3-Z- [1- (4- (N- (N- (2-Dimethylaminoethyl) -N-methyl) carbamoylmethyl) -N-methylsulfonylamino) anilino) -1-phenylmethylene ] -5- (phenylaminosulfonyl) -2-indolinone

(205) 3-Z- [1- (4- (N-Dimethylcarbamoylmethyl-N-methylsulfonylamino) anilino) -1-phenylmethylene] -5- (phenylaminosulfonyl) -2-indolinone

(206) 3-Z- [1- (4- (N-Diethylcarbamoylmethyl-N-methylsulfonylamino) anilino) -1-phenylmethylene] -5- (phenylaminosulfonyl) -2-indolinone

(207) 3-Z- [1- (4- (N- (pyrrolidin-1-ylcarbonylmethyl) -N-methylsulfonylamino) anilino) -1-phenylmethylene] -5- (phenylaminosulfonyl) -2-indolinone (208) 3-Z- [1- (4- (N- (piperidin-1-ylcarbonylmethyl) -N-methylsulfonylamino) anilino) -1-phenylmethylene] -5- (phenylaminosulfonyl) -2-indolinone

(209) 3-Z- [1- (4- (N- (piperazin-1-ylcarbonylmethyl) -N-methylsulfonylamino) anilino) -1-phenylmethylene] -5- (phenylaminosulfonyl) -2-indolinone

(210) 3-Z- [1- (4- (N- (morpholin-4-ylcarbonylmethyl) -N-methylsulfonylamino) anilino) -1-phenylmethylene] -5- (phenylaminosulfonyl) -2-indolinone

(211) 3-Z- [1- (4- (2-Dimethylaminoethoxy) anilino) -1-phenylmethylene] -5- (phenylaminosulfonyl) -2-indolinone

(212) 3-Z- [1- (4- (3-Dimethylamino-propoxy) anilino) -1-phenylmethylene] -5- (phenylaminosulfonyl) -2-indolinone

(213) 3-Z- [1- (4-carbamoylmethyl anilino) -1-phenylmethylene] - 5- (phenylaminosulfonyl) -2-indolinone

(214) 3-Z- [1- (4- (2-Carbamoyl-ethyl) anilino) -1-phenylmethylene] -5- (phenylaminosulfonyl) -2-indolinone

(215) 3-Z- [1- (4- (1H-Imidazol-4-yl) anilino) -1-phenylmethylene] -5- (phenylaminosulfonyl) -2-indolinone

(216) 3-Z- [1- (4- (pyridin-2-yl) anilino) -1-phenylmethylene] - 5- (phenylaminosulfonyl) -2-indolinone

(217) 3-Z- [1- (4- (pyridin-3-yl) anilino) -1-phenylmethylene] - 5- (phenylaminosulfonyl) -2-indolinone

(218) 3-Z- [1- (4- (pyridin-4-yl) anilino) -1-phenylmethylene] - 5- (phenylaminosulfonyl) -2-indolinone (219) 3-Z- [1- (4- (tetrazol-5-yl) anilino) -1-phenylmethylene] -5-diethoxyphosphoryl -2-indolinone

(220) 3-Z- [1- (4- (Tetrazol-5-yl-methyl) anilino) -1-phenyl-methy1en] -5-diethoxyphosphoryl-2-indolinone

(221) 3-Z- [1- (4- (2- (tetrazol-5-yl) ethyl) anilino) -1-phenylmethylene] -5-diethoxyphosphoryl-2-indolinone

(222) 3-Z- [1- (4- (3- (Tetrazol-5-yl) propyl) anilino) -1-phenylmethylene] - 5-diethoxyphosphoryl-2-indolinone

(223) 3-Z- [1- (4- (Tetrazol-5-yl) anilino) -1-phenylmethylene] - 5- (phenylaminosulfonyl) -2-indolinone

(224) 3-Z- [1- (4- (Tetrazol-5-ylmethyl) anilino) -1-phenylmethylene] -5- (phenylaminosulfonyl) -2-indolinone

(225) 3-Z- [1- (4- (2- (tetrazol-5-yl) ethyl) anilino) -1-phenylmethylene] -5- (phenylaminosulfonyl) -2-indolinone

(226) 3-Z- [1- (4- (3- (Tetrazol-5-yl) propyl) anilino) -1-phenylmethylene] -5- (phenylaminosulfonyl) -2-indolinone

(227) 3-Z- [1- (4- (pyrrolidin-1-ylmethyl) anilino) -1-phenylmethylene] -5-cyano-2-indolinone

(228) 3-Z- [1- (4- (ethylamino-methyl) anilino) -1-phenylmethylene] -5-cyano-2-indolinone

(229) 3-Z- [1- (4- (butylamino-methyl) anilino) -1-phenylmethylene] -5-cyano-2-indolinone

(230) 3-Z- [1- (4- (azepin-1-ylmethyl) anilino) -1-phenylmethylene] -5-cyano-2-indolinone (231) 3-Z- [1- (4- (ethanolaminoethyl) anilino) -1-phenylmethylene] -5-cyano-2-indolinone

(232) 3-Z- [1- (4- (Diethanolamino-methyl) anilino) -1-phenylmethylene] -5-cyano-2-indolinone

(233) 3-Z- [1- (4- (morpholin-4-ylmethyl) anilino) -1-phenylmethylene] -5-cyano-2-indolinone

(234) 3-Z- [1- (4- (Thiomorpholin-4-ylmethyl) anilino) -1-phenylmethylene] -5-cyano-2-indolinone

(235) 3-Z- [1- (4- (l-Oxo-thiomorpholin-4-yl-methyl) anilino) -1-phenylmethylene] -5-cyano-2-indolinone

(236) 3-Z- [1- (4- (1,1-dioxo-thiomorpholin-4-ylmethyl) anilino) -1-phenylmethylene] -5-cyano-2-indolinone

(237) 3-Z- [1- (4- (l-oxo-thiomorpholin-4-ylmethyl) anilino) -1-phenylmethylene] -5-cyano-2-indolinone

(238) 3-Z- [1- (4- (piperazin-1-ylmethyl) anilino) -1-phenylmethylene] -5-cyano-2-indolinone

(239) 3-Z- [1- (4- (4-Methylpiperazin-l-ylmethyl) anilino) -1-phenylmethylene] -5-cyano-2-indolinone

(240) 3-Z- [1- (4- (N-benzylmethylamino-methyl) anilino) -1-phenylmethylene] -5-cyano-2-indolinone

(241) 3-Z- [1- (4- (N- (4-Chlorobenzyl) methylamino-methyl) anilino) -1-phenylmethylene] -5-cyano-2-indolinone

(242) 3-Z- [1- (4- (N- (3,4-Dimethoxybenzyl) methylamino-methyl) anilino) -1-phenylmethylene] -5-cyano-2-indolinone (243) 3-Z- [1- (4- (7, 8-dimethoxy-2, 3,4,5-tetrahydrobenz [d] azepin-3-yl-methyl) -anilino) -1 -phenyl- methylene] -5-cyano-2-indolinone

(244) 3-Z- [1- (4-chloroanilino) -1-phenylmethylene] -5-cyano-2-indolinone

(245) 3-Z- [1- (4-bromoanilino) -1-phenylmethylene] -5-cyano-2-indolinone

(246) 3-Z- (1-anilino-1-phenylmethylene) -5-cyano-2-indolinone

(247) 3-Z- [1- ((4- (Pyrrolidin-1-ylmethyl) anilino) -1-phenylmethylene] -5- (phenylaminosulfonyl) -2-indolinone

(248) 3-Z- [1- ((4- (Pyrrolidin-1-ylmethyl) anilino) -1-phenylmethylene] -5- (pyridin-3-ylaminosulfonyl) -2-indolinone

(249) 3-Z- [1- ((4- (Pyrrolidin-1-ylmethyl) anilino) -1-phenylmethylene] -5- (3 -nitro-phenylaminosulfonyl) -2-indolinone

Example] 4.

Dry ampoule with 75 mg of active ingredient per 10 ml

Composition:

Active ingredient 75.0 mg

Mannitol 50 mg

Water for injections ad 10.0 ml

production:

Active ingredient and mannitol are dissolved in water. After filling, freeze-drying. The ready-to-use solution is dissolved with water for injections. Example 5

Trorkenampnl 1 ml 35 mg active ingredient per 2 ml

Composition:

Active ingredient 35.0 mg

Mannitol 100.0 mg

Water for injections ad 2.0 ml

Manufacture long:

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

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

Example 6

Tablet with 50 mg Wi fsto f

Composition:

(1) Active ingredient 50.0 mg

(2) milk sugar 98.0 mg

(3) Corn starch 50.0 mg

(4) Polyvinylpyrrolidone 15.0 mg

(5) Magnesium stearate 2.0 mg

215.0 mg

production:

(1), (2) and (3) are mixed and granulated with an aqueous solution of (4). (5) is added to the dried granulate. Tablets are pressed from this mixture, biplan with a facet on both sides and a partial notch on one side. Tablet diameter: 9 mm. Example 7

Tablet with 350 mg of wi

Composition:

(1) Active ingredient 350.0 mg

(2) milk sugar 136.0 mg

(3) corn starch 80.0 mg

(4) Polyvinylpyrrolidone 30.0 mg

(5) Magnesium stearate 4th mg

600.0 mg

Manufacturing:

(1), (2) and (3) are mixed and granulated with an aqueous solution of (4). (5) is added to the dried granulate. Tablets are pressed from this mixture, biplan with a facet on both sides and a partial notch on one side. Tablet diameter: 12 mm.

B ispi ei a

Capsules with 50 mg of wi cin

Composition:

^" (1) Active ingredient 50.0 mg

(2) Corn starch dried 58.0 mg

(3) Milk sugar powdered 50.0 mg

(4) Magnesium stearate 2. mg

160.0 mg

production:

(1) is triturated with (3). This trituration is added to the mixture of (2) and (4) with intensive mixing. This powder mixture is filled on a capsule filling machine into size 3 hard gelatin capsules.

Example] 9_

Capsules with 350 mg wi

Composition:

(1) Active ingredient 350.0 mg

(2) Corn starch dried 46.0 mg

(3) Milk sugar powdered 30.0 mg

(4) Magnesium stearate 4.0 mg

430.0 mg

production:

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

This powder mixture is filled in a size 0 hard gelatin capsule on a capsule filling machine.

At spi l lü

Sυpposi tori n with 100 mg of active ingredient

1 suppository contains:

Active ingredient 100.0 mg

Polyethylene glycol (M.G. 1500) 600.0 mg

Polyethylene glycol (M.G. 6000) 460.0 mg

Polyethylene sorbitan monostearate 840.0 mg

2,000.0 mg

Manufacture 1:

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

Claims

claims

1. Indolinones of the general formula substituted in the 5-position

in the

X is an oxygen or sulfur atom,

R- _{L is} a hydrogen atom or a prodrug residue,

R _{2 is} a hydroxy, C ₁ . ₃ alkoxy, aryloxy, phenyl-C _1-3 alkoxy, cyano, (HO) ₂ PO-, (HO) (C _{1. 4,} alkoxy) PO-, (HO) (aryloxy) PO , (HO) (benzyloxy) PO-, (C _1-4 alkoxy) ₂ PO-, (aryloxy) ₂ PO-, (benzyloxy) ₂ P0-, (C _1-3 alkylenedioxy) PO-, H (C ^ -Alkoxy) PO-, H (aryloxy) PO-, H (benzyloxy) PO-, mercapto-, , Aryl-mercapto-, phenyl-C ^ - _j -alkylmercapto-, C ^ -alkylsulfinyl-, arylsulfinyl-, phenyl-C ₁ _ ₃ -alkylsulfinyl-, C ₁ , ₃ -alkylsulfonyl-, aryl-sulfonyl-, phenyl- C ^ - _j -alkylsulfonyl-, sulfo-, C _1-3 -alkoxysulfonyl-, aryloxysulfonyl-, phenyl-C ^ - _j -alkoxysulfonyl-, aminosulfonyl-, C - ^ - alkylaminosulfonyl-, arylaminosulfonyl-, heteroarylaminosulfonyl-, Phenyl-C ₁ . ₃ alkylaminosulfonyl -, di (C _1-4 alkyl -AL-) -aminosulfonyl-, di (aryl) -aminosulfonyl-, di- (phenyl - C _{1 3} alkyl.) -Aminosulfonyl-, N- (C _x . ₃ -Alkyl) -arylaminosulfonyl-, N- (C _j ^ -alkyl) -heteroarylaminosulfonyl-, N- (C ^ -Alky!) -phe- nyl-C _{j ^} - _j -alkylaminosulfonyl or a 4- to 7-membered cycloalkyleneiminosulfonyl group,

R _{3 is} a hydrogen atom, a C ₃ . _7- cycloalkyl, trifluoromethyl or heteroaryl group,

a phenyl or naphthyl group, by a fluorine, chlorine, bromine or iodine atom, by a trifluoromethyl, C ^ alkyl or C _{j ^} ^ alkoxy mono- or disubstituted phenyl or naphthyl, wherein in the case of Disubstitution the substituents may be the same or different and the above-mentioned unsubstituted, mono- and disubstituted phenyl and naphthyl groups additionally

by a hydroxy, hydroxy-C ^ - _j -alkyl or C ^ - _j -alkoxy- C ^ -alkyl group,

by a cyano, cyano-C _1-3 alkyl, cyano-C ₂ . _3- alkenyl, cyano-C ₂ . _3- alkynyl, carboxy, carboxy-C 1-4 alkyl, carboxy-C ₂ . _3- alkenyl, carboxy-C ₂ . _3- alkynyl, C ₁ . ₃ -alkoxycarbonyl-, C ^ - _j -alkoxycarbonyl-C ^ - _j -alkyl-, C ₁ . ₃ -alkoxycarbonyl-C ₂ . ₃ -alkenyl- or C ₁ . ₃ -alkoxycarbonyl-C ₂ . _3- alkynyl group,

by a C ₁ _ ₃ -alkylcarbonyl-, C ^ -alkylcarbonyl-C - ^ - alkyl-, C ₁ . _3- alkylcarbonyl-C ₂ . _3- alkenyl- or C _x _ ₃ -alkylcarbonyl-C ₂ . _3- alkynyl group,

by an aminocarbonyl, aminocarbonyl-C _1-3 alkyl, amino carbonyl C ₂ _ ₃ alkenyl, aminocarbonyl C ₂ . ₃ -alkynyl-, C ^ -alkylaminocarbonyl-, C ₁ _ ₃ -alkylaminocarbonyl-C ₁ _ ₃ -alkyl-, C ^ - _j -alkylaminocarbonyl-C ^ -alkenyl-, C ₁ . ₃ -alkylaminocarbonyl-C _2-3 -alkynyl-, di- (C ^ -alkyl) -aminocarbonyl-, di- (C ^ -alkyl) -aminocarbonyl -C ₁ _ ₃ -alkyl-, di- (C _{1 3} -alkyl) - aminocarbonyl-C ₂ . _3- alkenyl or di- (C _{1. 3} -alkyl) -aminocarbonyl-C ₂ _ ₃ -alkynyl group, by a nitro, nitro-C ^ alkyl, nitro-C ₂ . _3- alkenyl or nitro-C ₂ . _3- alkynyl group,

by an amino, C _1-3 alkylamino, di (C _1-3 alkyl) amino, amino C ^ alkyl, C ^ alkylamino C ^ alkyl or di (C _{1, 3} -alkyl) amino-C ₁ . ₃ -alkyl group,

by a C ^ _j -alkylcarbonylamino-, C ^ -alkylcarbonylamino- C ^ -alkyl-, N- (C ^ -alkyl) -C ^ _j -alkylcarbonylamino- or N- (C ^ -alkyl) -C ₁ . _3- alkylcarbonylamino-C ₁ . ₃ -alkyl group,

by a C - ^ - alkylsulfonylamino-, C ^ -alkylsulfonylamino- Ci. _j -alkyl-, N- (C ^ -alkyl) -C ^ -alkylsulfonylamino- or N- (C ^ -alkyl) -C ^ -alkylsulfonylamino-C ^ -alkyl group,

by a C ^ alkylaminosulfonyl, C ₁ . ₃ -alkylaminosulfonyl- ^ alkyl-, N- (C ^ alkyl) -C ₁ . _3- alkylaminosulfonyl or N- (C 1-4 alkyl) -C ₁ _ ₃ -alkylaminosulfonyl-C ₁ _ ₃ -alkyl group,

by a Cycloalkylenimino-, Cycloalkyleniminocarbonyl-, Cycloalkyleniminosulfonyl-, Cycloalkylenimino-C ₁ _ ₃ -alkyl-, Cycloalkyleniminocarbonyl -C ^ alkyl or Cycloalkyleniminosulfonyl-C ^ alkyl group with 4 to 7 ring members each, each with the methylene group in position 4 in a 6- or 7-membered cycloalkyleneimino group can be replaced by an oxygen or sulfur atom, by a sulfinyl, sulfonyl, -NH or -N (C _1-3 -alkyl) group,

or can be substituted by a heteroaryl or heteroaryl-C 1-4 alkyl group,

R _{4 is} a phenyl group,

one by a fluorine, chlorine, bromine or iodine atom, by a cyano, nitro, C ₁ . ₃ -alkyl or trifluoromethyl group, optionally substituted by 1 to 3 fluorine atoms C ^ _j alkoxy group, by an amino C ₂ . ₃ -alkoxy-, C ^ -alkylamino-C ₂ . _3- alkoxy-, di- (C ^ alkyl) amino-C ₂ . _3- alkoxy- or benzyl-amino-C ₂ . ₃ -alkoxy group, by a cycloalkyleneimino-C ₂ . _3- alkoxy group with 4 to 7 ring members, phenyl group substituted by a C 1-4 alkylmercapto, carboxy, C 1-4 alkoxycarbonyl, tetrazolyl or heteroaryl group,

one by a 4- to 7-membered cycloalkyleneimino group in which

a methylene group linked to the imino group can be replaced by a carbonyl or sulfonyl group or

the cycloalkylene part can be condensed with a phenyl ring or

one or two hydrogen atoms can each be replaced by a C 1-4 alkyl group or / and

each the methylene group in position 4 of a 6- or 7-membered cycloalkyleneimino group by a carboxy, C - ^ - alkoxycarbonyl, aminocarbonyl, C ^ -alkylaminocarbonyl, di- (C ^ alkyl) aminocarbonyl, phenyl -C ₁ . ₃ -alkylamino- or N- (C _x . ₃ -alkyl) -phenyl-C ^ - _j -alkylamino group substituted or

through an oxygen or sulfur atom, through a sulfonyl, sulfonyl, -NH-, -N (C ^ alkyl) -, -N (phenyl) -, -N (C _1-3 alkylcarbonyl) - or -N (benzoyl) - group can be replaced,

substituted phenyl group,

a C ^ alkylphenyl group in the alkyl part

by an amino-, C _1.4 -alkylamino-, di- (C _x . ₄ -alkyl) -amino-, N- (phenyl-C _x . ₄ -alkyl) -C _1-4 -alkylamino-, ω-hydroxy- C ₂ . ₄ -alkyl- amino, di- (ω-hydroxy-C _{2. 4,} alkyl) amino or C. _{3 7-} cycloalkylamino group,

by a 4- to 7-membered cycloalkyleneimino group in which

a methylene group linked to the imino group can be replaced by a carbonyl or sulfonyl group or

the cycloalkylene part with a phenyl group or with an oxazolo, imidazolo, thiazolo, pyridino, optionally substituted by a fluorine, chlorine, bromine or iodine atom, by a nitro, C 1-4 alkyl, C 1-4 alkoxy or amino group , Pyrazino or pyrimidino group can be condensed or

one or two hydrogen atoms each through a C ^ alkyl, C ₅ . _7- cycloalkyl or phenyl group can be replaced or / and

each the methylene group in position 4 of a 6- or 7-membered cycloalkyleneimino group by a hydroxy, carboxy, C - ^ - alkoxycarbonyl, aminocarbonyl, C ₁ . ₃ -alkylaminocarbonyl-, di- (C ^ - _j -alkyl) -aminocarbonyl-, phenyl-Ci. _j -alkylamino- or N- (C ^ - _j -alkyl) -phenyl-C _1-3 -alkylamino group substituted or

through an oxygen or sulfur atom, through a sulfonyl, sulfonyl, -NH,, -N (C ^ alkyl) -, -N (phenyl) -, -N (C _{1, 3} alkyl carbonyl) - or -N (benzoyl) - group can be replaced,

by a 5- to 7-membered cycloalkenyleneimino group in which the double bond is isolated from the nitrogen atom, by a phenylamino-, N- (C _{1, 3} -alkyl) -phenylamino-, phenyl-C ₁ . ₃ -alkylamino-, N- (C _1-3 -alkyl) -phenyl-C _1-3 -alkylamino- or di- (phenyl-C ^ - _j -alkyl) -amino group, by a hydroxy, C _x . ₃ -alkoxy-, tetrazolyl-, carboxy-,

C ^ _j alkoxycarbonyl, aminocarbonyl, C ^ _j alkylaminocarbonyl, di (C ^ alkyl) aminocarbonyl, C ^ alkylcarbonylamino or N- (C ^ alkyl) -C ^ alkylcarbonylamino group or substituted by a 4- to 7-membered cycloalkyleneiminocarbonyl group,

one by the group of formula

-N (R _a ) -CO- (CH ₂ ) _n -Rb (D

substituted phenyl group in which

R _{a is} a hydrogen atom or a C ₁ . ₃ -alkyl group,

n one of the numbers 0, 1, 2 or 3 and

R _{b is} an amino, C ^ alkylamino, phenylamino, N- (C ^ alkyl) phenylamino, benzylamino, N- (C - ^ - alkyl) benzylamino or di (C _{1 -4-} alkyl) -amino group, a 4- to 7-membered cycloalkyleneimino group, the methylene group in position 4 of a 6- or 7-membered cycloalkyleneimino group being represented by an oxygen or sulfur atom, by a sulfinyl, sulfonyl, -NH- , -N (C ^ alkyl) -, -N (phenyl) -, -N (C- _L. - _J- alkylcarbonyl) - or -N (benzoyl) - group can be replaced, or, if n is a which represents numbers 1, 2 or 3, also denote a hydrogen atom,

or one through the group of formula

-N (R _c ) - (CH ₂ ) _m - (C0) _o -R _d (III),

substituted phenyl group in which R _{c is} a hydrogen atom, a C - ^ - alkyl group, a C ^ - 1-alkylcarbonyl, arylcarbonyl, phenyl-C ^ alkylcarbonyl, C _x . _3- alkylsulfonyl, arylsulfonyl or phenyl-C _1-3 -alkylsulfonyl group,

m one of the numbers 1, 2, 3 or 4,

o one of the numbers 0 or 1 and

R _d is an amino, C _1-4 alkylamino, phenylamino, N- (C _{1. 4,} -Al- alkyl) -phenylamino-, benzylamino, N- (C _1-4 alkyl) or -benzylamino- Di- (C _x _ ₄ -alkyl) -amino group, a 4- to 7-membered cycloalkyleneimino group, where the cycloalkylene part can be fused with a phenyl ring or the methylene group in position 4 of a 6- or 7-membered cycloalkyleneimino group by an oxygen or sulfur atom, by a sulfinyl, sulfonyl, -NH, -N (C _{1, 3} -A1-kyl) -, -N (phenyl) -, -N (C ^ -alkylcarbonyl) - or -N (Benzoyl) group can be replaced, a C _x . ₃ -alkoxy group or a di- (C - ^ - alkyl) -amino-C ^ -alkylamino group optionally substituted in the 1-position by a C - ^ - alkyl group,

or, if R _{3 is} not the meaning of a hydrogen atom, one C ₃ . _7- cycloalkyl or trifluoromethyl group, also an arylsulfonylaminophenyl or N- (C 1-4 alkyl) arylsulfonylaminophenyl group,

all of the phenyl groups attached or fused in the radicals mentioned under R ₄ by fluorine, chlorine, bromine or iodine atoms, by C _1-5 alkyl, trifluoromethyl, C ^ - _j alkoxy, carboxy -, C ^ - _j -alkoxycarbonyl, aminosulfonyl, nitro or cyano groups can be mono- or disubstituted, where the substituents can be the same or different, or two adjacent hydrogen atoms of the phenyl groups can be replaced by a methylenedioxy group, and

R _{5 is} a hydrogen atom or a C ₁ . ₃ -alkyl group,

where an existing carboxy, amino or imino group can additionally be substituted by a residue which can be split off in vivo and

under the expression an aryl group, optionally by a fluorine, chlorine or bromine atom, by a trifluoromethyl, C 1-4 alkyl, C _x . ₃ -alkoxy or nitro group mono- or disubstituted phenyl or naphthyl group and

under the expression a heteroaryl group is a monocyclic 5- or 6-membered heteroaryl group which is optionally substituted by a C 1-4 alkyl group, the 6-membered heteroaryl group having one, two or three nitrogen atoms and the 5-membered heteroaryl group one optionally having a C ^ - Alkyl group substituted imino group, an oxygen or sulfur atom or an imino group optionally substituted by a C 1-4 alkyl group and an oxygen or sulfur atom or one or two nitrogen atoms, and also to the abovementioned monocyclic heterocyclic groups via two neighboring carbon atoms can be fused to a phenyl ring, it is to be understood

their isomers and their salts.

2. Indolinones of the general formula I according to claim 1, in which

X is an oxygen atom,

R _{x is} a hydrogen atom, a C - ^ - alkoxycarbonyl or C ₂ . ₄ -alkanoyl group, R _{2 is} a C ^ alkoxy, C ^ alkylmercapto, C ^ alkylsulfinyl, C ^ alkylsulfonyl, cyano, (C _1-4 alkoxy) ₂ P0, (C _{1, 3} alkylene di oxy) PO-, aminosulfonyl-, C - ^ - alkylaminosulfonyl-, di- (C _1.4 -alkyl) -aminosulfonyl-, phenylaminosulfonyl-, N- (C _{1, 3} -alkyl) -phenylaminosulfonyl-, pyridylaminosulfonyl- or N- (C - ^ - Alkyl) - pyridylammosulfonylgruppe, where the phenyl radicals contained in the groups mentioned by fluorine, chlorine or bromine atoms, by C ^ alkyl, trifluoromethyl, C _x . ₃ -alkoxy, carboxy, C - ^ - alkoxycarbonyl, aminosulfonyl, nitro or cyano groups can be mono- or disubstituted, where the substituents can be the same or different,

R _{3 is} a phenyl or naphthyl group,

one by a fluorine, chlorine, bromine or iodine atom, by a C ₁ . _3- alkyl-, trifluoromethyl-, hydroxy-, C ₁ . ₃ -alkoxy, nitro, cyano, amino, C ₁ . ₃ alkylamino, di- (C _j ^ alkyl) -amino, C ^ -Al- kylcarbonylamino-, N- (C _{1. 3,} alkyl) C ^ alkylcarbonylamino, C ^ alkylcarbonyl _j , carboxy, C ^ _j alkoxycarbonyl, aminocarbonyl, C _j ^ alkylaminocarbonyl or di- (C ^ alkyl) -aminocar- bonylgruppe substituted phenyl or naphthyl,

R _{4 is} a phenyl group,

one by a fluorine, chlorine, bromine or iodine atom, by a cyano, nitro, C ^ alkyl, trifluoromethyl, C ₁ _ ₃ alkoxy, di (C ^ alkyl) amino C ^ alkoxy, C _{j ^} . _j -Alkylmercapto, carboxy, C ^ -alkoxycarbonyl, pyrrolyl, furanyl, thienyl, oxazolyl, thiazolyl, imidazolyl, pyridinyl or pyrimidinyl group substituted phenyl group,

one by a 5- to 7-membered cycloalkyleneimino group in which

a methylene group linked to the imino group can be replaced by a carbonyl or sulfonyl group or the cycloalkylene part can be condensed with a phenyl ring or

one or two hydrogen atoms each through a C ₁ . ₃ alkyl group can be replaced or / and

each the methylene group in position 4 of a 6- or 7-membered cycloalkyleneimino group by a carboxy, Ci. _j -Alkoxycarbonyl, aminocarbonyl, C ^ alkylaminocarbonyl or di (C ^ alkyl) aminocarbonyl group substituted or

can be replaced by an oxygen or sulfur atom, by a sulfonyl, sulfonyl, -NH or -N (C _x . ₃ -alkyl) group,

substituted phenyl group,

a C ₁ _ ₄ -n-alkylphenyl group, which is terminal in the alkyl part

by an amino, C - ^ - alkylamino, di- (C ^ alkyl) amino, N- (phenyl-C _{1, 2-} alkyl) -C ₁ . ₄ -alkylamino-, 2 -hydroxyethylamino-, di- (2-hydroxyethyl) -amino- or C ₅ . _s cycloalkylamino group,

by a 5- to 7-membered cycloalkyleneimino group in which

one or two hydrogen atoms by a C ^ respectively - may be replaced _j alkyl group or

the methylene group in position 4 of a piperidino group by a carboxy, , Aminocarbonyl, C ^ alkylaminocarbonyl or di (C ^ alkyl) aminocarbonyl group substituted or the cycloalkylene with a phenyl group or an optionally by a fluorine, chlorine or bromine atom, by a C. _{1 3} -Alkyl- or C - ^ - alkoxy group substituted imidazolo or pyridino group can be condensed or

can be replaced by an oxygen or sulfur atom, by a sulfinyl, sulfonyl, -NH or -N (C _x . ₃ -alkyl) group,

pe by a 3-pyrroline-l-yl or 3, 4-Dehydropiperidinogrup- by a phenylamino, N- (C ^ - _j alkyl) -phenylamino-, phenyl-C ^ -. alkylamino, N- ( C ^ - _j -alkyl) -phenyl-C ₁ . _3- alkylamino or di- (phenyl-C _1-3 -alkyl) -amino group,

by an aminocarbonyl, C ^ alkylaminocarbonyl,

Di- (C _{1, 3} -alkyl) -aminocarbonyl-, C ^ -alkylcarbonylamino- or

N- (C - ^ - alkyl) -C ^ alkylcarbonylamino group is substituted,

one by the group of formula

-N ⁽ R _a ⁾ -CO- ⁽ CH ₂ ⁾ _n -Rb ⁽ II ⁾ ,

substituted phenyl group in which

R _{a is} a hydrogen atom or a C ^ alkyl group,

n one of the numbers 0, 1 or 2 and

R _b an amino, C _x . ₄ -Alkylamino-, di- (C - ^ - alkyl) -amino-, phenylamino or benzylamino group or a 5- to 6-membered cycloalkyleneimino group, the methylene group in position 4 of the piperidino group by an oxygen or sulfur atom, by a sulfinyl -, Sulfonyl-, -NH- or -N (C _x . ₃ alkyl) group can be replaced, or, if n represents the number 1 or 2, also denote a hydrogen atom,

or one through the group of formula

-N (R _c ) - (CH ₂ ) _m - (C0) _o -R _d (III),

substituted phenyl group in which

R _{c is} a hydrogen atom, a C ^ alkyl, C ^ alkylcarbonyl or C _ ₃ alkylsulfonyl group,

m one of the numbers 1, 2 or 3,

o mean one of the numbers 0 or 1 and

R _{d is} an amino, C ₁ . ₄ -alkylamino-, di- (C ^ -alkyl) -amino-, phenylamino or benzylamino group or a 5- to 6-membered cycloalkyleneimino group, the methylene group in position 4 of the piperidino group being represented by an oxygen or sulfur atom, by a sulfinyl , Sulfonyl, -NH or -N (C ^ alkyl) group can be replaced, a di- (C _1-3 alkyl) -amino- ^ - optionally substituted in the 1-position by a C ^ alkyl group alkylamino group or, if n represents the number 1 or 2, also represent a hydrogen atom,

where all the single-bonded or fused phenyl groups contained in the radicals mentioned under R ₄ by fluorine, chlorine or bromine atoms, by C ₁ _ ₃ alkyl, trifluoromethyl, C ^ alkoxy, carboxy, C _x . ₃ -alkoxycarbonyl, aminosulfonyl, nitro or cyano groups can be mono- or disubstituted, where the substituents can be the same or different, or two adjacent hydrogen atoms of the phenyl groups can be replaced by a methylenedioxy group, and R _{5 represents} a hydrogen atom or a methyl group,

their isomers and their salts.

3. Indolinones of the general formula I according to claim 1, in which

X is an oxygen atom,

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

R _{2 is} a C ^ alkoxy, C ₁ . ₃ alkylmercapto, C - ^ - alkylsulfinyl, C ^ alkylsulfonyl, cyano, ₂ PO-, aminosulphonyl, C (C _{1 -C 4} alkoxy.) - ^ - alkylaminosulfonyl, di (C ^ alkyl ) -aminosulfonyl-, phenylaminosulfonyl-, N- (C - ^ - alkyl) -phenylaminosulfonyl-, 3-pyridylaminosulfonyl- or N- (C - ^ - alkyl) -3 -pyridylaminosulfonylgruppe, where in the groups mentioned contained phenyl residues by a fluorine, chlorine or bromine atom, a C ₁ . _3- alkyl, trifluoromethyl, C 1-4 alkoxy, nitro or cyano group can be substituted,

R _{3 is} a phenyl or naphthyl group, but especially the phenyl group,

R _{4 is} a phenyl group,

one by a fluorine, chlorine, bromine or iodine atom, by a cyano, nitro, C ₁ . _3- alkyl-, trifluoromethyl-, C ₁ _ ₃ -alkoxy-, di- (C ^ -alkyl) -amino-C ^ -alkoxy-, C ^ -alkylmercapto-, carboxy-, C ^ -alkoxycarbonyl-, pyridinyl- or imidazolyl group substituted phenyl group,

a phenyl group substituted by a pyrrolidino, piperidino, 2, 6-dimethylpiperidino, 3, 5-dimethylpiperidino or azepino group, where the methylene group in position 4 of the piperidino group by a carboxy, C ^ alkoxycarbonyl, aminocarbonyl, C ₁ . ₃ -Alkylaminocarbonyl- or di- (C ^ alkyl) aminocarbonyl group substituted or

can be replaced by an oxygen or sulfur atom, by a sulfonyl, sulfonyl, -NH or -N (C _{1, 3} -alkyl) group,

a C ^ -n-alkylphenyl group, which is terminal in the alkyl part

by an amino, C _j ^ alkylamino or di (C ^ alkyl) amino group,

by an N- (phenylmethyl) -C ^ alkylamino group which is monosubstituted in the phenyl part by a fluorine, chlorine or bromine atom, a C ^ alkyl, C - ^ - alkoxy, trifluoromethyl or cyano group or by two C - ^ - alkyl or C ^ alkoxy groups can be disubstituted,

by a 2-hydroxyethylamino, di (2-hydroxyethyl) amino, cyclopentylamino or cyclohexylamino group,

by a pyrrolidino, piperidino, 2, 6-dimethyl-piperidino, 3, 5-dimethyl-piperidino or cyclohexyleneimino group, where

the methylene group in position 4 of the piperidino group by a carboxy, C ₁ . ₃ -Alkoxycarbonyl, aminocarbonyl, C _j ^ alkylaminocarbonyl or di (C - ^ - alkyl) aminocarbonyl group substituted or

can be replaced by an oxygen or sulfur atom, by a sulfinyl, sulfonyl, -NH or -N (C ^ -alkyl) group, or the cycloalkylene part can be condensed with a phenyl group,

by a 3-pyrrolin-l-yl or 3,4-dehydropiperidino group, by a phenylamino, N- (C 1-4 alkyl) -phenylamino, phenyl-Ci. ₃ -alkylamino-, N- (C - ^ - alkyl) -phenyl -C ₁ . Kylamino- ₃ -AL- or di- (phenyl-C ^ - _j alkyl) amino group,

by an aminocarbonyl, C ^ alkylaminocarbonyl,

Di- (C _{1, 3} -alkyl) -aminocarbonyl-, C ^ - _j -alkylcarbonylamino- or

N- (C _{1. 3,} alkyl) -C. _{1 3} -alkylcarbonylamino group is substituted,

one by the group of formula

-N (R _a ) -CO- (CH ₂ ) _n -R _b (II),

substituted phenyl group in which

R _{a is} a C ^ alkyl group,

n one of the numbers 0, 1 or 2 and

R _{b is} an amino, C 1-4 alkylamino, di (C _{1, 4} alkyl) amino, pyrrolidino or piperidino group, the methylene group in position 4 of the piperidino group being represented by an oxygen or sulfur atom, by a sulfinyl or sulfonyl group -, -NH- or -N (C _{1, 3} -alkyl) group can be replaced, mean

or one through the group of formula

-N (R _C ) - (CH ₂ ) _m - (C0) _o -R _d (III),

substituted phenyl group in which

R _{c is} a C 1-4 alkylcarbonyl or C 1-4 alkyl sulfonyl group, m one of the numbers 1, 2 or 3,

o mean one of the numbers 0 or 1 and

R _{d is} an amino, C _j ^ alkylamino, di (C _{1, 4} alkyl) amino, pyrrolidino or piperidino group, the methylene group in position 4 of the piperidino group being represented by an oxygen or sulfur atom, by a sulfinyl, sulphonyl, -NH- or -N (C _{1. 3,} alkyl) group may be replaced, or in 1-position is optionally substituted by a C ^ alkyl group substituted di (C ^ _j alkyl) amino-C _j ^ represents alkylamino group,

or Phenylsulfonylaminophenyl- or N- (C _{1 3} alkyl.) -phenyl - sulfonylaminophenylgruppe,

where all the single-bonded or fused-on phenyl groups contained in the radicals mentioned under R _{4 are} replaced by a fluorine, chlorine or bromine atom, by a methyl, trifluoromethyl, methoxy, carboxy, methoxycarbonyl, ethoxycarbonyl, aminosulfonyl, Nitro or cyano group can be substituted or two adjacent hydrogen atoms of the phenyl groups can be replaced by methoxy groups or by a methylenedioxy group, and

R _{s represents} a hydrogen atom,

their isomers and their salts.

4. The following substituted indolinones of the general formula I according to claim 1:

(a) 3-Z- [1- (4- (piperidin-1-ylmethyl) anilino) -1-phenylmethylene] -5-methylsulfinyl-2-indolinone, (b) 3-Z- [1- (4- (piperidin-1-ylmethyl) anilino) -1-phenylmethylene] -5-methylsulfonyl-2-indolinone,

(c) 3-Z- [1- (4- (Piperidin-1-ylmethyl) anilino) -1-phenylmethylene] -5- (N-methyl-N-phenylaminosulfonyl) -2-indolinone .

(d) 3-Z- [1- (4- (Piperidin-1-ylmethyl) anilino) -1-phenylmethylene] -5- (N-butyl-N-methylaminosulfonyl) -2-indolinone .

(e) 3-Z- [1- (4- (piperidin-1-ylmethyl) anilino) -1-phenylmethylene] -5- (phenylaminosulfonyl) -2-indolinone,

(f) 3-Z- [1- (4- (piperidin-1-ylmethyl) anilino) -1-phenylmethylene] -5-diethoxyphosphoryl-2-indolinone,

(g) 3-Z- [1- (4- ((N-benzyl-N-methylamino) methyl) anilino) -1-phenylmethylene] -5-diethoxyphosphoryl-2-indolinone,

(h) 3-Z- [1- (4- (N- (2-Dimethylamino-ethyl) -N-methylsulfonylamino) anilino) -1-phenylmethylene] -5-diethoxyphosphoryl-2-indolinone,

(i) 3-Z- [1- (4- (N- (dimethylaminocarbonyl-methyl) -N-methylsulfonylamino) anilino) -1-phenylmethylene] -5-diethoxyphosphoryl - 2 -indolinone,

(j) 3-Z- [1- (4- (N-dimethylaminomethylcarbonyl-N-methylamino) anilino) -1-phenylmethylene] -5-diethoxyphosphoryl-2-indolinone,

(k) 3-Z- [1- (4- (2-dimethylaminoethyl) anilino) -1-phenylmethylene] -5- (phenylaminosulfonyl) -2-indolinone,

(1) 3-Z- [1- (4- (dimethylamino-methyl) anilino) -1-phenylmethylene] -5- (phenylaminosulfonyl) -2-indolinone,

(m) 3-Z- [1- (4- (N-methylacetylamino) anilino) -1-phenylmethylene] -5- (phenylaminosulfonyl) -2-indolinone and (n) 3-Z- [1- (4- (N-methylpiperazin-1-yl) anilino) -1-phenylmethylene] -5- (phenylaminosulfonyl) -2-indolinone,

their isomers and their salts.

5. Physiologically acceptable salts of the compounds according to claims 1 to 4.

6. Medicament containing a compound according to at least one of claims 1 to 4 or a salt according to claim 5 in addition to optionally one or more inert carriers and / or diluents.

7. Use of a compound according to at least one of claims 1 to 4 or a salt according to claim 5 for the manufacture of a medicament which is suitable for the treatment of excessive or abnormal cell proliferation.

8. A method for producing a medicament according to claim 6, characterized in that a compound according to at least one of claims 1 to 4 or a salt according to claim 5 is incorporated in one or more inert carriers and / or diluents by a non-chemical route.

9. A process for the preparation of the compounds according to claims 1 to 5, characterized in that

a. a compound of the general formula

in the X, R ₂ and R _{3 are} as defined in claims 1 to 4 and

Rg can represent a hydrogen atom, a protective group for the nitrogen atom of the lactam group or a bond to a solid phase, and

Z- _{L represents} a halogen atom, a hydroxyl, alkoxy or aryloxy group,

with an amine of the general formula

in the

R ₄ and R ₅ are as defined in claims 1 to 4, reacted and, if necessary, a protective group used for the nitrogen atom of the lactam group or a compound thus obtained is split off from a solid phase or

b. for the preparation of a compound of the general formula I in which R _{2 represents} one of the substituted sulfinyl or sulfonyl groups mentioned at the outset,

a compound of the general formula

in the Rj _. and R ₃ to R _{5 are} as defined in claims 1 to 4 and

R ₂ 'represents one of the substituted mercapto or sulfinyl groups mentioned for R ₂ in claims 1 to 4, is oxidized and

if desired, a compound of the general formula I thus obtained which contains an alkoxycarbonyl group is subsequently converted into a corresponding carboxy compound by hydrolysis or

a compound of the general formula I thus obtained, which contains an amino or alkylamino group, is converted into a corresponding alkylamino, dialkylamino or pyrrolidino compound by means of alkylation or reductive alkylation, or

a compound of the general formula I thus obtained, which contains an amino or alkylamino group, is converted into a corresponding acyl compound by acylation or

a compound of the general formula I thus obtained, which contains a carboxy group, is converted into a corresponding ester or aminocarbonyl compound by esterification or amidation, or

a compound of the general formula I which contains a nitro group is converted into a corresponding amino compound by reduction or

if necessary, a protective residue used during the reactions to protect reactive groups is split off or

if desired, a compound of the general formula I thus obtained is subsequently separated into its stereoisomers or a compound of the general formula I thus obtained is converted into its salts, in particular for pharmaceutical use into its physiologically tolerable salts with an inorganic or organic acid or base.