Indian Patents. 252271:"THE COMPOUND 1-ACETYL-6-FLUORO-2-INDOLINONE"

Title of Invention	"THE COMPOUND 1-ACETYL-6-FLUORO-2-INDOLINONE"
Abstract	The compound l-acetyl-6-fluoro-2-indolinone, wherein said compound is used as starting material for the manufacture of a substituted 2-indolinone of the formula (I) as in which R2 is a fluorine atom.

Full Text	The present invention relates to indolinone derivatives, substituted in the 6-position, of the formula (Formula Removed) to their tautorners, enantiomers, diastereomers, their mixtures and their salts, in particular their physiologically acceptable salts, which have useful pharmacological properties, to medicaments comprising these compounds to their use and to processes for their preparation. The above compounds of the formula I have useful pharmacological properties, in particular an inhibition action on Various kinases, especially on receptor tyrosine kinases, such as VEGFR1, VEGFR2, VEGFR3, PDGFRα, PDGFRß, FGFR1, FGFR3, EGFR, HER2, c-Kit, IGF1R and HGFR, Flt-3, and on the proliferation of cultivated human cells, in particular that of endothelial cells, for example in angiogenesis, but also on the proliferation of other cells, in particular tumour cells. Accordingly, the present invention provides the above compounds of the formula I, which have useful pharmacological properties, medicaments comprising these pharmacologically active compounds, their use and processes for their preparation. Moreover, the present invention provides the physiologically acceptable salts of the compounds according to the invention, medicaments comprising these compounds which in addition, if appropriate, contain one or more inert carrier materials and/or diluents, and their use for preparing a medicament suitable in particular for treating excessive or anormal cell proliferations. The present invention furthermore provides processes for preparing this medicament, characterized in particular in that the compounds according to the invention or their physiologically acceptable salts are incorporated into one or more inert carrier materials and/or diluents. I. In the above formula I, X is an oxygen atom, R1 is a hydrogen atom, R2 is a fluorine, chlorine or bromine atom or a cyano group, R3 is a phenyl group or a phenyl group which is monosubstituted by a fluorine, chlorine, bromine or iodine atom or by a Ci.s-alkoxy group, where the abovementioned unsubstituted and the monosubstituted phenyl groups may additionally be substituted in the 3- or4-position by a fluorine, chlorine or bromine atom, by a cyano group, by a C1-3-alkoxy or C1-2-alkyI-carbonyl-amino group, by a cyano-C1-3-alkyI, carboxy-C1-3-alkyl, carboxy-C1-3-alkoxy, carboxy-C1-3-alkylamino, carboxy-C1-3-alkyl-N-C1-3-alkyO-amino, C1-3-alkoxy-carbonyl-C1-3-alkyl, C1-3-alkoxy-carbonyl-Ci-3-alkoxy,. C1-3alkoxy- carbonyI-C1-3-alkyIamino, amino, amino-C1-3-alkyl, aminocarbonyI-C1-3-alkyl, (C1-2-alkylarnino)-carbonyl-C1-3-alkyl, di-(C1-3-alky[)-aminocarbonyl-C1-3-aBcyl, (C1-3-alkyl-carbonyI)-amino-C1-3-a!ky!, (C1-3-aikoxy-carbonyO-amino-C1-3-aikyl, (C3. 6-aIkyl-carbony])-amino-C1-3-alkyl, (phenyl-carbonyl)-amino-C1-3-alkyl, (C3-6-cycloalkyl-carbony[)-amino-C1-3-aIkyl, (C3-6-cycloalkyl-C1-3-aIkyl-carbonyl)-amino-C1-3-alkyi, (thiophen^-yl-carbonylJ-ammo-C1-3-alkyl, (furan-2-yl-carbonyl)-amino-C1-3-alky!, (phenyl-C1-3-aIkyk;arbonyl)-amino-C1-3-alkyl, (2-(C1-3-alkoxy)-benzoyl-carbonyl)-amino-C1-3-alkyl, (pyridin-2-yl-carbonyl)-amino-Ci-3-alkyl, (pyridin-3-y!-carbonyl)-amino-C1-3-alkyl-, (pyridin-4-yl-carbony[)-amino-C1-3-alkyl- or C1-3alkyl-piperazin-1-yl-carbonyl-C1-3-alkyl group, by a carboxy-C2-3-alkenyl, aminocarbonyl-C2-3-alkenyl, (G)-3-alkyl-amino)-carbonyl-C2-3-alkenyl, di-(C1-3-alky!)-amino-carbonyl-C2.3-alkenyl or C1-3-alkoxy-earbonyl-C2-3-alkenyl group, where the substituents may be identical or different, R4 is a phenyl group or a phenyl group which is monosubstituted by a C1-3-alkyl group which is terminally substituted by an amino, guanidino, mono- or dHC1-3alkyO-amino-, N-[oo-di-(C1-3-a!kyl)-amino-C2. 3-alkyl]-N-(C1-3-alkyl)-amino, N-methyl-(C3-4-alkyl)-amino, N-(C1-3-alkyl)-N-benzy(amino, N-fC^-alkoxycarbonyO-amino, !4-(C1-oxycarbonyO-Ci^-alkylamino, 4-(Ci_3-alkyI)-piperazin-1-yl, imidazol-1-yl, pyrroIidin-1-yl, azetidin-1-yl, morpholin-4-yl, piperazln-1-yl, thiomorpholin-4-yl group, by a di-(C1-3-alkyl)-amino-(Ct-3-alkyl)-sulphonyI, 2-[di-(Ct^-alkyl)-amino]-ethoxy, 4-(Ci.3-alkyl)-piperazin-1-yl-carbonyl, {o)-[di-(C1-3-aikyl)-amino]-(C2.3-alky[)}-N-(C1-3-alkyl)-amino-carbonyl, 1-(C1-3-afkyljimidazof-2-yI, (C1-3-alkyl)-sufphonyl group, or by a group of the formula (Formula Removed) in which R7 is a Ct-2-alkyl, C1.2-alkyl-carbonyl, di-(Ci-2-alkyl)-amino-carbonyl-Ci-3-alkyl or C1.3-alkylsulphonyl group and R8 is C-i.s-alkyl, m-[dKCi-2-alkyl)-amino]-C2-3-alky!, co-j alkyl)-amino]-C1-3-alkyl group, or a (C1-3-alkylJ-carbonyl, (C1-3s-alkyl)-carbonyl or carbony!-(C1-3 alkyl) group which is terminally substituted by a di-(C1-3-alkyl)-amino, piperazin-1-yl or 4-(C1-3-alkyl)-piperazin-1-yl group, where all dia/kylamino groups present in the radical R4 may also be present in quaternized form, for example as an N-methyl-(N,N-dialkyl)-amrnoniurn group, where the counterion is preferably selected from the group consisting of iodide, chloride, bromide, methylsulphonate, para-toluenesufphonate and trifluoroacetate, R5 is a hydrogen atom and R6 is a hydrogen atom, where the abovementioned alkyl groups include linear and branched alkyl groups in which additionally one to 3 hydrogen atoms may be replaced by fluorine atoms, where additionally a carboxyl, amino or imino group present may be substituted by an in vivo cteavable radical or may be present in the form of a prodrug radical, for example in the form of a group which can be converted in vivo into a carboxyi group or in the form of a group which can be converted in vivo into an imino or amino group, their tautomers, enantiomers, diastereomers, their mixtures and their salts. Particularly preferred compounds of the above formula I are those compounds in which X, R1, R5 and R6 are as defined under I. and: II.i. R2 and R4 are as defined under I. and R3 is a phenyl group or a phenyl group which is monosubstituted by a fluorine, chlorine, bromine or iodine atom or by a C1-3-alkoxy group, where the abovementioned unsubstituted and the monosubstituted phenyl groups may additionally be substituted in the 3- or 4-position by a fluorine, chlorine or bromine atom, by a cyano group, by a C1-3-alkoxy or C1-3-alkyl-carbonyl-amino group, by a cyano-C1-3-alkyl, carboxy-C1-3-alkyl, carboxy-C1-3-alkoxy, carboxy-C1-3-alkylamino, carboxy-C1-3-alky!-N-(C1-3-alky()-amino, C1-3-alkoxy-carbonyl-C1-3-alkyl, C-1-3-alkoxy-carbonyl-C1-3-alkoxy, C1-3-alkoxy-carbonyl-C1-3aJkylamino, C1-3-alkoxy-carbonyl-C1-3-alkyf-N-fC1-3-aJkyl)-arnino, amino-Ci.3-alkyl, aminocarbonyl-Ci.3-a[kyl, (Ci.2-alkylammo)-carbonyl-C1-3-alkyl, di-(C1-3-a[kyl)-aminocarbony[-C1-3-alkyI, (C-[_2-alkyl-carbony()-amino-C1-3-alkyl, {C1-3-alkoxy-carbonyl)-amino-C1-3-alky!, (C3 6-alkyl-carbonyl)-amino-C1-3-alkyl, (phenyl-carbony!)-amino-C1-3-a!kyl, (C1-3-cycIoalkyl-carbonyO-amino-C1-3-alkyl, (C1-3-cycloalkyl-C1-3alkyl-carbonyI)-amino-C1-3-aIkyl, (thiophen-2-yl-carbonyl)-amino-C1-3-aIkyl, (furan1-3-yl-carbonyO-amino-C1-3-alkyl, (phenyl-C1-3-alkyl-carbonyl)-amino-C1-3-aikyl, (2-(C1-3-aikoxy)-benzoyi-carbony!)-amino-C1-3-a!ky!I (pyridin-2-yl-carbonyl)-amino-Ci-3-alkyl, (pyridin-3-yl-carbonyl)-amino-C1-3-alkyl, (pyridin-4-yl-carbonyl)-amino-C1-3alkyl or C1-3-alkyl-piperazin-1-yl-carbonyl-Ci-3-alkyl group, by a carboxy-C2-3-alkenyl, aminocarbonyl-C2-3-alkenyl-, (C1-3-alkyl-amino)-carbonyl-C2-3-alkenyl-, di-(C1-3-alkyl)-amino-carbonyl-C2-3-alkenyl or C1-3-alkoxy-carbonyl-C1-3-alkenyl group, where the substituents may be identical or different; II.ii. R2 and R4 are as defined under I. and R3 is a phenyl group which is substituted by a Ci-2-alkyl-carbonyl-amino group, by a oarboxy-C1-3alkyl, carboxy-C1-3alkoxy, C-V-alkoxy-carbonyl-C1-3-alkyl, C1-3-alkoxy-carbonyl-C1-3-alkoxy, aminocarbonyl-C1-3alkyl, (C1-3-alkylamino)-carbonyl-C1-3-alkyl, di-(C1-3alkyl)-aminocarbonyl-C1-3-alkyl, (C1-3-alkyl-carbonyl)-amino-CValkyl, (C1-3alkoxy-carbonyl)-amino-C1-3-alkyl, (phenyl-carbonyl)-amino-C1-3-alkyl, (C1-3-cycloalkyl-carbonyl)-amino-C1-3-alkyl, (C3-6-cycloalkyl-C1-3-alkyl-carbonyI)-amino-C1-3-alkyl, (thiophen-2-yl-carbonyl)-amino-Ci.3-alkyl, (furan-2-yl-carbonyl)-amino-C1-3-alkyl, (phenyl-C1-3-alkyl-carbonyI)-amino-C1-3-alkyl, (2-(C1-3 alkoxy)-benzoyI-carbonyl)-amino-C1-3-alkyl, (pyridin-2-yl-carbonyl)-amino-C1-3-alkyl, (pyridin-3-yl-carbonyl)-amino-C1-3-alkyl, (pyridin-4-yl-carbonyi)-amino-C1-3-alkyI or C1-3-alkyl-piperazin-1-yl-carbonyl-C1-3-alkyl group, ' by an arninocarbonyl-C2-3-aIkenyl, (C1-3-a[kylamino)-carbonyI-C1-3 alkenyl, di-(C1-3-alkyl)-arnino-carbonyl-C21-3-alkenyl or C-1-3-alkoxy-carbonyl-C1-3-aikenyl group; ll.iii. R2 and R4 are as defined under I. and R3 is a phenyl group substituted by a carboxy-Ci.3-alkyI or Ci-4-alkoxy-carbonyl-Ci-3-aIkyl group; II.iv. R3 and R4 are as defined under I. and R2 is a fluorine or chlorine atom; II.v. R2 and R3 are as defined under I. and R4 is a phenyl group or a phenyl group which is monosubstituted by a C1-3-alkyl group which is terminally substituted by an amino, guanidino, mono- or di-(C1-3-alkyl)-amino-, N-[o-di-(C1-3-aIkyl)-amino-C2. 3-alkyl]-N-(Ci-3-alkyl)-amino, N-methyl-(C1-3-a[kyl)-amino, N-(C1-3 alkyi)-N-benzylamino, N-(C1-3-alkoxycarbonyl}-amino, N-(C1-3 alkoxycarbonyl)-C1-3-alkylamino, 4-(C1-3-aIkyl)-piperazin-1-yl, imidazol-1-yl, pyrrolidin-1-yl, azetidin-1-yl, morpholin-4-yl, piperazin-1-yl, thiomorpholin-4-yl group, by a di-(C1-3-alkyl)-amino-(C1-3-alky!)-sulphonyIJ 2-[di-(C1-3-alkyl)-amino]-ethoxy, 4-(C1-3-alkyl)-piperazin-1-yl-carbonyl, {co-[di-(C1-3-alkyl}-amino]-(C2-3-alkyI)}-N-(C1-3-aIkyI)-amino-carbonyl, 1-(C1-3-alkyl)imidazoI-2-yl, (C1-3alkyl)-sulphonyl group, or (Formula Removed) (Formula Removed) group of the formula (Formula Removed) in which R7 is a C1-3-alky!, C1-3alkyl-carbonyl, di-(C1-3-alkyi)~amino-carbonyl-C1-3-alkyl or C-1-3-alkylsulphonyl group and R8 is C1-3-alkyl, o-[di-(C1-3alkyf)-amino]-C2-3-alkyl, o-a!kyl)-amino]-C2-3-alkyl group, or a (C1-3-a!kyl)-carbonyl, (C1-3-alkyl)-carbonyl or carbonyl-(C1-3 alkyl) group which is terminally substituted by a di-(C1-3-alkyl)-amino, piperazin-1-yl or 4-(C1-3-alkyl)-piperazin-1-yl group, where all dialkylamino groups present in the radical R4 may also be present in quaternized form, for example as an N-methyl-(N,N-dialkyl)-ammonium group, where the counterion is preferably selected from the group consisting of iodide, chloride, bromide, methyJsurphbnate, para-toruenesulphonate and trifluoroacetate. Subgroups of particularly preferred compounds of the above formula I which are to be mentioned in particular are those in which: lll.i. X, R1, R2, R5 and Rs are as defined under I., R3 is as defined under II.i. and R4 is as defined under ll.v.; lll.ii. X, R1, R2, R5 and R5 are as defined under I., R3 is as defined under It.ii. and R4 is as defined under ll.v.; lll.iii. X, R1, R2, R5 and R6 are as defined under I., R3 is as defined under If.iii. and R4 is as defined under II.v.; lll.iv. X, R1, R5 and R6 are as defined under I., R2 is as defined under II.iv., R3 is as defined under ILL, II.ii. or ll.iii. and'R4 is as defined under II.v. A further preferred group of compounds of the above formula I are those in which X is an oxygen atom, R1 is a hydrogen atom, R2 is a fluorine, chlorine or bromine atom or a cyano group, R3 is a phenyl group or a phenyl group which is monosubstituted by a fluorine, chlorine, bromine or iodine atom or by a C1-3-alkoxy group, where the abovementioned unsubstituted and the monosubstituted phenyj groups may additionally be substituted in the 3- or 4-position by a fluorine, chlorine or bromine atom, by a C1-3-alkoxy or C1-3-aIkyl-carbonyl-amino group, by a carboxy-C1-3-alkyl, aminocarbonyl-C1-3-alkyl, (C1-3alkylamino)-carbonyl-C1-3-alkyl, dKC1-3-alkyO-aminocarbonyl-C1-3-alkyl, (C1-3alkyl-carbony!)-amino-C1-3-alkyl or (phenyl-carbonyO-amino-C1-3-alkyl group, where the substituents may be identical or different, (Formula Removed) is a phenyl group which is substituted by a C1-3-alky! group terminally substituted by a di-(C1-3-alky])-amino group, or by a group of the formula (Formula Removed) in which R7 is a C-1-3-alkyl, C1-3-alkyl-carbonyl, di-(C1-3-aIkyl)-amino-carbonyl-C1-3 alkyl or C1-3-alkylsulphonyl group and R8 is a C1-3-alkyl or oa-[di-(C1-3-aIkyl)-amino]-C2-3-alkyl group, or a C1-3-alkyl-carbonyl group terminally substituted by a di-(C1-3-alkyl)-amino, piperazino orC1-3-alkyO-piperazin-l-yl group, R5 is a hydrogen atom and R6 is a hydrogen atom, where the abovementioned alky! groups include linear and branched alkyl groups in which additionally one to 3 hydrogen atoms may be replaced by fluorine atoms, where additionally a carboxyl, amino or imino group present may be substituted by an in vivo cleavabfe radical, their tautomers, enantiomers, diastereomers, their mixtures and their salts. The following compounds of the formula 1 are particularly preferred: (a) 3-Z-[1-(4-dimethyIaminomethylaniIind)-1-(3-(2-carboxyethyl)phenyl)methylene]-6- chIoro-2-indolinone (b) 3-Z-[1-(4-dimethyIaminomethyIanilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6- fluoro-2-indo!inone (c) 3-Z-[1-(4-dimethylaminomethy!anilino)-1-(3-(2-carboxyethyl)phenyl)methylene]-6- fluoro-2-indolinone (d) 3-Z-[1-(4-(N-(4-methylpiperazin-1-ylmethyIcarbonyl)-N-methylamino)anilino)-1-(4- (2-carboxyethyl)phenyI)methyleneI-6-fIuoro-2-indolinone (e) 3-Z-[1-(4-(N-(2-dimethylaminoethyl)-N-methylsulphonyIamino)anilino)-1-(4-(2- carboxyethyl)phenyl)methylene]-6-fluoro-2-indo!inone (f) 3-Z-[1-(4-(N-(3-dimethylaminopropyl)-N-acetylamino)anilino)-1-(4-(2- carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone (g) 3-Z-[1-(4-(1-methylimidazol-2-yl)anHino)-1-(4-(2-carboxyethyl)phenyl)methylene]- 6-fluoro-2-indolinone (h)3-Z-[1-(4-(N-(dimethylaminomethylcarbonyl)-N-methylamino)aniIino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone (i) 3-Z-[1 -(4-(N-(2-dimethylaminoethylcarbonyl)-N-methy!amino)anilino)-1 -(4-(2-carboxyethyl)phenyl)methy!ene]-6-fluoro-2-indolinone 0') 3-Z-[1 -(4-(pyrrolidin-1 -ylmethyl)anilino)-1 -(4-(2-carboxyethyI)phenyl)methylene]-6-fluoro-2-indblinone (k) 3-Z-[1-(4-(diethylaminomethyl)anilino)-1-(4-(2-carboxyethy!)phenyl)metfiylene]-6-fluoro-2-indoIinone (I) 3-Z-[1-(4-(2-dimethyiaminoethyl)anilino)-1-(4-(2-carboxyethy!)pheny!)methyIene]-6-chloro-2-indolinone (m) 3-Z-[1-(4-dimethylaminomethylanilino)-1-(4-(2-carboxyethyI)phenyl)methylene]-6-chloro-2-indolinone (n) 3-Z-[1-(4-(pyrrolidin-1-ylmethyl)anilino)-1-(4-(2-carboxyethy!)phenyl)methylene]-6-chIoro-2-indolinone (o)3-Z-[1-(4-(pyrrolidin-1-ylmethyl)anilino}-1-(4-(2-carboxyethyl)phenyl)methylene]-6-bromo-2-indolinone (p) 3-Z-[1-(4-(dimethylaminomethyl)anilino)-1-(4-(2-carboxyethyl)pheny!)methylene]-6-bromo-2-indolinone (q) 3-Z-[1 -(4-(diethylaminomethyl)aniIino)-1 -(4-(2-carboxyethyl)-methyIene]-6-bromo-2-indolinone where additionally a carboxyf, amino or imino group present may be substituted by an in vivo cleavable radical or may be present in the form of a prodrug radical, for example in the form of a group which can be converted in vivo into a carboxyl group or in the form of a group which can be converted in vivo into an imino or amino group, and their salts. A group which can be converted in vivo into a carboxyl group is to be understood as meaning, for example, a hydroxymethyl group, a carboxyl group which is esterified with an alcohol in which the alcoholic moiety is preferably a C1-6-alkanol, a phenyl-C1-3-alkanol, a C1-3-cycloalkanol, where a C1-3-cycloalkanol may additionally be substituted by one or two C1-3-alkyl groups, a C1-3-cycloalkanol in which one methylene group in the 3- or 4-position is replaced by an oxygen atom or by an imino group optionally substituted by a C1-3alkyl, phenyl-C1-3-alkyl, phenyl-C1-3alkoxy-carbonyl or C1-3alkyl-carbony! group and in which the cycloalkanol moiety may additionally be substituted by one or two C1-3-alkyl groups, a C1-3-cycloalkenol, a C1-3 alkenol, a phenyl-C3-5-alkenol, a C3_5-alkynol or a phenyl-C1-3aikynol, with the proviso that no bond to the oxygen atom originates from a carbon atom which carries a double or triple bond, a C1-3cycloalkyl-Ci-a-alkanol, a bicycloalkano! having a total of 8 to 10 carbon atoms which may additionally be substituted in the bicycloalkyl moiety by one or two C1-3-alkyl groups, a 1,3-dihydro-3-oxo-1-isobenzofuranol or an alcohol of the formula Ra-CO-0-(RbCR0)-OH, in which Ra is a d-B-alkyl, C5-7-cycfoalkyI, phenyl or phenyl-C1-3-a[kyl group, Rb is a hydrogen atom, a d-s-alkyl, C1-3-cycloalkyl or phenyl group, and Rc is a hydrogen atom or a C1-3-a!ky! group, and a radical cleavable in vivo from an imino or arnino group is to be understood as meaning, for example, a hydroxyl group, an acy! group, such as the benzoyl or pyridihoyl group, or a C1-3-alkylcarbonyl group, such as the formyl, acetyl, propionyi, biitanoyl, pentanoyl or hexanoyl group, an allyloxycarbonyl group, a C1-3-a!koxy-carbonyl group, such as the methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, tert-butoxycarbonyl, pentoxycarbonyl, hexyloxycarbonyl, octyloxycarbonyl, nonyloxycarbonyl, decyloxycarbonyl, undecyloxycarbonyl, dodecyloxycarbonyl or hexadecyloxycarbonyl group, a phenyl-C1-3-alkoxy-carbonyl group, such as the benzylbxycarbonyl, phenylethoxycarbonyl or phenylpropoxycarbonyl group, a Ci-s-alkylsulphonyl-Ci^-alkoxy-carbonyl, Ci_3-alkoxy-C2-4-alkoxy-C2-4-alkoxy-carbonyI or RaCO-O-(RbCRc)-O-CO- group, in which Ra is a C1-3-alkyI, C5-7-cyc!oa[kyl, phenyl or phenyl-Ci.3-alkyl group, Rb is a hydrogen atom, a C1-3-alkyl, C1-3-cycloalkyl or phenyl group and RC is a hydrogen atom, a C1-3-alkyl or RaCO-O-(RbCRc)-O- group, in which Ra to Rc are as defined above, and additionally, for an ammo group, the phthalimido group, where the ester radicals mentioned above can also be used as a group which can be converted in vivo into a carboxy! group. Preferred prodrug radicals for a carboxyl group are a C1-6-alkoxy-carbonyl group, such as the methoxycarbonyl, ethoxycarbonyl, n-propyloxycarbonyl, isopropyloxycarbonyl, n-butyloxycarbonyl, n-penty[oxycarbonylr n-hexyloxycarbonyl or cyclohexyloxycarbonyl group, or a phenyJ-Ci-s-alkoxy-carbonyl group, such as the benzyloxycarbonyl group, and, for an imino or amino group, a C1-3-alkoxy-carboriyl group, such as the methoxy-carbonyl, ethoxycarbonyl, n-propyloxycarbonyl, isopropyloxycarbonyl, n-butyloxy-carbonyl, n-pentyloxycarbonyl, n-hexyloxycarbohyl, cyclohexyloxycarbonyl, n-heptyfoxycarbonyi, n-octy!oxycarbonyl or n-nony!oxycarbony! group, a pheny!-C1-3-alkoxy-carbonyl group, such as the benzyloxycarbonyl group, a phenylcarbonyl group optionally substituted by a C1-3-alkyl group, such as the benzoyl or 4-ethyl-benzoyl group, a pyridinoyl group, such as the nicotinoyl group, a C1-3-a!kylsulphonyl-n-C1-3-alkoxy-carbonyl or C1-3-aIkoxy-C2-3-a[koxy-C1-3-alkoxy-carbonyl group, such as the 2-methylsulphonylethoxycarbonyt or 2-(2-ethoxy)-ethoxycarbony! group. According to the invention, the novel compounds are obtained, for example, by the following processes, which are known in principle from the literature: a. reaction of a compound of the formula in which the radicals Z1 and R3 may, if appropriate, change their positions, X, R2, R3 and R6 are as defined at the outset, R1' has the meanings mentioned at the outset for R1 or is a protective group for the nitrogen atom of the lactam group, where R1 may also, if appropriate, represent a bond, formed via a spacer, to a solid phase, and Z1 is a halogen atom, a hydroxyl, alkoxy or arylalkoxy group, for example a chlorine or bromine atom, a methoxy, ethoxy or benzyloxy group, with an amine of the formula (Formula Removed) which R4 and R5 are defined as mentioned at the outset, and, if required, the product is subsequently cleaved from a protective group used for the nitrogen atom of the lactam group or from a solid phase. Suitable protective groups for the nitrogen atom of the lactam group are, for example, an acetyl, benzoyl, ethoxycarbonyl, tert-butyloxycarbonyl or benzyloxycarbonyl group and suitable solid phases are a resin, such as a 4-(2',4'-dimethoxyphenylaminomethyl)-phenoxy resin, where the attachment is expediently via the amino group, or a p-benzyloxybenzyl alcohol resin, where the attachment is expediently via a spacer, such as a 215-dimethoxy-4-hydroxybenzyl derivative. The reaction is expediently carried out in a solvent, such as dimethylformamide, toluene, acetonitrile, tetrahydrofuran, dimethyl sulphoxide, methylene chloride or a mixture thereof, if appropriate in the presence of an inert base, such as triethylamine, N-ethyldiisopropylamine or sodium bicarbonate, at temperatures between 20 and 175°C, where any protective groups used may be simultaneously removed owing to transamidation. If, in a compound of the formula V, Z1 is a halogen atom, the reaction is preferably carried out in the presence of an inert base at temperatures between 20 and 120°C. If, in a compound of the formula V, Z1 is a hydroxyl, alkoxy or arylalkoxy group, the reaction is preferably carried out at temperatures between 20 and 200°C. The subsequent removal of a protective group used, which may be required, If appropriate, is expediently carried oat either hydrolytically in an aqueous or alcoholic solvent, for example in methanol/water, ethanol/water, isopropanol/water, tetrahydrofuran/water, dioxane/water, dimethylformamide/water, methanol orethanol, in the presence of an alkali metal base, such as lithium hydroxide, sodium hydroxide or potassium hydroxide, at temperatures between 0 and 100DC, 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. Cleavage from a solid phase employed is preferably carried out using trifluoroacetic acid and water at temperatures between 0 and 35°C, preferably at room temperature. b. To prepare a compound of the formula I in which R3 is a phenyl or naphthyl group substituted by a carboxy-C2-3-a!kenyl, aminocarbonyI-C2-3-alkenyl, (C1-3-alkylamino)-carbonyl-C2.3-alkenyl, dKC1-3alkylamino)-carbonyl-C2-3-alkenyl or C1-3-alkoxy-carbonyl-C1-3-alkenyi group, reaction of a compound of the formula (Formula Removed) which R2, R4, R5, R6 and X are as defined at the outset, R1' has the meanings mentioned at the outset for R1 or is a protective group for the nitrogen atom of the lactam group, where R1' may also, if appropriate, represent a bond, formed via a spacer, to a solid phase, and Z3 is a leaving group, for example a halogen atom or an alkyi- or arylsulpnonylcxy group, such as a chlorine, bromine or iodine atom or a methylsulphonyloxy, ethylsulphonyloxy, p-toluenesulphonyloxy or trifluoromethanesulphonyloxy group, with an alkene of the formula (Formula Removed) in which R3' is an amino, (C1-3alky!amino), di-{C1-3-alky]amino) or C1-3-alkoxy group and n is the number 0 or 1. The reaction is expediently carried out with palladium catalysis, using, for example, palladium(ll) acetate, palladium(ll) chloride, bis(triphenylphosphine)palladium(ll) acetate, bis(triphenylphosphine)palladium(ll) chloride, palladium/carbon, bis-[1,2-bls(diphenylphosphino)ethane]pa!ladium(0), dichloro-(1,2-bis(diphenylphosphino)-ethane)palladium(Jl), tetrakistriphenyiphosphinepalladium(O), tris(dibenzylidene-acetone)dipalladium(O), 1,1'-bis(diphenylphosphino)ferrocenedichloropalladium(ll)or tris(dibenzylideneacetone)dipalladium(0)/chloroform adduct, in the presence of a base, such as triethylamine, diisopropylethylamine, lithium carbonate, potassium carbonate, sodium carbonate, caesium carbonate, and a ligand, such as triphenylphosphine, tri-ortho-tolylphosphine or tri-(tert-butyl)phosphine, in solvents such as acetonitrile, N-methylpyrrolidinone, dioxane or dimethylformamide and mixtures thereof. The cleavage of a protective group used for the nitrogen atoms of the lactam group or from a solid phase, which may be required, if appropriate, is carried out as described above under process (a). c. To prepare a compound of the formula I in which R3 is a phenyl or naphthyl group substituted by a carboxy-C1-3-alkyl, C1-3-aikoxy-carbonyl-C1-3-alkyl, aminocarbonyl-C1-3-aIkyl, (C1-3-alkylamino)-carbonyl-C1-3-alkyl or di-(C1 group, hydrogenation of a compound of the formulain which R2, R4, R5, R6 and X are as defined at the outset, R1> has the meanings mentioned at the outset for R1 or is a protective group for the nitrogen atom of the lactam group, where R1 may also, if appropriate, represent a bond, formed via a spacer, to a solid phase, A is a C1-3-alkenyl group and R3 is a hydroxyl, C1-3-alkoxy, amino, (C1-3-alkylamino) or dKC1-3-alkyOamino group. The hydrogenation is preferably carried out using catalytic hydrogenation with hydrogen in the presence of a catalyst, such as palladium/carbon or platinum, in a solvent, such as methanol, ethanol, ethyl acetate, dimethylformamide, dimethylformamide/acetone or glacial acetic acid, if appropriate with addition of an acid, such as hydrochloric 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 3 to 5 bar. The cleavage of a protective group used for the nitrogen atom of the lactafn group or from a solid phase, which may be required, if appropriate, is carried out as described under process (a). If, according to the invention, a compound of the formula I is obtained which contains an alkoxycarbonyl group, this can be converted by hydrolysis into a corresponding carboxyi compound, or if a compound of the formula I is obtained which contains an amino or alkyfemino group, this can be converted by reduction alkylation into a corresponding alkylamino or dialkylamino compound, or if a compound of the formula I is obtained which contains a dialkylamino group, this can be converted by alkylation into a corresponding trialkylammonium compound, or if a compound of the formula I is obtained which contains an amino or alkylamino group, this can be converted by acylation or sulphonation into a corresponding acyl or sulphonyl compound, respectively, or if a compound of the formula I is obtained which contains a carboxyi group, this can be converted by esterification or amidation into a corresponding ester or aminocarbonyl compound, respectively, or if a compound of the formula I is obtained which contains a nitro group, this can be converted by reduction into a corresponding amino compound, or if a compound of the formula I is obtained which contains a cyano group, this can be converted by reduction into a corresponding aminomethyl compound, or if a compound of the formula I is obtained which contains an arylalkyloxy group, this can be converted with acid into a corresponding hydroxyl compound, or if a compound of the formula I is obtained which contains an alkoxycarbony! group, this can be converted by hydrolysis into a corresponding carboxyl compound; or if a compound of the formula I is obtained in which R4 is a phenyl group substituted by an amino, alkylamino, aminoalkyl or N-alkylamino group, this can then be converted by reaction with a corresponding cyanate, isocyanate or carbamoyi halide into a corresponding urea compound of the formula I, or if a compound of the formula I is obtained in which R4 is a phenyl group substituted by an amino, alkylamino, aminoalkyl or N-alkylamino group, this can subsequently be converted by reaction with a corresponding amidino-group-transferring compound or by reaction with a corresponding nitrile into a corresponding guanidino compound of the formula I. 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 sulphuric acid, or in the presence of an alkali metal base, such as lithium hydroxide, sodium hydroxide or potassium hydroxide, at tempefares between 0 and 100°C, preferably at temperatures between TO 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, tetrahy^drofuran, dioxane or dimethylformamide, if appropriate with addition of an acid, such as hydrochloric acid, in the presence of catalytically activated hydrogen, for example bfhydrogen in thepresence of Rahey nTckeT,"pIatinum or palladium/carbon, or in the presence of a metal hydride, such as sodium borohydride, lithium borohydride, sodium cyanoborohydride or lithium aluminium hydride, at temperatures between 0 and 100°C, preferably at temperatures between 20 and 80°C. The subsequent aikyiation is preferably carried out in a suitabie solvent, such as ether, tetrahydrofuran, dioxane, dichloromethane, acetone or acetonitrile, in the presence of alky!ating agents, such as alkyl iodides, alkyl bromides, alky! chlorides, methanesulphonic acid alkyl esters, para-toluenesulphonic acid alkyi esters or alkyl trifluoroacetates, at temperatures between 0 and 100°Cr preferably at temperatures between 20 and 60°C, The subsequent acylation or sulphonylation is expediently carried out using the corresponding free acid or a corresponding reactive compound, such as its anhydride, ester, imidazolide or halide, preferably in a solvent, such as methylene chJoride, diethyl ether, tetrahydrofuran, toluene, dioxane, acetonitrife, dimethyl sulphoxide or dimethylformamide, rf appropriate in the presence of an inorganic or a tertiary organic base, at temperatures between -20 and 200°C, preferably at temperatures between 20°C and the boiling point of the solvent used. The reaction with the free acid can, if appropriate, be carried out in the presence of an agent which activates the acid or of a dehydrating agent, for example in the presence of isobutyl chloroformate, tetraethyl orthocarbonate, trimethy! orthoacetate, 2,2-dimethoxypropane, tetramethoxysilane, thionyl chloride, trimethylchlorosiiane, phosphorus trichloride, phosphorus pentoxide, N,N'-dicydohexy!carbodiimide, N.N'-dicyclohexylcarbodiimide/N-hydroxysuccinimide, N,N'-dicycIohexyl-carbodiimide/1-hydroxybenzotriazole, 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate, 2-(1 H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate/1 -hydroxybenzotriazole, N.N'-carbonyldiimidazole or triphenylphosphine/carbon tetrachloride, and, if appropriate, with addition of a base, such as pyridine, 4-dimethylaminopyridine, N-methylmorpholine or triethylamine, expediently at temperatures between 0 and 150°C, preferably at temperatures between 0 and'TOTTC. The reaction with a corresponding reactive compound can, if appropriate, be carried out in the presence of a tertiary organic base, such as triethylamine, N-ethyl-diisopropylamine, 4 N-methylmorpholine or pyridine, or, if an anhydride is used, in the presence of the (Formula Removed) corresponding acids, at temperatures between 0 and 150°C, preferably at temperatures between 50 and 100°C. The subsequent esterification or amia'ation is expediently carried out by reacting a reactive corresponding carboxylic acid derivative with an appropriate alcohol or amine, as described above. The esterification or amidation is preferably carried out in a solvent, such as methylene chloride, diethyi ether, tetrahydrofuran, toluene, dioxane, acetonitrile, dimethyl sulphoxide or dimethylformamide, if appropriate in the presence of an inorganic or a tertiary organic base, preferably at temperatures between 20°C and the boiting point of the solvent used. Here, the reaction with a corresponding acid is preferably carried out in the presence of a dehydrating agent, for example in the presence of isobutyl chioroformate, tetraethyl orthocarbonate, trimethyl orthoacetate, 2,2-dimethoxypropane, tetramethoxysilane, thionyl chloride, trimethylchlorosilane, phosphorus trichloride, phosphorus pentoxide, N.N'-dicyclohexylcarbodiimide, N,N'-dicyclohexylcarbodiimide/N-hydroxysuccinimide, N,N'-dicyclohexylcarbodi-imide/1 -hydroxybenzotriazole, 2-(1 H-benzotriazoM -yl)-1,1,3,3-tetramethyluronium-tetrafluoroborate, 2-(1H-benzotriazol-1-y!)-1,1,3,3-tetramethyfuronium tetraf!uoroborate/1-hydroxybenzotriazole, N,N'-carbonyldiimidazole or triphenyl-phosphine/carbon tetrachloride, and, if appropriate, with addition of a base, such as pyridine, 4-dimethyIaminopyridine, N-methylmorpholine or triethyiamine, expediently 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, is, if appropriate, carried out in the presence of a tertiary organic base, such triethyiamine, N-ethyldiisopropylamine or N-methylmorpholine, at temperatures between Oand 150°C, preferably at temperatures between 50 and 10CTC. The subsequent reduction of a nitro group is preferably earned out hydrogenoiytically, for example 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, if appropriate with addition of an add, 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 from 1 to 7 bar, but preferably from 3 to 5 bar. The subsequent hydrogenation of a cyano group is preferably carried out hydrogenolytically, for example using hydrogen in the presence of a catalyst, such as palladium/carbon or Raney nickel, in a solvent, such as methanol, ethanol, ethyl acetate, methylene chloride, dimethylformamide, dimethylformamide/acetone or glacial acetic acid, if appropriate with 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 from 1 to 7 bar, but preferably of from 3 to 5 bar. The subsequent preparation of a corresponding guanidino compound of the formula I is expediently carried out by reaction with an amidino-group-transferring compound, such as 3,5-dimethylpyrazole-1-carboxamidine, preferably in a solvent, such as dimethylformamide, and, if appropriate, in the presence of a tertiary organic base, such as triethylamine, at temperatures between 0 and 50°C, preferably at room temperature. In the reactions described above, any reactive groups present, such as carboxyl, hydroxyl, amino, alkylamino or imino groups, can be protected during the reaction by customary protective groups which are removed again after the reaction, A protective radical for a carboxyl group is, for example, the trimethylsilyl, methyl, ethyl, tert-butyl, benzyl or tetrahydropyranyl group, and a protective group for a hydroxyl, amino, alkylamino or imino group is, for example, the acetyl, trifluoroacetyl, benzoyl, ethoxycarbonyl, tert-butoxycarbonyl, benzyloxycarbonyl, benzyl, methoxybenzyl or 2,4-d!rriethoxy6enzyI group, and, for the amino group> additionally the phthalyl group. The subsequent removal of a protective radical used is, if appropriate, carried out, for example, hydrolytically in an aqueous solvent, for example in water, isopropanol/water, tetrahydrofuran/water or dioxane/water, in the presence of an acid, such as trifluoroacetic acid, hydrochloric acid or sulphuric acid, or in tha presence of an alkali metal base, such as lithium hydroxide, sodium hydroxide or potassium hydroxide, at temperatures between 0 and 100°C, preferably at temperatures between 10 and 50°C. However, a benzyl, methoxybenzyl or benzyloxycarbonyl radical is removed, for example, hydrogenolytically, for example using hydrogen in the presence of a catalyst, such as palladium/carbon, in a solvent such as methanol, ethanol, ethyl acetate, dimethyiformamide, dimethylformamide/acetone or glacial acetic acid, if appropriate with 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 from 1 to 7 bar, but preferably of from 3 to 5 bar. A methoxybenzyl group can also be removed in the presence of an oxidizing agent, such as cerium(IV) ammonium nitrate, in a solvent, such as methylene chloride, acetonitrile oracetonitrile/water, at temperatures between 0 and 50°C, but preferably at room temperature. However, a 2,4-dimethoxybenzy! radical is preferably removed in trifluoroacetic acid in the presence of anisole. A tert-butyf or tert-butyloxycarbonyl radical is preferably removed by treatment with an acid, such as trifluoroacetic acid or hydrochloric acid, using, if appropriate, a solvent, such as methylene chloride, dioxane, ethyl acetate or ether. A phthalyl radical is preferably removed in the presence of hydrazine or a primary arriine, such as methylamine, ethylamine or n-butylamine, in arsolvent," such"as" methanol, ethanol, isopropanol, toluene/water or dioxane, at temperatures between 20 and 50°C. Furthermore, chiral compounds of the formula I obtained can be separated into their enantiomers and/or diastereomers. Thus, for example, compounds of the formula I obtained which occur as racemates can be separated by methods known per se (see Allinger N. L. and Elie! E. L. in "Topics in Stereochemistry", Vol. 6, Wiley Interscience, 1971) into their enantiomers, and compounds of the formula I having at least 2 asymmetric carbon atoms can, owing to their physicochemical differences, be separated by methods known per se, for example by chromatography and/or fractional crystallization, into their diastereomers, which, if they are obtained in racemicform, can then be separated into the enantiomers as mentioned above. The separation of enantiomers is preferably carried out by column separation on chiral phases or by recrystallization from an optically active solvent or by reaction with an optically active substance which forms salts or derivatives, such as, for example, esters or amides, with the racemic compound, in particular acids and their activated derivatives or alcohols, and separating the mixture of diastereomeric salts or derivatives obtained in this manner, for example owing to different solubilities, whereupon the free enantiomers can be released from the pure diastereomeric salts or derivatives by action of suitable agents. Particularly common optically active acids are, for example, the D and L forms of tartaric acid, dibenzoyltartaric acid, di-o-tolyltartaric acid, malic acid, mandelic acid, camphorsulphonic acid, glutamic acid, N-acety!glutamic acid, aspartic acid, N-acetylaspartic acid or quinic acid. A suitable optically active alcohol is, for example, (+)- or (-)-menthol, and a suitable optically active acyl radical in amides is, 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 acceptable salts, with inorganic or organic acids. Acids suitable for this purpose are, for example, hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid, fumaric acid, succinic acid, lactic acid, citric acid, tartaric acid, maleic acid, methanesulphonic acid, ethanesulphonic acid, para-toluenesulphonio acid, phenylsulphonlc acid or L-(+)-mandelic acid. Moreover, the resulting novel compounds of the formula ! can, if they contain a carboxyl group, then, if desired, be converted into their salts with inorganic or organic bases, in particular, for pharmaceutical use, into their physiologically acceptable salts. Bases suitable for this purpose are, for example, sodium hydroxide, potassium hydroxide, cyclohexylamine, ethanolamine, diethanolamine and triethanolamine. Also suitable, for compounds of the formula I which contain 2 or more acidic or basic groups, are salts with 2 or more inorganic or organic bases or acids (disalts etc.). Some of the compounds of the general formulae V to XI used as starting materials 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. Compounds of the general formula IX, for example, are described in the German patent application 19844 003. As already mentioned at the outset, the novel compounds of the formula (I) have useful pharmacological properties, in particular in inhibiting action on various kinases, especially on receptor tyrosine kinases, such as VEGFR1, VEGFR2, VEGFR3, PDGFRot, PDGFRp, FGFR1, FGFR3, EGFR, HER2, c-Kit, IGFIRand HGFR, Flt-3, and on the proliferation of cultivated human cells, in particular that of endothelial cells, for example in angiogenesis, but also on the proliferation of other cells, in particular of tumour cells. The biological properties of the novel compounds were examined by the following standard methods: Human umbilical cord endothelial cells (HUVEC) were cultivated in IMDM (Gibco BRL), supplemented with 10% foetal bovine serum (FBS) (Sigma), 50 pM B-mercaptoethanol (Fluka), standard antibiotics, 15 ug/ml of endothefial cell growth factor (EGGS, Collaborative Biornedical Products) and 100 ug/ml of heparin (Sigma) on gelatin-coated culture bottles (0.2 % gelatin, Sigma) at 37°C, 5% CO2, in an atmosphere saturated with water. To examine the inhibitory activity of the compounds according to the invention, the cells were "starved" for 16 hours, i.e. kept in culture medium without growth factors (EGGS + heparin). Using trypsin/EDTA, the cells were detached from the culture bottles and washed once with serum-containing medium. 2.5 x 103 cells were then seeded in each well. The proliferation of the cells was stimulated using 5 ng/ml of VEGF-\|65 (vascular endothelial growth factor; H. Weich, GBF Brunswick) and 10 ug/ml of heparin. Per plate, as control value, in each case 6 wells were not stimulated. The compounds according to the invention were dissolved in 100% dimethyl sulphoxide and, in triplicate, added to the cultures in different dilutions, the maximum dimethyl sulphoxide concentration being 0.3%. The cells were incubated at 37°C for 76 hours, and 3H-thymidine (0.1 u Ci/well, Amersham) was then added for a further 16 hours to determine DMA synthesis. The radioactively labelled celte were then immobilized on filter mats and the incorporated radioactivity was determined in a p counter. To determine the inhibitory activity of the compounds according to the invention, the mean value for the non-stimulated cells was subtracted from the mean value of the factor-stimulated cells (in the presence or absence of the compounds according to the invention). The relative cell proliferation was calculated in percent of the control (HUVEC without inhibitor), and the concentration of active compound at which the proliferation of the cells is inhibited by 50% (lC5Owas derived therefrom. The compounds of the formula I according to the invention have an IC50 between 50µM and 1 nM. Owing to their inhibitory action on the proliferation of cells, in particular of endothelian cells and of tumour cells, the compounds of the formula I are suitable for treating diseases in which the proliferation of ceils, in particular that of endothelial ceils, plays a role. Thus, for example, the proliferation of endothelial cells and the related neovascularization is a decisive step in tumour progression (Folkman J. et al., Nature 339. 58-61, (1989); Hanahan D. and Folkman J., Cell 86, 353-365, (1996)). Furthermore, the proliferation of endothelial cells is also of importance in haemangiomes, in metastasization, in rheumatoid arthritis, in psoriasis and in ocular neovascularization (Folkman J., Nature Med. 1, 27-31, (1995); Carmeliet P & Rakeh J., Nature 407, 249-257, (2000)). The therapeutic benefit of inhibitors of endothelial cell proliferation in the animal model was shown, for example, by O'Reilly et al. and Parangiet al. (O'Reilly M.S. et al., Cell 88, 277-285, (1997); Parangi S. et al., Proc Natl Acad Sci USA 93, 2002-2007, (1996)). Thus, the compounds of the formula I, their tautomers, their stereoisomers or their physiologically acceptable salts are suitable, for example, for treating tumours (for example squamous epithelium carcinoma, astrocytoma, Kaposi sarcoma, glioblastoma, lung cancer, cancer of the bladder, neck carcinoma, oesophagus carcinoma, melanoma, ovarial carcinoma, prostate carcinoma, breast cancer, small-ceil lung carcinoma, glioma, colorectal carcinoma, pancreas carcinoma, urogenital cancer and gastrointestinal carcinoma, and also haematological cancers, such as, for example, multiple myeloma and acute myelotic leukaemia), psoriasis, arthritis (for example rheumatoid arthritis), haemangioma, angiofibroma, disorders of the eye (for example diabetic retinopathy), neovascular glaucoma, disorders of the kidneys (for example glomerulonephritis), diabetic nephropathy, malignant nephrosclerosis, thrombic microangiopathic syndromes, transplantation rejections and glomerulopathy, fibrotic disorders (for example cirrhosis of the liver), mesarigfal-celt proliferate disorders, atherosclerosis, injuries of the nerve tissue and for inhibiting the reocclusion of vessels after balloon catheter treatment, in vessel prosthetics or after implantation of mechanical devices for keeping vessels open (for example stents) or other disorders in which cell proliferation or angiogenesis play a rote. Owing to their biological properties, the compounds according to the invention can b« used alone or in combination with other pharmacologically active compounds, for example in tumour therapy in monotherapy or in combination with other antitumor therapeutics, for example in combination with topoisomerase inhibitors (for example etoposide), mitosis inhibitors (for example vinblastine, Taxol), compounds which interact with nucleic acids (for example cisplatin, cyclophosphamide, adriamycin), hormone antagonists (for example tamoxifen), steroids and analogues thereof (for example dexamethasone), inhibitors of metabolic processes (for example 5-FU etc.), cytokines (for example interferons), kinase inhibitors (for example EGFR kinase inhibitoren, such as, for example, Iressa; Gleevec), allosterically acting receptor tyrosine kinase inhibitors, antibodies (for example Herceptin), COX-2 inhibitors or else in combination with radiotherapy, etc. These combinations can be administered either simultaneously or sequentially. The invention is illustrated in more detail by the examples below: (Table Removed) breviations used: HOBt = 1 -hydroxy-1 H-benzotriazole TBTU = O-benzotriazol-l-yi-N.N.N'.N'-tetramethyluronium tetrafluoroborate Preparation of the starting materials: Example I: Dimethyl 2-(4-fluoro-2-nitrophenvl)malonate With ice-cooling, 185 g of potassium ferf-butoxide are added to a solution of 188 ml of dimethyl malonate in 970 ml of N-methylpyrrolidone, and the mixture is stirred for 2 hours. Over a period of 30 minutes, 150 ml of 2,5-difluoronitrobenzene are added dropwise to the resulting slurry, and the mixture is then, stirred at 85°C for 6 hours. The mixture is poured into 4 liters of ice-water and 250 ml of concentrated hydrochloric acid and extracted with 2 liters of ethyl acatate. The organic phase is dried with sodium sulphate and concentrated. The oily residue is triturated twice with water and then taken up in 600 ml of ethyl acetate. The solution is dried with sodium sulphate and concentrated to dryness. The resulting crude product is recrystallized from 600 ml of ethyl acetate/hexane = 2:8 and dried. Yield: 222 g (59% of theory) Rf value: 0.40 (silica gel, cyclohexane/ethyl acetate = 5:1) Mass spectrum: m/z = 270 [M-H]~ The following compounds are prepared analogously to Example (1.1) Diethyl 2-(4-bromo-2-nitrophenyl)malonate from 2,5-dibrorrionitrobenzene and diethyl malonate Rf value: 0.40 (silica gel, petroleum ether/ethyl acetate = 5:1) Mass spectrum: m/z = 359/361 [M]+ (1. 2) Dimethyl 2-(4-cyano-2-nitrophenyl)malonate from 4-chloro-3-nitrobenzonitriIe and dimethyl maionate Rf value: 0.50 (silica gel, methylene chloride/methanol = 50:1) Mass spectrum: m/z = 277 [M-H]~ Example II: Methyl 4-cyano-2-nitrophenylacetate 14.2 g of dimethyl 2-(4-cyano-2-nitrophenyl)malonate (starting material 1.2) are dissolved in 200 ml of dimethyl sulphbxide, and 4.5 g of lithium chloride and 1 .0 ml of water are added. The solution is stirred at 100°C for 3.5 hours, 300 ml of ice-water are then added and the mixture is allowed to stand for 12 hours. The resulting precipitate is filtered off with suction, taken up in methylene chloride and washed with water. The organic phase is dried over sodium sulphate, concentrated using a rotary evaporator and dried. Yield: 7.7 g (68% of theory) Rf value: 0.40 (silica gel, methylene chloride/methanol) = 50:1 C10H8N2O4 Mass spectrum: m/z = 219 [M-H]~ Example III: 4-Fluoro-2-nitrophenvlaceticacid At 100°C, 50.0 g of dimethyl 2-(4-fluoro-2-nitrophenyl)malonate (starting material I) are stirred in 400 ml of 6 molar hydrochloric acid for 20 hours, 400 ml of water are then added and the mixture is cooled to 0°C. The resulting precipitate is filtered off with suction, washed with water and 100 ml of petroleum ether ana anea. Yield: 34.5 g (94% of theory) Rf value: 0.30 (silica gel, cyclohexane/ethyl acetate) = 5:2 Mass spectrum: m/z =154 [M-COO-H]' Example IV: 6-Fluoro-2-indolinone With addition of 20 g of palladium on activated carbon (10%), 119 g of 4-fluoro-2- nitrophenylacetic acid (starting material III) are hydrogenated in 600 ml of acetic acid under a hydrogen pressure of 50 psi. The catalyst is filtered off with suction and the solvent is distilled off. The crude product is triturated with 500 ml of petroleum ether, filtered off with suction, washed with water and dried. Yield: 82.5 g (91 % of theory) . Rf value: 0.30 (silica gel, petroleum ether/ethyl acetate =1:1) C8H6FNO Mass spectrum: m/z =150 [M-H]~ The following compounds are prepared analogously to Example IV: (IV.1) 6-Brbmo-2-indolinone from diethyl 2-(4-bromo-2-nitrophenyl)malonate (starting material 1.1) using Raney nickel as hydrogenatlon catalyst Rf value: 0.45 (silica gel, petroleum ether/ethyl acetate =1:1) C8H6BrNO Mass spectrum: m/z = 210/212 [M-H]" (IV.2) 6-Cyano-2-indolinone from methyl 4-cyano-2-nitrophenylacetate (starting material II) using palladium/calcium carbonate as hydrogenation catalyst Rf value: 0.45 (silica gel, methylene chloride/methanol = 9:1) C9H6N2O Mass spectrum: m/z =157 [M-H]" Example V: 1.-acetvl-6-fluoro-2-indoiihone At 130°C, 82.5 g of 6-fluoro-2-indolinone (starting material IV) are stirred in 180 m! acetic anhydride for 3 hours. After cooiing to room temperature, the precipitate is filtered off with suction, washed with 100 ml of petroleum ether and dried. Yield: 64.8 g (61 % of theory) Rf value: 0.75 (silica gel, petroleum ether/ethyl acetate = 1:1) C10H3FNO2 Mass spectrum: m/z = 192 [M-H]~ The following compounds are prepared analogously to Example V: (V.1 ) 1 -acetyI-6-chloro-2-indolinone from 6-chloro-2-indolinone and acetic anhydride Rf value: 0.55 (silica gel, petroleum ether/ethyl acetate = 2:3) Mass spectrum: m/z = 208/210 [M-H]~ (V.2) 1-acetyl-6-bromo-2-indolinone from 6-bromo-2-indolinone (starting material IV. 1) and acetic anhydride Rf value: 0.60 (silica gel, petroleum ether/ethyl acetate = 2:1) C10H8BrNO2 Mass spectrum: m/z = 253/255 [M]+ (V.3) 1 -acetyl-6-cyano-2-indo[inone from 6-cyano-2-indolinone (starting material IV.2) and acetic anhydride Rf value: 0.60 (silica gel, methylene chloride/methanol = 50:1) Mass spectrum: m/z =199 [M-H]~ Example VI: 1-acetvl-3-f1-hvdroxv-1-f3-iodophenvl)methylene1-6-chloro-2-indolfnone 10.5 g of 1-aeetyl-6-chloro-2-indolinone (starting material V.1), 13.6 g of 3-iodobenzoic acid and 17.7 g of TBTU are initially charged in 100ml of dimethylformamide, 35 ml of triethylamine are added and the mixture is stirred at room temperature for 12 hours. After this time, the solvent is removed under reduced pressure, water is added to the residue and the residue is filtered off with suction, washed with a little water, methanol and ether and dried at 100°C under reduced pressure. Yield: 12.9 g (59 % of theory) Rf value: 0.80 (silica gel, methylene chloride/methanol = 9:1) Ci7HiiCIINO3 Mass spectrum: m/z = 438/440 [M-H]' The following compounds are prepared analogously to Example Vt (VI. 1) 1 -acetyl-3-[1 -hydroxy-1 -(4-methoxycarbonyImethylphenyl)methylene]-6-fluoro- 2-indolinone from 1-acetyl-6-fluoro-2-indolinone (starting material V) and methyl (4-carboxyphenyl)acetate (preparation according to Tetrahedron 1997, 53, 7335- 7340) (VI.2) 1-acetyl-3-[1-hydroxy-1-(4-chlorophenyl)methylene]-6-chIoro-2-indolihone from 1-acetyl-6-chloro-2-indolinone (starting material V.1) and 4-chlorobenzoic acid (VI.3) 1-acetyl-3-[1-hydroxy-1-(3,4-dimethoxyphenyl)methylene]-6-chloro-2- indolinone from 1-acetyl-6-chloro-2-indolinone (starting material V.1) and 3,4-dimethoxybenzoic acid (VI .4) 1-acetyl-3-[1-hydroxy-1-(3,4-dimethoxyphenyI)methylene>€-cyano-2- indolinone from 1-acetyl-6-cyano-2-indolinone (starting material V.3) and 3,4-dimethoxybenzoic (VI.5) 1-acetyl-3-[1-hydroxy-1-(3-fluorophenyl)methylene]-6-fIuoro-2-indolinone from 1-acetyl-6-fluoro-2-indolinone (starting material V) and 3-fluorobenzoic acid (V1.6) 1 -acetyl-3-[1 -hydroxy-1 -(4^(2-acetyIaminoethyl)phenyl)methy iene]-6-fluoro-2- indolinone from 1-acetyl-6-fluoro-2-indolinone (starting material V) and 4-(2-acetylaminoethyl)- benzoic acid (preparation according to J. Am. Chem. Soc. 1943, 65, 2377) (VI.7) 1-acetyl-3-[1-hydroxy-1-(3-methoxycarbonylmethylphenyl)methylene]-6-fluoro- 2-indolinone from 1-acetyl-6-fluoro-2-indolinone (starting material V) and ii.dthyl (3-carboxyphenyl)acetate (preparation analogously to Tetrahedron 1997, 53, 7335- 7340) (VI.8) 1-acetyl-3-[1 -hydroxy-1 -(3-(N-tert-butoxycarbonylaminomethyl)phenyl)- methylene]-6-fluoro-2-indolinone from 1-acetyl-6-fluoro-2-indolinone (starting material V) and 3-(N-tert-butoxycarbonyl- aminomethyl)benzoic acid (preparation according to Tetrahedron 1997, 53, 7335- 7340) (VI.9) 1-acetyl-3-[1-hydroxy-1-(3-cyanomethylphenyl)methylene]-6-fluoro-2- indolinone from 1-acetyl-6-fluoro-2-indolinone (starting material V) and (3-carboxyphenyl)- acetonitrile (preparation according to J. Prakt. Chem. 1998, 340, 367-374) (VI.10) 1-acetyl-3-[1-hydroxy-1-(4-(N-tert-butoxycarbonylaminomethyl)phenyl)- methylene]-6-fluoro-2-indolinone from 1-acetyl-6-fluoro-2-indolinone (starting material V) and 4-(N-tert-butoxycarbonyl- aminomethyl)benzoic acid (preparation according to Bioorg. Med. Chem. Lett 2000, 10,553-557) (VL11) 1-acetyl-3-[1-hydroxy-1-(4-iodophenyl)methyIene]-6-fluoro-2-indolinone from 1-acetyl-6-fluoro-2-indolinone (starting material V) and 4-iodobenzoic acid (VI.12) 1-acetyl-3-[1-hydroxy-1-(4-iodophenyI)methylene]-6-chloro-2-indolinone from 1-acetyl-6-chloro-2-indolinone (starting material V.1) and 4-iodobenzoic acid (VI. 13) 1-acetyl-3-[1-hydroxy-1-(3-iodophenyl)methyIene]-6-fluoro-2-indolinone from 1-acetyl-6-fluoro-2-indolinone (starting material V) and 3-iodobenzoic acid (VI.14) 1-acetyl-3-[1-hydroxy-1-(4-(2-methoxycarbonylethyl)phenyl)methylene]-6- fluoro-2-indolinone from 1-acetyl-6-fluoro-2-indolinone (starting material V) and 4-(2- methoxycarbonylethyl)benzoic acid (preparation analogously to Tetrahedron 1997, 53, 7335-7340) (VI. 15) 1-acetyl-3-[1-hydroxy-1-(3-(2-methoxycarbonylethyl)phenyl)methyIene]-6- fluoro-2-indolinone from 1-acetyl-6-fluoro-2-indolinone (starting material V) and 3-(2- methoxycarbonylethyl)benzoic acid (preparation analogously to Tetrahedron 1997, 53, 7335-7340) (VI. 16) 1 -acetyl-3-[1 -hydroxy-1-(3-(N-tert-butoxycarbonyl-2- aminoethyl)phenyl)methylene]-6-fluoro-2-indolinone from 1-acetyl-6-fluoro-2-indolinone (starting material V) and 3-(N-tert-butoxycarbonyl- 2-aminoethyl)benzoic acid (preparation analogously to Bioorg. Med. Chem. Lett 2000, 10, 553-557) (VI. 17) 1 -acetyl-3-[1 -hydroxy-1 -(4-(N-tert-butoxycarbonyl-2- aminoethyI)phenyl)methylene]-6-fluoro-2-indolinone from 1-acetyl-6-fluoro-2-indorinone (starting material V) and 4-(N-tert-butoxycarbonyl- 2-aminoethyl)benzoic acid (preparation analogously to Bioorg. Med. Chem. Lett 2000, 10, 553-557) (VI. 18) 1-acetyl-3-[1-hydroxy-1-(4-cyanophenyl)methylene]-6-chloro-2- indolinone from 1-acetyI-6-chloro-2-indolinone (starting material V.1) and 4-cyanobenzoic acid (VI. 19) 1 -acetyl-3-[1 -hydroxy-1 -(3-acetylaminomethylphenyl)rnethy lene]-6- fluoro-2-indoliiione from 1-acetyI-6-fluoro-2-indolinone (starting material V) and 3-acetylaminomethyi- benzoic acid (prepared according to J. Med. Chem. 1997, 40, 4030-4052) (VI .20) 1 -acetyl-3-[1 -hydroxy-1 -(3-(2-ethoxycarbonylethyl)phenyI)methylene]-6-f luoro- 2-indolinone from 1-acetyl-6-fluoro-2-indolinone (starting material V) and 3-(2- ethoxycarbonylethyl)benzoic acid (preparation analogously to Tetrahedron 1997, 53, 7335-7340) (VI.21) 1-acetyl-3-[1 -hydroxy-1 -(4-(2-methoxycarbonylethyl)phenyl)methylene]-6- chloro-2-indolinone from 1-acetyl-6-chloro-2-indolinone (starting material V.1) and 4-(2- methoxycarbonylethyl)benzoic acid (preparation analogously to Tetrahedron 1997, 53, 7335-7340) (VI.22) 1-acetyl-3-[1 -hydroxy-1 -(4-(2-ethoxycarbonylethyl)phenyl)rnethylene]-6-fluoro- 2-indolinone from 1-acetyl-6-fIuoro-2-indolinone (starting material V) and 4-(2- ethoxycarbonylethyl)benzoic acid (preparation analogously to Tetrahedron 1997, 53, 7335-7340) (VI.23) 1 -acetyl-3-[1 -hydroxy-1 -(3-methoxycarbonylmethyloxy-phenyl)rnethylene]-6- fluoro-2-indolinone from 1-acetyI-6-fluoro-2-indolinone (starting material V) and 3-methoxycarbonylmethyloxybenzoic acid (preparation see Tetrahedron Letters 1998, 39, 8563-8566) (VI.24) 1 -acetyI-3-[1 -hydroxy-1 -(4-methoxycarbonylmethyloxyphenyI)methyIene]-6- -i fluoro-2-indolinone from 1-acetyl-6-fluoro-2-indolinone (starting material V) and 4-methoxycarbonylmethyloxybenzoic acid (preparation analogously to Tetrahedron Letters 1998, 39, 8563-8566) (VI. 25) 1-aceiyi-3-[1-hydroxy-1-(3-(2-ethoxycarbonyiethy!oxy)phenyl)methyIene]-6- fIuoro-2-indolinone from 1-acetyl-6-fluoro-2-indolinone (starting material V) and 3-(2- eth6xyearbonylethyloxy)benzoic acid (preparation see PCT Int. Appl. WO9620173, 60) (VI.26) 1-acetyl-3-[1-hydroxy-1-(4-(2-ethoxycarbonyIethyloxy)phenyl)methylene]-6- fluoro-2-indolinone from 1-acetyl-6-fluoro-2-indolinone (starting material V) and 4-(2- ethoxycarbonylethyloxy)benzoicacid (preparation see PCT Int. Appl. WO9620173, 58) (VI.27) 1-acetyl-3-[1-hydroxy-1-(4-(2-methoxycarbonylethyl)phenyI)methylene]-6- bromo-2-indolinone from 1-acetyl-6-bromo-2-indoIinone (starting material V.2) and 4-(2- methoxycarbonylethyl)-benzoic acid (preparation analogously to Tetrahedron 1997, 53, 7335-7340) Example VII: 1-acetvl-3-f1-methoxy-1-(3-iodophenyl)methylene]-6-chloro-2-indolinone A little at a time, 2.36 g of trimethyloxonium tetrafluoroborate are added to a solution of 3.52 g of 1-acetyl-3-[i-hydroxy-1-(3-iodophenyI)methylene]-6-chloro-2-indolinone (starting material VI) and 2.72 ml of ethyldiisopropylamine in 80 ml of dichioromethane, and the mixture is stirred at room temperature for one hour. Another 1.4 ml of ethyldiisopropylamine and 1.2 g of trimethyloxonium tetrafluoroborate are added, and the mixture is stirred at room temperature for another two hours. The mixture is then extracted with water and the organic phase is dried over magnesium sulphate and evaporated to dryness. The residue is recrystallized from ether and dried at 80°C under reduced pressure. Yield: 2.40 g (66 % of theory) Rf value: 0.60 (silica gel, petroleum ether/a'ichioromethane/ethyi acetate = 5:4:1) C18H13CIIN03 Mass spectrum: m/z = 438/440 [M-H]~ m.p. 185-187 °C The following compounds are prepared analogously to Example VII: (VI 1.1) 1 -acetyl-3-[1 -methoxy-1 -(4-methoxycarbonylmethylphenyl)methylene]-6- fluoro-2-indolinone from 1 -acetyl-3-[1 -hydroxy-1 -(4-methoxycarbonylmethylphenyl)methylene]-6-fluoro-2- indolinone (starting material VI.1) (VII.2) 1-acetyl-3-[1 -methoxy-1 -(4-chlorophenyl)methylene]-6-chloro-2-indolinone from 1-acetyl-3-[1 -hydroxy-1 -(4-chlorophenyl)methylene]-6-chloro-2-indolinone (starting material VI .2) (VII. 3) 1 -acetyl-3-[1 -methoxy-1 -(3,4-dimethoxyphenyl)methylene]-6-chioro-2- indolinone from 1-acetyl-3-[1-hydroxy-1-(3,4-dimethoxyphenyl)methylene]-6-chloro-2-indolinone (starting material VI.3) (VII.4) 1-acetyl-3-[1-methoxy-1-(3,4-dimethoxyphenyI)methylene]-6-cyano-2- indolinone from 1 -acetyl-3-[1 -hydroxy-1 -(3,4-dimethoxyphenyl)-methylene]-6-cyano-2-indolinone (starting material VI.4) (VII.5) 1-acetyl-3-[1 -methoxy-1 -(3-fluorophenyI)methylene]-6-fIuoro-2-ihd6linone from1-acetyl-3-[1-hydroxy-1-(3-fIuorophenyl)methyIene]-6-fluoro-2-indolinone / (starting material VI.5) (VII.6) 1 -acetyl-3-[1 -methoxy-1-(4-(2-acetyIaminoethyl)phenyl)methylene]-6-fluoro-2- indolinone from 1 -acetyl-3-[1 -hydroxy-1-(4-(2-acetylaminoethyl)phenyl)methylene]-6-fluoro-2- indolinone (starting material VI.6) (VII.7) 1-acetyl-3-[1-methoxy-1-(3-methoxycarbonylmethylphehyl)methylene]-6- fluoro-2-indolinone from 1-acetyl-3-[1-hydroxy-1-(3-methoxycarbonylmethylphenyl)methylene]-6-fluoro-2- indolinone (starting material VI .7) (VII.8) 1-acetyl-3-[1-methoxy-1-(3-(N-tert-butoxycarbonylaminomethyl)phenyl)- methylene]-6-fluoro-2-indolinone from 1 -acetyl-3-[1 -hydroxy-1 -(3-(N-tert-butoxycarbonyl- aminomethyl)phenyl)methylene]-6-ffuoro-2-indolinone (starting material VI.8) (VII.9) 1-acetyl-3-[1-methoxy-1-(3-cyanomethylphenyl)methylene]-6-fluoro-2- indolinone from 1-acetyl-3-[1 -hydroxy-1 -(3-cyanomethylphenyl)methylene]-6-fluoro-2-indolinone (starting material VI.9) (VII.10) 1-acetyl-3-[1-methoxy-1-(4-(N-tert-butoxycarbonyl-aminomethyl)phenyl)methylene]-6-fluoro-2-indolinone from 1 -acetyl-3-[1 -hydroxy-1 -(4-(N-tert-butoxycarbonyl-aminomethyl)phenyl)methylene]-6-fluoro-2-indolinone (starting material VI.10) (VI1.11) 1 -acetyl-3-[1 -methoxy-1 -(4-iodophenyl)methylene]-6-fluoro-2-indoli none from 1-aoetyl-3-[1-hydroxy-1-(4-iodophenyl)methylene]-6-fluoro-2-indolinone (starting material VI. 11) (VII .12) 1 -acetyl-3-[1 -methoxy-1 -(4-iodophenyl)methylene]-6-chroro-2- indolinone from 1-acetyl-3-[1-hydroxy-1-(4-iodophenyl)methylene]-6-chloro-2-indolinone (starting material VI. 12) (VII. 13) 1-acetyl-3-[1-methoxy-1-(3-iodophenyl)methyIene]-6-fIuoro-2-indolinone from 1-acetyl-3-[1-hydroxy-1-(3-iodophenyl)methylene]-6-fIuoro-2-indolinone (starting material VI. 13) 1-acetyJ-3-[1-methoxy-1-(3-(2-methoxycarbonylethy!)phenyl)methylene]-6-fluoro-2-indolinone from 1-acetyl-3-[1-hydroxy-1-(3-(2-methoxycarbony!ethyl)phenyl)methyIene]-6-fluoro-2-indo!inone (starting material VI. 14) (VII. 15) 1-acetyl-3-[1-methoxy-1-(4-(2-methoxycarbonyIethyI)phenyl)methyIene]- 6-fluoro-2-indolinone from 1 -acetyl-3-[1 -hydroxy-1 -(4-(2-methoxycarbonylethyl)phenyl)methylene]-6-fluoro- 2-indolinone (starting material VI. 15) (VII. 1 6) 1-acetyl-3-[1-methoxy-1-(4-(N-tert-butoxycarbonyl-2-aminoethyl)phenyl)methylene]-6-fluoro-2-indolihone from 1 -acetyl-3-[1 -hydroxy-1 -(4-(N-tert-butoxycarbonyl-2-aminoethyl)phenyOmethylene]-6-fluoro-2-indolinone (starting material VI. 17) (VII. 17) 1-acety]-3-[1-methoxy-1-(3-(N-tert-butoxycarbonyI-2-aminoethyl)phenyl)methylene]-6-fluoro-2-indolinone from 1 -acety!-3-[ 1 -hydroxy-1 -(3-(N-tert-butoxycarbony!-2-aminoethyl)phenyl)methylene]-6-fluoro-2-indolinone (starting material VI. 16) (VII. 18) 1-acetyl-3-[1-methoxy-1-(3-acetylaminomethylphenyl)methylene]-6- fluoro-2-indoIinone from 1-acetyl-3-[1-hydroxy-1-(3-acetylaminomethylphenyl)methylene]-6-fluoro-2- indolinone (starting material VI. 19) (VII. 19) 1-acetyl-3-[1-methoxy-1-(3-(2-ethoxycarbonylethyl)phenyl)methylene]-6-fluoro-2-indolinone from 1 -acetyl-3-[1 -hydroxy-1 -(3-(2-ethoxycarbonylethyl)phenyl)methylene]-6-fluoro-2-indolinone (starting material VI.20) (Vli.20) . 1-acetyl-3-[1-methoxy-1-(4-(2-methoxycarbonylethyl)pheny])methyiene]- 6-chloro-2-indolinone from 1-acetyl-3-[1-hydr6xy-1-(4-(2-methoxycarbony!ethyl)phenyl)methylene]-6-chloro- 2-indolinone (starting material VI.21) (VII.21) 1-acety[-3-[1-methoxy-1-(4-(2-ethoxycarbonylethyl)phenyl)methyIene]- 6-f!uoro-2-indolinone from 1 -acetyl-3-[1 -hydroxy-1 -(4-(2-ethoxycarbony!ethyl)phenyl)methylene]-6-fluoro-2- indolinone (starting material VI.22) (VII.22) 1-acetyl-3-[1-methoxy-1-(4-methoxycarbonylmethyloxyphenyl)- methylene]-6-fluoro-2-indolinone from 1-acetyl-3-[1 -hydroxy-1 -(4-methoxycarbonylmethyloxyphenyl)methylene]-6- fluoro-2-indolinone (starting material VI.23) (VII.23) 1 -acetyl-3-[1 -methoxy-1 -(3-methoxycarbonylmethy[oxyphenyl)- methylene]-6-fluoro-2-indolinone from 1-acetyl-3-[1-hydroxy-1-(3-methoxycarbonylmethyloxypheny[)methylene]-6- fluoro-2-indolinone (starting material VI.24) (VII.24) 1-acetyl-3-[1-methoxy-1-(3-(2- ethoxycarbonylethyloxy)phenyl)methylene]-6-fluoro-2-indolinone from 1-acetyl-3-[1-hydroxy-1-(3-(2-ethoxycarbonylethyloxy)phenyl)methylene]-6- fluoro-2-indolinone (starting material VI.25) (VII.25) 1-acetyl-3-[1-methoxy-1 -(4-(2- ethoxycarbonylethyIoxy)phenyl)methyIene]-6-fluoro-2-indolinone from 1 -acetyl-3-[1 -hydroxy-1 -(4-(2-ethoxycarbonylethyldxy)phenyl)methylene]-6- fluoro-2-indolinone (starting material VI.26) (VII.26) 1-acetyl-3-[1-methoxy-1-(4-(2-methoxycarbonylethyl)phenyl)methyIene]- 6-bromo-2-indoIinone from 1-acetyI-3-[1-hydrpxy-1-(4-(2-methoxycarbonylethyl)phenyl)methylene]-6- bromo-2-indolinone (starting material VI. 27) Example VII I: 1-Acetyt-3-ri-chloro-1-(4-cvanophenvl)methylene]-6-chloro-2-indolinone A suspension of 7.0 g of 1-acetyl-3-[1-hydroxy-1-(4-cyanpphenyl)rnethylene]-6- chloro-2-indolinone (starting material VI. 18) and 6.39 g of phosphorus pentachloride in 1 50 ml of dioxane is stirred at 1 00°C for 6 hours. After addition of a further 1 .0 g of phosphorus pentachloride, the mixture is stirred at 1 10°C for another 4 hours. The solvent is then distilled off and the residue is washed with ethyl acetate. Yield: 4.5 g (61 % of theory) Rf value: 0.70 (silica gel, methylene chloride/methanol = 50:1) Example IX: The syntheses of the following compounds have already been described in the international application WO 01/27081 : (IX. 1) 4-(diethylaminomethyI)aniline (IX.2) N-(2-dimethylaminoethyl)-N-methylsulphonyl-p-phenylenediamine (IX.3) 3-(dimethylaminomethyl)aniline (IX.4)4-(dimethylaminomethyl)aniline (IX.5)4-(2-dimethyIaminoethyl)aniline (lX.6)4-[N-(2-dimethylaminoethyl)-N-acetylamino]aniIine (IX.7) 4-[N-(3-dimethylaminopropyl)-N-acetylaminoJaniline (IX.8)4-[(N-dimethylaminocarbQny!methyl-N-methylsuiphonyi)amindjaniiine (IX.9) N-(4-aminophenyl)-N-methylmethanesulphonamide (IX. 10) N-(dimethylaminomethylcarbonyl)-N-methyl-p-phenylenediam!ne (IX.11) N-[(2-dimethylaminoethyl)carbonyl]-N-methyl-p-phenylenediamine (IX. 12) 4-(N-tert-butoxycarbonylaminomethyl)aniline (IX. 13) 4-(N-ethyl-N-tert-butoxycarbonylaminomethyl)aniline (IX.14)4-[(4-methylpiperazin-1-yl)methyl]aniline (IX. 15) 4-(imidazol-1-ylmethyl)aniline (IX. 16) 4-(1 -methylimidazoI-2-yl)aniiine (IX.17)4-[(N-(2-dimethylaminoethyl)-N-methylamino)methyl]aniline (IX. 18) 4-(N-methyl-N-tert-butoxycarbonylaminomethyl)aniline (IX. 19) N-[(4-methylpiperazin-1 -yl)methylcarbonyI]-N-methyl-p-phenytenediamine (IX.20) 4-(4-tert-butoxycarbonylpiperazin-1 -ylmethyl)aniline (1X.21) 4-(thiomorpholin-4-ylmethyl)aniline (IX.22)4-(pyrrolidin-1-ylmethyl)aniIine (IX.23)4-(morphoIin-4-yl-methyl)aniline (IX.24)4-(N-benzyl-N-methylaminomethyl)aniline (IX.25)4-(N-ethyl-N-methyIaminomethyl)aniline (IX.26)4-[N-(2-dimethylaminoethyl)-N-methylamino]aniline (IX.27)4-[(N-propyl-N-methylamino)methyl]aniline The following compounds are prepared analogously to Example IX: (IX.28)4-[N-(2-(N-benzyl-N-methylamino)ethyl)-N-acetylamino]aniline (IX.29)4-amino-N-(2-dimethyIaminoethyl)-N-methylbenzamide (IX.30)4-(4-methylpiperazin-1-ylcarbonyl)aniline (IX.31) 4-(2-dimethylaminoethoxy)aniline (IX.32) N-(4-dimethylaminobutylcarbonyl)-N-methyl-p-phenylenediamine (IX.33) N-[(3-dimethylaminopropyl)carbonyI]-N-methy!-p-phenylenediamine Preparation of the end products: Example 1.0 3-Z-f1-(4-(N-Methyl-N-rnethylsulphonylamino)anilino)-1-(3-iodophenynmethylene]-6- chloro-2-indolinone 0.9 g of 1-acetyl-3-(1-methoxy-1-(3-iodophenyl)methylene)-6-ch!oro-2-indol!none (starting material VII) and 0.5 g of N-methyl-N-methylsulphonyl-p-phenylenediamine (starting material iX.9) are dissolved in 10 ml of dimethylformamide and stirred at 120°C for 3 hours. After cooling, 1 .5 ml of piperidine are added and the mixture is stirred at room temperature for another hour. Water is added and the resulting precipitate is filtered off with suction, washed with a little water, methanol and ether and finally dried under reduced pressure at 100°C. Yield: 0.9 g (74% of theory), Rf value: 0.6 (silica gel, methylene chloride/methanol = 9:1) m.p. 292-294 °C Mass spectrum: m/z = 578/580 [M-H]' The following compounds of the formula 1-1 are prepared analogously to Example 1.0: (Table Removed) Eluent mixtures: (A): silica gel, methylene chloride/methanol 9:1 (B): silica gel, methylene chloride/ethanol 10:1 (C): silica gel, methylene chloride/methanol 4:1 Example 2.0 3-Z-ri-(4-fDimethvlaminomethvl)anilino)-1-f4-cvanophenvl)methytene1-6-chloro-2- indolinone 1.07 g of 1-acetyl-3-[1-chloro-1-(4-cyanopheny!)methy!ene]-6-chlofD-2-indolinone (starting material VII) and 0.54 g of 4-(dimethylaminornethyl)aniline (starting material IX.4) are dissolved in 10 ml of dimethytformamide and stirred at 80°C for 3 hours. After cooling, 1 ml of 6N aqueous sodium hydroxide is added, and the mixture is stirred at room temperature for 30 minutes. Water is added and the mixture is extracted three times with methylene chloride. The combined organic phases are washed twice with water, dried over sodium sulphate and concentrated using a rotary evaporator, and the product is recrystallized from diethyl ether. Yield: 0.92 g (72% of theory), Revalue: 0.1 (silica gel, methylene chloride/methanol = 9:1) Mass spectrum: m/z = 427/429 [M-HJ' Example 3.0 3-Z-f1-(4-(rdimethvlaminomethvl)an!linoV1-f4-iodophenvl)methvlene1-6-fluoro-2-indolinone 3.5 g of 1-acety!-3-(1-methoxy-1-(4-iodophenyI)methylene)-6-fluoro-2-indoIinone (starting material VI!. 11) and 1.6 g of 4-(dimethylaminomethyl)anifine (starting material IX.4) are dissolved in 30 ml of dimethylformamide and stirred at 120°C for 2 hours. After cooling, the solvent is removed under reduced" pressure, the residue is taken up in 30 ml of methanol and 2 spatula tips of sodium methoxide are added. Once a yellow precipitate has formed, this is filtered off with suction from the solvent and the residue is washed with a little methanot and ether and finally dried under reduced pressure at 100°C. Yield: 1.9 g (46% of theory), Rf value: 0.3 (silica gel, methylene chloride/methanol = 9:1) m.p. 243-246 °C Mass spectrum: m/z = 514 [M+Hf The following compounds of the formula l-3a are prepared analogously to Example 3.0: (Table Removed) Eluent mixtures: (A): silica gel, methylene chloride/methanol 9:1 (B): silica gel, methylene chloride/methanol/ammonia 9:1:0.1 Example 4.0 3-Z-ri-(4-(Dimethvlaminomethvl)anilinoV1-(3.4-dimeth6xyphenvl)methvlene]-6- cvano-2-indolinone 130 mg of l-acetyl-S-CI-methoxy-I^S^-dimethoxyphenyOmethyleneJ-e-cyanb^- indolinone (starting material VII.4) and 58 mg of 4-(dimethylaminomethyl)ani\|ine {-starting- material4X,4) are dissolved in 5 ml of dimethylformamide and stirred at 80°C for 2 hours. After cooling, the solvent is removed under reduced pressure and the residue is purified on a silica gel column using the mobile phase methylene chloride/methanol 9:1. Yield: 21 mg (12% of theory), Rf value: 0.35 (silica gel, methylene chloride/methanol = 9:1) m.p. 265 °C Example 5.0 3-Z-[1-(4-(N-Methvl-N-methvlsulphonvlamino)anilino)-1-(3-(2-methoxvcarbonvl- vinyl)phenvl)methylene]-6-chloro-2-indolinone 580 mg of 3-Z-[1-(4-(N-methyl-N-methylsulphonyIamino)anilino)-1-(3-iodophenyl)- methylene]-6-chIoro-2-indolinone (starting material 1.0) and 140 ml of methyl acrylate are dissolved in 20 ml of acetonitrile and 11 ml of dimethylformamide, and 11 mg of palladium(II) acetate, 2 ml of triethylamine and 30 mg of tri-ortho-tolylphosphine are added. Under nitrogen as protective gas, the solution is stirred at 90°C for 10 hours. After cooling, the solution is filtered through Celite, the solvent is removed under reduced pressure and the residue is purified on a silica gel column using the mobile phase methylene chloride/methanol 20:1 . Yield: 450 mg (84% of theory), Rf value: 0.30 (silica gel, toluene/ethyl acetate = 1:1) m.p. 228-232 °C Mass spectrum: m/z = 537/539 [M] The following compounds of the formula 1-5 are prepared analogously to Example 5.0: (Table Removed) Eluent mixtures: (A): silica gel, methylene chloride/methane! 5:1 (B): silica gel, methylene criloride/methanol/ammonia 9:1:0.01 Example 6.0 3-Z-F1 -(4-Dtmeth vlaminomethvlani[ino)-1 -(3-(2-methoxvcarbonvlethvnpheny[)methvlene1-6-chloro-2-indolinone 1.0 g of 3-Z-[1-(4-(dirriethylaminomethyl)anilino)-1-(3-(2-methoxycarbonyl-vinyl)pheny[)methylene]-6-chloro-2-indolinone (starting material 5.1) is dissolved in 100 ml of methanol, and 200 mg of 10 per cent palladium/carbon as catalyst are added. The mixture is then hydrogenated at room temperature and a hydrogen pressure or 50 psi for 6 hours. Aner the reaction has ended,"the cataTysTTsWered"off, the solvent is removed under reduced pressure and the residue is dried under reduced pressure at 100°C. Yield: 900 mg (90% of theory), Rf value: 0.40 (silica gel, methylene chloride/methanol = 9:1) m.p. 160 °C Mass spectrum: m/z = 490/492 [M+H]+ The following compounds of the formula I-6 are prepared analogously to Example 6.0:(I-6) (Table Removed) EIuent mixtures: (A): silica gel, methylene chloride/methanol 9:1 (B): silica gel, methylene chloride/methanol/ammonia 5:1:0.01 Example 7.0 3^Z-[1"f4-Dimethylaminomethylanilino)-1-(4-aminomethylphenyl)methylene]-6-chloro- 2-indoiinone 900 mg of 3-Z-[1-(4-dimethy(aminomethylanilino)-1-(4-cyanophenyl)methylene]-6- chloro-2-indolinone (starting material 2.0) are dissolved in 20 ml of methylene chloride and 30 ml of methanolic ammonia and, as catalyst, 200 mg of Raney nickel are added. The mixture is then hydrogenated at room temperature and a hydrogen pressure of 50 psi for 2 hours and 15 minutes. After the reaction has ended, the catalyst is filtered off, the solvent is removed under reduced pressure and the residue is washed with" a little mefhahor arid dietftyl etrTef . To liberate the base, the residue is taken up in 1 N aqueous sodium hydroxide solution and extracted four times with methylene chloride/methanol 9:1. The combined organic phases are washed with water and dried over sodium sulphate. The product is washed with a little diethyl ether and dried under reduced pressure. Yield: 680 mg (75% of theory), Rf value: 0.60 (silica gel, methylene chloride/methanol/ammonia = 9:1:0.1) m.p. 21 1-214 °C Mass spectrum: m/z = 433/435 [M+H]+ Example 8.0 3-Z-ri-(4-(N-f(4-Methvlpiperazin-1-vl')methvlcarbohvn-N-methvlamino)anilinoV1-(4-aminomethylphenyl)methvlene]-6-chloro-2-indolinone 1.39 g of 1-acetyl-3-Z-[1-(4-(N-((4-methylpiperazin-1-yl)methylcarbonyl)-N-methylamino)anilino)-1-(4-cyanophenyl)methylehe]-6-chlpro-2-indolinone are dissolved in 20 ml of methylene chloride and 30 ml of methanolic ammonia and, as catalyst, 200 mg of Raney nickel are added. The mixture is then hydrogenated at room temperature at a hydrogen pressure of 50 psi for 2 hours. After the reaction has ended, the catalyst is filtered, the solvent is removed under reduced pressure and the residue is washed with a little methanol and diethyl ether. To liberate the base, the residue is taken up in 1N aqueous sodium hydroxide solution and extracted four times with methylene chloride/methanol 9:1. The combined organic phases are washed with water and dried over sodium sulphate. The product is purified on a silica gel column using, as mobile phase, a gradient of methylene chloride and methylene chloride/methanol/ammonia 8:1:0.1. The product is washed with a little diethyl ether and dried under reduced pressure. Yield : 700 mg (54% of theory) , Rf value: 0.15 (silica gel, methylene chloride/methanol/ammonia = 9:1:0.1) m.p. 232-235 °C Mass spectrum: m/z = 544/546 [M] Example 9.0 3-Z-[1-(4-(Dimethvlaminomethyl)anilino)-1-(3-aminomethylphenyl)methylene1-6-fluoro-2-indolinone 2.72 g of 3-Z-[1-(4-(dimethylaminomethyl)anilino)-1-(3-(N-tert-butoxycarbonyl-aminomethyl)phenyl)methylene]-6-flubro-2-indolinone (starting material 3.10) are dissolved in 50 ml of methylene chloride, and 10 ml of trifluoroacetic acid are aaaea. The mixture is stirred at room temperature for 3 hours. After this time, most of the solvent is removed under reduced pressure and the residue is taken up in ethyl acetate and washed twice with 1N aqueous sodium hydroxide solution. The organic phase is dried over sodium sulphate, the solvent is removed using a rotary evaporator and the residue is purified on a silica gel column using the mobile phase methylene chloride/methanol/ammonia 9:1:0.1. The product is washed with a little diethyl ether and dried under reduced pressure. Yield: 1.77 g (81% of theory), Rf value: 0.25 (silica gel, methylene chloride/methanol/ammonia 9:1:0.1) m.p. 168-175 °C C25H25FN40 Mass spectrum: m/z = 415 [M-H]~ The following compounds of the formula I-9 are prepared analogously to Example 9.0: (Table Removed) EIuent mixtures; (A): silica gel, methylene chloride/methanol/ammonia 9:1:0.1 (B): silica gel, methylene chloride/methanol/ammonia 9:1:0.01 (C): silica gel, methylene chloride/methanol/ammonia 8:2:0.2 (D): Reversed phase RP8, methanol/sodium chloride solution(5%) = 3:2 Example 10.0 3-Z-ri-(4-Dimethvlaminomethvlanilino)-1-f3-(2-carboxvethv()phenvnmethvlene1-6- chloro-2-indolinbne 900 mg of 3-Z-[1-(4-dimethylaminomethylanilino)-1-(3-(2- methoxycarbonylethyl)phenyl)methylene]-6-chloro-2-indolinone (starting material 6.0) are dissolved in 10 ml of ethanol, and 5 ml of 1N aqueous sodium hydroxide solution are added. The mixture is stirred at room temperature for 5 hours. After cooling, 5 ml of 1N hydrochloric acid are added. The resulting precipitate is filtered off with suction and washed with water. Yield: 830 mg (95% of theory), Rf value: 0.50 (reversed phase RP8, methanol/sodium chloride solution (5%) = 4:1) m.p. 210-215 °C Mass spectrum: m/z = 476/478 [M+Hf The following compounds of the formula 1-1 Oa are prepared analogously to Example 10.0:(1-1 Oa) (Table Removed) Eluent mixtures: (A): reversed phase RP8, methanol/sodium chloride solution (5%) = 4:1 (B): silica gel, methylene chloride/methanol = 8:2 (C): silica gel, methylene chloride/methanol = 5:1 (D): reversed phase RP8, methanol/sodium chloride solution (5%) = 3:2 (E): silica gel, methylene chloride/methanol = 9:1 (F): reversed phase RP8, methanol/sodium chloride solution (5%) = 7:3 (G): silica gel, methylene chloride/methanol/ammonia = 9:1:0.1 (H):-alumina,-methylene chloride/methanol = 19:1 (I): reversed phase RP8, methanol/sodium chloride solution (5%) = 4:2 (K): silica gel, petroleum ether/ethyl acetate =1:1 (M): silica gel, methylene chloride/methanol = 4:1 The following compounds of the formula 1-1 Ob are prepared analogously to Example 10.0: (Table Removed) Eluent mixtures: (A): silica gel, methylene chloride/methanol = 5:1 (B): silica gel, methylene chloride/methanol = 9:1 (C): reversed phase RP8, methanol/sodium chloride solution (5%) = 4:1 Example 11.0 3-Z-ri-(4-Dimethvlaminomethvlanilino)-1-(3-(2-carbamovlethyl)phenvl)methylene]-6- chloro-2-indolinone 480 mg of 3-Z-[1-(4-dimethylaminomethylanilino)-1-(3-(2- carboxyethyl)phenyl)methylene]-6-chloro-2-indoIinone (starting material 10.0), 350 mg of TBTU, 150 mg of HOBt and 420 ml of triethylamine are dissolved in 10 ml of dimethylformamide, and 620 mg of N-hydroxysuccinimide ammonium salt are added. The mixture is stirred at room temperature for 20 hours. After removal of the solvent under reduced pressure, the residue is suspended in a little ethyl acetate and water, filtered off and washed with water. The residue is purified on an alumina column (activity 2-3) using the mobile phase methylehe chloride/ethanol 20:1. The product is recrystallized from diethyl ether and dried under reduced pressure at 100°C. Yield: 370 mg (78% of theory), Rf value: 0.40 (alumina, methylene chloride/ethanol = 20:1) m.p. 222-225 °C Mass spectrum: m/z = 475/477 [M+Hf The following compounds of the formula 1-1 1 are prepared analogously to Example 11.0: (Table Removed) Eluent mixtures: (A): silica gel, methylene chloride/methanol/ammonia = 5:1:0.01 (B): alumina, methylene chloride/ethanol = 20:1 (C): silica gel, methylene chloride/methanol/ammonia = 9:1:0.1 (D): silica gel, methylene chloride/methanol/ammonia = 6:1:0.1 (E): silica gel, methylene chloride/methanol/ammonia = 5:1:0.1 (F): silica gel, methylene chloride/methanol/ammonia - 7:1:0.1 (G): silica gel, methylene chloride/methanol = 9:1 using methylammonium chloride as base equivalent * using dirriethylammonium chloride as base equivalent ** using piperidine hydrochloride as base equivalent Example 12.0 3-Z-[1-(4-Dimethylaminomethylanilino)-1-('4-acetylaminomethvlphenyl)methylene1-6- chloro-2-indolinone 100 mg of 3-Z-[1-(4-dimethylaminomethylanilino)-1-(4-aminomethylphenyl)- methylene]-6-chloro-2-indolinone (starting material 7.0) are dissolved in 5 ml of methylene chloride and 5 ml of pyridine, and 20 ul of acetyl chloride are added at 0°C. The mixture is stirred at 0°C for 10 minutes and at room temperature for a further 4~hours. Another 20 ul of acetyl chloride are then added, and the mixture is stirred at room temperature for 12 hours. After this time, the solvent is removed under reduced pressure and the residue is taken up in methylene chloride and washed with water. The aqueous phase is extracted twice with methylene chloride and the combined organic phases are dried over sodium sulphate. The solvent is removed using a rotary evaporator and the residue is washed with ether. Yield: 51 mg (47% of theory), Rf value: 0.30 (silica gel, methyierie chloride/methanolAartimonia = 9: 1 :ff. m.p. 21 9-220 °C Mass spectrum: m/z = 473/475 [M-H]~ The following compounds of the formula 1-12 are prepared analogously to Example 12.0: (Table Removed) Eluent mixtures: (A): silica gel, methylene chloride/ethanol/ammonia = 20:1:0.01 (B): silica gel, methylene chloride/methanol/ammonia = 9:1:0.01 (C): alumina, methylene chloride/methanol =19:1 (D): silica gel, methylene chloride/methanol/ammonia = 9:1:0.1 (E): silica gel, methylene chloride/methanol/ammonia = 8:2:0.2 (F): alumina, methylene chloride/methanol = 9:1 Alternatively, the following acylating agents were used: benzoyl chloride, propionyl chloride, phenylacetyl chloride, cyclopropanecarbonyl chloride, cyclobutanecarbonyl chloride, pyridm-2-ylcarbonyl chloride, pyridin-3-ylcarbonyl chloride, pyridin-4-ylcarbonyl chloride, cyclohexylcarbdnyl chloride, isobutyryl chloride, 3-methylbutyryl chloride, cyclohexylmethylcarbonyl chloride, methoxyacetyl chloride, 2-methoxybenzoyl chloride, tert-butylacetyl chloride, thiophene-2-carbonyI chloride, pivaloyl chloride, 2-furoyl chloride Example 13.0 3-Z-ri-(4-Trimethvlammoniummethvlanilino)-1-(4-(2-carboxvethvnphenvnmethvlene1- 6-fluoro-2-indolinone iodide 200 mg of 3-Z-[1-(4-dimethylaminomethylanilino)-1-(4-(2- carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone (starting material 10.1) are dissolved in 40 ml of acetone, and 250 ml of methyl iodide are added. The mixture is stirred at room temperature for 20 hours. After this time, the resulting residue is filtered off with suction. The product is dried at 80°C under reduced pressure. Yield: 200 mg (83% of theory), Rf value: 0.50 (reversed phase RP8, methanol/sodium chloride solution (5%) = 4:1) m.p.210°C Mass spectrum: m/z = 474 [M+H]+ The following compound of the formula 1-13 is prepared analogously to Example 13.0: (Table Removed) Eluent mixture: (A): reversed phase RP8, methanol/sodium chloride solution (5%) = 4:1 Example 14.0 3-Z-f1-(4-Guanidinomethylanilino)-1-(4-(2-carboxvethYl)phenvnmethylene]-6-fluoro-2-indolinone iodide 170 mg of 3-Z-[1-(4-aminomethyIanilino)-1 -(4-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone (starting material 10.50) are dissolved in 20 ml of tetrahydrofuran, and 390 mg of 3,5-dimethylpyrazole-1-carboxamidine nitrate and 330 ml of diethylisopropylamine are added. The mixture is stirred under reflux for 10 hours. After this time, the solvent is concentrated, water is added and the resulting residue is filtered off with suction. The product is dried at 80°C. Yield: 150 mg (81% of theory), Rf value: 0.40 (silica gel, methylene chloride/methanol/acetic acid = 5:1:0.1) m.p. 290 °C Mass spectrum: m/z = 474 [M+H]* The following compound of the formula 1-14 is prepared analogously to Example 14.0: (Table Removed) *Eluent mixture: (A): reversed phase RP8, methanol/sodium chloride solution (5%) = 4:1 Example 15 Dry vial with 75 mg of active compound per 10 ml Composition: Active compound 75.0 mg Mannitol 50.0 mg Water for injection ad 10.0 ml Preparation: Active compound and mannitol were dissolved in water. After filling, the product is freeze-dried. The ready-to-use solution is obtained by dissolving the product in Water for injection. Example 16 Dry vial with 35 mg of active compound per 2 ml Composition: Active compound 35,0 mg Mannitol 100,0mg Water for injection ad 2.0 ml Preparation: Active compound and mannitol were dissolved in water. After filling, the product is freeze-dried. The ready-to-use solution is obtained by dissolving the product in water for injection. Example 17 Tablet with 50 mg of active compound Composition: (1) Active compound 50.0 mg (2) Lactose 98.0 mg (3) Maize starch 50.0 mg (4) Polyvinylpyrroiidone 15.0mg (5) Magnesium stearate 2.0 mq 215.0 mg Preparation: (1), (2) and (3) are mixed and granulated using an aqueous solution of (4). (5) is added to the dried granules. From this mixture, biplanar tablets having a facet on both sides and being partially scored on one side are pressed. Diameter of the tablets: 9 mm. Example 18 Tablet with 350 mg of active compound Composition: (1) Active compound 350.0 mg (2) Lactose 136.0mg (3) Maize starch 80.0 mg (4) Polyvinylpyrroiidone 30.0 mg (5) Magnesium stearate 4.0mq 600.0 mq Preparation: 123 (1), (2) and (3) are mixed and granulated using an aqueous solution of (4). (5) is added to the dried granules. From this mixture, biplanar tablets having a facet on both sides and being partially scored on one side are pressed. Diameter of the tablets: 12 mm. Example 19 Capsules with 50 mg of active compound Composition: (1) Active compound 50.0mg (2) Maize starch, dried 58.0 mg (3) Lactose, powaerea 50.0 mg. (4) Magnesium stearate 2.0 mg 160.0j7ig Preparation: (1) is ground with (3). This ground material is, with vigorous mixing, added to the mixture of (2) and (4). This powder mixture is, in a capsule filling machine, filled into hard gelatin capsules size 3. Example 20 Capsules with 350 mg of active compound Composition:, (1) Active compound 350.0 mg (2) Maize starch, dried 46.0 mg (3> Lactose, powdered 30.0 mg. (4) Magnesium stearate 4.0 mg 430.0 mg Preparation: (1) is ground with (3). This ground material is, with vigorous mixing, added to the mixture of (2) and (4). This powder mixture is, in a capsule filling machine, filled into hard gelatin capsules size 0. Example 21 Suppositories with 100 mg of active compound 1 suppository contains: Active cojTippund 100-Omg Polyethylene glycol (MW 1500) 600.0 mg Polyethylene glycol (MW 6000) 460.0 mg Polyethylene sorbitan monostearate 840.0 mg 2 000.0 mg Preparation: The polyethylene glycol is melted together with polyethylene sorbitan monostearate. At 40°C, the ground active substance is homogeneously dispersed in the melt. The melt is cooled to 38°C and poured into slightly pre-cooled suppository moulds. Analogously-to the examples above, it is possible to prepare the following compounds: (1) 3-Z-[1-(4-(N-(2-dimethylaminoethyl)-N-methylsulphonylamino)anilino)-1-(4-(2-carboxyethyl)phenyI)methylene]-6-chloro-2-indolinone (2) 3-Z-[1-(4-(N-(dimethyIaminomethylcarbonyl)-N-methyfamino)aniIino)-1-(4-(2- carboxyethyl)phenyI)methylene]-6-chloro-2-indolinone (3)3-Z-[1-(4-(N-(2-dimethyIaminoethyl)-N-acetyIamino)anilino)-1-(4-(2- carboxyethyl)phenyl)methyIene]-6-chbro-2-indolinone (4)3-Z-[1-(4-(N-(2-methyIaminoethyl)-N-acetylamino)anifino)-1-(4-(2- carboxyethyl)phenyl)methylene]-6-chloro-2-indolinone (5) 3-Z-[1-(4-(N-(3-dimethylaminopropyl)-N-acety!amino)anilino)-1-(4-(2- carboxyethyl)phenyl)methylene]-6-chloro-2-indo!inone (6) 3-Z-[1-(4-(N-(3-methylaminopropyl)-N-acetylamino)anilino)-1-(4-(2- carboxyethyl)phenyl)methylene]-6-chloro-2-indolinone (7) 3-Z-[1-(4-(3-dimethylaminopropyl)anilino)-1-(4-(2-caiboxyethyl)phenyl)methylene]- 6-chloro-2-indolinone (8) 3-Z-[1-(4-ethylaminomethylanilino)-1-(4-(2-carboxyetfiyl)phenyl)methylene]-6- chloro-2-indoIinone (9) 3-Z-[1-(4-methylaminomethylanilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6- chloro-2-indolinone (10) 3-Z-[1 -(4-(N-(4-methylpiperazin-1 -ylmethylcarbonyl)-N-methylamino)anilino)-1 - (4-(2-carboxyethyl)phenyl)methylene]-6-chloro-2-indolinone (11) 3-Z-[1 -(4-(4-methylpiperazin-1-ylcarbonyl)anilino)-1-(4-(2- carboxyethyl)phenyl)methylene]-6-chloro-2-indolinone (12) 3-Z-[1 -(4-(N-(3-dimethyIaminopropyl)-N-methylsi^)honylamino)aniHrio)-1 -(4- (2-carboxyethyl)phenyl)methylene]-6-chloro-2-indofinone (13) 3-Z-[1 -(4-(N-(2-dimethylaminoethyl)-N-propylsulfrfionylamino)ani!ino)-1 -(4-(2- carboxyethyl)phenyl)methylene]-6-chloro-2-indormone (14) 3-Z-[1-(4-aminomethylanilino)-1-(4-(2-carboxyetftyl)phenyl)methylene]-6- chloro-2-indolinone (15) 3-Z-[1-(3-(methylaminomethyI)anilino)-1-(4-(2- carboxyethyI)phenyI)methylene]-6-chloro-2-indoIinone r 16) 3-Z-M -f 3-(2-dimethy!aminoethyl)anilino)-1 -(4-(2- carboxyethyl)phenyl)methylene]-6-chloro-2-indolinone (17) 3-Z-[1-(3-(3-dimethylaminopropyl)anilino)-1-(4-(2- carboxyethyl)phenyl)methylene]-6-chlofo-2-indolinone (18) 3-Z-[1-(4-(N-(dimethylamino-carbonylmethyl)-N- methyIsulphonylamino)aniIino)-1-(4-(2-carboxyethy[)phenyl)methylene]-6-ch!oro-2-indoIinone (19) 3-Z-[1-(4-(N-methyl-N-methyIsuIphonylamino)aniIino)-1-(4-(2- carboxyethyl)phenyl)methylene]-6-chloro-2-indolinone (20) 3-Z-[1-(4-(N-methyl-N-acetylamino)anilino)-1-(4-(2- carboxyethyl)phenyl)methylene]-6-chIoro-2-indolinone (21) 3-Z-[1-(4-(N-(N-(2-dimethylaminoethyl)-N-methylaminomethy!carbonyl)-N- methylamino)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-chloro-2- indolinone (22) 3-Z-[1-(4-(2-diethylaminoethylsulphonyl)anilino)-1-(4-(2- carboxyethyl)phenyl)methylene]-6-chloro-2-indolinone (23) 3-Z-[1-(4-(N-(2-dimethylaminoethyl-carbonyl)-N-methylamino)aniiino)-1-(4-(2- carboxyethyl)phenyl)methylene]-6-chIoro-2-indolinone (24) 3-Z-[1 -(4-(N-(2-dimethylaminoethyl)-N-methylaminomethyl)anilino)-1 -(4-(2- carboxyethyI)phenyl)methylene]-6-chloro-2-indolinone (25) 3-Z-[1 -(4-(2-dimethylaminoethoxy)anilino)-1 -(4-(2- carboxyethyl)phenyl)methylene]-6-chl6ro-2-indolmone (26) 3-Z-[1 -(4-(N-(4-dimethylaminobutylcarbonyl)-N-methylamino)anilino)-1 -(4-(2- carboxyethyI)phenyl)methylene]-6-chloro-2-indolinone (27) 3-Z-[1-(4-(N-(3-dimethylaminopropylcarbonyl)-N-methylarnino)anilino)-1-(4:(2- carboxyethyl)phenyl)methylene]-6-chloro-2-indolinone (28) 3-Z-[1 -(4-(methylethylaminomethyl)aniIino)-1 -(4-(2- carboxyethyl)phenyl)methylene]-6-chloro-2-indolinone (29) 3-Z-[1 -(4-(methylpropylaminomethyl)anilino)-1 -(4-(2- carboxyethyl)phenyl)methylene]-6-chloro-2-indoIinone (30) 3-Z-[1-(4-(methylbenzylaminomethyl)aniIino)-1-(4-(2- carboxyethyI)phenyl)methylene]-6-chlorp-2-indolinone (31) 3-Z-[1-(4-(N-(2-dimethylamjnoethyI)-N-methyIaminomethy[)anilino)-1-(4-(2- carboxyethyl)phenylmethylene]-6-chloro-2-indoIinone (32) 3-Z-[1 -(4-(azetidin-1 -y Imethyl)anilino)-1 -(4-(2-carboxyethyl)phenyl)methylenej- 6-chloro-2-indoIinone (33) 3-Z-[1-(4-((4-methylpiperazin-1-yl)methyl)anilino)-1-(4-(2- carboxyethyl)phenyl)methylene]-6-chloro-2-indolinone (34) 3-Z-[1-(4-(piperazin-1-yImethyl)anilino)-1-(4-(2- carboxyethyl)phenyl)methylene]-6-chloro-2-indolinone (35) 3-Z-[1-(4-(morpholin-4-ylmethyl)anilino)-1-(4-(2- carboxyethyl)phenyl)methylene]-6-chloro-2-indolinone (36) 3-Z-[1-(4-(thiomorpho!in-4-ylmethyl)ani!ino)-1-(4-(2- carboxyethyl)phenyl)methylene]-6-ch!oro-2-indo!inone (37) 3-Z-[1-(4-(imidazol-1-ylmethyl)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]- 6-chloro-2-indoIinone (38) 3-Z-[1-(4-(N-(2-dimethylaminoethyl)-N-methylsulphonylamino)anilino)-1-(3-(2- carboxyethyl)phenyl)methylene]-6-chloro-2-indolinone (39) 3-Z-[1-(4-(N-(dimethylaminomethylcarbonyl)-N-methylamino)anilino)-1-(3-(2- carboxyethyI)phenyl)methylene]-6-chloro-2-indolinone (40) 3-Z-[1-(4-(N-(2-dimethylaminoethyl)-N-acetylamino)anilino)-1-(3-(2- carboxyethyl)phenyl)methylene]-6-chroro-2-indolinone (41) 3-Z-[1-(4-(N-(2-methylaminoethyl)-N-acetylamino)anilino)-1-(3-(2- carboxyethyl)phenyl)methylene]-6-chloro-2-indolinone (42) 3-Z-[1-(4-(N-(3-dimethylaminopropyl)-N-acetylamino)anilino)-1-(3-(2- carboxyethyI)phenyl)methylene]-6-chloro-2-iridolinone (43) 3-Z-[1-(4-(N-(3-methylaminopropyl)-N-acetylamino)anilino)-1-(3-(2- carboxyethyl)phenyl)methylene]-6-chloro-2-indolinone (44) 3-Z-[1 -(4-(3-dimethylaminopropyI)anilino)-1 -(3-(2- carboxyethyl)phenyl)methylene]-6-chloro-2-indolinone (45) 3-Z-[1 -(4-ethylaminomethylanilino)-1 -(3-(2-carboxyethyl)phenyl)methylene]-6- chIoro-2-indolinone (46) 3-Z-[1 -(4-methylaminomethylaniIino)-1 -(3-(2-carboxyethyl)phenyl)methylene]- 6-chloro-2-indolinone (47) 3-Z-[1-(4-(N-(4-methyIpiperazin-1-ylinethylcarbonyl)-N-methylamino)anilino)-1- (3-(2-carboxyethyl)phenyl)methylene]-6-chloro-2-indolinone (48) 3-Z-[1 -(4-(4-methylpiperazin-1 -ylcarbony[)anilino)-1 -(3-(2- carboxyethyl)phenyl)methylene]-6-chloro-2-indolinone (49) 3-Z-[1-(4-(N-(3-dimethylaminopropyl)-N-methyIsulphonylamino)anilino)-1-(3- (2-carboxyethyl)phenyl)methylene]-6-chloro-2-indolinone (50) 3-Z-[1-(4-(N-(2-dimethylaminoethyI)-N-propyIsulphonylamino)anilino)-1 -(3-(2- carboxyethyl)phenyl)methylene]-6-chloro-2-indolinone (51) 3-Z-[1-(4-aminomethylaniliho)-1-(3-(2-carboxyethyl)phenyl)methyIene]-6- chloro-2-indolinone (52) 3-Z-[1-(3-(dimethylaminomethyl)aniiino)-1-(3-(2- carboxyethyl)phenyl)methyIene]-6-ch!oro-2-indo!inone (53) 3-Z-[1-(3-(methylaminomethyl)anilino)-1-(3-(2- carboxyethyl)phenyl)methylene]-6-chloro-2-indolinone (54) 3-Z-[1-(3-(2-dimethylaminoethyl)anilino)-1-(3-(2- carboxyethyl)phenyl)methylene]-6-chloro-2-indolinone (55) 3-Z-[1 -(3-(3-dimethylaminopropyl)anilino)-1 -(3-(2- carboxyethyl)phenyl)methylene]-6-chloro-2-indolinone (56) 3-Z-[1-(4-(2-dimethylaminoethyl)anilino)-1-(3-(2- carboxyethyl)phenyl)methylene]-6-chloro-2-indQlinone (57) 3-Z-[1-(4-(N-(dimethylaminocarbonylmethyI)-N-methylsulphonyIamino)anilino)- 1-(3-(2-carboxyethyl)phenyl)methylene]-6-chloro-2-indolinone (58) 3-Z-[1 -(4-(N-methyl-N-methylsulphonylamino)anilino)-1 -(3-(2- carboxyethyl)phenyl)methylene]-6-chloro-2-indolinone (59) 3-Z-[1 -(4-(N-methyl-N-acetylamino)anilino)-1 -(3-(2- carboxyethyl)phenyl)methylene]-6-chloro-2-indolinone (60) 3-Z-[1-(4-(1-methylimidazol-2-yl)anilino)-1 -(3-(2- carboxyethyl)phenyl)methylene]-6-chloro-2-indolinone (61) 3-Z-[1-(4-(N-(N-(2-dimethylaminoethyl)-N-methylaminomethylcarbonyl)-N- methylamino)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene]-6-chloro-2- indolinone (62) 3-Z-[1 -(4-(2-diethylaminoethylsuIphonyl)anilino)-1 -(3-(2- carboxvethyl)phenyl)methyIene]-6-chloro-2-indolinone (63) 3-Z-[1-(4-(N-(2-dimethylaminoethylcarbonyl)-N-methylamino)anilino)-1-(3-(2- carboxyethyl)phenyl)methylene]-6-chloro-2-indolinone (64) 3-Z-[1-(4-(N-(2-dimethyIaminoethyl)-N-methy!aminomethyl)anilino)-1-(3-(2- carboxyethyI)phenyl)methylene]-6-chloro-2-indolinone (65) 3-Z-[1 -(4-(2-dimethylaminoethoxy)anilino)-1 -(3-(2- carboxyethyl)phenyI)methylene]-6-chloro-2-indolinone (66) 3-Z-[1-(4-(N-(4-dimethylaminobutylcarbonyl)-N-methylamino)aniIino)-1-(3-(2- carboxyethyl)phenyl)methylene]-6-chloro-2-indolinone (67) 3-Z-[1-(4-(N-(3-dimethylaminopropylcarbonyl)-^4-methylamino)anilino)-1-(3-(2- carboxyethyl)phenyl)methylene]-6-chloro-2-indolinone (68) 3-Z-[1-(4-(methylethylaminomethyl)ani!ino)-1-(3-(2- carboxyethyl)phenyl)methy!ene]-6-ch!oro-2-indolinone (69) 3-Z-[1-(4-(methylpropylaminomethyl)anilino)-1-(3-(2- carboxyethyl)phenyl)methylene]-6-chloro-2-indolinone (70) 3-Z-[1-(4-(methylbenzylaminomethyl)anilino)-1-(3-(2- carboxyethyl)phenyl)methylene]-6-chloro-2-indolinone (71) 3-Z-[1 -(4-(diethylaminomethyl)anilino)-1 -(3-(2-carboxyethyl)phenyl)methylene]- 6-chloro-2-indolinone (72) 3-Z-[1 -(4-(N-(2-dimethylaminoethyl)-N-methylaminomethyl)anilino)-1 -(3-(2- carboxyethyl)phenylmethylene]-6-chloro-2-indolinone (73) 3-Z-[1 -(4-(pyrrolidin-1-ylmethyl)anilino)-1-(3-(2- carboxyethyl)phenyl)methylene]-6-chloro-2-indolinone (74) 3-Z-[1 -(4-(azetidin-1 -ylmethyl)anilino)-1 -(3-(2-carboxyethyl)phenyl)methylene]- 6-chloro-2-indolinone (75) 3-Z-[1 -(4-((4-methylpiperazin-1 -yl)methyl)anilino)-1 -(3-(2- carboxyethyl)phenyl)methylene]-6-chloro-2-indolinone (76) 3-Z-[1 -(4-(piperazin-1 -ylmethyl)anilino)-1 -(3-(2- carboxyethyI)phenyl)methylehe]-6-chloro-2-indolinone (77) 3-Z-[1 -(4-(morpholin-4-ylmethyl)aniIino)-1-(3-(2- carboxyethyl)phenyl)methylene]-6-chloro-2-indolinone (78) 3-Z-[1 -(4-(thiomorpholin-4-ylmethyl)anilino)-1 -(3-(2- carboxyethyl)phenyl)methylene]-6-chloro-2-indo!inone (79) 3-Z-[1-(4-(imidazol-1-ylmethyi)anilino)-1-(3-(2-carboxyethyI)phenyl)methyienej- 6-chloro-2-indolinone (80) 3-Z-[1-(4-(N-(2-methylaminoethyI)-N-acetylamino)anilino)-1-(4-(2- carboxyethyl)phenyI)methylene]-6-fluoro-2-indoIinone (81) 3-Z-[1-(4-(N-(3-methyIaminopropyl)-N-acetylamino)anilino)-i-(4-(2- carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone (82) 3-Z-[1-(4-(3-dimethylaminopropyl)anilino)-1-(4-(2- carboxyethyl)phenyl)methylene]-6-fIuoro-2-indoiinone (83) 3-Z-[1-(4-ethylaminomethylanilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6- fluoro-2-indolinone (84) 3-Z-[1-(4-(N-(3-dimethylaminopropyl)-N-methylsulphonylamino)anilino)-1-(4- (2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indo!inone (85) 3-Z-[1 -(4-(N-(2-dimethylaminoethyl)-N-propyIsuIphonylamino)anilino)-1 -(4-(2- carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone (86) 3-Z-[1 -(3-(methylaminomethyl)anilino)-1 -(4-(2- carboxyethyI)phenyl)methylene]-6-fluoro-2-indolinone (87) 3-Z-[1-(3-(2-dimethylaminoethyl)anilino)-1-(4-(2- carboxyethyl)phenyl)methylene]-6-fluoro-2-indoIinone (88) 3-Z-[1 -(3-(3-dimethylaminopropyl)anilino)-1 -(4-(2- carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone (89) 3-Z-[1-(4-(N-(dimethylaminocarbonylmethyl)-N-methylsuIphonylamino)anilino)- 1 -(4-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone (90) 3-Z-[1 -(4-(N-methyl-N-methylsulphonylamino)anilino)-1 -(4-(2- carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone (91) 3-Z-[1-(4-(N-(N-(2-dimethylaminoethyl)-N-methylaminomethylcarbonyl)-N- methylamino)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2- indolinone (92) 3-Z-[1-(4-(2-diethyIaminoethylsulphonyl)anilino)-1-(4-(2- carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone (93) 3-Z-[1 -(4-(2-dimethylaminoethoxy)anilino)-1 -(4-(2- carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone (94) 3-Z-[1 -(4-(N-(3-dimethyIaminopropyIcarbonyl)-N-methylamino)anilino)-1 -( carboxyethyl)phenyl)methylene]-6-fIuoro-2-indolinone (95) 3-Z-i1-(4-(methylethyIaminomethyl)aniIino)-1-(4-(2- carboxyethyI)phenyl)methylene]-6-fIuor6-2-indolinone (96) 3-Z-[1 -(4-(methylpropylaminomethyI)aniIino)r1-(4-(2- carboxyethyl)phenyl)methylene]-6-fIuoro-2-indolinone (97) 3-Z-[1-(4-(methylbenzylaminomethyl)anilino)-1-(4-(2- carboxyethyl)phenyl)methylene]-6-fluoro-2-iridolinone (98) 3-Z-[1-(4-(azetidin-1-ylmethyl)anilino)-1-(4-(2-carboxyethyI)phenyl)methylene]- 6-fIuoro-2-indolinone (99) 3-Z-[1-(4-(piperazin-1-ylmethyl)anilino)-1-(4-(2- carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone (100) 3-Z-[1-(4-(morpholin-4-ylmethy!)ani!ino)-1-(4-(2- carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone (101) 3-Z-[1 -(4-(thiomorpholin-4-yimethyl)ani[ino)-1-(4-(2- carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone (102) 3-Z-[1 -(4-(N-(2-dimethylaminoethyl)-N-acetylamino)anilino)-1 -(3-(2- carboxyethyl)phenyl)methylene]-6-fIuoro-2-indolinone (103) 3-Z-[1 -(4-(N-(2-methylaminoethyl)-N-acetylamino)anilino)-1 -(3-(2- carboxyethyI)phenyl)methylene]-6-fluoro-2-indolinone (104) 3-Z-[1 -(4-(N-(3-methylaminopropyl)-N-acetylamino)anilino)-1 -(3-(2- Garboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone (105) 3-Z-[1 -(4-(3-dimethylaminopropyl)aniIino)-1 -(3-(2- carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone (106) 3-Z-[1 -(4-ethylaminomethylahiliho)-1 -(3-(2-carboxyethyl)phenyl)methylene]-6- fluoro-2-indolinone (107) 3-Z-[1 -(4-(4-methylpiperazin-1 -ylcarbonyl)anilino)-1 -(3-(2- carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone (108) 3-Z-[1 -(4-(N-(3-dimethylaminopropyl)-N-methylsulphonylamino)anilino)-1 -(3- (2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone (109) 3-Z-[1-(4-(N-(2-dimethylaminoethyl)-N-propylsulphonylamino)anilino)-1-(3-(2- carboxyethyl)phenyl)methylene]-6-fIuoro-2-indolinone (110) 3-Z-[1 -(3-(methylaminomethyl)anilino)-1 -(3-(2- carboxyethyI)phenyl)methyIene]-6-fIuoro-2-indolinone (111) 3-Z-[1-(3-(2-dimethylaminoethyl)anilino)-1-(3-(2- carboxyethyI)phenyI)methylene]-6-fIuoro-2-indolinone (112) 3-Z-[1-(3-(3-dimethylaminopropyI)ani!ino)-1-(3-(2- carboxyethyI)phenyl)methylene]-6-fIuoro-2-indoIinone (113) 3-Z-[1-(4-(N-(dimethylaminocafbonylmethyI)-N-methylsuIphonylamino)ani[ino)- 1-(3-(2-carboxyethyl)phenyl)methyIaie]-6-fIuoro-2-indolinone (114) 3-Z-[1-(4-(N-methyl-N-methy!suIphonylamino)anilino)-1-(3-(2- carboxyethyl)phenyl)methylene]-6-flooro-2-indolin6ne (115) 3-Z-[1-(4-(N-methyl-N-acetylamino)anilino)-1-(3-(2- carboxyethyI)phenyl)methylene]-6-fluoro-2-indolinone (116) 3-Z-[1 -(4-(N-(N-(2-dimethylaminoethyl)-N-methylaminomethylcarbonyl)-N- methylamino)anilino)-1-(3-(2-carboxyethy!)phenyl)nnethy!ene]-6-f!uoro-2- indoiinone (117) 3-Z-[1-(4-(2-diethylaminoethytei4>hony!)anilino)-1-(3-(2- carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone (118) 3-Z-[1-(4-(N-(2-dimethylaminoeftylcarbonyl)-N-methylamino)anilino)-1-(3-(2- carboxyethyl)phenyl)methylene]-6^fluoro-2-indolinone (119) 3-Z-[1-(4-(N-(2-dimethyIamino^fiyl)-N-methylaminomethyl)anilino)-1-(3-(2- carboxyethyOphenyOmethylenej-e^fluoro^-indolinone (120) 3-Z-[1-(4-(2-dimethylaminoetho^)ani[ino)-1-(3-(2- carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone (121) 3-Z-[1-(4-(methylethylaminometfiyl)anilino)-1-(3-(2- carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone (122) 3-Z-[1-(4-(methylpropylaminomeftiyl)anilino)-1-(3-(2- carboxyethyOphenyOmethylenej-emjoro^-indolinone (123) 3-Z-[1-(4-(methylbenzylaminom€thyl)anilino)-1-(3-(2- carboxyethyl)phenyI)methylene]-&4ioro-2-indolinone (124) 3-Z-[1-(4-(diethylaminomethyI)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene]- 6-fluoro-2-indolinone (125) 3-Z-[1-(4-(pyrrolidin-1-ylmethyl)aiilino)-1-(3-(2- carboxyethyl)phenyl)methylene]-6-§uoro-2-indcilinone (126) 3-Z-[1-(4-(azetidin-1-ylmethyI)anflino)-1-(3-(2-carboxyethyI)phenyI)methylene]- 6-fIuoro-2-indoljnone (127) 3-Z-[1 -(4-(piperazin-1 -ylmethyl)anilino)-1 -(3-(2- carboxyethyl)phenyl)methylene]-64luoro-2-indolinone (128) 3-Z-[1-(4-(morpholin-4-ylmethyl)anilino)-1-(3-(2- carboxyethyl)phenyl)methyiene]-6-fluoro-2-indolinone (129) 3-Z-[1-(4-(thiomorpholin-4-ylmethyl)anilino)-1-(3-(2- carboxyethyl)phenyl)methylene]-6-f!uoro-2-indolinone (130) 3-Z-[1-(4-(N-(2-dimethylaminoethyl)-N-methylsulphonyIamino)aniIino)-1-(4-(2- carboxyethyl)phenyI)methylene]-6-bromo-2-indolinone (131) 3-Z-[1 -(4-(N-(dimethyIaminomethylcarbonyl)-N-methylamino)anilino)-1 -(4-(2- carboxyethy!)phenyl)methy!ene]-6-bromo-2-indolinone (132) 3-Z-[1-(4-(N-(2-dimethylaminoethyl)-N-acetylamino)ani[ino)-1-(4-(2- carboxyethyl)phenyl)methylene]-6-bromo-2-indolinone (133) 3-Z-[1-(4-(N-(2-methylaminoethyl)-N-acetylamino)anHino)-1-(4-(2- carboxyethyl)phenyl)methylene]-6-bromo-2-indolinone (134) 3-Z-[1-(4-(N-(3-dimethylaminopropyl)-N-acetylamino)anilino)-1-(4-(2- carboxyethyl)phenyl)methylene]-6-bromo-2-indolinone (135) 3-Z-[1-(4-(N-(3-methylaminopropyl)-N-acetylamino)anilino)-1-(4-(2- carboxyethyl)phenyl)methylene]-6-bromo-2-indolinone (136) 3-Z-[1-(4-(3-dimethylaminopropyl)aniIino)-1-(4-(2- carboxyethyl)phenyl)methylene]-6-bromo-2-indolinone (137) 3-Z-[1 -(4-ethylaminomethylanilino)-1 -(4-(2-carboxyethyl)phehyl)methylene]-6- bromo-2-indolinone (138) 3-Z-[1-(4-methylaminomethylanilino)-1 -(4-(2-carbo>^ethyl)plienyl)r^ethyrene]:: 6-bromo-2-indolinone (139) 3-Z-[1-(4-(N-(4-methylpiperazin-1-ylmethylcarbonyI)-N-methylamino)anilino)-1- (4-(2-carboxyethyl)phenyl)methylene]-6-bromo-2-indolinone (140) 3-Z-[1-(4-(4-methylpiperazin-1-ylcarbonyl)anilino)-1-(4-(2- carboxyethyl)phenyl)methylene]-6-bromo-2-indolinone (141) 3-Z-[1 -(4-(N-(3-dimethylaminopropyl)-N-methylsulphonylamino)anilino)-1 -(4- (2-carboxyethyI)phenyl)methylene]-6-bromo-2-indoIinone (142) 3-Z-[1-(4-(N-(2-dimethyIaminoethyl)-N-propyIsulphonylamino')anilino)-1-(4-(2- carboxyethyl)phenyl)methylene]-6-bromo-2-indolinone (143) 3-Z-[1-{4-aminomethylaniIino)-1-(4-(2-carboxyethyl)phenyI)methylene]-6- bromo-2-indolinohe (144) 3-Z-[1 -(3-(dimethylaminomethyl)anilino)-1 -(4-(2- carboxyethyl)phenyI)methylene]-6-bromo-2-indoIinone (145) 3-Z-[1-(3-(methylaminomethyl)anilino)-1-(4-(2- carboxyethyl)phenyl)methylene]-6-bromo-2-indolinone (146) 3-Z-[1 -(3-(2-dimethylaminoethyl)anilino)-1 -(4-(2- carboxyethyl)phenyl)methylene]-6-bromo-2-indolinone (147) 3-Z-[1-(3-(3-dimethylaminopropyi)ani!ino)-1-(4-(2- carboxyethyl)phenyl)methy!ene]-6-bromo-2-indo!inone (148) 3-Z-[1 -(4-(2-dimethyiaminoethyl)anilino)-1 -(4-(2- carboxyethyl)phenyl)methylene]-6-bromo-2-indolinone (149) 3-Z-[1-(4-(N-(dimethylaminocarbonyimethyl)-N-me.thylsulphonylamino)aniIino)- 1-(4-(2-carboxyethyl)phenyl)methylene]-6-bromo-2-indolinone (150) 3-Z-[1-(4-(N-methyl-N-methylsulphonylamino)anilino)-1-(4-(2- carboxyethyl)phenyl)methylene]-6-bromo-2-indolinone (151) 3-Z-[1 -(4-(N-methyl-N-acetylamino)anilino)-1 -(4^(2- carboxyethyl)phenyI)methylene]-6-bromo-2-indolinone (152) 3-Z-[1-(4-(1-methylimidazol-2-yl)anilino)-1-(4-(2- carboxyethyl)phenyl)methylene]-6-bromo-2-indolinone (153) 3-Z-[1-(4-(N-(N-(2-dimethylaminoethyI)-N-methylaminomethylcarbonyl)-N- methylamino)aniIino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-bromo-2- indolinone (154) 3-Z-[1 -(4-(2-diethylaminoethylsulphonyl)ani!ino)-1 -(4-(2- carboxyethyl)phenyl)rnethylene]-6-bromo-2-indolinone (155) 3-Z-[1-(4-(N-(2-dimethylaminoethylcarbonyl)-N-methylamino)anilino)-1-(4-(2- carboxyethyl)phenyl)methylene]-6-bromo-2-indolinone (156) 3-Z-[1-(4-(N-(2-dimethylaminoethyl)-N-methylaminomethyl)anilino)-1-(4-(2- carboxyethyl)phenyl)methylene]-6-bromo-2-indoIinone (157) 3-Z-[1-(4-(2-dimethylaminoethoxy)anilino)-1-(4-(2- carboxyethyl)phenyI)methylene]-6-bromo-2-indoIinone (158) 3-Z-[1-(4-(N-(4-dimethyIaminobutylcarbonyI)-N-methylamino)aniIino)-1-(4-(2- carboxyethyl)phenyl)methylene]-6-bromo-2-indolinone (159) 3-Z-[1 -(4-(N-(3-dimethylaminopropylcarbonyl)-N-methylamino)anilino)-1 -( carboxyethyI)phenyl)methylene]-6-bromo-2-indoIinone (160) 3-Z-[1-(4-(methylethylaminomethyl)anilino)-1-(4-(2- carboxyethyl)phenyl)methyIene]-6-bromo-2-indolinone (161) 3-Z-[1 -(4-(methylpropy!aminomethyl)anilino)-1 -(4-(2- carboxyethyl)phenyl)methylene]-6-bromo-2-indoIinone (162) 3-Z-[1-(4-(methylbenzylaminomethyl)aniIino)-1-(4-(2- carboxyethyl)phenyI)methylene]-6-bromo-2-indolinone (163) 3-Z-[1-(4-(diethylaminomethyl)anilino)-1-(4-(2-carboxyethyl)phenyl)methy!ene]- 6-bromo-2-indolinone (164) 3-Z-[1-(4-(N-(2-dimethylaminoethy[)-N-methylaminomethyl)anilino)-1-(4-(2- carboxyethyl)-phenyImethylene]-6-bromo-2-indolinone (165) 3-Z-[1-(4-(pyrrolidin-1-ylmethyl)anilino)-1-(4-(2- carboxyethyl)phenyl)methylene]-6-bromo-2-indolinone (166) 3-Z-[1-(4-(azetidin-1-ylmethyl)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]- 6-bromo-2-indolinone (167) 3-Z-[1-(4-((4-methylpiperazin-1-yl)methyl)anilino)-1-(4-(2- carboxyethyl)phenyl)methylene]-6-bromo-2-indolinone (168) 3-Z-[1 -(4-(piperazin-1 -ylmethyl)anilino)-1 -(4-(2- carboxyethyl)phenyl)methylene]-6-bromo-2-indo[inone (169) 3-Z-[1-(4-(morpholin-4-ylmethyl)aniIino)-1-(4-(2- carboxyethyl)phenyl)methylene]-6-bromo-2-indolinone (170) 3-Z-[1-(4-(thiomorpholin-4-ylmethyl)aniIino)-1-(4-(2- carboxyethyl)phenyl)methylene]-6-bromo-2-indolinone (171) 3-Z-[1-(4-(imidazol-1-ylmethyl)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]- 6-bromo-2-indolinone (172) 3-Z-[1-(4-dimethylaminomethylanilino)-1-(3-(2- carboxyethyl)phenyl)methylene]-6-bromo-2-indoIinone (173) 3-Z-[1-(4-(N-(2-dimethylaminoethyl)-N-methylsulphonylamino)anilino)-1-(3-(2- carboxyethyl)phenyl)methylene]-6-bromo-2-indolinone (174) 3-Z-[1-(4-(N-(dimethylaminomethylcarbonyI)-N-methylamino)anilino)-1-(3-(2- carboxyethyl)phenyl)methylene]-6-bromo-2-indoIinone (175) 3-Z-[1-(4-(N-(2-dimethylaminoethyI)-N-acety!amino)aniIino)-1-(3-(2- carboxyethyl)phenyl)methylene]-6-bromo-2-indolinone (176) 3-Z-i1-(4-(N-(2-methyIaminoethyl)-N-acetylamino)anilino)-1-(3-(2- carboxyethyl)phenyl)methylene]-6-bromo-2-indolinone (177) 3-Z-[1-(4-(N-(3-dimethylaminopropyl)-N-acetylamino)anilino)-1-(3-(2- carboxyethyl)phenyl)methylene]-6-bromo-2-indolihone (178) 3-Z-[1-(4-(N-(3-methyIaminopropyl)-N-acetylamino)aniIino)-1-(3-(2- carboxyethyl)phenyl)methylene]-6-bromo-2-indolinone (179) 3-Z-[1-(4-(3-dimethy!aminopropyl)anilino)-1-(3-(2- carboxyethyl)phenyl)methylene]-6-bromo-2-indolinone (180) 3-Z-[1-(4-ethylaminomethylanilino)-1-(3-(2-carboxyethyl)phenyl)methylene]-6- bromo-2-indolinone (181) 3-Z-[1-(4-methylaminomethylanilino)-1-(3-(2-carboxyethyl)phenyl)methylene]- 6-bromo-2-indolinone (182) 3-Z-[1-(4-(N-(4-methyIpiperazin-1-y1methylcarbonyl)-N-methylamino)anilino)-1- (3-(2-carboxyethyl)phenyl)methylene]-6-bromo-2-indolinone (183) 3-Z-[1 -(4-(4-methylpiperazin-1 -ylcarbonyl)anilino)-1 -(3-(2- carboxyethyl)phenyl)methylene]-6-bromo-2-indolinone (184) 3-Z-[1-(4-(N-(3-dimethylaminopropyl)-N-methylsulphonylamino)anilino)-1-(3- (2-carboxyethyl)phenyl)methylene]-6-bromo-2-indolinone (185) 3-Z-[1-(4-(N-(2-dimethylaminoethyl)-N-propylsulphonylamino)anilino)-1-(3-(2- carboxyethyl)phenyI)methylene]-6-bromo-2-indolinone (186) 3-Z-[1 -(4-aminomethylanilino)-1 -(3-(2-carboxyethyl)phenyl)methylene]:6- bromo-2-indolinone (187) 3-Z-[1-(3-(dimethylaminomethyl)anilino)-1-(3-(2- carboxyethyl)phenyl)methylene]-6-bromo-2-indolinone (188) 3-Z-[ 1 -(3-(methylaminomethyl)aniIino)-1 -(3-(2- carboxyethyI)phenyl)methylene]-6-bromo-2-indolinone (189) 3-Z-[1-(3-(2-dimethylaminoethyl)anilino)-1 -(3-(2- carboxyethyl)phenyl)methylene]-6-bromo-2-indolinone M 90) 3-Z-[1-(3-(3-dimethylaminopropyI)anilino)-1-(3-(2- carboxyethyI)phenyl)methylene]-6-bromo-2-indoIinone (191) 3-Z-[1-(4-(2-dimethyIaminoethyl)aniIino)-1-(3-(2- carboxyethyl)phenyl)methyIene]-6-bromo-2-indolinone (192) 3-Z-[1-(4-(N-(dimethylaminocarbonylmethyl)-N-methylsulphonyIamino)anilino)- 1-(3-(2-carboxyethyl)phenyl)methylene]-6-bromo-2-indolinone (193) 3-Z-[1-(4-(N-methyl-N-methyisulphonylamino)aniIino)-1-(3-(2- carboxyethyl)phenyl)methylene]-6-brdmo-2-indolihone (194) 3-Z-[1-(4-(N-methyl-N-acetylamino)anilino)-1 -(3-(2- carboxyethyl)phenyl)methylene]-6-bromo-2-indolinone (195) 3-Z-[1-(4-(1-methy!imidazol-2-yI)an[Iino)-1-(3-(2- carboxyethyl)phenyl)methylene]-6-bromo-2-indo!inone (196) 3-Z-[1-(4-(N-(N-(2-dimethylaminoethyl)-N-methylaminomethylcarbonyl)-N- methylamino)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene]-6-bromo-2- indolinone (197) 3-Z-[1-(4-(2-diethylaminoethylsulphonyl)anilino)-1-(3-(2- carboxyethyl)phenyl)methylene]-6-bromo-2-indolinone (198) 3-Z-[1-(4-(N-(2-dimethylaminoeth^carbonyl)-N-methylamino)anilino)-1-(3-(2- carboxyethyl)phenyl)methylene]-6rbramo-2-indolinone (199) 3-Z-[1-(4-(N-(2-dimethylaminoeth^-N-methylaminomethyl)anilino)-1-(3-(2- carboxyethyl)phenyl)methylene]-6-bromo-2-indolinone (200) 3-Z-[1-(4-(2-dimethylaminoethoxy)anilino)-1-(3-(2- carboxyethyI)phenyl)methylene]-6-bromo-2-indolinone (201) 3-Z-[1-(4-(N-(4-dimethylaminobulylcarbonyl)-N-methylamino)anilino)-1-(3-(2- carboxyethyl)phenyl)methylene]-6-bromo-2-indolinone (202) 3-Z-[1 -(4-(N-(3-dimethylaminopro\|^lcarbonyl)-N-methylamino)anilino)-1 -(3-(2- carboxyethy[)phenyl)methylene]-6-bn3mo-2-indolinone (203) 3-Z-[1 -(4-(methylethylaminomethyl)anilino)-1-(3-(2- carboxyethyl)phenyl)methylene]-6-bromo-2-indolinone (204) 3-Z-[1-(4-(methylpropylaminomethyl)anilino)-1 -(3-(2- carboxyethyl)phenyl)methylene]-6-bromo-2-indoIinone (205) 3-Z-[1-(4-(methylbenzylaminomejhyl)anilino)-1-(3-(2- carboxyethyl)phenyl)methylene]-6-bromo-2-indolinone (206) 3-Z-[1-(4-(diethylaminomethyI)anlno)-1-(3-(2-carboxyethyl)phenyl)methylene]- 6-bromo-2-indolinone (207) 3-Z-[1-(4-(N-(2-dimethyIaminoetfTyO^N-methylaminomethyl)ani[ino)-1-(3-(2- carboxyethyI)phenylmethylene]-6-bromo-2-indolinone (208)- 3-Z-[1-(4-(pyrrolidin-1-ylmethyl)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene]-6-bromo-2-indoIinone (209) 3-Z-[1-(4-(azetidin-1-ylmethyl)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene]- 6-bromo2-indolinone (210) 3-Z-[1-(4-((4-methylpiperazin-1-yl)methyl)aniliho)-1-(3-(2- carboxyethyl)phenyl)methyIene]-6-bromo-2-indolinone (211) 3-Z-[1-(4-(piperazin-1-ylmethy!)ani!ino)-1-(3-(2- carboxyethyl)phenyl)methylene]-6-bromo-2-indolinone (212) 3-Z-[1-(4-(morpholin-4-ylmethyl)anilino)-1-(3-(2- carboxyethyl)phenyl)methylene]-6-bromo-2-indolinone (213) 3-Z-[1-(4-(thiomorpholin-4-ylmethyl)anilino)-1-(3-(2- carboxyethyl)phenyl)methylene]-6-bromo-2-indolinone (214) 3-Z-[1-(4-(imidazol-1-ylmethyl)anilino)-1-(3-(2-carboxyethyl)phenyl)rnethylene]- 6-bromo-2-indolinone (215) 3-Z-[1-(4-dimethylaminomethylanilino)-1-(4-carboxymethylaminophenyl)- methylene]-6-fIuoro-2-indolinone (216) 3-Z-[1-(4-dimethylaminomethylanilino)-1-(3-carboxymethylamino-phenyl): methylene]-6-fIuoro-2-indolinone (217) 3-Z-[1-(4-dimethyIaminomethylanilino)-1-(4-(N-methyl- carboxymethylamino)phenyl)methylene]-6-fIuoro-2-indorinone (218) 3-Z-[1-(4-dimethylaminomethylanilino)-1-(3-(N-methyI- carboxymethylamino)phenyl)methylene]-6-fIuoro-2-indolinone (219) 3-Z-[1-(4-dimethylaminomethylanilino)-1-(4-earboxymethoxyphenyl)- methylene]-6-chloro-2-indolinone (220) 3-Z-[1-(4-dimethylaminomethylanilino)-1-(3-carboxymethoxyphenyl)- methy!ene]-6-chloro-2-indolinone (221) 3-Z-[1-(4-dimethylaminomethylanilino)-1-(4-carboxymethylaminophenyl)- methyIene]-6-chloro-2-indolinone (222) 3-Z-[1-(4-dimethylaminomethylanilino)-1-(3-carboxymethyIaminophenyl)- methy!ehe]-6-chloro-2-indolinone (223) 3-Z-[1-(4-dimethylaminomethylanilino)-1-(4-(N-methyl- carboxymethylamino)phenyl)methylene]-6-chloro-2-indolinone (224) 3-Z-[1 -(4-dimethylaminomethylanilino)-1 -(3-(N-methyi- carboxymethylamino)phenyl)methyIene]-6-chloro-2-indolinone (225) 3-Z-[1-(4-dimethylaminomethylanilino)-1-(4-carboxymethoxyphenyl)- methyIene]-6~bromo-2-iridolinone (226) 3-Z-[1-(4-dimethylaminomethylanilino)-1-(3-carboxymethoxyphenyl)- methylene]-6-bromo-2-indolinone (227) 3-Z-[1-(4-dimethylaminomethylanilino)-1-(4-carboxymethylaminophenyl)- methy!ene]-6-bromo-2-indolinone (228) 3-Z-[1-(4-dimethylaminomethylanilino)-1-(3-carboxymethylaminophenyl)- methylene]-6-bromo-2-indolinone (229) 3-Z-[1 -(4-dimethylaminomethylanilino)-1-(4-(N-methyl- carboxymethylamino)phenyl)methylene]-6-bromo-2-indolinone (230) 3-Z-[1 -(4-dimethylaminomethylanilino)-1-(3-(N-methyl- carboxymethylamino)phenyl)methylene]-6-bromo-2-indolinone In the tables above, Me is methyl, Et is ethyl, Pr is propyl, nPr is n-propyi, iPr is isopropyl, nBu is n-butyl, tBu is tert-butyl and Bn is. benzyl. We Claim: 1. The compound l-acetyl-6-fluoro-2-indolinone, wherein said compound is used as starting material for the manufacture of a substituted 2-indolinone of the formula (I) as in which R2 is a fluorine atom.

Full Text

The present invention relates to indolinone derivatives, substituted in the 6-position, of the formula
(Formula Removed)
to their tautorners, enantiomers, diastereomers, their mixtures and their salts, in particular their physiologically acceptable salts, which have useful pharmacological properties, to medicaments comprising these compounds to their use and to processes for their preparation.
The above compounds of the formula I have useful pharmacological properties, in particular an inhibition action on Various kinases, especially on receptor tyrosine kinases, such as VEGFR1, VEGFR2, VEGFR3, PDGFRα, PDGFRß, FGFR1, FGFR3, EGFR, HER2, c-Kit, IGF1R and HGFR, Flt-3, and on the proliferation of cultivated human cells, in particular that of endothelial cells, for example in angiogenesis, but also on the proliferation of other cells, in particular tumour cells.
Accordingly, the present invention provides the above compounds of the formula I, which have useful pharmacological properties, medicaments comprising these pharmacologically active compounds, their use and processes for their preparation.
Moreover, the present invention provides the physiologically acceptable salts of the compounds according to the invention, medicaments comprising these compounds which in addition, if appropriate, contain one or more inert carrier materials and/or diluents, and their use for preparing a medicament suitable in particular for treating excessive or anormal cell proliferations.
The present invention furthermore provides processes for preparing this medicament, characterized in particular in that the compounds according to the invention or their physiologically acceptable salts are incorporated into one or more inert carrier materials and/or diluents.
I. In the above formula I, X is an oxygen atom, R1 is a hydrogen atom, R2 is a fluorine, chlorine or bromine atom or a cyano group,
R3 is a phenyl group or a phenyl group which is monosubstituted by a fluorine, chlorine, bromine or iodine atom or by a Ci.s-alkoxy group, where the abovementioned unsubstituted and the monosubstituted phenyl groups may additionally be substituted in the 3- or4-position
by a fluorine, chlorine or bromine atom,
by a cyano group,
by a C1-3-alkoxy or C1-2-alkyI-carbonyl-amino group,
by a cyano-C1-3-alkyI, carboxy-C1-3-alkyl, carboxy-C1-3-alkoxy, carboxy-C1-3-alkylamino, carboxy-C1-3-alkyl-N-C1-3-alkyO-amino, C1-3-alkoxy-carbonyl-C1-3-alkyl, C1-3-alkoxy-carbonyl-Ci-3-alkoxy,. C1-3alkoxy-
carbonyI-C1-3-alkyIamino, amino, amino-C1-3-alkyl, aminocarbonyI-C1-3-alkyl, (C1-2-alkylarnino)-carbonyl-C1-3-alkyl, di-(C1-3-alky[)-aminocarbonyl-C1-3-aBcyl, (C1-3-alkyl-carbonyI)-amino-C1-3-a!ky!, (C1-3-aikoxy-carbonyO-amino-C1-3-aikyl, (C3. 6-aIkyl-carbony])-amino-C1-3-alkyl, (phenyl-carbonyl)-amino-C1-3-alkyl, (C3-6-cycloalkyl-carbony[)-amino-C1-3-aIkyl, (C3-6-cycloalkyl-C1-3-aIkyl-carbonyl)-amino-C1-3-alkyi, (thiophen^-yl-carbonylJ-ammo-C1-3-alkyl, (furan-2-yl-carbonyl)-amino-C1-3-alky!, (phenyl-C1-3-aIkyk;arbonyl)-amino-C1-3-alkyl, (2-(C1-3-alkoxy)-benzoyl-carbonyl)-amino-C1-3-alkyl, (pyridin-2-yl-carbonyl)-amino-Ci-3-alkyl, (pyridin-3-y!-carbonyl)-amino-C1-3-alkyl-, (pyridin-4-yl-carbony[)-amino-C1-3-alkyl- or C1-3alkyl-piperazin-1-yl-carbonyl-C1-3-alkyl group,
by a carboxy-C2-3-alkenyl, aminocarbonyl-C2-3-alkenyl, (G)-3-alkyl-amino)-carbonyl-C2-3-alkenyl, di-(C1-3-alky!)-amino-carbonyl-C2.3-alkenyl or C1-3-alkoxy-earbonyl-C2-3-alkenyl group,
where the substituents may be identical or different, R4 is a phenyl group or a phenyl group which is monosubstituted
by a C1-3-alkyl group which is terminally substituted by an amino, guanidino, mono- or dHC1-3alkyO-amino-, N-[oo-di-(C1-3-a!kyl)-amino-C2. 3-alkyl]-N-(C1-3-alkyl)-amino, N-methyl-(C3-4-alkyl)-amino, N-(C1-3-alkyl)-N-benzy(amino, N-fC^-alkoxycarbonyO-amino, !4-(C1-oxycarbonyO-Ci^-alkylamino, 4-(Ci_3-alkyI)-piperazin-1-yl, imidazol-1-yl, pyrroIidin-1-yl, azetidin-1-yl, morpholin-4-yl, piperazln-1-yl, thiomorpholin-4-yl group,
by a di-(C1-3-alkyl)-amino-(Ct-3-alkyl)-sulphonyI, 2-[di-(Ct^-alkyl)-amino]-ethoxy, 4-(Ci.3-alkyl)-piperazin-1-yl-carbonyl, {o)-[di-(C1-3-aikyl)-amino]-(C2.3-alky[)}-N-(C1-3-alkyl)-amino-carbonyl, 1-(C1-3-afkyljimidazof-2-yI, (C1-3-alkyl)-sufphonyl group, or
by a group of the formula
(Formula Removed)
in which
R7 is a Ct-2-alkyl, C1.2-alkyl-carbonyl, di-(Ci-2-alkyl)-amino-carbonyl-Ci-3-alkyl or C1.3-alkylsulphonyl group and
R8 is C-i.s-alkyl, m-[dKCi-2-alkyl)-amino]-C2-3-alky!, co-j alkyl)-amino]-C1-3-alkyl group, or
a (C1-3-alkylJ-carbonyl, (C1-3s-alkyl)-carbonyl or carbony!-(C1-3 alkyl) group which is terminally substituted by a di-(C1-3-alkyl)-amino, piperazin-1-yl or 4-(C1-3-alkyl)-piperazin-1-yl group,
where all dia/kylamino groups present in the radical R4 may also be present in quaternized form, for example as an N-methyl-(N,N-dialkyl)-amrnoniurn group, where the counterion is preferably selected from the group consisting of iodide, chloride, bromide, methylsulphonate, para-toluenesufphonate and trifluoroacetate,
R5 is a hydrogen atom and R6 is a hydrogen atom,
where the abovementioned alkyl groups include linear and branched alkyl groups in which additionally one to 3 hydrogen atoms may be replaced by fluorine atoms,
where additionally a carboxyl, amino or imino group present may be substituted by an in vivo cteavable radical or may be present in the form of a prodrug radical, for example in the form of a group which can be converted in vivo into a carboxyi group or in the form of a group which can be converted in vivo into an imino or amino group,
their tautomers, enantiomers, diastereomers, their mixtures and their salts.
Particularly preferred compounds of the above formula I are those compounds in which X, R1, R5 and R6 are as defined under I. and:
II.i. R2 and R4 are as defined under I. and
R3 is a phenyl group or a phenyl group which is monosubstituted by a fluorine, chlorine, bromine or iodine atom or by a C1-3-alkoxy group, where the abovementioned unsubstituted and the monosubstituted phenyl groups may additionally be substituted in the 3- or 4-position
by a fluorine, chlorine or bromine atom,
by a cyano group,
by a C1-3-alkoxy or C1-3-alkyl-carbonyl-amino group,
by a cyano-C1-3-alkyl, carboxy-C1-3-alkyl, carboxy-C1-3-alkoxy, carboxy-C1-3-alkylamino, carboxy-C1-3-alky!-N-(C1-3-alky()-amino, C1-3-alkoxy-carbonyl-C1-3-alkyl, C-1-3-alkoxy-carbonyl-C1-3-alkoxy, C1-3-alkoxy-carbonyl-C1-3aJkylamino, C1-3-alkoxy-carbonyl-C1-3-alkyf-N-fC1-3-aJkyl)-arnino, amino-Ci.3-alkyl, aminocarbonyl-Ci.3-a[kyl, (Ci.2-alkylammo)-carbonyl-C1-3-alkyl, di-(C1-3-a[kyl)-aminocarbony[-C1-3-alkyI, (C-[_2-alkyl-carbony()-amino-C1-3-alkyl, {C1-3-alkoxy-carbonyl)-amino-C1-3-alky!, (C3 6-alkyl-carbonyl)-amino-C1-3-alkyl, (phenyl-carbony!)-amino-C1-3-a!kyl,
(C1-3-cycIoalkyl-carbonyO-amino-C1-3-alkyl, (C1-3-cycloalkyl-C1-3alkyl-carbonyI)-amino-C1-3-aIkyl, (thiophen-2-yl-carbonyl)-amino-C1-3-aIkyl, (furan1-3-yl-carbonyO-amino-C1-3-alkyl, (phenyl-C1-3-alkyl-carbonyl)-amino-C1-3-aikyl, (2-(C1-3-aikoxy)-benzoyi-carbony!)-amino-C1-3-a!ky!I (pyridin-2-yl-carbonyl)-amino-Ci-3-alkyl, (pyridin-3-yl-carbonyl)-amino-C1-3-alkyl, (pyridin-4-yl-carbonyl)-amino-C1-3alkyl or C1-3-alkyl-piperazin-1-yl-carbonyl-Ci-3-alkyl group,
by a carboxy-C2-3-alkenyl, aminocarbonyl-C2-3-alkenyl-, (C1-3-alkyl-amino)-carbonyl-C2-3-alkenyl-, di-(C1-3-alkyl)-amino-carbonyl-C2-3-alkenyl or C1-3-alkoxy-carbonyl-C1-3-alkenyl group,
where the substituents may be identical or different;
II.ii. R2 and R4 are as defined under I. and R3 is a phenyl group which is substituted by a Ci-2-alkyl-carbonyl-amino group,
by a oarboxy-C1-3alkyl, carboxy-C1-3alkoxy, C-V-alkoxy-carbonyl-C1-3-alkyl, C1-3-alkoxy-carbonyl-C1-3-alkoxy, aminocarbonyl-C1-3alkyl, (C1-3-alkylamino)-carbonyl-C1-3-alkyl, di-(C1-3alkyl)-aminocarbonyl-C1-3-alkyl, (C1-3-alkyl-carbonyl)-amino-CValkyl, (C1-3alkoxy-carbonyl)-amino-C1-3-alkyl, (phenyl-carbonyl)-amino-C1-3-alkyl, (C1-3-cycloalkyl-carbonyl)-amino-C1-3-alkyl, (C3-6-cycloalkyl-C1-3-alkyl-carbonyI)-amino-C1-3-alkyl, (thiophen-2-yl-carbonyl)-amino-Ci.3-alkyl, (furan-2-yl-carbonyl)-amino-C1-3-alkyl, (phenyl-C1-3-alkyl-carbonyI)-amino-C1-3-alkyl, (2-(C1-3 alkoxy)-benzoyI-carbonyl)-amino-C1-3-alkyl, (pyridin-2-yl-carbonyl)-amino-C1-3-alkyl, (pyridin-3-yl-carbonyl)-amino-C1-3-alkyl, (pyridin-4-yl-carbonyi)-amino-C1-3-alkyI or C1-3-alkyl-piperazin-1-yl-carbonyl-C1-3-alkyl group, '
by an arninocarbonyl-C2-3-aIkenyl, (C1-3-a[kylamino)-carbonyI-C1-3 alkenyl, di-(C1-3-alkyl)-arnino-carbonyl-C21-3-alkenyl or C-1-3-alkoxy-carbonyl-C1-3-aikenyl group;
ll.iii. R2 and R4 are as defined under I. and
R3 is a phenyl group substituted by a carboxy-Ci.3-alkyI or Ci-4-alkoxy-carbonyl-Ci-3-aIkyl group;
II.iv. R3 and R4 are as defined under I. and R2 is a fluorine or chlorine atom;
II.v. R2 and R3 are as defined under I. and
R4 is a phenyl group or a phenyl group which is monosubstituted
by a C1-3-alkyl group which is terminally substituted by an amino, guanidino, mono- or di-(C1-3-alkyl)-amino-, N-[o-di-(C1-3-aIkyl)-amino-C2. 3-alkyl]-N-(Ci-3-alkyl)-amino, N-methyl-(C1-3-a[kyl)-amino, N-(C1-3 alkyi)-N-benzylamino, N-(C1-3-alkoxycarbonyl}-amino, N-(C1-3 alkoxycarbonyl)-C1-3-alkylamino, 4-(C1-3-aIkyl)-piperazin-1-yl, imidazol-1-yl, pyrrolidin-1-yl, azetidin-1-yl, morpholin-4-yl, piperazin-1-yl, thiomorpholin-4-yl group,
by a di-(C1-3-alkyl)-amino-(C1-3-alky!)-sulphonyIJ 2-[di-(C1-3-alkyl)-amino]-ethoxy, 4-(C1-3-alkyl)-piperazin-1-yl-carbonyl, {co-[di-(C1-3-alkyl}-amino]-(C2-3-alkyI)}-N-(C1-3-aIkyI)-amino-carbonyl, 1-(C1-3-alkyl)imidazoI-2-yl, (C1-3alkyl)-sulphonyl group, or
(Formula Removed)
(Formula Removed)
group of the formula
(Formula Removed)
in which
R7 is a C1-3-alky!, C1-3alkyl-carbonyl, di-(C1-3-alkyi)~amino-carbonyl-C1-3-alkyl or C-1-3-alkylsulphonyl group and
R8 is C1-3-alkyl, o-[di-(C1-3alkyf)-amino]-C2-3-alkyl, o-a!kyl)-amino]-C2-3-alkyl group, or
a (C1-3-a!kyl)-carbonyl, (C1-3-alkyl)-carbonyl or carbonyl-(C1-3 alkyl) group which is terminally substituted by a di-(C1-3-alkyl)-amino, piperazin-1-yl or 4-(C1-3-alkyl)-piperazin-1-yl group,
where all dialkylamino groups present in the radical R4 may also be present in quaternized form, for example as an N-methyl-(N,N-dialkyl)-ammonium group, where the counterion is preferably selected from the group consisting of iodide, chloride, bromide, methyJsurphbnate, para-toruenesulphonate and trifluoroacetate.
Subgroups of particularly preferred compounds of the above formula I which are to be mentioned in particular are those in which:
lll.i. X, R1, R2, R5 and Rs are as defined under I., R3 is as defined
under II.i. and R4 is as defined under ll.v.;
lll.ii. X, R1, R2, R5 and R5 are as defined under I., R3 is as defined
under It.ii. and R4 is as defined under ll.v.;
lll.iii. X, R1, R2, R5 and R6 are as defined under I., R3 is as defined
under If.iii. and R4 is as defined under II.v.;
lll.iv. X, R1, R5 and R6 are as defined under I., R2 is as defined under
II.iv., R3 is as defined under ILL, II.ii. or ll.iii. and'R4 is as defined under II.v.
A further preferred group of compounds of the above formula I are those in which
X is an oxygen atom,
R1 is a hydrogen atom,
R2 is a fluorine, chlorine or bromine atom or a cyano group,
R3 is a phenyl group or a phenyl group which is monosubstituted by a fluorine, chlorine, bromine or iodine atom or by a C1-3-alkoxy group, where the abovementioned unsubstituted and the monosubstituted phenyj groups may additionally be substituted in the 3- or 4-position
by a fluorine, chlorine or bromine atom,
by a C1-3-alkoxy or C1-3-aIkyl-carbonyl-amino group,
by a carboxy-C1-3-alkyl, aminocarbonyl-C1-3-alkyl, (C1-3alkylamino)-carbonyl-C1-3-alkyl, dKC1-3-alkyO-aminocarbonyl-C1-3-alkyl, (C1-3alkyl-carbony!)-amino-C1-3-alkyl or (phenyl-carbonyO-amino-C1-3-alkyl group,
where the substituents may be identical or different,
(Formula Removed)
is a phenyl group which is substituted
by a C1-3-alky! group terminally substituted by a di-(C1-3-alky])-amino group, or by a group of the formula
(Formula Removed)
in which
R7 is a C-1-3-alkyl, C1-3-alkyl-carbonyl, di-(C1-3-aIkyl)-amino-carbonyl-C1-3 alkyl or C1-3-alkylsulphonyl group and
R8 is a C1-3-alkyl or oa-[di-(C1-3-aIkyl)-amino]-C2-3-alkyl group, or
a C1-3-alkyl-carbonyl group terminally substituted by a di-(C1-3-alkyl)-amino, piperazino orC1-3-alkyO-piperazin-l-yl group,
R5 is a hydrogen atom and R6 is a hydrogen atom,
where the abovementioned alky! groups include linear and branched alkyl groups in which additionally one to 3 hydrogen atoms may be replaced by fluorine atoms,
where additionally a carboxyl, amino or imino group present may be substituted by an in vivo cleavabfe radical,
their tautomers, enantiomers, diastereomers, their mixtures and their salts. The following compounds of the formula 1 are particularly preferred:
(a) 3-Z-[1-(4-dimethyIaminomethylaniIind)-1-(3-(2-carboxyethyl)phenyl)methylene]-6-
chIoro-2-indolinone
(b) 3-Z-[1-(4-dimethyIaminomethyIanilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-
fluoro-2-indo!inone
(c) 3-Z-[1-(4-dimethylaminomethy!anilino)-1-(3-(2-carboxyethyl)phenyl)methylene]-6-
fluoro-2-indolinone
(d) 3-Z-[1-(4-(N-(4-methylpiperazin-1-ylmethyIcarbonyl)-N-methylamino)anilino)-1-(4-
(2-carboxyethyl)phenyI)methyleneI-6-fIuoro-2-indolinone
(e) 3-Z-[1-(4-(N-(2-dimethylaminoethyl)-N-methylsulphonyIamino)anilino)-1-(4-(2-
carboxyethyl)phenyl)methylene]-6-fluoro-2-indo!inone

(f) 3-Z-[1-(4-(N-(3-dimethylaminopropyl)-N-acetylamino)anilino)-1-(4-(2-
carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone
(g) 3-Z-[1-(4-(1-methylimidazol-2-yl)anHino)-1-(4-(2-carboxyethyl)phenyl)methylene]-
6-fluoro-2-indolinone
(h)3-Z-[1-(4-(N-(dimethylaminomethylcarbonyl)-N-methylamino)aniIino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone
(i) 3-Z-[1 -(4-(N-(2-dimethylaminoethylcarbonyl)-N-methy!amino)anilino)-1 -(4-(2-carboxyethyl)phenyl)methy!ene]-6-fluoro-2-indolinone
0') 3-Z-[1 -(4-(pyrrolidin-1 -ylmethyl)anilino)-1 -(4-(2-carboxyethyI)phenyl)methylene]-6-fluoro-2-indblinone
(k) 3-Z-[1-(4-(diethylaminomethyl)anilino)-1-(4-(2-carboxyethy!)phenyl)metfiylene]-6-fluoro-2-indoIinone
(I) 3-Z-[1-(4-(2-dimethyiaminoethyl)anilino)-1-(4-(2-carboxyethy!)pheny!)methyIene]-6-chloro-2-indolinone
(m) 3-Z-[1-(4-dimethylaminomethylanilino)-1-(4-(2-carboxyethyI)phenyl)methylene]-6-chloro-2-indolinone
(n) 3-Z-[1-(4-(pyrrolidin-1-ylmethyl)anilino)-1-(4-(2-carboxyethy!)phenyl)methylene]-6-chIoro-2-indolinone
(o)3-Z-[1-(4-(pyrrolidin-1-ylmethyl)anilino}-1-(4-(2-carboxyethyl)phenyl)methylene]-6-bromo-2-indolinone
(p) 3-Z-[1-(4-(dimethylaminomethyl)anilino)-1-(4-(2-carboxyethyl)pheny!)methylene]-6-bromo-2-indolinone
(q) 3-Z-[1 -(4-(diethylaminomethyl)aniIino)-1 -(4-(2-carboxyethyl)-methyIene]-6-bromo-2-indolinone
where additionally a carboxyf, amino or imino group present may be substituted by an in vivo cleavable radical or may be present in the form of a prodrug radical, for example in the form of a group which can be converted in vivo into a carboxyl group or in the form of a group which can be converted in vivo into an imino or amino group,
and their salts.
A group which can be converted in vivo into a carboxyl group is to be understood as meaning, for example, a hydroxymethyl group, a carboxyl group which is esterified with an alcohol in which the alcoholic moiety is preferably a C1-6-alkanol, a phenyl-C1-3-alkanol, a C1-3-cycloalkanol, where a C1-3-cycloalkanol may additionally be substituted by one or two C1-3-alkyl groups, a C1-3-cycloalkanol in which one methylene group in the 3- or 4-position is replaced by an oxygen atom or by an imino group optionally substituted by a C1-3alkyl, phenyl-C1-3-alkyl, phenyl-C1-3alkoxy-carbonyl or C1-3alkyl-carbony! group and in which the cycloalkanol moiety may additionally be substituted by one or two C1-3-alkyl groups, a C1-3-cycloalkenol, a C1-3 alkenol, a phenyl-C3-5-alkenol, a C3_5-alkynol or a phenyl-C1-3aikynol, with the proviso that no bond to the oxygen atom originates from a carbon atom which carries a double or triple bond, a C1-3cycloalkyl-Ci-a-alkanol, a bicycloalkano! having a total of 8 to 10 carbon atoms which may additionally be substituted in the bicycloalkyl moiety by one or two C1-3-alkyl groups, a 1,3-dihydro-3-oxo-1-isobenzofuranol or an alcohol of the formula
Ra-CO-0-(RbCR0)-OH,
in which
Ra is a d-B-alkyl, C5-7-cycfoalkyI, phenyl or phenyl-C1-3-a[kyl group,
Rb is a hydrogen atom, a d-s-alkyl, C1-3-cycloalkyl or phenyl group, and
Rc is a hydrogen atom or a C1-3-a!ky! group,
and a radical cleavable in vivo from an imino or arnino group is to be understood as meaning, for example, a hydroxyl group, an acy! group, such as the benzoyl or pyridihoyl group, or a C1-3-alkylcarbonyl group, such as the formyl, acetyl, propionyi, biitanoyl, pentanoyl or hexanoyl group, an allyloxycarbonyl group, a C1-3-a!koxy-carbonyl group, such as the methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, tert-butoxycarbonyl, pentoxycarbonyl, hexyloxycarbonyl, octyloxycarbonyl, nonyloxycarbonyl, decyloxycarbonyl, undecyloxycarbonyl, dodecyloxycarbonyl or hexadecyloxycarbonyl group, a phenyl-C1-3-alkoxy-carbonyl group, such as the benzylbxycarbonyl, phenylethoxycarbonyl or phenylpropoxycarbonyl group, a Ci-s-alkylsulphonyl-Ci^-alkoxy-carbonyl, Ci_3-alkoxy-C2-4-alkoxy-C2-4-alkoxy-carbonyI or RaCO-O-(RbCRc)-O-CO- group, in which
Ra is a C1-3-alkyI, C5-7-cyc!oa[kyl, phenyl or phenyl-Ci.3-alkyl group, Rb is a hydrogen atom, a C1-3-alkyl, C1-3-cycloalkyl or phenyl group and
RC is a hydrogen atom, a C1-3-alkyl or RaCO-O-(RbCRc)-O- group, in which Ra to Rc are as defined above,
and additionally, for an ammo group, the phthalimido group, where the ester radicals mentioned above can also be used as a group which can be converted in vivo into a carboxy! group.
Preferred prodrug radicals for a carboxyl group are a C1-6-alkoxy-carbonyl group, such as the methoxycarbonyl, ethoxycarbonyl, n-propyloxycarbonyl, isopropyloxycarbonyl, n-butyloxycarbonyl, n-penty[oxycarbonylr n-hexyloxycarbonyl or cyclohexyloxycarbonyl group, or a phenyJ-Ci-s-alkoxy-carbonyl group, such as the benzyloxycarbonyl group, and,
for an imino or amino group, a C1-3-alkoxy-carboriyl group, such as the methoxy-carbonyl, ethoxycarbonyl, n-propyloxycarbonyl, isopropyloxycarbonyl, n-butyloxy-carbonyl, n-pentyloxycarbonyl, n-hexyloxycarbohyl, cyclohexyloxycarbonyl, n-heptyfoxycarbonyi, n-octy!oxycarbonyl or n-nony!oxycarbony! group, a pheny!-C1-3-alkoxy-carbonyl group, such as the benzyloxycarbonyl group, a phenylcarbonyl group optionally substituted by a C1-3-alkyl group, such as the benzoyl or 4-ethyl-benzoyl group, a pyridinoyl group, such as the nicotinoyl group, a C1-3-a!kylsulphonyl-n-C1-3-alkoxy-carbonyl or C1-3-aIkoxy-C2-3-a[koxy-C1-3-alkoxy-carbonyl group, such as the 2-methylsulphonylethoxycarbonyt or 2-(2-ethoxy)-ethoxycarbony! group.
According to the invention, the novel compounds are obtained, for example, by the following processes, which are known in principle from the literature:
a. reaction of a compound of the formula
in which
the radicals Z1 and R3 may, if appropriate, change their positions,
X, R2, R3 and R6 are as defined at the outset,
R1' has the meanings mentioned at the outset for R1 or is a protective group for the
nitrogen atom of the lactam group, where R1 may also, if appropriate, represent a
bond, formed via a spacer, to a solid phase,
and Z1 is a halogen atom, a hydroxyl, alkoxy or arylalkoxy group, for example a
chlorine or bromine atom, a methoxy, ethoxy or benzyloxy group,
with an amine of the formula
(Formula Removed)
which
R4 and R5 are defined as mentioned at the outset,
and, if required, the product is subsequently cleaved from a protective group used for the nitrogen atom of the lactam group or from a solid phase.
Suitable protective groups for the nitrogen atom of the lactam group are, for example, an acetyl, benzoyl, ethoxycarbonyl, tert-butyloxycarbonyl or benzyloxycarbonyl group and
suitable solid phases are a resin, such as a 4-(2',4'-dimethoxyphenylaminomethyl)-phenoxy resin, where the attachment is expediently via the amino group, or a p-benzyloxybenzyl alcohol resin, where the attachment is expediently via a spacer, such as a 215-dimethoxy-4-hydroxybenzyl derivative.
The reaction is expediently carried out in a solvent, such as dimethylformamide, toluene, acetonitrile, tetrahydrofuran, dimethyl sulphoxide, methylene chloride or a mixture thereof, if appropriate in the presence of an inert base, such as triethylamine, N-ethyldiisopropylamine or sodium bicarbonate, at temperatures between 20 and 175°C, where any protective groups used may be simultaneously removed owing to transamidation.
If, in a compound of the formula V, Z1 is a halogen atom, the reaction is preferably carried out in the presence of an inert base at temperatures between 20 and 120°C.
If, in a compound of the formula V, Z1 is a hydroxyl, alkoxy or arylalkoxy group, the reaction is preferably carried out at temperatures between 20 and 200°C.
The subsequent removal of a protective group used, which may be required, If appropriate, is expediently carried oat either hydrolytically in an aqueous or alcoholic
solvent, for example in methanol/water, ethanol/water, isopropanol/water, tetrahydrofuran/water, dioxane/water, dimethylformamide/water, methanol orethanol, in the presence of an alkali metal base, such as lithium hydroxide, sodium hydroxide or potassium hydroxide, at temperatures between 0 and 100DC, 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.
Cleavage from a solid phase employed is preferably carried out using trifluoroacetic acid and water at temperatures between 0 and 35°C, preferably at room temperature.
b. To prepare a compound of the formula I in which R3 is a phenyl or naphthyl group substituted by a carboxy-C2-3-a!kenyl, aminocarbonyI-C2-3-alkenyl, (C1-3-alkylamino)-carbonyl-C2.3-alkenyl, dKC1-3alkylamino)-carbonyl-C2-3-alkenyl or C1-3-alkoxy-carbonyl-C1-3-alkenyi group,
reaction of a compound of the formula
(Formula Removed)
which R2, R4, R5, R6 and X are as defined at the outset,
R1' has the meanings mentioned at the outset for R1 or is a protective group for the nitrogen atom of the lactam group, where R1' may also, if appropriate, represent a bond, formed via a spacer, to a solid phase, and
Z3 is a leaving group, for example a halogen atom or an alkyi- or arylsulpnonylcxy group, such as a chlorine, bromine or iodine atom or a methylsulphonyloxy, ethylsulphonyloxy, p-toluenesulphonyloxy or trifluoromethanesulphonyloxy group, with an alkene of the formula
(Formula Removed)
in which
R3' is an amino, (C1-3alky!amino), di-{C1-3-alky]amino) or C1-3-alkoxy group and n is the number 0 or 1.
The reaction is expediently carried out with palladium catalysis, using, for example, palladium(ll) acetate, palladium(ll) chloride, bis(triphenylphosphine)palladium(ll) acetate, bis(triphenylphosphine)palladium(ll) chloride, palladium/carbon, bis-[1,2-bls(diphenylphosphino)ethane]pa!ladium(0), dichloro-(1,2-bis(diphenylphosphino)-ethane)palladium(Jl), tetrakistriphenyiphosphinepalladium(O), tris(dibenzylidene-acetone)dipalladium(O), 1,1'-bis(diphenylphosphino)ferrocenedichloropalladium(ll)or tris(dibenzylideneacetone)dipalladium(0)/chloroform adduct, in the presence of a base, such as triethylamine, diisopropylethylamine, lithium carbonate, potassium carbonate, sodium carbonate, caesium carbonate, and a ligand, such as triphenylphosphine, tri-ortho-tolylphosphine or tri-(tert-butyl)phosphine, in solvents such as acetonitrile, N-methylpyrrolidinone, dioxane or dimethylformamide and mixtures thereof.
The cleavage of a protective group used for the nitrogen atoms of the lactam group or from a solid phase, which may be required, if appropriate, is carried out as described above under process (a).

c. To prepare a compound of the formula I in which R3 is a phenyl or naphthyl group substituted by
a carboxy-C1-3-alkyl, C1-3-aikoxy-carbonyl-C1-3-alkyl, aminocarbonyl-C1-3-aIkyl,
(C1-3-alkylamino)-carbonyl-C1-3-alkyl or di-(C1
group,
hydrogenation of a compound of the formulain which
R2, R4, R5, R6 and X are as defined at the outset,
R1> has the meanings mentioned at the outset for R1 or is a protective group for the
nitrogen atom of the lactam group, where R1 may also, if appropriate, represent a
bond, formed via a spacer, to a solid phase,
A is a C1-3-alkenyl group and
R3 is a hydroxyl, C1-3-alkoxy, amino, (C1-3-alkylamino) or dKC1-3-alkyOamino group.
The hydrogenation is preferably carried out using catalytic hydrogenation with hydrogen in the presence of a catalyst, such as palladium/carbon or platinum, in a solvent, such as methanol, ethanol, ethyl acetate, dimethylformamide, dimethylformamide/acetone or glacial acetic acid, if appropriate with addition of an acid, such as hydrochloric 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 3 to 5 bar.
The cleavage of a protective group used for the nitrogen atom of the lactafn group or from a solid phase, which may be required, if appropriate, is carried out as described under process (a).
If, according to the invention, a compound of the formula I is obtained which contains an alkoxycarbonyl group, this can be converted by hydrolysis into a corresponding carboxyi compound, or
if a compound of the formula I is obtained which contains an amino or alkyfemino group, this can be converted by reduction alkylation into a corresponding alkylamino or dialkylamino compound, or
if a compound of the formula I is obtained which contains a dialkylamino group, this can be converted by alkylation into a corresponding trialkylammonium compound, or
if a compound of the formula I is obtained which contains an amino or alkylamino group, this can be converted by acylation or sulphonation into a corresponding acyl or sulphonyl compound, respectively, or
if a compound of the formula I is obtained which contains a carboxyi group, this can be converted by esterification or amidation into a corresponding ester or aminocarbonyl compound, respectively, or
if a compound of the formula I is obtained which contains a nitro group, this can be converted by reduction into a corresponding amino compound, or
if a compound of the formula I is obtained which contains a cyano group, this can be converted by reduction into a corresponding aminomethyl compound, or
if a compound of the formula I is obtained which contains an arylalkyloxy group, this can be converted with acid into a corresponding hydroxyl compound, or
if a compound of the formula I is obtained which contains an alkoxycarbony! group, this can be converted by hydrolysis into a corresponding carboxyl compound; or
if a compound of the formula I is obtained in which R4 is a phenyl group substituted by an amino, alkylamino, aminoalkyl or N-alkylamino group, this can then be converted by reaction with a corresponding cyanate, isocyanate or carbamoyi halide into a corresponding urea compound of the formula I, or
if a compound of the formula I is obtained in which R4 is a phenyl group substituted by an amino, alkylamino, aminoalkyl or N-alkylamino group, this can subsequently be converted by reaction with a corresponding amidino-group-transferring compound or by reaction with a corresponding nitrile into a corresponding guanidino compound of the formula I.
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 sulphuric acid, or in the presence of an alkali metal base, such as lithium hydroxide, sodium hydroxide or potassium hydroxide, at tempefares between 0 and 100°C, preferably at temperatures between TO 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, tetrahy^drofuran, dioxane or dimethylformamide, if appropriate with addition of an acid, such as hydrochloric acid, in the presence of catalytically activated hydrogen, for example bfhydrogen in thepresence of Rahey nTckeT,"pIatinum or palladium/carbon, or in the presence of a metal hydride, such as sodium borohydride, lithium borohydride, sodium cyanoborohydride or lithium aluminium hydride, at
temperatures between 0 and 100°C, preferably at temperatures between 20 and 80°C.
The subsequent aikyiation is preferably carried out in a suitabie solvent, such as ether, tetrahydrofuran, dioxane, dichloromethane, acetone or acetonitrile, in the presence of alky!ating agents, such as alkyl iodides, alkyl bromides, alky! chlorides, methanesulphonic acid alkyl esters, para-toluenesulphonic acid alkyi esters or alkyl trifluoroacetates, at temperatures between 0 and 100°Cr preferably at temperatures between 20 and 60°C,
The subsequent acylation or sulphonylation is expediently carried out using the corresponding free acid or a corresponding reactive compound, such as its anhydride, ester, imidazolide or halide, preferably in a solvent, such as methylene chJoride, diethyl ether, tetrahydrofuran, toluene, dioxane, acetonitrife, dimethyl sulphoxide or dimethylformamide, rf appropriate in the presence of an inorganic or a tertiary organic base, at temperatures between -20 and 200°C, preferably at temperatures between 20°C and the boiling point of the solvent used. The reaction with the free acid can, if appropriate, be carried out in the presence of an agent which activates the acid or of a dehydrating agent, for example in the presence of isobutyl chloroformate, tetraethyl orthocarbonate, trimethy! orthoacetate, 2,2-dimethoxypropane, tetramethoxysilane, thionyl chloride, trimethylchlorosiiane, phosphorus trichloride, phosphorus pentoxide, N,N'-dicydohexy!carbodiimide, N.N'-dicyclohexylcarbodiimide/N-hydroxysuccinimide, N,N'-dicycIohexyl-carbodiimide/1-hydroxybenzotriazole, 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate, 2-(1 H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate/1 -hydroxybenzotriazole, N.N'-carbonyldiimidazole or triphenylphosphine/carbon tetrachloride, and, if appropriate, with addition of a base, such as pyridine, 4-dimethylaminopyridine, N-methylmorpholine or triethylamine, expediently at temperatures between 0 and 150°C, preferably at temperatures between 0 and'TOTTC. The reaction with a corresponding reactive compound can, if appropriate, be carried out in the presence of a tertiary organic base, such as triethylamine, N-ethyl-diisopropylamine,
4
N-methylmorpholine or pyridine, or, if an anhydride is used, in the presence of the
(Formula Removed)
corresponding acids, at temperatures between 0 and 150°C, preferably at temperatures between 50 and 100°C.
The subsequent esterification or amia'ation is expediently carried out by reacting a reactive corresponding carboxylic acid derivative with an appropriate alcohol or amine, as described above.
The esterification or amidation is preferably carried out in a solvent, such as methylene chloride, diethyi ether, tetrahydrofuran, toluene, dioxane, acetonitrile, dimethyl sulphoxide or dimethylformamide, if appropriate in the presence of an inorganic or a tertiary organic base, preferably at temperatures between 20°C and the boiting point of the solvent used. Here, the reaction with a corresponding acid is preferably carried out in the presence of a dehydrating agent, for example in the presence of isobutyl chioroformate, tetraethyl orthocarbonate, trimethyl orthoacetate, 2,2-dimethoxypropane, tetramethoxysilane, thionyl chloride, trimethylchlorosilane, phosphorus trichloride, phosphorus pentoxide, N.N'-dicyclohexylcarbodiimide, N,N'-dicyclohexylcarbodiimide/N-hydroxysuccinimide, N,N'-dicyclohexylcarbodi-imide/1 -hydroxybenzotriazole, 2-(1 H-benzotriazoM -yl)-1,1,3,3-tetramethyluronium-tetrafluoroborate, 2-(1H-benzotriazol-1-y!)-1,1,3,3-tetramethyfuronium tetraf!uoroborate/1-hydroxybenzotriazole, N,N'-carbonyldiimidazole or triphenyl-phosphine/carbon tetrachloride, and, if appropriate, with addition of a base, such as pyridine, 4-dimethyIaminopyridine, N-methylmorpholine or triethyiamine, expediently 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, is, if appropriate, carried out in the presence of a tertiary organic base, such triethyiamine, N-ethyldiisopropylamine or N-methylmorpholine, at temperatures between Oand 150°C, preferably at temperatures between 50 and 10CTC.
The subsequent reduction of a nitro group is preferably earned out hydrogenoiytically, for example 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, if
appropriate with addition of an add, 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 from 1 to 7 bar, but preferably from 3 to 5 bar.
The subsequent hydrogenation of a cyano group is preferably carried out hydrogenolytically, for example using hydrogen in the presence of a catalyst, such as palladium/carbon or Raney nickel, in a solvent, such as methanol, ethanol, ethyl acetate, methylene chloride, dimethylformamide, dimethylformamide/acetone or glacial acetic acid, if appropriate with 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 from 1 to 7 bar, but preferably of from 3 to 5 bar.
The subsequent preparation of a corresponding guanidino compound of the formula I is expediently carried out by reaction with an amidino-group-transferring compound, such as 3,5-dimethylpyrazole-1-carboxamidine, preferably in a solvent, such as dimethylformamide, and, if appropriate, in the presence of a tertiary organic base, such as triethylamine, at temperatures between 0 and 50°C, preferably at room temperature.
In the reactions described above, any reactive groups present, such as carboxyl, hydroxyl, amino, alkylamino or imino groups, can be protected during the reaction by customary protective groups which are removed again after the reaction,
A protective radical for a carboxyl group is, for example, the trimethylsilyl, methyl, ethyl, tert-butyl, benzyl or tetrahydropyranyl group, and
a protective group for a hydroxyl, amino, alkylamino or imino group is, for example, the acetyl, trifluoroacetyl, benzoyl, ethoxycarbonyl, tert-butoxycarbonyl, benzyloxycarbonyl, benzyl, methoxybenzyl or 2,4-d!rriethoxy6enzyI group, and, for the amino group> additionally the phthalyl group.
The subsequent removal of a protective radical used is, if appropriate, carried out, for example, hydrolytically in an aqueous solvent, for example in water, isopropanol/water, tetrahydrofuran/water or dioxane/water, in the presence of an acid, such as trifluoroacetic acid, hydrochloric acid or sulphuric acid, or in tha presence of an alkali metal base, such as lithium hydroxide, sodium hydroxide or potassium hydroxide, at temperatures between 0 and 100°C, preferably at temperatures between 10 and 50°C.
However, a benzyl, methoxybenzyl or benzyloxycarbonyl radical is removed, for example, hydrogenolytically, for example using hydrogen in the presence of a catalyst, such as palladium/carbon, in a solvent such as methanol, ethanol, ethyl acetate, dimethyiformamide, dimethylformamide/acetone or glacial acetic acid, if appropriate with 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 from 1 to 7 bar, but preferably of from 3 to 5 bar.
A methoxybenzyl group can also be removed in the presence of an oxidizing agent, such as cerium(IV) ammonium nitrate, in a solvent, such as methylene chloride, acetonitrile oracetonitrile/water, at temperatures between 0 and 50°C, but preferably at room temperature.
However, a 2,4-dimethoxybenzy! radical is preferably removed in trifluoroacetic acid in the presence of anisole.
A tert-butyf or tert-butyloxycarbonyl radical is preferably removed by treatment with an acid, such as trifluoroacetic acid or hydrochloric acid, using, if appropriate, a solvent, such as methylene chloride, dioxane, ethyl acetate or ether.
A phthalyl radical is preferably removed in the presence of hydrazine or a primary arriine, such as methylamine, ethylamine or n-butylamine, in arsolvent," such"as" methanol, ethanol, isopropanol, toluene/water or dioxane, at temperatures between 20 and 50°C.
Furthermore, chiral compounds of the formula I obtained can be separated into their enantiomers and/or diastereomers.
Thus, for example, compounds of the formula I obtained which occur as racemates can be separated by methods known per se (see Allinger N. L. and Elie! E. L. in "Topics in Stereochemistry", Vol. 6, Wiley Interscience, 1971) into their enantiomers, and compounds of the formula I having at least 2 asymmetric carbon atoms can, owing to their physicochemical differences, be separated by methods known per se, for example by chromatography and/or fractional crystallization, into their diastereomers, which, if they are obtained in racemicform, can then be separated into the enantiomers as mentioned above.
The separation of enantiomers is preferably carried out by column separation on chiral phases or by recrystallization from an optically active solvent or by reaction with an optically active substance which forms salts or derivatives, such as, for example, esters or amides, with the racemic compound, in particular acids and their activated derivatives or alcohols, and separating the mixture of diastereomeric salts or derivatives obtained in this manner, for example owing to different solubilities, whereupon the free enantiomers can be released from the pure diastereomeric salts or derivatives by action of suitable agents. Particularly common optically active acids are, for example, the D and L forms of tartaric acid, dibenzoyltartaric acid, di-o-tolyltartaric acid, malic acid, mandelic acid, camphorsulphonic acid, glutamic acid, N-acety!glutamic acid, aspartic acid, N-acetylaspartic acid or quinic acid. A suitable optically active alcohol is, for example, (+)- or (-)-menthol, and a suitable optically active acyl radical in amides is, 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 acceptable salts, with inorganic or organic acids. Acids suitable for this purpose are, for example, hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid, fumaric acid, succinic acid, lactic acid, citric acid, tartaric acid, maleic acid, methanesulphonic acid,
ethanesulphonic acid, para-toluenesulphonio acid, phenylsulphonlc acid or L-(+)-mandelic acid.
Moreover, the resulting novel compounds of the formula ! can, if they contain a carboxyl group, then, if desired, be converted into their salts with inorganic or organic bases, in particular, for pharmaceutical use, into their physiologically acceptable salts. Bases suitable for this purpose are, for example, sodium hydroxide, potassium hydroxide, cyclohexylamine, ethanolamine, diethanolamine and triethanolamine.
Also suitable, for compounds of the formula I which contain 2 or more acidic or basic groups, are salts with 2 or more inorganic or organic bases or acids (disalts etc.).
Some of the compounds of the general formulae V to XI used as starting materials 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. Compounds of the general formula IX, for example, are described in the German patent application 19844 003.
As already mentioned at the outset, the novel compounds of the formula (I) have useful pharmacological properties, in particular in inhibiting action on various kinases, especially on receptor tyrosine kinases, such as VEGFR1, VEGFR2, VEGFR3, PDGFRot, PDGFRp, FGFR1, FGFR3, EGFR, HER2, c-Kit, IGFIRand HGFR, Flt-3, and on the proliferation of cultivated human cells, in particular that of endothelial cells, for example in angiogenesis, but also on the proliferation of other cells, in particular of tumour cells.
The biological properties of the novel compounds were examined by the following standard methods:
Human umbilical cord endothelial cells (HUVEC) were cultivated in IMDM (Gibco BRL), supplemented with 10% foetal bovine serum (FBS) (Sigma), 50 pM B-mercaptoethanol (Fluka), standard antibiotics, 15 ug/ml of endothefial cell growth
factor (EGGS, Collaborative Biornedical Products) and 100 ug/ml of heparin (Sigma) on gelatin-coated culture bottles (0.2 % gelatin, Sigma) at 37°C, 5% CO2, in an atmosphere saturated with water.
To examine the inhibitory activity of the compounds according to the invention, the cells were "starved" for 16 hours, i.e. kept in culture medium without growth factors (EGGS + heparin). Using trypsin/EDTA, the cells were detached from the culture bottles and washed once with serum-containing medium. 2.5 x 103 cells were then seeded in each well.
The proliferation of the cells was stimulated using 5 ng/ml of VEGF-|65 (vascular endothelial growth factor; H. Weich, GBF Brunswick) and 10 ug/ml of heparin. Per plate, as control value, in each case 6 wells were not stimulated.
The compounds according to the invention were dissolved in 100% dimethyl sulphoxide and, in triplicate, added to the cultures in different dilutions, the maximum dimethyl sulphoxide concentration being 0.3%.
The cells were incubated at 37°C for 76 hours, and 3H-thymidine (0.1 u Ci/well, Amersham) was then added for a further 16 hours to determine DMA synthesis. The radioactively labelled celte were then immobilized on filter mats and the incorporated radioactivity was determined in a p counter. To determine the inhibitory activity of the compounds according to the invention, the mean value for the non-stimulated cells was subtracted from the mean value of the factor-stimulated cells (in the presence or absence of the compounds according to the invention).
The relative cell proliferation was calculated in percent of the control (HUVEC without inhibitor), and the concentration of active compound at which the proliferation of the cells is inhibited by 50% (lC5Owas derived therefrom.
The compounds of the formula I according to the invention have an IC50 between 50µM and 1 nM.
Owing to their inhibitory action on the proliferation of cells, in particular of endothelian cells and of tumour cells, the compounds of the formula I are suitable for treating diseases in which the proliferation of ceils, in particular that of endothelial ceils, plays a role.
Thus, for example, the proliferation of endothelial cells and the related neovascularization is a decisive step in tumour progression (Folkman J. et al., Nature 339. 58-61, (1989); Hanahan D. and Folkman J., Cell 86, 353-365, (1996)). Furthermore, the proliferation of endothelial cells is also of importance in haemangiomes, in metastasization, in rheumatoid arthritis, in psoriasis and in ocular neovascularization (Folkman J., Nature Med. 1, 27-31, (1995); Carmeliet P & Rakeh J., Nature 407, 249-257, (2000)). The therapeutic benefit of inhibitors of endothelial cell proliferation in the animal model was shown, for example, by O'Reilly et al. and Parangiet al. (O'Reilly M.S. et al., Cell 88, 277-285, (1997); Parangi S. et al., Proc Natl Acad Sci USA 93, 2002-2007, (1996)).
Thus, the compounds of the formula I, their tautomers, their stereoisomers or their physiologically acceptable salts are suitable, for example, for treating tumours (for example squamous epithelium carcinoma, astrocytoma, Kaposi sarcoma, glioblastoma, lung cancer, cancer of the bladder, neck carcinoma, oesophagus carcinoma, melanoma, ovarial carcinoma, prostate carcinoma, breast cancer, small-ceil lung carcinoma, glioma, colorectal carcinoma, pancreas carcinoma, urogenital cancer and gastrointestinal carcinoma, and also haematological cancers, such as, for example, multiple myeloma and acute myelotic leukaemia), psoriasis, arthritis (for example rheumatoid arthritis), haemangioma, angiofibroma, disorders of the eye (for example diabetic retinopathy), neovascular glaucoma, disorders of the kidneys (for example glomerulonephritis), diabetic nephropathy, malignant nephrosclerosis, thrombic microangiopathic syndromes, transplantation rejections and glomerulopathy, fibrotic disorders (for example cirrhosis of the liver), mesarigfal-celt proliferate disorders, atherosclerosis, injuries of the nerve tissue and for inhibiting the reocclusion of vessels after balloon catheter treatment, in vessel prosthetics or
after implantation of mechanical devices for keeping vessels open (for example stents) or other disorders in which cell proliferation or angiogenesis play a rote.
Owing to their biological properties, the compounds according to the invention can b« used alone or in combination with other pharmacologically active compounds, for example in tumour therapy in monotherapy or in combination with other antitumor therapeutics, for example in combination with topoisomerase inhibitors (for example etoposide), mitosis inhibitors (for example vinblastine, Taxol), compounds which interact with nucleic acids (for example cisplatin, cyclophosphamide, adriamycin), hormone antagonists (for example tamoxifen), steroids and analogues thereof (for example dexamethasone), inhibitors of metabolic processes (for example 5-FU etc.), cytokines (for example interferons), kinase inhibitors (for example EGFR kinase inhibitoren, such as, for example, Iressa; Gleevec), allosterically acting receptor tyrosine kinase inhibitors, antibodies (for example Herceptin), COX-2 inhibitors or else in combination with radiotherapy, etc. These combinations can be administered either simultaneously or sequentially.
The invention is illustrated in more detail by the examples below:

(Table Removed)
breviations used:
HOBt = 1 -hydroxy-1 H-benzotriazole
TBTU = O-benzotriazol-l-yi-N.N.N'.N'-tetramethyluronium tetrafluoroborate
Preparation of the starting materials: Example I:
Dimethyl 2-(4-fluoro-2-nitrophenvl)malonate
With ice-cooling, 185 g of potassium ferf-butoxide are added to a solution of 188 ml of dimethyl malonate in 970 ml of N-methylpyrrolidone, and the mixture is stirred for 2 hours. Over a period of 30 minutes, 150 ml of 2,5-difluoronitrobenzene are added dropwise to the resulting slurry, and the mixture is then, stirred at 85°C for 6 hours. The mixture is poured into 4 liters of ice-water and 250 ml of concentrated hydrochloric acid and extracted with 2 liters of ethyl acatate. The organic phase is dried with sodium sulphate and concentrated. The oily residue is triturated twice with water and then taken up in 600 ml of ethyl acetate. The solution is dried with sodium sulphate and concentrated to dryness. The resulting crude product is recrystallized from 600 ml of ethyl acetate/hexane = 2:8 and dried. Yield: 222 g (59% of theory) Rf value: 0.40 (silica gel, cyclohexane/ethyl acetate = 5:1)
Mass spectrum: m/z = 270 [M-H]~
The following compounds are prepared analogously to Example
(1.1) Diethyl 2-(4-bromo-2-nitrophenyl)malonate
from 2,5-dibrorrionitrobenzene and diethyl malonate
Rf value: 0.40 (silica gel, petroleum ether/ethyl acetate = 5:1)
Mass spectrum: m/z = 359/361 [M]+
(1. 2) Dimethyl 2-(4-cyano-2-nitrophenyl)malonate
from 4-chloro-3-nitrobenzonitriIe and dimethyl maionate
Rf value: 0.50 (silica gel, methylene chloride/methanol = 50:1)
Mass spectrum: m/z = 277 [M-H]~ Example II:
Methyl 4-cyano-2-nitrophenylacetate
14.2 g of dimethyl 2-(4-cyano-2-nitrophenyl)malonate (starting material 1.2) are
dissolved in 200 ml of dimethyl sulphbxide, and 4.5 g of lithium chloride and 1 .0 ml of
water are added. The solution is stirred at 100°C for 3.5 hours, 300 ml of ice-water
are then added and the mixture is allowed to stand for 12 hours. The resulting
precipitate is filtered off with suction, taken up in methylene chloride and washed with
water. The organic phase is dried over sodium sulphate, concentrated using a rotary
evaporator and dried.
Yield: 7.7 g (68% of theory)
Rf value: 0.40 (silica gel, methylene chloride/methanol) = 50:1
C10H8N2O4
Mass spectrum: m/z = 219 [M-H]~
Example III:
4-Fluoro-2-nitrophenvlaceticacid
At 100°C, 50.0 g of dimethyl 2-(4-fluoro-2-nitrophenyl)malonate (starting material I)
are stirred in 400 ml of 6 molar hydrochloric acid for 20 hours, 400 ml of water are
then added and the mixture is cooled to 0°C. The resulting precipitate is filtered off
with suction, washed with water and 100 ml of petroleum ether ana anea.
Yield: 34.5 g (94% of theory)
Rf value: 0.30 (silica gel, cyclohexane/ethyl acetate) = 5:2
Mass spectrum: m/z =154 [M-COO-H]'
Example IV:
6-Fluoro-2-indolinone
With addition of 20 g of palladium on activated carbon (10%), 119 g of 4-fluoro-2-
nitrophenylacetic acid (starting material III) are hydrogenated in 600 ml of acetic acid
under a hydrogen pressure of 50 psi. The catalyst is filtered off with suction and the
solvent is distilled off. The crude product is triturated with 500 ml of petroleum ether,
filtered off with suction, washed with water and dried.
Yield: 82.5 g (91 % of theory) .
Rf value: 0.30 (silica gel, petroleum ether/ethyl acetate =1:1)
C8H6FNO
Mass spectrum: m/z =150 [M-H]~
The following compounds are prepared analogously to Example IV:
(IV.1) 6-Brbmo-2-indolinone
from diethyl 2-(4-bromo-2-nitrophenyl)malonate (starting material 1.1) using Raney
nickel as hydrogenatlon catalyst
Rf value: 0.45 (silica gel, petroleum ether/ethyl acetate =1:1)
C8H6BrNO
Mass spectrum: m/z = 210/212 [M-H]"
(IV.2) 6-Cyano-2-indolinone
from methyl 4-cyano-2-nitrophenylacetate (starting material II) using
palladium/calcium carbonate as hydrogenation catalyst
Rf value: 0.45 (silica gel, methylene chloride/methanol = 9:1)
C9H6N2O
Mass spectrum: m/z =157 [M-H]"
Example V:
1.-acetvl-6-fluoro-2-indoiihone
At 130°C, 82.5 g of 6-fluoro-2-indolinone (starting material IV) are stirred in 180 m!
acetic anhydride for 3 hours. After cooiing to room temperature, the precipitate is
filtered off with suction, washed with 100 ml of petroleum ether and dried.
Yield: 64.8 g (61 % of theory)
Rf value: 0.75 (silica gel, petroleum ether/ethyl acetate = 1:1)
C10H3FNO2
Mass spectrum: m/z = 192 [M-H]~
The following compounds are prepared analogously to Example V:
(V.1 ) 1 -acetyI-6-chloro-2-indolinone
from 6-chloro-2-indolinone and acetic anhydride
Rf value: 0.55 (silica gel, petroleum ether/ethyl acetate = 2:3)
Mass spectrum: m/z = 208/210 [M-H]~
(V.2) 1-acetyl-6-bromo-2-indolinone
from 6-bromo-2-indolinone (starting material IV. 1) and acetic anhydride
Rf value: 0.60 (silica gel, petroleum ether/ethyl acetate = 2:1)
C10H8BrNO2
Mass spectrum: m/z = 253/255 [M]+
(V.3) 1 -acetyl-6-cyano-2-indo[inone
from 6-cyano-2-indolinone (starting material IV.2) and acetic anhydride
Rf value: 0.60 (silica gel, methylene chloride/methanol = 50:1)
Mass spectrum: m/z =199 [M-H]~
Example VI:
1-acetvl-3-f1-hvdroxv-1-f3-iodophenvl)methylene1-6-chloro-2-indolfnone
10.5 g of 1-aeetyl-6-chloro-2-indolinone (starting material V.1), 13.6 g of
3-iodobenzoic acid and 17.7 g of TBTU are initially charged in 100ml of
dimethylformamide, 35 ml of triethylamine are added and the mixture is stirred at
room temperature for 12 hours. After this time, the solvent is removed under reduced
pressure, water is added to the residue and the residue is filtered off with suction,
washed with a little water, methanol and ether and dried at 100°C under reduced
pressure.
Yield: 12.9 g (59 % of theory)
Rf value: 0.80 (silica gel, methylene chloride/methanol = 9:1)
Ci7HiiCIINO3
Mass spectrum: m/z = 438/440 [M-H]'
The following compounds are prepared analogously to Example Vt
(VI. 1) 1 -acetyl-3-[1 -hydroxy-1 -(4-methoxycarbonyImethylphenyl)methylene]-6-fluoro-
2-indolinone
from 1-acetyl-6-fluoro-2-indolinone (starting material V) and methyl
(4-carboxyphenyl)acetate (preparation according to Tetrahedron 1997, 53, 7335-
7340)
(VI.2) 1-acetyl-3-[1-hydroxy-1-(4-chlorophenyl)methylene]-6-chIoro-2-indolihone from 1-acetyl-6-chloro-2-indolinone (starting material V.1) and 4-chlorobenzoic acid
(VI.3) 1-acetyl-3-[1-hydroxy-1-(3,4-dimethoxyphenyl)methylene]-6-chloro-2-
indolinone
from 1-acetyl-6-chloro-2-indolinone (starting material V.1) and 3,4-dimethoxybenzoic
acid
(VI .4) 1-acetyl-3-[1-hydroxy-1-(3,4-dimethoxyphenyI)methylene>€-cyano-2-
indolinone
from 1-acetyl-6-cyano-2-indolinone (starting material V.3) and 3,4-dimethoxybenzoic

(VI.5) 1-acetyl-3-[1-hydroxy-1-(3-fluorophenyl)methylene]-6-fIuoro-2-indolinone from 1-acetyl-6-fluoro-2-indolinone (starting material V) and 3-fluorobenzoic acid
(V1.6) 1 -acetyl-3-[1 -hydroxy-1 -(4^(2-acetyIaminoethyl)phenyl)methy iene]-6-fluoro-2-
indolinone
from 1-acetyl-6-fluoro-2-indolinone (starting material V) and 4-(2-acetylaminoethyl)-
benzoic acid (preparation according to J. Am. Chem. Soc. 1943, 65, 2377)
(VI.7) 1-acetyl-3-[1-hydroxy-1-(3-methoxycarbonylmethylphenyl)methylene]-6-fluoro-
2-indolinone
from 1-acetyl-6-fluoro-2-indolinone (starting material V) and ii.dthyl
(3-carboxyphenyl)acetate (preparation analogously to Tetrahedron 1997, 53, 7335-
7340)
(VI.8) 1-acetyl-3-[1 -hydroxy-1 -(3-(N-tert-butoxycarbonylaminomethyl)phenyl)-
methylene]-6-fluoro-2-indolinone
from 1-acetyl-6-fluoro-2-indolinone (starting material V) and 3-(N-tert-butoxycarbonyl-
aminomethyl)benzoic acid (preparation according to Tetrahedron 1997, 53, 7335-
7340)
(VI.9) 1-acetyl-3-[1-hydroxy-1-(3-cyanomethylphenyl)methylene]-6-fluoro-2-
indolinone
from 1-acetyl-6-fluoro-2-indolinone (starting material V) and (3-carboxyphenyl)-
acetonitrile (preparation according to J. Prakt. Chem. 1998, 340, 367-374)
(VI.10) 1-acetyl-3-[1-hydroxy-1-(4-(N-tert-butoxycarbonylaminomethyl)phenyl)-
methylene]-6-fluoro-2-indolinone
from 1-acetyl-6-fluoro-2-indolinone (starting material V) and 4-(N-tert-butoxycarbonyl-
aminomethyl)benzoic acid (preparation according to Bioorg. Med. Chem. Lett 2000,
10,553-557)
(VL11) 1-acetyl-3-[1-hydroxy-1-(4-iodophenyl)methyIene]-6-fluoro-2-indolinone
from 1-acetyl-6-fluoro-2-indolinone (starting material V) and 4-iodobenzoic acid
(VI.12) 1-acetyl-3-[1-hydroxy-1-(4-iodophenyI)methylene]-6-chloro-2-indolinone
from 1-acetyl-6-chloro-2-indolinone (starting material V.1) and 4-iodobenzoic acid
(VI. 13) 1-acetyl-3-[1-hydroxy-1-(3-iodophenyl)methyIene]-6-fluoro-2-indolinone
from 1-acetyl-6-fluoro-2-indolinone (starting material V) and 3-iodobenzoic acid
(VI.14) 1-acetyl-3-[1-hydroxy-1-(4-(2-methoxycarbonylethyl)phenyl)methylene]-6-
fluoro-2-indolinone
from 1-acetyl-6-fluoro-2-indolinone (starting material V) and 4-(2-
methoxycarbonylethyl)benzoic acid (preparation analogously to Tetrahedron 1997,
53, 7335-7340)
(VI. 15) 1-acetyl-3-[1-hydroxy-1-(3-(2-methoxycarbonylethyl)phenyl)methyIene]-6-
fluoro-2-indolinone
from 1-acetyl-6-fluoro-2-indolinone (starting material V) and 3-(2-
methoxycarbonylethyl)benzoic acid (preparation analogously to Tetrahedron 1997,
53, 7335-7340)
(VI. 16) 1 -acetyl-3-[1 -hydroxy-1-(3-(N-tert-butoxycarbonyl-2-
aminoethyl)phenyl)methylene]-6-fluoro-2-indolinone
from 1-acetyl-6-fluoro-2-indolinone (starting material V) and 3-(N-tert-butoxycarbonyl-
2-aminoethyl)benzoic acid (preparation analogously to Bioorg. Med. Chem. Lett
2000, 10, 553-557)
(VI. 17) 1 -acetyl-3-[1 -hydroxy-1 -(4-(N-tert-butoxycarbonyl-2-
aminoethyI)phenyl)methylene]-6-fluoro-2-indolinone
from 1-acetyl-6-fluoro-2-indorinone (starting material V) and 4-(N-tert-butoxycarbonyl-
2-aminoethyl)benzoic acid (preparation analogously to Bioorg. Med. Chem. Lett
2000, 10, 553-557)
(VI. 18) 1-acetyl-3-[1-hydroxy-1-(4-cyanophenyl)methylene]-6-chloro-2-
indolinone
from 1-acetyI-6-chloro-2-indolinone (starting material V.1) and 4-cyanobenzoic acid
(VI. 19) 1 -acetyl-3-[1 -hydroxy-1 -(3-acetylaminomethylphenyl)rnethy lene]-6-
fluoro-2-indoliiione
from 1-acetyI-6-fluoro-2-indolinone (starting material V) and 3-acetylaminomethyi-
benzoic acid (prepared according to J. Med. Chem. 1997, 40, 4030-4052)
(VI .20) 1 -acetyl-3-[1 -hydroxy-1 -(3-(2-ethoxycarbonylethyl)phenyI)methylene]-6-f luoro-
2-indolinone
from 1-acetyl-6-fluoro-2-indolinone (starting material V) and 3-(2-
ethoxycarbonylethyl)benzoic acid (preparation analogously to Tetrahedron 1997, 53,
7335-7340)
(VI.21) 1-acetyl-3-[1 -hydroxy-1 -(4-(2-methoxycarbonylethyl)phenyl)methylene]-6-
chloro-2-indolinone
from 1-acetyl-6-chloro-2-indolinone (starting material V.1) and 4-(2-
methoxycarbonylethyl)benzoic acid (preparation analogously to Tetrahedron 1997,
53, 7335-7340)
(VI.22) 1-acetyl-3-[1 -hydroxy-1 -(4-(2-ethoxycarbonylethyl)phenyl)rnethylene]-6-fluoro-
2-indolinone
from 1-acetyl-6-fIuoro-2-indolinone (starting material V) and 4-(2-
ethoxycarbonylethyl)benzoic acid (preparation analogously to Tetrahedron 1997, 53,
7335-7340)
(VI.23) 1 -acetyl-3-[1 -hydroxy-1 -(3-methoxycarbonylmethyloxy-phenyl)rnethylene]-6-
fluoro-2-indolinone
from 1-acetyI-6-fluoro-2-indolinone (starting material V) and
3-methoxycarbonylmethyloxybenzoic acid (preparation see Tetrahedron Letters
1998, 39, 8563-8566)
(VI.24) 1 -acetyI-3-[1 -hydroxy-1 -(4-methoxycarbonylmethyloxyphenyI)methyIene]-6-
-i
fluoro-2-indolinone

from 1-acetyl-6-fluoro-2-indolinone (starting material V) and 4-methoxycarbonylmethyloxybenzoic acid (preparation analogously to Tetrahedron Letters 1998, 39, 8563-8566)
(VI. 25) 1-aceiyi-3-[1-hydroxy-1-(3-(2-ethoxycarbonyiethy!oxy)phenyl)methyIene]-6-
fIuoro-2-indolinone
from 1-acetyl-6-fluoro-2-indolinone (starting material V) and 3-(2-
eth6xyearbonylethyloxy)benzoic acid (preparation see PCT Int. Appl. WO9620173,
60)
(VI.26) 1-acetyl-3-[1-hydroxy-1-(4-(2-ethoxycarbonyIethyloxy)phenyl)methylene]-6-
fluoro-2-indolinone
from 1-acetyl-6-fluoro-2-indolinone (starting material V) and 4-(2-
ethoxycarbonylethyloxy)benzoicacid (preparation see PCT Int. Appl. WO9620173,
58)
(VI.27) 1-acetyl-3-[1-hydroxy-1-(4-(2-methoxycarbonylethyl)phenyI)methylene]-6-
bromo-2-indolinone
from 1-acetyl-6-bromo-2-indoIinone (starting material V.2) and 4-(2-
methoxycarbonylethyl)-benzoic acid (preparation analogously to Tetrahedron 1997,
53, 7335-7340)
Example VII:
1-acetvl-3-f1-methoxy-1-(3-iodophenyl)methylene]-6-chloro-2-indolinone A little at a time, 2.36 g of trimethyloxonium tetrafluoroborate are added to a solution of 3.52 g of 1-acetyl-3-[i-hydroxy-1-(3-iodophenyI)methylene]-6-chloro-2-indolinone (starting material VI) and 2.72 ml of ethyldiisopropylamine in 80 ml of dichioromethane, and the mixture is stirred at room temperature for one hour. Another 1.4 ml of ethyldiisopropylamine and 1.2 g of trimethyloxonium tetrafluoroborate are added, and the mixture is stirred at room temperature for another two hours. The mixture is then extracted with water and the organic phase is

dried over magnesium sulphate and evaporated to dryness. The residue is
recrystallized from ether and dried at 80°C under reduced pressure.
Yield: 2.40 g (66 % of theory)
Rf value: 0.60 (silica gel, petroleum ether/a'ichioromethane/ethyi acetate = 5:4:1)
C18H13CIIN03
Mass spectrum: m/z = 438/440 [M-H]~
m.p. 185-187 °C
The following compounds are prepared analogously to Example VII:
(VI 1.1) 1 -acetyl-3-[1 -methoxy-1 -(4-methoxycarbonylmethylphenyl)methylene]-6-
fluoro-2-indolinone
from 1 -acetyl-3-[1 -hydroxy-1 -(4-methoxycarbonylmethylphenyl)methylene]-6-fluoro-2-
indolinone (starting material VI.1)
(VII.2) 1-acetyl-3-[1 -methoxy-1 -(4-chlorophenyl)methylene]-6-chloro-2-indolinone from 1-acetyl-3-[1 -hydroxy-1 -(4-chlorophenyl)methylene]-6-chloro-2-indolinone (starting material VI .2)
(VII. 3) 1 -acetyl-3-[1 -methoxy-1 -(3,4-dimethoxyphenyl)methylene]-6-chioro-2-
indolinone
from 1-acetyl-3-[1-hydroxy-1-(3,4-dimethoxyphenyl)methylene]-6-chloro-2-indolinone
(starting material VI.3)
(VII.4) 1-acetyl-3-[1-methoxy-1-(3,4-dimethoxyphenyI)methylene]-6-cyano-2-
indolinone
from 1 -acetyl-3-[1 -hydroxy-1 -(3,4-dimethoxyphenyl)-methylene]-6-cyano-2-indolinone
(starting material VI.4)
(VII.5) 1-acetyl-3-[1 -methoxy-1 -(3-fluorophenyI)methylene]-6-fIuoro-2-ihd6linone
from1-acetyl-3-[1-hydroxy-1-(3-fIuorophenyl)methyIene]-6-fluoro-2-indolinone
/
(starting material VI.5)

(VII.6) 1 -acetyl-3-[1 -methoxy-1-(4-(2-acetyIaminoethyl)phenyl)methylene]-6-fluoro-2-
indolinone
from 1 -acetyl-3-[1 -hydroxy-1-(4-(2-acetylaminoethyl)phenyl)methylene]-6-fluoro-2-
indolinone (starting material VI.6)
(VII.7) 1-acetyl-3-[1-methoxy-1-(3-methoxycarbonylmethylphehyl)methylene]-6-
fluoro-2-indolinone
from 1-acetyl-3-[1-hydroxy-1-(3-methoxycarbonylmethylphenyl)methylene]-6-fluoro-2-
indolinone (starting material VI .7)
(VII.8) 1-acetyl-3-[1-methoxy-1-(3-(N-tert-butoxycarbonylaminomethyl)phenyl)-
methylene]-6-fluoro-2-indolinone
from 1 -acetyl-3-[1 -hydroxy-1 -(3-(N-tert-butoxycarbonyl-
aminomethyl)phenyl)methylene]-6-ffuoro-2-indolinone (starting material VI.8)
(VII.9) 1-acetyl-3-[1-methoxy-1-(3-cyanomethylphenyl)methylene]-6-fluoro-2-
indolinone
from 1-acetyl-3-[1 -hydroxy-1 -(3-cyanomethylphenyl)methylene]-6-fluoro-2-indolinone
(starting material VI.9)
(VII.10) 1-acetyl-3-[1-methoxy-1-(4-(N-tert-butoxycarbonyl-aminomethyl)phenyl)methylene]-6-fluoro-2-indolinone from 1 -acetyl-3-[1 -hydroxy-1 -(4-(N-tert-butoxycarbonyl-aminomethyl)phenyl)methylene]-6-fluoro-2-indolinone (starting material VI.10)
(VI1.11) 1 -acetyl-3-[1 -methoxy-1 -(4-iodophenyl)methylene]-6-fluoro-2-indoli none from 1-aoetyl-3-[1-hydroxy-1-(4-iodophenyl)methylene]-6-fluoro-2-indolinone (starting material VI. 11)
(VII .12) 1 -acetyl-3-[1 -methoxy-1 -(4-iodophenyl)methylene]-6-chroro-2-
indolinone
from 1-acetyl-3-[1-hydroxy-1-(4-iodophenyl)methylene]-6-chloro-2-indolinone
(starting material VI. 12)

(VII. 13) 1-acetyl-3-[1-methoxy-1-(3-iodophenyl)methyIene]-6-fIuoro-2-indolinone from 1-acetyl-3-[1-hydroxy-1-(3-iodophenyl)methylene]-6-fIuoro-2-indolinone (starting material VI. 13)
1-acetyJ-3-[1-methoxy-1-(3-(2-methoxycarbonylethy!)phenyl)methylene]-6-fluoro-2-indolinone
from 1-acetyl-3-[1-hydroxy-1-(3-(2-methoxycarbony!ethyl)phenyl)methyIene]-6-fluoro-2-indo!inone (starting material VI. 14)
(VII. 15) 1-acetyl-3-[1-methoxy-1-(4-(2-methoxycarbonyIethyI)phenyl)methyIene]-
6-fluoro-2-indolinone
from 1 -acetyl-3-[1 -hydroxy-1 -(4-(2-methoxycarbonylethyl)phenyl)methylene]-6-fluoro-
2-indolinone (starting material VI. 15)
(VII. 1 6) 1-acetyl-3-[1-methoxy-1-(4-(N-tert-butoxycarbonyl-2-aminoethyl)phenyl)methylene]-6-fluoro-2-indolihone from 1 -acetyl-3-[1 -hydroxy-1 -(4-(N-tert-butoxycarbonyl-2-aminoethyl)phenyOmethylene]-6-fluoro-2-indolinone (starting material VI. 17)
(VII. 17) 1-acety]-3-[1-methoxy-1-(3-(N-tert-butoxycarbonyI-2-aminoethyl)phenyl)methylene]-6-fluoro-2-indolinone from 1 -acety!-3-[ 1 -hydroxy-1 -(3-(N-tert-butoxycarbony!-2-aminoethyl)phenyl)methylene]-6-fluoro-2-indolinone (starting material VI. 16)
(VII. 18) 1-acetyl-3-[1-methoxy-1-(3-acetylaminomethylphenyl)methylene]-6-
fluoro-2-indoIinone
from 1-acetyl-3-[1-hydroxy-1-(3-acetylaminomethylphenyl)methylene]-6-fluoro-2-
indolinone (starting material VI. 19)
(VII. 19) 1-acetyl-3-[1-methoxy-1-(3-(2-ethoxycarbonylethyl)phenyl)methylene]-6-fluoro-2-indolinone

from 1 -acetyl-3-[1 -hydroxy-1 -(3-(2-ethoxycarbonylethyl)phenyl)methylene]-6-fluoro-2-indolinone (starting material VI.20)
(Vli.20) . 1-acetyl-3-[1-methoxy-1-(4-(2-methoxycarbonylethyl)pheny])methyiene]-
6-chloro-2-indolinone
from 1-acetyl-3-[1-hydr6xy-1-(4-(2-methoxycarbony!ethyl)phenyl)methylene]-6-chloro-
2-indolinone (starting material VI.21)
(VII.21) 1-acety[-3-[1-methoxy-1-(4-(2-ethoxycarbonylethyl)phenyl)methyIene]-
6-f!uoro-2-indolinone
from 1 -acetyl-3-[1 -hydroxy-1 -(4-(2-ethoxycarbony!ethyl)phenyl)methylene]-6-fluoro-2-
indolinone (starting material VI.22)
(VII.22) 1-acetyl-3-[1-methoxy-1-(4-methoxycarbonylmethyloxyphenyl)-
methylene]-6-fluoro-2-indolinone
from 1-acetyl-3-[1 -hydroxy-1 -(4-methoxycarbonylmethyloxyphenyl)methylene]-6-
fluoro-2-indolinone (starting material VI.23)
(VII.23) 1 -acetyl-3-[1 -methoxy-1 -(3-methoxycarbonylmethy[oxyphenyl)-
methylene]-6-fluoro-2-indolinone
from 1-acetyl-3-[1-hydroxy-1-(3-methoxycarbonylmethyloxypheny[)methylene]-6-
fluoro-2-indolinone (starting material VI.24)
(VII.24) 1-acetyl-3-[1-methoxy-1-(3-(2-
ethoxycarbonylethyloxy)phenyl)methylene]-6-fluoro-2-indolinone
from 1-acetyl-3-[1-hydroxy-1-(3-(2-ethoxycarbonylethyloxy)phenyl)methylene]-6-
fluoro-2-indolinone (starting material VI.25)
(VII.25) 1-acetyl-3-[1-methoxy-1 -(4-(2-
ethoxycarbonylethyIoxy)phenyl)methyIene]-6-fluoro-2-indolinone
from 1 -acetyl-3-[1 -hydroxy-1 -(4-(2-ethoxycarbonylethyldxy)phenyl)methylene]-6-
fluoro-2-indolinone (starting material VI.26)

(VII.26) 1-acetyl-3-[1-methoxy-1-(4-(2-methoxycarbonylethyl)phenyl)methyIene]-
6-bromo-2-indoIinone
from 1-acetyI-3-[1-hydrpxy-1-(4-(2-methoxycarbonylethyl)phenyl)methylene]-6-
bromo-2-indolinone (starting material VI. 27)
Example VII I:
1-Acetyt-3-ri-chloro-1-(4-cvanophenvl)methylene]-6-chloro-2-indolinone
A suspension of 7.0 g of 1-acetyl-3-[1-hydroxy-1-(4-cyanpphenyl)rnethylene]-6-
chloro-2-indolinone (starting material VI. 18) and 6.39 g of phosphorus pentachloride
in 1 50 ml of dioxane is stirred at 1 00°C for 6 hours. After addition of a further 1 .0 g of
phosphorus pentachloride, the mixture is stirred at 1 10°C for another 4 hours. The
solvent is then distilled off and the residue is washed with ethyl acetate.
Yield: 4.5 g (61 % of theory)
Rf value: 0.70 (silica gel, methylene chloride/methanol = 50:1)
Example IX:
The syntheses of the following compounds have already been described in the international application WO 01/27081 :
(IX. 1) 4-(diethylaminomethyI)aniline
(IX.2) N-(2-dimethylaminoethyl)-N-methylsulphonyl-p-phenylenediamine
(IX.3) 3-(dimethylaminomethyl)aniline
(IX.4)4-(dimethylaminomethyl)aniline
(IX.5)4-(2-dimethyIaminoethyl)aniline
(lX.6)4-[N-(2-dimethylaminoethyl)-N-acetylamino]aniIine

(IX.7) 4-[N-(3-dimethylaminopropyl)-N-acetylaminoJaniline
(IX.8)4-[(N-dimethylaminocarbQny!methyl-N-methylsuiphonyi)amindjaniiine
(IX.9) N-(4-aminophenyl)-N-methylmethanesulphonamide
(IX. 10) N-(dimethylaminomethylcarbonyl)-N-methyl-p-phenylenediam!ne
(IX.11) N-[(2-dimethylaminoethyl)carbonyl]-N-methyl-p-phenylenediamine
(IX. 12) 4-(N-tert-butoxycarbonylaminomethyl)aniline
(IX. 13) 4-(N-ethyl-N-tert-butoxycarbonylaminomethyl)aniline
(IX.14)4-[(4-methylpiperazin-1-yl)methyl]aniline
(IX. 15) 4-(imidazol-1-ylmethyl)aniline
(IX. 16) 4-(1 -methylimidazoI-2-yl)aniiine
(IX.17)4-[(N-(2-dimethylaminoethyl)-N-methylamino)methyl]aniline
(IX. 18) 4-(N-methyl-N-tert-butoxycarbonylaminomethyl)aniline
(IX. 19) N-[(4-methylpiperazin-1 -yl)methylcarbonyI]-N-methyl-p-phenytenediamine
(IX.20) 4-(4-tert-butoxycarbonylpiperazin-1 -ylmethyl)aniline
(1X.21) 4-(thiomorpholin-4-ylmethyl)aniline
(IX.22)4-(pyrrolidin-1-ylmethyl)aniIine

(IX.23)4-(morphoIin-4-yl-methyl)aniline
(IX.24)4-(N-benzyl-N-methylaminomethyl)aniline
(IX.25)4-(N-ethyl-N-methyIaminomethyl)aniline
(IX.26)4-[N-(2-dimethylaminoethyl)-N-methylamino]aniline
(IX.27)4-[(N-propyl-N-methylamino)methyl]aniline
The following compounds are prepared analogously to Example IX:
(IX.28)4-[N-(2-(N-benzyl-N-methylamino)ethyl)-N-acetylamino]aniline
(IX.29)4-amino-N-(2-dimethyIaminoethyl)-N-methylbenzamide
(IX.30)4-(4-methylpiperazin-1-ylcarbonyl)aniline
(IX.31) 4-(2-dimethylaminoethoxy)aniline
(IX.32) N-(4-dimethylaminobutylcarbonyl)-N-methyl-p-phenylenediamine
(IX.33) N-[(3-dimethylaminopropyl)carbonyI]-N-methy!-p-phenylenediamine
Preparation of the end products:
Example 1.0
3-Z-f1-(4-(N-Methyl-N-rnethylsulphonylamino)anilino)-1-(3-iodophenynmethylene]-6-
chloro-2-indolinone
0.9 g of 1-acetyl-3-(1-methoxy-1-(3-iodophenyl)methylene)-6-ch!oro-2-indol!none
(starting material VII) and 0.5 g of N-methyl-N-methylsulphonyl-p-phenylenediamine
(starting material iX.9) are dissolved in 10 ml of dimethylformamide and stirred at
120°C for 3 hours. After cooling, 1 .5 ml of piperidine are added and the mixture is
stirred at room temperature for another hour. Water is added and the resulting
precipitate is filtered off with suction, washed with a little water, methanol and ether
and finally dried under reduced pressure at 100°C.
Yield: 0.9 g (74% of theory),
Rf value: 0.6 (silica gel, methylene chloride/methanol = 9:1)
m.p. 292-294 °C
Mass spectrum: m/z = 578/580 [M-H]'
The following compounds of the formula 1-1 are prepared analogously to Example 1.0:
(Table Removed)
*Eluent mixtures:
(A): silica gel, methylene chloride/methanol 9:1 (B): silica gel, methylene chloride/ethanol 10:1 (C): silica gel, methylene chloride/methanol 4:1
Example 2.0
3-Z-ri-(4-fDimethvlaminomethvl)anilino)-1-f4-cvanophenvl)methytene1-6-chloro-2-
indolinone
1.07 g of 1-acetyl-3-[1-chloro-1-(4-cyanopheny!)methy!ene]-6-chlofD-2-indolinone
(starting material VII) and 0.54 g of 4-(dimethylaminornethyl)aniline (starting material
IX.4) are dissolved in 10 ml of dimethytformamide and stirred at 80°C for 3 hours.
After cooling, 1 ml of 6N aqueous sodium hydroxide is added, and the mixture is
stirred at room temperature for 30 minutes. Water is added and the mixture is
extracted three times with methylene chloride. The combined organic phases are
washed twice with water, dried over sodium sulphate and concentrated using a rotary
evaporator, and the product is recrystallized from diethyl ether.
Yield: 0.92 g (72% of theory),
Revalue: 0.1 (silica gel, methylene chloride/methanol = 9:1)
Mass spectrum: m/z = 427/429 [M-HJ'
Example 3.0
3-Z-f1-(4-(rdimethvlaminomethvl)an!linoV1-f4-iodophenvl)methvlene1-6-fluoro-2-indolinone
3.5 g of 1-acety!-3-(1-methoxy-1-(4-iodophenyI)methylene)-6-fluoro-2-indoIinone (starting material VI!. 11) and 1.6 g of 4-(dimethylaminomethyl)anifine (starting material IX.4) are dissolved in 30 ml of dimethylformamide and stirred at 120°C for 2 hours. After cooling, the solvent is removed under reduced" pressure, the residue is taken up in 30 ml of methanol and 2 spatula tips of sodium methoxide are added. Once a yellow precipitate has formed, this is filtered off with suction from the solvent and the residue is washed with a little methanot and ether and finally dried under reduced pressure at 100°C. Yield: 1.9 g (46% of theory),
Rf value: 0.3 (silica gel, methylene chloride/methanol = 9:1) m.p. 243-246 °C
Mass spectrum: m/z = 514 [M+Hf
The following compounds of the formula l-3a are prepared analogously to Example 3.0:
(Table Removed)
Eluent mixtures:
(A): silica gel, methylene chloride/methanol 9:1
(B): silica gel, methylene chloride/methanol/ammonia 9:1:0.1
Example 4.0
3-Z-ri-(4-(Dimethvlaminomethvl)anilinoV1-(3.4-dimeth6xyphenvl)methvlene]-6-
cvano-2-indolinone
130 mg of l-acetyl-S-CI-methoxy-I^S^-dimethoxyphenyOmethyleneJ-e-cyanb^-
indolinone (starting material VII.4) and 58 mg of 4-(dimethylaminomethyl)ani|ine
{-starting- material4X,4) are dissolved in 5 ml of dimethylformamide and stirred at 80°C
for 2 hours. After cooling, the solvent is removed under reduced pressure and the
residue is purified on a silica gel column using the mobile phase methylene
chloride/methanol 9:1.
Yield: 21 mg (12% of theory),
Rf value: 0.35 (silica gel, methylene chloride/methanol = 9:1)
m.p. 265 °C
Example 5.0
3-Z-[1-(4-(N-Methvl-N-methvlsulphonvlamino)anilino)-1-(3-(2-methoxvcarbonvl-
vinyl)phenvl)methylene]-6-chloro-2-indolinone
580 mg of 3-Z-[1-(4-(N-methyl-N-methylsulphonyIamino)anilino)-1-(3-iodophenyl)-
methylene]-6-chIoro-2-indolinone (starting material 1.0) and 140 ml of methyl acrylate
are dissolved in 20 ml of acetonitrile and 11 ml of dimethylformamide, and 11 mg of
palladium(II) acetate, 2 ml of triethylamine and 30 mg of tri-ortho-tolylphosphine are
added. Under nitrogen as protective gas, the solution is stirred at 90°C for 10 hours.
After cooling, the solution is filtered through Celite, the solvent is removed under
reduced pressure and the residue is purified on a silica gel column using the mobile
phase methylene chloride/methanol 20:1 .
Yield: 450 mg (84% of theory),
Rf value: 0.30 (silica gel, toluene/ethyl acetate = 1:1)
m.p. 228-232 °C
Mass spectrum: m/z = 537/539 [M]*
The following compounds of the formula 1-5 are prepared analogously to Example 5.0:
(Table Removed)
*Eluent mixtures:
(A): silica gel, methylene chloride/methane! 5:1
(B): silica gel, methylene criloride/methanol/ammonia 9:1:0.01
Example 6.0
3-Z-F1 -(4-Dtmeth vlaminomethvlani[ino)-1 -(3-(2-methoxvcarbonvlethvnpheny[)methvlene1-6-chloro-2-indolinone 1.0 g of 3-Z-[1-(4-(dirriethylaminomethyl)anilino)-1-(3-(2-methoxycarbonyl-vinyl)pheny[)methylene]-6-chloro-2-indolinone (starting material 5.1) is dissolved in 100 ml of methanol, and 200 mg of 10 per cent palladium/carbon as catalyst are added. The mixture is then hydrogenated at room temperature and a hydrogen pressure or 50 psi for 6 hours. Aner the reaction has ended,"the cataTysTTsWered"off, the solvent is removed under reduced pressure and the residue is dried under reduced pressure at 100°C. Yield: 900 mg (90% of theory),

Rf value: 0.40 (silica gel, methylene chloride/methanol = 9:1) m.p. 160 °C
Mass spectrum: m/z = 490/492 [M+H]+
The following compounds of the formula I-6 are prepared analogously to Example 6.0:(I-6)

(Table Removed)

*EIuent mixtures:
(A): silica gel, methylene chloride/methanol 9:1
(B): silica gel, methylene chloride/methanol/ammonia 5:1:0.01
Example 7.0
3^Z-[1"f4-Dimethylaminomethylanilino)-1-(4-aminomethylphenyl)methylene]-6-chloro-
2-indoiinone
900 mg of 3-Z-[1-(4-dimethy(aminomethylanilino)-1-(4-cyanophenyl)methylene]-6-
chloro-2-indolinone (starting material 2.0) are dissolved in 20 ml of methylene
chloride and 30 ml of methanolic ammonia and, as catalyst, 200 mg of Raney nickel
are added. The mixture is then hydrogenated at room temperature and a hydrogen
pressure of 50 psi for 2 hours and 15 minutes. After the reaction has ended, the
catalyst is filtered off, the solvent is removed under reduced pressure and the residue
is washed with" a little mefhahor arid dietftyl etrTef . To liberate the base, the residue is
taken up in 1 N aqueous sodium hydroxide solution and extracted four times with
methylene chloride/methanol 9:1. The combined organic phases are washed with
water and dried over sodium sulphate. The product is washed with a little diethyl
ether and dried under reduced pressure.
Yield: 680 mg (75% of theory),
Rf value: 0.60 (silica gel, methylene chloride/methanol/ammonia = 9:1:0.1)

m.p. 21 1-214

°C

Mass spectrum: m/z = 433/435 [M+H]+
Example 8.0

3-Z-ri-(4-(N-f(4-Methvlpiperazin-1-vl')methvlcarbohvn-N-methvlamino)anilinoV1-(4-aminomethylphenyl)methvlene]-6-chloro-2-indolinone 1.39 g of 1-acetyl-3-Z-[1-(4-(N-((4-methylpiperazin-1-yl)methylcarbonyl)-N-methylamino)anilino)-1-(4-cyanophenyl)methylehe]-6-chlpro-2-indolinone are dissolved in 20 ml of methylene chloride and 30 ml of methanolic ammonia and, as catalyst, 200 mg of Raney nickel are added. The mixture is then hydrogenated at room temperature at a hydrogen pressure of 50 psi for 2 hours. After the reaction has ended, the catalyst is filtered, the solvent is removed under reduced pressure and the residue is washed with a little methanol and diethyl ether. To liberate the base, the residue is taken up in 1N aqueous sodium hydroxide solution and extracted four times with methylene chloride/methanol 9:1. The combined organic phases are washed with water and dried over sodium sulphate. The product is purified on a silica gel column using, as mobile phase, a gradient of methylene chloride and methylene chloride/methanol/ammonia 8:1:0.1. The product is washed with a little diethyl ether and dried under reduced pressure. Yield : 700 mg (54% of theory) ,
Rf value: 0.15 (silica gel, methylene chloride/methanol/ammonia = 9:1:0.1) m.p. 232-235 °C
Mass spectrum: m/z = 544/546 [M]
Example 9.0
3-Z-[1-(4-(Dimethvlaminomethyl)anilino)-1-(3-aminomethylphenyl)methylene1-6-fluoro-2-indolinone
2.72 g of 3-Z-[1-(4-(dimethylaminomethyl)anilino)-1-(3-(N-tert-butoxycarbonyl-aminomethyl)phenyl)methylene]-6-flubro-2-indolinone (starting material 3.10) are dissolved in 50 ml of methylene chloride, and 10 ml of trifluoroacetic acid are aaaea. The mixture is stirred at room temperature for 3 hours. After this time, most of the solvent is removed under reduced pressure and the residue is taken up in ethyl acetate and washed twice with 1N aqueous sodium hydroxide solution. The organic

phase is dried over sodium sulphate, the solvent is removed using a rotary
evaporator and the residue is purified on a silica gel column using the mobile phase
methylene chloride/methanol/ammonia 9:1:0.1. The product is washed with a little
diethyl ether and dried under reduced pressure.
Yield: 1.77 g (81% of theory),
Rf value: 0.25 (silica gel, methylene chloride/methanol/ammonia 9:1:0.1)
m.p. 168-175 °C
C25H25FN40
Mass spectrum: m/z = 415 [M-H]~
The following compounds of the formula I-9 are prepared analogously to Example 9.0:

(Table Removed)
*EIuent mixtures;
(A): silica gel, methylene chloride/methanol/ammonia 9:1:0.1 (B): silica gel, methylene chloride/methanol/ammonia 9:1:0.01 (C): silica gel, methylene chloride/methanol/ammonia 8:2:0.2

(D): Reversed phase RP8, methanol/sodium chloride solution(5%) = 3:2
Example 10.0
3-Z-ri-(4-Dimethvlaminomethvlanilino)-1-f3-(2-carboxvethv()phenvnmethvlene1-6-
chloro-2-indolinbne
900 mg of 3-Z-[1-(4-dimethylaminomethylanilino)-1-(3-(2-
methoxycarbonylethyl)phenyl)methylene]-6-chloro-2-indolinone (starting material 6.0)
are dissolved in 10 ml of ethanol, and 5 ml of 1N aqueous sodium hydroxide solution
are added. The mixture is stirred at room temperature for 5 hours. After cooling, 5 ml
of 1N hydrochloric acid are added. The resulting precipitate is filtered off with suction
and washed with water.
Yield: 830 mg (95% of theory),
Rf value: 0.50 (reversed phase RP8, methanol/sodium chloride solution (5%) = 4:1)
m.p. 210-215 °C
Mass spectrum: m/z = 476/478 [M+Hf
The following compounds of the formula 1-1 Oa are prepared analogously to Example 10.0:(1-1 Oa)

(Table Removed)
*Eluent mixtures:
(A): reversed phase RP8, methanol/sodium chloride solution (5%) = 4:1
(B): silica gel, methylene chloride/methanol = 8:2
(C): silica gel, methylene chloride/methanol = 5:1
(D): reversed phase RP8, methanol/sodium chloride solution (5%) = 3:2
(E): silica gel, methylene chloride/methanol = 9:1
(F): reversed phase RP8, methanol/sodium chloride solution (5%) = 7:3
(G): silica gel, methylene chloride/methanol/ammonia = 9:1:0.1
(H):-alumina,-methylene chloride/methanol = 19:1
(I): reversed phase RP8, methanol/sodium chloride solution (5%) = 4:2 (K): silica gel, petroleum ether/ethyl acetate =1:1 (M): silica gel, methylene chloride/methanol = 4:1
The following compounds of the formula 1-1 Ob are prepared analogously to Example 10.0:
(Table Removed)
*Eluent mixtures:
(A): silica gel, methylene chloride/methanol = 5:1
(B): silica gel, methylene chloride/methanol = 9:1
(C): reversed phase RP8, methanol/sodium chloride solution (5%) = 4:1
Example 11.0
3-Z-ri-(4-Dimethvlaminomethvlanilino)-1-(3-(2-carbamovlethyl)phenvl)methylene]-6-
chloro-2-indolinone
480 mg of 3-Z-[1-(4-dimethylaminomethylanilino)-1-(3-(2-
carboxyethyl)phenyl)methylene]-6-chloro-2-indoIinone (starting material 10.0),
350 mg of TBTU, 150 mg of HOBt and 420 ml of triethylamine are dissolved in 10 ml
of dimethylformamide, and 620 mg of N-hydroxysuccinimide ammonium salt are
added. The mixture is stirred at room temperature for 20 hours. After removal of the
solvent under reduced pressure, the residue is suspended in a little ethyl acetate and
water, filtered off and washed with water. The residue is purified on an alumina
column (activity 2-3) using the mobile phase methylehe chloride/ethanol 20:1. The
product is recrystallized from diethyl ether and dried under reduced pressure at
100°C.
Yield: 370 mg (78% of theory),
Rf value: 0.40 (alumina, methylene chloride/ethanol = 20:1)
m.p. 222-225 °C
Mass spectrum: m/z = 475/477 [M+Hf
The following compounds of the formula 1-1 1 are prepared analogously to Example 11.0:

(Table Removed)
*Eluent mixtures:
(A): silica gel, methylene chloride/methanol/ammonia = 5:1:0.01
(B): alumina, methylene chloride/ethanol = 20:1
(C): silica gel, methylene chloride/methanol/ammonia = 9:1:0.1
(D): silica gel, methylene chloride/methanol/ammonia = 6:1:0.1
(E): silica gel, methylene chloride/methanol/ammonia = 5:1:0.1
(F): silica gel, methylene chloride/methanol/ammonia - 7:1:0.1
(G): silica gel, methylene chloride/methanol = 9:1

using methylammonium chloride as base equivalent * using dirriethylammonium chloride as base equivalent ** using piperidine hydrochloride as base equivalent
Example 12.0
3-Z-[1-(4-Dimethylaminomethylanilino)-1-('4-acetylaminomethvlphenyl)methylene1-6-
chloro-2-indolinone
100 mg of 3-Z-[1-(4-dimethylaminomethylanilino)-1-(4-aminomethylphenyl)-
methylene]-6-chloro-2-indolinone (starting material 7.0) are dissolved in 5 ml of
methylene chloride and 5 ml of pyridine, and 20 ul of acetyl chloride are added at
0°C. The mixture is stirred at 0°C for 10 minutes and at room temperature for a
further 4~hours. Another 20 ul of acetyl chloride are then added, and the mixture is
stirred at room temperature for 12 hours. After this time, the solvent is removed
under reduced pressure and the residue is taken up in methylene chloride and
washed with water. The aqueous phase is extracted twice with methylene chloride
and the combined organic phases are dried over sodium sulphate. The solvent is
removed using a rotary evaporator and the residue is washed with ether.
Yield: 51 mg (47% of theory),
Rf value: 0.30 (silica gel, methyierie chloride/methanolAartimonia = 9: 1 :ff.
m.p. 21 9-220 °C
Mass spectrum: m/z = 473/475 [M-H]~
The following compounds of the formula 1-12 are prepared analogously to Example 12.0:
(Table Removed)
*Eluent mixtures:
(A): silica gel, methylene chloride/ethanol/ammonia = 20:1:0.01
(B): silica gel, methylene chloride/methanol/ammonia = 9:1:0.01
(C): alumina, methylene chloride/methanol =19:1
(D): silica gel, methylene chloride/methanol/ammonia = 9:1:0.1
(E): silica gel, methylene chloride/methanol/ammonia = 8:2:0.2
(F): alumina, methylene chloride/methanol = 9:1
Alternatively, the following acylating agents were used:
benzoyl chloride, propionyl chloride, phenylacetyl chloride, cyclopropanecarbonyl chloride, cyclobutanecarbonyl chloride, pyridm-2-ylcarbonyl chloride, pyridin-3-ylcarbonyl chloride, pyridin-4-ylcarbonyl chloride, cyclohexylcarbdnyl chloride, isobutyryl chloride, 3-methylbutyryl chloride, cyclohexylmethylcarbonyl chloride, methoxyacetyl chloride, 2-methoxybenzoyl chloride, tert-butylacetyl chloride, thiophene-2-carbonyI chloride, pivaloyl chloride, 2-furoyl chloride
Example 13.0
3-Z-ri-(4-Trimethvlammoniummethvlanilino)-1-(4-(2-carboxvethvnphenvnmethvlene1-
6-fluoro-2-indolinone iodide
200 mg of 3-Z-[1-(4-dimethylaminomethylanilino)-1-(4-(2-
carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone (starting material 10.1) are
dissolved in 40 ml of acetone, and 250 ml of methyl iodide are added. The mixture is
stirred at room temperature for 20 hours. After this time, the resulting residue is
filtered off with suction. The product is dried at 80°C under reduced pressure.
Yield: 200 mg (83% of theory),
Rf value: 0.50 (reversed phase RP8, methanol/sodium chloride solution (5%) = 4:1)
m.p.210°C
Mass spectrum: m/z = 474 [M+H]+
The following compound of the formula 1-13 is prepared analogously to Example 13.0:

(Table Removed)
*Eluent mixture:
(A): reversed phase RP8, methanol/sodium chloride solution (5%) = 4:1
Example 14.0
3-Z-f1-(4-Guanidinomethylanilino)-1-(4-(2-carboxvethYl)phenvnmethylene]-6-fluoro-2-indolinone iodide
170 mg of 3-Z-[1-(4-aminomethyIanilino)-1 -(4-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone (starting material 10.50) are dissolved in 20 ml of tetrahydrofuran, and 390 mg of 3,5-dimethylpyrazole-1-carboxamidine nitrate and 330 ml of diethylisopropylamine are added. The mixture is stirred under reflux for 10 hours. After this time, the solvent is concentrated, water is added and the resulting residue is filtered off with suction. The product is dried at 80°C. Yield: 150 mg (81% of theory),
Rf value: 0.40 (silica gel, methylene chloride/methanol/acetic acid = 5:1:0.1) m.p. 290 °C
Mass spectrum: m/z = 474 [M+H]*
The following compound of the formula 1-14 is prepared analogously to Example 14.0:
(Table Removed)
*Eluent mixture:
(A): reversed phase RP8, methanol/sodium chloride solution (5%) = 4:1
Example 15

Dry vial with 75 mg of active compound per 10 ml
Composition:
Active compound 75.0 mg
Mannitol 50.0 mg
Water for injection ad 10.0 ml
Preparation:
Active compound and mannitol were dissolved in water. After filling, the product is freeze-dried. The ready-to-use solution is obtained by dissolving the product in Water for injection.
Example 16
Dry vial with 35 mg of active compound per 2 ml
Composition:
Active compound 35,0 mg
Mannitol 100,0mg
Water for injection ad 2.0 ml
Preparation:
Active compound and mannitol were dissolved in water. After filling, the product is freeze-dried. The ready-to-use solution is obtained by dissolving the product in water for injection.
Example 17

Tablet with 50 mg of active compound
Composition:
(1) Active compound 50.0 mg
(2) Lactose 98.0 mg
(3) Maize starch 50.0 mg
(4) Polyvinylpyrroiidone 15.0mg
(5) Magnesium stearate 2.0 mq
215.0 mg
Preparation:
(1), (2) and (3) are mixed and granulated using an aqueous solution of (4). (5) is
added to the dried granules. From this mixture, biplanar tablets having a facet on
both sides and being partially scored on one side are pressed.
Diameter of the tablets: 9 mm.
Example 18
Tablet with 350 mg of active compound
Composition:
(1) Active compound 350.0 mg
(2) Lactose 136.0mg
(3) Maize starch 80.0 mg
(4) Polyvinylpyrroiidone 30.0 mg
(5) Magnesium stearate 4.0mq
600.0 mq
Preparation:

123
(1), (2) and (3) are mixed and granulated using an aqueous solution of (4). (5) is added to the dried granules. From this mixture, biplanar tablets having a facet on both sides and being partially scored on one side are pressed. Diameter of the tablets: 12 mm.
Example 19
Capsules with 50 mg of active compound
Composition:
(1) Active compound 50.0mg
(2) Maize starch, dried 58.0 mg
(3) Lactose, powaerea 50.0 mg.
(4) Magnesium stearate 2.0 mg
160.0j7ig
Preparation:
(1) is ground with (3). This ground material is, with vigorous mixing, added to the
mixture of (2) and (4).
This powder mixture is, in a capsule filling machine, filled into hard gelatin capsules
size 3.
Example 20
Capsules with 350 mg of active compound
Composition:,
(1) Active compound 350.0 mg
(2) Maize starch, dried 46.0 mg
(3> Lactose, powdered 30.0 mg.
(4) Magnesium stearate 4.0 mg

430.0 mg
Preparation:
(1) is ground with (3). This ground material is, with vigorous mixing, added to the
mixture of (2) and (4).
This powder mixture is, in a capsule filling machine, filled into hard gelatin capsules size 0.
Example 21
Suppositories with 100 mg of active compound
1 suppository contains:
Active cojTippund 100-Omg
Polyethylene glycol (MW 1500) 600.0 mg
Polyethylene glycol (MW 6000) 460.0 mg
Polyethylene sorbitan monostearate 840.0 mg
2 000.0 mg
Preparation:
The polyethylene glycol is melted together with polyethylene sorbitan monostearate. At 40°C, the ground active substance is homogeneously dispersed in the melt. The melt is cooled to 38°C and poured into slightly pre-cooled suppository moulds.
Analogously-to the examples above, it is possible to prepare the following compounds:
(1) 3-Z-[1-(4-(N-(2-dimethylaminoethyl)-N-methylsulphonylamino)anilino)-1-(4-(2-carboxyethyl)phenyI)methylene]-6-chloro-2-indolinone

(2) 3-Z-[1-(4-(N-(dimethyIaminomethylcarbonyl)-N-methyfamino)aniIino)-1-(4-(2-
carboxyethyl)phenyI)methylene]-6-chloro-2-indolinone (3)3-Z-[1-(4-(N-(2-dimethyIaminoethyl)-N-acetyIamino)anilino)-1-(4-(2-
carboxyethyl)phenyl)methyIene]-6-chbro-2-indolinone (4)3-Z-[1-(4-(N-(2-methyIaminoethyl)-N-acetylamino)anifino)-1-(4-(2-
carboxyethyl)phenyl)methylene]-6-chloro-2-indolinone
(5) 3-Z-[1-(4-(N-(3-dimethylaminopropyl)-N-acety!amino)anilino)-1-(4-(2-
carboxyethyl)phenyl)methylene]-6-chloro-2-indo!inone
(6) 3-Z-[1-(4-(N-(3-methylaminopropyl)-N-acetylamino)anilino)-1-(4-(2-
carboxyethyl)phenyl)methylene]-6-chloro-2-indolinone
(7) 3-Z-[1-(4-(3-dimethylaminopropyl)anilino)-1-(4-(2-caiboxyethyl)phenyl)methylene]-
6-chloro-2-indolinone
(8) 3-Z-[1-(4-ethylaminomethylanilino)-1-(4-(2-carboxyetfiyl)phenyl)methylene]-6-
chloro-2-indoIinone
(9) 3-Z-[1-(4-methylaminomethylanilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-
chloro-2-indolinone

(10) 3-Z-[1 -(4-(N-(4-methylpiperazin-1 -ylmethylcarbonyl)-N-methylamino)anilino)-1 -
(4-(2-carboxyethyl)phenyl)methylene]-6-chloro-2-indolinone
(11) 3-Z-[1 -(4-(4-methylpiperazin-1-ylcarbonyl)anilino)-1-(4-(2-
carboxyethyl)phenyl)methylene]-6-chloro-2-indolinone
(12) 3-Z-[1 -(4-(N-(3-dimethyIaminopropyl)-N-methylsi^)honylamino)aniHrio)-1 -(4-
(2-carboxyethyl)phenyl)methylene]-6-chloro-2-indofinone
(13) 3-Z-[1 -(4-(N-(2-dimethylaminoethyl)-N-propylsulfrfionylamino)ani!ino)-1 -(4-(2-
carboxyethyl)phenyl)methylene]-6-chloro-2-indormone
(14) 3-Z-[1-(4-aminomethylanilino)-1-(4-(2-carboxyetftyl)phenyl)methylene]-6-
chloro-2-indolinone
(15) 3-Z-[1-(3-(methylaminomethyI)anilino)-1-(4-(2-
carboxyethyI)phenyI)methylene]-6-chloro-2-indoIinone
r 16) 3-Z-M -f 3-(2-dimethy!aminoethyl)anilino)-1 -(4-(2-
carboxyethyl)phenyl)methylene]-6-chloro-2-indolinone (17) 3-Z-[1-(3-(3-dimethylaminopropyl)anilino)-1-(4-(2-
carboxyethyl)phenyl)methylene]-6-chlofo-2-indolinone

(18) 3-Z-[1-(4-(N-(dimethylamino-carbonylmethyl)-N-
methyIsulphonylamino)aniIino)-1-(4-(2-carboxyethy[)phenyl)methylene]-6-ch!oro-2-indoIinone
(19) 3-Z-[1-(4-(N-methyl-N-methyIsuIphonylamino)aniIino)-1-(4-(2-
carboxyethyl)phenyl)methylene]-6-chloro-2-indolinone
(20) 3-Z-[1-(4-(N-methyl-N-acetylamino)anilino)-1-(4-(2-
carboxyethyl)phenyl)methylene]-6-chIoro-2-indolinone
(21) 3-Z-[1-(4-(N-(N-(2-dimethylaminoethyl)-N-methylaminomethy!carbonyl)-N-
methylamino)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-chloro-2-
indolinone
(22) 3-Z-[1-(4-(2-diethylaminoethylsulphonyl)anilino)-1-(4-(2-
carboxyethyl)phenyl)methylene]-6-chloro-2-indolinone
(23) 3-Z-[1-(4-(N-(2-dimethylaminoethyl-carbonyl)-N-methylamino)aniiino)-1-(4-(2-
carboxyethyl)phenyl)methylene]-6-chIoro-2-indolinone
(24) 3-Z-[1 -(4-(N-(2-dimethylaminoethyl)-N-methylaminomethyl)anilino)-1 -(4-(2-
carboxyethyI)phenyl)methylene]-6-chloro-2-indolinone
(25) 3-Z-[1 -(4-(2-dimethylaminoethoxy)anilino)-1 -(4-(2-
carboxyethyl)phenyl)methylene]-6-chl6ro-2-indolmone
(26) 3-Z-[1 -(4-(N-(4-dimethylaminobutylcarbonyl)-N-methylamino)anilino)-1 -(4-(2-
carboxyethyI)phenyl)methylene]-6-chloro-2-indolinone
(27) 3-Z-[1-(4-(N-(3-dimethylaminopropylcarbonyl)-N-methylarnino)anilino)-1-(4:(2-
carboxyethyl)phenyl)methylene]-6-chloro-2-indolinone
(28) 3-Z-[1 -(4-(methylethylaminomethyl)aniIino)-1 -(4-(2-
carboxyethyl)phenyl)methylene]-6-chloro-2-indolinone
(29) 3-Z-[1 -(4-(methylpropylaminomethyl)anilino)-1 -(4-(2-
carboxyethyl)phenyl)methylene]-6-chloro-2-indoIinone
(30) 3-Z-[1-(4-(methylbenzylaminomethyl)aniIino)-1-(4-(2-
carboxyethyI)phenyl)methylene]-6-chlorp-2-indolinone
(31) 3-Z-[1-(4-(N-(2-dimethylamjnoethyI)-N-methyIaminomethy[)anilino)-1-(4-(2-
carboxyethyl)phenylmethylene]-6-chloro-2-indoIinone
(32) 3-Z-[1 -(4-(azetidin-1 -y Imethyl)anilino)-1 -(4-(2-carboxyethyl)phenyl)methylenej-
6-chloro-2-indoIinone

(33) 3-Z-[1-(4-((4-methylpiperazin-1-yl)methyl)anilino)-1-(4-(2-
carboxyethyl)phenyl)methylene]-6-chloro-2-indolinone
(34) 3-Z-[1-(4-(piperazin-1-yImethyl)anilino)-1-(4-(2-
carboxyethyl)phenyl)methylene]-6-chloro-2-indolinone
(35) 3-Z-[1-(4-(morpholin-4-ylmethyl)anilino)-1-(4-(2-
carboxyethyl)phenyl)methylene]-6-chloro-2-indolinone
(36) 3-Z-[1-(4-(thiomorpho!in-4-ylmethyl)ani!ino)-1-(4-(2-
carboxyethyl)phenyl)methylene]-6-ch!oro-2-indo!inone
(37) 3-Z-[1-(4-(imidazol-1-ylmethyl)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-
6-chloro-2-indoIinone
(38) 3-Z-[1-(4-(N-(2-dimethylaminoethyl)-N-methylsulphonylamino)anilino)-1-(3-(2-
carboxyethyl)phenyl)methylene]-6-chloro-2-indolinone
(39) 3-Z-[1-(4-(N-(dimethylaminomethylcarbonyl)-N-methylamino)anilino)-1-(3-(2-
carboxyethyI)phenyl)methylene]-6-chloro-2-indolinone
(40) 3-Z-[1-(4-(N-(2-dimethylaminoethyl)-N-acetylamino)anilino)-1-(3-(2-
carboxyethyl)phenyl)methylene]-6-chroro-2-indolinone
(41) 3-Z-[1-(4-(N-(2-methylaminoethyl)-N-acetylamino)anilino)-1-(3-(2-
carboxyethyl)phenyl)methylene]-6-chloro-2-indolinone
(42) 3-Z-[1-(4-(N-(3-dimethylaminopropyl)-N-acetylamino)anilino)-1-(3-(2-
carboxyethyI)phenyl)methylene]-6-chloro-2-iridolinone
(43) 3-Z-[1-(4-(N-(3-methylaminopropyl)-N-acetylamino)anilino)-1-(3-(2-
carboxyethyl)phenyl)methylene]-6-chloro-2-indolinone
(44) 3-Z-[1 -(4-(3-dimethylaminopropyI)anilino)-1 -(3-(2-
carboxyethyl)phenyl)methylene]-6-chloro-2-indolinone
(45) 3-Z-[1 -(4-ethylaminomethylanilino)-1 -(3-(2-carboxyethyl)phenyl)methylene]-6-
chIoro-2-indolinone
(46) 3-Z-[1 -(4-methylaminomethylaniIino)-1 -(3-(2-carboxyethyl)phenyl)methylene]-
6-chloro-2-indolinone
(47) 3-Z-[1-(4-(N-(4-methyIpiperazin-1-ylinethylcarbonyl)-N-methylamino)anilino)-1-
(3-(2-carboxyethyl)phenyl)methylene]-6-chloro-2-indolinone
(48) 3-Z-[1 -(4-(4-methylpiperazin-1 -ylcarbony[)anilino)-1 -(3-(2-
carboxyethyl)phenyl)methylene]-6-chloro-2-indolinone

(49) 3-Z-[1-(4-(N-(3-dimethylaminopropyl)-N-methyIsulphonylamino)anilino)-1-(3-
(2-carboxyethyl)phenyl)methylene]-6-chloro-2-indolinone
(50) 3-Z-[1-(4-(N-(2-dimethylaminoethyI)-N-propyIsulphonylamino)anilino)-1 -(3-(2-
carboxyethyl)phenyl)methylene]-6-chloro-2-indolinone
(51) 3-Z-[1-(4-aminomethylaniliho)-1-(3-(2-carboxyethyl)phenyl)methyIene]-6-
chloro-2-indolinone
(52) 3-Z-[1-(3-(dimethylaminomethyl)aniiino)-1-(3-(2-
carboxyethyl)phenyl)methyIene]-6-ch!oro-2-indo!inone
(53) 3-Z-[1-(3-(methylaminomethyl)anilino)-1-(3-(2-
carboxyethyl)phenyl)methylene]-6-chloro-2-indolinone
(54) 3-Z-[1-(3-(2-dimethylaminoethyl)anilino)-1-(3-(2-
carboxyethyl)phenyl)methylene]-6-chloro-2-indolinone
(55) 3-Z-[1 -(3-(3-dimethylaminopropyl)anilino)-1 -(3-(2-
carboxyethyl)phenyl)methylene]-6-chloro-2-indolinone
(56) 3-Z-[1-(4-(2-dimethylaminoethyl)anilino)-1-(3-(2-
carboxyethyl)phenyl)methylene]-6-chloro-2-indQlinone
(57) 3-Z-[1-(4-(N-(dimethylaminocarbonylmethyI)-N-methylsulphonyIamino)anilino)-
1-(3-(2-carboxyethyl)phenyl)methylene]-6-chloro-2-indolinone
(58) 3-Z-[1 -(4-(N-methyl-N-methylsulphonylamino)anilino)-1 -(3-(2-
carboxyethyl)phenyl)methylene]-6-chloro-2-indolinone
(59) 3-Z-[1 -(4-(N-methyl-N-acetylamino)anilino)-1 -(3-(2-
carboxyethyl)phenyl)methylene]-6-chloro-2-indolinone
(60) 3-Z-[1-(4-(1-methylimidazol-2-yl)anilino)-1 -(3-(2-
carboxyethyl)phenyl)methylene]-6-chloro-2-indolinone
(61) 3-Z-[1-(4-(N-(N-(2-dimethylaminoethyl)-N-methylaminomethylcarbonyl)-N-
methylamino)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene]-6-chloro-2-
indolinone
(62) 3-Z-[1 -(4-(2-diethylaminoethylsuIphonyl)anilino)-1 -(3-(2-
carboxvethyl)phenyl)methyIene]-6-chloro-2-indolinone
(63) 3-Z-[1-(4-(N-(2-dimethylaminoethylcarbonyl)-N-methylamino)anilino)-1-(3-(2-
carboxyethyl)phenyl)methylene]-6-chloro-2-indolinone
(64) 3-Z-[1-(4-(N-(2-dimethyIaminoethyl)-N-methy!aminomethyl)anilino)-1-(3-(2-
carboxyethyI)phenyl)methylene]-6-chloro-2-indolinone

(65) 3-Z-[1 -(4-(2-dimethylaminoethoxy)anilino)-1 -(3-(2-
carboxyethyl)phenyI)methylene]-6-chloro-2-indolinone
(66) 3-Z-[1-(4-(N-(4-dimethylaminobutylcarbonyl)-N-methylamino)aniIino)-1-(3-(2-
carboxyethyl)phenyl)methylene]-6-chloro-2-indolinone
(67) 3-Z-[1-(4-(N-(3-dimethylaminopropylcarbonyl)-^4-methylamino)anilino)-1-(3-(2-
carboxyethyl)phenyl)methylene]-6-chloro-2-indolinone
(68) 3-Z-[1-(4-(methylethylaminomethyl)ani!ino)-1-(3-(2-
carboxyethyl)phenyl)methy!ene]-6-ch!oro-2-indolinone
(69) 3-Z-[1-(4-(methylpropylaminomethyl)anilino)-1-(3-(2-
carboxyethyl)phenyl)methylene]-6-chloro-2-indolinone
(70) 3-Z-[1-(4-(methylbenzylaminomethyl)anilino)-1-(3-(2-
carboxyethyl)phenyl)methylene]-6-chloro-2-indolinone
(71) 3-Z-[1 -(4-(diethylaminomethyl)anilino)-1 -(3-(2-carboxyethyl)phenyl)methylene]-
6-chloro-2-indolinone
(72) 3-Z-[1 -(4-(N-(2-dimethylaminoethyl)-N-methylaminomethyl)anilino)-1 -(3-(2-
carboxyethyl)phenylmethylene]-6-chloro-2-indolinone
(73) 3-Z-[1 -(4-(pyrrolidin-1-ylmethyl)anilino)-1-(3-(2-
carboxyethyl)phenyl)methylene]-6-chloro-2-indolinone
(74) 3-Z-[1 -(4-(azetidin-1 -ylmethyl)anilino)-1 -(3-(2-carboxyethyl)phenyl)methylene]-
6-chloro-2-indolinone
(75) 3-Z-[1 -(4-((4-methylpiperazin-1 -yl)methyl)anilino)-1 -(3-(2-
carboxyethyl)phenyl)methylene]-6-chloro-2-indolinone
(76) 3-Z-[1 -(4-(piperazin-1 -ylmethyl)anilino)-1 -(3-(2-
carboxyethyI)phenyl)methylehe]-6-chloro-2-indolinone
(77) 3-Z-[1 -(4-(morpholin-4-ylmethyl)aniIino)-1-(3-(2-
carboxyethyl)phenyl)methylene]-6-chloro-2-indolinone
(78) 3-Z-[1 -(4-(thiomorpholin-4-ylmethyl)anilino)-1 -(3-(2-
carboxyethyl)phenyl)methylene]-6-chloro-2-indo!inone
(79) 3-Z-[1-(4-(imidazol-1-ylmethyi)anilino)-1-(3-(2-carboxyethyI)phenyl)methyienej-
6-chloro-2-indolinone
(80) 3-Z-[1-(4-(N-(2-methylaminoethyI)-N-acetylamino)anilino)-1-(4-(2-
carboxyethyl)phenyI)methylene]-6-fluoro-2-indoIinone

(81) 3-Z-[1-(4-(N-(3-methyIaminopropyl)-N-acetylamino)anilino)-i-(4-(2-
carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone
(82) 3-Z-[1-(4-(3-dimethylaminopropyl)anilino)-1-(4-(2-
carboxyethyl)phenyl)methylene]-6-fIuoro-2-indoiinone
(83) 3-Z-[1-(4-ethylaminomethylanilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-
fluoro-2-indolinone
(84) 3-Z-[1-(4-(N-(3-dimethylaminopropyl)-N-methylsulphonylamino)anilino)-1-(4-
(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indo!inone
(85) 3-Z-[1 -(4-(N-(2-dimethylaminoethyl)-N-propyIsuIphonylamino)anilino)-1 -(4-(2-
carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone
(86) 3-Z-[1 -(3-(methylaminomethyl)anilino)-1 -(4-(2-
carboxyethyI)phenyl)methylene]-6-fluoro-2-indolinone
(87) 3-Z-[1-(3-(2-dimethylaminoethyl)anilino)-1-(4-(2-
carboxyethyl)phenyl)methylene]-6-fluoro-2-indoIinone
(88) 3-Z-[1 -(3-(3-dimethylaminopropyl)anilino)-1 -(4-(2-
carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone
(89) 3-Z-[1-(4-(N-(dimethylaminocarbonylmethyl)-N-methylsuIphonylamino)anilino)-
1 -(4-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone
(90) 3-Z-[1 -(4-(N-methyl-N-methylsulphonylamino)anilino)-1 -(4-(2-
carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone
(91) 3-Z-[1-(4-(N-(N-(2-dimethylaminoethyl)-N-methylaminomethylcarbonyl)-N-
methylamino)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-
indolinone
(92) 3-Z-[1-(4-(2-diethyIaminoethylsulphonyl)anilino)-1-(4-(2-
carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone
(93) 3-Z-[1 -(4-(2-dimethylaminoethoxy)anilino)-1 -(4-(2-
carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone
(94) 3-Z-[1 -(4-(N-(3-dimethyIaminopropyIcarbonyl)-N-methylamino)anilino)-1 -(
carboxyethyl)phenyl)methylene]-6-fIuoro-2-indolinone
(95) 3-Z-i1-(4-(methylethyIaminomethyl)aniIino)-1-(4-(2-
carboxyethyI)phenyl)methylene]-6-fIuor6-2-indolinone
(96) 3-Z-[1 -(4-(methylpropylaminomethyI)aniIino)r1-(4-(2-
carboxyethyl)phenyl)methylene]-6-fIuoro-2-indolinone

(97) 3-Z-[1-(4-(methylbenzylaminomethyl)anilino)-1-(4-(2-
carboxyethyl)phenyl)methylene]-6-fluoro-2-iridolinone
(98) 3-Z-[1-(4-(azetidin-1-ylmethyl)anilino)-1-(4-(2-carboxyethyI)phenyl)methylene]-
6-fIuoro-2-indolinone
(99) 3-Z-[1-(4-(piperazin-1-ylmethyl)anilino)-1-(4-(2-
carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone
(100) 3-Z-[1-(4-(morpholin-4-ylmethy!)ani!ino)-1-(4-(2-
carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone
(101) 3-Z-[1 -(4-(thiomorpholin-4-yimethyl)ani[ino)-1-(4-(2-
carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone
(102) 3-Z-[1 -(4-(N-(2-dimethylaminoethyl)-N-acetylamino)anilino)-1 -(3-(2-
carboxyethyl)phenyl)methylene]-6-fIuoro-2-indolinone
(103) 3-Z-[1 -(4-(N-(2-methylaminoethyl)-N-acetylamino)anilino)-1 -(3-(2-
carboxyethyI)phenyl)methylene]-6-fluoro-2-indolinone
(104) 3-Z-[1 -(4-(N-(3-methylaminopropyl)-N-acetylamino)anilino)-1 -(3-(2-
Garboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone
(105) 3-Z-[1 -(4-(3-dimethylaminopropyl)aniIino)-1 -(3-(2-
carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone
(106) 3-Z-[1 -(4-ethylaminomethylahiliho)-1 -(3-(2-carboxyethyl)phenyl)methylene]-6-
fluoro-2-indolinone
(107) 3-Z-[1 -(4-(4-methylpiperazin-1 -ylcarbonyl)anilino)-1 -(3-(2-
carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone
(108) 3-Z-[1 -(4-(N-(3-dimethylaminopropyl)-N-methylsulphonylamino)anilino)-1 -(3-
(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone
(109) 3-Z-[1-(4-(N-(2-dimethylaminoethyl)-N-propylsulphonylamino)anilino)-1-(3-(2-
carboxyethyl)phenyl)methylene]-6-fIuoro-2-indolinone
(110) 3-Z-[1 -(3-(methylaminomethyl)anilino)-1 -(3-(2-
carboxyethyI)phenyl)methyIene]-6-fIuoro-2-indolinone
(111) 3-Z-[1-(3-(2-dimethylaminoethyl)anilino)-1-(3-(2-
carboxyethyI)phenyI)methylene]-6-fIuoro-2-indolinone
(112) 3-Z-[1-(3-(3-dimethylaminopropyI)ani!ino)-1-(3-(2-
carboxyethyI)phenyl)methylene]-6-fIuoro-2-indoIinone

(113) 3-Z-[1-(4-(N-(dimethylaminocafbonylmethyI)-N-methylsuIphonylamino)ani[ino)-
1-(3-(2-carboxyethyl)phenyl)methyIaie]-6-fIuoro-2-indolinone
(114) 3-Z-[1-(4-(N-methyl-N-methy!suIphonylamino)anilino)-1-(3-(2-
carboxyethyl)phenyl)methylene]-6-flooro-2-indolin6ne
(115) 3-Z-[1-(4-(N-methyl-N-acetylamino)anilino)-1-(3-(2-
carboxyethyI)phenyl)methylene]-6-fluoro-2-indolinone
(116) 3-Z-[1 -(4-(N-(N-(2-dimethylaminoethyl)-N-methylaminomethylcarbonyl)-N-
methylamino)anilino)-1-(3-(2-carboxyethy!)phenyl)nnethy!ene]-6-f!uoro-2-
indoiinone
(117) 3-Z-[1-(4-(2-diethylaminoethytei4>hony!)anilino)-1-(3-(2-
carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone
(118) 3-Z-[1-(4-(N-(2-dimethylaminoeftylcarbonyl)-N-methylamino)anilino)-1-(3-(2-
carboxyethyl)phenyl)methylene]-6^fluoro-2-indolinone
(119) 3-Z-[1-(4-(N-(2-dimethyIamino^fiyl)-N-methylaminomethyl)anilino)-1-(3-(2-
carboxyethyOphenyOmethylenej-e^fluoro^-indolinone
(120) 3-Z-[1-(4-(2-dimethylaminoetho^)ani[ino)-1-(3-(2-
carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone
(121) 3-Z-[1-(4-(methylethylaminometfiyl)anilino)-1-(3-(2-
carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone
(122) 3-Z-[1-(4-(methylpropylaminomeftiyl)anilino)-1-(3-(2-
carboxyethyOphenyOmethylenej-emjoro^-indolinone
(123) 3-Z-[1-(4-(methylbenzylaminom€thyl)anilino)-1-(3-(2-
carboxyethyl)phenyI)methylene]-&4ioro-2-indolinone
(124) 3-Z-[1-(4-(diethylaminomethyI)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene]-
6-fluoro-2-indolinone
(125) 3-Z-[1-(4-(pyrrolidin-1-ylmethyl)aiilino)-1-(3-(2-
carboxyethyl)phenyl)methylene]-6-§uoro-2-indcilinone
(126) 3-Z-[1-(4-(azetidin-1-ylmethyI)anflino)-1-(3-(2-carboxyethyI)phenyI)methylene]-
6-fIuoro-2-indoljnone
(127) 3-Z-[1 -(4-(piperazin-1 -ylmethyl)anilino)-1 -(3-(2-
carboxyethyl)phenyl)methylene]-64luoro-2-indolinone

(128) 3-Z-[1-(4-(morpholin-4-ylmethyl)anilino)-1-(3-(2-
carboxyethyl)phenyl)methyiene]-6-fluoro-2-indolinone
(129) 3-Z-[1-(4-(thiomorpholin-4-ylmethyl)anilino)-1-(3-(2-
carboxyethyl)phenyl)methylene]-6-f!uoro-2-indolinone
(130) 3-Z-[1-(4-(N-(2-dimethylaminoethyl)-N-methylsulphonyIamino)aniIino)-1-(4-(2-
carboxyethyl)phenyI)methylene]-6-bromo-2-indolinone
(131) 3-Z-[1 -(4-(N-(dimethyIaminomethylcarbonyl)-N-methylamino)anilino)-1 -(4-(2-
carboxyethy!)phenyl)methy!ene]-6-bromo-2-indolinone
(132) 3-Z-[1-(4-(N-(2-dimethylaminoethyl)-N-acetylamino)ani[ino)-1-(4-(2-
carboxyethyl)phenyl)methylene]-6-bromo-2-indolinone
(133) 3-Z-[1-(4-(N-(2-methylaminoethyl)-N-acetylamino)anHino)-1-(4-(2-
carboxyethyl)phenyl)methylene]-6-bromo-2-indolinone
(134) 3-Z-[1-(4-(N-(3-dimethylaminopropyl)-N-acetylamino)anilino)-1-(4-(2-
carboxyethyl)phenyl)methylene]-6-bromo-2-indolinone
(135) 3-Z-[1-(4-(N-(3-methylaminopropyl)-N-acetylamino)anilino)-1-(4-(2-
carboxyethyl)phenyl)methylene]-6-bromo-2-indolinone
(136) 3-Z-[1-(4-(3-dimethylaminopropyl)aniIino)-1-(4-(2-
carboxyethyl)phenyl)methylene]-6-bromo-2-indolinone
(137) 3-Z-[1 -(4-ethylaminomethylanilino)-1 -(4-(2-carboxyethyl)phehyl)methylene]-6-
bromo-2-indolinone
(138) 3-Z-[1-(4-methylaminomethylanilino)-1 -(4-(2-carbo>^ethyl)plienyl)r^ethyrene]::
6-bromo-2-indolinone
(139) 3-Z-[1-(4-(N-(4-methylpiperazin-1-ylmethylcarbonyI)-N-methylamino)anilino)-1-
(4-(2-carboxyethyl)phenyl)methylene]-6-bromo-2-indolinone
(140) 3-Z-[1-(4-(4-methylpiperazin-1-ylcarbonyl)anilino)-1-(4-(2-
carboxyethyl)phenyl)methylene]-6-bromo-2-indolinone
(141) 3-Z-[1 -(4-(N-(3-dimethylaminopropyl)-N-methylsulphonylamino)anilino)-1 -(4-
(2-carboxyethyI)phenyl)methylene]-6-bromo-2-indoIinone
(142) 3-Z-[1-(4-(N-(2-dimethyIaminoethyl)-N-propyIsulphonylamino')anilino)-1-(4-(2-
carboxyethyl)phenyl)methylene]-6-bromo-2-indolinone
(143) 3-Z-[1-{4-aminomethylaniIino)-1-(4-(2-carboxyethyl)phenyI)methylene]-6-
bromo-2-indolinohe

(144) 3-Z-[1 -(3-(dimethylaminomethyl)anilino)-1 -(4-(2-
carboxyethyl)phenyI)methylene]-6-bromo-2-indoIinone
(145) 3-Z-[1-(3-(methylaminomethyl)anilino)-1-(4-(2-
carboxyethyl)phenyl)methylene]-6-bromo-2-indolinone
(146) 3-Z-[1 -(3-(2-dimethylaminoethyl)anilino)-1 -(4-(2-
carboxyethyl)phenyl)methylene]-6-bromo-2-indolinone
(147) 3-Z-[1-(3-(3-dimethylaminopropyi)ani!ino)-1-(4-(2-
carboxyethyl)phenyl)methy!ene]-6-bromo-2-indo!inone
(148) 3-Z-[1 -(4-(2-dimethyiaminoethyl)anilino)-1 -(4-(2-
carboxyethyl)phenyl)methylene]-6-bromo-2-indolinone
(149) 3-Z-[1-(4-(N-(dimethylaminocarbonyimethyl)-N-me.thylsulphonylamino)aniIino)-
1-(4-(2-carboxyethyl)phenyl)methylene]-6-bromo-2-indolinone
(150) 3-Z-[1-(4-(N-methyl-N-methylsulphonylamino)anilino)-1-(4-(2-
carboxyethyl)phenyl)methylene]-6-bromo-2-indolinone
(151) 3-Z-[1 -(4-(N-methyl-N-acetylamino)anilino)-1 -(4^(2-
carboxyethyl)phenyI)methylene]-6-bromo-2-indolinone
(152) 3-Z-[1-(4-(1-methylimidazol-2-yl)anilino)-1-(4-(2-
carboxyethyl)phenyl)methylene]-6-bromo-2-indolinone
(153) 3-Z-[1-(4-(N-(N-(2-dimethylaminoethyI)-N-methylaminomethylcarbonyl)-N-
methylamino)aniIino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-bromo-2-
indolinone
(154) 3-Z-[1 -(4-(2-diethylaminoethylsulphonyl)ani!ino)-1 -(4-(2-
carboxyethyl)phenyl)rnethylene]-6-bromo-2-indolinone
(155) 3-Z-[1-(4-(N-(2-dimethylaminoethylcarbonyl)-N-methylamino)anilino)-1-(4-(2-
carboxyethyl)phenyl)methylene]-6-bromo-2-indolinone
(156) 3-Z-[1-(4-(N-(2-dimethylaminoethyl)-N-methylaminomethyl)anilino)-1-(4-(2-
carboxyethyl)phenyl)methylene]-6-bromo-2-indoIinone
(157) 3-Z-[1-(4-(2-dimethylaminoethoxy)anilino)-1-(4-(2-
carboxyethyl)phenyI)methylene]-6-bromo-2-indoIinone
(158) 3-Z-[1-(4-(N-(4-dimethyIaminobutylcarbonyI)-N-methylamino)aniIino)-1-(4-(2-
carboxyethyl)phenyl)methylene]-6-bromo-2-indolinone
(159) 3-Z-[1 -(4-(N-(3-dimethylaminopropylcarbonyl)-N-methylamino)anilino)-1 -(
carboxyethyI)phenyl)methylene]-6-bromo-2-indoIinone

(160) 3-Z-[1-(4-(methylethylaminomethyl)anilino)-1-(4-(2-
carboxyethyl)phenyl)methyIene]-6-bromo-2-indolinone
(161) 3-Z-[1 -(4-(methylpropy!aminomethyl)anilino)-1 -(4-(2-
carboxyethyl)phenyl)methylene]-6-bromo-2-indoIinone
(162) 3-Z-[1-(4-(methylbenzylaminomethyl)aniIino)-1-(4-(2-
carboxyethyl)phenyI)methylene]-6-bromo-2-indolinone
(163) 3-Z-[1-(4-(diethylaminomethyl)anilino)-1-(4-(2-carboxyethyl)phenyl)methy!ene]-
6-bromo-2-indolinone
(164) 3-Z-[1-(4-(N-(2-dimethylaminoethy[)-N-methylaminomethyl)anilino)-1-(4-(2-
carboxyethyl)-phenyImethylene]-6-bromo-2-indolinone
(165) 3-Z-[1-(4-(pyrrolidin-1-ylmethyl)anilino)-1-(4-(2-
carboxyethyl)phenyl)methylene]-6-bromo-2-indolinone
(166) 3-Z-[1-(4-(azetidin-1-ylmethyl)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-
6-bromo-2-indolinone
(167) 3-Z-[1-(4-((4-methylpiperazin-1-yl)methyl)anilino)-1-(4-(2-
carboxyethyl)phenyl)methylene]-6-bromo-2-indolinone
(168) 3-Z-[1 -(4-(piperazin-1 -ylmethyl)anilino)-1 -(4-(2-
carboxyethyl)phenyl)methylene]-6-bromo-2-indo[inone
(169) 3-Z-[1-(4-(morpholin-4-ylmethyl)aniIino)-1-(4-(2-
carboxyethyl)phenyl)methylene]-6-bromo-2-indolinone
(170) 3-Z-[1-(4-(thiomorpholin-4-ylmethyl)aniIino)-1-(4-(2-
carboxyethyl)phenyl)methylene]-6-bromo-2-indolinone
(171) 3-Z-[1-(4-(imidazol-1-ylmethyl)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-
6-bromo-2-indolinone
(172) 3-Z-[1-(4-dimethylaminomethylanilino)-1-(3-(2-
carboxyethyl)phenyl)methylene]-6-bromo-2-indoIinone
(173) 3-Z-[1-(4-(N-(2-dimethylaminoethyl)-N-methylsulphonylamino)anilino)-1-(3-(2-
carboxyethyl)phenyl)methylene]-6-bromo-2-indolinone
(174) 3-Z-[1-(4-(N-(dimethylaminomethylcarbonyI)-N-methylamino)anilino)-1-(3-(2-
carboxyethyl)phenyl)methylene]-6-bromo-2-indoIinone
(175) 3-Z-[1-(4-(N-(2-dimethylaminoethyI)-N-acety!amino)aniIino)-1-(3-(2-
carboxyethyl)phenyl)methylene]-6-bromo-2-indolinone
(176) 3-Z-i1-(4-(N-(2-methyIaminoethyl)-N-acetylamino)anilino)-1-(3-(2-
carboxyethyl)phenyl)methylene]-6-bromo-2-indolinone
(177) 3-Z-[1-(4-(N-(3-dimethylaminopropyl)-N-acetylamino)anilino)-1-(3-(2-
carboxyethyl)phenyl)methylene]-6-bromo-2-indolihone
(178) 3-Z-[1-(4-(N-(3-methyIaminopropyl)-N-acetylamino)aniIino)-1-(3-(2-
carboxyethyl)phenyl)methylene]-6-bromo-2-indolinone
(179) 3-Z-[1-(4-(3-dimethy!aminopropyl)anilino)-1-(3-(2-
carboxyethyl)phenyl)methylene]-6-bromo-2-indolinone
(180) 3-Z-[1-(4-ethylaminomethylanilino)-1-(3-(2-carboxyethyl)phenyl)methylene]-6-
bromo-2-indolinone
(181) 3-Z-[1-(4-methylaminomethylanilino)-1-(3-(2-carboxyethyl)phenyl)methylene]-
6-bromo-2-indolinone
(182) 3-Z-[1-(4-(N-(4-methyIpiperazin-1-y1methylcarbonyl)-N-methylamino)anilino)-1-
(3-(2-carboxyethyl)phenyl)methylene]-6-bromo-2-indolinone
(183) 3-Z-[1 -(4-(4-methylpiperazin-1 -ylcarbonyl)anilino)-1 -(3-(2-
carboxyethyl)phenyl)methylene]-6-bromo-2-indolinone
(184) 3-Z-[1-(4-(N-(3-dimethylaminopropyl)-N-methylsulphonylamino)anilino)-1-(3-
(2-carboxyethyl)phenyl)methylene]-6-bromo-2-indolinone
(185) 3-Z-[1-(4-(N-(2-dimethylaminoethyl)-N-propylsulphonylamino)anilino)-1-(3-(2-
carboxyethyl)phenyI)methylene]-6-bromo-2-indolinone
(186) 3-Z-[1 -(4-aminomethylanilino)-1 -(3-(2-carboxyethyl)phenyl)methylene]:6-
bromo-2-indolinone
(187) 3-Z-[1-(3-(dimethylaminomethyl)anilino)-1-(3-(2-
carboxyethyl)phenyl)methylene]-6-bromo-2-indolinone
(188) 3-Z-[ 1 -(3-(methylaminomethyl)aniIino)-1 -(3-(2-
carboxyethyI)phenyl)methylene]-6-bromo-2-indolinone
(189) 3-Z-[1-(3-(2-dimethylaminoethyl)anilino)-1 -(3-(2-
carboxyethyl)phenyl)methylene]-6-bromo-2-indolinone
M 90) 3-Z-[1-(3-(3-dimethylaminopropyI)anilino)-1-(3-(2-
carboxyethyI)phenyl)methylene]-6-bromo-2-indoIinone (191) 3-Z-[1-(4-(2-dimethyIaminoethyl)aniIino)-1-(3-(2-
carboxyethyl)phenyl)methyIene]-6-bromo-2-indolinone
(192) 3-Z-[1-(4-(N-(dimethylaminocarbonylmethyl)-N-methylsulphonyIamino)anilino)-
1-(3-(2-carboxyethyl)phenyl)methylene]-6-bromo-2-indolinone
(193) 3-Z-[1-(4-(N-methyl-N-methyisulphonylamino)aniIino)-1-(3-(2-
carboxyethyl)phenyl)methylene]-6-brdmo-2-indolihone
(194) 3-Z-[1-(4-(N-methyl-N-acetylamino)anilino)-1 -(3-(2-
carboxyethyl)phenyl)methylene]-6-bromo-2-indolinone
(195) 3-Z-[1-(4-(1-methy!imidazol-2-yI)an[Iino)-1-(3-(2-
carboxyethyl)phenyl)methylene]-6-bromo-2-indo!inone
(196) 3-Z-[1-(4-(N-(N-(2-dimethylaminoethyl)-N-methylaminomethylcarbonyl)-N-
methylamino)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene]-6-bromo-2-
indolinone
(197) 3-Z-[1-(4-(2-diethylaminoethylsulphonyl)anilino)-1-(3-(2-
carboxyethyl)phenyl)methylene]-6-bromo-2-indolinone
(198) 3-Z-[1-(4-(N-(2-dimethylaminoeth^carbonyl)-N-methylamino)anilino)-1-(3-(2-
carboxyethyl)phenyl)methylene]-6rbramo-2-indolinone
(199) 3-Z-[1-(4-(N-(2-dimethylaminoeth^-N-methylaminomethyl)anilino)-1-(3-(2-
carboxyethyl)phenyl)methylene]-6-bromo-2-indolinone
(200) 3-Z-[1-(4-(2-dimethylaminoethoxy)anilino)-1-(3-(2-
carboxyethyI)phenyl)methylene]-6-bromo-2-indolinone
(201) 3-Z-[1-(4-(N-(4-dimethylaminobulylcarbonyl)-N-methylamino)anilino)-1-(3-(2-
carboxyethyl)phenyl)methylene]-6-bromo-2-indolinone
(202) 3-Z-[1 -(4-(N-(3-dimethylaminopro|^lcarbonyl)-N-methylamino)anilino)-1 -(3-(2-
carboxyethy[)phenyl)methylene]-6-bn3mo-2-indolinone
(203) 3-Z-[1 -(4-(methylethylaminomethyl)anilino)-1-(3-(2-
carboxyethyl)phenyl)methylene]-6-bromo-2-indolinone
(204) 3-Z-[1-(4-(methylpropylaminomethyl)anilino)-1 -(3-(2-
carboxyethyl)phenyl)methylene]-6-bromo-2-indoIinone
(205) 3-Z-[1-(4-(methylbenzylaminomejhyl)anilino)-1-(3-(2-
carboxyethyl)phenyl)methylene]-6-bromo-2-indolinone
(206) 3-Z-[1-(4-(diethylaminomethyI)anlno)-1-(3-(2-carboxyethyl)phenyl)methylene]-
6-bromo-2-indolinone
(207) 3-Z-[1-(4-(N-(2-dimethyIaminoetfTyO^N-methylaminomethyl)ani[ino)-1-(3-(2-
carboxyethyI)phenylmethylene]-6-bromo-2-indolinone
(208)- 3-Z-[1-(4-(pyrrolidin-1-ylmethyl)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene]-6-bromo-2-indoIinone
(209) 3-Z-[1-(4-(azetidin-1-ylmethyl)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene]-
6-bromo2-indolinone
(210) 3-Z-[1-(4-((4-methylpiperazin-1-yl)methyl)aniliho)-1-(3-(2-
carboxyethyl)phenyl)methyIene]-6-bromo-2-indolinone
(211) 3-Z-[1-(4-(piperazin-1-ylmethy!)ani!ino)-1-(3-(2-
carboxyethyl)phenyl)methylene]-6-bromo-2-indolinone
(212) 3-Z-[1-(4-(morpholin-4-ylmethyl)anilino)-1-(3-(2-
carboxyethyl)phenyl)methylene]-6-bromo-2-indolinone
(213) 3-Z-[1-(4-(thiomorpholin-4-ylmethyl)anilino)-1-(3-(2-
carboxyethyl)phenyl)methylene]-6-bromo-2-indolinone
(214) 3-Z-[1-(4-(imidazol-1-ylmethyl)anilino)-1-(3-(2-carboxyethyl)phenyl)rnethylene]-
6-bromo-2-indolinone
(215) 3-Z-[1-(4-dimethylaminomethylanilino)-1-(4-carboxymethylaminophenyl)-
methylene]-6-fIuoro-2-indolinone
(216) 3-Z-[1-(4-dimethylaminomethylanilino)-1-(3-carboxymethylamino-phenyl):
methylene]-6-fIuoro-2-indolinone
(217) 3-Z-[1-(4-dimethyIaminomethylanilino)-1-(4-(N-methyl-
carboxymethylamino)phenyl)methylene]-6-fIuoro-2-indorinone
(218) 3-Z-[1-(4-dimethylaminomethylanilino)-1-(3-(N-methyI-
carboxymethylamino)phenyl)methylene]-6-fIuoro-2-indolinone
(219) 3-Z-[1-(4-dimethylaminomethylanilino)-1-(4-earboxymethoxyphenyl)-
methylene]-6-chloro-2-indolinone
(220) 3-Z-[1-(4-dimethylaminomethylanilino)-1-(3-carboxymethoxyphenyl)-
methy!ene]-6-chloro-2-indolinone
(221) 3-Z-[1-(4-dimethylaminomethylanilino)-1-(4-carboxymethylaminophenyl)-
methyIene]-6-chloro-2-indolinone
(222) 3-Z-[1-(4-dimethylaminomethylanilino)-1-(3-carboxymethyIaminophenyl)-
methy!ehe]-6-chloro-2-indolinone
(223) 3-Z-[1-(4-dimethylaminomethylanilino)-1-(4-(N-methyl-
carboxymethylamino)phenyl)methylene]-6-chloro-2-indolinone
(224) 3-Z-[1 -(4-dimethylaminomethylanilino)-1 -(3-(N-methyi-
carboxymethylamino)phenyl)methyIene]-6-chloro-2-indolinone
(225) 3-Z-[1-(4-dimethylaminomethylanilino)-1-(4-carboxymethoxyphenyl)-
methyIene]-6~bromo-2-iridolinone
(226) 3-Z-[1-(4-dimethylaminomethylanilino)-1-(3-carboxymethoxyphenyl)-
methylene]-6-bromo-2-indolinone
(227) 3-Z-[1-(4-dimethylaminomethylanilino)-1-(4-carboxymethylaminophenyl)-
methy!ene]-6-bromo-2-indolinone
(228) 3-Z-[1-(4-dimethylaminomethylanilino)-1-(3-carboxymethylaminophenyl)-
methylene]-6-bromo-2-indolinone
(229) 3-Z-[1 -(4-dimethylaminomethylanilino)-1-(4-(N-methyl-
carboxymethylamino)phenyl)methylene]-6-bromo-2-indolinone
(230) 3-Z-[1 -(4-dimethylaminomethylanilino)-1-(3-(N-methyl-
carboxymethylamino)phenyl)methylene]-6-bromo-2-indolinone
In the tables above,
Me is methyl,
Et is ethyl,
Pr is propyl,
nPr is n-propyi,
iPr is isopropyl,
nBu is n-butyl,
tBu is tert-butyl and Bn is. benzyl.

We Claim:
1. The compound l-acetyl-6-fluoro-2-indolinone, wherein said compound is used as starting material for the manufacture of a substituted 2-indolinone of the formula (I) as
in which R2 is a fluorine atom.

Documents:

5042-DELNP-2007-Abstract-(06-03-2012).pdf

5042-DELNP-2007-Claims-(06-03-2012).pdf

5042-delnp-2007-claims.pdf

5042-DELNP-2007-Correspondence Others-(06-03-2012).pdf

5042-delnp-2007-correspondence-others 1.pdf

5042-delnp-2007-correspondence-others.pdf

5042-DELNP-2007-Description (Complete)-(06-03-2012).pdf

5042-delnp-2007-description (complete).pdf

5042-delnp-2007-form-1.pdf

5042-delnp-2007-form-18.pdf

5042-delnp-2007-form-2.pdf

5042-DELNP-2007-Form-3-(06-03-2012).pdf

5042-delnp-2007-form-3.pdf

5042-delnp-2007-form-5.pdf

5042-DELNP-2007-GPA-(06-03-2012).pdf

5042-DELNP-2007-Petition-137-(06-03-2012).pdf

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Patent Number

252271

Indian Patent Application Number

5042/DELNP/2007

PG Journal Number

19/2012

Publication Date

11-May-2012

Grant Date

04-May-2012

Date of Filing

29-Jun-2007

Name of Patentee

BOEHRINGER INGELHEIM PHARMA GMBH & CO. KG

Applicant Address

BINGER STRASSE 173 D-55216 INGELHEIM AM RHEIN GERMANY.

Inventors:

#	Inventor's Name	Inventor's Address
1	ARMIN HECKEL	GESCHWISTER-SCHOLL-STR. 71 88400 BIBERACH AN DER RISS 1 GERMANY.
2	THORSTEN LEHMANN-LINTZ	AMEISENBERG 1, 88416 OCHSENHAUSEN GERMANY.
3	JORG KLEY	POSTSTRASSE 5/4, 88441 MITTEELBIBERACH GERMANY.
4	FRANK HILBERG	PILGRAMGASSE 18/22, A-1050 WIEN, AUSTRIA.
5	JACOBUS C. A. VAN MEEL	KARNTNERGASSE 6, A-2340, MODLING, AUSTRIA.
6	ULRIKE TONTSCH-GRUNT	OETKERWEG 23, 2500 BADEN, AUSTRIA.
7	GERALD JURGEN ROTH	AKAZIENWEG 47, 88400 BIBERACH GERMANY.

PCT International Classification Number

C07D 209/34

PCT International Application Number

PCT/EP03/007961

PCT International Filing date

2003-07-22

PCT Conventions:

#	PCT Application Number	Date of Convention	Priority Country
1	10328 33.4	2003-06-24	Germany
2	10233 66.1	2002-07-23	Germany