New substituted indolinones, their manufacture and their use as medicaments

Abstract

The present invention relates to substituted indolinones of general formula wherein R 1 to R 6 and X are defined as in claim 1 , the isomers and the salts thereof, in particular the physiologically acceptable salts thereof which have valuable pharmacological properties, especially an inhibitory effect on various receptor-tyrosine kinases, and cycline/CDK complexes as well as on the proliferation of endothelial cells and various tumour cells, pharmaceutical compositions containing these compounds, their use and processes for preparing them.

1 . A compound of the formula (I):  
       
         
           
           
               
               
           
         
       
       wherein: 
 X denotes an oxygen or sulphur atom;  
 R 1  denotes a C 2-3 -alkenyl, C 2-3 -alkynyl, aryl, aryl-C 1-3 -alkyl, heteroaryl, heteroaryl-C 1-3 -alkyl, trifluoromethyl or cyano group, 
 a hydroxy, C 1-3 -alkoxy, hydroxy-C 1-3 -alkyl, C 1-3 -alkoxy-C 1-3 -alkyl, aryloxy or heteroaryloxy group,  
 a mercapto, C 1-3 -alkylsulphenyl, phenylsulphenyl, benzylsulphenyl, C 1-3 -alkylsulphinyl, phenylsulphinyl, benzylsulphinyl, C 1-3 -alkylsulphonyl, phenylsulphonyl, benzylsulphonyl, sulpho, C 1-3 -alkoxysulphonyl, phenoxysulphonyl or benzyloxysulphonyl group,  
 an amino, C 1-3 -alkylamino, di-(C 1-3 -alkyl)-amino, hydroxycarbonyl-C 1-3 -alkylamino, N—(C 1-3 -alkyl)-hydroxycarbonyl-C 1-3 -alkylamino, C 1-3 -alkoxycarbonyl-C 1-3 -alkylamino, N—(C 1-3 -alkyl)-C 1-3 -alkoxycarbonyl-C 1-3 -alkylamino, phenylamino, N-phenyl-C 1-3 -alkylamino, N,N-diphenylamino, benzylamino, N-benzyl-C 1-3 -alkylamino, N,N-dibenzylamino, C 1-3 -alkylcarbonylamino, benzoylamino, benzylcarbonylamino group or an N—(C 1-3 -alkyl)-C 1-3 -alkylcarbonylamino group wherein the two alkyl groups are optionally replaced by a C 2-5 -n-alkylene bridge or wherein one or both alkyl groups are optionally replaced by a phenyl or benzyl group,  
 a C 1-3 -alkylsulphonylamino, phenylsulphonylamino or benzylsulphonylamino group or an N—(C 1-3 -alkyl)-C 1-3 -alkylsulphonylamino group wherein the two alkyl groups are optionally replaced by a C 2-5 -n-alkylene bridge or wherein one or both alkyl groups are optionally replaced by a phenyl or benzyl group,  
 an aminosulphonyl, C 1-3 -alkylaminosulphonyl, phenylaminosulphonyl, benzylaminosulphonyl, di-(C 1-3 -alkyl)-aminosulphonyl, N,N-diphenyl-aminosulphonyl or N,N-dibenzyl-aminosulphonyl group,  
 a phosphono, (C 1-3 -alkoxy)PO(H), (C 1-3 -alkoxy)PO(C 1-3 -alkyl), (C 1-3 -alkoxy)PO(OH), di-(C 1-3 -alkoxy)-PO or (C 2-4 -n-alkylenedioxy)-PO group,  
 a ureido group optionally mono-, di- or trisubstituted by C 1-3 -alkyl groups,  
 a 4- to 7-membered cycloalkyleneimino or cycloalkyleneiminosulphonyl group, wherein in each case the methylene group in the 4 position of a 6- or 7-membered cycloalkyleneimino group is optionally replaced by an oxygen or sulphur atom, by a sulphinyl, sulphonyl, —NH or —N(C 1-3 -alkyl) group;  
 
 R 2  denotes a hydrogen, fluorine, chlorine, bromine or iodine atom, 
 a C 1-6 -alkyl or trifluoromethyl group,  
 a hydroxy, C 1-3 -alkoxy, mercapto, C 1-3 -alkylsulphenyl, C 1-3 -alkylsulphinyl, C 1-3 -alkylsulphonyl, sulpho, C 1-3 -alkoxysulphonyl, aminosulphonyl, C 1-3 -alkylaminosulphonyl or di-(C 1-3 -alkyl)-aminosulphonyl group,  
 a nitro, amino, C 1-3 -alkylamino or di-(C 1-3 -alkyl)-amino group,  
 a C 1-3 -alkylcarbonyl, cyano, carboxy, C 1-3 -alkoxycarbo-nyl, aminocarbonyl, C 1-3 -alkylaminocarbonyl or di-(C 1-3 -alkyl)-aminocarbonyl group,  
 a phosphono, (C 1-3 -alkoxy)PO(H), (C 1-3 -alkoxy)PO(C 1-3 -alkyl), (C 1-3 -alkoxy)PO(OH) or di-(C 1-3 -alkoxy)-PO group,  
 a 4- to 7-membered cycloalkyleneimino, cycloalkyleneiminocarbonyl or cycloalkyleneiminosulphonyl group, wherein in each case the methylene group in the 4 position of a 6- or 7-membered cycloalkyleneimino group is optionally replaced by an oxygen or sulphur atom, by a sulphinyl, sulphonyl, —NH or —N(C 1-3 -alkyl) group, or  
 R 1  and R 2  together denote a methylenedioxy, ethylenedioxy, n-propylene, n-butylene or 1,4-butadienylene group;  
 
 R 3  denotes a hydrogen atom, denotes a C 1-6 -alkyl, C 3-7 -cycloalkyl, trifluoromethyl or heteroaryl group, 
 a phenyl or naphthyl group mono- or disubstituted by a fluorine, chlorine, bromine or iodine atom, by a trifluoromethyl, C 1-3 -alkyl or C 1-3 -alkoxy group, wherein if the phenyl or naphthyl group are disubstituted the substituents are identical or different and are optionally substituted by: 
 a hydroxy, hydroxy-C 1-3 -alkyl or C 1-3 -alkoxy-C 1-3 -alkyl group,  
 by a cyano, cyano-C 1-3 -alkyl, cyano-C 2-3 -alkenyl, cyano-C 2-3 -alkynyl, carboxy, carboxy-C 1-3 -alkyl, carboxy-C 2-3 -alkenyl, carboxy-C 2-3 -alkynyl, C 1-3 -alkoxycarbonyl, C 1-3 -alkoxycarbonyl-C 1-3 -alkyl, C 1-3 -alkoxycarbonyl-C 2-3 -alkenyl or C 1-3 -alkoxycarbonyl-C 2-3 -alkynyl group,  
 by a C 1-3 -alkylcarbonyl, C 1-3 -alkylcarbonyl-C 1-3 -al-kyl, C 1-3 -alkylcarbonyl-C 2-3 -alkenyl or C 1-3 -alkylcarbo-nyl-C 2-3 -alkynyl group,  
 
 by an aminocarbonyl, aminocarbonyl-C 1-3 -alkyl, amino-carbonyl-C 2-3 -alkenyl, aminocarbonyl-C 2-3 -alkynyl, C 1-3 -alkylaminocarbonyl, C 1-3 -alkylaminocarbonyl-C 1-3 -alkyl, C 1-3 -alkylaminocarbonyl-C 2-3 -alkenyl, C 1-3 -alkylaminocarbonyl-C 2-3 -alkynyl, di-(C 1-3 -alkyl)-aminocarbonyl, di-(C 1-3 -alkyl)-aminocarbonyl-C 1-3 -alkyl, di-(C 1-3 -alkyl)-aminocarbonyl-C 2-3 -alkenyl or di-(C 1-3 -alkyl)-aminocarbonyl-C 2-3 -alkynyl group, 
 by a nitro, nitro-C 1-3 -alkyl, nitro-C 2-3 -alkenyl or nitro-C 2-3 -alkynyl group,  
 by an amino, C 1-3 -alkylamino, di-(C 1-3 -alkyl)-amino, amino-C 1-3 -alkyl, C 1-3 -alkylamino-C 1-3 -alkyl or di-(C 1-3 -alkyl)-amino-C 1-3 -alkyl group,  
 by a C 1-3 -alkylcarbonylamino, C 1-3 -alkylcarbonylamino-C 1-3 -alkyl, N—(C 1-3 -alkyl)-C 1-3 -alkylcarbonylamino, N—(C 1-3 -alkyl)-C 1-3 -alkylcarbonylamino-C 1-3 -alkyl, C 1-3 -alkylsulphonylamino, C 1-3 -alkylsulphonylamino-C 1-3 -alkyl, N—(C 1-3 -alkyl)-C 1-3 -alkylsulphonylamino or N—(C 1-3 -alkyl)-C 1-3 -alkylsulphonylamino-C 1-3 -alkyl group,  
 by a 4- to 7-membered cycloalkyleneimino, cycloalkyleneiminocarbonyl, cycloalkyleneiminosulphonyl, cycloalkyleneimino-C 1-3 -alkyl, cycloalkyleneiminocarbonyl-C 1-3 -alkyl or cycloalkyleneiminosulphonyl-C 1-3 -alkyl group, wherein in each case the methylene group in the 4 position of a 6- or 7-membered cycloalkyleneimino group is optionally replaced by an oxygen or sulphur atom, by a sulphinyl, sulphonyl, —NH or —N(C 1-3 -alkyl) group, or by a heteroaryl or heteroaryl-C 1-3 -alkyl group  
 
 
 R 4  denotes a hydrogen atom or a C 1-3 -alkyl group;  
 R 5  denotes a hydrogen atom or a C 1-3 -alkyl group and  
 R 6  denotes a hydrogen, fluorine, chlorine, bromine or iodine atom, 
 a trifluoromethyl or heteroaryl group, a C 1-3 -alkoxy group optionally substituted by 1 to 3 fluorine atoms, an amino-C 1-3 -alkoxy, C 1-3 -alkylamino-C 2-3 -alkoxy or benzylamino-C 2-3 -alkoxy group, a cycloalkyleneimino-C 2-3 -alkoxy group with 4 to 7 ring members, a di-(C 1-3 -alkyl)-amino-C 2-3 -alkoxy or C 1-3 -alkylmercapto group,  
 a nitro, cyano, carboxy, C 1-3 -alkoxycarbonyl, amino-carbonyl, C 1-3 -alkylaminocarbonyl, di-(C 1-3 -alkyl)-amino-carbonyl, piperidinocarbonyl or tetrazolyl group,  
 a C 1-3 -alkylcarbonylamino group optionally substituted at the nitrogen atom by a C 1-3 -alkyl group,  
 an imidazolyl or piperazino group optionally substituted at the imino group by a C 1-3 -alkyl group,  
 a C 1-4 -alkyl group, which may be terminally substituted 
 by a hydroxy, C 1-3 -alkoxy, carboxy, C 1-3 -alkoxy-carbonyl, amino, C 1-4 -alkylamino, di-(C 1-4 -alkyl)-amino, phenylamino, N-phenyl-C 1-3 -alkylamino, phenyl-n-C 1-3 -alkylamino, N—(C 1-3 -alkyl)-phenyl-n-C 1-3 -alkylamino or di-(phenyl-n-C 1-3 -alkyl)-amino group,  
 by a 4- to 7-membered cycloalkyleneimino group wherein 
 a methylene group linked to the imino group is optionally replaced by a carbonyl or sulphonyl group or  
 one or two hydrogen atoms is optionally replaced by a C 1-3 -alkyl group and/or  
 in each case the methylene group in the 4 position of a 6- or 7-membered cycloalkyleneimino group is optionally substituted by a carboxy, C 1-3 -alkoxycarbonyl, aminocarbonyl, C 1-3 -alkylaminocarbonyl, di-(C 1-3 -alkyl)-aminocarbonyl, phenyl-n-C 1-3 -alkylamino or N—(C 1-3 -alkyl)-phenyl-n-C 1-3 -alkylamino group or  
 is optionally replaced by an oxygen or sulphur atom, by a sulphinyl, sulphonyl, —NH or —N(C 1-3 -alkyl) group,  
 
 by a 5- to 7-membered cycloalkenyleneimino group wherein the double bond is isolated from the nitrogen atom,  
 by a C 4-7 -cycloalkylamino, N—(C 1-3 -alkyl)-C 4-7 -cycloalkylamino or C 5-7 -cycloalkenylamino group wherein position 1 of the ring is not involved in the double bond and wherein the nitrogen atom is optionally substituted by a C 1-3 -alkyl group,  
 by a C 1-3 -alkylcarbonylamino, N—(C 1-3 -alkyl)-C 1-3 -alkylcarbonylamino, aminocarbonyl, C 1-3 -alkyl-aminocarbonyl or di-(C 1-3 -alkyl)-aminocarbonyl group,  
 
 
 or R 6  denotes a group of formula  
   —N(R a )—CO—(CH 2 ) n —R b   (II),  
 wherein  
 R a  denotes a C 1-3 -alkyl group,  
 n one of the numbers 0, 1 or 2 and  
 R b  denotes an amino, C 1-4 -alkylamino, phenylamino, N—(C 1-4 -alkyl)-phenylamino, benzylamino, N—(C 1-4 -alkyl)-benzylamino or di-(C 1-4 -alkyl)-amino group or a 4- to 7-membered cycloalkyleneimino group, wherein in each case the methylene group in the 4 position of a 6- or 7-membered cycloalkyleneimino group is optionally replaced by an oxygen or sulphur atom, by a sulphinyl, sulphonyl, —NH or —N(C 1-3 -alkyl) group,  
 a group of formula  
   —N(R c )—(CH 2 ) m —(CO) o —R d   (III),  
 wherein  
 R c  denotes a C 1-3 -alkyl, C 1-3 -alkylcarbonyl, arylcarbonyl, benzylcarbonyl, C 1-3 -alkylsulphonyl, arylsulphonyl or benzylsulphonyl group,  
 m denotes one of the numbers 1, 2, 3 or 4,  
 o denotes one of the numbers 0 or 1 and  
 R d  has the meanings given for R b  hereinbefore or denotes a di-(C 1-4 -alkyl)-amino-C 1-3 -alkylamino group optionally substituted in the 1 position by a C 1-3 -alkyl group,  
 or R 6  denotes an N—(C 1-3 -alkyl)-C 1-3 -alkylsulphonylamino group;  
 wherein any carboxy, amino or imino group present is optionally substituted by a group which can be cleaved in vivo,  
 wherein when there is an imino or amino group they are optionally substituted by the following groups which can be cleaved in vivo:  
 a hydroxy group, an acyl group, an allyloxycarbonyl group, a C 1-16 -alkoxycarbonyl group, a phenyl-C 1-6 -alkoxycarbonyl group, a C 1-3 -alkylsulphonyl-C 2-4 -alkoxycarbonyl, C 1-3 -alkoxy-C 2-4 -alkoxy-C 2-4 -alkoxycarbonyl or R e CO—O—(R f CR g )—O—CO group wherein 
 R e  denotes a C 1-8 -alkyl, C 5-7 -cycloalkyl, phenyl or phenyl-C 1-3 -alkyl group,  
 R f  denotes a hydrogen atom, a C 1-3 -alkyl, C 5-7 -cycloalkyl or phenyl group and  
 R g  denotes a hydrogen atom, a C 1-3 -alkyl or R e CO—O—(R f CR 9 )—O group wherein R e  to R g  are as hereinbefore defined,  
 
 and additionally a phthalimido group may be used for an amino group,  
 wherein when there is a carboxy group it is optionally substituted by the abovementioned ester groups which can be converted in vivo into a carboxy group,  
 or the physiologically acceptable salts and isomers thereof.  
 
     
     
         2 . The compound according to  claim 1 , wherein 
 X denotes an oxygen atom;    R 1  denotes a C 1-3 -alkoxy, trifluoromethyl, di-(C 1-3 -alkyl)-amino, pyrrolidino or pyrrolo group, 
 an amino or C 1-3 -alkylamino group wherein an amino-hydrogen atom is optionally replaced by a C 1-3 -alkylcarbonyl, phenyl-C 1-3 -alkylcarbonyl, benzoyl, aminocarbonyl, C 1-3 -alkylsulphonyl, phenylsulphonyl, carboxy-C 1-3 -alkyl or C 1-3 -alkyloxycarbonyl-C 1-3 -alkyl group, or  
 a phenyl group optionally substituted by a C 1-3 -alkyl group;  
   R 2  denotes a hydrogen atom or a C 1-3 -alkoxy group or    R 1  and R 2  together denote a methylenedioxy group;    R 3  denotes a C 1-3 -alkyl or a phenyl group substituted by a cyano, amino-C 1-3 -alkyl or N—(C 1-3 -alkanoyl)-amino-C 1-3 -alkyl group;    R 4  denotes a hydrogen atom;    R 5  denotes a hydrogen atom and    R 6  denotes a hydrogen, fluorine, chlorine, bromine or iodine atom, 
 a trifluoromethyl, 4-(C 1-3 -alkyl)-piperazino, pyridinyl, imidazolyl, tetrazolyl, C 1-3 -alkoxy or C 1-3 -alkylmercapto group,  
 a nitro, cyano, carboxy or C 1-3 -alkyloxycarbonyl group or a C 1-3 -alkylcarbonylamino group optionally substituted at the nitrogen atom by a C 1-3 -alkyl group,  
 a piperidinocarbonyl group or an aminocarbonyl group optionally substituted by one or two C 1-3 -alkyl groups,  
 a C 1-3 -alkyl group optionally terminally substituted 
 by an amino, C 1-4 -alkylamino, di-(C 1-4 -alkyl)-amino, phenylamino, N-phenyl-C 1-3 -alkylamino, phenyl-n-C 1-3 -alkylamino, N—(C 1-3 -alkyl)-phenyl-n-C 1-3 -alkylamino or di-(phenyl-n-C 1-3 -alkyl)-amino group, by a pyrrolidino, piperidino, hexamethyleneimino, morpholino, thiomorpholino, 1-oxido-thiomorpholino or piperazino group wherein the piperidino group may additionally be substituted by one or two C 1-3 -alkyl groups or by a carboxy, C 1-3 -alkoxycarbonyl, aminocarbonyl, C 1-3 -alkylaminocarbonyl-di-(C 1-3 -alkyl)-aminocarbonyl or N—(C 1-3 -alkyl)-phenyl-n-C 1-3 -alkylamino group,  
 
 by a C 5-7 -cycloalkylamino or C 5-7 -cycloalkenylamino group wherein position 1 of the ring is not involved in the double bond,  
 by a C 1-3 -alkylcarbonylamino, N—(C 1-3 -alkyl)-C 1-3 -alkylcarbonylamino, carboxy, C 1-3 -alkoxycarbonyl, aminocarbonyl, C 1-3 -alkylaminocarbonyl or di-(C 1-3 -alkyl)-aminocarbonyl group,  
 a C 1-3 -alkoxy group, which is terminally substituted by an amino, C 1-3 -alkylamino or di-(C 1-3 -alkyl)-amino group,  
 a group of formula  
   —N(R a )—CO—(CH 2 ) n —R b   (II),  
 wherein  
   R a  denotes a C 1-3 -alkyl group,    n denotes one of the numbers 0, 1 or 2 and    R b  denotes an amino, C 1-4 -alkylamino or di-(C 1-4 -alkyl)-amino group or a pyrrolidino, piperidino, hexamethyleneimino, morpholino, thiomorpholino, 1-oxido-thiomorpholino or piperazino group,    a group of formula      —N(R c )—(CH 2 ) m —(CO) o —R d   (III),    wherein    R c  denotes a C 1-3 -alkyl, C 1-3 -alkylcarbonyl or C 1-3 -alkylsulphonyl group, 
 m denotes one of the numbers 1, 2, 3 or 4,  
 o denotes one of the numbers 0 or 1 and  
 R d  has the meanings given for Rb hereinbefore or denotes a di-(C 1-4 -alkyl)-amino-C 1-3 -alkylamino group optionally substituted in the 1 position by a C 1-3 -alkyl group,  
   or R 6  denotes an N—(C 1-3 -alkyl)-C 1-3 -alkylsulphonylamino group.    
     
     
         3 . The compound according to  claim 2 , wherein 
 X denotes an oxygen atom;    R 1  denotes a methoxy, ethoxy, trifluoromethyl, phenyl, methylphenyl, dimethylamino, pyrrolidino or pyrrolo group, 
 an amino group which is optionally substituted by a methyl, carboxymethyl, methoxycarbonylmethyl, acetyl, phenylacetyl, benzoyl, methanesulphonyl, benzenesulphonyl or aminocarbonyl group;  
   R 2  denotes a hydrogen atom, a methoxy or ethoxy group or    R 1  and R 2  together denote a methylenedioxy group;    R 3  denotes an ethyl group or a phenyl group substituted by a cyano, aminomethyl or N-acetyl-aminomethyl group;    R 4  denotes a hydrogen atom;    R 5  denotes a hydrogen atom and    R 6  denotes a hydrogen, fluorine, chlorine, bromine or iodine atom,    a methyl, trifluoromethyl, methoxy, ethoxy, methylmercapto, cyano, carboxy, methoxycarbonyl, ethoxycarbonyl, aminocarbonyl, dimethylaminocarbonyl, piperidinocarbonyl, nitro, 4-methyl-piperazino, imidazolyl, pyridinyl or tetrazolyl group,    an ethyloxy or n-propyloxy group terminally substituted by a dimethylamino group,    a methyl or ethyl group substituted by a carboxy, methoxycarbonyl, ethoxycarbonyl, aminocarbonyl or dimethylaminocarbonyl group,    a C 1-3 -alkyl group, which is optionally terminally substituted 
 by an amino, C 1-4 -alkylamino, cyclohexylamino, benzylamino or phenylamino group wherein a hydrogen atom of the amino-nitrogen atom is optionally replaced in each case by a C 1-3 -alkyl, benzyl, acetyl or dimethylaminocarbonyl group,  
 by a piperidino group optionally substituted by one or two methyl groups, 
 by a piperidino group substituted by a carboxy, methoxycarbonyl, ethoxycarbonyl or dimethylaminocarbonyl group,  
 by a pyrrolidino, 3,4-dehydro-piperidino, hexa-methyleneimino, morpholino, thiomorpholino, 1-oxo-thio-morpholino or piperazino group,  
 
   a C 1-3 -alkylamino group wherein the hydrogen atom of the amino-nitrogen atom is replaced 
 by an ethyl or n-propyl group, each of which is terminally substituted by a dimethylamino group,  
 by a C 2-3 -alkanoyl group which is optionally substituted in the 2 or 3 position by an amino, C 1-3 -alkylamino, di-(C 1-3 -alkyl)-amino, pyrrolidino, piperidino, morpholino or piperazino group,  
 by an aminocarbonyl, methylaminocarbonyl, dimethylaminocarbonyl, piperidinocarbonyl or methanesulphonyl group,  
 wherein the C 1-3 -alkyl moiety of the C 1-3 -alkylamino group is further optionally substituted 
 by an aminocarbonyl group,  
 by a C 1-3 -alkylaminocarbonyl or di-(C 1-3 -alkyl)-aminocarbonyl group wherein a C 2-3 -alkyl moiety may additionally be terminally substituted by a dimethylamino group,  
 by a pyrrolidinocarbonyl, piperidinocarbonyl, morpholinocarbonyl or piperazinocarbonyl group,  
 
 and wherein the C 2-3 -alkyl moiety of the above-mentioned C 1-3 -alkylamino group is also further optionally terminally substituted by an amino, C 1-3 -alkylamino, di-(C 1-3 -alkyl)-amino, pyrrolidino, piperidino, morpholino or piperazino group.  
   
     
     
         4 . The compound according to  claim 3 ,  
       wherein 
 R 2  denotes a hydrogen atom.  
 
     
     
         5 . The compound according to  claim 4 ,  
       wherein 
 R 1  and R 2 , which are identical or different, each denote a C 1-3 -alkoxy group.  
 
     
     
         6 . The compound according to  claim 1 , wherein 
 X denotes an oxygen atom;    R 1  denotes an amino, methoxy or ethoxy group;    R 2  denotes a hydrogen atom or in position 5 a methoxy or ethoxy group;    R 3  denotes a C 1-3 -alkyl or a phenyl group substituted by a cyano, amino-C 1-3 -alkyl or N—(C 1-3 -alkanoyl)-amino-C 1-3 -alkyl group;    R 4  and R 5  each denote a hydrogen atom and    R 6  denotes a methyl or ethyl group substituted by a methylamino, ethylamino, piperidino or 4-(dimethylaminocarbonyl)-piperidino group, wherein the amino-hydrogen atom of the methylamino- and ethylamino group is replaced by a methyl or benzyl group, an N-dimethylaminomethylcarbonyl-N-methyl-amino group or an N-acetyl-N—(C 2-3 -alkyl)-amino group wherein the C 2-3 -alkyl moiety in each case is terminally substituted by a dimethylamino group.    
     
     
         7 . A compound, wherein the compound is 
 3-(Z)-{1-[4-(N-dimethylaminomethylcarbonyl-N-methyl-amino)-anilino]-1-ethyl-methylidene}-5,6-dimethoxy-2-indolinone 
 or the physiologically acceptable salts and isomers thereof.  
   
     
     
         8 . A pharmaceutical composition comprising a therapeutically effective amount of a compound according to  claim 1  and one or more inert carriers and/or diluents.  
     
     
         9 . A method of treating haemangiomas, metastasisation, rheumatoid arthritis, psoriasis, ocular neovascularisation or diabetic retinopathy, comprising administering to a patient in need thereof a therapeutically effective amount of a compound according  claim 1 .  
     
     
         10 . A method of inhibiting tumour cell proliferation comprising contacting a cell with an effective amount of a compound according to  claim 1 .  
     
     
         11 . A method of inhibiting tumour cell proliferation comprising administering to a patient a therapeutically effective of a compound according to  claim 1 .  
     
     
         12 . A method of treating solid tumours, comprising administering to a patient in need thereof a therapeutically effective amount of a compound according  claim 1 .  
     
     
         13 . A method of inhibiting endothelial cell proliferation comprising contacting a cell with an effective amount of a compound according to  claim 1 .  
     
     
         14 . A method of inhibiting endothelial cell proliferation comprising administering to a patient a therapeutically effective amount of a compound according to  claim 1.