CA2493436C - Indolinone derivatives, substituted in the 6-position, their preparation and their use as medicaments - Google Patents
Indolinone derivatives, substituted in the 6-position, their preparation and their use as medicaments Download PDFInfo
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Abstract
The present invention relates to indolinone derivatives, substituted in the 6-position, of the formula (see formula I) in which X is oxygen; R1, R5 and R6 are hydrogen; R2 is halo or cyano; and R3 and R4 are optionally substituted phenyl, to their tautomers, enantiomers, diastereomers, to their mixtures and to their salts, in particular their physiologically acceptable salts, which have useful pharmacological properties, in particular in inhibiting action on various receptor tyrosine kinases and on the proliferation of endothelial cells and various tumour cells, to medicaments comprising these compounds, to their use and to processes for their preparation.
Description
Boehringer Ingelheim Pharma GmbH & Co. KG 1-1504 foreign filing text Indolinone derivatives, substituted in the 6-position, their preparation and their use as medicaments The present invention relates to indolinone derivatives, substituted in the 6-position, of the formula N
R6 \ R5 X
R1 (I), to their tautomers, 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, PDGFRa, PDGFRI3, FGFR1, FGFR3, EGFR, HER2, c-Kit, IGF1 R 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.
R6 \ R5 X
R1 (I), to their tautomers, 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, PDGFRa, PDGFRI3, FGFR1, FGFR3, EGFR, HER2, c-Kit, IGF1 R 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.
1. In the above formula I, X is an oxygen atom, R' 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 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_2-alkyl-carbonyl-amino group, by a cyano-C1.3-alkyl, carboxy-C1.3-alkyl, carboxy-Cl.4-alkoxy, carboxy-C1_3-alkylamino, carboxy-C1.3-alkyl-N-(C1_3-alkyl)-amino, C1.4-alkoxy-carbonyl-C1.3-alkyl, C1_4-alkoxy-carbonyl-C1_3-alkoxy, C1.4-alkoxy-carbonyl-C1_3-alkylamino, C1_4-alkoxy-carbonyl-C1_3-alkyl-N-(C1_3-alkyl)-amino, amino-C1_3-alkyl, aminocarbonyl-C1.3-alkyl, (C1.2-alkylamino)-carbonyl-C1.3-alkyl, di-(C1.2-alkyl)-aminocarbonyl-C1.3-alkyl, (C1.2-alkyl-carbonyl)-amino-C1_3-alkyl, (C1_4-alkoxy-carbonyl)-amino-C1.3-alkyl, (C3-6-alkyl-carbonyl)-amino-C1_3-alkyl, (phenyl-carbonyl)-amino-C1_3-alkyl, (C3.6-cycloalkyl-carbonyl)-amino-C1_3-alkyl, (C3_6-cycloalkyl-C1_3-alkyl-carbonyl)-amino-C1_3-alkyl, (thiophen-2-yl-carbonyl)-amino-C1_3-alkyl, (furan-2-yl-carbonyl)-amino-C1.3-alkyl, (phenyl-C1.3-alkyl-carbonyl)-amino-C1.3-alkyl, (2-(C1_4-alkoxy)-benzoyl-carbonyl)-amino-C1.3-alkyl, (pyridin-2-yl-carbonyl)-amino-C1.3-alkyl, (pyridin-3-yl-carbonyl)-amino-C1_3-alkyl-, (pyridin-4-yl-carbonyl)-amino-C1_3-alkyl- or C1_3-alkyl-piperazin-1-yi-carbonyl-C1.3-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_4-alkoxy-carbonyl-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 di-(C1_2-alkyl)-amino-, N-[w-di-(C1_3-alkyl)-amino-C2_ 3-alkyl]-N-(C1.3-alkyl)-amino, N-methyl-(C3.4-alkyl)-amino, N-(C1_3-alkyl)-N-benzylamino, N-(C1.4-alkoxycarbonyl)-amino, N-(C1.4-alkoxycarbonyl)-C1.4-alkylamino, 4-(C1.3-alkyl)-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-alkyl)-sulphonyl, 2-[di-(C1_3-alkyl)-amino]-ethoxy, 4-(C1.3-alkyl)-piperazin-1-yl-carbonyl, {co-[di-(C1_3-alkyl)-amino]-(C2_3-alkyl)}-N-(C1.3-alkyl)-amino-carbonyl, 1-(C1_3-alkyl)imidazol-2-yl, (C1.3-alkyl)-sulphonyl group, or by a group of the formula in which R7 is a C1.2-alkyl, C1_2-alkyl-carbonyl, di-(C1.2-alkyl)-amino-carbonyl-C1.3-alkyl or C1.3-alkylsulphonyl group and R8 is C1.3-alkyl, w-[di-(C1_2-alkyl)-amino]-C2_3-alkyl, co-[mono-(C1_2-alkyl)-amino]-C2_3-alkyl group, or a (C1_3-alkyl)-carbonyl, (C4_6-alkyl)-carbonyl or carbonyl-(C1.3-alkyl) group which is terminally substituted by a di-(C1_2-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, methylsulphonate, para-toluenesuI phonate 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 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, 5 their tautomers, enantiomers, diastereomers, their mixtures and their salts.
II. Particularly preferred compounds of the above formula I are those compounds in which X, R1, R5 and R6 are as defined under I. and:
I1.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 C1.2-alkyl-carbonyl-amino group, by a cyano-C1_3-alkyl, carboxy-C1_3-alkyl, carboxy-C1.4-alkoxy, carboxy-C1.3-alkylamino, carboxy-C1_3-alkyl-N-(C1.3-alkyl)-amino, C1_4-alkoxy-carbonyl-Cl.3-alkyl, C1.4-alkoxy-carbonyl-C1_3-alkoxy, C1-4-alkoxy-carbonyl-C1_3-alkylamino, C1_4-alkoxy-carbonyl-C1.3-alkyl-N-(C1_3-alkyl)-amino, amino-C1.3-alkyl, aminocarbonyl-C1_3-alkyl, (C1.2-alkylamino)-carbonyl-C1_3-alkyl, di-(C1.2-alkyl)-aminocarbonyl-C1_3-alkyl, (C1_2-alkyl-carbonyl)-amino-C1.3-alkyl, (C1.4-alkoxy-carbonyl)-amino-C1_3-alkyl, (C3_ 6-alkyl-carbonyl)-amino-C1.3-alkyl, (phenyl-carbonyl)-amino-C1_3-alkyl, (C3.6-cycloalkyl-carbonyl)-amino-C1.3-alkyl, (C3_6-cycloalkyl-C1_3-alkyl-carbonyl)-amino-C1.3-alkyl, (thiophen-2-yl-carbonyl)-amino-C1.3-alkyl, (furan-2-yl-carbonyl)-amino-C1.3-alkyl, (phenyl-C13-alkyl-carbonyl)-amino-C1_3-alkyl, (2-(C1.4-alkoxy)-benzoyl-carbonyl)-amino-C1.3-alkyl, (pyridin-2-yl-carbonyl)-amino-Cl.3-alkyl, (pyridin-3-yl-carbonyl)-amino-C1.3-alkyl, (pyridin-4-yl-carbonyl)-amino-C1.3-alkyl or C1.3-alkyl-piperazin-1-yi-carbonyl-C1.3-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 C1.4-alkoxy-carbonyl-C2.3-alkenyl group, where the substituents may be identical or different;
Il.ii. R2 and R4 are as defined under I. and R3 is a phenyl group which is substituted by a C1.2-alkyl-carbonyl-amino group, by a carboxy-Cl.3-alkyl, carboxy-C1.4-alkoxy, C1.4-alkoxy-carbonyl-C1.3-alkyl, C1_4-alkoxy-carbonyl-C1 3-alkoxy, aminocarbonyl-Cl.3-alkyl, (C1-2-alkylamino)-carbonyl-Cl.3-alkyl, di-(C1.2-alkyl)-aminocarbonyl-C1 3-alkyl, (C1.2-alkyl-carbonyl)-amino-C1 3-alkyl, (C1-4-alkoxy-carbonyl)-amino-C1.3-alkyl, (phenyl-carbonyl)-amino-C13-alkyl, (C8.6-cycloalkyl-carbonyl)-amino-C1_3-alkyl, (C3.6-cycloalkyl-C1.3-alkyl-carbonyl)-amino-C1.3-alkyl, (thiophen-2-yl-carbonyl)-amino-C1.3-alkyl, (furan-2-yl-carbonyl)-amino-C1.3-alkyl, (phenyl-C1.3-alkyl-carbonyl)-amino-C1.3-alkyl, (2-(C14-alkoxy)-benzoyl-carbonyl)-amino-Cl.3-alkyl, (pyridin-2-yl-carbonyl)-amino-Cl.3-alkyl, (pyridin-3-yl-carbonyl)-amino-Cl.3-alkyl, (pyridin-4-yl-carbonyl)-amino-C1.3-alkyl or C1.3-alkyl-piperazin-1-yl-carbonyl-Cl.3-alkyl group, by an aminocarbonyl-C2_3-alkenyl, (C1_3-alkylamino)-carbonyl-C2_3-alkenyl, di-(C1.3-alkyl)-amino-carbonyl-C2_3-alkenyl or C1-4-alkoxy-carbonyl-C2_3-alkenyl group;
ll.iii. R2 and R4 are as defined under I. and R3 is a phenyl group substituted by a carboxy-C1.3-alkyl or C1_4-alkoxy-carbonyl-C1.3-alkyl group;
11. iv. R3 and R4 are as defined under I. and R2 is a fluorine or chlorine atom;
ll.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-(C1.2-alkyl)-amino-, N-[o -di-(C1.3-alkyl)-amino-C2_ 3-alkyl]-N-(C1.3-alkyl)-amino, N-methyl-(C3.4-alkyl)-amino, N-(C1_3-alkyl)-N-benzylamino, N-(C1.4-alkoxycarbonyl)-amino, N-(C1_4-alkoxycarbonyl)-C1.4-alkylamino, 4-(C1_3-alkyl)-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-alkyl)-sulphonyl, 2-[di-(C1.3-alkyl)-amino]-ethoxy, 4-(C1.3-alkyl)-piperazin-1-yl-carbonyl, {c -[di-(C1_3-alkyl)-amino]-(C2_3-alkyl)}-N-(C1_3-alkyl)-amino-carbonyl, 1-(C1_3-alkyl)imidazol-2-yl, (C1.3-alkyl)-sulphonyl group, or by a group of the formula in which R7 is a C1.2-alkyl, C1.2-alkyl-carbonyl, di-(C1.2-alkyl)-amino-carbonyl-C1_3-alkyl or C,_3-alkylsulphonyl group and R8 is C1.3-alkyl, co-[di-(C1.2-alkyl)-amino]-C2.3-alkyl, co-[mono-(C1.2-alkyl)-amino]-C2.3-alkyl group, or a (C1.3-alkyl)-carbonyl, (C4.6-alkyl)-carbonyl or carbonyl-(C1.3-alkyl) group which is terminally substituted by a di-(C1.2-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, methylsuIphonate, para-toluenesuI phonate and trifluoroacetate.
Ill. Subgroups of particularly preferred compounds of the above formula I
which are to be mentioned in particular are those in which:
Ill.i. X, R', R2, R5 and R6 are as defined under I., R3 is as defined under ILl. and R4 is as defined under ll.v.;
Ill.ii. X, R', R2, R5 and R6 are as defined under I., R3 is as defined under ll.ii. and R4 is as defined under ll.v.;
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.
1. In the above formula I, X is an oxygen atom, R' 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 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_2-alkyl-carbonyl-amino group, by a cyano-C1.3-alkyl, carboxy-C1.3-alkyl, carboxy-Cl.4-alkoxy, carboxy-C1_3-alkylamino, carboxy-C1.3-alkyl-N-(C1_3-alkyl)-amino, C1.4-alkoxy-carbonyl-C1.3-alkyl, C1_4-alkoxy-carbonyl-C1_3-alkoxy, C1.4-alkoxy-carbonyl-C1_3-alkylamino, C1_4-alkoxy-carbonyl-C1_3-alkyl-N-(C1_3-alkyl)-amino, amino-C1_3-alkyl, aminocarbonyl-C1.3-alkyl, (C1.2-alkylamino)-carbonyl-C1.3-alkyl, di-(C1.2-alkyl)-aminocarbonyl-C1.3-alkyl, (C1.2-alkyl-carbonyl)-amino-C1_3-alkyl, (C1_4-alkoxy-carbonyl)-amino-C1.3-alkyl, (C3-6-alkyl-carbonyl)-amino-C1_3-alkyl, (phenyl-carbonyl)-amino-C1_3-alkyl, (C3.6-cycloalkyl-carbonyl)-amino-C1_3-alkyl, (C3_6-cycloalkyl-C1_3-alkyl-carbonyl)-amino-C1_3-alkyl, (thiophen-2-yl-carbonyl)-amino-C1_3-alkyl, (furan-2-yl-carbonyl)-amino-C1.3-alkyl, (phenyl-C1.3-alkyl-carbonyl)-amino-C1.3-alkyl, (2-(C1_4-alkoxy)-benzoyl-carbonyl)-amino-C1.3-alkyl, (pyridin-2-yl-carbonyl)-amino-C1.3-alkyl, (pyridin-3-yl-carbonyl)-amino-C1_3-alkyl-, (pyridin-4-yl-carbonyl)-amino-C1_3-alkyl- or C1_3-alkyl-piperazin-1-yi-carbonyl-C1.3-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_4-alkoxy-carbonyl-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 di-(C1_2-alkyl)-amino-, N-[w-di-(C1_3-alkyl)-amino-C2_ 3-alkyl]-N-(C1.3-alkyl)-amino, N-methyl-(C3.4-alkyl)-amino, N-(C1_3-alkyl)-N-benzylamino, N-(C1.4-alkoxycarbonyl)-amino, N-(C1.4-alkoxycarbonyl)-C1.4-alkylamino, 4-(C1.3-alkyl)-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-alkyl)-sulphonyl, 2-[di-(C1_3-alkyl)-amino]-ethoxy, 4-(C1.3-alkyl)-piperazin-1-yl-carbonyl, {co-[di-(C1_3-alkyl)-amino]-(C2_3-alkyl)}-N-(C1.3-alkyl)-amino-carbonyl, 1-(C1_3-alkyl)imidazol-2-yl, (C1.3-alkyl)-sulphonyl group, or by a group of the formula in which R7 is a C1.2-alkyl, C1_2-alkyl-carbonyl, di-(C1.2-alkyl)-amino-carbonyl-C1.3-alkyl or C1.3-alkylsulphonyl group and R8 is C1.3-alkyl, w-[di-(C1_2-alkyl)-amino]-C2_3-alkyl, co-[mono-(C1_2-alkyl)-amino]-C2_3-alkyl group, or a (C1_3-alkyl)-carbonyl, (C4_6-alkyl)-carbonyl or carbonyl-(C1.3-alkyl) group which is terminally substituted by a di-(C1_2-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, methylsulphonate, para-toluenesuI phonate 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 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, 5 their tautomers, enantiomers, diastereomers, their mixtures and their salts.
II. Particularly preferred compounds of the above formula I are those compounds in which X, R1, R5 and R6 are as defined under I. and:
I1.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 C1.2-alkyl-carbonyl-amino group, by a cyano-C1_3-alkyl, carboxy-C1_3-alkyl, carboxy-C1.4-alkoxy, carboxy-C1.3-alkylamino, carboxy-C1_3-alkyl-N-(C1.3-alkyl)-amino, C1_4-alkoxy-carbonyl-Cl.3-alkyl, C1.4-alkoxy-carbonyl-C1_3-alkoxy, C1-4-alkoxy-carbonyl-C1_3-alkylamino, C1_4-alkoxy-carbonyl-C1.3-alkyl-N-(C1_3-alkyl)-amino, amino-C1.3-alkyl, aminocarbonyl-C1_3-alkyl, (C1.2-alkylamino)-carbonyl-C1_3-alkyl, di-(C1.2-alkyl)-aminocarbonyl-C1_3-alkyl, (C1_2-alkyl-carbonyl)-amino-C1.3-alkyl, (C1.4-alkoxy-carbonyl)-amino-C1_3-alkyl, (C3_ 6-alkyl-carbonyl)-amino-C1.3-alkyl, (phenyl-carbonyl)-amino-C1_3-alkyl, (C3.6-cycloalkyl-carbonyl)-amino-C1.3-alkyl, (C3_6-cycloalkyl-C1_3-alkyl-carbonyl)-amino-C1.3-alkyl, (thiophen-2-yl-carbonyl)-amino-C1.3-alkyl, (furan-2-yl-carbonyl)-amino-C1.3-alkyl, (phenyl-C13-alkyl-carbonyl)-amino-C1_3-alkyl, (2-(C1.4-alkoxy)-benzoyl-carbonyl)-amino-C1.3-alkyl, (pyridin-2-yl-carbonyl)-amino-Cl.3-alkyl, (pyridin-3-yl-carbonyl)-amino-C1.3-alkyl, (pyridin-4-yl-carbonyl)-amino-C1.3-alkyl or C1.3-alkyl-piperazin-1-yi-carbonyl-C1.3-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 C1.4-alkoxy-carbonyl-C2.3-alkenyl group, where the substituents may be identical or different;
Il.ii. R2 and R4 are as defined under I. and R3 is a phenyl group which is substituted by a C1.2-alkyl-carbonyl-amino group, by a carboxy-Cl.3-alkyl, carboxy-C1.4-alkoxy, C1.4-alkoxy-carbonyl-C1.3-alkyl, C1_4-alkoxy-carbonyl-C1 3-alkoxy, aminocarbonyl-Cl.3-alkyl, (C1-2-alkylamino)-carbonyl-Cl.3-alkyl, di-(C1.2-alkyl)-aminocarbonyl-C1 3-alkyl, (C1.2-alkyl-carbonyl)-amino-C1 3-alkyl, (C1-4-alkoxy-carbonyl)-amino-C1.3-alkyl, (phenyl-carbonyl)-amino-C13-alkyl, (C8.6-cycloalkyl-carbonyl)-amino-C1_3-alkyl, (C3.6-cycloalkyl-C1.3-alkyl-carbonyl)-amino-C1.3-alkyl, (thiophen-2-yl-carbonyl)-amino-C1.3-alkyl, (furan-2-yl-carbonyl)-amino-C1.3-alkyl, (phenyl-C1.3-alkyl-carbonyl)-amino-C1.3-alkyl, (2-(C14-alkoxy)-benzoyl-carbonyl)-amino-Cl.3-alkyl, (pyridin-2-yl-carbonyl)-amino-Cl.3-alkyl, (pyridin-3-yl-carbonyl)-amino-Cl.3-alkyl, (pyridin-4-yl-carbonyl)-amino-C1.3-alkyl or C1.3-alkyl-piperazin-1-yl-carbonyl-Cl.3-alkyl group, by an aminocarbonyl-C2_3-alkenyl, (C1_3-alkylamino)-carbonyl-C2_3-alkenyl, di-(C1.3-alkyl)-amino-carbonyl-C2_3-alkenyl or C1-4-alkoxy-carbonyl-C2_3-alkenyl group;
ll.iii. R2 and R4 are as defined under I. and R3 is a phenyl group substituted by a carboxy-C1.3-alkyl or C1_4-alkoxy-carbonyl-C1.3-alkyl group;
11. iv. R3 and R4 are as defined under I. and R2 is a fluorine or chlorine atom;
ll.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-(C1.2-alkyl)-amino-, N-[o -di-(C1.3-alkyl)-amino-C2_ 3-alkyl]-N-(C1.3-alkyl)-amino, N-methyl-(C3.4-alkyl)-amino, N-(C1_3-alkyl)-N-benzylamino, N-(C1.4-alkoxycarbonyl)-amino, N-(C1_4-alkoxycarbonyl)-C1.4-alkylamino, 4-(C1_3-alkyl)-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-alkyl)-sulphonyl, 2-[di-(C1.3-alkyl)-amino]-ethoxy, 4-(C1.3-alkyl)-piperazin-1-yl-carbonyl, {c -[di-(C1_3-alkyl)-amino]-(C2_3-alkyl)}-N-(C1_3-alkyl)-amino-carbonyl, 1-(C1_3-alkyl)imidazol-2-yl, (C1.3-alkyl)-sulphonyl group, or by a group of the formula in which R7 is a C1.2-alkyl, C1.2-alkyl-carbonyl, di-(C1.2-alkyl)-amino-carbonyl-C1_3-alkyl or C,_3-alkylsulphonyl group and R8 is C1.3-alkyl, co-[di-(C1.2-alkyl)-amino]-C2.3-alkyl, co-[mono-(C1.2-alkyl)-amino]-C2.3-alkyl group, or a (C1.3-alkyl)-carbonyl, (C4.6-alkyl)-carbonyl or carbonyl-(C1.3-alkyl) group which is terminally substituted by a di-(C1.2-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, methylsuIphonate, para-toluenesuI phonate and trifluoroacetate.
Ill. Subgroups of particularly preferred compounds of the above formula I
which are to be mentioned in particular are those in which:
Ill.i. X, R', R2, R5 and R6 are as defined under I., R3 is as defined under ILl. and R4 is as defined under ll.v.;
Ill.ii. X, R', R2, R5 and R6 are as defined under I., R3 is as defined under ll.ii. and R4 is as defined under ll.v.;
Ill.iii. X, R', R2, R5 and R6 are as defined under I., R3 is as defined under Il.iii. and R4 is as defined under II.v.;
Ill.iv. X, R', R5 and R6 are as defined under I., R2 is as defined under ll.iv., R3 is as defined under II.i., ll.ii. or ll.iii. and R4 is as defined under Il.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 phenyl 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_2-alkyl-carbonyl-amino group, by a carboxy-C1_3-alkyl, aminocarbonyl-C1_3-alkyl, (C1.2-alkylamino)-carbonyl-C1_3-alkyl, di-(C1.2-alkyl)-aminocarbonyl-C1.3-alkyl, (C1.2-alkyl-carbonyl)-amino-C1.3-alkyl or (phenyl-carbonyl)-amino-C1.3-alkyl group, where the substituents may be identical or different, R4 is a phenyl group which is substituted by a C1.3-alkyl group terminally substituted by a di-(C1_2-alkyl)-amino group, or by a group of the formula -N
in which R7 is a C1_2-alkyl, C1.2-alkyl-carbonyl, di-(C1_2-alkyl)-amino-carbonyl-C1_3-alkyl or C1.3-alkylsulphonyl group and R8 is a C1.3-alkyl or co-[di-(C1_2-alkyl)-amino]-C2.3-alkyl group, or a C1.3-alkyl-carbonyl group terminally substituted by a di-(C1_2-alkyl)-amino, piperazino or 4-(C1.3-alkyl)-piperazin-1-yl group, 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 cleavable radical, their tautomers, enantiomers, diastereomers, their mixtures and their salts.
The following compounds of the formula I are particularly preferred:
(a) 3-Z-[1-(4-dimethylaminomethylanilino)-1-(3-(2-carboxyethyl)phenyl)methylene]-6-chloro-2-indolinone (b) 3-Z-[1-(4-dimethylaminomethylanilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone (c) 3-Z-[1-(4-dimethylaminomethylanilino)-1-(3-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone (d) 3-Z-[1-(4-(N-(4-methylpiperazin-1-ylmethylcarbonyl)-N-methylamino)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone (e) 3-Z-[1-(4-(N-(2-dimethylaminoethyl)-N-methylsulphonylamino)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone (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)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone (h) 3-Z-[1-(4-(N-(dimethylaminomethylcarbonyl)-N-methylamino)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone (i) 3-Z-[1-(4-(N-(2-dimethylaminoethylcarbonyl)-N-methylamino)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone Q) 3-Z-[1-(4-(pyrrolidin-1-ylmethyl)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone (k) 3-Z-[1-(4-(diethylaminomethyl)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone (I) 3-Z-[1-(4-(2-dimethylaminoethyl)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-chloro-2-indolinone (m) 3-Z-[1-(4-dimethylaminomethylanilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-chloro-2-indolinone (n) 3-Z-[1-(4-(pyrrolidin-1-ylmethyl)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-chloro-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)phenyl)methylene]-6-bromo-2-indolinone (q) 3-Z-[1-(4-(diethylaminomethyl)anilino)-1-(4-(2-carboxyethyl)-methylene]-6-bromo-2-indolinone where additionally a carboxyl, 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 C3_9-cycloalkanol, where a C5_8-cycloalkanol may additionally be substitituted by one or two C1_3-alkyl groups, a C5_8-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 C1.3-alkyl, phenyl-C1.3-alkyl, phenyl-C1_3-alkoxy-carbonyl or C1.6-alkyl-carbonyl group and in which the cycloalkanol moiety may additionally be substituted by one or two C1_3-alkyl groups, a C4_7-cycloalkenol, a C3_5-alkenol, a phenyl-C3_5-alkenol, a C3_5-alkynol or a phenyl-C3.5-alkynol, with the proviso that no bond to the oxygen atom originates from a carbon atom which carries a double or triple bond, a C3_8-cycloalkyl-C1.3-alkanol, a bicycloalkanol 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-O-(RbCRc)-OH, in which Ra is a C1.8-alkyl, C5_7-cycloalkyl, phenyl or phenyl-C1.3-alkyl group, Rb is a hydrogen atom, a C1.3-alkyl, C5.7-cycloalkyl or phenyl group, and Rc is a hydrogen atom or a C,_3-alkyl group, and a radical cleavable in vivo from an imino or amino group is to be understood as meaning, for example, a hydroxyl group, an acyl group, such as the benzoyl or pyridinoyl group, or a C1_16-alkylcarbonyl group, such as the formyl, acetyl, propionyl, butanoyl, pentanoyl or hexanoyl group, an allyloxycarbonyl group, a C1_16-alkoxy-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_6-alkoxy-carbonyl group, such as the benzyloxycarbonyl, phenylethoxycarbonyl or phenylpropoxycarbonyl group, a C1.3-alkylsulphonyl-C1_4-alkoxy-carbonyl, C1.3-alkoxy-C2-4-alkoxy-C2_4-alkoxy-carbonyl or RaCO-O-(RbCRc)-O-CO- group, in which Ra is a C1_8-alkyl, C5_7-cycloalkyl, phenyl or phenyl-C1.3-alkyl group, Rb is a hydrogen atom, a C1_3-alkyl, C5_7-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 amino 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 carboxyl 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-pentyloxycarbonyl, n-hexyloxycarbonyl or cyclohexyloxycarbonyl group, or a phenyl-C1_3-alkoxy-carbonyl group, such as the benzyloxycarbonyl group, and, for an imino or amino group, a C,_9-alkoxy-carbonyl group, such as the methoxy-carbonyl, ethoxycarbonyl, n-propyloxycarbonyl, isopropyloxycarbonyl, n-butyloxy-carbonyl, n-pentyloxycarbonyl, n-hexyloxycarbonyl, cyclohexyloxycarbonyl, n-heptyloxycarbonyl, n-octyloxycarbonyl or n-nonyloxycarbonyl group, a phenyl-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-alkylsulphonyl-n-C2_3-alkoxy-carbonyl or C1.3-alkoxy-C2_3-alkoxy-C1.4-alkoxy-carbonyl group, such as the 2-methylsulphonylethoxycarbonyl or 2-(2-ethoxy)-ethoxycarbonyl 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 N
R1 (V) in which the radicals Z' and R3 may, if appropriate, change their positions, X, R2, R3 and R6 are as defined at the outset, R" 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 Z' 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 I
H (VI), in which R4 and R5 are defined as mentioned at the outset, 5 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 10 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, 15 such as a 2,5-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, Z' 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, Z' 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 out either hydrolytically in an aqueous or alcoholic solvent, for example in methanol/water, ethanol/water, isopropanol/water, tetra hyd rofu ra n/wate r, dioxane/water, dimethylformamide/water, methanol or ethanol, in the 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, 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-alkenyl, aminocarbonyl-C2.3-alkenyl, (C,.3-alkylamino)-carbonyl-C2.3-alkenyl, di-(C,.3-alkylamino)-carbonyl-C2_3-alkenyl or C1.4-alkoxy-carbonyl-C2_3-alkenyl group, reaction of a compound of the formula N
N
R
R" (IX), in which R2, R4, R5, R6 and X are as defined at the outset, R" has the meanings mentioned at the outset for R1 or is a protective group for the nitrogen atom of the lactam group, where R'' 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 alkyl- or arylsulphonyloxy group, such as a chlorine, bromine or iodine atom or a methylsulphonyloxy, ethylsulphonyloxy, p-toluenesulphonyloxy or trifluoromethanesulphonyloxy group, with an alkene of the formula O
R3, n \
(X), in which R3" is an amino, (C1_3-alkylamino), di-(C1.3-alkylamino) or C1-4-alkoxy group and n is the number 0 or 1.
The reaction is expediently carried out with palladium catalysis, using, for example, palladium(II) acetate, palladium(II) chloride, bis(triphenylphosphine)palladium(ll) acetate, bis(triphenylphosphine)palladium(II) chloride, palladium/carbon, bis-[1,2-bis(diphenylphosphino)ethane]palladium(0), dichloro-(1,2-bis(diphenylphosphino)-ethane)palladium(II), tetrakistriphenylphosphinepaIladium(0), tris(dibenzylidene-acetone)dipalladium(0), 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, C1.4-alkoxy-carbonyl-C1.3-alkyl, aminocarbonyl-C1.3-alkyl, (C1.3-alkylamino)-carbonyl-C1.3-alkyl or di-(C1_3-alkyl)-aminocarbonyl-C1.3-alkyl group, hydrogenation of a compound of the formula R3, YO
A
N
N
R
R1 (XI), in 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 C2_3-alkenyl group and R3. is a hydroxyl, C1_4-alkoxy, amino, (C1_3-alkylamino) or di-(C1.3-alkyl)amino 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 bar.
The cleavage of a protective group used for the nitrogen atom of the lactam group or 5 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 carboxyl compound, or if a compound of the formula I is obtained which contains an amino or alkylamino 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 suiphonation into a corresponding acyl or sulphonyl compound, respectively, or if a compound of the formula I is obtained which contains a carboxyl 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 alkoxycarbonyl group, 5 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 carbamoyl halide 10 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 15 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, 20 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 temperatures between 0 and 100 C, preferably at temperatures between 10 and 50 C.
The subsequent reductive alkylation is preferably carried out in a suitable solvent, such as methanol, methanol/water, methanol/water/ammonia, ethanol, ether, tetrahydrofuran, dioxane or dimethylformamide, if appropriate with addition of an acid, such as hydrochloric acid, in the presence of catalytically activated hydrogen, for example of hydrogen in the presence of Raney nickel, platinum or palladium/carbon, or in the presence of a metal hydride, such as sodium borohydride, lithium borohydride, sodium cyanoborohydride or lithium aluminium hydride, at temperatures between 0 and 100 C, preferably at temperatures between 20 and 80 C.
The subsequent alkylation is preferably carried out in a suitable solvent, such as ether, tetrahydrofuran, dioxane, dichloromethane, acetone or acetonitrile, in the presence of alkylating agents, such as alkyl iodides, alkyl bromides, alkyl chlorides, methanesulphonic acid alkyl esters, para-toluenesulphonic acid alkyl esters or alkyl trifluoroacetates, at temperatures between 0 and 100 C, 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 chloride, diethyl ether, tetrahydrofuran, toluene, dioxane, acetonitrile, dimethyl sulphoxide or dimethylformamide, if 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, trimethyl orthoacetate, 2,2-dimethoxypropane, tetramethoxysilane, thionyl chloride, trimethylchIorosilane, phosphorus trichioride, phosphorus pentoxide, N,N'-dicyclohexylcarbodiimide, N,N'-dicyclohexylcarbodiimide/N-hydroxysuccinimide, N,N'-dicyclohexyl-carbodiimide/1-hydroxybenzotriazole, 2-(1 H-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 100 C. 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, N-methylmorpholine or pyridine, or, if an anhydride is used, in the presence of the corresponding acids, at temperatures between 0 and 150 C, preferably at temperatures between 50 and 100 C.
The subsequent esterification or amidation 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, diethyl 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 boiling 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 chloroformate, 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-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium-tetrafluoroborate, 2-(1 H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate/ 1-hydroxybenzotriazo le, N,N'-carbonyldiimidazole or triphenyl-phosphine/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 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 triethylamine, N-ethyldiisopropylamine or N-methylmorpholine, at temperatures between 0 and 150 C, preferably at temperatures between 50 and 100 C.
The subsequent reduction of a nitro group is preferably carried out hydrogenolytically, 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 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 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, trifiuoroacetyl, benzoyl, ethoxycarbonyl, tert-butoxycarbonyl, benzyloxycarbonyl, benzyl, methoxybenzyl or 2,4-dimethoxybenzyl 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 the 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, 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.
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 or acetonitrile/water, at temperatures between 0 and 50 C, but preferably at room temperature.
However, a 2,4-dimethoxybenzyl radical is preferably removed in trifluoroacetic acid in the presence of anisole.
A tert-butyl 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 amine, such as methylamine, ethylamine or n-butylamine, in a solvent, such as methanol, ethanol, isopropanol, toluene/water or dioxane, at temperatures between 20 and 50 C.
Furthermore, chiral compounds of the 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 5 can be separated by methods known per se (see Allinger N. L. and Eliel 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 10 diastereomers, which, if they are obtained in racemic form, 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 15 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 20 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, camphorsuIphonic acid, glutamic acid, N-acetylglutamic acid, aspartic acid, N-acetylaspartic acid or quinic acid. A
suitable optically active alcohol is, for example, (+)- or (-)-menthol, and a suitable optically 25 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-toluenesulphonic acid, phenylsulphonic acid or L-(+)-mandelic acid.
Moreover, the resulting novel compounds of the formula I 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 198 44 003.
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, PDGFR X, PDGFR3, FGFR1, FGFR3, EGFR, HER2, c-Kit, IGF1 R and HGFR, Fit-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
R-mercaptoethanol (Fluka), standard antibiotics, 15 pg/ml of endothelial cell growth factor (ECGS, Collaborative Biomedical Products) and 100 pg/ml of heparin (Sigma) on gelatin-coated culture bottles (0.2 % gelatin, Sigma) at 37 C, 5% C02, 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 VEGF165 (vascular endothelial growth factor; H. Weich, GBF Brunswick) and 10 pg/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 p Ci/well, Amersham) was then added for a further 16 hours to determine DNA synthesis.
The radioactively labelled cells were then immobilized on filter mats and the incorporated radioactivity was determined in a R 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% (IC50) was derived therefrom.
The compounds of the formula I according to the invention have an IC50 between 50 pM 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 cells, in particular that of endothelial cells, 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 Parangi et at. (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-cell 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), mesangial-cell-proliferative disorders, atherosclerosis, injuries of the nerve tissue and for inhibiting the reocciusion 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 role.
Owing to their biological properties, the compounds according to the invention can be 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:
Example Name 1.0 3-Z-[1 -(4-(N-methyl-N-methylsulphonylamino)anilino)-1 -(3-iodophenyl)-methylene]-6-chloro-2-indolinone 1.1 3-Z-[1 -(4-(dimethylaminomethyl)anilino)-1 -(3-iodophenyl)methylene]-6-chloro-2-indolinone 1.2 3-Z-[1-(4-(N-(dimethylaminomethylcarbonyl)-N-methylamino)anilino)-1-(4-chlorophenyl)methylene]-6-chloro-2-indolinone 1.3 3-Z-[1 -(4-(N-(2-dimethylaminoethyl)-N-acetylamino)anilino)-1 -(4-chlorophenyl)methylene]-6-chloro-2-indolinone 3-Z-[1-(4-(N-(4-methylpiperazin-1-ylmethylcarbonyl)-N-1.4 methylamino)anilino)-1-(4-chlorophenyl)methylene]-6-chloro-2-indolinone 1.5 3-Z-[1 -(4-(N-(3-dimethylaminopropyl)-N-acetylamino)anilino)-1 -(4-chlorophenyl)methylene]-6-chloro-2-indolinone 1.6 3-Z-[1 -(4-(dimethylaminomethyl)anilino)-1 -(4-chlorophenyl)methylene]-6-ch loro-2-indolinone 1.7 3-Z-[1 -(4-(N-(2-dimethylaminoethyl)-N-acetylamino)anilino)-1 -(3,4-d imethoxyphenyl)methylene]-6-chloro-2-indolinone 3-Z-[1 -(4-(N-(4-methylpiperazin-1 -ylmethylcarbonyl)-N-1.8 methylamino)anilino)-1-(3,4-dimethoxyphenyl)methylene]-6-chloro-2-indolinone 1.9 3-Z-[1 -(4-(N-(2-dimethylaminoethyl)-N-methylsulphonylamino)anilino)-1-(3,4-dimethoxyphenyl)methylene]-6-chloro-2-indolinone 1.10 3-Z-[1 -(4-(dimethylaminomethyl)anilino)-1 -(3,4-dimethoxyphenyl)-methylene]-6-chloro-2-indolinone 1.11 3-Z-[1-(4-(N-(2-dimethylaminoethyl)-N-methylcarbamoyl)anilino)-1-(3,4-dimethoxyphenyl)methylene]-6-chloro-2-indolinone 2.0 3-Z-[1-(4-(dimethylaminomethyl)anilino)-1-(4-cyanophenyl)-methylene]-6-chloro-2-indolinone 3.0 3-Z-[1-(4-(dimethylaminomethyl)anilino)-1-(4-iodophenyl)methylene]-6-fluoro-2-indolinone 3.1 3-Z-[1-(4-(dimethylaminomethyl)anilino)-1-(3-fluorophenyl)methylene]-6-fluoro-2-indolinone 3.2 3-Z-[1-(4-(N-(3-dimethylaminopropyl)-N-acetylamino)anilino)-1-(3-fluorophenyl)methylene]-6-fluoro-2-indolinone 3-Z-[1-(4-(N-(4-methylpiperazin-1-ylmethylcarbonyl)-N-3.3 methylamino)anilino)-1-(3-fluorophenyl)methylene]-6-fluoro-2-indolinone 3.4 3-Z-[1-(4-(dimethylaminomethyl)anilino)-1-(4-(2-acetylaminoethyl)phenyl)methylene]-6-fluoro-2-indolinone 3.5 3-Z-[1 -(4-(N-(3-dimethylaminopropyl)-N-acetylamino)anilino)-1-(4-(2-acetylaminoethyl)phenyl)methylene]-6-fluoro-2-indolinone 3-Z-[1-(4-(N-(4-methylpiperazin-1-ylmethylcarbonyl)-N-3.6 methylamino)anilino)-1-(4-(2-acetylaminoethyl)phenyl)methylene]-6-fluoro-2-indolinone 3.7 3-Z-[1-(4-(dimethylaminomethyl)anilino)-1-(4-methoxycarbonylmethylphenyl)methylene]-6-fluoro-2-indolinone 3.8 3-Z-[1-(4-(dimethylaminomethyl)anilino)-1-(3-iodophenyl)methylene]-6-fluoro-2-indolinone 3.9 3-Z-[1-(4-(dimethylaminomethyl)anilino)-1-(3-methoxycarbonylmethylphenyl)methylene]-6-fluoro-2-indolinone 3.10 3-Z-[1-(4-(dimethylaminomethyl)anilino)-1-(3-(N-tert-butoxycarbonyl-aminomethyl)phenyl)methylene]-6-fluoro-2-indolinone 3.11 3-Z-[1-(4-(N-(2-dimethylaminoethyl)-N-methylsulphonylamino)anilino)-1-(4-methoxycarbonylmethylphenyl)methylene]-6-fluoro-2-indolinone 3-Z-[1-(4-(N-(4-methylpiperazin-1-ylmethylcarbonyl)-N-3.12 methylamino)anilino)-1-(4-methoxycarbonylmethylphenyl)methylene]-6-fluoro-2-indolinone 3.13 3-Z-[1-(4-(dimethylaminomethyl)anilino)-1-(3-cyanomethyiphenyl)-methylene]-6-fluoro-2-indolinone 3-Z-[1-(4-(N-(4-methylpiperazin-1-ylmethylcarbonyl)-N-3.14 methylamino)anilino)-1-(4-(N-tert-butoxycarbonyl-aminomethyl)phenyl)methylene]-6-fluoro-2-indolinone 3.15 3-Z-[1-(4-(dimethylaminomethyl)anilino)-1-(4-(N-tent-butoxycarbonyl-aminomethyl)phenyl)methylene]-6-fluoro-2-indolinone 3.16 3-Z-[1-(4-(dimethylaminomethyl)anilino)-1-(3-(N-tert-butoxycarbonyl-2-aminoethyl)phenyl)methylene]-6-fluoro-2-indolinone 3.17 3-Z-[1-(4-(N-Acetyl-N-methylamino)anilino)-1-(4-(2-methoxycarbonylethyl)phenyl)methylene]-6-fluoro-2-indolinone 3-Z-[1-(4-(N-(4-methylpiperazin-1-ylmethylcarbonyl)-N-3.18 methylamino)anilino)-1-(4-(2-methoxycarbonylethyl)phenyl)methylene]-6-fluoro-2-indolinone 3.19 3-Z-[1-(4-(N-(2-dimethylaminoethyl)-N-methylsulphonylamino)anilino)-1-(4-methoxycarbonylmethylphenyl)methylene]-6-fluoro-2-indolinone 3.20 3-Z-[1-(4-(N-(3-dimethylaminopropyl)-N-acetylamino)anilino)-1-(4-(2-methoxycarbonylethyl)phenyl)methylene]-6-fluoro-2-indolinone 3.21 3-Z-[1-(4-(N-tert-butoxycarbonylmethylaminomethyl)anilino)-1-(4-(2-methoxycarbonylethyl)phenyl)methylene]-6-fluoro-2-indolinone 3.22 3-Z-[1-(4-(4-methylpiperazin-1-yl-carbonyl )anilino)-1-(4-(2-methoxycarbonylethyl)phenyl)methylene]-6-fluoro-2-indolinone 3.23 3-Z-[1-(4-(1-methylimidazol-2-yl)anilino)-1-(4-(2-methoxycarbonylethyl)phenyl)methylene]-6-fluoro-2-indolinone 3.24 3-Z-[1-(4-methylsulphonylanilino)-1-(4-(2-methoxycarbonylethyl)phenyl)methylene]-6-fluoro-2-indolinone 3-Z-[1-(4-(N-(4-methylpiperazin-1-ylmethylcarbonyl)-N-3.25 methylamino)anilino)-1-(3-methoxycarbonylmethylphenyl)methylene]-6-fluoro-2-indolinone 3.26 3-Z-[1-(4-(N-(2-dimethylaminoethyl)-N-methylsulphonylamino)anilino)-1-(3-methoxycarbonylmethylphenyl)methylene]-6-fluoro-2-indolinone 3.27 3-Z-[1-(4-(4-methylpiperazin-1-yl-carbonyl)anilino)-1-(3-methoxycarbonylmethylphenyl)methylene]-6-fluoro-2-indolinone 3.28 3-Z-[l -(4-(N-(dimethylaminomethylcarbonyl)-N-methylamino)anilino)-1-(3-methoxycarbonylmethyl phenyl)methylene]-6-fluoro-2-indolinone 3.29 3-Z-[1-(4-(N-(3-dimethylaminopropyl)-N-acetylamino)anilino)-1-(3-methoxycarbonylmethylphenyl)methylene]-6-fluoro-2-indolinone 3.30 3-Z-[1-(4-(N-(2-dimethylaminoethyl)-N-acetylamino)anilino)-1-(3-methoxycarbonylmethylphenyl)methylene]-6-fluoro-2-indolinone 3.31 3-Z-[1-(4-(N-(4-dimethylamino-butylcarbonyl)-N-methylamino)anilino)-1-(3-methoxycarbonylmethylphenyl)methylene]-6-fluoro-2-indolinone 3-Z-[1-Anilino-1-(4-methoxycarbonylmethylphenyl)methylene]-6-fluoro-3.32 2-indolinone 3.33 3-Z-[1-(4-(1-methylimidazol-2-yl)anilino)-1-(4-methoxycarbonylmethylphenyl)methylene]-6-:fluoro-2-indolinone 3.34 3-Z-[1-(4-(4-methylpiperazin-1-ylcarbonyl)anilino)-1-(4-methoxycarbonylmethylphenyl)methylene]-6-fluoro-2-indolinone 3-Z-[1-(4-(N-(dimethylaminocarbonylmethyl)-N-3.35 methylsulphonylamino)anilino)-1-(4-methoxycarbonylmethyiphenyl)-methylene]-6-fluoro-2-indolinone 3.36 3-Z-[1-(4-(N-(dimethylaminomethylcarbonyl)-N-methylamino)anilino)-1-(4-methoxycarbonylmethylphenyl)methylene]-6-fluoro-2-indolinone 3.37 3-Z-[1-(4-(N-methyl-N-acetylamino)anilino)-1-(4-methoxycarbonylmethylphenyl)methylene]-6-fluoro-2-indolinone 3.38 3-Z-[1-(4-(N-(2-dimethylaminoethylcarbonyl)-N-methylamino)anilino)-1-(4-methoxycarbonylmethylphenyl)methylene]-6-fluoro-2-indolinone 3.39 3-Z-[1-(4-methylsulphonylanilino)-1-(4-methoxycarbonylmethylphenyl)methylene]-6-fluoro-2-indolinone 3.40 3-Z-[1-(4-(N-(3-dimethylaminopropylcarbonyl)-N-methyiamino)anilino)-1-(4-methoxycarbonylmethylphenyl)methylene]-6-fluoro-2-indolinone 3.41 3-Z-[1-(4-(N-(3-dimethylaminopropyl)-N-acetylamino)anilino)-1-(4-methoxycarbonylmethylphenyl)methylene]-6-fluoro-2-indolinone 3.42 3-Z-[1-Anilino-1-(3-methoxycarbonylmethylphenyl)methylene]-6-fluoro-2-indolinone 3.43 3-Z-[1-(4-methylsulphonylanilino)-1-(3-methoxycarbonylmethylphenyl)-methylene]-6-fluoro-2-indolinone 3.44 3-Z-[1-(4-(1-methylimidazol-2-yl)anilino)-1-(3-methoxycarbonylmethylphenyl)methylene]-6-fluoro-2-indolinone 3-Z-[l-(4-(N-(dimethylaminocarbonylmethyl)-N-3.45 methylsulphonylamino)anilino)-1-(3-methoxycarbonylmethylphenyl)-methyiene]-6-fluoro-2-indolinone 3.46 3-Z-[1-(4-(N-(3-dimethylaminopropylcarbonyl)-N-methylamino)anilino)-1-(3-methoxycarbonylmethylphenyl)methylene]-6-fluoro-2-indolinone 3.47 3-Z-[1-(4-(N-(2-dimethylaminoethylcarbonyl)-N-methylamino)anilino)-1-(3-methoxycarbonylmethyl phenyl)methylene]-6-fluoro-2-indolinone 3-Z-[1-(4-(N-(4-methylpiperazin-l -ylmethylcarbo,nyl)-N-3.48 methylamino)anilino)-1-(3-(2-methoxycarbonylethyl)phenyi)methylene]-6-fluoro-2-indolinone 3.49 3-Z-[1-(4-(N-(2-dimethylaminoethyl)-N-methylsulphonylamino)anilino)-1-(3-(2-methoxycarbonylethyl)phenyl)methylene]-6-fluoro-2-indolinone 3.50 3-Z-[1-(4-(N-(dimethylaminomethylcarbonyl)-N-methylamino)anilino)-1-(3-(2-methoxycarbonylethyl)phenyl)methylene]-6-fluoro-2-indolinone 3.51 3-Z-[1-(4-(N-(3-dimethylaminopropyl)-N-acetylamino)anilino)-1-(3-(2-methoxycarbonylethyl)phenyl)methylene]-6-fluoro-2-indolinone 3-Z-[1-(4-(N-(4-methylpiperazin-1-ylmethylcarbonyl)-N-3.52 methylamino)anilino)-1-(3-(N-tert-butoxycarbonyl-aminomethyl)phenyl)methylene]-6-fluoro-2-indolinone 3.53 3-Z-[1-(4-(N-methyl-N-acetylamino)anilino)-1-(3-acetylaminomethylphenyl)methylene]-6-chloro-2-indolinone 3.54 3-Z-[1-(4-(N-(3-dimethylaminopropyl)-N-acetylamino)anilino)-1-(3-acetylaminomethylphenyl)methylene]-6-chloro-2-indolinone 3.55 3-Z-[1-(4-(N-(2-dimethylaminoethyl)-N-methylsulphonylamino)anilino)-1-(3-acetylaminomethylphenyl)methylene]-6-chloro-2-indolinone 3.56 3-Z-[1-(4-(N-(dimethylaminomethylcarbonyl)-N-methylamino)anilino)-1-(3-acetylaminomethylphenyl)methylene]-6-chloro-2-indolinone 3.57 3-Z-[1-(4-(2-dimethylaminoethyl)anilino)-1-(4-(2-methoxycarbonylethyl)phenyl)methylene]-6-fluoro-2-indolinone 3.58 3-Z-[1-(4-(N-(2-dimethylaminoethylcarbonyl)-N-methylamino)anilino)-1-(4-(2-methoxycarbonylethyl)phenyl)methylene]-6-fluoro-2-indolinone 3.59 3-Z-[1-(4-(N-(dimethylaminomethylcarbonyl)-N-methylamino)anilino)-1-(4-(2-methoxycarbonylethyl)phenyl)methylene]-6-fluoro-2-indolinone 3.60 3-Z-[1-(4-(2-dimethylaminoethyl)anilino)-1-(3-(2-ethoxycarbonylethyl)phenyl)methylene]-6-fluoro-2-indolinone 3.61 3-Z-[1-(4-(N-(2-dimethylaminoethyl)-N-acetylamino)anilino)-1-(4-(2-methoxycarbonylethyl)phenyl)methylene]-6-fluoro-2-indolinone 3.62 3-Z-[1-(4-(N-(3-dimethylaminopropylcarbonyl)-N-methylamino)anilino)-1-(3-(2-ethoxycarbonylethyl)phenyl)methylene]-6-fluoro-2-indolinone 3.63 3-Z-[1-(4-(N-(4-dimethylaminobutylcarbonyl)-N-methylamino)anilino)-1-(3-(2-ethoxycarbonylethyl)phenyl)methylene]-6-fluoro-2-indolinone 3.64 3-Z-[1-(4-(1-methylimidazol-2-yl)anilino)-1-(3-(2-ethoxycarbonylethyl)phenyl)methylene]-6-fluoro-2-indolinone 3.65 3-Z-[1-(4-(N-(4-dimethylaminobutylcarbonyl)-N-methylamino)anilino)-1-(4-(2-methoxycarbonylethyl)phenyl)methylene]-6-fluoro-2-indolinone 3.66 3-Z-[1 anilino-1 -(4-(2-methoxycarbonylethyl)phenyl)methylene]-6-fluoro-2-indolinone 3.67 3-Z-[1-(4-(pyrrolidin-1-ylmethyl)anilino)-1-(4-(2-methoxycarbonylethyl)phenyl)methylene]-6-fluoro-2-indolinone 3.68 3-Z-[1-(4-(diethylaminomethyl)anilino)-1-(4-(2-methoxycarbonylethyl)phenyl)methylene]-6-fluoro-2-indolinone 3.69 3-Z-[1-(4-(N-tert-butoxycarbonylaminomethyl)anilino)-1-(4-(2-methoxycarbonylethyl)phenyl)methylene]-6-fluoro-2-indolinone 3.70 3-Z-[1-(4-(2-dimethylaminoethyl)anilino)-1-(3-methoxycarbonylmethylphenyl)methylene]-6-fluoro-2-indolinone 3.71 3-Z-[1-(4-(2-dimethylaminoethyl)anilino)-1-(4-methoxycarbonylmethylphenyl)methylene]-6-fluoro-2-indolinone 3.72 3-Z-[1-(4-(dimethylaminomethyl)anilino)-1-(3-(2-ethoxycarbonylethyl)phenyl)methylene]-6-fluoro-2-indolinone 3.73 3-Z-[1-(4-(2-dimethylaminoethyl)anilino)-1-(4-(2-methoxycarbonylethyl)phenyl)methylene]-6-chloro-2-indolinone 3.74 3-Z-[1-(4-(1-methylimidazol-2-yl)anilino)-1-(4-(2-ethoxycarbonylethyl)phenyl)methylene]-6-chloro-2-indolinone 3.75 3-Z-[1-(4-dimethylaminomethylanilino)-1-(4-(2-methoxycarbonylethyl)phenyl)methylene]-6-chloro-2-indolinone ------ ------ -3.76 3-Z-[1-(4-dimethylaminomethylanilino)-1-(4-(2-ethoxycarbonylethyl)phenyl)methylene]-6-fluoro-2-indolinone 3.77 3-Z-[1-(4-((4-methylpiperazin-1-yl)methyl)anilino)-1-(3-(2-methoxycarbonylethyl)phenyl)methylene]-6-fluoro-2-indolinone 3.78 3-Z-[1-(4-(imidazol-1-ylmethyl)anilino)-1-(3-(2-methoxycarbonylethyl)phenyl)methylene]-6-fluoro-2-indolinone 3.79 3-Z-[1-(4-((4-methylpiperazin-1-yl)methyl)anilino)-1-(4-(2-methoxycarbonylethyl)phenyl)methylene]-6-fluoro-2-indolinone 3.80 3-Z-[1-(4-(imidazol-1-ylmethyl)anilino)-1-(4-(2-methoxycarbonylethyl)phenyl)methylene]-6-fluoro-2-indolinone 3.81 3-Z-[1-(4-(N-(2-dimethylaminoethyl)-N-methylaminomethyl)anilino)-1-(4-(2-methoxycarbonylethyl)phenyl)methylene]-6-fluoro-2-indolinone 3.82 3-Z-[1-(4-(N-(2-dimethylaminoethyl)-N-methylaminomethyl)anilino)-1-(3-(2-ethoxycarbonylethyl)phenyl)methylene]-6-fluoro-2-indolinone 3.83 3-Z-[1-(4-(pyrrolidin-1-ylmethyl)anilino)-1-(4-(2-methoxycarbonylethyl)phenyl)methylene]-6-chloro-2-indolinone 3.84 3-Z-[1 anilino-1 -(3-(2-ethoxycarbonylethyl)phenyl)methylene]-6-fluoro-2-indolinone 3.85 3-Z-[1-(4-(N-tert-butoxycarbonylaminomethyl)anilino)-1-(3-(2-ethoxycarbonylethyl)phenyl)methylene]-6-fluoro-2-indolinone 3.86 3-Z-[1-(4-(N-tert-butoxycarbonylmethylaminomethyl)anilino)-1-(3-(2-ethoxycarbonylethyl)phenyl)methylene]-6-fluoro-2-indolinone 3.87 3-Z-[1 -(4-dimethylaminomethylan iii no)-1-(3-methoxycarbonylmethoxy-phenyl)methylene]-6-fluoro-2-indolinone 3.88 3-Z-[1-(4-dimethylaminomethylanilino)-1-(4-methoxycarbonylmethoxy-phenyl)methylene]-6-fluoro-2-indolinone 3.89 3-Z-[1-(4-dimethylaminomethylanilino)-1-(3-(2-ethoxycarbonyl-ethoxy)phenyl)methylene]-6-fluoro-2-indolinone 3.90 3-Z-[1-(4-(pyrrolidin-1-ylmethyl)anilino)-1-(4-(2-methoxycarbonylethyl)phenyl)methylene]-6-bromo-2-indolinone 3.91 3-Z-[1-(4-(dimethylaminomethyl)anilino)-1-(4-(2-methoxycarbonylethyl)phenyl)methylene]-6-bromo-2-indolinone 3.92 3-Z-[1-(4-(diethylaminomethyl)anihlino)-1-(4-(2-methoxycarbonylethyl)phenyl)methylene]-6-bromo-2-indolinone 3.93 3-Z-[1-(3-dimethylaminomethylanilino)-1-(4-(2-methoxycarbonylethyl)phenyl)methylene]-6-fluoro-2-indolinone 3.94 3-Z-[1-(3-dimethylaminomethylanilino)-1-(3-(2-ethoxycarbonylethyl)phenyl)methylene]-6-fluoro-2-indolinone 3.95 3-Z-[1-(3-dimethylaminomethylanilino)-1-(4-(2-methoxycarbonylethyl)phenyl)methylene]-6-chloro-2-indolinone 4.0 3-Z-[1-(4-(dimethylaminomethyl)anilino)-1-(3,4-dimethoxyphenyl)-methylene]-6-cyano-2-indolinone 5.0 3-Z-[1-(4-(N-methyl-N-methylsulphonylamino)anilino)-1-(3-(2-methoxycarbonylvinyi)phenyl)methylene]-6-chloro-2-indolinone 5.1 3-Z-[1-(4-(dimethylaminomethyl)anilino)-1-(4-(2-methoxycarbonyl-vinyl)phenyl)methylene]-6-chloro-2-indolinone 5.2 3-Z-[1-(4-(dimethylaminomethyl)anilino)-1-(4-(2-carbamoyl-vinyl)phenyl)methylene]-6-fluoro-2-indolinone 5.3 3-Z-[1-(4-(dimethylaminomethyl)anilino)-1-(4-(2-methoxycarbonyl-vinyl)phenyl)methylene]-6-fluoro-2-indolinone 5.4 3-Z-[1-(4-(dimethylaminomethyl)anilino)-1-(3-(2-methoxycarbonyl-vinyl)phenyl)methylene]-6-fluoro-2-indolinone 6.0 3-Z-[1-(4-dimethylaminomethylanilino)-1-(3-(2-methoxycarbonylethyl)phenyi)methylene]-6-chloro-2-indolinone 6.1 3-Z-[1-(4-(N-methyl-N-methylsulphonylamino)anilino)-1-(3-(2-methoxycarbonylethyl)phenyl)methylene]-6-chloro-2-indolinone ------- - ------6.2 3-Z-[1-(4-dimethylaminomethylanilino)-1-(4-(2-carbamoyl-ethyl)phenyl)methylene]-6-fluoro-2-indolinone 6.3 3-Z-[1-(4-dimethylaminomethylanilino)-1-(4-(2-methoxycarbonylethyl)phenyl)methylene]-6-fluoro-2-indolinone 6.4 3-Z-[1-(4-dimethylaminomethylanilino)-1-(3-(2-methoxycarbonylethyl)phenyl)methylene]-6-fluoro-2-indolinone 7.0 3-Z-[1-(4-dimethylaminomethylanilino)-1-(4-aminomethyiphenyl)-methylene]-6-chloro-2-indolinone 3-Z-[1-(4-(N-((4-methylpiperazin-1-yl)methylcarbonyl)-N-8.0 methylamino)anilino)-1-(4-aminomethylphenyl)methylene]-6-chloro-2-indolinone 9.0 3-Z-[1-(4-(dimethylaminomethyl)anilino)-1-(3-aminomethylphenyl)-methylene]-6-fluoro-2-indolinone 9.1 3-Z-[1-(4-(dimethylaminomethyl)anilino)-1-(3-(2-aminoethyl)phenyl)methylene]-6-fluoro-2-indolinone 9.2 3-Z-[1-(4-(dimethylaminomethyl)anilino)-1-(4-aminomethylphenyl)-methylene]-6-fluoro-2-indolinone 3-Z-[1-(4-(N-(4-methylpiperazin-1-ylmethylcarbonyl)-N-9.3 methylamino)anilino)-1-(4-aminomethylphenyl)methylene]-6-fluoro-2-indolinone 9.4 3-Z-[1-(4-(methylaminomethyl)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone 9.5 3-Z-[1-(4-(methylaminomethyl)anilino)-1-(4-(2-methylcarbamoyl-ethyl)phenyl)methylene]-6-fluoro-2-indolinone 3-Z-[1-(4-(N-(4-methylpiperazin-1-ylmethylcarbonyl)-N-9.6 methylamino)anilino)-1-(3-aminomethylphenyl)methylene]-6-fluoro-2-indolinone 9.7 3-Z-[1-(4-(aminomethyl)anilino)-1-(4-(2-methoxycarbonylethyl)phenyl)methylene]-6-fluoro-2-indolinone 9.8 3-Z-[1-(4-(aminomethyl)anilino)-1-(3-(2-ethoxycarbonylethyl)phenyl)methylene]-6-fluoro-2-indolinone 9.9 3-Z-[1 -(4-(methylaminomethyl)anilino)-1 -(3-(2-ethoxycarbonylethyl)phenyl)methylene]-6-fluoro-2-indolinone 10.0 3-Z-[1 -(4-dimethylaminomethylanilino)-1 -(3-(2-carboxyethyl)phenyl)methylene]-6-chloro-2-indolinone 10.1 3-Z-[1 -(4-dimethylaminomethylanilino)-1 -(4-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone 10.2 3-Z-[1 -(4-dimethylaminomethylanilino)-1 -(3-carboxymethylphenyl)-methylene]-6-fluoro-2-indolinone 10.3 3-Z-[1-(4-dimethylaminomethylanilino)-1-(3-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone 10.4 3-Z-[1-(4-dimethylaminomethylanilino)-1-(4-carboxymethyl phenyl)-methylene]-6-fluoro-2-indolinone 3-Z-[1-(4-(N-(4-methylpiperazin-1 -ylmethylcarbonyl)-N-10.5 methylamino)anilino)-1-(4-carboxymethylphenyl)methylene]-6-fluoro-2-indolinone 10.6 3-Z-[1 -(4-(N-(2-dimethylaminoethyl)-N-methylsulphonylamino)anilino)-1-(4-carboxymethylphenyl)methylene]-6-fluoro-2-indolinone 10.7 3-Z-[1 -(4-(N-methyl-N-acetylamino)an ilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone 3-Z-[1 -(4-(N-(4-methylpiperazin-1 -ylmethylcarbonyl)-N-10.8 methylamino)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone 10.9 3-Z-[1 -(4-(N-(2-dimethylaminoethyl)-N-methylsulphonylamino)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone 10.10 3-Z-[1-(4-(N-(3-dimethylaminopropyl)-N-acetylamino)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone 10.11 3-Z-[1-(4-(N-tert-butoxycarbonylmethylaminomethyl)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone 10.12 3-Z-[1-(4-(4-methylpiperazin-1-ylcarbonyl)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone 10.13 3-Z-[1-(4-(1-methylimidazol-2-yl)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone 10.14 3-Z-[1-(4-methylsulphonylanilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone 10.15 3-Z-[1-(4-(4-methylpiperazin-1-ylcarbonyl)anilino)-1-(3-carboxymethylphenyl)methylene]-6-fluoro-2-indolinone 3-Z-[1-(4-(N-(4-methylpiperazin-1-ylmethylcarbonyl)-N-10.16 methylamino)anilino)-1-(3-carboxymethylphenyl)methylene]-6-fluoro-2-indolinone 10.17 3-Z-[1-(4-(N-(dimethylaminomethylcarbonyl)-N-methylamino)anilino)-1-(3-carboxymethylphenyl)methylene]-6-fluoro-2-i ndoli none 10.18 3-Z-[1-(4-(N-(4-dimethylaminobutylcarbonyl)-N-methylamino)anilino)-1-(3-carboxymethylphenyl)methylene]-6-fluoro-2-indolinone 10.19 3-Z-[1-Anilino-1-(3-carboxymethylphenyl)-methylene]-6-fluoro-2-indolinone 10.20 3-Z-[1-(4-methylsulphonylanilino)-1-(3-carboxymethyiphenyl)-methylene]-6-fluoro-2-indolinone 10.21 3-Z-[1-(4-(1-methylimidazol-2-yl)anilino)-1-(3-carboxymethylphenyl)-methylene]-6-fluoro-2-indolinone 3-Z-[1-(4-(N-(dimethylaminocarbonylmethyl)-N-10.22 methylsulphonylamino)anilino)-1-(3-carboxymethylphenyl)-methylene]-6-fluoro-2-indolinone 3-Z-[1 anilino-1-(4-carboxymethylphenyl)methylene]-6-fluoro-2-10.23 indolinone 10.24 3-Z-[1-(4-(1-methylimidazol-2-yl)anilino)-1-(4-carboxymethylphenyl)-methylene]-6-fluoro-2-indolinone 10.25 3-Z-[1-(4-(N-(3-dimethylaminopropylcarbonyl)-N-methylamino)anilino)-1-(4-carboxymethylphenyl)methylene]-6-fluoro-2-indolinone 10.26 3-Z-[1-(4-(N-(dimethylaminomethylcarbonyl)-N-methylamino)anilino)-1-(4-carboxymethylphenyl)methylene]-6-fluoro-2-indolinone 10.27 3-Z-[1-(4-(4-methylpiperazin-1-yl-carbonyl)anilino)-1-(4-carboxymethylphenyl)methylene]-6-fluoro-2-indolinone 10.28 3-Z-[1-(4-methylsulphonylanilino)-1-(4-carboxymethylphenyl)-methylene]-6-fluoro-2-indolinone 10.29 3-Z-[1-(4-(N-methyl-N-acetylamino)anilino)-1-(4-carboxymethylphenyl)-methylene]-6-fluoro-2-indolinone 3-Z-[1-(4-(N-(dimethylaminocarbonylmethyl)-N-10.30 methylsulphonylamino)anilino)-1-(4-carboxymethylphenyl)methylene]-6-fluoro-2-indolinone 10.31 3-Z-[1-(4-(N-(2-dimethylaminoethylcarbonyl)-N-methylamino)anilino)-1-(4-carboxymethylphenyl)methylene]-6-fluoro-2-indolinone 10.32 3-Z-[1-(4-(N-(3-dimethylaminopropylcarbonyl)-N-methylamino)anilino)-1-(4-carboxymethylphenyl )methylene]-6-fluoro-2-indol i none 3-Z-[1-(4-(N-(4-methylpiperazin-1-ylmethylcarbonyl)-N-10.33 methylamino)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone 10.34 3-Z-[1-(4-(N-(2-dimethylaminoethyl)-N-methylsulphonylamino)anilino)-1-(3-carboxymethylphenyl)methylene]-6-fluoro-2-indolinone 10.35 3-Z-[1-(4-(N-(2-dimethylaminoethyl)-N-methylsulphonylamino)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indoli none 3-Z-[1-(4-(N-(dimethylaminomethylcarbonyl)-N-methylamino)anilino)-1-10.36 (3-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone 10.37 3-Z-[1 -(4-(N-(3-dimethylaminopropyl)-N-acetylamino)anilino)-1 -(3-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone 10.38 3-Z-[1-(4-(N-(dimethylaminomethylcarbonyl)-N-methylamino)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone 10.39 3-Z-[1 -(4-(2-dimethylaminoethyl)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone 10.40 3-Z-[1-(4-(N-(2-dimethylaminoethylcarbonyl)-N-methylamino)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone 10.41 3-Z-[1 -(4-(2-dimethylaminoethyl)anilino)-1 -(3-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone 10.42 3-Z-[1 -(4-(N-(2-dimethylaminoethyl)-N-acetylamino)anilino)-1 -(4-(2-ca rboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone 10.43 3-Z-[1 -(4-(N-(3-dimethylaminopropylcarbonyl)-N-methylamino)anilino)-1 -(3-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone 10.44 3-Z-[1 -(4-(N-(4-dimethylamino-butylcarbonyl)-N-methylamino)anilino)-1 -(3-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone 10.45 3-Z-[1 -(4-(1 -methylimidazol-2-yl)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone 10.46 3-Z-[1-(4-(N-(4-dimethylaminobutylcarbonyl)-N-methylamino)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone 10.47 3-Z-[1 anilino-1-(4-(2-carboxyethyl)phenyl)methyl en e]-6-fl u o ro-2-indolinone 10.48 3-Z-[1-(4-(pyrrolidin-1-ylmethyl)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone 10.49 3-Z-[1 -(4-(diethylaminomethyl)anilino)-1 -(4-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone 3-Z-[1-(4-aminomethylanilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-10.50 6-fluoro-2-indolinone 10.51 3-Z-[1-(4-(2-dimethylaminoethyl)anilino)-1-(3-carboxymethylphenyl)-methylene]-6-fluoro-2-indolinone 10.52 3-Z-[1-(4-(2-dimethylaminoethyl)anilino)-1-(4-carboxymethylphenyl)-methylene]-6-fluoro-2-indolinone 10.53 3-Z-[1-(4-(2-dimethylaminoethyl)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-chloro-2-indolinone 3-Z-[1-(4-(1-methylimidazol-2-yl)anilino)-1-(4-(2-10.54 carboxyethyl)phenyl)methylene]-6-chloro-2-indolinone 10.55 3-Z-[1-(4-dimethylaminomethylanilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-chloro-2-indolinone 10.56 3-Z-[1-(4-((4-methylpiperazin-1-yl)methyl)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone 10.57 3-Z-[1-(4-(imidazol-1-ylmethyl )anilino)-1-(3-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone 10.58 3-Z-[1-(4-(N-(2-dimethylaminoethyl)-N-methylaminomethyl)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone 10.59 3-Z-[1-(4-((4-methylpiperazin-1-yl)methyl)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone 10.60 3-Z-[1-(4-(imidazol-1-ylmethyl)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone 10.61 3-Z-[1-(4-(pyrrolidin-1-ylmethyl)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-chloro-2-indolinone 10.62 3-Z-[1-(4-(N-(2-dimethylaminoethyl)-N-methylaminomethyl)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone 10.63 3-Z-[1 anilino-1 -(3-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone 3-Z-[1-(4-aminomethylanilino)-1-(3-(2-carboxyethyl)phenyl)methylene]-10.64 6-fluoro-2-indolinone 10.65 3-Z-[1-(4-methylaminomethylanilino)-1-(3-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone 10.66 3-Z-[1 -(4-dimethylaminomethylanilino)-1 -(3-carboxymethoxy-phenyl)-methylene]-6-fluoro-2-indolinone 10.67 3-Z-[1 -(4-dimethylaminomethylanilino)-1 -(4-carboxymethoxy-phenyl)phenyl)methylene]-6-fluoro-2-indolinone 10.68 3-Z-[1-(4-(pyrrolidin-1-ylmethyl)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-bromo-2-indolinone 10.69 3-Z-[1-(4-(dimethylaminomethyl)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-bromo-2-indolinone 10.70 3-Z-[1 -(4-(diethylaminomethyl)anilino)-1 -(4-(2-carboxyethyl)-methylene]-6-bromo-2-indolinone 10.71 3-Z-[1 -(3-dimethylaminomethylanilino)-1 -(4-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone 10.72 3-Z-[1 -(3-dimethylaminomethylanilino)-1 -(3-(2-ca rboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone 3-Z-[1 -(3-dimethylaminomethylanilino)-1 -(4-(2-10.73 carboxyethyl)phenyl)methylene]-6-chloro-2-indolinone 11.0 3-Z-[1 -(4-dimethylaminomethylanilino)-1 -(3-(2-carbamoyl-ethyl)phenyl)methylene]-6-chloro-2-indolinone 11.1 3-Z-[1-(4-dimethylaminomethylanilino)-1-(3-(2-methyl carbamoyl-ethyl)phenyl)methylene]-6-chloro-2-indolinone 11.2 3-Z-[1 -(4-dimethylaminomethylanilino)-1 -(4-(2-methylcarbamoyl-ethyl)phenyl)methylene]-6-fluoro-2-indolinone 11.3 3-Z-[1 -(4-dimethylaminomethylanilino)-1 -(3-dimethylcarbamoylmethylphenyl)methylene]-6-fluoro-2-indolinone 11.4 3-Z-[1 -(4-dimethylaminomethylanilino)-1 -(3-(2-carbamoyl-ethyl)p henyl)methylene]-6-fluoro-2-indolinone 11.5 3-Z-[1 -(4-dimethylaminomethylanilino)-1 -(3-(2-methylcarbamoyl-ethyl)phenyl)methylene]-6-fluoro-2-indolinone 11.6 3-Z-[1 -(4-dimethylaminomethylanilino)-1 -(3-(2-dimethylcarbamoyl-ethyl)phenyl)methylene]-6-fluoro-2-indolinone 11.7 3-Z-[1-(4-dimethylaminomethylanilino)-1-(3-carbamoylmethyiphenyl)-methylene]-6-fluoro-2-indolinone 11.8 3-Z-[1 -(4-dimethylaminomethylanilino)-1 -(3-methylcarbamoylmethylphenyl)methylene]-6-fluoro-2-indolinone 11.9 3-Z-[1 -(4-dimethylaminomethylanilino)-1 -(4-carbamoylmethylphenyl)-methylene]-6-fluoro-2-indolinone 11.10 3-Z-[1 -(4-dimethylaminomethylanilino)-1 -(4-(2-dimethylcarbamoyl-ethyl)phenyl)methylene]-6-fluoro-2-indolinone 11.11 3-Z-[1 -(4-dimethylaminomethylanilino)-1 -(4-(2-(4-methylpiperazin-1 -yl-carbonyl)ethyl)phenyl)methylene]-6-fluoro-2-indolinone 3-Z-[1 -(4-(N-(4-methylpiperazin-1 -ylmethylcarbonyl)-N-11.12 methylamino)anilino)-1-(4-carbamoylm ethyl phenyl)methylene]-6-fluoro-2-indolinone 11.13 3-Z-[1 -(4-(N-(2-dimethylaminoethyl)-N-methylsulphonylamino)anilino)-1-(4-carbamoylmethylphenyl)methylene]-6-fluoro-2-indolinone 11.14 3-Z-[1-(4-dimethylaminomethylanilino)-1-(4-dimethylcarbamoylmethylphenyl)methylene]-6-fluoro-2-indolinone 11.15 3-Z-[1 -(4-dimethylaminomethylanilino)-1 -(4-methylca rbamoylmethylphenyl)methylene]-6-fluoro-2-indolinone 11.16 3-Z-[1 -(4-(N-(2-dimethylaminoethyl)-N-methylsulphonylamino)anilino)-1 -(4-methylcarbamoylmethylphenyl)methylene]-6-fluoro-2-indolinone 3-Z-[1-(4-(N-(2-dimethylaminoethyl)-N-methylsulphonylamino)anilino)-11.17 1-(4-dimethylcarbamoylmethylphenyl)methylene]-6-fluoro-2-indolinone 3-Z-[1-(4-(N-(4-methylpiperazin-1-ylmethylcarbonyl)-N-11.18 methylamino)anilino)-1-(4-methylcarbamoylmethylphenyl)methylene]-6-fluoro-2-indolinone 11.19 3-Z-[1-(4-(N-methyl-N-acetylamino)anilino)-1-(4-(2-methylcarbamoyl-ethyl)phenyl)methylene]-6-fluoro-2-indolinone 3-Z-[1 -(4-(N-(4-methylpiperazin-1 -ylmethylcarbonyl)-N-11.20 methylamino)anilino)-1-(4-(2-methylcarbamoyl-ethyl)phenyl)methylene]-6-fluoro-2-indolinone 11.21 3-Z-[1 -(4-(N-(2-dimethylaminoethyl)-N-methylsulphonylamino)anilino)-1-(4-(2-methylcarbamoylethyl)phenyl)methylene]-6-fluoro-2-indolinone 11.22 3-Z-[1 -(4-(N-tert-butoxycarbonylmethylaminomethyl)anilino)-1 -(4-(2-methylcarbamoylethyl)phenyl)methylene]-6-fluoro-2-indolinone 11.23 3-Z-[1-(4-(1-methylimidazol-2-yl)anilino)-1-(4-(2-methylcarbamoyl-ethyl)phenyl)methylene]-6-fluoro-2-indolinone 11.24 3-Z-[1-(4-methylsulphonylanilino)-1-(4-(2-methylcarbamoyl-ethyl)phenyl)methylene]-6-fluoro-2-indolinone 11.25 3-Z-[1-(4-(4-methylpiperazin-1-ylcarbonyl)anilino)-1-(4-(2-methylcarbamoylethyl)phenyl)methylene]-6-fluoro-2-indolinone 11.26 3-Z-[1-(4-(4-methylpiperazin-1-ylcarbonyl)anilino)-1-(3-methylcarbamoylmethylphenyl)methylene]-6-fluoro-2-indolinone 3-Z-[1 -(4-(N-(4-methylpiperazin-1 -ylmethylcarbonyl)-N-11.27 methylamino)anilino)-1-(3-methylcarbamoylmethylphenyl)methylene]-6-fluoro-2-indolinone 12.0 3-Z-[1 -(4-dimethylaminomethylanilino)-1 -(4-acetylaminomethylphenyl)-methylene]-6-chloro-2-indolinone 3-Z-[1 -(4-(N-(4-methylpiperazin-1 -ylmethylcarbonyl)-N-12.1 methylamino)anilino)-1-(4-acetylaminomethylphenyl)methylene]-6-chloro-2-indolinone 12.2 3-Z-[1-(4-dimethylaminomethylanilino)-1-(4-benzoylaminophenyl)-methylene]-6-chloro-2-indolinone 3-Z-[1-(4-(N-(4-methylpiperazin-1 -ylmethylcarbonyl)-N-12.3 methylamino)anilino)-1-(4-benzoylaminomethylphenyl)methylene]-6-chloro-2-indolinone 12.4 3-Z-[1 -(4-dimethylaminomethylanilino)-1 -(3-acetylaminomethylphenyl)-methyl ene]-6-fluoro-2-indolinone 12.5 3-Z-[1 -(4-dimethylaminomethylanilino)-1 -(3-propionylaminomethylphenyl)methylene]-6-fluoro-2-indolinone 12.6 3-Z-[1 -(4-dimethylaminomethylanilino)-1 -(3-benzoylaminomethylphenyl)methylene]-6-fluoro-2-indolinone 12.7 3-Z-[1 -(4-dimethylaminomethylanilino)-1 -(3-phenylacetylaminomethylphenyl)methylene]-6-fluoro-2-indolinone 12.8 3-Z-[1-(4-dimethylaminomethylanilino)-1-(3-(2-acetylaminoethyl)phenyl)methylene]-6-fluoro-2-indolinone 12.9 3-Z-[1-(4-dimethylaminomethylanilino)-1-(3-(2-benzoylaminoethyl)phenyl)methylene]-6-fluoro-2-indolinone 12.10 3-Z-[1 -(4-dimethylaminomethylanilino)-1 -(3-(2-propionylaminoethyl)phenyl)methylene]-6-fluoro-2-indolinone 12.11 3-Z-[1 -(4-dimethylaminomethylanilino)-1 -(3-(2-phenylacetylaminoethyl)phenyl)methylene]-6-fluoro-2-indolinone 12.12 3-Z-[1 -(4-dimethylaminomethylanilino)-1 -(4-acetylaminomethylphenyl)-methylene]-6-fluoro-2-indolinone 12.13 3-Z-[1 -(4-dimethylaminomethylanilino)-1 -(4-propionylaminomethylphenyl)methylene]-6-fluoro-2-indolinone 3-Z-[1-(4-dimethylaminomethylanilino)-1-(4-12.14 phenylacetylaminomethylphenyl)methylene]-6-fluoro-2-indolinone 3-Z-[1 -(4-(N-(4-methylpiperazin-1 -ylmethylcarbonyl)-N-12.15 methylamino)anilino)-1-(4-acetylaminomethylphenyl)methylene]-6-fluoro-2-indolinone 3-Z-[1 -(4-(N-(4-methylpiperazin-1 -ylmethylcarbonyl)-N-12.16 methylamino)anilino)-1-(4-propionylaminomethylphenyl)methylene]-6-fluoro-2-indolinone 3-Z-[1-(4-(N-(4-methylpiperazin-l-ylmethyl carbonyl)-N-12.17 methylamino)anilino)-1-(4-phenylacetylaminomethylphenyl)-methylene]-6-fluoro-2-indolinone 3-Z-[1 -(4-(N-(4-methylpiperazin-1 -ylmethylcarbonyl)-N-12.18 methylamino)anilino)-1-(3-cyclopropylcarbonylaminomethylphenyl)-methylene]-6-fluoro-2-indolinone 3-Z-[1-(4-(N-(4-methylpiperazin-1 -ylmethylcarbonyl)-N-12.19 methylamino)anilino)-1-(3-cyclobutylcarbonylaminomethylphenyl)-methylene]-6-fluoro-2-indolinone 3-Z-[1-(4-(N-(4-methylpiperazin-1 -ylmethylcarbonyl)-N-12.20 methylamino)anilino)-1-(3-(pyridin-2-yl-carbonylaminomethyl)phenyl)methylene]-6-fluoro-2-indolinone 3-Z-[1-(4-(N-(4-methylpiperazin-1 -ylmethylcarbonyl)-N-12.21 methylamino)anilino)-1-(3-cyclohexylcarbonylaminomethylphenyl)-methylene]-6-fluoro-2-indolinone 3-Z-[1-(4-(N-(4-methylpiperazin-1 -ylmethylcarbonyl)-N-12.22 methylamino)anilino)-1-(3-(pyridin-3-yl-carbonylaminomethyl)phenyl)methylene]-6-fluoro-2-indolinone 3-Z-[1-(4-(N-(4-methylpiperazin-1 -ylmethylcarbonyl)-N-12.23 methylamino)anilino)-1-(3-isobutyrylaminomethylphenyl)methylene]-6-fluoro-2-indolinone 3-Z-[1-(4-(N-(4-methylpiperazin-1 -ylmethylcarbonyl)-N-12.24 methylamino)anilino)-1-(3-(3-methylbutyrylaminomethylphenyl)-methylene]-6-fluoro-2-indolinone 3-Z-[1-(4-(N-(4-methylpiperazin-1-ylmethylcarbonyl)-N-12.25 methylamino)anilino)-1-(3-cyclohexylmethylcarbonylaminomethylphenyl)methylene]-6-fluoro-2-indolinone 3-Z-[1-(4-(N-(4-methylpiperazin-1-ylmethylcarbonyl)-N-12.26 methylamino)anilino)-1-(3-methoxyacetylaminomethylphenyl)-methylene]-6-fluoro-2-indolinone 3-Z-[1-(4-(N-(4-methylpiperazin-1-ylmethylcarbonyl)-N-12.27 methylamino)anilino)-1-(3-(2-methoxybenzoyl-aminomethyl)phenyl)methylene]-6-fluoro-2-indolinone 3-Z-[1-(4-(N-(4-methylpiperazin-1 -ylmethylcarbonyl)-N-12.28 methylamino)anilino)-1-(3-tert-butylacetylaminomethylphenyl)-methylene]-6-fluoro-2-indolinone 3-Z-[1-(4-(N-(4-methylpiperazin-1-ylmethylcarbonyl)-N-12.29 methylamino)anilino)-1-(3-(2-thiophen-carbonylaminomethyl)phenyl)methylene]-6-fluoro-2-indolinone 3-Z-[1-(4-(N-(4-methylpiperazin-1 -ylmethylcarbonyl)-N-12.30 methylamino)anilino)-1-(3-pivaloylaminomethylphenyl)methylene]-6-fluoro-2-indolinone 3-Z-[1 -(4-(N-(4-methylpiperazin-1-ylmethylcarbonyl)-N-12.31 methylamino)anilino)-1-(3-(2-furoylaminomethyl)phenyl)methylene]-6-fluoro-2-indolinone 3-Z-[1-(4-(N-(4-methylpiperazin-1-ylmethylcarbonyl)-N-12.32 methylamino)anilino)-1-(3-acetylaminomethylphenyl)methylene]-6-fluoro-2-indolinone 3-Z-[1 -(4-(N-(4-methylpiperazin-1 -ylmethylcarbonyl)-N-12.33 methylamino)anilino)-1-(3-propionylaminomethylphenyl)methylene]-6-fluoro-2-indoli none 3-Z-[1 -(4-(N-(4-methylpiperazin-1 -ylmethylcarbonyl)-N-12.34 methylamino)anilino)-1-(3-benzoylaminomethylphenyl)methylene]-6-fluoro-2-indolinone 3-Z-[1 -(4-(N-(4-methylpiperazin-1 -ylmethylcarbonyl)-N-12.35 methylamino)anilino)-1-(3-phenylacetylaminomethylphenyl)-methylene]-6-fluoro-2-indolinone 3-Z-[1 -(4-dimethylaminomethylanilino)-1 -(3-12.36 cyclopropylcarbonylaminomethylphenyl)methylene]-6-fluoro-2-indolinone 12.37 3-Z-[1 -(4-dimethylaminomethylanilino)-1 -(3-cyclobutylcarbonylaminomethylphenyl)methylene]-6-fluoro-2-indolinone 12.38 3-Z-[1 -(4-dimethylaminomethylanilino)-1 -(3-(pyridin-2-yl-carbonylaminomethyl)phenyl)methylene]-6-fluoro-2-indolinone 3-Z-[1-(4-dimethylaminomethylanilino)-1-(3-12.39 cyclohexylcarbonylaminomethylphenyl)methylene]-6-fluoro-2-indolinone 12.40 3-Z-[1 -(4-dimethylaminomethylanilino)-1 -(3-(pyridin-3-yl-carbonyla minomethyl)phenyl)methylene]-6-fluoro-2-indolinone 12.41 3-Z-[1-(4-dimethylaminomethylanilino)-1-(3-isobutyrylaminomethylphenyl)methylene]-6-fluoro-2-indolinone 12.42 3-Z-[1-(4-dimethylaminomethylanilino)-1-(3-(3-methyl butyryl-aminomethylphenyl)methylene]-6-fluoro-2-indolinone 3-Z-[1 -(4-dimethylaminomethylanilino)-1 -(3-12.43 cyclohexylmethylcarbonylaminomethylphenyl)methylene]-6-fluoro-2-indolinone 3-Z-[1-(4-dimethylaminomethylanilino)-1-(3-12.44 methoxyacetylaminomethylphenyl)methylene]-6-fluoro-2-indolinone 12.45 3-Z-[1-(4-dimethylaminomethylanilino)-1-(3-(2-methoxybenzoyl-aminomethyl)phenyl)methylene]-6-fluoro-2-indolinone 12.46 3-Z-[1-(4-dimethylaminomethylanilino)-1-(3-tert-butylacetylaminomethylphenyl)methylene]-6-fluoro-2-indolinone 3-Z-[1-(4-dimethylaminomethylanilino)-1-(3-(2-12.47 thiophenecarbonylaminomethyl)phenyl)methylene]-6-fluoro-2-indolinone 12.48 3-Z-[1-(4-dimethylaminomethylanilino)-1-(3-pivaloylaminomethylphenyl)methylene]-6-fluoro-2-indolinone 12.49 3-Z-[1-(4-dimethylaminomethylanilino)-1-(3-(2-furoylaminomethyl)phenyl)methylene]-6-fluoro-2-indolinone 12.50 3-Z-[1-(4-dimethylaminomethylanilino)-1-(3-(pyridin-4-yl-carbonyl aminomethyl)phenyl)methylene]-6-fluoro-2-indolinone 13.0 3-Z-[1-(4-trimethylammon iummethylanilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone iodide 13.1 3-Z-[1-(4-trimethylammoniummethylanilino)-1-(3-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone iodide 14.0 3-Z-[1-(4-guanidinomethylanilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone 14.1 3-Z-[1-(4-guanidinomethylanilino)-1-(3-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone Abbreviations used:
HOBt = 1-hydroxy-1 H-benzotriazole TBTU = O-benzotriazol-1-yl-N,N,N',N'-tetramethyluronium tetrafluoroborate Preparation of the starting materials:
Example I:
Dimethyl 2-(4-fluoro-2-nitropheny)malonate With ice-cooling, 185 g of potassium tert-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) C11H1oFN06 Mass spectrum: m/z = 270 [M-H]-The following compounds are prepared analogously to Example I:
(1.1) Diethyl 2-(4-bromo-2-nitrophenyl)maIonate from 2,5-dibromonitrobenzene and diethyl malonate Rf value: 0.40 (silica gel, petroleum ether/ethyl acetate = 5:1) C13H14BrNO6 Mass spectrum: m/z = 359/361 [M]+
(1.2) Dimethyl 2-(4-cyano-2-nitrophenyl)malonate from 4-chloro-3-nitrobenzonitrile and dimethyl malonate Rf value: 0.50 (silica gel, methylene chloride/methanol = 50:1) C12H1oN2O6 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 sulphoxide, 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 C1oH8N2O4 Mass spectrum: m/z = 219 [M-H]-Example III:
4-Fluoro-2-nitrophenylacetic acid 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 and dried.
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 10 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) 15 Mass spectrum: m/z = 150 [M-H]-The following compounds are prepared analogously to Example IV:
(IV.1) 6-Bromo-2-indolinone 20 from diethyl 2-(4-bromo-2-nitrophenyl)malonate (starting material 1.1) using Raney nickel as hydrogenation 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) Mass spectrum: m/z = 157 [M-H]-Example V:
1 -acetyl-6-fluoro-2-indoli none At 130 C, 82.5 g of 6-fluoro-2-indolinone (starting material IV) are stirred in 180 ml acetic anhydride for 3 hours. After cooling 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) Mass spectrum: m/z = 192 [M-H]-The following compounds are prepared analogously to Example V:
(V.1) 1-acetyl-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-indolinone 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-acetyl-3-[1-hydroxy-1 -(3-iodoghenyl)methylenel-6-chloro-2-indolinone 10.5 g of 1-acetyl-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 100 ml 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) Mass spectrum: m/z = 438/440 [M-H]-The following compounds are prepared analogously to Example VI:
(VI.1) 1-acetyl-3-[1-hydroxy-1-(4-methoxycarbonylmethylphenyl)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 -hyd roxy- 1 -(4-chlorophenyl) methylene]-6-ch loro-2- i ndoli none 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-dimethoxyphenyl)methylene]-6-cyano-2-indolinone from 1-acetyl-6-cyano-2-indolinone (starting material V.3) and 3,4-dimethoxybenzoic acid (VI.5) 1-acetyl-3-[1-hydroxy-1-(3-fluorophenyl)methylene]-6-fluoro-2-indolinone from 1-acetyl-6-fluoro-2-indolinone (starting material V) and 3-fluorobenzoic acid (VI.6) 1-acetyl-3-[1-hydroxy-1-(4-(2-acetylaminoethyl)phenyl)methylene]-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 methyl (3-carboxyphenyl)acetate (preparation analogously to Tetrahedron 1997, 53, 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) (VI.11) 1 -acetyl-3-[1 -hydroxy-1 -(4- iodoph enyl)methyle ne]-6-fl uoro-2-i ndol i none from 1-acetyl-6-fluoro-2-indolinone (starting material V) and 4-iodobenzoic acid (VI. 12) 1-acetyl-3-[1-hydroxy-1-(4-iodophenyl)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)methylene]-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)methylene]-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. Left 2000, 10, 553-557) (VI.17) 1-acetyl-3-[1-hydroxy-1-(4-(N-tert-butoxycarbonyl-2-aminoethyl)phenyl)methylene]-6-fluoro-2-indolinone from 1 -acetyl-6-fl uoro-2-i ndoli none (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-acetyl-6-chloro-2-indolinone (starting material V.1) and 4-cyanobenzoic acid (Vi. 19) 1 -acetyl-3-[1 -hydroxy-1 -(3-acetylaminomethylphenyl)methylene]-6-fluoro-2-indolinone 5 from 1-acetyl-6-fluoro-2-indolinone (starting material V) and 3-acetylaminomethyl-benzoic acid (prepared according to J. Med. Chem. 1997, 40, 4030-4052) (VI.20) 1-acetyl-3-[1-hydroxy-1-(3-(2-ethoxycarbonylethyl)phenyl)methylene]-6-fluoro-2-indolinone 10 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]-6-15 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) 20 (VI.22) 1-acetyl-3-[1-hydroxy-1-(4-(2-ethoxycarbonylethyl)phenyl)methylene]-6-fluoro-2-indolinone from 1-acetyl-6-fluoro-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)methylene]-fluoro-2-indolinone from 1-acetyl-6-fluoro-2-indolinone (starting material V) and 3-methoxycarbonylmethyloxybenzoic acid (preparation see Tetrahedron Letters 1998, 39, 8563-8566) (VI.24) 1-acetyl-3-[1-hydroxy-1-(4-methoxycarbonylmethyloxyphenyl)methylene]-6-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-acetyl-3-[1-hydroxy-1-(3-(2-ethoxycarbonylethyloxy)phenyl)methylene]-fluoro-2-indolinone from 1-acetyl-6-fluoro-2-indolinone (starting material V) and 3-(2-ethoxycarbonylethyloxy)benzoic acid (preparation see PCT Int. Appl. W09620173, 60) (VI.26) 1-acetyl-3-[1-hydroxy-1-(4-(2-ethoxycarbonylethyloxy)phenyl)methylene]-fluoro-2-indolinone from 1-acetyl-6-fluoro-2-indolinone (starting material V) and 4-(2-ethoxycarbonylethyloxy)benzoic acid (preparation see PCT Int. Appl. W09620173, 58) (VI.27) 1-acetyl-3-[1-hydroxy-1-(4-(2-methoxycarbonylethyl)phenyl)methylene]-6-bromo-2-indolinone from 1-acetyl-6-bromo-2-indolinone (starting material V.2) and 4-(2-methoxycarbonylethyl)-benzoic acid (preparation analogously to Tetrahedron 1997, 53, 7335-7340) Example VII:
1-acetyl-3-[1-methoxy-1-(3-iodophenyl)methylenel-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-[1-hydroxy-1-(3-iodophenyl)methylene]-6-chloro-2-indolinone (starting material VI) and 2.72 ml of ethyldiisopropylamine in 80 ml of dichloromethane, 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/dichloromethane/ethyl acetate =
5:4:1) Mass spectrum: m/z = 438/440 [M-H]"
m.p. 185 - 187 C
The following compounds are prepared analogously to Example VII:
(VI I.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) (VI I.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-chloro-2-indolinone from 1 -acetyl-3-[1 -hydroxy- 1 -(3,4-dimethoxyphenyl)methylene]-6-chloro-2-indoli none (starting material VI.3) (VI 1.4) 1 -acetyl-3-[1 -methoxy-1 -(3,4-dimethoxyphenyl)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-fl uoro phenyl)m ethylene]-6-fl uoro-2-i nd ol i none from 1-acetyl-3-[1-hydroxy-1-(3-fluorophenyl)methylene]-6-fluoro-2-indolinone (starting material V1.5) 63 (VI 1.6)1-acetyl-3-[1-methoxy-1-(4-(2-acetylaminoethyl)phenyl)methylene]-6-fluoro-2-indolinone from 1-acetyl-3-[1-hydroxy-1-(4-(2-acetylaminoethyl)phenyl)methylene]-6-fluoro-indolinone (starting material VI.6) (VII .7)1-acetyl-3-[1-methoxy-1-(3-methoxycarbonylmethylphenyl)methylene]-6-fluoro-2-indoli none from 1-acetyl-3-[1-hydroxy-l -(3-methoxycarbonylmethylphenyl)methylene]-6-fluoro-2-indolinone (starting material V1.7) 1:0 (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-fluoro-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) (VII.11) 1-acetyl-3-[1-methoxy-1-(4-iodophenyl)methylene]-6-fluoro-2-indolinone from 1-acetyl-3-[1-hydroxy-1-(4-iodophenyl)methylene]-6-fluoro-2-indolinone (starting material VI.11) (VI I.12) 1-acetyl-3-[1-methoxy-1-(4-iodophenyl)methylene]-6-chloro-2-indolinone from 1-acetyl-3-[1-hydroxy-1-(4-iodophenyl)methylene]-6-chloro-2-indolinone (starting material VI.12) = CA 02493436 2005-01-21 (VII.13) 1-acetyl-3-[1-methoxy-1-(3-iodophenyl)methylene]-6-fluoro-2-indolinone from 1-acetyl-3-[1-hydroxy-1-(3-iodophenyl)methylene]-6-fluoro-2-indolinone (starting material VI.13) (VII.14) 1-acetyl-3-[1-methoxy-1-(3-(2-methoxycarbonylethyl)phenyl)methylene]-6-fluoro-2-indolinone from 1-acetyl-3-[1-hydroxy-1-(3-(2-methoxycarbonylethyl)phenyl)methylene]-6-fluoro-2-indolinone (starting material VI.14) (VI I.15) 1 -acetyl-3-[1 -methoxy-1 -(4-(2-methoxycarbonylethyl)phenyl)methylene]-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.16) 1-acetyl-3-[1-methoxy-1-(4-(N-tert-butoxycarbonyl-2-aminoethyl)phenyl)methylene]-6-fluoro-2-indolinone from 1-acetyl-3-[1-hydroxy-1-(4-(N-tert-butoxycarbonyl-2-aminoethyl)phenyl)methylene]-6-fluoro-2-indolinone (starting material VI.17) (VII.17) 1 -acetyl-3-[1 -methoxy-1 -(3-(N-tert-butoxycarbonyl-2-ami n oethyl)phenyl)m ethyle ne]-6-fl uoro-2-i ndol in one from 1-acetyl-3-[1-hydroxy-1-(3-(N-tert-butoxycarbonyl-2-aminoethyl)phenyl)methylene]-6-fluoro-2-indolinone (starting material VI.16) (VI I.18) 1 -acetyl-3-[1 -methoxy-1 -(3-acetylaminomethylphenyl)methylene]-6-fluoro-2-indolinone 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)methyl ene]-6-fluoro-2-indolinone from 1-acetyl-3-[1-hydroxy-1-(3-(2-ethoxycarbonylethyl)phenyl)methylene]-6-fluoro-2-indolinone (starting material VI.20) (VI 1.20) 1 -acetyl-3-[1 -methoxy-1 -(4-(2-methoxycarbonylethyl)phenyl)methylene]-5 6-chloro-2-indolinone from 1-acetyl-3-[1-hydroxy-1-(4-(2-methoxycarbonylethyl)phenyl)methylene]-6-chloro-2-indolinone (starting material VI.21) (VI I.21) 1-acetyl-3-[1-methoxy-1-(4-(2-ethoxycarbonylethyl)phenyl)methylene]-10 6-fluoro-2-indolinone from 1-acetyl-3-[1-hydroxy-1-(4-(2-ethoxycarbonylethyl)phenyl)methylene]-6-fluoro-2-indolinone (starting material Vl.22) (VI I.22) 1-acetyl-3-[1-methoxy-1-(4-methoxycarbonylmethyloxyphenyl)-15 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-methoxycarbonylmethyloxyphenyl)-20 methylene]-6-fluoro-2-indolinone from 1-acetyl-3-[1-hydroxy-1-(3-methoxycarbonylmethyloxyphenyl)methylene]-6-fluoro-2-indolinone (starting material VI.24) (VI I.24) 1 -acetyl-3-[1 -methoxy-1 -(3-(2-25 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) (VI I.25) 1 -acetyl-3-[1 -methoxy-1 -(4-(2-30 ethoxycarbonylethyloxy)phenyl)methylene]-6-fluoro-2-indolinone from 1-acetyl-3-[1-hydroxy-1-(4-(2-ethoxycarbonylethyloxy)phenyl)methylene]-6-fluoro-2-indolinone (starting material VI.26) (VI I.26) 1-acetyl-3-[1-methoxy-1-(4-(2-methoxycarbonylethyl)phenyl)methyl ene]-6-bromo-2-indoli none from 1-acetyl-3-[1-hydroxy-1-(4-(2-methoxycarbonylethyl)phenyl)methylene]-6-bromo-2-indolinone (starting material VI.27) Example VIII:
1-Acetyl-3-[1-chloro-1-(4-cyanophenyl methyl enel-6-chloro-2-indolinone A suspension of 7.0 g of 1-acetyl-3-[1-hydroxy-1-(4-cyanophenyl)methylene]-6-chloro-2-indolinone (starting material VI.18) and 6.39 g of phosphorus pentachloride in 150 ml of dioxane is stirred at 100 C for 6 hours. After addition of a further 1.0 g of phosphorus pentachloride, the mixture is stirred at 110 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-(diethylaminomethyl)aniline (IX.2) N-(2-dimethylaminoethyl)-N-methylsulphonyl-p-phenylenediamine (IX.3) 3-(dimethylaminomethyl)aniline (IX.4) 4-(dimethylaminomethyl)aniline (IX.5) 4-(2-dimethylaminoethyl)aniline (IX.6) 4-[N-(2-dimethylaminoethyl)-N-acetylamino]aniline (IX.7) 4-[N-(3-dimethylaminopropyl)-N-acetylamino]aniline (IX.8) 4-[(N-dimethylaminocarbonylmethyl-N-methylsulphonyl)amino]aniline (IX.9) N-(4-aminophenyl)-N-methylmethanesulphonamide (IX.10) N-(dimethylaminomethylcarbonyl)-N-methyl-p-phenylenediamine (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-methylimidazol-2-yl)aniline (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)methylcarbonyl]-N-methyl-p-phenylenediamine (IX.20) 4-(4-tert-butoxycarbonylpiperazin-1-ylmethyl)aniline (IX.21) 4-(thiomorpholin-4-ylmethyl)aniline (IX.22) 4-(pyrrolidin-1-ylmethyl)aniline (IX.23) 4-(morpholin-4-yl-methyl)aniline (1X.24) 4-(N-benzyl-N-methylaminomethyl)aniline (1X.25) 4-(N-ethyl-N-methylaminomethyl)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-dimethylaminoethyl)-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)carbonyl]-N-methyl-p-phenylenediamine Preparation of the end products:
Example 1.0 3-Z-[1 -(4-(N-Methyl-N-methylsulphonylamino)anilino)-1-(3-iodophenyl)methylenel-6-chloro-2-indolinone 0.9 g of 1-acetyl-3-(1-methoxy-1-(3-iodophenyl)methyl ene)-6-chloro-2-indolinone (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 I-1 are prepared analogously to Example 1.0:
H
O
C 1 H (I-1 ) Ex- Starting Rf Empirical Mass M.P. amp/ R3 R4' materi-formula spectrum [ C] value*
e als VII 529/531 238- 0.30 -CH2-NMe2 C24H21CIIN3O
IX.4 [M+H]+ 240 (A) Cl -N(Me)-(CO)- VII.2 495/497 277- 0.20 1.2 C26H24C12N402 CH2-NMe2 IX.10 [M+H]+ 279 (B) Cl -N(COMe)- Vll.2 C27H26C12N4O2 507/509 241- 0.10 1.3 CH2)2-NMe2 IX.6 [M-H]" 243 (B) CI T"N-Me VII.2 548/550 266- 0.10 1.4 Me,N-~-NJ C29H29C12N502 "i, 0 IX.19 [M-H]- 268 (B) ci -N(COMe)- VII.2 521/523 241- 0.10 1.5 C28H28C12N4O2 (CH2)3-NMe2 IX.7 [M-H]- 242 (B) ci VIl.2 438/440 243- 0.10 1.6 -CH2-NMe2 C24H21C12N3O
IX.4 [M+H]+ 244 (B) Meo OMe -N(COMe)- VII.3 533/535 128- 0.75 1.7 I ` C29H31CIN4O4 (CH2)2-NMe2 IX.6 [M-H]- 130 (C) MeO OMe r--"N-Me VII.3 574/576 208- 0.65 1.8 Ox Me,N~ C31H34CIN5O4 "1, o IX.19 [M-H]" 210 (C) MeO OMe -N(S02Me)- VII.3 569/571 198- 0.75 1.9 C2aH31 CIN4O5S
(CH2)2-NMe2 IX.2 [M-H]" 200 (C) Meo oMe VII.3 462/464 239- 0.70 1.10 Ox, -CH2-NMe2 C26H26CIN3O3 IX.4 [M-H]" 240 (C) Meo oMe o Me VII.3 533/535 147- 0.70 1.11 NMe2 IX 29 [M-H]" 149 (C) *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-[1-(4-(Dimethylaminomethyl)anilino)-l-(4-cyanophenvl)methvlenel-6-chloro-2-indolinone 1.07 g of 1 -acetyl-3- [1 -ch loro- 1 -(4-cyanophe nyl) methylene]-6-ch loro-2-i ndol i none (starting material VII) and 0.54 g of 4-(dimethylaminomethyl)aniline (starting material IX.4) are dissolved in 10 ml of dimethylformamide 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), Rf value: 0.1 (silica gel, methylene chloride/methanol = 9:1) Mass spectrum: m/z = 427/429 [M-HI-Example 3.0 3-Z-[1-(4- dimethylaminomethyl)anilino)-1-(4-iodophenyl)methvlenel-6-fluoro-2-indolinone 3.5 g of 1-acetyl-3-(1-meth oxy-1-(4-iodophenyl)methylene)-6-fluoro-2-indolinone (starting material V11.11) and 1.6 g of 4-(dimethylaminomethyl)aniline (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 methanol 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+H]+
The following compounds of the formula I-3a are prepared analogously to Example 3.0:
R4' H
O
R2 N (I-3a) H
Ex- Starting Empirical Mass m. p. Rf amp R2 R3 R4' materi-formula spectrum [ C] value*
le als F V11.5 404 225- 0.20 3.1 -F / -CH2-NMe2 C24H21F2N3O
IX.4 [M-H]" 227 (A) = CA 02493436 2005-01-21 F -N(COMe)- NITS 491 160- 0.20 3.2 -F C23H28F2N402 (CH2)3-NMe2 IX.7 [M+H]+ 163 (A) F Me NN j VII.5 518 218- 0.40 3.3 -F Me,N C29H29F2N502 IX.19 [M+H]+ 220 (A) Cr0 N VII.6 471 106- 0.25 3.4 -F -CH2-NMe2 C28H29FN402 / IX.4 [M-Hl- 110 (A) H3Cr0 N -N(COMe)- VII.6 558 194- 0.25 3.5 -F C32H36FN503 / (CH2)3-NMe2 IX.7 [M+H]+ 196 (A) H3cN JN Me VII.6 583 238- 0.25 3.6 -F Me~NO C33H37FN603 / 1X.19 [M-Hl- 240 (A) F. OMe VII.1 460 173- 0.30 3.7 -F -CH2-NMe2 C27H26FN303 IX.4 [M+H]+ 176 (A) VII.13 514 198- 0.30 3.8 -F -CH2-NMe2 C24H21FIN30 IX.4 [M+H]+ 200 (B) VII.7 458 195- 0.25 3.9 -F OMe -CH2-NMe2 C27H26FN303 IX.4 [M-H]" 198 (A) tBuO 0 NH V11.8 517 230- 0.30 3.10 -F -CH2-NMe2 C30H33FN403 IX.4 [M+H]+ 240 (A) 3.11 -F oMe V11.1 C29H31FN405S 567 188- 0.40 (CH2)2-NMe2 IX.2 [M+H]+ 189 (A) 0 OMe Me J Me VI1.1 572 200- 0.35 3.12 -F N 0 C32H34FN504 +
IX.19 [M+H] 203 (C) 3.13 -F CN -CH2-NMe2 V11.9 C26H23FN40 427 130- 0.25 I
IX.4 [M+H]+ 135 (A) OtBu r''`N-Me HN'~0 Me. ~N VII.10 629 215- 0.35 3.14 -F N C35H41 FN604 0 IX.19 [M+H]+ 220 (A) OtBu HN'~0 VII.10 517 186- 0.35 3.15 -F -CH2-NMe2 C30H33FN403 +
IX.4 [M+H] 190 (A) OtBu NH V11.17 531 0.40 3.16 -F -CH2-NMe2 C31H35FN403 + n.d.
OMe o VII.15 488 166- 0.40 3.17 -F / -NMe-(COMe) - C28H26FN304 [M+H]+ 170 (A) OMe N-Me VI1.15 586 176- 0.30 3.18 -F Me~N 0 C33H36FN504 +
IX.19 [M+H] 180 (A) lux, OMe o -N(SO2Me)- VII.15 581 195- 0.45 3.19 -F C30H33FN405S
(CH2)2-NMe2 IX.2 [M+H]+ 198 (A) OMe o -N(COMe)- VII.15 559 100- 0.50 3.20 -F C32H35FN404 (CH2)3-NMe2 IX.7 [M+H]+ 104 (A) OMe o Me VII.15 558 132- 0.80 3.21 -F r 0tBu C32H34FN305 / 0 IX.18 [M-Hl- 137 (D) OMe 0 0 rN-Me VII.15 543 234- 0.60 3.22 -FIX.30 C31H31FN404 LM+Hl+ 236 (A) OMe 0 NI VII.15 497 110- 0.40 3.23 -F N C29H25FN403 Me IX.16 [M+H]+ 115 (A) lox OMe 0 VII.15 495 130- 0.60 3.24 -F -SO2Me C26H23FN205S
[M+H]+ 137 (A) NMe 3OMe Me. N V11.7 572 189 0.60 3.25 -F N 0 C32H34FN504 +
IX.19 [M+H] (B) OMe -N(SO2Me)- VII.7 567 0.60 3.26 -F C29H31FN405S
(CH2)2-NMe2 IX.2 [ M+H ]+ n.d. (B) oMe or'N-Me V11.7 529 201- 0.60 3.27 -F N. C3oH29FN404 IX.30 [M+HJ+ 203 (B) 3.28 -F OMe -N(Me)-(CO)- VII.7 C29H29FN404 517 126 0.60 CH2-NMe2 IX.10 [M+HI+ (B) 3.29 -F OMe -N(COMe)- VII.7 C30H31FN404 531 179 0.50 (CH2)2-NMe2 IX.6 [M+H]+ (B) 3.30 -F OMe -N(COMe)- VII.7 C31H33FN404 545 123 0.20 (CH2)3-NMe2 IX.7 [M+H]+ (B) 3.31 -F OMe -N(Me)-(CO)- VII.7 C32H35FN404 559 201 0.20 (CH2)4-NMe2 IX.32 [M+H]+ (B) 3.32 -F O OMe -H V11.1 C24H19FN203 403 198- 0.80 _ [M+H]+ 206 (A) 0 ,e N-3 V11.1 483 223- 0.75 3.33 -F N C28H23FN403 Me IX.16 [M+H]+ 226 (A) O OMe 0 N-Me VI1.1 529 215- 0.30 3.34 -F N\---/ C3oH29FN404 IX.30 [M+H]+ 220 (A) 0 oMe -N(S02Me)- V11.1 581 227- 0.65 3.35 -F (CH2)-(CO)- C29H29FN406S
= IX.8 [M+H)+ 230 (A) NMe2 oMe -N(Me)-(CO)- VII-1 517 128- 0.45 3.36 -F C29H29FN4O4 CH2-NMe2 IX.10 [M+H]+ 130 (A) OMe -N(COMe)- VII.1 474 218- 0.40 3.37 -F C27H24FN304 CH3 _ [M+H]+ 223 (A) oMe -N(Me)-(CO)- V11.1 531 192- 0.40 3.38 -F C30H31FN404 (CH2)2-NMe2 IX.11 [M+H]+ 194 (A) 0 OMe V11.1 481 205- 0.65 3.39 -F -SO2Me C25H21FN205S
~. _ [M+H]+ 214 (A) OMe -N(Me)-(CO)- VI1.1 545 190- 0.15 3.40 -F C31H33FN404 (CH2)3-NMe2 IX.33 [M+H]+ 193 (A) 3.41 -F 0 oMe V11.1 C31H33FN404 545 184- 0.50 (CH2)3-NMe2 IX.7 [M+H]+ 188 (A) V11.7 403 0.70 3.42 -F OMe -H C24H19FN203 [M+H]+ 114 (B) VII.7 481 0.60 3.43 -F OMe _S02Me C25H21FN205S [M+H]+ 129 (B) OMe N-3 V11.7 483 0.60 3.44 -F N C28H23FN403 125 Me IX.16 [M+H]+ (B) o -N(SO2Me)-VI I.7 581 0.60 3.45 -F oMe (CH2)-(CO)- C29H29FN406S 163 IX.8 [M+H] (B) NMe2 3.46 -F OMe -N(Me)-(CO)- VII.7 C31H33FN404 545 101 0.10 r (CH2)3-NMe2 IX.33 [M+H]+ (B) 3.47 -F oMe -N(Me)-(CO)- VII.7 C30H31FN404 531 161 0.20 (CH2)2-NMe2 IX.11 [M+H]+ (B) Me0 O Me Me VII.14 586 181- 0.20 3.48 -F N O C30H31 FN404 IX. 19 [M+H]+ 183 (B) MeO O
3.49 -F -N(SO2Me)- VII.14 C30H33FN405S 581 158- 0.35 I ` (CH2)2-NMe2 IX.2 [M+H]+ 160 (B) MeO f O
3.50 -F -N(Me)-(CO)- VII.14 C30H31FN404 531 0.40 ` CH2-NMe2 IX.10 [M+H]+ n.d. (B) MeO O
3.51 -F -N(COMe)- VII.14 C32H35FN404 559 0.50 ` (CH2)3-NMe2 IX.7 [M+H]+ n.d. (E) tBuO
o Me, Me H VI1.8 629 0.35 3.52 -F N-41 C35H41FN604 + n.d.
0 IX=19 [M+H] (A) O~-CH3 HN -NMe-(CO)- VI1.26 473 122- 0.50 3.53 -F CH3 - C27H25FN403 [M+H]+ 126 (F) O.--CH3 HN -N(COMe)- VII.26 544 80- 0.25 3.54 -F CH2 3-NMe2 C31H34FN503 ( ) IX.7 [M+H]+ 83 (A) O~-CH3 HN -N(S02Me)- VII.18 566 190- 0.30 3.55 -F C29H32FN504S
(CH2)2-NMe2 IX.2 [M+H]+ 195 (A) O~-CH3 3.56 -F HN -N(Me)-(CO)- VII.18 C29H30FN503 516 238- 0.30 CH2-NMe2 IX.10 [M+H]+ 241 (G) OMe VII.15 488 205- 0.55 3.57 -F -(CH2)2-NMe2 C29H3oFN303 IX.5 [M+H]+ 208 (G) OMe -N(Me)-(CO)- VII.15 543 196- 0.20 3.58 -F C31H31FN404 ` (CH2)2-NMe2 IX.11 [M-H]" 202 (A) OMe -N(Me)-(CO)- VII.15 531 177- 0.30 3.59 -F C30H31FN404 ` CH2-NMe2 IX.10 [M+H]+ 182 (A) EtO O
VI1.19 500 100- 0.35 3.60 -F -(CH2)2-NMe2 C3oH32FN303 M-H " 105 (B) [ ] ) OMe O -N(COMe)- VII.15 C31H33FN404 545 167- 0.40 3.61 -F (CH2)2-NMe2 IX.6 [M+H]+ 169 (A) EtO O
3.62 -F -N(Me)-(CO)- VII-19 C33H37FN404 571 n.d. 0.35 I (CH2)3-NMe2 IX.33 [M-H]" (A) EtO O
3.63 -F -N(Me)-(CO)- VII-19 C34H39FN404 585 n.d. 0.40 (CH2)4-NMe2 IX.32 [M-H]" (A) EtO O
N3 VII.19 511 95- 0.25 3.64 - F C3oH27FN403 Me IX.16 [M+H]+ 105 (B) OMe 3.65 O -N(Me)-(CO)- VII.15 573 173- 0.20 I (CH2)4-NMe2 IX.32 [M+H]+ 175 (A) OMe o VII.15 417 168- 0.65 3.66 -F -H C25H21 FN203 - [M+H]+ 174 (A) OMe o VII.15 500 168- 0.40 3.67 -F rN~ C30H30FN303 IX.22 [M+H]+ 173 (B) OMe o VII.15 502 0.45 -CH2-NEt2 C3oH32FN303 + n.d.
3.68 -F
lox OMe 0 H V11.15 544 0.30 3.69 -F N1rotBu C31H32FN305 n.d.
o IX.12 [M-H] (G) OMe VII.7 472 165- 0.25 3.70 -F -(CH2)2-NMe2 C28H28FN303 IX.5 [M-Hl- 170 (B) O OMe VII.1 472 193- 0.25 3.71 -F -(CH2)2-NMe2 C28H28FN303 IX.5 [M-H]" 197 (B) EtO O
V11.19 488 48- 0.45 3.72 -F -CH2-NMe2 C29H30FN303 IX.4 [M+H]+ 52 (B) OMe o VII.20 504/506 156- 0.30 3.73 -Cl -(CH2)2-NMe2 C29H30CIN303 IX.5 [M+H]+ 160 (H) OMe O N VII.20 513/515 0.40 3.74 -Cl N C29H25CIN403 [M+H]+ 110 (H) Me IX.16 OMe O VII.20 490/492 173- 0.70 3.75 -Cl -CH2-NMe2 C28H28CIN303 IX.4 [M+H]+ 175 (I) ,lax, OEt o VII.21 488 158- 0.35 3.76 -F -CH2-NMe2 C29H30FN303 IX.4 [M+H]+ 161 (B) MeO O
r--",N-Me VII.14 529 147- 0.50 3.77 -F rN,J C31H33FN403 IX.14 [M+H]+ 150 (1) MeO O
N VII.14 497 182- 0.60 3.78 -F ,rNJ C29H25FN403 IX.15 [M+H] 185 (K) OMe 0 r--\N-Me VII.15 529 0.35 3.79 -F N,.J C31 H33FN403 + 184 IX. 14 OMe O N VII.15 497 0.45 3.80 -F C29H25FN403 233 IX.15 [M+H]+ (B) OMe 3.81 -F -CH2-NMe- VII.15 C31H35FN403 531 120 0.40 a (CH2)2-NMe2 IX.17 [M+H]+ (B) EtO O
3.82 -F -CH2-NMe- VII.19 C32H37FN403 545 0.40 (CH2)2-NMe2 IX.17 [M+H]+ n.d. (K) OMe o VII.20 516/518 195- 0.30 3.83 -Cl rN0 C30H30CIN303 IX.22 [M+H]+ 197 (H) EtO O
VII.19 431 156- 0.80 3.84 -F -H C26H23FN203 [M+H]+ 160 (M) EtO O
H V11.19 560 0.50 3.85 -F r-NrOtBu C32H34FN305 n.d.
o IX.12 [M+H]+ (~) EtO O
Me VII.19 574 0.60 3.86 -F i o otBu C33H36FN305 n.d.
MeO O
of VII.22 476 0.25 3.87 -F -CH2-NMe2 C27H26FN304 + 129 OMe o VII.23 476 0.25 3.88 -F O -CH2-NMe2 C27H26FN304 + 155 OEt 3.89 -F O O -CH2-NMe2 V11.24 C29H3oFN304 504 0.20 IX.4 [M+H]+ n.d. (B) OMe o VII.26 560/562 230- 0.45 3.90 -Br rN C30H30BrN3O3 +
IX.22 [NI+H] 235 (B) lux OMe o V11.26 534/536 178- 0.35 3.91 -Br -CH2-NMe2 C28H28BrN3O3 IX.4 [M+H]+ 180 (B) OMe o VII.26 562/564 173- 0.40 3.92 -Br -CH2-NEt2 C30H32BrN3O3 IX.1 [M+H]+ 176 (B) lux *Eluent mixtures:
(A): silica gel, methylene chloride/methanol/ammonia 9:1:0.1 (B): silica gel, methylene chloride/methanol 9:1 (C): silica gel, methylene chloride/methanol/ammonia 8:1:0.1 (D): silica gel, methylene chloride/methanol/ammonia 10:1:0.1 (E): silica gel, methylene chloride/methanol/ammonia 5:1:0.01 (F): silica gel, ethyl acetate/methanol/ammonia = 9:1:0,1 (G): alumina, methylene chloride/methanol = 19:1 (H): silica gel, methylene chloride/methanol/ammonia 9:1:0.01 (I): silica gel, methylene chloride/methanol 5:1 (K): alumina, methylene chloride/ethanol = 20:1 (L): silica gel, petroleum ether/ethyl acetate 1:1 (M): silica gel, petroleum ether/ethyl acetate 1:2 The following compounds of the formula I-3b are prepared analogously to Example 3.0:
R4' H
O
R2 N (I-3b) H
Ex- Starting Rf Empirical Mass m. p.
amp R2 R3 R4' materi- formula spectrum [ C] value le als OMe o V11.15 474 176- 0.40 3.93 -F -CH2-NMe2 C28H28FN303 IX.3 [M+H]+ 179 (A) VI1.19 486 0.45 EtO 6:0 3.94 -F -CH2-NMe2 C29H30FN303 n.d.
IX.3 [M-H]" (B) OMe o VII.20 490/492 163- 0.40 3.95 -Cl -CH2-NMe2 C28H28CIN303 IX.3 [M+H]+ 165 (A) lux *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-[1-(4-(Dimethylaminomethyl)anilino)-1-(3,4-dimethoxyphenyl)methylene]-6-10 cyano-2-indolinone 130 mg of 1-acetyl-3-(1-methoxy-1-(3,4-dimethoxyphenyl)methylene)-6-cyano-2-indolinone (starting material VII.4) and 58 mg of 4-(dimethylaminomethyl)aniline (starting material IX.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 15 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-Methyl-N-methylsulphonylamino)anilino)-1-(3-(2-methoxycarbonyl-vinyl)phen rI methylenel-6-chloro-2-indolinone 580 mg of 3-Z-[1-(4-(N-methyl-N-methylsulphonylamino)anilino)-1-(3-iodophenyl)-methylene]-6-chloro-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.
TM
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:
R4' H
O
R N (1-5) Start-Ex-ampi R 2 R3 R4' ing Empirical Mass m.p. Rr mate- formula spectrum [ C] value*
e rials I I I I
O OMe 486/488 150- 0.50 5.1 -Cl -CH2-NMe2 1.1 C28H26CIN303 / " [M-H]- 155 (A) NHZ
0 455 269- 0.20 5.2 -F -CH2-NMe2 3.0 C27H25FN402 I [M-H] 270 (B) OMe 5.3 -F la CH2-NMe2 3.0 C28H26FN303 470 205- 0.65 [M-H]' 208 (A) O OMe 472 138- 0.45 5.4 -F -CH2-NMe2 1.1 C28H26FN303 [M+H]+ 140 (A) *Eluent mixtures:
(A): silica gel, methylene chloride/methanol 5:1 (B): silica gel, methylene chloride/methanol/ammonia 9:1:0.01 Example 6.0 3-Z-[1-(4-Dimethylaminomethylanilino) 1-(3-(2-methoxycarbonylethyl)phenyl)methylenel-6-chloro-2-indolinone 1.0 g of 3-Z-[1-(4-(dimethylaminomethyl)anilino)-1-(3-(2-methoxycarbonyl-vinyl)phenyl)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 of 50 psi for 6 hours. After the reaction has ended, the catalyst is filtered 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 1-6 are prepared analogously to Example 6.0:
H
O
R2 N (1-6) Start-Ex-ing Empirical Mass m.p. Rf am- R2 R3 R4`
pie mate- formula spectrum [ C] value*
rials O OMe 6.1 -Cl -N(Me)- 5.0 C27H26C1N305S 538/540 148- 0.50 l S02Me [M-H]" 150 (A) NHZ
0 459 0.70 6.2 -F -CH2-NMe2 5.2 C27H27FN402 [M+H]+ 150 (B) OMe 0 474 0.35 6.3 -F -CH2-NMe2 5.3 C28H28FN303 [M+H]+ 140 (A) O OMe 474 140- 0.30 6.4 -F -CH2-NMe2 5.4 C28H28FN303 [M+H]+ 142 (A) *Eluent 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 -(4-Dimethylaminomethlaanilino)-1-(4-aminomethylphenyl)methylene]-6-chloro-2-indolinone 900 mg of 3-Z-[1-(4-dimethylaminomethylanilino)-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 methanol and diethyl ether. 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. 211-214 C
Mass spectrum: m/z = 433/435 [M+H]+
Example 8.0 3-Z-[1 -4-(N-((4-Methylpiperazin-1-yl)methylcarbonyl)-N-methylamino)anilino)-1-(4-aminomethylPhenyl)methvlenel-6-chloro-2-indolinone 1.39 g of 1-acetyl-3-Z-[1-(4-(N-((4-methylpiperazin-1-yl)methylcarbonyl)-N-5 methylamino)anilino)-1-(4-cyanophenyl)methylene]-6-chloro-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 10 residue is washed with a little methanol and diethyl ether. 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 purified on a silica gel column using, as mobile phase, a gradient of methylene chloride and methylene 15 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-(Dimethylaminomethvl)anilino)-I -(3-aminomethIy Shen l methvlenel-6-fluoro-2-indolinone 2.72 g of 3-Z-[1-(4-(dimethylaminomethyl)anilino)-1-(3-(N-tert-butoxycarbonyl-aminomethyl)phenyl)methylene]-6-fluoro-2-indolinone (starting material 3.10) are dissolved in 50 ml of methylene chloride, and 10 ml of trifluoroacetic acid are added.
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 1 N 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
Mass spectrum: m/z = 415 [M-H]-The following compounds of the formula 1-9 are prepared analogously to Example 9.0:
R4' H
O
R2 N (1-9) Start-Ex-ing Empirical Mass m.p. Rf am- R2 R3 R4`
ple mate- formula spectrum [ C] valu' rials NHZ
431 155- 0.45 9.1 -F -CH2-NMe2 3.16 C26H27FN40 [M+H]+ 160 (C) NHZ
417 203- 0.25 9.2 -F -CH2-NMe2 3.15 C25H25FN40 [M+H]+ 207 (A) NH2 r--'NMe 529 170- 0.15 9.3 -F H3CNr N`J 3.14 C30H33FN602 M+H + 175 (A) OH
O
446 245- 0.20 9.4 -F \ -CH2-NHMe 10.11 C26H24FN303 [M+H]+ 251 (D) 459 239- 0.30 9.5 -F -CH2-NHMe 11.22 C26H24FN303 +
[M+H] 243 (A) NH2 f--\NMe 529 9.6 -F H 3 c 'r N J 3.52 C30H33FN602 n.d. n.d.
" o [M+H]
+
OMe 444 158- 0.25 9.7 -F -CH2-NH2 3.69 C26H24FN303 [M-H]" 163 (A) EtO 4 60 205- 0.30 9.8 -F E$:T -CH2-NH2 3.85 C27H26FN303 [M+H]+ 210 (B) EtO 4 74 148- 0.30 -CH2-NHMe 3.86 C28H28FN303 [M+H]+ 150 (B) 9.9 -F 6:0 *Eluent 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-f1-(4-Dimethylaminomethylanilino)-1-(3-(2-carbo yethyl)phenyl)methylenel-6-chloro-2-indoli none 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 1 N aqueous sodium hydroxide solution are added. The mixture is stirred at room temperature for 5 hours. After cooling, 5 ml of I N 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+H]+
The following compounds of the formula 1-1 Oa are prepared analogously to Example 10.0:
H
O
R2 N (I-10a) H
Start-Ex- Rf ing Empirical Mass m.p.
am- R2 R3 R4' mate- formula spectrum ['Cl value*
pie rials OH
460 0.65 10.1 -F / \ -CH2-NMe2 6.3 C27H26FN303 [M+H]+ 250 (A) OH
O 444 278- 0.10 10.2 -F -CH2-NMe2 3.9 C26H24FN303 M-H - 282 (B) [ ] O OH
458 198- 0.20 10.3 -F r -CH2-NMe2 6.4 C27H26FN303 [M-H]' 200 (C) O OH
444 212- 0.30 10.4 -F -CH2-NMe2 3.7 C26H24FN303 [M-H]- 216 (D) 0 OH ~NMe 558 260- 0.20 10.5 -F H3CN 0 3.12 C311-13, FN504 [M+H]+ 263 (D) OH
10.6 -F -N(SO2Me)- 3.11 C28H29FN405S 553 246- 0.30 (CH2)2-NMe2 [M+H]+ 249 (D) OH
O -NMe-(CO)- 3.17 474 286- 0.60 10.7 -F CH3 C27H24FN304 []+ 290 (E) M+H
OH
O H3O ~NMe 570 215- 0.20 10.8 -F N o 3.18 C32H34FN504 [M-Hl- 222 O
D
OH
10.9 -F -N(SO2Me)- 3.19 C29H31FN405S 567 160- 0.20 1 ` (CH2)2-NMe2 [M+H]+ 165 (D) OH
10.10 -F -N(COMe)- 3.20 C31H33FN404 545 153- 0.15 ` (CH2)3-NMe2 [M+H]+ 158 (D) OH
o Me 546 215- 0.60 10.11 -F / ' o OtBu 3.21 C31H32FN305 [M+H]+ 219 (E) OH
O 0 rN-Me 529 179- 0.25 10.12 -F 3.22 C3oH29FN404 [M H 186 (E) OH
o N-3 483 264- 0.65 10.13 -F >'Me 3.23 C28H23FN403 M+H 267 (E) []+ OH
0 481 146- 0.70 10.14 -F / -SO2Me 3.24 C25H21FN205S [M+H]+ 155 E
O
OH
O 0 r'N-Me 515 0.70 10.15 -F N 3.27 C29H27FN404 251 OH
O H3G ~NMe 558 0.10 10.16 -F N 3.25 C31H32FN504 [M+H]+ 234 (E) OH
-N(Me)-(CO)- 503 0.60 10.17 -F 3.28 C28H27FN404 203 CH2-NMe2 [M+H]+ (E) OH
-N(Me)-(CO)- 545 10.18 -F 3.31 C31H33FN404 + 251 n.d.
(CH2)4-NMe2 [M+H]
OH
O 387 0.60 10.19 -F -H 3.42 C23H17FN203 [M-H]_ 130 (E) OH
467 0.55 10.20 -F -SO2Me 3.43 C24H19FN205S [M+H]+ 139 (E) OH
O N1 469 0.35 10.21 -F ~N 3.44 C27H21FN403 157 Me [M+H]+ (E) O OH _N(SO2Me)-567 0.55 10.22 -F (CH2)-(CO)- 3.45 C28H27FN406S [M+H]+ 183 (E) NMe2 OH
389 237- 0.10 10.23 -F -H 3.32 C23H17FN203 [M+H]+ 240 (D) NI 469 259- 0.15 10.24 -F N~ 3.33 C27H21FN403 Me [M+H]+ 265 (D) -N(COMe)- 3.41 C30H31FNaO4 531 274- 0.15 10.25 -F
(CH2)3-NMe2 [M+H]+ 278 (D) ~H -N(Me)-(CO)- 3.36 C28H27FN404 503 258- 0.20 10.26 -F
CH2-NMe2 [M+H]+ 264 (D) 515 279- 0.15 10.27 -F / O ~N Me 3.34 C29H27FN404 [M+H]+ 282 (D) O OH
467 260- 0.35 10.28 -F -SO2Me 3.39 C24H19FN205S
[M+H]+ 266 (F) -N(COMe)- 3.37 C26H22FN304 460 290- 0.30 10.29 -F OH
CH3 [M+H]+ 294 (F) OH -N(S02Me)-567 238- 0.30 10.30 -F CH2-(CO)- 3.35 C28H27FN406S
[M+H]+ 242 (F) NMe2 ~H -N(Me)-(CO)-3.38 C29H29FN404 517 250- 0.35 10.31 -F
(CH2)2-NMe2 [M+H]+ 255 (F) ~H -N(Me)-(CO)- 3.40 C30H31FN404 531 184- 0.25 10.32 -F
(CH2)3-NMe2 [M+H]+ 190 (F) O OH
NM
H C ~e 572 170- 0.40 10.33 -F 3 'N 3.48 C32H34FN504 '1, 0 [M-H]' 175 (C) OH
-N(SO2Me)- 553 0.60 10.34 -F 3.26 C28H29FN405S 180 (CH2)2-NMe2 [M+H] (C) O OH
10.35 -F -N(SO2Me)- 3.49 C29H31FN405S 567 196- 0.30 1 (CH2)2-NMe2 [M+H]+ 199 (C) O OH
c -N(Me)-(CO)- 517 0.20 10.36 -F 3.50 C29H29FN404 + 150 CH2-NMe2 [M+H] (C) O OH
10.37 -F -N(COMe)- 3.51 C31H33FN404 545 206- 0.30 (CH2)3-NMe2 [M+H]+ 210 (A) OH
10.38 -F 0 -N(Me)-(CO)- 3.59 C29H29FN404 517 231- 0.60 1 ` CH2-NMe2 [M+H]+ 236 (A) OH
474 218- 0.50 10.39 -F -(CH2)2-NMe2 3.57 C28H28FN303 [M+H]+ 222 (A) OH
10.40 -F 0-N(Me)-(CO)- 3.58 C30H31FN404 531 215- 0.50 ` (CH2)2-NMe2 [M+H]+ 218 (A) O OH
474 172- 0.15 10.41 -F -(CH2)2-NMe2 3.60 C28H28FN303 [M+H]+ 177 (G) OH
10.42 -F 0 -N(COMe)- 3.61 C30H31 FN404 531 230- 0.50 ` (CH2)2-NMe2 [M+H]+ 234 (A) -N(Me)-(CO)- 3.62 C 545 170- 0.30 10.43 -F (CH2)3-NMe2 31 H33FNa0a [M+H]+ 175 (E) 10.44 -F -N(Me)-(CO)- 3.63 C32H35FN404 559 142- 0.10 (CH2)4-NMe2 [M+H]+ 146 (G) N 483 262- 0.20 10.45 -F xkN 3.64 C28H23FN403 Me [M+H]+ 269 (E) OH
10.46 -F 0 -N(Me)-(CO)- 3.65 C32H35FN404 559 234- 0.30 lux (CH2)4-NMe2 [M+H]+ 236 (A) OH
0 403 231- 0.20 10.47 -F / -H 3.66 C24H19FN203 M+H 233 (A) OH
0 486 205- 0.10 10.48 -F NO 3.67 C29H28FN303 M+H 210 (E) [ ]+ OH
0 488 145- 0.15 10.49 -F -CH2-NEt2 3.68 C29H30FN303 M+H 150 E
OH
0 430 280- 0.05 10.50 -F -CH2-NH2 9.7 C25H22FN303 / [M-H] 285 (H) OH
O 460 273- 0.15 10.51 -F / -(CH2)2-NMe2 3.70 C27H26FN303 [M+H]+ 276 (E) O OH
460 230- 0.05 10.52 -F -(CH2)2-NMe2 3.71 C27H26FN303 [M+H]+ 235 (E) OH
0 490/492 255- 0.50 10.53 -Cl / -(CH2)2-NMe2 3.73 C28H28CIN303 [M H 258 A
+ ]+ ( ) OH
e N-3 499/501 296- 0.50 10.54 -Cl / Me 3.74 C28H23CIN403 M H 300 (A) ` [ +]+ OH
O 476/478 228- 0.50 10.55 -Cl / -CH2-NMe2 3.75 C27H26CIN303 [M H 230 A
+ ]+ ( ) lx, O OH
r--",N-Me 515 210- 0.40 10.56 -F N,--j 3.77 C30H31 FN403 / [M+H]+ 215 (A) O OH
N 483 240- 0.50 10.57 -F ~NJ 3.78 C28H23FN403 / [M+H]+ 245 (A) O OH
c -CH2-NMe- 517 0.30 10.58 -F 3.82 C30H33FN403 n.d.
I (CH2)2-NMe2 [M+H]+ (I) OH
r--,N-Me 515 0.35 NJ 3.79 C30H31FN4O3 275 10.59 -F r lox OH
N 483 0.55 10.60 -F r N.~ 3.80 C28H23FN403 280 OH
502/504 260- 0.50 10.61 -Cl NO 3.83 C29H28CIN303 M+H 266 (A) [ ]+ OH
-CH2-NMe- 517 0.05 10.62 -F 3.81 C30H33FNa03 n.d.
(CH2)2-NMe2 [M+H]+ (E) 03 110- 0.60 -H 3.84 C24H19FN203 M+H 112 (K) 10.63 -F aIrO
[ l+ HO 4 32 260- 0.60 -CH2-NH2 9.8 C25H22FN303 M+H 263 (A) 10.64 -F 6:rO
[ l+ HO c5:rO 446 265- 0.60 10.65 -F -CH2-NHMe 9.9 C26H24FN303 M+H 270 (A) [ l+
HO O
462 0.10 250 (M) 10.66 -F -CH2-NMe2 3.87 C26H24FN304 [M+H]+ (M) 462 0.15 10.67 -F O -CH2-NMe2 3.88 C26H24FN304 247 OH
546/548 290- 0.30 10.68 -Br / N0 3.90 C29H28BrN3O3 M+H 293 (E) [ ]+ OH
520/522 243- 0.25 10.69 -Br / -CH2-NMe2 3.91 C27H26BrN3O3 M+H 246 (E) [ ]+ OH
548/550 252- 0.35 10.70 -Br / -CH2-NEt2 3.92 C29H30BrN3O3 [M+H]+ 255 (E) *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 I-1 Ob are prepared analogously to Example 10.0:
H
O
R2 H (I-1Ob) Start-Ex-am- R 2 R3 R 4` ing Empirical Mass m.p. Rt-pie mate- formula spectrum [ C] value*
rials OH
0 460 0.20 10.71 -F / -CH2-NMe2 3.93 C27H26FN303 [M+H]+ 150 (A) O OH
460 105- 0.30 10.72 -F -CH2-NMe2 3.94 C27H26FN303 [M+H]+ 109 (B) OH
0 476/478 230- 0.50 10.73 -CI / -CH2-NMe2 3.95 C27H26CIN303 M+H 235 (C) [ ]+ *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-[1-(4-Dimethylaminomethylanilino)-1-(3-(2-carbamovlethyl phenyl)methylene]-chloro-2-indolinone 480 mg of 3-Z-[1-(4-dimethylaminomethylanilino)-1-(3-(2-carboxyethyl)phenyl)methylene]-6-chloro-2-indolinone (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 methylene 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+H]+
The following compounds of the formula I-11 are prepared analogously to Example 11.0:
H
O
R2 H (I-11) Start-Ex-ing Empirical Mass m.p. Rf am- R2 R3 R4' pie mate- formula spectrum [ C] value*
rials o NHCH3 10.0 489/491 223- 0.50 11.1 -Cl -CH2-NMe2 C28H29CIN4O2 / ** [M+H]+ 225 (A) 0 10.1 473 148- 0.40 11.2 -F -CH2-NMe2 C28H29FN402 M+H 150 (B) NMe2 0 10.2 473 98- 0.30 11.3 -F -CH2-NMe2 C28H29FN402 / _ *** [M+H]+ 103 (C) o NH2 459 223- 0.50 11.4 -F -CH2-NMe2 10.3 C27H27FN402 / \ [M+H]+ 225 (A) 0 NHMe 10.3 473 210- 0.70 11.5 -F -CH2-NMe2 C28H29FN402 [M+H]+ 213 (A) ** O NMez 10.3 487 213- 0.80 11.6 -F / -CH2-NMe2 *** C29H31FN402 [M+H]+ 215 (A) 0 443 115- 0.25 11.7 -F -CH2-NMe2 10.2 C26H25FN402 [M-Hl- 120 (C) NHMe 0 10.2 457 222- 0.25 11.8 -F -CH2-NMe2 ** C27H27FN402 [M-H]' 225 (C) 0 NHz 443 143- 0.40 11.9 -F / -CH2-NMe2 10.4 C26H25FN402 [M-H]' 146 (D) NMe2 0 10.1 487 198- 0.60 11.10 -F / -CH2-NMe2 *** C29H31FN402 M+H + 200 (B) [ l Me N 10.1 542 0.60 11.11 -F 0 -CH2-NMe2 C32H36FN502 175 **** [M+H]+ (B) N
Me 557 150- 0.40 11.12 -F H3C'N 10.5 C31H33FN603 0 [M+H]+ 156 (E) 11.13 -F -N(SO2Me)- 10.6 C28H30FN5O4S 552 197- 0.50 (CH2)2-NMe2 [M+H]+ 199 (D) 11.14 -F NMe2 -CH2-NMe2 10.4 C28H29FN402 473 147- 0.35 *** [M+H]+ 152 (D) 0 NHMe 10.4 459 208- 0.35 11.15 -F -CH2-NMe2 C27H27FN402 ** [M+H]+ 214 (D) 0 NHMe 11.16 -F -N(S02Me)- 10.6 C29H32FN504S 566 218- 0.70 (CH2)2-NMe2 ** [M+H]+ 222 (F) 1 1 . 1 7 -F 0 ,e2 -N(S02Me)- 10.6 C30H34FN5O4S 580 199- 0.40 (CH2)2-NMe2 *** [M+H]+ 205 (C) 0 NHMe H3C ~NMe 10.5 571 155- 0.20 11.18 -F TN C32H35FN603 0 ** [M+H]+ 160 (C) -N(Me)-(CO)- 10.7 C28H27FN403 487 137- 0.50 11.19 -F
CH3 ** [M+H]+ 145 (C) 0 ~NMe 10.8 585 211- 0.40 11.20 -F H3 0 ** C33H37FN603 M+H + 219 [ ] (C) NHCH3 0 11.21 -F -N(S02Me)- 10.9 C30H34FN5O4S 578 192- 0.50 / (CH2)2-NMe2 ** [M-H]" 200 (C) o Me 10.11 559 180- 0.50 N
11.22 -F / r o oteu C32H35FN404 M+H 187 (C) o N-3 10.13 496 262- 0.40 11.23 -F / >'NN e C29H26FN502 M+H 266 (C) ** [ ]+ NHCH3 0 10.14 494 180- 0.60 11.24 -F / -SO2Me C26H24FN304S M+H 188 (C) 0 0 ''N-Me 10.12 542 226- 0.50 11.25 -F N,--j C31H32FN503 M+H 230 (C) NHMe o H JMe 10.16 571 0.10 11.26 -F 3clv o ** C32H35FN603 213 [M+H] (G) NHMe 0 0 r'N-Me 10.15 528 0.40 11.27 -F N,J C30H30FN5O3 245 *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 dimethylammonium chloride as base equivalent **** using piperidine hydrochloride as base equivalent Example 12.0 3-Z-[1- 4-Dimethylaminomethylanilino)-1-(4-acetylaminomethylphenyl)methylenel-chloro-2-indoli none 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 pi 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 pI 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, methylene chloride/methanol/ammonia = 9:1:0.01) m.p. 219-220 C
Mass spectrum: m/z = 473/475 [M-H]-The following compounds of the formula 1-12 are prepared analogously to Example 12.0:
H
R2 N (1-12) Start-Ex-ing Empirical Mass m.p. Rf-am- R2 R3 Ra, mate- formula spectrum [ C] value*
pie rials HN'~~3 H3JNCH3 585/587 252- 0.25 12.1 -Cl J 8.0 C32H35CIN6O3 M-H " 255 (B) r~
535/537 238 0.45 12.2 -CI HN 0 -CH2-NMe2 7.0 C32H29CIN4O2 (de_ comp.) 2 ~NJ CH3 647/649 282- 0.40 12.3 -CI HN H3v o 8.0 C37H37CIN6O3 [M-H]" 284 (B) 0.1-CH3 HN 457 245- 0.40 12.4 -F -CH2-NMe2 9.0 C27H27FN402 [M-H]" 250 (C) 0~- Et HN 471 212- 0.35 12.5 -F -CH2-NMe2 9.0 C28H29FN402 [M-H]" 214 (D) o /
HN 519 237- 0.40 12.6 -F -CH2-NMe2 9.0 C32H29FN402 [M-H] 240 (D) 0 533 187- 0.30 12.7 -F HN -CH2-NMe2 9.0 C33H31FN402 [M-H]" 190 (D) NH
471 234- 0.30 12.8 -F -CH2-NMe2 9.1 C28H29FN402 / \ [M-H]" 237 (D) 0 533 144- 0.45 12.9 -F NH -CH2-NMe2 9.1 C33H31FN402 [M-H]" 150 (C) Et o NH
485 235- 0.25 12.10 -F -CH2-NMe2 9.1 C29H31FN402 / \ [M-H]" 237 (D) NH
547 217- 0.30 12.11 -F -CH2-NMe2 9.1 C34H33FN402 [M-H]" 220 (D) HN40 457 112- 0.25 12.12 -F -CH2-NMe2 9.2 C27H27FN402 M-H " 120 (D) Et HN4 0 586 176- 0.30 12.13 -F -CH2-NMe2 9.2 C28H29FN4O2 [M+H]+ 180 (D) 535 80- 0.35 12.14 -F HN 0 -CH2-NMe2 9.2 C33H31 FN4O2 4 H3 rNCH3 HN 0 H 1-NJ 569 230- 0.35 12.15 -F 3c1v 0 9.3 C32H35FN603 [M-H]" 235 O
D
Et HN 40 H3~NCH3 583 205- 0.30 12.16 -F ev o 9.3 C33H37FN603 M-H " 210 (D) [ J ~NCH3 645 217- 0.35 12.17 -F HN 0 H3v 0 9.3 C38H39FN603 [M-H]" 220 (D) H N`J CH3 597 209- 0.30 0o 12.18 -F 3-j= 9.6 C34H37FN603 M+H 212 (D) a H ~CH611 190- 0.30 12.19 F 3 9.6 C35H39FN603 M+H 193 (D) o NCH, 12.20 -F 9.6 C36H36FN703 [M+H]+ 163 (D) 0 ~-o J
HN H3 CH3 639 223- 0.30 12.21 -Fv 9.6 C37H43FN603 [M+H]+ 227 (D) N
o \NCH3 HN H -N 634 170- 0.25 12.22 -F 3 v C36H36FN703 o 9.6 [M+H]+ 175 (D) 0,7 CH3 HN CH3 H3 CH3 599 194- 0.20 12.23 -F \ 9.6 C34H39FN603 M+H + 196 (D) H3CH3 ow HN H~NCH3 613 197- 0.70 12.24 -F 3 v o 9.6 C35H41 FN6O3 [M+H]+ 200 (E) _N.J CH3 653 130- 0.75 12.25 -F HN H3 0 9.6 C38H45FN603 [M+H]+ 135 (E) O OMe H N H3 J CH3 601 155- 0.60 12.26 -F v 9.6 C33H37FN604 M+H + 159 (E) [ ] MeO
o / ~NCH3 663 168- 0.35 12.27 -F H3clv 9.6 C38H39FN604 [M+H]+ 172 (C) C(CH3)3 1~ r--"NCH 627 85- 0.35 12.28 -F HN H3C1v-~ 9.6 C36H43FN603 [M+H]+ 90 (C) s HN H ~NCH3 639 170- 0.25 12.29 -F 3 9.6 C35H35FN603S M+H + 175 (C) (CH3)3C`7~--HN rN J CH3 613 242- 0.30 12.30 -F H3"'N 9.6 C35H41 FN603 [M+H]+ 245 (C) HN H ( ~NCH3 623 155- 0.65 12.31 -F 30'N- 9.6 C35H35FN604 [M+H]+ 160 O
F
HN H ~NCH3 571 190- 0.60 12.32 -F 3C 9.6 C32H35FN603 [M+H]+ 195 (F) Et HN H JNCH3 585 203- 0.65 12.33 -F 3 9.6 C33H37FN603 o [M+H]+ 209 (E) HN O H3 J CH3 633 145- 0.60 12.34 -Fvo 9.6 C37H37FN603 [M+H]+ 150 (F) o H3 CNCH3 647 148- 0.65 12.35 -F HNe1v o 9.6 C38H39FN603 [M+H]+ 151 (F) o~
HN 485 216- 0.35 12.36 -F -CH2-NMe2 9.0 C29H29FN402 M+H 220 (D) HN 499 214- 0.35 12.37 -F -CH2-NMe2 9.0 C3oH31FN402 M+H 217 (D) HN 522 205- 0.35 12.38 -F -CH2-NMe2 9.0 C31H28FN502 [M+H]+ 210 (D) 0 ~-o HN 527 235- 0.35 12.39 -F -CH2-NMe2 9.0 C32H35FN402 [M+H]+ 237 (D) o HN 520 135- 0.20 12.40 -F -CH2-NMe2 9.0 C31H28FN502 [M-H]" 140 (D) H N H3 487 210- 0.20 12.41 -F -CH2-NMe2 9.0 C29H31FN402 D
[M+H] 215 O
O
HN 501 202- 0.25 12.42 -F -CH2-NMe2 9.0 C30H33FN402 [M+H]+ 206 (D) 541 198- 0.35 12.43 -F HN -CH2-NMe2 9.0 C33H37FN402 [M+H]+ 203 (D) O OMe H N 489 173- 0.35 12.44 -F -CH2-NMe2 9.0 C28H29FN403 [M+H]+ 177 (D) MeO
12.45 -F HN -CH2-NMe2 9.0 C33H31FN403 549 202- 0.50 [M-H]" 207 (C) O
12.46 -F HN -CH2-NMe2 9.0 C31H35FN402 513 203- 0.45 [M-H]" 209 (C) o s HN 527 245- 0.35 12.47 -F -CH2-NMe2 9.0 C30H27FN402S M+H 250 (C) [ ] (CH3>3Cro HN
501 248- 0.45 12.48 -F -CH2-NMe2 9.0 C30H33FN402 [M+H]+ 252 (C) o 1 HN 511 216- 0.30 12.49 -F -CH2-NMe2 9.0 C3oH27FN403 M+H 219 (C) [ l+ O CN
HN 522 167- 0.20 12.50 -F -CH2-NMe2 9.0 C31H28FN502 [M+H] 170 (D) *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, pyridin-2-ylcarbonyl chloride, pyridin-ylcarbonyl chloride, pyridin-4-ylcarbonyl chloride, cyclohexylcarbonyl chloride, isobutyryl chloride, 3-methylbutyryl chloride, cyclohexylmethylcarbonyl chloride, methoxyacetyl chloride, 2-methoxybenzoyl chloride, tert-butylacetyl chloride, thiophene-2-carbonyl chloride, pivaloyl chloride, 2-furoyl chloride Example 13.0 3-Z-[1-(4-Trimethylammoniummethylanilino)-1-(4-(2-carboxyethyl)phenyl)methylenel-6-fluoro-2-indoli none 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:
R4' H
O
H (1-13) R
Start-Ex-ing Empirical Mass m.p. Rf am- R2 R3 R4' mate- formula spectrum [ C] value*
ple rials O OH
Me 474 0.50 13.1 -F N= Me 10.3 C28H29FN3031 150 / "Me [M+H]+ (A) *Eluent mixture:
(A): reversed phase RP8, methanol/sodium chloride solution (5%) = 4:1 Example 14.0 3-Z-[1-(4-Guanidinomethylanilino)-1-(4-(2-carboxyethyl)phenyl)methylenel-6-fluoro-2-indolinone iodide 170 mg of 3-Z-[1-(4-aminomethylanilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-fluoro-2-indoli none (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:
R4.
H
O
R H (1-14) Start-Ex-ing Empirical Mass m.p. Rf am- R2 R3 R4`
pie mate- formula spectrum [ C] value*
rials O OH
H
14.1 -F {HN NH2 10.64 C26H24FN503 M+H + 305 0.70 [ ] (A) *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 100,0 mg 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) Polyvinylpyrrolidone 15.0 mg (5) Magnesium stearate 2.0 ma 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 136.0 mg (3) Maize starch 80.0 mg (4) Polyvinylpyrrolidone 30.0 mg (5) Magnesium stearate 4,0 ma 600.0 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: 12 mm.
Example 19 Capsules with 50 mg of active compound Composition:
(1) Active compound 50.0 mg (2) Maize starch, dried 58.0 mg (3) Lactose, powdered 50.0 mg (4) Magnesium stearate 2.0 ma 160.0 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 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 compound 100.0 mg 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)phenyl)methylene]-6-chloro-2-indolinone (2) 3-Z-[1-(4-(N-(dimethylaminomethylcarbonyl)-N-methylamino)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-chloro-2-indolinone (3) 3-Z-[1 -(4-(N-(2-dimethylaminoethyl)-N-acetylamino)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-chloro-2-indolinone (4) 3-Z-[1-(4-(N-(2-methylaminoethyl)-N-acetylamino)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-chloro-2-indolinone (5) 3-Z-[1-(4-(N-(3-dimethylaminopropyl)-N-acetylamino)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-chloro-2-indolinone (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-carboxyethyl)phenyl)methylene]-6-chloro-2-indolinone (8) 3-Z-[1-(4-ethylaminomethylanilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-chloro-2-indolinone (9) 3-Z-[1-(4-methylaminomethylanilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-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-dimethylaminopropyl)-N-methylsulphonylamino)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-chloro-2-indolinone (13) 3-Z-[1-(4-(N-(2-dimethylaminoethyl)-N-propylsulphonylamino)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-chloro-2-indolinone (14) 3-Z-[1-(4-aminomethylanilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-chloro-2-indolinone (15) 3-Z-[1-(3-(methylaminomethyl)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-chloro-2-indolinone (16) 3-Z-[1-(3-(2-dimethylaminoethyl)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-chloro-2-indolinone (18) 3-Z-[1-(4-(N-(dimethylamino-carbonylmethyl)-N-methylsulphonylamino)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-chloro-2-indolinone (19) 3-Z-[1-(4-(N-methyl-N-methylsulphonylamino)anilino)-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-chloro-2-indolinone (21) 3-Z-[1-(4-(N-(N-(2-dimethylaminoethyl)-N-methylaminomethylcarbonyl)-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)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-chloro-2-indolinone (24) 3-Z-[1-(4-(N-(2-dimethylaminoethyl)-N-methylaminomethyl)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-chloro-2-indolinone (25) 3-Z-[1-(4-(2-dimethylaminoethoxy)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-chloro-2-indolinone (26) 3-Z-[1-(4-(N-(4-dimethylaminobutylcarbonyl)-N-methylamino)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-chloro-2-indolinone (27) 3-Z-[1-(4-(N-(3-dimethylaminopropylcarbonyl)-N-methylamino)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-chloro-2-indolinone (28) 3-Z-[1-(4-(methylethylaminomethyl)anilino)-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-indolinone (30) 3-Z-[1-(4-(methylbenzylaminomethyl)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-chloro-2-indolinone (31) 3-Z-[1-(4-(N-(2-dimethylaminoethyl)-N-methylaminomethyl)anilino)-1-(4-(2-carboxyethyl)phenylmethylene]-6-chloro-2-indolinone (32) 3-Z-[1-(4-(azetidin-l-ylmethyl)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-chloro-2-indolinone (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-ylmethyl)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-(thiomorpholin-4-ylmethyl)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-chloro-2-indolinone (37) 3-Z-[1-(4-(imidazol-1-ylmethyl)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-chloro-2-indolinone (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-carboxyethyl)phenyl)methylene]-6-chloro-2-indolinone (40) 3-Z-[1-(4-(N-(2-dimethylaminoethyl)-N-acetylamino)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene]-6-chloro-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-carboxyethyl)phenyl)methylene]-6-chloro-2-indolinone (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-dimethylaminopropyl)anilino)-1-(3-(2-carboxyethyl)phenyl) methylene]-6-chloro-2-indolinone (45) 3-Z-[1-(4-ethylaminomethylanilino)-1-(3-(2-carboxyethyl)phenyl)methylene]-chloro-2-indolinone (46) 3-Z-[1-(4-methylaminomethylanilino)-1-(3-(2-carboxyethyl)phenyl)methylene]-6-chloro-2-indolinone (47) 3-Z-[1-(4-(N-(4-methylpiperazin-1-ylmethylcarbonyl)-N-methylamino)anilino)-1-(3-(2-ca rboxyethyl)phenyl)methylene]-6-chloro-2-indolinone (48) 3-Z-[1-(4-(4-methylpiperazin-1-ylcarbonyl)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene]-6-chloro-2-indolinone (49) 3-Z-[1-(4-(N-(3-dimethylaminopropyl)-N-methylsulphonylamino)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene]-6-chloro-2-indolinone (50) 3-Z-[1-(4-(N-(2-dimethylaminoethyl)-N-propylsulphonylamino)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene]-6-chloro-2-indolinone (51) 3-Z-[1-(4-aminomethylanilino)-1-(3-(2-carboxyethyl)phenyl)methylene]-6-chloro-2-indolinone (52) 3-Z-[1-(3-(dimethylaminomethyl)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene]-6-chloro-2-indolinone (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-indolinone (57) 3-Z-[1-(4-(N-(dimethylaminocarbonylmethyl)-N-methylsulphonylamino)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-diethylaminoethylsulphonyl)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene]-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-dimethylaminoethyl)-N-methylaminomethyl)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene]-6-chloro-2-indolinone (65) 3-Z-[1-(4-(2-dimethylaminoethoxy)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene]-6-chloro-2-indolinone (66) 3-Z-[1-(4-(N-(4-dimethylaminobutylcarbonyl)-N-methylamino)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene]-6-chloro-2-indolinone (67) 3-Z-[1-(4-(N-(3-dimethylaminopropylcarbonyl)-N-methylamino)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene]-6-chloro-2-indolinone (68) 3-Z-[1-(4-(methylethylaminomethyl)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene]-6-chloro-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-carboxyethyl)phenyl)methylene]-6-chloro-2-indolinone (77) 3-Z-[1-(4-(morpholin-4-ylmethyl)anilino)-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-indolinone (79) 3-Z-[1 -(4-(imidazol-1-ylmethyl)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene]-6-chloro-2-indolinone (80) 3-Z-[1-(4-(N-(2-methylaminoethyl)-N-acetylamino)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone (81) 3-Z-[1-(4-(N-(3-methylaminopropyl)-N-acetylamino)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone (82) 3-Z-[1-(4-(3-dimethylaminopropyl)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone (83) 3-Z-[1-(4-ethylaminomethylanilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-fl uoro-2-indolinone (84) 3-Z-[1-(4-(N-(3-dimethylaminopropyl)-N-methylsulphonylamino)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone (85) 3-Z-[1-(4-(N-(2-dimethylaminoethyl)-N-propylsulphonylamino)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone (86) 3-Z-[1-(3-(methylaminomethyl)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone (87) 3-Z-[1-(3-(2-dimethylaminoethyl)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone (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-methylsulphonylamino)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone (90) 3-Z-[l-(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-diethylaminoethylsulphonyl)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-dimethylaminopropylcarbonyl)-N-methylamino)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone (95) 3-Z-[1-(4-(methylethylaminomethyl)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone (96) 3-Z-[1-(4-(methylpropylaminomethyl)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone (97) 3-Z-[1-(4-(methylbenzylaminomethyl)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone (98) 3-Z-[1-(4-(azetidin-1-ylmethyl)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-fluoro-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-ylmethyl)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone (101) 3-Z-[1-(4-(thiomorpholin-4-ylmethyl)anilino)-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-fluoro-2-indolinone (103) 3-Z-[1-(4-(N-(2-methylaminoethyl)-N-acetylamino)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone (104) 3-Z-[1-(4-(N-(3-methylaminopropyl)-N-acetylamino)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone (105) 3-Z-[1-(4-(3-dimethylaminopropyl)anilino)-1-(3-(2-carboxyethyl)phenyl) methylene]-6-fluoro-2-indolinone (106) 3-Z-[1-(4-ethylaminomethylanilino)-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-fluoro-2-indolinone (110) 3-Z-[1-(3-(methylaminomethyl)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone (111) 3-Z-[1-(3-(2-dimethylaminoethyl)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone (112) 3-Z-[1-(3-(3-dimethylaminopropyl)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone (113) 3-Z-[1-(4-(N-(dimethylaminocarbonylmethyl)-N-methylsulphonylamino)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone (114) 3-Z-[1-(4-(N-methyl-N-methylsulphonylamino)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone (115) 3-Z-[1-(4-(N-methyl-N-acetylamino)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone (116) 3-Z-[1-(4-(N-(N-(2-dimethylaminoethyl)-N-methylaminomethylcarbonyl)-N-methylamino)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone (117) 3-Z-[1-(4-(2-diethylaminoethylsulphonyl)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone (118) 3-Z-[1-(4-(N-(2-dimethylaminoethylcarbonyl)-N-methylamino)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone (119) 3-Z-[1-(4-(N-(2-dimethylaminoethyl)-N-methylaminomethyl)anilino)-1-(3-(2-carboxyethyl)phenyl) methylene]-6-fluoro-2-indolinone (120) 3-Z-[1-(4-(2-dimethylaminoethoxy)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone (121) 3-Z-[1-(4-(methylethylaminomethyl)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone (122) 3-Z-[1-(4-(methylpropylaminomethyl)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone (123) 3-Z-[1-(4-(methylbenzylaminomethyl)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone (124) 3-Z-[1-(4-(diethylaminomethyl)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone (125) 3-Z-[1-(4-(pyrrolidin-1-ylmethyl)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone (126) 3-Z-[1-(4-(azetidin-1-ylmethyl)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone (127) 3-Z-[1-(4-(piperazin-1-ylmethyl)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone (128) 3-Z-[1-(4-(morpholin-4-ylmethyl)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene]-6-fIuoro-2-indolinone (129) 3-Z-[1-(4-(thiomorpholin-4-ylmethyl)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene]-6-fIuoro-2-indolinone (130) 3-Z-[1-(4-(N-(2-dimethylaminoethyl)-N-methylsulphonylamino)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-bromo-2-indolinone (131) 3-Z-[1-(4-(N-(dimethylaminomethylcarbonyl)-N-methylamino)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-bromo-2-indolinone (132) 3-Z-[1-(4-(N-(2-dimethylaminoethyl)-N-acetylamino)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-bromo-2-indolinone (133) 3-Z-[1-(4-(N-(2-methylaminoethyl)-N-acetylamino)anilino)-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)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-bromo-2-indolinone (137) 3-Z-[1-(4-ethylaminomethylanilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-bromo-2-indolinone (138) 3-Z-[1-(4-methylaminomethylanilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-bromo-2-indolinone (139) 3-Z-[1-(4-(N-(4-methylpiperazin-1-ylmethylcarbonyl)-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-carboxyethyl)phenyl)methylene]-6-bromo-2-indolinone (142) 3-Z-[1-(4-(N-(2-dimethylaminoethyl)-N-propylsulphonylamino)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-bromo-2-indolinone (143) 3-Z-[1-(4-aminomethylanilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-bromo-2-indolinone (144) 3-Z-[1-(3-(dimethylaminomethyl)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-bromo-2-indolinone (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-dimethylaminopropyl)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-bromo-2-indolinone (148) 3-Z-[1-(4-(2-dimethylaminoethyl)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-bromo-2-indolinone (149) 3-Z-[1-(4-(N-(dimethylaminocarbonylmethyl)-N-methylsulphonylamino)anilino)-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)phenyl)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-dimethylaminoethyl)-N-methylaminomethylcarbonyl)-N-methylamino)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-bromo-2-indolinone (154) 3-Z-[1-(4-(2-diethylaminoethylsulphonyl)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-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-indolinone (157) 3-Z-[1-(4-(2-dimethylaminoethoxy)anilino)-1-(4-(2-carboxyethyl)phenyl) methylene]-6-bromo-2-indolinone (158) 3-Z-[1-(4-(N-(4-dimethylaminobutylcarbonyl)-N-methylamino)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-bromo-2-indolinone (159) 3-Z-[1-(4-(N-(3-dimethylaminopropylcarbonyl)-N-methylamino)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-bromo-2-indolinone (160) 3-Z-[1-(4-(methylethylaminomethyl)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-bromo-2-indolinone (161) 3-Z-[1-(4-(methylpropylaminomethyl)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-bromo-2-indolinone (162) 3-Z-[1-(4-(methylbenzylaminomethyl)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-bromo-2-indolinone (163) 3-Z-[1-(4-(diethylaminomethyl)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-bromo-2-indolinone (164) 3-Z-[1-(4-(N-(2-dimethylaminoethyl)-N-methylaminomethyl)anilino)-1-(4-(2-carboxyethyl)-phenylmethylene]-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-l-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-indolinone (169) 3-Z-[1-(4-(morpholin-4-ylmethyl)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-bromo-2-indolinone (170) 3-Z-[1-(4-(thiomorpholin-4-ylmethyl)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-bromo-2-indolinone (171) 3-Z-[1-(4-(imidazol-l-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-indolinone (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-(dimethylaminomethylcarbonyl)-N-methylamino)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene]-6-bromo-2-indolinone (175) 3-Z-[1-(4-(N-(2-dimethylaminoethyl)-N-acetylamino)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene]-6-bromo-2-indolinone (176) 3-Z-[1-(4-(N-(2-methylaminoethyl)-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-indolinone (178) 3-Z-[1-(4-(N-(3-methylaminopropyl)-N-acetylamino)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene]-6-bromo-2-indolinone (179) 3-Z-[1-(4-(3-dimethylaminopropyl)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-methylpiperazin-1-ylmethylcarbonyl)-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)phenyl)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)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene]-6-bromo-2-indolinone (189) 3-Z-[1-(3-(2-dimethylaminoethyl)anilino)-1-(3-(2-carboxyethyl)phenyl) methylene]-6-bromo-2-indolinone (190) 3-Z-[1-(3-(3-dimethylaminopropyl)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene]-6-bromo-2-indolinone (191) 3-Z-[1-(4-(2-dimethylaminoethyl)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene]-6-bromo-2-indolinone (192) 3-Z-[1-(4-(N-(dimethylaminocarbonylmethyl)-N-methylsulphonylamino)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene]-6-bromo-2-indolinone (193) 3-Z-[1-(4-(N-methyl-N-methylsulphonylamino)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene]-6-bromo-2-indolinone (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-methylimidazol-2-yl)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene]-6-bromo-2-indolinone (196) 3-Z-[1-(4-(N-(N-(2-dimethylaminoethyl)-N-methylaminomethylcarbonyl)-N-methylamino)anilino)-1-(3-(2-carboxyethyl)phenyl)methyl ene]-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-dimethylaminoethylcarbonyl)-N-methylamino)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene]-6-bromo-2-indolinone (199) 3-Z-[1-(4-(N-(2-dimethylaminoethyl)-N-methylaminomethyl)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene]-6-bromo-2-indolinone (200) 3-Z-[1-(4-(2-dimethylaminoethoxy)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene]-6-bromo-2-indolinone (201) 3-Z-[1-(4-(N-(4-dimethylaminobutylcarbonyl)-N-methylamino)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene]-6-bromo-2-indolinone (202) 3-Z-[1-(4-(N-(3-dimethylaminopropylcarbonyl)-N-methylamino)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene]-6-bromo-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-indolinone (205) 3-Z-[1-(4-(methylbenzylaminomethyl)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene]-6-bromo-2-indolinone (206) 3-Z-[1-(4-(diethylaminomethyl)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene]-6-bromo-2-indolinone (207) 3-Z-[1-(4-(N-(2-dimethylaminoethyl)-N-methylaminomethyl)anilino)-1-(3-(2-carboxyethyl)phenylmethylene]-6-bromo-2-indolinone (208) 3-Z-[1-(4-(pyrrolidin-1-ylmethyl)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene]-6-bromo-2-indolinone (209) 3-Z-[1-(4-(azetidin-1-ylmethyl)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene]-6-bromo-2-indolinone (210) 3-Z-[1-(4-((4-methylpiperazin-1-yl)methyl)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene]-6-bromo-2-indolinone (211) 3-Z-[1-(4-(piperazin-1-ylmethyl)anilino)-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)methylene]-6-bromo-2-indolinone (215) 3-Z-[1-(4-dimethylaminomethylanilino)-1-(4-carboxymethylaminophenyl)-methylene]-6-fluoro-2-indolinone (216) 3-Z-[1-(4-dimethylaminomethylanilino)-1-(3-carboxymethylamino-phenyl)-methylene]-6-fluoro-2-indolinone (217) 3-Z-[1-(4-dimethylaminomethylanilino)-1-(4-(N-methyl-carboxymethylamino)phenyl)methylene]-6-fluoro-2-indolinone (218) 3-Z-[1-(4-dimethylaminomethylanilino)-1-(3-(N-methyl-carboxymethylamino)phenyl)methylene]-6-fluoro-2-indolinone (219) 3-Z-[1-(4-dimethylaminomethylanilino)-1-(4-carboxymethoxyphenyl)-methylene]-6-chloro-2-indolinone (220) 3-Z-[1-(4-dimethylaminomethylanilino)-1-(3-carboxymethoxyphenyl)-methylene]-6-chloro-2-indolinone (221) 3-Z-[1-(4-dimethylaminomethylanilino)-1-(4-carboxymethylaminophenyl)-methylene]-6-chloro-2-indolinone (222) 3-Z-[1-(4-dimethylaminomethylanilino)-1-(3-carboxymethylaminophenyl)-methylene]-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-methyl-carboxymethylamino)phenyl)methylene]-6-chloro-2-indolinone (225) 3-Z-[1-(4-d imethylaminomethylanilino)-1-(4-carboxymethoxyphenyl)-methylene]-6-bromo-2-indolinone (226) 3-Z-[1-(4-d imethylaminomethylanilino)-1-(3-carboxymethoxyphenyl)-methylene]-6-bromo-2-indolinone (227) 3-Z-[1-(4-dimethylaminomethylanilino)-1-(4-carboxymethylaminophenyl)-methylene]-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-propyl, Pr is isopropyl, nBu is n-butyl, tBu is tert-butyl and Bn is benzyl.
Ill.iv. X, R', R5 and R6 are as defined under I., R2 is as defined under ll.iv., R3 is as defined under II.i., ll.ii. or ll.iii. and R4 is as defined under Il.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 phenyl 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_2-alkyl-carbonyl-amino group, by a carboxy-C1_3-alkyl, aminocarbonyl-C1_3-alkyl, (C1.2-alkylamino)-carbonyl-C1_3-alkyl, di-(C1.2-alkyl)-aminocarbonyl-C1.3-alkyl, (C1.2-alkyl-carbonyl)-amino-C1.3-alkyl or (phenyl-carbonyl)-amino-C1.3-alkyl group, where the substituents may be identical or different, R4 is a phenyl group which is substituted by a C1.3-alkyl group terminally substituted by a di-(C1_2-alkyl)-amino group, or by a group of the formula -N
in which R7 is a C1_2-alkyl, C1.2-alkyl-carbonyl, di-(C1_2-alkyl)-amino-carbonyl-C1_3-alkyl or C1.3-alkylsulphonyl group and R8 is a C1.3-alkyl or co-[di-(C1_2-alkyl)-amino]-C2.3-alkyl group, or a C1.3-alkyl-carbonyl group terminally substituted by a di-(C1_2-alkyl)-amino, piperazino or 4-(C1.3-alkyl)-piperazin-1-yl group, 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 cleavable radical, their tautomers, enantiomers, diastereomers, their mixtures and their salts.
The following compounds of the formula I are particularly preferred:
(a) 3-Z-[1-(4-dimethylaminomethylanilino)-1-(3-(2-carboxyethyl)phenyl)methylene]-6-chloro-2-indolinone (b) 3-Z-[1-(4-dimethylaminomethylanilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone (c) 3-Z-[1-(4-dimethylaminomethylanilino)-1-(3-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone (d) 3-Z-[1-(4-(N-(4-methylpiperazin-1-ylmethylcarbonyl)-N-methylamino)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone (e) 3-Z-[1-(4-(N-(2-dimethylaminoethyl)-N-methylsulphonylamino)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone (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)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone (h) 3-Z-[1-(4-(N-(dimethylaminomethylcarbonyl)-N-methylamino)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone (i) 3-Z-[1-(4-(N-(2-dimethylaminoethylcarbonyl)-N-methylamino)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone Q) 3-Z-[1-(4-(pyrrolidin-1-ylmethyl)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone (k) 3-Z-[1-(4-(diethylaminomethyl)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone (I) 3-Z-[1-(4-(2-dimethylaminoethyl)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-chloro-2-indolinone (m) 3-Z-[1-(4-dimethylaminomethylanilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-chloro-2-indolinone (n) 3-Z-[1-(4-(pyrrolidin-1-ylmethyl)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-chloro-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)phenyl)methylene]-6-bromo-2-indolinone (q) 3-Z-[1-(4-(diethylaminomethyl)anilino)-1-(4-(2-carboxyethyl)-methylene]-6-bromo-2-indolinone where additionally a carboxyl, 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 C3_9-cycloalkanol, where a C5_8-cycloalkanol may additionally be substitituted by one or two C1_3-alkyl groups, a C5_8-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 C1.3-alkyl, phenyl-C1.3-alkyl, phenyl-C1_3-alkoxy-carbonyl or C1.6-alkyl-carbonyl group and in which the cycloalkanol moiety may additionally be substituted by one or two C1_3-alkyl groups, a C4_7-cycloalkenol, a C3_5-alkenol, a phenyl-C3_5-alkenol, a C3_5-alkynol or a phenyl-C3.5-alkynol, with the proviso that no bond to the oxygen atom originates from a carbon atom which carries a double or triple bond, a C3_8-cycloalkyl-C1.3-alkanol, a bicycloalkanol 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-O-(RbCRc)-OH, in which Ra is a C1.8-alkyl, C5_7-cycloalkyl, phenyl or phenyl-C1.3-alkyl group, Rb is a hydrogen atom, a C1.3-alkyl, C5.7-cycloalkyl or phenyl group, and Rc is a hydrogen atom or a C,_3-alkyl group, and a radical cleavable in vivo from an imino or amino group is to be understood as meaning, for example, a hydroxyl group, an acyl group, such as the benzoyl or pyridinoyl group, or a C1_16-alkylcarbonyl group, such as the formyl, acetyl, propionyl, butanoyl, pentanoyl or hexanoyl group, an allyloxycarbonyl group, a C1_16-alkoxy-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_6-alkoxy-carbonyl group, such as the benzyloxycarbonyl, phenylethoxycarbonyl or phenylpropoxycarbonyl group, a C1.3-alkylsulphonyl-C1_4-alkoxy-carbonyl, C1.3-alkoxy-C2-4-alkoxy-C2_4-alkoxy-carbonyl or RaCO-O-(RbCRc)-O-CO- group, in which Ra is a C1_8-alkyl, C5_7-cycloalkyl, phenyl or phenyl-C1.3-alkyl group, Rb is a hydrogen atom, a C1_3-alkyl, C5_7-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 amino 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 carboxyl 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-pentyloxycarbonyl, n-hexyloxycarbonyl or cyclohexyloxycarbonyl group, or a phenyl-C1_3-alkoxy-carbonyl group, such as the benzyloxycarbonyl group, and, for an imino or amino group, a C,_9-alkoxy-carbonyl group, such as the methoxy-carbonyl, ethoxycarbonyl, n-propyloxycarbonyl, isopropyloxycarbonyl, n-butyloxy-carbonyl, n-pentyloxycarbonyl, n-hexyloxycarbonyl, cyclohexyloxycarbonyl, n-heptyloxycarbonyl, n-octyloxycarbonyl or n-nonyloxycarbonyl group, a phenyl-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-alkylsulphonyl-n-C2_3-alkoxy-carbonyl or C1.3-alkoxy-C2_3-alkoxy-C1.4-alkoxy-carbonyl group, such as the 2-methylsulphonylethoxycarbonyl or 2-(2-ethoxy)-ethoxycarbonyl 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 N
R1 (V) in which the radicals Z' and R3 may, if appropriate, change their positions, X, R2, R3 and R6 are as defined at the outset, R" 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 Z' 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 I
H (VI), in which R4 and R5 are defined as mentioned at the outset, 5 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 10 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, 15 such as a 2,5-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, Z' 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, Z' 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 out either hydrolytically in an aqueous or alcoholic solvent, for example in methanol/water, ethanol/water, isopropanol/water, tetra hyd rofu ra n/wate r, dioxane/water, dimethylformamide/water, methanol or ethanol, in the 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, 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-alkenyl, aminocarbonyl-C2.3-alkenyl, (C,.3-alkylamino)-carbonyl-C2.3-alkenyl, di-(C,.3-alkylamino)-carbonyl-C2_3-alkenyl or C1.4-alkoxy-carbonyl-C2_3-alkenyl group, reaction of a compound of the formula N
N
R
R" (IX), in which R2, R4, R5, R6 and X are as defined at the outset, R" has the meanings mentioned at the outset for R1 or is a protective group for the nitrogen atom of the lactam group, where R'' 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 alkyl- or arylsulphonyloxy group, such as a chlorine, bromine or iodine atom or a methylsulphonyloxy, ethylsulphonyloxy, p-toluenesulphonyloxy or trifluoromethanesulphonyloxy group, with an alkene of the formula O
R3, n \
(X), in which R3" is an amino, (C1_3-alkylamino), di-(C1.3-alkylamino) or C1-4-alkoxy group and n is the number 0 or 1.
The reaction is expediently carried out with palladium catalysis, using, for example, palladium(II) acetate, palladium(II) chloride, bis(triphenylphosphine)palladium(ll) acetate, bis(triphenylphosphine)palladium(II) chloride, palladium/carbon, bis-[1,2-bis(diphenylphosphino)ethane]palladium(0), dichloro-(1,2-bis(diphenylphosphino)-ethane)palladium(II), tetrakistriphenylphosphinepaIladium(0), tris(dibenzylidene-acetone)dipalladium(0), 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, C1.4-alkoxy-carbonyl-C1.3-alkyl, aminocarbonyl-C1.3-alkyl, (C1.3-alkylamino)-carbonyl-C1.3-alkyl or di-(C1_3-alkyl)-aminocarbonyl-C1.3-alkyl group, hydrogenation of a compound of the formula R3, YO
A
N
N
R
R1 (XI), in 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 C2_3-alkenyl group and R3. is a hydroxyl, C1_4-alkoxy, amino, (C1_3-alkylamino) or di-(C1.3-alkyl)amino 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 bar.
The cleavage of a protective group used for the nitrogen atom of the lactam group or 5 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 carboxyl compound, or if a compound of the formula I is obtained which contains an amino or alkylamino 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 suiphonation into a corresponding acyl or sulphonyl compound, respectively, or if a compound of the formula I is obtained which contains a carboxyl 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 alkoxycarbonyl group, 5 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 carbamoyl halide 10 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 15 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, 20 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 temperatures between 0 and 100 C, preferably at temperatures between 10 and 50 C.
The subsequent reductive alkylation is preferably carried out in a suitable solvent, such as methanol, methanol/water, methanol/water/ammonia, ethanol, ether, tetrahydrofuran, dioxane or dimethylformamide, if appropriate with addition of an acid, such as hydrochloric acid, in the presence of catalytically activated hydrogen, for example of hydrogen in the presence of Raney nickel, platinum or palladium/carbon, or in the presence of a metal hydride, such as sodium borohydride, lithium borohydride, sodium cyanoborohydride or lithium aluminium hydride, at temperatures between 0 and 100 C, preferably at temperatures between 20 and 80 C.
The subsequent alkylation is preferably carried out in a suitable solvent, such as ether, tetrahydrofuran, dioxane, dichloromethane, acetone or acetonitrile, in the presence of alkylating agents, such as alkyl iodides, alkyl bromides, alkyl chlorides, methanesulphonic acid alkyl esters, para-toluenesulphonic acid alkyl esters or alkyl trifluoroacetates, at temperatures between 0 and 100 C, 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 chloride, diethyl ether, tetrahydrofuran, toluene, dioxane, acetonitrile, dimethyl sulphoxide or dimethylformamide, if 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, trimethyl orthoacetate, 2,2-dimethoxypropane, tetramethoxysilane, thionyl chloride, trimethylchIorosilane, phosphorus trichioride, phosphorus pentoxide, N,N'-dicyclohexylcarbodiimide, N,N'-dicyclohexylcarbodiimide/N-hydroxysuccinimide, N,N'-dicyclohexyl-carbodiimide/1-hydroxybenzotriazole, 2-(1 H-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 100 C. 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, N-methylmorpholine or pyridine, or, if an anhydride is used, in the presence of the corresponding acids, at temperatures between 0 and 150 C, preferably at temperatures between 50 and 100 C.
The subsequent esterification or amidation 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, diethyl 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 boiling 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 chloroformate, 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-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium-tetrafluoroborate, 2-(1 H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate/ 1-hydroxybenzotriazo le, N,N'-carbonyldiimidazole or triphenyl-phosphine/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 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 triethylamine, N-ethyldiisopropylamine or N-methylmorpholine, at temperatures between 0 and 150 C, preferably at temperatures between 50 and 100 C.
The subsequent reduction of a nitro group is preferably carried out hydrogenolytically, 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 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 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, trifiuoroacetyl, benzoyl, ethoxycarbonyl, tert-butoxycarbonyl, benzyloxycarbonyl, benzyl, methoxybenzyl or 2,4-dimethoxybenzyl 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 the 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, 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.
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 or acetonitrile/water, at temperatures between 0 and 50 C, but preferably at room temperature.
However, a 2,4-dimethoxybenzyl radical is preferably removed in trifluoroacetic acid in the presence of anisole.
A tert-butyl 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 amine, such as methylamine, ethylamine or n-butylamine, in a solvent, such as methanol, ethanol, isopropanol, toluene/water or dioxane, at temperatures between 20 and 50 C.
Furthermore, chiral compounds of the 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 5 can be separated by methods known per se (see Allinger N. L. and Eliel 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 10 diastereomers, which, if they are obtained in racemic form, 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 15 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 20 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, camphorsuIphonic acid, glutamic acid, N-acetylglutamic acid, aspartic acid, N-acetylaspartic acid or quinic acid. A
suitable optically active alcohol is, for example, (+)- or (-)-menthol, and a suitable optically 25 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-toluenesulphonic acid, phenylsulphonic acid or L-(+)-mandelic acid.
Moreover, the resulting novel compounds of the formula I 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 198 44 003.
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, PDGFR X, PDGFR3, FGFR1, FGFR3, EGFR, HER2, c-Kit, IGF1 R and HGFR, Fit-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
R-mercaptoethanol (Fluka), standard antibiotics, 15 pg/ml of endothelial cell growth factor (ECGS, Collaborative Biomedical Products) and 100 pg/ml of heparin (Sigma) on gelatin-coated culture bottles (0.2 % gelatin, Sigma) at 37 C, 5% C02, 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 VEGF165 (vascular endothelial growth factor; H. Weich, GBF Brunswick) and 10 pg/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 p Ci/well, Amersham) was then added for a further 16 hours to determine DNA synthesis.
The radioactively labelled cells were then immobilized on filter mats and the incorporated radioactivity was determined in a R 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% (IC50) was derived therefrom.
The compounds of the formula I according to the invention have an IC50 between 50 pM 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 cells, in particular that of endothelial cells, 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 Parangi et at. (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-cell 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), mesangial-cell-proliferative disorders, atherosclerosis, injuries of the nerve tissue and for inhibiting the reocciusion 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 role.
Owing to their biological properties, the compounds according to the invention can be 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:
Example Name 1.0 3-Z-[1 -(4-(N-methyl-N-methylsulphonylamino)anilino)-1 -(3-iodophenyl)-methylene]-6-chloro-2-indolinone 1.1 3-Z-[1 -(4-(dimethylaminomethyl)anilino)-1 -(3-iodophenyl)methylene]-6-chloro-2-indolinone 1.2 3-Z-[1-(4-(N-(dimethylaminomethylcarbonyl)-N-methylamino)anilino)-1-(4-chlorophenyl)methylene]-6-chloro-2-indolinone 1.3 3-Z-[1 -(4-(N-(2-dimethylaminoethyl)-N-acetylamino)anilino)-1 -(4-chlorophenyl)methylene]-6-chloro-2-indolinone 3-Z-[1-(4-(N-(4-methylpiperazin-1-ylmethylcarbonyl)-N-1.4 methylamino)anilino)-1-(4-chlorophenyl)methylene]-6-chloro-2-indolinone 1.5 3-Z-[1 -(4-(N-(3-dimethylaminopropyl)-N-acetylamino)anilino)-1 -(4-chlorophenyl)methylene]-6-chloro-2-indolinone 1.6 3-Z-[1 -(4-(dimethylaminomethyl)anilino)-1 -(4-chlorophenyl)methylene]-6-ch loro-2-indolinone 1.7 3-Z-[1 -(4-(N-(2-dimethylaminoethyl)-N-acetylamino)anilino)-1 -(3,4-d imethoxyphenyl)methylene]-6-chloro-2-indolinone 3-Z-[1 -(4-(N-(4-methylpiperazin-1 -ylmethylcarbonyl)-N-1.8 methylamino)anilino)-1-(3,4-dimethoxyphenyl)methylene]-6-chloro-2-indolinone 1.9 3-Z-[1 -(4-(N-(2-dimethylaminoethyl)-N-methylsulphonylamino)anilino)-1-(3,4-dimethoxyphenyl)methylene]-6-chloro-2-indolinone 1.10 3-Z-[1 -(4-(dimethylaminomethyl)anilino)-1 -(3,4-dimethoxyphenyl)-methylene]-6-chloro-2-indolinone 1.11 3-Z-[1-(4-(N-(2-dimethylaminoethyl)-N-methylcarbamoyl)anilino)-1-(3,4-dimethoxyphenyl)methylene]-6-chloro-2-indolinone 2.0 3-Z-[1-(4-(dimethylaminomethyl)anilino)-1-(4-cyanophenyl)-methylene]-6-chloro-2-indolinone 3.0 3-Z-[1-(4-(dimethylaminomethyl)anilino)-1-(4-iodophenyl)methylene]-6-fluoro-2-indolinone 3.1 3-Z-[1-(4-(dimethylaminomethyl)anilino)-1-(3-fluorophenyl)methylene]-6-fluoro-2-indolinone 3.2 3-Z-[1-(4-(N-(3-dimethylaminopropyl)-N-acetylamino)anilino)-1-(3-fluorophenyl)methylene]-6-fluoro-2-indolinone 3-Z-[1-(4-(N-(4-methylpiperazin-1-ylmethylcarbonyl)-N-3.3 methylamino)anilino)-1-(3-fluorophenyl)methylene]-6-fluoro-2-indolinone 3.4 3-Z-[1-(4-(dimethylaminomethyl)anilino)-1-(4-(2-acetylaminoethyl)phenyl)methylene]-6-fluoro-2-indolinone 3.5 3-Z-[1 -(4-(N-(3-dimethylaminopropyl)-N-acetylamino)anilino)-1-(4-(2-acetylaminoethyl)phenyl)methylene]-6-fluoro-2-indolinone 3-Z-[1-(4-(N-(4-methylpiperazin-1-ylmethylcarbonyl)-N-3.6 methylamino)anilino)-1-(4-(2-acetylaminoethyl)phenyl)methylene]-6-fluoro-2-indolinone 3.7 3-Z-[1-(4-(dimethylaminomethyl)anilino)-1-(4-methoxycarbonylmethylphenyl)methylene]-6-fluoro-2-indolinone 3.8 3-Z-[1-(4-(dimethylaminomethyl)anilino)-1-(3-iodophenyl)methylene]-6-fluoro-2-indolinone 3.9 3-Z-[1-(4-(dimethylaminomethyl)anilino)-1-(3-methoxycarbonylmethylphenyl)methylene]-6-fluoro-2-indolinone 3.10 3-Z-[1-(4-(dimethylaminomethyl)anilino)-1-(3-(N-tert-butoxycarbonyl-aminomethyl)phenyl)methylene]-6-fluoro-2-indolinone 3.11 3-Z-[1-(4-(N-(2-dimethylaminoethyl)-N-methylsulphonylamino)anilino)-1-(4-methoxycarbonylmethylphenyl)methylene]-6-fluoro-2-indolinone 3-Z-[1-(4-(N-(4-methylpiperazin-1-ylmethylcarbonyl)-N-3.12 methylamino)anilino)-1-(4-methoxycarbonylmethylphenyl)methylene]-6-fluoro-2-indolinone 3.13 3-Z-[1-(4-(dimethylaminomethyl)anilino)-1-(3-cyanomethyiphenyl)-methylene]-6-fluoro-2-indolinone 3-Z-[1-(4-(N-(4-methylpiperazin-1-ylmethylcarbonyl)-N-3.14 methylamino)anilino)-1-(4-(N-tert-butoxycarbonyl-aminomethyl)phenyl)methylene]-6-fluoro-2-indolinone 3.15 3-Z-[1-(4-(dimethylaminomethyl)anilino)-1-(4-(N-tent-butoxycarbonyl-aminomethyl)phenyl)methylene]-6-fluoro-2-indolinone 3.16 3-Z-[1-(4-(dimethylaminomethyl)anilino)-1-(3-(N-tert-butoxycarbonyl-2-aminoethyl)phenyl)methylene]-6-fluoro-2-indolinone 3.17 3-Z-[1-(4-(N-Acetyl-N-methylamino)anilino)-1-(4-(2-methoxycarbonylethyl)phenyl)methylene]-6-fluoro-2-indolinone 3-Z-[1-(4-(N-(4-methylpiperazin-1-ylmethylcarbonyl)-N-3.18 methylamino)anilino)-1-(4-(2-methoxycarbonylethyl)phenyl)methylene]-6-fluoro-2-indolinone 3.19 3-Z-[1-(4-(N-(2-dimethylaminoethyl)-N-methylsulphonylamino)anilino)-1-(4-methoxycarbonylmethylphenyl)methylene]-6-fluoro-2-indolinone 3.20 3-Z-[1-(4-(N-(3-dimethylaminopropyl)-N-acetylamino)anilino)-1-(4-(2-methoxycarbonylethyl)phenyl)methylene]-6-fluoro-2-indolinone 3.21 3-Z-[1-(4-(N-tert-butoxycarbonylmethylaminomethyl)anilino)-1-(4-(2-methoxycarbonylethyl)phenyl)methylene]-6-fluoro-2-indolinone 3.22 3-Z-[1-(4-(4-methylpiperazin-1-yl-carbonyl )anilino)-1-(4-(2-methoxycarbonylethyl)phenyl)methylene]-6-fluoro-2-indolinone 3.23 3-Z-[1-(4-(1-methylimidazol-2-yl)anilino)-1-(4-(2-methoxycarbonylethyl)phenyl)methylene]-6-fluoro-2-indolinone 3.24 3-Z-[1-(4-methylsulphonylanilino)-1-(4-(2-methoxycarbonylethyl)phenyl)methylene]-6-fluoro-2-indolinone 3-Z-[1-(4-(N-(4-methylpiperazin-1-ylmethylcarbonyl)-N-3.25 methylamino)anilino)-1-(3-methoxycarbonylmethylphenyl)methylene]-6-fluoro-2-indolinone 3.26 3-Z-[1-(4-(N-(2-dimethylaminoethyl)-N-methylsulphonylamino)anilino)-1-(3-methoxycarbonylmethylphenyl)methylene]-6-fluoro-2-indolinone 3.27 3-Z-[1-(4-(4-methylpiperazin-1-yl-carbonyl)anilino)-1-(3-methoxycarbonylmethylphenyl)methylene]-6-fluoro-2-indolinone 3.28 3-Z-[l -(4-(N-(dimethylaminomethylcarbonyl)-N-methylamino)anilino)-1-(3-methoxycarbonylmethyl phenyl)methylene]-6-fluoro-2-indolinone 3.29 3-Z-[1-(4-(N-(3-dimethylaminopropyl)-N-acetylamino)anilino)-1-(3-methoxycarbonylmethylphenyl)methylene]-6-fluoro-2-indolinone 3.30 3-Z-[1-(4-(N-(2-dimethylaminoethyl)-N-acetylamino)anilino)-1-(3-methoxycarbonylmethylphenyl)methylene]-6-fluoro-2-indolinone 3.31 3-Z-[1-(4-(N-(4-dimethylamino-butylcarbonyl)-N-methylamino)anilino)-1-(3-methoxycarbonylmethylphenyl)methylene]-6-fluoro-2-indolinone 3-Z-[1-Anilino-1-(4-methoxycarbonylmethylphenyl)methylene]-6-fluoro-3.32 2-indolinone 3.33 3-Z-[1-(4-(1-methylimidazol-2-yl)anilino)-1-(4-methoxycarbonylmethylphenyl)methylene]-6-:fluoro-2-indolinone 3.34 3-Z-[1-(4-(4-methylpiperazin-1-ylcarbonyl)anilino)-1-(4-methoxycarbonylmethylphenyl)methylene]-6-fluoro-2-indolinone 3-Z-[1-(4-(N-(dimethylaminocarbonylmethyl)-N-3.35 methylsulphonylamino)anilino)-1-(4-methoxycarbonylmethyiphenyl)-methylene]-6-fluoro-2-indolinone 3.36 3-Z-[1-(4-(N-(dimethylaminomethylcarbonyl)-N-methylamino)anilino)-1-(4-methoxycarbonylmethylphenyl)methylene]-6-fluoro-2-indolinone 3.37 3-Z-[1-(4-(N-methyl-N-acetylamino)anilino)-1-(4-methoxycarbonylmethylphenyl)methylene]-6-fluoro-2-indolinone 3.38 3-Z-[1-(4-(N-(2-dimethylaminoethylcarbonyl)-N-methylamino)anilino)-1-(4-methoxycarbonylmethylphenyl)methylene]-6-fluoro-2-indolinone 3.39 3-Z-[1-(4-methylsulphonylanilino)-1-(4-methoxycarbonylmethylphenyl)methylene]-6-fluoro-2-indolinone 3.40 3-Z-[1-(4-(N-(3-dimethylaminopropylcarbonyl)-N-methyiamino)anilino)-1-(4-methoxycarbonylmethylphenyl)methylene]-6-fluoro-2-indolinone 3.41 3-Z-[1-(4-(N-(3-dimethylaminopropyl)-N-acetylamino)anilino)-1-(4-methoxycarbonylmethylphenyl)methylene]-6-fluoro-2-indolinone 3.42 3-Z-[1-Anilino-1-(3-methoxycarbonylmethylphenyl)methylene]-6-fluoro-2-indolinone 3.43 3-Z-[1-(4-methylsulphonylanilino)-1-(3-methoxycarbonylmethylphenyl)-methylene]-6-fluoro-2-indolinone 3.44 3-Z-[1-(4-(1-methylimidazol-2-yl)anilino)-1-(3-methoxycarbonylmethylphenyl)methylene]-6-fluoro-2-indolinone 3-Z-[l-(4-(N-(dimethylaminocarbonylmethyl)-N-3.45 methylsulphonylamino)anilino)-1-(3-methoxycarbonylmethylphenyl)-methyiene]-6-fluoro-2-indolinone 3.46 3-Z-[1-(4-(N-(3-dimethylaminopropylcarbonyl)-N-methylamino)anilino)-1-(3-methoxycarbonylmethylphenyl)methylene]-6-fluoro-2-indolinone 3.47 3-Z-[1-(4-(N-(2-dimethylaminoethylcarbonyl)-N-methylamino)anilino)-1-(3-methoxycarbonylmethyl phenyl)methylene]-6-fluoro-2-indolinone 3-Z-[1-(4-(N-(4-methylpiperazin-l -ylmethylcarbo,nyl)-N-3.48 methylamino)anilino)-1-(3-(2-methoxycarbonylethyl)phenyi)methylene]-6-fluoro-2-indolinone 3.49 3-Z-[1-(4-(N-(2-dimethylaminoethyl)-N-methylsulphonylamino)anilino)-1-(3-(2-methoxycarbonylethyl)phenyl)methylene]-6-fluoro-2-indolinone 3.50 3-Z-[1-(4-(N-(dimethylaminomethylcarbonyl)-N-methylamino)anilino)-1-(3-(2-methoxycarbonylethyl)phenyl)methylene]-6-fluoro-2-indolinone 3.51 3-Z-[1-(4-(N-(3-dimethylaminopropyl)-N-acetylamino)anilino)-1-(3-(2-methoxycarbonylethyl)phenyl)methylene]-6-fluoro-2-indolinone 3-Z-[1-(4-(N-(4-methylpiperazin-1-ylmethylcarbonyl)-N-3.52 methylamino)anilino)-1-(3-(N-tert-butoxycarbonyl-aminomethyl)phenyl)methylene]-6-fluoro-2-indolinone 3.53 3-Z-[1-(4-(N-methyl-N-acetylamino)anilino)-1-(3-acetylaminomethylphenyl)methylene]-6-chloro-2-indolinone 3.54 3-Z-[1-(4-(N-(3-dimethylaminopropyl)-N-acetylamino)anilino)-1-(3-acetylaminomethylphenyl)methylene]-6-chloro-2-indolinone 3.55 3-Z-[1-(4-(N-(2-dimethylaminoethyl)-N-methylsulphonylamino)anilino)-1-(3-acetylaminomethylphenyl)methylene]-6-chloro-2-indolinone 3.56 3-Z-[1-(4-(N-(dimethylaminomethylcarbonyl)-N-methylamino)anilino)-1-(3-acetylaminomethylphenyl)methylene]-6-chloro-2-indolinone 3.57 3-Z-[1-(4-(2-dimethylaminoethyl)anilino)-1-(4-(2-methoxycarbonylethyl)phenyl)methylene]-6-fluoro-2-indolinone 3.58 3-Z-[1-(4-(N-(2-dimethylaminoethylcarbonyl)-N-methylamino)anilino)-1-(4-(2-methoxycarbonylethyl)phenyl)methylene]-6-fluoro-2-indolinone 3.59 3-Z-[1-(4-(N-(dimethylaminomethylcarbonyl)-N-methylamino)anilino)-1-(4-(2-methoxycarbonylethyl)phenyl)methylene]-6-fluoro-2-indolinone 3.60 3-Z-[1-(4-(2-dimethylaminoethyl)anilino)-1-(3-(2-ethoxycarbonylethyl)phenyl)methylene]-6-fluoro-2-indolinone 3.61 3-Z-[1-(4-(N-(2-dimethylaminoethyl)-N-acetylamino)anilino)-1-(4-(2-methoxycarbonylethyl)phenyl)methylene]-6-fluoro-2-indolinone 3.62 3-Z-[1-(4-(N-(3-dimethylaminopropylcarbonyl)-N-methylamino)anilino)-1-(3-(2-ethoxycarbonylethyl)phenyl)methylene]-6-fluoro-2-indolinone 3.63 3-Z-[1-(4-(N-(4-dimethylaminobutylcarbonyl)-N-methylamino)anilino)-1-(3-(2-ethoxycarbonylethyl)phenyl)methylene]-6-fluoro-2-indolinone 3.64 3-Z-[1-(4-(1-methylimidazol-2-yl)anilino)-1-(3-(2-ethoxycarbonylethyl)phenyl)methylene]-6-fluoro-2-indolinone 3.65 3-Z-[1-(4-(N-(4-dimethylaminobutylcarbonyl)-N-methylamino)anilino)-1-(4-(2-methoxycarbonylethyl)phenyl)methylene]-6-fluoro-2-indolinone 3.66 3-Z-[1 anilino-1 -(4-(2-methoxycarbonylethyl)phenyl)methylene]-6-fluoro-2-indolinone 3.67 3-Z-[1-(4-(pyrrolidin-1-ylmethyl)anilino)-1-(4-(2-methoxycarbonylethyl)phenyl)methylene]-6-fluoro-2-indolinone 3.68 3-Z-[1-(4-(diethylaminomethyl)anilino)-1-(4-(2-methoxycarbonylethyl)phenyl)methylene]-6-fluoro-2-indolinone 3.69 3-Z-[1-(4-(N-tert-butoxycarbonylaminomethyl)anilino)-1-(4-(2-methoxycarbonylethyl)phenyl)methylene]-6-fluoro-2-indolinone 3.70 3-Z-[1-(4-(2-dimethylaminoethyl)anilino)-1-(3-methoxycarbonylmethylphenyl)methylene]-6-fluoro-2-indolinone 3.71 3-Z-[1-(4-(2-dimethylaminoethyl)anilino)-1-(4-methoxycarbonylmethylphenyl)methylene]-6-fluoro-2-indolinone 3.72 3-Z-[1-(4-(dimethylaminomethyl)anilino)-1-(3-(2-ethoxycarbonylethyl)phenyl)methylene]-6-fluoro-2-indolinone 3.73 3-Z-[1-(4-(2-dimethylaminoethyl)anilino)-1-(4-(2-methoxycarbonylethyl)phenyl)methylene]-6-chloro-2-indolinone 3.74 3-Z-[1-(4-(1-methylimidazol-2-yl)anilino)-1-(4-(2-ethoxycarbonylethyl)phenyl)methylene]-6-chloro-2-indolinone 3.75 3-Z-[1-(4-dimethylaminomethylanilino)-1-(4-(2-methoxycarbonylethyl)phenyl)methylene]-6-chloro-2-indolinone ------ ------ -3.76 3-Z-[1-(4-dimethylaminomethylanilino)-1-(4-(2-ethoxycarbonylethyl)phenyl)methylene]-6-fluoro-2-indolinone 3.77 3-Z-[1-(4-((4-methylpiperazin-1-yl)methyl)anilino)-1-(3-(2-methoxycarbonylethyl)phenyl)methylene]-6-fluoro-2-indolinone 3.78 3-Z-[1-(4-(imidazol-1-ylmethyl)anilino)-1-(3-(2-methoxycarbonylethyl)phenyl)methylene]-6-fluoro-2-indolinone 3.79 3-Z-[1-(4-((4-methylpiperazin-1-yl)methyl)anilino)-1-(4-(2-methoxycarbonylethyl)phenyl)methylene]-6-fluoro-2-indolinone 3.80 3-Z-[1-(4-(imidazol-1-ylmethyl)anilino)-1-(4-(2-methoxycarbonylethyl)phenyl)methylene]-6-fluoro-2-indolinone 3.81 3-Z-[1-(4-(N-(2-dimethylaminoethyl)-N-methylaminomethyl)anilino)-1-(4-(2-methoxycarbonylethyl)phenyl)methylene]-6-fluoro-2-indolinone 3.82 3-Z-[1-(4-(N-(2-dimethylaminoethyl)-N-methylaminomethyl)anilino)-1-(3-(2-ethoxycarbonylethyl)phenyl)methylene]-6-fluoro-2-indolinone 3.83 3-Z-[1-(4-(pyrrolidin-1-ylmethyl)anilino)-1-(4-(2-methoxycarbonylethyl)phenyl)methylene]-6-chloro-2-indolinone 3.84 3-Z-[1 anilino-1 -(3-(2-ethoxycarbonylethyl)phenyl)methylene]-6-fluoro-2-indolinone 3.85 3-Z-[1-(4-(N-tert-butoxycarbonylaminomethyl)anilino)-1-(3-(2-ethoxycarbonylethyl)phenyl)methylene]-6-fluoro-2-indolinone 3.86 3-Z-[1-(4-(N-tert-butoxycarbonylmethylaminomethyl)anilino)-1-(3-(2-ethoxycarbonylethyl)phenyl)methylene]-6-fluoro-2-indolinone 3.87 3-Z-[1 -(4-dimethylaminomethylan iii no)-1-(3-methoxycarbonylmethoxy-phenyl)methylene]-6-fluoro-2-indolinone 3.88 3-Z-[1-(4-dimethylaminomethylanilino)-1-(4-methoxycarbonylmethoxy-phenyl)methylene]-6-fluoro-2-indolinone 3.89 3-Z-[1-(4-dimethylaminomethylanilino)-1-(3-(2-ethoxycarbonyl-ethoxy)phenyl)methylene]-6-fluoro-2-indolinone 3.90 3-Z-[1-(4-(pyrrolidin-1-ylmethyl)anilino)-1-(4-(2-methoxycarbonylethyl)phenyl)methylene]-6-bromo-2-indolinone 3.91 3-Z-[1-(4-(dimethylaminomethyl)anilino)-1-(4-(2-methoxycarbonylethyl)phenyl)methylene]-6-bromo-2-indolinone 3.92 3-Z-[1-(4-(diethylaminomethyl)anihlino)-1-(4-(2-methoxycarbonylethyl)phenyl)methylene]-6-bromo-2-indolinone 3.93 3-Z-[1-(3-dimethylaminomethylanilino)-1-(4-(2-methoxycarbonylethyl)phenyl)methylene]-6-fluoro-2-indolinone 3.94 3-Z-[1-(3-dimethylaminomethylanilino)-1-(3-(2-ethoxycarbonylethyl)phenyl)methylene]-6-fluoro-2-indolinone 3.95 3-Z-[1-(3-dimethylaminomethylanilino)-1-(4-(2-methoxycarbonylethyl)phenyl)methylene]-6-chloro-2-indolinone 4.0 3-Z-[1-(4-(dimethylaminomethyl)anilino)-1-(3,4-dimethoxyphenyl)-methylene]-6-cyano-2-indolinone 5.0 3-Z-[1-(4-(N-methyl-N-methylsulphonylamino)anilino)-1-(3-(2-methoxycarbonylvinyi)phenyl)methylene]-6-chloro-2-indolinone 5.1 3-Z-[1-(4-(dimethylaminomethyl)anilino)-1-(4-(2-methoxycarbonyl-vinyl)phenyl)methylene]-6-chloro-2-indolinone 5.2 3-Z-[1-(4-(dimethylaminomethyl)anilino)-1-(4-(2-carbamoyl-vinyl)phenyl)methylene]-6-fluoro-2-indolinone 5.3 3-Z-[1-(4-(dimethylaminomethyl)anilino)-1-(4-(2-methoxycarbonyl-vinyl)phenyl)methylene]-6-fluoro-2-indolinone 5.4 3-Z-[1-(4-(dimethylaminomethyl)anilino)-1-(3-(2-methoxycarbonyl-vinyl)phenyl)methylene]-6-fluoro-2-indolinone 6.0 3-Z-[1-(4-dimethylaminomethylanilino)-1-(3-(2-methoxycarbonylethyl)phenyi)methylene]-6-chloro-2-indolinone 6.1 3-Z-[1-(4-(N-methyl-N-methylsulphonylamino)anilino)-1-(3-(2-methoxycarbonylethyl)phenyl)methylene]-6-chloro-2-indolinone ------- - ------6.2 3-Z-[1-(4-dimethylaminomethylanilino)-1-(4-(2-carbamoyl-ethyl)phenyl)methylene]-6-fluoro-2-indolinone 6.3 3-Z-[1-(4-dimethylaminomethylanilino)-1-(4-(2-methoxycarbonylethyl)phenyl)methylene]-6-fluoro-2-indolinone 6.4 3-Z-[1-(4-dimethylaminomethylanilino)-1-(3-(2-methoxycarbonylethyl)phenyl)methylene]-6-fluoro-2-indolinone 7.0 3-Z-[1-(4-dimethylaminomethylanilino)-1-(4-aminomethyiphenyl)-methylene]-6-chloro-2-indolinone 3-Z-[1-(4-(N-((4-methylpiperazin-1-yl)methylcarbonyl)-N-8.0 methylamino)anilino)-1-(4-aminomethylphenyl)methylene]-6-chloro-2-indolinone 9.0 3-Z-[1-(4-(dimethylaminomethyl)anilino)-1-(3-aminomethylphenyl)-methylene]-6-fluoro-2-indolinone 9.1 3-Z-[1-(4-(dimethylaminomethyl)anilino)-1-(3-(2-aminoethyl)phenyl)methylene]-6-fluoro-2-indolinone 9.2 3-Z-[1-(4-(dimethylaminomethyl)anilino)-1-(4-aminomethylphenyl)-methylene]-6-fluoro-2-indolinone 3-Z-[1-(4-(N-(4-methylpiperazin-1-ylmethylcarbonyl)-N-9.3 methylamino)anilino)-1-(4-aminomethylphenyl)methylene]-6-fluoro-2-indolinone 9.4 3-Z-[1-(4-(methylaminomethyl)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone 9.5 3-Z-[1-(4-(methylaminomethyl)anilino)-1-(4-(2-methylcarbamoyl-ethyl)phenyl)methylene]-6-fluoro-2-indolinone 3-Z-[1-(4-(N-(4-methylpiperazin-1-ylmethylcarbonyl)-N-9.6 methylamino)anilino)-1-(3-aminomethylphenyl)methylene]-6-fluoro-2-indolinone 9.7 3-Z-[1-(4-(aminomethyl)anilino)-1-(4-(2-methoxycarbonylethyl)phenyl)methylene]-6-fluoro-2-indolinone 9.8 3-Z-[1-(4-(aminomethyl)anilino)-1-(3-(2-ethoxycarbonylethyl)phenyl)methylene]-6-fluoro-2-indolinone 9.9 3-Z-[1 -(4-(methylaminomethyl)anilino)-1 -(3-(2-ethoxycarbonylethyl)phenyl)methylene]-6-fluoro-2-indolinone 10.0 3-Z-[1 -(4-dimethylaminomethylanilino)-1 -(3-(2-carboxyethyl)phenyl)methylene]-6-chloro-2-indolinone 10.1 3-Z-[1 -(4-dimethylaminomethylanilino)-1 -(4-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone 10.2 3-Z-[1 -(4-dimethylaminomethylanilino)-1 -(3-carboxymethylphenyl)-methylene]-6-fluoro-2-indolinone 10.3 3-Z-[1-(4-dimethylaminomethylanilino)-1-(3-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone 10.4 3-Z-[1-(4-dimethylaminomethylanilino)-1-(4-carboxymethyl phenyl)-methylene]-6-fluoro-2-indolinone 3-Z-[1-(4-(N-(4-methylpiperazin-1 -ylmethylcarbonyl)-N-10.5 methylamino)anilino)-1-(4-carboxymethylphenyl)methylene]-6-fluoro-2-indolinone 10.6 3-Z-[1 -(4-(N-(2-dimethylaminoethyl)-N-methylsulphonylamino)anilino)-1-(4-carboxymethylphenyl)methylene]-6-fluoro-2-indolinone 10.7 3-Z-[1 -(4-(N-methyl-N-acetylamino)an ilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone 3-Z-[1 -(4-(N-(4-methylpiperazin-1 -ylmethylcarbonyl)-N-10.8 methylamino)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone 10.9 3-Z-[1 -(4-(N-(2-dimethylaminoethyl)-N-methylsulphonylamino)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone 10.10 3-Z-[1-(4-(N-(3-dimethylaminopropyl)-N-acetylamino)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone 10.11 3-Z-[1-(4-(N-tert-butoxycarbonylmethylaminomethyl)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone 10.12 3-Z-[1-(4-(4-methylpiperazin-1-ylcarbonyl)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone 10.13 3-Z-[1-(4-(1-methylimidazol-2-yl)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone 10.14 3-Z-[1-(4-methylsulphonylanilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone 10.15 3-Z-[1-(4-(4-methylpiperazin-1-ylcarbonyl)anilino)-1-(3-carboxymethylphenyl)methylene]-6-fluoro-2-indolinone 3-Z-[1-(4-(N-(4-methylpiperazin-1-ylmethylcarbonyl)-N-10.16 methylamino)anilino)-1-(3-carboxymethylphenyl)methylene]-6-fluoro-2-indolinone 10.17 3-Z-[1-(4-(N-(dimethylaminomethylcarbonyl)-N-methylamino)anilino)-1-(3-carboxymethylphenyl)methylene]-6-fluoro-2-i ndoli none 10.18 3-Z-[1-(4-(N-(4-dimethylaminobutylcarbonyl)-N-methylamino)anilino)-1-(3-carboxymethylphenyl)methylene]-6-fluoro-2-indolinone 10.19 3-Z-[1-Anilino-1-(3-carboxymethylphenyl)-methylene]-6-fluoro-2-indolinone 10.20 3-Z-[1-(4-methylsulphonylanilino)-1-(3-carboxymethyiphenyl)-methylene]-6-fluoro-2-indolinone 10.21 3-Z-[1-(4-(1-methylimidazol-2-yl)anilino)-1-(3-carboxymethylphenyl)-methylene]-6-fluoro-2-indolinone 3-Z-[1-(4-(N-(dimethylaminocarbonylmethyl)-N-10.22 methylsulphonylamino)anilino)-1-(3-carboxymethylphenyl)-methylene]-6-fluoro-2-indolinone 3-Z-[1 anilino-1-(4-carboxymethylphenyl)methylene]-6-fluoro-2-10.23 indolinone 10.24 3-Z-[1-(4-(1-methylimidazol-2-yl)anilino)-1-(4-carboxymethylphenyl)-methylene]-6-fluoro-2-indolinone 10.25 3-Z-[1-(4-(N-(3-dimethylaminopropylcarbonyl)-N-methylamino)anilino)-1-(4-carboxymethylphenyl)methylene]-6-fluoro-2-indolinone 10.26 3-Z-[1-(4-(N-(dimethylaminomethylcarbonyl)-N-methylamino)anilino)-1-(4-carboxymethylphenyl)methylene]-6-fluoro-2-indolinone 10.27 3-Z-[1-(4-(4-methylpiperazin-1-yl-carbonyl)anilino)-1-(4-carboxymethylphenyl)methylene]-6-fluoro-2-indolinone 10.28 3-Z-[1-(4-methylsulphonylanilino)-1-(4-carboxymethylphenyl)-methylene]-6-fluoro-2-indolinone 10.29 3-Z-[1-(4-(N-methyl-N-acetylamino)anilino)-1-(4-carboxymethylphenyl)-methylene]-6-fluoro-2-indolinone 3-Z-[1-(4-(N-(dimethylaminocarbonylmethyl)-N-10.30 methylsulphonylamino)anilino)-1-(4-carboxymethylphenyl)methylene]-6-fluoro-2-indolinone 10.31 3-Z-[1-(4-(N-(2-dimethylaminoethylcarbonyl)-N-methylamino)anilino)-1-(4-carboxymethylphenyl)methylene]-6-fluoro-2-indolinone 10.32 3-Z-[1-(4-(N-(3-dimethylaminopropylcarbonyl)-N-methylamino)anilino)-1-(4-carboxymethylphenyl )methylene]-6-fluoro-2-indol i none 3-Z-[1-(4-(N-(4-methylpiperazin-1-ylmethylcarbonyl)-N-10.33 methylamino)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone 10.34 3-Z-[1-(4-(N-(2-dimethylaminoethyl)-N-methylsulphonylamino)anilino)-1-(3-carboxymethylphenyl)methylene]-6-fluoro-2-indolinone 10.35 3-Z-[1-(4-(N-(2-dimethylaminoethyl)-N-methylsulphonylamino)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indoli none 3-Z-[1-(4-(N-(dimethylaminomethylcarbonyl)-N-methylamino)anilino)-1-10.36 (3-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone 10.37 3-Z-[1 -(4-(N-(3-dimethylaminopropyl)-N-acetylamino)anilino)-1 -(3-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone 10.38 3-Z-[1-(4-(N-(dimethylaminomethylcarbonyl)-N-methylamino)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone 10.39 3-Z-[1 -(4-(2-dimethylaminoethyl)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone 10.40 3-Z-[1-(4-(N-(2-dimethylaminoethylcarbonyl)-N-methylamino)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone 10.41 3-Z-[1 -(4-(2-dimethylaminoethyl)anilino)-1 -(3-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone 10.42 3-Z-[1 -(4-(N-(2-dimethylaminoethyl)-N-acetylamino)anilino)-1 -(4-(2-ca rboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone 10.43 3-Z-[1 -(4-(N-(3-dimethylaminopropylcarbonyl)-N-methylamino)anilino)-1 -(3-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone 10.44 3-Z-[1 -(4-(N-(4-dimethylamino-butylcarbonyl)-N-methylamino)anilino)-1 -(3-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone 10.45 3-Z-[1 -(4-(1 -methylimidazol-2-yl)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone 10.46 3-Z-[1-(4-(N-(4-dimethylaminobutylcarbonyl)-N-methylamino)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone 10.47 3-Z-[1 anilino-1-(4-(2-carboxyethyl)phenyl)methyl en e]-6-fl u o ro-2-indolinone 10.48 3-Z-[1-(4-(pyrrolidin-1-ylmethyl)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone 10.49 3-Z-[1 -(4-(diethylaminomethyl)anilino)-1 -(4-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone 3-Z-[1-(4-aminomethylanilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-10.50 6-fluoro-2-indolinone 10.51 3-Z-[1-(4-(2-dimethylaminoethyl)anilino)-1-(3-carboxymethylphenyl)-methylene]-6-fluoro-2-indolinone 10.52 3-Z-[1-(4-(2-dimethylaminoethyl)anilino)-1-(4-carboxymethylphenyl)-methylene]-6-fluoro-2-indolinone 10.53 3-Z-[1-(4-(2-dimethylaminoethyl)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-chloro-2-indolinone 3-Z-[1-(4-(1-methylimidazol-2-yl)anilino)-1-(4-(2-10.54 carboxyethyl)phenyl)methylene]-6-chloro-2-indolinone 10.55 3-Z-[1-(4-dimethylaminomethylanilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-chloro-2-indolinone 10.56 3-Z-[1-(4-((4-methylpiperazin-1-yl)methyl)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone 10.57 3-Z-[1-(4-(imidazol-1-ylmethyl )anilino)-1-(3-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone 10.58 3-Z-[1-(4-(N-(2-dimethylaminoethyl)-N-methylaminomethyl)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone 10.59 3-Z-[1-(4-((4-methylpiperazin-1-yl)methyl)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone 10.60 3-Z-[1-(4-(imidazol-1-ylmethyl)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone 10.61 3-Z-[1-(4-(pyrrolidin-1-ylmethyl)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-chloro-2-indolinone 10.62 3-Z-[1-(4-(N-(2-dimethylaminoethyl)-N-methylaminomethyl)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone 10.63 3-Z-[1 anilino-1 -(3-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone 3-Z-[1-(4-aminomethylanilino)-1-(3-(2-carboxyethyl)phenyl)methylene]-10.64 6-fluoro-2-indolinone 10.65 3-Z-[1-(4-methylaminomethylanilino)-1-(3-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone 10.66 3-Z-[1 -(4-dimethylaminomethylanilino)-1 -(3-carboxymethoxy-phenyl)-methylene]-6-fluoro-2-indolinone 10.67 3-Z-[1 -(4-dimethylaminomethylanilino)-1 -(4-carboxymethoxy-phenyl)phenyl)methylene]-6-fluoro-2-indolinone 10.68 3-Z-[1-(4-(pyrrolidin-1-ylmethyl)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-bromo-2-indolinone 10.69 3-Z-[1-(4-(dimethylaminomethyl)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-bromo-2-indolinone 10.70 3-Z-[1 -(4-(diethylaminomethyl)anilino)-1 -(4-(2-carboxyethyl)-methylene]-6-bromo-2-indolinone 10.71 3-Z-[1 -(3-dimethylaminomethylanilino)-1 -(4-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone 10.72 3-Z-[1 -(3-dimethylaminomethylanilino)-1 -(3-(2-ca rboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone 3-Z-[1 -(3-dimethylaminomethylanilino)-1 -(4-(2-10.73 carboxyethyl)phenyl)methylene]-6-chloro-2-indolinone 11.0 3-Z-[1 -(4-dimethylaminomethylanilino)-1 -(3-(2-carbamoyl-ethyl)phenyl)methylene]-6-chloro-2-indolinone 11.1 3-Z-[1-(4-dimethylaminomethylanilino)-1-(3-(2-methyl carbamoyl-ethyl)phenyl)methylene]-6-chloro-2-indolinone 11.2 3-Z-[1 -(4-dimethylaminomethylanilino)-1 -(4-(2-methylcarbamoyl-ethyl)phenyl)methylene]-6-fluoro-2-indolinone 11.3 3-Z-[1 -(4-dimethylaminomethylanilino)-1 -(3-dimethylcarbamoylmethylphenyl)methylene]-6-fluoro-2-indolinone 11.4 3-Z-[1 -(4-dimethylaminomethylanilino)-1 -(3-(2-carbamoyl-ethyl)p henyl)methylene]-6-fluoro-2-indolinone 11.5 3-Z-[1 -(4-dimethylaminomethylanilino)-1 -(3-(2-methylcarbamoyl-ethyl)phenyl)methylene]-6-fluoro-2-indolinone 11.6 3-Z-[1 -(4-dimethylaminomethylanilino)-1 -(3-(2-dimethylcarbamoyl-ethyl)phenyl)methylene]-6-fluoro-2-indolinone 11.7 3-Z-[1-(4-dimethylaminomethylanilino)-1-(3-carbamoylmethyiphenyl)-methylene]-6-fluoro-2-indolinone 11.8 3-Z-[1 -(4-dimethylaminomethylanilino)-1 -(3-methylcarbamoylmethylphenyl)methylene]-6-fluoro-2-indolinone 11.9 3-Z-[1 -(4-dimethylaminomethylanilino)-1 -(4-carbamoylmethylphenyl)-methylene]-6-fluoro-2-indolinone 11.10 3-Z-[1 -(4-dimethylaminomethylanilino)-1 -(4-(2-dimethylcarbamoyl-ethyl)phenyl)methylene]-6-fluoro-2-indolinone 11.11 3-Z-[1 -(4-dimethylaminomethylanilino)-1 -(4-(2-(4-methylpiperazin-1 -yl-carbonyl)ethyl)phenyl)methylene]-6-fluoro-2-indolinone 3-Z-[1 -(4-(N-(4-methylpiperazin-1 -ylmethylcarbonyl)-N-11.12 methylamino)anilino)-1-(4-carbamoylm ethyl phenyl)methylene]-6-fluoro-2-indolinone 11.13 3-Z-[1 -(4-(N-(2-dimethylaminoethyl)-N-methylsulphonylamino)anilino)-1-(4-carbamoylmethylphenyl)methylene]-6-fluoro-2-indolinone 11.14 3-Z-[1-(4-dimethylaminomethylanilino)-1-(4-dimethylcarbamoylmethylphenyl)methylene]-6-fluoro-2-indolinone 11.15 3-Z-[1 -(4-dimethylaminomethylanilino)-1 -(4-methylca rbamoylmethylphenyl)methylene]-6-fluoro-2-indolinone 11.16 3-Z-[1 -(4-(N-(2-dimethylaminoethyl)-N-methylsulphonylamino)anilino)-1 -(4-methylcarbamoylmethylphenyl)methylene]-6-fluoro-2-indolinone 3-Z-[1-(4-(N-(2-dimethylaminoethyl)-N-methylsulphonylamino)anilino)-11.17 1-(4-dimethylcarbamoylmethylphenyl)methylene]-6-fluoro-2-indolinone 3-Z-[1-(4-(N-(4-methylpiperazin-1-ylmethylcarbonyl)-N-11.18 methylamino)anilino)-1-(4-methylcarbamoylmethylphenyl)methylene]-6-fluoro-2-indolinone 11.19 3-Z-[1-(4-(N-methyl-N-acetylamino)anilino)-1-(4-(2-methylcarbamoyl-ethyl)phenyl)methylene]-6-fluoro-2-indolinone 3-Z-[1 -(4-(N-(4-methylpiperazin-1 -ylmethylcarbonyl)-N-11.20 methylamino)anilino)-1-(4-(2-methylcarbamoyl-ethyl)phenyl)methylene]-6-fluoro-2-indolinone 11.21 3-Z-[1 -(4-(N-(2-dimethylaminoethyl)-N-methylsulphonylamino)anilino)-1-(4-(2-methylcarbamoylethyl)phenyl)methylene]-6-fluoro-2-indolinone 11.22 3-Z-[1 -(4-(N-tert-butoxycarbonylmethylaminomethyl)anilino)-1 -(4-(2-methylcarbamoylethyl)phenyl)methylene]-6-fluoro-2-indolinone 11.23 3-Z-[1-(4-(1-methylimidazol-2-yl)anilino)-1-(4-(2-methylcarbamoyl-ethyl)phenyl)methylene]-6-fluoro-2-indolinone 11.24 3-Z-[1-(4-methylsulphonylanilino)-1-(4-(2-methylcarbamoyl-ethyl)phenyl)methylene]-6-fluoro-2-indolinone 11.25 3-Z-[1-(4-(4-methylpiperazin-1-ylcarbonyl)anilino)-1-(4-(2-methylcarbamoylethyl)phenyl)methylene]-6-fluoro-2-indolinone 11.26 3-Z-[1-(4-(4-methylpiperazin-1-ylcarbonyl)anilino)-1-(3-methylcarbamoylmethylphenyl)methylene]-6-fluoro-2-indolinone 3-Z-[1 -(4-(N-(4-methylpiperazin-1 -ylmethylcarbonyl)-N-11.27 methylamino)anilino)-1-(3-methylcarbamoylmethylphenyl)methylene]-6-fluoro-2-indolinone 12.0 3-Z-[1 -(4-dimethylaminomethylanilino)-1 -(4-acetylaminomethylphenyl)-methylene]-6-chloro-2-indolinone 3-Z-[1 -(4-(N-(4-methylpiperazin-1 -ylmethylcarbonyl)-N-12.1 methylamino)anilino)-1-(4-acetylaminomethylphenyl)methylene]-6-chloro-2-indolinone 12.2 3-Z-[1-(4-dimethylaminomethylanilino)-1-(4-benzoylaminophenyl)-methylene]-6-chloro-2-indolinone 3-Z-[1-(4-(N-(4-methylpiperazin-1 -ylmethylcarbonyl)-N-12.3 methylamino)anilino)-1-(4-benzoylaminomethylphenyl)methylene]-6-chloro-2-indolinone 12.4 3-Z-[1 -(4-dimethylaminomethylanilino)-1 -(3-acetylaminomethylphenyl)-methyl ene]-6-fluoro-2-indolinone 12.5 3-Z-[1 -(4-dimethylaminomethylanilino)-1 -(3-propionylaminomethylphenyl)methylene]-6-fluoro-2-indolinone 12.6 3-Z-[1 -(4-dimethylaminomethylanilino)-1 -(3-benzoylaminomethylphenyl)methylene]-6-fluoro-2-indolinone 12.7 3-Z-[1 -(4-dimethylaminomethylanilino)-1 -(3-phenylacetylaminomethylphenyl)methylene]-6-fluoro-2-indolinone 12.8 3-Z-[1-(4-dimethylaminomethylanilino)-1-(3-(2-acetylaminoethyl)phenyl)methylene]-6-fluoro-2-indolinone 12.9 3-Z-[1-(4-dimethylaminomethylanilino)-1-(3-(2-benzoylaminoethyl)phenyl)methylene]-6-fluoro-2-indolinone 12.10 3-Z-[1 -(4-dimethylaminomethylanilino)-1 -(3-(2-propionylaminoethyl)phenyl)methylene]-6-fluoro-2-indolinone 12.11 3-Z-[1 -(4-dimethylaminomethylanilino)-1 -(3-(2-phenylacetylaminoethyl)phenyl)methylene]-6-fluoro-2-indolinone 12.12 3-Z-[1 -(4-dimethylaminomethylanilino)-1 -(4-acetylaminomethylphenyl)-methylene]-6-fluoro-2-indolinone 12.13 3-Z-[1 -(4-dimethylaminomethylanilino)-1 -(4-propionylaminomethylphenyl)methylene]-6-fluoro-2-indolinone 3-Z-[1-(4-dimethylaminomethylanilino)-1-(4-12.14 phenylacetylaminomethylphenyl)methylene]-6-fluoro-2-indolinone 3-Z-[1 -(4-(N-(4-methylpiperazin-1 -ylmethylcarbonyl)-N-12.15 methylamino)anilino)-1-(4-acetylaminomethylphenyl)methylene]-6-fluoro-2-indolinone 3-Z-[1 -(4-(N-(4-methylpiperazin-1 -ylmethylcarbonyl)-N-12.16 methylamino)anilino)-1-(4-propionylaminomethylphenyl)methylene]-6-fluoro-2-indolinone 3-Z-[1-(4-(N-(4-methylpiperazin-l-ylmethyl carbonyl)-N-12.17 methylamino)anilino)-1-(4-phenylacetylaminomethylphenyl)-methylene]-6-fluoro-2-indolinone 3-Z-[1 -(4-(N-(4-methylpiperazin-1 -ylmethylcarbonyl)-N-12.18 methylamino)anilino)-1-(3-cyclopropylcarbonylaminomethylphenyl)-methylene]-6-fluoro-2-indolinone 3-Z-[1-(4-(N-(4-methylpiperazin-1 -ylmethylcarbonyl)-N-12.19 methylamino)anilino)-1-(3-cyclobutylcarbonylaminomethylphenyl)-methylene]-6-fluoro-2-indolinone 3-Z-[1-(4-(N-(4-methylpiperazin-1 -ylmethylcarbonyl)-N-12.20 methylamino)anilino)-1-(3-(pyridin-2-yl-carbonylaminomethyl)phenyl)methylene]-6-fluoro-2-indolinone 3-Z-[1-(4-(N-(4-methylpiperazin-1 -ylmethylcarbonyl)-N-12.21 methylamino)anilino)-1-(3-cyclohexylcarbonylaminomethylphenyl)-methylene]-6-fluoro-2-indolinone 3-Z-[1-(4-(N-(4-methylpiperazin-1 -ylmethylcarbonyl)-N-12.22 methylamino)anilino)-1-(3-(pyridin-3-yl-carbonylaminomethyl)phenyl)methylene]-6-fluoro-2-indolinone 3-Z-[1-(4-(N-(4-methylpiperazin-1 -ylmethylcarbonyl)-N-12.23 methylamino)anilino)-1-(3-isobutyrylaminomethylphenyl)methylene]-6-fluoro-2-indolinone 3-Z-[1-(4-(N-(4-methylpiperazin-1 -ylmethylcarbonyl)-N-12.24 methylamino)anilino)-1-(3-(3-methylbutyrylaminomethylphenyl)-methylene]-6-fluoro-2-indolinone 3-Z-[1-(4-(N-(4-methylpiperazin-1-ylmethylcarbonyl)-N-12.25 methylamino)anilino)-1-(3-cyclohexylmethylcarbonylaminomethylphenyl)methylene]-6-fluoro-2-indolinone 3-Z-[1-(4-(N-(4-methylpiperazin-1-ylmethylcarbonyl)-N-12.26 methylamino)anilino)-1-(3-methoxyacetylaminomethylphenyl)-methylene]-6-fluoro-2-indolinone 3-Z-[1-(4-(N-(4-methylpiperazin-1-ylmethylcarbonyl)-N-12.27 methylamino)anilino)-1-(3-(2-methoxybenzoyl-aminomethyl)phenyl)methylene]-6-fluoro-2-indolinone 3-Z-[1-(4-(N-(4-methylpiperazin-1 -ylmethylcarbonyl)-N-12.28 methylamino)anilino)-1-(3-tert-butylacetylaminomethylphenyl)-methylene]-6-fluoro-2-indolinone 3-Z-[1-(4-(N-(4-methylpiperazin-1-ylmethylcarbonyl)-N-12.29 methylamino)anilino)-1-(3-(2-thiophen-carbonylaminomethyl)phenyl)methylene]-6-fluoro-2-indolinone 3-Z-[1-(4-(N-(4-methylpiperazin-1 -ylmethylcarbonyl)-N-12.30 methylamino)anilino)-1-(3-pivaloylaminomethylphenyl)methylene]-6-fluoro-2-indolinone 3-Z-[1 -(4-(N-(4-methylpiperazin-1-ylmethylcarbonyl)-N-12.31 methylamino)anilino)-1-(3-(2-furoylaminomethyl)phenyl)methylene]-6-fluoro-2-indolinone 3-Z-[1-(4-(N-(4-methylpiperazin-1-ylmethylcarbonyl)-N-12.32 methylamino)anilino)-1-(3-acetylaminomethylphenyl)methylene]-6-fluoro-2-indolinone 3-Z-[1 -(4-(N-(4-methylpiperazin-1 -ylmethylcarbonyl)-N-12.33 methylamino)anilino)-1-(3-propionylaminomethylphenyl)methylene]-6-fluoro-2-indoli none 3-Z-[1 -(4-(N-(4-methylpiperazin-1 -ylmethylcarbonyl)-N-12.34 methylamino)anilino)-1-(3-benzoylaminomethylphenyl)methylene]-6-fluoro-2-indolinone 3-Z-[1 -(4-(N-(4-methylpiperazin-1 -ylmethylcarbonyl)-N-12.35 methylamino)anilino)-1-(3-phenylacetylaminomethylphenyl)-methylene]-6-fluoro-2-indolinone 3-Z-[1 -(4-dimethylaminomethylanilino)-1 -(3-12.36 cyclopropylcarbonylaminomethylphenyl)methylene]-6-fluoro-2-indolinone 12.37 3-Z-[1 -(4-dimethylaminomethylanilino)-1 -(3-cyclobutylcarbonylaminomethylphenyl)methylene]-6-fluoro-2-indolinone 12.38 3-Z-[1 -(4-dimethylaminomethylanilino)-1 -(3-(pyridin-2-yl-carbonylaminomethyl)phenyl)methylene]-6-fluoro-2-indolinone 3-Z-[1-(4-dimethylaminomethylanilino)-1-(3-12.39 cyclohexylcarbonylaminomethylphenyl)methylene]-6-fluoro-2-indolinone 12.40 3-Z-[1 -(4-dimethylaminomethylanilino)-1 -(3-(pyridin-3-yl-carbonyla minomethyl)phenyl)methylene]-6-fluoro-2-indolinone 12.41 3-Z-[1-(4-dimethylaminomethylanilino)-1-(3-isobutyrylaminomethylphenyl)methylene]-6-fluoro-2-indolinone 12.42 3-Z-[1-(4-dimethylaminomethylanilino)-1-(3-(3-methyl butyryl-aminomethylphenyl)methylene]-6-fluoro-2-indolinone 3-Z-[1 -(4-dimethylaminomethylanilino)-1 -(3-12.43 cyclohexylmethylcarbonylaminomethylphenyl)methylene]-6-fluoro-2-indolinone 3-Z-[1-(4-dimethylaminomethylanilino)-1-(3-12.44 methoxyacetylaminomethylphenyl)methylene]-6-fluoro-2-indolinone 12.45 3-Z-[1-(4-dimethylaminomethylanilino)-1-(3-(2-methoxybenzoyl-aminomethyl)phenyl)methylene]-6-fluoro-2-indolinone 12.46 3-Z-[1-(4-dimethylaminomethylanilino)-1-(3-tert-butylacetylaminomethylphenyl)methylene]-6-fluoro-2-indolinone 3-Z-[1-(4-dimethylaminomethylanilino)-1-(3-(2-12.47 thiophenecarbonylaminomethyl)phenyl)methylene]-6-fluoro-2-indolinone 12.48 3-Z-[1-(4-dimethylaminomethylanilino)-1-(3-pivaloylaminomethylphenyl)methylene]-6-fluoro-2-indolinone 12.49 3-Z-[1-(4-dimethylaminomethylanilino)-1-(3-(2-furoylaminomethyl)phenyl)methylene]-6-fluoro-2-indolinone 12.50 3-Z-[1-(4-dimethylaminomethylanilino)-1-(3-(pyridin-4-yl-carbonyl aminomethyl)phenyl)methylene]-6-fluoro-2-indolinone 13.0 3-Z-[1-(4-trimethylammon iummethylanilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone iodide 13.1 3-Z-[1-(4-trimethylammoniummethylanilino)-1-(3-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone iodide 14.0 3-Z-[1-(4-guanidinomethylanilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone 14.1 3-Z-[1-(4-guanidinomethylanilino)-1-(3-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone Abbreviations used:
HOBt = 1-hydroxy-1 H-benzotriazole TBTU = O-benzotriazol-1-yl-N,N,N',N'-tetramethyluronium tetrafluoroborate Preparation of the starting materials:
Example I:
Dimethyl 2-(4-fluoro-2-nitropheny)malonate With ice-cooling, 185 g of potassium tert-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) C11H1oFN06 Mass spectrum: m/z = 270 [M-H]-The following compounds are prepared analogously to Example I:
(1.1) Diethyl 2-(4-bromo-2-nitrophenyl)maIonate from 2,5-dibromonitrobenzene and diethyl malonate Rf value: 0.40 (silica gel, petroleum ether/ethyl acetate = 5:1) C13H14BrNO6 Mass spectrum: m/z = 359/361 [M]+
(1.2) Dimethyl 2-(4-cyano-2-nitrophenyl)malonate from 4-chloro-3-nitrobenzonitrile and dimethyl malonate Rf value: 0.50 (silica gel, methylene chloride/methanol = 50:1) C12H1oN2O6 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 sulphoxide, 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 C1oH8N2O4 Mass spectrum: m/z = 219 [M-H]-Example III:
4-Fluoro-2-nitrophenylacetic acid 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 and dried.
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 10 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) 15 Mass spectrum: m/z = 150 [M-H]-The following compounds are prepared analogously to Example IV:
(IV.1) 6-Bromo-2-indolinone 20 from diethyl 2-(4-bromo-2-nitrophenyl)malonate (starting material 1.1) using Raney nickel as hydrogenation 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) Mass spectrum: m/z = 157 [M-H]-Example V:
1 -acetyl-6-fluoro-2-indoli none At 130 C, 82.5 g of 6-fluoro-2-indolinone (starting material IV) are stirred in 180 ml acetic anhydride for 3 hours. After cooling 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) Mass spectrum: m/z = 192 [M-H]-The following compounds are prepared analogously to Example V:
(V.1) 1-acetyl-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-indolinone 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-acetyl-3-[1-hydroxy-1 -(3-iodoghenyl)methylenel-6-chloro-2-indolinone 10.5 g of 1-acetyl-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 100 ml 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) Mass spectrum: m/z = 438/440 [M-H]-The following compounds are prepared analogously to Example VI:
(VI.1) 1-acetyl-3-[1-hydroxy-1-(4-methoxycarbonylmethylphenyl)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 -hyd roxy- 1 -(4-chlorophenyl) methylene]-6-ch loro-2- i ndoli none 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-dimethoxyphenyl)methylene]-6-cyano-2-indolinone from 1-acetyl-6-cyano-2-indolinone (starting material V.3) and 3,4-dimethoxybenzoic acid (VI.5) 1-acetyl-3-[1-hydroxy-1-(3-fluorophenyl)methylene]-6-fluoro-2-indolinone from 1-acetyl-6-fluoro-2-indolinone (starting material V) and 3-fluorobenzoic acid (VI.6) 1-acetyl-3-[1-hydroxy-1-(4-(2-acetylaminoethyl)phenyl)methylene]-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 methyl (3-carboxyphenyl)acetate (preparation analogously to Tetrahedron 1997, 53, 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) (VI.11) 1 -acetyl-3-[1 -hydroxy-1 -(4- iodoph enyl)methyle ne]-6-fl uoro-2-i ndol i none from 1-acetyl-6-fluoro-2-indolinone (starting material V) and 4-iodobenzoic acid (VI. 12) 1-acetyl-3-[1-hydroxy-1-(4-iodophenyl)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)methylene]-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)methylene]-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. Left 2000, 10, 553-557) (VI.17) 1-acetyl-3-[1-hydroxy-1-(4-(N-tert-butoxycarbonyl-2-aminoethyl)phenyl)methylene]-6-fluoro-2-indolinone from 1 -acetyl-6-fl uoro-2-i ndoli none (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-acetyl-6-chloro-2-indolinone (starting material V.1) and 4-cyanobenzoic acid (Vi. 19) 1 -acetyl-3-[1 -hydroxy-1 -(3-acetylaminomethylphenyl)methylene]-6-fluoro-2-indolinone 5 from 1-acetyl-6-fluoro-2-indolinone (starting material V) and 3-acetylaminomethyl-benzoic acid (prepared according to J. Med. Chem. 1997, 40, 4030-4052) (VI.20) 1-acetyl-3-[1-hydroxy-1-(3-(2-ethoxycarbonylethyl)phenyl)methylene]-6-fluoro-2-indolinone 10 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]-6-15 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) 20 (VI.22) 1-acetyl-3-[1-hydroxy-1-(4-(2-ethoxycarbonylethyl)phenyl)methylene]-6-fluoro-2-indolinone from 1-acetyl-6-fluoro-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)methylene]-fluoro-2-indolinone from 1-acetyl-6-fluoro-2-indolinone (starting material V) and 3-methoxycarbonylmethyloxybenzoic acid (preparation see Tetrahedron Letters 1998, 39, 8563-8566) (VI.24) 1-acetyl-3-[1-hydroxy-1-(4-methoxycarbonylmethyloxyphenyl)methylene]-6-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-acetyl-3-[1-hydroxy-1-(3-(2-ethoxycarbonylethyloxy)phenyl)methylene]-fluoro-2-indolinone from 1-acetyl-6-fluoro-2-indolinone (starting material V) and 3-(2-ethoxycarbonylethyloxy)benzoic acid (preparation see PCT Int. Appl. W09620173, 60) (VI.26) 1-acetyl-3-[1-hydroxy-1-(4-(2-ethoxycarbonylethyloxy)phenyl)methylene]-fluoro-2-indolinone from 1-acetyl-6-fluoro-2-indolinone (starting material V) and 4-(2-ethoxycarbonylethyloxy)benzoic acid (preparation see PCT Int. Appl. W09620173, 58) (VI.27) 1-acetyl-3-[1-hydroxy-1-(4-(2-methoxycarbonylethyl)phenyl)methylene]-6-bromo-2-indolinone from 1-acetyl-6-bromo-2-indolinone (starting material V.2) and 4-(2-methoxycarbonylethyl)-benzoic acid (preparation analogously to Tetrahedron 1997, 53, 7335-7340) Example VII:
1-acetyl-3-[1-methoxy-1-(3-iodophenyl)methylenel-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-[1-hydroxy-1-(3-iodophenyl)methylene]-6-chloro-2-indolinone (starting material VI) and 2.72 ml of ethyldiisopropylamine in 80 ml of dichloromethane, 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/dichloromethane/ethyl acetate =
5:4:1) Mass spectrum: m/z = 438/440 [M-H]"
m.p. 185 - 187 C
The following compounds are prepared analogously to Example VII:
(VI I.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) (VI I.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-chloro-2-indolinone from 1 -acetyl-3-[1 -hydroxy- 1 -(3,4-dimethoxyphenyl)methylene]-6-chloro-2-indoli none (starting material VI.3) (VI 1.4) 1 -acetyl-3-[1 -methoxy-1 -(3,4-dimethoxyphenyl)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-fl uoro phenyl)m ethylene]-6-fl uoro-2-i nd ol i none from 1-acetyl-3-[1-hydroxy-1-(3-fluorophenyl)methylene]-6-fluoro-2-indolinone (starting material V1.5) 63 (VI 1.6)1-acetyl-3-[1-methoxy-1-(4-(2-acetylaminoethyl)phenyl)methylene]-6-fluoro-2-indolinone from 1-acetyl-3-[1-hydroxy-1-(4-(2-acetylaminoethyl)phenyl)methylene]-6-fluoro-indolinone (starting material VI.6) (VII .7)1-acetyl-3-[1-methoxy-1-(3-methoxycarbonylmethylphenyl)methylene]-6-fluoro-2-indoli none from 1-acetyl-3-[1-hydroxy-l -(3-methoxycarbonylmethylphenyl)methylene]-6-fluoro-2-indolinone (starting material V1.7) 1:0 (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-fluoro-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) (VII.11) 1-acetyl-3-[1-methoxy-1-(4-iodophenyl)methylene]-6-fluoro-2-indolinone from 1-acetyl-3-[1-hydroxy-1-(4-iodophenyl)methylene]-6-fluoro-2-indolinone (starting material VI.11) (VI I.12) 1-acetyl-3-[1-methoxy-1-(4-iodophenyl)methylene]-6-chloro-2-indolinone from 1-acetyl-3-[1-hydroxy-1-(4-iodophenyl)methylene]-6-chloro-2-indolinone (starting material VI.12) = CA 02493436 2005-01-21 (VII.13) 1-acetyl-3-[1-methoxy-1-(3-iodophenyl)methylene]-6-fluoro-2-indolinone from 1-acetyl-3-[1-hydroxy-1-(3-iodophenyl)methylene]-6-fluoro-2-indolinone (starting material VI.13) (VII.14) 1-acetyl-3-[1-methoxy-1-(3-(2-methoxycarbonylethyl)phenyl)methylene]-6-fluoro-2-indolinone from 1-acetyl-3-[1-hydroxy-1-(3-(2-methoxycarbonylethyl)phenyl)methylene]-6-fluoro-2-indolinone (starting material VI.14) (VI I.15) 1 -acetyl-3-[1 -methoxy-1 -(4-(2-methoxycarbonylethyl)phenyl)methylene]-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.16) 1-acetyl-3-[1-methoxy-1-(4-(N-tert-butoxycarbonyl-2-aminoethyl)phenyl)methylene]-6-fluoro-2-indolinone from 1-acetyl-3-[1-hydroxy-1-(4-(N-tert-butoxycarbonyl-2-aminoethyl)phenyl)methylene]-6-fluoro-2-indolinone (starting material VI.17) (VII.17) 1 -acetyl-3-[1 -methoxy-1 -(3-(N-tert-butoxycarbonyl-2-ami n oethyl)phenyl)m ethyle ne]-6-fl uoro-2-i ndol in one from 1-acetyl-3-[1-hydroxy-1-(3-(N-tert-butoxycarbonyl-2-aminoethyl)phenyl)methylene]-6-fluoro-2-indolinone (starting material VI.16) (VI I.18) 1 -acetyl-3-[1 -methoxy-1 -(3-acetylaminomethylphenyl)methylene]-6-fluoro-2-indolinone 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)methyl ene]-6-fluoro-2-indolinone from 1-acetyl-3-[1-hydroxy-1-(3-(2-ethoxycarbonylethyl)phenyl)methylene]-6-fluoro-2-indolinone (starting material VI.20) (VI 1.20) 1 -acetyl-3-[1 -methoxy-1 -(4-(2-methoxycarbonylethyl)phenyl)methylene]-5 6-chloro-2-indolinone from 1-acetyl-3-[1-hydroxy-1-(4-(2-methoxycarbonylethyl)phenyl)methylene]-6-chloro-2-indolinone (starting material VI.21) (VI I.21) 1-acetyl-3-[1-methoxy-1-(4-(2-ethoxycarbonylethyl)phenyl)methylene]-10 6-fluoro-2-indolinone from 1-acetyl-3-[1-hydroxy-1-(4-(2-ethoxycarbonylethyl)phenyl)methylene]-6-fluoro-2-indolinone (starting material Vl.22) (VI I.22) 1-acetyl-3-[1-methoxy-1-(4-methoxycarbonylmethyloxyphenyl)-15 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-methoxycarbonylmethyloxyphenyl)-20 methylene]-6-fluoro-2-indolinone from 1-acetyl-3-[1-hydroxy-1-(3-methoxycarbonylmethyloxyphenyl)methylene]-6-fluoro-2-indolinone (starting material VI.24) (VI I.24) 1 -acetyl-3-[1 -methoxy-1 -(3-(2-25 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) (VI I.25) 1 -acetyl-3-[1 -methoxy-1 -(4-(2-30 ethoxycarbonylethyloxy)phenyl)methylene]-6-fluoro-2-indolinone from 1-acetyl-3-[1-hydroxy-1-(4-(2-ethoxycarbonylethyloxy)phenyl)methylene]-6-fluoro-2-indolinone (starting material VI.26) (VI I.26) 1-acetyl-3-[1-methoxy-1-(4-(2-methoxycarbonylethyl)phenyl)methyl ene]-6-bromo-2-indoli none from 1-acetyl-3-[1-hydroxy-1-(4-(2-methoxycarbonylethyl)phenyl)methylene]-6-bromo-2-indolinone (starting material VI.27) Example VIII:
1-Acetyl-3-[1-chloro-1-(4-cyanophenyl methyl enel-6-chloro-2-indolinone A suspension of 7.0 g of 1-acetyl-3-[1-hydroxy-1-(4-cyanophenyl)methylene]-6-chloro-2-indolinone (starting material VI.18) and 6.39 g of phosphorus pentachloride in 150 ml of dioxane is stirred at 100 C for 6 hours. After addition of a further 1.0 g of phosphorus pentachloride, the mixture is stirred at 110 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-(diethylaminomethyl)aniline (IX.2) N-(2-dimethylaminoethyl)-N-methylsulphonyl-p-phenylenediamine (IX.3) 3-(dimethylaminomethyl)aniline (IX.4) 4-(dimethylaminomethyl)aniline (IX.5) 4-(2-dimethylaminoethyl)aniline (IX.6) 4-[N-(2-dimethylaminoethyl)-N-acetylamino]aniline (IX.7) 4-[N-(3-dimethylaminopropyl)-N-acetylamino]aniline (IX.8) 4-[(N-dimethylaminocarbonylmethyl-N-methylsulphonyl)amino]aniline (IX.9) N-(4-aminophenyl)-N-methylmethanesulphonamide (IX.10) N-(dimethylaminomethylcarbonyl)-N-methyl-p-phenylenediamine (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-methylimidazol-2-yl)aniline (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)methylcarbonyl]-N-methyl-p-phenylenediamine (IX.20) 4-(4-tert-butoxycarbonylpiperazin-1-ylmethyl)aniline (IX.21) 4-(thiomorpholin-4-ylmethyl)aniline (IX.22) 4-(pyrrolidin-1-ylmethyl)aniline (IX.23) 4-(morpholin-4-yl-methyl)aniline (1X.24) 4-(N-benzyl-N-methylaminomethyl)aniline (1X.25) 4-(N-ethyl-N-methylaminomethyl)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-dimethylaminoethyl)-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)carbonyl]-N-methyl-p-phenylenediamine Preparation of the end products:
Example 1.0 3-Z-[1 -(4-(N-Methyl-N-methylsulphonylamino)anilino)-1-(3-iodophenyl)methylenel-6-chloro-2-indolinone 0.9 g of 1-acetyl-3-(1-methoxy-1-(3-iodophenyl)methyl ene)-6-chloro-2-indolinone (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 I-1 are prepared analogously to Example 1.0:
H
O
C 1 H (I-1 ) Ex- Starting Rf Empirical Mass M.P. amp/ R3 R4' materi-formula spectrum [ C] value*
e als VII 529/531 238- 0.30 -CH2-NMe2 C24H21CIIN3O
IX.4 [M+H]+ 240 (A) Cl -N(Me)-(CO)- VII.2 495/497 277- 0.20 1.2 C26H24C12N402 CH2-NMe2 IX.10 [M+H]+ 279 (B) Cl -N(COMe)- Vll.2 C27H26C12N4O2 507/509 241- 0.10 1.3 CH2)2-NMe2 IX.6 [M-H]" 243 (B) CI T"N-Me VII.2 548/550 266- 0.10 1.4 Me,N-~-NJ C29H29C12N502 "i, 0 IX.19 [M-H]- 268 (B) ci -N(COMe)- VII.2 521/523 241- 0.10 1.5 C28H28C12N4O2 (CH2)3-NMe2 IX.7 [M-H]- 242 (B) ci VIl.2 438/440 243- 0.10 1.6 -CH2-NMe2 C24H21C12N3O
IX.4 [M+H]+ 244 (B) Meo OMe -N(COMe)- VII.3 533/535 128- 0.75 1.7 I ` C29H31CIN4O4 (CH2)2-NMe2 IX.6 [M-H]- 130 (C) MeO OMe r--"N-Me VII.3 574/576 208- 0.65 1.8 Ox Me,N~ C31H34CIN5O4 "1, o IX.19 [M-H]" 210 (C) MeO OMe -N(S02Me)- VII.3 569/571 198- 0.75 1.9 C2aH31 CIN4O5S
(CH2)2-NMe2 IX.2 [M-H]" 200 (C) Meo oMe VII.3 462/464 239- 0.70 1.10 Ox, -CH2-NMe2 C26H26CIN3O3 IX.4 [M-H]" 240 (C) Meo oMe o Me VII.3 533/535 147- 0.70 1.11 NMe2 IX 29 [M-H]" 149 (C) *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-[1-(4-(Dimethylaminomethyl)anilino)-l-(4-cyanophenvl)methvlenel-6-chloro-2-indolinone 1.07 g of 1 -acetyl-3- [1 -ch loro- 1 -(4-cyanophe nyl) methylene]-6-ch loro-2-i ndol i none (starting material VII) and 0.54 g of 4-(dimethylaminomethyl)aniline (starting material IX.4) are dissolved in 10 ml of dimethylformamide 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), Rf value: 0.1 (silica gel, methylene chloride/methanol = 9:1) Mass spectrum: m/z = 427/429 [M-HI-Example 3.0 3-Z-[1-(4- dimethylaminomethyl)anilino)-1-(4-iodophenyl)methvlenel-6-fluoro-2-indolinone 3.5 g of 1-acetyl-3-(1-meth oxy-1-(4-iodophenyl)methylene)-6-fluoro-2-indolinone (starting material V11.11) and 1.6 g of 4-(dimethylaminomethyl)aniline (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 methanol 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+H]+
The following compounds of the formula I-3a are prepared analogously to Example 3.0:
R4' H
O
R2 N (I-3a) H
Ex- Starting Empirical Mass m. p. Rf amp R2 R3 R4' materi-formula spectrum [ C] value*
le als F V11.5 404 225- 0.20 3.1 -F / -CH2-NMe2 C24H21F2N3O
IX.4 [M-H]" 227 (A) = CA 02493436 2005-01-21 F -N(COMe)- NITS 491 160- 0.20 3.2 -F C23H28F2N402 (CH2)3-NMe2 IX.7 [M+H]+ 163 (A) F Me NN j VII.5 518 218- 0.40 3.3 -F Me,N C29H29F2N502 IX.19 [M+H]+ 220 (A) Cr0 N VII.6 471 106- 0.25 3.4 -F -CH2-NMe2 C28H29FN402 / IX.4 [M-Hl- 110 (A) H3Cr0 N -N(COMe)- VII.6 558 194- 0.25 3.5 -F C32H36FN503 / (CH2)3-NMe2 IX.7 [M+H]+ 196 (A) H3cN JN Me VII.6 583 238- 0.25 3.6 -F Me~NO C33H37FN603 / 1X.19 [M-Hl- 240 (A) F. OMe VII.1 460 173- 0.30 3.7 -F -CH2-NMe2 C27H26FN303 IX.4 [M+H]+ 176 (A) VII.13 514 198- 0.30 3.8 -F -CH2-NMe2 C24H21FIN30 IX.4 [M+H]+ 200 (B) VII.7 458 195- 0.25 3.9 -F OMe -CH2-NMe2 C27H26FN303 IX.4 [M-H]" 198 (A) tBuO 0 NH V11.8 517 230- 0.30 3.10 -F -CH2-NMe2 C30H33FN403 IX.4 [M+H]+ 240 (A) 3.11 -F oMe V11.1 C29H31FN405S 567 188- 0.40 (CH2)2-NMe2 IX.2 [M+H]+ 189 (A) 0 OMe Me J Me VI1.1 572 200- 0.35 3.12 -F N 0 C32H34FN504 +
IX.19 [M+H] 203 (C) 3.13 -F CN -CH2-NMe2 V11.9 C26H23FN40 427 130- 0.25 I
IX.4 [M+H]+ 135 (A) OtBu r''`N-Me HN'~0 Me. ~N VII.10 629 215- 0.35 3.14 -F N C35H41 FN604 0 IX.19 [M+H]+ 220 (A) OtBu HN'~0 VII.10 517 186- 0.35 3.15 -F -CH2-NMe2 C30H33FN403 +
IX.4 [M+H] 190 (A) OtBu NH V11.17 531 0.40 3.16 -F -CH2-NMe2 C31H35FN403 + n.d.
OMe o VII.15 488 166- 0.40 3.17 -F / -NMe-(COMe) - C28H26FN304 [M+H]+ 170 (A) OMe N-Me VI1.15 586 176- 0.30 3.18 -F Me~N 0 C33H36FN504 +
IX.19 [M+H] 180 (A) lux, OMe o -N(SO2Me)- VII.15 581 195- 0.45 3.19 -F C30H33FN405S
(CH2)2-NMe2 IX.2 [M+H]+ 198 (A) OMe o -N(COMe)- VII.15 559 100- 0.50 3.20 -F C32H35FN404 (CH2)3-NMe2 IX.7 [M+H]+ 104 (A) OMe o Me VII.15 558 132- 0.80 3.21 -F r 0tBu C32H34FN305 / 0 IX.18 [M-Hl- 137 (D) OMe 0 0 rN-Me VII.15 543 234- 0.60 3.22 -FIX.30 C31H31FN404 LM+Hl+ 236 (A) OMe 0 NI VII.15 497 110- 0.40 3.23 -F N C29H25FN403 Me IX.16 [M+H]+ 115 (A) lox OMe 0 VII.15 495 130- 0.60 3.24 -F -SO2Me C26H23FN205S
[M+H]+ 137 (A) NMe 3OMe Me. N V11.7 572 189 0.60 3.25 -F N 0 C32H34FN504 +
IX.19 [M+H] (B) OMe -N(SO2Me)- VII.7 567 0.60 3.26 -F C29H31FN405S
(CH2)2-NMe2 IX.2 [ M+H ]+ n.d. (B) oMe or'N-Me V11.7 529 201- 0.60 3.27 -F N. C3oH29FN404 IX.30 [M+HJ+ 203 (B) 3.28 -F OMe -N(Me)-(CO)- VII.7 C29H29FN404 517 126 0.60 CH2-NMe2 IX.10 [M+HI+ (B) 3.29 -F OMe -N(COMe)- VII.7 C30H31FN404 531 179 0.50 (CH2)2-NMe2 IX.6 [M+H]+ (B) 3.30 -F OMe -N(COMe)- VII.7 C31H33FN404 545 123 0.20 (CH2)3-NMe2 IX.7 [M+H]+ (B) 3.31 -F OMe -N(Me)-(CO)- VII.7 C32H35FN404 559 201 0.20 (CH2)4-NMe2 IX.32 [M+H]+ (B) 3.32 -F O OMe -H V11.1 C24H19FN203 403 198- 0.80 _ [M+H]+ 206 (A) 0 ,e N-3 V11.1 483 223- 0.75 3.33 -F N C28H23FN403 Me IX.16 [M+H]+ 226 (A) O OMe 0 N-Me VI1.1 529 215- 0.30 3.34 -F N\---/ C3oH29FN404 IX.30 [M+H]+ 220 (A) 0 oMe -N(S02Me)- V11.1 581 227- 0.65 3.35 -F (CH2)-(CO)- C29H29FN406S
= IX.8 [M+H)+ 230 (A) NMe2 oMe -N(Me)-(CO)- VII-1 517 128- 0.45 3.36 -F C29H29FN4O4 CH2-NMe2 IX.10 [M+H]+ 130 (A) OMe -N(COMe)- VII.1 474 218- 0.40 3.37 -F C27H24FN304 CH3 _ [M+H]+ 223 (A) oMe -N(Me)-(CO)- V11.1 531 192- 0.40 3.38 -F C30H31FN404 (CH2)2-NMe2 IX.11 [M+H]+ 194 (A) 0 OMe V11.1 481 205- 0.65 3.39 -F -SO2Me C25H21FN205S
~. _ [M+H]+ 214 (A) OMe -N(Me)-(CO)- VI1.1 545 190- 0.15 3.40 -F C31H33FN404 (CH2)3-NMe2 IX.33 [M+H]+ 193 (A) 3.41 -F 0 oMe V11.1 C31H33FN404 545 184- 0.50 (CH2)3-NMe2 IX.7 [M+H]+ 188 (A) V11.7 403 0.70 3.42 -F OMe -H C24H19FN203 [M+H]+ 114 (B) VII.7 481 0.60 3.43 -F OMe _S02Me C25H21FN205S [M+H]+ 129 (B) OMe N-3 V11.7 483 0.60 3.44 -F N C28H23FN403 125 Me IX.16 [M+H]+ (B) o -N(SO2Me)-VI I.7 581 0.60 3.45 -F oMe (CH2)-(CO)- C29H29FN406S 163 IX.8 [M+H] (B) NMe2 3.46 -F OMe -N(Me)-(CO)- VII.7 C31H33FN404 545 101 0.10 r (CH2)3-NMe2 IX.33 [M+H]+ (B) 3.47 -F oMe -N(Me)-(CO)- VII.7 C30H31FN404 531 161 0.20 (CH2)2-NMe2 IX.11 [M+H]+ (B) Me0 O Me Me VII.14 586 181- 0.20 3.48 -F N O C30H31 FN404 IX. 19 [M+H]+ 183 (B) MeO O
3.49 -F -N(SO2Me)- VII.14 C30H33FN405S 581 158- 0.35 I ` (CH2)2-NMe2 IX.2 [M+H]+ 160 (B) MeO f O
3.50 -F -N(Me)-(CO)- VII.14 C30H31FN404 531 0.40 ` CH2-NMe2 IX.10 [M+H]+ n.d. (B) MeO O
3.51 -F -N(COMe)- VII.14 C32H35FN404 559 0.50 ` (CH2)3-NMe2 IX.7 [M+H]+ n.d. (E) tBuO
o Me, Me H VI1.8 629 0.35 3.52 -F N-41 C35H41FN604 + n.d.
0 IX=19 [M+H] (A) O~-CH3 HN -NMe-(CO)- VI1.26 473 122- 0.50 3.53 -F CH3 - C27H25FN403 [M+H]+ 126 (F) O.--CH3 HN -N(COMe)- VII.26 544 80- 0.25 3.54 -F CH2 3-NMe2 C31H34FN503 ( ) IX.7 [M+H]+ 83 (A) O~-CH3 HN -N(S02Me)- VII.18 566 190- 0.30 3.55 -F C29H32FN504S
(CH2)2-NMe2 IX.2 [M+H]+ 195 (A) O~-CH3 3.56 -F HN -N(Me)-(CO)- VII.18 C29H30FN503 516 238- 0.30 CH2-NMe2 IX.10 [M+H]+ 241 (G) OMe VII.15 488 205- 0.55 3.57 -F -(CH2)2-NMe2 C29H3oFN303 IX.5 [M+H]+ 208 (G) OMe -N(Me)-(CO)- VII.15 543 196- 0.20 3.58 -F C31H31FN404 ` (CH2)2-NMe2 IX.11 [M-H]" 202 (A) OMe -N(Me)-(CO)- VII.15 531 177- 0.30 3.59 -F C30H31FN404 ` CH2-NMe2 IX.10 [M+H]+ 182 (A) EtO O
VI1.19 500 100- 0.35 3.60 -F -(CH2)2-NMe2 C3oH32FN303 M-H " 105 (B) [ ] ) OMe O -N(COMe)- VII.15 C31H33FN404 545 167- 0.40 3.61 -F (CH2)2-NMe2 IX.6 [M+H]+ 169 (A) EtO O
3.62 -F -N(Me)-(CO)- VII-19 C33H37FN404 571 n.d. 0.35 I (CH2)3-NMe2 IX.33 [M-H]" (A) EtO O
3.63 -F -N(Me)-(CO)- VII-19 C34H39FN404 585 n.d. 0.40 (CH2)4-NMe2 IX.32 [M-H]" (A) EtO O
N3 VII.19 511 95- 0.25 3.64 - F C3oH27FN403 Me IX.16 [M+H]+ 105 (B) OMe 3.65 O -N(Me)-(CO)- VII.15 573 173- 0.20 I (CH2)4-NMe2 IX.32 [M+H]+ 175 (A) OMe o VII.15 417 168- 0.65 3.66 -F -H C25H21 FN203 - [M+H]+ 174 (A) OMe o VII.15 500 168- 0.40 3.67 -F rN~ C30H30FN303 IX.22 [M+H]+ 173 (B) OMe o VII.15 502 0.45 -CH2-NEt2 C3oH32FN303 + n.d.
3.68 -F
lox OMe 0 H V11.15 544 0.30 3.69 -F N1rotBu C31H32FN305 n.d.
o IX.12 [M-H] (G) OMe VII.7 472 165- 0.25 3.70 -F -(CH2)2-NMe2 C28H28FN303 IX.5 [M-Hl- 170 (B) O OMe VII.1 472 193- 0.25 3.71 -F -(CH2)2-NMe2 C28H28FN303 IX.5 [M-H]" 197 (B) EtO O
V11.19 488 48- 0.45 3.72 -F -CH2-NMe2 C29H30FN303 IX.4 [M+H]+ 52 (B) OMe o VII.20 504/506 156- 0.30 3.73 -Cl -(CH2)2-NMe2 C29H30CIN303 IX.5 [M+H]+ 160 (H) OMe O N VII.20 513/515 0.40 3.74 -Cl N C29H25CIN403 [M+H]+ 110 (H) Me IX.16 OMe O VII.20 490/492 173- 0.70 3.75 -Cl -CH2-NMe2 C28H28CIN303 IX.4 [M+H]+ 175 (I) ,lax, OEt o VII.21 488 158- 0.35 3.76 -F -CH2-NMe2 C29H30FN303 IX.4 [M+H]+ 161 (B) MeO O
r--",N-Me VII.14 529 147- 0.50 3.77 -F rN,J C31H33FN403 IX.14 [M+H]+ 150 (1) MeO O
N VII.14 497 182- 0.60 3.78 -F ,rNJ C29H25FN403 IX.15 [M+H] 185 (K) OMe 0 r--\N-Me VII.15 529 0.35 3.79 -F N,.J C31 H33FN403 + 184 IX. 14 OMe O N VII.15 497 0.45 3.80 -F C29H25FN403 233 IX.15 [M+H]+ (B) OMe 3.81 -F -CH2-NMe- VII.15 C31H35FN403 531 120 0.40 a (CH2)2-NMe2 IX.17 [M+H]+ (B) EtO O
3.82 -F -CH2-NMe- VII.19 C32H37FN403 545 0.40 (CH2)2-NMe2 IX.17 [M+H]+ n.d. (K) OMe o VII.20 516/518 195- 0.30 3.83 -Cl rN0 C30H30CIN303 IX.22 [M+H]+ 197 (H) EtO O
VII.19 431 156- 0.80 3.84 -F -H C26H23FN203 [M+H]+ 160 (M) EtO O
H V11.19 560 0.50 3.85 -F r-NrOtBu C32H34FN305 n.d.
o IX.12 [M+H]+ (~) EtO O
Me VII.19 574 0.60 3.86 -F i o otBu C33H36FN305 n.d.
MeO O
of VII.22 476 0.25 3.87 -F -CH2-NMe2 C27H26FN304 + 129 OMe o VII.23 476 0.25 3.88 -F O -CH2-NMe2 C27H26FN304 + 155 OEt 3.89 -F O O -CH2-NMe2 V11.24 C29H3oFN304 504 0.20 IX.4 [M+H]+ n.d. (B) OMe o VII.26 560/562 230- 0.45 3.90 -Br rN C30H30BrN3O3 +
IX.22 [NI+H] 235 (B) lux OMe o V11.26 534/536 178- 0.35 3.91 -Br -CH2-NMe2 C28H28BrN3O3 IX.4 [M+H]+ 180 (B) OMe o VII.26 562/564 173- 0.40 3.92 -Br -CH2-NEt2 C30H32BrN3O3 IX.1 [M+H]+ 176 (B) lux *Eluent mixtures:
(A): silica gel, methylene chloride/methanol/ammonia 9:1:0.1 (B): silica gel, methylene chloride/methanol 9:1 (C): silica gel, methylene chloride/methanol/ammonia 8:1:0.1 (D): silica gel, methylene chloride/methanol/ammonia 10:1:0.1 (E): silica gel, methylene chloride/methanol/ammonia 5:1:0.01 (F): silica gel, ethyl acetate/methanol/ammonia = 9:1:0,1 (G): alumina, methylene chloride/methanol = 19:1 (H): silica gel, methylene chloride/methanol/ammonia 9:1:0.01 (I): silica gel, methylene chloride/methanol 5:1 (K): alumina, methylene chloride/ethanol = 20:1 (L): silica gel, petroleum ether/ethyl acetate 1:1 (M): silica gel, petroleum ether/ethyl acetate 1:2 The following compounds of the formula I-3b are prepared analogously to Example 3.0:
R4' H
O
R2 N (I-3b) H
Ex- Starting Rf Empirical Mass m. p.
amp R2 R3 R4' materi- formula spectrum [ C] value le als OMe o V11.15 474 176- 0.40 3.93 -F -CH2-NMe2 C28H28FN303 IX.3 [M+H]+ 179 (A) VI1.19 486 0.45 EtO 6:0 3.94 -F -CH2-NMe2 C29H30FN303 n.d.
IX.3 [M-H]" (B) OMe o VII.20 490/492 163- 0.40 3.95 -Cl -CH2-NMe2 C28H28CIN303 IX.3 [M+H]+ 165 (A) lux *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-[1-(4-(Dimethylaminomethyl)anilino)-1-(3,4-dimethoxyphenyl)methylene]-6-10 cyano-2-indolinone 130 mg of 1-acetyl-3-(1-methoxy-1-(3,4-dimethoxyphenyl)methylene)-6-cyano-2-indolinone (starting material VII.4) and 58 mg of 4-(dimethylaminomethyl)aniline (starting material IX.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 15 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-Methyl-N-methylsulphonylamino)anilino)-1-(3-(2-methoxycarbonyl-vinyl)phen rI methylenel-6-chloro-2-indolinone 580 mg of 3-Z-[1-(4-(N-methyl-N-methylsulphonylamino)anilino)-1-(3-iodophenyl)-methylene]-6-chloro-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.
TM
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:
R4' H
O
R N (1-5) Start-Ex-ampi R 2 R3 R4' ing Empirical Mass m.p. Rr mate- formula spectrum [ C] value*
e rials I I I I
O OMe 486/488 150- 0.50 5.1 -Cl -CH2-NMe2 1.1 C28H26CIN303 / " [M-H]- 155 (A) NHZ
0 455 269- 0.20 5.2 -F -CH2-NMe2 3.0 C27H25FN402 I [M-H] 270 (B) OMe 5.3 -F la CH2-NMe2 3.0 C28H26FN303 470 205- 0.65 [M-H]' 208 (A) O OMe 472 138- 0.45 5.4 -F -CH2-NMe2 1.1 C28H26FN303 [M+H]+ 140 (A) *Eluent mixtures:
(A): silica gel, methylene chloride/methanol 5:1 (B): silica gel, methylene chloride/methanol/ammonia 9:1:0.01 Example 6.0 3-Z-[1-(4-Dimethylaminomethylanilino) 1-(3-(2-methoxycarbonylethyl)phenyl)methylenel-6-chloro-2-indolinone 1.0 g of 3-Z-[1-(4-(dimethylaminomethyl)anilino)-1-(3-(2-methoxycarbonyl-vinyl)phenyl)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 of 50 psi for 6 hours. After the reaction has ended, the catalyst is filtered 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 1-6 are prepared analogously to Example 6.0:
H
O
R2 N (1-6) Start-Ex-ing Empirical Mass m.p. Rf am- R2 R3 R4`
pie mate- formula spectrum [ C] value*
rials O OMe 6.1 -Cl -N(Me)- 5.0 C27H26C1N305S 538/540 148- 0.50 l S02Me [M-H]" 150 (A) NHZ
0 459 0.70 6.2 -F -CH2-NMe2 5.2 C27H27FN402 [M+H]+ 150 (B) OMe 0 474 0.35 6.3 -F -CH2-NMe2 5.3 C28H28FN303 [M+H]+ 140 (A) O OMe 474 140- 0.30 6.4 -F -CH2-NMe2 5.4 C28H28FN303 [M+H]+ 142 (A) *Eluent 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 -(4-Dimethylaminomethlaanilino)-1-(4-aminomethylphenyl)methylene]-6-chloro-2-indolinone 900 mg of 3-Z-[1-(4-dimethylaminomethylanilino)-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 methanol and diethyl ether. 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. 211-214 C
Mass spectrum: m/z = 433/435 [M+H]+
Example 8.0 3-Z-[1 -4-(N-((4-Methylpiperazin-1-yl)methylcarbonyl)-N-methylamino)anilino)-1-(4-aminomethylPhenyl)methvlenel-6-chloro-2-indolinone 1.39 g of 1-acetyl-3-Z-[1-(4-(N-((4-methylpiperazin-1-yl)methylcarbonyl)-N-5 methylamino)anilino)-1-(4-cyanophenyl)methylene]-6-chloro-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 10 residue is washed with a little methanol and diethyl ether. 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 purified on a silica gel column using, as mobile phase, a gradient of methylene chloride and methylene 15 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-(Dimethylaminomethvl)anilino)-I -(3-aminomethIy Shen l methvlenel-6-fluoro-2-indolinone 2.72 g of 3-Z-[1-(4-(dimethylaminomethyl)anilino)-1-(3-(N-tert-butoxycarbonyl-aminomethyl)phenyl)methylene]-6-fluoro-2-indolinone (starting material 3.10) are dissolved in 50 ml of methylene chloride, and 10 ml of trifluoroacetic acid are added.
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 1 N 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
Mass spectrum: m/z = 415 [M-H]-The following compounds of the formula 1-9 are prepared analogously to Example 9.0:
R4' H
O
R2 N (1-9) Start-Ex-ing Empirical Mass m.p. Rf am- R2 R3 R4`
ple mate- formula spectrum [ C] valu' rials NHZ
431 155- 0.45 9.1 -F -CH2-NMe2 3.16 C26H27FN40 [M+H]+ 160 (C) NHZ
417 203- 0.25 9.2 -F -CH2-NMe2 3.15 C25H25FN40 [M+H]+ 207 (A) NH2 r--'NMe 529 170- 0.15 9.3 -F H3CNr N`J 3.14 C30H33FN602 M+H + 175 (A) OH
O
446 245- 0.20 9.4 -F \ -CH2-NHMe 10.11 C26H24FN303 [M+H]+ 251 (D) 459 239- 0.30 9.5 -F -CH2-NHMe 11.22 C26H24FN303 +
[M+H] 243 (A) NH2 f--\NMe 529 9.6 -F H 3 c 'r N J 3.52 C30H33FN602 n.d. n.d.
" o [M+H]
+
OMe 444 158- 0.25 9.7 -F -CH2-NH2 3.69 C26H24FN303 [M-H]" 163 (A) EtO 4 60 205- 0.30 9.8 -F E$:T -CH2-NH2 3.85 C27H26FN303 [M+H]+ 210 (B) EtO 4 74 148- 0.30 -CH2-NHMe 3.86 C28H28FN303 [M+H]+ 150 (B) 9.9 -F 6:0 *Eluent 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-f1-(4-Dimethylaminomethylanilino)-1-(3-(2-carbo yethyl)phenyl)methylenel-6-chloro-2-indoli none 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 1 N aqueous sodium hydroxide solution are added. The mixture is stirred at room temperature for 5 hours. After cooling, 5 ml of I N 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+H]+
The following compounds of the formula 1-1 Oa are prepared analogously to Example 10.0:
H
O
R2 N (I-10a) H
Start-Ex- Rf ing Empirical Mass m.p.
am- R2 R3 R4' mate- formula spectrum ['Cl value*
pie rials OH
460 0.65 10.1 -F / \ -CH2-NMe2 6.3 C27H26FN303 [M+H]+ 250 (A) OH
O 444 278- 0.10 10.2 -F -CH2-NMe2 3.9 C26H24FN303 M-H - 282 (B) [ ] O OH
458 198- 0.20 10.3 -F r -CH2-NMe2 6.4 C27H26FN303 [M-H]' 200 (C) O OH
444 212- 0.30 10.4 -F -CH2-NMe2 3.7 C26H24FN303 [M-H]- 216 (D) 0 OH ~NMe 558 260- 0.20 10.5 -F H3CN 0 3.12 C311-13, FN504 [M+H]+ 263 (D) OH
10.6 -F -N(SO2Me)- 3.11 C28H29FN405S 553 246- 0.30 (CH2)2-NMe2 [M+H]+ 249 (D) OH
O -NMe-(CO)- 3.17 474 286- 0.60 10.7 -F CH3 C27H24FN304 []+ 290 (E) M+H
OH
O H3O ~NMe 570 215- 0.20 10.8 -F N o 3.18 C32H34FN504 [M-Hl- 222 O
D
OH
10.9 -F -N(SO2Me)- 3.19 C29H31FN405S 567 160- 0.20 1 ` (CH2)2-NMe2 [M+H]+ 165 (D) OH
10.10 -F -N(COMe)- 3.20 C31H33FN404 545 153- 0.15 ` (CH2)3-NMe2 [M+H]+ 158 (D) OH
o Me 546 215- 0.60 10.11 -F / ' o OtBu 3.21 C31H32FN305 [M+H]+ 219 (E) OH
O 0 rN-Me 529 179- 0.25 10.12 -F 3.22 C3oH29FN404 [M H 186 (E) OH
o N-3 483 264- 0.65 10.13 -F >'Me 3.23 C28H23FN403 M+H 267 (E) []+ OH
0 481 146- 0.70 10.14 -F / -SO2Me 3.24 C25H21FN205S [M+H]+ 155 E
O
OH
O 0 r'N-Me 515 0.70 10.15 -F N 3.27 C29H27FN404 251 OH
O H3G ~NMe 558 0.10 10.16 -F N 3.25 C31H32FN504 [M+H]+ 234 (E) OH
-N(Me)-(CO)- 503 0.60 10.17 -F 3.28 C28H27FN404 203 CH2-NMe2 [M+H]+ (E) OH
-N(Me)-(CO)- 545 10.18 -F 3.31 C31H33FN404 + 251 n.d.
(CH2)4-NMe2 [M+H]
OH
O 387 0.60 10.19 -F -H 3.42 C23H17FN203 [M-H]_ 130 (E) OH
467 0.55 10.20 -F -SO2Me 3.43 C24H19FN205S [M+H]+ 139 (E) OH
O N1 469 0.35 10.21 -F ~N 3.44 C27H21FN403 157 Me [M+H]+ (E) O OH _N(SO2Me)-567 0.55 10.22 -F (CH2)-(CO)- 3.45 C28H27FN406S [M+H]+ 183 (E) NMe2 OH
389 237- 0.10 10.23 -F -H 3.32 C23H17FN203 [M+H]+ 240 (D) NI 469 259- 0.15 10.24 -F N~ 3.33 C27H21FN403 Me [M+H]+ 265 (D) -N(COMe)- 3.41 C30H31FNaO4 531 274- 0.15 10.25 -F
(CH2)3-NMe2 [M+H]+ 278 (D) ~H -N(Me)-(CO)- 3.36 C28H27FN404 503 258- 0.20 10.26 -F
CH2-NMe2 [M+H]+ 264 (D) 515 279- 0.15 10.27 -F / O ~N Me 3.34 C29H27FN404 [M+H]+ 282 (D) O OH
467 260- 0.35 10.28 -F -SO2Me 3.39 C24H19FN205S
[M+H]+ 266 (F) -N(COMe)- 3.37 C26H22FN304 460 290- 0.30 10.29 -F OH
CH3 [M+H]+ 294 (F) OH -N(S02Me)-567 238- 0.30 10.30 -F CH2-(CO)- 3.35 C28H27FN406S
[M+H]+ 242 (F) NMe2 ~H -N(Me)-(CO)-3.38 C29H29FN404 517 250- 0.35 10.31 -F
(CH2)2-NMe2 [M+H]+ 255 (F) ~H -N(Me)-(CO)- 3.40 C30H31FN404 531 184- 0.25 10.32 -F
(CH2)3-NMe2 [M+H]+ 190 (F) O OH
NM
H C ~e 572 170- 0.40 10.33 -F 3 'N 3.48 C32H34FN504 '1, 0 [M-H]' 175 (C) OH
-N(SO2Me)- 553 0.60 10.34 -F 3.26 C28H29FN405S 180 (CH2)2-NMe2 [M+H] (C) O OH
10.35 -F -N(SO2Me)- 3.49 C29H31FN405S 567 196- 0.30 1 (CH2)2-NMe2 [M+H]+ 199 (C) O OH
c -N(Me)-(CO)- 517 0.20 10.36 -F 3.50 C29H29FN404 + 150 CH2-NMe2 [M+H] (C) O OH
10.37 -F -N(COMe)- 3.51 C31H33FN404 545 206- 0.30 (CH2)3-NMe2 [M+H]+ 210 (A) OH
10.38 -F 0 -N(Me)-(CO)- 3.59 C29H29FN404 517 231- 0.60 1 ` CH2-NMe2 [M+H]+ 236 (A) OH
474 218- 0.50 10.39 -F -(CH2)2-NMe2 3.57 C28H28FN303 [M+H]+ 222 (A) OH
10.40 -F 0-N(Me)-(CO)- 3.58 C30H31FN404 531 215- 0.50 ` (CH2)2-NMe2 [M+H]+ 218 (A) O OH
474 172- 0.15 10.41 -F -(CH2)2-NMe2 3.60 C28H28FN303 [M+H]+ 177 (G) OH
10.42 -F 0 -N(COMe)- 3.61 C30H31 FN404 531 230- 0.50 ` (CH2)2-NMe2 [M+H]+ 234 (A) -N(Me)-(CO)- 3.62 C 545 170- 0.30 10.43 -F (CH2)3-NMe2 31 H33FNa0a [M+H]+ 175 (E) 10.44 -F -N(Me)-(CO)- 3.63 C32H35FN404 559 142- 0.10 (CH2)4-NMe2 [M+H]+ 146 (G) N 483 262- 0.20 10.45 -F xkN 3.64 C28H23FN403 Me [M+H]+ 269 (E) OH
10.46 -F 0 -N(Me)-(CO)- 3.65 C32H35FN404 559 234- 0.30 lux (CH2)4-NMe2 [M+H]+ 236 (A) OH
0 403 231- 0.20 10.47 -F / -H 3.66 C24H19FN203 M+H 233 (A) OH
0 486 205- 0.10 10.48 -F NO 3.67 C29H28FN303 M+H 210 (E) [ ]+ OH
0 488 145- 0.15 10.49 -F -CH2-NEt2 3.68 C29H30FN303 M+H 150 E
OH
0 430 280- 0.05 10.50 -F -CH2-NH2 9.7 C25H22FN303 / [M-H] 285 (H) OH
O 460 273- 0.15 10.51 -F / -(CH2)2-NMe2 3.70 C27H26FN303 [M+H]+ 276 (E) O OH
460 230- 0.05 10.52 -F -(CH2)2-NMe2 3.71 C27H26FN303 [M+H]+ 235 (E) OH
0 490/492 255- 0.50 10.53 -Cl / -(CH2)2-NMe2 3.73 C28H28CIN303 [M H 258 A
+ ]+ ( ) OH
e N-3 499/501 296- 0.50 10.54 -Cl / Me 3.74 C28H23CIN403 M H 300 (A) ` [ +]+ OH
O 476/478 228- 0.50 10.55 -Cl / -CH2-NMe2 3.75 C27H26CIN303 [M H 230 A
+ ]+ ( ) lx, O OH
r--",N-Me 515 210- 0.40 10.56 -F N,--j 3.77 C30H31 FN403 / [M+H]+ 215 (A) O OH
N 483 240- 0.50 10.57 -F ~NJ 3.78 C28H23FN403 / [M+H]+ 245 (A) O OH
c -CH2-NMe- 517 0.30 10.58 -F 3.82 C30H33FN403 n.d.
I (CH2)2-NMe2 [M+H]+ (I) OH
r--,N-Me 515 0.35 NJ 3.79 C30H31FN4O3 275 10.59 -F r lox OH
N 483 0.55 10.60 -F r N.~ 3.80 C28H23FN403 280 OH
502/504 260- 0.50 10.61 -Cl NO 3.83 C29H28CIN303 M+H 266 (A) [ ]+ OH
-CH2-NMe- 517 0.05 10.62 -F 3.81 C30H33FNa03 n.d.
(CH2)2-NMe2 [M+H]+ (E) 03 110- 0.60 -H 3.84 C24H19FN203 M+H 112 (K) 10.63 -F aIrO
[ l+ HO 4 32 260- 0.60 -CH2-NH2 9.8 C25H22FN303 M+H 263 (A) 10.64 -F 6:rO
[ l+ HO c5:rO 446 265- 0.60 10.65 -F -CH2-NHMe 9.9 C26H24FN303 M+H 270 (A) [ l+
HO O
462 0.10 250 (M) 10.66 -F -CH2-NMe2 3.87 C26H24FN304 [M+H]+ (M) 462 0.15 10.67 -F O -CH2-NMe2 3.88 C26H24FN304 247 OH
546/548 290- 0.30 10.68 -Br / N0 3.90 C29H28BrN3O3 M+H 293 (E) [ ]+ OH
520/522 243- 0.25 10.69 -Br / -CH2-NMe2 3.91 C27H26BrN3O3 M+H 246 (E) [ ]+ OH
548/550 252- 0.35 10.70 -Br / -CH2-NEt2 3.92 C29H30BrN3O3 [M+H]+ 255 (E) *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 I-1 Ob are prepared analogously to Example 10.0:
H
O
R2 H (I-1Ob) Start-Ex-am- R 2 R3 R 4` ing Empirical Mass m.p. Rt-pie mate- formula spectrum [ C] value*
rials OH
0 460 0.20 10.71 -F / -CH2-NMe2 3.93 C27H26FN303 [M+H]+ 150 (A) O OH
460 105- 0.30 10.72 -F -CH2-NMe2 3.94 C27H26FN303 [M+H]+ 109 (B) OH
0 476/478 230- 0.50 10.73 -CI / -CH2-NMe2 3.95 C27H26CIN303 M+H 235 (C) [ ]+ *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-[1-(4-Dimethylaminomethylanilino)-1-(3-(2-carbamovlethyl phenyl)methylene]-chloro-2-indolinone 480 mg of 3-Z-[1-(4-dimethylaminomethylanilino)-1-(3-(2-carboxyethyl)phenyl)methylene]-6-chloro-2-indolinone (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 methylene 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+H]+
The following compounds of the formula I-11 are prepared analogously to Example 11.0:
H
O
R2 H (I-11) Start-Ex-ing Empirical Mass m.p. Rf am- R2 R3 R4' pie mate- formula spectrum [ C] value*
rials o NHCH3 10.0 489/491 223- 0.50 11.1 -Cl -CH2-NMe2 C28H29CIN4O2 / ** [M+H]+ 225 (A) 0 10.1 473 148- 0.40 11.2 -F -CH2-NMe2 C28H29FN402 M+H 150 (B) NMe2 0 10.2 473 98- 0.30 11.3 -F -CH2-NMe2 C28H29FN402 / _ *** [M+H]+ 103 (C) o NH2 459 223- 0.50 11.4 -F -CH2-NMe2 10.3 C27H27FN402 / \ [M+H]+ 225 (A) 0 NHMe 10.3 473 210- 0.70 11.5 -F -CH2-NMe2 C28H29FN402 [M+H]+ 213 (A) ** O NMez 10.3 487 213- 0.80 11.6 -F / -CH2-NMe2 *** C29H31FN402 [M+H]+ 215 (A) 0 443 115- 0.25 11.7 -F -CH2-NMe2 10.2 C26H25FN402 [M-Hl- 120 (C) NHMe 0 10.2 457 222- 0.25 11.8 -F -CH2-NMe2 ** C27H27FN402 [M-H]' 225 (C) 0 NHz 443 143- 0.40 11.9 -F / -CH2-NMe2 10.4 C26H25FN402 [M-H]' 146 (D) NMe2 0 10.1 487 198- 0.60 11.10 -F / -CH2-NMe2 *** C29H31FN402 M+H + 200 (B) [ l Me N 10.1 542 0.60 11.11 -F 0 -CH2-NMe2 C32H36FN502 175 **** [M+H]+ (B) N
Me 557 150- 0.40 11.12 -F H3C'N 10.5 C31H33FN603 0 [M+H]+ 156 (E) 11.13 -F -N(SO2Me)- 10.6 C28H30FN5O4S 552 197- 0.50 (CH2)2-NMe2 [M+H]+ 199 (D) 11.14 -F NMe2 -CH2-NMe2 10.4 C28H29FN402 473 147- 0.35 *** [M+H]+ 152 (D) 0 NHMe 10.4 459 208- 0.35 11.15 -F -CH2-NMe2 C27H27FN402 ** [M+H]+ 214 (D) 0 NHMe 11.16 -F -N(S02Me)- 10.6 C29H32FN504S 566 218- 0.70 (CH2)2-NMe2 ** [M+H]+ 222 (F) 1 1 . 1 7 -F 0 ,e2 -N(S02Me)- 10.6 C30H34FN5O4S 580 199- 0.40 (CH2)2-NMe2 *** [M+H]+ 205 (C) 0 NHMe H3C ~NMe 10.5 571 155- 0.20 11.18 -F TN C32H35FN603 0 ** [M+H]+ 160 (C) -N(Me)-(CO)- 10.7 C28H27FN403 487 137- 0.50 11.19 -F
CH3 ** [M+H]+ 145 (C) 0 ~NMe 10.8 585 211- 0.40 11.20 -F H3 0 ** C33H37FN603 M+H + 219 [ ] (C) NHCH3 0 11.21 -F -N(S02Me)- 10.9 C30H34FN5O4S 578 192- 0.50 / (CH2)2-NMe2 ** [M-H]" 200 (C) o Me 10.11 559 180- 0.50 N
11.22 -F / r o oteu C32H35FN404 M+H 187 (C) o N-3 10.13 496 262- 0.40 11.23 -F / >'NN e C29H26FN502 M+H 266 (C) ** [ ]+ NHCH3 0 10.14 494 180- 0.60 11.24 -F / -SO2Me C26H24FN304S M+H 188 (C) 0 0 ''N-Me 10.12 542 226- 0.50 11.25 -F N,--j C31H32FN503 M+H 230 (C) NHMe o H JMe 10.16 571 0.10 11.26 -F 3clv o ** C32H35FN603 213 [M+H] (G) NHMe 0 0 r'N-Me 10.15 528 0.40 11.27 -F N,J C30H30FN5O3 245 *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 dimethylammonium chloride as base equivalent **** using piperidine hydrochloride as base equivalent Example 12.0 3-Z-[1- 4-Dimethylaminomethylanilino)-1-(4-acetylaminomethylphenyl)methylenel-chloro-2-indoli none 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 pi 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 pI 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, methylene chloride/methanol/ammonia = 9:1:0.01) m.p. 219-220 C
Mass spectrum: m/z = 473/475 [M-H]-The following compounds of the formula 1-12 are prepared analogously to Example 12.0:
H
R2 N (1-12) Start-Ex-ing Empirical Mass m.p. Rf-am- R2 R3 Ra, mate- formula spectrum [ C] value*
pie rials HN'~~3 H3JNCH3 585/587 252- 0.25 12.1 -Cl J 8.0 C32H35CIN6O3 M-H " 255 (B) r~
535/537 238 0.45 12.2 -CI HN 0 -CH2-NMe2 7.0 C32H29CIN4O2 (de_ comp.) 2 ~NJ CH3 647/649 282- 0.40 12.3 -CI HN H3v o 8.0 C37H37CIN6O3 [M-H]" 284 (B) 0.1-CH3 HN 457 245- 0.40 12.4 -F -CH2-NMe2 9.0 C27H27FN402 [M-H]" 250 (C) 0~- Et HN 471 212- 0.35 12.5 -F -CH2-NMe2 9.0 C28H29FN402 [M-H]" 214 (D) o /
HN 519 237- 0.40 12.6 -F -CH2-NMe2 9.0 C32H29FN402 [M-H] 240 (D) 0 533 187- 0.30 12.7 -F HN -CH2-NMe2 9.0 C33H31FN402 [M-H]" 190 (D) NH
471 234- 0.30 12.8 -F -CH2-NMe2 9.1 C28H29FN402 / \ [M-H]" 237 (D) 0 533 144- 0.45 12.9 -F NH -CH2-NMe2 9.1 C33H31FN402 [M-H]" 150 (C) Et o NH
485 235- 0.25 12.10 -F -CH2-NMe2 9.1 C29H31FN402 / \ [M-H]" 237 (D) NH
547 217- 0.30 12.11 -F -CH2-NMe2 9.1 C34H33FN402 [M-H]" 220 (D) HN40 457 112- 0.25 12.12 -F -CH2-NMe2 9.2 C27H27FN402 M-H " 120 (D) Et HN4 0 586 176- 0.30 12.13 -F -CH2-NMe2 9.2 C28H29FN4O2 [M+H]+ 180 (D) 535 80- 0.35 12.14 -F HN 0 -CH2-NMe2 9.2 C33H31 FN4O2 4 H3 rNCH3 HN 0 H 1-NJ 569 230- 0.35 12.15 -F 3c1v 0 9.3 C32H35FN603 [M-H]" 235 O
D
Et HN 40 H3~NCH3 583 205- 0.30 12.16 -F ev o 9.3 C33H37FN603 M-H " 210 (D) [ J ~NCH3 645 217- 0.35 12.17 -F HN 0 H3v 0 9.3 C38H39FN603 [M-H]" 220 (D) H N`J CH3 597 209- 0.30 0o 12.18 -F 3-j= 9.6 C34H37FN603 M+H 212 (D) a H ~CH611 190- 0.30 12.19 F 3 9.6 C35H39FN603 M+H 193 (D) o NCH, 12.20 -F 9.6 C36H36FN703 [M+H]+ 163 (D) 0 ~-o J
HN H3 CH3 639 223- 0.30 12.21 -Fv 9.6 C37H43FN603 [M+H]+ 227 (D) N
o \NCH3 HN H -N 634 170- 0.25 12.22 -F 3 v C36H36FN703 o 9.6 [M+H]+ 175 (D) 0,7 CH3 HN CH3 H3 CH3 599 194- 0.20 12.23 -F \ 9.6 C34H39FN603 M+H + 196 (D) H3CH3 ow HN H~NCH3 613 197- 0.70 12.24 -F 3 v o 9.6 C35H41 FN6O3 [M+H]+ 200 (E) _N.J CH3 653 130- 0.75 12.25 -F HN H3 0 9.6 C38H45FN603 [M+H]+ 135 (E) O OMe H N H3 J CH3 601 155- 0.60 12.26 -F v 9.6 C33H37FN604 M+H + 159 (E) [ ] MeO
o / ~NCH3 663 168- 0.35 12.27 -F H3clv 9.6 C38H39FN604 [M+H]+ 172 (C) C(CH3)3 1~ r--"NCH 627 85- 0.35 12.28 -F HN H3C1v-~ 9.6 C36H43FN603 [M+H]+ 90 (C) s HN H ~NCH3 639 170- 0.25 12.29 -F 3 9.6 C35H35FN603S M+H + 175 (C) (CH3)3C`7~--HN rN J CH3 613 242- 0.30 12.30 -F H3"'N 9.6 C35H41 FN603 [M+H]+ 245 (C) HN H ( ~NCH3 623 155- 0.65 12.31 -F 30'N- 9.6 C35H35FN604 [M+H]+ 160 O
F
HN H ~NCH3 571 190- 0.60 12.32 -F 3C 9.6 C32H35FN603 [M+H]+ 195 (F) Et HN H JNCH3 585 203- 0.65 12.33 -F 3 9.6 C33H37FN603 o [M+H]+ 209 (E) HN O H3 J CH3 633 145- 0.60 12.34 -Fvo 9.6 C37H37FN603 [M+H]+ 150 (F) o H3 CNCH3 647 148- 0.65 12.35 -F HNe1v o 9.6 C38H39FN603 [M+H]+ 151 (F) o~
HN 485 216- 0.35 12.36 -F -CH2-NMe2 9.0 C29H29FN402 M+H 220 (D) HN 499 214- 0.35 12.37 -F -CH2-NMe2 9.0 C3oH31FN402 M+H 217 (D) HN 522 205- 0.35 12.38 -F -CH2-NMe2 9.0 C31H28FN502 [M+H]+ 210 (D) 0 ~-o HN 527 235- 0.35 12.39 -F -CH2-NMe2 9.0 C32H35FN402 [M+H]+ 237 (D) o HN 520 135- 0.20 12.40 -F -CH2-NMe2 9.0 C31H28FN502 [M-H]" 140 (D) H N H3 487 210- 0.20 12.41 -F -CH2-NMe2 9.0 C29H31FN402 D
[M+H] 215 O
O
HN 501 202- 0.25 12.42 -F -CH2-NMe2 9.0 C30H33FN402 [M+H]+ 206 (D) 541 198- 0.35 12.43 -F HN -CH2-NMe2 9.0 C33H37FN402 [M+H]+ 203 (D) O OMe H N 489 173- 0.35 12.44 -F -CH2-NMe2 9.0 C28H29FN403 [M+H]+ 177 (D) MeO
12.45 -F HN -CH2-NMe2 9.0 C33H31FN403 549 202- 0.50 [M-H]" 207 (C) O
12.46 -F HN -CH2-NMe2 9.0 C31H35FN402 513 203- 0.45 [M-H]" 209 (C) o s HN 527 245- 0.35 12.47 -F -CH2-NMe2 9.0 C30H27FN402S M+H 250 (C) [ ] (CH3>3Cro HN
501 248- 0.45 12.48 -F -CH2-NMe2 9.0 C30H33FN402 [M+H]+ 252 (C) o 1 HN 511 216- 0.30 12.49 -F -CH2-NMe2 9.0 C3oH27FN403 M+H 219 (C) [ l+ O CN
HN 522 167- 0.20 12.50 -F -CH2-NMe2 9.0 C31H28FN502 [M+H] 170 (D) *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, pyridin-2-ylcarbonyl chloride, pyridin-ylcarbonyl chloride, pyridin-4-ylcarbonyl chloride, cyclohexylcarbonyl chloride, isobutyryl chloride, 3-methylbutyryl chloride, cyclohexylmethylcarbonyl chloride, methoxyacetyl chloride, 2-methoxybenzoyl chloride, tert-butylacetyl chloride, thiophene-2-carbonyl chloride, pivaloyl chloride, 2-furoyl chloride Example 13.0 3-Z-[1-(4-Trimethylammoniummethylanilino)-1-(4-(2-carboxyethyl)phenyl)methylenel-6-fluoro-2-indoli none 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:
R4' H
O
H (1-13) R
Start-Ex-ing Empirical Mass m.p. Rf am- R2 R3 R4' mate- formula spectrum [ C] value*
ple rials O OH
Me 474 0.50 13.1 -F N= Me 10.3 C28H29FN3031 150 / "Me [M+H]+ (A) *Eluent mixture:
(A): reversed phase RP8, methanol/sodium chloride solution (5%) = 4:1 Example 14.0 3-Z-[1-(4-Guanidinomethylanilino)-1-(4-(2-carboxyethyl)phenyl)methylenel-6-fluoro-2-indolinone iodide 170 mg of 3-Z-[1-(4-aminomethylanilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-fluoro-2-indoli none (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:
R4.
H
O
R H (1-14) Start-Ex-ing Empirical Mass m.p. Rf am- R2 R3 R4`
pie mate- formula spectrum [ C] value*
rials O OH
H
14.1 -F {HN NH2 10.64 C26H24FN503 M+H + 305 0.70 [ ] (A) *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 100,0 mg 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) Polyvinylpyrrolidone 15.0 mg (5) Magnesium stearate 2.0 ma 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 136.0 mg (3) Maize starch 80.0 mg (4) Polyvinylpyrrolidone 30.0 mg (5) Magnesium stearate 4,0 ma 600.0 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: 12 mm.
Example 19 Capsules with 50 mg of active compound Composition:
(1) Active compound 50.0 mg (2) Maize starch, dried 58.0 mg (3) Lactose, powdered 50.0 mg (4) Magnesium stearate 2.0 ma 160.0 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 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 compound 100.0 mg 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)phenyl)methylene]-6-chloro-2-indolinone (2) 3-Z-[1-(4-(N-(dimethylaminomethylcarbonyl)-N-methylamino)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-chloro-2-indolinone (3) 3-Z-[1 -(4-(N-(2-dimethylaminoethyl)-N-acetylamino)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-chloro-2-indolinone (4) 3-Z-[1-(4-(N-(2-methylaminoethyl)-N-acetylamino)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-chloro-2-indolinone (5) 3-Z-[1-(4-(N-(3-dimethylaminopropyl)-N-acetylamino)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-chloro-2-indolinone (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-carboxyethyl)phenyl)methylene]-6-chloro-2-indolinone (8) 3-Z-[1-(4-ethylaminomethylanilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-chloro-2-indolinone (9) 3-Z-[1-(4-methylaminomethylanilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-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-dimethylaminopropyl)-N-methylsulphonylamino)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-chloro-2-indolinone (13) 3-Z-[1-(4-(N-(2-dimethylaminoethyl)-N-propylsulphonylamino)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-chloro-2-indolinone (14) 3-Z-[1-(4-aminomethylanilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-chloro-2-indolinone (15) 3-Z-[1-(3-(methylaminomethyl)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-chloro-2-indolinone (16) 3-Z-[1-(3-(2-dimethylaminoethyl)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-chloro-2-indolinone (18) 3-Z-[1-(4-(N-(dimethylamino-carbonylmethyl)-N-methylsulphonylamino)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-chloro-2-indolinone (19) 3-Z-[1-(4-(N-methyl-N-methylsulphonylamino)anilino)-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-chloro-2-indolinone (21) 3-Z-[1-(4-(N-(N-(2-dimethylaminoethyl)-N-methylaminomethylcarbonyl)-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)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-chloro-2-indolinone (24) 3-Z-[1-(4-(N-(2-dimethylaminoethyl)-N-methylaminomethyl)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-chloro-2-indolinone (25) 3-Z-[1-(4-(2-dimethylaminoethoxy)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-chloro-2-indolinone (26) 3-Z-[1-(4-(N-(4-dimethylaminobutylcarbonyl)-N-methylamino)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-chloro-2-indolinone (27) 3-Z-[1-(4-(N-(3-dimethylaminopropylcarbonyl)-N-methylamino)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-chloro-2-indolinone (28) 3-Z-[1-(4-(methylethylaminomethyl)anilino)-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-indolinone (30) 3-Z-[1-(4-(methylbenzylaminomethyl)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-chloro-2-indolinone (31) 3-Z-[1-(4-(N-(2-dimethylaminoethyl)-N-methylaminomethyl)anilino)-1-(4-(2-carboxyethyl)phenylmethylene]-6-chloro-2-indolinone (32) 3-Z-[1-(4-(azetidin-l-ylmethyl)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-chloro-2-indolinone (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-ylmethyl)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-(thiomorpholin-4-ylmethyl)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-chloro-2-indolinone (37) 3-Z-[1-(4-(imidazol-1-ylmethyl)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-chloro-2-indolinone (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-carboxyethyl)phenyl)methylene]-6-chloro-2-indolinone (40) 3-Z-[1-(4-(N-(2-dimethylaminoethyl)-N-acetylamino)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene]-6-chloro-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-carboxyethyl)phenyl)methylene]-6-chloro-2-indolinone (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-dimethylaminopropyl)anilino)-1-(3-(2-carboxyethyl)phenyl) methylene]-6-chloro-2-indolinone (45) 3-Z-[1-(4-ethylaminomethylanilino)-1-(3-(2-carboxyethyl)phenyl)methylene]-chloro-2-indolinone (46) 3-Z-[1-(4-methylaminomethylanilino)-1-(3-(2-carboxyethyl)phenyl)methylene]-6-chloro-2-indolinone (47) 3-Z-[1-(4-(N-(4-methylpiperazin-1-ylmethylcarbonyl)-N-methylamino)anilino)-1-(3-(2-ca rboxyethyl)phenyl)methylene]-6-chloro-2-indolinone (48) 3-Z-[1-(4-(4-methylpiperazin-1-ylcarbonyl)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene]-6-chloro-2-indolinone (49) 3-Z-[1-(4-(N-(3-dimethylaminopropyl)-N-methylsulphonylamino)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene]-6-chloro-2-indolinone (50) 3-Z-[1-(4-(N-(2-dimethylaminoethyl)-N-propylsulphonylamino)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene]-6-chloro-2-indolinone (51) 3-Z-[1-(4-aminomethylanilino)-1-(3-(2-carboxyethyl)phenyl)methylene]-6-chloro-2-indolinone (52) 3-Z-[1-(3-(dimethylaminomethyl)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene]-6-chloro-2-indolinone (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-indolinone (57) 3-Z-[1-(4-(N-(dimethylaminocarbonylmethyl)-N-methylsulphonylamino)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-diethylaminoethylsulphonyl)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene]-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-dimethylaminoethyl)-N-methylaminomethyl)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene]-6-chloro-2-indolinone (65) 3-Z-[1-(4-(2-dimethylaminoethoxy)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene]-6-chloro-2-indolinone (66) 3-Z-[1-(4-(N-(4-dimethylaminobutylcarbonyl)-N-methylamino)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene]-6-chloro-2-indolinone (67) 3-Z-[1-(4-(N-(3-dimethylaminopropylcarbonyl)-N-methylamino)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene]-6-chloro-2-indolinone (68) 3-Z-[1-(4-(methylethylaminomethyl)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene]-6-chloro-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-carboxyethyl)phenyl)methylene]-6-chloro-2-indolinone (77) 3-Z-[1-(4-(morpholin-4-ylmethyl)anilino)-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-indolinone (79) 3-Z-[1 -(4-(imidazol-1-ylmethyl)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene]-6-chloro-2-indolinone (80) 3-Z-[1-(4-(N-(2-methylaminoethyl)-N-acetylamino)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone (81) 3-Z-[1-(4-(N-(3-methylaminopropyl)-N-acetylamino)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone (82) 3-Z-[1-(4-(3-dimethylaminopropyl)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone (83) 3-Z-[1-(4-ethylaminomethylanilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-fl uoro-2-indolinone (84) 3-Z-[1-(4-(N-(3-dimethylaminopropyl)-N-methylsulphonylamino)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone (85) 3-Z-[1-(4-(N-(2-dimethylaminoethyl)-N-propylsulphonylamino)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone (86) 3-Z-[1-(3-(methylaminomethyl)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone (87) 3-Z-[1-(3-(2-dimethylaminoethyl)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone (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-methylsulphonylamino)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone (90) 3-Z-[l-(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-diethylaminoethylsulphonyl)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-dimethylaminopropylcarbonyl)-N-methylamino)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone (95) 3-Z-[1-(4-(methylethylaminomethyl)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone (96) 3-Z-[1-(4-(methylpropylaminomethyl)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone (97) 3-Z-[1-(4-(methylbenzylaminomethyl)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone (98) 3-Z-[1-(4-(azetidin-1-ylmethyl)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-fluoro-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-ylmethyl)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone (101) 3-Z-[1-(4-(thiomorpholin-4-ylmethyl)anilino)-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-fluoro-2-indolinone (103) 3-Z-[1-(4-(N-(2-methylaminoethyl)-N-acetylamino)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone (104) 3-Z-[1-(4-(N-(3-methylaminopropyl)-N-acetylamino)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone (105) 3-Z-[1-(4-(3-dimethylaminopropyl)anilino)-1-(3-(2-carboxyethyl)phenyl) methylene]-6-fluoro-2-indolinone (106) 3-Z-[1-(4-ethylaminomethylanilino)-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-fluoro-2-indolinone (110) 3-Z-[1-(3-(methylaminomethyl)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone (111) 3-Z-[1-(3-(2-dimethylaminoethyl)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone (112) 3-Z-[1-(3-(3-dimethylaminopropyl)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone (113) 3-Z-[1-(4-(N-(dimethylaminocarbonylmethyl)-N-methylsulphonylamino)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone (114) 3-Z-[1-(4-(N-methyl-N-methylsulphonylamino)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone (115) 3-Z-[1-(4-(N-methyl-N-acetylamino)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone (116) 3-Z-[1-(4-(N-(N-(2-dimethylaminoethyl)-N-methylaminomethylcarbonyl)-N-methylamino)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone (117) 3-Z-[1-(4-(2-diethylaminoethylsulphonyl)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone (118) 3-Z-[1-(4-(N-(2-dimethylaminoethylcarbonyl)-N-methylamino)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone (119) 3-Z-[1-(4-(N-(2-dimethylaminoethyl)-N-methylaminomethyl)anilino)-1-(3-(2-carboxyethyl)phenyl) methylene]-6-fluoro-2-indolinone (120) 3-Z-[1-(4-(2-dimethylaminoethoxy)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone (121) 3-Z-[1-(4-(methylethylaminomethyl)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone (122) 3-Z-[1-(4-(methylpropylaminomethyl)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone (123) 3-Z-[1-(4-(methylbenzylaminomethyl)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone (124) 3-Z-[1-(4-(diethylaminomethyl)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone (125) 3-Z-[1-(4-(pyrrolidin-1-ylmethyl)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone (126) 3-Z-[1-(4-(azetidin-1-ylmethyl)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone (127) 3-Z-[1-(4-(piperazin-1-ylmethyl)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone (128) 3-Z-[1-(4-(morpholin-4-ylmethyl)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene]-6-fIuoro-2-indolinone (129) 3-Z-[1-(4-(thiomorpholin-4-ylmethyl)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene]-6-fIuoro-2-indolinone (130) 3-Z-[1-(4-(N-(2-dimethylaminoethyl)-N-methylsulphonylamino)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-bromo-2-indolinone (131) 3-Z-[1-(4-(N-(dimethylaminomethylcarbonyl)-N-methylamino)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-bromo-2-indolinone (132) 3-Z-[1-(4-(N-(2-dimethylaminoethyl)-N-acetylamino)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-bromo-2-indolinone (133) 3-Z-[1-(4-(N-(2-methylaminoethyl)-N-acetylamino)anilino)-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)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-bromo-2-indolinone (137) 3-Z-[1-(4-ethylaminomethylanilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-bromo-2-indolinone (138) 3-Z-[1-(4-methylaminomethylanilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-bromo-2-indolinone (139) 3-Z-[1-(4-(N-(4-methylpiperazin-1-ylmethylcarbonyl)-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-carboxyethyl)phenyl)methylene]-6-bromo-2-indolinone (142) 3-Z-[1-(4-(N-(2-dimethylaminoethyl)-N-propylsulphonylamino)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-bromo-2-indolinone (143) 3-Z-[1-(4-aminomethylanilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-bromo-2-indolinone (144) 3-Z-[1-(3-(dimethylaminomethyl)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-bromo-2-indolinone (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-dimethylaminopropyl)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-bromo-2-indolinone (148) 3-Z-[1-(4-(2-dimethylaminoethyl)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-bromo-2-indolinone (149) 3-Z-[1-(4-(N-(dimethylaminocarbonylmethyl)-N-methylsulphonylamino)anilino)-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)phenyl)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-dimethylaminoethyl)-N-methylaminomethylcarbonyl)-N-methylamino)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-bromo-2-indolinone (154) 3-Z-[1-(4-(2-diethylaminoethylsulphonyl)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-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-indolinone (157) 3-Z-[1-(4-(2-dimethylaminoethoxy)anilino)-1-(4-(2-carboxyethyl)phenyl) methylene]-6-bromo-2-indolinone (158) 3-Z-[1-(4-(N-(4-dimethylaminobutylcarbonyl)-N-methylamino)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-bromo-2-indolinone (159) 3-Z-[1-(4-(N-(3-dimethylaminopropylcarbonyl)-N-methylamino)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-bromo-2-indolinone (160) 3-Z-[1-(4-(methylethylaminomethyl)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-bromo-2-indolinone (161) 3-Z-[1-(4-(methylpropylaminomethyl)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-bromo-2-indolinone (162) 3-Z-[1-(4-(methylbenzylaminomethyl)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-bromo-2-indolinone (163) 3-Z-[1-(4-(diethylaminomethyl)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-bromo-2-indolinone (164) 3-Z-[1-(4-(N-(2-dimethylaminoethyl)-N-methylaminomethyl)anilino)-1-(4-(2-carboxyethyl)-phenylmethylene]-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-l-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-indolinone (169) 3-Z-[1-(4-(morpholin-4-ylmethyl)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-bromo-2-indolinone (170) 3-Z-[1-(4-(thiomorpholin-4-ylmethyl)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-bromo-2-indolinone (171) 3-Z-[1-(4-(imidazol-l-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-indolinone (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-(dimethylaminomethylcarbonyl)-N-methylamino)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene]-6-bromo-2-indolinone (175) 3-Z-[1-(4-(N-(2-dimethylaminoethyl)-N-acetylamino)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene]-6-bromo-2-indolinone (176) 3-Z-[1-(4-(N-(2-methylaminoethyl)-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-indolinone (178) 3-Z-[1-(4-(N-(3-methylaminopropyl)-N-acetylamino)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene]-6-bromo-2-indolinone (179) 3-Z-[1-(4-(3-dimethylaminopropyl)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-methylpiperazin-1-ylmethylcarbonyl)-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)phenyl)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)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene]-6-bromo-2-indolinone (189) 3-Z-[1-(3-(2-dimethylaminoethyl)anilino)-1-(3-(2-carboxyethyl)phenyl) methylene]-6-bromo-2-indolinone (190) 3-Z-[1-(3-(3-dimethylaminopropyl)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene]-6-bromo-2-indolinone (191) 3-Z-[1-(4-(2-dimethylaminoethyl)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene]-6-bromo-2-indolinone (192) 3-Z-[1-(4-(N-(dimethylaminocarbonylmethyl)-N-methylsulphonylamino)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene]-6-bromo-2-indolinone (193) 3-Z-[1-(4-(N-methyl-N-methylsulphonylamino)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene]-6-bromo-2-indolinone (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-methylimidazol-2-yl)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene]-6-bromo-2-indolinone (196) 3-Z-[1-(4-(N-(N-(2-dimethylaminoethyl)-N-methylaminomethylcarbonyl)-N-methylamino)anilino)-1-(3-(2-carboxyethyl)phenyl)methyl ene]-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-dimethylaminoethylcarbonyl)-N-methylamino)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene]-6-bromo-2-indolinone (199) 3-Z-[1-(4-(N-(2-dimethylaminoethyl)-N-methylaminomethyl)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene]-6-bromo-2-indolinone (200) 3-Z-[1-(4-(2-dimethylaminoethoxy)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene]-6-bromo-2-indolinone (201) 3-Z-[1-(4-(N-(4-dimethylaminobutylcarbonyl)-N-methylamino)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene]-6-bromo-2-indolinone (202) 3-Z-[1-(4-(N-(3-dimethylaminopropylcarbonyl)-N-methylamino)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene]-6-bromo-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-indolinone (205) 3-Z-[1-(4-(methylbenzylaminomethyl)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene]-6-bromo-2-indolinone (206) 3-Z-[1-(4-(diethylaminomethyl)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene]-6-bromo-2-indolinone (207) 3-Z-[1-(4-(N-(2-dimethylaminoethyl)-N-methylaminomethyl)anilino)-1-(3-(2-carboxyethyl)phenylmethylene]-6-bromo-2-indolinone (208) 3-Z-[1-(4-(pyrrolidin-1-ylmethyl)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene]-6-bromo-2-indolinone (209) 3-Z-[1-(4-(azetidin-1-ylmethyl)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene]-6-bromo-2-indolinone (210) 3-Z-[1-(4-((4-methylpiperazin-1-yl)methyl)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene]-6-bromo-2-indolinone (211) 3-Z-[1-(4-(piperazin-1-ylmethyl)anilino)-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)methylene]-6-bromo-2-indolinone (215) 3-Z-[1-(4-dimethylaminomethylanilino)-1-(4-carboxymethylaminophenyl)-methylene]-6-fluoro-2-indolinone (216) 3-Z-[1-(4-dimethylaminomethylanilino)-1-(3-carboxymethylamino-phenyl)-methylene]-6-fluoro-2-indolinone (217) 3-Z-[1-(4-dimethylaminomethylanilino)-1-(4-(N-methyl-carboxymethylamino)phenyl)methylene]-6-fluoro-2-indolinone (218) 3-Z-[1-(4-dimethylaminomethylanilino)-1-(3-(N-methyl-carboxymethylamino)phenyl)methylene]-6-fluoro-2-indolinone (219) 3-Z-[1-(4-dimethylaminomethylanilino)-1-(4-carboxymethoxyphenyl)-methylene]-6-chloro-2-indolinone (220) 3-Z-[1-(4-dimethylaminomethylanilino)-1-(3-carboxymethoxyphenyl)-methylene]-6-chloro-2-indolinone (221) 3-Z-[1-(4-dimethylaminomethylanilino)-1-(4-carboxymethylaminophenyl)-methylene]-6-chloro-2-indolinone (222) 3-Z-[1-(4-dimethylaminomethylanilino)-1-(3-carboxymethylaminophenyl)-methylene]-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-methyl-carboxymethylamino)phenyl)methylene]-6-chloro-2-indolinone (225) 3-Z-[1-(4-d imethylaminomethylanilino)-1-(4-carboxymethoxyphenyl)-methylene]-6-bromo-2-indolinone (226) 3-Z-[1-(4-d imethylaminomethylanilino)-1-(3-carboxymethoxyphenyl)-methylene]-6-bromo-2-indolinone (227) 3-Z-[1-(4-dimethylaminomethylanilino)-1-(4-carboxymethylaminophenyl)-methylene]-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-propyl, Pr is isopropyl, nBu is n-butyl, tBu is tert-butyl and Bn is benzyl.
Claims (17)
1. A compound of the formula 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 which is substituted by a C1-2-alkyl-carbonyl-amino group, by a carboxy-C1-3-alkyl, carboxy-C1-4-alkoxy, C1-4-alkoxy-carbonyl-C1-3-alkyl, C1-4-alkoxy-carbonyl-C1-3-alkoxy, aminocarbonyl-C1-3-alkyl, (C1-2-alkylamino)-carbonyl-C1-3-alkyl, di-(C1-2-alkyl)-aminocarbonyl-C1-3-alkyl, (C1-2-alkyl-carbonyl)-amino-C1-3-alkyl, (C1-4-alkoxy-carbonyl)-amino-C1-3-alkyl, (phenyl-carbonyl)-amino-C1-3-alkyl, (C3-6-cycloalkyl-carbonyl)-amino-C1-3-alkyl, (C3-6-cycloalkyl-C1-3-alkyl-carbonyl)-amino-C1-3-alkyl, (thiophen-2-yl-carbonyl)-amino-C1-3-alkyl, (furan-2-yl-carbonyl)-amino-C1-3-alkyl, (phenyl-C1-3-alkyl-carbonyl)-amino-C1-3-alkyl, (2-(C1-9-alkoxy)-benzoyl-carbonyl)-amino-C1-3-alkyl, (pyridin-2-yl-carbonyl)-amino-C1-3-alkyl, (pyridin-3-yl-carbonyl)-amino-C1-3-alkyl, (pyridin-4-yl-carbonyl)-amino-C1-3-alkyl or C1-3-alkyl-piperazin-1-yl-carbonyl-C1-3-alkyl group, or by an aminocarbonyl-C2-3-alkenyl, (C1-3-alkylamino)-carbonyl-C2-3-alkenyl, di- (C1-3-alkyl)-amino-carbonyl-C2-3-alkenyl or C1-4-alkoxy-carbonyl-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 di-(C1-2-alkyl)-amino-, N-[.omega.-di-(C1-3-alkyl)-amino-C2-3-alkyl]-N-(C1-3-alkyl)-amino, N-methyl-(C3-4-alkyl)-amino, N-(C1-3-alkyl)-N-benzylamino, N-(C1-4-alkoxycarbonyl)-amino, N-(C1-4-alkoxycarbonyl)-C1-4-alkylamino, 4-(C1-3-alkyl)-piperazin-1-yl, imidazol-1-yl, pyrrolidin-1-yl, azetidin-1-yl, morpholin-4-yl, piperazin-1-yl, or thiomorpholin-4-yl group, by a di-(C1-3-alkyl)-amino-(C1-3-alkyl)-sulphonyl, 2-[di-(C1-3-alkyl)-amino]-ethoxy, 4-(C1-3-alkyl)-piperazin-1-yl-carbonyl, {.omega.-[di-(C1-3-alkyl)-amino]-(C2-3-alkyl)}-N-(C1-3-alkyl)-amino-carbonyl, 1-(C1-3-alkyl)imidazol-2-yl, or (C1-3-alkyl)-sulphonyl group, or by a group of the formula in which R7 is a C1-2-alkyl, C1-2-alkyl-carbonyl, di-(C1-2-alkyl)-amino-carbonyl-C1-3-alkyl or C1-3-alkylsulphonyl group and R8 is C1-3-alkyl, .omega.-[di-(C1-2-alkyl)-amino]-C2-3-alkyl, .omega.-[mono-(C1-2-alkyl)-amino]-C2-3-alkyl group, or a (C1-3-alkyl)-carbonyl, (C4-6-alkyl)-carbonyl or carbonyl-(C1-3-alkyl) group which is terminally substituted by a di-(C1-2-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, 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, or a tautomer, enantiomer, or diastereomer thereof, or a mixture thereof, or a salt thereof.
2. A compound according to claim 1 wherein the dialkyl amino groups present in the radical R4 are an N-methyl-(N,N-dialkyl)-ammonium group.
3. A compound according to claim 2, wherein the counterion for the N-methyl-(N,N-dialkyl)-ammonium group is selected from the group consisting of iodide, chloride, bromide, methylsulphonate, para-toluenesulphonate and trifluoroacetate.
4. A compound of the formula I according to claim 1 in which X, R1, R2, R4, R5 and R6 are as defined in claim 1 and R3 is a phenyl group substituted by a carboxy-C1-3-alkyl or C1-4-alkoxy-carbonyl-C1-3-alkyl group.
5. A compound of the formula I according to any one of claims 1 to 4, in which X, R1, R3, R4, R5 and R6 are as defined in any one of claims 1 to 3 and R2 is a fluorine or chlorine atom.
6. A compound:
(a) 3-Z-[1-(4-dimethylaminomethylanilino)-1-(3-(2-carboxyethyl)phenyl)methylene]-6-chloro-2-indolinone;
(b) 3-Z-[1-(4-dimethylaminomethylanilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone;
(c) 3-Z-[1-(4-dimethylaminomethylanilino)-1-(3-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone;
(d) 3-Z-[1-(4-(N-(4-methylpiperazin-1-ylmethylcarbonyl)-N-methylamino)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone;
(e) 3-Z-[1-(4-(N-(2-dimethylaminoethyl)-N-methylsulphonylamino)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone;
(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)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone;
(h) 3-Z-[1-(4-(N-(dimethylaminomethylcarbonyl)-N-methylamino)anilino)-1-(4-(2-carboxyethyl)phenyl)-methylene]-6-fluoro-2-indolinone;
(i) 3-Z-[1-(4-(N-(2-dimethylaminoethylcarbonyl)-N-methylamino)anilino)-1-(4-(2-carboxyethyl)phenyl)-methylene]-6-fluoro-2-indolinone;
(j) 3-Z-[1-(4-(pyrrolidin-1-ylmethyl)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone;
(k) 3-Z-[1-(4-(diethylaminomethyl)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone;
(l) 3-Z-[1-(4-(2-dimethylaminoethyl)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-chloro-2-indolinone;
(m) 3-Z-[1-(4-dimethylaminomethylanilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-chloro-2-indolinone;
(n) 3-Z-[1-(4-(pyrrolidin-1-ylmethyl)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-chloro-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)phenyl)methylene]-6-bromo-2-indolinone;
or (q) 3-Z-[1-(4-(diethylaminomethyl)anilino)-1-(4-(2-carboxyethyl)-methylene]-6-bromo-2-indolinone;
or a salt of any one of compounds (a) to (q).
(a) 3-Z-[1-(4-dimethylaminomethylanilino)-1-(3-(2-carboxyethyl)phenyl)methylene]-6-chloro-2-indolinone;
(b) 3-Z-[1-(4-dimethylaminomethylanilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone;
(c) 3-Z-[1-(4-dimethylaminomethylanilino)-1-(3-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone;
(d) 3-Z-[1-(4-(N-(4-methylpiperazin-1-ylmethylcarbonyl)-N-methylamino)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone;
(e) 3-Z-[1-(4-(N-(2-dimethylaminoethyl)-N-methylsulphonylamino)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone;
(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)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone;
(h) 3-Z-[1-(4-(N-(dimethylaminomethylcarbonyl)-N-methylamino)anilino)-1-(4-(2-carboxyethyl)phenyl)-methylene]-6-fluoro-2-indolinone;
(i) 3-Z-[1-(4-(N-(2-dimethylaminoethylcarbonyl)-N-methylamino)anilino)-1-(4-(2-carboxyethyl)phenyl)-methylene]-6-fluoro-2-indolinone;
(j) 3-Z-[1-(4-(pyrrolidin-1-ylmethyl)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone;
(k) 3-Z-[1-(4-(diethylaminomethyl)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone;
(l) 3-Z-[1-(4-(2-dimethylaminoethyl)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-chloro-2-indolinone;
(m) 3-Z-[1-(4-dimethylaminomethylanilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-chloro-2-indolinone;
(n) 3-Z-[1-(4-(pyrrolidin-1-ylmethyl)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-chloro-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)phenyl)methylene]-6-bromo-2-indolinone;
or (q) 3-Z-[1-(4-(diethylaminomethyl)anilino)-1-(4-(2-carboxyethyl)-methylene]-6-bromo-2-indolinone;
or a salt of any one of compounds (a) to (q).
7. A compound: 3-Z-[1-(4-dimethylaminomethylanilino)-1-(4-(2-ethoxycarbonylethyl)phenyl)methylene]-6-fluoro-2-indolinone or a salt thereof.
8. 1-acetyl-6-fluoro-2-indolinone or a salt thereof.
9. A physiologically acceptable salt of a compound as defined in any one of claims 1 to 7.
10. A medicament, comprising a compound as defined in any one of claims 1 to 7 or a physiologically acceptable salt as defined in claim 9, and one or more components selected from inert carrier materials and diluents.
11. The use of a compound as defined in any one of claims 1 to 7 or of a physiologically acceptable salt as defined in claim 9 in preparing a medicament for treating excessive or abnormal cell proliferation.
12. A process for preparing a medicament as defined in claim 10, wherein, by a non-chemical route, a compound as defined in any one of claims 1 to 7 or a physiologically acceptable salt as defined in claim 9 is incorporated into one or more components selected from inert carrier materials and diluents.
13. A process for preparing a compound of the formula (I) as defined in claim 1, wherein:
a. 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 in claim 1, R1' has the meaning defined in claim 1 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, is reacted with an amine of the formula in which R4 and R5 are defined as in claim 1, 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, b. for preparing a compound of the formula I in which R3 is a phenyl group substituted by an aminocarbonyl-C2-3-alkenyl, (C1-3-alkyl-amino) -carbonyl-C2-3-alkenyl, di-(C1-3-alkylamino)-carbonyl-C2-3-alkenyl or C1-4-alkoxy-carbonyl-C2-3-alkenyl group, a compound of the formula in which R2, R4, R5, R6 and X are as defined in claim 1, R1' has the meaning defined in claim 1 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, is reacted with an alkene of the formula in which R3 is an amino, (C1-3-alkylamino), di-(C1-3-alkylamino) or C1-4-alkoxy group and n is the number 0 or 1, c. to prepare a compound of the formula I, in which R3 is a phenyl group substituted by a carboxy-C1-3-alkyl, C1-4-alkoxy-carbonyl-C1-3-alkyl, (C1-2-alkylamino)-carbonyl-C1-3-alkyl or di-(C1-2-alkyl)aminocarbonyl-C1-3-alkyl group, a compound of the formula in which R2, R4, R5, R6 and X are as defined in claim 1, R1' has the meaning defined in claim 1 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 C2-3-alkenyl group and R3' is a C1-4-alkoxy, amino, (C1-3-alkylamino) or di-(C1-3-alkyl)amino group, is hydrogenated and the product is subsequently cleaved from any protective groups used for the nitrogen atom of the lactam group or from a solid phase, and an alkoxycarbonyl group is, if appropriate, subsequently converted by hydrolysis into a corresponding carboxyl compound, or an amino or alkylamino group is converted by reductive alkylation into a corresponding alkylamino or dialkylamino compound, or a dialkylamino group is converted by alkylation into a corresponding trialkylammonium compound, or an amino or alkylamino group is converted by acylation or sulphonation into a corresponding acyl or sulphonyl compound, respectively, or a carboxyl group is converted by esterification or amidation into a corresponding ester or aminocarbonyl compound, respectively, or a nitro group is converted by reduction into a corresponding amino compound, or a cyano group is converted by reduction into a corresponding aminomethyl compound, or an arylalkyloxy group is converted with an acid into a corresponding hydroxyl compound, or an alkoxycarbonyl group is converted by hydrolysis into a corresponding carboxyl compound, or a phenyl group substituted by an amino, alkylamino, aminoalkyl or N-alkyl-amino group is converted by reaction with an appropriate amidino-group-transferring compound or by reaction with an appropriate nitrile into a corresponding guanidine compound of the formula I.
a. 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 in claim 1, R1' has the meaning defined in claim 1 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, is reacted with an amine of the formula in which R4 and R5 are defined as in claim 1, 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, b. for preparing a compound of the formula I in which R3 is a phenyl group substituted by an aminocarbonyl-C2-3-alkenyl, (C1-3-alkyl-amino) -carbonyl-C2-3-alkenyl, di-(C1-3-alkylamino)-carbonyl-C2-3-alkenyl or C1-4-alkoxy-carbonyl-C2-3-alkenyl group, a compound of the formula in which R2, R4, R5, R6 and X are as defined in claim 1, R1' has the meaning defined in claim 1 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, is reacted with an alkene of the formula in which R3 is an amino, (C1-3-alkylamino), di-(C1-3-alkylamino) or C1-4-alkoxy group and n is the number 0 or 1, c. to prepare a compound of the formula I, in which R3 is a phenyl group substituted by a carboxy-C1-3-alkyl, C1-4-alkoxy-carbonyl-C1-3-alkyl, (C1-2-alkylamino)-carbonyl-C1-3-alkyl or di-(C1-2-alkyl)aminocarbonyl-C1-3-alkyl group, a compound of the formula in which R2, R4, R5, R6 and X are as defined in claim 1, R1' has the meaning defined in claim 1 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 C2-3-alkenyl group and R3' is a C1-4-alkoxy, amino, (C1-3-alkylamino) or di-(C1-3-alkyl)amino group, is hydrogenated and the product is subsequently cleaved from any protective groups used for the nitrogen atom of the lactam group or from a solid phase, and an alkoxycarbonyl group is, if appropriate, subsequently converted by hydrolysis into a corresponding carboxyl compound, or an amino or alkylamino group is converted by reductive alkylation into a corresponding alkylamino or dialkylamino compound, or a dialkylamino group is converted by alkylation into a corresponding trialkylammonium compound, or an amino or alkylamino group is converted by acylation or sulphonation into a corresponding acyl or sulphonyl compound, respectively, or a carboxyl group is converted by esterification or amidation into a corresponding ester or aminocarbonyl compound, respectively, or a nitro group is converted by reduction into a corresponding amino compound, or a cyano group is converted by reduction into a corresponding aminomethyl compound, or an arylalkyloxy group is converted with an acid into a corresponding hydroxyl compound, or an alkoxycarbonyl group is converted by hydrolysis into a corresponding carboxyl compound, or a phenyl group substituted by an amino, alkylamino, aminoalkyl or N-alkyl-amino group is converted by reaction with an appropriate amidino-group-transferring compound or by reaction with an appropriate nitrile into a corresponding guanidine compound of the formula I.
14. The process according to claim 13, wherein, in the compound of formula (V), Z1 is a chlorine or bromine atom, or a methoxy, ethoxy or benzyloxy group.
15. The process according to claim 13, wherein, in the compound of formula (IX), the leaving group Z3 is a halogen atom or an alkyl- or arylsulphonyloxy group.
16. The process according to claim 15, wherein Z3 is a halogen atom and the halogen atom is selected from chlorine, bromine and iodine.
17. The process according to claim 15, wherein Z3 is an alkyl- or arylsulphonyloxy group and the alkyl- or arylsulphonyloxy group is selected from a methylsulphonyloxy, ethylsulphonyloxy, p-toluenesulphonyloxy and trifluoromethanesulphonyloxy group.
Applications Claiming Priority (5)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE10233366.1 | 2002-07-23 | ||
| DE10233366A DE10233366A1 (en) | 2002-07-23 | 2002-07-23 | Indolinone derivatives substituted in the 6-position, their preparation and their use as medicaments |
| DE10328533.4 | 2003-06-24 | ||
| DE10328533A DE10328533A1 (en) | 2003-06-24 | 2003-06-24 | New 6-amino-substituted indolinone derivatives, useful e.g. for treating tumours and angiogenesis, are inhibitors of receptor tyrosine kinases |
| PCT/EP2003/007961 WO2004009547A1 (en) | 2002-07-23 | 2003-07-22 | Indoline derivatives substituted in position 6, production and use thereof as medicaments |
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| CA2493436C true CA2493436C (en) | 2011-11-08 |
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| US7169936B2 (en) | 2002-07-23 | 2007-01-30 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Indolinone derivatives substituted in the 6-position, their preparation and their use as medicaments |
| US7514468B2 (en) | 2002-07-23 | 2009-04-07 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Indolinone derivatives substituted in the 6 position, the preparation thereof and their use as pharmaceutical compositions |
| US20060058311A1 (en) * | 2004-08-14 | 2006-03-16 | Boehringer Ingelheim International Gmbh | Combinations for the treatment of diseases involving cell proliferation |
| PE20061155A1 (en) * | 2004-12-24 | 2006-12-16 | Boehringer Ingelheim Int | INDOLINONE DERIVATIVES AS AGENTS FOR THE TREATMENT OR PREVENTION OF FIBROTIC DISEASES |
| BRPI0609899A2 (en) * | 2005-04-28 | 2010-05-11 | Boehringer Ingelheim International Gmbh | compounds for the treatment of inflammatory diseases, their use, pharmaceutical formulations, drug combinations and intermediate products |
| WO2007057399A2 (en) * | 2005-11-15 | 2007-05-24 | Boehringer Ingelheim International Gmbh | Treatment of cancer with indole derivatives |
| BRPI0906379A2 (en) * | 2008-01-25 | 2019-09-24 | Boehringer Ingelheim Int | process for making a 6-fluoro-1,2-dihydro-2-oxo-3h-indyl-3-ylidene derivative |
| JP2011510032A (en) * | 2008-01-25 | 2011-03-31 | ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング | Salt forms of 6-fluoro-1,2-dihydro-2-oxo-3H-indole-3-ylidene derivatives, processes for their preparation and pharmaceutical compositions containing them |
| PE20110213A1 (en) | 2008-07-29 | 2011-04-16 | Boehringer Ingelheim Int | INDOLINONE DERIVATIVES AS KINASE INHIBITORS |
| HUE034106T2 (en) * | 2012-10-17 | 2018-01-29 | Univ Okayama | Compound; tautomer and geometric isomer thereof; salt of said compound, tautomer, or geometric isomer; method for manufacturing said compound, tautomer, isomer, or salt; antimicrobial agent; and anti-infective drug |
| CN104936944B (en) * | 2012-12-06 | 2017-09-12 | 山东亨利医药科技有限责任公司 | It is used as the dihydroindole ketone derivate of tyrosine kinase inhibitor |
| CN105461609B (en) * | 2015-12-25 | 2019-08-23 | 杭州新博思生物医药有限公司 | A kind of preparation method of Nintedanib |
| CN114213396B (en) * | 2022-01-27 | 2023-03-24 | 深圳市乐土生物医药有限公司 | Indole-2-ketone compound and preparation method and application thereof |
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| WO2000018734A1 (en) * | 1998-09-25 | 2000-04-06 | Boehringer Ingelheim Pharma Kg | Novel substituted indolinones with an inhibitory effect on various kinases and cyclin/cdk complexes |
| GB9904933D0 (en) * | 1999-03-04 | 1999-04-28 | Glaxo Group Ltd | Compounds |
| US7005444B2 (en) * | 2001-09-27 | 2006-02-28 | Allergan, Inc. | 3-(heteroarylamino)methylene-1, 3-dihydro-2H-indol-2-ones as kinase inhibitors |
| US6765012B2 (en) * | 2001-09-27 | 2004-07-20 | Allergan, Inc. | 3-(Arylamino)methylene-1,3-dihydro-2H-indol-2-ones as kinase inhibitors |
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- 2003-07-22 PL PL397821A patent/PL397821A1/en unknown
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- 2003-07-22 WO PCT/EP2003/007961 patent/WO2004009547A1/en active Application Filing
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