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AU2010202845A1 - Indoline derivatives substituted in position 6, production and use thereof as medicaments - Google Patents

Indoline derivatives substituted in position 6, production and use thereof as medicaments Download PDF

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Publication number
AU2010202845A1
AU2010202845A1 AU2010202845A AU2010202845A AU2010202845A1 AU 2010202845 A1 AU2010202845 A1 AU 2010202845A1 AU 2010202845 A AU2010202845 A AU 2010202845A AU 2010202845 A AU2010202845 A AU 2010202845A AU 2010202845 A1 AU2010202845 A1 AU 2010202845A1
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Prior art keywords
alkyl
phenyl
methylene
group
amino
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AU2010202845A
Inventor
Armin Heckel
Frank Hilberg
Jorg Kley
Thorsten Lehmann-Lintz
Gerald Jurgen Roth
Ulrike Tontsch-Grunt
Jacobus Van Meel (Jacques)
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Boehringer Ingelheim Pharma GmbH and Co KG
Original Assignee
Boehringer Ingelheim Pharma GmbH and Co KG
Boehringer Ingelheim Pharmaceuticals Inc
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Priority claimed from DE10233366A external-priority patent/DE10233366A1/en
Priority claimed from DE10328533A external-priority patent/DE10328533A1/en
Application filed by Boehringer Ingelheim Pharma GmbH and Co KG, Boehringer Ingelheim Pharmaceuticals Inc filed Critical Boehringer Ingelheim Pharma GmbH and Co KG
Priority to AU2010202845A priority Critical patent/AU2010202845A1/en
Publication of AU2010202845A1 publication Critical patent/AU2010202845A1/en
Ceased legal-status Critical Current

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    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
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    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links

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Description

Australian Patents Act 1990 - Regulation 3.2A ORIGINAL COMPLETE SPECIFICATION STANDARD PATENT Invention Title "INDOLINE DERIVATIVES SUBSTITUTED IN POSITION 6, PRODUCTION AND USE THEREOF AS MEDICAMENTS" The following statement is a full description of this invention, including the best method of performing it known to us:- IA INDOLINE DERIVATIVES SUBSTITUTED IN POSITION 6, PRODUCTION AND USE THEREOF AS MEDICAMENTS This is a divisional of Australian patent application No. 2003254557, the entire contents of which are incorporated herein by reference. The present invention relates to indolinone derivatives, substituted in the 6-position, of the formula R4
R
3 N X N R2' 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 inhibiting effect on various kinases, especially on receptor tyrosine kinases, such as VEGFR1, VEGFR2, VEGFR3, PDGFRa, PDGFRP, 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 1, which have useful pharmacological properties, medicaments comprising these pharmacologically active compounds, their use and processes for their preparation.
2 Moreover, the present invention provides the physiologically acceptable salts of the compounds according to the invention, medicaments comprising these compounds which in addition, if appropriate, contain one or more inert carrier materials and/or diluents, and their use for preparing a medicament suitable in particular for treating excessive or anormal cell proliferations. The present invention furthermore provides processes for preparing this medicament, characterized in particular in that the compounds according to the invention or their physiologically acceptable salts are incorporated into one or more inert carrier materials and/or diluents. I. In the above formula 1, X is an oxygen atom, R' is a hydrogen atom,
R
2 is a fluorine, chlorine or bromine atom or a cyano group,
R
3 is a phenyl group or a phenyl group which is monosubstituted by a fluorine, chlorine, bromine or iodine atom or by a C 1
-
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 C 1
.
3 -alkoxy or C 1
-
2 -alkyl-carbonyl-amino group, by a cyano-C 1
-
3 -alkyl, carboxy-C 1
-
3 -alkyl, carboxy-CI.4-alkoxy, carboxy
C
1
.
3 -alkylamino, carboxy-C 1
-
3 -alkyl-N-(C 1
.
3 -alkyl)-amino, C1.4-alkoxy carbonyl-C 1
.
3 -alkyl, C 1
.
4 -alkoxy-carbonyl-C 1
.
3 -alkoxy, C 1 .4-alkoxy- 3 carbonyl-C1- 3 -alkylamino, C 1 .4-alkoxy-carbonyl-C.
3 -alkyl-N-(C1- 3 -alkyl) amino, amino-C 1
.
3 -alkyl, aminocarbonyl-C 1
-
3 -alkyl, (C 1
-
2 -alkylamino) carbonyl-C 1
-
3 -alkyl, di-(C 1
-
2 -alkyl)-aminocarbonyl-C 1
-
3 -alkyl, (C 1
.
2 -alkyl carbonyl)-amino-C1- 3 -alkyl, (C 1 .4-alkoxy-carbonyl)-amino-C 1
.
3 -alkyl, (C 3 e-alkyl-carbonyl)-amino-CI- 3 -alkyl, (phenyl-carbonyl)-amino-C 1
-
3 -alkyl, (C3-cycloalkyl-carbonyl)-amino-C 1 .3-alkyl, (C3-cycloalkyl-C1.
3 -alkyl carbonyl)-emino-C- 3 -alkyl, (thiophen-2-yl-carbonyl)-amino-C 1
-
3 -alkyl, (furan-2-yl-carbonyl)-amino-C 1
.
3 -alkyl, (phenyl-C 1
-
3 -alkyl-carbonyl) amino-C 1
-
3 -alkyl, (2-(CI.4-alkoxy)-benzoyl-carbonyl)-amino-C 1
-
3 -alkyl, (pyrdin-2-yl-carbonyl)-amino-C 1 -3-alkyl, (pyridin-3-yl-carbonyl)-amino
C
1
.
3 -alkyl-, (pyridin-4-yl-carbonyl)-amino-C 1
-
3 -alkyl- or C 1
-
3 -alkyl piperazin-1-yI-carbonyl-C 1
-
3 -alky group, by a carboxy-C 2
-
3 -alkenyl,. aminocarbonyl-C 2
-
3 -alkenyl, (C 1
-
3 -alkyl amino)-carbonyl-C 2
-
3 -alkenyl, di-(C 1
-
3 -alkyl)-amino-carbonyl-C 2
-
3 -alkeny or C 1
.
4 -alkoxy-carbonyl-C 2
-
3 -alkeny group, where the substituents may be identical or different,
R
4 is a phenyl group or a phenyl group which is monosubstituted by a CI.
3 -alkyl group which is terminally substituted by an amino, guanidino, mono- or di-(C 1
-
2 -alkyl)-amino-, N-[o-di-(C1- 3 -alkyl)-amino-C2 3-alkyl]-N-(C-3-alkyl)-amino, N-methyl-(C 3 .4-alkyl)-amino, N-(C 1 -3 alkyl)-N-benzylamino, N-(C 1 .4-alkoxycarbonyl)-amino, N-(C alkoxycarbonyl)-C 1
.
4 -alkylamino, 4-(C 1
.
3 -alkyl)-piperazin-1-yi, 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)-sulphonyt, 2-[di-(C 1
-
3 -alkyl)-amino] ethoxy, 4-(C 1
.
3 -alkyl)-piperazin-1-yl-carbonyl, {o-[di-(C1- 3 -alkyl)-amino] (C2-3-alkyl)}-N-(C1.
3 -alkyl)-amino-carbonyl, 1-(CI- 3 -alkyl)imidazol-2-yl, (Cl-3-alkyl)-sulphonyl group, or 4 by a group of the formula /R -N NR7 in which
R
7 is a C1- 2 -alkyl, C 1
.
2 -alkyl-carbonyl, di-(C 1
-
2 -alkyl)-amino carbonyl-C 1
-
3 -alkyl or C 1
-
3 -alkylsulphonyl group and
R
8 is CI- 3 -alkyl, o-[di-(CI- 2 -alkyl)-amino]-C 2
-
3 -alkyl, CO-[mono-(C1-2 alkyl)-amino]-C 2
-
3 -alkyl group, or a (C 1
.
3 -alkyl)-carbonyl, (C 4 -- alkyl)-carbonyl or carbonyl-(C 1
.
3 alkyl) group which is terminally substituted by a di-(C 1
-
2 -alkyl) amino, piperazin-1 -yl or 4-(C 1
-
3 -alkyl)-piperazin-1 -yl group, where all dialkylamino groups present in the radical R 4 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-toluenesulphonate and trifluoroacetate,
R
5 is a hydrogen atom and
R
6 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, 5 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, their tautomers, enantiomers. diastereomers. their mixtures and their salts. ) II. Particularly preferred compounds of the above formula I are those compounds in which X, R', R 5 and R 6 are as defined under I. and: Il.i. R 2 and R 4 are as defined under I. and
R
3 is a phenyl group or a phenyl group which is monosubstituted by a fluorine, chlorine, bromine or iodine atom or by a C 1
.
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 C 1
.
3 -alkoxy or C 1
-
2 -alkyl-carbonyl-amino group, 5 by a cyano-C 1
.
3 -alkyl, carboxy-C 1
-
3 -alkyl, carboxy-Cl-alkoxy, carboxy
C
1
.
3 -alkylamino, carboxy-C 1
.
3 -alkyl-N-(C 1
.
3 -alkyl)-amino, Cw4-alkoxy carbonyl-C 1
.
3 -alkyl, Cw-alkoxy-carbonyl-C 1
.
3 -alkoxy, Cw4-alkoxy carbonyl-C 1
-
3 -alkylamino, C-alkoxy-carbonyl-C 1
-
3 -alkyl-N-(C 1
.
3 -alkyl) 0 amino, amino-C 1
.
3 -alkyl, aminocarbonyl-C 1
-
3 -alkyl, (C 1
-
2 -alkylamino) carbonyl-C 1
-
3 -alkyl, di-(C1.2-alkyl)-aminocarbonyl-C.
3 -alkyl, (C 2 -alkyl carbonyl)-amino-C1- 3 -alkyl, (C1w-alkoxy-carbonyl)-amino-C 1
.
3 -alkyl, (C 3 . 6-alkyl-carbonyl)-amino-C1 - 3 -alkyl, (phenyl-carbonyl)-amino-C 1
-
3 -alkyl, 6 (C3.-cycloalky-carbonyI )-amino-C,..
3 -alkyl, (Cm-cycloaI kyl-Ci .
3 -alkyl carbony)-amino-CI-3-alkyI, (phenyl-carbonyl)-amilo-Cl-.3 -alkyl, (thiophen-2-y-carbony)-amilo-C-3-alky, (furan-2-yI-carbonyl)-ano
C
1
-.
3 -alkyl, (phenYl-C 1
..
3 -alkyl-carbofl)-amiflo-Cl-.3 -alkyl, (2-(C 1 4 alkoxy)-benzoyI-carbony)-afio-C-3-alky, (pyndin-2-yI -carbonyl ) amino-C- 3 -alkyI, (pyridin-3-yI-carbony)-ailo-Cl-3-alkyI, (pyridin-4-yI carbony)-amino-Cl3-alkyI or C 1
.
3 -alkyl-piperazin-1 -yI-carbonyl -Cl-3-alkyl group, by a carboxy-C 2
.
3 -alkenyl, aminocarbonyl-C 2 .3-alkeflyl-, (Cv .
3 -alkyl amino)-carbony-C 2 -3-alkel-, di-(C 1
..
3 -alkyl)-amino-carbolyl-C2-3.
alkenyl or C 1 -alkoxy-carbony-C 2 -3-alkelyI group, where the substituents may be identical or different; lI.ii. W a nd W 4 are as defined under 1. and
R
3 is a phenyl group which is substituted by a C 1
.
2 -alkyl-carbonyl-amino group, by a carboxy-Ci .
3 -alkyl, carboxy-C,4-alkoxy, C 1 -4-alkoxy-carbony-Ci-3 alkyl, Cj1s-alkoxy-carbony-C3-akxy, aminocarbonyl-Ci .
3 -alkyl, (Ci2z alkylamino)-carbony-C-3-alky, di-(Ci-.
2 -alkyl)-aminocarbonyl-CI
.
3 -a Ikyl,
(C
1
..
2 -alkyI-carbony)-amino-Cl-3-alkyI, (CIA-alkoxy-carbony)-amino-Cl-3 alkyl, (pheny-carbony)-aminO-C-3-alkyI,
(C
3
.
6 -cycloalkyl-carbonyl) amino-Cl-.
3 -alkyl, (C 3 ..- cYCloalkyl-CI-.
3 -alkyl-carbonyl)-amino-CI-.3 -alkyl, (thio phen-2-yI-carbonyl )-amino-CI..
3 -alkyl, (furan-.2-yi-carbonyl)-ami no
C
1
.
3 -alkyl, (pheny-Cl.
3 -alkyI-carbony)-amino-C3-alkyI, (2-(C 1
I
alkoxy)-benzoyI-carbony)-anino-C1-3-alkyl, (pyddin-2-yI -carbonyl) amino-C 1
..
3 -alkyl, (pyridin-3-yl-carbonyI)-amino-Ci-3-alky, (pyridin-4-yl- 7 carbonyl)-amino-C- 3 -alkyl or C 1
-
3 -alkyl-piperazin-1-yl-carbonyl-C 1 -3-alky group, by an aminocarbonyl-C 2
-
3 -alkenyl, (CI.
3 -alkylamino)-carbonyl-C 23 alkenyl, di-(C 1
-
3 -alkyl)-amino-carbonyl-C 2
-
3 -alkenyl or C 1
.
4 -alkoxy carbonyl-C 2 -3-alkenyl group; ll.iii. R 2 and R 4 are as defined under I. and
R
3 is a phenyl group substituted by a carboxy-C 1
-
3 -alkyl or C1.4-alkoxy carbonyl-C 1
-
3 -alkyl group; ll.iv. R 3 and R 4 are as defined under I. and
R
2 is a fluorine or chlorine atom; II.v. R 2 and R 3 are as defined under 1. and
R
4 is a phenyl group or a phenyl group which is monosubstituted by a C 1
-
3 -alkyl group which is terminally substituted by an amino, guanidino, mono- or di-(C1-2-alkyl)-amino-, N-[o-di-(C- 3 -alkyl)-amino-C 2 3-alkyl]-N-(C1-3-alkyl)-amino, N-methyl-(C3-4-alkyl)-amino, N-(C1-3 alkyl)-N-benzylamino, N-(C 1
.
4 -alkoxycarbonyl)-amino, N-(C1.4 alkoxycarbonyl)-CI-4-alkylamino, 4-(C 1 -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-(C 1
-
3 -alkyl)-amino-(C 1
-
3 -alkyl)-sulphony, 2-[di-(C 1
-
3 -alkyl)-amino] ethoxy, 4-(C 1
-
3 -alkyl)-piperazin-1-yl-carbonyl, {o-[di-(C 1
-
3 -alkyl)-amino]- 8
(C
2
-
3 -alkyl)}-N-(C 1
-
3 -alkyl)-amino-carbonyl, 1-(C 1
-
3 -alkyl)imidazol-2-yl,
(CI-
3 -alkyl)-sulphonyl group, or by a group of the formula / R8 -N \R7 in which R is a C 1
-
2 -alkyl, C 1
-
2 -alkyl-carbonyl, di-(C 1
-
2 -alkyl)-amino carbonyl-C 1
-
3 -alkyl or C 1
-
3 -alkylsulphonyl group and
R
8 is C 1
-
3 -alkyl, o-[di-(C1- 2 -alkyl)-amino]-C 2
-
3 -alkyl, a,-[mono-(CI-2 alkyl)-aminol-C 2
-
3 -alkyl group, or a (C 1
-
3 -alkyl)-carbonyl, (C 4
.
6 -alkyl)-carbonyl or carbonyl-(C1- 3 alkyl) group which is terminally substituted by a di-(C 1
-
2 -alkyl) amino, piperazin-1 -yl or 4-(C 1
-
3 -alkyl)-piperazin-1 -yl group, where all dialkylamino groups present in the radical R 4 may also be present in quatemized 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-toluenesulphonate and trifluoroacetate. Ill. Subgroups of particularly preferred compounds of the above formula I which are to be mentioned in particular are those in which: Il.i. X, R 1 , R 2 , R' and R 6 are as defined under I., R 3 is as defined under ILi. and R 4 is as defined under ll.v.; 9 lil.ii. X, R, R R' and R 6 are as defined under I., R 3 is as defined under ll.ii. and R 4 is as defined under ll.v.; Ill.iii. X, R', R 2 , R' and R are as defined under I., R 3 is as defined under ll.iii. and R 4 is as defined under ll.v.; lIL.iv. X, R', R 5 and R 6 are as defined under I., R 2 is as defined under ll.iv., R 3 is as defined under IL.i., 11.ii. or II.iii. and R 4 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, R' is a hydrogen atom,
R
2 is a fluorine, chlorine or bromine atom or a cyano group,
R
3 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 C 1
-
3 -alkoxy or C 1
-
2 -alkyl-carbonyl-amino group, by a carboxy-CI- 3 -alkyl, aminocarbonyl-C 1
-
3 -alkyl, (C 1
-
2 -alkylamino)-carbonyl
C
1
-
3 -alkyl, di-(C 1
-
2 -alkyl)-aminocarbonyl-C 1
-
3 -alkyl, (C 1
-
2 -alkyl-carbonyl)-amino
C
1
-
3 -alkyl or (phenyl-carbonyl)-amino-C1- 3 -alkyl group, 10 where the substituents may be identical or different,
R
4 is a phenyl group which is substituted by a C 1
-
3 -alkyl group terminally substituted by a di-(C 1
-
2 -alkyl)-amino group, or by a group of the formula --N \R7 in which
R
7 is a C1- 2 -alkyl, C 1
-
2 -alkyl-carbonyl, di-(Cl- 2 -alkyl)-amino-carbonyl-C1-3 alkyl or C 1
-
3 -alkylsulphonyl group and
R
8 is a C 1
-
3 -alkyl or o-[di-(C 1
-
2 -alkyl)-amino]-C 2
-
3 -alky group, or a C 1
-
3 -alkyl-carbonyl group terminally substituted by a di-(C 1
-
2 -alkyl) amino, piperazino or 4-(CI- 3 -alkyl)-piperazin-1-yl group,
R
5 is a hydrogen atom and R' 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, 11 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 (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 fl uoro-2-i ndoli none (1) 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)methylenej-6 ch loro-2-indol i none 12 (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)methylenel 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
C
1
.
3 -alkanol, a C3-9-cycloalkanol, where a C5-a-cycloalkanol may additionally be substitituted by one or two Ci- 3 -alkyl groups, a Cs-a-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 C 1 .3-alkyl, phenyl-C 1
-
3 -alkyl, phenyl-C 1
.
3 -alkoxy carbonyl or C 1 .e-alkyl-carbonyl group and in which the cycloalkanol moiety may additionally be substituted by one or two C 1
.
3 -alkyl groups, a C4-rcycloalkenol, a C 3
-
5 alkenol, a phenyl-C 3
-
5 -alkenol, a C 3 -s-alkynol or a phenyl-C 3
-
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-a-cycloalkyl-C 1
-
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-(RCRe)-OH, 13 in which Ra is a CI.-alkyl, Cs.
7 -cycloalkyl, phenyl or phenyl-C 1
-
3 -alkyl group, Rb is a hydrogen atom, a CI-3-alkyl, C-7-cycloalkyl or phenyl group, and Re is a hydrogen atom or a CI- 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 C1.1-alkylcarbonyl group, such as the formyl, acetyl, propionyl, butanoyl, pentanoyl or hexanoyl group, an allyloxycarbonyl group, a C1.
1 -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.e-alkoxy-carbonyl group, such as the benzyloxycarbonyl, phenylethoxycarbonyl or phenylpropoxycarbonyl group, a CI.3-alkylsulphonyl-C 1 4-alkoxy-carbonyl,
C
1 -3 alkoxy-C24-alkoxy-C 2 -4-alkoxy-carbonyl or R.CO-0-(RbCRe)-O-CO- group, in which Ra is a CI-a-alkyl, Cs.7-cycloalkyl, phenyl or phenyl-C 1
-
3 -alkyl group, Rb is a hydrogen atom, a C 1
-
3 -alkyl, C5.7-cycloalkyl or phenyl group and Re is a hydrogen atom, a C 1
.
3 -alkyl or RaCO-O-(RbCRO)-0- group, in which Ra to R, 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 CI.-alkoxy-carbonyl group, such as the methoxycarbonyl, ethoxycarbonyl, n-propyloxycarbonyl, isopropyloxycarbonyl, n-butyloxycarbonyl, n-pentyloxycarbonyl, n-hexyloxycarbonyl 14 or cyclohexyloxycarbonyl group, or a phenyl-C 1
-
3 -alkoxy-carbonyl group, such as the benzyloxycarbonyl group, and, for an imino or amino group, a C1..-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-C 1
.
3 alkoxy-carbonyl group, such as the benzyloxycarbonyl group, a phenylcarbonyl group optionally substituted by a CI.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-C 2
-
3 alkoxy-carbonyl or C13-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 ZI R3
R
6 X R2N (V), in which the radicals Z' and R 3 may, if appropriate, change their positions, X, R 2 , R 3 and R are as defined at the outset, R' has the meanings mentioned at the outset for R 1 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 Z' is a halogen atom, a hydroxyl, alkoxy or arylalkoxy group, for example a chlorine or bromine atom, a methoxy, ethoxy or benzyloxy group, 15 with an amine of the formula R4x R 5 N H (VI), in which
R
4 and R 5 are defined as mentioned at the outset, and, if required, the product is subsequently cleaved from a protective. group used for the nitrogen atom of the lactam group or from a solid phase. Suitable protective groups for the nitrogen atom of the lactam group are, for example, an acetyl, benzoyl, ethoxycarbonyl, tert-butyloxycarbonyl or benzyloxycarbonyl group and suitable solid phases are a resin, such as a 4
-(
2 ',4'-dimethoxyphenylaminomethyl) phenoxy resin, where the attachment is expediently via the amino group, or a p-benzyloxybenzyl alcohol resin, where the attachment is expediently via a spacer, such as a 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 0 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 2000C.
16 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 hydrofura n/water, 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 0 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 500C. Cleavage from a solid phase employed is preferably carried out using trifluoroacetic acid and water at temperatures between 0 and 35 0 C, preferably at room temperature. b. To prepare a compound of the formula I in which R 3 is a phenyl or naphthyl group substituted by a carboxy-C 2
-
3 -alkenyl, aminocarbonyl-C 2
-
3 -alkenyl, (C1-3-alkylamino) carbonyl-C2- 3 -alkenyl, di-(C1.3-alkylamino)-carbonyl-C2-3-alkeny or CI--alkoxy carbonyl-C 2
-
3 -alkenyl group, reaction of a compound of the formula Z3 R4 N
R
5 R4 X N R R1 (IX), in which 17
R
2 , R 4 , R', R 6 and X are as defined at the outset, R" has the meanings mentioned at the outset for R 1 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
3 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 0 R3 (X), in which
R
3 ' is an amino, (C1- 3 -alkylamino), di-(C1.
3 -alkylamino) or C 1
.
4 -alkoxy group and n is the number 0 or 1. The reaction is expediently carried out with palladium catalysis, using, for example, palladium(ll) acetate, palladium(ll) chloride, bis(triphenylphosphine)palladium(ll) acetate, bis(triphenylphosphine)palladium(lI) chloride, palladium/carbon, bis-[1,2 bis(diphenylphosphino)ethanepalladium(o), dichloro-(1,2-bis(diphenylphosphino) ethane)palladium(lI), tetrakistriphenylphosphinepalladium(O), tris(dibenzylidene acetone)dipalladium(O), 1,1'-bis(diphenylphosphino)ferrocenedichloropalladium(l 1) or tris(dibenzylideneacetone)dipalladium(o)/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.
18 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 R 3 is a phenyl or naphthyl group substituted by a carboxy-C1- 3 -alkyl, C 1
.
4 -alkoxy-carbonyl-C 1
-
3 -alkyl, aminocarbonyl-CI- 3 -alkyl,
(CI-
3 -alkylamino)-carbonyl-C 1
-
3 -alkyl or di-(C1- 3 -alkyl)-aminocarbonyl-C1- 3 -alky group, hydrogenation of a compound of the formula R3- O A R4 N N R 5 RS X N R
R
1 ' (XI), in which
R
2 , R 4 , R , R 6 and X are as defined at the outset, R" has the meanings mentioned at the outset for R 1 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, A is a C 2
-
3 -alkenyl group and
R
3 is a hydroxyl, C 1 -4-alkoxy, amino, (C 1
-
3 -alkylamino) or di-(C 1
-
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 19 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 0 C, but preferably at room temperature, and at a hydrogen pressure of 1 to 7 bar, but preferably 3 to 5 bar. The cleavage of a protective group used for the nitrogen atom of the lactam group or from a -solid phase, which may be required, if appropriate, is carried out as described under process (a). If, according to the invention, a compound of the formula I is obtained which contains an alkoxycarbonyl group, this can be converted by hydrolysis into a corresponding 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 sulphonation 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 20 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, this can be converted by hydrolysis into a corresponding carboxyl compound, or if a compound of the formula I is obtained in which R 4 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 into a corresponding urea compound of the formula I, or if a compound of the formula I is obtained in which R 4 is a phenyl group substituted by an amino, alkylamino, aminoalkyl or N-alkylamino group, this can subsequently be converted by reaction with a corresponding amidino-group-transferring compound or by reaction with a corresponding nitrile into a corresponding guanidino compound of the formula 1. The subsequent hydrolysis is preferably carried out in an aqueous solvent, for example in water, methanol/water, ethanol/water, isopropanol/water, tetrahydrofuran/water or dioxane/water, in the presence of an acid, such as trifluoroacetic acid, hydrochloric acid or sulphuric acid, or in the presence of an alkali metal base, such as lithium hydroxide, sodium hydroxide or potassium hydroxide, at temperatures between 0 and 100"C, preferably at temperatures between 10 and 500C. 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 21 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 1 00*C, preferably at temperatures between 20 and 80 0 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 0 C, preferably at temperatures between 20 and 60 0 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 0 C, preferably at temperatures between 20 0 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, trimethylchlorosilane, phosphorus trichloride, 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 tetra methyl u roni um tetrafluoroborate/1 -hydroxybenzotriazole, N,N'-carbonyldiimidazole or triphenylphosphine/carbon tetrachloride, and, if appropriate, with addition of a base, such as pyridine, 4-dimethylaminopyrdine, N-methylmorpholine or triethylamine, expediently at temperatures between 0 and 150 0 C, preferably at temperatures between 0 and 1 00*C. The reaction with a corresponding reactive compound can, if appropriate, be carried out in the presence 22 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 1500C, preferably at temperatures between 50 and 1000C. 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 200C 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 -hydroxybenzotriazole, 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 1500C, preferably at temperatures between 0 and 100C, 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 1000C. The subsequent reduction of a nitro group is preferably.carried out hydrogenolytically, for example with hydrogen in the presence of a catalyst, such as 23 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 0 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 0 C, preferably at room temperature. In the reactions described above, any reactive groups present, such as carboxyl, hydroxyl, amino, alkylamino or imino groups, can be protected during the reaction by customary protective groups which are removed again after the reaction. A protective radical for a carboxyl group is, for example, the trimethylsilyl, methyl, ethyl, tert-butyl, benzyl or tetrahydropyranyl group, and a protective group for a hydroxyl, amino, alkylamino or imino group is, for example, the acetyl, trifluoroacetyl, benzoyl, ethoxycarbonyl, tert-butoxycarbonyl, benzyloxycarbonyl, benzyl, methoxybenzyl or 2,4-dimethoxybenzyl group, and, for the amino group, additionally the phthalyl group.
24 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 0 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 0 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 0 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 0
C.
25 Furthermore, chiral compounds of the formula I obtained can be separated into their enantiomers and/or diastereomers. Thus, for example, compounds of the formula I obtained which occur as racemates can be separated by methods known per se (see Allinger N. L. and 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 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 with an optically active substance which forms salts or derivatives, such as, for example, esters or amides, with the racemic compound, in particular acids and their activated derivatives or alcohols, and separating the mixture of diastereomeric salts or derivatives obtained in this manner, for example owing to different solubilities, whereupon the free enantiomers can be released from the pure diastereomeric salts or derivatives by action of suitable agents. Particularly common optically active acids are, for example, the D and L forms of tartaric acid, dibenzoyltartaric acid, di-o tolyltartaric acid, malic acid, mandelic acid, camphorsulphonic acid, glutamic acid, N-acetylglutamic acid, aspartic acid, N-acetylaspartic acid or quinic acid. A suitable optically active alcohol is, for example, (+)- or (-)-menthol, and a suitable optically active acyl radical in amides is, for example, the (+)- or (-)-menthyloxycarbonyl radical. Furthermore, the compounds of the formula I obtained can be converted into their salts, in particular, for pharmaceutical use, into their physiologically acceptable salts, with inorganic or organic acids. Acids suitable for this purpose are, for example, hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid, fumaric acid, succinic acid, lactic acid, citric acid, tartaric acid, maleic acid, methanesulphonic acid, 26 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 Xl 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 (1) have useful pharmacological properties, in particular in inhibiting action on various kinases, especially on receptor tyrosine kinases, such as VEGFR1, VEGFR2, VEGFR3, PDGFRa, PDGFR3, FGFR1, FGFR3, EGFR, HER2, c-Kit, IGF1 R and HGFR, Ft-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 thefollowing standard methods: Human umbilical cord endothelial cells (HUVEC) were cultivated in IMDM (Gibco BRL), supplemented with 10% foetal bovine serum (FBS) (Sigma), 50 pM B-mercaptoethanol (Fluka), standard antibiotics, 15 pg/ml of endothelial cell growth factor (ECGS, Collaborative Biomedical Products) and 100 pg/ml of heparin (Sigma) 27 on gelatin-coated culture bottles (0.2 % gelatin, Sigma) at 37 0 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 (ECGS + heparin). Using trypsin/EDTA, the cells were detached from the culture bottles and washed once with serum-containing medium. 2.5 x 10 cells were then seeded in each well. The proliferation of the cells was stimulated using 5 ng/ml of VEGF1 65 (vascular endothelial growth factor; H. Weich, GBF Brunswick) and 10 pg/mI 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 3 H-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 0 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% (IC 5 o) was derived therefrom. The compounds of the formula I according to the invention have an IC 5 0 between 50 pM and 1 nM.
28 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 al. (O'Reilly M.S. et al., Cell 88, 277-285, (1997); Parangi S. et al., Proc Natl Acad Sci USA 93, 2002-2007, (1996)). Thus, the compounds of the formula I, their tautomers, their stereoisomers or their physiologically acceptable salts are suitable, for example, for treating tumours (for example squamous epithelium carcinoma, astrocytoma, Kaposi sarcoma, glioblastoma, lung cancer, cancer of the bladder, neck carcinoma, oesophagus carcinoma, melanoma, ovarial carcinoma, prostate carcinoma, breast cancer, small 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 reocclusion of vessels after balloon catheter treatment, in vessel prosthetics or after implantation of mechanical devices for keeping vessels open (for example stents) or other disorders in which cell proliferation or angiogenesis play a role.
29 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, adramycin), 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.
30 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)methylenej 6-chloro-2-indolinone 1.7 3-Z-[1 -(4-(N-(2-dimethylaminoethyl)-N-acetylamino)anilino)-1 -(3,4 dimethoxyphenyl)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 31 1.11 3-Z-[1 -(4-(N -(2-dimethylaminoethyl)-N-methylcarbamoyl)anlino)-l -(3,4 d imethoxyph enyl)meth yl enej-6-ch loro-2-i nd olin one 20 3-Z-[1 -(4-(dimethylaminomethyl)anilino)-1 -(4-cyanophenyl)-methylenel 6-chloro-2-indolinone 3.0 3-Z-[1 -(4-(dimethylaminomethyl)anilino)-1 -(4-iodophenyl)methylene]-6 fl uoro-2-indoli none 3.1 3-Z-[1 -(4-(dimethylaminomethyl)anilino)-1 -(3-fluorophenyl)methyiene] 6-fluoro-2-indolinone 3.2 3-Z-[1 -(4-(N -(3-dimethylaminopropyl)-N-acetyla min o)anil ino)- 1 -(3 fl uorophenyl )meth ylen e] -6-flu oro-2-i ndol in one 3-Z-[1 -(4-(N -(4-methylpiperazin- I -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 acetyla m inoethyl)phen yl)methyl en el-6-fl uoro-2-i n dolin one 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 flujoro-2-indoli none 3.7 3-Z-I1-(4-(dimethylaminomethyl)anilino)-1 -(4 methoxycarbonylmethyl phenyl)methylen e] -6-fluoro-2-i ndoli none 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 meth oxycarbonyl methyl ph enyl)meth ylen e]-6-fl uoro-2-i n dol none 3.10 3-Z-[1 -(4-(dimethylaminomethyl)anlino)-1 -(3-(N-tert-butoxycarbony aminomethyl)phenyl)methylene]-6-fluoro-2-indolinone 32. 3.11 3-Z-[1 -(4-(N-(2-dimethylaminoethyl)-N-methylsulphonylamino)anilino) 1 -(4-methoxyca rbon ylmethylph en yl)methylene] -6-fl uoro-2-i ndol none 3-Z-[ I -(4-(N -(4-methylpiperazin- I -ylmethylca rbonyl )-N 3.12 methylamino)anilino)-1 -(4-methoxycarbonylmethylphenyl)methylene]-6 fluoro-2-indolinori 3.13 3-Z-[1 -(4-(dimethylaminomethyl)anilino)-1 -(3-cyanomethyiphenyl
)
methylene]-6-fluoro-2-i ndol none 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-I1 -(4-(dimethylaminomethyl)anilino)-1 -(4-(N-tert-butoxycarbonyl aminomethyl)phenyl)methylene]-6-fluoro-2-indolinone 3.16 3-Z-[1 -(4-(dimethylaminomethyl)anilino)-1 -(3-(N-tert-butoxycarbonyl-2 am inoeth yl)ph enyl)methylene] -6-fl uoro-2-i ndol none 3.17 3-Z-[1 -(4-(N-Acetyl-N-methylamino)anilino)-1 -(4-(2 meth oxycarbonyl ethyl)p henyl)methyl en e]-6-fl uoro-2 -in dol none 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-methylsulphonylaminio)anilino) 1 -(4-methoxyca rbonymethylphenyl)methylene]-6-f uoro-2-indolin one 3.20 3-Z-[.l -(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 33 3-Z-[1 -(4-(1 -methylimidazol-2-yI)anilino)-1 -(4-(2 3.23 methoxycarbonylethyl)phenyl)methylene-6-fluoro-2-ildolilofe 3.24 .3-Z-[1 -(4-methylsulphonylanilino)-1 -(4-(2 methoxycarbonylethyl)phenyl)methylene] -6-fluoro-2-ildolinonle 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-methylsulphonylamiIo)ahlio) 1 -(3-methoxyca rbonyl meth ylph enyl)methyl ene-6-fl uoro-2-i ndol in one 3.27 3-Z-[1 -(4-(4-methylpiperazin-I -yI-carbonyl)anilino)-1 -(3 methoxycarbonylmethyl phenyl)methylen e-6-fluoro-2-indoli none 3.28 3-Z-[1 -(4-(N -(dimethylaminomethylcarbonyl)-N-methylamino)anililo)- 1 (3-methoxycarbonylmethylphenyl)methylene-6-fluoro-2-ildolilofe 3.29 3-Z-[1 -(4-(N -(3-dimethylaminopropyl)-N-acetylamino)anilino)- 1 -(3 meth oxycarbonyl methyl ph enyl)meth ylen e]-6-fluoro-2 -in doli nonle 3.30 3-Z-[1 -(4-(N -(2-dimethylaminoethyl)-N-acetylamino)anilino)-1 -(3 meth oxyca rb onyl methyl ph enyl)meth ylen e]-6-fl uoro-2 -in doli none 3.31 3-Z-[l -(4-(N -(4-dimethylamino-butylcarbonyl)-N-methylamino)aniifo) I -(3-methoxyca rbonylmethylphenyl)methylene]-6-fluoro-2-i ndolin one 3.23-Z-[1 -Anilino-1 -(4-methoxyca rbonyl methyl phen yl )methylen e]-6-fl uoro 2-indolinone 3.33 3-Z-j1 -(4-(1 -methylimidazol-2-y )anilino)-1 -(4 m eth oxyca rbonyl methylph en yl)methyl en e]-6-flu oro-2 -indol none 3.34 3-Z-[1 -(4-(4-methylpiperazin-1 -ylcarbonyl)anilino)-1 -(4 methoxycarbonylmethylphenyl)methylenel-6-fluoro-2-indoli none 3-Z-[1 -(4-(N-(dimethylaminocarbonylmethyl)- N 3.35 methylsulphonylamino)anilino)-1 -(4-methoxycarbonylmethyiphenyl) methylene]-6-fluoro-2-indoli none 34 3.36 3-Z-[1 -(4-(N -(d imethyla mi nomethyl carbon yl)- N-meth ylami no)an i lno)- 1 (4-meth oxyca rbonylmethyl phenyl)meth ylen e] -6-fl uoro-2-i nd ol none 3.37 3-Z-[1 -(4-(N-methyl-N-acetylamino)anilino)-1 -(4 meth oxyca rbon ylmethylphenyl)meth ylen e]-6-fluoro-2 -in dol none 3.38 3-Z-[1 -(4-(N -(2-dimethylaminoethylcarbonyl)-N-methylamino)anilino)- (4-methoxyca rbonyl methyl ph enyl)methyl en e-6-fl uoro-2-i ndol none 3-Z-[1 -(4-methylsulphonylanilino)-1 -(4 m eth oxycarbon ymethylph en yl)m ethyl en e]-6-flu oro-2 -i ndol none 3.40 3-Z-[1 -(4-(N -(3-d imeth yla min opropyl ca rbonyl)-N -meth ylami no)ani Iin o) I -(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 -Aniiino-1 -(3-methoxycarbonylmethylphenyl)methylene]-6-fluoro 2-indolinone 3-Z-[1 -(4-methylsulphonylanilino)-l -(3-methoxycarbonylmethyiphenyl) methylene]-6-fluoro-2-indolinone 3.44 3-Z-[1 -(4-(lI -methylimidazol-2-yI)anilino)-1 -(3 methoxycarbonylmethylphenyl)methylenel-6-fluoro-2..indolinone 3-Z-[1 -(4-(N -(dimethylaminocarbonylmethyl)-
N
3.45 methylsulphonylamino)anilino)-l -(3-methoxycarbonylmethylphenyl) methylene]-6-fluoro-2-indol none 3.46 3-Z-[1 -(4- (N -(3-dimethylaminopropylcarbonyl)-N-methylamino)anilino) 1 -(3-methoxycarbonylmethylphenyl)methylenel-6-fluoro-2..indolinone 3.47 3-Z-[1 -(4-(N -(2-dimethylaminoethylcarbonyl)-N-methylamino)anilino)-1 (3-methoxycarbonyl methylphenyl)methylenel -6-fluoro-2-indoli none 3-Z-[1 -(4-(N-(4-methylpiperazin-1 -ylmethylcarbonyl)-N 3.48 methylamino)anilino)-1 -(3-(2-methoxycarbonylethyl)phenyl)methylene] 6-fluoro-2-indolinone 35 3-Z .- [1 -(4-(N-(2-dimethylaminoethyl)-N-methylsulphonylamino)anilino) 1 -( 3 -(2-methoxycarbonylethyI)phenyI)methyleneI..6-fluoro2indolinone 3.50 3-Z-[1 -(4-(N-(dimethylaminomethylcarbonyl)-N-methylamino)anilino)-1 _________( 3 -(2-methoxycarbonylethyl)phenyl)methylenel-6fluoro.2indolinone 3.51 3-Z-[1 -(4-(N-(3-dimethylaminopropyl)-N-a 'cetylamino)anilino)-1 -(3-(2 methoxycarbonyl eth yl)ph enyl)m ethylene] -6-fluoro-2 -in dol none 3-Z-[1 -(4-(N -(4-methylpiperazin-1 -ylmethylcarbonyl)-N 3.52 methylamino)anilino)-1 -(3-(N-tert-butoxycarbonyl aminomethyl)pheny)methylene]-6-fluoro-2..indolinone 3.53 3-Z-[1 -(4-(N-methyl-N-acetylamino)anilino)-1 -(3 acetylaminomethylphenyl)methylene-6chloro-2indolinone 3.54 3-Z-[1 -(4-(N-(3-dimethylaminopropyl)-N-acetylamino)anilino)-1 -(3 acetylaminomethylphenyl)methylene]-6-chloro.2-indolinone 3-Z-[1 -( 4 -(N-(2-dimethylaminoethyl)-N-methylsulphonylamino)anilno). 1 -( 3 -acetylaminomethylphenyl)methylene-6-chloro2indo i none 3.56 3-Z741 -(4-(N-(dimethylaminomethylcarbonyl)- N-methylamino)anilino)- 1
(
3 -a cetyla mi nomethyl ph enyl)mpeth ylen el -6-ch loro.2 -in dol inone 3.57 3-Z-[1 -(4-(2-dimethylaminoethyl)anilno)-l1-(4-(2 methoxycarbonylethyl)phenyl)methylenej -6-fluoro.2.indolin one 3.58 3-Z-[1 -( 4 -(N-(2-dimethylaminoethylcarbony).N-methylamino)anilino)- 1
(
4
-(
2 -methoxyca rbonyleth yl)ph enyl)meth ylen ej6fl uoro2-indo i none 3.59 3 -Z-[l -( 4 -(N-(dimethylaminomethylcarbonyl)..Nmethylamino)anilino)-1 . (4-(2-methoxyca rbonyl eth yl )ph en yl)meth ylen e]-6-fl uoro-2-i n dol none 3.60 3-Z-[l -(4-(2-dimethylaminoethyl)anilino)- I -(3-(2 ethoxycarbonylethy)phenyl)methylene-6fluoro.2in dolinone 3.61 3-Z-[1 -( 4 -(N-(2-dimethylaminoethyl)-N-acetylamino)anilino)-1 -(4-(2 methoxycarbonylethyl)phenyl)methylene..6fluoro.2.indolinone 36 3.62 3-Z-[1 -(4-(N-(3-dimethylaminopropylcarbonyl)-N-methylamino)aniliflo) 1 -(3-(2-eth oxycarbon ylethyl)phen yl)methylen e-6-fl uoro-2-i ndol inonle 3-Z-[1 -(4-(N-(4-dimethylaminobutylcarbonyl)-N-methylamino)anilino)- 1 3.63 (3-(2-ethoxyca rbonyl ethyl)ph en yl)methyl ene-6-fl uoro-2-i ndol inonle 3.64 3-Z-[1 -(4-(l -methylimidazol-2-yI)anilino)- 1 -(3-(2 ethoxycarbonylethyl)phenyl)methylene-6-fluoro-2-indo i none 3.65 3-Z-[1 -(4-(N-(4-dimethylaminobutylcarbonyl)-N-methylamino)anilino)- 1 (4-(2-meth oxyca rbonyl eth yl)phen yl)methylen e-6-fl uoro-2-i ndol none 3.66 3-Z-[1 anilino-1 -(4-(2-methoxycarbonylethyl)phenyl)methylene]-6-fluoro 2-indolinone 3.67 3-Z-[1 -(4-(pyrrolidin -1 -yimethyl)anilino)-1 -(4-(2 meth oxyca rbo nyl ethyl)ph enyl )m ethyl en e]-6-fl uoro-2-i nd olin one 3.68 3-Z-[1 -(4-(diethylaminomethyl )anilino)-1 -(4-(2 methoxycarbonylmethylphenyl)methylene]-6-fluoro-2-indolinone 3.71 -- Z-1 -(-2-dithxcrylaminomethyl)anilino)-1 -(4-(2 methoxycarbonylmethylphenyl)methylene]-6-fluoro-2-indolinone 3.72 3-Z-[ -(4-(dimethylaminoethyl)anilino)-1 -(3-2 meth oxycarbon ylethyl ph enyl)methyl en e]-6-fluoro-2 -in dol none 3.73 3-Z-[ -(4-(2-dimethylaminoethyl )anilino)- 1 -(4-2 meth oxycarbonyl ethylphenyl )methylene]-6-luoro-2-i ndoli none 3.74 3-Z-[1 -(4-(d1 methylimidaol-2-yI)anilino)-1 -(4-(2 ethoxycarbonylethyl)phenyl)methylene]-6-luoro-2-indolin one 3.753-Z-[1 -(4(-dimethylaminoethylanilino)-1 -(4-(2 methoxycarbonylethyl)phenyl)methylenel-6-chloro-2-indolinone 37 3.76 3-Z-[1 -(4-dimethylaminomethylanilino)-1 -(4-(2 ethoxyca rbonylethyl)phenyl)methylene]-6-fluoro-2-indoli none 3.773-Z-[1 -(4-((4- methylpiperazin-1 -yI)methyl)anilino)-1 -(3-(2 meth oxyca rbon ylethyl)ph enyl)meth ylen e] -6-fl uoro-2 -in dol in one 3.78 3-Z-[1 -(4-(imidazol-1 -ylmethyl)anilino)-1 -(3-(2 meth oxycarbon yleth yl)ph enyl)meth yl ene] -6-fl uoro-2 -in dol in one 3.79 3-Z41l -(4-((4- methylpiperazin-1 -yI)methyl)anilino)-1 -(4-(2 methoxycarbonylethyl)phenyl)methylene]-6-fluoro-2-i ndol in one 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-dimethylamin oethyl)-N-methyla min omethyl)a nIi no)- 1 (4-(2-meth oxyca rbon yleth yl)phen yl)meth ylen e-6-fl uoro.2.i n dol none 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 methoxycaprbonylethyl)phenyl)methylene] -6-chloro-2indolin one 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)aniino)-l -(3-(2 eth oxyca rbon yl ethyi)ph en yl)methylen e]-6-fl uoro-2-in doli none 3-Z-[1 -(4-(N-terl-butoxycarbonylmethylaminomethyl)anilino)-1 -(3-(2 3.6ethoxyca rbonylethyl)ph enyl)methylen e]-6-fl uoro-2-i ndoli none 3.87 3-Z-[1 -(4-dimethylaminomethylanilino)-1 -(3-methoxycarbonylmethoxy phenyl)methylene]-6-fluoro-2-indolinone 3.88 3-Z-[1 -(4-dimethylaminomethylanilino)-1 -(4-methoxycarbonylmeth oxy phenyi)methylene]-6-fluoro-2-indolinone 3.93-Z-[1 -(4-dimethylaminomethylaniiino)-1 -(3-(2-ethoxycar bonyl ethoxy)phenyl )methylenel-6-fluoro-2-indoli none 38 3.90 3-Z-[1 -(4-(pyrrolidin -1 -ylmethyl)anilino)-1 -(4-(2 methoxyca rbon yleth yl)ph en yl)meth ylen el-6-bromo-2 -in do i none 3.91 3-Z-[1 -(4-(dimethylaminomethyl)anilino)-1 -(4-(2 methoxycarbonylethyl)phenyl)methylene]-6-bromo-2-indoli none 3.92 3-Z-[1 -(4-(diethylaminomethyl )anilino)-1 -(4-(2 methoxycarbonylethyl)phenyl)methylene]-6-bromo-2-indolinone 3.93 3-Z-[1 -(3-dimethylaminomethyanilino)-l -(4-(2 methoxycarbonylethyl)phenyl)methylene] -6-fluoro-2-indoli none 3.94 3-Z-[1 -(3-dimethylaminomethylanilino)-1 -(3-(2 eth oxycarbonylethyl)ph enyl)meth ylen e]-6-fl uoro-2-in dol in one 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-indolin one 5.0 3-Z-[1 -(4-(N -methyl-N-methylsulphonylamino)anilino)- I -(3-(2 methoxycarbonylvinyl)phenyl)methylene]-6-chloro-2-indo i none 5.1 3-Z-[1 -(4-(dimethylaminomethyl)anilino)-1 -(4-(2-methoxycarbonyl vi nyl)ph en yl)meth ylene]-6-ch loro-2-ind ol none 5.2 3-Z-[1 -(4-(dimethylaminomethyl)anilino)-l -(4-(2-carbamoyl vinyl)phenyl)methylenel-6-fluoro-2-indolinone 5.3 3-Z-[1 -(4-(dimethylaminomethyl)anilino)-I -(4-(2-methoxycarbonyl vinyl)phenyl)methylene]-6-fluoro-2-indolinone 5.4 3-Z-I1 -(4-(dimethylaminomethyl)anilino)-l -(3-(2-methoxycarbonyl vi nyl)ph enyl)methylene]-6-fl uoro-2-i ndol none 6.0 3-Z-[1 -(4-dimethylaminomethylanilino)- 1 -(3-(2 methoxycarbonylethyl)phenyl)methylene]-6-chloro-2..indolinone * .6.13-Z-[1 -(4-(N-methyl-N-methylsulphonylamino)aniino>.1 -(3-(2 methoxycarbonylethyI)phenyI)methyleneI -6-chloro-2.i ndolin one 39 6.2 3-Z-[1 -(4-dimethylaminomethylanilino)-1 -(4(2crmol ethyl)phen yl)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 meth oxycarbonylethyl)phenyl)methylene] -6-fl uoro-2-i ndol none 7.0 3-Z-[1 -(4-dimethylaminomethylanilino)-1 -(4-aminomethyiphenyl) methylene]-6-chloro-2-indolinone 3-Z-[1 -(4-(N -((4-methylpiperazin-1 -yI)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) methyiene]-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 3-Z-[1 -(4-( methylaminomethyl)anilino)-1 -(4-(2 carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone 9.5 3-Z-[1 -(4-(methylaminomethyl)anilino)-1l -(4-(2-methylcarbamoyl eth yl)ph enyl)methylen e] -6-fl uoro-2-in dol none 3-Z-[1 -(4-(N -(4-methylpiperazin-1 -ylmethylcarbonyl)-N 9.6 methylamino)a nilino)-1 -(3-aminomethylphenyl)methylene]-6-fluoro-2 indolinone 40 9.7 3-Z-[1 -(4-(aminomethyl)anilino)- 1 -(4-(2 methoxycarbonylethyl)phenyl)methylenel-6-fl uoro-2-ildol inone 9.8 3-Z-[1 -(4-(aminomethyl)anilino)- 1 -(3-(2 9.8 ethoxyca rbonylethyl)phenyl)methylene]-6-fluoro-2-ildol ifnone 9.9 3-Z-[1 -(4-(methylaminomethyl)anilino)-1 -(3-(2 ethoxyca rbonylethyl)phenyl)methylene] -6-fluoro-2-indol i none 10.0 3-Z-[1 -(4-dimethylaminomethylanilino)-1 -(3-(2 carboxyethyl)phenyl)methylene]-6-chloro-2-indolinone 3-Z-[1 -(4-dimethylaminomethylanilino) -1 -(4-(2 10.1 carboxyethyl)phenyl)methylene]-6-fl uoro-2-indol none 10.2 3-Z-[1 -(4-dimethylaminomethylanilino)-1 -(3-carboxymethyiphenyl) methyl ene]-6-fluoro-2-indol none 10.3 3-Z-[I1 -(4-dimethylaminomethylanilino)-1 -(3-(2 carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone 10.4 3-Z-[1 -(4-dimethylaminomethylanilino)-1 -(4-carboxymethyiphenyl) methylene]-6-fluoro-2-indol none 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-ca rboxymeth yl phenyl) methylene] -6-fl uoro-2-i nd ol none. 10.7. 3-Z-(1 -(4-(N-methyl-N-acetylamino)anilino)-1 -(4-(2 ca rboxyethyl)phenyl)methylene]-6-fl uoro-2-indoli none 3-Z-[I1 -(4-(N -(4-methylpiperazin-1 -ylmethylcarbonyl)-N 10.8 methylamino)anilino)-1 -(4-(2-carboxyethyl )phenyl )methylene]-6-fl uoro 2-indolinone 10.9 3-Z-[1 -(4-(N-(2-dimethylaminoethyl)-N-methylsulphonylamino)anilino) 1 -(4-(2-carboxyethyl)phenyl)methylene]-6-fl uoro-2-indol none 41 10.10 3-Z-[1 -(4-(N-(3-dimethylaminopropyl)-N-acetylamino)anilino)- 1 -(4-(2 carboxyethyl)phenyl)methylene]-6-fl uoro-2-i ndolin one 10.11 3-Z-[1 -(4-(N-tert-butoxycarbonylmethylaminomethyl)anilino)-1 -(4-(2 ca rboxyethyl)ph enyl)meth ylene] -6-fl uoro-2-i ndol in one 10.12 3-Z-[1 -(4-(4-methylpiperazin-1 -ylcarbonyl)anilino)-1 -(4-(2 ca rboxyeth yl)phenyl)methyl en e]-6-fl uoro-2-i ndol in one 10.13 3-Z-[1 -(4-(l -methylimidazol-2-y)anilino)-1 -(4-(2 carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone 10.143-Z-[1 -(4-methylsulphonylanilino)-1 -(4-(2 ca rboxyethyl)phenyl)methylene]-6-fl uoro-2-i ndolin one 10.15 3-Z-[1 -(4-(4-methylpiperazin-1 -ylcarbonyl)anilino)- 1 -(3 carboxymethylphenyl)methylenej-6-fluoro-2-indolinone 3-Z-[1 -(4-(N-(4-methylpiperazin-1 -ylmethylcarbonyl)-N 10.16 methylamino)anilino)-1 -(3-carboxymethyiphenyI)methylene]-6-fluoro-2 indolinone 10.17 3-Z-[1 -(4-(N-(dimethylaminomethylcarbonyl)- N-methyiamino)anilino)- 1 (3-carboxymethylphenyl)methylene]-6-fluoro-2-indolinone 10.18 3-Z-[1 -(4-(N -(4-dirnethylaminobutylcarbonyl)-N-methylamino)anilino)- 1 (3-carboxymethylphenyl)methylene]-6-fluoro-2-indolinone 10.19 3-Z-[1 -Aniino-1 -(3-carboxymethylphenyl)-methylenel-6-fluoro-2 indolinone 10203-Z-[1 -(4-methylsulphonylanilino )-l -(3-carboxymethylphenyl) methylene]-6-fluoro-2-indolinone 10.21 3-Z-[1 -(4-(l -methylimidazo-2-y)anilino)-1 -(3-carboxymethylphenyI) methylene]-6-fluoro-2-indolinone 3-Z-[1 -(4-(N -(di methylaminocarbonyimethyl)- N 10.22 methyisulphonylamino)aniino)-1 -(3-carboxymethylphenyl)-methyl ene] 6-fluoro-2-indoiinone 42 10.233-Z-[1 anilino-1 -(4-carboxymethylphenyl)methylene]-6-fluoro-2 10.23 indolinone. 10.24 3-Z-[1 -(4-(l -methylimidazol-2-y)anilino)-1 -(4-carboxymethyiphenyl) methylene]-6-fluoro-2-indolinone 10.25 3-Z-[1 -(4-(N-(3-dimethylaminopropylcarbonyl)-N-methylamino)anlilo) 1 -(4-ca rboxymrethyl ph enyl)m ethyl ene]-6-fl uoro-2-i n dol none 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 -yI-carbonyl )anilino)-1 -(4 carboxymethylphenyl)methylene]-6-fluoro-2-indolinone 10.283-Z-[1 -(4-methylsulphonylanilino)-1 -(4-carboxymethyiphenyl) methylene]-6-fluoro-2-indol in one 10.29 3-Z-[1 -(4-(N -methyl-N-acetylamino)a nil ino)-1 -(4-carboxymethyiphenyl) methylen e]-6-fluoro-2-indolin one 3-Z-[1 -(4-(N-(dimethylaminocarbonylmehyl)- N 10.30 methylsulphonylamino)anilino)-1 -(4-carboxymethylphenyl)methylene] 6-fluoro-2-indol none 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-ca rboxymethyl ph enyl)methyl ene-6-fl uoro-2-i n dol none 3-Z-[1 -(4-(N-(4-methylpiperazin-1 -ylmethylcarbonyl)-N 10.33 methylamino)anilino)-1 -(3-(2-carboxyethyl)phenyl)methylenej-6-fluoro 2-indolinone 10.34 3-Z-[1 -(4-(N-(2-dimethylaminoethyl)-N-methylsulphonylamino)anili mo) 1 -(3-ca rboxymethyl ph enyl) methyl ene]-6-fl uoro-2-i n dol none 10 .3S 3-Z-[1 -(4-(N-(2-dimethylaminoethyl )-N-methylsulphonylamino)anilino) 1 -(3-(2-ca rboxyeth yl)ph enyl)meth ylen e] -6-flu oro-2-i ndol in one 43 10.36 3-Z-[1 -(4-(N -(dimethylaminomethyicarbonyl)- N-methylamino)anilino)- 1 (3-(2-ca rboxyethyl)phenyl)m ethylene] -6-fl uoro-2-indol none 10.37 3-Z-[1 -(4-(N-(3-dimethylaminopropyl)-N-acetylamino)anilino)- I -(3-(2 ca rb oxyethyl)ph enyl)methylen e] -6-fl uoro-2-i n doli none 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-ca rboxyeth yl)phen yl)methyl en e]-6-fl uoro-2-ndolminone 10.41 3-Z-[1 -(4-(2-dimethylaminoethyl )anilino)- 1 -(3-(2 ca rboxyeth yl)phenyl)meth yl ene] -6-fl uoro-2-i ndol in one 10.42 3-Z-[1 -(4-(N-(2-dimethylaminoethyl)-N-acetylamino)anilino)-1 -(4-(2 ca rboxyeth yl)ph enyl)meth ylen e]-6-fl uoro-2-i ndoljinone 3-Z-[1 -(4-(N-(3-dimethylaminopropylcarbonyl)-N-methylamino)anilino) 10.43 1 -(3-(2-carboxyethyl)phenyl)methylene]-6-fl uoro-2-indolin one 10.44 3-Z-[1 -(4-(N -(4-dimethylamino-butylcarbonyl)-N-methylamino)anili no) 1 -(3-(2-ca rboxyethyl)phenyl)methylene]-6-fluoro-2-in dolin one 10.45 3-Z-[1 -(4-(lI -methylimidazol-2-y)anilino)-1 -(3-(2 ca rboxyethyl)phenyl)methylene]-6-fl uoro-2-indoli none 10.46 3-Z-[1 -(4-(N-(4-dimethylaminobutylcarbonyl)-N-methylamino)anilino)- 1 (4-(2-carboxyeth yl)ph enyl)meth ylen e]-6-fl uoro-2-i n doli none 10.473-Z-[1 anilino-1 -(4-(2-carboxyethyl)phenyl)methylenej-6-fluoro-2, indolinone 10.48 3-Z-[1 -(4-(pyrrolidin-1 -ylmethyl)anilino)-1 -(4-(2 carboxyethyl)phenyl)methylenel-6-fluoro-2-indolinone 10.49 3-Z-[1 -(4-(diethylaminomethyl )anilino)-1 -(4-(2 10.49 ~ca rboxyeth yl)ph enyl)m ethylene-6-fl uoro-2-i ndolminone 44 10.50 3-Z-[1 -(4-aminomethylanilino)-1 -(4-(2-carboxyethyl)phenyl)methylene] 6-fl uoro-2-indoli none 10.51 3-Z-[1 -(4-(2-dimethylaminoethyl)anilino)- I -(3-carboxymethyiphenyl) methylene]-6-fluoro-2-indolinone 10.52 3-Z-[1 -(4-(2-dimethylaminoethyl)anilino)-1 -(4-carboxymethyiphenyl ) methylene]-6-fluoro-2-indoli none 10.53 3-Z-[1 -(4-(2-dimethylaminoethyl)anilino)- I -(4-(2 carboxyethyl)phenyl)methylene-6-chloro-2-indolinone 10.54 3-Z-[1 -(4-(l -methylimidazol-2-y)anilino)-1 -(4-(2 carboxyethyl)phenyl)methylene]-6-chloro-2-indolinone 10.55 3-Z-[1 -(4-dimethylaminomethylanilino)-1 -(4-(2 ca rboxyethyl)phenyl)methylene]-6-ch loro-2-i ndolin one 10.56 3-Z-[1 -(4-((4-methylpiperazin-1 -yI )methyl)anilino)-1 -(3-(2 ca rboxyethyl)phen yl)meth ylen el-6-fl uoro-2-i ndol none 10.57 3-Z-[1 -(4-(imidazol-1 -ylmethyl)anilino)-1 -(3-(2 ca rboxyethyl)ph enyl)meth ylen e-6-fl uoro-2-i ndol none 10.58 3-Z-[1 -(4-(N -(2-d imethylaminoethyl)-N-methyla min omethyl)anili no)-1 (3-(2-ca rboxyethyl)p henyl)meth ylen e]-6-fl uoro-2-i ndol none 10.59 3-Z-[1 -(4-((4- methylpiperazin-1 -yI)methyl)anilino)-1 -(4-(2 carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone 10.603-Z-[1 -(4-(imidazol-.1 -ylmethyl)anilino)-1 -(4-(2 carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone 10.613-Z-[1 -(4-(pyrrolidin-1 -ylmethyl)anilino)-1 -(4-(2 ca rboxyethyl)ph enyl)meth ylen e] -6-chlIoro-2 -i ndol none 10.62 3-Z-[1 -(4-(N-(2-dimethylaminoethyl)-N-rnethylaminomethyl)anilino)-1 (4-(2-ca rboxyethyl)ph en yl)methylen e] -6-fl uoro-2-i ndol none 10.633-Z-[1 anilino-1 -(3-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2 indolinone 45 10.64 3-Z-[1 -(4-aminomethylanilino)-1 -(3-(2-carboxyethyl)phenyl)methylenej 10.64 6-fluoro-2-indoli none 10.65 3-Z-[1 -(4-methylaminomethylanilino)- 1 -(3-(2 ca rboxyeth yl)phen yl)meth ylen e]-6-fl uoro-2-i ndol in one 1 0.66~ 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-fl uoro-2-indolin one 10.68 3-Z-[1 -(4-(pyrrolidin -1 -ylmethyl)anilino)-1 -(4-(2 ca rb oxyethyl)ph en yl)meth ylen e]-6-bromo-2-i ndol in one 10.69 3-Z-[1 -(4-(dimethylaminomethyl)anilino)- 1 -(4-(2 carboxyethyl)ph enyl)methylene]-6-bromo-2-indoli none 10.70 3-Z-[1 -(4-(diethylaminomethyl )anilino)-1 -(4-(2-carboxyethyl) methylenel-6-bromo-2-indolinone 10.71 3-Z-[1 -(3-dimethylaminomethylanilino)-1 -(4-(2 ca rboxyeth yl)ph en yl)m ethylen e]-6-fl uoro-2-i ndol none 10.72 3-Z-[1 -(3-dimethylaminomethyla nil ino) -1 -(3-(2 carboxyethy)phenyl)methylene-6-fluoro-2-indolinone 10.7 3-Z-[1 -(3-dimethylaminomethylanilino)-1 -(4-(2 carboxyethyl)phenyl)methylene]-6-chloro-2-indoli none 11.0 3-Z-[1 -(4-dimethylaminomethylanilino)-1 -(3-(2-carbamoyl ethyl)ph en yl)methylen e-6-chIoro-2-i ndol none 11.2 3-Z-[1 -(4-dimethylaminomethylanilino)-1 -(4-(2-.methylcarbamnoyl ethyl)phenyl)methylene]-6-floro-2-indoli none 11.3 3-Z-[1 -(4-dimethylaminomethylanilino)-1 -(3 __________ dimethylcarbamoylmethylphenyl)methylene] -6-fluoro-2-indolinone 46 11.4 3-Z-[1 -(4-dimethylaminomethylanilino)-1 -(3-(2-carbamoyl ethyl)phenyl)methylene]-6-fluoro-2-indolinone 11.53-Z-[1 -(4-dimethylaminomethylanilino)-1 -(3-(2-methylcarbamoyl ethyl)phenyl)methylene-6-fluoro-2-indoli none 11.6 3-Z-[1 -(4-dimethylaminomethyianilino)-1 -(3-(2-dimethylcarbamoyl ethyl)phenyl)methylene]-6-fluoro-2-indolinone 11.7 3-Z-[1 -(4-dimethylaminomethylanilino)- 1 -(3-carbamoylmethylphenyl) methylene]-6-fluoro-2-indolinone 11.8 3-Z-[1 -(4-dimethylaminomethylanlino)-1 -(3 meth ylca rba moylmethyl phenyl)methyl en e] -6-fl uoro-2 -in dol none 11.9 3-Z-I1 -(4-dimethylaminomethylanilino)-1 -(4-carbamoylmethyiphenyl) methylene]-6-fluoro-2-indolinone 11.10 3 -Z-[1 -(4-dimethylaminomethylanilino)-1 -(4-(2-dimethylcarbamoyl ethyl )phenyl)methylene]-6-fluoro-2-indolinone ~ ~ .11 3-Z-[1 -(4-dimethylaminomethylanilino)-1 -(4-(2-(4-mnethylpiperazin-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-ca rba moyl meth ylp hen yl)meth ylen e-6-fl uoro 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 11.153-Z-[1 -(4-dimethylaminomethylanilino)-1 -(4 methyl ca rba moyl methylpheny)methyl en e] 6-flu oro-2 -in d o none 11.63-Z-[1 -(4-(N -(2-di methylaminoethyl)-N-methylsu lphonyla mi no)a nil ino) I -(4-methylcarbamoylmethylphenyl)methylene-6-!fluoro.2-indolin one.
47 11.17 3-Z-[1 -(4-(N-(2-dimethylaminoethyl)-N-methylsulphonylamino)anililo) 1 -(4-d methyl carbamnoyl meth ylph en yl) methylen e-6-fl uoro-2-i ndol inonle 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-indoIiinone 3-Z-[1 -(4-(N-(4-methylpiperazin- I -ylmethylcarbonyl)-N 11.20 methylamino)anilino)-1 -(4-(2-methylcarbamoyl eth yl)phenyl)meth ylen el-6-fl uoro-2-i ndol none 11.21 3-Z-[1 -(4-(N -(2-dimethylaminoethyl)-N-methylsulphonylamino)ahlino) 1 -(4-(2-methylcarbamoylethyl)phenyl)methylene]-6-fluoro-2-indolinone 11.22 3-Z-[1 -(4-(N-tert-butoxycarbonylmethylaminomethyl)ainilino)-1 -(4-(2 methylcarbamoylethyl)phenyl)methylene] -6-fluoro-2-in doli none 11.23 3-Z-[1 -(4-(l -methylimidazol-2-yI)anilino)-1 -(4-(2-methylcarbamoyl ethyl)phenyl )meth ylen e] -6-fl uoro-2-.in dol none 11.243-Z-[1 -(4-methylsulphonylanilino)-1 -(4-(2-methylcarbamoyl eth yl)phen yl)methylen el-6-fl uoro-2-i n dol none 11.25. 3-Z-[1 -(4-(4-methylpiperazin-1 -ylcarbonyl )anil .ino)-1 -(4-(2 methyl ca rbamnoyl eth yl)ph en yl)methyl en e] -6-fl uoro-2-i n dol none methylca rbamoylmethylphenyl)methylene]-6-fluoro-2-indo i none 3-Z-[1 -(4-(N -(4-methylpiperazin-1 -ylmethylcarbonyl )-N 11.27 methylamino)anilino)-1 -(3-methylcarbamoylmethylphenyl)methylene]-6 fi uoro-2-indolinone 12..0 3-Z-[1 -(4-dimethylaminomethylanilino)-1 -(4-acetylaminomethylphenyl) 12.0 methylene]-6-chloro-2-indolinone 48 3-Z-[1 -(4-(N-(4-methylpiperazin-1 -ylmethylcarbonyl)-N 12.1 mhethylamino)anilino)-1 -(4-acetylaminomethylphenyl)methylenel-6 ch Ioro-2-indolinone 12.2 3-Z-II1 -(4-dimethylaminomethylanilino)-1 -(4-benzoyla min oph enyl) 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 1 .2.4 3-Z-[1 -(4-dimethylaminomethylanilino)-1 -(3-acetylaminomethyiphenyl) methylene]-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 benzoyla mi nomethyl phen yl)methyl ene] -6-f u oro-2-i ndol none 12.7 3-Z-I1 -(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 propi on ylami noeth yi)phen yl)meth ylen e]-6-fl uoro-2-i ndol in one 12.11 3-Z-[1 -(4-dimethylaminomethylanilino)- 1 -(3-(2 phenylacetylaminoethyl)phenyl)methylen e]-6-fl uoro-2 -i ndol none 12.12 3-Z-[1 -(4-dimethylaminomethylanilino)-1 -(4-acetylaminomethylphenyl) methylene]-6-fluoro-2-indolinone 12.13 3-Z-[1 -(4-dimethylaminomethylanilino)-1 -(4 propionylaminomethylphenyi)methylene]-6-fluoro-2-indolinone 49 12.14 3-Z-[1 -(4-dimethylaminomethylanilino)-I -(4 phen yla cetylami nomethylph enyl)meth ylene] -6-fl uoro-2.i ndol none 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-m ethyl piperazi n -1 -ylmethylcarbonyl)-N 12.16 methylamino)anilino)-1 -( 4 -propionylaminomethylphenyl)methylene]-6 fluoro-2-indolinone 3-Z-[1 -(4-(N -(4-methylpiperazin- 1 -ylmethylcarbonyl)-N 12.17 methylamino)aniino)-1 -(4-phenylacetylaminomethylphenyl) methylen el-6-fluoro-2-indoli none 3-Z-[1 -(4-(N -(4-methylpiperazin-1 -ylmethylcarbonyl)-N 12.18 methylamino)anilino)-1 -(3-cyclopropylcarbonylaminomethylphen yI) methyleneJ-6-fluoro-2-indol none 3-Z-[I1 -(4-(N -(4-methylpiperazin-1 -ylmethylcarbonyl)-N 12.19 methylamino)anilino)-1
-(
3 -cyclobutylcarbonylaminomethylphenyl) methylenel-6-fluoro-2-indolinone 3-Z-[1 -(4-(N -(4-methylpiperazin-1 -ylmethylcarbonyl)-N 12.20 methylamino)anilino)-1 -(3-(pyridin-2-yI carbon yla min ometh yl)phen yl)meth ylen e]-6fluoro.2.i n dol in one 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-mrethylpiperazin-1 -ylmethylcarbonyl)-N 12.22 methylamino)anilino)-1 -(3-(pyridin-3-yl carbonylaminomethyl )phenyl)methylene] -6-fluoro-2-indol in one 3-Z-[1 -(4-(N-(4-methylpiperazin-i, -ylmethylcarbonyl)-N 12.23 methylamino)anilino)-1
-(
3 -isobutyrylaminomethylphenyl)methylene]-6 fluoro-2-indolinone 50 3-Z-[1 -(4-(N -(4-methylpiperazin- 1 -ylmethylca rbonyl )-N 12.24 methylamino)anilino)-1 -(3-(3-methylbutyrylaminomethylphenyl) methyleneJ-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 carbonylai nomethy)pheny)methylene] -6fluoro-2-indoli none 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-m ethyl piperazin -1 -ylmethylcarbonyl )-N 12.31 methylamino)anilino)-1
-(
3 -(2-furoyiaminomethyl)phenyl)methylene]-6 fi uoro-2-indolinone 3-Z-[1 -(4-(N-(4-methylpiperazin-1 -ylmethylcarbonyl)-N 12.32 methylamino)anilino)-1 -(3-acetylaminomethylphenyl)methylene]-6 fluoro-2-indolinone 51 3-Z-[1-(4-(N-(4-methylpiperazin-1-ylmethylcarbonyl)-N 12.33 methylamino)anilino)-1 -(3-propionylaminomethylphenyl)methylene]-6 fluoro-2-indolinone 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-(pyrdin-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-(pyrdin-3-yl carbonylaminomethyl)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-methylbutyryl aminomethylphenyl)methylene-6-fluoro-2-indolinone 3-Z-[1 -(4-dimethylaminomethylanilino)-1 -(3 12.43 cyclohexylmethylcarbonylaminomethylphenyl)methylene]-6-fluoro-2 indolinone 52 3-Z-[1 -(4-dimethylaminomethylanilino)-1 -(3 12.44 methoxyacetylaminomethylphenyl)methylene]-6-fluoro-2-indolinone 3-Z-[1 -(4-dimethylaminome thylanilino)-1 -(3-(2-methoxybenzoyl 12.45 aminomethyl)phenyl)methylene-6-fluoro-2-ildolilofe 12.463-Z-[1 -(4-dimethylaminomethylanilino)-1 -(3-tert 12.46 butylacetylaminomethylphenyl)methylene]-6-fluoro-2-ildolilofe 3-Z-[1 -(4-dimethylaminomethylanilino)-1 -(3-(2 12.47 thiophenecarbonylaminomethyl)phenyl)methylee-6-fluoro-2 indolinone 12.483-Z-[1 -(4-dimethylaminomethylanilino)-1 -(3 12.48pivaloylaminomethylphenyl)methylene]-6-fluoro-2 -idolilofe 3-Z-[1 -(4-dimethylaminomethylanilino)-1 -(3-(2 12.49 fu royla mi nomethyl )phenyl)methyl en e]-6-fl uoro-2-i ndol inonle 12.503-Z-[1 -(4-dimethylaminomethylanilino)-1 -(3-(pyndin-4-yI 12.50carbonylaminomethyl)phenyl)methylene] -6-fluoro-2-indol in one 13.03-Z-[1 -(4-trimethylammoniummethylanilino) -1 -(4-(2 13.0 carboxyethyl)phenyl)methylene]-6-fluoro-2-ildoliflofe iodide 13.1 3-Z-[1 -(4-trimethylammoni ummethyla nil ino) -1 -(3-(2 13.1 ca rboxyethyl)phenyl)methylene]-6-fluoro-2-ildolifnonle iodide 14.*03-Z-[1 -(4-guanidinomethylanilino)-1 -(4-(2 carboxyethyl)phenyl)methylene]-6-fluoro-2-ildolilofe 3-Z-[1 -(4-guanidinomethylanilino)-1 -(3-(2 14.1 carboxyethyl)phenyl)methylene-6-fluoro-2-ildolilofe 53 Abbreviations used: HOBt = 1 -hydroxy-1 H-benzotriazole TBTU O-benzotrazol-1-yl-N,N,N',N'-tetramethyluronium tetrafluoroborate Preparation of the starting materials: Example 1: Dimethyl 2-(4-fluoro-2-nitrophenyl)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 0 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)
C
11
H
10 FN0 6 Mass spectrum: m/z = 270 [M-H] The following compounds are prepared analogously to Example 1: (1.1) Diethyl 2-(4-bromo-2-nitrophenyl)malonate from 2,5-dibromonitrobenzene and diethyl malonate Rf value: 0.40 (silica gel, petroleum ether/ethyl acetate = 5:1) C1 3
H
14 BrNO 6 54 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)
C
1 2
H
1 oN 2 0 6 Mass spectrum: m/z = 277 [M-H] Example 11: 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 rnl 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) Rr value: 0.40 (silica gel, methylene chloride/methanol) = 50:1
C,
0
H
8
N
2 0 4 Mass spectrum: m/z = 219 [M-H] Example IlIl: 4-Fluoro-2-nitrophenylacetic acid At 1 00"C, 50.0 g of dimethyl 2-(4-fluoro-2-nitrophenyl)malonate (starting material 1) 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 O'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
C
8
H
6
FNO
4 55 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 1ll) are hydrogenated in 600 ml of acetic acid under a hydrogen pressure of 50 psi. The catalyst is filtered off with suction and the solvent is distilled off. The crude product is triturated with 500 ml of petroleum ether, filtered off with suction, washed with water and dried. Yield: 82.5 g (91 % of theory) Rf value: 0.30 (silica gel, petroleum ether/ethyl acetate = 1:1)
C
8
H
6 FNO Mass spectrum: m/z = 150 [M-H] The following compounds are prepared analogously to Example IV: (IV.1) 6-Bromo-2-indolinone 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)
C
8
H
6 BrNO Mass spectrum: m/z = 210/212 [M-H} (IV.2) 6-Cyano-2-indolinone from methyl 4-cyano-2-nitrophenylacetate (starting material 11) using palladium/calcium carbonate as hydrogenation catalyst Rf value: 0.45 (silica gel, methylene chloride/methanol 9:1) CqH 6
N
2 0 Mass spectrum: m/z = 157 [M-H]~ 56 Example V: 1 -acetyl-6-fluoro-2-indolinone 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)
C
10
H
8 FN0 2 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)
C
1 1
H
1 CIlNO 6 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) C1oHaBrNO 2 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)
C
1
,H
8
N
2 0 2 Mass spectrum: m/z = 199 [M-H]~ 57 Example VI: I -acetyl-3-[1 -hydroxy-1 -(3-iodophenyl)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 trethylamine 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 1 00'C under reduced pressure. Yield: 12.9 g (59 % of theory) Rf value: 0.80 (silica gel, methylene chloride/methanol = 9:1)
C
1 7
H
11 CllN0 3 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-hydroxy-1-(4-chlorophenyl)methylene]-6-chloro-2-indolinone 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 58 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, 7335 7340) (VI.8) 1-acetyl-3-[1-hydroxy-1-(3-(N-tert-butoxycarbonylaminomethyl)phenyl) methylene]-6-fluoro-2-indolinone from 1-acetyl-6-fluoro-2-indolinone (starting material V) and 3-(N-tert-butoxycarbonyl aminomethyl)benzoic acid (preparation according to Tetrahedron 1997, 53, 7335 7340) (VI.9) 1-acetyl-3-[1-hydroxy-1-(3-cyanomethylphenyl)methylene]-6-fluoro-2 indolinone from 1 -acetyl-6-fluoro-2-indolinone (starting material V) and (3-carboxyphenyl) acetonitrile (preparation according to J. Prakt. Chem. 1998, 340, 367-374) (VI.10) 1-acetyl-3-[1-hydroxy-1-(4-(N-tert-butoxycarbonylaminomethyl)phenyl) methylene]-6-fluoro-2-indolinone from 1-acetyl-6-fluoro-2-indolinone (starting material V) and 4-(N-tert-butoxycarbonyl aminomethyl)benzoic acid (preparation according to Bioorg. Med. Chem. Lett 2000, 10, 553-557).
59 (VI.1-1) I -acetyl-3-[1 -hydroxy-1 -(4-iodophenyl)methylene]-6-fluoro-2-indolinone from 1-acetyl-6-fluoro-2-indolinone (starting material V) and 4-iodobenzoic acid (VI.12) 1 -acetyl-3-[1 -hydroxy-1 -(4-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 fl uoro-2-i ndol i none from 1 -acetyl-6-fluoro-2-indolinone (starting material V) and 3-(2 methoxycarbonylethyl)benzoic acid (preparation analogously to Tetrahedron 1997, 53, 7335-7340) (VI.16) 1-acetyl-3-[1-hydroxy-1-(3-(N-tert-butoxycarbonyl-2 aminoethyl)phenyl)methylene]-6-fluoro-2-indolinone from 1 -acetyl-6-fluoro-2-indolinone (starting material V) and 3-(N-tert-butoxycarbonyl 2-aminoethyl)benzoic acid (preparation analogously to Bioorg. Med. Chem. Lett 2000, 10, 553-557) (VI.17) 1-acetyl-3-[1-hydroxy-1-(4-(N-tert-butoxycarbonyl-2 aminoethyl)phenyl)methylene]-6-fluoro-2-indolinone from 1-acetyl-6-fluoro-2-indolinone (starting material V) and 4-(N-tert-butoxycarbonyl 2-aminoethyl)benzoic acid (preparation analogously to Bioorg. Med. Chem. Lett 2000, 10, 553-557) 60 (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 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 from 1 -acetyl-6-fluoro-2-indolinone (starting material V) and 3-(2 ethoxycarbonylethyl)benzoic acid (preparation analogously to Tetrahedron 1997, 53, 7335-7340) (VI.21) 1-acetyl-3-[1-hydroxy-1-(4-(2-methoxycarbonylethyl)phenyl)methylene]-6 chloro-2-indolinone from 1-acetyl-6-chloro-2-indolinone (starting material V.1) and 4-(2 methoxycarbonylethyl)benzoic acid (preparation analogously to Tetrahedron 1997, 53, 7335-7340) (VI.22) 1-acetyl-3-[1-hydroxy-1-(4-(2-ethoxycarbonylethyl)phenyl)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]-6 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) 61 (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]-6 fluoro-2-indolinone from 1-acetyl-6-fluoro-2-indolinone (starting material V) and 3-(2 ethoxycarbonylethyloxy)benzoic acid (preparation see PCT Int. Apple. W09620173, 60) (VI.26) 1 -acetyl-3-[1 -hydroxy-1 -(4-(2-ethoxycarbonylethyloxy)phenyl)methylene]-6 fluoro-2-indolinone from 1-acetyl-6-fluoro-2-indolinone (starting material V) and 4-(2 ethoxycarbonylethyloxy)benzoic acid (preparation see PCT Int. Apple. 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-acetVl-3-l1-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.
62 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)
C
1 8
H
1 3 CilN0 3 Mass spectrum: m/z = 438/440 [M-H]~ m.p. 185 - 187 "C The following compounds are prepared analogously to Example VII: (VII. 1) 1 -acetyl-3-[1 -methoxy-1 -(4-methoxycarbonylmethylphenyl)methylene]-6 fluoro-2-indol i none from 1-acetyl-3-[1-hydroxy-1-(4-methoxycarbonylmethylphenyl)methylene]-6-fluoro-2 indolinone (starting material VI.1) (VI l.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-I -(3,4-dimethoxyphenyl)methylene]-6-chloro-2-indolinone (starting material VI.3) (VI l.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-indoli none (starting material VI.4) (VI l.5) 1 -acetyl-3-[1 -methoxy- 1 -(3-fluorophenyl)methylene]-6-fluoro-2-indolinone 63 from 1-acetyl-3-[1-hydroxy-1-(3-fluorophenyl)methylene]-6-fluoro-2-indolinone (starting material VI.5) (VII.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-2 indolinone (starting material VI.6) (VII.7) 1-acetyl-3-[1-methoxy-1-(3-methoxycarbonylmethylphenyl)methylene]-6 fluoro-2-indolinone from 1-acetyl-3-[I-hydroxy-1-(3-methoxycarbonylmethylphenyl)methylene]-6-fluoro-2 indolinone (starting material VI.7) (VII.8) 1-acetyl-3-[1-methoxy-1-(3-(N-tert-butoxycarbonylaminomethyl)phenyl) methylene]-6-fluoro-2-indolinone from 1-acetyl-3-[1-hydroxy-1-(3-(N-tert-butoxycarbonyl aminomethyl)phenyl)methylene]-6-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) 64 (VII.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) (VII.13) . 1 -acetyl-3-[1 -methoxy-1 -(3-iodophenyl)methylene]-6-fluoro-2-indolinone from 1-acetyl-3-[1-hydroxy-1-(3-iodophenyl)methylenej-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) (VII.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 aminoethyl)phenyl)methylene]-6-fluoro-2-indolinone from 1 -acetyl-3-[1 -hydroxy-1 -(3-(N-tert-butoxycarbonyl-2 aminoethyl)phenyl)methylene]-6-fluoro-2-indolinone (starting material VI. 16) (VII.18) 1 -acetyl-3-[1 -methoxy-1 -(3-acetylaminomethylphenyl)methylene]-6 fluoro-2-indolinone from 1-acetyl-3-[1-hydroxy-1-(3-acetylaminomethylphenyl)methylene]-6-fluoro-2 indolinone (starting material VI.19) 65 (VII.19) 1 -acetyl-3-[1 -methoxy-1 -(3-(2-ethoxycarbonylethyl)phenyl)methylenel 6-fluoro-2-indolinone from 1-acetyl-3-[1-hydroxy-1-(3-(2-ethoxycarbonylethyl)phenyl)methylene]-6-fluoro-2 indolinone (starting material VI.20) (VII.20) 1-acetyl-3-[1-methoxy-1-(4-(2-methoxycarbonylethyl)phenyl)methylene] 6-chloro-2-indolinone from 1-acetyl-3-[1-hydroxy-1-(4-(2-methoxycarbonylethyl)phenyl)methylene]-6-chloro 2-indolinone (starting material VI.21) (VII.21) 1 -acetyl-3-[1 -methoxy-1 -(4-(2-ethoxycarbonylethyl)phenyl)methylene] 6-fluoro-2-indolinone from 1-acetyl-3-[1-hydroxy-1-(4-(2-ethoxycarbonylethyl)phenyl)methylene]-6-fluoro-2 indolinone (starting material VI.22) (VII.22) 1 -acetyl-3-[1 -methoxy-1 -(4-methoxycarbonylmethyloxyphenyl) methylene]-6-fluoro-2-indolinone from 1-acetyl-3-[1-hydroxy-1-(4-methoxycarbonylmethyloxyphenyl)methylene]-6 fluoro-2-indolinone (starting material VI.23) (VII.23) 1 -acetyl-3-[1 -methoxy-1 -(3-methoxycarbonylmethyloxyphenyl) methylene]-6-fluoro-2-indolinone from 1-acetyl-3-[1-hydroxy-1-(3-methoxycarbonylmethyloxyphenyl)methylene]-6 fluoro-2-indolinone (starting material VI.24) (VIl.24) 1 -acetyl-3-[1-methoxy-1 -(3-(2 ethoxycarbonylethyloxy)phenyl)methylene]-6-fluoro-2-indolinone from 1-acetyl-3-[1-hydroxy-1-(3-(2-ethoxycarbonylethyloxy)phenyl)methylene]-6 fluoro-2-indolinone (starting material VI.25) (VII.25) 1-acetyl-3-[1-methoxy-1 -(4-(2 ethoxycarbonylethyloxy)phenyl)methylene]-6-fluoro-2-indolinone 66 from 1-acetyl-3-[1-hydroxy-1-(4-(2-ethoxycarbonylethyloxy)phenyl)methylene]-6 fluoro-2-indolinone (starting material VI.26) (VII.26) 1 -acetyl-3-[1 -methoxy-1 -(4-(2-methoxycarbonylethyl)phenyl)methylene] 6-bromo-2-indolinone 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)methylenel-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 1 00*C for 6 hours. After addition of a further 1.0 g of phosphorus pentachloride, the mixture is stirred at 1 10 0 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)
C
1 8
H
1 0 C1 2
N
2 0 2 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 67 (IX.5) 4-(2-d imethylaminoethyl)a nil ine (IX.6) 4-[N-(2-dimethylaminoethyl)-N-acetylaminolaniline (IX.7) 4-[N-(3-dimethylaminopropyl )-N-acetylamino]aniline (IX.8) 4-[(N -d imeth ylami noca rbonyl methyl-N- meth ylsuIph onyl)a min o]aniline (IX.9) N-(4-aminophenyl)-N-methylmethanesulphonamide (IX. 10) N-(d imethylaminomethylcarbonyl)-N-methyl-p-phenylenedia mine (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 -yI )methyl]aniline (IX.1 5) 4-(imidazol-1 -ylmethyl)aniline (IX. 16) 4-(1 -methylimidazol-2-y)aniline (IX. 17) 4-[(N-(2-d imethylani noethyl )-N-methyla min o)methylla niline (IX. 18) 4-(N-methyl-N-tert-butoxycarbonylaminomethyl)aniline (IX. 19) N-[(4-methylpiperazin-1 -yI)methylcarbonyl-N-methyl-p-phenylenediamine (IX.20) 4-(4-tert-butoxycarbonylpiperazin-1 -yI methyl )aniline (IX.2 1) 4-(thiomorpholin-4-ylmethyl)aniline 68 (IX.22) 4-(pyrrolidin-1-ylmethyl)aniline (IX.23) 4-(morpholin-4-yl-methyl)aniline (IX.24) 4-(N-benzyl-N-methylaminomethyl)aniline (IX.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 69 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)methylene)-6 -chloro-2-indolinone (starting material VII) and 0.5 g of N-methyl-N-methylsulphonyI-p-phenylenediamine (starting material IX.9) are dissolved in 10 ml of dimethylformamide and stirred at 120 0 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 1 00*C. Yield: 0.9 g (74% of theory), Rf value: 0.6 (silica gel, methylene chloride/methanol = 9:1) m.p. 292-294 *C
C
23 Hi 9 CilN 3 0 3 S Mass spectrum: m/z = 578/580 [M-H]~ The following compounds of the formula 1-1 are prepared analogously to Example 1.0: 4' R 3 N /H 0 CN (I-I)
H
70 Ex- 3 Starting Empirical Mass m.p. Rf ampl R3 R mate- formula spectrum [*C] value* e als VII 529/531 238- 0.30 1.1
-CH
2 -NMe 2 IX. C 24
H
21 CllN 3 0 [M+H]* 240 (A) Ci -N(Me)-(CO)- VII.2 495/497 277- 0.20 1.2 C26H24Cl2N40249/7 27- 00
CH
2 -NMe 2 IX.10 [M+H]* 279 (B) CI -N(COMe)- VII.2 507/509 241- 0.10
(CH
2
)
2 -NMe 2 IX.6 [M-H]- 243 (B) Cl f--N-Me VII.2 548/550 266- 0.10 1.4 e. 0 IX.19 C 2 9H29Cl 2
N
5
O
2 [M-H] 268 (B) 1.5 N(COMe)- V.2 521/523 241- 0.10
(CH
2 )3-NMe 2 IX.7 [M-H]- 242 (B) ci VII.2 438/440 243- 0.10 1.6
-CH
2 -NMe 2 IX. C 24
H
21
C
2
N
3 0 [M+H]* 244 (B) MeO OMe -N(COMe)- VII.3 533/535 128- 0.75 (CH2)2-NMe2 IX.6 [M-H]- 130 (C) MeO OMe ICN-Me VII.3 574/576 208- 0.65 1.8 Me. N IX.19 C 3 1 H34CIN 5
O
4 [M-H- 210 (C) MeO OMe -N(SO 2 Me)- V1l.3 569/571 198- 0.75 1.9 C 28
H
31
CIN
4 0sS [MH 20 (C
(CH
2
)
2 -NMe 2 IX.2 [M-H]- 200 (C) MeO OMe VII.3 462/464 239- 0.70 1.10
-CH
2 -NMe 2 IX. C 2 6
H
26
CIN
3 0 3 [M-Hj- 240
(C)
71 MeO OMe O Me V11.3 533/535 147- 0.70 1.11 -N 29
H
31
CN
4 0 4 M- 149 (C) NMe 2 IX.29 *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)-1 -(4-cyanophenyl)methylenel-6-chloro-2 indolinone 1.07 g of 1-acetyl-3-[1-chloro-1-(4-cyanophenyl)methylene]-6-chloro-2-indolinone (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 0 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)
C
2 5
H
21
CIN
4 0 Mass spectrum: m/z = 427/429 [M-H] Example 3.0 3-Z-[1-(4-(dimethylaminomethyl)anilino)-1 -(4-iodophenyl)methylenel-6-fluoro-2 indolinone 3.5 g of 1 -acetyl-3-(1 -methoxy-1 -(4-iodophenyl)methylene)-6-fluoro-2-indolinone (starting material VII.1 1) and 1.6 g of 4-(dimethylaminomethyl)aniline (starting 72 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 1 00"C. Yield: 1.9 g (46% of theory), Rf value: 0.3 (silica gel, methylene chloride/methanol = 9:1) m.p. 243-246 *C
C
24
H
21
FIN
3 0 Mass spectrum: m/z = 514 [M+H]* The following compounds of the formula 1-3a are prepared analogously to Example 3.0: R4' R3 N /H 0 R2 N (1-3a) Ex- Starting Empirical Mass m.p. Rf amp R2 R 3
R
4 ' materi formula spectrum ["C] value* le als F VII.5 404 225- 0.20 3.1 -F -CH 2 -NMe 2
C
24
H
21
F
2
N
3 0 '''IX.4 [M-H]- 227 (A) F -N(COMe). VII.5 491 160- 0.20 3.2 -F
(CH
2
)
3 -NMe 2 X.7 C 28
H
28
F
2
N
4 2 M+H] 163 (A) 73 F r--N-Me F e N. 1 VII.5 518 218- 0.40 3.3 -F M IX. C 2 9
H
29
F
2
N
6
O
2 [M+H] + 220 (A)
H
3 Cy.O N VII.6 471 106- 0.25 3.4 -F -CH 2 -NMe 2
C
2 aH 29
FN
4 0 2 [MH 10 (A IX.4 [M-H]- 110 (A)
H
3 Cy.O N -N(COMe)- VII.6 558 194- 0.25 3.5 -F C32HaeFNsO3
(CH
2
)
3 -NMe 2 IX.7 [M+H]* 196 (A)
H
3 Cr 0 H3N- r N-Me 3.6 -F Me 4 N "MN VII.6 583 238- 0.25 O 0 IX.19 [M-H]- 240 (A) O e VIl.1 460 173- 0.30 3.7 -F -CH 2 -NMe 2
C
27
H
26
FN
3 0 3 IX.4 [M+H]* 176 (A) Vll.13 514 198- 0.30 3.8 -F -CH 2 -NMe 2
C
2 4
H
21
FIN
3 0 IX.4 [M+H]* 200 (B) 0 OMe V11.7 458 195- 0.25 3.9 -F O e -CH 2 -NMe 2
C
2 7
H
26
FN
3 0 3 IX.4 [M-H]- 198 (A) tBuOy.o NH Vll.8 .517 230- 0.30 3.1.0 -F NH -CH2-NMe2 VI8 CoH33FN403 51 23-00 IX.4 [M+H]* 240 (A) 74 3.11 -F OMe -N(SO 2 Me)- VII.1 567 188- 0.40 31 -FC 29
H
31
FN
4 0sS .MH~18 A
(CH
2
)
2 -NMe 2 IX.2 [M+HJ 189 (A) 0O-- eM O.12 OF. N N, V1.1 572 200- 0.35 3.12 -F Me.N~-~ O iX.19 C3 2 HMFN5O4 [M+H]* 203 (C) CN VII.9 427 130- 0.25 3.13 -F -CH 2 -NMe 2 I.4 C 26
H
23
FN
4 0 [ +] 13 5 (A) IX.4 [M+Hf+ 135 (A) OtBu /-N.Me
HN
4 0 N V1l.10 629 215- 0.35 '.14-F 0 IX.19 CasH 41
FN
6
O
4 [M+H]* 220 (A) OtBu HN O Vll.10 517 186- 0.35 3.15 -F -CH 2 -NMe 2 I.4 C 3 oH 33
FN
4 0 3 [ +] 1 9 0 .(A IX.4 [M+H]+ 190 (A) OtBu 0 ' NH VIl.17 531 0.40 3.16 -F -CH 2 -NMe 2
C
31
H
35
FN
4 0 3 , n.d. / \ IX.4 [M+H]~ (A) OMe O VIl.15 488 166- 0.40 3.17 -F -NMe-(COMe)
C
28
H
26
FN
3 0 4 [ +] 17 0 .(A /N[M+H]+ 170 (A) OMe -- Ne 3.18 -F O Me. N
C
33
H
36
FN
5 0 4 586 176- 0.30 3 0 IX.19 [M+H]* 180 (A) 75 OMe o -N(SO 2 Me)- VII.15 581 195- 0.45 3.19 -F CaoH 33
FN
4 0 5 S,
(CH
2
)
2 -NMe 2 IX.2 [M+H]+ 198 (A) OMe o -N(COMe)- VII.15 559 100- 0.50 3.20 -F C 32 HasFN 4 0 4 .
(CH
2
)
3 -NMe 2 IX.7 [M+H]+ 104 (A) OMe o Me VII.15 558 132- 0.80 3.21 -F -(N OtBu IX.18 C 32 H34FN 3 0 5 [M-H 137 (D) OMe oVll.15 543 234- 0.60 3.22 -F -N C31HIFN40 3.22 F. N -Me IX.30 C 3 1H 31
FN
4 0 4 [M+H]* 236 (A) OMe O N-3 Vll.15 497 110- 0.40 3.23 -F N C 29
H
25
FN
4 0 3 . Me IX.16
[M+H]
4 115 (A) OMe VII.15 495 130- 0.60 3.24 -F
-SO
2 Me
C
26
H
23
FN
2 0 5 S [M+H]* 137 (A) lox 0 r-N-Me O~ eN~ VIl.7 572 0.60 3.25 -F OMe Me.
C
3 2 H34FNsO 4 189 3 IX.19 [M+H]* (B) OMe -N(SO 2 Me)- VII.7 567 0.60 3.26 -F * C 29
H
31
FN
4 0 5 S n.d. - . (CH 2
)
2 -NMe 2 IX.2 [M+H]* (B) 76 0 OMe 0 f'N-Me VI.7 529 201- 0.60 3.27 -F Oe NN-Me IX.30 CaoH2FN 4 0 4 [M+H]* 203 (B) 0 OMe -N(Me)-(CO)- VII.7 517 0.60 3.28 -F * C 29 H29FN 4 0 4 , 126
CH
2 -NMe 2 IX.10 [M+H] (B) OMe -N(COMe)- V1I.7 531 0.50 3.29 -F *C 30
H
31
FN
4 0 4 179
(CH
2
)
2 -NMe 2 IX.6 [M+H]* (B) 0 OMe -N(COMe)- VII.7 545 0.20 3.30 -F ""C 31
H
33
FN
4 0 4 123
(CH
2
)
3 -NMe 2 IX.7 [M+H]* (B) 0 OMe -N(Me)-(CO)- VII.7 559 0.20 3.31 -F * C 32 HasFN 4 0 4 201
(CH
2
)
4 -NMe 2 IX.32 [M+H]* (B) OOMe VIl.1 403 198- 0.80 3.32 -F -H C 24
H
19
FN
2 0 3 [ +] 2 0 8A 3.33 -F~N C28H23FN403 Me IX.16 [M+H]* 226 (A) 0 e O N-Me VII.1 529 215- 0.30 3.34 -F NC30H29FN404 IX.30 [M+H]* 220 (A) 0OMe -(0M) OMe -N(SO 2 Me)- Vl.1 581 227- 0.65 3.35 -F (CH 2 )-(CO)- C 29 H29FN 4 0 6 S IX.8 [M+H]* 230 (A) .- NMe2 77 0 OMe -N(Me)-(CO)- VII.1 517 128- 0.45 3.36 -F CH 2 -NMe 2 ix.10 C 29
H
29
FN
4 0 4 [M+H] 130 (A) O OMe -N(COMe)- VIl.1 474 218- 0.40 3.37 -F
CH
3
C
27
H
24
FN
3 0 4 [M+H]* 223 (A) O OMe -N(Me)-(CO)- Vll.1 531 192- 0.40 33 -(CH 2
)
2 -NMe 2 IX.11 C 3
H
31
FN
4 0 4 [M+H]* 194 (A) 0 OMe VIl.1 481 205- 0.65 3.39 -F
-SO
2 Me
C
25
H
21
FN
2 0 5 S [M+H]* 214 (A) 0OMe 3 OF -N(Me)-(CO)- VIl.1 545 190- 0.15
(CH
2
)
3 -NMe 2 IX.33 [M+H]* 193 (A) - e N(COMe)- VII-1 545 184- 0.50
(CH
2
)
3 -NMe 2 IX.7 [M+H]* 188 (A) 0 O~e VIl.7 403 0.70 3.42 -F OMe -H C 24
H
19
FN
2 0 3 114 [M+H]* (B) 0 O~e VIl.7 481 0.60 3.43 -F OMe -SO 2 Me C 25
H
21
FN
2 0 5 S 129 [M+H] (B) 0 NO VI1.7 483 0.60 3.44 -F N C 28
H
23
FN
4 0 3 125 Me IX.16 [M+H]+ (B) 78 o -N(SO 2 Me)- V1l.7 581 0.60 3.45 -F OMe (CH 2 )-(CO)- C 29 H29FN 4 0 6 S . 163 -. ~ e 2 IX.8 [M+H] (B) .- ' NMe2 0 OMe -N(Me)-(CO)- VII.7 545 0.10 3.46 -F *C 31
H
33
FN
4 0 4 ,101
(CH
2
)
3 -NMe 2 IX.33 [M+H] (B) 0 OMe -N(Me)-(CO)- VII.7 531 0.20 3.47 -F ,,~CaoH 31
FN
4 0 4 161
(CH
2
)
2 -NMe 2 IX.1 1 [M+H]* (B) MeO 0 r-N-Me M N Vll.14 586 181- 0.20 3.48 -F Me.N I.19 C 30
H
31
FN
4 0 4 [ + * 18 3 (B) 'j0 IX.19 [M+H]+ 183 (B) MeO O 3.49 -F
-N(SO
2 Me)- VII.14 581 158- 0.35
(CH
2
)
2 -NMe 2 IX.2 C 3
H
33
FN
4 0 5 S [M+H]* 160 (B) MeO 3.50 -F -N(Me)-(CO)- VII.14 531 0.40
CH
2 -NMe 2 IX.10 [M+H]* (B) MeO O 3.51 -F -N(COMe)- VII.14 559 0.50 35 -FC 32
H
3 sFN 4 0 4 n.d.
(CH
2
)
3 -NMe 2 IX.7 [M+H] .(E) tBuO 0 'NMe NH Me N I N VII.8 629 0.35 O IX.19 C 35
H
4
FN
6 0 4 [M+H]
(A)
79 Oy-CH 3 HN -NMe-(CO)- VII.26 473 122- 0.50 3.53 -F
CC
2 7
H
2
FN
4 0 3 [M+H]* 126 (F) OCCHH3 HN -N(COMe)- VII.26 544 80- 0.25
(CH
2
)
3 -NMe 2 IX.7 [M+H] 83 (A) Oy CH 3 HN -N(SO 2 Me)- VI1.18 566 190- 0.30 3.55 -F C 29
H
32
FN
5
O
4 S ,MH 4 19 A
(CH
2
)
2 -NMe 2 IX.2 [M+H] 195 (A) O yCH 3 HN -N(Me)-(CO)- VII.18 516 238- 0.30
CH
2 -NMe 2 IX.10 [M+H]* 241 (G) OMe o VII.15 488 205- 0.55 3.57 -F -(CH 2
)
2 -NMe 2 X C 2 9
H
3 oFN 3 0 3 [M+H]* 208 (G) OMe o -N(Me)-(CO)- VII.15 543 196- 0.20 3.58 -F C 31
H
31
FN
4 0 4
(CH
2
)
2 -NMe 2 IX.11 [M-H]- 202 (A) OMe o -N(Me)-(CO)- VI1.15 531 177- 0.30 3.59 -F C 30
H
31
FN
4 0 4
CH
2 -NMe 2 IX.10 [M+H]* 182 (A) EtO O Vll.19 500 100- 0.35 3.60 -F
-(CH
2
)
2 -NMe 2
IX.H
32
FN
3 0 3 [M-H]- 105 (B) 80 OMe O -N(COMe)- V11.15 545 167- 0.40
(CH
2
)
2 -NMe 2 IX.6 [M+H]* 169 (A) EtO -N(Me)-(CO)- VII-19 571 0.35 6 -F (CH 2
)
3 -NMe 2 IX.33 [M-H]- (A) EtO O 3.63 -F -N(Me)-(CO)- VII.19 585 0.40 I '~ (CH 2
)
4 -NMe 2 IX.32 [M-H]- (A) EtO O N VII.19 511 95- 0.25 3.64 -F N30H27FN403 hMe IX.16 .[M+H]* 105 (B) OMe O -N(Me)-(CO)- VII.15 573 173- 0.20 3.65 -FC3HFN0 6 -F (CH 2
)
4 -NMe 2 IX.32 [M+H]* 175 (A) OMe o VIl.15 417 168- 0.65 3.66 -F -H C 25
H
21
FN
2 0 3 [17 174 (A) [M+H]* 174 (A) OMe 3.67 -F 0VII.15 500 168- 0.40 3.67-F NC30HaoFN303 IX.22 [M+H]* 173 (B) OMe O VII.15 502 0.45 3.68 -F -CH 2 -NEt 2
C
3 oH 32
FN
3 0 3 n.d. 3.68 IX.1 [M+H]* (B) 81 OMe o H VIl.15 544 0.30 3.69 -F .-- NyOtBu C 31
H
32
FN
3 0 5 n.d. / O IX.12 [M-H]- (G) 0 OMe VIl.7 472 165- 0.25 3.70 -F ,, -(CH 2
)
2 -NMe 2
C
2 eH 2 8
FN
3 0 3 IX.5 [M-H]- 170 (B) 0 OMe VIl.1 472 193- 0.25 3.71 -F -(CH 2
)
2 -NMe 2
C
28
H
28
FN
3 0 3 [M-H] 197 (B) EtO O VII.19 488 48- 0.45 3.72 -F -CH 2 -NMe 2
C
29
H
3 oFN 3 0 3 IX.4 [M+H]* 52 (B) OMe o VII.20 504/506 156- 0.30 3.73 -CI -(CH 2
)
2 -NMe 2
C
29
H
30
CIN
3 0 3 [M+H]+ 160 (H) IX.5 [+] 6 H OMe o N3 VII.20 513/515 0.40 3.74 -CI '- N C 29
H
25
CIN
4 0 3 110 nMe IX.16 [M+H]* (H) OMe 0 VII.20 490/492 173- 0.70 3.75 -CI -CH 2 -NMe 2
C
28
H
28
CIN
3 0 3 [M+H]+ 175 (I) IX.4 [+] 7 l OEt O VII.21 488 158- 0.35 3.76 -F -CH 2 -NMe 2
C
29
H
3 oFN 3 0 3 IX.4 [M+H]* 161 (B) 82 MeO 3.77 -F r N-Me VII.14 529 147- 0.50 IX.4 C 31
HFN
4 0 3 [M+H]* 150 (I) MeO O N VII.14 497 182- 0.60 3.78 -F .rN ,,3 IX.15 C 29
H
25
FN
4 0 3 [M+H]* 185 (K) OMe 3.O 0r-N-Me Vll.15 529 0.35 -F r Ne C 3 1 H33FN 4 0 3 529 184 (B3 / - IX.14 [M+H]* (B) OMe O =N V11.15 497 0.45 3.80 -F /N\ ) C 29
H
2 5
FN
4 0 3 233 IX.15 [M+H] (B) OMe O -CH 2 -NMe- VII.15 531 0.40 3.81 -F C 31 HasFN 4 0 3 120
(CH
2
)
2 -NMe 2 IX.17 [M+H]* (B) EtO
-CH
2 -NMe- V1l.19 545 0.40 3.82 -F C 32
H
3 7
FN
4 0 3 n.d.
(CH
2
)
2 -NMe 2 IX.17 [M+H]. (K) OMe o V1l.20 516/518 195- 0.30 3.83 -CI . N7 C 30
H
30 C1N 3 0 3 38 NIX.22 [M+H]* 197 (H) EtO O Vi1.19 431 156- 0.80 3.84 -F -H
C
2 H23FN 2 0 3 [M+H]* 160 (M) 83 EtO O H VIl.19 560 0.50 3.85 -F -NyOtBu C 32 H34FN 3 0 5 n.d. o IX.12 [M+H]( EtO Me VIl.19 574 0.60 3.86 -F f-NOtBu C33HasFN30s . n.d. 30 IX.18 [M+H] (L) MeO VI1.22 476 0.25 3.87 -F -CH 2 -NMe 2 IX.4 C 27
H
26
FN
3 0 4 [M+H], 129 (B) OMe O e VII.23 476 0.25 3.88 -F 0 -CH 2 -NMe 2
C
2 7
H
26
FN
3 0 4 , 155 IX.4 [M+H] ~ (B) OEt Vll.24 504 0.20 3.89 -F O -CH 2 -NMe 2
C
29
H
30
FN
3 0 4 , n.d. IX.4 [M+H]+ (B) OMe o V1I.26 560/562 230- 0.45 3.90 -Br . -N' C 30
H
30 BrN 3 0 3 , 9 - r /IX .22 [M +H] + 235 (B) OMe VII.26 534/536 178- 0.35 3.91 -Br
-CH
2 -NMe 2 IX.4 C 28
H
28 BrN 3 0 3 [M+H]* 180 (B) OMe O VII.26 562/564 173- 0.40 3.92 -Br -CH 2 -NEt 2
C
3 oH 3 2 BrN 3 03 [M+H]+ 176 (B) 84 *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 (1): 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 1-3b are prepared analogously to Example 3.0: R4'
R
3 N / H O R N (1-3b) Ex- Starting Empirical Mass m.p. Rf amp R R
R
4 ' materi formula spectrum [*C] value* le als OMe 0 V1l.15 474 176- 0.40 3.93 -F
-CH
2 -NMe 2 IX.3 C 28
H
28
FN
3 0 3 [M+H]* 179 (A) 85 EtO O VIl.19 486 0.45 3.94 -F -CH2-NMe2 C29HaoFN303 n.d. / HFIX.3 [M-H]- (B) OMe O VIl.20 490/492 163- 0.40 3.95 -Cl -CH 2 -NMe 2
C
28
H
28
CIN
3 0 3 [M+H]* 165 (A) / \ ~~~IX.3 [+] 6 A *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)methylenel-6 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 0 C for 2 hours. After cooling, the solvent is removed under reduced pressure and the residue is purified on a silica gel column using the mobile phase methylene chloride/methanol 9:1. Yield: 21 mg (12% of theory), Rf value: 0.35 (silica gel, methylene chloride/methanol 9:1) m.p. 265 C
C
27
H
26
N
4 0 3 86 Example 5.0 3-Z-[1 -(4-(N-Methyl-N-methylsulphonylamino)anilino)-1 -(3-(2-methoxycarbonyl vinyl)phenyl)methylenel-6-choro-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(ll) 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 0 C for 10 hours. After cooling, the solution is filtered through Celite, the solvent is removed under reduced pressure and the residue is purified on a silica gel column using the mobile phase methylene chloride/methanol 20:1. Yield: 450 mg (84% of theory), Rf value: 0.30 (silica gel, toluene/ethyl acetate = 1:1) m.p. 228-232 "C
C
27
H
2 4
CIN
3 0 5 S Mass spectrum: m/z = 537/539 [M]* The following compounds of the formula 1-5 are prepared analogously to Example 5.0: R4' R3 N /H 0 E N R N (1-5) 87 Start Ex- 2 3 ing Empirical Mass m.p. Rr ampl R R mate- formula spectrum [*C] value* rials OMe 486/488 150- 0.50 5.1 -Cl
-CH
2 -NMe 2 1.1 C 28
H
26
CIN
3 0 3 [M-H]- 155 (A)
NH
2 o -455 269- 0.20 5.2 -F -CH 2 -NMe 2 3.0 C 27
H
25
FN
4 0 2 [M-H]- 270 (B) OMe / 470 205- 0.65 5.3 -F -CH 2 -NMe 2 3.0 C 28
H
2 6
FN
3 0 3 [M-H] 206 (A) SOMe 472 138- 0.45 5.4 -F
-CH
2 -NMe 2 1.1 C 28
H
26
FN
3 0 3 [M+HJ 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-indolifnone (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 88 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
C
28
H
28
CIN
3 0 3 Mass spectrum: m/z = 490/492 [M+H]* The following compounds of the formula 1-6 are prepared analogously to Example 6.0: R4'
R
3 N /H 0 R2H N (1-6) H Start Ex am- 4. ing Empirical Mass m.p. Rf am- mate- formula spectrum [C] value* pie rials 0 OMe -N(Me)- 538/540 148- 0.50 6.1 -Cl 5.0 C IN / \ SO 2 Me 50 CH 2 CN0S [M-H]- 150 (A) 89 NH2 459 0.70 6.2 -F -CH 2 -NMe 2 5.2 C 27
H
27
FN
4 0 2 150 / "' [M+H]* (B) OMe 0 474 0.35 6.3 -F -CH 2 -NMe 2 5.3 C 28
H
28
FN
3 0 3 140 / - [M+H]* (A) O OMe 474 140- 0.30 6.4 -F -CH 2 -NMe 2 5.4 C 28
H
28
FN
3 0 3 [M+HJ+ 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-Dimethylaminomethylanilino)-1-(4-aminomethylphenyl)methylenel-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.
90 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
C
2 5
H
2 5
CIN
4 0 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 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 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 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
C
3 0
H
3 3 CINs0 2 Mass spectrum: m/z = 544/546 [M] 91 Example 9.0 3-Z-1 -(4-(Dimethylaminomethyl)anilino)-1 -(3-aminomethylphenyl)methylenel-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 1N aqueous sodium hydroxide solution. The organic phase is dried over sodium sulphate, the solvent is removed using a rotary evaporator and the residue is purified on a silica gel column using the mobile phase methylene chloride/methanol/ammonia 9:1:0.1. The product is washed with a little diethyl ether and dried under reduced pressure. Yield: 1.77 g (81 % of theory), Rr value: 0.25 (silica gel, methylene chloride/methanol/ammonia 9:1:0.1) m.p. 168-175 *C
C
2 5
H
25
FN
4 0 Mass spectrum: m/z = 415 [M-H] The following compounds of the formula 1-9 are prepared analogously to Example 9.0: R4'
R
3 N /H 0 H2N (1-9)
H
92 Start Ex- 2 ing Empirical Mass m.p. Rf mate- formula spectrum ["C] value* ple rials
NH
2 431 155- 0.45 9.1 -F -CH 2 -NMe 2 3.16 C 2 6
H
2 7
FN
4 0 [M+H]* 160 (C)
NH
2 417 203- 0.25 9.2 -F -CH 2 -NMe 2 3.15 C 25
H
2 5
FN
4 0 [M+H]+ 207 (A)
NH
2 rNMe 529 170- 0.15 9.3 -F H 3 C NI 3.14 C 30 H33FN 6
O
2 [M+H]+ 175 (A) OH 0 446 245- 0.20 9.4 -F \ -CH 2 -NHMe 10.11 C 2
H
24
FN
3 0 3 [M+H]* 251 (D)
NHCH
3 0 459 239- 0.30 9.5 -F -CH 2 -NHMe 11.22 C 26
H
2 4
FN
3 0 3 [M+H]* 243 (A)
NH
2 <-NMe 529 9.6 -F H OC'NG 3.52 C 3 0
H
3 3
FN
6 0 2 [M+H] n.d. n.d. OMe 444 158- 0.25 9.7 -F -CH 2
-NH
2 3.69 C 2 6
H
24
FN
3 0 3 [ -] 1 63 (A) -[M-H]- 163 (A) 93 EtO 0 460 205- 0.30 9.6 -F
-CH
2
-NH
2 3.85 C 27
H
26
FN
3 0 3 [M+H]* 210 (B) EtO 474 148- 0.30 9.9 -F
-CH
2 -NHMe 3.86 C 28
H
28
FN
3 0 3 [M+H]* 150 (B) *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-[1 -(4-Dimethylaminomethylanilino)-1 -(3-(2-carboxyethyl)phenvl)methylenel-6 chloro-2-indolinone 900 mg of 3-Z-[1 -(4-dimethylaminomethylanilino)-1 -(3-(2 methoxycarbonylethyl)phenyl)methylenel-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 1 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 0 C
C
27
H
26
CIN
3 0 3 Mass spectrum: m/z = 476/478 [M+H]* 94 The following compounds of the formula 1-10a are prepared analogously to Example 10.0: 41
R
3 N H 0 R2 N (1-10a) Start Ex am- 2 4 3ing Empirical Mass m.p. Rf am- R2 R3 R' pie mate- formula spectrum [C] value* rials OH 0 460 0.65 10.1 -F -CH 2 -NMe 2 6.3 C 27
H
26
FN
3 0 3 250 l x[M+H] (A) OH O 444 278- 0.10 10.2 -F -CH 2 -NMe 2 3.9 C 2 6
H
24
FN
3 0 3 [M-H]- 282 (B) 0 OH 458 198- 0.20 10.3 -F -CH 2 -NMe 2 6.4 C 27
H
2 6
FN
3 0 3 [M-H]- 200 (C) oOH 10.4 -F -CH 2 -NMe 2 3.7 C 2 6
H
24
FN
3 0 3 [M-H] 216 (D) 95 0 OH N NMe 558 260- 0.20 10.5 -F H C 3.12 C 31
H
32
FN
5 0 4 0 -[M+H]* 263 (D) 0OH O O -NSO2e)-553 246- 0.30 10.6 -F 3.11 C 28 H29FN 4 0 5 S 53 249 0)
(CH
2
)
2 -NMe 2 [M+H]* 249 (D) OH O -NMe-(CO)- 474 286- 0.60 10.7 -F 3.17 C 27
H
24
FN
3 0 4 [M+H]+ 290 (E) O OH <NMe H3CN'J 570 215- 0.20 10.8 -F ch 3.18 C 32 H34FN 5
O
4 [M-H]- 222 (D) OH 0 -N(SO 2 Me)- 567 160- 0.20 10.9 -F 3.19 C 29
H
3 1FN 4 0 5 S [M+H 165 (D) I ' (CH 2
)
2 -NMe 2 [+] 6 D OH -N(COMe)- 545 153- 0.15 10.10 -F 3.20 C 31
H
33
FN
4 0 4 (CH2)3-NMe2 [M+H]* 158 (D) OH O Me 546 215- 0.60 10.11 -F -N OtBu 3.21 C 31
H
32
FN
3 0 5 [46 219 (E) 0 [M+H]* 219 (E) OH O O N-Me. 529 179- 0.25 10.12 -F 3.22 C 30
H
29
FN
4 0 4 [ [M+H]* 186 (E) 96 OH O Ng 483 264- 0.65 10.13 -F - 3.23 C 28
H
23
FN
4 0 3 [M+H]* 267 (E) OH O 481 146- 0.70 10.14 -F
-SO
2 Me 3.24 C 25
H
21
FN
2 0 5 S [M+H]* 155 (E) OH 0 0 515 0.70 10.15 -F N- M 3.27 C 29
H
27
FN
4 0 4 251 - - M+H]f (E) OH rNMe O H3N4J 558 0.10 10.16 -F H - O 3.25 C 31
H
32
FN
5 0 4 [ + * 234 (E) 0 [M+H]+ (E) OH O -N(Me)-(CO)- 503 0.60 10.17 -F CH2-NMe2 3.28 C 28
H
27
FN
4 0 4 [M+H* 203 (E) OH 10. 18 -F 0 -N(Me)-(CO)- 3.31 C 31 H33FN 4 0 4 545 251 n.d.
(CH
2
)
4 -NMe 2 [M+H] OH O 387 0.60 10.19 -F -H 3.42 C 23
H
17
FN
2 0 3 [M-H] 130 (E) OH O 467 0.55 10.20 -F 0 -SO 2 Me 3.43 C 24
H
1
FN
2 0 5 S M+H 139 (E) 97 OH O 469 0.35 10.21 -F -4
C
27
H
2 1
FN
4 0 3 [M+H] 157 (E) O OH -N(SO 2 Me)- . 567 0.55 10.22 -F
(CH
2 )-(CO)- 3.45 C 2 eH 27
FN
4 0S [M+H]* 183 (E) NMe 2 389 237- 0.10 10.23 -F -H 3.32 C 23
H
17
FN
2 0 3 [M+H]* 240 (D) 0 OH N 469 259- 0.15 10.24 -F 3.33 C 27
H
21
FN
4 0 3 -' e [M+H]+ 265 (D) 0 O -N(COMe)- 531 274- 0.15 10.25 -F (CH2)3-NMe2 3.41 C 3 oH 31
FN
4 0 4 [M+H]* 278 (D) - CH 2 )-NMe 2 [M+H]+ 278 (D) O H -N(Me)-(CO)- 503 258- 0.20 10.26 -F - CH 2 -NMe 2 3.36 C 28
H
27
FN
4 0 4 [M+H]* 264 (D) O OH 0 <'N-Me 515 279- 0.15 10.27 -F . N-j 3.34 C29H27FN404 [+] 8 D -[M+HJ+ 282 (D) 10.28 -F -SO 2 Me 3.39 C 24
H
1
FN
2 0 5 S 467 260- 0.35 OH 10.29 -F -(Oe 3.37 C 26
H
22
FN
3 0 4 46 29-03
CH
3 [M+H]+ 294 (F) 98 O OH -N(SO 2 Me)- 567 238- 0.30 10.30 -F CH 2 -(CO)- 3.35 C 28
H
27
FN
4 0 6 S [M+H]* 242 (F) . NMe 2 0 O o OH -N(Me)-(CO)- 517 250- 0.35 10.31 -F / j (CH 2
)
2 -NMe 2 3.3 C 29
HFN
4 4 [M+H] 255 (F) 0OH 10.32 -F -N(Me)-(CO)- 531 184- 0.25 10.3 -F3.40 CaoH 31
FN
4 0 4 . (CH 2
)
3 -NMe 2 [M+H]* 190 (F) O OH CNMe H3CNJ 572 170- 0.40 10.33 -F ,cN 3.48 C 32 H34FN 5
O
4 0j [M-H]~ 175 (C) OH o -N(SO 2 Me)- 553 0.60 10.34 -F 3.26 C 28
H
29
FN
4 0 5 S 180
(CH
2
)
2 -NMe 2 [M+H]* (C) O OH
-N(SO
2 Me)- 567 196- 0.30 10.35 -F 3.49 C 29
H
31
FN
4 0 5 S
(CH
2
)
2 -NMe 2 [M+H]* 199 (C) 0 OH 10.36 -F 3.50 C 29 H29FN 4 0 4 150 020
CH
2 -NMe 2 [M+H]+ (C) 0 OH 10.37 -F -N(COMe)- 3.51 C 3 1H 33
FN
4 0 4 545 206- 0.30
(CH
2
)
3 -NMe 2 [M+H]* 210 (A) 99 OH 0 -N(Me)-(CO)- 517 231- 0.60 10.38 -F
CH
2 -NMe 2 3.59 C 29 H2FN 4 0 4 [M+H]* 236 (A) OH 0 474 -218- 0.50 10.39 -F -(CH 2
)
2 -NMe 2 3.57 C 28
H
28
FN
3 0 3 [M+H]+ 222 (A) OH o -N(Me)-(CO)- 531 215- 0.50 14 -(CH 2
)
2 -NMe 2 [M+H]* 218 (A) 0 OH 474 172- 0.15 10.41 -F
-(CH
2
)
2 -NMe 2 3.60 C 2 8
H
2 8
FN
3 0 3 [M+H]* 177 (G) OH 0 -N(COMe)- 531 230- 0.50 10.42 -F (CH2)2-NMe2 3.61 C 30
H
3 1
FN
4 0 4 [M+H] 234 (A) 0 OIH -N(Me)-(CO)- 545 170- 0.30 10.43 -F
(CH
2
)
3 -NMe 2 3.62 C 3 1
H
33
FN
4 0 4 [M+H]* 175 (E) 0 OH -N(Me)-(CO)- 559 142- 0.10 10.44 -F
(CH
2
)
4 -NMe 2 3.63 C 32
H
3
FN
4 0 4 [M+H] 146 (G) 0 OH N 483 262- 0.20 10.45 -F N 3.64 C 28
H
23
FN
4 0 3 Me [M+H]' 269 (E) 100 OH O -N(Me)(CO)- 559 234- 0.30 10.46 -F -NMe 3.65 C 32
H
35
FN
4 0 4 + 236 (A)
/--(CH
2
)
4 -NMe 2 [MH 23 (A OH . 403 231- 0.20 10.47 -F -H 3.66 C 24
H
19
FN
2 0 3 [M+H]* 233 (A) OH 0 r486 205- 0.10 10.48 -F N 3.67 C 29
H
28
FN
3 0 3 [M+H]* 210 (E) OH O 488 145- 0.15 10.49 -F
-CH
2 -NEt 2 3.68 C 29
H
30
FN
3 0 3 [M+H]* 150 (E) OH O 430 280- 0.05 10.50 -F
-CH
2
-NH
2 9.7 C 2 5 H22FN 3 0 3 [M-H]- 285 (H) OH O 460 273- 0.15 10.51 -F -(CH 2
)
2 -NMe 2 3.70 C 27
H
26
FN
3 0 3 [M+H]* 276 (E) 0 O O OH460 230- 0.05 10.52 -F -(CH 2
)
2 -NMe 2 3.71 C 27
H
26
FN
3 0 3 [M+H] 235 (E) OH O 490/492 255- 0.50 10.53 -CI
-(CH
2
)
2 -NMe 2 3.73 C 2 sH 28
CIN
3 0 3 [M+H]* 258 (A) 101 OH O N- 499/501 296- 0.50 10.54 -CI '- N 3.74 C 28
H
23
CN
4 0 3 [M+H]* 300 (A) OH O 476/478 228- 0.50 10.55 -CI
-CH
2 -NMe 2 3.75 C 27
H
26
CIN
3 0 3 [M+H]* 230 (A) 0 OH NMe 515 210- 0.40 10.56 -F . N 3.77 C 30
H
31
FN
4 0 3 [M+H]* 215 (A) 0 OH N 483 240- 0.50 10.57 -F
-
3.78 C 28 H23FN 4 03 [M+H]* 245 (A) O OH
-CH
2 -NMe- 517 0.30 10.58 -F 3.82 C 30
H
33
FN
4 0 3 n.d.
(CH
2
)
2 -NMe 2 [M+H]+ (1) OH 0 INMe 515 0.35 10.59 -F N-M 3.79 C 30
H
31
FN
4 0 3 275 I ~[M+H]+ (A) OH O =N 483 0.55 10.60 -F N 3.80 C 28
H
23
FN
4 0 3 [M+H], 280 (A) OH 502/504 260- 0.50 10.61 -CI .N 3.83 C 29
H
2
CN
3 0 3 [M+H 266 (A) 102 OH O -CH2-NMe. 517 0.05 10.62 -F CH 2 -NMe 3.81 C 3 oH 33
FN
4 0 3 [M+H] n.d.(E) / (CH 2
)
2 -NMe 2 [MH(E HO O 403 110- 0.60 10.63 -F -H -3.84 C 24
H
1
FN
2 0 3 [M+H]* 112 (K) HO O 432 260- 0.60 10.64 -F -CH 2
-NH
2 9.8 C 25 H22FN 3 0 3 [M+H]* 263 (A) HO 0 446 265- 0.60 10.65 -F
-CH
2 -NHMe 9.9 C 26
H
24
FN
3 0 3 [M+H]* 270 (A) HO 0 462 0.10 10.66 -F
-CH
2 -NMe 2 3.87 C 26
H
24
FN
3 0 4 [M+H]* 250 (M) OH O 462 0.15 10.67 -F 0
-CH
2 -NMe 2 3.88 C 26
H
24
FN
3 0 4 [M+H]* 247 (M) OH o 546/548 290- 0.30 10.68 -Br . N 3.90 C 29
H
28 BrN 3 03 [M+H]* 293 (E) OH 0 520/522 243- 0.25 10.69 -Br
-CH
2 -NMe 2 3.91 C 27
H
26 BrN 3 0 3 [M+H]* 246 (E) 103 OH 548/550 252- 0.35 10.70 -Br -CH 2 -NEt 2 3.92 C 29
H
3 oBrN 3 0 3 [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 1-10b are prepared analogously to Example 10.0: R*1 R3 N / H 0 R2 N (1-1Ob)
H
104 Start Ex am- R2 R3 R4' ing Empirical Mass m.p. Rr pe mate- formula spectrum [C] value* rials OH 460 0.20 10.71 -F -CH 2 -NMe 2 3.93. C 27
H
26
FN
3 0 3 150 / "' [M+H]* (A) 0 OH 460 105- 0.30 10.72 -F -CH 2 -NMe 2 3.94 C 27
H
26
FN
3 0 3 [60 109 (B) [M+H]* 109 (B) OH 476/478 230- 0.50 10.73 -Cl -CH 2 -NMe 2 3.95 C 27
H
26 ClN 3 0 3 [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-carbamoylethyl)phenyl)methylenel-6 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 105 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 0 C
C
2 7
H
2 7
CIN
4 0 2 Mass spectrum: m/z = 475/477 [M+H]* The following compounds of the formula 1-11 are prepared analogously to Example 11.0: R4'
R
3 N /H | 0 R2 N (11 Start Ex am- 23ing Empirical Mass m.p. Rf am- R2 R3 R' mate- formula spectrum ["C] value* ple rials 0
NHCH
3 10.0 489/491 223- 0.50 11.1 -Cl -CH 2 -NMe 2
C
28
H
29
CIN
4 0 2 [M+H]' 225 (A) 106 NHCH3 0 10.1 473 148- 0.40 11.2 -F -CH 2 -NMe 2
C
28
H
29
FN
4 0 2 / ' *[M+H]+ 150 (B) NMe 2 0 10.2 473 98- 0.30 11.3 -F -CH 2 -NMe 2
C
28
H
29
FN
4 0 2 [M+H]+ 103 (C) 0
NH
2 459 223- 0.50 11.4 -F -CH 2 -NMe 2 10.3 C 27
H
27
FN
4 0 2 + 225 (A) O NHMe 10.3 473 210- 0.70 11.5 -F -CH 2 -NMe 2
C
2 8
H
29
FN
4 0 2 [M+H]+ 213 (A) 0 NMe 2 10.3 487 213- 0.80 11.6 -F -CH 2 -NMe 2
C
29
H
31
FN
4 0 2 [M+H] 215 (A)
NH
2 0 443 115- 0.25 11.7 -F -CH 2 -NMe 2 10.2 C 26
H
25
FN
4 0 2 -- [M-H]- 120 (C) NHMe o 10.2 457 222- 0.25 11.8 -F -CH 2 -NMe 2
C
2 7
H
2 7
FN
4 0 2 -** [M-H]- 225 (C) O NH 2 44 14-00 11.9 -F -CH 2 -NMe 2 10.4 C 2 6
H
2 5
FN
4 0 2 [M-H]~ 146 (D) 107 NMe2 0 e 10.1 487 198- 0.60 11.10 -F
-CH
2 -NMe 2
C
29
H
31
FN
4 0 2 [M+H]* 200 (B) Me N (N 10.1 542 0.60 11.11 -F 0 -CH 2 -NMe 2
C
32
H
3 6
FN
5 0 2 [M+H]* 175 (B) [M.+H]4'(B) o NNNMe 557 150- 0.40 11.12 -F H o 10.5 C 3 1
H
33
FN
6 03 [ +] 15 6 (E) 0 [M+H]- 156 (E) 0NH O NH -N(SO 2 Me)- 552 197- 0.50 11.13 -F (H)-e 2 10.6 C 2 aHaoFN 5
O
4 S 19 (0 (CH2)2-NMe2 [M+H]* 199 (D) 11.14 -F -CH 2 -NMe 2
C
28 H29FN 4 0 2 [M+H]* 152 (D) 10.4 459 208- 0.35 11.15 -F -CH 2 -NMe 2 ,, C 2 7
H
2 7
FN
4 0 2 [M+H]* 214 (D) o NHMe -N(SO2Me)- 10.6 566 218- 0.70
(CH
2
)
2 -NMe 2 ** 2 [M+H]* 222 (F) o N02 -N(SO 2 Me)- 10.6 580 199- 0.40 11.17 -F . (CH 2
)
2 -NMe 2
C
3 0H3FN 5
O
4 S [M+Hj 205 (C) 108 NHMe N Me571 155- 0.20 11.18 -F H3 CN C32Ha.FN53 1 ** [M+H] 160 (C)
NHCH
3 .0 -N(Me)-(CO)- 10.7 487 137- 0.50 11.19 -FCeH7N0
CH
3 ** C 28
H
27
FN
4 0 3 [M+H]* 145 (C)
NHCH
3 rNMe 11.20 -F
H
3 CN 10.8
C
33
H
37
FN
6 0 3 585 211- 0.40 - 0 ** [M+H]* 219 (C)
NHCH
3 0 -N(SO 2 Me)- 10.9 578 192- 0.50 11.21 -F Co3Fs4
(CH
2
)
2 -NMe 2 ** [M-H]- 200 (C)
NHCH
3 0 Me 10.11 559 180- 0.50 11.22 -F -fNyOtBu 1. C 32
H
35
FN
4 0 4 o [M+H]* 187 (C)
NHCH
3 N 0.13 496 262- 0.40 11.23 -F 'N C 29
H
2 6
FN
5 0 2 Me **[M+H]* 266 (C)
NHCH
3 0 10.14 494 180- 0.60 11.24 -F -SO 2 Me ,, C 26
H
24
FN
3 0 4 S [ + * 18 8 (C) / ' *[M+H]+ 188 (C) NHCH, 0 o -Me -. 2 542 226- 0.50 11.25 -F N C31H32FNO3 ** H[M+H]* 230 (C) 109 NHMe CNMe o NJ 10.16 571 23 0.10 11.26 -F 0 0H3CN 0 32
H
3 5
FN
6 0 3 .71 213 (01 0.o* [M+H]+ (G) NHMe o0 0 'Nme 10.15 528 0.40 11.27 -F
C
30
H
3 0
FN
5 0 3 [M+H], 245 (G) *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-6 chloro-2-indolinone 100 mg of 3-Z-[1-(4-dimethylaminomethylanilino)-1-(4-aminomethylphenyl) methylene]-6-chloro-2-indolinone (starting material 7.0) are dissolved in 5 ml of methylene chloride and 5 ml of pyridine, and 20 pl of acetyl chloride are added at 0*C. The mixture is stirred at 00C for 10 minutes and at room temperature for a further 4 hours. Another 20 pl of acetyl chloride are then added, and the mixture is stirred at room temperature for 12 hours. After this time, the solvent is removed 110 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
C
27
H
27
CIN
4 0 2 Mass spectrum: m/z = 473/475 [M-H] The following compounds of the formula 1-12 are prepared analogously to Example 12.0: R4' 3 N /H 0 R2 N (1-12) Start Ex am- R R 3 ing Empirical Mass m.p. Rr mate- formula spectrum [*C] value* pie rials
CH
3 NC55/8 25-02 4 3 4 NCHJ HN 0 HC, N'_ NC3 585/587 252- 0.25 12.1 -Cl H 8.0 C 32
H
35
CIN
6 0 3 [M-H]- 255 (B) 111 2535/537 238 0.45 12.2 -CI H
-CH
2 -NMe 2 7.0 C 32
H
29
CIN
4 0 2 [M-H]- (de- (B) camp.) f--'NCH H1. -C N N N 647/649 282- 0.40 13 0[M-H]- 284 (B) Oy CH3 HN 457 245- 0.40 12.4 -F
-CH
2 -NMe 2 9.0 C 27
H
27
FN
4 0 2 [M-H]- 250 (C) o 0 Et HN 471 212- 0.35 12.5 -F
-CH
2 -NMe 2 9.0 C 28
H
29
FN
4 0 2 [M-H]- 214 (D) 0 HN 519 237- 0.40 12.6 -F
-CH
2 -NMe 2 9.0 C 32
H
29
FN
4 0 2 [-] 4 D [M-H] 240 (D) rp533 187- 0.30 12.7 -F HN -CH 2 -NMe 2 9.0 C 33
H
31
FN
4 0 2 [M-HI[ 190 (D)
CH
3 12.8 -F NH -CH 2 -NMe 2 9.1 C 28
H
29
FN
4 0 2 471 234- 0.30 [M-H]- 237 (D) 112 533 144- 0.45 12.9 -F NH -CH 2 -NMe 2 9.1 C 33
H
31
FN
4 0 2 [M-H]- 150 (C) Et NH 485 235- 0.25 12.10 -F -CH 2 -NMe 2 9.1 C 29
H
31
FN
4 0 2 [ -] 237 (D) [M-Hf- 237 (0) NH 547 217- 0.30 12.11 -F -CH 2 -NMe 2 9.1 C34H 33
FN
4 0 2 [M-H] 220 (0)
CH
3 HNo 457 112- 0.25 12.12 -F -CH 2 -NMe 2 9.2 C 27
H
27
FN
4 0 2 [M-H] 120 (D) Et HN o 586 176- 0.30 12.13 -F
-CH
2 -NMe 2 9.2 C 28
H
29
FN
4 0 2 [M+H]* 180 (D) 535 80- 0.35 12.14 -F HN O -CH 2 -NMe 2 9.2 C 33
H
3 1
FN
4 0 2 [M+H]* 85 (D)
OH
3 r--NCH
HN
4 3N CH 3
C
4 .J 569 230- 0.35 12.15 -F H3 0 9.3 C 32
H
35
FN
6 03 [ -] 23 5 (D) 0 ~[M-H]- 235 (D) 113 Et -- NCH 3 583 205- 0.30 12.16 -F HN4 O 9.3 C 33
H
37
FN
6 0 3 [M-H]~ 210 (D) r<'NCH H H NCj 3 645 217- 0.35 12.17 -F HN O H 9.3 C 3 8H 3 9FN 6 0 3 1 [M+H]* 212 (D) O NCH HN H C N 3 611 190- 0.30 12.19 -F H9.6 35
H
39
FN
6 3 [M+H]* 193 (D) O NCH HN H Nl. 3634 1 60- 0.30 12.20 -F 3 O 9.6 C 3 6
H
3 9FN0 3 0[M+H1+ 163 (D) O NCH HN N' 3639 223- 0.30 HN N C3634 170- 0.25 12.21 -F H3 9.6 C 3 6Ha 3 FN70 3 .. 0 [M+H]+ 227 (0) 0 -o r<'NCH 12.22 -F HN HC\-,_ 9.6 C 3 7H4 3 FN60 3 634 170- 0.25 -0 [M+H]+ 175 (D) 114 CH N NC 599 194- 0.20 13 H3C0 9.6 C 3
FN
6
O
3 [M+H]* 196 (D)
H
3 C CH Oy 3 -- NCH3 HN <NCH 3 613 197- 0.70 12.24 -F H3CN4' 9.6 C 35
H
4 1
FN
6 03 [+] 20 7E 0[M+H]+ 200 (E) o.r NCH3 5 3-07 12.25 -F HN H3 N 9.6 638H45FN3O3 [+3 130- 0.75 ~.0 CH 4 F0 3 [M+H]+ 135 (E) OMe r-<'rNCH 3 6 HNNCH3 96 601 155- 0.60 12.26 -F H 9.6 C 33 HaFNO 4 [M+H)* 159 (E) MeO 0 r-<'NCH HN .6N4 NC 663 168- 0.35 12.27 -F HN H 0 9.6 CH 39
FNO
4 [M+H]* 172 (C)
C(CH
3
)
3 -0; <rNCH 3 HN N NCH 627 85- 0.35 12.28 -- F H HC O- 9.6 C 36
H
43
FN
6 0 3 [M+H] 90 (C) O NCH HN H 4
N
2 3 639 170- 0.25 12.29 -F 0H3 9.6 C 35
H
35
FN
6 0 3 S [M+H] 17 5 (C) 0[M+Hl+ 175 (C) 115
(CH
3
)
3 CrO HN H N CH 613 242- 0.30 123 -0 ' [M+H]* 245 (C) 12.30 -F960 6 H N0 tNCH 12.31 -F HN
H
3 CN( 3 9.6 C 35
H
3
FN
6 0 4 623 155- 0.65 1 O [M+H]* 160 (F) OrCH, 3'NCH HN HCCN 3 571 190- 0.60 12.32 -F H 9.6 C 32
H
35
FN
6 03 [M+H]* 195 (F) 0 r~t r-NCH HN N NCj 585 203- 0.65 12.33 -F H O 9.6 C 33
H
37
FN
6 0 3 0. [M4-HJ" 209 (E) 0' / <'NCH O N NCH3 633 145- 0.60 1234 -F H O9.6
C
37
H
37
FN
6
O
3 [M+-H]* 150 (F) 12.35 -F HN H 3 C4- 9.6 C 3 7H 3 7FN 6 0 3 64 18-05 j0 [M+H]+ 151 (F) ?O HN- N NC3 647 148- 0.65. 12.35 -F HN H 0 9.6 C38H39FN6O3 [M+H]* 151 (F) HN 485 216- 0.35 12.36 -F
-CH
2 -NMe 2 9.0 C 29 H2FN 4 0 2 [M+H]* 220 (D) 116 HN 499 214- 0.35 12.37 -F
-CH
2 -NMe 2 9.0 C 30
H
3 1
FN
4 0 2 [M+H]* 217 (D) HN 522 205- 0.35 12.38 -F -CH 2 -NMe 2 9.0 C 31
H
28
FN
5 0 2 [M+H]* 210 (D) HN 527 235- 0.35 12.39 -F -CH 2 -NMe 2 9.0 C 32 HaFN 4 0 2 [M+H]* 237 (D) 520 135- 0.20 12.40 -F HN -CH 2 -NMe 2 9.0 C 31
H
2 FN402 [ -] 14 0 .(D [M-H]+ 140 (D) oCH 3 HNCH3 ..- 487 210- 0.20 12.41 -F -CH 2 -NMe 2 9.0 C 29
H
31
FN
4 0 2 [+] 1 D 0 HN 501 202- 0.25 12.42 -F -CH 2 -NMe 2 9.0 C 3 aH3FN 4 0 2 [M+H* 206 (D) 0 3541 198- 0.35 12.43 -F HN -CH 2 -NMe 2 9.0 C 33
H
37
FN
4 0 2 [M+H]* 203 (D) 117 OMe HN 489 173- 0.35 12.44 -F -CH 2 -NMe 2 9.0 C 28 H29FN 4 0 3 [M+H 177 (D) MeO 549 202- 0.50 12.45 -F HN -CH 2 -NMe 2 9.0 C 33
H
3 1
FN
4 0 3 [M-H]- 207 (C)
C(CH
3
)
3 513 203- 0.45 12.46 -F HN -CH 2 -NMe 2 9.0 C 31
H
3 5
FN
4 0 2 [M-H]- 209 (C) HN 527 245- 0.35 12.47 -F -CH 2 -NMe 2 9.0 C 3 oH 27
FN
4 0 2 S [M+Hj+ 250 (C)
(CH
3
)
3 CrO HN 501 248- 0.45 12.48 -F ' -CH 2 -NMe 2 9.0 CaH 33
FN
4 0 2 [M+H]* 252 (C) HN 511 216- 0.30 12.49 -F
-CH
2 -NMe 2 9.0 C 30
H
27
FN
4 0 3 [M+H]* 219 (C) HN 522 167- 0.20 12.50 -F
-CH
2 -NMe 2 9.0 C 3 1
H
2 8
FN
5
O
2 [M+H] 170 (D) *Eluent mixtures: 118 (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-3 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-indolinone iodide 200 mg of 3-Z-[1 -(4-dimethylaminomethylanilino)-1 -(4-(2 carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone (starting material 10.1) are dissolved in 40 ml of acetone, and 250 ml of methyl iodide are added. The mixture is stirred at room temperature for 20 hours. After this time, the resulting residue is filtered off with suction. The product is dried at 80*C under reduced pressure. Yield: 200 mg (83% of theory), Rf value: 0.50 (reversed phase RP8, methanol/sodium chloride solution (5%) = 4:1) m.p. 210 0C
C
28
H
2 9
FN
3 0 3 1 Mass spectrum: m/z = 474 [M+H]* 119 The following compound of the formula 1-13 is prepared analogously to Example 13.0: R4' 3 N /H 0 R N (1-13) Start Ex- ing Empirical Mass m.p. Rf am- R2 R3 R' mate- formula spectrum [*C] value* rials 0 OH Me 474 0.50 13.1 -F -Me - 10.3 C 2 sH 2 9
FN
3 0 3 1 . 150 fMe '[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)phenvl)methylenel-6-fluoro-2 indolinone iodide 170 mg of 3-Z-[I-(4-aminomethylanilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6 fluoro-2-indolinone (starting material 10.50) are dissolved in 20 ml of tetrahydrofuran, and 390 mg of 3,5-dimethylpyrazole-1-carboxamidine nitrate and 330 ml of diethylisopropylamine are added. The mixture is stirred under reflux for 10 hours.
120 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 0 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
C
26
H
2 4
FN
5 0 3 Mass spectrum: m/z = 474 [M+H]* The following compound of the formula 1-14 is prepared analogously to Example 14.0: R4' 3 N /H II o 0 R H (1-14) Start Ex a 34,ing Empirical Mass m.p. Rf am- R2 R3 R' mate- formula spectrum [*C] value* ple rials 0 OH H 474 0.70 14.1 -F y-N NH 2 10.64 C 26
H
24
FN
5 0 3 .H 305 fHN [M+H]* (A) *Eluent mixture: (A): reversed phase RP8, methanol/sodium chloride solution (5%) = 4:1 121 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.
122 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 mg 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 mgq 600.0 mg 123 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 mg 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 124 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 0 C, the ground active substance is homogeneously dispersed in the melt. The melt is cooled to 38 0 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 125 ca rboxyethyl)ph enyl)methylele-6-ch Ioro-2 idol inone (4)b3-Ze[1 yl(pheNyl2-methylmflehl)--acI tOyldmio~ifliole -4 carboxyethyl)phenyl)lethyleel-6-choro-2-ildo ifnone (6) 3-Z-[1 -(4-(N-(3-dmethyaminopropy)-N-acetyamio)alio)- -(4-(2 carboxyethyl)phenyl)methylee-6-choro-2-ildolilofe (7) 3-Z-[1 -(4-(3-di-methylaminopropyl)Nae lmn)anilino)-1 -(-2-aboythIphnI( ehYele 6chrboy2-indophnnetyee]--hlr2A d ion (8) 3-Z-I1 -(4-(-ethylaminohylal~ililO )-1-(4-(2-carboxyethyl)phenyl )methylene] 6ch oro-2-i ndol none (9) 3-Z-[1 -(4-ethylaminomethylaniliflo)- -(4-(2-carboxyethyl)phenyl)lethylefe- 6 chloro-2-indolinone (10) 3-Z-[1 -(4-(N-(4-methylpiperazin-1 -ylmethylcarbonyl)-N-methylamiflo)afliliflo)l (4-(2-carboxyethy)pheny)methylfle]-6-chloro-2-ild Oilofe (11) 3-Z-[ 1 -(4-(4-methyl pi perazi n-1 -ylcarbonyl)a nil ino)- 1 -(4-(2 carboxyethyl)phenyl)methylee]-6-choro-2-ildolilofe (12) 3-Z-[1 -(4-(N-(3-dimethylaminopropy)-N-mfethysuIphoflamiflo)aflinifo)-l-(4 (2-carboxyethyl )phenyl)methylene]-6-choro-2-ildolilofe (13) 3-Z-[1 -(4-(N-(2-dimethylaminoethy)-N-propysulphoflamiflo)aflinfo)-l -(4-(2 ca rboxyethyl)phenyl)methylee]-6-choro-2 -ido ifnone (14) 3-Z-[1 -(4-aminomethylanilino)-1 -(4-(2-carboxyethyl )phenyl)methylene] -6 ch Ioro-2-indol inone (15) 3-Z-[1 -(3-(methylaminomethyl)alililo)-1 -(4-(2 carboxyethyl)phenyl)methylee-6-choro-2-ildolilofe (16) 3-Z-I1 -(3-(2-dimethylaminoethyl )anilino)-l1-(4-(2 carboxyethyl)phenyl)methylee]-6-chloro-2-ildol inone (17) 3-Z-[1 -(3.(3-dimethylaminopropyl )anilino)-1 -(4-(2 carboxyethyl)phenyl)methylee]-6-choro-2-il~iflofe (18) 3-Z-[1 -(4-(N-(dimethylamino-carbonylmfethyl)-N methylsuiphonylami no)anilino)-1 -(4-(2-carboxyethyl)phenyl )methylene] -6-ch loro 2-indolinone 126 (19) 3-Z-11 -(4-(N-methyI-N-methysulphoflaio)aliflH-(4-(2 ca rboxyethyl)phenyl)methyl enle]-6-ch I0r0-2ido inonle (20) 3-Z-[1 -(4-(N -methyl-N-acetylailo)alliflo)-l -(4-(2 carboxyethyl)phenyl)methylee]-6-choro-2-ildoliflofe (21) 3-Z-[1 -(4-(N-(N-(2-dimethylaminoethyl ).N-methylaminomethylcarboflyl)-N methylamino)anilino)-1 -(4-(2-carboxyethyl)pheny)methylefle]-6-choro- 2 indolinone (22) 3-Z-[1 -(4-(2-diethylaminoethylsulphoflyl)alililo)- I-(4-(2 carboxyethyl)phenyl)methylele]-6-choro-2-ildoliflofe (23) 3-Z-[1 -(4-(N -(2-dimethylaminoethy-carbofl)-N-methylamilo)alinlO1-(4-*(2 carboxyethyl)phenyl)methylee-6-choro-2-ildolilofe (24) 3-Z-[1 -(4-(N-(2-dimethylamifloethyI )-N-methylaminomethyl)alililo)-1 -(4-(2 carboxyethyl)phenyl)methylee]-6-choro-2-ildoliflofe (25) 3-Z-[1 -(4-(2-dimethylaminoethoxy)alililo)-1 -(4-(2 carboxyethyl)phenyl)methylele-6-choro-2-ildoliflofe (26) 3-Z-[1 -(4-(N -(4-dimethylaminobutycarbofl)-N-methyamilo)alifolO1-(4-(2 carboxyethyl)phenyl)methylee]-6-choro-2-ildolilofe (27) 3-Z-[1 -(4-(N -(3-dimethylaminopropylcarboflyl )-N-methylamino)anliflO)-lI-(4-(2 carboxyethyl)phenyl)methylele-6-choro-2-ildoliflofe (28) 3-Z-[1 -(4-(methylethylaminomethyl )anilino)-1 -(4-(2 carboxyethyl)phenyl)methylee]-6-choFo-2-ildoliflofe (29) 3-Z-[1 -(4-(methylpropylaminomethyl )anilino)-l-(4-(2 carboxyethyl)phenyl)methyl ee]-6-chloFo-2-ildol in one (30) 3-Z-[1 -(4-( methylbenzylami nomethyl )a nilino)- 1 -(4-(2 carboxyethy)pheny)methylfle]-6-chloro-2-ildo inlonle (31) 3-Z-[1 -(4-(N -(2-dimethylaminoethyl)-N-methylamilomethyl )anilino)-1 -(4-(2 carboxyethyl)phenylmethylee]-6-ch Ioro-2-ildol ifnone (32) 3-Z-[1 -(4-(azetidin-1I-ylmethyl)anilino)-l -(4-(2-carboxyethyl)phenyl)mlethyleflel 6-ch loro-2-indol none (33) 3-Z-[1 -(4-((4- methylpiperazin-1 -yI)methyl)anilino)-1 -(4-(2 ca rboxyethyl)phenyl)methyl enel-6-chloro-2-ildo ifnonle (34) 3-Z-[1 -(4-(piperazin -1 -ylmethyl)anilino)-lI-(4-(2 carboxyethyl)phenyl)methyfle]-6-chloro-2-ildol ifnone 127 (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)methyene]-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-indolilnone (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 carboxyethy)phenyl)methylene]-6-chloro-2-indolinone (45) 3-Z-[1 -(4-ethylaminomethylanilino)-1 -(3-(2-ca rboxyethyl)phenyl)methylene]-6 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-carboxyethyl)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-indolilnone (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 128 (51) 3-Z-[1 -(4-aminomethylanilino)-1 -(3-(2-carboxyethyl )phenyl)methylene] -6 chloro-2-indol i none (52) 3-Z-[1 -(3-(d imethylaminomethyl)anilino)-1 -(3-(2 carboxyethyl)phenyl)methylene]-6-choro-2-ildolilofe (53) 3-Z-[1 -(3-(methylaminomethyl)anilino)-1 -(3-(2 carboxyethyl)phenyl)methylene]-6-choro-2-ildolinonle (54) 3-Z-[1 -(3-(2-dimethylaminoethyl)anilin o)-1 -(3-(2 ca rboxyethyl)ph enyl)methyl ene]-6-ch Ioro-2 -ind ol inlone (55) 3-Z-[1 -(3-(3-dimethylaminopropyl )anilino)-1 -(3-(2 ca rb oxyethyl)ph en yl)methylen e]-6-ch Ioro-2 -ind olinonle (56) 3-Z-[1 -(4-(2-dimethylaminoethyl)anillino)-l1-(3-(2 carboxyethyl)phenyl)methylene-6-choro-2-ildoliflofe (57) 3-Z-[1 -(4-(N -(dimethylaminocarbonylmethyl)- N-methylsulphonylamino)alililo) 1 -(3-(2-ca rboxyethyl)phenyl)methylene-6-ch loro-2 -i ndoli none (58) 3-Z-t1 -(4-(N-methyl-N-methylsulphonylamino)anilino)-1 -(3-(2 carboxyethyl)phenyl)methylene-6-chloro-2-ildolilofe (59) 3-Z-[1 -(4-(N -methyl-N-acetylamino)anilino)-1 -(3-(2 .carboxyethyl)phenyl)methylene]-6-chloro-2-indolilofe (60) 3-Z-Il -(4-(l1-methylimidazol-2-yI)anilino)-1 -(3-(2 carboxyethyl)phenyl)methylene]-6-chloro-2-indolinone (61) 3-Z-[1 -(4-(N -(N-(2-dimethylaminoethyl)-N-methylaminomethylcarbonyl)-N methylamino)an ilino)-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-i ndoli none (63) 3-Z-[1 -(4-(N -(2-dimethylaminoethylcarbonyl)-N-methylamino)anilino)-lI-(3-(2 carboxyethyl)phenyl)methylene]-6-chloro-2-ildolilofe (64) 3-Z-[1 -(4-(N -(2-dimethylaminoethyl)-N-methylaminomethyl)a nilino)-1 -(3-(2 ca rboxyethyl)ph enyl)methylene]-6-ch loro-2-indoli nonle (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)aniiino)-l1-(3-(2 ca rboxyeth yl)ph enyl)methyl en e]-6-chlIoro-2-i nd olin one 12 9 (67) 3-Z-[1 -(4-(N -(3-dimethylaminopropylcarbonyl)-N-methylamino)alililo)-1 -(3-(2 carboxyethyl)phenyl)methylene-6-chloro-2-indolinonle (68) 3-Z-[1 -(4-(methylethyla minomethyl)a nilino)- 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 ca rboxyethyl)phen ylmethylen e]-6-ch loro-2-indoli none (73) 3-Z-[1 -(4-(pyrrolidin -1 -ylmethyl)anilino)-1 -(3-(2 ca rboxyethyl)phenyl)methylene]-6-chl oro-2-indoli none (74) 3-Z-[1 -(4-(azetidin-1I-yimethyl)anilino)-1 -(3-(2-carboxyethyl)phenyl)methylene] 6-ch loro-2-indoli none (75) 3-Z-[1 -(4-((4- methylpiperazin-1 -yI)methyl)anilino)-1 -(3-(2 ca rboxyethyl)phenyl)methylene] -6-chloro-2-i ndol none (76) 3-Z-[1 -(4-(piperazin-1 -ylmethyl)anilino)-1 -(3-(2 ca rboxyethyl)phenyl)methylene]-6-chloro-2-indo i none (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 ca rboxyeth yl)phenyl)methyiene]-6-ch loro-2-i ndol in one (79) 3-Z-[1 -(4-(imidazol-1 -ylmethyl)anilino)-1 -(3-(2-carboxyethyl)phenyl)methyl enel 6-chloro-2-indolinone (80) 3-Z-[1 -(4-(N -(2-methylami noethyl)-N-acetylamin o)a nl ino)- 1 -(4-(2 ca rboxyethyl)phen yl)methylene]-6-fluoro-2-indoli none (81) 3-Z-[1 -(4-(N -(3-methylaminopropyl )-N-acetylamino)anilino)-1 -(4-(2 ca rboxyethyl)phenyl)methylen e]-6-fl uoro-2-indol none (82) 3-Z-[1 -(4-(3-dimethylaminopropyl )anilino)-1 -(4-(2 carboxyethyl)phenyl)methylene]-6-fluoro-2-indoli none 130 (83) 3-Z-[1-(4-ethylaminomethylanilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6 fluoro-2-i ndoli none (84) 3-Z-[1-(4-(N-(3-dimethylaminopropyl)-N-methylsulphonylamino)anilino)-l-(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-indoliinone (90) 3-Z-[1-(4-(N-methyl-N-methylsulphonylamino)anilino)-1-(4-(2 carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone (91) 3-Z-[1-(4-(N-(N-(2-dimethylaminoethyl)-N-methylaminomethylcarbonyl)-N methylamino)anilino)-1 -(4-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2 indolinone (92) 3-Z-[1-(4-(2-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 carboxyethy)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-1I-ylmethyl)anilino)-1 -(4-(2-carboxyethyl)phenyl)methylefle] 6-fluoro-2-indolinone (99) 3-Z41 -(4-(piperazin -1 -ylmethyl)anilino)-l1-(4-(2 ca rboxyethyl)phenyl)methylee]-6-fluoro-2-ildol inone (100) 3-Z-[1 -(4-(morpholin-4 -ylmethyl )anilino)-1 -(4-(2 ca rboxyethyl)phenyl)methylene]-6-fl uoro-2-ildol ifnone (101) 3-Z-[1 -(4-(thiomorpholin -4-ylmethyl)a nilino)-1 -(4-(2 ca rb oxyethyl)ph enyl)m ethyl en e-6-fl uoro-2-ifnldOifnonle (102) 3-Z-[lI-(4-(N-(2-dimethylaminoethyl)-N-acetylailo)aliliflo)-1 -(3-(2 ca rboxyethyl)phenyl)methyl ene]-6-fluoro-2-ildol ifnone (103) 3-Z-[1 -(4-(N -(2-methylaminoethyl)-N-acetylamino)alililo)-1 -(3-(2 ca rboxyethyl)phenyl)methylene]-6-fl uoro-2-ildol ifnone (104) 3-Z-[1 -(4-(N-(3-methylaminopropyl)-N-acetylaio)alililo)-1-(3-(2 carboxyethyl)phenyl)methyl ene]-6-fluoro-2-ildol ifnone (105) 3-Z-[1 -(4-(3-dimethylaminopropyl )anilino)-1 -(3-(2 ca rboxyethyl)phenyl)methylene]-6-fluoro-2-ildolifnonle (106) 3-Z-[1 -(4-ethylaminomethylanilino )-1 -(3-(2-carboxyethyl )phenyl)methylenel-6 fluoro-2-indolinone (107) 3-Z-[1 -(4-(4-methyipiperazin-1 -ylcarbonyl)anilino)-1 -(3-(2 ca rboxyethyl)phenyl)methylene]-6-fl uoro-2-ildol ifnone (108) 3-Z-[1 -(4-(N-(3-dimethylaminopropyl)-N-methysuphoflamilo)alililo)-1 -(3 (2-carboxyethyl)phenyl)methylene]-6-fl uoro-2-ild ol inone (109) 3-Z-[1 -(4-(N-(2-dimethylaminoethyl)-N-propylsulphonylamino)alililo)-1 -(3-(2 carboxyethyl)phenyl)methylene]-6-fluoro-2-ildoliflofe (110) 3-Z-[1 -(3-(methylaminomethyl)anilino)-1 -(3-(2 ca rboxyethyl)phenyl)methylene]-6-fluoro-2-indol inone (111) 3-Z-[1 -(3-(2-dimethylaminoethyl)anilino)-1 -(3-(2 ca rboxyethyl)phenyl)methyl ene]-6-fl uoro-2-ildol ifnone (112) 3-Z-[1 -(3-(3-dimethylaminopropyl)anilino)-1 -(3-(2 carboxyethyl)phenyl)methylene]-6-fluoro-2-indolilofe (113) 3-Z-I1 -(4-(N-(dimethylarninocarbonylmethy)-N-methysuphoflaio)alino) 1 -(3-(2-ca rboxyethyl)phenyl)methylene]-6-fluoFo-2-ildol inone 132 (114) 3-Z-[1 -(4-(N-methylN-methylsulphonylano)alhlilo)-1-(3-(2 ca rboxyethyl)ph en yl)meth yl ene] -6-fl uoro-2-ildolifnonle (115) 3-Z-[1 -(4-(N -methyl-N-acetylamino)anilino)-1 -(3-(2 carboxyethyl)phenyl)methylee]-6-fluoro-2-ildolilofe (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-indolilofe (118) 3-Z-[1 -(4-(N-(2-dimethylaminoethylcarbonyl)-N-methylamilo)alililo)-l1-(3-(2 carboxyethyl)phenyl)methylene]-6-fluoro-2-ildoliflofe (119) 3-Z-[1 -(4-(N-(2-dimethylaminoethyl)-N-methylaminomlethyl)alhlilo)-1-(3-(2 carboxyethyl)phenyl)methylene]-6-fl uoro-2-i ndolifnonle (120) 3-Z-[1 -(4-(2-dimethylaminoethoxy)anilino)-1 -(3-(2 ca rboxyethyl)ph enyl)methylene]-6-fl uoro-2-i ndoli none (121) 3-Z-[1 -(4-(methylethyla min omethyl)a nili no)- 1 -(3-(2 carboxyethyl)phenyl)methylene]-6-fluoro-2-ildolifnonle (122) 3-Z-[1 -(4-(methylpropylaminomethyl)anilino)-1 -(3-(2 carboxyethyl)phenyl)methylene-6-fl uoro-2-i dolinonle (123) 3-Z-[1 -(4-(methylbenzylaminomethyl)anilino)-1 -(3-(2 carboxyethyl)phenyl)methylene]-6-fluOro-2-i ndolinone (124) 3-Z-[1 -(4-(diethylaminomethyl )anilino)-1 -(3-(2-carboxyethyl)phenyl)methylefle] 6-fl uoro-2-i ndoli none (125) 3-Z-[1 -(4-(pyrrolidin-1 -ylmethyl)anilino)-1 -(3-(2 carboxyethyl)phenyl)methylene]-6-fl uoro-2-i dolinonle (126) 3-Z-[1 -(4-(azetidin-1 -ylmethyl)anilino)-1 -(3-(2-carboxyethyl)phenyl)methyleflel 6-flu oro-2-ind ol inone (127) 3-Z-[1 -(4-(piperazin-1 -ylmethyl)anilino)-1 -(3-(2 ca rboxyethyl)ph enyl)methylene]-6-fl uoro-2-i ndoli none (128) 3-Z-[1 -(4-(morpholin-4-ylmethyl)anilino)-1 -(3-(2 carboxyethyl)phenyl)methylene]-6-fluoro-2-ildolilofe 133 (129) 3-Z-[1 -(4-(thiomorpholin-4-ylmethyl)anilino)-1 -(3-(2 carboxyethyl)phenyl)methylene-6-fluoro-2-indoiinone (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)-lI-(4-(2 carboxyethyl)phenyl)methylenel-6-bromo-2-indolinone (132) 3-Z-[1 -(4-(N-(2-dimethylaminoethyl)-N-acetylamino)anilino)-1 -(4-(2 carboxyethyl)phenyl)methylenel-6-bromo-2-indolinone (133) 3-Z-[1 -(4-(N -(2-methylaminoethyl)-N-acetylamino)anilino)-l1-(4-(2 carboxyethyl)phenyl)methylenel-6-bromo-2-indolinone (134) 3-Z-[1 -(4-(N-(3-dimethylaminopropyl )-N-acetylamino)anilino)-lI-(4-(2 car-boxyethyl)phenyl)methylenej-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 ca rboxyethyl)phenyl)methylene]-6-bromo-2-i ndoli none (137) 3-Z-[1 -(4-ethylaminomethylanilino )-1 -(4-(2-carboxyethyl)phenyl)methylene]-6 bromno-2-indolinone (138) 3 -Z-[1 -(4-methylaminomethylanilino)- 1 -(4-(2-carboxyethyl)phenyl)methylene] 6-bromo-2-i ndoli none (139) 3-Z-[1 -(4-(N-(4-methylpiperazin-1 -ylmethylcarbonyl)-N-methylamino)aniino)-1 (4-(2-ca rboxyethyl)phenyl)methylene]-6-bromo-2-indolinone (140) 3-Z-[1 -(4-(4-methylpiperazin-1 -ylcarbonyl)anilino)-1 -(4-(2 ca rboxyethyl)ph enyl)m ethyl en e]-6-bromo-2-i nd oli none (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)- -(4-(2 carboxyethyl)phenyl)methylene]-6-bromo-2-indolinone (143) 3-Z-[1 -(4-aminomethylanilino)-1 -(4-(2-carboxyethyl)phenyl)methylene] -6 bromno-2-indol none (144) 3-Z-[1 -(3-(dimethylaminomethyl)anilino)-lI-(4-(2 ca rboxyethyl)phenyl)methylenel-6-bromo-2-i ndol in one 134 (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 ca rboxyethyl)phenyl)methyleneJ-6-bromo-2-indo i none (148) 3-Z-[1 -(4-(2-dimethylaminoethyl)anilino)-l1-(4-(2 carboxyethyl)phenyl)methylene]-6-bromo-2-indoI in one (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)anlino)-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-, ca rboxyethyl)phenyl)methylene]-6-bromo-2-indolin one (153) 3-141 -(4-(N -(N-(2-dimethylaminoethyl )-N-methylaminomethylcarbonyl)-N methyla mino)anilino)-1 -(4-(2-carboxyethyl)phenyl)methylene]-6-bromo-2 iridolinone (154) 3-Z-[1 -(4-(2-diethylaminoethylsulphonyl)anilino)-1 -(4-(2 ca rboxyethyi)ph enyl)methylene]-6-bromo-2-indol none (155) 3-Z-[1 -(4-(N -(2-dimethylaminoethylcarbonyl)-N-methylamino)anilino)-l1-(4-(2 carboxyethyl)phenyl)methylene]-6-bromo-2-indolinone (156) 3-Z-[1I -(4-(N -(2-di methylaminoethyl)-N-methyla min omethy)a ni ino)-1 -(4-(2 ca rboxyethyl)phenyl)methylen e]-6-bromo-2-indol in one (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)-l1-(4-(2 carboxyethyl)phenyl)methylen.e]-6-bromo-2-indolinone (159) 3-Z-[1 -(4-(N-(3-dimethylaminopropylcarbonyl)-N-methylamino)anlino)-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 135 (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-1-ylmethyl)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene] 6-bromo-2-indolinone (167) 3-Z-[1-(4-((4-methylpiperazin-1-yl)methyl)anilino)-1-(4-(2 carboxyethyl)phenyl)methylene]-6-bromo-2-indoli none (168) 3-Z-[1-(4-(piperazin-1-ylmethyl)anilino)-1-(4-(2 carboxyethyl)phenyl)methylene]-6-bromo-2-indoli none (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-1-ylmethyl)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene] 6-bromo-2-indolinone (172) 3-Z-[1-(4-dimethylaminomethylanilino)-1-(3-(2 carboxyethyl)phenyl)methylene]-6-bromo-2-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 136 (177). 3-Z-[l -(4-(N -(3-dimethylaminopropyl)-N-acetylamino)anilino)- 1 -(3-(2 carboxyethyl)phenyl)methylene]-6-bromo-2-indolinone (176) 3-Z-[1 -(4-(N-(3-methylaminopropyl)-N-acetylamino)anlino)-1 -(3-(2 carboxyethyl)phenyl)methylene]-6-bromo-2-indolin one (179) 3-Z-[1 -(4-(3-dimethylaminopropyl )anilino)-1 -(3-(2 carboxyethyl)phenyl)methylene]-6-bromo-2-indolinone (180) 3-Z-[1 -(4-ethyla mi nomethyla nil ino )-1 -(3-(2-carboxyethyl)phenyl)methylene]-6 bromo-2-indol none (181) 3-Z-[1 -(4-methylaminomethylanilino)-l1 (3-(2-carboxyethyl)phenyl)methylene] 6-bromo-2-indol inone (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)anhlino)-1 -(3-(2 ca rboxyethyl)ph en yl)meth ylen e] -6-bro mo-2-i nd oli none (184) 3-Z-[1 -(4-(N-(3-dimethylaminopropyl)-N-methylsulphonylamino)anilino)- -(3 (2-ca rboxyethyl)ph enyl)methylene]-6-bromo-2-indol none (185) 3-Z-[l1-(4-(N -(2-dimethylaminoethyl)-N-propylsulphonylamino)anilino)-1 -(3-(2 carboxyethyl)phenyl)methylene]-6-bromo-2-indolinone (186) 3-Z-[1 -(4-a min omethyla n i lino) -1 -(3-(2-carboxyethyl)phenyl)methylene] -6 bromo-2-indolinone (187) 3-Z-[1 -(3-(dimethylaminomethyl)an ilino)-1 -(3-(2 ca rboxyethyl)ph en yl)methylene]-6-bromo-2-indol in one (188) 3-Z-[1 -(3-(methylaminomethyl)anilino)-1 -(3-(2 carboxyethyl)phenyl)methylene]-6-bromo-2-indolinone (189) 3-Z-[1 -(3-(2-dimethylaminoethy )anilino)-l1-(3-(2 ca rboxyethyl)phenyl)methylene]-6-bromo-2-indoli none (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-indolin one (192) 3-Z-[1 -(4-(N-(dimethylaminocarbonylmethyl)-N-methylsulphonylamino)anilino) 1 -(3-(2-carboxyethyl)phenyl)methylene]-6- bromo-2-indoli none 137 (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)methylene]-6-bromo-2 indolinone (197) 3-Z-[1-(4-(2-diethylaminoethylsulphonyl)anilino)-1-(3-(2 carboxyethyl)phenyl)methylene]-6-bromo-2-indolinone (198) 3-Z-[1-(4-(N-(2-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 138 (208) 3-Z-[1-(4-(pyrrolidin-1-ylmethyl)anilino)-1-(3-(2 carboxyethyl)phenyl)methylene]-6-bromo-2-indollnone (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-indolilnone (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-indollnone (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)methylenel 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)pheny)methylene]-6-chloro-2-indolinone -139 (224) 3-Z-[1-(4-dimethylaminomethylanilino)-1-(3-(N-methyl carboxymethylamino)pheny)methylene]-6-chloro-2-indoli none (225) 3-Z-[1-(4-dimethylaminomethylanilino)-1-(4-carboxymethoxyphenyl) methylene]-6-bromo-2-indolinone (226) 3-Z-[1-(4-dimethylaminomethylanilino)-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-dimethylarninomethylanilino)-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)methyleriel-6-bromo-2-indolinone In the tables above, Me is methyl, Et is ethyl, Pr is propyl, nPr is n-propyl, iPr is isopropyl, nBu is n-butyl, tBu is tert-butyl and Bn is benzyl. Throughout this specification and the claims which follow, unless the context requires otherwise, the word "comprise", and variations such as "comprises" and "comprising", will be understood to imply the inclusion of a stated integer or step or group of integers or steps but not the exclusion of any other integer or step or group of integers or steps.
C.\NRPorbl\DCC\AM3(N44945 1.DOC-5/A7121010 - 139A The reference in this specification to any prior publication (or information derived from it), or to any matter which is known, is not, and should not be taken as an acknowledgment or admission or any form of suggestion that that prior publication (or information derived from it) or known matter forms part of the common general 5 knowledge in the field of endeavour to which this specification relates.

Claims (9)

1. Compounds of general formula R 3 / N R 6 \/ R X N R2N R1(I), in which X is an oxygen atom, R' is a hydrogen atom, R 2 is a fluorine, chlorine or bromine atom or a cyano group, R 3 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 C-1- 2 -alkyl-carbonyl-amino group, 141 by a cyano-C1- 3 -alkyl, carboxy-C1- 3 -alkyl, carboxy-C1.4-alkoxy, carboxy-C1-3 alkylamino, carboxy-C 1 - 3 -alkyl-N-(C 1 - 3 -alkyl)-amino, C1. 4 -alkoxy-carbonyl-C 1 . 3 alkyl, Cl4-alkoxy-carbonyl-C 1 - 3 -alkoxy, C 1 . 4 -alkoxy-carbonyl-C1. 3 -alkylamino, C14-alkoxy-carbonyl-C 1 . 3 -alkyl-N-(C 1 - 3 -alkyl)-amino, amino-C 1 . 3 -alkyl, amino carbonyl-C 1 - 3 -alkyl, (C 1 - 2 -alkylamino)-carbonyl-C 1 - 3 -alkyl, di-(C1- 2 -alkyl)-amino carbonyl-C 1 - 3 -alkyl, (C1- 2 -alkyl-carbonyl)-amino-C 1 - 3 -alkyl, (C1.4-alkoxy carbonyl)-amino-C 1 - 3 -alkyl, (C 3 - 6 -alkyl-carbonyl)-amino-C1- 3 -alkyl, (phenyl carbonyl)-amino-C 1 - 3 -alkyl, (C 3 -6-cycloalkyl-carbonyl)-amino-C 1 - 3 -alkyl, (C 3 -6 cycloalkyl-C 1 - 3 -alkyl-carbonyl)-amino-C 1 - 3 -alkyl, (thiophen-2-yl-carbonyl) amino-C 1 - 3 -alkyl, (furan-2-yl-carbonyl)-amino-C 1 - 3 -alkyl, (phenyl-C 1 . 3 -alkyl carbonyl)-amino-C 1 . 3 -alkyl, (2-(Cl4-alkoxy)-benzoyl-carbonyl)-amino-Cl- 3 -alkyl, (pyridin-2-yl-carbonyl)-amino-C 1 - 3 -alkyl, (pyridin-3-yl-carbonyl)-amino-C 1-3 alkyl-, (pyridin-4-yl-carbonyl)-amino-C. 3 -alkyl- or C 1 - 3 -alkyl-piperazin-1 -yl carbonyl-C 13 -alkyl group, by a carboxy-C 2 - 3 -alkenyl, aminocarbonyl-C 2 - 3 -alkenyl, (C1- 3 -alkylamino) carbonyl-C 2 - 3 -alkenyl, di-(C 1 - 3 -alkyl)-amino-carbonyl-C 2 - 3 -alkeny or C1.4 alkoxy-carbonyl-C 2 - 3 -alkenyl group, where the substituents may be identical or different, R 4 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-[co-di-(C 1 - 3 -alkyl)-amino-C 2 - 3 -alkyl]-N-(C 1 - 3 alkyl)-amino, N-methyl-(C 3
4-alkyl)-amino, N-(C 1 - 3 -alkyl)-N-benzylamino, N-(C 14 -alkoxycarbonyl)-amino, N-(C14-alkoxycarbonyl)-Cl4-alkylamino, 4-(C 1 . 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-(C- 3 -alkyl)-sulphonyl, 2-[di-(C 1 . 3 -alkyl)-amino] ethoxy, 4-(C 1 - 3 -alkyl)-piperazin-1-yl-carbonyl, {o-[di-(C 1 - 3 -alkyl)-amino]-(C 2 - 3 - 142 alkyl)}-N-(C1- 3 -alkyl)-amino-carbonyl, 1-(C 1 - 3 -alkyl)imidazol-2-yl, (C1- 3 -alkyl) sulphonyl group, or by a group of the formula /R -N \R7 in which R 7 is a C 1 . 2 -alkyl, C 1 - 2 -alkyl-carbonyl, di-(C 1 - 2 -alkyl)-amino-carbonyl-C 1 - 3 alkyl or C1. 3 -alkylsulphonyl group and Ra is C 1 . 3 -alkyl, o-[di-(C1- 2 -alkyl)-amino]-C 2 - 3 -alkyl, CO-[mono-(C 1 - 2 -alkyl) amino]-C 2 - 3 -alkyl group, or a (C 1 - 3 -alkyl)-carbonyl, (C 4 .- alkyl)-carbonyl or carbonyl-(C 1 . 3 -alkyl) group which is terminally substituted by a di-(C 1 - 2 -alkyl)-amino, piperazin-1 -yl or 4-(C 1 - 3 -alkyl)-piperazin-1 -yl group, where all dialkylamino groups present in the radical R 4 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-toluenesulphonate and trifluoroacetate, R 5 is a hydrogen atom and 5 R 6 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, 143 where additionally a carboxyl, amino or imino group present may be substituted by an in vivo cleavable radical or may be presenti4n-the-form-of-a prodrug radical, for examplelin 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 its tautomers, enantiomers, diastereomers, mixtures thereof and salts thereof. 2. Compounds-of general formula I-according to Claim 1 in which X, R 1 , R 2 , R 4 , R 5 and R 6 are as defined in Claim 1 and R 3 is a phenyl group which is substituted by a C 1 - 2 -alkyl-carbonyl-amino group, by a carboxy-C 1 - 3 -alkyl, carboxy-ClA-alkoxy, C 1 .4-alkoxy-carbonyl-C1-3-alkyl, C 1 . 4 -alkoxy-carbonyl-Cl-3-alkoxy, aminocarbonyl-C 1 -3-alkyl, (C 1 - 2 -alkylamino) carbonyl-C 1 . 3 -alkyl, di-(C 1 - 2 -alkyl)-aminocarbonyl-C 1 - 3 -alkyl, (C 1 - 2 -alkyl carbonyl)-amino-Cl.3-alkyl, (C14-alkoxy-carbonyl)-amino-C1.3-alkyl, (phenyl carbonyl)-amino-C 1 .3-alkyl, (C 3 - 6 -cycloalkyl-carbonyl)-amino-C1. 3 -alkyl, (C 3 - 6 cycloalkyl-C 1 - 3 -alkyl-carbonyl)-amino-C1.3-alkyl, (thiophen-2-yl-carbonyl) amino-C 1 - 3 -alkyl, (furan-2-yl-carbonyl)-amino-Cl-3-alkyl, (phenyl-C 1 - 3 -alkyl 5 carbonyl)-amino-C 1 - 3 -alkyl, (2-(C 1 .4-alkoxy)-benzoyl-carbonyl)-amino-C 1 - 3 -alkyl, (pyridin-2-yl-carbonyl)-amino-CI 3 -alkyl, (pyridin-3-yl-carbonyl)-amino-C1-3 alkyl, (pyridin-4-yl-carbonyl)-amino-Cl.3-alky or C 1 . 3 -alkyl-piperazin-1 -yl carbonyl-Cl-3-alkyl group, 0 by an aminocarbonyl-C 2 - 3 -alkenyl, (C 1 - 3 -alkylamino)-carbonyl-C 2 . 3 -alkenyl, di (C 1 . 3 -alkyl)-amino-carbonyl-C 2 . 3 -alkenyl or C 1 -4-alkoxy-carbonyl-C 2 - 3 -alkeny group. 144 /3. Compounds of general formula I according to Claim 1 in which 5 X, R 1 , R 2 , R 4 , R' and R 6 are as defined in Claim 1 and R 3 is a phenyl group substituted by a carboxy-C 1 . 3 -alkyl or C1.4-alkoxy-carbonyl-CI. 3 alkyl group. 4. Compounds of general formula I according to any of Claims 1 to 3, in which X, R1, R 3 , R 4 , R' and R 6 are as defined in any of Claims 1 to 3 and R 2 is a fluorine or chlorine atom.
5. The following compounds of general formula I according to Claim 1: (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 fl uoro-2-in d oi none (c) 3-Z-[1 -(4-dimethylaminomethylanilino)-1 -(3-(2-carboxyethyl)phenyl)methylene]-6 fluoro-2-indolinone 0 (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)aniino)-1 -(4-(2 5 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 0 (g) 3-Z-[1 -(4-(1 -methylimidazol-2-yl)anilino)-1 -(4-(2-carboxyethyl)phenyl)methylene]
6-fluoro-2-indolinone 145 (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 (1) 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 and their salts. 6. Physiologically acceptable salts of the compounds according to any of Claims 1 to 5. 5
7. A medicament, comprising a compound of general formula I according to any of Claims 1 to 5 or a physiologically acceptable salt according to Claim 6, if appropriate in addition to one or more inert carrier materials and/or diluents.
8. The use of a compound of general formula I according to at least one of ) Claims 1 to 5 or of a physiologically acceptable salt according to Claim 6 for preparing a medicament suitable for treating excessive or abnormal cell proliferation. 146
9. A process for preparing a medicament according to Claim 7, characterized-in-that; by a non-chemical route, a compound of the formula I according to at least one of Claims 1 to 5 or a physiologically acceptable salt according to Claim 6 is incorporated into one or more inert carrier materials and/or diluents.
10. A process for preparing the compounds according to Claims 1 to 5, characterized in that a. a compound of the formula Zi R 3 R6 X R2 N R 2 . R1'(V), in which the radicals Z' and R 3 may, if appropriate, change their positions, X, R 2 , R 3 and R 6 are as defined in Claim 1, R"' has the meanings mentioned at the outset for R 1 or is a protective group for the nitrogen atom of the lactam group, where R 1 may also, if appropriate, represent a D 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, is reacted with an amine of general formula 5 R4 N R5 H (VI), 147 in which R 4 and R 5 are defined as mentioned at the outset, and, if required, the product is subsequently cleaved from a protective group used for the nitrogen atom of the lactam group or from a solid phase, b. for preparing a compound of the formula I in which R 3 is a phenyl or naphthyl group substituted by a carboxy-C 2 - 3 -alkenyl, aminocarbonyl-C 2 .3-alkenyl, (C 1 . 3 -alkyl amino)-carbonyl-C 2 -3-alkenyl, di-(C 1 - 3 -alkylamino)-carbonyl-C 2 -3-alkenyl or CI4 alkoxy-carbonyl-C2-3-alkenyl group, a compound of the formula Z3 N R 5 R6 X N R Ri' (IX), in which R 2 , R 4 , R , R 6 and X are as defined in Claim 1, 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 1 may also, if appropriate, represent a bond, formed via a spacer, to a solid phase, and Z 3 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, is reacted with an alkene of general formula 0 R 3 148 (X), in which R 3 ' is an amino, (C 1 . 3 -alkylamino), di-(C 1 - 3 -alkylamino) or C 1 . 4 -alkoxy group and n is the number 0 or 1, c. to prepare a compound of the formula 1, in which R 3 is a phenyl or naphthyl group substituted by a carboxy-C1. 3 -alkyl, C 1 . 4 -alkoxy-carbonyl-CI-3 -alkyl, aminocarbonyl C1. 3 -alkyl, (Cl. 3 -alkylamino)-carbonyl-C1.3-alkyl or di-(C1- 3 -alkyl)aminocarbonyl-Cl-3 alkyl group, a compound of general formula R3 A R4 N R5 R 6 X N R Ri' (XI), in which R 2 , R 4 , R', R 6 and X are as defined in claim 1, R' has the meanings mentioned at the outset for R 1 or is a protective group for the nitrogen atom of the lactam group, where R 1 ' may also, if appropriate, represent a bond, formed via a spacer, to a solid phase, A is a C 2 - 3 -alkenyl group and R 3 -is a hydroxyl, C 1 .4-alkoxy, amino, (C 1 . 3 -alkylamino) or di-(C 1 - 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, as described above under process (a), 149 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 general formula I. 150
11. The compound of general formula I according to claim 1: (i) the compound 3-Z-[1-(4-dimethylaminomethylanilino)-1-(4-(2 ethoxycarbonylethyl)phenyl)methylene]-6-fluoro-2-indolinone. 5 12. The compound 1-acetyl-6-fluoro-2-indolinone.
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DE10233366A DE10233366A1 (en) 2002-07-23 2002-07-23 Indolinone derivatives substituted in the 6-position, their preparation and their use as medicaments
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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
AU2003254557A AU2003254557B2 (en) 2002-07-23 2003-07-22 Indoline derivatives substituted in position 6, production and use thereof as medicaments
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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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
AU2006239389B2 (en) 2005-04-28 2012-06-28 Boehringer Ingelheim International Gmbh Novel compounds for treating inflammatory diseases
WO2007057399A2 (en) * 2005-11-15 2007-05-24 Boehringer Ingelheim International Gmbh Treatment of cancer with indole derivatives
US20110046395A1 (en) * 2008-01-25 2011-02-24 Boehringer Ingelheim International Gmbh Process for the manufacture of a 6-fluoro-1,2-dihydro-2-oxo-3h-indol-3-ylidene derivative
US20110130437A1 (en) * 2008-01-25 2011-06-02 Boehringer Ingelheim International Gmbh Salt forms of a 6-fluoro-1,2-dihydro-2-oxo-3h-indol-3-ylidene derivative, process for their manufacture and pharmaceutical compositions containing same
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