AU4370799A - Substituted indolinones, the production thereof and their use as medicaments - Google Patents

Description

S018548aus Boehringer Ingelheim Pharma KG Case 5/1239-FL D-55216 INGELHEIM Foreign filing text 5 New substituted indolinones, the preparation thereof and their use as pharmaceutical compositions 10 The present invention relates to new substituted indoli nones of general formula

R

3 I R4 N

R

5 R2 X (I), Ri the isomers thereof and the salts thereof, particularly the 15 physiologically acceptable salts thereof which have valuable properties. The above compounds of general formula I wherein R 1 denotes a hydrogen atom or a prodrug group have valuable 20 pharmacological properties, particularly an inhibitory effect on various kinases, particularly on complexes of CDKs (CDK1, CDK2, CDK3, CDK4, CDK6, CDK7, CDK8 and CDK9) with their specific cyclines (A, B1, B2, C, D1, D2, D3, E, F, G1, G2, H, I and K) and viral cycline (cf. L. Mengtao in 25 J. Virology 1;_(3), 1984-1991 (1997)), and the other compounds of the above general formula I wherein R 1 does not represent a hydrogen atom or a prodrug group, are valuable intermediate products for preparing the abovementioned compounds. 30 -2 The present invention thus relates to the above compounds of general formula I, whilst the compounds wherein R 1 denotes a hydrogen atom or a prodrug group have valuable pharmacological properties, the pharmaceutical compositions 5 containing the pharmacologically active compounds, their use and processes for preparing them. In the above general formula I 10 X denotes an oxygen or sulphur atom,

R

1 denotes a hydrogen atom, a C 1 4 -alkoxy-carbonyl or

C

24 -alkanoyl group, 15 R 2 denotes a carboxy or CI 4 -alkoxy-carbonyl group or an aminocarbonyl group optionally substituted by one or two

C

1 3 -alkyl groups, whilst the substituents may be identical or different, 20 R 3 denotes a hydrogen atom or a CI 6 -alkyl group which may be substituted at the 2 position, in relation to the carbon atom of the R 3

-C(R

4 NR)= group by a fluorine, chlorine or bromine atom, by a hydroxy, C 13 -alkoxy, C 1 3 -alkylsulphenyl,

C

1 3 -alkylsulphinyl, Cl.-alkylsulphonyl, phenylsulphenyl, 25 phenylsulphinyl, phenylsulphonyl, amino, C 1 3 -alkylamino, di- (C 1 3 -alkyl) -amino, C 2 -s-alkanoylamino or

N-(C

13 -alkylamino)-C 2 -s-alkanoylamino group,

R

4 denotes a hydrogen atom, a CI 6 -alkyl group or a 30 C 5

-

7 -cycloalkyl group optionally substituted by a C 1 3 -alkyl group wherein a methylene group in the 3 or 4 position in relation to the carbon atom of the R 3

-C(R

4 NR,)= group may be substituted by an imino group optionally substituted by a

C

1 3 -alkyl group, 35 a phenyl or naphthyl group which may be substituted -3 by a fluorine, chlorine, bromine or iodine atom, by a methoxy group optionally substituted by 1 to 3 5 fluorine atoms, by a C 2 3 -alkoxy which may be substituted in the 2 or 3 position by a C 1 3 -alkylamino, di-(C 13 -alkyl)-amino or 5 to 7-membered cycloalkyleneimino group, whilst 10 additionally an alkyl moiety in the abovementioned alkylamino and dialkylamino groups may be substituted by a phenyl group, by a trifluoromethyl, amino, C- 3 -alkylamino, di 15 (C 13 -alkyl) -amino, C 2 -s-alkanoylamino, N- (C 13 -alkyl) C 2

-

5 -alkanoylamino, Cj.-alkylsulphonylamino, N- (C.

1 3 -alkyl) C 15 -alkylsulphonylamino, phenylsulphonylamino,

N-(C

13 -alkyl)-phenylsulphonylamino, aminosulphonyl,

C-

3 -alkylaminosulphonyl or di-(C 13 -alkyl)-aminosulphonyl 20 group, whilst additionally an alkyl moiety in the abovementioned alkylamino and dialkylamino groups may be substituted by a phenyl group, by a carbonyl group which is substituted by a hydroxy, 25 C 1 3 -alkoxy, amino, C 1 3 -alkylamino or N-(C 15 -alkyl)

C

13 -alkylamino group, whilst additionally an alkyl moiety in the abovementioned groups may be substituted by a carboxy, C 13 -alkoxycarbonyl or phenyl group or in the 2 or 3 position by a di-(C 1 3 -alkyl)-amino, pipera 30 zino, N-(C 1 3 -alkyl)-piperazino or 5- to 7-membered cyc loalkyleneimino group, by a C 13 -alkyl group which is substituted by an amino, C3- 7 -alkylamino,

C

5 7 -cycloalkylamino or phenyl 35 C 1 3 -alkylamino group which may additionally be substituted at the amino nitrogen atom by a C 1

.

3 -alkyl group wherein the hydrogen atoms are wholly or partially -4 replaced by fluorine atoms, by a C 57 -cycloalkyl,

C

2 4 -alkenyl or Cl-alkyl group, whilst the abovementioned C 1 4 -alkyl substituent may in each 5 case be additionally mono-, di- or trisubstituted by a cyano, carboxy, Cl-,-alkoxycarbonyl, pyridyl, imidazolyl, benzo[1,3]dioxole or phenyl group, wherein the phenyl group may be substituted by fluorine, chlorine or bromine atoms, by methyl, methoxy, 10 trifluoromethyl, cyano or nitro groups and the substituents may be identical or different, or may be substituted in the 2, 3 or 4 position by a hydroxy group, 15 by a C 3 -alkyl group which may be substituted by a hydroxy, carboxy, thiomorpholino, 1-oxido thiomorpholino, 1,1-dioxido-thiomorpholino, piperazino, N-(Cl 3 -alkyl)-piperazino or N-phenyl-piperazino group, by a 5- to 7-membered cycloalkenyleneimino group or by a 20 4- to 7-membered cycloalkyleneimino group, wherein the abovementioned 5- to 7-membered cycloalkyleneimino groups may be substituted by one or two C 1 3 -alkyl groups, by a CI 7 -cycloalkyl or phenyl group, by a

C

1 3 -alkyl, C 57 -cycloalkyl, phenyl, carboxy or 25 C 1 a 4 -alkoxy-carbonyl group and by a hydroxy group and in the abovementioned cycloalkyleneimino groups a methylene group adjacent to the nitrogen atom may be replaced by a carbonyl group, 30 by a C 1 3 -alkyl group which is substituted by a 5- to 7 membered cycloalkyleneimino group, whilst a phenyl group optionally mono- or disubstituted by fluorine, chlorine or bromine atoms or by methyl or methoxy groups, wherein the substituents may be identical or different, or an 35 oxazolo, imidazolo, thiazolo, pyridino, pyrazino or pyrimidino group, optionally substituted by a fluorine, chlorine, bromine or iodine atom or by a methyl, methoxy -5 or amino group, may be fused to the abovementioned 5- to 7-membered cycloalkyleneimino groups via two adjacent carbon atoms, 5 whilst additionally the abovementioned monosubstituted phenyl groups may be substituted by a fluorine, chlorine or bromine atom or by a methyl, methoxy or nitro group, a 5-membered heteroaromatic group which contains an imino 10 group, an oxygen or sulphur atom or an imino group, an oxygen or sulphur atom and one or two nitrogen atoms, or a 6-membered heteroaromatic group which contains one, two or three nitrogen atoms, whilst the abovementioned 5- and 15 6-membered heteroaromatic groups may additionally be substituted by a chlorine or bromine atom or by a methyl group, or a phenyl ring may be fused to the abovementioned 5- or 6-membered heteroaromatic groups via two adjacent carbon atoms, and 20

R

5 denotes a hydrogen atom or a C 1 3 -alkyl group. Furthermore, the carboxy-, amino or imino groups present in a compound of the above general formula I may be 25 substituted by groups which can be cleaved in vivo. In addition to the alkoxycarbonyl and alkanoyl groups already mentioned above, groups which can be cleaved in vivo include an acyl group such as the benzoyl, pyridinoyl, 30 pentanoyl or hexanoyl group, an allyloxycarbonyl group, a

C

116 -alkoxycarbonyl group such as the pentoxycarbonyl, hexyloxycarbonyl, octyloxycarbonyl, nonyloxycarbonyl, decyloxycarbonyl, undecyloxycarbonyl, dodecyloxycarbonyl or hexadecyloxycarbonyl group, a phenyl-Ca -alkoxycarbonyl 35 group such as the benzyloxycarbonyl, phenylethoxycarbonyl or phenylpropoxycarbonyl group, a Cs 3 -alkylsulphonyl-C 2 4

-

-6 alkoxycarbonyl, CiL- 3 -alkoxy-C 2

-

4 -alkoxy-C2- alkoxycarbonyl or RcCO-0- (RdCRe) -0-CO-group wherein R, denotes a C 1 8 -alkyl, CS 7 -cycloalkyl, phenyl or phenyl 5 C 1

-

3 -alkyl group, Re denotes a hydrogen atom, a C 1 3 -alkyl, C 5 7 -cycloalkyl or phenyl group and 10 Rd denotes a hydrogen atom or a C 1 3 -alkyl group or the RcCO-0- (RdCRe) -O- group, whilst the abovementioned ester groups may also be used as a group which can be converted in vivo into a carboxy 15 group. Preferred compounds of general formula I, however, are those wherein 20 X denotes an oxygen atom,

R

1 denotes a hydrogen atom,

R

2 denotes an aminocarbonyl group, 25

R

3 denotes a hydrogen atom or a C 1 4-alkyl group which may be substituted, at the 2 position in relation to the carbon atom of the R 3 -C(RNR,)= group by a chlorine or bromine atom or by a phenylsulphonyl group, 30

R

4 denotes a hydrogen atom, a C 1 3 -alkyl group or a cyclopentyl or cyclohexyl group optionally substituted by a methyl group, whilst in the cyclopentyl and cyclohexyl group a methylene group in the 3 or 4 position in relation 35 to the carbon atom of the R 3

-C(RNR

5 )= group may be replaced by an imino group optionally substituted by a methyl group, -7 a phenyl group which is substituted by a fluorine, chlorine, bromine or iodine atom, 5 by a methoxy group optionally substituted by 1 to 3 fluorine atoms, by a C 2 3 -alkoxy which is substituted in the 2 or 3 position by methylamino, dimethylamino or 5- to 7 10 membered cycloalkyleneimino group, whilst additionally a methyl group in the abovementioned amino groups may be substituted -by a phenyl group, by a trifluoromethyl, amino, C 25 -alkanoylamino, 15 N-(C 1 3 -alkyl)-C 25 -alkanoylamino,

C

15 ,-alkylsulphonylamino, N- (Cl- 3 -alkyl) C 15 -alkylsulphonylamino, phenylsulphonylamino,

N-(C

1 3 -alkyl)-phenylsulphonylamino or aminosulphonyl group, whilst additionally an alkyl moiety in the 20 abovementioned alkylamino and dialkylamino groups may be substituted by a phenyl group, by a carbonyl group which is substituted by a hydroxy,

C

3 -alkoxy, amino, C 1

-

3 -alkylamino or N- (C 1

_

5 -alkyl) 25 C 1 3 -alkylamino group, whilst additionally an alkyl moiety in the abovementioned groups may be substituted by a carboxy, C 13 -alkoxycarbonyl or phenyl group or in the 2 or 3 position by a di-(C 1 3 -alkyl)-amino, pipera zino, N-(C 1 3 -alkyl)-piperazino or 5- to 7-membered cyc 30 loalkyleneimino group, by a C 1 3 -alkyl group which is substituted by an amino,

C

1 ,-alkylamino,

C

5

_

7 -cycloalkylamino or phenyl

C

1 3 -alkylamino group which may additionally be 35 substituted at the amino nitrogen atom by a C 1 3 -alkyl group wherein the hydrogen atoms are wholly or partially -8 replaced by fluorine atoms, by a cyclohexyl, C 24 -alkenyl or C 1 4 -alkyl group, whilst the abovementioned C 1

-

4 -alkyl substituent may in each 5 case be additionally substituted by a cyano, carboxy,

C

1 3 -alkoxycarbonyl, pyridyl, imidazolyl, benzo[1,3]dioxole or phenyl group, wherein the phenyl group may be monosubstituted by a fluorine, chlorine or bromine atom or by a methyl, methoxy, cyano, 10 trifluoromethyl or nitro group, or di- or trisubstituted by fluorine, chlorine or bromine atoms or by methyl or methoxy groups, and the substituents may be identical or different, or may be substituted in the 2, 3 or 4 position by a hydroxy group, 15 by a C 13 -alkyl group which may be substituted by a hydroxy, carboxy, thiomorpholino, 1-oxido thiomorpholino, 1,1-dioxido-thiomorpholino, piperazino,

N-(C

13 -alkyl)-piperazino or N-phenyl-piperazino group, 20 by a 5- to 7-membered cycloalkenyleneimino group or by a 4- to 7-membered cycloalkyleneimino group, wherein the abovementioned 5- to 7-membered cycloalkyleneimino groups may be substituted by one or two C 13 -alkyl groups, by a cyclohexyl or phenyl group, by a C 1 3 -alkyl, 25 cyclohexyl, phenyl, carboxy or CI--alkoxy-carbonyl group and by a hydroxy group and in the abovementioned cycloalkyleneimino groups a methylene group adjacent to the nitrogen atom may be replaced by a carbonyl group, 30 by a C 13 -alkyl group which is substituted by a 5- to 7 membered cycloalkyleneimino group, whilst a phenyl group optionally mono- or disubstituted by fluorine, chlorine or bromine atoms or by methyl or methoxy groups, wherein the substituents may be identical or different, or a 35 pyrazino or thiazolo group, optionally substituted by an amino group, may be fused to the abovementioned 5- to 7- - 9 membered cycloalkyleneimino groups via two adjacent carbon atoms, whilst additionally the abovementioned monosubstituted 5 phenyl groups may be substituted by a fluorine, chlorine or bromine atom or by a methyl, methoxy or nitro group, a pyridyl group optionally substituted by a chlorine or bromine atom or by a methyl group, 10 an oxazolyl, isoxazolyl, imidazolyl or thiazolyl group optionally substituted by a methyl group, to which a phenyl ring may be fused via two adjacent carbon atoms, and 15 R, denotes a hydrogen atom or a Cl- alkyl group, particularly those compounds of general formula I wherein

R

1 to R 3 and R. are as hereinbefore defined and 20

R

4 denotes a hydrogen atom, a C 16 -alkyl group or a

C

57 -cycloalkyl group optionally substituted by a C 1

.

3 -alkyl group wherein a methylene group in the 3 or 4 position in relation to the carbon atom of the R 3

-C(R

4 NR,)= group may be 25 replaced by an imino group optionally substituted by a

C

1 3 -alkyl group, a phenyl or naphthyl group which may be substituted by a fluorine, chlorine or iodine atom, by a C, 3 -alkoxy, 30 amino,

C.

3 -alkylamino, di-(CI 3 -alkyl)-amino,

C

2 -s-alkanoylamino, N- (C 13 -alkylamino)

-C

2 -s-alkanoylamino,

C

15 -alkylsulphonylamino, N- (C 1

-

3 -alkyl) C 15 -alkylsulphonylamino, phenylsulphonylamino or N-(C13-alkyl)-phenylsulphonylamino group or by a C 1

.

3 -alkyl 35 group which may be substituted by a C,-s-alkylamino, di

(C

1 s-alkyl)-amino, thiomorpholino, 1-oxido-thiomorpholino, 1,1-dioxido-thiomorpholino, piperazino, N-(CI--alkyl)- - 10 piperazino, N-phenyl-piperazino,

C

5 7 -cycloalkenyleneimino group or by a C 4 7 -cycloalkyleneimino group, whilst the abovementioned

C

5 7 -cycloalkyleneimino groups may be substituted by one or two C 1

-

3 -alkyl groups, by a 5 C 5

-

7 -cycloalkyl or phenyl group, by a C1- alkyl,

C

5 7 -cycloalkyl, phenyl, carboxy or C 1 4 -alkoxy-carbonyl group and by a hydroxy group, the isomers and salts thereof. 10 Particularly preferred compounds of general formula I are those wherein -R 1 to R 5 are as hereinbefore defined and R 2 is in the 5 position, 15 particularly those compounds wherein X denotes an oxygen atom,

R

1 denotes a hydrogen atom, 20

R

2 in the 5 position denotes an aminocarbonyl group,

R

3 denotes a hydrogen atom or a C 1 4 -alkyl group which may be terminally substituted by a chlorine or bromine atom or 25 by a phenylsulphonyl group,

R

4 denotes a hydrogen atom, a C 13 -alkyl group or a cyclopentyl or cyclohexyl group optionally substituted by a methyl group, whilst in the cyclohexyl group a methylene 30 group in the 4 position in relation to the carbon atom of the R 3

-C(R

4

NR

5 )= group may be replaced by an imino group optionally substituted by a methyl group, a phenyl group which may be substituted 35 by a fluorine, chlorine, bromine or iodine atom, - 11 by a methyl or ethyl group, which may in each case be substituted by a CI- alkylamino, di- (C 1

-

3 -alkyl) -amino, thiomorpholino, 1-oxido-thiomorpholino, 1, 1-dioxido 5 thiomorpholino, N-phenyl-piperazino, 5- to 6-membered cycloalkenyleneimino group or by a 5- to 7 -membered cycloalkyleneimino group, whilst the abovementioned 5- to 7-membered cycloalkyleneimino groups may be substituted by one or two methyl groups, by a cyclohexyl or phenyl group, 10 by a methyl, cyclohexyl or phenyl group and by a hydroxy group, or by a methyl or ethyl group which may be substituted by a phenyl group which is substituted by a 5 to 7-membered 15 cycloalkyleneimino group, whilst additionally a phenyl ring is fused to the abovementioned cycloalkyleneimino groups via 2 adjacent carbon atoms, by a methyl or ethyl group substituted by an amino, 20 methylamino or ethylamino group, each of which is additionally substituted at the amino nitrogen atom by a benzyl or phenylethyl group, wherein the phenyl moiety in the abovementioned groups may be monosubstituted by a fluorine, chlorine or bromine atom or by a methyl, 25 methoxy, cyano, trifluoromethyl or nitro group or di- or trisubstituted by fluorine, chlorine or bromine atoms or by methyl or methoxy groups, and the substituents may be identical or different, 30 whilst additionally the abovementioned monosubstituted phenyl groups may be substituted by a fluorine, chlorine or bromine atom or by a methyl, methoxy or nitro group, and 35 R. denotes a hydrogen atom or a C 1 4 -alkyl group, the isomers and the salts thereof.

- 12 Most particularly preferred compounds of general formula I are those wherein 5 X denotes an oxygen atom,

R

1 denotes a hydrogen atom,

R

2 in the 5 position denotes an aminocarbonyl group, 10

R

3 denotes a hydrogen atom or a C, 4 -alkyl group,

R

4 denotes a phenyl group which may be substituted 15 by a fluorine, chlorine, bromine or iodine atom, by a methyl or ethyl group, which may be substituted in each case by a C 1 3 -alkylamino, di-(C 1 3 -alkyl)-amino, thiomorpholino, 1-oxido-thiomorpholino, 1,1-dioxido 20 thiomorpholino, N-phenyl-piperazino, 5- to 6-membered cycloalkenyleneimino group or by a 5- to 7-membered cycloalkyleneimino group, whilst the abovementioned 5- to 7-membered cycloalkyleneimino groups may be substituted by one or two methyl groups, by a cyclohexyl or phenyl group, 25 by a methyl, cyclohexyl or phenyl group and by a hydroxy group, or by a methyl or ethyl group which may be substituted by a phenyl group which is substituted in the 4 position by a 5 30 to 7-membered cycloalkyleneimino group, whilst additionally a phenyl ring is fused to the abovementioned cycloalkyleneimino groups via 2 adjacent carbon atoms, by a methyl or ethyl group substituted by an amino, 35 methylamino or ethylamino group, each of which is additionally substituted at the amino nitrogen atom by a benzyl or phenylethyl group, and wherein the phenyl moiety - 13 may be monosubstituted by a fluorine, chlorine or bromine atom or by a methyl, methoxy, cyano, trifluoromethyl or nitro group, disubstituted by methyl or methoxy groups or trisubstituted by methyl or methoxy groups, and the 5 substituents may be identical or different, whilst additionally the abovementioned monosubstituted phenyl groups may be substituted by a fluorine, chlorine or bromine atom or by a methyl, methoxy or nitro group, 10 and R. denotes a hydrogen atom or a CI 4 -alkyl group, the isomers and the salts thereof. 15 The following are mentioned as examples of particularly preferred compounds: (a) 3-Z-[1-(4-piperidinomethyl-phenylamino)-1-methyl-methy 20 lene]-5-amido-2-indolinone, (b) 3-Z-[1-(4-bromo-phenylamino)-1-methyl-methylene]-5 amido-2-indolinone, 25 (c) 3-Z-[1-(4-piperidinomethyl-phenylamino)-1-butyl methylene]-5-amido-2-indolinone, (d) 3-Z-[1-(4-chlorophenylamino)-1-methyl-methylene]-5 amido-2-indolinone and 30 (e) 3-Z-(1-phenylamino-methylene)-5-amido-2-indolinone (f) 3-Z-[1-(4-(N-benzyl-N-methyl-aminomethyl) phenylamino)-1-methyl-methylene]-5-amido-2-indolinone, 35 (g) 3-Z-[1-(4-(N-(4-chlorobenzyl)-aminomethyl) phenylamino)-1-methyl-methylene]-5-amido-2-indolinone, - 14 (h) 3-Z-[1-(4-(N-benzyl-N-ethyl-aminomethyl)-phenylamino] 1-methyl-methylene]-5-amido-2-indolinone, 5 (i) 3-Z-[1-(4-(N-benzyl-aminomethyl)-phenylamino)-1 methyl-methylene]-5-amido-2-indolinone, (j) 3-Z-[1-(4-(N-benzyl-N-methyl-aminomethyl) phenylamino)-methylene]-5-amido-2-indolinone, 10 (k) 3 -Z-[1-(4-(2,3,4,5-tetrahydro-benzo(d)azepin-3-yl methyl)-phenylamino)-1-methyl-methylene]-5-amido-2 indolinone, 15 (1) 3-Z-[1-(4-piperidinomethyl-3-nitro-phenylamino) 1-methyl-methylene]-5-amido-2-indolinone and (m) 3-Z-[1-(4-methyl-3-nitro-phenylamino)-1-methyl methylene)-5-amido-2-indolinone 20 as well as the isomers and the salts thereof. According to the invention, the new compounds may be obtained, for example, according to the following processes 25 known in principle from the literature: a. reacting a compound of general formula R3

-

zi RX (), N

R

6 30 wherein - 15 X and R 3 are as hereinbefore defined,

R

2 ' has the meanings given for R 2 hereinbefore,

R

6 denotes a hydrogen atom or a protecting group for the nitrogen atom of the lactam group, whilst one of the groups 5 R 2 ' or R 6 may also denote a bond to a solid phase optionally formed via a spacer and the other group R 2 ' or R 6 is as hereinbefore defined, and Z. denotes a halogen atom, a hydroxy, alkoxy or aralkoxy group, e.g. a chlorine or bromine atom or a methoxy, ethoxy 10 or benzyloxy group, with an amine 'of general formula Rs H- NR (III), R4 15 wherein

R

4 and R 5 are as hereinbefore defined, and if necessary subsequently cleaving any protecting groups used for the nitrogen atom of the lactam group or from a solid phase. 20 A suitable protecting group for the nitrogen atom of the lactam group might be, for example, an acetyl, benzoyl, ethoxycarbonyl, tert.butyloxycarbonyl or benzyloxycarbonyl group and 25 A suitable solid phase might be, for example, a resin such as a 4-(2',4'-dimethoxyphenylaminomethyl)-phenoxy resin, the bonding preferably taking place via the amino group, or a p-benzyloxybenzylalcohol resin, the bonding preferably 30 taking place via an intermediate member such as a 2,5 dimethoxy-4-hydroxy-benzyl derivative. The reaction is appropriately carried out in a solvent such as dimethylformamide, toluene, acetonitrile, - 16 tetrahydrofuran, dimethylsulphoxide, methylene chloride or mixtures thereof, optionally in the presence of an inert base such as triethylamine, N-ethyl-diisopropylamine or sodium hydrogen carbonate at temperatures between 20 and 5 175*C, whilst any protecting group used may be cleaved at the same time as a result of transamidation. If Z 1 in a compound of general formula II denotes a halogen atom, the reaction is preferably carried out in 10 the presence of an inert base at temperatures of between 20 and 120*C. If Zi in a compound of general formula II denotes a hydroxy, alkoxy or aralkoxy group, the reaction is 15 preferably carried out at temperatures between 20 and 200 0 C. The subsequent cleaving of any protecting group used, if necessary, is appropriately carried out either 20 hydrolytically in an aqueous or alcoholic solvent, e.g. in methanol/water, ethanol/water, isopropanol/water, tetrahydrofuran/water, dioxan/water, dimethylformamide/water, methanol or ethanol in the presence of an alkali metal base such as lithium 25 hydroxide, sodium hydroxide or potassium hydroxide at temperatures between 0 and 100 0 C, preferably at temperatures between 10 and 50*C, or more advantageously by transamidation with an organic 30 base such as ammonia, methylamine, 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 of between 0 and 100*C, preferably at temperatures between 10 and 50 0 C. 35 - 17 Any solid phase used is preferably cleaved by means of trifluoroacetic acid and water at temperatures of between 0 and 35 0 C, preferably at ambient temperatures. 5 b. in order to prepare a compound of general formula I wherein R 2 denotes one of the abovementioned aminocarbonyl groups: amidating a compound of general formula 10 R3 N R4 HO-CO O RIV N Ri 15 wherein R 1 and R 3 are as hereinbefore defined, or the reactive derivatives thereof, with an amine of general formula H - (R 7

NR

8 ) (V) 20 wherein R 7 andR. which may be identical or different denote hydrogen atoms or C 1 3 -alkyl groups. The amidation is preferably carried out in a solvent such 25 as methylene chloride, diethyl ether, tetrahydrofuran, toluene, dioxan, acetonitrile, dimethylsulphoxide or dimethylformamide, optionally in the presence of an inorganic or tertiary organic base, preferably at temperatures between 20 0 C and the boiling temperature of 30 the solvent used. The amidation is carried out with a - 18 corresponding acid, preferably in the presence of a dehydrating agent, e.g. in the presence of isobutyl chloroformate, tetraethyl orthocarbonate, trimethyl orthoacetate, 2,2-dimethoxypropane, tetramethyloxysilane, 5 thionylchloride, trimethylchlorosilane, phosphorus trichloride, phosphorus pentoxide, N,N' dicyclohexylcarbodiimide, N,N'-dicyclohexylcarbodiimide/N hydroxysuccinimide, N,N'-dicyclohexylcarbodiimide/1 hydroxy-benzotriazole, 2-(1H-benzotriazol-1-yl)-1,1,3,3 10 tetramethyluronium tetrafluoroborate, 2-(1H-benzotriazol 1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate/1 hydroxy-benzotriazole, N,N'-carbonyldiimidazole or triphenylphosphine/carbon tetrachloride, and optionally with the addition of a base such as pyridine, 4 15 dimethylaminopyridine, N-methylmorpholine or triethylamine, appropriately at temperatures between 0 and 150 0 C, preferably at temperatures between 0 and 100 0 C, and the acylation is carried out with a corresponding reactive compound such as the anhydride, ester, imidazolide or 20 halide thereof, optionally in the presence of a tertiary organic base such as triethylamine, N ethyldiisopropylamine or N-methylmorpholine at temperatures between 0 and 150*C, preferably at temperatures between 50 and 100 0 C. 25 If according to the invention a compound of general formula I is obtained which contains an alkoxycarbonyl group, this may be converted by hydrolysis into a corresponding carboxy compound, or 30 if a compound of general formula I is obtained which contains an amino or alkylamino group, this may be converted by alkylation or reductive alkylation into a corresponding alkylamino or dialkylamino compound, or 35 - 19 if a compound of general formula I is obtained which contains an amino or alkylamino group, this may be converted by acylation into a corresponding acyl compound, or 5 if a compound of general formula I is obtained which contains a carboxy group, this may be converted by esterification or amidation into a corresponding ester or aminocarbonyl compound, or 10 if a compound of general formula I is obtained which contains a nitro group, this may be converted by reduction into a corresponding amino compound. 15 The subsequent hydrolysis is preferably carried out in an aqueous solvent, e.g. in water, isopropanol/water, tetrahydrofuran/water or dioxan/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 20 such as lithium hydroxide, sodium hydroxide or potassium hydroxide at temperatures between 0 and 100*C, preferably at temperatures between 10 and 50*C. The subsequent reductive alkylation is preferably carried 25 out in a suitable solvent such as methanol, methanol/water, methanol/water/ammonia, ethanol ether, tetrahydrofuran, dioxan or dimethylformamide, optionally with the addition of an acid such as hydrochloric acid in the presence of catalytically activated hydrogen, e.g. 30 hydrogen in the presence of Raney nickel, platinum or palladium/charcoal, or in the presence of a metal hydride such as sodium borohydride, lithium borohydride or lithium aluminium hydride at temperatures between 0 and 100 0 C, preferably at temperatures between 20 and 80 0 C. 35 - 20 The subsequent alkylation is carried out with an alkylating agent such as an alkyl halide or dialkylsulphate such as methyl iodide, dimethylsulphate or propyl bromide, preferably in a solvent such as methanol, 5 ethanol, methylene chloride, tetrahydrofuran, toluene, dioxan, dimethylsulphoxide or dimethylformamide, optionally in the presence of an inorganic or tertiary organic base such as triethylamine, N-ethyl diisopropylamine or dimethylaminopyridine, preferably at 10 temperatures between 20 0 C and the boiling temperature of the solvent used. The subsequent acylation is preferably carried out in a solvent such as methylene chloride, diethyl ether, 15 tetrahydrofuran, toluene, dioxan, acetonitrile, dimethylsulphoxide or dimethyl formamide, optionally in the presence of an inorganic or tertiary organic base, preferably at temperatures between 20 0 C and the boiling temperature of the solvent used. The acylation is carried 20 out with a corresponding acid, preferably in the presence of a dehydrating agent, e.g. in the presence of isobutyl chloroformate, tetraethyl orthocarbonate, trimethyl orthoacetate, 2,2-dimethoxypropane, tetramethoxysilane, thionylchloride, trimethylchlorosilane, phosphorus 25 trichloride, phosphorus pentoxide, N,N' dicyclohexylcarbodiimide, N,N'-dicyclohexylcarbodiimide/N hydroxysuccinimide, N,N'-dicyclohexylcarbodiimide/1 hydroxy-benzotriazole, 2-(1H-benzotriazol-1-yl)-1,1,3,3 tetramethyluronium tetrafluoroborate, 2-(1H-benzotriazol 30 1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate/1 hydroxy-benzotriazole, N,N'-carbonyldiimidazole or triphenylphosphine/carbon tetrachloride, and optionally with the addition of a base such as pyridine, 4 dimethylamino-pyridine, N-methylmorpholine or 35 triethylamine, appropriately at temperatures of between 0 and 150 0 C, preferably at temperatures of between 0 and - 21 100 0 C, and the acylation is carried out with a corresponding reactive compound such as an anhydride, ester, imidazole or halide thereof, optionally in the presence of a tertiary organic base such as triethylamine, 5 N-ethyl-diisopropylamine or N-methyl-morpholine at temperatures of between 0 and 150 0 C, preferably at temperatures of between 50 and 100 C. The subsequent esterification or amidation is 10 appropriately carried out by reacting a corresponding reactive carboxylic acid derivative with a corresponding alcohol or amine as described hereinbefore. The subseqent reduction of a nitro group is preferably 15 carried out by hydrogenolysis, e.g. with hydrogen in the presence of a catalyst such as palladium/charcoal or Raney nickel in a solvent such as methanol, ethanol, ethyl acetate, dimethylformamide, dimethylformamide/acetone or glacial acetic acid, optionally with the addition of an 20 acid such as hydrochloric acid or glacial acetic acid at temperatures between 0 and 50*C, but preferably at ambient temperature, and at a hydrogen pressure of from 1 to 7 bar, but preferably from-3 to 5 bar. 25 In the reactions described hereinbefore, any reactive groups present such as carboxy, amino, alkylamino or imino groups may be protected during the reaction by conventional protecting groups which are cleaved again after the reaction. 30 For example, a protecting group for a carboxy group may be a trimethylsilyl, methyl, ethyl, tert.butyl, benzyl or tetrahydropyranyl group and 35 protecting groups for an amino, alkylamino or imino group may be an acetyl, trifluoroacetyl, benzoyl, ethoxycarbonyl, tert.butoxycarbonyl, benzyloxycarbonyl, - 22 benzyl, methoxybenzyl or 2,4-dimethoxybenzyl group and additionally, for the amino group, a phthalyl group. Any protecting group used is optionally subsequently 5 cleaved for example by hydrolysis in an aqueous solvent, e.g. in water, isopropanol/water, tetrahydrofuran/water or dioxan/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 10 hydroxide, sodium hydroxide or potassium hydroxide, at temperatures between 0 and 100 0 C, preferably at temperatures between 10 and 50 0 C. However, a benzyl, methoxybenzyl or benzyloxycarbonyl 15 group is cleaved, for example hydrogenolytically, e.g. with hydrogen in the presence of a catalyst such as palladium/charcoal in a suitable solvent such as methanol, ethanol, ethyl acetate, dimethylformamide, dimethylformamide/acetone or glacial acetic acid, 20 optionally with the addition of an acid such as hydrochloric acid or glacial acetic acid at temperatures between 0 and 50 0 C, but preferably at ambient temperature, and at a hydrogen pressure of 1 to 7 bar, but preferably 3 to 5 bar. 25 A methoxybenzyl group may also be cleaved in the presence of an oxidising agent such as cerium(IV)ammonium nitrate in a solvent such as methylene chloride, acetonitrile or acetonitrile/water at temperatures of between 0 and 50 0 C, 30 preferably at ambient temperature. A 2,4-dimethoxybenzyl group, however, is preferably cleaved in trifluoroacetic acid in the presence of anisole. 35 A tert.butyl or tert.butyloxycarbonyl group is preferably cleaved by treating with an acid such as trifluoroacetic - 23 acid or hydrochloric acid, optionally using a solvent such as methylene chloride, dioxan, ethyl acetate or ether. A phthalyl group is preferably cleaved in the presence of 5 hydrazine or a primary amine such as methylamine, ethylamine or n-butylamine in a solvent such as methanol, ethanol, isopropanol, toluene/water or dioxan at temperatures between 20 and 50 0 C. 10 Moreover, chiral compounds of general formula I obtained may be resolved into their enantiomers and/or diastereomers: Thus, for example, the compounds of general formula I 15 obtained which occur as racemates may be separated by methods known per se (cf. Allinger N. L. and Eliel E. L. in "Topics in Stereochemistry", Vol. 6, Wiley Interscience, 1971) into their optical antipodes and compounds of general formula I with at least 2 asymmetric 20 carbon atoms may be resolved into their diastereomers on the basis of their physical-chemical differences using methods known per se, e.g. by chromatography and/or fractional crystallisation, and, if these compounds are obtained in racemic form, they may subsequently be 25 resolved into the enantiomers as mentioned above. The enantiomers are preferably separated by column separation on chiral phases or by recrystallisation from an optically active solvent or by reacting with an 30 optically active substance which forms salts or derivatives such as e.g. esters or amides with the racemic compound, particularly acids and the activated derivatives or alcohols thereof, and separating the diastereomeric mixture of salts or derivatives thus obtained, e.g. on the 35 basis of their differences in solubility, whilst the free antipodes may be released from the pure diastereomeric - 24 salts or derivatives by the action of suitable agents. Optically active acids in common use are e.g. the D- and L-forms of tartaric acid or dibenzoyltartaric acid, di o-tolyltartaric acid, malic acid, mandelic acid, 5 camphorsulphonic acid, glutamic acid, aspartic acid, N acetyl-aspartic acid or quinic acid. An optically active alcohol may be for example (+) or (-)-menthol and an optically active acyl group in amides, for example, may be a (+)- or (-)-menthyloxycarbonyl group. 10 Furthermore, the compounds of formula I may be converted into the salts thereof, particularly for pharmaceutical use into the physiologically acceptable salts with inorganic or organic acids. Acids which may be used for 15 this purpose include for example hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid, fumaric acid, succinic acid, lactic acid, citric acid, tartaric acid, maleic or methanesulphonic acid. 20 Moreover, if the new compounds of formula I contain a carboxy group, they may subsequently, if desired, be converted into the salts thereof with inorganic or organic bases, particularly for pharmaceutical use into the physiologically acceptable salts thereof. Suitable bases 25 for this purpose include for example sodium hydroxide, potassium hydroxide, arginine, cyclohexylamine, etha nolamine, diethanolamine and triethanolamine. The compounds of general formulae I to V used as starting 30 materials are known from the literature in some cases or are described in the Examples. As already mentioned, the new compounds of general formula I wherein

R

1 denotes a hydrogen atom or a prodrug group 35 have valuable pharmacological properties, particularly an inhibitory effect on various kinases and cycline/CDK complexes, on the proliferation of cultivated human tumour - 25 cells and, when administered orally, on the growth of tumours in nude mice which have been infected with human tumour cells. 5 For example, the compounds listed in Table 1 were tested for their biological properties as follows: Test 1 10 Inhibition of cycline/CDK enzyme, in vitro activity High Five' insect cells (BTI-TN-5B1-4) which had been infected with a high titre of recombinant baculovirus were used to produce active human cycline/CDK holoenzymes. By 15 using a baculovirus vector which contained two promoters (polyhedrin enhancer promoter, P10 enhancer promoter), GST-tagged cyclines (e.g. cycline D1 or cycline D3) with the corresponding His,-tagged CDK subunit (e.g. for CDK4 or CDK6) were expressed in the same cell. The active 20 holoenzyme was isolated by affinity chromatography on glutathione sepharose. Recombinant GST-tagged pRB (aa 379-928) was produced in E. coli and purified by affinity chromatography on glutathione sepharose. 25 The substrates used for the kinase assays depended on the specific kinases. Histone H1 (Sigma) was used as the substrate for cycline E/CDK2, cycline A/CDK2, cycline B/CDK1 and for v-cycline/CDK6. GST-tagged pRB (aa 379 928) was used as substrate for cycline D1/CDK4, cycline 30 D3/CDK4, cycline D1/CDK6 and for cycline D3/CDK6. Lysates of the insect cells infected with recombinant baculovirus or recombinant kinases (obtained from the lysates by purification) were incubated together with 35 radiolabelled ATP in the presence of a suitable substrate with various concentrations of the inhibitor in a 1% DMSO (dimethyl sulphoxide) solution for 45 minutes at 30 0

C.

- 26 The substrate proteins with associated radioactivity were precipitated with 5% TCA (trichloroacetic acid) in water repellent PVDF multi-well microtitre plates (Millipore) or with 0.5% phosphoric acid solution on Whatman P81 filters. 5 After the addition of scintillation liquid the radioactivity was measured in a Wallace 1450 Microbeta Liquid Scintillation Counter. For each concentration of the substance double measurements were carried out; IC5 0 values were calculated for the enzyme inhibition. 10 Test 2 Inhibition of the proliferation of cultivated human tumour cells 15 Cells of the Leiomyosarcoma tumour cell line SK-UT-1B (obtained from the American Type Culture Collection (ATCC)) were cultivated in Minimum Essential Medium with non-essential amino acids (Gibco), supplemented with 20 sodium pyruvate (1 mmol), glutamine (2 mmol) and 10% foetal calf serum (Gibco) and harvested during the log growth phase. Then the SK-UT-1B cells were added to Cytostar* multi-well plates (Amersham) at a density of 4000 cells per well and incubated overnight in an 25 incubator. Various concentrations of the compounds (dissolved in DMSO; final concentration: <1%) were added to the cells. After 48 hours' incubation 14C thymidine (Amersham) was added to each well and incubation was continued for a further 24 hours. The quantity of 14

C

30 thymidine incorporated into the tumour cells in the presence of the inhibitor and representing the number of cells in the S phase was measured in a Wallace 1450 Microbeta Liquid Scintillation Counter. IC 50 values for the inhibition of proliferation (= inhibition of incorporated 35 14 C-thymidine) were calculated, correcting for the background radiation. All the measurements were done twice.

- 27 Test 3 In vivo effects on tumour-bearing nude mice 5 106 cells [SK-UT-1B, or non-small cell lung tumour NCI H460 (obtained from ATCC)] in a volume of 0.1 ml were injected subcutaneously into male and/or female nude mice (NMRI nu/nu; 25-35g; N = 10-20); alternatively, small 10 fragments of SK-UT-1B or NCI-H460 cell clumps were implanted subcutaneously. One to three weeks after the injection or implantation a kinase inhibitor was administered daily by oral route for a period of 2 to 4 weeks (by oesophageal tube). The size of the tumour was 15 measured three times a week using a digital sliding gauge. The effect of a kinase inhibitor on the tumour growth was determined as a percentage inhibition compared with a control group treated with placebo. 20 Table 2 which follows contains the results obtained in in vitro test 2: - 28 Compound Inhibition of SKUT (example no.) -1B proliferation IC,, [p1M] 1(11) 0.032 1(8) 0.060 1(26) 0.036 1(3) 0.040 1(1) 0.100 1(96) 0.005 1(91) 0.010 1(95) 0.008 1(51) 0.013 1(105) 0.019 1(110) 0.020 1(117) 0.020 1(71) 0.030 In view of their biological properties, the new compounds of general formula I, their isomers and physiologically 5 acceptable salts are suitable for the treatment of diseases characterised by excessive or abnormal cell proliferation. Such diseases include (with no claim to completeness): 10 viral infections (e.g. HIV and Kaposi's sarcoma); inflammation and autoimmune diseases (e.g. colitis, arthritis, Alzheimer's disease, glomerulonephritis and wound healing); bacterial, fungal and/or parasitic infections; leukaemias, lymphoma and solid tumours; skin 15 diseases (e.g. psoriasis); bone diseases; cardiovascular diseases (e.g. restenosis and hypertrophy). They are also useful for protecting proliferating cells (e.g. hair, intestinal, blood and progenitor cells) against DNA damage caused by radiation, UV treatment and/or cytostatic 20 treatment.

- 29 The new compounds may be used for the short-term or long term treatment of the abovementioned diseases, optionally in conjunction with other 'state of the art' compounds 5 such as other cytostatics. The dosage required to achieve such an effect is appropriately 0.1 to 30 mg/kg, preferably 0.3 to 10 mg/kg by intravenous route, and 0.1 to 100 mg/kg, preferably 0.3 10 to 30 mg/kg by oral route, in each case administered 1 to 4 times a day. For this purpose, the compounds of formula I prepared according to the invention may be formulated, optionally together with other active substances, with one or more inert conventional carriers and/or diluents, e.g. 15 with corn starch, lactose, glucose, microcrystalline cellulose, magnesium stearate, polyvinylpyrrolidone, citric acid, tartaric acid, water, water/ethanol, water/glycerol, water/sorbitol, water/polyethylene glycol, propylene glycol, cetylstearyl alcohol, 20 carboxymethylcellulose or fatty substances such as hard fat or suitable mixtures thereof, to produce conventional galenic preparations such as plain or coated tablets, capsules, powders, suspensions or suppositories. 25 The Examples which follow are intended to illustrate the invention: - 30 Example I Methyl 1-acetyl-2-indolinone-5-carboxylate 10.5 g of methyl 2 -indolinone-5-carboxylate (prepared 5 analogously to Ogawa, Hidenori et al. in Chem.Pharm.Bull 36. 2253-2258 (1988)) are stirred in 30 ml of acetic anhydride for 4 hours at 140 0 C. The mixture is then left to cool, poured onto ice water and the precipitate is suction filtered. The product is washed with water once 10 more, then taken up in methylene chloride, dried over sodium sulphate and concentrated by evaporation. Yield: 11 g (86 % of theory), R, value: 0.63 (silica gel, methylene chloride/methanol = 50:1) 15 Example II Methyl 1-acetyl-3-(l-ethoxy-l-butyl-methyleneJ-2 indolinone-5-carboxylate 20 11 g of methyl 1-acetyl-2-indolinone-5-carboxylate are stirred in 110 ml of acetic anhydride and 30 ml of triethyl orthovalerate for 2 hours at 100 0 C. Then it is concentrated by rotary evaporation, the residue is washed 25 with ether and suction filtered. Yield: 11.5 g (67 % of theory), Rf value: 0.55 (silica gel, methylene chloride/petroleum ether/ethyl acetate = 4:5:1) 30 The following compounds are prepared analogously to Example II: (1) methyl 1-acetyl-3-(1-ethoxy-methylene]-2-indolinone-5 carboxylate 35 Prepared from methyl 1-acetyl-2-indolinone-5-carboxylate and trimethyl orthoformate - 31 (2) methyl 1-acetyl-3-(1-ethoxy-1-methyl-methyleneJ-2 indolinone-5-carboxylate Prepared from methyl 1-acetyl-2-indolinone-5-carboxylate and triethyl orthoacetate 5 (3) methyl 1-acetyl-3-(1-ethoxy-l-ethyl-methylene]-2 indolinone-5-carboxylate Prepared from methyl 1-acetyl-2-indolinone-5-carboxylate and triethyl orthopropionate 10 Example III 28.0 g of Rink resin (MBHA resin made by Novobiochem) were allowed to swell in 330 m of dimethylformamide. Then 330 15 ml of 30% piperidine in dimethyl formamide were added and the mixture was shaken for 7 minutes to cleave the 9H fluoren-9-yl-methoxycarbonyl group. Then the resin was washed several times with dimethylformamide. Finally, 7.3 g 10.5 g of 2 -indolinone-5-carboxylic acid (prepared 20 analogously to Ogawa, Hidenori et al., Chem. Pharm. Bull 36, 2253-2258 (1988)), 5.6 g of hydroxybenzotriazole, 13.3 g of 0-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate and 5.7 ml of N-ethyl-diisopropylamine in 300 ml of dimethylformamide were added and the mixture 25 was shaken for 1 hour. The solution was suction filtered and the resin was washed five times with 300 ml of dimethylformamide and three times with 300 ml of methylene chloride. To dry it, nitrogen was blown through the resin. 30 Yield: 20 g of charged resin Example IV 0.4 g of the charged resin prepared in Example III were 35 stirred with 2.5 ml of acetic anhydride at 90 0 C for 1 hour. Then 2.5 ml of trimethyl orthovalerate were added and the mixture was shaken for a further 3 hours at 110 0

C.

- 32 Then the resin was suction filtered and washed with dimethylformamide, methanol and finally with methylene chloride. 5 Yield: 0.6 g of moist resin The following charged resins were prepared analogously to Example IV: 10 (1) resin charged with 3-Z-(1-ethoxy-methylene)-5-amido-2 indolinone by reacting the product of Example I and triethyl orthoformate (2) resin charged with 3-Z-(l-methoxy-l-methyl-methylene) 15 5-amido-2-indolinone by reacting the product of Example I and trimethyl orthoformate (3) resin charged with 3-Z-(l-methoxy-1-ethyl-methylene)-5 amido-2-indolinone by reacting the product of Example I and 20 trimethyl orthopropionate (4) resin charged with 3-Z-(l-methoxy-l-propyl-methylene) 5-amido-2-indolinone by reacting the product of Example I and trimethyl orthobutyrate 25 (5) resin charged with 3-Z-(1-methoxy-1-ethenyl-methylene) 5-amido-2-indolinone by reacting the product of Example I and 3,3,3-triethoxyprop-l-ene 30 (6) resin charged with 3-Z-(l-methoxy-1-(3-bromo-propyl) methylene)-5-amido-2-indolinone by reacting the product of Example I and trimethyl 4 -bromo-orthobutyrate (7) resin charged with 3-Z-(l-methoxy-1-(2-phenylsulphonyl 35 ethyl)-methylene)-5-amido-2-indolinone by reacting the product of Example I and triethyl 3 -phenylsulphonyl orthopropionate - 33 Example V 4-(N-Ethyl-aminomethyl)-nitrobenzene 5 6 g of 4-nitrobenzylbromide are dissolved in 25 ml of ethanol, mixed with 25 ml of 10% ethanolic ethylamine solution and refluxed for 2 hours. Then the solution is concentrated by rotary evporation, the residue is taken up in methylene chloride and washed with dilute sodium 10 hydroxide solution. Then the organic phase is concentrated by evaporation. Yield: 2.3 g (-46 % of theory), Rf value: 0.20 (silica gel, methylene chloride/methanol = 9:1) 15 The following compounds are prepared analogously to Example V: 4- [N- (4-chlorophenyl-methyl) -aminomethyl] -nitrobenzene 20 4- (N-cyclohexyl-aminomethyl) -nitrobenzene 4-(N-isopropyl-aminomethyl)-nitrobenzene 25 4-(N-butyl-aminomethyl)-nitrobenzene 4-(N-methoxycarbonylmethyl-aminomethyl)-nitrobenzene 4-(N-benzyl-aminomethyl)-nitrobenzene 30 4-(pyrrolidino-methyl)-nitrobenzene 4-(morpholino-methyl)-nitrobenzene 35 4-(piperidino-methyl)-nitrobenzene. 4-(hexamethyleneimino-methyl)-nitrobenzene - 34 4-(4-hydroxy-piperidino-methyl)-nitrobenzene 4-(4-methyl-piperidino-methyl)-nitrobenzene 5 4-(4-ethyl-piperidino-methyl)-nitrobenzene 4-(4-isopropyl-piperidino-methyl)-nitrobenzene 10 4-(4-phenyl-piperidino-methyl)-nitrobenzene 4-(4-benzyl-piperidino-methyl)-nitrobenzene 4-(4-ethoxycarbonyl-piperidino-methyl)-nitrobenzene 15 4-(dimethylamino-methyl)-nitrobenzene 4-(di-n-propylamino-methyl)-nitrobenzene 20 4-(4-tert.butoxycarbonyl-piperazino-methyl)-nitrobenzene 3-(dimethylamino-methyl)-nitrobenzene 4-(2-diethylamino-ethyl)-nitrobenzene 25 4-(2-morpholino-ethyl)-nitrobenzene 4-(2-pyrrolidino-ethyl)-nitrobenzene 30 4-(2-piperidino-ethyl)-nitrobenzene 4-(N-ethyl-N-benzyl-aminomethyl)-nitrobenzene 4-(N-n-propyl-N-benzyl-aminomethyl)-nitrobenzene 35 4-[N-methyl-N-(4-chlorophenylmethyl)-aminomethyl] nitrobenzene - 35 4-[N-methyl-N-(4-bromophenylmethyl)-aminomethyl] nitrobenzene 5 4-[N-methyl-N-(3-chlorophenylmethyl)-aminomethyl] nitrobenzene 4-[N-methyl-N-(3,4-dimethoxyphenylmethyl)-aminomethyl] nitrobenzene 10 4-[N-methyl-N-(4-methoxyphenylmethyl)-aminomethyl) nitrobenzene 4-[N-(2,2,2-trifluoroethyl)-N-benzyl-aminomethyl] 15 nitrobenzene 4-[N-(2,2,2-trifluoroethyl)-N-(4-chlorophenylmethyl) aminomethyl]-nitrobenzene 20 4-(2,6-dimethyl-piperidino-methyl)-nitrobenzene 4-(thiomorpholino-methyl)-nitrobenzene 4-(S-oxido-thiomorpholino-methyl)-nitrobenzene 25 4-(S,S-dioxido-thiomorpholino-methyl)-nitrobenzene 4-(azetidino-methyl)-nitrobenzene 30 4-(2,5-dihydropyrrol-1-yl-methyl)-nitrobenzene 4-(3,6-dihydro-2H-pyridin-1-yl-methyl)-nitrobenzene 4-(2-methoxycarbonyl-pyrrolidino-methyl)-nitrobenzene 35 4-(3,5-dimethyl-piperidino-methyl)-nitrobenzene - 36 4-(4-phenyl-piperazinyl-methyl)-nitrobenzene 4-(4-phenyl-4-hydroxy-piperidino-methyl)-nitrobenzene 5 4- [N- (3,4, 5-trimethoxy-benzyl) -N-methyl-aminomethyl] nitrobenzene 4-[N-(3,4-dimethoxy-benzyl)-N-ethyl-aminomethyl] nitrobenzene 10 4- [N- (3-chlorobenzyl) -N-methyl-aminomethyl] -nitrobenzene 4-[N-(2,6-dichlorobenzyl)-N-methyl-aminomethyl] nitrobenzene 15 4- [N- (4-trifluoromethylbenzyl) -N-methyl-aminomethyl] nitrobenzene 4-(N-benzyl-N-isopropyl-aminomethyl)-nitrobenzene 20 4- (N-benzyl-N-tert .butyl-aminomethyl) -nitrobenzene 4- (diisopropylamino-methyl) -nitrobenzene 25 4-(di-n-propylamino-methyl)-nitrobenzene 4-(diisobutylamino-methyl)-nitrobenzene 4-( 2 ,3,4,5-tetrahydro-benzo(d)azepin-3-yl-methyl) 30 nitrobenzene 4- (2, 3-dihydro-isoindol-2-yl-methyl) -nitrobenzene 4-(6, 7 -dimethoxy-1,2,3,4-tetrahydro-isoquinolin-2-yl 35 methyl)-nitrobenzene - 37 4- (1, 2 ,3,4-tetrahydro-isoquinolin-2-yl -methyl) nitrobenzene 4- [N- (2-hydroxyethyl) -N-benzyl-aminomethyl] -nitrobenzene 5 4- [N- (1-ethyl-pentyl) -N- (pyridin-2-yl-methyl) aminomethyl]-nitrobenzene 4- (N-phenethyl-N-methyl-aminomethyl) -nitrobenzene 10 4- [N- (3,4-dihydroxy-phenethyl) -N-methyl-aminomethyl] nitrobenzene 4- [N- (3,4, 5-trimethoxy-phenethyl) -N-methyl-aminomethyl] 15 nitrobenzene 4- [N- (3,4-dimethoxy-phenethyl) -N-methyl-aminomethyl] nitrobenzene 20 4- [N- (4-nitro-phenethyl) -N-methyl-aminomethyl] nitrobenzene 4-(N-phenethyl-N-benzyl-aminomethyl)-nitrobenzene 25 4-(N-phenethyl-N-cyclohexyl-aminomethyl)-nitrobenzene 4- [N- (2- (pyridin-2-yl) -ethyl) -N-methyl-aminomethyl] nitrobenzene 30 4- [N- (2- (pyridin-4-yl) -ethyl) -N-methyl-aminomethyl] nitrobenzene 4- [N- (pyridin-4-yl-methyl) -N-methyl-aminomethyl] nitrobenzene 35 4- (dibenzylamino-methyl) -nitrobenzene - 38 4-[N-(4-nitro-benzyl)-N-propyl-aminomethyl]-nitrobenzene 4-[N-benzyl-N-(3-cyano-propyl)-aminomethyl]-nitrobenzene 5 4-(N-benzyl-N-allyl-aminomethyl)-nitrobenzene 4-[N-(benzo(1,3)dioxol-5-yl-methyl)-N-methyl-aminomethyl] nitrobenzene 10 4-(7-chloro-2,3,4,5-tetrahydro-benzo(d)azepin-3-yl methyl)-nitrobenzene 4-(7,8-dichloro-2,3,4,5-tetrahydro-benzo(d)azepin-3-yl methyl)-nitrobenzene 15 4-(7-methoxy-2,3,4,5-tetrahydro-benzo(d)azepin-3-yl methyl)-nitrobenzene 4-(7-methyl-2,3,4,5-tetrahydro-benzo(d)azepin-3-yl 20 methyl)-nitrobenzene 4-(7,8-dimethoxy-2,3,4,5-tetrahydro-benzo(d)azepin-3-yl methyl)-nitrobenzene 25 4-(6,7-dichloro-1,2,3,4-tetrahydro-isoquinolin-2-yl methyl)-nitrobenzene 4-(6,7-dimethyl-1,2,3,4-tetrahydro-isoquinolin-2-yl methyl)-nitrobenzene 30 4-(6-chloro-1,2,3,4-tetrahydro-isoquinolin-2-yl-methyl) nitrobenzene 4-(7-chloro-1,2,3,4-tetrahydro-isoquinolin-2-yl-methyl) 35 nitrobenzene - 39 4-(6-methoxy-1,2,3,4-tetrahydro-isoquinolin-2-yl-methyl) nitrobenzene 4-(7-methoxy-1,2,3,4-tetrahydro-isoquinolin-2-yl-methyl) 5 nitrobenzene 4-(2,3,4,5-tetrahydro-azepino(4,5-b)pyrazin-3-yl)-methyl) nitrobenzene 10 4-(7-amino-2,3,4,5-tetrahydro-azepino(4,5-b)pyrazin-3-yl methyl)-nitrobenzene 4-(2-amino-5,6,7,8-tetrahydro-azepino(4,5-d)thiazol-6-yl methyl)-nitrobenzene 15 4-(5,6,7,8-tetrahydro-azepino(4,5-d)thiazol-6-yl-methyl) nitrobenzene Example VI 20 4-(N-Ethyl-N-tert.butoxvcarbonyl-aminomethyl)-nitrobenzene 2.2 g of 4-(N-ethyl-aminomethyl)-nitrobenzene are dissolved in 50 ml of ethyl acetate and stirred with 2.6 g 25 of di-tert.butyl-dicarbonate for 30 minutes at ambient temperature. Then the solution is washed with water and concentrated by evaporation. Yield: 3.4 g (97 % of theory), Rf value: 0.90 (silica gel, methylene chloride/methanol = 30 9:1) The following compounds are prepared analogously to Example VI: 35 4-[N-(4-chlorophenylmethyl)-N-tert.butoxycarbonyl aminomethyl]-nitrobenzene - 40 4- (N-cyclohexyl-N-tert .butoxycarbonyl-aminomethyl) nitrobenzene 5 4-(N-isopropyl-N-tert.butoxycarbonyl-aminomethyl) nitrobenzene 4-(N-butyl-N-tert.butoxycarbonyl-aminomethyl)-nitrobenzene 10 4- (N-methoxycarbonylmethyl-N-tert.butoxycarbonyl aminomethyl)-nitrobenzene 4- (N-benzyl-N-tert .butoxycarbonyl-aminomethyl) nitrobenzene 15 4-(N-ethyl-N-tert.butoxycarbonyl-aminomethyl)-nitrobenzene Example VII 20 4-(N-Ethyl-N-tert.butoxvcarbonyl-aminomethyl)-aniline 6.4 g of 4-(N-ethyl-N-tert.butoxycarbonyl-aminomethyl) nitrobenzene are dissolved in 60 ml of methanol and hydrogenated with 1.5 g of Raney nickel at ambient temperature under 3 bar. The catalyst is then filtered off 25 and the solution is evaporated down. Yield: 4.78 g Rf value: 0.70 (silica gel, methylene chloride/methanol = 50:1) 30 The following compounds are prepared analogously to Example VII: 4- [N- (4-chlorophenylmethyl) -N-tert .butoxycarbonyl aminomethyl)-aniline 35 4- (N-cyclohexyl-N-tert .butoxycarbonyl-aminomethyl) -aniline - 41 4-(N-isopropyl-N-tert.butoxycarbonyl-aminomethyl)-aniline 4-(N-butyl-N-tert.butoxycarbonyl-aminomethyl)-aniline 5 4-(N-methoxycarbonylmethyl-N-tert.butoxycarbonyl aminomethyl)-aniline 4-(N-benzyl-N-tert.butoxycarbonyl-aminomethyl)-aniline 10 4-(pyrrolidino-methyl)-aniline 4-(morpholino-methyl)-aniline 4-(piperidino-methyl)-aniline 15 4-(hexamethyleneimino-methyl)-aniline 4-(4-hydroxy-piperidino-methyl)-aniline 20 4-(4-methyl-piperidino-methyl)-aniline 4-(4-ethyl-piperidino-methyl)-aniline 4-(4-isopropyl-piperidino-methyl)-aniline 25 4-(4-phenyl-piperidino-methyl)-aniline 4-(4-benzyl-piperidino-methyl)-aniline 30 4-(4-ethoxycarbonyl-piperidino-methyl)-aniline 4-(dimethylamino-methyl)-aniline 4-(di-n-propylamino-methyl)-aniline 35 4-(4-tert.butoxycarbonyl-piperazino-methyl)-aniline - 42 3-(dimethylamino-methyl)-aniline 4-(2-diethylamino-ethyl)-aniline 5 4-(2-morpholino-ethyl)-aniline 4-(2-pyrrolidino-ethyl)-aniline 4-(2-piperidino-ethyl)-aniline 10 4-(N-ethyl-N-benzyl-aminomethyl)-aniline 4-(N-propyl-N-benzyl-aminomethyl)-aniline 15 4-(N-methyl-N-(4-chlorophenylmethyl)-aminomethyl)-aniline 4-(N-methyl-N-(4-bromophenylmethyl)-aminomethyl)-aniline 4-(N-methyl-N-(3-chlorophenylmethyl)-aminomethyl)-aniline 20 4-(N-methyl-N-(3,4-dimethoxyphenylmethyl)-aminomethyl) aniline 4-(N-methyl-N-(4-methoxyphenylmethyl)-aminomethyl)-aniline 25 4-[N-(2,2,2-trifluoroethyl)-N-benzyl-aminomethyl]-aniline 4-[N-(2,2,2-trifluoroethyl)-N-(4-chlorophenylmethyl) aminomethyl]-aniline 30 4-(2,6-dimethyl-piperidino-methyl)-aniline 4-(thiomorpholino-methyl)-aniline 35 4-(S-oxido-thiomorpholino-methyl)-aniline 4-(S,S-dioxido-thiomorpholino-methyl)-aniline - 43 4- (azetidino-methyl) -aniline 4-(2,5-dihydropyrrol-1-yl-methyl)-aniline 5 4-(3,6-dihydro-2H-pyridin-1-yl-methyl)-aniline 4-(2-methoxycarbonyl-pyrrolidino-methyl)-aniline 10 4-(3,5-dimethyl-piperidino-methyl)-aniline 4- (4-phenyl-pi-perazino-methyl) -aniline 4-(4-phenyl-4-hydroxy-piperidino-methyl)-aniline 15 4- [N- (3,4, 5-trimethoxybenzyl) -N-methyl-aminomethyl] aniline 4- [N- (3,4-dimethoxybenzyl) -N-ethyl-aminomethyl] -aniline 20 4-(N-benzyl-N-ethyl-aminomethyl)-aniline 4- [N- (3-chlorobenzyl) -N-methyl-aminomethyl] -aniline 25 4- [N- (2, 6-dichlorobenzyl) -N-methyl-aminomethyl] -aniline 4- [N- (4-trifluoromethylbenzyl) -N-methyl-aminomethyl) aniline 30 4-(N-benzyl-N-isopropyl-aminomethyl)-aniline 4-(N-benzyl-N-tert.butyl-aminomethyl)-aniline 4-(diisopropylamino-methyl)-aniline 35 4-(di-n-propylamino-methyl)-aniline - 44 4-(diisobutylamino-methyl)-aniline 4-(2,3,4,5-tetrahydro-benzo(d)azepin-3-yl-methyl)-aniline 5 4-(2,3-dihydro-isoindol-2-yl-methyl)-aniline 4-(6,7-dimethoxy-1,2,3,4-tetrahydro-isoquinolin-2-yl methyl)-aniline 10 4-(1,2,3,4-tetrahydro-isoquinolin-2-yl-methyl)-aniline 4-[N-(2-hydroxyethyl)-N-benzyl-aminomethyl]-aniline 4-[N-(1-ethyl-pentyl)-N-(pyridin-2-yl-methyl) 15 aminomethyl]-aniline 4-(N-phenethyl-N-methyl-aminomethyl)-aniline 4-[N-(3,4-dihydroxy-phenethyl)-N-methyl-aminomethyl) 20 aniline 4-[N-(3,4,5-trimethoxy-phenethyl)-N-methyl-aminomethyl] aniline 25 4-[N-(3,4-dimethoxy-phenethyl)-N-methyl-aminomethyl) aniline 4-[N-(4-nitro-phenethyl)-N-methyl-aminomethyl)-aniline 30 4-(N-phenethyl-N-benzyl-aminomethyl)-aniline 4-(N-phenethyl-N-cyclohexyl-aminomethyl)-aniline 4-[N-(2-(pyridin-2-yl)-ethyl)-N-methyl-aminomethyl] 35 aniline - 45 4- [N- (2- (pyridin-4-yl) -ethyl) -N-methyl-aminomethyl] aniline 4- [N- (pyridin-4-yl-methyl) -N-methyl-aminomethyl] -aniline 5 4- (dibenzylamino-methyl) -aniline 4- [N- (4-nitro-benzyl) -N-propyl-aminomethyl] -aniline 10 4- [N-benzyl-N- (3-cyano-propyl) -aminomethyl) -aniline 4- (N-benzyl-N-allyl-aminomethyl) -aniline 4- [N-benzyl-N- (2,2, 2-trifluoroethyl) -aminomethyll -aniline 15 4- [N- (benzo (1,3) dioxol-5-yl-methyl) -N-methyl-aminomethyl] aniline 4- ( 7 -chloro-2 ,3,4,5-tetrahydro-benzo(d)azepin-3-yl 20 methyl) -aniline 4- (7,8-dichloro-2,3,4,5-tetrahydro-benzo(d)azepin-3-yl methyl) -aniline 25 4- ( 7 -methoxy-2,3,4,5-tetrahydro-benzo(d)azepin-3-yl methyl) -aniline 4- (7-methyl-2,3,4,5-tetrahydro-benzo (d) azepin-3-yl methyl) -aniline 30 4- (7,8-dimethoxy-2,3,4,5-tetrahydro-benzo(d)azepin-3-yl methyl) -aniline 4- (6,7-dichloro-1,2,3,4-tetrahydro-isoquinolin-2-yl 35 methyl) -aniline - 46 4 -(6, 7 -dimethyl-1,2,3,4-tetrahydro-isoquinolin-2-yl methyl) -aniline 4- ( 6 -chloro-1,2,3,4-tetrahydro-isoquinolin-2-yl-methyl) 5 aniline 4- (7-chloro-1,2,3,4-tetrahydro-isoquinolin-2-yl-methyl) aniline 10 4-(6-methoxy-1,2,3,4-tetrahydro-isoquinolin-2-yl-methyl) aniline 4- (7-methoxy-1,2,3,4-tetrahydro-isoquinolin-2-yl-methyl) aniline 15 4-( 2 ,3,4,5-tetrahydro-azepino(4,5-b)pyrazin-3-yl-methyl) aniline 4- ( 7 -amino - 2,3,4,5-tetrahydro-azepino(4,5-b)pyrazin-3-yl 20 methyl) -aniline 4- ( 2 -amino-5,6,7,8-tetrahydro-azepino(4,5-d)thiazol-6-yl methyl) -aniline 25 4- (5, 6 ,7,8-tetrahydro-azepino(4,5-d)thiazol-6-yl-methyl) aniline - 47 Preparation of the end products: Example 1 BIBE 1790 5 3-Z- (l-phenylamino-1-butvl-methylene) -5-amido-2-indolinone 600 g of a resin prepared according to Example IV were suspended in 3 ml of dimethylformamide and shaken with 0.4 g of aniline for 10 hours at 70 0 C. Then the mixture was filtered and the resin was washed several times with 10 methylene chloride, methanol and dimethylformamide. Then 3 ml of methanolic ammonia were added for 2 hours in order to cleave the -acetyl group. Finally, after further washing with dimethylformamide and methylene chloride, 4 ml of 10% trifluoroacetic acid in methylene chloride were added over 15 90 minutes, the resin was separated off and the solution was concentrated by evaporation. The residue was taken up in a little 1N sodium hydroxide solution and extracted with a little methylene chloride. The organic phase was dried over sodium sulphate and concentrated by rotary 20 evaporation. Yield: 37 mg R, value: 0.6 (silica gel, methylene chloride/methanol = 9:1)

C

20

H

21

N

3 0 2 25 mass spectrum: m/z = 335 (M) The following compounds are prepared analogously to Example 1: 30 (1) 3-Z- (l-phenylamino-methylene) -5-amido-2-indolinone Prepared from the resin prepared according to Example IV(1) and aniline Rf value: 0.59 (silica gel, methylene chloride/methanol = 9:1) 35 C 16

H

13

N

3 0 2 mass spectrum: m/z = 279 (M*) - 48 (2) 3-Z-[1-(4-methyl-phenylamino)-1-methyl-methylene]-5 amido-2-indolinone Prepared from the resin according to Example IV(2) and 4 methylaniline 5 Rf value: 0.44 (silica gel, methylene chloride/methanol = 9:1)

C

18

H

17

N

3 0 2 mass spectrum: m/z = 307 (M*) 10 (3) 3-Z-[1-(4-Chloro-phenylamino)-1-methyl-methylene]-5 amido-2-indolinone Prepared from-the resin according to Example IV(2) and 4 chloroaniline Rf value: 0,45 (silica gel, methylene chloride/methanol = 15 9:1)

C

17 H 1 ClN 3 0 2 mass spectrum: m/z = 327/329 (M*) (4) 3-Z-[1-(4-ethyl-phenylamino)-1-methyl-methylene]-5 20 amido-2-indolinone Prepared from the resin according to Example IV(2) and 4 ethylaniline Rf value: 0.43 (silica gel, methylene chloride/methanol = 9:1) 25 C 19

H

1 9

N

3 0 2 mass spectrum: m/z = 321 (M*) (5) 3-Z-[1-(4-methoxy-phenylamino)-1-methyl-methylene]-5 amido-2-indolinone 30 Prepared from the resin according to Example IV(2) and 4 methoxyaniline Rf value: 0.46 (silica gel, methylene chloride/methanol = 9:1)

C

18

H

17

N

3 0 3 35 mass spectrum: m/z = 323 (M*) - 49 (6) 3-Z-[1-(4-iodo-phenylamino)-1-methyl-methylenel-5 amido-2-indolinone Prepared from the resin according to Example IV(2) and 4 iodoaniline 5 Rf value: 0.36 (silica gel, methylene chloride/methanol = 9:1)

C

17

HI

4

N

3 0 2 mass spectrum: m/z = 419 (M') 10 (7) 3-Z-[1-(4-fluoro-phenylamino)-1-methyl-methylene]-5 amido-2-indolinone Prepared from -the resin according to Example IV(2) and 4 fluoroaniline Rf value: 0.60 (silica gel, methylene chloride/methanol = 15 9:1)

C

17

H

14

FN

3 0 2 mass spectrum: m/z = 311 (M+) (8) 3-Z-[1-(4-bromo-phenylamino)-1-methyl-methylene]-5 20 amido-2-indolinone Prepared from the resin according to Example IV(2) and 4 bromoaniline R. value: 0.53 (silica gel, methylene chloride/methanol = 9:1) 25 C 17

H,

4 BrN 3 0 2 mass spectrum: m/z = 371/373 (M+) (9) 3-Z-(l-phenylamino-1-methyl-methylene)-5-amido-2 indolinone 30 Prepared from the resin according to Example IV(2) and aniline Rf value: 0,58 (silica gel, methylene chloride/methanol = 9:1)

C

17

H

15

N

3 0 2 35 mass spectrum: m/z = 293 (M*) (10) 3-Z-(l-amino-l-methyl-methylene)-5-amido-2-indolinone - 50 Prepared from the resin according to Example IV(2) and ammonia Rf value: 0,23 (silica gel, methylene chloride/methanol = 9:1) 5 C 11

H

11

N

3 0 2 mass spectrum: m/z = 217 (M*) (11) 3-Z- [1- (4-piperidinomethyl-phenylamino) -i-methyl methylene]-5-amido-2-indolinone 10 Prepared from the resin according to Example IV(2) and 4-(piperidinomethyl)-aniline R. value: 0,31' (silica gel, methylene chloride/methanol = 9:1)

C

2 3 H26N402 15 mass spectrum: m/z = 390 (M*) (12) 3-Z- [l- (4-pyrrolidinomethyl-phenylamino) -i-methyl methylene]-5-amido-2-indolinone Prepared from the resin according to Example IV(2) and 4 20 pyrrolidinomethyl-aniline Rf value: 0.20 (silica gel, methylene chloride/methanol = 4:1)

C

2 2

H

2 4

N

4 0 2 mass spectrum: m/z = 376 (M*) 25 (13) 3-Z- [1- (4-Dipropylaminomethyl-phenylamino) -1-methyl methylene]-5-amido-2-indolinone Prepared from the resin according to Example 11(2) and 4 dipropylaminomethyl-aniline 30 Rf value: 0.71 (silica gel, methylene chloride/methanol = 4:1)

C

24

H

3

N

4 0 2 mass spectrum: m/z = 406 (M*) 35 (14) 3-Z- [1- [4- (2-piperidinoethyl) -phenylamino] -1-methyl methylene]-5-amido-2-indolinone - 51 Prepared from the resin according to Example IV(2) and 4 (2-piperidinoethyl)-aniline Rf value: 0.38 (silica gel, methylene chloride/methanol = 4:1) 5 C 2 4

H

2 8

N

4 0 2 mass spectrum: m/z = 404 (M*) (15) 3-Z- [1- [4- (2-diethylaminoethyl) -phenylamino] -1-methyl methylene]-5-amido-2-indolinone 10 Prepared from the resin according to Example IV(2) and 4 (2-diethylaminoethyl)-aniline Rf value: 0.33- (silica gel, methylene chloride/methanol = 4:1)

C

23

H

28

N

4 0 2 15 mass spectrum: m/z = 393 (M*) (16) 3-Z- [1- (4-Hexamethyleneiminomethyl-phenylamino) -1 methyl-methylene]-5-amido-2-indolinone Prepared from the resin according to Example IV(2) and 20 4-hexamethyleneiminomethyl-aniline Rf value: 0.34 (silica gel, methylene chloride/methanol = 4:1)

C

24

H

28 N402 mass spectrum: m/z = 404 (M*) 25 (17) 3-Z- [1- [4- (N-methyl-N-methansulphonyl-amino) phenylamino -1-methyl-methylene] -5-amido-2-indolinone Prepared from the resin according to Example IV(2) and 4-(N-methyl-N-methanesulphonyl-amino)-aniline 30 Rf value: 0.36 (silica gel, methylene chloride/methanol = 9:1)

C

19

H

20

N

4 0 4 S mass spectrum: m/z = 400 (M*) 35 (18) 3-Z- [1- (4-methanesulphonylamino-phenylamino) -1-methyl methylene -5-amido-2-indolinone - 52 Prepared from the resin according to Example IV(2) and 4-methanesulphonylamino-aniline Rf value: 0.31(silica gel, methylene chloride/methanol = 9:1) 5 C 1 ,HjN 4 0 4 S mass spectrum: m/z = 386 (M') (19) 3-Z- [l- (4-Bromophenylamino) -1-ethyl-methylene] -5 amido-2-indolinone 10 Prepared from the resin according to Example IV(3) and 4 -bromoaniline Rf value: 0.52, (silica gel, methylene chloride/methanol = 9:1)

C

1

H

16 BrN 3 0 2 15 mass spectrum: m/z = 385/387 (M*/M+2*) (20) 3-Z-[l-(4-piperidinomethyl-phenylamino)-1-ethyl methylene)-5-amido-2-indolinone Prepared from the resin according to Example IV(3) and 20 4-piperidinomethyl-aniline Rf value: 0.42 (silica gel, methylene chloride/methanol = 4:1)

C

24

H

28

N

4 0 2 mass spectrum: m/z = 404 (M*) 25 (21) 3-Z- [1- (4-piperidinomethyl-phenylamino) -1-propyl methylene] -5-amido-2-indolinone Prepared from the resin according to Example IV(4) and 4-piperidinomethyl-aniline 30 Rf value: 0.49 (silica gel, methylene chloride/methanol = 4:1)

C

25

H

30

N

4 0 2 mass spectrum: m/z = 418 (M*) 35 (22) 3-Z- [1- (4-Bromophenylamino) -1-propyl-methylene] -5 amido-2-indolinone - 53 Prepared from the resin according to Example IV(4) and 4-bromoaniline Rf value: 0,53 (silica gel, methylene chloride/methanol = 9:1) 5 C 19

H

1 ,BrN 3 02 mass spectrum: m/z = 399/401 (M*/M+2*) (23) 3-Z-[(4-Bromophenylamino)-methylene]-5-amido-2 indolinone 10 Prepared from the resin prepared according to Example IV(1) and 4-bromoaniline

C

1 6

H

12 BrN 3 0 2 mass spectrum: m/z = 357/359 (M*/M+2*) 15 (24) 3-Z-[(4-piperidinomethyl-phenylamino)-methylene]-5 amido-2-indolinone Prepared from the resin prepared according to Example IV(1) and 4-piperidinomethyl-aniline

C

2 2

H

2 4

N

4 0 2 20 mass spectrum: m/z = 376 (M*) (25) 3-Z-[1-(4-Bromophenylamino)-1-butyl-methylene]-5 amido-2-indolinone Prepared from the resin according to Example IV and 25 4-bromoaniline Rf value: 0,53 (silica gel, methylene chloride/methanol = 9:1)

C

2 0

H

2 0 BrN 3 02 mass spectrum: m/z = 413/415 (M*/M+2*) 30 (26) 3-Z-[l-(4-piperidinomethyl-phenylamino)-1-butyl methylene]-5-amido-2-indolinone Prepared from the resin according to Example IV and 4-piperidinomethyl-aniline 35 Rf value: 0.48 (silica gel, methylene chloride/methanol = 4:1)

C

2 6

H

3 2

N

4 0 2 - 54 mass spectrum: m/z = 432 (M+) (27) 3-Z-[1-(4-piperidinomethyl-phenylamino)-1-ethenyl methylene]-5-amido-2-indolinone 5 Prepared from the resin according to Example IV(5) and 4-piperidinomethyl-aniline (28) 3-Z-[1-(4-piperidinomethyl-phenylamino)-1-(3 bromopropyl)-methylene]-5-amido-2-indolinone 10 Prepared from the resin according to Example IV(6) and 4-piperidinomethyl-aniline (29) 3-Z-[1-(4-piperidinomethyl-phenylamino)-1-(2 phenylsulphonylethyl)-methylene]-5-amido-2-indolinone 15 Prepared from the resin according to Example IV(7) and 4-piperidinomethyl-aniline (30) 3-Z-[1-[4-(2,6-dimethylpiperidinomethyl)-phenylamino] 1-methyl-methylene]-5-amido-2-indolinone 20 Prepared from the resin according to Example IV(2) and 4-(2,6-dimethylpiperidinomethyl)-aniline (31) 3-Z-[1-(4-Thiomorpholinomethyl-phenylamino)-1-methyl methylene]-5-amido-2-indolinone 25 Prepared from the resin according to Example IV(2) and 4-thiomorpholinomethyl-aniline Rf value: 0.53 (silica gel, methylene chloride/methanol = 9:1)

C

2 2

H

2 4

N

4 0 2 S 30 mass spectrum: m/z = 408 (M') (32) 3-Z-[1-[(4-Thiomorpholino-S-oxido-methyl) phenylamino]-1-methyl-methylene]-5-amido-2-indolinone Prepared from the resin according to Example IV(2) and 35 4-(thiomorpholino-S-oxido-methyl)-aniline Rf value: 0.21 (silica gel, methylene chloride/methanol = 9:1) - 55 C 2 2

H

24

N

4 0 3 S mass spectrum: m/z = 424 (M*) (33) 3-Z-[1-[4-(Thiomorpholino-S,S-dioxido-methyl) 5 phenylamino]-1-methyl-methylene]-5-amido-2-indolinone Prepared from the resin according to Example IV(2) and 4-(thiomorpholino-S,S-dioxido-methyl)-aniline (34) 3-Z-[1-(4-Azetidionomethyl-phenylamino)-1-methyl 10 methylenel-5-amido-2-indolinone Prepared from the resin according to Example IV(2) and 4-azetidionomethyl-aniline (35) 3-Z-[1-[4-(2,5-Dihydropyrrol-1-yl-methyl) 15 phenylamino]-1-methyl-methylene]-5-amido-2-indolinone Prepared from the resin according to Example IV(2) and 4-(2,5-dihydropyrrol-1-yl-methyl)-aniline Rf value: 0.10 (silica gel, methylene chloride/methanol = 9:1) 20 C 22

H

22

N

4 0 2 mass spectrum: m/z = 375 (M+H*) (36) 3-Z-[1-[4-(3,6-Dihydro-2H-pyridin-1-yl-methyl) phenylamino]-1-methyl-methylene]-5-amido-2-indolinone 25 Prepared from the resin according to Example IV(2) and 4-( 3 ,6-dihydro-2H-pyridin-1-yl-methyl)-aniline Rf value: 0.20 (silica gel, methylene chloride/methanol = 9:1)

C

2 3

H

24

N

4 0 2 30 mass spectrum: m/z = 389 (M+H)* (37) 3-Z-[1-[4-(2-ethoxycarbonyl-pyrrolidinomethyl) phenylamino]-1-methyl-methylene]-5-amido-2-indolinone Prepared from the resin according to Example IV(2) and 35 4-(2-ethoxycarbonyl-pyrrolidinomethyl)-aniline Rf value: 0.50 (silica gel, methylene chloride/methanol = 9:1) - 56 C 2 4 H N404 mass spectrum: m/z = 435 (M+H)* (38) 3-Z-[1-[4-(3,5-dimethyl-piperidinomethyl) 5 phenylamino]-1-methyl-methylene]-5-amido-2-indolinone Prepared from the resin according to Example IV(2) and 4-(3,5-dimethyl-piperidinomethyl)-aniline Rf value: 0.16 (silica gel, methylene chloride/methanol = 9:1) 10 C 2 5

H

30

N

4 0 2 mass spectrum: m/z = 418 (M*) (39) 3-Z-[1-[4-(4-phenyl-piperazinylmethyl)-phenylamino] 1-methyl-methylene]-5-amido-2-indolinone-trifluoroacetate 15 Prepared from the resin according to Example IV(2) and 4-(4-phenyl-piperazinylmethyl)-aniline Rf value: 0.40 (silica gel, methylene chloride/methanol = 9:1)

C

28

H

29

N

5 0 2 20 mass spectrum: m/z = 468 (M+H)* (40) 3-Z-[1-[4-(4-phenyl-4-hydroxy-piperidinylmethyl) phenylamino]-1-methyl-methylene]-5-amido-2-indolinone trifluoroacetate 25 Prepared from the resin according to Example IV(2) and 4-(4-phenyl-4-hydroxy-piperidinylmethyl)-aniline

C

29 H3ON 4 0 3 mass spectrum: m/z = 483 (M+H)+ 30 (41) 3-Z-[1-(3-methoxy-phenylamino)-1-methyl-methylene]-5 amido-2-indolinone Prepared from the resin according to Example IV(2) and 3-methoxy-aniline R, value: 0.40 (silica gel, methylene chloride/methanol = 35 9:1)

C

18

H

17

N

3 0 3 Mass spectrum: m/z = 323 (M*) - 57 (42) 3-Z-[1-(3-ethoxycarbonyl-phenylamino)-1-methyl methylene]-5-amido-2-indolinone Prepared from the resin according to Example IV(2) and ethyl 3-amino-benzoate 5 C 20

H

19

N

3 0 4 Mass spectrum: m/z = 365 (M*) (43) 3-Z-[1-(4-dimethylaminomethyl-phenylamino)-1 methylmethylen]-5-amido-2-indolinone trifluoroacetate 10 Prepared from the resin according to Example IV(2) and 4-dimethylaminomethyl-aniline

C

20

H

22

N

4 0 2 Mass spectrum: m/z = 351 (M+H*) 15 (44) 3-Z-[1-[4-(4-Cyclohexyl-piperidinylmethyl) phenylamino]-1-methyl-methylene]-5-amido-2-indolinone Prepared from the resin according to Example IV(2) and 4-(4-cyclohexyl-piperidinylmethyl)-aniline 20 (45) 3-Z-[l-(4-morpholinyl-phenylamino)-1-methyl methylene]-5-amido-2-indolinone Prepared from the resin according to Example IV(2) and 4-morpholinyl-aniline

C

21

H

22

N

4 0 3 25 Mass spectrum: m/z = 378 (M*) (46) 3-Z-[1-(N-methyl-piperidin-4-ylamino)-1-methyl methylene)-5-amido-2-indolinone Prepared from the resin according to Example IV(2) and 30 4-amino-N-methyl-piperidine

C

17

H

22

N

4 0 2 Mass spectrum: m/z = 314 (M*) (47) 3-Z-[1-(4-methylcyclohexylamino)-1-methyl-methylene] 35 5-amido-2-indolinone Prepared from the resin according to Example IV(2) and 4-methyl-cyclohexylamine - 58 CIBH 23

N

3 0 2 Mass spectrum: m/z = 313 (M*) (48) 3-Z- (l-Cyclopentylamino-1-methyl-methylene) -5-amido 5 2-indolinone Prepared from the resin according to Example IV(2) and cyclopentylamine Rf value: 0.70 (silica gel, methylene chloride/methanol = 4:1) 10 C 16

H

19

N

3 0 2 Mass spectrum: m/z = 285 (M) (49) 3-Z- (1-isopropylamino-1-methyl-methylene) -5-amido 2-indolinone 15 Prepared from the resin according to Example IV(2) and isopropylamine

C

14

H

17

N

3 0 2 Mass spectrum: m/z = 259 (M') 20 (50) 3-Z- [1- (4-ethoxycarbonylmethylaminomethyl phenylamino)-1-methyl-methylene]-5-amido-2-indolinone Prepared from the resin according to Example IV(2) and 4- (ethoxycarbonylmethyl-N-tert .butyloxycarbonyl aminomethyl)-aniline 25

C

21

H

2 2

N

4 0 4 Mass spectrum: m/z = 394 (M*) (51) 3-Z-[1-(4-benzylaminomethyl-phenylamino)-1-methyl methylene] -5-amido-2-indolinone 30 Prepared from the resin according to Example IV(2) and 4- (N-benzyl-N-tert .butyloxycarbonyl-aminomethyl) -aniline R, value: 0.24 (silica gel, methylene chloride/methanol = 9:1)

C

2 5

H

2 4

N

4 0 2 35 Mass spectrum: m/z = 412 (M*) - 59 (52) 3-Z-[l-(4-Butylaminomethyl-phenylamino)-1-methyl methylene]-5-amido-2-indolinone trifluoroacetate Prepared from the resin according to Example IV(2) and 4-(N-butyl-N-tert.butyloxycarbonyl-aminomethyl)-aniline 5 Rf value: 0.40 (silica gel, methylene chloride/methanol = 4:1)

C

22

H

26

N

4 0 2 Mass spectrum: m/z = 378 (M*) 10 (53) 3-Z-[1-(4-ethylaminomethyl-phenylamino)-1-methyl methylene]-5-amido-2-indolinone trifluoroacetate Prepared from'the resin according to Example IV(2) and 4-(N-ethyl-N-tert.butyloxycarbonyl-aminomethyl)-aniline Rf value: 0.20 (silica gel, methylene chloride/methanol = 15 4:1)

C

20

H

22

N

4 0 2 Mass spectrum: m/z = 351 (M+H*) (54) 3-Z-[1-(4-Cyclohexylaminomethyl-phenylamino)-1-methyl 20 methylene]-5-amido-2-indolinone trifluoroacetate Prepared from the resin according to Example IV(2) and 4-(cyclohexyl-(N-tert.butyloxycarbonyl-amino-methyl) aniline

C

24

H

28

N

4 0 2 25 Mass spectrum: m/z = 405 (M*) (55) 3-Z-[1-(4-isopropylaminomethyl-phenylamino)-1-methyl methylene]-5-amido-2-indolinone trifluoroacetate Prepared from the resin according to Example IV(2) and 30 4-(N-isopropyl-N-tert.butyloxycarbonyl-aminomethyl)-aniline

C

21

H

24

N

4 0 2 Mass spectrum: m/z = 365 (M*) (56) 3-Z-[l-(4-trifluoromethoxy-phenylamino)-1-methyl 35 methylene]-5-amido-2-indolinone Prepared from the resin produced in Example IV(2) and 4 trifluoromethoxy-aniline - 60 C 18

H

14

F

3

N

3 0 3 mass spectrum: m/z = 377 (M') (57) 3-Z-[l-(4-difluoromethoxy-phenylamino)-1-methyl 5 methylene]-5-amido-2-indolinone Prepared from the resin produced in Example IV(2) and 4 difluoromethoxy-aniline Rf value: 0.5 (silica gel, methylene chloride/methanol = 9:1 ) 10 C 18

H

15

F

2

N

3 0 3 mass spectrum: m/z = 359 (M+H*) (58) 3-Z-[1-(4-bromo-3-chloro-phenylamino)-1-methyl methylene]-5-amido-2-indolinone 15 Prepared from the resin produced in Example IV(2) and 4 bromo-3-chloro-aniline

C,

7

H

13 BrClN 3 02 mass spectrum: m/z = 405/407/409 (M*/M+2*/M+4*) 20 (59) 3-Z-[l-(4-trifluoromethyl-3-bromo-phenylamino)-1 methyl-methylene]-5-amido-2-indolinone Prepared from the resin produced in Example IV(2) and 4 trifluoromethyl-3-bromo-aniline

C

18

H,

3 BrF 3

N

3 02 25 mass spectrum: m/z = 439/441 (M*/M+2*) (60) 3-Z-[l-(4-chloro-phenylamino)-methylene]-5-amido-2 indolinone Prepared from the resin produced in Example IV(1) and 4 30 chloro-aniline

C

1 6

H

1 2 ClN 3 0 2 mass spectrum: m/z = 312/314 (M*) (61) 3-Z-[l-(3-bromo-phenylamino)-1-methyl-methylene]-5 35 amido-2-indolinone Prepared from the resin produced in Example IV(2) and 3 bromo-aniline - 61 C, 7

H

14 BrN 3 02 mass spectrum: m/z = 371/373 (M*) (62) 3-Z-[1-(3-chloro-phenylamino)-1-methyl-methylene]-5 5 amido-2-indolinone Prepared from the resin produced in Example IV(2) and 3 chloro-aniline

C

17

H

14 ClN 3 0 2 mass spectrum: m/z = 327/329 (M*) 10 (63) 3-Z-[1-(2-chloro-phenylamino)-1-methyl-methylene]-5 amido-2-indolinone Prepared from the resin produced in Example IV(2) and 2 chloro-aniline 15 C 17

H

14 ClN 3 0 2 mass spectrum: m/z = 327/329 (M*) (64) 3-Z-[1-(4-bromo-3-methyl-phenylamino)-1-methyl methylene]-5-amido-2-indolinone 20 Prepared from the resin produced in Example IV(2) and 4 bromo-3-methyl-aniline Rf value: 0.60 (silica gel, methylene chloride/methanol = 9:1 )

C

1 HLBrN 3 02 25 mass spectrum: m/z = 385/387 (M*) (65) 3-Z-[1-(4-bromo-3-methoxy-phenylamino)-1-methyl methylene]-5-amido-2-indolinone Prepared from the resin produced in Example IV(2) and 4 30 bromo-3-methoxy-aniline Rf value: 0.60 (silica gel, methylene chloride/methanol = 9:1

C

18

H

16 BrN 3 03 mass spectrum: m/z = 401/403 (M*) 35 (66) 3-Z-[1-(4-fluoro-3-nitro-phenylamino)-1-methyl methylene]-5-amido-2-indolinone - 62 Prepared from the resin produced in Example IV(2) and 4 fluoro-3-nitro-aniline Rf value: 0.40 (silica gel, methylene chloride/methanol = 9:1 ) 5 C, 7

H,

3

FN

4 0 4 mass spectrum: m/z = 356 (M*) (67) 3-Z-[1-(4-bromo-3-nitro-phenylamino)-1-methyl methylene]-5-amido-2-indolinone 10 Prepared from the resin produced in Example IV(2) and 4 bromo-3-nitro-aniline Rf value: 0.50' (silica gel, methylene chloride/methanol = 9:1 )

C

1 7

H,

3 BrN404 15 mass spectrum: m/z = 416/418 (M*) (68) 3-Z- [l- (4-Ethyl-3-nitro-phenylamino) -1-methyl methylene] -5-amido-2-indolinone Prepared from the resin produced in Example IV(2) and 4 20 ethyl-3-nitro-aniline Rf value: 0.70 (silica gel, methylene chloride/methanol = 9:1 )

C

19

H

18

N

4 0 4 mass spectrum: m/z = 366 (M*) 25 (69) 3-Z- [l- (4-chloro-3-nitro-phenylamino) -1-methyl methylene]-5-amido-2-indolinone Prepared from the resin produced in Example IV(2) and 4 chloro-3-nitro-aniline 30 C 17

H

1 3 ClN 4 0 4 mass spectrum: m/z = 371/373 (M*) (70) 3-Z- [1- (3-Nitro-phenylamino) -1-methyl-methylene] -5 amido-2-indolinone 35 Prepared from the resin produced in Example IV(2) and 3 nitro-aniline

C

17

H

14

N

4 0 4 - 63 mass spectrum: m/z = 338 (M+H*) (71) 3-Z-[1-(4-Methyl-3-nitro-phenylamino)-1-methyl methylene]-5-amido-2-indolinone 5 Prepared from the resin produced in Example IV(2) and 4 methyl-3-nitro-aniline Rf value: 0.50 (silica gel, methylene chloride/methanol = 9:1 )

C

18

H

16 N404 10 mass spectrum: m/z = 352 (M*) (72) 3-Z-[1-(4-bromo-3-methoxycarbonyl-phenylamino)-1 methyl-methylene]-5-amido-2-indolinone Prepared from the resin produced in Example IV(2) and 15 methyl 2-bromo-5-aminobenzoate Rf value: 0.50 (silica gel, methylene chloride/methanol = 9:1 )

C,

9

H

1 6BrN 3 04 mass spectrum: m/z = 429/431 (M+H*) 20 (73) 3-Z-[l-(4-Carbamoyl-phenylamino)-1-methyl-methylene] 5-amido-2-indolinone Prepared from the resin produced in Example IV(2) and 4 aminobenzamide 25 Rf value: 0,20 (silica gel, methylene chloride/methanol = 9:1 ) CiSH 16

N

4 0 3 mass spectrum: m/z = 336 (M*) 30 (74) 3-Z-[1-(4-(Piperidino-carbonyl)-phenylamino)-1 methyl-methylene]-5-amido-2-indolinone Prepared from the resin produced in Example IV(2) and 1 (4-amino-benzoyl)-piperidine Rf value: 0.50 (silica gel, methylene chloride/methanol = 35 9:1 )

C

2 3

H

24

N

4 0 3 mass spectrum: m/z = 404 (M*) -64 (75) 3-Z-[1-(4-(2-(diethylamino)-ethyl-carbamoyl) phenylamino)-1-methyl-methylene]-5-amido-2-indolinone trifluoracetate 5 Prepared from the resin produced in Example IV(2) and 4 amino-N-[2-(diethylamino)-ethyl]-benzamide Rf value: 0.30 (silica gel, methylene chloride/methanol = 9:1 )

C

24

H

29 NS0 3 10 mass spectrum: m/z = 436 (M+H*) (76) 3-Z-[1-(4-trifluoromethyl-phenylamino)-1-methyl methylene]-5-amido-2-indolinone Prepared from the resin produced in Example IV(2) and 4 15 trifluoromethyl-aniline

C

18

H

14

F

3

N

3 0 2 mass spectrum: m/z = 361 (M*) (77) 3-Z-[1-(3-Hydroxymethyl-phenylamino)-1-methyl 20 methylene]-5-amido-2-indolinone Prepared from the resin produced in Example IV(2) and 3 aminobenzylalcohol

C

18

H

17

N

3 0 3 mass spectrum: m/z = 323 (M*) 25 (78) 3-Z-[1-(4-(Hydroxycarbonyl-phenylamino)-1-methyl methylene]-5-amido-2-indolinone Prepared from the resin produced in Example IV(2) and 4 aminobenzoic acid 30 Rf value: 0.20 (silica gel, methylene chloride/methanol = 4:1 )

C

18

H

15

N

3 0 4 mass spectrum: m/z = 336 (M-H*) 35 (79) 3-Z-[1-(4-Ethoxycarbonylmethyl-3-nitro-phenylamino) 1-methyl-methylene]-5-amido-2-indolinone - 65 Prepared from the resin produced in Example IV(2) and ethyl 4-amino-2-nitro-phenylacetate Rf value: 0.70 (silica gel, methylene chloride/methanol = 9:1 ) 5 C 21

H

20

N

4 0 6 mass spectrum: m/z = 424 (M*) (80) 3-Z-[1-(3-Methoxycarbonyl-4-methyl-phenylamino)-1 methyl-methylene]-5-amido-2-indolinone 10 Prepared from the resin produced in Example IV(2) and methyl 3-amino-6-methyl-benzoate Rf value: 0.70' (silica gel, methylene chloride/methanol = 9:1 )

C

2 0

HI

9

N

3 0 4 15 mass spectrum: m/z = 365 (M*) (81) 3-Z-[l-(3-Diethylcarbamoyl-4-methyl-phenylamino)-1 methyl-methylene]-5-amido-2-indolinone Prepared from the resin produced in Example IV(2) and 3 20 amino-6-methyl-benzoic acid diethylamide Rf value: 0.50 (silica gel, methylene chloride/methanol = 9:1

C

2 3

H

26

N

4 0 3 mass spectrum: m/z = 406 (M*) 25 (82) 3-Z- [l- (3-Ethylcarbamoyl-4-methyl-phenylamino) -1 methyl-methylene -5-amido-2-indolinone Prepared from the resin produced in Example IV(2) and 3 amino-6-methyl-benzoic acid ethylamide 30 Rf value: 0.40 (silica gel, methylene chloride/methanol = 9:1)

C

21

H

22

N

4 0 3 mass spectrum: m/z = 378 (M*) 35 (83) 3-Z-[1-(3-Sulphamoyl-4-methyl-phenylamino)-1-methyl methylene)-5-amido-2-indolinone - 66 Prepared from the resin produced in Example IV(2) and 3 amino-6-methyl-phenylsulphonic acid amide Rf value: 0.30 (silica gel, methylene chloride/methanol = 9:1) 5 ClBHlBN 4 0 4 S mass spectrum: m/z = 386 (M*) (84) 3-Z-[l-(3-Acetylamino-4-methyl-phenylamino)-1-methyl methylene]-5-amido-2-indolinone 10 Prepared from the resin produced in Example IV(2) and 4 amino-2-acetylamino-toluene Rf value: 0.65' (silica gel, methylene chloride/methanol = 9:1)

C

20

H

20

N

4 0 3 15 mass spectrum: m/z = 364 (M*) (85) 3-Z-[1-(4-(2-Dimethylamino-ethoxy)-phenylamino)-1 methyl-methylene]-5-amido-2-indolinone-trifluoroacetate Prepared from the resin produced in Example IV(2) and 4 20 (2-dimethylamino-ethoxy)-aniline Rf value: 0,10 (silica gel, methylene chloride/methanol = 4:1 )

C

2 1

H

2 4

N

4 0 3 mass spectrum: m/z = 380 (M*) 25 (86) 3-Z-[1-(4-(2-Piperidino-ethoxy)-phenylamino)-1 methyl-methylene]-5-amido-2-indolinone-trifluoroacetate Prepared from the resin produced in Example IV(2) and 4 (2-piperidino-ethoxy)-aniline 30 Rf value: 0.70 (silica gel, methylene chloride/methanol = 4:1 )

C

24 H2 8

N

4 0 3 mass spectrum: m/z = 420 (M*) 35 (87) 3-Z-[1-(4-(3-Dimethylamino-propoxy)-phenylamino)-1 methyl-methylene]-5-amido-2-indolinone-trifluoroacetate - 67 Prepared from the resin produced in Example IV(2) and 4 (3-dimethylamino-propoxy)-aniline R, value: 0.10 (silica gel, methylene chloride/methanol = 4:1 ) 5 C 2 2

H

2 6

N

4 0 3 mass spectrum: m/z = 394 (M') (88) 3-Z-[1-(4-(3-Piperidino-propoxy)-phenylamino)-1 methyl-methylene]-5-amido-2-indolinone-trifluoroacetate 10 Prepared from the resin produced in Example IV(2) and 4 (3-piperidino-propoxy)-aniline Rf value: 0.20' (silica gel, methylene chloride/methanol = 4:1 )

C

2 sH 3

N

4 0 3 15 mass spectrum: m/z = 434 (M') (89) 3-Z-[1-(4-(3-(N-Benzyl-N-methylamino)-propoxy) phenylamino)-1-methyl-methylene)-5-amido-2-indolinone trifluoroacetate 20 Prepared from the resin produced in Example IV(2) and 4 [3-(N-benzyl-N-methylamino)-propoxy]-aniline Rf value: 0.60 (silica gel, methylene chloride/methanol = 4:1 )

C

28

H

3

N

4 0 3 25 mass spectrum: m/z = 470 (M') (90) 3-Z-[l-(4-(N-benzyl-aminomethyl)-phenylamino) methylene)-5-amido-2-indolinone-trifluoroacetate Prepared from the resin produced in Example IV(1) and 4 30 (N-benzyl-N-tert.butoxcarbonyl-aminomethyl)-aniline

C

2 4

H

2 2

N

4 0 2 mass spectrum: m/z = 399 (M+H*) (91) 3-Z-[1-(4-(N-(4-chlorobenzyl)-aminomethyl) 35 phenylamino)-1-methyl-methylene]-5-amido-2-indolinone trifluoroacetate Prepared from the resin produced in Example IV(2) and 4- - 68 [N- (4-chlorobenzyl-N-tert .butoxycarbonyl-aminomethyl) aniline R, value: 0.40 (silica gel, methylene chloride/methanol = 9:1) 5 C 2 sH 2 3 ClN 4 0 2 mass spectrum: m/z = 446/448 (M*) (92) 3-Z-[l-(4-(N-(3,4,5-Trimethoxybenzyl)-N-methyl aminomethyl)-phenylamino)-1-methyl-methylene]-5-amido-2 10 indolinone-trifluoroacetate Prepared from the resin produced in Example IV(2) and 4 [N- ((3,4,5-trimethoxy-benzyl) -N-methyl-aminomethyl] aniline Rf value: 0.50 (silica gel, methylene chloride/methanol = 15 9:1)

C

29

H

32

N

4 0 5 mass spectrum: m/z = 516 (M*) (93) 3-Z-[1-(4-(N-(3,4-Dimethoxy-benzyl)-N-methyl-amino 20 methyl) -phenylamino) -1-methyl-methylene] -5-amido-2 indolinone-trifluoroacetate Prepared from the resin produced in Example IV(2) and 4 [N- (3, 4-dimethoxy-benzyl) -N-methyl-aminomethyl] -aniline Rf value: 0.40 (silica gel, methylene chloride/methanol = 25 9:1)

C

28

H

30

N

4 0 4 mass spectrum: m/z = 486 (M*) (94) 3-Z-[l-(4-(N-(3,4-Dimethoxy-benzyl)-N-ethyl 30 aminomethyl) -phenylamino) -1-methyl-methylene] -5-amido-2 indolinone-trifluoroacetate Prepared from the resin produced in Example IV(2) and 4 [N- (3 ,4-dimethoxy-benzyl) -N-ethyl-aminomethyl] -aniline Rf value: 0.40 (silica gel, methylene chloride/methanol = 35 9:1)

C

29

H

32

N

4 0 4 mass spectrum: m/z = 500 (M*) - 69 (95) 3-Z-[1-(4-(N-Benzyl-N-ethyl-aminomethyl) phenylamino)-1-methyl-methylene]-5-amido-2-indolinone trifluoroacetate 5 Prepared from the resin produced in Example IV(2) and 4 (N-benzyl-N-ethyl-aminomethyl)-aniline Rf value: 0.50 (silica gel, methylene chloride/methanol = 9:1)

C

27

H

28

N

4 0 2 10 mass spectrum: m/z = 440 (M*) (96) 3-Z-[1-(4-(N-Benzyl-N-methyl-aminomethyl) phenylamino)-1-methyl-methylene]-5-amido-2-indolinone trifluoroacetate 15 Prepared from the resin produced in Example IV(2) and 4 (N-benzyl-N-methyl-aminomethyl)-aniline Rf value: 0,55 (silica gel, methylene chloride/methanol = 9:1)

C

26 H2 6

N

4 0 2 20 mass spectrum: m/z = 426 (M*) (97) 3-Z-[1-(4-(N-Benzyl-N-methyl-aminomethyl) phenylamino)-1-ethyl-methylene]-5-amido-2-indolinone trifluoroacetate 25 Prepared from the resin produced according to Example IV(3) and 4-(N-benzyl-N-methyl-aminomethyl)-aniline Rf value: 0.50 (silica gel, methylene chloride/methanol = 9:1)

C

27

H

28

N

4 0 2 30 mass spectrum: m/z = 440 (M*) (98) 3-Z-[1-(4-(N-Benzyl-N-methyl-aminomethyl) phenylamino)-1-propyl-methylene]-5-amido-2-indolinone trifluoroacetate 35 Prepared from the resin produced according to Example IV(4) and 4-(N-benzyl-N-methyl-amino-methyl)-aniline - 70 Rf value: 0.50 (silica gel, methylene chloride/methanol = 9:1)

C

28

H

30

N

4 0 2 mass spectrum: m/z = 454 (M*) 5 (99) 3-Z- [1- (4- (N- (4-chlorobenzyl) -N-methyl-aminomethyl) phenylamino) -1-methyl-methylene] -5-amido-2-indolinone trifluoroacetate Prepared from the resin produced in Example IV(2) and 4 10 [N- (4-chlorobenzyl) -N-methyl-aminomethyl] -aniline Rf value: 0.40 (silica gel, methylene chloride/methanol = 9:1)

C

26 H2 5 ClN 4 0 2 mass spectrum: m/z = 460/462 (M*) 15 (100) 3-Z- [1- (4- (N- (3-chlorobenzyl) -N-methyl-aminomethyl) phenylamino) -1-methyl-methylene] -5-amido-2-indolinone trifluoroacetate Prepared from the resin produced in Example IV(2) and 4 20 [N- (3-chlorobenzyl) -N-methyl-aminomethyl] -aniline Rf value: 0.40 (silica gel, methylene chloride/methanol = 9:1)

C

26

H

25 ClN 4 0 2 mass spectrum: m/z = 460/462 (M*) 25 (101) 3-Z-[l-(4-(N-(2,6-dichlorobenzyl)-N-methyl aminomethyl) -phenylamino) -1-methyl-methylene] -5-amido-2 indolinone-trifluoroacetate Prepared from the resin produced in Example IV(2) and 4 30 [N- (2, 6-dichlorobenzyl) -N-methyl-aminomethyl] -aniline Rf value: 0,38 (silica gel, methylene chloride/methanol = 9:1)

C

2 6H 2 4 Cl 2

N

4 02 mass spectrum: m/z = 494/496/498 (M+2*/M+4*) 35 (102) 3-Z- [1- (4- (N- (4-trifluoromethylbenzyl) -N-methyl aminomethyl) -phenylamino) -1-methyl-methylene] -5-amido-2- - 71 indolinone-trifluoroacetate Prepared from the resin produced in Example IV(2) and 4 [N- (4-trifluoromethylbenzyl) -N-methyl-aminomethyl] -aniline Rf value: 0,38 (silica gel, methylene chloride/methanol = 5 9:1)

C

27

H

25

F

3

N

4 0 2 mass spectrum: m/z = 494 (M*) (103) 3-Z-[1-(4-(N-Benzyl-N-isopropyl-aminomethyl) 10 phenylamino)-1-methyl-methylene]-5-amido-2-indolinone trifluoroacetate Prepared from'the resin produced in Example IV(2) and 4 (N-benzyl-N-isopropyl-aminomethyl)-aniline Rf value: 0.50 (silica gel, methylene chloride/methanol = 15 9:1)

C

28

H

30

N

4 0 2 mass spectrum: m/z = 454 (M*) (104) 3-Z- [1- (4- (N-benzyl-N-tert.butyl-aminomethyl) 20 phenylamino) -1-methyl-methylene) -5-amido-2-indolinone trifluoroacetate Prepared from the resin produced in Example IV(2) and 4 (N-benzyl-N-tert.butyl-aninomethyl)-aniline Rf value: 0.50 (silica gel, methylene chloride/methanol = 25 9:1)

C

29

H

32

N

4 0 2 mass spectrum: m/z = 468 (M*) (105) 3-Z-[1-(4-(N-benzyl-N-methyl-aminomethyl) 30 phenylamino) -methylene] -5-amido-2-indolinone trifluoroacetate Prepared from the resin produced in Example IV(1) and 4 (N-benzyl-N-methyl-aminomethyl)-aniline

C

2 5

H

2 4

N

4 0 2 35 mass spectrum: m/z = 413 (M+H*) - 72 (106) 3-Z-[1-(4-(N-benzyl-N-ethyl-aminomethyl) phenylamino)-1-methyl-methylene]-5-amido-2-indolinone trifluoroacetate Prepared from the resin produced in Example IV(1) and 4 5 (N-benzyl-N-ethyl-aminomethyl)-aniline

C

2 6H 26

N

4 02 mass spectrum: m/z = 427 (M+H*) (107) 3-Z-[1-(4-(Diisopropylamino-methyl)-phenylamino) 10 1-methyl-methylene]-5-amido-2-indolinone-trifluoroacetate Prepared from the resin produced in Example IV(2) and 4 (diisopropylamino-methyl)-aniline Rf value: 0.50 (silica gel, methylene chloride/methanol = 4:1) 15 C 24 H3ON 4 0 2 mass spectrum: m/z = 406 (M*) (108) 3-Z-[1-(4-(Di-n-propylamino-methyl)-phenylamino) methylene]-5-amido-2-indolinone-trifluoroacetate 20 Prepared from the resin produced in Example IV(2) and 4 (di-n-propylamino-methyl)-aniline

C

2 3

H

2 8

N

4 0 2 mass spectrum: m/z = 393 (M+H*) 25 (109) 3-Z-[1-(4-(diisobutylamino-methyl)-phenylamino) 1-methyl-methylene]-5-amido-2-indolinone-trifluoroacetate Prepared from the resin produced in Example IV(2) and 4 (diisobutylamino-methyl)-aniline Rf value: 0.50 (silica gel, methylene chloride/methanol = 30 9:1)

C

2 6

H

34

N

4 0 2 mass spectrum: m/z = 434 (M*) (110) 3-Z-[l-(4-(2,3,4,5-Tetrahydro-benzo(d)azepin-3-yl 35 methyl)-phenylamino)-1-methyl-methylene]-5-amido-2 indolinone-trifluoroacetate - 73 Prepared from the resin produced in Example IV(2) and 4 (2,3,4,5-tetrahydro-benzo(d)azepin-3-yl-methyl)-aniline Rf value: 0.30 (silica gel, methylene chloride/methanol = 9:1) 5 C 28

H

2 sN 4 0 2 mass spectrum: m/z = 452 (M*) (111) 3-Z-[1-(4-(1,3-Dihydro-isoindol-2-yl-methyl) phenylamino)-1-methyl-methylene]-5-amido-2-indolinone 10 trifluoroacetate Prepared from the resin produced in Example IV(2) and 4 (1,3-dihydro-isoindol-2-yl-methyl)-aniline Rf value: 0,35 (silica gel, methylene chloride/methanol = 9:1) 15 C 2 6

H

2 4

N

4 0 2 mass spectrum: m/z = 425 (M+H*) (112) 3-Z-[1-(4-(6,7-Dimethoxy-1,2,3,4-tetrahydro isoquinolin-2-yl-methyl)-phenylamino)-1-methyl-methylene] 20 5-amido-2-indolinone-trifluoroacetate Prepared from the resin produced in Example IV(2) and 4 (6,7-dimethoxy-1,2,3,4-tetrahydro-isoquinolin-2-yl methyl)-aniline Rf value: 0.50 (silica gel, methylene chloride/methanol = 25 9:1)

C

29

H

3

N

4 0 4 mass spectrum: m/z = 499 (M+H*) (113) 3-Z-[1-(4-(1,2,3,4-tetrahydro-isoquinolin-2-yl 30 methyl)-phenylamino)-1-methyl-methylene]-5-amido-2 indolinone-trifluoroacetate Prepared from the resin produced in Example IV(2) and 4 (1,2,3,4-tetrahydro-isoquinolin-2-yl-methyl)-aniline 35 - 74 (114) 3-Z-[1-(4-(N-(Ethoxycarbonylmethyl)-N-benzyl aminomethyl)-phenylamino)-1-methyl-methylene]-5-amido-2 indolinone-trifluoroacetate Prepared from the resin produced in Example IV(2) and 4 5 [N-(ethoxycarbonylmethyl)-N-benzyl-aminomethyl)-aniline Rf value: 0.60 (silica gel, methylene chloride/methanol = 9:1)

C

29

H

30

N

4 0 4 mass spectrum: m/z = 498 (M') 10 (115) 3-Z-[1-(4-(N-(2-Hydroxyethyl)-N-benzyl-aminomethyl) phenylamino)-I-methyl-methylene]-5-amido-2-indolinone trifluoroacetate Prepared from the resin produced in Example IV(2) and 4 15 [N-(2-hydroxyethyl)-N-benzyl-aminomethyl)-aniline Rf value: 0.40 (silica gel, methylene chloride/methanol = 9:1)

C

27

H

28

N

4 0 3 mass spectrum: m/z = 456 (M*) 20 (116) 3-Z-[l-(4-(N-(l-Ethyl-pentyl)-N-(pyridin-2-yl methyl)-aminomethyl)-phenylamino)-1-methyl-methylene]-5 amido-2-indolinone-trifluoroacetate Prepared from the resin produced in Example IV(2) and 4 25 [N-(1-ethyl-pentyl)-N-(pyridin-2-yl-methyl)-aminomethyl] aniline Rf value: 0,45 (silica gel, methylene chloride/methanol = 9:1)

C

31

H

37

N

5 0 2 30 mass spectrum: m/z = 511 (M*) (117) 3-Z-[1-(4-(Piperidino-methyl)-3-nitro-phenylamino) 1-methyl-methylene]-5-amido-2-indolinone Prepared from the resin produced in Example IV(2) and 4 35 (piperidino-methyl)-3-nitro-aniline Rf value: 0.70 (silica gel, methylene chloride/methanol = 9:1) - 75 C 23

H

25

N

5 0 4 mass spectrum: m/z = 436 (M+H*) (118) 3-Z-[1-(4-(N-Phenethyl-N-methyl-aminomethyl) 5 phenylamino)-1-methyl-methylene]-5-amido-2-indolinone trifluoroacetate Prepared from the resin produced in Example IV(2) and 4 (N-phenethyl-N-methyl-aminomethyl)-aniline Rf value: 0.50 (silica gel, methylene chloride/methanol = 10 9:1)

C

27

H

28

N

4 0 2 mass spectrum:' m/z = 441 (M+H*) (119) 3-Z-[1-(4-(N-phenethyl-N-ethyl-aminomethyl) 15 phenylamino)-1-methyl-methylene]-5-amido-2-indolinone (120) 3-Z-[1-(4-(N-(3,4-dihydroxy-phenethyl)-N-methyl amino-methyl)-phenylamino)-1-methyl-methylene]-5-amido-2 indolinone 20 (121) 3-Z-[l-(4-(N-(3,4,5-trimethoxy-phenethyl)-N-methyl aminomethyl)-phenylamino)-1-methyl-methylene]-5-amido 2-indolinone 25 (122) 3-Z-[1-(4-(N-(3,4-dimethoxy-phenethyl)-N-methyl amino-methyl)-phenylamino)-1-methyl-methylene]-5-amido-2 indolinone (123) 3-Z-[1-(4-(N-(4-nitro-phenethyl)-N-methyl 30 aminomethyl)-phenylamino)-1-methyl-methylene]-5-amido-2 indolinone (124) 3-Z-[1-(4-(N-phenethyl-N-benzyl-aminomethyl) phenylamino)-1-methyl-methylene]-5-amido-2-indolinone 35 - 76 (125) 3-Z-[1-(4- (N-phenethyl-N-cyclohexyl-aminomethyl) phenylamino)-1-methyl-methylene]-5-amido-2-indolinone (126) 3-Z-[1-(4-(N-(4-nitro-phenethyl)-N-isopropyl 5 aminomethyl)-phenylamino)-1-methyl-methylene]-5-amido-2 indolinone (127) 3-Z-[i-(4-(N-(2-(pyridin-2-yl)-ethyl)-N-methyl amino-methyl)-phenylamino)-l-methyl-methylene]-5-amido-2 10 indolinone (128) 3-Z-[1-(4-(N-(2-(pyridin-4-yl)-ethyl)-N-methyl amino-methyl)-phenylamino)-1-methyl-methylene]-5-amido-2 indolinone 15 (129) 3-Z-[1-(4-(N-(pyridin-2-yl-methyl)-N-methyl-amino methyl)-phenylamino)-1-methyl-methylene]-5-amido-2 indolinone 20 (130) 3-Z-[1-(4-(N-(pyridin-3-yl-methyl)-N-methyl-amino methyl)-phenylamino)-1-methyl-methylene]-5-amido-2 indolinone (131) 3-Z-[1-(4-(N-(pyridin-4-yl-methyl)-N-methyl-amino 25 methyl)-phenylamino)-1-methyl-methylene]-5-amido-2 indolinone (132) 3-Z-[1-(4-(dibenzylamino-methyl)-phenylamino)-1 methyl-methylene]-5-amido-2-indolinone 30 (133) 3-Z-[1-(4-(N-(4-nitro-benzyl)-N-propyl-aminomethyl) phenylamino)-l-methyl-methylene]-5-amido-2-indolinone (134) 3-Z-[1-(4-(N-benzyl-N-(3-cyano-propyl)-aminomethyl) 35 phenylamino)-l-methyl-methylene]-5-amido-2-indolinone - 77 (135) 3-Z-[1-(4-(N-benzyl-N-allyl-aminomethyl) phenylamino)-1-methyl-methylene]-5-amido-2-indolinone (136) 3-Z-[1-(4-(imidazol-1-yl-methyl)-phenylamino)-1 5 methyl-methylene]-5-amido-2-indolinone (137) 3-Z-[1-(4-(imidazol-2-yl-amino-methyl)-phenylamino) 1-methyl-methylene]-5-amido-2-indolinone 10 (138) 3 -Z-[1-(4-(N-benzyl-N-(2,2,2-trifluoroethyl) aminomethyl)-phenylamino)-1-methyl-methylene]-5-amido-2 indolinone (139) 3 -Z-[1-(4-(N-(benzo(1,3)dioxol-5-yl-methyl)-N 15 methyl-aminomethyl)-phenylamino)-1-methyl-methylene]-5 amido-2-indolinone (140) 3 -Z-[1-(4-(7-chloro-2,3,4,5-tetrahydro benzo(d)azepin-3-yl-methyl)-phenylamino)-1-methyl 20 methylene]-5-amido-2-indolinone (141) 3 -Z-[1-(4-(7,8-dichloro-2,3,4,5-tetrahydro benzo(d)azepin-3-yl-methyl)-phenylamino)-1-methyl methylene]-5-amido-2-indolinone 25 (142) 3 -Z-[1-(4-(7-bromo-2,3,4,5-tetrahydro benzo(d)azepin-3-yl-methyl)-phenylamino)-1-methyl methylene]-5-amido-2-indolinone 30 (143) 3 -Z-[1-(4-(7-fluoro-2,3,4,5-tetrahydro benzo(d)azepin-3-yl-methyl)-phenylamino)-1-methyl methylene]-5-amido-2-indolinone (144) 3 -Z-[1-(4-(7-methoxy-2,3,4,5-tetrahydro 35 benzo(d)azepin-3-yl-methyl)-phenylamino)-1-methyl methylene]-5-amido-2-indolinone - 78 (145) 3 -Z-[1-(4-(7-methyl-2,3,4,5-tetrahydro benzo(d)azepin-3-yl-methyl)-phenylamino)-1-methyl methylene]-5-amido-2-indolinone 5 (146) 3 -Z-[1-(4-(7,8-dimethoxy-2,3,4,5-tetrahydro benzo(d)azepin-3-yl-methyl)-phenylamino)-1-methyl methylene]-5-amido-2-indolinone 10 (147) 3 -Z-[1-(4-(6,7-dichloro-1,2,3,4-tetrahydro isoquinolin-2-yl-methyl)-phenylamino)-1-methyl-methylene] 5-amido-2-indolinone (148) 3 -Z-[1-(4-(6,7-dimethyl-1,2,3,4-tetrahydro 15 isoquinolin-2-yl-methyl)-phenylamino)-1-methyl-methylene] 5-amido-2-indolinone (149) 3 -Z-[1-(4-(6,7-difluoro-1,2,3,4-tetrahydro isoquinolin-2-yl-methyl)-phenylamino)-1-methyl-methylene] 20 5-amido-2-indolinone (150) 3 -Z-[l-(4-(6-chloro-1,2,3,4-tetrahydro-isoquinolin 2-yl-methyl)-phenylamino)-1-methyl-methylene]-5-amido-2 indolinone 25 (151) 3 -Z-[1-(4-(7-chloro-1,2,3,4-tetrahydro-isoquinolin 2-yl-methyl)-phenylamino)-1-methyl-methylene]-5-amido-2 indolinone 30 (152) 3 -Z-[1-(4-(6-methoxy-1,2,3,4-tetrahydro-isoquinolin 2-yl-methyl)-phenylamino)-1-methyl-methylene]-5-amido 2-indolinone (153) 3 -Z-[1-(4-(7-methoxy-1,2,3,4-tetrahydro-isoquinolin 35 2-yl-methyl)-phenylamino)-1-methyl-methylene]-5-amido-2 indolinone - 79 (154) 3 -Z-[1-(4-(2,3,4,5-tetrahydro-azepino(4,5-b)pyrazin 3-yl-methyl)-phenylamino)-1-methyl-methylene]-5-amido 2-indolinone 5 (155) 3 -Z-[1-(4-(7-Amino-2,3,4,5-tetrahydro-azepino(4,5 b)pyrazin-3-yl-methyl)-phenylamino)-1-methyl-methylene]-5 amido-2-indolinone (156) 3 -Z-[1-(4-(2-amino-5,6,7,8-tetrahydro-azepino(4,5 10 d)thiazol-6-yl-methyl)-phenylamino)-1-methyl-methylene]-5 amido-2-indolinone (157) 3 -Z-[l-(4-(5,6,7,8-tetrahydro-azepino(4,5-d)thiazol 6-yl-methyl)-phenylamino)-1-methyl-methylene]-5-amido 15 2-indolinone (158) 3-Z-[1-(pyridin-3-yl-amino)-1-methyl-methylene]-5 amido-2-indolinone 20 (159) 3 -Z-[1-(thiazol-2-yl-amino)-1-methyl-methylene]-5 amido-2-indolinone (160) 3 -Z-[1-(benzimidazol-2-yl-amino)-1-methyl methylene]-5-amido-2-indolinone 25 (161) 3 -Z-[1-(5-methyl-isoxazol-3-yl-amino)-1-methyl methylene]-5-amido-2-indolinone (162) 3-Z-[1-(imidazol-2-yl-amino)-1-methyl-methylene] 30 5-amido-2-indolinone (163) 3-Z-[1-(5-methyl-pyridin-2-yl-amino)-1-methyl methylene]-5-amido-2-indolinone 35 (164) 3-Z-[1-(5-bromo-pyridin-2-yl-amino)-1-methyl methylene]-5-amido-2-indolinone - 80 (165) 3-Z-[1-(2-chloro-pyridin-5-yl-amino)-1-methyl methylene]-5-amido-2-indolinone Example 2 5 3-Z-[l-(4-Diethylcarbamoyl-phenylamino)-1-methyl methylenel-5-amido-2-indolinone 2 g of the resin prepared in Example IVb are reacted 10 analogously to Example 1 with 2 g of ethyl 4-aminobenzoate in dimethylformamide at 110 0 C. The moist charged resin is suspended in 15 ml of dioxane and 15 ml of methanol and stirred with 12 ml of 1N sodium hydroxide solution for 40 hours. Then the mixture is neutralised with dilute 15 hydrochloric acid and washed with methylene chloride, methanol and dimethylformamide. 300 mg of the resin are then suspended in 3 ml of dimethylformamide and left to stand with 0.2 ml of diethylamine, 0.5 g of TBTU (0 benzotriazol-1-yl-N,N,N',N'-tetramethyluronium 20 tetrafluoroborate), and 0.8 ml of N-ethyl-diisopropylamine for 40 hours at ambient temperature. Finally, the product is cleaved from the resin as described in Example 1. Yield: 61 mg, Rf value: 0.30 (silica gel, methylene chloride/methanol = 25 9:1)

C

2 2

H

2 4

N

4 0 3 mass spectrum: m/z = 392 (M*) The following compounds are prepared analogously to 30 Example 2: (1) 3-Z-[l-(4-benzylcarbamoyl-phenylamino)-1-phenyl methylene]-5-amido-2-indolinone Prepared analogously to Example 2 with benzylamine 35 Rf value: 0.30 (silica gel, methylene chloride/methanol = 9:1)

C

25

H

22

N

4 0 3 - 81 mass spectrum: m/z = 426 (M*) (2) 3-Z-[1-(4-(N-methoxycarbonylmethyl-carbamoyl) phenylamino)-1-phenyl-methylene]-5-amido-2-indolinone 5 Prepared analogously to Example 2 with glycinethyl ester R, value: 0.50 (silica gel, methylene chloride/methanol = 9:1)

C

21

H

20

N

4 0 5 mass spectrum: m/z = 408 (M*) 10 (3) 3-Z-[1-(4-dimethylcarbamoyl-phenylamino)-1-phenyl methylene]-5-amido-2-indolinone Prepared analogously to Example 2 with dimethylamine Rf value: 0.40 (silica gel, methylene chloride/methanol = 15 9:1)

C

2 0H2 0

N

4 0 3 mass spectrum: m/z = 364 (M*) (4) 3-Z-[1-(4-(N-(2-piperidino-ethyl)-carbamoyl) 20 phenylamino)-1-methyl-methylene]-5-amido-2-indolinone trifluoroacetate Prepared analogously to Example 2 with 1-(2-amino-ethyl) piperidine Rf value: 0.30 (silica gel, methylene chloride/methanol = 25 4:1)

C

25

H

29

N

5 0 3 mass spectrum: m/z = 448 (M+H*) (5) 3-Z-[1-(4-(N-methyl-piperazino-carbamoyl) 30 phenylamino)-1-phenyl-methylene]-5-amido-2-indolinone trifluoroacetate Prepared analogously to Example 2 with N-methyl-piperazine Rf value: 0.40 (silica gel, methylene chloride/methanol = 4:1) 35 C 2

,H

2 sN0 3 mass spectrum: m/z = 419 (M*) - 82 () 3-Z--(4-(N-(2-Diethylamino-ethyl) -N-methyl carbamoyl) -phenylamino)-l-phenyl-methylene]-S-amido-2. indolinone -trifluoroacetate Prepared analogously to Example 2 with N,N-diethyl-N' -5 methyl-ehl eimn Rf value: 0.20 (silica gel, methylene chloride/methanol 4:1)

C

2 sH 3 .NIO mass spectrum: m/z = 449 (M') (7) 3-Z- [1- (4-Butylcarbamoyl - h 1 -phenyN methylene] -5-amido-2-indolinone Prepared analogously to Example 2 with butylamine Rf value: 0.80 (silica gel, methylene chloride/methanol = 15 4:1)

C

2 2

H

2 4

N

4 03 mass spectrum: m/z = 392 (M*) Ex am]-e 3 20 3-Z- [1- (4- (N-methyl-N-benzoyl-amino) -phenyl-ami)methylmeI lee 4.5 of a resin prepared according to Example IVb are 25 reacted analogously to Example 1 with 3.4 g Of 4 -(9H fluoren-9 -yl -methoxycarbonyl) -methylamin)aiiei dimethyl frmamidelThino) -aniline in - Then the 9 H-fluoren-9-yl methoxycarbonyl group is cleaved with 40 ml of 30% piperidine in dimeth l -mlff30 ylformamide and the resin is washed 30 several times. Then 400 mg of the resin are suspended in 4 ml of dimethylformamide and 0.3 ml of triethylame and reacted with 0.3 ml of benzoylchlofide for one hour at ambient temperature. Finally, the product is cleaved from the resin with trifluoroacetic acid as described in 35 Example 1. Yield: 25 mg, - 83 Rf value: 0.51 (silica gel, methylene chloride/methanol = 9:1)

C

3 0

H

24

N

4 0 3 mass spectrum: m/z = 426 (M*) 5 The following compounds are prepared analogously to Example 3: (1) 3-Z- [i- (4- (N-methyl -N-propionyl-amino) -phenylamino) 10 1-methyl-methylene] -5-amido-2-indolinone Prepared analogously to Example 3 with propionic acid chloride Rf value: 0.52 (silica gel, methylene chloride/methanol = 9:1) 15

C

21

H

22

N

4 0 3 mass spectrum: m/z = 378 (M*) (2) 3-Z- [1- (4- (N-methyl-N-butyryl-amino) -phenylamino) 1-methyl-methylene] -5-amido-2-indolinone 20 Prepared analogously to Example 3 with butyric acid chloride Rf value: 0.28 (silica gel, methylene chloride/methanol = 9:1)

C

2 2

H

24

N

4 0 3 25 mass spectrum: m/z = 392 (M*) (3) 3-Z- [1- (4- (N-methyl-N-ethanesulphonyl -amino) phenylamino) -1-methyl-methylene] -5-amido-2-indolinone Prepared analogously to Example 3 with ethanesulphonic 30 acid chloride Rf value: 0.30 (silica gel, methylene chloride/methanol = 9:1)

C

2 0

H

2 2

N

4 0 4 S mass spectrum: m/z = 413 (M-H*) 35 (4) 3-Z- [1- (4-(N-methyl-N-propanesulphonyl-amino) phenylamino) -1-methyl-methylene] -5-amido-2-indolinone - 84 Prepared analogously to Example 3 with propanesulphonic acid chloride Rf value: 0.31 (silica gel, methylene chloride/methanol = 9:1) 5

C

2 1

H

2 4

N

4 0 4 S mass spectrum: m/z = 451 (M+Na*) (5) 3-Z- [1- (4- (N-methyl-N-phenylsulphonylamino) phenylamino-1-methyl-methylene -S-amido-2-indolinone 10 Prepared analogously to Example 3 with phenylsulphonic acid chloride Rf value: 0.46' (silica gel, methylene chloride/methanol = 9:1)

C

2 4

H

2 2

N

4 0 4 S 15 mass spectrum: m/z = 462 (M*) (6) 3-Z- [1- (4- (N-methyl-N-acetyl-amino) -phenylamino) -1 methyl-methylene] -5-amido-2-indolinone Prepared analogously to Example 3 with acetylchloride 20 R, value: 0.20 (silica gel, methylene chloride/methanol = 9:1)

C

2 0H2 0

N

4 0 3 mass spectrum: m/z = 364- (M*) 25 (7) 3-Z- [l- (4- (N-methyl-N-phenylmethylsulphonyl-amino) phenylamino) -1-methyl-methylene] -5-amido-2-indolinone Prepared analogously to Example 3 with phenylmethanesulphonic acid chloride R, value: 0.43 (silica gel, methylene chloride/methanol = 30 9:1)

C

2 5

H

2 4

N

4 0 4 S mass spectrum: m/z = 475 (M-H*) 35 - 85 Example 4 Methyl 3-Z-[1-(4-(N-benzyl-N-methyl-aminomethyl) phenylamino)-l-methyl-methylenel-2-indolinone-5 5 carboxylate 8.0 g (28 mmol) of methyl 1-acetyl-3-(l-ethoxy-1-methyl methylene)-2-indolinone-5-carboxylate are dissolved in 60 ml of dimethylformamide and stirred with 6.3 g (28 mmol) of 4 -(N-benzyl-N-methyl-aminomethyl)-aniline for 6 hours 10 at 80 0 C. Then 30 ml of conc. ammonia are added and the mixture is left to stand for 2 hours at 45 0 C. The solution is evaporated'down and the residue is washed with ethanol and ether. Then it is chromatographed over a small silica gel column with ethyl acetate/ethanol (9:1). 15 Yield: 8.6 g (70 % of theory), melting point: 150-152 0 C

C

27

H

27

N

3 0 3 mass spectrum: m/z = 442 (M+) 20 The following compounds are prepared analogously to Example 4: (1) methyl 3-Z-[1-(4-(piperidino-methyl)-phenylamino)-i methyl-methylene]- 2 -indolinone-5-carboxylate 25

C

24

H

27

N

3 0 3 mass spectrum: m/z = 406 (M+H*) (2) methyl 3-Z-[1-(4-bromo-phenylamino)-1-methyl methylene]-2-indolinone-5-carboxylate 30

C,

8

H

1 5 BrN 2

C

3 mass spectrum: m/z = 386/388 (M+) (3) methyl 3-Z-[1-(4-chloro-phenylamino)-1-methyl methylene]- 2 -indolinone-5-carboxylate 35

C

18 HjClN 2 0 3 mass spectrum: m/z = 342/344

(M*)

- 86 (4) methyl 3-Z-[1-(4-(N-methyl-N-methylsulphonyl-amino) phenylamino)-1-ethyl-methylene]- 2 -indolinone-5-carboxylate

C

20

H

2

IN

3 0 5 S mass spectrum: m/z = 415 (M*) 5 (5) methyl 3 -Z-[l-(4-(2,3,4,5-tetrahydro-benzo(d)azepin-3 yl-methyl)-phenylamino)-1-methyl-methylene]-2-indolinone 5-carboxylate

C

29

H

29

N

3 0 2 10 mass spectrum: m/z = 467 (M*) Example 5 3-Z-[1-(4-(N-benzyl-N-methyl-aminomethyl)-phenylamino) 15 1-methyl-methylenel-2-indolinone-5-carboxylic acid 2.3 g (5 mmol) of methyl 3-Z-[l-(4-(N-benzyl-N-methyl aminomethyl)-phenylamino)-1-methyl-methylene]-2 indolinone-5-carboxylate are dissolved in 50 ml of 20 methanol and 50 ml of dioxane and stirred with 25 ml of 1N sodium hydroxide solution for 1 hour at 70 0 C. Then the mixture is neutralised with 25 ml of 1N hydrochloric acid and evaporated to dryness. The residue is washed several times with water and dried. 25 Yield: 1.9 g (85 % of theory),

C

26 H2 5

N

3 0 3 mass spectrum: m/z = 428 (M+H*) The following compounds are prepared analogously to 30 Example 5: (1) 3-Z-[1-(4-(Piperidino-methyl)-phenylamino)-1-methyl methylene]-2-indolinone-5-carboxylic acid

C

2 3

H

25

N

3 0 3 35 mass spectrum: m/z = 392 (M+H*) - 87 (2) 3-Z-[1-(4-bromo-phenylamino)-1-methyl-methylene]-2 indolinone-5-carboxylic acid (3) 3-Z-[1-(4-chloro-phenylamino)-1-methyl-methylene]-2 5 indolinone-5-carboxylic acid

C

17

H

1 3 ClN 2 0 3 mass spectrum: m/z = 327/329 (M-H*) (4) 3-Z-[1-(4-(N-methyl-N-methylsulphonyl-amino) 10 phenylamino)-1-methyl-methylene]-2-indolinone-5-carboxylic acid

C

19

H

1

N

9

N

3 0 5 S mass spectrum: m/z = 401 (M*) 15 (5) 3 -Z-[1-(4-(2,3,4,5-tetrahydro-benzo(d)azepin-3-yl methyl)-phenylamino)-1-methyl-methylene]-2-indolinone-5 carboxylic acid

C

28

H

27

N

3 0 3 mass spectrum: m/z = 453 (M*) 20 Example 6 3-Z-[1-(4-(N-benzyl-N-methyl-aminomethyl)-phenylamino) 1-methyl-methylenel-2-indolinone-5-diethylcarbamoyl-2 25 indolinone 0.3 g of 3-Z-[1-(4-(N-benzyl-N-methyl-aminomethyl) phenylamino)-1-methyl-methylene]-2-indolinone-2 indolinone-5-carboxylic acid are dissolved with 1.2 g of 30 N-ethyl-diisopropylethylamine in 8 ml of dimethylformamide. Then 0.1 g of diethylamine and 0.4 g of TBTU (O-benzotriazol-1-yl-N,N,N',N'-tetramethyluronium tetrafluoroborate) are added and the mixture is stirred for 20 hours at ambient temperature. It is then evaporated 35 down and the residue is suspended in water and extracted with methylene chloride. The organic phase is evaporated - 88 down and chromatographed over a silica gel column with methylene chloride/ethanol (19:1). Yield: 0.2 g (68% of theory), Rf value: 0.36 (silica gel, methylene chloride/ethanol = 5 19:1)

C

3 0

H

34

N

4 0 2 mass spectrum: m/z = 482 (M*) The following compounds are prepared analogously to 10 Example 6: (1) 3-Z-[1-(4- (Piperidino-methyl)-phenylamino)-1-methyl methylene]-2-indolinone-5-diethylcarbamoyl-2-indolinone Prepared from the compound produced in Example 5(1) and 15 diethylamine

C

27

H

34

N

4 0 2 mass spectrum: m/z = 446 (M*) (2) 3-Z-[1-(4-(N-methyl-N-methylsulphonyl-amino) 20 phenylamino)-1-methyl-methylene]-2-indolinone-5 diethylcarbamoyl-2-indolinone Prepared from the compound produced in Example 5(4) and diethylamine

C

2 3

H

2 8

N

4 0 4 S 25 mass spectrum: m/z = 457 (M+H*) (3) 3-Z-[l-(4-(2,3,4,5-tetrahydro-benzo(d)azepin-3-yl methyl)-phenylamino)-1-methyl-methylene]-5 diethylcarbamoyl-2-indolinone 30 (4) 3-Z-[l-(4-(2,3,4,5-tetrahydro-benzo(d)azepin-3-yl methyl)-phenylamino)-1-methyl-methylene]-5 dimethylcarbamoyl-2-indolinone 35 (5) 3-Z-[1-(4-(N-Phenylmethyl-N-methylamino-methyl) phenylamino)-1-methyl-methylene]-5-methylcarbamoyl-2- - 89 indolinone (6) 3-Z-[1-(4-(N-Phenylmethyl-N-methylamino-methyl) phenylamino)-1-methyl-methylene]-5-dimethylcarbamoyl-2 5 indolinone (7) 3-Z-[1-(4-(N-Phenylmethyl-N-methylamino-methyl) phenylamino)-1-methyl-methylene]-5-diethylcarbamoyl-2 indolinone 10 (8) 3-Z-[1-(4-(N-Phenylmethyl-N-methylamino-methyl) phenylamino)-l-methyl-methylene]-5-propylcarbamoyl-2 indolinone 15 (9) 3-Z-[1-(4-(N-Phenylmethyl-N-methylamino-methyl) phenylamino)-1-methyl-methylene]-5-dipropylcarbamoyl-2 indolinone (10) 3-Z-[1-(4-(dimethylamino-methyl)-phenylamino)-1 20 methyl-methylene]-5-methylcarbamoyl-2-indolinone (11) 3-Z-[1-(4-(dimethylamino-methyl)-phenylamino)-1 methyl-methylene)-5-dimethylcarbamoyl-2-indolinone 25 (12) 3-Z-[1-(4-(dimethylamino-methyl)-phenylamino)-1 methyl-methylene]-5-diethylcarbamoyl-2-indolinone (13) 3-Z-[1-(4-(dimethylamino-methyl)-phenylamino)-1 methyl-methylene]-5-propylcarbamoyl-2-indolinone 30 (14) 3-Z-[1-(4-(dimethylamino-methyl)-phenylamino)-1 methyl-methylenel-5-dipropylcarbamoyl-2-indolinone (15) 3-Z-[1-(3-(dimethylamino-methyl)-phenylamino)-1 35 methyl-methylene]-5-methylcarbamoyl-2-indolinone - 90 (16) 3-Z-[1-(3- (dimethylamino-methyl)-phenylamino)-1 methyl-methylene]-5-dimethylcarbamoyl-2-indolinone (17) 3-Z-[1-(3-(dimethylamino-methyl)-phenylamino)-1 5 methyl-methylene]-5-diethylcarbamoyl-2-indolinone (18) 3-Z-[1-(3-(dimethylamino-methyl)-phenylamino-1 methyl-methylene]-5-propylcarbamoyl-2-indolinone 10 (19) 3-Z-[1-(3-(dimethylamino-methyl)-phenylamino)-1 methyl-methylene]-5-dipropylcarbamoyl-2-indolinone (20) 3-Z-[1-(4-chloro-phenylamino)-1-methyl-methylene] 5-methylcarbamoyl-2-indolinone 15 (21) 3-Z-[1-(4-chloro-phenylamino)-1-methyl-methylene]-5 dimethylcarbamoyl-2-indolinone (22) 3-Z-[1-(4-chloro-phenylamino)-1-methyl-methylene]-5 20 diethylcarbamoyl-2-indolinone (23) 3-Z-[1-(4-chloro-phenylamino)-l-methyl-methylene]-5 propylcarbamoyl-2-indolinone 25 (24) 3-Z-[1-( 4 -chloro-phenylamino)-1-methyl-methylene]-5 dipropylcarbamoyl-2-indolinone (25) 3-Z-(1-phenylamino-1-mehyl-methylene)-5 methylcarbamoyl-2-indolinone 30 (26) 3-Z-(l-phenylamino-1-methyl-methylene)-5 dimethylcarbamoyl-2-indolinone (27) 3-Z-(1-Phenylamino-1-methyl-methylene)-5 35 diethylcarbamoyl-2-indolinone - 91 Example 7 3-Z-[1-(4-methyl-3-amino-phenylamino)-1-methyl-methylenel 5-amido-2-indolinone 5 130 mg of 3-Z-[1-(4-methyl-3-nitro-phenylamino)-1-methyl methylene]-5-amido-2-indolinone are dissolved in 9 ml of methanol and hydrogenated with 50 mg of Raney nickel at ambient temperature under 3 bar of hydrogen pressure. The catalyst is filtered off and the solution is evaporated 10 down. Yield: 97 mg (70 % of theory), R, value: 0.60- (silica gel, methylene chloride/Ethanol = 4:1)

C

18

H

18

N

4 0 2 15 mass spectrum: m/z = 322 (M*) The following compound is prepared analogously to Example 7: 20 (1) 3-Z-[1-(4-(piperidino-methyl)-3-amino-phenylamino)-1 methyl-methylene]-5-amido-2-indolinone Prepared aus 3-Z-[1-(4-(piperidino-methyl)-3-nitro-phenyl amino)-1-methyl-methylene]-5-amido-2-indolinone Rf value: 0,15 (silica gel, methylene chloride/ethanol = 25 9:1)

C

23

H

27

N

5 0 2 mass spectrum: m/z = 406 (M+H*) -92 Example 8 Dry ampoule containing 75 mg of active substance per 10 ml 5 Composition: Active substance 75.0 mg Mannitol 50.0 mg water for injections ad 10.0 ml 10 Preparation: Active substance and mannitol are dissolved in water. After packaging the solution is freeze-dried. To produce the solution ready for use, the product is dissolved in 15 water for injections. Example 9 Dry ampoule containing 35 mg of active substance per 2 ml 20 Composition: Active substance 35.0 mg 25 Mannitol 100.0 mg water for injections ad 2.0 ml Preparation: Active substance and mannitol are dissolved in water. 30 After packaging, the solution is freeze-dried. To produce the solution ready for use, the product is dissolved in water for injections. 35 - 93 Example 10 Tablet containing 50 mg of active substance 5 Composition: (1) Active substance 50.0 mg (2) Lactose 98.0 mg 10 (3) Maize starch 50.0 mg (4) Polyvinylpyrrolidone 15.0 mg (5) Magnesium stearate 2.0 mg 215.0 mg 15 Preparation: (1), (2) and (3) are mixed together and granulated with an aqueous solution of (4). (5) is added to the dried granulated material. From this mixture tablets are 20 pressed, biplanar, faceted on both sides and with a dividing notch on one side. Diameter of the tablets: 9 mm. Example 11 25 Tablet containing 350 mg of active substance Composition: 30 (1) Active substance 350.0 mg (2) Lactose 136.0 mg (3) Maize starch 80.0 mg (4) Polyvinylpyrrolidone 30.0 mg 35 (5) Magnesium stearate 4.0 mg 600.0 mg - 94 Preparation: (1), (2) and (3) are mixed together and granulated with an aqueous solution of (4). (5) is added to the dried 5 granulated material. From this mixture tablets are pressed, biplanar, faceted on both sides and with a dividing notch on one side. Diameter of the tablets: 12 mm. 10 Example 12 Capsules containing 50 mg of active substance 15 Composition: (1) Active substance 50.0 mg (2) Dried maize starch 58.0 mg (3) Powdered lactose 50.0 mg 20 (4) Magnesium stearate 2.0 mc 160.0 mg Preparation: (1) is triturated with (3). This trituration is added to 25 the mixture of (2) and (4) with vigorous mixing. This powder mixture is packed into size 3 hard gelatin capsules in a capsule filling machine.

- 95 Example 13 Capsules containing 350 mg of active substance 5 Composition: (1) Active substance 350.0 mg (2) Dried maize starch 46.0 mg 10 (3) Powdered lactose 30.0 mg (4) Magnesium stearate 4.0 mg 430.0 mg 15 Preparation: (1) is triturated with (3). This trituration is added to the mixture of (2) and (4) with vigorous mixing. This powder mixture is packed into size 0 hard gelatin 20 capsules in a capsule filling machine. Example 14 Suppositories containing 100 mg of active substance 25 1 suppository contains: Active substance 100.0 mg Polyethyleneglycol (M.W. 1500) 600.0 mg 30 Polyethyleneglycol (M.W. 6000) 460.0 mg Polyethylenesorbitan monostearate 840.0 mg 2,000.0 mg Preparation: 35 The polyethyleneglycol is melted with the polyethylene sorbitan monostearate. The milled active substance is - 96 homogeneously dispersed in the melt at 40 0 C. The melt is cooled to 38 0 C and poured into lightly pre-cooled suppository moulds.

Claims (7)

1. Substituted indolinones of general formula 5 R3 R4 R2 X (R5, N Ri wherein 10 X denotes an oxygen or sulphur atom, R 1 denotes a hydrogen atom, a C 1 4 -alkoxy-carbonyl or C2-4-alkanoyl group, 15 R 2 denotes a carboxy or Cl 4 -alkoxy-carbonyl group or an aminocarbonyl group optionally substituted by one or two C 1 3 -alkyl groups, whilst the substituents may be identical or different, 20 R 3 denotes a hydrogen atom or a C 1 6 -alkyl group which may be substituted at the 2 position, in relation to the carbon atom of the R 3 -C(R 4 NR,)= group by a fluorine, chlorine or bromine atom, by a hydroxy, Cl -alkoxy, C 1 3 -alkylsulphenyl, 25 C 1 3 -alkylsulphinyl, C 1 3 -alkylsulphonyl, phenylsulphenyl, phenylsulphinyl, phenylsulphonyl, amino, C 1 3 -alkylamino, di- (Cl 1 3 -alkyl) -amino, C 2 - 5 -alkanoylamino or N- (C. -alkylamino) -C 2 -s-alkanoylamino group, - 98 R 4 denotes a hydrogen atom, a C,- alkyl group or a C,--Cycloalkyl group optionally substituted by a C 13 -alkyl group wherein a methylene group in the 3 or 4 position in relation to the carbon atom of the R 3 -C(R 4 NR,)= group may be 5 substituted by an imino group optionally substituted by a C 1 3 -alkyl group, a phenyl or naphthyl group which may be substituted 10 by a fluorine, chlorine, bromine or iodine atom, by a methoxy group optionally substituted by 1 to 3 fluorine atoms, 15 by a C 2 3 -alkoxy which may be substituted in the 2 or 3 position by a C- 3 -alkylamino, di-(C 1 3 -alkyl) -amino or 5 to 7-membered cycloalkyleneimino group, whilst additionally an alkyl moiety in the abovementioned alkylamino and dialkylamino groups may be substituted by a 20 phenyl group, by a trifluoromethyl, amino, C 1 3 -alkylamino, di (Cl- 3 -alkyl) -amino, C 2 -s-alkanoylamino, N- (C 1 3 -alkyl) C 2 5 -alkanoylamino, C, 5 -alkylsulphonylamino, N- (C 1 3 -alkyl) 25 Cs 5 -alkylsulphonylamino, phenylsulphonylamino, N-(C 13 -alkyl)-phenylsulphonylamino, aminosulphonyl, C 1 3 -alkylaminosulphonyl or di-(C 13 -alkyl)-aminosulphonyl group, whilst additionally an alkyl moiety in the abovementioned alkylamino and dialkylamino groups may be 30 substituted by a phenyl group, by a carbonyl group which is substituted by a hydroxy, Cl- 3 -alkoxy, amino, Cl 1 3 -alkylamino or N- (C 1 5 -alkyl) C 1 3 -alkylamino group, whilst additionally an alkyl moiety 35 in the abovementioned groups may be substituted by a carboxy, C3 -alkoxycarbonyl or phenyl group or in the 2 or 3 position by a di-(C 1 3 -alkyl) -amino, piperazino, - 99 N-(C 1 3 -alkyl)-piperazino or 5- to 7-membered cyc loalkyleneimino group, by a CI 3 -alkyl group which is substituted by an amino, 5 C 17 -alkylamino, C 5 7 -cycloalkylamino or phenyl C 13 -alkylamino group which may additionally be substituted at the amino nitrogen atom by a C 1 3 -alkyl group wherein the hydrogen atoms are wholly or partially replaced by fluorine atoms, by a C 5 -- cycloalkyl, 10 C 2 4 -alkenyl or CI- alkyl group, whilst the abovementioned C 1 - 4 -alkyl substituent may in each case be additionally mono, di- or trisubstituted by a cyano, carboxy, C 1 3 -alkoxycarbonyl, pyridyl, 15 imidazolyl, benzo[1,3]dioxole or phenyl group, wherein the phenyl group may be substituted by fluorine, chlorine or bromine atoms, by methyl, methoxy, trifluoromethyl, cyano or nitro groups and the substituents may be identical or different, or may be 20 substituted in the 2, 3 or 4 position by a hydroxy group, by a C 13 -alkyl group which may be substituted by a hydroxy, carboxy, thiomorpholino, 1-oxido 25 thiomorpholino, 1,1-dioxido-thiomorpholino, piperazino, N-(C 1 3 -alkyl)-piperazino or N-phenyl-piperazino group, by a 5- to 7-membered cycloalkenyleneimino group or by a

4- to 7-membered cycloalkyleneimino group, wherein the abovementioned 5- to 7-membered cycloalkyleneimino 30 groups may be substituted by one or two C 1 3 -alkyl groups, by a CI 7 -cycloalkyl or phenyl group, by a C 1 - 3 -alkyl, C 5 7 -cycloalkyl, phenyl, carboxy or C 1 4 -alkoxy-carbonyl group and by a hydroxy group and in the abovementioned cycloalkyleneimino groups a methylene 35 group adjacent to the nitrogen atom may be replaced by a carbonyl group, - 100 by a C 1 3 -alkyl group which is substituted by a 5- to 7 membered cycloalkyleneimino group, whilst a phenyl group optionally mono- or disubstituted by fluorine, chlorine or bromine atoms or by methyl or methoxy groups, wherein 5 the substituents may be identical or different, or an oxazolo, imidazolo, thiazolo, pyridino, pyrazino or pyrimidino group, optionally substituted by a fluorine, chlorine, bromine or iodine atom or by a methyl, methoxy or amino group, may be fused to the abovementioned 5- to 10 7-membered cycloalkyleneimino groups via two adjacent carbon atoms, whilst additionally the abovementioned monosubstituted phenyl groups may be substituted by a fluorine, chlorine 15 or bromine atom or by a methyl, methoxy or nitro group, a 5-membered heteroaromatic group which contains an imino group, an oxygen or sulphur atom or an imino group, an oxygen or sulphur atom and one or two nitrogen atoms, or 20 a 6-membered heteroaromatic group which contains one, two or three nitrogen atoms, whilst the abovementioned 5- and

6-membered heteroaromatic groups may additionally be substituted by a chlorine or bromine atom or by a methyl 25 group, or a phenyl ring may be fused to the abovementioned 5- or 6-membered heteroaromatic groups via two adjacent carbon atoms, and R. denotes a hydrogen atom or a C1- alkyl group 30 whilst any carboxy, amino or imino groups present may be substituted by groups which can be cleaved in vivo, the isomers and salts thereof. 35 - 101 2. Substituted indolinones of general formula I according to claim 1, wherein X denotes an oxygen atom, 5 R 1 denotes a hydrogen atom, R 2 denotes an aminocarbonyl group, 10 R 3 denotes a hydrogen atom or a Cl- 4 -alkyl group which may be substituted, at the 2 position in relation to the carbon atom of the R 3 g-C(R 4 NR)= group, by a chlorine or bromine atom or by a phenylsulphonyl group, 15 R 4 denotes a hydrogen atom, a C 1 3 -alkyl group or a cyclopentyl or cyclohexyl group optionally substituted by a methyl group, whilst in the cyclopentyl and cyclohexyl group a methylene group in the 3 or 4 position in relation to the carbon atom of the R 3 -C(R 4 NR,)= group may be replaced 20 by an imino group optionally substituted by a methyl group, a phenyl group which is substituted by a fluorine, chlorine, bromine or iodine atom, 25 by a methoxy group optionally substituted by 1 to 3 fluorine atoms, by a C 2 - 3 -alkoxy which is substituted in the 2 or 3 30 position by methylamino, dimethylamino or 5- to 7 membered cycloalkyleneimino group, whilst additionally a methyl group in the abovementioned amino groups may be substituted by a phenyl group, 35 by a trifluoromethyl, amino, C 2 - 5 -alkanoylamino, N- (C, 3 -alkyl) -C 2 -s-alkanoylamino, C 1 _ -alkylsulphonylamino, N- (Cl 13 -alkyl) - - 102 C 15 -alkylsulphonylamino, phenylsulphonylamino, N-(C 13 -alkyl)-phenylsulphonylamino or aminosulphonyl group, whilst additionally an alkyl moiety in the abovementioned alkylamino and dialkylamino groups may be 5 substituted by a phenyl group, by a carbonyl group which is substituted by a hydroxy, C,- -alkoxy, amino, C 13 -alkylamino or N- (C,-,-alkyl) C 1 - 3 -alkylamino group, whilst additionally an alkyl 10 moiety in the abovementioned groups may be substituted by a carboxy, C 13 -alkoxycarbonyl or phenyl group or in the 2 or 3 position by a di-(C 1 3 -alkyl)-amino, pipera zino, N-(C 1 3 -alkyl)-piperazino or 5- to 7-membered cyc loalkyleneimino group, 15 by a C 1 3 -alkyl group which is substituted by an amino, C, 7 -alkylamino, C 5 --cycloalkylamino or phenyl C 1 - 3 -alkylamino group which may additionally be substituted at the amino nitrogen atom by a CI 3 -alkyl 20 group wherein the hydrogen atoms are wholly or partially replaced by fluorine atoms, by a cyclohexyl, C 2 - 4 -alkenyl or CI 4 -alkyl group, whilst the abovementioned C 1 4 -alkyl substituent may in each 25 case be additionally substituted by a cyano, carboxy, C 1 3 -alkoxycarbonyl, pyridyl, imidazolyl, benzo[1,3]dioxole or phenyl group, wherein the phenyl group may be monosubstituted by a fluorine, chlorine or bromine atom or by a methyl, methoxy, cyano, 30 trifluoromethyl or nitro group, or di- or trisubstituted by fluorine, chlorine or bromine atoms or by methyl or methoxy groups, and the substituents may be identical or different, or may be substituted in the 2, 3 or 4 position by a hydroxy group, 35 by a C 1 3 -alkyl group which may be substituted by a hydroxy, carboxy, thiomorpholino, 1-oxido- - 103 thiomorpholino, 1,1-dioxido-thiomorpholino, piperazino, N-(C 13 -alkyl)-piperazino or N-phenyl-piperazino group, by a 5- to 7-membered cycloalkenyleneimino group or by a 4- to 7-membered cycloalkyleneimino group, wherein the 5 abovementioned 5- to 7-membered cycloalkyleneimino groups may be substituted by one or two C 13 -alkyl groups, by a cyclohexyl or phenyl group, by a C 1 3 -alkyl, cyclohexyl, phenyl, carboxy or C 1 4 -alkoxy-carbonyl group and by a hydroxy group and in the abovementioned 10 cycloalkyleneimino groups a methylene group adjacent to the nitrogen atom may be replaced by a carbonyl group, by a C 1 - 3 -alkyl group which is substituted by a 5- to 7 membered cycloalkyleneimino group, whilst a phenyl group 15 optionally mono- or disubstituted by fluorine, chlorine or bromine atoms or by methyl or methoxy groups, wherein the substituents may be identical or different, or a pyrazino or thiazolo group, optionally substituted by an amino group, may be fused to the abovementioned 5- to 7 20 membered cycloalkyleneimino groups via two adjacent carbon atoms, whilst additionally the abovementioned monosubstituted phenyl groups may be substituted by a fluorine, chlorine 25 or bromine atom or by a methyl, methoxy or nitro group, a pyridyl group optionally substituted by a chlorine or bromine atom or by a methyl group, 30 an oxazolyl, isoxazolyl, imidazolyl or thiazolyl group optionally substituted by a methyl group, to which a phenyl ring may be fused via two adjacent carbon atoms, and 35 R 5 denotes a hydrogen atom or a CI 3 -alkyl group, the isomers and the salts thereof. - 104 3. Substituted indolinones of general formula I according to claim 2, wherein 5 R. is in the 5 position, the isomers and the salts thereof. 4. Substituted indolinones of general formula I according 10 to claim 1, wherein X denotes an oxygen atom, R 1 denotes a hydrogen atom, 15 R 2 in the 5 position denotes an aminocarbonyl group, R 3 denotes a hydrogen atom or a C 14 -alkyl group which may be terminally substituted by a chlorine or bromine atom or 20 by a phenylsulphonyl group, R 4 denotes a hydrogen atom, a C1- alkyl group or a cyclopentyl or cyclohexyl group optionally substituted by a methyl group, whilst in the cyclohexyl group a methylene 25 group in the 4 position in relation to the carbon atom of the R 3 -C(R 4 NR,)= group may be replaced by an imino group optionally substituted by a methyl group, a phenyl group which may be substituted 30 by a fluorine, chlorine, bromine or iodine atom, by a methyl or ethyl group, which may in each case be substituted by a C 1 3 -alkylamino, di-(C 13 -alkyl)-amino, 35 thiomorpholino, 1-oxido-thiomorpholino, 1,1-dioxido thiomorpholino, N-phenyl-piperazino, 5- to 6-membered cycloalkenyleneimino group or by a 5- to 7-membered - 105 cycloalkyleneimino group, whilst the abovementioned 5- to

7-membered cycloalkyleneimino groups may be substituted by one or two methyl groups, by a cyclohexyl or phenyl group, by a methyl, cyclohexyl or phenyl group and by a hydroxy 5 group, or by a methyl or ethyl group which may be substituted by a phenyl group which is substituted by a 5 to 7-membered cycloalkyleneimino group, whilst additionally a phenyl 10 ring is fused to the abovementioned cycloalkyleneimino groups via 2 adjacent carbon atoms, by a methyl or ethyl group substituted by an amino, methylamino or ethylamino group, each of which is 15 additionally substituted at the amino nitrogen atom by a benzyl or phenylethyl group, wherein the phenyl moiety in the abovementioned groups may be monosubstituted by a fluorine, chlorine or bromine atom or by a methyl, methoxy, cyano, trifluoromethyl or nitro group or di- or 20 trisubstituted by fluorine, chlorine or bromine atoms or by methyl or methoxy groups, and the substituents may be identical or different, whilst additionally the abovementioned monosubstituted 25 phenyl groups may be substituted by a fluorine, chlorine or bromine atom or by a methyl, methoxy or nitro group, and R, denotes a hydrogen atom or a C 1 4 -alkyl group, 30 the isomers and the salts thereof. 5. Substituted indolinones of general formula I according to claim 1, wherein 35 X denotes an oxygen atom, - 106 R 1 denotes a hydrogen atom, R 2 in the 5 position denotes an aminocarbonyl group, S R 3 denotes a hydrogen atom or a C 1 4 -alkyl group, R 4 denotes a phenyl group which may be substituted by a fluorine, chlorine, bromine or iodine atom, 10 by a methyl or ethyl group, which may be substituted in each case by a Cl. 3 -alkylamino, di-(C 1 3 -alkyl)-amino, thiomorpholino, 1-oxido-thiomorpholino, 1,1-dioxido thiomorpholino, N-phenyl-piperazino, 5- to 6-membered 15 cycloalkenyleneimino group or by a 5- to 7-membered cycloalkyleneimino group, whilst the abovementioned 5- to 7-membered cycloalkyleneimino groups may be substituted by one or two methyl groups, by a cyclohexyl or phenyl group, by a methyl, cyclohexyl or phenyl group and by a hydroxy 20 group, or by a methyl or ethyl group which may be substituted by a phenyl group which is substituted in the 4 position by a 5 to 7-membered cycloalkyleneimino group, whilst 25 additionally a phenyl ring is fused to the abovementioned cycloalkyleneimino groups via 2 adjacent carbon atoms, by a methyl or ethyl group substituted by an amino, methylamino or ethylamino group, each of which is 30 additionally substituted at the amino nitrogen atom by a benzyl or phenylethyl group, and wherein the phenyl moiety may be monosubstituted by a fluorine, chlorine or bromine atom or by a methyl, methoxy, cyano, trifluoromethyl or nitro group, disubstituted by methyl or methoxy groups or 35 trisubstituted by methyl or methoxy groups, and the substituents may be identical or different, - 107 whilst additionally the abovementioned monosubstituted phenyl groups may be substituted by a fluorine, chlorine or bromine atom or by a methyl, methoxy or nitro group, 5 and R, denotes a hydrogen atom or a C 1 4 -alkyl group, the isomers and the salts thereof. 10 6. The following substituted indolinones of general formula I according to claim 1: (a) 3-Z-[1-(4-piperidinomethyl-phenylamino)-1-methyl-methy 15 lene]-5-amido-2-indolinone, (b) 3-Z-[1-(4-bromo-phenylamino)-1-methyl-methylene]-5 amido-2-indolinone, 20 (c) 3-Z-[1-(4-piperidinomethyl-phenylamino)-1-butyl methylene]-5-amido-2-indolinone, (d) 3-Z-[1-(4-chlorophenylamino)-1-methyl-methylene]-5 amido-2-indolinone and 25 (e) 3-Z-(1-phenylamino-methylene)-5-amido-2-indolinone (f) 3-Z-[1-(4-(N-benzyl-N-methyl-aminomethyl) phenylamino)-1-methyl-methylene]-5-amido-2-indolinone, 30 (g) 3-Z-[1-(4-(N-(4-chlorobenzyl)-aminomethyl) phenylamino)-1-methyl-methylene]-5-amido-2-indolinone, (h) 3-Z-[1-(4-(N-benzyl-N-ethyl-aminomethyl)-phenylamino] 35 1-methyl-methylene]-5-amido-2-indolinone, - 108 (i) 3-Z-[1-(4-(N-benzyl-aminomethyl)-phenylamino)-1 methyl-methylene]-5-amido-2-indolinone, (j) 3-Z-[1-(4-(N-benzyl-N-methyl-aminomethyl) 5 phenylamino)-methylene]-5-amido-2-indolinone, (k) 3 -Z-[l-(4-(2,3,4,5-tetrahydro-benzo(d)azepin-3-yl methyl)-phenylamino)-1-methyl-methylene]-5-amido-2 indolinone, 10 (1) 3-Z-[l-(4-piperidinomethyl-3-nitro-phenylamino) 1-methyl-methylene]-5-amido-2-indolinone and (m) 3-Z-[1-(4-methyl-3-nitro-phenylamino)-1-methyl 15 methylene)-5-amido-2-indolinone as well as the isomers and the salts thereof. 7. 3-Z-[1-(4-(N-Benzyl-N-methyl-aminomethyl) 20 phenylamino)-1-methyl-methylene]-5-amido-2-indolinone and the salts thereof.

8. 3 -Z-[l-(4-(2,3,4,5-Tetrahydro-benzo(d)azepin-3-yl methyl)-phenylamino)-1-methyl-methylene]-5-amido-2 25 indolinone and the salts thereof.

9. Physiologically acceptable salts of the compounds according to claims 1 to 8. 30 10. Pharmaceutical compositions containing a compound according to at least one of claims 1 to 8 or a salt according to claim 9 and optionally one or more inert carriers and/or diluents. 35 11. Use of a compound according to at least one of claims 1 to 8 or a salt according to claim 9 for preparing - 109 a pharmaceutical composition which is suitable for treating excessive or anomalous cell proliferation.

12. Process for preparing a pharmaceutical composition 5 according to claim 10, characterised in that a compound according to at least one of claims 1 to 8 or a salt according to claim 9 is incorporated in one or more inert carriers and/or diluents by a non-chemical method. 10 13. Process for preparing the compounds according to claims 1 to 9, characterised in that a. a compound of general formula 15 R 3 ,- zi R2X (II), R 6 wherein X and R 3 are defined as in claims 1 to 8, R 2 ' has the meanings given for R 2 in claims 1 to 8, 20 R 6 denotes a hydrogen atom or a protecting group for the nitrogen atom of the lactam group, whilst one of the groups R 2 ' or R6 may also denote a bond to a solid phase optionally formed via a spacer and the other group R 2 ' or R 6 is as hereinbefore defined, and 25 Z. denotes a halogen atom, a hydroxy, alkoxy or aralkoxy group, is reacted with an amine of general formula - 111 a compound of general formula I thus obtained which contains an amino or alkylamino group may be converted by alkylation or reductive alkylation into a corresponding 5 alkylamino or dialkylamino compound, or a compound of general formula I thus obtained which contains an amino or alkylamino group may be converted by acylation into a corresponding acyl compound, or 10 a compound of general formula I thus obtained which contains a carboxy group may be converted by esterification or amidation into a corresponding ester or aminocarbonyl compound, or 15 a compound of general formula I thus obtained which contains a nitro group is converted by reduction into a corresponding amino compound, or 20 if necessary any protecting group used during the reactions to protect reactive groups is cleaved, or a compound of general formula I thus obtained is resolved into the stereoisomers thereof, or 25 a compound of general formula I thus obtained is converted into the salts thereof, more particularly, for pharmaceutical use, into the physiologically acceptable salts thereof with an inorganic or organic acid or base.