ZA200005435B - Substituted indolinones, the production thereof and their use as medicaments. - Google Patents

Description

S018548ausl

Boehringer Ingelheim Pharma KG Case 5/1239-FL

D-~55216 INGELHEIM Foreign filing text

New substituted indolinones, the preparation thereof and their use as pharmaceutical compositions

The present invention relates to new substituted indoli- nones of general formula o :. ®, _ eC

Rg

R, X (1),

R, the isomers thereof and the salts thereof, particularly the physiologically acceptable salts thereof which have valu- able properties.

The above compounds of general formula I wherein R, denotes 9 a hydrogen atom or a prodrug group have valuable pharmaco- logical properties, particularly an inhibitory effect on various kinases, particularly on complexes of CDKs (CDK1,

CDK2, CDK3, CDK4, CDKé6, CDK7, CDK8 and CDK9) with their specific cyclines (A, B1, B2, C, Di, D2, D3, E, F, G1, G2,

H, I and K) and viral cycline (cf. L. Mengtao in J. Viro- logy 71(3), 1984-1991 (1997)), and the other compounds of the above general formula I wherein R, does not represent a hydrogen atom or a prodrug group, are valuable intermediate products for preparing the abovementioned compounds.

o! - 2 =

The present invention thus relates to the above compounds of general formula I, whilst the compounds wherein R; denotes a hydrogen atom or a prodrug group have valuable pharmacological properties, the pharmaceutical compositions

S containing the pharmacologically active compounds, their use and processes for preparing them.

In the above general formula I

X denotes an oxygen or sulphur atom,

R, denotes a hydrogen atom, a C,..-alkoxy-carbonyl or

C,..-alkanoyl group,

R, denotes a carboxy or C...-alkoxy-carbonyl group or an aminocarbonyl group optionally substituted by one ox two

C,.,-alkyl groups, whilst the substituents may be identical or different,

R, denotes a hydrogen atom or a C, -alkyl group which may be substituted at the 2,3,4,5 or 6 position, in relation to the carbon atom of the R,-C(R,NR,)= group by a fluorine, chlorine or bromine atom, by a hydroxy, C,,-alkoxy, C,..-alkylsulphenyl,

C, ,-alkylsulphinyl, C,;-alkylsulphonyl, phenylsulphenyl, ! 25 phenylsulphinyl, phenylsulphonyl, amino, C,,-alkylamino, di- (C, ;-alkyl)-amino, C, -alkanoylamino or N-(C, ,-al- kylaminoc) -C, -alkanoylamino group, - R, denotes a hydrogen atom, a C,,-alkyl group or a C, ,-cyc- loalkyl group optionally substituted by a C,_,-alkyl group wherein a methylene group in the 3 or 4 position in rela- tion to the carbon atom of the R,-C(R,NR.)= group may be substituted by an imino group optionally substituted by a

C,.,-alkyl group, a phenyl or naphthyl group which may be substituted

AMENDED SHEET

. EE LS ® 2 - 3 - by a fluorine, chlorine, bromine or icdine atom, by a methoxy group optionally substituted by 1 to 3 fluorine atoms, by a C,;-alkoxy which may ke substituted in the 2 cr 2 position by a C, ;-alkylamino, di-(C,;-alkyl)-amino or 5- to 7-membered cycloalkyleneimino group, whilst additio- nally an alkyl moiety in the abovementioned alkylamino and dialkylamino groups may be substituted by a phenyl group, ® by a trifluoromethyl, amino, C,,-alkylamino, di- (C,.,-alkyl) -amino, CC, -alkanoylamino, N-(C, ,-alkyl)-

CC, .-alkanoylamino, C,.-alkylsulphonylamino, N-(C, ,-alkyl)-

C,.s-alkylsulphonylaminc, phenylsulphonylamino,

N- (C, ,-alkyl)-phenylsulphonylamino, aminosulphonyl,

C,.,-alkylaminosulphonyl or di- (C,;-alkyl)-aminosulphonyl group, whilst additionally an alkyl moiety in the above- mentioned alkylamino and dialkylamino groups may be sub- stituted by a phenyl group, by a carbonyl group which is substituted by a hydroxy,

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

C, ,-alkylamino, C, ,-cycloalkylamino, C, ,-cycloalkyl-

C, ;-alkylamino or phenyl-C, ;-alkylamino group which may additionally be substituted at the amino nitrogen atom by a C,,-alkyl group wherein the hydrogen atoms are

® wholly or partially replaced by fluorine atoms, by a

C,_,~cycloalkyl, C,,-alkenyl or C, ,-alkyl group, whilst the abovementioned C, ,-alkyl substituent may in each case be additionally mono-, di- or trisubstituted by a cyanc, carboxy, C, ;-alkoxycarbonyl, pyridyl, imidazo- lvl, benzoll,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 substituted in the ® 2, 3 or 4 position by a hydroxy group, by a C,,-alkyl group which may be substituted by a hydroxy, carboxy, thiomorpheclino, l-oxido-thiomorpho- lino, 1,1-dioxido-thiomorpholino, piperazino, N-(C,,-al- kyl) -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 abovemen- tioned 5- to 7-membered cycloalkyleneimino groups may be substituted by one or two C,;-alkyl groups, by a - Cg.,-cycloalkyl or phenyl group, by a C,;-alkyl,

Cs.,-cycloalkyl, phenyl, carboxy or C, ,-alkoxy-carbonyl group and by a hydroxy group and in the abovementioned [ 25 cycloalkyleneimino groups a methylene group adjacent to the nitrogen atom may be replaced by a carbonyl group, by a C,,-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 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

® 7-membered cycloalkyleneimino groups via two adjacent carbon atoms, 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 S-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 ® 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 sub- stituted by a chlorine or bromine atom cor 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

R; denotes a hydrogen atom or a C,,-alkyl group.

Furthermore, the carboxy, amino or imino groups present in a compound of the above general formula I may be substitu- ted by groups which can be cleaved in vivo. @® 25

In addition to the alkoxycarbonyl and alkanoyl groups al- ready mentioned above, groups which can be cleaved in vivo include an acyl group such as the benzoyl, pyridinoyl, pen- tanoyl or hexanoyl group, an allyloxycarbonyl group, a

C,.,s-alkoxycarbonyl group such as the pentoxycarbonyl, hexyloxycarbonyl, octyloxycarbonyl, nonyloxycarbonyl, decyloxycarbonyl, undecyloxycarbonyl, dodecyloxycarbonyl or hexadecyloxycarbonyl group, a phenyl-C, .-alkoxycarbonyl group such as the benzyloxycarbonyl, phenylethoxycarbonyl or phenylpropoxycarbonyl group, a C, ,-alkylsulphonyl-C, -

alkoxycarbonyl, C,j-alkoxy-C, ,-alkoxy-C, ,-alkoxycarbonyl or

R.CO-0- (R,CR,) -0-CO~-group wherein

R, denotes a C,4-alkyl, C,_,-cyclealkyl, phenyl or phenyl-

C,,-alkyl group,

R, denctes az hydrogen atcm, a C,,-alkyl, C.,-cycicalkyl cr phenyl grcup and

Ry denotes a hydrogen atom or a C, ;-alkyl group or the

R.CO-0- (R,CR,) -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 :

X denotes an oxygen atom,

R, denotes a hydrogen atom, Co

R, denotes an aminocarbonyl group, )

R, denotes a hydrogen atom or a C,_,-alkyl group which may be substituted, at the 2,3,4,5 or 6 position, in relation to the carbon atom of the R;-C(R,NR;)= group by a chlorine or bromine atom or by a phenylsulphonyl group, - © 30

R, denotes a hydrogen atom, a C,;-alkyl group cr a cyclo- pentyl 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,-C(R,NR,)= group may be replaced by an imino group optionally substituted by a methyl group,

AMENDED SHEET

® a phenyl group which is substituted by a fluorine, chlorine, bromine or iodine atom, by a methoxy group optionally substituted by 1 to 3 fluorine atoms, by a C, ,-alkoxy which is substituted in the 2 or 3 position by methylamino, dimethylamino or 5- to 7- membered cycloalkyleneimino group, whilst additionally a

C methyl group in the abovementioned amino groups may be substituted by a phenyl group, by a trifluoromethyl, amino, C, -alkanoylamino,

N-(C, ,-alkyl) -C, .~alkanoylamino, C, -alkylsulpho- nylamino, N-(C,,-alkyl)-C,.-alkylsulphonylamino, phe- nylsulphonylamino, N-(C, ;-alkyl)-phenylsulphonylamino or aminosulphonyl group, whilst additionally an alkyl moie- ty in the abovementioned alkylamino and dialkylamino groups may be substituted by a phenyl group, by a carbonyl group which is substituted by a hydroxy,

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

C,.,~alkylamino, C;,-cycloalkylamino, Cs.,-cycloalkyl-

C,.,-alkylamino or phenyl-C, -alkylamino group which may additionally be substituted at the amino nitrogen atom by a C,,-alkyl group wherein the hydrogen atoms are

® wholly or partially replaced by fluorine atoms, by a

Cs.,-cycloalkyl, C,,-alkenyl or C,_,-alkyl group, whilst the abovementioned C, ,-alkyl substituent may in each case be additionally substituted by a cyano, carboxy,

C,.;-alkoxycarbonyl, pyridyl, imidazolyl, benzo[1l,3]di- cxcle cor phenyl group, wherein the phenyl group may be monosubstituted by a fluorine, chlorine or bromine atom or by a methyl, methoxy, cyano, triflucromethyl 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 dif- ferent, or may be substituted in the 2, 3 or 4 posi- tion by a hydroxy group, by a C,;-alkyl group which may be substituted by a hydroxy, carboxy, thiomorpholino, l-oxido-thiomor- pholino, 1,1-dioxido~thiomorpholino, piperazino,

N- (C, ,-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- groups may be substituted by one or two C, ;-alkyl groups, by a cyclohexyl or phenyl group, by a C,,-alkyl, ® 25 cyclohexyl, phenyl, carboxy or C, ,-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, by a C,;-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 py- razino or thiazolo group, optionally substituted by an amino group, may be fused to the abovementioned 5- to 7-

® membered cycloalkyleneimino groups via two adjacent carbon atoms, 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 pyridyl group optionally substituted by a chlorine or bromine atom or by a methyl group, 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

R, denotes a hydrogen atom or a C,;-alkyl group, particularly those compounds of general formula I wherein

R, to R, and Ry; are as hereinbefore defined and

R, denotes a hydrogen atom, a C,,-alkyl group or a C,,-cyc- loalkyl group optionally substituted by a C, ;-alkyl group wherein a methylene group in the 3 or 4 position in rela- tion to the carbon atom of the R,-C(R,NR,)= group may be [ 25 replaced by an imino group optionally substituted by a

C,.,-alkyl group, a phenyl or naphthyl grcup which may be substituted by a fluorine, chlorine or iodine atom, by a C, ;-alkoxy, amino, C, ,-alkylamino, di-(C,,-alkyl)-amino, C, -al- kanoylamino, N-(C, ;-alkylamino) -C, -alkanoylamino,

C, .~alkylsulphonylamino, N-(C, ,-alkyl)-C, ;-alkylsul- phonylamino, phenylsulphonylamino or N- (C, ;-alkyl) -phenyl- sulphonylamino group or by a C,,-alkyl group which may be substituted by a C, -alkylamino, di-{(C, j-alkyl)-amino, thiomorpholino, l-oxido-thiomorpholino, 1,1-dioxido-thio-

morpholino, piperazino, N-(C,,-alkyl)-piperazino, N-phenyl- piperazino, C,.,-cycloalkenyleneimino group or by a C,,-CycC- loalkyleneimino group, whilst the abovementioned C._,-cycC- loalkyleneimino groups may be substituted by one or two

C, ,-alkyl groups, by a C,,-cycloalkyl or phenyl group, by a

C, ,-alkyl, C,,-cycloalkyl, phenyl, carboxy or C.,-alkoxy- carbonyl group and by a hydroxy group, the isomers and salts thereof.

Particularly preferred compounds of general formula I are ® those wherein R, to R; are as hereinbefore defined and R, is in the 5 position, particularly those compounds wherein

X denotes an oxygen atom,

R, denotes a hydrogen atom,

R, in the 5 position denotes an aminocarbonyl group,

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

R, denotes a hydrogen atom, a C, ;-alkyl group or a cyclo- pentyl or cyclohexyl group optionally substituted by a methyl group, whilst in the cyclohexyl group a methylene group in the 4 position in relation to the carbon atom of the R,-C(R,NR,) = group may be replaced by an imino group optionally substituted by a methyl group, a phenyl group which may be substituted by a fluorine, chlorine, bromine or iodine atom,

® by a methyl or ethyl group, which may in each case be substituted by a C,,;-alkylamino, di- (C,,-alkyl)-amino, thiomorpholino, 1l-oxido-thiomorpholino, 1,1l-dioxido-thio- morpholino, N-phenyl-piperazino, 5- tc 6-membered cyclo- alkenyleneimino group or by a 5- to 7-membered cyclcalky- leneimino group, whilst the abovementioned 5- to 7-membered cycloalkyleneimino groups may ke substituted by one cr two methyl groups, by a cyclohexyl or phenyl group, 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 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, methylamino or ethylamino group, each of which is additi- onally 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 fluo- rine, chlorine or brcmine atom or by a methyl, methoxy,

C 25 cyano, trifluoromethyl or nitro group or di- or tri- substituted 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 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, ,-alkyl group,

the isomers and the salts thereof.

Most particularly preferred compounds of general formula I are those wherein

X denotes an oxygen atom,

R, denotes a hydrcgen atom,

R, in the 5 position denotes an aminocarbonyl group, ® R, denotes a hydrogen atom or a C, ,-alkyl group,

R, denotes a phenyl group which may be substituted by a fluorine, chlorine, bromine or iodine atom, by a methyl or ethyl group, which may be substituted in each case by a C,,-alkylamino, di- (C,;-alkyl)-amino, thiomorpholino, 1l-oxido-thiomorpholino, 1,1-dioxido- thiomorphelino, N-phenyl-piperazino, 5- to 6-membered cycloalkenyleneimino group or by a 5- to 7-membered cyclo- alkyleneimino group, whilst the abovementioned 5- to 7- membered cycloalkyleneimino groups may be substituted by o 25 one or two methyl groups, by a cyclohexyl or phenyl group, 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 to 7-membered cycloalkyleneimino group, whilst additio- nally a phenyl ring is fused to the abovementioned cyclo- alkyleneimino groups via 2 adjacent carbon atoms, by a methyl or ethyl group substituted by an amino, 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 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 sub- stituents 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, ® and

R, denotes a hydrogen atom or a C, ,-alkyl group, the isomers and the salts thereof.

The following are mentioned as examples of particularly preferred compounds: (a) 3-z-[1-(4-piperidinomethyl-phenylamino)-1-methyl-methy- lene] -5-amido-2-indolinone, (b) 3-Z-[1-(4-bromo-phenylamino)-1l-methyl-methylene]-5- ® 25 amido-2-indolinone, (c) 3-Z-[1-(4-piperidinomethyl-phenylamino)-1-butyl- methylene] -5-amido-2-indolinone, (d) 3-Z2-[1-(4-chlorophenylamino)-1-methyl-methylene] -5- amido-2-indolinone and (e) 3-Z-(l-phenylamino-methylene)-5-amido-2-indolinone (f£) 3-Z2-[1-(4-(N-benzyl-N-methyl-aminomethyl) - phenylamino) -1-methyl-methylene] -5-amido-2-indolinone,

(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] -

1-methyl-methylene]-5-amido-2-indolinone, (1) 3-Z-[1-(4-(N-benzyl-aminomethyl) -phenylamino) -1- methyl -methylenel] -E-amido-2-indeolinocne,

(J) 3-2-[1-(4-(N-benzyl-N-methyl-aminomethyl) -phenyl- amino) -methylene] -5-amido-2-indolinone, (k) 3-2-[1-(4-(2,3,4,5-tetrahydro-benzo (d)azepin-3-yl- methyl) -phenylamino) -1-methyl-methylene] -5-amido-2-

indolinone, (1) 3-Z-{[1-(4-piperidincmethyl-3-nitro-phenylamino) - l1-methyl-methylene] -5-amido-2-indolinone and

(m) 3-Z-[1-(4-methyl-3-nitro-phenylamino)-1-methyl- methylene) -5-amido-2-indolinocne as well as the isomers and the salts thereof.

( 25 According to the invention, the new compounds may be ob- tained, for example, according to the following processes known in principle from the literature:

a. reacting a compound of general formula

®

Ry — z,

Nees (I1),

Rg wherein

X and R, are as hereinbefore defined,

R,' has the meanings given for R, hereinbefore, 5S R; denotes a hydrogen atom or a protecting group for the ® nitrogen atom of the lactam group, whilst one of the groups

R,' or R, may also denote a bond to a solid phase optionally formed via a spacer and the other group R,' or R, 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 or benzyloxy group, with an amine of general formula

J

H-N (111), ® ht wherein

R, and R, 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.

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

®

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 taking place via an intermediate member such as a 2,5-di- methoxy-4-hydroxy-benzyl derivative.

The reaction is appropriately carried cut in a solvent such as dimethylformamide, toluene, acetonitrile, tetrahydro- furan, dimethylsulphoxide, methylene chloride or mixtures thereof, optionally in the presence of an inert base such

C as triethylamine, N-ethyl-diisopropylamine or sodium hydrogen carbonate at temperatures between 20 and 175°C, whilst any protecting group used may be cleaved at the same time as a result of transamidation.

If Z, in a compound of general formula II denotes a ha- logen atom, the reaction is preferably carried out in the presence of an inert base at temperatures of between 20 and 120°C.

If Z, in a compound of general formula II denotes a hydroxy, alkoxy or aralkoxy group, the reaction is preferably carried out at temperatures between 20 and ® 25 200°C.

The subsequent cleaving of any protecting group used, if necessary, 1s appropriately carried out either hydrolyti- cally in an aqueous or alcoholic solvent, e.g. in metha- nol/water, ethanol/water, isopropanol/water, tetrahydro- furan/water, dioxan/water, dimethylformamide/water, metha- nol or ethanol in the presence of an alkali metal base such as lithium hydroxide, sodium hydroxide or potassium hydroxide at temperatures between 0 and 100°C, preferably at temperatures between 10 and 50°C,

or more advantageously by transamidation with an organic base such as ammonia, methylamine, butylamine, dimethyl- amine or piperidine in a solvent such as methanol, etha- nol, dimethylformamide and mixtures thereof or in an ex- cess of the amine used, at temperatures of between 0 and 100°C, preferably at temperatures between 10 and 50°C.

Any solid phase used is preferably cleaved by means of trifluorcacetic acid and water at temperatures of between 0 and 35°C, preferably at ambient temperatures. ( b. in order to prepare a compound of general formula I wherein R, denotes one of the abovementioned aminocarbonyl groups: amidating a compound of general formula

Ry

R,

Pe

N

~~

Rs

HO-CO o (IV), ® R, wherein R, and R, are as hereinbefore defined, or the reactive derivatives thereof, with an amine of general formula

H - (RNR) (V) wherein R, and R, which may be identical or different denote hydrogen atoms or C,.;-alkyl groups.

®

The amidation is preferably carried out in a solvent such as methylene chloride, diethyl ether, tetrahydrofuran, toluene, dioxan, acetonitrile, dimethylsulphoxide or di- methylformamide, optionally in the presence of an inor- ganic or tertiary organic base, preferably at temperatures between 20°C and the boiling temperature of the solvent used. The amidation is carried 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-dimethoxypro- pane, tetramethyloxysilane, thionylchloride, trimethyl- ® chlorosilane, phosphorus trichloride, phosphorus pentoxi- de, N,N'-dicyclohexylcarbodiimide, N,N'-dicyclohexylcar- bodiimide/N-hydroxysuccinimide, N,N'-dicyclohexylcarbo- diimide/l1-hydroxy-benzotriazole, 2-(1lH-benzotriazol-1-yl)- 1,1,3,3-tetramethyluronium tetrafluoroborate, 2-(1H-benzo- triazol-1-yl)-1,1,3,3-tetramethyluronium tetrafluorobo- rate/l-hydroxy-benzotriazole, N,N'-carbonyldiimidazole or triphenylphosphine/carbon tetrachloride, and optionally with the addition of a base such as pyridine, 4-dimethyl- aminopyridine, N-methylmorpholine or triethylamine, appro- priately at temperatures between 0 and 150°C, preferably at temperatures between 0 and 100°C, and the acylation is carried out with a corresponding reactive compound such as [ 25 the anhydride, ester, imidazolide or halide thereof, op- tionally in the presence of a tertiary organic base such as triethylamine, N-ethyldiisopropylamine or N-methylmor- pholine at temperatures between 0 and 150°C, preferably at temperatures between 50 and 100°C.

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 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 if a compound of general formula I is obtained which contains an amine or alkylamino group, this may be converted by acylaticn into a corresponding acyl compound, or 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 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.

The subsequent hydrolysis is preferably carried out in an aqueous solvent, e.g. in water, isopropancl/water, tetra- hydrofuran/water or dioxan/water, in the presence of an acid such as trifluorcacetic acid, hydrochloric acid or sulphuric acid or in the presence of an alkali metal base @ 25 such as lithium hydroxide, sodium hydroxide or potassium hydroxide at temperatures between 0 and 100°C, preferably at temperatures between 10 and 50°C.

The subsequent reductive alkylation is preferably carried out in a suitable solvent such as methanol, methanol/wa- ter, methanol/water/ammonia, ethanol ether, tetrahydrofu- ran, dioxan or dimethylformamide, optionally with the addition of an acid such as hydrochloric acid in the presence of catalytically activated hydrogen, e.g. hy- drogen in the presence of Raney nickel, platinum or palladium/charcoal, or in the presence of a metal hydride

® ~- 20 - such as sodium borohydride, lithium borohydride or lithium aluminium hydride at temperatures between 0 and 100°C, preferably at temperatures between 20 and 80°C.

The subsequent alkylation is carried out with an alkyla- ting agent such as an alkyl halide or dialkylsulphate such as methyl ilodide, dimethylsulphate or propyi bromide, pre- ferably in a solvent such as methanol, ethanol, methylene chloride, tetrahydrofuran, toluene, dioxan, dimethylsulph- oxide or dimethylformamide, optionally in the presence of an inorganic or tertiary organic base such as triethylami-

C ne, N-ethyl-diisopropylamine or dimethylaminopyridine, preferably at temperatures between 20°C and the boiling temperature of the sclvent used.

The subsequent acylation is preferably carried out in a solvent such as methylene chloride, diethyl ether, tetra- hydrofuran, toluene, dioxan, acetonitrile, dimethylsulph- oxide or dimethyl formamide, optionally in the presence of an lnorganic or tertiary organic base, preferably at tem- peratures between 20°C and the boiling temperature of the solvent used. The acylation is carried out with a cor- responding acid, preferably in the presence of a dehydra- ting agent, e.g. in the presence of isobutyl chlorofor- ® 25 mate, tetraethyl orthocarbonate, trimethyl orthoacetate, 2,2-dimethoxypropane, tetramethoxysilane, thionylchloride, trimethylchlorosilane, phosphorus trichloride, phosphorus pentoxide, N,N'-dicyclohexylcarbodiimide, N,N'-dicyclohe- xylcarbodiimide/N-hydroxysuccinimide, N,N'-dicyclohexyl- carbodiimide/1-hydroxy-benzotriazcle, 2- (1lH-benzotriazol- 1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate, 2- (1H- benzotriazol-1-vyl)-1,1,3,3-tetramethyluronium tetrafluo- roborate/l-hydroxy-benzotriazole, N,N'-carbonyldiimidazole or triphenylphosphine/carbon tetrachloride, and optionally with the addition of a base such as pyridine, 4-dimethyl- amino-pyridine, N-methylmorpholine or triethylamine,

® appropriately at temperatures of between 0 and 150°C, preferably at temperatures of between 0 and 100°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, N-ethyl-dilsopropylamine or N- methyl-morpholine at temperatures of between ¢ and 158°C, preferably at temperatures of between 50 and 100 C.

The subsequent esterification or amidation is appropri- ately carried out by reacting a corresponding reactive @® carboxylic acid derivative with a corresponding alcohol or amine as described hereinbefore.

The subsegent reduction of a nitro group is preferably carried out by hydrogenclysis, 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 ace- tate, dimethylformamide, dimethylformamide/acetone or gla- cial acetic acid, optionally with the addition of an acid such as hydrochloric acid or glacial acetic acid at tempe- ratures between 0 and 50°C, but preferably at ambient tem- perature, 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 conven- tional protecting groups which are cleaved again after the reaction.

For example, a protecting group for a carboxy group may be a trimethylsilyl, methyl, ethyl, tert.butyl, benzyl or tetrahydropyranyl group and

® protecting groups for an amino, alkylamino or imino group may be an acetyl, trifluorocacetyl, benzoyl, ethoxycar- bonyl, tert.butoxycarbonyl, benzyloxycarbonyl, benzyl, methoxybenzyl or 2,4-dimethoxybenzyl group and additionally, for the amino group, a phthalyl group.

Any protecting group used is optionally subsequentlwv cleaved for example by hydrolysis in an agueocus solvent, e.g. in water, isopropancl/water, tetrahydrofuran/water or dioxan/water, in the presence of an acid such as trifluo- roacetic acid, hydrochloric acid or sulphuric acid or in ® the presence of an alkali metal base such as lithium hydroxide, sodium- hydroxide or potassium hydroxide, at temperatures between 0 and 100°C, preferably at tempera- tures between 10 and 5C°C.

However, a benzyl, methoxybenzyl or benzyloxycarbonyl 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, dimethylform- amide/acetone or glacial acetic acid, optionally with the addition of an acid such as hydrochloric acid or glacial acetic acid at temperatures between 0 and 50°C, but pre- ( 25 ferably at ambient temperature, and at a hydrogen pressure of 1 to 7 bar, but preferably 3 to 5 bar.

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 acetconitrile/water at temperatures of between 0 and 50°C, preferably at ambient temperature.

A 2,4-dimethoxybenzyl group, however, is preferably cleaved in trifluoroacetic acid in the presence of anisole.

®

A tert.butyl or tert.butyloxycarbonyl group is preferably cleaved by treating with an acid such as trifluoroacetic 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 hydrazine or a primary amine such as methylamine, ethyl- amine or n-butylamine in a solvent such as methanci, ethanol, isopropanol, toluene/water or dioxan at tempera- tures between 20 and 50°C. ® Moreover, chiral compounds of general formula I obtained may be resolved into their enantiomers and/or diastere- omers.

Thus, for example, the compounds of general formula I 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 Inter- science, 1971) into their optical antipodes and compounds of general formula I with at least 2 asymmetric carbon atoms may be resolved into their diastereomers on the basis of their physical-chemical differences using methods ® 25 known per se, e.g. by chromatography and/or fractional crystallisation, and, if these compounds are obtained in racemic form, they may subsequently be resolved into the enantiomers as mentioned above.

The enantiomers are preferably separated by column sepa- ration on chiral phases or by recrystallisation from an optically active solvent or by reacting with an optically active substance which forms salts or derivatives such as e.g. esters or amides with the racemic compound, parti- cularly acids and the activated derivatives or alcohols thereof, and separating the diastereomeric mixture of salts or derivatives thus obtained, e.g. on the basis of their differences in solubility, whilst the free antipodes may be released from the pure diastereomeric 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-tolyltar- taric acid, malic acid, mandelic acid, 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 (-)-men- ® thyloxycarbonyl group.

Furthermore, the compounds of formula I may be converted into the salts thereof, particularly for pharmaceutical use into the physiclogically acceptable salts with in- organic or organic acids. Acids which may be used for this purpose include for example hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid, fumaric acid, suc- cinic acid, lactic acid, citric acid, tartaric acid, ma- leic or methanesulphonic acid.

Moreover, if the new compounds of formula I contain a carboxy group, they may subsequently, if desired, be ® 25 converted into the salts thereof with inorganic or organic bases, particularly for pharmaceutical use into the physiologically acceptable salts thereof. Suitable bases 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 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, denotes a hydrogen atom or a prodrug group have valuable pharmacological properties, particularly an inhibitory effect on various kinases and cycline/CDK complexes, on the proliferation of cultivated human tumour cells and, when administered orally, on the growth of tumours in nude mice which have been infected with human tumour cells.

For example, the compounds listed in Table 1 were tested for their biological properties as follows: ® Test 1

Iphibition of cycline/CDK enzyme, in vitro activity

High Five™ insect cells (BTI-TN-5B1-4) which had been in- fected with a high titre of recombinant baculovirus were used to produce active human cycline/CDK holoenzymes. By 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 ho- ( 25 loenzyme was isolated by affinity chromatography on glu- tathione sepharose. Recombinant GST-tagged pRB (aa 379- 928) was produced in E. coli and purified by affinity chromatography on glutathione sepharose.

The substrates used for the kinase assays depended on the specific kinases. Histone Hl (Sigma) was used as the substrate for cycline E/CDK2, cycline A/CDK2, cycline

B/CDK1 and for v-cycline/CDKé6. GST-tagged pRB (aa 379- 928) was used as substrate for cycline D1/CDK4, cycline

D3/CDK4, cycline D1/CDKé6 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 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°C.

The substrate proteins with associated radicactivity 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.

After the addition of scintillation liquid the radiocacti- ® vity was measured in a Wallace 1450 Microbeta Liquid Scin- tillation Counter. For each concentration of the substance double measurements were carried out; IC, values were cal- culated for the enzyme inhibiticn.

Test 2 cells

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 o 25 non-essential amino acids (Gibco), supplemented with 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 incubator. Various concentrations of the compounds (dissolved in DMSO; final concentration: <1%) were added to the cells. After 48 hours' incubation *C-thymidine (Amersham) was added to each well and incubation was continued for a further 24 hours. The quantity of C- 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 Mi- crobeta Liquid Scintillation Counter. IC,, values for the inhibition of proliferation (= inhibition of incorporated 'C-thymidine) were calculated, correcting for the back- ground radiation. All the measurements were done twice.

Test 3

In vivo effects on tumour-bearing nude mice ® 10° 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 fragments of SK-UT-1B cr NCI-H460 cell clumps were im- planted subcutaneously. One to three weeks after the injection or implantation a kinase inhibitor was admi- nistered daily by oral route for a period of 2 to 4 weeks (by oesophageal tube). The size of the tumour was mea- sured 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. ® 25

Table 2 which follows contains the results obtained in in vitro test 2:

_

Compound Inhibition of SKUT (example no.) -1B proliferation

IC,, [:M] 1(11) 0.032 1(8) | 0.060 1(26) 5.036 103) 5-040 ° 1(105) 0.019 1(110) g.020

In view of their biological properties, the new compounds of general formula I, their isomers and physiologically acceptable salts are suitable for the treatment of diseases characterised by excessive or abnormal cell proliferation. o Such diseases include (with no claim to completeness): 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 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 treatment.

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 such as other cytostatics.

The dosage required tc achieve such an effect is appropri- ately 0.1 to 30 mg/kg, preferably 0.3 to 10 mg/kg by in- travenous route, and 0.1 to 100 mg/kg, preferably 0.3 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. with corn starch, lactose, glucose, microcrystalline cellulose, magnesium stearate, polyvinylpyrrolidone, cit- ric acid, tartaric acid, water, water/ethanol, water/gly- cerol, water/sorbitol, water/polyethylene glycol, propy- lene glycol, cetylstearyl alcohol, 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:

®

Example T 10.5 g of methyl 2-indolinone-5-carboxylate (prepared 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°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 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)

Example TT

Methyl l-acetyl-3-(l-ethoxy-1l-butyl-methylene]-2- indo inone-5-carboxylate 11 g of methyl l-acetyl-2-indolinone-5-carboxylate are stirred in 110 ml of acetic anhydride and 30 ml of triethyl orthovalerate for 2 hours at 100°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)

The following compounds are prepared analogously to

Example II: (1) methyl l-acetyl-3-(l-ethoxy-methylene]-2-indolinone-s5- carboxylate

Prepared from methyl l-acetyl-2-indolinocne-5-carboxylate and trimethyl orthoformate

® (2) methyl l-acetyl-3-(l-ethoxy-l-methyl-methylene]-2- indolinone-5-carboxylate

Prepared from methyl l-acetyl-2-indolinone-5-carboxylate and triethyl orthoacetate (3) methyl l-acetyl-3-(l-ethoxy-l-ethvl-methvlene] -2- indeclincne-5-carboxylate

Prepared from methyl l-acetyl-2-indolinone-5-carboxylate and triethyl orthopropionate ® Example TTT 28.0 g of Rink resin (MBHA resin made by Novobiochem) were allowed to swell in 330 m of dimethylformamide. Then 330 ml of 30% piperidine in dimethyl formamide were added and the mixture was shaken for 7 minutes to cleave the 9H- flucren-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 analogously to Ogawa, Hidenori et al., Chem. Pharm. Bull 36, 2253-2258 (1988)), 5.6 g of hydroxybenzotriazole, 13.3 g of O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate and 5.7 ml of N-ethyl-diisopropylamine o 25 in 300 ml of dimethylformamide were added and the mixture was shaken for 1 hour. The solution was suction filtered and the resin was washed five times with 300 ml of dime- thylformamide and three times with 300 ml of methylene chloride. To dry it, nitrogen was blown through the resin.

Yield: 20 g of charged resin

Example IV 0.4 g of the charged resin prepared in Example III were stirred with 2.5 ml of acetic anhydride at 90°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°C.

Then the resin was suction filtered and washed with dimethylformamide, methanol and finally with methylene chloride.

Yield: 0.6 g of moist resin

The following charged resins were prepared analogously to

Example IV: ) (1) resin charged with 3-Z- (l-ethoxy-methylene)-5-amido-2- indolinone by reacting the product of Example I and triethyl orthoformate (2) resin charged with 3-Z- (1-methoxy-1l-methyl-methylene) - 5-amido-2-indolinone by reacting the product of Example I and trimethyl orthoformate (3) resin charged with 3-Z- (l1-methoxy-l-ethyl-methylene) -5- amido-2-indolinone by reacting the product of Example I and trimethyl orthopropionate (4) resin charged with 3-Z- (1-methoxy-1l-propyl-methylene) -

C 25 5-amido-2-indolinone by reacting the product of Example I and trimethyl orthobutyrate (5) resin charged with 3-Z- (1l-methoxy-l-ethenyl-methylene) - 5-amido-2-indolinone by reacting the product of Example I and 3,3,3-triethoxyprop-l-ene (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- (1-methoxy-1- (2-phenylsulphonyl- ethyl) -methylene) -5-amido-2-indolinone by reacting the product of Example I and triethyl 3-phenylsulphonyl- orthopropionate

Example V 4 — (N-FErhy! -aminomet hyl) -nitrobenzene 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 hy- droxide solution. Then the organic phase is concentrated by evaporation.

Yield: 2.3 g (46 % of theory),

R; value: 0.20 (silica gel, methylene chloride/methanol = 9:1)

The following compounds are prepared analogously to

Example V: 4- [N- (4-chlorophenyl-methyl) -aminomethyl] -nitrobenzene ® = 4- (N-cyclohexyl-aminomethyl) -nitrobenzene 4- (N-isopropyl-aminomethyl) -nitrockbenzene 4- (N-butyl-aminomethyl) -nitrobenzene 4 - (N-methexycarbonylmethyl-aminomethyl) ~nitrobenzene 4- (N-benzyl-aminomethyl) -nitrobenzene 4- (pyrrolidino-methyl) -nitrobenzene

Claims (13)

nN Patent Claims

1. Substituted indolinones of general formula

Rr. E KR oe TN ~~ Rs R, /~—X (I), N R, wherein X denotes an oxygen or sulphur atom, R, denctes a hydrogen atom, a C,.,~alkoxy-carbonyl or

C,.s-alkanoyl group, R, denotes a carboxy or C, ,-alkoxy-carbonyl group or an aminocarbonyl group optionally substituted by one or two

C,.;-alkyl groups, whilst the substituents may be identical

{ . or different, R; denotes a hydrogen atom or a C, .-alkyl group which may

} . be substituted, at the 2,3,4,5 or 6 position, in relation to the carbon atom of the R,-C{(R,NR,)= group by a fluorine, chlorine or bromine atom, by a hydroxy, C,.,-alkoxy, C,.;-alkylsulphenyl, Cy;-alkylsulphinyl, C,;-alkylsulphonyl, phenylsulphenyl, phenylsulphinyl, phenylsulphonyl, amino, C, ,-alkylamino, di-(C, ;-alkyl) -amino, C, -alkanoylaminoc or N- (C,_;-alkylamino) -C, .-alkanoylamino group, AMENDED SHEET

R, denotes a hydrogen atom, a C, ,-alkyl group or a C.,-Cyc- loalkyl group optionally substituted by a C,.;-alkyl group wherein a methylene group in the 3 or 4 position in rela- tion to the carbon atom of the R,-C(R,NR.)= group may be substituted by an imino group optionally substituted by a

C,.;-alkyl group, a phenyl or naphthyl group which may be substituted by a fluorine, chlorine, bromine or iodine atom, ® by a methoxy group optionally substituted by 1 to 3 fluorine atoms, by a C, ,-alkoxy which may be substituted in the 2 or 3 position by a C,_ j;-alkylamino, di-(C,,;-alkyl)-aminoc or 5- to 7-membered cycloalkyleneimino group, whilst additio- nally an alkyl moiety in the abovementioned alkylamino and dialkylamino groups may be substituted by a phenyl group, by a trifluoromethyl, amino, C, ,-alkylamino, di- (C,;-alkyl) -amino, C, -alkanoylamino, N-(C, ,-alkyl)-

C,.s-alkanoylamino, C, -alkylsulphonylamino, N-(C, ,-alkyl) -

Ci.s-alkylsulphonylamino, phenylsulphonylamino, N-(C, ,-al- o 25 kyl) -phenylsulphonylamino, aminosulphonyl, C,,-alkylamino- sulphonyl or di-(C, ;-alkyl) -aminosulphonyl group, whilst additionally an alkyl moiety in the abovementioned alkyl- amino and dialkylamino groups may be substituted by a phenyl group, by a carbonyl group which is substituted by a hydroxy, C, ;-alkoxy, amino, C, j-alkylamino or N-(C, -alkyl) -

C,.;-alkylamino group, whilst additionally an alkyl moiety in the abovementioned groups may be substituted by a carb- oxy, C,.;-alkoxycarbonyl or phenyl group or in the 2 or 3 position by a di-(C,,;-alkyl)-amino, piperazino,

® - 102 - N-(C,;-alkyl)-piperazino or 5- to 7-membered cyc- loalkyleneimino group, by a C,;-alkyl group which is substituted by an amino, C, ,-alkylamino, C, ,-cycloalkylamino, C;.,-cycloalkyl-

C..;-alkylamino or phenyl-C, ;-alkylamino group which may additionally be substituted at the amino nitrogen atom by a C. ;-alkyl group wherein the hydrogen atoms are wholly or partially replaced by fluorine atoms, by a

Cs.,-cycloalkyl, C,,-alkenyl or C,,-alkyl group, whilst [ the abovementioned C, ,-alkyl substituent may in each case be additionally mono, di- or trisubstituted by a cyano, carboxy, C,;-alkoxycarbonyl, pyridyl, imidazolyl, benzo[l,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 substituted in the 2, 3 or 4 position by a hydroxy group, by a C,;-alkyl group which may be substituted by a hydroxy, carboxy, thiomorpholino, l-oxido- ® 25 thiomorpholino, 1,1l-dioxideo-thiomorpholino, piperazino, N- (C, ,-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 groups may be substituted by one or two C, -alkyl groups, by a Cs ,-cycloalkyl or phenyl group, by a

C,.;-alkyl, C,,-cycloalkyl, phenyl, carboxy or

C,.,-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,

by a C,;-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 differant, or an oxazolo, imidazole, thiazcle, pyridinc, pyrazine cr py- rimidino 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 7-membered cycloalkyleneimino groups via two adjacent ® carbon atoms, 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 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 6 -membered heteroaromatic groups may additionally be sub- ( 25 stituted 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 R, denotes a hydrogen atom or a C, ,-alkyl group whilst any carboxy, amino or imino groups present may be substituted by groups which can be cleaved in vivo, the isomers and salts thereof.

2. Substituted indolinones of general formula I according to claim 1, wherein X denotes an oxygen atom,

R, denotes a hydrogen atom, R, denotes an aminccarbonyl group, R; denotes a hydrogen atom or a C, ,-alkyl group which may be substituted, at the 2,3,4,5 or 6 position, in relation to the carbon ( atom of the R,-C(RNR,)= group, by a chlorine or bromine atom or by a phenylsulphonyl group,

R, denotes a hydrogen atom, a C,,-alkyl group or a cyclo- pentyl or cyclohexyl group cptionally substituted by a methyl group, whilst in the cyclopentyl and cyclchexyl group a methylene group in the 3 or 4 position in relation to the carbon atom of the R,-C(R,NR;)= group may be replaced 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,;-alkoxy which is substituted in the 2 or 3 position by methylamino, dimethylamino or 5- to 7-mem- bered cycloalkyleneimino group, whilst additionally a methyl group in the abovementioned amino groups may be substituted by a phenyl group, by a trifluoromethyl, amino, C,,-alkancylamino, N-(C, ;-alkyl) -C, ;-alkanoylamino, AMENDED SHEET

®

Ci.s-alkylsulphonylamino, N-(C,,-alkyl)-C, .-al- kylsulphonylamino, phenylsulphonylamino, N-(C,,-alkyl)- phenylsulphonylamino or aminosulphonyl group, whilst additionally an alkyl moiety in the abovementioned al- kylamino and dialkylamino groups may be substituted by a vhenyl group, by a carbonyl group which is substituted by a hydroxy,

C..;-alkoxy, amino, C,,-alkylamino or N-(C, .-alkyl) -

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

C,.;-alkylamino or phenyl-C, ;-alkylamino group which may additionally be substituted at the amino nitrogen atom by a C, ;-alkyl group wherein the hydrogen atoms are wholly or partially replaced by fluorine atoms, by a

Cs.,-cycloalkyl, C,,-alkenyl or C,,-alkyl group, whilst o 25 the abovementioned C, ,-alkyl substituent may in each case be additionally substituted by a cyano, carboxy, C,;-alkoxycarbonyl, pyridyl, imidazolyl, benzol[l,3]di- oxole or phenyl group, wherein the phenyl group may be monosubstituted by a fluorine, chlorine or bromine atom or by a methyl, 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 dif- ferent, or may be substituted in the 2, 3 or 4 posi- tion by a hydroxy group,

® by a C, ;-alkyl group which may be substituted by a hydroxy, carboxy, thiomorpholino, 1l-oxido-thiomor- pholino, 1,1l-dioxido-thiomorpholino, piperazino, N-(C,;,-alkyl) -piperazino or N-phenyl-piperazino group,

by a 5- to 7-membered cycloalkenyleneimino group or by a 4- to 7-membered cyclcalkyleneimino group, wherein the abovementioned 5- to 7-membered cycloalkvleneiminc groups may be substituted by cone or two C, ,-alkyl groups, by a cyclohexyl or phenyl group, by a C,,-alkyl,

cyclohexyl, phenyl, carboxy or C, ,-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,

by a C, ;-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 py-

razino or thiazolo group, optionally substituted by an amino group, may be fused to the abovementioned 5- to 7- membered cycloalkyleneimino groups via two adjacent carbon atoms,

C 25 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 pyridyl group optionally substituted by a chlorine or bromine atom or by a methyl group,

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

Ry; denotes a hydrogen atom or a C,.;-alkyl group, the isomers and the salts thereof.

3. Substituted indolinones of general formula I according to claim 2, wherein R; is in the 5 position, the isomers and the salts thereof.

(

4. Substituted indolinones of general formula I according to claim 1, wherein X denotes an oxygen atom, R, denotes a hydrogen atom, R, in the 5 position denotes an aminocarbonyl group, R, denotes a hydrogen atom or a C,,-alkyl group which may be terminally substituted by a chlorine or bromine atom or by a phenylsulphonyl group, { 25 R, denotes a hydrogen atom, a Ci.s-alkyl group or a cyclo- pentyl or cyclohexyl group optionally substituted by a methyl group, whilst in the cyclohexyl group a methylene group in the 4 position in relation to the carbon atom of © the R,-C(R,NR;) = group may be replaced by an imino group optionally substituted by a methyl group, a phenyl group which may be substituted by a fluorine, chlorine, bromine or iodine atom, oo by a methyl or ethyl group, which may in each case be AMENDED SHEET

® substituted by a C, ;-alkylamino, di- (C, ,-alkyl)-amino, thiomorpholino, 1l-oxido-thiomorpholino, 1,1-dioxido-thio- morpholino, N-phenyl-piperazino, 5- to 6-membered cycloal- kenyleneimino group or by a 5- to 7-membered cycloalkylene- imino 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 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 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 additio- nally 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 fluo- rine, chlorine or bromine atom or by a methyl, methoxy, cyano, trifluoromethyl or nitro group or di- or trisub- stituted by fluorine, chlorine or bromine atoms or by ® 25 methyl or methoxy groups, and the 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, and R, denotes a hydrogen atom or a C,_,-alkyl group, the isomers and the salts thereof.

5. Substituted indolinones of general formula I according to claim 1, wherein X denotes an oxygen atom,

R, denotes a hydrogen atom, R, in the 5 position denotes an aminocarbonyl group,

RR; denotes a hydrogen atom or a C,,-alkyl group,

® R, denotes a phenyl group which may be substituted by a fluorine, chlorine, bromine or iodine atom,

by a methyl or ethyl group, which may be substituted in each case by a C,;-alkylamino, di-(C, ,-alkyl)-amino, thiomorpholino, 1l-oxido-thiomorpholino, 1,1-dioxido- thiomorpholino, N-phenyl-piperazino, 5- to 6-membered cyc-

loalkenyleneimino group or by a 5- to 7-membered cycloalky- leneimino 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 group,

o 25 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 additio-

nally a phenyl ring is fused to the abovementioned cyclo- alkyleneimino groups via 2 adjacent carbon atoms, by a methyl or ethyl group substituted by an amino, methylamino or ethylamino group, each of which is addi-

tionally 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 trisubstituted by methyl or methoxy groups, and the sub- stituents 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, and ® R; denotes a hydrogen atom or a C, ,-alkyl group, the isomers and the salts thereof.

6. The following substituted indolinones of general formula I according to claim 1: (a) 3-Z-[1-(4-piperidinomethyl-phenylamino) -1-methyl-methy- lene] -5-amido-2-indolinone, (b) 3-2-[1-(4-bromo-phenylamino)-1l-methyl-methylene]-5- amido-2-indolinone, (c) 3-Z-[1- (4-piperidinomethyl-phenylamino) -1-butyl- ® methylene] -5-amido-2-indolinone, (d) 3-2-[1- (4-chlorophenylamino) -1-methyl-methylene] -5- amido-2-indolinone and (e) 3-Z-(l-phenylamino-methylene)-5-amido-2-indolinone (£) 3-2-[1-(4-(N-benzyl-N-methyl-aminomethyl) - phenylamino) -1-methyl-methylene] -5-amido-2-indolinone, (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] - l1-methyl-methylene] -5-amido-2-indolinone, (1) 3-Z-[1-(4-(N-benzyl-aminomethyl) -phenylamino) -1- methyl -methylene] -5-amido-2-indolinone, (Jj) 3-2-[1-(4-(N-benzyl-N-methyl-aminomethyl) - phenylamino) -methylene] -5-amido-2-indolinone, (k) 3-2-[1-(4-(2,3,4,5-tetrahydro-benzo (d) azepin-3-yl- ® methyl) -phenylamino) -1-methyl-methylenel] -5-amido-2- indolinone, (1) 3-Z-[1-(4-piperidinomethyl-3-nitro-phenylamino) - l-methyl-methylene] -5-amido-2-indolinone and (m) 3-Z-[1-(4-methyl-3-nitro-phenylamino)-1-methyl- methylene) -5-amido-2-indolinone as well as the isomers and the salts thereof.

7. 3-2Z-[1-(4- (N-Benzyl-N-methyl-aminomethyl) - phenylamino) -1-methyl-methylene] -5-amido-2-indolinone and C 25 the salts thereof.

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

9. Physiologically acceptable salts of the compounds according to claims 1 to 8.

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.

11. Use of a compound according to at least one of claims 1 to 8 or a salt according to claim 9 for preparing a pharmaceutical composition which is suitable for trea- ting excessive or anomalous cell proliferation.

12. Process for preparing a pharmaceutical composition 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.

13. Process for preparing the compounds according to claims 1 to 9, characterised in that a. a compound of general formula i Z, ® Te Rg wherein X and R, are defined as in claims 1 to 8, R,' has the meanings given for R. in claims 1 to 8, Rg denotes a hydrogen atom or a protecting group for the nitrogen atom of the lactam group, whilst one of the groups R,' or R, may also denote a bond to a solid phase optionally formed via a spacer and the other group R,' or R, is as he- reinbefore defined, and

Z, denotes a halogen atom, a hydroxy, alkoxy or aralkoxy group, is reacted with an amine of general formula J H - SN (111), R, wherein R, and R; are defined as in claims 1 to 8, and if necessary any protecting group used for the nitrogen o 10 atom of the lactam group is cleaved or a compound thus obtained is cleaved from a solid phase, or b. in order to prepare a compound of general formula I wherein R, denotes one of the aminocarbonyl groups mentioned in claims 1 to 8, a compound of general formula R, ®, ~~ — N ~~ Rg HO-CO 0 (IV), ® hs wherein R, and R, are defined as in claims 1 to 6, or a reactive derivative thereof, is amidated with an amine of general formula H - (R,NR,) (Vv) wherein R, and Ry; which may be identical or different denote hydrogen atoms or C,_;-alkyl groups, and

® subsequently, if desired, a compound of general formula I thus obtained which contains an alkoxycarbonyl group may be converted by hydrolysis into a corresponding carboxy compound, or a compound of general formula I thus obtained which con- tains an amino or alkylamino group may be converted by alkylation or reductive alkylation into a corresponding alkylamino or dialkylamino compound, or ® a compound of general formula I thus obtained which con- tains an amino or alkylamino group may be converted by acylation into a corresponding acyl compound, or a compound of general formula I thus obtained which con- tains a carboxy group may be converted by esterification or amidation into a corresponding ester or aminocarbonyl compound, or a compound of general formula I thus obtained which con- tains a nitro group is converted by reduction into a corresponding amino compound, or [ 25 if necessary any protecting group used during the reac- tions to protect reactive groups is cleaved, or a compound of general formula I thus obtained is resolved into the stereoisomers thereof, or a compound of general formula I thus obtained is converted into the salts thereof, more particularly, for pharmaceu- tical use, into the physiologically acceptable salts thereof with an inorganic or organic acid or base.