Substituted indolinones, their manufacture and their use as...

Details Substituted indolinones, their manufacture and their use as... Substituted indolinones, their manufacture and their use as...

2002-07-22

2004-09-21

Solola, Taofiq (Department: 1626)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

C514S418000, C546S201000, C548S486000

Reexamination Certificate

active

06794395

ABSTRACT:

The present invention relates to new substituted indolinones of general formula
the isomers thereof, the salts thereof, particularly the physiologically acceptable salts thereof which have valuable properties.
The above compounds of general formula I wherein R
4
denotes a hydrogen atom or a prodrug group have valuable pharmacological properties, in particular an inhibiting effect on various kinases, especially receptor tyrosine kinases such as VEGFR2, PDGFR&agr;, PDGFR&bgr;, FGFR1, FGFR3, EGFR, HER2, IGF1R and HGFR, as well as complexes of CDK's (Cycline Dependent Kinases) such as CDK1, CDK2, CDK3, CDK4, CDK5, 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 to viral cycline (cf. L. Mengtao in J. Virology 71 (3), 1984-1991 (1997)), to the proliferation of cultivated human cells, in particular endothelial cells, e.g. in angiogenesis, but also to the proliferation of other cells, in particular tumour cells.
The other compounds of the above general formula I wherein R
4
does not denote a hydrogen atom or a prodrug group are valuable intermediate products for preparing the abovementioned compounds.
The present invention thus relates to the above compounds of general formula I, whilst those compounds wherein R
4
denotes a hydrogen atom or a prodrug group have valuable pharmacological properties, pharmaceutical compositions containing the pharmacologically active compounds, the use thereof and processes for preparing them.
In the above general formula I
X denotes an oxygen or sulphur atom,
R
1
denotes a C
2-3
-alkenyl, C
2-3
-alkynyl, aryl, aryl-C
1-3
-alkyl, heteroaryl, heteroaryl-C
1-3
-alkyl, trifluoromethyl or cyano group,
a hydroxy, C
1-3
-alkoxy, hydroxy-C
1-3
-alkyl, C
1-3
-alkoxy-C
1-3
-alkyl, aryloxy or heteroaryloxy group,
a mercapto, C
1-3
-alkylsulphenyl, phenylsulphenyl, benzylsulphenyl, C
1-3
-alkylsulphinyl, phenylsulphinyl, benzylsulphinyl, C
1-3
-alkylsulphonyl, phenylsulphonyl, benzylsulphonyl, sulpho, C
1-3
-alkoxysulphonyl, phenoxysulphonyl or benzyloxysulphonyl group,
an amino, C
1-3
-alkylamino, di-(C
1-3
-alkyl)-amino, hydroxycarbonyl-C
1-3
-alkylamino, N—(C
1-3
-alkyl)-hydroxycarbonyl-C
1-3
-alkylamino, C
1-3
-alkoxycarbonyl-C
1-3
-alkylamino, N—(C
1-3
-alkyl)-C
1-3
-alkoxycarbonyl-C
1-3
-alkylamino, phenylamino, N-phenyl-C
1-3
-alkylamino, N,N-diphenylamino, benzylamino, N-benzyl-C
1-3
-alkylamino, N,N-dibenzylamino, C
1-3
-alkylcarbonylamino, benzoylamino or benzylcarbonylamino group or an N—(C
1-3
-alkyl)-C
1-3
-alkylcarbonylamino group wherein the two alkyl groups may be replaced by a C
2-5
-n-alkylene bridge or wherein one or both alkyl groups may be replaced by a phenyl or benzyl group,
a C
1-3
-alkylsulphonylamino, phenylsulphonylamino or benzylsulphonylamino group or an N—(C
1-3
-alkyl)-C
1-3
-alkylsulphonylamino group wherein the two alkyl groups may be replaced by a C
2-5
-n-alkylene bridge or wherein one or both alkyl groups may be replaced by a phenyl or benzyl group,
an aminosulphonyl, C
1-3
-alkylaminosulphonyl, phenylaminosulphonyl, benzylaminosulphonyl, di-(C
1-3
-alkyl)-aminosulphonyl, oN,N-diphenyl-aminosulphonyl or N,N-dibenzyl-aminosulphonyl group,
a phosphono, (C
1-3
-alkoxy)PO(H), (C
1-3
-alkoxy)PO(C
1-3
-alkyl), (C
1-3
-alkoxy)PO(OH), di-(C
1-3
-alkoxy)-PO or (C
2-4
-n-alkylenedioxy)-PO group,
a ureido group optionally mono-, di- or trisubstituted by C
1-3
-alkyl groups,
a 4- to 7-membered cycloalkyleneimino or cycloalkyleneiminosulphonyl group, wherein in each case the methylene group in the 4 position of a 6- or 7-membered cycloalkyleneimino group may be replaced by an oxygen or sulphur atom, by a sulphinyl, sulphonyl, —NH or —N(C
1-3
-alkyl) group,
R
2
denotes a hydrogen, fluorine, chlorine, bromine or iodine atom,
a C
1-6
-alkyl or trifluoromethyl group,
a hydroxy, C
1-3
-alkoxy, mercapto, C
1-3
-alkylsulphenyl, C
1-3
-alkylsulphinyl, C
1-3
-alkylsulphonyl, sulpho, C
1-3
-alkoxysulphonyl, aminosulphonyl, C
1-3
-alkylaminosulphonyl or di-(C
1-3
-alkyl)-aminosulphonyl group,
a nitro, amino, C
1-3
-alkylamino or di-(C
1-3
-alkyl)-amino group,
a C
1-3
-alkylcarbonyl, cyano, carboxy, C
1-3
-alkoxycarbonyl, aminocarbonyl, C
1-3
-alkylaminocarbonyl or di-(C
1-3
-alkyl)-aminocarbonyl group,
a phosphono, (C
1-3
-alkoxy)PO(H), (C
1-3
-alkoxy)PO(C
1-3
-alkyl), (C
1-3
-alkoxy)PO(OH) or di-(C
1-3
-alkoxy)-PO group,
a 4- to 7-membered cycloalkyleneimino, cycloalkyleneiminocarbonyl or cycloalkyleneiminosulphonyl group, wherein in each case the methylene group in the 4 position of a 6- or 7-membered cycloalkyleneimino group may be replaced by an oxygen or sulphur atom, by a sulphinyl, sulphonyl, —NH or —N(C
1-3
-alkyl) group, or
R
1
and R
2
together denote a methylenedioxy, ethylenedioxy, n-propylene, n-butylene or 1,4-butadienylene group,
R
3
denotes a hydrogen atom, denotes a C
1-6
-alkyl, C
3-7
-cycloalkyl, trifluoromethyl or heteroaryl group,
a phenyl or naphthyl group optionally mono- or disubstituted by a fluorine, chlorine, bromine or iodine atom, by a trifluoromethyl, C
1-3
-alkyl or C
1-3
-alkoxy group, whilst in the case of disubstitution the substituents may be identical or different, which may additionally be substituted
by a hydroxy, hydroxy-C
1-3
-alkyl or C
1-3
-alkoxy-C
1-3
-alkyl group,
by a cyano, cyano-C
1-3
-alkyl, cyano-C
2-3
-alkenyl, cyano-C
2-3
-alkynyl, carboxy, carboxy-C
1-3
-alkyl, carboxy-C
2-3
-alkenyl, carboxy-C
2-3
-alkynyl, C
1-3
-alkoxycarbonyl, C
1-3
-alkoxycarbonyl-C
1-3
-alkyl, C
1-3
-alkoxycarbonyl-C
2-3
-alkenyl or C
1-3
-alkoxycarbonyl-C
2-3
-alkynyl group,
by a C
1-3
-alkylcarbonyl, C
1-3
-alkylcarbonyl-C
1-3
-alkyl, C
1-3
-alkylcarbonyl-C
2-3
-alkenyl or C
1-3
-alkylcarbonyl-C
2-3
-alkynyl group,
by an aminocarbonyl, aminocarbonyl-C
1-3
-alkyl, aminocarbonyl-C
2-3
-alkenyl, aminocarbonyl-C
2-3
-alkynyl, C
1-3
-alkylaminocarbonyl, C
1-3
-alkylaminocarbonyl-C
1-3
-alkyl, C
1-3
-alkylaminocarbonyl-C
2-3
-alkenyl, C
1-3
-alkylaminocarbonyl-C
2-3
-alkynyl, di-(C
1-3
-alkyl)-aminocarbonyl, di-(C
1-3
-alkyl)-aminocarbonyl-C
1-3
-alkyl, di-(C
1-3
-alkyl)-aminocarbonyl-C
2-3
-alkenyl or di-(C
1-3
-alkyl)-aminocarbonyl-C
2-3
-alkynyl group,
by a nitro, nitro-C
1-3
-alkyl, nitro-C
2-3
-alkenyl or nitro-C
2-3
-alkynyl group,
by an amino, C
1-3
-alkylamino, di-(C
1-3
-alkyl)-amino, amino-C
1-3
-alkyl, C
1-3
-alkylamino-C
1-3
-alkyl or di-(C
1-3
-alkyl)-amino-C
1-3
-alkyl group,
by a C
1-3
-alkylcarbonylamino, C
1-3
-alkylcarbonylamino-C
1-3
-alkyl, N—(C
1-3
-alkyl)-C
1-3
-alkylcarbonylamino, N—(C
1-3
-alkyl)-C
1-3
-alkylcarbonylamino-C
1-3
-alkyl, C
1-3
-alkylsulphonylamino, C
1-3
-alkylsulphonylamino-C
1-3
-alkyl, N—(C
1-3
-alkyl)-C
1-3
-alkylsulphonylamino or N—(C
1-3
-alkyl)-C
1-3
-alkylsulphonylamino-C
1-3
-alkyl group,
by a 4- to 7-membered cycloalkyleneimino, cycloalkyleneiminocarbonyl, cycloalkyleneiminosulphonyl, cycloalkyleneimino-C
1-3
-alkyl, cycloalkyleneiminocarbonyl-C
1-3
-alkyl or cycloalkyleneiminosulphonyl-C
1-3
-alkyl group, wherein in each case the methylene group in the 4 position of a 6- or 7-membered cycloalkyleneimino group may be replaced by an oxygen or sulphur atom, by a sulphinyl, sulphonyl, —NH or —N(C
1-3
-alkyl) group,
or by a heteroaryl or heteroaryl-C
1-3
-alkyl group,
R
4
denotes a hydrogen atom, a C
1-3
-alkyl group or a prodrug group,
R
5
denotes a hydrogen atom or a C
1-3
-alkyl group and
R
6
denotes a hydrogen, fluorine, chlorine, bromine or iodine atom,
a trifluoromethyl or heteroaryl group, a C
1-3
-alkoxy group optionally substituted by 1 to 3 fluorine atoms, an amino-C
1-3
-alkoxy, C
1-3
-alkylamino-C
2-3
-alkoxy or benzylamino-C
2-3
-alkoxy group, a cycloalkyleneimino-C
2-3
-alkoxy group with 4 to 7 ring members, a di-(C
1-3
-alkyl)-amino-C
2-3
-alkoxy or C
1-3
-alkylmercapto group,
a nitro, cyano, carboxy, C
1-3
-alkoxycarbonyl, aminocarbonyl, C
1-3
-alkylaminocarbonyl, di-(C
1-3
-alkyl)-aminocarbonyl, piperidinocarbonyl or tetrazolyl group,
a C
1-3
-alkylcarbonylamino group optionally substituted at the nitrogen-atom by a C
1-3
-alkyl group,
an imidazolyl or piperazino group optionally substituted

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