Substituted indolines which inhibit receptor tyrosine kinases

Details Substituted indolines which inhibit receptor tyrosine kinases Substituted indolines which inhibit receptor tyrosine kinases

2000-10-03

2004-07-13

Raymond, Richard L. (Department: 1624)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Heterocyclic carbon compounds containing a hetero ring...

C544S373000, C544S144000, C544S058200, C514S254090, C514S323000, C514S418000, C514S235200, C514S414000, C546S201000, C548S486000, C548S467000

Reexamination Certificate

active

06762180

ABSTRACT:

FIELD OF THE INVENTION
The present invention relates to novel indolinones that inhibit receptor tyrosine kinases, their use as pharmaceuticals, particularly in the treatment of proliferative diseases, and pharmaceutical compositions comprising these compounds.
DESCRIPTION OF THE INVENTION
The present invention provides new indolinones of general formula
substituted in the 6 position, the tautomers, the diastereomers, the enantiomers, the mixtures thereof and the salts thereof, particularly the 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 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 (Cyclin Dependent Kinases) such as CDK1, CDK2, CDK3, CDK4, CDK5, CDK6, CDK7, CDK8 and CDK9 with their specific cyclins (A, B1, B2, C, D1, D2, D3, E, F, G1, G2, H, I and K) and to viral cyclin (cf. L. Mengtao in J. Virology 71(3), 1984-1991 (1997)), and on the proliferation of cultivated human cells, in particular endothelial cells, e.g. in angiogenesis, but also on the proliferation of other cells, in particular tumour cells.
The other compounds of the above general formula I wherein R
1
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, whereby those compounds wherein R
1
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 hydrogen atom or a prodrug group such as a C
1-4
-alkoxycarbonyl or C
2-4
-alkanoyl group,
R
2
denotes a carboxy group, a straight-chain or branched C
1-6
-alkoxy-carbonyl group, a C
4-7
-cycloalkoxy-carbonyl or an aryloxycarbonyl group,
a straight-chain or branched C
1-6
-alkoxy-carbonyl group, which is terminally substituted in the alkyl moiety by a phenyl, heteroaryl, carboxy, C
1-3
-alkoxy-carbonyl, aminocarbonyl, C
1-3
-alkylamino-carbonyl or di-(C
1-3
-alkyl)-aminocarbonyl group,
a straight-chain or branched C
2-6
-alkoxy-carbonyl group, which is terminally substituted in the alkyl moiety by a chlorine atom or a hydroxy, C
1-3
-alkoxy, amino, C
1-3
-alkylamino or di-(C
1-3
-alkyl)-amino group,
an aminocarbonyl or methylaminocarbonyl group, an ethylaminocarbonyl group optionally substituted in the 2 position of the ethyl group by a hydroxy or C
1-3
-alkoxy group or, if R
4
does not denote an aminosulphonyl-phenyl or N—(C
1-5
-alkyl)-C
1-3
-alkylaminocarbonyl-phenyl group, it may also denote a di-(C
1-2
-alkyl)-aminocarbonyl group,
R
3
denotes a hydrogen atom, a C
1-6
-alkyl, C
3-7
-cycloalkyl, trifluoromethyl or heteroaryl group,
a phenyl or naphthyl group, a phenyl or naphthyl group 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 event of disubstitution the substituents may be identical or different and wherein the abovementioned unsubstituted as well as the mono- and disubstituted phenyl and naphthyl groups 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, carboxy, carboxy-C
1-3
-alkyl, C
1-3
-alkoxycarbonyl, aminocarbonyl, C
1-3
-alkylamino-carbonyl or di-(C
1-3
-alkyl)-aminocarbonyl group,
by a nitro group,
by an amino, C
1-3
-alkylamino, di-(C
1-3
-alkyl)-amino or amino-C
1-3
-alkyl group,
by a C
1-3
-alkylcarbonylamino, N—(C
1-3
-alkyl)-C
1-3
-alkyl-carbonylamino, C
1-3
-alkylcarbonylamino-C
1-3
-alkyl, N—(C
1-3
-alkyl)-C
1-3
-alkylcarbonylamino-C
1-3
-alkyl, C
1-3
-alkyl-sulphonylamino,
C
1-3
-alkylsulphonylamino-C
1-3
-alkyl, N—(C
1-3
-alkyl)-C
1-3
-alkylsulphonylamino-C
1-3
-alkyl or aryl-C
1-3
-alkylsulphonylamino group,
by a cycloalkylamino, cycloalkyleneimino, cycloalkyleneiminocarbonyl, cycloalkyleneimino-C
1-3
-alkyl, cycloalkyleneiminocarbonyl-C
1-3
-alkyl or cycloalkyleneiminosulphonyl-C
1-3
-alkyl group having 4 to 7 ring members in each case, whilst in each case the methylene group in position 4 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 C
3-7
-cycloalkyl group,
whilst the methylene group in the 4 position of a 6- or 7-membered cycloalkyl group may be substituted by an amino, C
1-3
-alkylamino or di-(C
1-3
-alkyl)-amino group or replaced by an —NH or —N(C
1-3
-alkyl) group,
or a phenyl group substituted by the group R
6
, which may additionally be mono- or disubstituted by fluorine, chlorine, bromine or iodine atoms, by C
1-5
-alkyl, trifluoromethyl, hydroxy, C
1-3
-alkoxy, carboxy, C
1-3
-alkoxycarbonyl, amino, acetylamino, C
1-3
-alkyl-sulphonylamnino, aminocarbonyl, C
1-3
-alkyl-aminocarbonyl, di-(C
1-3
-alkyl)-aminocarbonyl, aminosulphonyl, C
1-3
-alkyl-aminosulphonyl, di-(C
1-3
-alkyl)-aminosulphonyl, nitro or cyano groups, wherein the substituents may be identical or different and wherein
R
6
denotes a hydrogen, fluorine, chlorine, bromine or iodine atom,
a cyano, nitro, amino, C
1-5
-alkyl, C
3-7
-cycloalkyl, trifluoromethyl, phenyl, tetrazolyl or heteroaryl group,
the group of formula
wherein the hydrogen atoms bound to a nitrogen atom may in each case be replaced independently of one another by a C
1-3
-alkyl group,
a C
1-3
-alkoxy group, a C
1-3
-alkoxy-C
1-3
-alkoxy, phenyl-C
1-3
-alkoxy, amino-C
2-3
-alkoxy, C
1-3
-alkylamino-C
2-3
-alkoxy, di-(C
1-3
-alkyl)-amino-C
2-3
-alkoxy, phenyl-C
1-3
-alkylamino-C
2-3
-alkoxy, N—(C
1-3
-alkyl)-phenyl-C
1-3
-alkylamino-C
2-3
-alkoxy, C
5-7
-cycloalkyleneimino-C
2-3
-alkoxy or C
1-3
-alkylmercapto group,
a carboxy, C
1-4
-alkoxycarbonyl, aminocarbonyl, C
1-3
-alkylamino-carbonyl, N—(C
1-5
-alkyl)-C
1-3
-alkylaminocarbonyl, phenyl-C
1-3
-alkylamino-carbonyl, N—(C
1-3
-alkyl)-phenyl-C
1-3
-alkylamino-carbonyl, piperazinocarbonyl or N—(C
1-3
-alkyl)-piperazinocarbonyl group,
a C
1-3
-alkylaminocarbonyl or N—(C
1-5
-alkyl)-C
1-3
-alkylaminocarbonyl group wherein an alkyl moiety is substituted by a carboxy or C
1-3
-alkoxycarbonyl group or in the 2 or 3 position by a di-(C
1-3
-alkyl)amino, piperazino, N—(C
1-3
-alkyl)-piperazino or a 4- to 7-membered cycloalkyleneimino group,
a C
3-7
-cycloalkyl-carbonyl group,
wherein the methylene group in the 4 position of the 6- or 7-membered cycloalkyl moiety may be substituted by an amino, C
1-3
-alkylamino or di-(C
1-3
-alkyl)-amino group or replaced by an —NH or —N(C
1-3
-alkyl) group,
a 4- to 7-membered cycloalkyleneimino group wherein
a methylene group linked to the imino group may be replaced by a carbonyl or sulphonyl group or
the cycloalkylene moiety may be fused to a phenyl ring or
one or two hydrogen atoms may each be replaced by a C
1-3
-alkyl group and/or
in each case the methylene group in the 4 position of a 6- or 7-membered cycloalkyleneimino group may be substituted by a carboxy, C
1-3
-alkoxycarbonyl, aminocarbonyl, C
1-3
-alkylaminocarbonyl, di-(C
1-3
-alkyl)-aminocarbonyl, phenyl-C
1-3
-alkylamino or N—(C
1-3
-alkyl)-phenyl-C
1-3
-alkylamino group or
may be replaced by an oxygen or sulphur atom, by a sulphinyl, sulphonyl, —NH, —N(C
1-3
-alkyl), —N(phenyl), —N(C
1-3
-alkyl-carbonyl) or —N(benzoyl) group,
a C
1-4
-alkyl group substituted by the group R
7
, wherein
R
7
denotes a C
3-7
-cycloalkyl group,
whilst the methylene group in the 4 position of a 6- or 7-membered cycloalkyl group may be substituted by an amino, C
1-3
-alkylamino or di-(C
1-3
-alkyl)-amino group or replaced by an —NH or —N(C
1-3
-alkyl) group or
in a 5- to 7-membered cycloalkyl group a —(CH
2
)
2
group may be replaced by

Affiliated with

Also associated with

Rating

Substituted indolines which inhibit receptor tyrosine kinases does not yet have a rating. At this time, there are no reviews or comments for this patent.

If you have personal experience with Substituted indolines which inhibit receptor tyrosine kinases, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Substituted indolines which inhibit receptor tyrosine kinases will most certainly appreciate the feedback.

Rate now

Comments { 0 }

Profile ID: LFUS-PAI-O-3239672