Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Utility Patent
1999-04-06
2001-01-02
Shah, Mukund J. (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S418000, C514S414000, C548S452000, C548S468000
Utility Patent
active
06169106
ABSTRACT:
DESCRIPTION OF THE INVENTION
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
1
, denotes a hydrogen atom or a prodrug group have valuable pharmacological properties, particularly an inhibiting effect on various kinases, especially 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 on viral cycline (cf. L. Mengtao in J. Virology 71(3), 1984-1991 (1997)), and the other compounds of the above general formula I wherein R1 does not represent a hydrogen atom or a prodrug group are valuable intermediate products for preparing the abovementioned compounds.
Thus, the present invention relates to the above compounds of general formula I (the compounds wherein R1 denotes a hydrogen atom or A prodrug group having valuable pharmacological properties), the pharmaceutical compositions 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
1
denotes a hydrogen atom, a C
1-4
-alkoxy-carbonyl or C
2-4
-alkanoyl group,
R
2
denotes a carboxy-, C
1-4
-alkoxy-carbonyl or aminocarbonyl group wherein the amino moiety may be substituted by one or two C
1-3
-alkyl groups and the substituents may be identical or different,
R
3
denotes a phenyl or naphthyl group which may be substituted by fluorine, chlorine or bromine atoms, by C
1-3
-alkyl, C
1-3
-alkoxy, cyano, trifluoromethyl, nitro, amino, C
1-3
-alkylamino, di-(C
1-3
-alkyl) -amino, C
2-4
-alkanoyl-amino, N-(C
1-3
-alkyl)-C
2-4
-alkanoylamino, N-(C
1-3
-alkyl)-C
2-4
-alkanoylamino, C
1-3
-alkylsulphonylamino, amino-C
1-3
-alkyl, C
1-3
-alkylamino-C
1-3
-alkyl, di-(C
1-3
-alkyl)-amino-C
1-3
-alkyl, N-(C
2-4
-alkanoyl)-amino-C
1-3
-alkyl or N-(C
2-4
-alkanoyl)-C
1-3
-alkylamino-C
1-3
-alkyl groups and the substituents may be identical or different,
R
4
denotes a hydrogen atom or a C
1-3
-alkyl group and
R
5
denotes a hydrogen atom,
a C
1-5
-alkyl group optionally substituted by a phenyl, carboxy or C
1-3
-alkoxy-carbonyl group,
a C
3-7
-cycloalkyl group optionally substituted by a C
1-3
-alkyl group,
an indanyl group optionally substituted by a C
1-3
-aikyl group,
a 5-membered heteroaryl group which contains an imino group optionally substituted by a C
1-3
-alkyl group, an oxygen or sulphur atom or an imino group optionally substituted by a C
1-3
-alkyl group and an oxygen, sulphur or nitrogen atom or two nitrogen atoms or a 6-membered heteroaryl group which contains 1 to 3 nitrogen atoms, whilst additionally a 1,3-butadienylene bridge may be attached via two adjacent carbon atoms or via one carbon atom and an adjacent imino group of the abovementioned 5- and 6-membered heteroaryl groups and the carbon skeleton of the abovementioned mono- and bicyclic rings may be mono or disubstituted by fluorine, chlorine, bromine or iodine atoms, by C
1-5
-alkyl or cyano groups and the substituents may be identical or different,
a pyrrolidinyl or piperidinyl group linked via a carbon atom, which may be substituted at the nitrogen atom by a C
1-3
-alkyl group,
a phenyl group optionally disubstituted by fluorine, chlorine, bromine or iodine atoms, by C
1-5
-alkyl, C
1-3
-alkoxy, carboxy, C
1-3
-alkoxycarbonyl, aminosulphonyl, nitro or cyano groups, whilst the substituents may be identical or different,
a phenyl, pyridyl, pyrimidyl or thienyl group each of which is substituted by a trifluoromethoxy group,
by a fluorine, chlorine, bromine or iodine atom, by a C
1-3
-alkoxy group which may be substituted in the 2- or 3- position by an amino, C
1-3
-alkylamino, di-(C
1-3
-alkyl)amino, phenyl-C
1-3
-alkylamino, N-(C
1-3
-alkyl)-phenyl-C
1-3
-alkylamino, pyrrolidino or piperidino group,
by a phenyl-C
1-3
-alkylamino-C
1-3
-alkyl group which may be mono- or disubstituted in the phenyl nucleus by a trifluoromethyl group, by fluorine, chlorine, bromine or iodine atoms, by C
1-5
-alkyl or C
1-3
-alkoxy groups, whilst the substituents may be identical or different, and additionally may be replaced at the amine nitrogen atom by a C
1-3
-alkyl group wherein the hydrogen atoms from position 2 may be wholly or partially replaced by fluorine atoms,
by a C
1-5
-alkyl, phenyl, imidazolyl, C
3-7
-cycloalkyl, C
1-3
-alkoxy-C
1-3
-alkoxy, phenyl-C
1-3
-alkoxy, carboxy-C
1-3
-alkyl, C
1-3
-alkoxycarbonyl-C
1-3
-alkyl, carboxy, C
1-3
-alkoxycarbonyl, aminocarbonyl, C
1-3
-alkylaminocarbonyl, di-(C
1-3
-alkyl)-aminocarbonyl, phenyl-C
1-3
-alkylaminocarbonyl, N-(C
1-3
-alkyl)-phenyl-C
1-3
-alkylaminocarbonyl, piperazinocarbonyl, N-(C
1-3
-alkyl)- piperazinocarbonyl, nitro, amino, C
1-3
-alkylamino, di-(C
1-3
-alkyl)-amino, pyrrolidino, piperidino, morpholino, C
2-4
-alkanoyl-amino, N-(C
1-3
-alkyl)-C
2-4
-alkanoylamino, benzoylamino or N-(C
1-3
-alkyl)-benzoylamino group,
by an N-(C
1-3
-alkyl)-C
2-4
-alkanoylamino group which is additionally substituted in the alkyl moiety by a carboxy or C
1-3
-alko)xycarbonyl group,
by a C
1-3
-alkylaminocarbonyl or di-(C
1-3
-alkyl)-aminocarbonyl group wherein an alkyl moiety is additionally substituted by a di-(C
1-3
-alkyl)-amino group, or
by an N-(C
1-3
-alkyl)-C
1-3
-alkylsulphonylamino or N-(C
1-3
-alkyl)-phenylsulphonylamino group wherein the alkyl moiety may additionally be substituted by a cyano, carboxy, C
1-3
-alkoxycarbonyl, C
1-3
-alkylamino, di-(C
1-3
-alkyl)-amino group, eminocarbonyl, C
1-3
-alkylaminocarbonyl, di-(C
1-3
-alkyl)-aminocarbonyl, piperidinocarbonyl or 2-[di-(C
1-3
-alkylamino)]-ethylaminocarbonyl group,
a phenyl or thienyl group substituted by a C
1-3
-alkyl group wherein the alkyl moiety is substituted by a hydroxy, C
1-3
-alkoxy, carboxy, C
1-3
-alkoxy-carbonyl, amino, C
1-5
alkylamino, di-(C
1-5
-alkyl)-amino, C
2-4
-alkanoylamino, N-(C
1-3
-alkyl)-C
2-4
-alkanoylamino, pyrrolidino, dehydropyrrolidino, piperidino, dehydropiperidino, 3-hydroxypiperidino, 4-hydroxypiperidino, hexamethyleneimino, morpholino, thiomorpholino, piperazino, 4-(C
1-3
-alkyl)-piperazino, 4-phenyl-piperazino, 4-(C
2-4
-alkanoyl)-piperazino, 4-benzoyl-piperazino or imidazolyl group,
whilst the abovementioned saturated cycloalkyleneimino rings, C
1-5
-alkylamino or di-(C
1-5
-alkyl)-amino groups may additionally be substituted by one or two C
1-5
-alkyl groups, by a C
3-7
-cycloalkyl, hydroxy, C
1-3
-alkoxy, carboxy, C
1-3
-alkoxycarbonyl, aminocarbonyl, C
1-3
-alkylaminocarbonyl or di-(C
1-3
-alkyl)-aminocarbonyl group, by a phenyl-C
1-3
-alkyl or phenyl group optionally mono- or disubstituted in the phenyl nucleus by fluorine, chlorine, bromine or iodine atoms or by C
1-3
-alkyl or cyano groups, whilst the substituents may be identical or different,
or a methylene group adjacent to the nitrogen atom in the abovementioned cycloalkyleneimino rings may be replaced by a carbonyl or sulphonyl group, and the abovementioned monosubstituted phenyl groups may additionally be substituted by a fluorine, chlorine or bromine atom or by a methyl, amino, C
1-3
-alkylamino or di-(C
1-3
-alkyl-amino group, or
a phenyl ring optionally substituted by one or two C
1-3
-alkoxy groups may be fused to one of the abovementioned unsubstituted cycloalkyleneimino rings via two adjacent carbon atoms.
The carboxy groups mentioned in the definition of the groups above may also be replaced by a group which can be converted in vivo into a carboxy group and
the amino and imino groups mentioned in the definition of the groups above may also be replaced by a group which can be cleaved in vivo.
Moreover, the saturated alkyl and alkoxy moieties mentioned in the above definition containing more than 2 carbon atoms also include the branched isomers thereof, such as, for example, the isopropyl, tert.butyl, isobutyl group, etc.
Preferred compounds of general formula I are those wherein
X denotes an oxygen or sulphur atom,
R
1
denotes a hydrogen atom, a
Grell Wolfgang
Heckel Armin
Redemann Norbert
van Meel Jacobus C. A.
Walter Rainer
Boehringer Ingelheim Pharma KG
Devlin M-E M.
Patel Sudhaker B.
Raymond R. P.
Shah Mukund J.
LandOfFree
Indolinones having kinase inhibitory activity does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Indolinones having kinase inhibitory activity, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Indolinones having kinase inhibitory activity will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-2526649