Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2001-11-01
2003-10-28
McKane, Joseph K. (Department: 1626)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C548S486000
Reexamination Certificate
active
06638965
ABSTRACT:
DESCRIPTION OF THE INVENTION
The present invention relates to new substituted indolinones of general formula
the isomers, the salts thereof, particularly the physiologically acceptable salts thereof which have valuable properties.
The above compounds of general formula I wherein R
1
is a hydrogen atom or a prodrug group have valuable pharmacological properties, particularly an inhibiting effect on the proliferation of cultivated human tumour cells, but also on the proliferation of other cells, particularly endothelial cells, e.g. in angiogenesis, on various kinases, particularly on receptor tyrosine kinases (such as, for example, VEGFR2, EGFR, IGF1R), non-receptor tyrosine kinases (such as e.g. c-src), and serine/threonine kinases (such as e.g. cyclin-dependent kinases), and 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 the preparation of the compounds mentioned above.
The present invention thus relates to the above compounds of general formula I, wherein
X denotes an oxygen or sulphur atom,
R
1
denotes a hydrogen atom, a C
1-4
-alkoxycarbonyl or C
2-4
-alkanoyl group,
R
2
denotes a C
1-6
-alkyl group optionally substituted by one or more halogen atoms or a phenyl group or a C
2-6
-alkenyl group optionally substituted by a phenyl group, wherein the phenyl moiety may be substituted in each case by a fluorine, chlorine, bromine or iodine atom, by a C
1-3
-alkyl or C
1-3
-alkoxy group,
a phenyl group which may be mono- or disubstituted by fluorine, chlorine, bromine or iodine atoms, by C
1-3
-alkyl or C
1-3
-alkoxy groups, wherein the substituents may be identical or different,
a phenyl group substituted by a trifluoromethyl, carboxy, C
1-3
-alkoxycarbonyl, aminocarbonyl, cyano, aminomethyl, nitro or amino group,
a C
4-6
-alkyl, C
3-7
-cycloalkyl, trimethylphenyl or naphthyl group,
a 5-membered heteroaromatic group optionally substituted by a C
1-3
-alkyl group, which contains, in the heteroaromatic moiety,
an imino group optionally substituted by a C
1-3
-alkyl group, an oxygen or sulphur atom,
an imino group optionally substituted by a C
1-3
-alkyl group and an oxygen, sulphur or nitrogen atom,
an imino group optionally substituted by a C
1-3
-alkyl group and two nitrogen atoms, or an oxygen or sulphur atom and two nitrogen atoms, and to which a phenyl ring may be fused via two adjacent carbon atoms,
or denotes a 6-membered heteroaromatic group optionally substituted by a C
1-3
-alkyl group, which contains one or two heteroatoms in the heteroaromatic moiety and to which a phenyl ring may be fused via two adjacent carbon atoms,
R
3
denotes a hydrogen atom or a C
1-6
-alkyl group, a phenyl group optionally substituted by a fluorine, chlorine or bromine atom, by a C
1-3
-alkyl, hydroxy, C
1-3
-alkoxy, C
1-3
-alkylsulphenyl, C
1-3
-alkylsulphinyl, C
1-3
-alkylsulphonyl, phenylsulphenyl, phenylsulphinyl, phenylsulphonyl, nitro, amino, C
1-3
-alkylamino, di-(C
1-3
-alkyl)-amino, C
2-5
-alkanoylamino or N-(C
1-3
-alkylamino)-C
2-5
-alkanoylamino group,
R
4
denotes a phenyl or naphthyl group optionally substituted by R
7
, which may additionally be substituted by a chlorine or bromine atom or a 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, while the abovementioned 5- and 6-membered heteroaromatic groups may additionally be substituted by a chlorine or bromine atom or by a methyl group or wherein a phenyl ring may be fused to the abovementioned 5- and 6-membered heteroaromatic groups via 2 adjacent carbon atoms, or
R
5
and R
6
in each case independently of one another denote hydrogen atoms or C
1-3
-alkyl groups, and
R
7
denotes a fluorine, chlorine, bromine or iodine atom or a cyano group,
a methoxy group or a C
2-3
-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 or 5- to 7-membered cycloalkyleneimino group, while in each case an alkyl moiety in the abovementioned alkylamino and dialkylamino groups may additionally be substituted by a phenyl group, a trifluoromethyl, nitro, amino, C
1-3
-alkylamino, di-(C
1-3
-alkyl)-amino, C
2-5
-alkanoylamino, N-(C
1-3
-alkyl)-C
2-5
-alkanoylamino, C
1-5
-alkylsulphonylamino, N-(C
1-3
-alkyl)-C
1-5
-alkylsulphonylamino, phenylsulphonylamino, N-(C
1-3
-alkyl)-phenylsulphonylamino, aminosulphonyl, C
1-3
-alkylaminosulphonyl or di-(C
1-3
-alkyl)-aminosulphonyl group, while in each case an alkyl moiety in the abovementioned alkylamino and dialkylamino groups may additionally be substituted by a carboxy, C
1-3
-alkoxycarbonyl, aminocarbonyl, C
1-3
-alkylaminocarbonyl, di-(C
1-3
-alkyl)-aminocarbonyl, 2-dimethylaminoethylaminocarbonyl or N-methyl-(2-dimethylaminoethyl)-aminocarbonyl group and in each case the alkyl moiety of the abovementioned alkanoylamino or alkysulphonylamino groups may additionally be substituted by a phenyl, amino, C
1-3
-alkylamino, di-(C
1-3
-alkyl)-amino or a 4- to 7-membered cycloalkyleneimino group,
a C
2-4
-alkylamino group which is terminally substituted in the 2, 3- or 4 position by an amino, C
1-3
-alkylamino, di-(C
1-3
-alkyl)-amino, benzylamino, N-(C
1-3
-alkyl)-benzylamino, C
2-5
-alkanoylamino or N-(C
1-3
-alkyl)-C
2-5
-alkanoylamino group and wherein additionally the amino-hydrogen atom may be replaced by a C
2-5
-alkanoyl, benzoyl, C
1-5
-alkylsulphonyl- or phenylsulphonyl group, while the last-mentioned C
2-5
-alkanoyl or C
1-5
-alkylsulphonyl groups in the alkyl moiety may be substituted by a phenyl group,
a carbonyl group which is substituted by a hydroxy, C
1-3
-alkoxy, amino, C
1-3
-alkylamino, N-(C
1-5
-alkyl)-C
1-3
-alkylamino or C
5-7
-cycloalkyleneimino group;
a C
1-3
-alkyl group which may be substituted by an amino, C
1-5
-alkylamino, C
5-7
-cycloalkylamino or phenyl-C
1-3
-alkylamino group which may additionally be substituted at the amino nitrogen atom in each case by a C
1-4
-alkyl, C
5-7
-cycloalkyl or C
2-4
-alkenyl- or C
1-4
-alkyl group, while the abovementioned C
1-4
-alkyl substituent in each case may additionally be mono-, di- or trisubstituted by a cyano, carboxy, C
1-3
-alkoxycarbonyl, C
2-4
-alkanoyl, pyridyl, imidazolyl, benzo[1,3]dioxol or phenyl group, while 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 in the 2, 3 or 4 position by a hydroxy group,
a C
1-3
-alkyl group which is substituted by a hydroxy, carboxy, morpholino, thiomorpholino, 1-oxo-thiomorpholino, 1,1-dioxo-thiomorpholino, piperazino, N-(C
1-3
-alkyl)-piperazino or N-benzyl-piperazino group, by a 5- to 7-membered cycloalkenyleneimino group or by a 4- to 7-membered cycloalkyleneimino group, while the abovementioned 5- to 7-membered cycloalkyleneimino groups may be substituted by one or two C
1-3
-alkyl groups, which may in turn be terminally substituted by a hydroxy, amino or C
2-4
-alkanoylamino group, or by a C
5-7
-cycloalkyl or phenyl 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,
a C
1-3
-alkyl group which is substituted by a 5- to 7-membered cycloalkyleneimino group, while 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, by a methyl, methoxy or amino group is fused to the abovementioned 5- to 7-membered cycloalkyleneimino groups via 2 adjacent carbon atoms, while the abovementioned monosubstituted phenyl groups may additionally be substituted by a fluorine, chlorine or bromine atom, by
Heckel Armin
Kley Joerg
Lenter Martin
Roth Gerald
Schnapp Gisela
Anderson Rebecca
Boehringer Ingelheim Pharma KG
Devlin Mary-Ellen M.
McKane Joseph K.
Raymond Robert P.
LandOfFree
Substituted indolinones, preparation thereof and their use... 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 indolinones, preparation thereof and their use..., we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Substituted indolinones, preparation thereof and their use... will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-3147650