Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
1999-06-01
2001-11-20
Higel, Floyd D. (Department: 1626)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C540S523000, C548S486000, C514S418000
Reexamination Certificate
active
06319918
ABSTRACT:
DESCRIPTION OF THE INVENTION
The present invention relates to new substituted indolinones of general formula
the isomers 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, particularly an inhibitory effect on various kinases, particularly on 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 viral cycline (cf. L. Mengtao in J. Virology 71 (3), 1984-1991 (1997)), and the other compounds of the above general formula I wherein R
1
does not represent 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 the compounds wherein R
1
denotes a hydrogen atom or a prodrug group have 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 or C
1-4
-alkoxy-carbonyl group or an aminocarbonyl group optionally substituted by one or two C
1-3
-alkyl groups, whilst the substituents may be identical or different,
R
3
denotes a hydrogen atom or a C
1-6
-alkyl group which may be substituted at the 2 position, in relation to the carbon atom of the R
3
—C(R
4
NR
5
)=group by a fluorine, chlorine or bromine atom, by a hydroxy, C
1-3
-alkoxy, C
1-3
-alkylsulphenyl, C
1-3
-alkylsulphinyl, C
1-3
-alkylsulphonyl, phenylsulphenyl, phenylsulphinyl, phenylsulphonyl, 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 hydrogen atom, a C
1-6
-alkyl group or a C
5-7
-cycloalkyl group optionally substituted by a C
1-3
-alkyl group wherein a methylene group in the 3 or 4 position in relation to the carbon atom of the R
3
—C(R
4
NR
5
)=group may be substituted by an imino group optionally substituted by a C
1-3
-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
2-3
-alkoxy which may be substituted in the 2 or 3 position by a C
1-3
-alkylamino, di-(C
1-3
-alkyl)-amino or 5- to 7-membered cycloalkyleneimino group, whilst additionally an alkyl moiety in the abovementioned alkylamino and dialkylamino groups may be substituted by a phenyl group,
by a trifluoromethyl, 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, whilst additionally an alkyl moiety 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
1-3
-alkoxy, amino, C
1-3
-alkylamino or N—(C
1-5
-alkyl)-C
1-3
-alkylamino group, whilst additionally an alkyl moiety in the abovementioned groups may be substituted by a carboxy, C
1-3
-alkoxycarbonyl or phenyl group or in the 2 or 3 position by a di-(C
1-3
-alkyl)-amino, piperazino, N—(C
1-3
-alkyl)-piperazino or 5- to 7-membered cycloalkyleneimino group,
by a C
1-3
-alkyl group which is substituted by an amino, C
1-7
-alkylamino, C
5-7
-cycloalkylamino, C
5-7
-cycloalkyl-C
1-3
-alkylamino or phenyl-C
1-3
-alkylamino group which may additionally be substituted at the amino nitrogen atom by a C
1-3
-alkyl group wherein the hydrogen atoms are wholly or partially replaced by fluorine atoms, by a C
5-7
-cycloalkyl, C
2-4
-alkenyl or C
1-4
-alkyl group, whilst
the abovementioned C
1-4
-alkyl substituent may in each case be additionally mono-, di- or trisubstituted by a cyano, carboxy, C
1-3
-alkoxycarbonyl, pyridyl, imidazolyl, benzo[1,3]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
1-3
-alkyl group which may be substituted by a hydroxy, carboxy, thiomorpholino, 1-oxido-thiomorpholino, 1,1-dioxido-thiomorpholino, piperazino, N—(C
1-3
-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
1-3
-alkyl groups, by a C
5-7
-cycloalkyl or phenyl group, by a C
1-3
-alkyl, C
5-7
-cycloalkyl, phenyl, carboxy or C
1-4
-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
1-3
-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 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 substituted 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
5
denotes a hydrogen atom or a C
1-3
-alkyl group.
Furthermore, the carboxy, amino or imino groups present in a compound of the above general formula I may be substituted by groups which can be cleaved in vivo.
In addition to the alkoxycarbonyl and alkanoyl groups already mentioned above, groups which can be cleaved in vivo include an acyl group such as the benzoyl, pyridinoyl, pentanoyl or hexanoyl group, an allyloxycarbonyl group, a C
1-16
-alkoxycarbonyl group such as the pentoxycarbonyl, hexyloxycarbonyl, octyloxycarbonyl, nonyloxycarbonyl, decyloxycarbonyl, undecyloxycarbonyl, dodecyloxycarbonyl or hexadecyloxycarbonyl group, a phenyl-C
1-6-
alkoxycarbonyl group such as the benzyloxycarbonyl, phenylethoxycarbonyl or phenylpropoxycarbonyl group, a C
1-3
-alkylsulphonyl-C
2-4
-alkoxycarbonyl, C
1-3
-alkoxy-C
2-4
-alkoxy-C
2-4
-alkoxycarbonyl or R
c
CO—O—(R
d
CR
e
)—O—CO-group wherein
R
c
denotes a C
1-8
-alkyl, C
5-7
-cycloalkyl, phenyl or phenyl-C
1-3
-alkyl group,
R
e
denotes a hydrogen atom, a C
1-3
-alkyl, C
5-7
-cycloalkyl or phenyl group and
R
d
denotes a hydrogen atom or a C
1-3
-alkyl group or the R
c
CO—O—(R
d
CR
e
)—O-group,
whilst the abovementioned ester groups may also be used as a group which can be converted in vivo into a carboxy group.
Preferred compounds of general formula I, however, are those wherein
X denotes an oxygen atom,
R
1
denotes a hydrogen atom,
R
2
denotes an aminocarbonyl group,
R
3
denotes a hydrogen atom or a C
1-4
-alkyl group which may be substituted, at th
Grell Wolfgang
Heckel Armin
Redemann Norbert
van Meel Jacobus C. A.
Walter Rainer
Boehringer Ingelheim Pharma KG
Devlin Mary-Ellen M.
Higel Floyd D.
Raymond Robert P.
Sackey Ebenezer
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