Aminoquinazolines and their use as medicaments

Details Aminoquinazolines and their use as medicaments Aminoquinazolines and their use as medicaments

2001-08-23

2003-09-09

Shah, Mukund J. (Department: 1624)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Heterocyclic carbon compounds containing a hetero ring...

C514S252150, C514S252170, C514S227800, C514S234800, C514S211150, C540S596000, C544S061000, C544S111000, C544S115000, C544S119000, C544S284000, C544S293000

Reexamination Certificate

active

06617329

ABSTRACT:

DESCRIPTION OF THE INVENTION
The present invention relates to bicyclic heterocycles of general formula
the tautomers, the stereoisomers and the salts thereof, particularly the physiologically acceptable salts thereof with inorganic or organic acids or bases which have valuable pharmacological properties, particularly an inhibitory effect on signal transduction mediated by tyrosine kinases, the use thereof for treating diseases, particularly tumoral diseases, diseases of the lungs and respiratory tract, and the preparation thereof.
In the above general formula I
X denotes a methyne group substituted by a cyano group or a nitrogen atom,
R
a
denotes a hydrogen atom or a methyl group,
R
b
denotes a phenyl, benzyl or 1-phenylethyl group, wherein the phenyl nucleus in each case is substituted by the groups R
1
to R
3
, where
R
1
and R
2
, which may be identical or different, each denote a hydrogen, fluorine, chlorine, bromine or iodine atom,
a methyl, ethyl, hydroxy, methoxy, ethoxy, amino, cyano, vinyl or ethynyl group,
an aryl, aryloxy, arylmethyl or arylmethoxy group,
a methyl or methoxy group substituted by 1 to 3 fluorine atoms or
R
1
together with R
2
, if they are bound to adjacent carbon atoms, denotes a —CH═CH—CH═CH, —CH═CH—NH or —CH═N—NH group and
R
3
denotes a hydrogen, fluorine, chlorine or bromine atom,
one of the groups R
c
or R
d
denotes an —A—B group and
the other group R
c
or R
d
denotes a —C—D group, where
A denotes a C
1-6
-alkylene group, a —O—C
1-6
-alkylene group, where the alkylene moiety is linked to the group B, or an oxygen atom, while this may not be linked to a nitrogen atom of the group B, and
B denotes a pyrrolidino group wherein the two hydrogen atoms in the 2 position are replaced by a group E, wherein
E represents a —CH
2
—O—CO—CH
2
, —CH
2
CH
2
—O—CO, —CH
2
—O—CO—CH
2
CH
2
, —CH
2
CH
2
—O—CO—CH
2
or —CH
2
CH
2
CH
2
—O—CO— bridge optionally substituted by one or two C
1-2
-alkyl groups,
a pyrrolidino group wherein the two hydrogen atoms in the 3 position are replaced by a group F wherein
F denotes an —O—CO—CH
2
CH
2
, —CH
2
—O—CO—CH
2
, —CH
2
CH
2
—O—CO, —O—CO—CH
2
CH
2
CH
2
, —CH
2
—O—CO—CH
2
CH
2
, —CH
2
CH
2
—O—CO—CH
2
, —CH
2
CH
2
CH
2
—O—CO, —O—CO—CH
2
—NR
4
—CH
2
, —CH
2
—O—CO—CH
2
—NR
4
, —O—CO—CH
2
—O—CH
2
or —CH
2
—O—CO—CH
2
—O— bridge optionally substituted by one or two C
1-2
-alkyl groups, where R
4
denotes a hydrogen atom or a C
1-4
-alkyl group,
a piperidino or hexahydroazepino group, wherein the two hydrogen atoms in the 2 position are replaced by a group E, where E is as hereinbefore defined,
a piperidino or hexahydroazepino group, wherein in each case the two hydrogen atoms in the 3 position or in the 4 position are replaced by a group F, where F is as hereinbefore defined,
a piperazino or 4-(C
1-4
-alkyl)-piperazino group, wherein the two hydrogen atoms in the 2 position or in the 3 position of the piperazino ring are replaced by a group E, where E is as hereinbefore defined,
a pyrrolidino or piperidino group, wherein two neighbouring hydrogen atoms are replaced by a —O—CO—CH
2
, —CH
2
—O—CO, —O—CO—CH
2
CH
2
, —CH
2
—O—CO—CH
2
, —CH
2
CH
2
—O—CO, —O—CO—CH
2
—NR
4
or —O—CO—CH
2
—O— bridge optionally substituted by one or two C
1-2
-alkyl groups, where
R
4
is as hereinbefore defined and the heteroatoms of the abovementioned bridges are not bound to the 2 or 5 position of the pyrrolidino ring and are not bound to the 2 or 6 position of the piperidino ring,
a piperazino or 4-(C
1-4
-alkyl)-piperazino group, wherein a hydrogen atom in the 2 position together with a hydrogen atom in the 3 position of the piperazino ring are replaced by a —CH
2
—O—CO—CH
2
or —CH
2
CH
2
—O—CO— bridge optionally substituted by one or two C
1-2
-alkyl groups,
a piperazino group wherein a hydrogen atom in the 3 position together with the hydrogen atom in the 4 position are replaced by a —CO—O—CH
2
CH
2
or —CH
2
—O—CO—CH
2
— bridge optionally substituted by one or two C
1-2
-alkyl groups, where in each case the left-hand end of the abovementioned bridges is bound to the 3 position of the piperazino ring,
a pyrrolidino, piperidino or hexahydroazepino group substituted by the group R
5
wherein
R
5
represents a 2-oxo-tetrahydrofuranyl, 2-oxo-tetrahydropyranyl, 2-oxo-1,4-dioxanyl or 2-oxo-4-(C
1-4
-alkyl)-morpholinyl group optionally substituted by one or two C
1-2
-alkyl groups,
a pyrrolidino group substituted in the 3 position by a 2-oxo-morpholino group, while the 2-oxo-morpholino group may be substituted by one or two C
1-2
-alkyl groups,
a piperidino or hexahydroazepino group substituted in the 3 or 4 position by a 2-oxo-morpholino group, while the 2-oxo-morpholino group may be substituted by one or two C
1-2
-alkyl groups,
a 4-(C
1-4
-alkyl)-piperazino or 4-(C
1-4
-alkyl)-homopiperazino group substituted at a cyclic carbon atom by R
5
, wherein R
5
is as hereinbefore defined,
a piperazino or homopiperazino group substituted in the 4 position by the group R
6
, wherein
R
6
represents a 2-oxo-tetrahydrofuran-3-yl, 2-oxo-tetrahydrofuran-4-yl, 2-oxo-tetrahydropyran-3-yl, 2-oxo-tetrahydropyran-4-yl or 2-oxo-tetrahydropyran-5-yl group optionally substituted by one or two C
1-2
-alkyl groups,
a pyrrolidino group substituted in the 3 position by an (R
4
NR
6
), R
6
O, R
6
S, R
6
SO or R
6
SO
2
group, where R
4
and R
6
are as hereinbefore defined,
a piperidino or hexahydroazepino group substituted in the 3 or 4 position by an (R
4
NR
6
), (R
6
O, R
6
S, R
6
SO or R
6
SO
2
group, wherein R
4
and R
6
are as hereinbefore defined,
a pyrrolidino, piperidino or hexahydroazepino group substituted by an R
5
—C
1-4
-alkyl, R
4
NR
6
)—C
1-4
-alkyl, R
6
O—C
1-4
-alkyl, R
6
S—C
1-4
-alkyl, R
6
SO—C
1-4
-alkyl, R
6
SO
2
—C
1-4
-alkyl or R
4
NR
6
—CO group, wherein R
4
to R
6
are as hereinbefore defined,
a pyrrolidino group substituted in the 3 position by an R
5
—CO—NR
4
, R
5
—C
1-4
-alkylene-CONR
4
, (R
4
NR
6
)—C
1-4
-alkylene-CONR
4
, R
6
O—C
1-4
-alkylene-CONR
4
, R
6
S—C
1-4
-alkylene-CONR
4
, R
6
SO—C
1-4
-alkylene-CONR
4
, R
6
SO
2
—C
1-4
-alkylene-CONR
4
, 2-oxo-morpholino-C
1-4
-alkylene-CONR
4
, R
5
—C
1-4
-alkylene-Y or C
2-4
-alkyl-Y group, where the C
2-4
-alkyl moiety of the C
2-4
-alkyl-Y group in each case is substituted from position 2 by an (R
4
NR
6
), R
6
O, R
6
S, R
6
SO or R
6
SO
2
group and the 2-oxo-morpholino moiety may be substituted by one or two C
1-2
-alkyl groups, wherein
R
4
to R
6
are as hereinbefore defined and
Y represents an oxygen or sulphur atom, an imino, N—(C
1-4
-alkyl)-imino, sulphinyl or sulphonyl group,
a piperidino or hexahydroazepino group substituted in the 3 or 4 position by an R
5
—CO—NR
4
, R
5
—C
1-4
-alkylene-CONR
4
, (R
4
NR
6
)—C
1-4
-alkylene-CONR
4
, R
6
O—C
1-4
-alkylene-CONR
4
, R
6
S—C
1-4
-alkylene-CONR
4
, R
6
SO—C
1-4
-alkylene-CONR
4
, R
6
SO
2
—C
1-4
-alkylene-CONR
4
, 2-oxo-morpholino-C
1-4
-alkylene-CONR
4
, R
5
—C
1-4
-alkylene-Y or C
2-4
-alkyl-Y group, wherein
Y is as hereinbefore defined, the 2-oxo-morpholino moiety may be substituted by one or two C
1-2
-alkyl groups and the C
2-4
-alkyl moiety of the C
2-4
-alkyl-Y group is substituted in each case from position 2 by an (R
4
NR
6
), R
6
O, R
6
S, R
6
SO or R
6
SO
2
group, where R
4
to R
6
are as hereinbefore defined,
a 4-(C
1-4
-alkyl)-piperazino or 4-(C
1-4
-alkyl)-homopiperazino group substituted at a cyclic carbon atom by an R
5
—C
1-4
-alkyl, (R
4
NR
6
)—C
1-4
-alkyl, R
6
O—C
1-4
-alkyl, R
6
S—C
1-4
-alkyl, R
6
SO—C
1-4
-alkyl, R
6
SO
2
—C
1-4
-alkyl or R
4
NR
6
—CO group, wherein R
4
to R
6
are as hereinbefore defined,
a piperazino or homopiperazino group substituted in the 4 position by an R
5
—C
1-4
-alkyl, R
5
—CO, R
5
—C
1-4
-alkylene-CO, (R
4
NR
6
)—C
1-4
-alkylene-CO, R
6
O—C
1-4
-alkylene-CO, R
6
S—C
1-4
-alkylene-CO, R
6
SO—C
1-4
-alkylene-CO or R
6
SO
2
—C
1-4
-alkylene-CO group, wherein R
4
to R
6
are as hereinbefore defined,
a piperazino or homopiperazino group substituted in the 4 position by a C
2-4
-alkyl group, wherein the C
2-4
-alkyl group is substituted in each case from positi

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