Bicyclic heterocycles, pharmaceutical compositions...

Details Bicyclic heterocycles, pharmaceutical compositions... Bicyclic heterocycles, pharmaceutical compositions...

2001-03-23

2003-09-30

Raymond, Richard L. (Department: 1624)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

C514S266100, C514S266200, C514S266230, C514S234800, C514S212020, C540S543000, C544S070000, C544S116000, C544S283000, C544S284000, C544S290000, C544S293000

Reexamination Certificate

active

06627634

ABSTRACT:

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 C
1-4
-alkyl 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
, whilst
R
1
and R
2
, which may be identical or different, in each case denote a hydrogen, fluorine, chlorine, bromine, or iodine atom,
a C
14
-alkyl, hydroxy, C
1-4
-alkoxy, C
3-6
-cycloalkyl, C
4-6
-cycloalkoxy, C
2-5
-alkenyl, or C
2-5
-alkynyl group,
an aryl, aryloxy, arylmethyl, or arylmethoxy group,
a C
3-5
-alkenyloxy or C
3-5
-alkynyloxy group, whilst the unsaturated moiety may not be linked to the oxygen atom,
a C
1-4
-alkylsulfenyl, C
1-4
-alkylsulfinyl, C
1-4
-alkylsulfonyl, C
1-4
-alkylsulfonyloxy, trifluoromethylsulfenyl, trifluoromethylsulfinyl, or trifluoromethylsulfonyl group,
a methyl or methoxy group substituted by 1 to 3 fluorine atoms, an ethyl or ethoxy group substituted by 1 to 5 fluorine atoms,
a cyano or nitro group or an amino group optionally substituted by one or two C
1-4
-alkyl groups, whilst the substituents may be identical or different, or
R
1
together with R
2
, if they are bound to adjacent carbon atoms, denote a —CH═CH—CH═CH—, —CH═CH—NH—, or —CH═N—NH— group, and
R
3
denotes a hydrogen, fluorine, chlorine, or bromine atom,
a C
1-4
-alkyl, trifluoromethyl, or C
1-4
-alkoxy group,
R
c
denotes a hydrogen atom or a C
1-4
-alkyl group,
R
d
denotes a hydrogen atom, a C
1-6
-alkoxy, C
4-7
-cycloalkoxy, or C
3-7
-cycloalkyl-C
1-4
-alkoxy group,
a C
2-6
-alkoxy group, which is substituted from position 2 by a hydroxy, C
1-4
-alkoxy, C
4-7
-cycloalkoxy, C
3-7
-cycloalkyl-C
1-3
-alkoxy, di-(C
1-4
-alkyl)-amino, pyrrolidino, piperidino, morpholino, piperazino, or 4-(C
1-4
-alkyl)piperazino group, whilst the abovementioned cyclic imino groups may be substituted by one or two C
1-2
-alkyl groups,
a tetrahydrofuran-3-yloxy, tetrahydropyran-3-yloxy, tetrahydropyran-4-yloxy, tetrahydrofuranylmethoxy, or tetrahydropyranylmethoxy group,
A denotes a 1,1- or 1,2-vinylene group optionally substituted by a methyl or trifluoromethyl group or by two methyl groups,
a 1,3-butadien-1,4-ylene group optionally substituted by a methyl or trifluoromethyl group or by two methyl groups, or an ethynylene group,
B denotes a C
1-6
-alkylene group wherein one or two hydrogen atoms may be replaced by fluorine atoms, or, if B is bound to a carbon atom of group C, it may also denote a bond,
C denotes a pyrrolidino group wherein the two hydrogen atoms in the 2 position are replaced by a group D, wherein
D denotes 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 E, wherein
E 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,
whilst 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 D, whilst D is as hereinbefore defined,
a piperidino or hexahydroazepino group wherein the two hydrogen atoms in the 3 position or in the 4 position are replaced by a group E, whilst E 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 D, where D is as hereinbefore defined,
a pyrrolidino or piperidino group wherein two vicinal hydrogen atoms are replaced by an —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, whilst R
4
is as hereinbefore defined and the heteroatoms of the abovementioned bridges are not bound at the 2 or 5 position of the pyrrolidine ring and are not bound at 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, whilst 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
denotes a 2-oxotetrahydrofuranyl, 2-oxotetrahydropyranyl, 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-oxomorpholino group, whilst the 2-oxomorpholino 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-oxomorpholino group, whilst the 2-oxomorpholino group may be substituted by one or two CH
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
denotes a 2-oxotetrahydrofuran-3-yl, 2-oxotetrahydrofuran-4-yl, 2-oxotetrahydropyran-3-yl, 2-oxotetrahydropyran-4-yl, or 2-oxotetrahydropyran-5-yl group optionally substituted by one or two C
1-2
-alkyl groups,
a pyrrolidino group substituted in the 3 position by a (R
4
NR
6
), R
6
O, R
6
S, R
6
SO, or R
6
SO
2
group, whilst 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 P
6
SO
2
group wherein R
4
and R
6
are as hereinbefore defined,
a pyrrolidino, piperidino, or hexahydroazepino group substituted by a 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 a 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-oxomorpholino-C
1-4
-alkylene-CONR
4
, R
5
—C
1-4
-alkylene-Y, or C
2-4
-alkyl-Y group, whilst the C
2-4
-alkyl moiety of the C
2-4
-alkyl-Y group is substituted in each case from position 2 by a (R
4
NR
6
), R
6
O, R
6
S, R
6
SO, or R
6
SO
2
group and the 2-oxomorpholino 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 denotes an oxygen or sulfur atom, an imino, N—(C
1-4
-alkyl)-imino, sulfinyl, or sulfonyl group,
a piperidino or hexahydroazepino group substituted in the 3 or 4 position by a R
5
—CO—NR
4
, R
5
—C
1-4
-alkylene-CONR
4
, (R
4
NR
6
)—C
1-4
-

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