Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2001-08-22
2003-12-02
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...
C514S233500, C514S255030, C514S266100, C514S312000, C544S107000, C544S253000, C544S363000
Reexamination Certificate
active
06656946
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
R
a
denotes a benzyl or 1-phenylethyl group or a phenyl group substituted by the groups R
1
and R
2
, where
R
1
denotes a hydrogen, fluorine, chlorine or bromine atom, a methyl, trifluoromethyl, cyano or ethynyl group and
R
2
denotes a hydrogen or fluorine atom,
one of the groups R
b
or R
c
denotes an R
3
—(CH
2
)
m
—O group and the other group R
b
or R
c
denotes a methoxy, cyclobutyloxy, cyclopentyloxy, cyclopropylmethoxy, cyclobutylmethoxy, cyclopentylmethoxy, tetrahydrofuran-3-yloxy, tetrahydropyran-3-yloxy, tetrahydropyran-4-yloxy, tetrahydrofuranylmethoxy or tetrahydropyranylmethoxy group, where
R
3
denotes an N-(2-oxo-tetrahydrofuran-4-yl)-methylamino or N-(2-oxo-tetrahydrofuran-4-yl)-ethylamino group, an R
4
—O—CO—CH
2
—N—CH
2
CH
2
—OH group substituted at the methylene groups by one or two methyl or ethyl groups, wherein
R
4
represents a hydrogen atom or a C
1-4
-alkyl group,
or a 2-oxo-morpholin-4-yl group substituted by one or two methyl or ethyl groups and
m denotes the number 2, 3 or 4,
with the proviso that the compounds
4-[(3-chloro-4-fluorophenyl)amino]-6-cyclopentyloxy-7-(2-{N-(2-hydroxy-2-methyl-prop-1-yl)-N-[(ethoxycarbonyl)methyl]-amino}-ethoxy)-quinazoline,
4-[(3-chloro-4-fluorophenyl)amino]-6-cyclopentyloxy-7-[2-(6,6-dimethyl-2-oxo-morpholin-4-yl)-ethoxy]-quinazoline,
4-[(3-bromo-phenyl)amino]-6-[2-(6,6-dimethyl-2-oxo-morpholin-4-yl)-ethoxy]-7-methoxy-quinazoline and
4-[(3-bromo-phenyl)amino]-6-{2-[N-(2-oxo-tetrahydrofuran-4-yl)-N-methyl-amino]-thoxy}-7-methoxy-quinazoline
are excluded,
the tautomers, the stereoisomers and the salts thereof.
Preferred compounds of the above general formula I are those wherein
R
a
denotes a benzyl or 1-phenylethyl group or a phenyl group substituted by the groups R
1
and R
2
, where
R
1
denotes a hydrogen, fluorine, chlorine or bromine atom, a methyl, trifluoromethyl, cyano or ethynyl group and R
2
denotes a hydrogen or fluorine atom,
one of the groups R
b
or R
c
denotes a R
3
—(CH
2
)
m
—O group and the other group R
b
or R
c
denotes a methoxy, cyclobutyloxy, cyclopentyloxy, cyclopropylmethoxy, cyclobutylmethoxy, cyclopentylmethoxy, tetrahydrofuran-3-yloxy, tetrahydropyran-3-yloxy, tetrahydropyran-4-yloxy, tetrahydrofuranylmethoxy or tetrahydropyranylmethoxy group, where
R
3
denotes an N-(2-oxo-tetrahydrofuran-4-yl)-methylamino or N-(2-oxo-tetrahydrofuran-4-yl)-ethylamino group,
an R
4
—O—CO—CH
2
—N—CH
2
CH
2
—OH group substituted at the methylene groups by one or two methyl or ethyl groups wherein
R
4
represents a hydrogen atom or a C
1-4
-alkyl group,
or a 2-oxo-morpholin-4-yl group substituted by one or two methyl or ethyl groups and
m represents the number 2, 3 or 4,
with the proviso that the compounds
4-[(3-chloro-4-fluorophenyl)amino]-6-cyclopentyloxy-7-(2-{N-(2-hydroxy-2-methyl-prop-1-yl)-N-[(ethoxycarbonyl)methyl]-amino}-ethoxy)-quinazoline,
4-[(3-chloro-4-fluorophenyl)amino]-6-cyclopentyloxy-7-[2-(6,6-dimethyl-2-oxo-morpholin-4-yl)-ethoxy]-quinazoline,
4-[(3-bromo-phenyl)amino]-6-[2-(6,6-dimethyl-2-oxo-morpholin-4-yl)-ethoxy]-7-methoxy-quinazoline,
4-[(3-bromo-phenyl)amino]-6-{2-[N-(2-oxo-tetrahydrofuran-4-yl)-N-methyl-amino]-ethoxy}-7-methoxy-quinazoline,
4-[(3-bromo-phenyl)amino]-6-(2-{N-(2-hydroxy-2-methyl-prop-1-yl)-N-[(ethoxycarbonyl)methyl]-amino}-ethoxy)-7-methoxy-quinazoline,
4-[(3-bromo-phenyl)amino]-6-[2-(3-methyl-2-oxo-morpholin-4-yl)ethoxy)-7-methoxy-quinazoline,
4-[(3-bromo-phenyl)amino]-6-[2-(5, 5-dimethyl-2-oxo-morpholin-4-yl)ethoxy]-7-methoxy-quinazoline,
4-[(3-chloro-4-fluorophenyl)amino]-6-[2-(6,6-dimethyl-2-oxo-morpholin-4-yl)-ethoxy]-7-methoxy-quinazoline,
4-[(3-chloro-4-fluorophenyl)amino]-6-[2-(6,6-dimethyl-2-oxo-morpholin-4-yl)-ethoxy]-7-cyclobutyloxy-quinazoline,
4-[(3-chloro-4-fluorophenyl)amino]-6-[2-(6,6-dimethyl-2-oxo-morpholin-4-yl)-ethoxy]-7-cyclopentyloxy-quinazoline,
4-[(3-chloro-4-fluorophenyl)amino]-6-[2-(6,6-dimethyl-2-oxo-morpholin-4-yl)-ethoxy]-7-cyclopropylmethoxy-quinazoline,
4-[(3-chloro-4-fluorophenyl]amino]-6-[2-(6,6-dimethyl-2-oxo-morpholin-4-yl)-ethoxy]-7-cyclopentylmethoxy-quinazoline,
4-[(3-chloro-4-fluorophenyl)amino]-6-{2-[N-(2-oxo-tetrahydrofuran-4-yl)-N-methyl-amino]-ethoxy}-7-methoxy-quinazoline,
4-[(3-chloro-4-fluorophenyl)amino]-6-{2-[N-(2-oxo-tetrahydrofuran-4-yl)-N-methyl-amino]-ethoxy}-7-cyclopentyloxy-quinazoline,
4-[(3-chloro-4-fluorophenyl)amino]-6-{2-[N-(2-oxo-tetrahydrofuran-4-yl)-N-methyl-amino]-ethoxy}-7-cyclopentylmethoxy-quinazoline,
4-[(3-chloro-4-fluorophenyl)amino]-6-[3-(6,6-dimethyl-2-oxo-morpholin-4-yl)-propyloxy]-7-methoxy-quinazoline,
4-[(3-chloro-4-fluorophenyl)amino]-6-[3-(6,6-dimethyl-2-oxo-morpholin-4-yl)-propyloxy]-7-cyclopentyloxy-quinazoline,
4-[(3-chloro-4-fluorophenyl)amino]-6-[3-(6,6-dimethyl-2-oxo-morpholin-4-yl)-propyloxy]-7-cyclopentylmethoxy-quinazoline,
(R)-4-[(1-phenyl-ethyl)amino]-6-[3-(6,6-dimethyl-2-oxo-morpholin-4-yl)-propyloxy]-7-cyclopentyloxy-quinazoline,
4-[(3-chloro-4-fluorophenyl)amino]-7-[2-(6,6-dimethyl-2-oxo-morpholin-4-yl)-ethoxy]-6-methoxy-quinazoline,
4-[(3-chloro-4-fluorophenyl)amino]-7-[2-(6,6-dimethyl-2-oxo-morpholin-4-yl)-ethoxy]-6-cyclobutyloxy-quinazoline,
4-[(3-chloro-4-fluorophenyl)amino]-7-[2-(6,6-dimethyl-2-oxo-morpholin-4-yl)-ethoxy]-6-cyclopentyloxy-quinazoline,
4-[(3-chloro-4-fluorophenyl)amino]-7-[2-(6,6-dimethyl-2-oxo-morpholin-4-yl)-ethoxy]-6-cyclopropylmethoxy-quinazoline,
4-[(3-chloro-4-fluorophenyl)amino]-7-[2-(6,6-dimethyl-2-oxo-morpholin-4-yl)-ethoxy]-6-cyclopentylmethoxy-quinazoline,
4-[(3-chloro-4-fluorophenyl)amino]-7-{2-[N-(2-oxo-tetrahydrofuran-4-yl)-N-methyl-amino]-ethoxy}-6-methoxy-quinazoline,
4-[(3-chloro-4-fluorophenyl)amino]-7-{2-[N-(2-oxo-tetrahydrofuran-4-yl)-N-methyl-amino]-ethoxy}-6-cyclopentyloxy-quinazoline,
4-[(3-chloro-4-fluorophenyl)amino]-7-{2-[N-(2-oxo-tetrahydrofuran-4-yl)-N-methyl-amino]-ethoxy}-6-cyclopentylmethoxy-quinazoline,
4-[(3-chloro-4-fluorophenyl)amino]-7-[3-(6,6-dimethyl-2-oxo-morpholin-4-yl)-propyloxy]-6-methoxy-quinazoline,
4-[(3-chloro-4-fluorophenyl)amino]-7-[3-(6,6-dimethyl-2-oxo-morpholin-4-yl)-propyloxy]-6-cyclopentyloxy-quinazoline,
4-[(3-chloro-4-fluorophenyl)amino]-7-[3-(6,6-dimethyl-2-oxo-morpholin-4-yl)-propyloxy]-6-cyclopentylmethoxy-quinazoline and
(R)4-[(1-phenyl-ethyl)amino]-7-[3-(6,6-dimethyl-2-oxo-morpholin-4-yl)-propyloxy]-6-cyclopentyloxy-quinazoline
are excluded,
particularly those wherein
R
a
represents a 1-phenylethyl group or a phenyl group substituted by the groups R
1
and R
2
, where
R
1
represents a fluorine, chlorine or bromine atom, a methyl or ethynyl group and R
2
denotes a hydrogen or fluorine atom,
one of the groups R
b
or R
c
represents a R
3
—(CH
2
)
m
—O group and the other group R
b
or R
c
represents a methoxy, cyclobutyloxy, cyclopentyloxy
Blech Stefan
Himmelsbach Frank
Jung Birgit
Langkopf Elke
Solca Flavio
Boehringer Ingelheim Pharma KG
Devlin Mary-Ellen M.
Raymond Robert P.
Shah Mukund J.
Stempel Alan R.
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