DE10042058A1 - Bicyclic heterocycles, medicaments containing these compounds, their use and processes for their preparation - Google Patents

Abstract

The invention relates to bicyclic heterocycles of general formula (I), in which Ra to Rc are defined as referred to in Claims Nos. 1 to 7, to their tautomers, their stereoisomers, and to their salts, particularly their physiologically compatible salts with inorganic or organic acids or bases, which have valuable pharmacological properties, in particular, an inhibitive effect on the signal transduction imparted by tyrosine kinases. The invention also relates to the use of said bicyclic heterocycles for treating diseases, especially tumor diseases, disorders of the lung and of the respiratory tract, and to the production thereof.

Description

The present invention relates to bicyclic heterocycles of the general formula

their tautomers, their stereoisomers and their salts, esp especially their physiologically acceptable salts with anorgani or organic acids or bases, which valuable have pharmacological properties, in particular a Inhibitory effect on tyrosine kinase mediated signal transduction, their use for the treatment of diseases, in particular of tumor diseases, diseases of the lung and the respiratory tract and their production.

In the above general formula I means
R _{a represents} a benzyl or 1-phenylethyl group or a phenyl group substituted by the radicals R ₁ and R ₂ , where
R _{1 is} a hydrogen, fluorine, chlorine or bromine atom, a methyl, trifluoromethyl, cyano or ethynyl group and
R _{2 represents} a hydrogen or fluorine atom,
one of the radicals R _b or R _{c is} an R ₃ - (CH ₂ ) _m -O group and the other of the radicals R _b or R _{c is} a methoxy, cyclobutyloxy, cyclopenty loxy, cyclopropylmethoxy, cyclobutylmethoxy or Cyclopen tylmethoxygruppe , in which
R _{3 is} an N- (2-oxo-tetrahydrofuran-4-yl) -methylamino or -N- (2-oxo-tetrahydrofuran-4-yl) -ethylamino group,
a R ₄ -O-CO-CH ₂ -N-CH ₂ CH ₂ -OH group substituted on the methylene groups by one or two methyl or ethyl groups, in which
R _{4 represents} a hydrogen atom or a C _1-4 alkyl group,
or a substituted by one or two methyl or ethyl groups 2-oxo-morpholin-4-yl group and
m represent the number 2 or 3,
with the proviso that the connections
4 - [(3-Chloro-4-fluoro-phenyl) -amino] -6-cyclopentyloxy-7- (2- {N- (2-hydroxy-2-methyl-prop-1-yl) -N - [(ethoxycarbonyl ) - methyl] -amino} -ethoxy) -quinazoline,
4 - [(3-chloro-4-fluoro-phenyl) -amino] -6-cyclopentyloxy-7- [2- (6,6-dimethyl-2-oxomorpholin-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] -ethoxy} -7-methoxy-quinazoline
excluded are,
their tautomers, their stereoisomers and their salts.

Preferred compounds of the above general formula I are those in which
R _{a represents} a benzyl or 1-phenylethyl group or a phenyl group substituted by the radicals R ₁ and R ₂ , where
R _{1 is} a hydrogen, fluorine, chlorine or bromine atom, a methyl, trifluoromethyl, cyano or ethynyl group and
R _{2 represents} a hydrogen or fluorine atom,
one of R _b or R _{c is} an R ₃ - (CH ₂ ) _m -O group and the other of R _b or R _{c is} a methoxy, cyclobutyloxy, cyclopentyloxy, cyclopropylmethoxy, cyclobutylmethoxy or cyclopentylmethoxy group, wherein
R _{3 is} an N- (2-oxo-tetrahydrofuran-4-yl) -methylamino or N- (2-oxo-tetrahydrofuran-4-yl) -ethylamino group,
a R ₄ -O-CO-CH ₂ -N-CH ₂ CH ₂ -OH group substituted on the methylene groups by one or two methyl or ethyl groups, in which
R _{4 represents} a hydrogen atom or a C _1-4 alkyl group,
or a substituted by one or two methyl or ethyl groups 2-oxo-morpholin-4-yl group and
m represent the number 2 or 3,
with the proviso mean that the connections
4 - [(3-Chloro-4-fluoro-phenyl) -amino] -6-cyclopentyloxy-7- (2- {N- (2-hydroxy-2-methyl-prop-1-yl) -N - [(ethoxycarbonyl ) - methyl] -amino} -ethoxy) -quinazoline, 4 - [(3-chloro-4-fluoro-phenyl) -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-oxomorpholin-4-yl) -ethoxy] -7-methoxy-quinazoline,
4 - [(3-Bromo-phenyl) -amino] -6- [2- (5,5-dimethyl-2-oxomorpholin-4-yl) -ethoxy] -7-methoxy-quinazoline,
4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- [2- (6,6-dimethyl-2-oxomorpholin-4-yl) -ethoxy] -7-methoxy-quinazoline,
4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- [2- (6,6-dimethyl-2-oxomorpholin-4-yl) -ethoxy] -7-cyclobutyloxy-quinazoline,
4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- [2- (6,6-dimethyl-2-oxomorpholin-4-yl) -ethoxy] -7-cyclopentyloxy-quinazoline,
4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- [2- (6,6-dimethyl-2-oxomorpholin-4-yl) -ethoxy] -7-cyclopropylmethoxy-quinazoline,
4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- [2- (6,6-dimethyl-2-oxomorpholin-4-yl) -ethoxy] -7-cyclopentylmethoxy-quinazoline,
4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- {2- [N- (2-oxo-tetrahydro-furan-4-yl) -N-methyl-amino] -ethoxy} -7- methoxy-quinazoline,
4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- {2- [N- (2-oxo-tetrahydro-furan-4-yl) -N-methyl-amino] -ethoxy} -7- cyclopentyloxy-china zolin,
4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- {2- [N- (2-oxo-tetrahydro-furan-4-yl) -N-methyl-amino] -ethoxy} -7- cyclopentylmethoxy quinazoline,
4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- [3- (6,6-dimethyl-2-oxomorpholin-4-yl) -propyloxy] -7-methoxy-quinazoline,
4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- [3- (6,6-dimethyl-2-oxomorpholin-4-yl) -propyloxy] -7-cyclopentyloxy-quinazoline,
4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- [3- (6,6-dimethyl-2-oxomorpholin-4-yl) -propyloxy] -7-cyclopentylmethoxy-quinazoline,
(R) -4 - [(1-phenyl-ethyl) -amino] -6- [3- (6,6-dimethyl-2-oxomorpholin-4-yl) -propyloxy] -7-cyclopentyloxy-quinazoline,
4 - [(3-chloro-4-fluoro-phenyl) -amino] -7- [2- (6,6-dimethyl-2-oxomorpholin-4-yl) -ethoxy] -6-methoxy-quinazoline,
4 - [(3-chloro-4-fluoro-phenyl) -amino] -7- [2- (6,6-dimethyl-2-oxomorpholin-4-yl) -ethoxy] -6-cyclobutyloxy-quinazoline,
4 - [(3-chloro-4-fluoro-phenyl) -amino] -7- [2- (6,6-dimethyl-2-oxomorpholin-4-yl) -ethoxy] -6-cyclopentyloxy-quinazoline,
4 - [(3-chloro-4-fluoro-phenyl) -amino] -7- [2- (6,6-dimethyl-2-oxomorpholin-4-yl) -ethoxy] -6-cyclopropylmethoxy-quinazoline,
4 - [(3-chloro-4-fluoro-phenyl) -amino] -7- [2- (6,6-dimethyl-2-oxomorpholin-4-yl) -ethoxy] -6-cyclopentylmethoxy-quinazoline,
4 - [(3-chloro-4-fluoro-phenyl) -amino] -7- {2- [N- (2-oxo-tetrahydro-furan-4-yl) -N-methyl-amino] -ethoxy} -6- methoxy-quinazoline,
4 - [(3-chloro-4-fluoro-phenyl) -amino] -7- {2- [N- (2-oxo-tetrahydro-furan-4-yl) -N-methyl-amino] -ethoxy} -6- cyclopentyloxy-china zolin,
4 - [(3-chloro-4-fluoro-phenyl) -amino] -7- {2- [N- (2-oxo-tetrahydro-furan-4-yl) -N-methyl-amino] -ethoxy} -6- cyclopentylmethoxy quinazoline,
4 - [(3-chloro-4-fluoro-phenyl) -amino] -7- [3- (6,6-dimethyl-2-oxomorpholin-4-yl) -propyloxy] -6-methoxy-quinazoline,
4 - [(3-chloro-4-fluoro-phenyl) -amino] -7- [3- (6,6-dimethyl-2-oxomorpholin-4-yl) -propyloxy] -6-cyclopentyloxy-quinazoline,
4 - [(3-chloro-4-fluoro-phenyl) -amino] -7- [3- (6,6-dimethyl-2-oxomorpholin-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
excluded are,
especially those in which
R _{a represents} a 1-phenylethyl group or a phenyl group substituted by the radicals R ₁ and R ₂ , wherein
R _{1 is} a fluorine, chlorine or bromine atom, a methyl or ethynyl group and
R _{2 represents} a hydrogen or fluorine atom,
one of R _b or R _{c is} an R ₃ - (CH ₂ ) _m -O group and the other of R _b or R _{c is} a methoxy, cyclobutyloxy, cyclo pentyloxy, cyclopropylmethoxy, cyclobutylmethoxy or cyclopentylmethoxy group, in which
R _{3 is} an N- (2-oxo-tetrahydrofuran-4-yl) -methylamino group,
a substituted on the methylene groups by one or two methyl groups R ₄ -O-CO-CH ₂ -N-CH ₂ CH ₂ -OH group, in which
R _{4 represents} a C _1-4 alkyl group,
or a substituted by one or two methyl groups 2-oxo-morpholin-4-yl group and
m represent the number 2 or 3,
with the proviso mean that the connections
4 - [(3-Chloro-4-fluoro-phenyl) -amino] -6-cyclopentyloxy-7- (2- {N- (2-hydroxy-2-methyl-prop-1-yl) -N - [(ethoxycarbonyl ) - methyl] -amino} -ethoxy) -quinazoline,
4 - [(3-chloro-4-fluoro-phenyl) -amino] -6-cyclopentyloxy-7- [2- (6,6-dimethyl-2-oxomorpholin-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-oxomorpholin-4-yl) -ethoxy] -7-methoxy-quinazoline,
4 - [(3-Bromo-phenyl) -amino] -6- [2- (5,5-dimethyl-2-oxomorpholin-4-yl) -ethoxy] -7-methoxy-quinazoline,
4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- [2- (6,6-dimethyl-2-oxomorpholin-4-yl) -ethoxy] -7-methoxy-quinazoline,
4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- [2- (6,6-dimethyl-2-oxomorpholin-4-yl) -ethoxy] -7-cyclobutyloxy-quinazoline,
4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- [2- (6,6-dimethyl-2-oxomorpholin-4-yl) -ethoxy] -7-cyclopentyloxy-quinazoline,
4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- [2- (6,6-dimethyl-2-oxomorpholin-4-yl) -ethoxy] -7-cyclopropylmethoxy-quinazoline,
4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- [2- (6,6-dimethyl-2-oxomorpholin-4-yl) -ethoxy] -7-cyclopentylmethoxy-quinazoline,
4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- {2- [N- (2-oxo-tetrahydro-furan-4-yl) -N-methyl-amino] -ethoxy} -7- methoxy-quinazoline,
4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- {2- [N- (2-oxo-tetrahydro-furan-4-yl) -N-methyl-amino] -ethoxy} -7- cyclopentyloxy-china zolin,
4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- {2- [N- (2-oxo-tetrahydro-furan-4-yl) -N-methyl-amino] -ethoxy} -7- cyclopentylmethoxy quinazoline,
4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- [3- (6,6-dimethyl-2-oxomorpholin-4-yl) -propyloxy] -7-methoxy-quinazoline,
4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- [3- (6,6-dimethyl-2-oxomorpholin-4-yl) -propyloxy] -7-cyclopentyloxy-quinazoline,
4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- [3- (6,6-dimethyl-2-oxomorpholin-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-fluoro-phenyl) -amino] -7- [2- (6,6-dimethyl-2-oxomorpholin-4-yl) -ethoxy] -6-methoxy-quinazoline,
4 - [(3-chloro-4-fluoro-phenyl) -amino] -7- [2- (6,6-dimethyl-2-oxomorpholin-4-yl) -ethoxy] -6-cyclobutyloxy-quinazoline,
4 - [(3-chloro-4-fluoro-phenyl) -amino] -7- [2- (6,6-dimethyl-2-oxomorpholin-4-yl) -ethoxy] -6-cyclopentyloxy-quinazoline,
4 - [(3-chloro-4-fluoro-phenyl) -amino] -7- [2- (6,6-dimethyl-2-oxomorpholin-4-yl) -ethoxy] -6-cyclopropylmethoxy-quinazoline,
4 - [(3-chloro-4-fluoro-phenyl) -amino] -7- [2- (6,6-dimethyl-2-oxomorpholin-4-yl) -ethoxy] -6-cyclopentylmethoxy-quinazoline,
4 - [(3-chloro-4-fluoro-phenyl) -amino] -7- {2- [N- (2-oxo-tetrahydro-furan-4-yl) -N-methyl-amino] -ethoxy} -6- methoxy-quinazoline,
4 - [(3-chloro-4-fluoro-phenyl) -amino] -7- {2- [N- (2-oxo-tetrahydro-furan-4-yl) -N-methyl-amino] -ethoxy} -6- cyclopentyloxy-china zolin,
4 - [(3-chloro-4-fluoro-phenyl) -amino] -7- {2- [N- (2-oxo-tetrahydro-furan-4-yl) -N-methyl-amino] -ethoxy} -6- cyclopentylmethoxy quinazoline,
4 - [(3-chloro-4-fluoro-phenyl) -amino] -7- [3- (6,6-dimethyl-2-oxomorpholine-4-1) -propyloxy] -6-methoxy-quinazoline,
4 - [(3-chloro-4-fluoro-phenyl) -amino] -7- [3- (6,6-dimethyl-2-oxomorpholin-4-yl) -propyloxy] -6-cyclopentyloxy-quinazoline,
4 - [(3-chloro-4-fluoro-phenyl) -amino] -7- [3- (6,6-dimethyl-2-oxomorpholin-4-yl) -propyloxy] -6-cyclopentylmethoxy-quinazoline and
(R) -4 - [(1-Phenylethyl) amino] -7- [3- (6,6-dimethyl-2-oxo-morpholin-4-yl) -propyloxy] -6-cyclopentyloxy-quinazoline
excluded are,
their tautomers, their stereoisomers and their salts.

Particularly preferred compounds of general formula I are those in which
R _{a represents} a 1-phenylethyl group or a phenyl group substituted by the radicals R ₁ and R ₂ , wherein
R _{1 is} a fluorine, chlorine or bromine atom and
R _{2 represents} a hydrogen or fluorine atom,
one of the radicals R _b or R _{c is} an R ₃ - (CH ₂ ) _m -O group and the other of the radicals R _b or R _{c is} a methoxy, cyclobutyloxy, Cyclopen tyloxy, cyclopropylmethoxy, cyclobutylmethoxy or cyclo pentylmethoxy , in which
R _{3 represents} an N- (2-oxo-tetrahydrofuran-4-yl) -methylamino group or a 2-oxo-morpholin-4-yl group substituted by one or two methyl groups and
m represent the number 2 or 3,
with the proviso mean that the connections
4 - [(3-chloro-4-fluoro-phenyl) -amino] -6-cyclopentyloxy-7- [2- (6,6-dimethyl-2-oxomorpholin-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- (3-methyl-2-oxomorpholin-4-yl) -ethoxy] -7-methoxy-quinazoline,
4 - [(3-Bromo-phenyl) -amino] -6- [2- (5,5-dimethyl-2-oxomorpholin-4-yl) -ethoxy] -7-methoxy-quinazoline,
4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- [2- (6,6-dimethyl-2-oxomorpholin-4-yl) -ethoxy] -7-methoxy-quinazoline,
4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- [2- (6,6-dimethyl-2-oxomorpholin-4-yl) -ethoxy] -7-cyclobutyloxy-quinazoline,
4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- [2- (6,6-dimethyl-2-oxomorpholin-4-yl) -ethoxy] -7-cyclopentyloxy-quinazoline,
4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- [2- (6,6-dimethyl-2-oxomorpholin-4-yl) -ethoxy] -7-cyclopropylmethoxy-quinazoline,
4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- [2- (6,6-dimethyl-2-oxomorpholin-4-yl) -ethoxy] -7-cyclopentylmethoxy-quinazoline,
4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- {2- [N- (2-oxo-tetrahydro-furan-4-yl) -N-methyl-amino] -ethoxy} -7- methoxy-quinazoline,
4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- {2- [N- (2-oxo-tetrahydro-furan-4-yl) -N-methyl-amino] -ethoxy} -7- cyclopentyloxy-china zolin,
4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- {2- [N- (2-oxo-tetrahydrofuran-4-yl) -N-methyl-amino] -ethoxy} -7- cyclopentylmethoxy-china zoline,
4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- [3- (6,6-dimethyl-2-oxomorpholin-4-yl) -propyloxy] -7-methoxy-quinazoline,
4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- [3- (6,6-dimethyl-2-oxomorpholin-4-yl) -propyloxy] -7-cyclopentyloxy-quinazoline,
4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- [3- (6,6-dimethyl-2-oxomorpholin-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-fluoro-phenyl) -amino] -7- [2- (6,6-dimethyl-2-oxomorpholin-4-yl) -ethoxy] -6-methoxy-quinazoline,
4 - [(3-chloro-4-fluoro-phenyl) -amino] -7- [2- (6,6-dimethyl-2-oxomorpholin-4-yl) -ethoxy] -6-cyclobutyloxy-quinazoline,
4 - [(3-chloro-4-fluoro-phenyl) -amino] -7- [2- (6,6-dimethyl-2-oxomorpholin-4-yl) -ethoxy] -6-cyclopentyloxy-quinazoline,
4 - [(3-chloro-4-fluoro-phenyl) -amino] -7- [2- (6,6-dimethyl-2-oxomorpholin-4-yl) -ethoxy] -6-cyclopropylmethoxy-quinazoline,
4 - [(3-chloro-4-fluoro-phenyl) -amino] -7- [2- (6,6-dimethyl-2-oxomorpholin-4-yl) -ethoxy] -6-cyclopentylmethoxy-quinazoline,
4 - [(3-chloro-4-fluoro-phenyl) -amino] -7- {2- [N- (2-oxo-tetrahydro-furan-4-yl) -N-methyl-amino] -ethoxy} -6- methoxy-quinazoline,
4 - [(3-chloro-4-fluoro-phenyl) -amino] -7- {2- [N- (2-oxo-tetrahydro-furan-4-yl) -N-methyl-amino] -ethoxy} -6- cyclopentyloxy-china zolin,
4 - [(3-chloro-4-fluoro-phenyl) -amino] -7- {2- [N- (2-oxo-tetrahydro-furan-4-yl) -N-methyl-amino] -ethoxy} -6- cyclopentylmethoxy quinazoline,
4 - [(3-chloro-4-fluoro-phenyl) -amino] -7- [3- (6,6-dimethyl-2-oxomorpholin-4-yl) -propyloxy] -6-methoxy-quinazoline,
4 - [(3-chloro-4-fluoro-phenyl) -amino] -7- [3- (6,6-dimethyl-2-oxomorpholin-4-yl) -propyloxy] -6-cyclopentyloxy-quinazoline,
4 - [(3-chloro-4-fluoro-phenyl) -amino] -7- [3- (6,6-dimethyl-2-oxomorpholin-4-yl) -propyloxy] -6-cyclopentylmethoxy-quinazoline and
(R) -4 - [(1-Phenylethyl) amino] -7- [3- (6,6-dimethyl-2-oxomorpholin-4-yl) -propyloxy] -6-cyclopentyloxy-quinazoline
excluded are,
their tautomers, their stereoisomers and their salts.

Very particularly preferred compounds of general formula I are those in which
R _{a represents} a 1-phenylethyl, 3-bromophenyl or 3-chloro-4-fluorophenyl group,
R _{b is} an R ₃ - (CH ₂ ) _m -O- group in which
R _{3 is} a substituted by one or two methyl groups 2-oxo-morpholin-4-yl group and
m represent the number 2 or 3,
and R _{c is} a methoxy, cyclobutyloxy or cyclopropylmethoxy group with the proviso that the compounds
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- (3-methyl-2-oxomorpholin-4-yl) -ethoxy] -7-methoxy-quinazoline,
4 - [(3-Bromo-phenyl) -amino] -6- [2- (5,5-dimethyl-2-oxomorpholin-4-yl) -ethoxy] -7-methoxy-quinazoline,
4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- [2- (6,6-dimethyl-2-oxomorpholin-4-yl) -ethoxy] -7-methoxy-quinazoline,
4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- [2- (6,6-dimethyl-2-oxomorpholin-4-yl) -ethoxy] -7-cyclobutyloxy-quinazoline,
4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- [2- (6,6-dimethyl-2-oxomorpholin-4-yl) -ethoxy] -7-cyclopropylmethoxy-quinazoline and
4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- [3- (6,6-dimethyl-2-oxomorpholin-4-yl) -propyloxy] -7-methoxy-quinazoline
excluded are,
their tautomers, their stereoisomers and their salts.

Very particularly preferred compounds of general formula I are also those in which
R _{a is} a 3-chloro-4-fluoro-phenyl group,
R _{b is} a cyclopentyloxy, cyclopropylmethoxy or cyclopentyl methoxy group and
R _{c is} an R ₃ - (CH ₂ ) _m -O- group in which
R _{3 is} an N- (2-oxo-tetrahydrofuran-4-yl) -methylamino group or a 2-oxomorpholin-4-yl group substituted by two methyl groups;
m represent the number 2,
with the proviso mean that the connections
4 - [(3-chloro-4-fluoro-phenyl) -amino] -6-cyclopentyloxy-7- [2- (6,6-dimethyl-2-oxomorpholin-4-yl) -ethoxy] -quinazoline,
4 - [(3-chloro-4-fluoro-phenyl) -amino] -7- [2- (6,6-dimethyl-2-oxomorpholin-4-yl) -ethoxy] -6-cyclopentyloxy-quinazoline,
4 - [(3-chloro-4-fluoro-phenyl) -amino] -7- [2- (6,6-dimethyl-2-oxomorpholin-4-yl) -ethoxy] -6-cyclopropylmethoxy-quinazoline,
4 - [(3-chloro-4-fluoro-phenyl) -amino] -7- [2- (6,6-dimethyl-2-oxomorpholin-4-yl) -ethoxy] -6-cyclopentylmethoxy-quinazoline,
4 - [(3-chloro-4-fluoro-phenyl) -amino] -7- {2- [N- (2-oxo-tetrahydro-furan-4-yl) -N-methyl-amino] -ethoxy} -6- cyclopentyloxy-china zolin and
4 - [(3-chloro-4-fluoro-phenyl) -amino] -7- {2- [N- (2-oxo-tetrahydro-furan-4-yl) -N-methyl-amino] -ethoxy} -6- cyclopentylmethoxyquinazoline
excluded are,
their tautomers, their stereoisomers and their salts.

As very particularly preferred compounds, the following may be mentioned, for example:
(1) 4 - [(3-Chloro-4-fluoro-phenyl) -amino] -6-cyclopentylmethoxy-7- [2- (2,2-dimethyl-6-oxo-morpholin-4-yl) -ethoxy] - quinazoline,
(2) 4 - [(3-Chloro-4-fluoro-phenyl) -amino] -6-cyclopentyloxy-7- {2- [N- (2-oxo-tetrahydrofuran-4-yl) -N-methyl-amino] -ethoxy} - quinazoline,
(3) 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6-cyclopropylmethoxy-7- [2- (2,2-dimethyl-6-oxo-morpholin-4-yl) -ethoxy] - quinazoline,
(4) 4 - [(3-Chloro-4-fluoro-phenyl) -amino] -7-cyclobutyloxy-6- [3- (2,2-dimethyl-6-oxo-morpholin-4-yl) -propyloxy] - china zolin,
(5) 4 - [(3-chloro-4-fluoro-phenyl) -amino] -7-cyclopropylmethoxy-6- [3- (2,2-dimethyl-6-oxomorpholin-4-yl) -propyloxy] - china zolin,
(7) 4 - [(3-Chloro-4-fluoro-phenyl) -amino] -6-cyclopropylmethoxy-7- {2- [N- (2-oxo-tetrahydrofuran-4-yl) -N-methyl-amino] -ethoxy} - quinazoline,
(8) 4 - [(3-Bromo-phenyl) -amino] -6- [2 - ((S) -6-methyl-2-oxo-morpholin-4-yl) -ethoxy] -7-methoxy-quinazoline .
(9) 4 - [(3-Bromo-phenyl) -amino] -6- [2 - ((R) -6-methyl-2-oxo-morpholin-4-yl) -ethoxy] -7-methoxy-quinazoline .
(10) 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- [2 - ((R) -6-methyl-2-oxo-morpholin-4-yl) -ethoxy] -7- -methoxy-quinazoline,
(11) 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- [3 - ((R) -6-methyl-2-oxo-morpholin-4-yl) -propyloxy] -7- methoxy-quinazoline,
(12) 4 - [(R) - (1-phenylethyl) amino] -6- [3 - ((S) -6-methyl-2-oxomorpholin-4-yl) -propyloxy] -7- methoxy-quinazoline and
(13) 4 - [(R) - (1-phenylethyl) amino] -6- [2 - ((S) -6-methyl-2-oxomorpholin-4-yl) -ethoxy] -7- methoxy-quinazoline,
their tautomers, their stereoisomers and their salts.

The compounds of general formula I can be prepared, for example, by the following processes:

• a) reaction of a compound of the general formula
  in the
  R _a is defined as mentioned above,
  one of R _b 'or R _c ' represents a methoxy, cyclobutyloxy, cyclopentyloxy, cyclopropylmethoxy, cyclobutylmethoxy or cyclopentylmethoxy group and
  the other of R _b 'or R _c ' represents a Z ₁ - (CH ₂ ) _m -O- group in which
  m is defined as mentioned above and
  Z _{1 represents} a leaving group such as a halogen atom or a sulphonyloxy group such as a chlorine or bromine atom, a methanesulphonyloxy or p-toluenesulphonyloxy group, with a compound of the general formula
  H - R ₃ , (III)
  in the
  R ₃ is defined as mentioned above.

The reaction is optionally carried out in a solvent or Solvent mixture such as methylene chloride, acetonitrile, dime thylformamide, dimethyl sulfoxide, sulfolane, benzene, toluene, Chlorobenzene, tetrahydrofuran, benzene / tetrahydrofuran or Dioxane expediently in the presence of a tertiary or ganic base such as triethylamine or N-ethyldiisopropylamine, these organic bases are also used as solutions can serve, or in the presence of an inorganic Base such as sodium carbonate or potassium carbonate expediently at temperatures between -20 and 200 ° C, preferably at Temperatures between 0 and 150 ° C, performed.

• a) cyclization of an optionally formed in the reaction mixture of the general formula
  in the
  R _a is defined as mentioned above,
  one of R _b "or R _c " represents a methoxy, cyclobutyloxy, cyclopentyloxy, cyclopropylmethoxy, cyclobutylmethoxy or cyclopentylmethoxy group and
  the other of R _b "or R _c " represents an R ₃ '- (CH ₂ ) _m -O- group in which
  m is defined as mentioned above and
  R ₃ 'represents a R ₄ -O-CO-CH ₂ -N-CH ₂ CH ₂ -OH group substituted on the methylene groups by one or two methyl or ethyl groups, in which
  R _{4 represents} a hydrogen atom or a C _1-4 alkyl group.

The reaction is optionally carried out in a solvent or Solvent mixture such as methylene chloride, acetonitrile, dime thylformamide, dimethyl sulfoxide, sulfolane, benzene, toluene, Chlorobenzene, tetrahydrofuran, benzene / tetrahydrofuran or Dioxane conveniently in the presence of an anhydrous acid such as trifluoroacetic acid, methanesulfonic acid or sulfuric acid or in the presence of a dehydrating agent, e.g. In The presence of isobutyl chloroformate, thionyl chloride, Trimethylchlorosilane, phosphorus trichloride, phosphorus pentoxide, N, N'-dicyclohexylcarbodiimide, N, N'-dicyclohexylcarbodi imide / N-hydroxysuccinimide or 1-hydroxybenzotriazole, N, N'-carbonyldiimidazole or triphenylphosphine / carbon tetrachloride Leristoff, at temperatures between -20 and 200 ° C, vorzugswei However, at temperatures between -10 and 160 ° C, Runaway leads.

In the reactions described above can be given if existing reactive groups such as hydroxy, carboxy or Imino groups during the reaction by conventional protecting groups be protected, which split off again after the implementation become.

For example, the protective radical for a hydroxy group is trimethylsilyl, acetyl, benzoyl, methyl, ethyl, tert.butyl, trityl, benzyl or tetrahydropyranyl,
as protecting groups for a carboxy group, the trimethylsilyl, methyl, ethyl, tert-butyl, benzyl or tetrahydropyran yl group and
as protecting groups for an imino group, the formyl, acetyl, trifluoroacetyl, ethoxycarbonyl, tert.-butoxycarbonyl, benzyloxycarbonyl, benzyl, methoxybenzyl or 2,4-dimethoxybenzyl group into consideration.

The optional subsequent cleavage of a used Protective remnant takes place for example hydrolytically in one aqueous solvent, for. In water, isopropanol / water, Acetic acid / water, tetrahydrofuran / water or dioxane / water, in the presence of an acid such as trifluoroacetic acid, hydrochloric acid or sulfuric acid or in the presence of an alkali metal base such as Sodium hydroxide or potassium hydroxide or aprotic, z. In Presence of iodotrimethylsilane, at temperatures between 0 and 120 ° C, preferably at temperatures between 10 and 100 ° C.

The cleavage of a benzyl, methoxybenzyl or benzyloxy However, carbonyl radical is hydrogenolytically, for example, z. B. with hydrogen in the presence of a catalyst such as Pal ladium / coal in a suitable solvent such as methanol, Ethanol, ethyl acetate or glacial acetic acid, if appropriate with the addition of an acid such as hydrochloric acid at temperatures between 0 and 100 ° C, but preferably at room temperatures between 20 and 60 ° C, and at a hydrogen pressure of 1 to 7 bar, but preferably from 3 to 5 bar. The spin-off However, a 2,4-dimethoxybenzyl radical is preferably carried out in Trifluoroacetic acid in the presence of anisole.

The cleavage of a tert-butyl or tert-butyloxycarbonyl The rest is preferably carried out by treatment with an acid such as trifluoroacetic acid or hydrochloric acid or by treatment with iodotrimethylsilane optionally using a  Solvent such as methylene chloride, dioxane, methanol or Diethyl ether.

The cleavage of a Trifluoracetylrestes is preferably carried out by treatment with an acid such as hydrochloric acid if necessary in the presence of a solvent such as acetic acid at tempera between 50 and 120 ° C or by treatment with soda optionally in the presence of a solvent such as Te trahydrofuran at temperatures between 0 and 50 ° C.

Further, the obtained compounds of the general For mel I, as already mentioned, into their enantiomers ren and / or diastereomers are separated. So can at For example, cis / trans mixtures into their cis and trans iso mers, and compounds having at least one optically active Carbon atom are separated into their enantiomers.

For example, the resulting cis- / trans-Ge mix by chromatography in their cis and trans isomers, the resulting compounds of general formula I, which occur in racemates, according to methods known per se (see Allinger N.L. and Eliel E.L. in "Topics in Stereochemistry", Vol. 6, Wiley Interscience, 1971)) into their optical antipodes and compounds of the general formula I with at least 2 asymmetric carbon atoms due to their physical chemical differences according to known methods, eg. B. by chromatography and / or fractional crystallisation, into their diastereomers, which, if they are in racemi shear form, then as mentioned above in the Enantiomers can be separated.

The enantiomer separation is preferably carried out by columns separation on chiral phases or by recrystallization an optically active solvent or by reacting with one, with the racemic compound salts or derivatives like z. As esters or amides-forming optically active substance, ins  particular acids and their activated derivatives or alcohols, and separating the diastereomers thus obtained Salt mixture or derivative, e.g. B. due to different Solubilities, wherein from the pure diastereomeric salts or Derivatives the free antipodes by action appropriate Funds can be released. Especially common, optically active acids are, for. B. the D and L forms of wine acid or dibenzoyltartaric acid, di-o-toluenoic acid, malic acid almic acid, camphorsulfonic acid, glutamic acid, asparagine acid or quinic acid. As optically active alcohol comes for example, (+) - or (-) - menthol and as optically active Acyl radical in amides, for example, (+) - or (-) - Menthyloxycar consider bonyl.

Furthermore, the compounds of the formula I can be obtained in their salts, in particular for pharmaceutical use in their physiologically acceptable salts with inorganic or organic acids are transferred. When acids come for example, hydrochloric acid, hydrobromic acid, sw felsic acid, methanesulfonic acid, phosphoric acid, fumaric acid, Bern tartaric acid, lactic acid, citric acid, tartaric acid or malein acid into consideration.

In addition, the new compounds thus obtained can be Formula I, if these are a carboxy, hydroxyphosphoryl, Contain sulfo or 5-tetrazolyl, if desired then in their salts with inorganic or organic Bases, especially for the pharmaceutical application in their physiologically acceptable salts. As bases For example, sodium hydroxide, potassium hydroxide, Arginine, cyclohexylamine, ethanolamine, diethanolamine and Triethanolamine into consideration.

The compounds used as starting materials of the general NEN Formulas II to IV are partially known from the literature or man  receives these according to the literature known methods (see Examples I to XIV).

As already mentioned, the inventive Compounds of general formula I and their physiological Compatible salts have valuable pharmacological properties on, in particular, an inhibitory effect on that through the epidermis Growth Factor Receptor (EGF-R) mediated signal transduction, this being due, for example, to inhibition of the ligands binding, receptor dimerization or tyrosine kinase itself can be effected. It is also possible that the Signal transmission to further downstream components is blocked.

The biological properties of the new compounds were tested as follows:
The inhibition of EGF-R-mediated signal transmission can e.g. B. can be detected with cells that express human EGF-R and their survival and proliferation depends on stimulation by EGF or TGF-alpha. Here, an interleukin 3- (IL-3) -dependent cell line of murine origin was used, which was genetically engineered to express functional human EGF-R. The proliferation of these cells called F / L-HERc can therefore be stimulated either by murine IL-3 or by EGF (see by Rüden, T. et al., EMBO J. 7, 2749-2756 (1988) and Pierce, JH et in Science 239, 628-631 (1988)).

The starting material for the F / L-HERc cells was the cell line FDC-P ₁ , the preparation of which was obtained from Dexter, TM et al. in J. Exp. Med. 152, 1036-1047 (1980). Alternatively, however, other growth factor-dependent cells may be used (see, for example, Pierce, JH et al., Science 239, 628-631 (1988), Shibuya, H. et al., Cell 70, 57-67 (1992) and Alexander, WS et al., EMBO J. 10, 3683-3691 (1991)). For expression of the human EGF-R cDNA (see Ullrich, A. et al., Nature 309, 418-425 (1984)), recombinant retroviruses were used as described in Rüden, T. et al., EMBO J. 7, 2749-2756 (1988), except that the retroviral vector LXSN (see Miller, AD et al., BioTechniques 7, 980-990 (1989)) was used to express the EGF-R cDNA and the line as the packaging cell GP + E86 (see Markowitz, D. et al., J. Virol., 62, 1120-1124 (1988)).

The test was carried out as follows:
F / L-HERc cells were transfected into RPMI / 1640 medium (BioWhittaker) supplemented with 10% fetal bovine serum (FCS, Boehringer Mannheim), 2 mM glutamine (BioWhittaker), standard antibiotics and 20 ng / ml human EGF (Promega) at 37 ° C and 5% CO ₂ cultivated. To investigate the inhibitory activity of the compounds according to the invention, 1.5 × 10 ⁴ cells per well were cultivated in triplicates in 96-well plates in the above medium (200 μl), the proliferation of the cells either with EGF (20 ng / ml) or murine IL-3. Culture supernatants of the cell line X63 / mIL-3 served as a source of IL-3 (see Karasuyama, H. et al., Eur. J. Immunol., 18, 97-104 (1988)). The compounds according to the invention were dissolved in 100% dimethyl sulfoxide (DMSO) and added to the cultures in various dilutions, the maximum DMSO concentration being 1%. The cultures were incubated for 48 hours at 37 ° C.

To determine the inhibitory activity of the compounds according to the invention the relative cell number of the Cell Titer 96 ™ AQ _ueous Non-Radioactive Cell Proliferation Assay (Promega) was measured in OD units. The relative cell count was calculated as a percentage of the control (F / LHERc cells without inhibitor) and the drug concentration, which inhibits the proliferation of the cells to 50% (IC ₅₀ ) derived. The following results were obtained:

The compounds of general formula I according to the invention thus inhibit signal transduction by tyrosine kinases, such as has been shown by the example of the human EGF receptor, and are therefore useful for the treatment of pathophysiological processes, caused by hyperfunction of tyrosine kinases become. These are z. Benign or malignant tumors, especially tumors epithelial and neuroepithelial Origin, metastasis and abnormal proliferation vascular endothelial cells (neoangiogenesis).

The compounds of the invention are also useful for Prevention and treatment of respiratory diseases and the lungs that multiplied or changed Mucus production is accompanied by stimulation of Tyrosine kinases is caused, such. B. in inflammatory Respiratory diseases such as chronic bronchitis, chronic obstructive bronchitis, asthma, bronchiectasis, allergic or non-allergic rhinitis or sinusitis, cystic Fibrosis, α1-antitrypsin deficiency, or in cough, lungs emphysema, pulmonary fibrosis and hyperreactive airways.

The compounds are also suitable for the treatment of disorders of the gastrointestinal tract and the bile ducts and bladder, which are associated with a disrupted activity of tyrosine kinases, as z. B. in chronic inflammatory changes, such as cholecystitis, Crohn's disease, ulcerative colitis, and ulcers in the gastrointestinal tract or as they occur in diseases of the gastrointestinal tract, which are associated with increased secretion, such as M. Menetrier, secreting adenomas and protein loss syndromes,
Furthermore, for the treatment of nasal polyps and polyps of the gastrointestinal tract of different genesis such. As villous or adenomatous polyps of the colon, but also of polyps in familial polyposis coli, intestinal polyps in the context of Gardner syndrome, in polyps throughout the gastrointestinal tract in Peutz-Jeghers syndrome, in inflammatory pseudopolyps, in juvenile Polyps, in colitis cystica profunda and in pneumatosis cystoides intestinales.

In addition, the compounds of general formula I and their physiologically acceptable salts for the treatment of Kidney disease, especially in cystic changes as in cystic kidney, for the treatment of renal cysts, the idiopathic genesis or in the context of syndromes occur such. In tuberous sclerosis, in the case of Hippel-Lindau syndrome, in nephronophthisis and Medullary sponge kidney as well as other diseases are used, which causes by aberrant function of tyrosine kinases be such. B. epidermal hyperproliferation (psoriasis), inflammatory processes, diseases of the immune system, Hyperproliferation of hematopoietic cells, etc.

Due to their biological properties, the Compounds of the invention alone or in combination with applied to other pharmacologically active compounds be, for example in tumor therapy in monotherapy or in combination with other anti-tumor therapeutics, for example in combination with topoisomerase inhibitors (eg, etoposide), mitotic inhibitors (eg, vinblastine), with  Nucleic acid interacting compounds (eg, cis-platin, Cyclophosphamide, adriamycin), hormone antagonists (eg. Tamoxifen), inhibitors of metabolic processes (eg 5-FU etc.), cytokines (eg interferons), antibodies etc. For the Respiratory treatments can use these compounds alone or in combination with other respiratory therapies, such as B. secretolytic, broncholytic and / or anti-inflammatory substances are used. For the treatment of diseases in the area of the gastrointestinal tract Traktes may also be used alone or in these compounds Combination with motility or secretion-influencing or anti-inflammatory substances. These Combinations can be performed either simultaneously or sequentially be submitted.

The application of these compounds either alone or in Combination with other active substances may be intravenous, subcutaneous, intramuscular, intrarectal, intraperitoneal, intranasal, through Inhalation or transdermally or orally, wherein the Inhalation in particular aerosol formulations are suitable.

In the pharmaceutical application, the Compounds according to the invention usually in warm-blooded Vertebrates, especially in humans, in dosages of 0.01-100 mg / kg body weight, preferably at 0.1-15 mg / kg used. For administration, these are with one or several customary inert carriers and / or Diluents, z. With cornstarch, lactose, Cane sugar, microcrystalline cellulose, magnesium stearate, Polyvinylpyrrolidone, citric acid, tartaric acid, water, Water / ethanol, water / glycerin, water / sorbitol, Water / polyethylene glycol, propylene glycol, stearyl alcohol, Carboxymethylcellulose or fatty substances such as Hard fat or their suitable mixtures in usual galenic Preparations such as tablets, dragees, capsules, powder, suspension ions, solutions, sprays or suppositories.  

The following examples are intended to illustrate the present invention explain in more detail without limiting it:  

Preparation of the starting compounds example 1 4 - [(3-chloro-4-fluoro-phenyl) amino] -6-cyclopentylmethoxy- 7- (2-bromo-ethoxy-quinazoline

To 3.50 g of 4 - [(3-chloro-4-fluorophenyl) amino] -6-cyclopentylmethoxy-7-hydroxyquinazoline and 6.89 ml of 1,2-dibromoethane in 40 ml of N, N-dimethylformamide are added 4.84 g of potassium carbonate give it. The reaction mixture is stirred under nitrogen atmosphere at 80 ° C for 1.5 hours. After cooling to room tempera ture, the reaction mixture is filtered and the filtrate concentrated in vacuo. The oily, brown residue is cooled in an ice bath and triturated with a little methanol, wherein a yellow Licher solid crystallized out. The precipitate is filtered off with suction, washed with cold methanol and dried in a vacuum desiccator.
Yield: 2.60 g (58% of theory),
R _f value: 0.82 (silica gel, methylene chloride / methanol 9: 1)
Mass Spectrum (ESI ⁺ ): m / z = 494, 496, 498 [M + H] ⁺

Analogously to Example I, the following compounds are obtained:
(1) 4 - [(3-Chloro-4-fluoro-phenyl) -amino] -6-cyclopropylmethoxy-7- (2-bromo-ethoxy) -quinazoline (The reaction is carried out in acetonitrile as a solvent)
R _f value: 0.72 (silica gel, methylene chloride / methanol / concentrated te, aqueous ammonia solution = 90: 10: 0.1)
Mass spectrum (ESI ^-): m / z = 464, 466, 468 [MH] ^-
(2) 4 - [(3-Chloro-4-fluoro-phenyl) -amino] -6-cyclopentyloxy-7- (2-bromo-ethoxy) -quinazoline
R _f value: 0.65 (silica gel, methylene chloride / methanol / concentrated te, aqueous ammonia solution = 90: 10: 0.1)
Mass spectrum (ESI ^- ): m / z = 478, 480, 482 [MH] ^-
(3) 4 - [(3-Chloro-4-fluoro-phenyl) -amino] -7-cyclobutyloxy-6- (3-bromo-propyloxy) -quinazoline (The reaction is carried out in aceto-nitrile as a solvent)
R _f value: 0.62 (silica gel, methylene chloride / methanol 9: 1)
Mass spectrum (ESI ^- ): m / z = 478, 480, 482 [MH] ^-
(4) 4 - [(3-Chloro-4-fluoro-phenyl) -amino] -7-cyclopropylmethoxy-6- (3-bromo-propyloxy) -quinazoline (The reaction is carried out in aceto-nitrile as a solvent)
R _f value: 0.74 (silica gel, methylene chloride / methanol 9: 1)
Mass spectrum (ESI ^- ): m / z = 478, 480, 482 [MH] ^-
(5) 4 - [(3-Bromo-phenyl) -amino] -6- (2-bromo-ethoxy) -7-methoxy-quinazoline
Melting point: 244 ° C
Mass Spectrum (ESI ⁺ ): m / z = 452, 454, 456 [M + H] ⁺
(6) 4 - [(R) - (1-Phenyl-ethyl) amino] -6- (3-bromo-propyloxy) -7-methoxy-quinazoline (The reaction is carried out with potassium tert-butylate as the base)
R _f value: 0.60 (silica gel, ethyl acetate / methanol 9: 1)
(7) 4 - [(R) - (1-phenyl-ethyl) amino] -6- (2-bromo-ethoxy) -7-methoxy-quinazoline (The reaction is carried out with potassium tert -butylate as the base)
Melting point: 255 ° C
Mass spectrum (ESI ⁺ ): m / z = 402, 404 [M + H] ⁺

Example II 4 - [(3-chloro-4-fluoro-phenyl) amino] -6-cyclopentylmethoxy-7-hy droxy-quinazoline

4.99 g of 4 - [(3-chloro-4-fluorophenyl) amino] -6-cyclopentylmethoxy-7-methylcarbonyloxy-quinazoline are suspended in 80 ml of methanol and treated with 1.80 ml of concentrated, aqueous ammonia solution. The reaction mixture is stirred overnight at room temperature. For workup, the reaction mixture is diluted with 500 ml of methylene chloride, washed with water and saturated sodium chloride solution, dried over magnesium sulfate and concentrated. 4.30 g of a brownish solid are obtained. The crude product is stirred with tert.butyl methyl ether, filtered off with suction, washed with a little tert-butyl methyl ether and dried at room temperature in a vacuum.
Yield: 3.59 g (80% of theory),
R _f value: 0.48 (silica gel, methylene chloride / methanol / concentrated te, aqueous ammonia solution = 90: 10: 0.1)
Mass Spectrum (ESI ⁺ ): m / z = 388, 340 [M + H] ⁺

The following compounds are obtained analogously to Example II:
(1) 4 - [(3-Chloro-4-fluoro-phenyl) -amino] -6-cyclopropylmethoxy-7-hydroxy-quinazoline
R _f value: 0.56 (silica gel, methylene chloride / methanol 9: 1)
Mass spectrum (ESI ^- ): m / z = 358, 360 [MH] ^-
(2) 4 - [(3-Chloro-4-fluoro-phenyl) -amino] -6-cyclopentyloxy-7-hydroxy-quinazoline
R _f value: 0.53 (silica gel, methylene chloride / methanol / concentrated te, aqueous ammonia solution = 90: 10: 0.1)
Mass spectrum (ESI ⁺ ): m / z = 374, 376 [M + H] ⁺
(3) 6-Benzyloxy-4 - [(3-chloro-4-fluoro-phenyl) -amino] -7-hydroxy-quinazoline
R _f value: 0.54 (silica gel, methylene chloride / methanol / concentrated te, aqueous ammonia solution = 90: 10: 0.1)
Mass spectrum (ESI ⁺ ): m / z = 396, 398 [M + H] ⁺
(4) 4 - [(3-Bromo-phenyl) -amino] -6-hydroxy-7-methoxy-quinazoline (The reaction is carried out with sodium hydroxide in ethanol as a solvent)
R _f value: 0.23 (silica gel, ethyl acetate)
Mass spectrum (ESI ⁺ ): m / z = 346, 348 [M + H] ⁺

Example III 4 - [(3-chloro-4-fluoro-phenyl) amino] -6-cyclopentylmethoxy-7-me thylcarbonyloxy-quinazoline

4.03 g of 4-chloro-6-cyclopentylmethoxy-7-methylcarbonyloxy-china zoline are suspended in 70 ml of isopropanol and treated with 1.95 g of 3-chloro-4-fluoroaniline. The reaction mixture is refluxed for two hours under a nitrogen atmosphere. After cooling to room temperature, the resulting light precipitate is filtered off, washed with a little isopropanol and dried in air.
Yield: 4.99 g (92% of theory),
R _f value: 0.80 (silica gel, methylene chloride / methanol / concentrated te, aqueous ammonia solution = 90: 10: 0.1)
Mass spectrum (ESI ⁺ ): m / z = 430, 432 [M + H] ⁺

The following compounds are obtained analogously to Example II:
(1) 4 - [(3-Chloro-4-fluoro-phenyl) -amino] -6-cyclopropylmethoxy-7-methylcarbonyloxy-quinazoline
R _f value: 0.86 (silica gel, methylene chloride / methanol = 9: 1)
Mass spectrum (ESI ⁺ ): m / z = 402, 404 [M + H] ⁺
(2) 4 - [(3-Chloro-4-fluoro-phenyl) -amino] -6-cyclopentyloxy-7-methylcarbonyloxy-quinazoline
R _f value: 0.73 (silica gel, methylene chloride / methanol / concentrated te, aqueous ammonia solution = 90: 10: 0.1)
Mass Spectrum (ESI ⁺ ): m / z = 416, 418 [M + H] ⁺
(3) 6-Benzyloxy-4 - [(3-chloro-4-fluoro-phenyl) -amino] -7-methyl-carbonyloxy-quinazoline
R _f value: 0.76 (silica gel, methylene chloride / methanol / concentrated te, aqueous ammonia solution = 90: 10: 0.1)
Mass spectrum (ESI ⁺ ): m / z = 438, 440 [M + H] ⁺
(4) 4 - [(3-Bromo-phenyl) -amino] -6-methylcarbonyloxy-7-methoxy-quinazoline
R _f value: 0.50 (silica gel, ethyl acetate)
Mass Spectrum (ESI ⁺ ): m / z = 388, 390 [M + H] ⁺
(5) 4 - [(R) - (1-phenylethyl) amino] -6-hydroxy-7-methoxy-china zoline (The acetoxy protecting group is already split off under the reaction conditions)
R _f value: 0.46 (silica gel, ethyl acetate)
Mass spectrum (ESI ⁺ ): m / z = 296 [M + H] ⁺

Example IV 4-chloro-6-cyclopentylmethoxy-7-methylcarbonyloxy-quinazoline

3.80 g of 4-hydroxy-6-cyclopentylmethoxy-7-methylcarbonyloxy-quinazoline are suspended in 90 ml of thionyl chloride and heated to boiling under nitrogen atmosphere. After addition of four drops of N, N-dimethylformamide, the reaction mixture is heated for a further two hours under reflux. After cooling to room temperature, the excess thionyl chloride is distilled off in a water-jet vacuum. The brown residue is stirred with 30 ml of toluene. The solvent is distilled off and 4.30 g of a gray-brown solid remain, which is reacted further without further purification.
R _f value: 0.89 (silica gel, methylene chloride / methanol / concentrated te, aqueous ammonia solution = 90: 10: 0.1)

Analogously to Example IV, the following compounds are obtained:
(1) 4-Chloro-6-cyclopropylmethoxy-7-methylcarbonyloxy-china zolin
R _f value: 0.84 (silica gel, methylene chloride / methanol = 9: 1)
(2) 4-Chloro-6-cyclopentyloxy-7-methylcarbonyloxy-quinazoline
R _f value: 0.69 (silica gel, methylene chloride / methanol / concentrated te, aqueous ammonia solution = 90: 10: 0.1)
(3) 6-Benzyloxy-4-chloro-7-methylcarbonyloxy-quinazoline
R _f value: 0.77 (silica gel, methylene chloride / methanol / concentrated te, aqueous ammonia solution = 90: 10: 0.1)

Example V 4-hydroxy-6-cyclopentylmethoxy-7-methylcarbonyloxy-quinazoline

4.30 g of 4,7-dihydroxy-6-cyclopentylmethoxy-quinazoline in 100 ml of pyridine are heated to 80 ° C. under a nitrogen atmosphere. 1.80 ml of acetic anhydride are added to the dark brown suspension. The reaction mixture is stirred for three hours at 80 ° C, whereby a complete solution is formed. After cooling to room temperature, the reaction mixture is poured onto about 800 ml of ice water. The resulting precipitate is filtered off and washed thoroughly with water. The light gray solid is dried in a vacuum desiccator.
Yield: 3.82 g (77% of theory),
R _f value: 0.49 (silica gel, methylene chloride / methanol = 9: 1)
Mass spectrum (ESI ^-): m / z = 301 [MH] ^-

Analogously to Example V, the following compounds are obtained:
(1) 4-Hydroxy-6-cyclopropylmethoxy-7-methylcarbonyloxy-china zolin
R _f value: 0.53 (silica gel, methylene chloride / methanol = 9: 1)
Mass spectrum (ESI ^- ): m / z = 273 [MH] ^-
(2) 4-hydroxy-6-cyclopentyloxy-7-methylcarbonyloxy-quinazoline
Melting point: 209-212 ° C
Mass spectrum (ESI ^-): m / z = 287 [MH] ^-
(3) 6-Benzyloxy-4-hydroxy-7-methylcarbonyloxy-quinazoline
R _f value: 0.48 (silica gel, methylene chloride / methanol / concentrated te, aqueous ammonia solution = 90: 10: 0.1)
Mass spectrum (ESI ^-): m / z = 309 [MH] ^-

Example VI 4.7-dihydroxy-6-quinazoline cyclopentylmethoxy

5.76 g of 2-amino-5-cyclopentylmethoxy-4-hydroxybenzoic acid and 6.52 g of formamidine acetate in 140 ml of ethanol are refluxed for about three hours. For workup, the reaction mixture is concentrated to about 100 ml and treated with 300 ml of ice water, wherein a gray precipitate precipitates. The precipitate is filtered off with suction, washed with water and dried in a vacuum desiccator.
Yield: 4.57 g (77% of theory),
R _f value: 0.25 (silica gel, methylene chloride / methanol = 95: 5)
Mass spectrum (ESI ^-): m / z = 259 [MH] ^-

The following compounds are obtained analogously to Example VI:
(1) 4,7-Dihydroxy-6-cyclopropylmethoxy-quinazoline
R _f value: 0.45 (silica gel, methylene chloride / methanol / concentrated te, aqueous ammonia solution = 90: 10: 0.1)
Mass spectrum (ESI ^- ): m / z = 231 [MH] ^-
(2) 4,7-Dihydroxy-6-cyclopentyloxy-quinazoline
R _f value: 0.42 (silica gel, methylene chloride / methanol / concentrated te, aqueous ammonia solution = 90: 10: 0.1)
Mass spectrum (EI): m / z = 246 [M] ⁺
(3) 6-Benzyloxy-4,7-dihydroxy-quinazoline
R _f value: 0.44 (silica gel, methylene chloride / methanol / concentrated te, aqueous ammonia solution = 90: 10: 0.1)
Mass spectrum (ESI ^-): m / z = 267 [MH] ^-

Example VII 2-amino-5-cyclopentylmethoxy-4-hydroxy-benzoic acid

6.50 g of 5-cyclopentylmethoxy-4-hydroxy-2-nitro-benzoic acid who dissolved in 130 mL of methanol, with 2.00 g Raney nickel ver and hydrogenated under a hydrogen pressure of 50 psi for about three hours at room temperature until the calculated amount of hydrogen is included. The catalyst is filtered off and washed with hot methanol. The filtrate is concentrated in vacuo. It remains a brownish solid back, which is further reacted without further purification.
Yield: 5.79 g (100% of theory),
R _f value: 0.67 (silica gel, methylene chloride / methanol = 9: 1)
Mass spectrum (ESI ^-): m / z = 250 [MH] ^-

The following compounds are obtained analogously to Example VII:
(1) 2-Amino-5-cyclopropylmethoxy-4-hydroxybenzoic acid R _f value: 0.51 (silica gel, methylene chloride / methanol / concentrated te, aqueous ammonia solution = 90: 10: 0.1)
Mass spectrum (ESI ^- ): m / z = 222 [MH] ^-
(2) 2-Amino-5-cyclopentyloxy-4-hydroxybenzoic acid
R _f value: 0.38 (silica gel, methylene chloride / methanol / concentrated te, aqueous ammonia solution = 90: 10: 0.1)
Mass spectrum (ESI ⁺ ): m / z = 238 [M + H] ⁺
(3) 2-Amino-5-benzyloxy-4-hydroxybenzoic acid
R _f value: 0.52 (silica gel, methylene chloride / methanol / concentrated te, aqueous ammonia solution = 90: 10: 0.1)
Mass spectrum (ESI ^-): m / z = 258 [MH] ^-

Example VIII 5-cyclopentylmethoxy-4-hxrdroxy-2-nitro-benzoic acid

15.37 g of 4,5-methylenedioxy-2-nitro-benzoic acid and 51.84 ml of cyclopentylmethanol are dissolved in 100 ml of dimethyl sulfoxide and cooled under a nitrogen atmosphere in an ice bath. Now who added the portionwise 3.90 g of sodium. The reaction mixture is stirred for 30 minutes under ice bath cooling, then briefly heated to 35-40 ° C and then stirred for a further three hours under ice-bath cooling. Then the ice bath is removed and the reaction mixture is stirred overnight at room temperature. The dark brown red reaction solution is poured onto about 800 ml of acetone, whereby a dark brown Never precipitate precipitates. The precipitate is filtered off with suction, washed with acetone, dissolved in 300-400 ml of water and adjusted to about pH 2 with 60 ml of 2N hydrochloric acid. The aqueous solution is extracted several times with methylene chloride. The combined extracts are washed with saturated sodium chloride solution, dried over sodium sulfate and concentrated. The dark brown, oily flask residue is dissolved in 800 ml of methylene chloride and purified over a silica gel packing with methylene chloride / methanol (9: 1). A brown oil is obtained, which is made to crystallize by stirring with water under ice-bath cooling. The resulting brownish precipitate is filtered off with suction, washed with a little water and dried in a vacuum desiccator.
Yield: 9.55 g (47% of theory),
R _f value: 0.67 (silica gel, toluene / dioxane / ethanol / glacial acetic acid = 90: 10: 10: 6)
Mass spectrum (ESI ^- ): m / z = 280 [MH] ^-

The following compounds are obtained analogously to Example VIII:
(1) 5-Cyclopropylmethoxy-4-hydroxy-2-nitrobenzoic acid
R _f value: 0.61 (silica gel, toluene / dioxane / ethanol / glacial acetic acid = 90: 10: 10: 6)
Mass spectrum (ESI ^-): m / z = 252 [MH] ^-
(2) 5-Cyclopentyloxy-4-hydroxy-2-nitrobenzoic acid
R _f value: 0.62 (silica gel, toluene / dioxane / ethanol / glacial acetic acid = 90: 10: 10: 6)
Mass spectrum (ESI ^-): m / z = 266 [MH] ^-
(3) 5-Benzyloxy-4-hydroxy-2-nitrobenzoic acid
Melting point: 176-178 ° C
Mass spectrum (ESI ^-): m / z = 288 [MH] ^-

Example IX (2-hydroxy-2-methyl-propylamino) -acetic acid ethyl ester

100.00 g of sodium carbonate are added with cooling to 50.00 g of glycine ethyl ester hydrochloride in 100 ml of saturated potassium carbonate solution. The resulting mass is extracted several times with a total of about 600 ml of diethyl ether. The combined ether extracts are dried over sodium sulfate and concentrated to dryness. There remain 28.60 g of glycine ethyl ester. This is mixed with 26.00 ml of isobutylene oxide and 40 ml of absolute ethanol and heated in a Roth bomb at 90 ° C for six hours. After cooling to room temperature, the reac tion mixture is concentrated, leaving a thin liquid oil remains.
Yield: 45.80 g (73% of theory), mass spectrum (ESI ⁺ ): m / z = 176 [M + H] ⁺

Example X 4-methylamino-dihydro-furan-2-one

2.00 g of 4- (N-benzyl-N-methyl-amino) -dihydrofuran-2-one in 25 ml of methanol in the presence of 250 mg of palladium (10% on activated carbon) at a hydrogen pressure of 50 psi for about two hours Room temperature hydrogenated until the calculated amount of hydrogen is absorbed. For workup, the Kata analyzer is filtered off and the filtrate concentrated in vacuo. It remains a colorless oil, which is reacted immediately without further purification.
Yield: 1.20 g
R _f value: 0.13 (silica gel, ethyl acetate)
Mass spectrum (ESI ⁺ ): m / z = 116 [M + H] ⁺

Example XI 4- (N-benzyl-N-methyl-amino) -dihydro-furan-2-one

To 15.00 g of 5H-furan-2-one in 150 ml of methylene chloride are added 23.20 ml of N-methylbenzylamine. The reaction mixture is stirred for about 48 hours at room temperature. For workup, the reaction mixture is concentrated and chromatographed in portions over a silica gel column with ethyl acetate / petroleum ether (3: 1) as the eluent. The desired product is obtained as a yellowish oil.
Yield: 19.77 g (54% of theory),
R _f value: 0.67 (silica gel, ethyl acetate)
Mass spectrum (ESI ⁺ ): m / z = 228 [M + Na] ⁺

Example XII 4 - [(3-chloro-4-fluoro-phenyl) amino] -7-cyclobutyloxy-6-hydroxy- quinazoline

To 5.60 g of 6-benzyloxy-4 - [(3-chloro-4-fluoro-phenyl) amino] - 7-cyclobutyloxy-quinazoline are added dropwise with stirring 10 ml of trifluoroacetic acid. The reaction mixture is heated to about 40 ° C. After stirring for 20 hours at room temperature, another 3 ml of trifluoroacetic acid are added. After the reaction has hardly progressed even after stirring for a further three hours in Raumtem petatur, the reaction mixture is heated to 50 ° C. After four hours, the reaction is fully continuous and the excess trifluoroacetic acid is largely distilled off on Ro tationsverdampfer. The residue is mixed with water and made alkaline with concentrated aqueous ammonia solution. The resulting light brown precipitate is filtered off, washed with plenty of water and dried in a desiccator. The product obtained still contains trifluoroacetic acid.
Yield: 5.82 g
R _f value: 0.61 (silica gel, methylene chloride / methanol = 9: 1)
Mass spectrum (ESI ⁺ ): m / z = 360, 362 [M + H] ⁺

The following compounds are obtained analogously to Example XII:
(1) 4 - [(3-Chloro-4-fluoro-phenyl) -amino] -7-cyclopropylmethoxy-6-hydroxy-quinazoline
R _f value: 0.65 (silica gel, methylene chloride / methanol = 9: 1)
Mass spectrum (ESI ⁺ ): m / z = 360, 362 [M + H] ⁺

Example XIII 6-benzyloxy-4 - [(3-chloro-4-fluoro-phenyl) amino] -7-cyclobutyloxy quinazoline

To 7.00 g of 6-benzyloxy-4 - [(3-chloro-4-fluorophenyl) amino] -7-hydroxy-quinazoline in 60 ml of N, N-dimethylformamide are added 7.50 g of potassium carbonate and 4.50 g of methanesulfonic acid cyclobutylester. The reaction mixture is stirred for two hours at 80.degree. Then another 2.00 g of methanesulfonic acid cyclo butyl ester and 3.00 g of potassium carbonate are added and the mixture is stirred at 60 ° C over the weekend. Since the reaction is still not complete, 3.50 g of methanesulfonic acid cyclobutylester and 5.00 g of potassium carbonate are added again. After a further 20 hours at 80 ° C, the reaction is almost complete. For workup, the reaction mixture is mixed with 300 ml of ethyl acetate and washed with water and saturated sodium chloride solution. The organic phase is dried over magnesium sulfate and concentrated. The residue is stirred with methanol to give a brownish precipitate. This is filtered off, washed with methanol and dried in a desiccator.
Yield: 5.10 g (64% of theory),
R _f value: 0.69 (silica gel, methylene chloride / methanol = 9: 1)
Mass spectrum (ESI ^-): m / z = 448, 450 [MH] ^-

The following compounds are obtained analogously to Example XIII:
(1) 6-Benzyloxy-4 - [(3-chloro-4-fluoro-phenyl) -amino] -7-cyclopropylmethoxy-quinazoline (bromomethylcyclopropane is used)
R _f value: 0.72 (silica gel, methylene chloride / methanol = 9: 1)
Mass spectrum (ESI ^-): m / z = 448, 450 [MH] ^-

Example XIV (S) - (2-hydroxy-propylamino) -acetic acid tert.-butyl ester

15.00 g of (S) - (+) - 1-amino-2-propanol are dissolved in 100 ml of N, N-Di methylformamide and treated with 6.97 ml of diisopropylethylamine. Then 5.91 ml bromoacetic acid tert.butylester are added dropwise within 30 minutes under ice bath cooling. The cooling bath is removed and reaction mixture is stirred overnight at room temperature. For workup, the reaction mixture is concentrated in vacuo. The flask residue is dissolved in 50 ml of water and saturated with 15 g of sodium chloride ge. The aqueous solution is extracted several times with ethyl acetate ex tracted. The combined extracts are washed with saturated Na triumchlorid solution, dried over magnesium sulfate and concentrated in vacuo, leaving a yellowish oil remains.
Yield: 7.36 g (97% of theory),
R _f value: 0.46 (silica gel, ethyl acetate / methanol = 9: 1)
Mass spectrum (ESI ⁺ ): m / z = 190 [M + H] ⁺

The following compounds are obtained analogously to Example XIV:
(1) (R) - (2-Hydroxy-propylamino) -acetic acid-tert-butyl ester
R _f value: 0.46 (silica gel, ethyl acetate / methanol = 9: 1)
Mass spectrum (ESI ⁺ ): m / z = 190 [M + H] ⁺

Preparation of the end compounds example 1 4 - [(3-chloro-4-fluoro-phenyl) amino] -6-cyclopentylmethoxy- 7- [2- (2,2-dimethyl-6-oxo-morpholin-4-yl) -ethoxy] -quinazoline

250 mg of 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6-cyclopentylmethoxy-7- (2-bromo-ethoxy) -quinazoline and 341 mg of (2-hydroxy-2-methyl-propylamino) -acetic acid Ethyl acetate are dissolved in 20 ml of acetonitrile and treated with 50 mg of sodium iodide, 275 mg of potassium carbonate and 0.70 ml of diisopropylethylamine. The reaction mixture is refluxed for about 90 hours. After cooling to room temperature, the reaction mixture is filtered and the filtrate is concentrated in vacuo. The flask residue is chromatographed on a silica gel column with petroleum ether / ethyl acetate (50:50, later 0: 100) as the eluent. The cyclized product is obtained as a beige solid.
Yield: 62 mg (23% of theory),
R _f value: 0.29 (silica gel, ethyl acetate)
Mass spectrum (ESI ^- ): m / z = 541, 543 [MH] ^-

Analogously to Example 1, the following compounds are obtained:
(1) 4 - [(3-Chloro-4-fluoro-phenyl) -amino] -6-cyclopropylmethoxy-7- [2- (2,2-dimethyl-6-oxo-morpholin-4-yl) -ethoxy] - quinazoline
R _f value: 0.58 (silica gel, methylene chloride / methanol = 9: 1)
Mass spectrum (ESI ^-): m / z = 513, 515 [MH] ^-
(2) 4 - [(3-Chloro-4-fluoro-phenyl) -amino] -7-cyclobutyloxy-6- [3- (2,2-dimethyl-6-oxo-morpholin-4-yl) -propyloxy] - quinazoline
Melting point: 212-214 ° C
Mass spectrum (ESI ^- ): m / z = 527, 529 [MH] ^-
(3) 4 - [(3-chloro-4-fluoro-phenyl) -amino] -7-cyclopropylmethoxy-6- [3- (2,2-dimethyl-6-oxomorpholin-4-yl) -propyloxy] - quinazoline
Melting point: 200-202 ° C
Mass spectrum (ESI ^- ): m / z = 527, 529 [MH] ^-

Example 2 4 - [(3-chloro-4-fluoro-phenyl) amino] -6-cyclopropylmethoxy 7- {2- [N- (2-oxo-tetrahydrofuran-4-yl) -N-methyl-amino] -ethoxy} - quinazoline

300 mg of 4 - [(3-chloro-4-fluorophenyl) amino] -6-cyclopropylmethoxy-7- (2-bromoethoxy) quinazoline and 400 mg of 4-methylamino-dihydro-furan-2-one in 20 ml Acetonitrile are mixed with 240 mg Kaliumcar carbonate and 70 mg of sodium iodide and heated for 24 hours under reflux. After cooling to room temperature, the reaction mixture is filtered and the filtrate concentrated in vacuo. The flask residue is chromatographed on a silica gel column with methylene chloride / methanol / concentrated aqueous ammonia solution (97: 3: 0.05) as the eluent. The title compound is obtained as a light beige solid.
Yield: 70 mg (22% of theory),
R _f value: 0.47 (silica gel, methylene chloride / methanol / concentrated te, aqueous ammonia solution = 90: 10: 0.1)
Mass spectrum (ESI ⁺ ): m / z = 501, 503 [M + H] ⁺

Analogously to Example 2, the following compounds are obtained:
(1) 4 - [(3-Chloro-4-fluoro-phenyl) -amino] -6-cyclopentyloxy-7- {2- [N- (2-oxo-tetrahydrofuran-4-yl) -N-methyl-amino] -ethoxy} - quinazoline
R _f value: 0.42 (silica gel, methylene chloride / methanol / concentrated te, aqueous ammonia solution = 90: 10: 0.1)
Mass Spectrum (ESI ⁺ ): m / z = 515, 517 [M + H] ⁺

Example 3 4 - [(3-bromo-phenyl) amino] -6- [2 - ((S) -6-methyl-2-oxo-morpholine 4-yl) -ethoxy] -7-methoxy-quinazoline

To 380 mg of 4 - [(3-bromo-phenyl) -amino] -6- (2- {N - [(tert-butyl-oxo-carbonyl) -methyl] -N - ((S) -2-hydroxy-propyl) -amino} -ethoxy) -7-methoxy-quinazoline in 8 ml of acetonitrile are added to 90 ul of methanesulfonic acid. The reaction mixture is refluxed for about three hours, then another equivalent of Me sulfonic acid is added and further heated to reflux until the reaction is complete. For workup, the reaction mixture is diluted with ethyl acetate and washed with saturated sodium bicarbonate solution and saturated sodium chloride solution. The organic phase is dried over magnesium sulfate and concentrated in vacuo. The flask residue is stirred with diethyl ether and filtered with suction. The title compound is obtained as a white solid.
Yield: 280 mg (85% of theory),
Melting point: 190 ° C
Mass spectrum (ESI ^-): m / z = 485, 487 [MH] ^-

Analogously to Example 3, the following compounds are obtained:
(1) 4 - [(3-Bromo-phenyl) -amino] -6- [2 - ((R) -6-methyl-2-oxo-morpholin-4-yl) -ethoxy] -7-methoxy-quinazoline
Melting point: 193 ° C
Mass spectrum (ESI ⁺ ): m / z = 487, 489 [M + H] ⁺
(2) 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- [2 - ((R) -6-methyl-2-oxo-morpholin-4-yl) -ethoxy] -7- methoxy quinazoline (The reaction is carried out with trifluoroacetic acid in acetonitrile)
Melting point: 208 ° C
Mass spectrum (ESI ^-): m / z = 459, 461 [MH] ^-
(3) 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- [3 - ((R) -6-methyl-2-oxo-morpholin-4-yl) -propyloxy] -7- methoxy quinazoline (The reaction is carried out with trifluoroacetic acid in acetonitrile)
R _f value: 0.33 (silica gel, ethyl acetate)
Mass spectrum (ESI ^- ): m / z = 473, 475 [MH] ^-
(4) 4 - [(R) - (1-phenylethyl) amino] -6- [3 - ((S) -6-methyl-2-oxomorpholin-4-yl) -propyloxy] -7- methoxy quinazoline (The reaction is carried out with trifluoroacetic acid in acetonitrile)
R _f value: 0.41 (silica gel, ethyl acetate / methanol = 9: 1)
Mass spectrum (ESI ^-): m / z = 449 [MH] ^-
(5) 4 - [(R) - (1-phenylethyl) amino] -6- [2 - ((S) -6-methyl-2-oxomorpholin-4-yl) -ethoxy] -7- methoxy quinazoline (The reaction is carried out with trifluoroacetic acid in acetonitrile)
R _f value: 0.49 (silica gel, ethyl acetate / methanol / concentrated, aqueous ammonia solution = 9: 1: 0.1)
Mass spectrum (ESI ^-): m / z = 435 [MH] ^-

Example 4 4 - [(3-bromo-phenyl) amino] -6- (2- {N - [(butyloxycarbonyl) me thyl] -N - ((S) -2-hydroxy-propyl) -amino} ethoxy) -7-methoxy-china Zolin

To 650 mg of 4 - [(3-bromophenyl) amino] -6- (2-bromoethoxy) -7-methoxyquinazoline and 1.10 g of (S) - (2-hydroxypropylamino) acetic acid tert-butyl ester in 15 ml of acetonitrile are added 0.25 ml of diisopropylethylamine. The reaction mixture is stirred overnight at 50.degree. Since no reaction is recognizable, the reaction mixture is concentrated, treated with 20 ml of N, N-dimethylformamide and stirred at 60 ° C for eight hours. Then the temperature is raised to 80 ° C. After another eight hours, the implementation is complete. The reaction mixture is concentrated and chromatographed on a silica gel column with ethyl acetate as the eluent. The desired product is obtained as a white solid.
Yield: 410 mg (51% of theory),
R _f value: 0.27 (silica gel, ethyl acetate)
Mass spectrum (ESI ^- ): m / z = 559, 561 [MH] ^-

The following compounds are obtained analogously to Example 4:
(1) 4 - [(3-Bromo-phenyl) -amino] -6- (2- {N - [(tert -butyloxycarbonyl) -methyl] -N - ((R) -2-hydroxy-propyl) -amino} -ethoxy) -7-methoxy-quinazoline
Melting point: 130 ° C
Mass spectrum (ESI ^- ): m / z = 559, 561 [MH] ^-
(2) 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- (2- {N - [(tert -butyloxy-carbonyl) -methyl] -N - ((R) -2-hydroxy-propyl ) -amino} -ethoxy) - 7-methoxy-quinazoline (The reaction is carried out in N, N-dimethylformamide)
R _f value: 0.40 (silica gel, ethyl acetate / petroleum ether = 4: 1)
(3) 4 - [(3-Chloro-4-fluoro-phenyl) -amino] -6- (3- {N - [(tert -butyloxy-carbonyl) -methyl] -N - ((R) -2-hydroxy-propyl ) -amino} -propyloxy) - 7-methoxy-quinazoline (The reaction is carried out in N, N-dimethylformamide)
R _f value: 0.37 (silica gel, ethyl acetate / petroleum ether = 4: 1)
Mass spectrum (ESI ^- ): m / z = 547, 549 [MH] ^-
(4) 4 - [(R) - (1-Phenyl-ethyl) amino] -6- (3- {N - [(tert-butyl-oxycarbonyl) -methyl] -N - ((S) -2-hydroxy-propyl ) -amino} -propyloxy) - 7-methoxy-quinazoline (The reaction is carried out in N, N-dimethylformamide)
R _f value: 0.65 (silica gel, ethyl acetate / methanol = 9: 1)
Mass spectrum (EI): m / z = 524 [M] ⁺
(5) 4 - [(R) - (1-Phenylethyl) amino] -6- (2- {N - [(tert -butyloxy-carbonyl) -methyl] -N - ((S) -2-hydroxy-propyl ) -amino} -ethoxy) - 7-methoxy-quinazoline (The reaction is carried out in N, N-dimethylformamide)
R _f value: 0.57 (silica gel, ethyl acetate / methanol / concentrated, aqueous ammonia solution = 9: 1: 0.1)

Analogously to the above examples and other methods known from the literature, the following compounds can be prepared:
(1) 4 - [(3-chloro-4-fluoro-phenyl) -amino] -7- [2- (6-methyl-2-oxomorpholin-4-yl) -ethoxy] -6-methoxy-quinazoline
(2) 4 - [(3-Chloro-4-fluoro-phenyl) -amino] -7- [3- (6-methyl-2-oxomorpholin-4-yl) -propyloxy] -6-methoxy-quinazoline
(3) 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- [2 - ((S) -6-methyl-2-oxo-morpholin-4-yl) -ethoxy] -7- methoxy-quinazoline
(4) 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- [3 - ((S) -6-methyl-2-oxo-morpholin-4-yl) -propyloxy] -7- methoxy-quinazoline
(5) 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- [3- (5,5-dimethyl-2-oxo-morpholin-4-yl) -propyloxy] -7-methoxy quinazoline
(6) 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- [2- (5,5-dimethyl-2-oxomorpholin-4-yl) -ethoxy] -7-methoxy quinazoline
(7) 4 - [(3-Chloro-4-fluoro-phenyl) -amino] -6- [3- (3-methyl-2-oxomorpholin-4-yl) -propyloxy] -7-methoxy-quinazoline
(8) 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- [2- (3-methyl-2-oxomorpholin-4-yl) -ethoxy] -7-methoxy-quinazoline
(9) 4 - [(R) - (1-phenylethyl) amino] -6- [3 - ((R) -6-methyl-2-oxomorpholin-4-yl) -propyloxy] -7- methoxy-quinazoline
(10) 4 - [(R) - (1-phenylethyl) amino] -6- [2 - ((R) -6-methyl-2-oxomorpholin-4-yl) -ethoxy] -7- methoxy-quinazoline

Example 5 Dragées with 75 mg active substance

AL = L <1 drag core contains: active substance 75.0 mg calcium phosphate 93.0 mg corn starch 35.5 mg polyvinylpyrrolidone 10.0 mg hydroxypropyl methylcellulose 15.0 mg magnesium stearate 1.5 mg           230.0 mg         

manufacturing

The active substance is mixed with calcium phosphate, corn starch, polyvinylpyrrolidone, hydroxypropylmethylcellulose and half of the stated amount of magnesium stearate. On a tabletting machine compacts are produced with a diameter of about 13 mm, these are ground on a suitable machine through a sieve with a mesh size of 1.5 mm and mixed with the remaining amount of magnesium stearate. This granulate is pressed on a tabletting machine into tablets of the desired shape.
Core weight: 230 mg
Stamp: 9 mm, curved

The thus prepared dragee cores are coated with a film consisting essentially of hydroxypropylmethylcellulose. The finished Filmdragées are shined with beeswax.
Dragée weight: 245 mg.

Example 6 Tablets with 100 mg active substance composition

AL = L <1 tablet contains: active substance 100.0 mg lactose 80.0 mg corn starch 34.0 mg polyvinylpyrrolidone 4.0 mg magnesium stearate 2.0 mg           220.0 mg         

production method

Active ingredient, lactose and starch are mixed and uniformly moistened with an aqueous solution of polyvinylpyrrolidone. After screening of the moist mass (2.0 mm mesh size) and drying in a rack oven at 50 ° C is again sieved (1.5 mm mesh size) and admixed with the lubricant. The ready-to-use mixture is processed into tablets.
Tablet weight: 220 mg
Diameter: 10 mm, biplan with facet on both sides and one-sided part notch.

Example 7 Tablets with 150 mg active substance composition

AL = L <1 tablet contains: active substance 150.0 mg Milk sugar powder. 89.0 mg corn starch 40.0 mg Colloidal silicic acid 10.0 mg polyvinylpyrrolidone 10.0 mg magnesium stearate 1.0 mg           300.0 mg         

manufacturing

The mixed with lactose, corn starch and silica active substance is moistened with a 20% aqueous Polyvinylpyr rolidonlösung and beaten through a sieve with 1.5 mm Ma mesh size.
The granules dried at 45 ° C are again rubbed through the same sieve and mixed with the stated amount of magnesium stearate. From the mixture tablets are pressed.
Tablet weight: 300 mg
Stamp: 10 mm, flat

Example 8 Hard gelatine capsules with 150 mg active substance

AL = L <1 capsule contains: active substance 150.0 mg Corn starch drink. about 180.0 mg Milk sugar powder. about 87.0 mg magnesium stearate 3.0 mg           about 420.0 mg         

manufacturing

The active ingredient is mixed with the excipients, passed through a sieve of 0.75 mm mesh size and mixed homogeneously in a suitable device.
The final mixture is filled into hard gelatin capsules of size 1.
Capsule filling: approx. 320 mg
Capsule shell: hard gelatin capsule size 1.

Example 9 Suppositories with 150 mg active substance

AL = L <1 suppository contains: active substance 150.0 mg Polyethylene glycol 1500 550.0 mg Polyethylene glycol 6000 460.0 mg Polyoxyäthylensorbitanmonostearat 840.0 mg           2000.0 mg         

manufacturing

After melting the suppository mass of the Active substance homogeneously distributed in it and the melt in poured precooled molds.

Example 10 Suspensions with 50 mg active substance

AL = L <100 ml suspension contain: active substance 1.00 g Carboxymethylcellulose-Na-salt 0.10 g p-hydroxybenzoate 0.05 g p-hydroxybenzoate 0.01 g cane sugar 10.00 g glycerin 5.00 g Sorbitol solution 70% 20.00 g Aroma 0.30 g Water dist. ad 100 ml

manufacturing

Dest. Water is heated to 70 ° C. Herein, p-hydroxybenzoic acid methyl ester and propyl ester and glycerol and carboxymethyl cellulose sodium salt are dissolved with stirring. It witd cooled to room temperature and added with stirring, the active ingredient and dispersed homogeneously. After addition and dissolution of the sugar, the sorbitol solution and the aroma, the suspension is evacuated to vent with stirring.
5 ml of suspension contain 50 mg of active ingredient.

Example 11 Ampoules with 10 mg active substance composition

active substance 10.0 mg AL = L <0.01 N hydrochloric acid s.q. Aqua bidest ad 2.0 ml

manufacturing

The active substance is in the required amount 0.01 N HCl dissolved, isotonic with saline, sterile filtered and bottled in 2 ml ampoules.  

Example 12 Ampoules with 50 mg active substance composition

active substance 50.0 mg AL = L <0.01 N hydrochloric acid s.q. Aqua bidest ad 10.0 ml

manufacturing

The active substance is added in the required amount of 0.01N HCl dissolved, isotonic with saline, sterile filtered and filled in 10 ml ampoules.

Example 13 Capsules for powder inhalation with 5 mg active substance

AL = L <1 capsule contains: active substance 5.0 mg Lactose for inhalation purposes 5.0 mg           20.0 mg         

manufacturing

The active substance is mixed with lactose for inhalation purposes. The mixture is filled into capsules on a capsule machine (weight of the empty capsule approx. 50 mg).
Capsule weight: 70.0 mg
Capsule size: 3

Example 14 Inhalation solution for handheld nebulizer with 2.5 mg active substance

AL = L <1 Hub contains: active substance 2,500 mg benzalkonium chloride 0.001 mg AL = L <1 N hydrochloric acid q.s. Ethanol / water (50/50) ad 15,000 mg

manufacturing

The active substance and benzalkonium chloride are dissolved in ethanol / water (50/50). The pH of the solution is adjusted with 1 N hydrochloric acid. The adjusted solution is filtered and filled into containers suitable for the hand nebulizer (cartridges).
Fill weight of the container: 4.5 g

Claims (12)

1. Bicyclic heterocycles of the general formula
in the
R _{a represents} a benzyl or 1-phenylethyl group or a phenyl group substituted by the radicals R ₁ and R ₂ , where
R _{1 is} a hydrogen, fluorine, chlorine or bromine atom, a methyl, trifluoromethyl, cyano or ethynyl group and
R _{2 represents} a hydrogen or fluorine atom,
one of the radicals R _b or R _{c is} an R ₃ - (CH ₂ ) _m -O group and the other of the radicals R _b or R _{c is} a methoxy, cyclobutyloxy, cyclopenty loxy, cyclopropylmethoxy, cyclobutylmethoxy or Cyclopen tylmethoxygruppe , in which
R _{3 is} an N- (2-oxo-tetrahydrofuran-4-yl) -methylamino or N- (2-oxo-tetrahydrofuran-4-yl) -ethylamino group,
a R ₄ -O-CO-CH ₂ -N-CH ₂ CH ₂ -OH group substituted on the methylene groups by one or two methyl or ethyl groups, in which
R _{4 represents} a hydrogen atom or a C _1-4 alkyl group,
or a substituted by one or two methyl or ethyl groups 2-oxo-morpholin-4-yl group and
m represent the number 2 or 3,
with the proviso mean that the connections
4 - [(3-Chloro-4-fluoro-phenyl) -amino] -6-cyclopentyloxy-7- (2- {N- (2-hydroxy-2-methyl-prop-1-yl) -N - [(ethoxycarbonyl ) - methyl] -amino} -ethoxy) -quinazoline,
4 - [(3-chloro-4-fluoro-phenyl) -amino] -6-cyclopentyloxy-7- [2- (6,6-dimethyl-2-oxomorpholin-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] -ethoxy} -7-methoxy-quinazoline
excluded are,
their tautomers, their stereoisomers and their salts. 2. Compounds of general formula I according to claim 1, in which
R _{a represents} a benzyl or 1-phenylethyl group or a phenyl group substituted by the radicals R ₁ and R ₂ , where
R _{1 is} a hydrogen, fluorine, chlorine or bromine atom, a methyl, trifluoromethyl, cyano or ethynyl group and
R _{2 represents} a hydrogen or fluorine atom,
one of R _b or R _{c is} an R ₃ - (CH ₂ ) _m -O group and the other of R _b or R _{c is} a methoxy, cyclobutyloxy, cyclopentyloxy, cyclopropylmethoxy, cyclobutylmethoxy or cyclopentylmethoxy group, wherein
R _{3 is} an N- (2-oxo-tetrahydrofuran-4-yl) -methylamino or N- (2-oxo-tetrahydrofuran-4-yl) -ethylamino group,
one at the methylene groups by one or two methyl or ethyl groups substituted R ₄ -O-C _O -CH ₂ -N-CH ₂ CH ₂ -OH group, in which
R _{4 represents} a hydrogen atom or a C _1-4 alkyl group,
or a substituted by one or two methyl or ethyl groups 2-oxo-morpholin-4-yl group and
m represent the number 2 or 3,
with the proviso that the compounds are 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6-cyclopentyloxy-7- (2- {N- (2-hydroxy-2-methyl-prop-1-) yl) -N - [(ethoxycarbonyl) -methyl] -amino} -ethoxy) -quinazoline,
4 - [(3-chloro-4-fluoro-phenyl) -amino] -6-cyclopentyloxy-7- [2- (6,6-dimethyl-2-oxomorpholin-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-oxomorpholin-4-yl) -ethoxy] -7-methoxy-quinazoline,
4 - [(3-Bromo-phenyl) -amino] -6- [2- (5,5-dimethyl-2-oxomorpholin-4-yl) -ethoxy] -7-methoxy-quinazoline,
4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- [2- (6,6-dimethyl-2-oxomorpholin-4-yl) -ethoxy] -7-methoxy-quinazoline,
4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- [2- (6,6-dimethyl-2-oxomorpholin-4-yl) -ethoxy] -7-cyclobutyloxy-quinazoline,
4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- [2- (6,6-dimethyl-2-oxomorpholin-4-yl) -ethoxy] -7-cyclopentyloxy-quinazoline,
4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- [2- (6,6-dimethyl-2-oxomorpholin-4-yl) -ethoxy] -7-cyclopropylmethoxy-quinazoline,
4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- [2- (6,6-dimethyl-2-oxomorpholin-4-yl) -ethoxy] -7-cyclopentylmethoxy-quinazoline,
4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- {2- [N- (2-oxo-tetrahydro-furan-4-yl) -N-methyl-amino] -ethoxy} -7- methoxy-quinazoline,
4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- {2- [N- (2-oxo-tetrahydro-furan-4-yl) -N-methyl-amino] -ethoxy} -7- cyclopentyloxy-china zolin,
4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- {2- [N- (2-oxo-tetrahydro-furan-4-yl) -N-methyl-amino] -ethoxy} -7- cyclopentylmethoxy quinazoline,
4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- [3- (6,6-dimethyl-2-oxomorpholin-4-yl) -propyloxy) -7-methoxy-quinazoline,
4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- [3- (6,6-dimethyl-2-oxomorpholin-4-yl) -propyloxy] -7-cyclopentyloxy-quinazoline,
4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- [3- (6,6-dimethyl-2-oxomorpholin-4-yl) -propyloxy] -7-cyclopentylmethoxy-quinazoline,
(R) -4 - [(1-phenyl-ethyl) -amino] -6- [3- (6,6-dimethyl-2-oxomorpholin-4-yl) -propyloxy] -7-cyclopentyloxy-quinazoline,
4 - [(3-chloro-4-fluoro-phenyl) -amino] -7- [2- (6,6-dimethyl-2-oxomorpholin-4-yl) -ethoxy] -6-methoxy-quinazoline,
4 - [(3-chloro-4-fluoro-phenyl) -amino] -7- [2- (6,6-dimethyl-2-oxomorpholin-4-yl) -ethoxy] -6-cyclobutyloxy-quinazoline,
4 - [(3-chloro-4-fluoro-phenyl) -amino] -7- [2- (6,6-dimethyl-2-oxomorpholin-4-yl) -ethoxy] -6-cyclopentyloxy-quinazoline,
4 - [(3-chloro-4-fluoro-phenyl) -amino] -7- [2- (6,6-dimethyl-2-oxomorpholin-4-yl) -ethoxy] -6-cyclopropylmethoxy-quinazoline,
4 - [(3-chloro-4-fluoro-phenyl) -amino] -7- [2- (6,6-dimethyl-2-oxomorpholin-4-yl) -ethoxy] -6-cyclopentylmethoxy-quinazoline,
4 - [(3-chloro-4-fluoro-phenyl) -amino] -7- {2- [N- (2-oxo-tetrahydro-furan-4-yl) -N-methyl-amino] -ethoxy} -6- methoxy-quinazoline,
4 - [(3-chloro-4-fluoro-phenyl) -amino] -7- {2- [N- (2-oxo-tetrahydro-furan-4-yl) -N-methyl-amino] -ethoxy} -6- cyclopentyloxy-china zolin,
4 - [(3-chloro-4-fluoro-phenyl) -amino] -7- {2- [N- (2-oxo-tetrahydro-furan-4-yl) -N-methyl-amino] -ethoxy} -6- cyclopentylmethoxy quinazoline,
4 - [(3-chloro-4-fluoro-phenyl) -amino] -7- [3- (6,6-dimethyl-2-oxomorpholin-4-yl) -propyloxy] -6-methoxy-quinazoline,
4 - [(3-chloro-4-fluoro-phenyl) -amino] -7- [3- (6,6-dimethyl-2-oxomorpholin-4-yl) -propyloxy] -6-cyclopentyloxy-quinazoline,
4 - [(3-chloro-4-fluoro-phenyl) -amino] -7- [3- (6,6-dimethyl-2-oxomorpholin-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
excluded are,
their tautomers, their stereoisomers and their salts. 3. Compounds of general formula I according to claim 1, in which
R _{a represents} a 1-phenylethyl group or a phenyl group substituted by the radicals R ₁ and R ₂ , wherein
R _{1 is} a fluorine, chlorine or bromine atom, a methyl or ethynyl group and
R _{2 represents} a hydrogen or fluorine atom,
one of R _b or R _{c is} an R ₃ - (CH ₂ ) _m -O group and the other of R _b or R _{c is} a methoxy, cyclobutyloxy, cyclo pentyloxy, cyclopropylmethoxy, cyclobutylmethoxy or cyclopentylmethoxy group, in which
R _{3 is} an N- (2-oxo-tetrahydrofuran-4-yl) -methylamino group,
a substituted on the methylene groups by one or two methyl groups R ₄ -O-CO-CH ₂ -N-CH ₂ CH ₂ -OH group, in which
R _{4 represents} a C _1-4 alkyl group,
or a substituted by one or two methyl groups 2-oxo-morpholin-4-yl group and
m represent the number 2 or 3,
with the proviso mean that the connections
4 - [(3-Chloro-4-fluoro-phenyl) -amino] -6-cyclopentyloxy-7- (2- {N- (2-hydroxy-2-methyl-prop-1-yl) -N - [(ethoxycarbonyl ) - methyl] -amino} -ethoxy) -quinazoline,
4 - [(3-chloro-4-fluoro-phenyl) -amino] -6-cyclopentyloxy-7- [2- (6,6-dimethyl-2-oxomorpholin-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-oxomorpholin-4-yl) -ethoxy] -7-methoxy-quinazoline,
4 - [(3-Bromo-phenyl) -amino] -6- [2- (5,5-dimethyl-2-oxomorpholin-4-yl) -ethoxy] -7-methoxy-quinazoline,
4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- [2- (6,6-dimethyl-2-oxomorpholin-4-yl) -ethoxy] -7-methoxy-quinazoline,
4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- [2- (6,6-dimethyl-2-oxomorpholin-4-yl) -ethoxy] -7-cyclobutyloxy-quinazoline,
4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- [2- (6,6-dimethyl-2-oxomorpholin-4-yl) -ethoxy] -7-cyclopentyloxy-quinazoline,
4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- [2- (6,6-dimethyl-2-oxomorpholin-4-yl) -ethoxy] -7-cyclopropylmethoxy-quinazoline,
4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- [2- (6,6-dimethyl-2-oxomorpholin-4-yl) -ethoxy] -7-cyclopentylmethoxy-quinazoline,
4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- {2- [N- (2-oxo-tetrahydro-furan-4-yl) -N-methyl-amino] -ethoxy} -7- methoxy-quinazoline,
4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- {2- [N- (2-oxo-tetrahydro-furan-4-yl) -N-methyl-amino] -ethoxy} -7- cyclopentyloxy-china zolin,
4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- {2- [N- (2-oxo-tetrahydro-furan-4-yl) -N-methyl-amino] -ethoxy} -7- cyclopentylmethoxy quinazoline,
4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- [3- (6,6-dimethyl-2-oxomorpholin-4-yl) -propyloxy] -7-methoxy-quinazoline,
4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- [3- (6,6-dimethyl-2-oxomorpholin-4-yl) -propyloxy] -7-cyclopentyloxy-quinazoline,
4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- [3- (6,6-dimethyl-2-oxomorpholin-4-yl) -propyloxy] -7-cyclopentylmethoxy-quinazoline,
(R) -4 - [(1-phenyl-ethyl) -amino] -6- [3- (6,6-dimethyl-2-oxo-morpholino-4-yl) -propyloxy] -7-cyclopentyloxy-quinazoline .
4 - [(3-chloro-4-fluoro-phenyl) -amino] -7- [2- (6,6-dimethyl-2-oxomorpholin-4-yl) -ethoxy] -6-methoxy-quinazoline,
4 - [(3-chloro-4-fluoro-phenyl) -amino] -7- [2- (6,6-dimethyl-2-oxomorpholin-4-yl) -ethoxy] -6-cyclobutyloxy-quinazoline,
4 - [(3-chloro-4-fluoro-phenyl) -amino] -7- [2- (6,6-dimethyl-2-oxomorpholin-4-yl) -ethoxy] -6-cyclopentyloxy-quinazoline,
4 - [(3-chloro-4-fluoro-phenyl) -amino] -7- [2- (6,6-dimethyl-2-oxomorpholin-4-yl) -ethoxy] -6-cyclopropylmethoxy-quinazoline,
4 - [(3-chloro-4-fluoro-phenyl) -amino] -7- [2- (6,6-dimethyl-2-oxomorpholin-4-yl) -ethoxy] -6-cyclopentylmethoxy-quinazoline,
4 - [(3-chloro-4-fluoro-phenyl) -amino] -7- {2- [N- (2-oxo-tetrahydro-furan-4-yl) -N-methyl-amino] -ethoxy} -6- methoxy-quinazoline,
4 - [(3-chloro-4-fluoro-phenyl) -amino] -7- {2- [N- (2-oxo-tetrahydro-furan-4-yl) -N-methyl-amino] -ethoxy} -6- cyclopentyloxy-china zolin,
4 - [(3-chloro-4-fluoro-phenyl) -amino] -7- {2- [N- (2-oxo-tetrahydro-furan-4-yl) -N-methyl-amino] -ethoxy} -6- cylopentyl methoxy quinazoline,
4 - [(3-chloro-4-fluoro-phenyl) -amino] -7- [3- (6,6-dimethyl-2-oxomorpholine-4-1) -propyloxy] -6-methoxy-quinazoline,
4 - [(3-chloro-4-fluoro-phenyl) -amino] -7- [3- (6,6-dimethyl-2-oxomorpholin-4-yl) -propyloxy] -6-cyclopentyloxy-quinazoline,
4 - [(3-chloro-4-fluoro-phenyl) -amino] -7- [3- (6,6-dimethyl-2-oxomorpholin-4-yl) -propyloxy] -6-cyclopentylmethoxy-quinazoline and
(R) -4 - [(1-Phenylethyl) amino] -7- [3- (6,6-dimethyl-2-oxo-morpholin-4-yl) -propyloxy] -6-cyclopentyloxy-quinazoline
excluded are,
their tautomers, their stereoisomers and their salts. 4. Compounds of general formula I according to claim 1, in which
R _{a represents} a 1-phenylethyl group or a phenyl group substituted by the radicals R ₁ and R ₂ , wherein
R _{1 is} a fluorine, chlorine or bromine atom and
R _{2 represents} a hydrogen or fluorine atom,
one of the radicals R _b or R _{c is} an R ₃ - (CH ₂ ) _m -O group and the other of the radicals R _b or R _{c is} a methoxy, cyclobutyloxy, Cyclopen tyloxy, cyclopropylmethoxy, cyclobutylmethoxy or cyclo pentylmethoxy , in which
R _{3 represents} an N- (2-oxo-tetrahydrofuran-4-yl) -methylamino group or a 2-oxo-morpholin-4-yl group substituted by one or two methyl groups and
m represent the number 2 or 3,
with the proviso mean that the connections
4 - [(3-chloro-4-fluoro-phenyl) -amino] -6-cyclopentyloxy-7- [2- (6,6-dimethyl-2-oxomorpholin-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- (3-methyl-2-oxomorpholin-4-yl) -ethoxy] -7-methoxy-quinazoline,
4 - [(3-Bromo-phenyl) -amino] -6- [2- (5,5-dimethyl-2-oxomorpholin-4-yl) -ethoxy] -7-methoxy-quinazoline,
4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- [2- (6,6-dimethyl-2-oxomorpholin-4-yl) -ethoxy] -7-methoxy-quinazoline,
4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- [2- (6,6-dimethyl-2-oxomorpholin-4-yl) -ethoxy] -7-cyclobutyloxy-quinazoline,
4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- [2- (6,6-dimethyl-2-oxomorpholin-4-yl) -ethoxy] -7-cyclopentyloxy-quinazoline,
4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- [2- (6,6-dimethyl-2-oxomorpholin-4-yl) -ethoxy] -7-cyclopropylmethoxy-quinazoline,
4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- [2- (6,6-dimethyl-2-oxomorpholin-4-yl) -ethoxy] -7-cyclopentylmethoxy-quinazoline,
4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- {2- [N- (2-oxo-tetrahydro-furan-4-yl) -N-methyl-amino] -ethoxy} -7- methoxy-quinazoline,
4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- {2- [N- (2-oxo-tetrahydro-furan-4-yl) -N-methyl-amino] -ethoxy} -7- cyclopentyloxy-china zolin,
4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- {2- [N- (2-oxo-tetrahydrofuran-4-yl) -N-methyl-amino] -ethoxy} -7- cyclopentylmethoxy-china zoline,
4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- [3- (6,6-dimethyl-2-oxomorpholin-4-yl) -propyloxy] -7-methoxy-quinazoline,
4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- [3- (6,6-dimethyl-2-oxomorpholin-4-yl) -propyloxy] -7-cyclopentyloxy-quinazoline,
4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- [3- (6,6-dimethyl-2-oxomorpholin-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-fluoro-phenyl) -amino] -7- [2- (6,6-dimethyl-2-oxomorpholin-4-yl) -ethoxy] -6-methoxy-quinazoline,
4 - [(3-chloro-4-fluoro-phenyl) -amino] -7- [2- (6,6-dimethyl-2-oxomorpholin-4-yl) -ethoxy] -6-cyclobutyloxy-quinazoline,
4 - [(3-chloro-4-fluoro-phenyl) -amino] -7- [2- (6,6-dimethyl-2-oxomorpholin-4-yl) -ethoxy] -6-cyclopentyloxy-quinazoline,
4 - [(3-chloro-4-fluoro-phenyl) -amino] -7- [2- (6,6-dimethyl-2-oxomorpholin-4-yl) -ethoxy] -6-cyclopropylmethoxy-quinazoline,
4 - [(3-chloro-4-fluoro-phenyl) -amino] -7- [2- (6,6-dimethyl-2-oxomorpholin-4-yl) -ethoxy] -6-cyclopentylmethoxy-quinazoline,
4 - [(3-chloro-4-fluoro-phenyl) -amino] -7- {2- [N- (2-oxo-tetrahydro-furan-4-yl) -N-methyl-amino] -ethoxy} -6- methoxy-quinazoline,
4 - [(3-chloro-4-fluoro-phenyl) -amino] -7- {2- [N- (2-oxo-tetrahydro-furan-4-yl) -N-methyl-amino] -ethoxy} -6- cyclopentyloxy-china zolin,
4 - [(3-chloro-4-fluoro-phenyl) -amino] -7- {2- [N- (2-oxo-tetrahydro-furan-4-yl) -N-methyl-amino] -ethoxy} -6- cyclopentylmethoxy quinazoline,
4 - [(3-chloro-4-fluoro-phenyl) -amino] -7- [3- (6,6-dimethyl-2-oxomorpholin-4-yl) -propyloxy] -6-methoxy-quinazoline,
4 - [(3-chloro-4-fluoro-phenyl) -amino] -7- [3- (6,6-dimethyl-2-oxomorpholin-4-yl) -propyloxy] -6-cyclopentyloxy-quinazoline,
4 - [(3-chloro-4-fluoro-phenyl) -amino] -7- [3- (6,6-dimethyl-2-oxomorpholin-4-yl) -propyloxy] -6-cyclopentylmethoxy-quinazoline and
(R) -4 - [(1-Phenylethyl) amino] -7- [3- (6,6-dimethyl-2-oxomorpholin-4-yl) -propyloxy-6-cyclopentyloxy-quinazoline
excluded are,
their tautomers, their stereoisomers and their salts. 5. Compounds of general formula I according to claim 1, in which
R _{a represents} a 1-phenylethyl, 3-bromophenyl or 3-chloro-4-fluorophenyl group,
R _{b is} an R ₃ - (CH ₂ ) _m -O- group in which
R _{3 is} a substituted by one or two methyl groups 2-oxo-morpholin-4-yl group and
m represent the number 2 or 3,
and R _{c is} a methoxy, cyclobutyloxy or cyclopropylmethoxy group with the proviso that the compounds
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- (3-methyl-2-oxomorpholin-4-yl) -ethoxy] -7-methoxy-quinazoline,
4 - [(3-Bromo-phenyl) -amino] -6- [2- (5,5-dimethyl-2-oxomorpholin-4-yl) -ethoxy] -7-methoxy-quinazoline,
4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- [2- (6,6-dimethyl-2-oxomorpholin-4-yl) -ethoxy] -7-methoxy-quinazoline,
4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- [2- (6,6-dimethyl-2-oxomorpholin-4-yl) -ethoxy] -7-cyclobutyloxy-quinazoline,
4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- [2- (6,6-dimethyl-2-oxomorpholin-4-yl) -ethoxy] -7-cyclopropylmethoxy-quinazoline and
4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- [3- (6,6-dimethyl-2-oxomorpholin-4-yl) -propyloxy] -7-methoxy-quinazoline
excluded are,
their tautomers, their stereoisomers and their salts. 6. Compounds of general formula I according to claim 1, in which
R _{a is} a 3-chloro-4-fluoro-phenyl group,
R _{b is} a cyclopentyloxy, cyclopropylmethoxy or cyclopentyl methoxy group and
R _{c is} an R ₃ - (CH ₂ ) _m -O- group in which
R _{3 represents} an N- (2-oxo-tetrahydrofuran-4-yl) -methylamino group or a 2-oxo-morpholin-4-yl group substituted by two methyl groups;
m represent the number 2,
with the proviso mean that the connections
4 - [(3-chloro-4-fluoro-phenyl) -amino] -6-cyclopentyloxy-7- [2- (6,6-dimethyl-2-oxomorpholin-4-yl) -ethoxy] -quinazoline,
4 - [(3-chloro-4-fluoro-phenyl) -amino) -7- [2- (6,6-dimethyl-2-oxomorpholin-4-yl) -ethoxy] -6-cyclopentyloxy-quinazoline,
4 - [(3-chloro-4-fluoro-phenyl) -amino] -7- [2- (6,6-dimethyl-2-oxomorpholin-4-yl) -ethoxy] -6-cyclopropylmethoxy-quinazoline,
4 - [(3-chloro-4-fluoro-phenyl) -amino] -7- [2- (6,6-dimethyl-2-oxomorpholin-4-yl) -ethoxy] -6-cyclopentylmethoxy-quinazoline,
4 - [(3-chloro-4-fluoro-phenyl) -amino] -7- {2- [N- (2-oxo-tetrahydro-furan-4-yl) -N-methyl-amino] -ethoxy} -6- cyclopentyloxy-china zolin and
4 - [(3-chloro-4-fluoro-phenyl) -amino] -7- {2- [N- (2-oxo-tetrahydro-furan-4-yl) -N-methyl-amino] -ethoxy} -6- cyclopentylmethoxyquinazoline
excluded are,
their tautomers, their stereoisomers and their salts. 7. The following compounds of general formula I according to claim 1:
(1) 4 - [(3-Chloro-4-fluoro-phenyl) -amino] -6-cyclopentylmethoxy-7- [2- (2,2-dimethyl-6-oxo-morpholin-4-yl) -ethoxy] - quinazoline,
(2) 4 - [(3-Chloro-4-fluoro-phenyl) -amino] -6-cyclopentyloxy-7- {2- [N- (2-oxo-tetrahydrofuran-4-yl) -N-methyl-amino] -ethoxy} - quinazoline,
(3) 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6-cyclopropylmethoxy-7- [2- (2,2-dimethyl-6-oxo-morpholin-4-yl) -ethoxy] - quinazoline,
(4) 4 - [(3-Chloro-4-fluoro-phenyl) -amino] -7-cyclobutyloxy-6- [3- (2,2-dimethyl-6-oxo-morpholin-4-yl) -propyloxy] - china zolin,
(5) 4 - [(3-chloro-4-fluoro-phenyl) -amino] -7-cyclopropylmethoxy-6- [3- (2,2-dimethyl-6-oxomorpholin-4-yl) -propyloxy] - china zolin,
(7) 4 - [(3-Chloro-4-fluoro-phenyl) -amino] -6-cyclopropylmethoxy-7- {2- [N- (2-oxo-tetrahydrofuran-4-yl) -N-methyl-amino] -ethoxy} - quinazoline,
(8) 4 - [(3-Bromo-phenyl) -amino] -6- [2 - ((S) -6-methyl-2-oxo-morpholin-4-yl) -ethoxy] -7-methoxy-quinazoline .
(9) 4 - [(3-Bromo-phenyl) -amino] -6- [2 - ((R) -6-methyl-2-oxo-morpholin-4-yl) -ethoxy] -7-methoxy-quinazoline .
(10) 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- [2 - ((R) -6-methyl-2-oxo-morpholin-4-yl) -ethoxy] -7- methoxy-quinazoline,
(11) 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- [3 - ((R) -6-methyl-2-oxo-morpholin-4-yl) -propyloxy] -7- methoxy-quinazoline,
(12) 4 - [(R) - (1-phenylethyl) amino] -6- [3 - ((S) -6-methyl-2-oxomorpholin-4-yl) -propyloxy] -7- methoxy-quinazoline and
(13) 4 - [(R) - (1-phenylethyl) amino] -6- [2 - ((S) -6-methyl-2-oxomorpholin-4-yl) -ethoxy] -7- methoxy-quinazoline,
their tautomers, their stereoisomers and their salts. 8. Physiologically acceptable salts of the compounds according to the Claims 1 to 7 with inorganic or organic acids or bases. 9. A pharmaceutical composition containing a compound according Ansprü chen 1 to 7 or a physiologically acceptable salt according to Claim 8 next to optionally one or more inert Carriers and / or diluents. 10. Use of a compound according to claims 1 to 8 for the manufacture of a medicament for the treatment of benign or malignant tumors, for prevention and treatment of respiratory and pulmonary diseases, for treatment of polyps, diseases of the gastrointestinal tract, the Bile ducts and bladder as well as the kidney and skin is suitable. 11. A process for the preparation of a medicament according to An Claim 9, characterized in that non-chemical way A compound according to claims 1 to 8 in one or several inert carriers and / or diluents is incorporated. 12. A process for the preparation of the compounds of general formula I according to claims 1 to 8, characterized in that

• a) a compound of the general formula
  in the
  R _{a is} as defined in claims 1 to 7, one of R _b 'or R _c ' represents a methoxy, cyclobutyloxy, cyclopentyloxy, cyclopropylmethoxy, cyclobutylmethoxy or cyclopentylmethoxy group and
  the other of R _b 'or R _c ' represents a Z ₁ - (CH ₂ ) _m -O- group in which
  m as defined in claims 1 to 7 mentioned and
  Z ₁ denotes a leaving group,
  with a compound of the general formula
  H - R ₃ , (III)
  in the
  R _{3 is defined} as defined in claims 1 to 7, or is reacted
• b) an optionally formed in the reaction mixture connec tion of the general formula
  in the
  R _{a is} as defined in claims 1 to 7, one of R _b "or R _c " represents a methoxy, cyclobutyloxy, cyclopentyloxy, cyclopropylmethoxy, cyclobutylmethoxy or cyclopentylmethoxy group and
  the other of R _b "or R _c " represents an R ₃ '- (CH ₂ ) _m -O- group in which
  m as defined in claims 1 to 7 mentioned and
  R ₃ 'represents a R ₄ -O-CO-CH ₂ -N-CH ₂ CH ₂ -OH group substituted on the methylene groups by one or two methyl or ethyl groups, in which
  R _{4 represents} a hydrogen atom or a C _1-4 alkyl group,
  is cyclized and
  if necessary, a protective moiety used in the reactions described above is split off again and / or
  if desired, a compound of general formula I thus obtained is separated into its stereoisomers and / or
  a compound of the general formula I thus obtained is converted into its salts, in particular for the pharmaceutical application, into its physiologically tolerated salts.