BG107929A - Quinazoline derivatives, medicaments containing said compounds, their utilization and method for the production thereof - Google Patents

Abstract

The invention relates to quinazoline derivatives of general formula wherein Ra, Rb and Rc have the meaning defined in the description, to their tautomers, their stereoisomers and their salts, especially their physiologically acceptable salts with inorganic or organic acids. Said compounds have valuable pharmacological properties, especially an inhibiting effect upon signal transduction caused by tyrosine kinase. The invention further relates to their utilization in treatment of diseases, especially of tumoral diseases, diseases of the lung and the respiratory tract and to the production of said compounds.

Description

TECHNICAL FIELD

The invention relates to quinazoline derivatives containing medicaments, their use and method for their preparation.

SUMMARY OF THE INVENTION

The present invention relates to quinazoline derivatives of the general formula:

Rb

(I) their tautomers, stereoisomers and salts, in particular their physiologically acceptable salts of inorganic or organic acids, which exhibit valuable pharmacological properties, in particular inhibitory effects on the signal transduction mediated by tyrosine kinases, and their use for the treatment of diseases, especially tumors and diseases of the lungs and respiratory tract, as well as their production.

In the above general formula I:

R _a represents a benzyl, 1-phenylethyl or 3-chloro-4-fluorophenyl group;

R _b stands for one of the groups: dimethylamino, N-methyl-N-ethylamino, diethylamino, N-methyl-N-isopropylamino, N-methyl-N-cyclopropylamino, N-methyl-N- (2-methoxyethyl) amino, N- ethyl-N- (2-methoxyethyl) amino, bis- (2methoxyethyl) amino, morpholino, N-methyl-N- (tetrahydrofuran-3-yl) amino, N '-methyl-N- (tetrahydrofuran-2-ylmethyl) amino, N-methyl-1- (1- (tetrahydrofuran-3-ylmethyl) amino, N-methyl-1- (tetrahydropyran-4-yl) amino or N-methyl-N- (tetrahydropyran-4-ylmethyl) ) amino and

R _c stands for one of the groups: cyclopropylmethoxy, cyclobutyloxy, cyclopentyloxy, tetrahydrofuran-3-yloxy, tetrahydrofuran-2-ylmethoxy, tetrahydrofuran-3-ylmethoxy, tetrahydropyran-4-yloxy or tetrahydropyroxy-4-yl:

(1) 3-Chloro-4-fluorophenyl) amino] -6 - {[4- (1,1 ', N-diethylamino) -1-oxo-2-butene-

1-yl] amino} -7-cyclopropylmethoxy-quinazoline, (2) 4 - [(3-chloro-4-fluorophenyl) amino] -6 - {[4- (morpholin-4-yl) -1-oxo-2 -but-

1-yl] amino} -7-cyclopropylmethoxy-quinazoline, (3) 4 - [(3-chloro-4-fluorophenyl) amino] -6 - {[4- (dimethylamino) -1-oxo-2-butene-

1-yl] amino} -7-cyclopropylmethoxy-quinazoline, (4) 4 - [(3-chloro-4-fluorophenyl) amino] -6 - {[4- (morpholin-4-yl) -1-oxo-2 -Bugen3

1-yl] amino} -7-cyclobushloxy-quinazoline, (S) 4 - [(3-chloro-4-fluorophenyl) amino] -6 - {[4- (morpholin-4-yl) -1-oxo-2 -but-

1-yl] amino} -7-cyclopentyloxy-quinazoline, (6) 4 - [(3-chloro-4-fluorophenyl) amino] -6 - {[4- (diethylamino) -1-oxo-2-butene-1 yl] amino} -7-cyclobutyloxy-quinazoline, (7) 4 - [(3-chloro-4-fluorophenyl) amino] -6 - {[4- (diethylamino) -1-oxo-2-buten-1-yl] amino} -7-cyclopentyloxy-quinazoline, (S) 4 - [(R) - (1-phenylethyl) amino] -6 - {[4- (morpholin-4-yl) -1-oxo-2-butene-1 -yl] amino} -7-cyclobutyloxy-quinazoline, (9) 4 - [(R) - (1-phenylethyl) amino] -6 - {[4- (morpholin-4-yl) -1-oxo-2- buten-1-yl] amino} -7-cyclopropylmethoxy-quinazoline, (10) 4 - [(R) - (1-phenylethyl) amino] -6 - {[4- (morpholin-4-yl) -1-oxo -2-buten-1-yl] amino} -7-cyclopentyloxy-quinazoline, (11) 4 - ((S) - (1-phenyl) yl) amino] -6 - {[4- (diethylamino) -1-oxo-2-buten-1-yl] -amino} -7-cyclobutyloxy-quinazoline, (12) 4 - ((/ 7) - (1 -phenylethyl) amino] -6 - {[4- (diethylamino) -1-oxo-2-buten-1-yl] amino} -7-cyclopentyloxy-quinazoline, (13) 4- [(/ 7) - (1 -phenylethyl) amino] -6 - {[4- (diethylamino) -1-oxo-2-buten-1-yl] amino} -7-cyclopropylmethoxy-quinazoline, (14) 4 - [(3-chloro-4- fluorophenyl) amino] -6 - ({4- [bis- (2-methoxyethyl) amino] -1-oxo-2-buten-1-yl} amino) -7-cyclopropylmethoxy-quinazoline, (15) 4 - [(3 -chloro-4-fluorophenyl) amino] -6 - ({4- [N-ethyl-N- (2-methoxyethyl) amino] -1-oxo-2-buten-1-yl} amino) -7- cyclopropylmethoxy-quinazoline, (16) 4 - [(3-chloro-4-fluorophenyl) amino] -6 - ({4- [ N-methyl-N- (tetrahydropyran-4-yl) amino] -1-oxo-2-buten-1-yl} amino) -7-cyclopropylmethoxy-quinazoline, (17) 4 - [(3-chloro-4- fluorophenyl) amino] -6 - {[4- (diethylamino) -1-oxo-2-boogen-1-yl] -amino} -7 - [(tetrahydrofuran-2-yl) methoxy] -quinazole / 1H, (18) 4 - [(3-chloro-4-fluorophenyl) amino] -6 - {[4- (diethylamino) -1-oxo-2-buten-1-yl] amino} -7 - ((5) - (tetrahydrofuran- 3-yl) oxy] -quinazoline, (19) 4 - [(3-chloro-4-fluorophenyl) amino] -6 - {[4- (diethylamino) -1-oxo-2-buten-1-yl] amino} -7 - [(tetrahydropyran-4-yl) oxy] -quinazoline, (20) 4 - [(3-chloro-4-fluorophenyl) amino] -6 - ({4- [N-methyl-N- (tetrahydrofuran- 2ylmethyl) amino] -1-oxo-2-buten-1-yl} amino) -7-cyclopropyl methoxyquinazoline and (21) 4 - [(3-chloro-4-fluorophenyl) amino] -6 - ({4- [N-methyl-N- (tetrahydrofuran-3-yl) amino] -1-oxo-2-butene-1 -yl} amino) -7-cyclopropylmethoxy-quinazoline.

Preferred compounds of the general formula I above are those wherein R _a , R _b and R _c are as defined above but excluding the compounds:

(1) 4 - [(3-chloro-4-fluorophenyl) amino] -6 - {[4- (N, 1-diethylamino) -1-oxo-2-boogen-1-yl] amino} -7-cyclopropylmethoxy-quinazoline , (2) 4 - [(3-chloro-4-fluorophenyl) amino] -6 - {[4- (morpholin-4-yl) -1-oxo-2-boogene-

1-yl] amino} -7-cyclopropylmethoxy-quinazoline, (3) 4 - [(3-chloro-4-fluorophenyl) amino] -6 - {[4- (dimethylamino) -1-oxo-2-boogene-

1-yl] amino} -7-cyclopropylmethoxy-quinazoline, (4) 4 - [(3-chloro-4-fluorophenyl) amino] -6 - {[4- (morpholin-4-yl) -1-oxo-2 -bugen1-yl] amino} -7-cyclobutyloxy-quinazoline, (S) 4 - [(3-chloro-4-fluorophenyl) amino] -6 - {[4- (morpholin-4-yl) -1-oxo- 2-Butene-yl] amino} -7-cyclopentyloxy-quinazoline, (6) 4 - [(3-chloro-4-fluorophenyl) amino] -6 - {[4- (diethylamino) -1-oxo-2-butene -1-yl] amino} -7-cyclobutyloxy-quinazoline, (7) 4 - [(3-chloro-4-fluorophenyl) amino] -6 - {[4- (diethylamino) -1-oxo-2-butene-1 yl] amino} -7-cyclopentyloxy-quinazoline, (S) 4- [(S) - (1-phenylethyl) amino] -6 - {[4- (morpholin-4-yl) -1-oxo-2- buten-1-yl] amino} -7-cyclobugyloxy-quinazoline, (9) 4- [(R) - (1-phen (ethyl) amino] -6 - {[4- (morpholin-4-yl) -1-oxo-2-buten-1-yl] amino} -7-cyclopropylmethoxy-quinazoline, (10) 4 - [(R) - (1-phenylethyl) amino] -6 - {[4- (morpholin-4-yl) -1-oxo-2-boogen-1-yl] amino} -7-cyclopentyloxy-quinazoline, (11) 4- ( (R) - (1-Phenylethyl) amino] -6 - {[4- (diethylamino) -1-oxo-2-buten-1-yl] amino} -7-cyclobutyloxy-quinazoline, (12) 4- ( (R) - (1-phenylethyl) amino] -6 - {(4- (diethylamino) -1-oxo-2-buten-1-yl] amino} -7-cyclopentyloxy-quinazoline, (13) 4 - (( (7) - (1-phenylethyl) amino] -6 - {[4- (diethylamino) -1-oxo-2-buten-1-yl] amino} -7-cyclopropylmethoxy-quinazoline, (14) 4 - [( 3-chloro-4-fluorophenyl) amino] -6 - ({4- [bis- (2-methoxyethyl) amino] -1 oxo-2-but en-1-yl} amino) -7-cyclopropylmethoxy-quinazoline, (15) 4 - [(3-chloro-4-fluorophenyl) amino] -6 - ({4- [N-ethyl-N- (2-methoxyethyl) ) amino] -1-oxo-2-boogen-1-yl} amino) -7-cyclopropylmethoxy-quinazoline, (16) 4 - [(3-chloro-4-fluorophenyl) amino] -6 - ({4- [ N-methyl-1- (1- (tetrahydropyran-4-yl) amino] -1-oxo-2-buten-1-yl} amino) -7-cyclopropylmethoxy-quinazoline, (17) 4 - [(3-chloro-4- fluorophenyl) amino] -6 - {[4- (diethylamino) -1-oxo-2-buten-1-yl] -amino} -7 - [(tetrahydrofuran-2-yl) methoxy] -quinazoline, (18) 4- [(3-chloro-4-fluorophenyl) amino] -6 - {[4- (diethylamino) -1-oxo-2-buten-1-yl] amino} -7 - [(5) - (tetrahydrofuran-3-yl ) oxy] -quinazoline, (19) 4 - [(3-chloro-4-fluorophenyl) am but] -6 - {[4- (diethylamino) -1-oxo-2-buten-1-yl] amino} -7 - [(tetrahydropyran-4-yl) oxy] -quinazoline, (20) 4 - [(3 -chloro-4-fluorophenyl) amino] -6 - ({4- [N-methyl-N- (tetrahydrofuran-2-ylmethyl) amino] -1-oxo-2-buten-1-yl} amino) -7-cyclopropylmethoxyquinazoline, (21) 4 - [(3-chloro-4-fluorophenyl) amino] -6 - ({4- [N-methyl-1 \ 1- (tetrahydrofuran-3-yl) amino] -1-oxo-2-butene-1 -yl} amino) -7-cyclopropylmethoxy-quinazoline, (22) 4 - [(3-chloro-4-fluorophenyl) amino] -6 - ({4- [N- (2-methoxyethyl-N-methylamino) -1 -oxo-2-boogen-1-yl} amino) -7-cyclopropylmethoxy-quinazoline, (23) 4 - [(3-chloro-4-fluorophenyl) amino] -6 - ({4- [bis- (2- methoxyethyl) amino] -1-oxo-2-buten-1-yl} amino) -7-c clobutyloxy-quinazoline, (24) 4 - [(3-chloro-4-fluorophenyl) amino] -6 - ({4- [N-methyl-N- (2-methoxyethyl) amino] -1-oxo-2-butene -1-yl} amino) -7-cyclobutyloxy-quinazoline, (25) 4 - [(3-chloro-4-fluorophenyl) amino] -6 - ({4 - [(5) -1 N-methyl-N - ( tetrahydrofuran-3-yl) amino] -1-oxo-2-buten-1-yl} amino) -7-cyclobutyloxy-quinazoline, (26) 4 - [(3-chloro-4-fluorophenyl) amino] -6- ({4 - [(R) -N-methyl-N- (tetrahydrofuran-3-yl) amino] -1-oxo-2-boogen-1-yl} amino) -7-cyclobutyloxy-quinazoline, (27) 4 - [(3-chloro-4-fluorophenyl) amino] -6 - ({4- [N-methyl-N- (tetrahydropyran-4-yl) amino] -1-oxo-2-buten-1-yl} amino) - 7-cyclobutyloxy-quinazoline, (28) 4 - [(3-chloro-4-fluorophenyl) amino] -6 - ({4 - [(R) 4M-methyl-N- (tetrahydrofuran-2-ylmethyl) amino] -1-oxo-2-buten-1-yl} amino) -7-cyclobutyloxyquinazoline, (29) 4- [ (3-chloro-4-fluorophenyl) amino] -6 - ({4 - [(5) -N-methyl-N- (tetrahydrofuran-2-ylmethyl) amino] -1-oxo-2-buten-1-yl } amino) -7-cyclobugyloxyquinazoline, (30) 4 - [(3-chloro-4-fluorophenyl) amino] -6 - ({4- [1'-methyl-N- (2-methoxyethyl) amino] -1 -oxo-2-buten-1-yl} amino) -7- (tetrahydrofuran-3-yloxy) quinazoline, (31) 4 - [(3-chloro-4-fluorophenyl) amino] -6 - ({4- [ N-methyl-N- (2-methoxyethyl) amino] -1-oxo-2-buten-1-yl} amino) -7- (tetrahydropyran-4-yloxy) quinazoline, (32) 4 - [(3-chloro) -4-fluorophenyl) amino] -6 - ({4- [N-methyl-1 '1- (2-methoxyethyl) amino] - 1-oxo-2-buten-1-yl} amino) -7- (tetrahydrofuran-2-ylmethoxy) quinazoline and (33) 4 - [(3-chloro-4-fluorophenyl) amino] -6 - ({4- (1-Cyclopropyl-N-methylamino) 1-oxo-2-buten-1-yl] amino} -7-cyclopropylmethoxy-quinazoline, their tautomers, stereoisomers and salts.

Particularly preferred compounds of general formula I are those in which:

R _a represents one of the groups: 1-phenylethyl or 3-chloro-4-fluorophenyl,

R _b denotes one of the groups: dimethylamino, N-methyl-N-ethylamino, diethylamino, N-methyl-N-isopropylamino, N-methyl-N-cyclopropylamino,

N-methyl-N- (2-methoxyethyl) amino, N-ethyl-N-1- (2-methoxyethyl) amino, bis- (2methoxyethyl) amino, morpholino, N-methyl-N- (tetrahydrofuran-3-yl) amino,

N-methyl-N4- (tetrahydrofuran-2-ylmethyl) amino, N-1-methyl-N- (tetrahydrofuran-3-ylmethyl) amino, N-methyl-N- (tetrahydropyran-4-yl) amino or N-methyl -N- (tetrahydropyran-4-ylmethyl) amino and

R _c stands for one of the groups: cyclopropylmethoxy, cycloxy, cyclopentyloxy, tetrahydrofuran-3-yloxy, tetrahydrofuran-2-ylmethoxy, tetrahydrofuran-3-yl methoxy, tetrahydropyran-4-yloxy or tetrahydropyran-4-ylmethoxy, tetrahydropyran-4-ylmethoxy :

(1) 4 - [(3-chloro-4-fluorophenyl) amino] -6 - {[4- (1M, 1'-diethylamino) -1-oxo-2-buten-1-yl] amino} -7-cyclopropylmethoxy -quinazoline, (2) 4 - [(3-chloro-4-fluorophenyl) amino] -6 - {[4- (morpholin-4-yl) -1-oxo-2-butyl-yl] amino} -7- cyclopropylmethoxy-quinazoline, (3) 4 - [(3-chloro-4-fluorophenyl) amino] -6 - {[4- (dimethylamino) -1-oxo-2-butene-

1-yl] amino} -7-cyclopropylmethoxy-quinazoline, (4) 4 - [(3-chloro-4-fluorophenyl) amino] -6 - {[4- (morpholin-4-yl) -1-oxo-2 -butyl-yl] amino} -7-cyclobutyloxy-quinazoline, (S) 4 - [(3-chloro-4-fluorophenyl) amino] -6 - {[4- (morpholin-4-yl) -1-oxo- 2-Butene-yl] amino} -7-cyclopentyloxy-quinazoline, (6) 4 - [(3-chloro-4-fluorophenyl) amino] -6 - {[4- (diethylamino) -1-oxo-2-butene -1-yl] amino} -7-cyclobutyloxy-quinazoline, (7) 4 - [(3-chloro-4-fluorophenyl) amino] -6 - {[4- (diethylamino) -1-oxo-2-butene-1 yl] amino} -7-cyclopentyloxy-quinazoline, (S) 4 - [(R) - (1-phenylethyl) amino] -6 - {[4- (morpholin-4-yl) -1-oxo-2-butene -1-yl] amino} -7-cyclobutyloxy-quinazoline, (9) 4 - [(R) - (1-phenyl) ethyl) amino] -6 - {[4- (morpholin-4-yl) -1-oxo-2-buten-1-yl] amino} -7-cyclopropylmethoxy-quinazoline, (10) 4 - [(R) - (1-phenylethyl) amino] -6 - {[4- (morpholin-4-yl) -1-oxo-2-buten-1-yl] amino} -7-cyclopentyloxy-quinazoline, (11) 4 - [( N) - (1-phenylethyl) amino] -6 - {[4- (diethylamino) -1-oxo-2-buten-1-yl] amino} -7-cyclobutyloxy-quinazoline, (12) 4 - [(I ) - (1-phenylethyl) amino] -6 - {[4- (diethylamino) -1-oxo-2-buten-1-yl] amino} -7-cyclopentyloxy-quinazoline, (13) 4 - [(R) - (1-phenylethyl) amino] -6 - {[4- (diethylamino) -1-oxo-2-buten-1-yl] amino} -7-cyclopropylmethoxy-quinazoline, (14) 4 - [(3-chloro) -4-fluorophenyl) amino] -6 - ({4- [bis- (2-methoxyethyl) amino] -1-oxo-2-butyl n-1-yl} amino) -7-cyclopropylmethoxy-quinazoline, (15) 4 - [(3-chloro-4-fluorophenyl) amino] -6 - ({4- [N-ethyl-N- (2-methoxyethyl) ) amino] -1-oxo-2-buten-1-yl} amino) -7-cyclopropylmethoxy-quinazoline, (16) 4 - [(3-chloro-4-fluorophenyl) amino] -6 - ({4 - [N-methyl-1- {1- (tetrahydropyran-4-yl) amino] -1-oxo-2-buten-1-yl} amino) -7-cyclopropylmethoxy-quinazoline, (17) 4 - [(3-chloro- 4-fluorophenyl) amino] -6 - {[4- (diethylamino) -1-oxo-2-buten-1-yl] -amino} -7 - [(tetrahydrofuran-2-yl) methoxy] -quinazoline, (18) 4 - [(3-chloro-4-fluorophenyl) amino] -6 - {[4- (diethylamino) -1-oxo-2-buten-1-yl] amino} -7 - [(5) - (tetrahydrofuran-3 -yl) oxy] -quinazoline, (19) 4 - [(3-chloro-4-fluorophenyl) amine o] -6 - {[4- (diethylamino) -1-oxo-2-buten-1-yl] amino} -7 - [(tetrahydropyran-4-yl) oxy] -quinazoline, (20) 4 - [(3 -chloro-4-fluorophenyl) amino] -6 - ({4- [N-methyl-N-1- (tetrahydrofuran-3-ylmethyl) amino] -1-oxo-2-buten-1-yl} amino) -7- cyclopropylmethoxyquinazoline, (21) 4 - [(3-chloro-4-fluorophenyl) amino] -6 - ({4- [N- (2-methoxyethyl-N-methylamino) -1-oxo-2-buten-1-yl } amino) -7-cyclopropylmethoxy-quinazoline, (22) 4 - [(3-chloro-4-fluorophenyl) amino] -6 - ({4- [bis- (2-methoxyethyl) amino] -1-oxo-2-butene -1-yl} amino) -7-cyclobutyloxy-quinazoline, (23) 4 - [(3-chloro-4-fluorophenyl) amino] -6 - ({4- [N-methyl-N- (2-methoxyethyl) amino] -1-oxo-2-buten-1-yl} amino) -7-cyclobutyl cy-quinazoline, (24) 4 - [(3-chloro-4-fluorophenyl) amino] -6 - ({4 - [(5) -N-methyl-N- (tetrahydrofluoro-3-yl) amino] - 1-oxo-2-buten-1-yl} amino) -7-cyclobutyloxy-quinazoline, (25) 4 - [(3-chloro-4-fluorophenyl) amino] -6 - ({4 - [(R) - N-methyl-N- (tetrahydrofuran-3-yl) amino] -1-oxo-2-buten-1-yl} amino) -7-cyclobutyloxy-quinazoline, (26) 4 - [(3-chloro-4- fluorophenyl) amino] -6 - ({4- [N-1-methyl-N- (tetrahydropyran-4yl) amino] -1-oxo-2-buten-1-yl} amino) -7-cyclobutyloxy-quinazoline, ( 27) 4 - [(3-chloro-4-fluorophenyl) amino] -6 - ({4- [N-methyl-N-1- (2-methoxyethyl) amino] -1-oxo-2-butene-1- yl} amino) -7- (tetrahydrofuran-3-yloxy) quinazoline, (2S) 4 - [(3-chloro-4-fluorophenyl) amino] -6- ({4- [N-methyl-N- (2-methoxyethyl) amino] -1-oxo-2-buten-1-yl} amino) -7- (tetrahydropyran-4-yloxy) quinazoline, (29) 4- [(3-chloro-4-fluorophenyl) amino] -6 - ({4- [N-methyl-1 \ 1- (2-methoxyethyl) amino] -1-oxo-2-buten-1-yl} amino) -7- (tetrahydrofuran-2-ylmethoxy) quinazoline, (30) 4 - [(3-chloro-4-fluorophenyl) amino] -6 - ({4- (N-cyclopropyl-1 \ 1-methylamino) -

-oxo-2-buten-1-yl] amino} -7-cyclopropylmethoxy-quinazoline, (31) 4 - [(3-chloro-4-fluorophenyl) amino] -6 - ({4- [N-methyl-1 \ 1- (tetrahydrofuran-2ylmethyl) amino] -1-oxo-2-buten-1-yl} amino) -7-cyclopropylmethoxyquinazoline, (32) 4 - [(3-chloro-4-fluorophenyl) amino] -6- ({4 - [(L) -1 \ 1-methyl-N- (tetrahydrofuran-2-ylmethyl) amino] -1-oxo-2-buten-1-yl} amino) -7-cyclobutyloxyquinazoline and (33) 4 - [(3-chloro-4-fluorophenyl) amino] -6 - ({4 - [(5) -N-methyl-N- (tetrahydrofuran-2-ylmethyl) amino] -1-oxo-2-butene-1 -yl} amino) -7-cyclobutyloxyquinazoline, their tautomers, stereoisomers and salts.

As examples, the following particularly preferred compounds of general formula I may be mentioned:

(a) 4 - [(3-chloro-4-fluorophenyl) amino] -6 - {[4- (N, N-dimethylamino) -1-oxo-2-buten-1-yl] amino} -7-cyclobutyloxy- quinazoline, (b) 44 (3-chloro-4-fluorophenyl) amino] -6 - {[4- (N, N-dimethylamino) -1-oxo-2-buten-1-yl] amino} -7-cyclopentyloxy-quinazoline , (c) 4 - [(R) - (1-phenylethyl) amino] -6 - {[4- (N, N-bis- (2-methoxyethyl) amino) -1 oxo-2-buten-1-yl ] amino} -7-cyclopropylmethoxy-quinazoline, (d) 4 - [(R) - (1-phenylethyl) amino] -6 - ({4- [N- (2-methoxyethyl) -N-ethylamino] -1 oxo -2-buten-1-yl} amino] -7-cyclopropylmethoxy-quinazoline, (e) 4 - [(R) - (1-phenylethyl) amino] -6 - ({4- [N- (2-methoxyethyl) -N-methylamino] -1-oxo-2-buten-1-yl} amino] -7-cyclopropylmethoxy-quinazole yn, (e) 4f (N - (1-phenylethyl) amino] -6 - ({4- [N- (tetrahydropyran-4-yl) -1H-methylamino] -1-oxo-2-butene-1 - yl} amino) -7-cyclopropylmethoxy-quinazoline, (g) 4 - [(R) - (1-phenylethyl) amino] -6 - ({4- [N- (tetrahydrofuran-3-yl) -N-methylamino] -1-oxo-2-buten-1-yl} amino) -7-cyclopropylmethoxy-quinazoline, (3) 4 - [(3-chloro-4-fluorophenyl) amino] -6 - [(4- {M - [ (tetrahydrofuran-3-yl) methyl] -N-methylamino} -1-oxo-2-buten-1-yl) amino] -7-cyclopropylmethoxyquinazoline, (i) 4 - [(3-chloro-4-fluorophenyl) amino ] -6 - {[4- (N, N-dimethylamino) -1-oxo-2-buten-1-yl] amino} -7 - ((R) -tetrahydrofuran-3-yloxy) -quinazoline, (j) 4- [(3-chloro-4-fluorophenyl) amino] -6 - {[4- (N, N-dimethyl) but) -1-oxo-2-buten-1-yl] amino} -7 - ((5) -tetrahydrofuran-3-yloxy) -quinazoline, (k) 4f (3-chloro-4-fluorophenyl) amino] -6- {[4- (N, N-dimethylamino) -1-oxo-2-buten-1-yl] amino} -7- (tetrahydropyran-4-yloxy) -x1 / 1azoline, (1) 4f (3-chloro-4- fluorophenyl) amino] -6 - {[4- (N, N-dimethylamino) -1-oxo-2-buten-1-yl] amino} -7 - [(tetrahydrofuran-2-yl) methoxy] -quinazoline, (m) 4f (3-chloro-4-fluorophenyl) amino] -6 - {[4- (N, N-dimethylamino) -1-oxo-2-buten-1-yl] amino} -7 - [(tetrahydrofuran-3-yl) methoxy] -quinazoline, (o) 4 - [(3-chloro-4-fluorophenyl) amino] -6 - {[4- (N, diethylamino) -1-oxo-2-buten-1-yl] amino} -7 - [(tetrahydrofuran-3-yl) methoxy] -quinazoline, (n) 4 - [(R) - (1-phenyl) yl) amino] -6 - {[4- (N, N-dimethylamino) -1-oxo-2-buten-11 yl] amino} -7-cyclopropylmethoxy-quinazoline, (h) 4 - [(3-chloro) -4-fluorophenyl) amino] -6 - ({4- [N, N-bis- (2-methoxyethyl) amino] 1-oxo-2-buten-1-yl} amino) -7 - [(tetrahydrofuran-2 -yl) methoxy] -quinazoline, (p) 4 - [(3-chloro-4-fluorophenyl) amino] -6 - {[4- (morpholin-4-yl) -1-oxo-2-butenyl-yl] amino} -7 - [(tetrahydrofuran-2-yl) methoxy] -quinazoline, (c) 4 - [(3-chloro-4-fluorophenyl) amino] -6 - {[4- (N-cyclopropyl-N-methylamino) 1-oxo-2-buten-1-yl] amino} -7-cyclopentyloxy-quinazoline and (m) 4 - [(3-chloro-4-fluorophenyl) amino] -6 - {[4- (1H, M) -dimethylamino) -1-oxo-2-buten-1-yl] amino} -7 - [(5) - (tetrahydrofuran-2-yl) ethoxy] -quinazoline, the tautomers, stereoisomers and salts thereof.

The compounds of general formula I can be prepared, for example, according to the following methods:

a) reaction of a compound of the general formula:

wherein:

R _a and R _c are as defined initially with a compound of the general formula:

ο (III) in which:

R _b is defined as in the beginning and

Ζτ means a leaving group such as a halogen atom, e.g. chlorine or bromine atom or hydroxyl group.

In this case, the reaction is carried out in a solvent or in a mixture of solvent vapors. methylene chloride, dimethylformamide, benzene, toluene, chlorobenzene, tetrahydrofuran, benzene / tetrahydrofuran or dioxane, optionally in the presence of an inorganic or organic base and optionally in the presence of a dehydrating agent, preferably at temperatures between

-50 ° C to 150 ° C, preferably at temperatures between -20 ° C and 80 ° C.

For a compound of general formula III, in which _7.y is a leaving group, the reaction is optionally carried out in a solvent or in a mixture of solvents such as methylene chloride, dimethylformamide, benzene, toluene, chlorobenzene, tetrahydrofuran, benzene / tetrahydrofuran or dioxane, as appropriate in the presence of on a tertiary organic base such as triethylamine, pyridine or 4-dimethylaminopyridine; in the presence of N-ethyldiisopropylamine (Huenig base), in which these organic bases may also serve as a solvent or in the presence of an inorganic base such as sodium carbonate, potassium carbonate or sodium hydroxide, preferably at temperatures between -50 ° C. and 150 ° C, preferably at temperatures between -20 ° C and 80 ° C.

For a compound of general formula III in which f is a hydroxyl group, it is preferable to carry out the reaction in the presence of a dehydrating agent, e.g. in the presence of hydrochloric acid isobutyl ester, thionyl chloride, trimethylchlorosilane, phosphorus trichloride, phosphorus petoxide, hexamethyldisilazane, Ν, Ν'-dicyclohexylcarbodiimide, N, 1 \ 1-dicyclohexidine / hydroxybicyclohexidine / hydroxybicyclohexidine -carbonyldiimidazole or triphenylphosphine / tetrachloromethane, optionally in a solvent such as methylene chloride, tetrahydrofuran, dioxane, toluene, chlorobenzene, dimethylformamide, dimethylsulfoxide, ethyl ether of ethylene glycol, or sulpholethane, sulpholene, o 4-dimethylaminopyridine, at temperatures between -50 ° C and 150 ° C, but preferably at temperatures between -20 ° C and 80 ° C.

b) reaction of a compound of the general formula:

Η Ν.

(Iv) in which:

R _a and R _c are as defined above and

Z ₂ means a leaving group such as a halogen atom or a substituted hydroxy or sulfonyloxy group, e.g. chlorine or boron atom, methanesulfonyloxy or p-toluenesulfonyloxy group, with a compound of the general formula:

HR _b (V) in which R _b is as defined above.

It is advantageous to carry out the reaction in a solvent such as isopropanol, butanol, tetrahydrofuran, dioxane, toluene, chlorobenzene, dimethylformamide, dimethylsulfoxide, methylene chloride, monomethyl ether of ethylene glycol, diethyl ether of ethylene glycol, sulphanol glycol, sulphanol glycol, sulphanol tertiary organic base, e.g. sodium carbonate or potassium hydroxide, a tertiary organic base, e.g. triethylamine or N-ethyldiisopropylamine (Huenig base), in which these organic bases can serve simultaneously as solvents and optionally in the presence of a reaction catalyst, such as an alkali halide, at temperatures between -20 ° C and 150 ° C , but preferably at temperatures between -10 ° C and 100 ° C. The reaction may also be carried out without solvent or in excess of the compound of general formula V used.

In the above interactions, the quinazoline represented by the general formulas II or IV secondary amino groups can be protected during the reaction by traditional protecting groups which, once the reaction is complete, will be removed again. Like

Examples of protecting groups may include the following: benzyl, acetyl, trifluoroacetyl, ethoxycarbonyl, tert-butoxycarbonyl, benzyloxycarbonyl, benzyl, methoxybenzyl or 2,4-dimethoxybenzyl.

Subsequent removal, in the case of the use of a protecting group, is carried out, for example, by hydrolysis in an aqueous solvent, e.g. water, isopropanol / water, acetic acid / water, tetrahydrofuran / water or dioxane / water, in the presence of an acid such as trifluoroacetic, hydrochloric or sulfur or in the presence of an alkaline base such as sodium hydroxide or potassium hydroxide or aprotic, e.g. in the presence of iodtrimethylsilane at temperatures between 0 and 120 ° C, preferably at temperatures between 10 ° C and 100 ° C.

The cleavage of a benzyl, methoxybenzyl or benzyloxycarbonyl radical proceeds successfully by hydrogenolysis, e.g. with hydrogen in the presence of a catalyst such as palladium / charcoal in a suitable solvent such as methanol, ethanol, ethyl acetate or glacial acetic acid, optionally with the addition of an acid such as hydrochloric acid, at temperatures between 0 and 100 ° C, preferably at room temperature - between 20 ° C and 60 ° C and at a hydrogen pressure of from 1 to 7 bars, preferably from 3 to 5 bars.

The cleavage of 2,4-dimethoxybenzyl radical proceeds favorably in trifluoroacetic acid in the presence of anisole.

The cleavage of t-butyl or t-butyloxycarbonyl radical proceeds favorably by treatment with an acid such as trifluoroacetic or hydrochloric acid or by treatment with iodtrimethylsilane using a solvent such as methylene chloride, dioxane, methanol or diethyl ether.

The cleavage of the trifluoroacetyl radical proceeds favorably by treatment with an acid, for example hydrochloric acid, optionally in the presence of a solvent such as acetic acid, at temperatures between 50 and 120 ° C, or by treatment with sodium hydroxide, optionally in the presence of a solvent such as tetrahydrofuran, at temperatures between 0 and 50 ° C.

The compounds of general formula I obtained may, as mentioned initially, be separated into their enantiomers and / or diastereomers. For example, the cis / trans mixtures can be separated into the corresponding cis and trans isomers, and the compounds with at least one optically active carbon atom are separated into their enantiomers.

Thus, for example, the resulting cis / trans mixtures can be separated chromatographically into their cis and trans isomers, the resulting compounds of general formula I, which are obtained as racemates, can be separated into their optical antipodes by known methods (see Allinger NL and Eliel EL in "Topics in Stereochemistry", Vol. 6, Wiley Interscience, 1971), and compounds of general formula I with at least 2 asymmetric carbon atoms, based on physicochemicals their differences can be separated according to known methods, e.g. by chromatography and / or fractional crystallization, of their diastereomers and, if obtained in racemic form, these, then, as mentioned above, are separated into the corresponding enantiomers.

Enantiomeric separation proceeds favorably as column separation on chiral phases or by recrystallization from an optically active solvent or by reaction with an optically active substance which forms salts or other derivatives with the racemic compound, e.g. esters or amides, especially acids and their active derivatives or alcohols, and separation of the diastereomeric salt mixtures or derivatives thus obtained, e.g. based on their different solubilities, whereby free antipodes can be separated from pure diastereomer salts or derivatives under the influence of suitable agents. Particularly useful optically active acids are, for example, the D- and L-forms of tartaric acid or dibenzoyltartaric acid, di-o-tolyltartaric acid, malic acid, almond acid, camphorsulfonic acid, glutamic acid, aspartic acid or quinic acid.

As optically active alcohol, (+) - or (-) - methanol may be mentioned, and as optically active acyl radical in the amides, e.g. (+) - or (-) - menthyloxycarbonyl.

Further, the compounds of formula I obtained can be converted into their salts, especially for pharmaceutical use, into their physiologically acceptable salts with inorganic or organic acids. Hydrochloric, hydrobromic, sulfuric, methanesulfonic, phosphoric, fumaric, succinic, lactic, citric, tartaric or maleic acids may be used as acids.

The compounds of general formulas II to V used as starting materials are partly known in the literature or can be prepared by methods known in the literature.

For example, a starting compound of general formula II is prepared by the reaction of a suitably substituted 4-position 7-fluoro-6-nitro compound with a suitable alcoholate and subsequent reduction of the thus obtained nitro compound or a starting compound of general formula III can be obtained, for example, by reaction of a suitable bromo crotonic acid derivative with a known formula amine of general formula V or a starting compound of general formula IV can be obtained by acylation of a compound of general formula II with a suitable crotonic acid derivative.

As mentioned at the outset, the compounds of the invention of the general Formula I and their physiologically acceptable salts exhibit valuable pharmacological properties, namely, an epidermal growth factor receptor (EGF-R) receptor mediated signal transduction effect, such as that inhibiting action, for example, may be shown to inhibit ligand binding, receptor dimerization, or tyrosine kinase itself. In addition, the transmission of the signal to other downstream elements may be blocked.

The biological properties of the new compounds were tested by the following method:

Inhibition of human EGF receptor kinase has been demonstrated by cytoplasmic tyrosine kinase domains (methionine 664 to alanine 1186 based on a published sequence in Nature 309 (1984), 418). For this purpose, the protein is expressed in Sf9 insect cells in the form of a GST-binding protein using a baculovirus expression system.

Measurement of enzyme activity is performed in the presence or absence of test compounds at serial dilutions. The PEU polymer (4: 1) from SIGMA was used as a substrate. Biotinylated pEY (bio-pEY) will be used as a tracer substrate. Each 100 μl (microliter) reaction solution contains 10 μl of the inhibitor in 50% DMSO (dimethyl sulfoxide), 20 μl of substrate solution (200 mmol HEPES, pH 7.4, 50 mmol magnesium acetate, 2.5 mg / ml p-EY, 5 μg / ml bio-pEY and 20 µl enzyme preparation The enzyme reaction is initiated by introducing 50 µl of 100 µmol ATP solution into 10 mmol magnesium chloride The dilution of the enzyme preparation is such that the incorporation of phosphate into the bio-pEY according to the time and amount of enzyme The enzyme preparation is diluted in 20 mmol HEPES, pH 7.4, 1 mmol EDTA, 130 mmol sodium chloride, 0.05% Triton X-100 , 1 mmol DTT (dithiothreitol) and 10% glycerol.

The enzyme tests were performed at room temperature for 30 minutes and quenched with the addition of a stop solution (250 mmol EDTA in 20 mmol HEPES, pH 7.4). 100 μl was applied to a microtiter plate coated with streptavidin and incubated for 60 minutes at room temperature. The plate was then washed with 200 μl of wash solution (50 mmol Tris, 0.05% Tween 20 (Tween)). After addition of 100 μl of HRPO (horseradish peroxidase) labeled anti-PY antibodies (PY20H Anti-PTyr: HRP from Transduction Laboratories (250 ng / ml), the plate was incubated for 60 minutes then the samples were mixed with 100 μl of TMB-peroxidase solution (A: B = 1: 1, Kirkegaard Perry Laboratories) After 10 minutes, the reaction is quenched The extinction is measured at OD ₄₅ o _HM (optical density) with an ELISA device All data are determined three times.

Data are processed by an iterative equation using a Graph Pad Prism Version 3.0 program with a Hill variable slope. All iterated data released show correlation coefficients above 0.9 and all maximum and minimum values of the curves show at least a factor of 5. The concentration of the active ingredient that inhibits the action of the EGF receptor kinase by 50% (1C ₅₀ ) is deduced from the curves. .

The following results were obtained:

Compound (Example #) Inhibition of EGF receptor kinase 1C ₅₀ [nanomol] 1 0.7 1 (2) 0.6 1 (3) 4.0 1 (5) 3.0 1 (S) 0.5 1 (22) 1-0 1 (32) 0.3 1 (33) 0.5 1 (34) 0.4

Accordingly, the compounds of the invention of general formula I inhibit signaling by tyrokinases, as shown for example at the human EGF receptor, and are therefore useful for treating pathophysiological processes induced by tyrosine kinase overactivation. These are e.g. benign or malignant tumors, especially tumors of epithelial and neuroepithelial origin, metastasis as well as abnormal proliferation of vascular endothelial cells (neoangiogenesis).

The compounds of the invention are also useful for the prevention and treatment of diseases of the respiratory tract and lungs that occur with increased or altered mucus production, which is caused by tyrosine kinase stimulation, e.g. in inflammatory diseases of the respiratory tract such as chronic bronchitis, chronic obstructive bronchitis, asthma, bronchiectasis, allergic or non-allergic rhinitis or sinusitis, dietary fibrosis, lack of A1-antitrypsin or cough, pulmonary emphysema, fibrosis, fibrosis, fibrosis.

The compounds of the invention are also suitable for the treatment of diseases of the gastrointestinal tract and of the biliary tract and bladder arising from impaired tyrosine kinase activity, e.g. in which chronic inflammatory changes such as cholecystitis, Crohn's disease, ulcerative colitis and complaints in the gastrointestinal tract are detected or in those with advanced secretion, such as Menetrier's disease, adenoma secretion and protein loss syndrome.

In addition, the compounds of general formula I and their physiologically acceptable salts can be used to treat other diseases that are caused by impaired tyrosine kinase function, e.g. 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 can be used alone or in combination with other pharmacologically active compounds, e.g. in tumor therapy, as monotherapy or in combination with other antitumor therapeutic agents, e.g. in combination with topoisomerase inhibitors (eg etoposide), mitotic inhibitors (eg vinblastine), with nucleic acid-responsive compounds (eg cis-platinum, cyclophosphamide, adriamycin), hormone antagonists (eg metabox, inhibitors) processes (eg 5-FU, etc.), cytokines (eg interferons), antibodies, etc. In the treatment of respiratory diseases, these compounds may be used alone or in combination with other therapeutic agents for such diseases, e.g. secretolytic, bronchodilator and / or anti-inflammatory substances. For the treatment of diseases in the gastrointestinal tract, these compounds may also be used alone or in combination with substances that affect motility or secretion. These combinations may be administered simultaneously or sequentially.

Administration of these compounds, alone or in combination with other active ingredients, may be performed intravenously, subcutaneously, intramuscularly, intraperitoneally, intranasally, by inhalation or transdermally, in which aerosol compositions are particularly suitable for inhalation.

For pharmacological use, the compounds of the invention are generally used in warm-blooded vertebrates, especially in humans, at doses of 0.01-100 mg / kg body weight, preferably 0.1-15 mg / kg. For the preparation of a pharmaceutical composition, these compounds are mixed with one or more conventional inert carriers and / or diluents, e.g. corn starch, milk sugar, raw sugar, microcrystalline cellulose, magnesium stearate, polyvinylpyrrolidone, citric acid, tartaric acid, water, water / ethanol, water / glycerin, water / sorbitol, water / polyethylene glycol, propylene glycol, stearyl alcohol or carbolyl alcohol as solid fat, or a suitable mixture thereof, from which conventional forms of administration are obtained, such as tablets, dragees, capsules, powders, suspensions, solutions, sprays or suppositories.

The following examples should further illustrate the present invention without limiting it:

EXAMPLES FOR THE IMPLEMENTATION OF THE INVENTION

Preparation of starting compounds Example I

3-methylaminotetrahydrofuran

3.43 g of lithium aluminum hydride are added portionwise to 25 ml of tetrahydrofuran while cooling in an ice bath. A solution of 5.00 g of 3 - [(benzyloxycarbonyl) amino] tetrahydrofuran in 20 ml of tetrahydrofuran was then added dropwise to the mixture, keeping the temperature below 10 ° C. After 10 minutes, the cooling bath was removed and the reaction mixture was heated to reflux for about 3 hours. For further processing, 3.7 ml of water, 3.7 ml of 15% sodium hydroxide solution and 3 ml of water are added dropwise to the reaction mixture. Finally a little tetrahydrofuran was added and the mixture was stirred for another 15 minutes. The resulting aluminum hydroxide precipitate was filtered off under vacuum and washed with a total of 150 ml of tetrahydrofuran. The filtrate was concentrated in a rotary evaporator. A colorless oil was obtained, which was used without further purification.

Mass spectrum (ECI ⁺ = electrospray ionization): m / z = 102 [M + H] ⁺ R _f : 0.20 (silica gel, methylene chloride / methanol = 9: 1).

Example II

3 - [(benzyloxycarbonyl) amino] tetrahydrofuran

12.36 ml of tetrahydrofuran-3-carboxylic acid and 27.84 ml of diphenylphosphorylase in 500 ml of dioxane are mixed with 41.91 g of benzyl alcohol and 35.81 ml of triethylamine. The reaction mixture was heated at 100 ° C for about seven hours. After cooling to room temperature, the mixture was concentrated in a rotary evaporator. The residue was taken up in 500 ml of methylene chloride and washed twice with 100 ml of 1N sodium hydroxide each time. The organic phase was dried over magnesium sulfate and concentrated. The crude product was purified by chromatography on a silica gel column and eluent cyclohexane / ethyl acetate (3: 1 to 1: 2).

Yield: 15.60 g (55% of theory) Mass Spectrum (ECI): m / z = 220 [MH] 'R _f : 0.78 (silica gel, methylene chloride / methanol = 9: 1).

Example III

6-amino-4 - [(3-chloro-4-fluorophenyl) amino] -7 - ((R) -tetrahydrofuran-3-yloxy) quinazoline

A mixture of 12.80 g of 4 - [(3-chloro-4-fluorophenyl) amino] -6-nitro-7 - ((R) -tetrahydrofuran-3-yloxy) quinazoline, 200 ml of ethanol, 100 ml of water and 17.20 ml of glacial acetic acid the acid is heated to reflux. A total of 7.00 g of iron powder were added in portions. The reaction mixture was refluxed for about 4 hours, then cooled to room temperature overnight. For further processing, the mixture was concentrated in a rotary evaporator. The residue was taken up in methylene chloride / methanol (9: 1), mixed with 20 ml of concentrated ammonia solution and filtered through a pad of silica gel. Wash thoroughly with methylene chloride / methanol (9: 1) and concentrate the collected filtrates. The residue was stirred with diethyl ether and separated by filtration in vacuo. Yield: 8.59 g (73% of theory).

Mass Spectrum (ESI): m / z = 373, 375 [M-H] '

R _f : 0.27 (silica gel, ethyl acetate / methanol = 9: 1).

The following compounds were prepared analogously to Example III:

(1) 6-amino-4 - [(3-chloro-4-fluorophenyl) amino] -7 - ((5) -tetrahydrofuran-3-yloxy) quinazoline

Mass Spectrum (ESI '): m / z = 373, 375 [MH]'

R _f : 0.27 (silica gel, ethyl acetate / methanol = 9: 1);

(2) 6-amino-4 - [(3-chloro-4-fluorophenyl) amino] -7- (tetrahydropyran-4-yloxy) quinazoline

Mass Spectrum (ESI): m / z = 387, 389 [MH] '

R _f : 0.20 (silica gel, ethyl acetate);

(3) 6-amino-4 - [(3-chloro-4-fluorophenyl) amino] -7 - [(tetrahydrofuran-2-yl) methoxy] quinazoline

Mass Spectrum (ECS): m / z = 387, 389 [MH] '

R _f : 0.55 (silica gel, ethyl acetate / methanol = 9: 1);

(4) 6-amino-4 - [(3-chloro-4-fluorophenyl) amino] -7 - [(tetrahydrofuran-3-yl) methoxy] quinazoline

Mass Spectrum (ESI): m / z = 387, 389 [MH] '

R _f : 0.40 (silica gel, ethyl acetate / methanol = 9: 1);

Example IV

4 - [(3-chloro-4-fluorophenyl) amino] -6-nitro-7 - ((R) -tetrahydrofuran-3-yloxy) quinazoline

To a solution of 10.80 g of (R) -3-hydroxytetrahydrofuran in 100 ml Ν, dimethylformamide was added in portions, while cooling with an ice bath, 13.80 g of potassium tert -bugylate. The reaction mixture was stirred for about 1 hour and then 10.40 g of 4 - [(3-chloro-4-fluorophenyl) amino] -6-nitro-7-fluoroquinazoline were added portionwise. Finally, the cooling bath was removed and the dark red reaction mixture was stirred for two hours at room temperature. In the subsequent treatment, the reaction mixture was poured into about 500 ml of water and neutralized with 2 N hydrochloric acid. The resulting yellow precipitate was filtered off under vacuum and dried in an air circulation oven at 70 ° C.

Yield: 12.80

Melting point: 244 ° C

MS (ESI '): m / z = 403, 405 [MH]'

The following compounds were prepared analogously to Example IV:

(1) 4 - [(3-chloro-4-fluorophenyl) amino] -6-nitro-7 - ((5) -tetrahydrofuran-3-yloxy) quinazoline

Mass Spectrum (ECI): m / z = 403, 405 [M-H] 1 ^W R _f : 0.45 (silica gel, ethyl acetate);

(2) 4 - [(3-chloro-4-fluorophenyl) amino] -6-nitro-7- (tetrahydropyran-4-yloxy) quinazoline

Mass Spectrum (ECS): m / z = 417, 419 [M-H] '

R _f : 0.42 (silica gel, ethyl acetate);

(3) 4 - [(3-chloro-4-fluorophenyl) amino] -6-nitro-7 - [(tetrahydrofuran-2-yl) methoxy] quinazoline

MS (ESI): m / z = 417, 419 [M-H] '

R _f : 0.47 (silica gel, ethyl acetate);

(4) 4 - [(3-chloro-4-fluorophenyl) amino] -6-nitro-7 - [(tetrahydrofuran-3-yl) methoxy] quinazoline

MS (ESI): m / z = 417, 419 [M-H] '

R _f : 0.41 (silica gel, ethyl acetate);

(5) 4 - [(3-chloro-4-fluorophenyl) amino] -6-nitro-7 - [(tetrahydropyran-4-yl) methoxy] quinazoline

MS (ESI ⁺ ): m / z = 433, 435 [M + H] ⁺

R _f : 0.79 (silica gel, ethyl acetate / methanol = 9: 1);

(6) 4 - [(3-chloro-4-fluorophenyl) amino] -6-nitro-7 - [(R) - (tetrahydrofuran-2-yl) methoxy] quinazoline

MS (ESI ⁺ ): m / z = 419, 421 [M + H] ⁺

R _f : 0.44 (silica gel, ethyl acetate);

(7) 4 - [(3-chloro-4-fluorophenyl) amino] -6-nitro-7 - [(5) - (tetrahydrofuran-2-yl) methoxy] quinazoline

MS (ESI ⁺ ): m / z = 419, 421 [M + H] ⁺

R _f : 0.44 (silica gel, ethyl acetate).

Example V (N-M - [(tetrahydrofuran-2-yl) methyl] -1 \ 1-methylamine

21.10 g of (R) -N - [(tetrahydrofuran-2-yl) methyl] -N-benzyl-1'-methylamine (the crude product of Example VI) were dissolved in 200 ml of methanol and hydrogenated in the presence of 4.00 g of palladium on activated carbon (10% Pd) at room temperature until hydrogen absorption ceases. The catalyst was then filtered off and the filtrate was concentrated in a rotary evaporator. A rare yellowish oil is obtained, which is further used without further purification.

Yield: 8.60 g (73% of theory)

MS (ESI ⁺ ): m / z = 116 [M + H] ⁺

The following compounds were prepared analogously to Example V:

(1) (5) -N - [(tetrahydrofuran-2-yl) methyl] -1H-methylamine

Mass Spectrum (ECCI ⁺ ): m / z = 116 [M + H] ⁺ ;

(2) N - [(tetrahydropyran-4-yl) methyl] -1'-1-methylamine Mass Spectrum (ECI ⁺ ): m / z = 130 [M + H] ⁺ .

Example VI (R) -N - [(tetrahydrofuran-2-yl) methyl] -N-benzyl-1 N-methylamine

To a solution of 17.00 g of lithium aluminum hydride in 150 ml of tetrahydrofuran was added dropwise a solution of 24.60 g of (R) -tetrahydrofuran-2-carboxylic acid N-benzyl-N-methylamide in 90 ml of tetrahydrofuran. The reaction mixture was refluxed for 2 hours. Finally, it was cooled in an ice bath to 0 ° C, mixed with 20 ml of water and 10 ml of 15N sodium hydroxide and stirred for another 20 minutes. It was then filtered through a pad of magnesium sulfate and washed with a total of about 500 ml of tetrahydrofuran. The filtrate was concentrated in vacuo to give a yellowish oil, which was used without further purification.

Yield: 21.10 g (92% of theory) Mass spectrum (ECI ⁺ ): m / z = 206 [M + H] ⁺ .

The following compounds were prepared analogously to Example VI:

(1) (S) -N - [(tetrahydrofuran-2-yl) methyl] -1,1-benzyl-N-methylamine R _f : 0.20 (silica gel, ethyl acetate / methanol = 9: 1);

(2) N - [(tetrahydropyran-4-yl) methyl] -N-benzyl-1'-methylamine Mass Spectrum (ECI ⁺ ): m / z = 220 [M + H] ⁺ .

Example VII

(R) -Tetrahydrofuran-2-carboxylic acid N-benzyl-N-methylamide

To a solution of 20.00 g of (R) -tetrahydrofuran-2-carboxylic acid in 200 ml of tetrahydrofuran was added 25.30 g of N-benzyl-N-methylamine. A total of 67.10 g of O (benzotriazol-1-yl) -M, M, M ', M'-tetramethyluronium tetrafluoroborate are then added portionwise and ice-cold cooling, and the reaction mixture is stirred for 48 hours at room temperature. The precipitate formed is filtered off under vacuum, the filtrate is concentrated, mixed with water and filtered again. The resulting filtrate was basified with sodium hydrogen carbonate solution and extracted with ethyl acetate. The combined ethyl acetate extracts were washed with water and with saturated sodium chloride solution, dried over magnesium sulfate and concentrated. A yellowish oil is obtained which is used without further purification.

Yield: 24.60 g (54% of theory) Mass Spectrum (ECI ⁺ ): m / z = 220 [M + H] ⁺ ;

R _f : 0.62 (silica gel, ethyl acetate).

The following compounds were prepared analogously to Example VII:

(1) (5) -tetrahydrofuran-2-carboxylic acid (5) -tetrahydrofuran-2-carboxylic acid (1) N-benzyl-N-methylamide Mass spectrum (ECI ⁺ ): m / z = 242 [M + Na] ⁺ ;

R _f : 0.62 (silica gel, ethyl acetate).

(2) tetrahydropyran-4-carboxylic acid N-benzyl-N-methylamide (Performing amide coupling with 1,1'-carbonyldiimidazole in tetrahydrofuran)

MS (ESI ⁺ ): m / z = 256 [M + Na] ⁺ ;

R _f : 0.45 (silica gel, ethyl acetate).

Example VIII 6-amino-4 - [(3-chloro-4-fluorophenyl) amino] -7 - [(tetrahydropyran-4-yl) methoxy] quinazoline

22.80 g of 4 - [(3-chloro-4-fluorophenyl) amino] -6-nitro-7 - [(tetrahydropyran-4yl) methoxy] quinazoline are hydrogenated at room temperature in 300 ml of tetrahydropyran in the presence of 3.50 g of platinum dioxide to absorption of the calculated amount of hydrogen. The catalyst was removed by filtration and the filtrate was concentrated to dryness in a rotary evaporator. The residue was stirred with diethyl ether, separated by filtration in vacuo, washed with diethyl ether and dried at room temperature.

Yield: 19.95 g (93% of theory);

MS (ESI ⁺ ): m / z = 403, 405 [M + H] ⁺ ;

Melting point: 221 ° C.

The following compounds were prepared analogously to Example VIII:

(1) 6-amino-4 - [(3-chloro-4-fluorophenyl) amino] -7 - [(R) - (tetrahydrofuran-2-yl) methoxy] quinazoline

MS (ESI ⁺ ): m / z = 389, 391 [M + H] ⁺ ;

R _f : 0.11 (silica gel, ethyl acetate).

(2) 6-amino-4 - [(3-chloro-4-fluorophenyl) amino] -7 - [(S) - (tetrahydrofuran-2-yl) methoxy] quinazoline

MS (ESI ⁺ ): m / z = 389, 391 [M + H] ⁺ ;

R _f : 0.33 (silica gel, ethyl acetate / methanol = 9: 1).

Preparation of the final compounds Example 1

4 - [(3-chloro-4-fluorophenyl) amino] -6 - ({4- [N- (2-methoxyethyl) -N-methylamino] -1oxo-2-buten-1-yl} amino) -7- cyclopropylmethoxy-quinazoline

4.70 ml of oxalyl chloride were added dropwise to a solution of 4.50 g of bromo crotonic acid in 60 ml of methylene chloride. Finally, one drop of N, N-dimethylformamide was added. After about 30 minutes, the gas evolution was complete and the reaction mixture was concentrated in a rotary evaporator. The crude bromo crotonic acid chloride was captured in 30 ml of methyl chloride and, upon cooling with an ice bath, 7 - g of 4 - [(3-chloro-4-fluorophenyl) amino] -6-amino-7-cyclopropylmethoxyquinazoline and 10.20 ml were added dropwise. of Huenig in 150 ml of tetrahydrofuran. The reaction mixture was stirred for 1.5 hours with ice-bath cooling and another 2 hours at room temperature. Then they are added

5.20 g of N- (2-methoxyethyl) -N-methylamine and the reaction was stirred overnight at room temperature. It is then diluted with methylene chloride and washed mainly with water. The organic phase was dried over magnesium sulfate and concentrated. The crude product was purified by chromatography on a silica gel column, eluting with ethyl acetate followed by ethyl acetate / methanol (19: 1).

Yield: 5.07 g (51% of theory) Mass Spectrum (ECI): m / z = 512, 514 [M-H] ';

Rf. 0.25 (silica gel, ethyl acetate / methanol = 9: 1).

The following compounds were prepared analogously to Example 1:

(1) 4 - [(3-chloro-4-fluorophenyl) amino] -6 - {[4- (N, N-diethylamino) -1-oxo-2-buten-1-yl] amino} -7-cyclobutyloxy-quinazoline ,

Mass Spectrum (ECI): m / z = 468, 470 [M-H] ';

R _f : 0.09 (silica gel, ethyl acetate / methanol = 9: 1).

(2) 4 - [(3-chloro-4-fluorophenyl) amino] -6 - {[4- (N, N-dimethylamino) -1-oxo-2-buten-1-yl] amino} -7-cyclopentyloxy-quinazoline ,

Mass Spectrum (ECI): m / z = 482, 484 [M-H] ';

R _f : 0.11 (silica gel, ethyl acetate / methanol = 9: 1).

(3) 4- [(R) - (1-phenylethyl) amino] -6 - {[4- (1M, N-bis- (2-methoxyethyl) amino) -1 oxo-2-buten-1-yl] -amino} -7-cyclopropylmethoxy-quinazoline,

Mass Spectrum (ECI): m / z = 532 [M-H] ';

R _f : 0.40 (silica gel, ethyl acetate / methanol = 9: 1).

(4) 4 - [(R) - (1-phenylethyl) amino] -6 - ({4 - [(N- (2-methoxyethyl) -N-ethylamino] -1 oxo-2-buten-1-yl} -amino) -7-cyclopropylmethoxy-quinazoline,

Mass Spectrum (ECI): m / z = 502 [M-H] ';

R _f : 0.20 (silica gel, ethyl acetate / methanol = 9: 1).

(5) 4 - [(R) - (1-phenylethyl) amino] -6 - ({4 - [(N- (2-methoxyethyl) -N-methylamino] -1 oxo-2-buten-1-yl} -amino) -7-cyclopropylmethoxy-quinazoline,

Mass Spectrum (ECI): m / z = 488 [M-H] ';

R _f : 0.25 (silica gel, ethyl acetate / methanol = 9: 1).

(6) 4 - [(R) - (1-phenylethyl) amino] -6 - ({4 - [(N- (tetrahydropyran-4-yl) -N-methylamino] -1-oxo-2-butene-1 -yl} -amino) -7-cyclopropylmethoxy-quinazoline, Mass Spectrum (ECI): m / z = 514 [M-H] ';

R _f : 0.15 (silica gel, ethyl acetate / methanol = 9: 1).

(7) 4 - [(R) - (1-phenylethyl) amino] -6 - ({4 - [(1-tetrahydrofuran-3-yl) -N-methylamino] -1-oxo-2-butene -1-yl} -amino) -7-cyclopropylmethoxy-quinazoline, Mass Spectrum (ECI): m / z = 500 [M-H] ';

R _f : 0.18 (silica gel, ethyl acetate / methanol = 9: 1).

(S) 4 - [(3-chloro-4-fluorophenyl) amino] -6 - [(4- {N - [(tetrahydrofuran-3-yl) methyl] -N-methylamino} -1-oxo-2-butene -1-yl) amino] -7-cyclopropylmethoxyquinazoline,

Mass Spectrum (ECI '): m / z = 538, 540 [MH]';

R _f : 0.27 (silica gel, ethyl acetate / methanol = 9: 1).

(9) 4 - [(3-chloro-4-fluorophenyl) amino] -6 - {[4- (N, 1-dimethylamino) -1-oxo-2-buten-1-yl] amino} -7- ( (R) -tetrahydrofuran-3-yloxy) -quinazoline, Mass spectrum (ECI ⁺ ): m / z = 486, 488 [M + H] ⁺ .

(10) 4 - [(3-chloro-4-fluorophenyl) amino] -6 - {[4- (N, N-dimethylamino) -1-oxo-2-buten-1-yl] amino} -7 - ((5 ) -tetrahydrofuran-3-yloxy) -quinazoline, Mass spectrum (ECI ⁺ ): m / z = 486, 488 [M + H] ⁺ ;

R _f : 0.45 (silica gel, methylene chloride / methanol = 5: 1).

(11) 4 - [(3-chloro-4-fluorophenyl) amino] -6 - {[4- (N, N-dimethylamino) -1-oxo-2-buten-1-yl] amino} -7- (tetrahydropyran- 4-yloxy) -quinazoline,

Mass Spectrum (ECI ⁺ ): m / z = 500, 502 [M + H] ⁺ ;

R _f : 0.55 (silica gel, methylene chloride / methanol = 5: 1).

(12) 4 - [(3-chloro-4-fluorophenyl) amino] -6 - {[4- (N, 1,1'-dimethylamino) -1-oxo-2-buten-1-yl] amino} -7 - [(tetrahydrofuran-2-yl) methoxy] -quinazoline, Mass spectrum (ECI ⁺ ): m / z = 500, 502 [M + H] ⁺ ;

R _f : 0.60 (silica gel, methylene chloride / methanol = 5: 1).

(13) 4 - [(3-chloro-4-fluorophenyl) amino] -6 - {[4- (N, N-dimethylamino) -1-oxo-2bugen-1-yl] amino} -7 - [(tetrahydrofuran) -3-yl) methoxy] -quinazoline, Mass spectrum (ECI ⁺ ): m / z = 500, 502 [M + H] ⁺ ;

R _f : 0.50 (silica gel, methylene chloride / methanol = 5: 1).

(14) 4 - [(3-chloro-4-fluorophenyl) amino] -6 - {[4- (N, N-diethylamino) -1-oxo-2-buten-1-yl] amino} -7 - [(tetrahydrofuran) -3-yl) methoxy] -quinazoline, Mass spectrum (ECI ⁺ ): m / z = 528, 530 [M + H] ⁺ ;

R _f : 0.31 (silica gel, ethyl acetate / methanol = 9: 1).

(15) 4- [(R) - (1-phenylethyl) amino] -6 - {[4- (N, N-dimethylamino) -1-oxo-2-buten-1-yl] -amino} -7-cyclopropylmethoxy -quinazoline,

Mass Spectrum (ECCI ⁺ ): m / z = 446 [M + H] ⁺ ;

R _f : 0.11 (silica gel, ethyl acetate / methanol = 9: 1).

(16) 4 - [(3-chloro-4-fluorophenyl) amino] -6 - ({4- [N, 1-bis- (2-methoxyethyl) amino] 1-oxo-2-butene-1- yl} amino) -7 - [(tetrahydrofuran-2-yl) methoxy] -quinazoline,

Mass Spectrum (ECCI ⁺ ): m / z = 588, 590 [M + H] ⁺ ;

R _f : 0.55 (silica gel, methylene chloride / methanol = 9: 1).

(17) 4 - [(3-chloro-4-fluorophenyl) amino] -6 - {[4- (morpholin-4-yl) -1-oxo-2-butenyl-amino] amino} -7 - [(tetrahydrofuran) -2-yl) methoxy)] - quinazoline,

Mass Spectrum (ECI ⁺ ): m / z = 542, 544 [M + H] ⁺ ;

R _f : 0.55 (silica gel, methylene chloride / methanol = 9: 1).

(18) 4 - [(3-chloro-4-fluorophenyl) amino] -6 - ({4- [1 '1- (2-methoxyethyl) -N-methylamino] -1-oxo-2-butene-1 - yl} amino) -7-cyclopentyloxy-quinazoline, Mass spectrum (ECI ⁺ ): m / z = 528, 530 [M + H] ⁺ ;

R _f : 0.25 (silica gel, ethyl acetate / methanol = 9: 1).

(19) 4 - [(3-chloro-4-fluorophenyl) amino] -6 - [(4 - {(L) -1 \ 1 - [(tetrahydrofuran-2-yl) methyl] -N-methylamino} -1 -oxo-2-buten-1-yl) amino] -7-cyclopropylmethoxyquinazoline,

Mass Spectrum (ECCI ⁺ ): m / z = 540, 542 [M + H] ⁺ ;

Melting point: 149-153 ° C.

(20) 4 - [(3-chloro-4-fluorophenyl) amino] -6 - [(4 - {(5) -N - [(tetrahydrofuran-2-yl) methyl] -N-methylamino} -1-oxo -2-buten-1-yl) amino] -7-cyclopropylmethoxyquinazoline,

Mass Spectrum (ECCI ⁺ ): m / z = 540, 542 [M + H] ⁺ ;

w R _f : 0.29 (silica gel, ethyl acetate / methanol = 9: 1).

(21) 4 - [(R) - (1-phenylethyl) amino] -6 - {[4- (N, N-dimethylamino) -1-oxo-2-buten-1-yl] -amino} -7-cyclopentyloxy -quinazoline,

Mass Spectrum (ECCI ⁺ ): m / z = 560 [M + H] ⁺ ;

R _f : 0.17 (silica gel, ethyl acetate / methanol = 9: 1).

(22) 4 - [(3-chloro-4-fluorophenyl) amino] -6 - {[4- (N-cyclopropyl) -1 N-methylamino} -1-oxo-2-buten-1-yl] amino} - 7-cyclopentyloxy-quinazoline, Mass Spectrum (ECI-): m / z = 508, 510 [MH] -;

Melting point: 140 ° C.

(23) 4 - [(3-chloro-4-fluorophenyl) amino] -6 - {[4- (N-cyclopropyl-N-methylamino) -1-oxo-2-buten-1-yl] amino} - 7-cyclopropylmethoxy-quinazoline, Mass spectrum (ECI ⁺ ): m / z = 496, 498 [M + H] ⁺ ;

R _f : 0.42 (silica gel, ethyl acetate / methanol = 9: 1).

(24) 4 - [(3-chloro-4-fluorophenyl) amino] -6 - [(4- {1 \ 1 - [(tetrahydrofuran-2-yl) methyl] -N-methylamino} -1-oxo-2 -butyl-1-yl) amino] -7-cyclopropylmethoxyquinazoline,

Mass spectrum (ESI ⁺ ): m / z = 554, 556 [M + H] ⁺ ;

Melting point: 141 ° C.

(25) 4 - [(R) - (1-phenylethyl) amino] -6 - [(4- {N - [(tetrahydropyran-4-yl) -methyl] -methylamino} -1-oxo-2-butene- 1-yl) amino] -7-cyclopropylmethoxy-quinazoline, Mass spectrum (ECI ⁺ ): m / z = 530 [M + H] ⁺ ;

R _f : 0.32 (silica gel, ethyl acetate / methanol / conc. Aqueous ammonia = 90: 10: 0.5).

(26) 4 - [(3-chloro-4-fluorophenyl) amino] -6 - [(4 - {(R) -1 \ 1 - [(tetrahydrofuran-2-yl) -methyl] -N-methylamino} - 1-oxo-2-buten-1-yl) amino] -7-cyclopentyloxyquinazoline,

Mass spectrum (ESI ⁺ ): m / z = 554, 556 [M + H] ⁺ ;

Melting point: 117 -121 ° C.

(27) 4 - [(3-chloro-4-fluorophenyl) amino] -6 - [(4 - {(5) -1 \ 1 - [(tetrahydrofuran-2-yl) methyl] -N-methylamino} -1 -oxo-2-boogen-1-yl) amino] -7-cyclopentyloxyquinazoline,

Mass spectrum (ESI ⁺ ): m / z = 554, 556 [M + H] ⁺ ;

R _f : 0.32 (silica gel, ethyl acetate / methanol / conc. Aqueous ammonia = 90: 10: 0.5).

(28) 4 - [(3-chloro-4-fluorophenyl) amino] -6 - {[4- (N, N-dimethylamino) -1-oxo-2-boogen-1-yl] amino} -7 - [(tetrahydropyran) -4-yl) methoxy] -quinazoline, Mass spectrum (ECI ⁺ ): m / z = 514, 516 [M + H] ⁺ ;

R _f : 0.19 (silica gel, methylene chloride / methanol / conc. Aqueous ammonia = 90: 10: 0.5).

(29) 4 - [(3-chloro-4-fluorophenyl) amino] -6 - {[4- (morpholin-4-yl) -1-oxo-2-butene-

-yl] amino} -7 - [(tetrahydropyran-4-yl) methoxy] -quinazoline,

Mass Spectrum (ESI): m / z = 554, 556 [MH] ';

Melting point: 174 ° C.

(30) 4 - [(3-chloro-4-fluorophenyl) amino] -6 - ({4- [N, N-bis- (2-methoxyethyl) amino] 1-oxo-2-buten-1-yl} amino) -7 - [(tetrahydropyran-4-yl) methoxy] -quinazoline, Mass spectrum (ECI ⁺ ): m / z = 602, 604 [M + H] ⁺ ;

Melting point: 100-102 ° C.

(31) 4 - [(3-chloro-4-fluorophenyl) amino] -6 - {[4- (1 N, N-dimethylamino) -1-oxo-2-buten-1-yl] amino} -7- [ (I) - (tetrahydrofuran-2-yl) methoxy] -quinazoline, Mass spectrum (ECI ⁺ ): m / z = 500, 502 [M + H] ⁺ ;

Melting point: 110-112 ° C.

(32) 4 - [(3-chloro-4-fluorophenyl) amino] -6 - {[4- (N, N-dimethylamino) -1-oxo-2-buten-1-yl] amino} -7 - [(5 ) - (tetrahydrofuran-2-yl) methoxy] -quinazoline, Mass spectrum (ECI ⁺ ): m / z = 500, 502 [M + H] ⁺ ;

R _f : 0.23 (silica gel, ethyl acetate / methanol / conc. Aqueous ammonia = 90: 10: 0.1).

(33) 4 - [(3-chloro-4-fluorophenyl) amino] -6 - {[4- (N-ethyl-N-methylamino) -1-oxo-2-buten-1-yl] amino} -7- [ (5) - (tetrahydrofuran-3-yl) oxy] -quinazoline, Mass spectrum (ECI ⁺ ): m / z = 500, 502 [M + H] ⁺ ;

Melting point: 154-157 ° C.

(34) 4 - [(3-chloro-4-fluorophenyl) amino] -6 - {[4- (N-isopropyl-N-methylamino) -1-oxo-2-buten-1-yl] amino} -7- [ (5) - (tetrahydrofuran-3-yl) oxy] -quinazoline, Mass spectrum (ECI ⁺ ): m / z = 514, 516 [M + H] ⁺ ;

R _f : 0.34 (silica gel, ethyl acetate / methanol / conc. Aqueous ammonia = 90: 10: 1).

(35) 4 - [(3-chloro-4-fluorophenyl) amino] -6 - {[4- (morpholin-4-yl) -1-oxo-2-butenyl-amino] amino} -7 - [(6) ) - (tetrahydrofuran-3-yl) oxy] -quinazoline,

Mass Spectrum (ECH ⁺ ): m / z = 528, 530 [M + H] ⁺ ;

Melting point: 184-185 ° C.

(36) 4 - [(3-chloro-4-fluorophenyl) amino] -6 - {[4- (N-isopropyl-N-methylamino) -1-oxo-2-buten-1-yl] amino} -7-cyclopentyloxy -quinazoline,

Mass Spectrum (ESI ⁺ ): m / z = 512, 514 [M + H] ⁺ ;

R _f : 0.53 (silica gel, ethyl acetate / methanol / conc. Aqueous ammonia = 90: 10: 0.5).

(37) 4 - [(3-chloro-4-fluorophenyl) amino] -6 - {[4- (N-isopropyl-N-methylamino) -1-oxo-2-buten-1-yl] amino} -7- [ (5) - (tetrahydrofuran-2-yl) methoxy] -quinazoline, Mass Spectrum (ECI): m / z = 512, 514 [M-H] ';

R _f : 0.15 (silica gel, ethyl acetate / methanol / conc. Aqueous ammonia = 90: 10: 1).

(38) 4 - [(3-chloro-4-fluorophenyl) amino] -6 - {[4- (N, N-diethylamino) -1-oxo-2-buten-1-yl] amino} -7 - [(5 ) - (tetrahydrofuran-2-yl) methoxy] -quinazoline, Mass Spectrum (ECI): m / z = 526, 528 [MH];

R _f : 0.27 (silica gel, methylene chloride / methanol = 90: 1).

(39) 4 - [(3-chloro-4-fluorophenyl) amino] -6 - {[4- (N-isopropyl-N-methylamino) -1-oxo-2-buten-1-yl] amino} -7- [ (5) - (tetrahydrofuran-2-yl) methoxy] -quinazoline, Mass spectrum (ECI ⁺ ): m / z = 528, 530 [M + H] ⁺ ;

R _f : 0.31 (silica gel, methylene chloride / methanol = 90: 1).

Similarly to the above examples, and according to other methods known in the literature, the following compounds may also be prepared:

(1) 4-benzylamino-6 - {[4- (1,1'-N-diethylamino) -1-oxo-2-buten-1-yl] amino} -7cyclopropylmethoxy-quinazoline;

(2) 4 - [(3-chloro-4-fluorophenyl) amino] -6 - [(4- {N - [(tetrahydropyran-4-yl) methyl] N-methylamino} -1-oxo-2-butene- 1-yl) amino] -7-cyclopropylmethoxyquinazoline;

(3) 4 - [(3-chloro-4-fluorophenyl) amino] -6 - {[4- (N, N-dimethylamino) -1-oxo-2-buten-1-yl] amino} -7- [ (tetrahydropyran-4-yl) methoxy] -quinazoline;

(4) 4 - [(R) - (1-phenylethyl) amino] -6 - [(4- {M - [(tetrahydrofuran-2-yl) methyl] -1 \ 1methylamino} -1-oxo-2-butene -1-yl) amino] -7-cyclopropylmethoxy-quinazoline;

(5) 4 - [(R) - (1-phenylethyl) amino] -6 - {[4- (N, 1-dimethylamino) -1-oxo-2-buten-1-yl] amino} -7- [(tetrahydrofuran-2-yl) methoxy] -quinazoline;

(6) 4 - [(R) - (1-phenylethyl) amino] -6 - ({4- (N, N-bis- (2-methoxyethyl) amino] -1-oxo-

2-buten-1-yl} amino) -7 - [(tetrahydrofuran-2-yl) methoxy] -quinazoline;

(7) 4 - ((S) - (1-phenylethyl) amino] -6 - {[4- (morpholin-4-yl) -1-oxo-2-buten-1 35 yl] amino} -7- [(tetrahydrofuran-2-yl) methoxy] -quinazoline.

Example 2

Dragees with 75 mg of active ingredient dragee core contains:

active ingredient 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

Receive:

The active ingredient is mixed with calcium phosphate, corn starch, polyvinylpyrrolidone, hydroxypropyl methylcellulose and half of the given amount of magnesium stearate. The tabletting machine produces compresses of about 13 mm in diameter, which are then ground and sieved in a suitable 1.5 mm sieve device and mixed with the remaining magnesium stearate. This granulate is compressed into a tablet machine into tablets of the desired shape.

Weight: 230 mg

Panson: 9 mm, convex.

The dragee cores thus obtained are coated with a film consisting essentially of hydroxypropyl methylcellulose. Finished film dragees are glossed with beeswax.

Dragee Weight: 245 mg.

Example 3

Tablets with 100 mg of active ingredient

Composition:

1 tablet contains: Active ingredient 100.0 mg milk sugar 80.0 mg cornstarch 34.0 mg polyvinylpyrrolidone 4.0 mg magnesium stearate 2.0 mg

220.0 mg

Method of production:

The active ingredient, milk sugar and starch are mixed and moistened evenly with an aqueous solution of pilivinylpyrrolidone. After sifting the wet mass (2.0 mm sieve size) and drying in a shelf oven at 50 ° C, the material was sieved again (1.5 mm sieve) and mixed with the lubricant. The ready-to-press mixture is processed into tablets.

Tablet weight: 220 mg

Diameter: 10 mm, with two planes, two-sided bevel and one-sided separation channel.

Example 4

150 mg tablets of the active ingredient

Composition:

tablet contains:

active ingredient 150.0 mg milk powder powdered 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

Method of production:

The active ingredient is mixed with milk sugar, corn starch and colloidal silicic acid, and the mixture is moistened with a 20% aqueous solution of polyvinylpyrrolidone and then passed through a 1.5 mm sieve. The granulate is dried at 45 ° C and again triturated through the same sieve, then mixed with the given amount of magnesium stearate. Tablets are pressed from this mixture.

Tablet weight: 300 mg

Poonson:

mm flat.

Example 5

Hard gelatin capsules with 150 mg of active ingredient capsule contains:

Active ingredient

150.0 mg corn starch, ground milk sugar powdered magnesium stearate approx.

approx. 180.0 mg approx. 87.0 mg

3.0 mg

420.0 mg

Receive:

The active ingredient is mixed with the auxiliary materials, passed through a 0.75 mm sieve and homogenized in a suitable device. The final mixture is filled with hard gelatin capsules No. 1.

Capsule filling: approx. 320 mg

Capsule: N91 hard gelatin capsules.

Example 6

Suppositories with 150 mg active ingredient suppository contains:

active ingredient 150.0 mg polyethylene glycol 1500 550.0 mg polyethylene glycol 6000

460.0 mg

Polyoxyethylene sorbitan monostearate 840.0 mg

2000.0 mg

Receive:

After melting the candle table, the active ingredient is homogeneously distributed and the melt is poured into pre-cooled forms.

Example 7

Suspension with 50 mg of active ingredient

100 ml suspension contains:

active ingredient 1.00 g carboxymethylcellulose Na-salt 0.10 g methyl ester of p-hydroxybenzoic acid 0.05 g propyl ester of p-hydroxybenzoic acid 0.01 g crude sugar 10.00 g glycerin 5.00 g sorbitol solution 70% 20.00 g flavors 0.30 g distilled water up to 100.00 ml

Preparation:

The distilled water was heated to 70 ° C. The methyl and propyl esters of p-hydroxybenzoic acid, as well as glycerol and the sodium salt of carboxymethylcellulose are dissolved therein. The mixture was cooled to room temperature and with constant stirring the active ingredient was added which dispersed evenly. After the sugar, sorbitol solution and flavors were added and dissolved, the suspension was evacuated with stirring to remove air.

ml of suspension contain 50 mg of active ingredient.

Example 8

Ampoules with 10 mg of active ingredient

Composition:

active ingredient 10.0 mg

0.01 η hydrochloric acid s.q.

bidistilled water up to 2.0 ml Receive:

The active ingredient was dissolved in the required amount of 0.01 η HCl, the solution made isotonic with sodium chloride, filtered sterile and filled in 2 ml ampoules.

Example 9

Ampoules with 50 mg of active ingredient

Composition:

active ingredient 50.0 mg

0.01 η hydrochloric acid s.q.

bidistilled water up to 10.0 ml Receive:

The active ingredient was dissolved in the required amount of 0.01 η HCl, the solution made isotonic with sodium chloride, filtered sterile and filled in 10 ml ampoules.

Example 10

Powder inhalation capsules with 5 mg of active ingredient capsule contains the active ingredient 5.0 mg of lactose for inhalation 15.0 mg

20.0 mg

Receive:

The active ingredient is mixed with lactose for inhalation. With this mixture, capsules (empty capsule weight: approx. 50 mg) are filled in a capsule machine.

Capsule Weight: 70.0 mg. Capsule size: 3.

Example 11

Manual nebuliser inhalation solution with 2.5 mg active ingredient 1 serving contains:

Active ingredient 2.500 mg benzalkonium chloride 0.001 mg 1N hydrochloric acid q.s. ethanol / water (50/50) to 15.000 mg

Receive:

The active ingredient and benzalkonium chloride were dissolved in a mixture of ethanol water (50/50). The pH of the solution was adjusted with 1N hydrochloric acid. The solution thus prepared is filtered and filled into suitable containers (cartridges) for manual nebulizers.

Total weight of container: 4.5 g

Claims (9)

1. Quinazoline derivatives of the general formula: R _a represents a benzyl, 1-phenylethyl or 3-chloro-4-fluorophenyl group; R _b means one of the groups: dimethylamino, N-methyl-N-ethylamino, diethylamino, N-methyl-N-isopropylamino, N-methyl-N-cyclopropylamino, N-methyl-N- (2-methoxyethyl) amino, N- ethyl-1- (2-methoxyethyl) amino, bis- (2-methoxyethyl) amino, morpholino, 1-methyl-N- (tetrahydrofuran-3-yl) amino, N-methyl-1- (tetrahydrofuran) 2-ylmethyl) amino, N-methyl-N- (tetrahydrofuran-3-ylmethyl) amino, N '-methyl-N- (tetrahydropyran-4-yl) amino or N-methyl-N- (tetrahydropyran-4-ylmethyl) ) amino and R _c stands for one of the groups: cyclopropylmethoxy, cyclobutyloxy, cyclopentyloxy, tetrahydrofuran-3-yloxy, tetrahydrofuran-2-ylmethoxy, tetrahydrofuran-3-ylmethoxy, tetrahydropyran-4-yloxy or tetrahydropyroxy-4-yl: (1) 3-chloro-4-fluorophenyl) amino] -6 - {[4- (N, N-diethylamino) -1-oxo-2-butyl-yl] amino} -7-cyclopropylmethoxy-quinazoline, (2) 4 - [(3-chloro-4-fluorophenyl) amino] -6 - {[4- (morpholin-4-yl) -1-oxo-2-butene- 1-yl] amino} -7-cyclopropylmethoxy-quinazoline, (3) 4 - [(3-chloro-4-fluorophenyl) amino] -6 - {[4- (dimethylamino) -1-oxo-2-butenyl-yl] ] amino} -7-cyclopropylmethoxy-quinazoline, (4) 4 - [(3-chloro-4-fluorophenyl) amino] -6 - {[4- (morpholin-4-yl) -1-oxo-2-butenyl- yl] amino} -7-cyclobugyloxy-quinazoline, (S) 4 - [(3-chloro-4-fluorophenyl) amino] -6 - {[4- (morpholin-4-yl) -1-oxo-2-butene - 1-yl] amino} -7-cyclopentyloxy-quinazoline, (6) 4 - [(3-chloro-4-fluorophenyl) amino] -6 - {[4- (diethylamino) -1-oxo-2-boogen-1 yl] amino} -7-cyclobutyloxy-quinazoline, (7) 4 - [(3-chloro-4-fluorophenyl) amino] -6 - {[4- (diethylamino) -1-oxo-2-buten-1-yl] amino} -7-cyclopentyloxy-quinazoline, (S) 4 - ((S) - (1-phenylethyl) amino] -6 - {[4- (morpholin-4-yl) -1-oxo-2-butene- 1-yl] amino} -7-cyclobutyloxy-quinazoline, (9) 4 - [(R) - (1-phenylethyl) amino] -6 - {[4- (morpholin-4-yl) -1-oxo-2 -buten-1-yl] amino} -7-cyclopropylmethoxy-quinazoline, f '(10) 4 - [(R) - (1-phenylethyl) amino] -6 - {[4- (morpholin-4-yl) - 1-oxo-2-buten-1-yl] amino} -7-cyclopentyloxy-quinazoline, (11) 4 - [(R) - (1-phenyl) ethyl) amino] -6 - {[4- (diethylamino) -1-oxo-2-buten-1-yl] amino} -7-cyclobutyloxy-quinazoline, (12) 4 - [(R) - (1-phenylethyl) ) amino] -6 - {[4- (diethylamino) -1-oxo-2-buten-1-yl] amino} -7-cyclopentyloxy-quinazoline, (13) 4 - [(R) - (1-phenylethyl) amino] -6 - {[4- (diethylamino) -1-oxo-2-buten-1-yl] amino} -7-cyclopropylmethoxy-quinazoline, (14) 4 - [(3-chloro-4-fluorophenyl) amino ] -6 * ({4- [bis- (2-methoxyethyl) amino] -1-oxo-2-buten-1-yl} amino) -7-cyclopropylmethoxy-quinazoline, (15) 4 - [(3-chloro-4) -fluorophenyl) amino] -6 - ({4- [N-ethyl-N- (2-methoxyethyl) amino] -1-oxo-2-buten-1-yl} amino) -7-cyclopropylmethoxy-quinazoline, (16 ) 4 - [(3-chloro-4-fluorophenyl) amino] -6 - ({4- [M -methyl-N- (tetrahydropyran-4yl) amino] -1-oxo-2-buten-1-yl} amino) -7-cyclopropylmethoxy-quinazoline, (17) 4 - [(3-chloro-4-fluorophenyl) amino ] -6 - {[4- (diethylamino) -1-oxo-2-bungen-1-yl] -amino} -7 - [(tetrahydrofuran-2-yl) methoxy] -quinazoline, (18) 4 - [(3 -chloro-4-fluorophenyl) amino] -6 - {[4- (diethylamino) -1-oxo-2-buten-1-yl] amino} -7 - [(5) - (tetrahydrofuran-3-yl) oxy] -quinazoline, (19) 4 - [(3-chloro-4-fluorophenyl) amino] -6 - {[4- (diethylamino) -1-oxo-2-boogen-1 yl] amino} -7 - [(tetrahydropyran) -4-yl) oxy] -quinazoline, (20) 4 - [(3-chloro-4-fluorophenyl) amino] -6 - ({4- [N-methyl-N- (tetrahydrofuran-2ylmethyl) amino] -1 -oxo-2-buten-1-yl} amino) -7-cyclopropylmethyl oxyquinazoline and (21) 4 - [(3-chloro-4-fluorophenyl) amino] -6 - ({4- [N-methyl-1 \ 1- (tetrahydrofuran-3-yl) amino] -1-oxo-2-butene -1-yl} amino) -7-cyclopropylmethoxy-quinazoline. their tautomers, stereoisomers and salts. Compounds of general formula I according to claim 1, in which: R _a , R _b and R _c are as defined in claim 1, but with the exception of the compounds: (1) 4 - [(3-chloro-4-fluorophenyl) amino] -6 - {[4- (N, N-diethylamino) -1-oxo-2-buten-1-yl] amino} -7-cyclopropylmethoxy-quinazoline , (2) 4 - [(3-chloro-4-fluorophenyl) amino] -6 - {[4- (morpholin-4-yl) -1-oxo-2-butene- 1-yl] amino} -7-cyclopropylmethoxy-quinazoline, (3) 4 - [(3-chloro-4-fluorophenyl) amino] -6 - {[4- (dimethylamino) -1-oxo-2-butene- 1-yl] amino} -7-cyclopropylmethoxy-quinazoline, (4) 4 - [(3-chloro-4-fluorophenyl) amino] -6 - {[4- (morpholin-4-yl) -1-oxo-2 -butyl-yl] amino} -7-cyclobutyloxy-quinazoline, (S) 4 - [(3-chloro-4-fluorophenyl) amino] -6 - {[4- (morpholin-4-yl) -1-oxo- 2-Butene-yl] amino} -7-cyclopentyloxy-quinazoline, (6) 4 - [(3-chloro-4-fluorophenyl) amino] -6 - {[4- (diethylamino) -1-oxo-2-butene -1-yl] amino} -7-cyclobutyloxy-quinazoline, (7) 4 - [(3-chloro-4-fluorophenyl) amino] -6 - {[4- (diethylamino) -1-oxo-2-butene-1 yl] amino} -7-cyclopentyloxy-quinazoline, (S) 4 - [(R) - (1-phenylethyl) amino] -6 - {[4- (morpholin-4-yl) -1-oxo-2-butene -1-yl] amino} -7-cyclobutyloxy-quinazoline, (9) 4 - [(R) - (1-phenyl) ethyl) amino] -6 - {[4- (morpholin-4-yl) -1-oxo-2-buten-1-yl] amino} -7-cyclopropylmethoxy-quinazoline, (10) 4- [(/ 7) - (1-phenylethyl) amino] -6 - {[4- (morpholin-4-yl) -1-oxo-2-buten-1-yl] amino} -7-cyclopentyloxy-quinazoline, (11) 4- ( (R) - (1-phenylethyl) amino] -6 - {[4- (diethylamino) -1-oxo-2-buten-1-yl] amino} -7-cyclobutyloxy-quinazoline, (12) 4- [ (R) - (1-phenylethyl) amino] -6 - {[4- (diethylamino) -1-oxo-2-buten-1-yl] amino} -7-cyclopentyloxy-quinazoline, (13) 4 - [( N) - (1-phenylethyl) amino] -6 - {[4- (diethylamino) -1-oxo-2-buten-1-yl] amino} -7-cyclopropylmethoxy-quinazoline, (14) 4 - [(3 -chloro-4-fluorophenyl) amino] -6 - ({4- [bis- (2-methoxyethyl) amino] -1 oxo-2-butyl n-1-yl} amino) -7-cyclopropylmethoxy-quinazoline, (15) 4 - [(3-chloro-4-fluorophenyl) amino] -6 - ({4- [N-ethyl-N- (2-methoxyethyl) ) amino] -1-oxo-2-boogen-1-yl} amino) -7-cyclopropylmethoxy-quinazoline, (16) 4 - [(3-chloro-4-fluorophenyl) amino] -6 - ({4 - [N-methyl-1- {1- (tetrahydropyran-4-yl) amino] -1-oxo-2-buten-1-yl} amino) -7-cyclopropylmethoxy-quinazoline, (17) 4 - [(3-chloro- 4-fluorophenyl) amino] -6 - {[4- (diethylamino) -1-oxo-2-buten-1-yl] -amino} -7 - [(tetrahydrofuran-2-yl) methoxy] -quinazoline, (18) 4 - [(3-chloro-4-fluorophenyl) amino] -6 - {[4- (diethylamino) -1-oxo-2-buten-1-yl] amino} -7 - [(5) - (tetrahydrofuran-3 -yl) oxy] -quinazoline, (19) 4 - [(3-chloro-4-fluorophenyl) amine o] -6 - {[4- (diethylamino) -1-oxo-2-buten-1-yl] amino} -7 - [(tetrahydropyran-4-yl) oxy] -quinazoline, (20) 4 - [(3 -chloro-4-fluorophenyl) amino] -6 - ({4 - [(1-methyl-N- (tetrahydrofuran-2-ylmethyl) amino] -1-oxo-2-buten-1-yl} amino) -7- cyclopropylmethoxyquinazoline, (21) 4 - [(3-chloro-4-fluorophenyl) amino] -6 - ({4- [N-methyl-1 \ 1- (tetrahydrofuran-3yl) amino] -1-oxo-2-butene -1-yl} amino) -7-cyclopropylmethoxy-quinazoline, (22) 4 - [(3-chloro-4-fluorophenyl) amino] -6 - ({4- [N- (2-methoxyethyl-1- \ 1- methylamino] -1-oxo-2-buten-1-yl} amino) -7-cyclopropylmethoxy-quinazoline, (23) 4 - [(3-chloro-4-fluorophenyl) amino] -6 - ({4- [bis - (2-methoxyethyl) amino] -1-oxo-2-buten-1-yl} amino) -7-cy clobutyloxy-quinazoline, (24) 4 - [(3-chloro-4-fluorophenyl) amino] -6 - ({4- [lH-methyl-N- (2-methoxyethyl) amino] -1-oxo-2-butene -1-yl} amino) -7-cyclobutyloxy-quinazoline, (25) 4 - [(3-chloro-4-fluorophenyl) amino] -6 - ({4 - [(5) -N-methyl-N - ( tetrahydrofuran-3-yl) amino] -1-oxo-2-buten-1-yl} amino) -7-cyclobutyloxy-quinazoline, (26) 4 - [(3-chloro-4-fluorophenyl) amino] -6- ({4 - [(R) -] \ 1-methyl-N- (tetrahydrofuran-3-yl) amino] -1-oxo-2-buten-1-yl} amino) -7-cyclobutyloxy-quinazoline, (27 ) 4 - [(3-chloro-4-fluorophenyl) amino] -6 - ({4- [N-methyl-N- (tetrahydropyran-4-yl) amino] -1-oxo-2-buten-1-yl} amino ) -7-cyclobugyloxy-quinazoline, (28) 4 - [(3-chloro-4-fluorophenyl) amino] -6- ( {4 - ^[(/:?) - N-methyl-N- (tetrahydrofuran-2-ylmethyl) amino] -1-oxo-2-buten-1-yl} amino) -7-tsiklobutiloksihinazolin, (29) 4- [(3-chloro-4-fluorophenyl) amino] -6 - ({4 - [(5) -N-methyl-N- (tetrahydrofuran-2-ylmethyl) amino] -1-oxo-2-butene-1- yl} amino) -7-cyclobutyloxyquinazoline, (30) 4 - [(3-chloro-4-fluorophenyl) amino] -6 - ({4- [N-methyl-N- (2-methoxyethyl) amino] -1- oxo-2-buten-1-yl} amino) -7- (tetrahydrofuran-3-yloxy) quinazoline, (31) 4 - [(3-chloro-4-fluorophenyl) amino] -6 - ({4- [M -methyl-N- (2-methoxyethyl) amino] -1-oxo-2-buten-1-yl} amino) -7- (tetrahydropyran-4-yloxy) quinazoline, (32) 4 - [(3-chloro- 4-fluorophenyl) amino] -6 - ({4- [N-methyl-N- (2-methoxyethyl) amino] -1- oxo-2-buten-1-yl} amino) -7- (tetrahydrofuran-2-ylmethoxy) quinazoline and (33) 4 - [(3-chloro-4-fluorophenyl) amino] -6 - ({4- (M -cyclopropyl-N-methylamino) - 1-oxo-2-buten-1-yl] amino} -7-cyclopropylmethoxy-quinazoline, their tautomers, stereoisomers and salts. Compounds of general formula I according to claim 1, in which: R _a represents one of the groups: 1-phenylethyl or 3-chloro-4-fluorophenyl, R _b denotes one of the groups: dimethylamino, N-methyl-N-ethylamino, diethylamino, N-methyl-N-isopropylamino, N-methyl-N-cyclopropylamino, N-methyl-N- (2-methoxyethyl) amino, N-ethyl-N- (2-methoxyethyl) amino, bis- (2methoxyethyl) amino, morpholino, N-methyl-N- (tetrahydrofuran-3-yl) amino, N-methyl-1 N- (tetrahydrofuran- 2-ylmethyl) amino, N-methyl-1- {1- (tetrahydrofuran-3-ylmethyl) amino, N-methyl-N- (tetrahydropyran-4-yl) amino or N-methyl-N- (tetrahydropyran-4-ylmethyl) ) amino and R _c stands for one of the groups: cyclopropylmethoxy, cyclobutyloxy, cyclopentyloxy, tetrahydrofuran-3-yloxy, tetrahydrofuran-2-ylmethoxy, tetrahydrofuran-3-ylmethoxy, tetrahydropyran-4-yloxy or tetrahydropyroxy-4-yl: (1) 4 - [(3-chloro-4-fluorophenyl) amino] -6 - {[4- (N, 1-diethylamino) -1-oxo-2bugen-1-yl] amino} -7-cyclopropylmethoxy -quinazoline, (2) 4 - [(3-chloro-4-fluorophenyl) amino] -6 - {[4- (morpholin-4-yl) -1-oxo-2-butyl-yl] amino} -7- cyclopropylmethoxy-quinazoline, (3) 4 - [(3-chloro-4-fluorophenyl) amino] -6 - {[4- (dimethylamino) -1-oxo-2-butene- 1-yl] amino} -7-cyclopropylmethoxy-quinazoline, (4) 4 - [(3-chloro-4-fluorophenyl) amino] -6 - {[4- (morpholin-4-yl) -1-oxo-2 -butyl-yl] amino} -7-cyclobutyloxy-quinazoline, (S) 4 - [(3-chloro-4-fluorophenyl) amino] -6 - {[4- (morpholin-4-yl) -1-oxo- 2-Butene-yl] amino} -7-cyclopentyloxy-quinazoline, (6) 4 - [(3-chloro-4-fluorophenyl) amino] -6 - {[4- (diethylamino) -1-oxo-2-butene -1-yl] amino} -7-cyclobutyloxy-quinazoline, (7) 4 - [(3-chloro-4-fluorophenyl) amino] -6 - {[4- (diethylamino) -1-oxo-2-boogen-1 yl] amino} -7-cyclopentyloxy-quinazoline, (S) 4 - [(R) - (1-phenylethyl) amino] -6 - {[4- (morpholin-4-yl) -1-oxo-2-butene -1-yl] amino} -7-cyclobugyloxy-quinazoline, (9) 4 - [(R) - (1-phenyl) ethyl) amino] -6 - {[4- (morpholin-4-yl) -1-oxo-2-buten-1-yl] amino} -7-cyclopropylmethoxy-quinazoline, (10) 4- [(/ 7) - (1-phenylethyl) amino] -6 - {(4- (morpholin-4-yl) -1-oxo-2-buten-1-yl] amino} -7-cyclopentyloxy-quinazoline, (11) 4- ( (R) - (1-Phenylethyl) amino] -6 - {[4- (diethylamino) -1-oxo-2-buten-1-yl] amino} -7-cyclobutyloxy-quinazoline, (12) 4- ( (R) - (1-phenylethyl) amino] -6 - {[4- (diethylamino) -1-oxo-2-buten-1-yl] amino} -7-cyclopentyloxy-quinazoline, (13) 4- ( (R) - (1-phenylethyl) amino] -6 - {[4- (diethylamino) -1-oxo-2-buten-1-yl] amino} -7-cyclopropylmethoxy-quinazoline, (14) 4- [ (3-chloro-4-fluorophenyl) amino] -6 - ({4- [bis- (2-methoxyethyl) amino] -1 oxo-2-buto n-1-yl} amino) -7-cyclopropylmethoxy-quinazoline, (15) 4 - [(3-chloro-4-fluorophenyl) amino] -6 - ({4- [N-ethyl-N- (2-methoxyethyl) ) amino] -1-oxo-2-buten-1-yl} amino) -7-cyclopropylmethoxy-quinazoline, (16) 4 - [(3-chloro-4-fluorophenyl) amino] -6 - ({4 - [N-methyl-N- (tetrahydropyran-4-yl) amino] -1-oxo-2-boogen-1-yl} amino) -7-cyclopropylmethoxy-quinazoline, (17) 4 - [(3-chloro-4- fluorophenyl) amino] -6 - {[4- (diethylamino) -1-oxo-2-buten-1-yl] -amino} -7 - [(tetrahydrofuran-2-yl) methoxy] -quinazoline, (18) 4- [(3-chloro-4-fluorophenyl) amino] -6 - {[4- (diethylamino) -1-oxo-2-buten-1-yl] amino} -7 - [(O) - (tetrahydrofuran-3-yl ) oxy] -quinazoline, (19) 4 - [(3-chloro-4-fluorophenyl) amine o] -6 - {[4- (diethylamino) -1-oxo-2-buten-1-yl] amino} -7 - [(tetrahydropyran-4-yl) oxy] -quinazoline, (20) 4 - [(3 -chloro-4-fluorophenyl) amino] -6 - ({4- [N-methyl-1 \ 1- (tetrahydrofuran-3ylmethyl) amino] -1-oxo-2-buten-1-yl} amino) -7- cyclopropylmethoxyquinazoline, (21) 4 - ((3-chloro-4-fluorophenyl) amino] -6 - ({4- (N- (2-methoxyethyl-1 \ 1-methylamino) -1-oxo-2-butene-1 -yl} amino) -7-cyclopropylmethoxy-quinazoline, (22) 4 - ((3-chloro-4-fluorophenyl) amino] -6 - ({4- [bis- (2-methoxyethyl) amino] -1-oxo-2 -Buten-1-yl} amino) -7-cyclobugyloxy-quinazoline, (23) 4 - [(3-chloro-4-fluorophenyl) amino] -6 - ({4- [N-methyl-N- (2- methoxyethyl) amino] -1-oxo-2-buten-1-yl} amino) -7-cyclobutylo cy-quinazoline, (24) 4 - [(3-chloro-4-fluorophenyl) amino] -6 - ({4 - [(S) -N-methyl-N- (tetrahydrofuran-3-yl) amino] -1 -oxo-2-buten-1-yl} amino) -7-cyclobutyloxy-quinazoline, (25) 4 - [(3-chloro-4-fluorophenyl) amino] -6 - ({4 - [(N - 1 1-methyl-N- (tetrahydrofuran-3-yl) amino] -1-oxo-2-buten-1-yl} amino) -7-cyclobutyloxy-quinazoline, (26) 4 - [(3-chloro-4 -fluorophenyl) amino] -6 - ({4- [N-methyl-N- (tetrahydropyran-4yl) amino] -1-oxo-2-boogen-1-yl} amino) -7-cyclobutyloxy-quinazoline, (27 ) 4 - [(3-chloro-4-fluorophenyl) amino] -6 - ({4- [N-methyl-N- (2-methoxyethyl) amino] -1-oxo-2-buten-1-yl} amino ) -7- (tetrahydrofuran-3-yloxy) quinazoline, (28) 4 - [(3-chloro-4-fluorophenyl) amino] -6 - ({ 4- [N-methyl-N- (2-methoxyethyl) amino] -1-oxo-2-buten-1-yl} amino) -7- (tetrahydropyran-4-yloxy) quinazoline, (29) 4 - [( 3-chloro-4-fluorophenyl) amino] -6 - ({4- [N-methyl-N- (2-methoxyethyl) amino] -1-oxo-2-buten-1-yl} amino) -7- ( tetrahydrofuran-2-ylmethoxy) quinazoline, (30) 4 - [(3-chloro-4-fluorophenyl) amino] -6 - ({4- (1-cyclopropyl-N-methylamino) - 1-oxo-2-buten-1-yl] amino} -7-cyclopropylmethoxy-quinazoline, (31) 4 - [(3-chloro-4-fluorophenyl) amino] -6 - ({4- [1M-methyl- N- (tetrahydrofuran-2ylmethyl) amino] -1-oxo-2-buten-1-yl} amino) -7-cyclopropylmethoxyquinazoline, (32) 4 - [(3-chloro-4-fluorophenyl) amino] -6- ( {4 - [(R) -N-methyl-N4- (tetrahydrofuran-2-ylmethyl) amino] -1-oxo-2-buten-1-yl} amino) -7-cyclobutyloxyquinazoline and (33) 4 - [( 3-chloro-4-fluorophenyl) amino] -6 - ({4 - [(5) -N-methyl-1 N- (tetrahydrofuran-2-ylmethyl) amino] -1-oxo-2-buten-1-yl} amino) -7-cyclobugyloxyquinazoline, their tautomers, stereoisomers and salts. The following compounds of general formula I according to claim 1: (a) 4 - [(3-chloro-4-fluorophenyl) amino] -6 - {[4- (N, N-dimethylamino) -1-oxo-2-buten-1-yl] amino} -7-cyclobutyloxy- quinazoline, (b) 4 - [(3-chloro-4-fluorophenyl) amino] -6 - {[4- (N, N-dimethylamino) -1-oxo-2-buten-1-yl] amino} -7-cyclopentyloxy -quinazoline, (c) 4 - [(S) - (1-phenylethyl) amino] -6 - {[4- (N, N-bis- (2-methoxyethyl) amino) -1-oxo-2-butene- 1-yl] amino} -7-cyclopropylmethoxy-quinazoline, (d) 4 - [(S) - (1-phenylethyl) amino] -6 - ({4- [N- (2-methoxyethyl) -N-ethylamino) ] -1 oxo-2-buten-1-yl} amino] -7-cyclopropylmethoxy-quinazoline, (e) 4 - [(S) - (1-phenylethyl) amino] -6 - ({4- [N- (2-Methoxyethyl) -N-methylamino] -1 oxo-2-buten-1-yl} amino] -7-cyclopropylmethoxyquinaz lin, (e) 4- [(R) - (1-phenylethyl) amino] -6 - ({4- [N- (tetrahydropyran-4-yl) -N-methyl-amino] -1-oxo-2-butene -1-yl} amino) -7-cyclopropylmethoxy-quinazoline, (g) 4 - [(S) - (1-phenylethyl) amino] -6 - ({4- [N- (tetrahydrofuran-3-yl) - N-1-methylamino] -1-oxo-2-buten-1-yl} amino) -7-cyclopropylmethoxy-quinazoline, (3) 4 - [(3-chloro-4-fluorophenyl) amino] -6 - [( 4- {N - [(tetrahydrofuran-3-yl) methyl] -N-methylamino} -1-oxo-2-buten-1-yl) amino] -7-cyclopropylmethoxyquinazoline, (i) 4 - [(3-chloro -4-fluorophenyl) amino] -6 - {[4- (N, N-dimethylamino) -1-oxo-2-buten-1-yl] amino} -7 - ((R) -tetrahydrofuran-3-yloxy) -quinazoline , (j) 4 - [(3-chloro-4-fluorophenyl) amino] -6 - {[4- (N, N-dim thylamino) -1-oxo-2-buten-1-yl] amino} -7 - ((5) -tetrahydrofuran-3-yloxy) -quinazoline, (k) 4 - [(3-chloro-4-fluorophenyl) amino] - 6 - {[4- (N, N-dimethylamino) -1-oxo-2-buten-1-yl] amino} -7- (tetrahydropyran-4-yloxy) -quinazoline, (l) 4 - [(3-chloro- 4-fluorophenyl) amino] -6 - {[4- (N, N-dimethylamino) -1-oxo-2-buten-1-yl] amino} -7 - [(tetrahydrofuran-2-yl) methoxy] -quinazoline, ( m) 4 - [(3-chloro-4-fluorophenyl) amino] -6 - {[4- (N, N-dimethylamino) -1-oxo-2-buten-1-yl] amino} -7 - [(tetrahydrofuran- 3-yl) methoxy] -quinazoline ₎ (o) 4 - [(3-chloro-4-fluorophenyl) amino] -6 - {[4- (N, N-diethylamino) -1-oxo-2-buten-1-yl ] amino} -7 - [(tetrahydrofuran-3-yl) methoxy] -quinazoline, (n) 4 - ((/ 7) - (1 -phenylethyl) amino] -6 - {[4- (N, N-dimethylamino) -1-oxo-2-buten-1-yl] amino} -7-cyclopropylmethoxy-quinazoline, (h) 4 - [(3-chloro) -4-fluorophenyl) amino] -6 - ({4- [N, N-bis- (2-methoxyethyl) amino] 1-oxo-2-buten-1-yl} amino) -7 - [(tetrahydrofuran-2 -yl) methoxy] -quinazoline, (p) 4 - [(3-chloro-4-fluorophenyl) amino] -6 - {[4- (morpholin-4-yl) -1-oxo-2-bungen-yl] amino} -7 - [(tetrahydrofuran-2-yl) methoxy] -quinazoline, (c) 4 - [(3-chloro-4-fluorophenyl) amino] -6 - {[4- (N-cyclopropyl-1 \ 1 -methylamino) 1-oxo-2-buten-1-yl] amino} -7-cyclopentyloxy-quinazoline and (m) 4 - [(3-chloro-4-fluorophenyl) amino] -6 - {[4- (M , N-dimethylamino) -1-oxo-2-buten-1-yl] amino} -7 - [(5) - (tetrahydrofuran -2-yl) methoxy] -quinazoline, the tautomers, stereoisomers and salts thereof. / ..... 5. Physiologically acceptable salts of the compounds according to at least one of claims 1 to 4 with inorganic or organic acids or bases. A medicament comprising a compound according to at least one of claims 1 to 4 or a physiologically acceptable salt thereof according to claim 5 and optionally together with one or more carriers and / or diluents. Use of a compound according to at least one of claims 1 to 5 for the preparation of a medicament suitable for the treatment of benign or malignant tumors, for the prevention and treatment of diseases of the respiratory tract and lungs, and for the treatment diseases of the gastrointestinal tract and of the biliary tract and gall bladder. A method for the preparation of a medicament according to claim 6, characterized in that a compound according to at least one of claims 1 to 5 is incorporated in one or more carriers and / or diluents by a non-chemical route. A process for the preparation of compounds of general formula I according to claims 1 to 5, characterized in that: a) compound of general formula: wherein: (II). R _a and R _c are as defined in claims 1 to 5, reacted with a compound of the general formula: (III). wherein: R _b is as defined in claims 1 to 5 and Z1 denotes a leaving or hydroxyl group or (b) a compound of the general formula wherein: R _a and R _c are as defined in claims 1 to 5 and Z ₂ means a leaving group, reacted with a compound of the general formula: H - R _b (V) wherein R _b is defined as in claims 1 to 5 and, if necessary, one of the protecting radicals used in the reactions described above is cleaved off and / or if necessary , one of the protecting radicals used in the reactions described above is cleaved off and / or, if desired, one thus obtained compound of general formula I is separated into its stereoisomers and / or one thus obtained with general formula I is converted into its salts, in particular for pharmaceutical use, into its physiologically acceptable and salts.