HRP20030138A2 - Bicyclic heterocycles, medicaments containing these compound, their use, and methods for the production thereof - Google Patents

Description

The proposed invention relates to bicyclic heterocycles of the general formula

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to their tautomers, stereoisomers and their salts, especially their physiologically tolerable salts with inorganic or organic acids or bases. These compounds have valuable pharmacological properties, especially inhibitory action on signal transmission mediated by tyrosine kinases. The invention also relates to their use for the treatment of diseases, especially tumor diseases, lung and respiratory diseases, and to their production.

In the general formula I above

Ra represents a benzyl or 1-phenylethyl group or a phenyl group substituted with radicals R1 and R2, where

R1 is hydrogen, fluorine, chlorine or bromine atom, methyl, trifluoromethyl, cyano or ethynyl group and

R2 is hydrogen or a fluorine atom,

one of the radicals Rb and Rc represents the group R3-(CH2)m-O-, and the other of the radicals Rb or Rc is methoxy, cyclobutyloxy, cyclopentyloxy, cyclopropylmethoxy, cyclobutylmethoxy, cyclopentylmethoxy, tetrahydrofuran-3-yloxy, tetrahydropyran-3-yloxy, tetrahydropyran- 4-yloxy, tetrahydrofuranylmethoxy or tetrahydropyranylmethoxy group, where

R3 represents N-(2-oxo-tetrahydrofuran-4-yl)-methyl-amino or N-(2-oxo-tetrahydrofuran-4-yl)-ethylamino group, group R4-O-CO-CH2-N-CH2CH2-OH which is substituted on the methylene groups with one or two methyl or ethyl groups, in which

R4 represents a hydrogen atom or a C1-4-alkyl group, or a 2-oxo-morpholin-4-yl group which is substituted with one or two methyl or ethyl groups, and

m is the number 2, 3 or 4, provided that the following compounds are excluded:

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 and

4-[(3-bromo-phenyl)amino]-6-{2-[N-(2-oxo-tetrahydrofuran-4-yl)-N-methyl-amino]-ethoxy}-7-methoxy-quinazoline,

their tautomers, stereoisomers and their salts.

Preferred compounds of the above general formula I are those in which

Ra is a benzyl or 1-phenylethyl group or a phenyl group substituted with radicals R1 and R2, where

R1 is hydrogen, fluorine, chlorine or bromine atom, methyl, trifluoromethyl, cyano or ethynyl group and

R2 is hydrogen or a fluorine atom,

one of the radicals Rb and Rc is the group R3-(CH2)m-O-, and the other of the radicals Rb and Rc is methoxy, cyclobutyloxy, cyclopentyloxy, cyclopropylmethoxy, cyclobutylmethoxy, cyclopentylmethoxy, tetrahydrofuran-3-yloxy, tetrahydropyran-3-yloxy, tetrahydropyran- 4-yloxy, tetrahydro-furanylmethoxy or tetrahydropyranylmethoxy group, where

R3 represents N-(2-oxo-tetrahydrofuran-4-yl)-methyl-amino or N-(2-oxo-tetrahydrofuran-4-yl)-ethylamino group, group R4-O-CO-CH2-N-CH2CH2-OH which is substituted on methylene groups with one or two methyl or ethyl groups,

R4 is a hydrogen atom or a C1-4-alkyl group, or a 2-oxo-morpholin-4-yl group which is substituted with one or two methyl or ethyl groups, and

m is the number 2, 3 or 4, provided that connections are excluded:

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-oxo-morpholin-4-yl)ethoxy]-7-methoxy-quinazoline,

4-[(3-bromo-phenyl)amino]-6-[2-(5,5-dimethyl-2-oxo-morpholin-4-yl)ethoxy]-7-methoxy-quinazoline,

4-[(3-chloro-4-fluoro-phenyl)amino]-6-[2-(6,6-dimethyl-2-oxo-morpholin-4-yl)-ethoxy]-7-methoxy-quinazoline,

4-[(3-chloro-4-fluoro-phenyl)amino]-6-[2-(6,6-dimethyl-2-oxo-morpholin-4-yl)-ethoxy]-7-cyclobutyloxy-quinazoline,

4-[(3-chloro-4-fluoro-phenyl)amino]-6-[2-(6,6-dimethyl-2-oxo-morpholin-4-yl)-ethoxy]-7-cyclopentyloxy-quinazoline,

4-[(3-chloro-4-fluoro-phenyl)amino]-6-[2-(6,6-dimethyl-2-oxo-morpholin-4-yl)-ethoxy]-7-cyclopropylmethoxy-quinazoline,

4-[(3-chloro-4-fluoro-phenyl]amino]-6-[2-(6,6-dimethyl-2-oxo-morpholin-4-yl)-ethoxy]-7-cyclopentylmethoxy-quinazoline,

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

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

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

4-[(3-chloro-4-fluoro-phenyl)amino]-6-[3-(6,6-dimethyl-2-oxo-morpholin-4-yl)-propyloxy]-7-methoxy-quinazoline,

4-[(3-chloro-4-fluoro-phenyl)amino]-6-[3-(6,6-dimethyl-2-oxo-morpholin-4-yl)-propyloxy]-7-cyclopentyloxy-quinazoline,

4-[(3-chloro-4-fluoro-phenyl)amino]-6-[3-(6,6-dimethyl-2-oxo-morpholin-4-yl)-propyloxy]-7-cyclopentylmethoxy-quinazoline,

(R)-4-[(1-phenyl-ethyl)amino]-6-[3-(6,6-dimethyl-2-oxo-morpholin-4-yl)-propyloxy]-7-cyclopentyloxy-quinazoline,

4-[(3-chloro-4-fluoro-phenyl)amino]-7-[2-(6, 6-dimethyl-2-oxo-morpholin-4-yl)-ethoxy]-6-methoxy-quinazoline,

4-[(3-chloro-4-fluoro-phenyl)amino]-7-[2-(6,6-dimethyl-2-oxo-morpholin-4-yl)-ethoxy]-6-cyclobutyloxy-quinazoline,

4-[(3-chloro-4-fluoro-phenyl)amino]-7-[2-(6, 6-dimethyl-2-oxo-morpholin-4-yl)-ethoxy]-6-cyclopentyloxy-quinazoline,

4-[(3-chloro-4-fluoro-phenyl)amino]-7-[2-(6, 6-dimethyl-2-oxo-morpholin-4-yl)-ethoxy]-6-cyclopropylmethoxy-quinazoline,

4-[(3-chloro-4-fluoro-phenyl]amino]-7-[2-(6, 6-dimethyl-2-oxo-morpholin-4-yl)-ethoxy]-6-cyclopentylmethoxy-quinazoline,

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

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

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

4-[(3-chloro-4-fluoro-phenyl)amino]-7-[3-(6,6-dimethyl-2-oxo-morpholin-4-yl)-propyloxy]-6-methoxy-quinazoline,

4-[(3-chloro-4-fluoro-phenyl)amino]-7-[3-(6,6-dimethyl-2-oxo-morpholin-4-yl)-propyloxy]-6-cyclopentyloxy-quinazoline,

4-[(3-chloro-4-fluoro-phenyl)amino]-7-[3-(6,6-dimethyl-2-oxo-morpholin-4-yl)-propyloxy]-6-cyclopentylmethoxy-quinazoline and

(R)-4-[(1-phenyl-ethyl)amino]-7-[3-(6,6-dimethyl-2-oxo-morpholin-4-yl)-propyloxy]-6-cyclopentyloxy-quinazoline,

their tautomers, stereoisomers and their salts,

especially those in which

Ra is a 1-phenylethyl group or a phenyl group substituted with radicals R1 and R2, where

R1 represents fluorine, chlorine or bromine atom, methyl or ethynyl group and

R2 is hydrogen or a fluorine atom,

one of the radicals Rb and Rc is the group R3-(CH2)m-O-, the other of the radicals Rb and Rc is methoxy, cyclobutyloxy, cyclopentyloxy, cyclopropylmethoxy, cyclobutylmethoxy, cyclopentylmethoxy, tetrahydrofuran-3-yloxy, tetrahydropyran-3-yloxy, tetrahydropyran-4 -yloxy, tetrahydrofuran-ylmethoxy or tetrahydropyranylmethoxy group, where

R3 is the group N-(2-oxo-tetrahydrofuran-4-yl)-methylamino, the group R4-O-CO-CH2-N-CH2CH2-OH substituted on methylene groups with one or two methyl groups,

R4 is a C1-4-alkyl group, or a 2-oxo-morpholin-4-yl group substituted with one or two methyl groups, and

m is the number 2, 3 or 4, provided that connections are excluded:

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-oxo-morpholin-4-yl)ethoxy]-7-methoxy-quinazoline,

4-[(3-bromo-phenyl)amino]-6-[2--(5,5-dimethyl-2-oxo-morpholin-4-yl)ethoxy]-7-methoxy-quinazoline,

4-[(3-chloro-4-fluoro-phenyl)amino]-6-[2-(6, 6-dimethyl-2-oxo-morpholin-4-yl)-ethoxy]-7-methoxy-quinazoline,

4-[(3-chloro-4-fluoro-phenyl)amino]-6-[2-(6,6-dimethyl-2-oxo-morpholin-4-yl)-ethoxy]-7-cyclobutyloxy-quinazoline,

4-[(3-chloro-4-fluoro-phenyl)amino]-6-[2-(6,6-dimethyl-2-oxo-morpholin-4-yl)-ethoxy]-7-cyclopentyloxy-quinazoline,

4-[(3-chloro-4-fluoro-phenyl)amino]-6-[2-(6,6-dimethyl-2-oxo-morpholin-4-yl)-ethoxy]-7-cyclopropylmethoxy-quinazoline,

4-[(3-chloro-4-fluoro-phenyl]amino]-6-[2-(6,6-dimethyl-2-oxo-morpholin-4-yl)-ethoxy]-7-cyclopentylmethoxy-quinazoline,

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

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

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

4-[(3-chloro-4-fluoro-phenyl)amino]-6-[3-(6,6-dimethyl-2-oxo-morpholin-4-yl)-propyloxy]-7-methoxy-quinazoline,

4-[(3-chloro-4-fluoro-phenyl)amino]-6-[3-(6,6-dimethyl-2-oxo-morpholin-4-yl)-propyloxy]-7-cyclopentyloxy-quinazoline,

4-[(3-chloro-4-fluoro-phenyl)amino]-6-[3-(6,6-dimethyl-2-oxo-morpholin-4-yl)-propyloxy]-7-cyclopentylmethoxy-quinazoline,

(R)-4-[(1-phenyl-ethyl)amino]-6-[3-(6,6-dimethyl-2-oxo-morpholin-4-yl)-propyloxy]-7-cyclopentyloxy-quinazoline,

4-[(3-chloro-4-fluoro-phenyl)amino]-7-[2-(6,6-dimethyl-2-oxo-morpholin-4-yl)-ethoxy]-6-methoxy-quinazoline,

4-[(3-chloro-4-fluoro-phenyl)amino]-7-[2-(6,6-dimethyl-2-oxo-morpholin-4-yl)-ethoxy]-6-cyclobutyloxy-quinazoline,

4-[(3-chloro-4-fluoro-phenyl)amino]-7-[2-(6,6-dimethyl-2-oxo-morpholin-4-yl)-ethoxy]-6-cyclopentyloxy-quinazoline,

4-[(3-chloro-4-fluoro-phenyl)amino]-7-[2-(6, 6-dimethyl-2-oxo-morpholin-4-yl)-ethoxy]-6-cyclopropylmethoxy-quinazoline,

4-[(3-chloro-4-fluoro-phenyl]amino]-7-[2-(6,6-dimethyl-2-oxo-morpholin-4-yl)-ethoxy]-6-cyclopentylmethoxy-quinazoline,

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

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

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

4-[(3-chloro-4-fluoro-phenyl)amino]-7-[3-(6,6-dimethyl-2-oxo-morpholine-4-1)-propyloxy]-6-methoxy-quinazoline,

4-[(3-chloro-4-fluoro-phenyl)amino]-7-[3-(6,6-dimethyl-2-oxo-morpholin-4-yl)-propyloxy]-6-cyclopentyloxy-quinazoline,

4-[(3-chloro-4-fluoro-phenyl)amino]-7-[3-(6,6-dimethyl-2-oxo-morpholin-4-yl)-propyloxy]-6-cyclopentylmethoxy-quinazoline and

(R)-4-[(1-phenyl-ethyl)amino]-7-[3-(6,6-dimethyl-2-oxo-morpholin-4-yl)-propyloxy]-6-cyclopentyloxy-quinazoline,

their tautomers, stereoisomers and their salts.

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

Ra is a 1-phenylethyl group or a phenyl group substituted with radicals R1 and R2, where

R1 represents a fluorine, chlorine or bromine atom, and

R2 is hydrogen or a fluorine atom,

one of the radicals Rb or Rc is the group R3-(CH2)m-O-, and the other of the radicals Rb or Rc is methoxy, cyclobutyloxy, cyclopentyloxy, cyclopropylmethoxy, cyclobutylmethoxy, cyclopentylmethoxy, tetrahydrofuran-3-yloxy, tetrahydropyran-3-yloxy, tetrahydropyran- 4-yloxy, tetrahydrofuran-ylmethoxy or tetrahydropyranylmethoxy group, where

R3 represents the group N-(2-oxo-tetrahydrofuran-4-yl)-methylamino or 2-oxo-morpholin-4-yl group which is substituted with one or two methyl groups, and

m is the number 2, 3 or 4, provided that connections are excluded:

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-(3-methyl-2-oxo-morpholin-4-yl)-ethoxy]-7-methoxy-quinazoline,

4-t(3-bromo-phenyl)amino]-6-[2-(5,5-dimethyl-2-oxo-morpholin-4-yl)ethoxy]-7-methoxy-quinazoline,

4-[(3-chloro-4-fluoro-phenyl)amino]-6-[2-(6,6-dimethyl-2-oxo-morpholin-4-yl)-ethoxy]-7-methoxy-quinazoline,

4-[(3-chloro-4-fluoro-phenyl)amino]-6-[2-(6,6-dimethyl-2-oxo-morpholin-4-yl)-ethoxy]-7-cyclobutyloxy-quinazoline,

4-[(3-chloro-4-fluoro-phenyl)amino]-6-[2-(6,6-dimethyl-2-oxo-morpholin-4-yl)-ethoxy]-7-cyclopentyloxy-quinazoline,

4-[(3-chloro-4-fluoro-phenyl)amino]-6-[2-(6,6-dimethyl-2-oxo-morpholin-4-yl)-ethoxy]-7-cyclopropylmethoxy-quinazoline,

4-[(3-chloro-4-fluoro-phenyl]amino]-6-[2-(6,6-dimethyl-2-oxo-morpholin-4-yl)-ethoxy]-7-cyclopentylmethoxy-quinazoline,

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

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

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

4-[(3-chloro-4-fluoro-phenyl)amino]-6-[3-(6,6-dimethyl-2-oxo-morpholin-4-yl)-propyloxy]-7-methoxy-quinazoline,

4-[(3-chloro-4-fluoro-phenyl)amino]-6-[3-(6,6-dimethyl-2-oxo-morpholin-4-yl)-propyloxy]-7-cyclopentyloxy-quinazoline,

4-[(3-chloro-4-fluoro-phenyl)amino]-6-[3-(6,6-dimethyl-2-oxo-morpholin-4-yl)-propyloxy]-7-cyclopentylmethoxy-quinazoline,

(R)-4-[(1-phenyl-ethyl)amino]-6-[3-(6,6-dimethyl-2-oxo-morpholin-4-yl)-propyloxy]-7-cyclopentyloxy-quinazoline,

4-[(3-chloro-4-fluoro-phenyl)amino]-7-[2-(6,6-dimethyl-2-oxo-morpholin-4-yl)-ethoxy]-6-methoxy-quinazoline,

4-[(3-chloro-4-fluoro-phenyl)amino]-7-[2-(6,6-dimethyl-2-oxo-morpholin-4-yl)-ethoxy]-6-cyclobutyloxy-quinazoline,

4-[(3-chloro-4-fluoro-phenyl)amino]-7-[2-(6,6-dimethyl-2-oxo-morpholin-4-yl)-ethoxy]-6-cyclopentyloxy-quinazoline,

4-[(3-chloro-4-fluoro-phenyl)amino]-7-[2-(6,6-dimethyl-2-oxo-morpholin-4-yl)-ethoxy]-6-cyclopropylmethoxy-quinazoline,

4-[(3-chloro-4-fluoro-phenyl]amino]-7-[2-(6,6-dimethyl-2-oxo-morpholin-4-yl)-ethoxy]-6-cyclopentylmethoxy-quinazoline,

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

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

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

4-[(3-chloro-4-fluoro-phenyl)amino]-7-[3-(6,6-dimethyl-2-oxo-morpholin-4-yl)-propyloxy]-6-methoxy-quinazoline,

4-[(3-chloro-4-fluoro-phenyl)amino]-7-[3-(6,6-dimethyl-2-oxo-morpholin-4-yl)-propyloxy]-6-cyclopentyloxy-quinazoline,

4-[(3-chloro-4-fluoro-phenyl)amino]-7-[3-(6,6-dimethyl-2-oxo-morpholin-4-yl)-propyloxy]-6-cyclopentylmethoxy-quinazoline and

(R)-4-[(1-phenyl-ethyl)amino]-7-[3-(6,6-dimethyl-2-oxo-morpholin-4-yl)-propyloxy]-6-cyclopentyloxy-quinazoline,

their tautomers, stereoisomers and their salts.

Particular preference is given to compounds of the general formula I in which

Ra represents 1-phenylethyl, 3-bromophenyl or 3-chloro-4-fluorophenyl group,

Rb is the group R3-(CH2)m-O- in which

R3 represents a 2-oxo-morpholin-4-yl group substituted with one or two methyl groups, and m is 2 or 3, and

Rc is a methoxy, cyclobutyloxy, cyclopentylmethoxy, cyclopropylmethoxy, tetrahydrofuran-3-yloxy or tetrahydrofuranylmethoxy group, provided 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-oxo-morpholin-4-yl)ethoxy]-7-methoxy-quinazoline,

4-[(3-bromo-phenyl)amino]-6-[2-(5,5-dimethyl-2-oxo-morpholin-4-yl)ethoxy]-7-methoxy-quinazoline,

4-[(3-chloro-4-fluoro-phenyl)amino]-6-[2-(6,6-dimethyl-2-oxo-morpholin-4-yl)-ethoxy]-7-methoxy-quinazoline,

4-[(3-chloro-4-fluoro-phenyl)amino]-6-[2-(6,6-dimethyl-2-oxo-morpholin-4-yl)-ethoxy]-7-cyclobutyloxy-quinazoline,

4-[(3-chloro-4-fluoro-phenyl)amino]-6-[2-(6,6-dimethyl-2-oxo-morpholin-4-yl)-ethoxy]-7-cyclopropylmethoxy-quinazoline,

4-[(3-chloro-4-fluoro-phenyl)amino]-6-[3-(6,6-dimethyl-2-oxo-morpholin-4-yl)-propyloxy]-7-methoxy-quinazoline,

4-[(3-chloro-4-fluoro-phenyl)amino]-6-[3-(6,6-dimethyl-2-oxo-morpholin-4-yl)-ethoxy]-7-cyclopentyloxy-quinazoline,

4-[(3-chloro-4-fluoro-phenyl)amino]-6-[3-(6,6-dimethyl-2-oxo-morpholin-4-yl)-propyloxy]-7-cyclopentyloxy-quinazoline, and

(R)-4-[(1-phenyl-ethyl)amino]-6-[3-(6, 6-dimethyl-2-oxo-morpholin-4-yl)-propyloxy]-7-cyclopentyloxy-quinazoline,

their tautomers, stereoisomers and their salts.

A very particular preference is also given to compounds of the general formula I in which

Ra represents a 3-chloro-4-fluoro-phenyl group,

Rb is a cyclopentyloxy, cyclopropylmethoxy, cyclopentylmethoxy, tetrahydrofuran-3-yloxy or tetrahydrofuranylmethoxy group and

Rc is the group R3-(CH2)m-O- in which

R3 represents a 2-oxo-morpholin-4-yl group which is substituted with one or two methyl groups, and

m is the number 2,

provided that connections are excluded:

4-[(3-chloro-4-fluoro-phenyl)amino]-6-cyclopentyloxy-7-[2-(6,6-dimethyl-2-oxo-morpholin-4-yl)-ethoxy]-quinazoline,

4-[(3-chloro-4-fluoro-phenyl)amino]-7-[2-(6,6-dimethyl-2-oxo-morpholin-4-yl)-ethoxy]-6-cyclopentyloxy-quinazoline,

4-[(3-chloro-4-fluoro-phenyl)amino]-7-[2-(6,6-dimethyl-2-oxo-morpholin-4-yl)-ethoxy]-6-cyclopropylmethoxy-quinazoline, and

4-[(3-chloro-4-fluoro-phenyl]amino]-7-[2-(6,6-dimethyl-2-oxo-morpholin-4-yl)-ethoxy]-6-cyclopentylmethoxy-quinazoline,

their tautomers, stereoisomers and their salts.

As compounds that are given a very special advantage, the following can 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]- quinazoline,

(5) 4-[(3-chloro-4-fluoro-phenyl)amino]-7-cyclopropylmethoxy-6-[3-(2,2-dimethyl-6-oxo-morpholin-4-yl)-propyloxy]- quinazoline,

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

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

(8) 4-[(3-bromo-phenyl)amino]-6-[2-((R)-6-methyl-2-oxo-morpholin-4-yl)-ethoxy]-7-methoxy-quinazoline,

(9) 4-[(3-chloro-4-fluoro-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-[3-((R)-6-methyl-2-oxo-morpholin-4-yl)-propyloxy]-7- methoxy-quinazoline,

(11) 4-[(R)-(1-phenyl-ethyl)amino]-6-[3-((S)-6-methyl-2-oxo-morpholin-4-yl)-propyloxy]-7- methoxy-quinazoline,

(12) 4-[(R)-(1-phenyl-ethyl)amino]-6-[2-((S)-6-methyl-2-oxo-morpholin-4-yl)-ethoxy]-7- methoxy-quinazoline, i

(13) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-[3-((S)-6-methyl-2-oxo-morpholin-4-yl)-ethoxy]-7- methoxy-quinazoline,

their tautomers, stereoisomers and their salts.

Compounds of general formula I can be produced, for example, by the following procedures:

a) by the reaction of a compound of the general formula

[image]

where

Ra is defined as introductory,

one of the radicals Rb' or Rc' is a methoxy, cyclobutyl-oxy, cyclopentyloxy, cyclopropylmethoxy, cyclobutyl-methoxy or cyclopentylmethoxy group, and the other of the radicals Rb' or Rc' is a group Z1-(CH2)m-O-, in which

m is defined as introductory, i

Z1 is a leaving group as a halogen atom or a sulfonyloxy group, as a chlorine or bromine atom, a methanesulfonyloxy or a p-toluenesulfonyloxy group, with a compound of the general formula

H-R3(III)

where

R3 is defined as introductory.

The conversion is carried out as necessary in a solvent or a mixture of solvents such as methylene chloride, acetonitrile, dimethylformamide, dimethylsulfoxide, sulfolane, benzene, toluene, chlorobenzene, tetrahydrofuran, benzene/tetrahydrofuran or dioxane, expediently in the presence of a tertiary organic base such as triethylamine or N -ethyl-diisopropylamine, whereby these organic bases can also serve simultaneously as a solvent, or in the presence of an inorganic base such as sodium carbonate or potassium carbonate, expediently at a temperature between -20 and 200°C, preferably at a temperature between 0 and 150 °C;

b) by cyclization of the compound of general formula IV, formed as necessary in the reaction mixture:

[image]

where

Ra is defined as introductory,

one of the radicals Rb" and Rc" is a methoxy, cyclo-butyloxy, cyclopentyloxy, cyclopropylmethoxy, cyclo-butylmethoxy or cyclopentylmethoxy group, and the other of the radicals Rb" and Rc" is a group R3'-(CH2)m-O-, in which

m is defined as introductory, i

R3' is the group R4-O-CO-CH2-N-CH2CH2-OH which is substituted on the methylene groups with one or two methyl or ethyl groups, where

R4 represents a hydrogen atom or a C1-4-alkyl group.

The conversion is carried out as necessary in a solvent or a mixture of solvents such as methylene chloride, acetonitrile, dimethylformamide, dimethylsulfoxide, sulfolane, benzene, toluene, chlorobenzene, tetrahydrofuran, benzene/tetrahydrofuran or dioxane, expediently in the presence of an anhydrous acid such as trifluoroacetic acid, methanesulfonic acid acid or sulfuric acid or in the presence of a dehydrating agent, e.g. in the presence of chloroformic acid isobutyl ester, thionyl chloride, trimethylchlorosilane, phosphorus trichloride, phosphorus pentoxide, N,N'-dicyclohexylcarbodiimide, N,N'-dicyclohexylcarbodiimide/N-hydroxy- succinimide or 1-hydroxy-benztriazole, N,N'-carbonyl-diimidazole or triphenylphosphine/carbon tetrachloride, at a temperature between -20 and 200°C, preferably however at a temperature between -10 and 160°C.

In the reactions described above, if necessary, reactive groups such as hydroxy, carboxy or imino groups can be protected during the reaction with the usual protective groups, which are separated again after the reaction.

For example, trimethylsilyl, acetyl, benzoyl, methyl, ethyl, tert.butyl, trityl, benzyl or tetrahydropyranyl group can be used as a protecting group for a hydroxy group, trimethylsilyl, methyl, ethyl, tert. can be used as a protecting group for a carboxy group. butyl, benzyl or tetrahydropyranyl group i

formyl, acetyl, trifluoroacetyl, ethoxycarbonyl, tert.butoxycarbonyl, benzyloxycarbonyl, benzyl, methoxybenzyl or 2,4-dimethoxybenzyl group can be used as a protecting group for the imino group.

Then, if necessary, the protective groups used are removed, for example by hydrolysis in an aqueous solvent, for example 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 alkaline base such as sodium hydroxide or potassium hydroxide or an aprotic agent, e.g. in the presence of iodotrimethylsilane, at a temperature between 0 and 120°C, preferably at a temperature between 10 and 100°C .

However, the cleavage of the benzyl, methoxybenzyl or benzyloxycarbonyl residue is carried out, for example, hydrogenolytically, e.g. with hydrogen in the presence of a catalyst such as palladium on carbon, in a suitable solvent such as methanol, ethanol, ethyl acetic acid or glacial acetic acid, if necessary with the addition of an acid such as hydrochloric acid, at a temperature between 0 and 100°C, preferably, however, at room temperature, or between 20 and 60°C, and under a hydrogen pressure of 1 to 7 bar, preferably however of 3 up to 5 bars. However, cleavage of the 2,4-di-methoxybenzyl residue is preferably carried out in trifluoroacetic acid in the presence of anisole.

Separation of the tert.butyl or tert.butyloxy-carbonyl group is performed primarily by treatment with an acid such as trifluoroacetic acid or hydrochloric acid or treatment with iodotrimethylsilane, if necessary with the use of solvents such as methylene chloride, dioxane, methanol or diethyl ether.

Separation of the trifluoroacetyl group is primarily carried out by treatment with an acid such as hydrochloric acid, if necessary in the presence of a solvent such as acetic acid at a temperature between 50 and 120°C, or by treatment with sodium alkali, if necessary in the presence of a solvent such as tetrahydrofuran, at a temperature between 0 and 50°C.

Furthermore, the obtained compounds of the general formula I, as already mentioned in the introduction, can be separated into their enantiomers and/or diastereomers. Thus, for example, a cis/trans mixture can be resolved into cis and trans isomers, and compounds with at least one optically active carbon atom can be resolved into their enantiomers.

Thus, for example, the resulting cis/trans mixtures can be resolved by chromatography into their cis and trans isomers, the resulting compounds of general formula I, which appear as racemates, can be resolved by known methods (see Allinger N.L. and Eliel E.L. in "Topics in Stereochemistry ", vol. 6, Wiley Interscience, 1971)) to their optical antipodes, and compounds of the general formula I with at least 2 asymmetric carbon atoms can be separated into their diastereomers by known methods based on their physicochemical differences, e.g. chromatography and/or fractionation by crystallization, which, if obtained in racemic form, can then be resolved into enantiomers as mentioned above.

Separation of enantiomers is performed primarily on columns on chiral phases or by recrystallization from an optically active solvent or by reaction with an optically active substance that forms salts or derivatives such as esters or amides with a racemic compound, especially with acids and their activated derivatives or alcohols, and separation obtained mixtures of diastereomers or derivatives, for example on the basis of differences in solubility, while free antipodes can be released from pure diastereomer salts or derivatives by the action of suitable means. Optically active acids that are most often used are, for example, D and L forms of tartaric acid or dibenzoyltartaric acid, di-o-tolylvic acid, malic acid, mandelic acid, camphor-sulfonic acid, glutamic acid, aspartic acid or quinic acid. (+)-or (-)-menthol can be used as an optically active alcohol, and (+)- or (-)-menthyloxycarbonyl can be used as an optically active acyl group in amides, for example.

Furthermore, the obtained compounds of formula I can be translated into their salts, especially for pharmaceutical use into their physiologically acceptable salts with inorganic or organic acids. Acids that can be used here are, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, methanesulfonic acid, phosphoric acid, fumaric acid, succinic acid, lactic acid, citric acid, tartaric acid or maleic acid.

In addition, if the new compounds of formula I obtained in this way contain a carboxy, hydroxyphosphoryl, sulfo or 5-tetrazolyl group, they can then, if desired, be converted into their salts with inorganic or organic bases, especially for pharmaceutical use into their physiologically acceptable salts. Suitable bases here are, for example, sodium hydroxide, potassium hydroxide, arginine, cyclohexylamine, ethanolamine, diethanolamine and triethanolamine.

The compounds of the general formulas II to IV, which were used as starting materials, are partially known from the literature or can be produced by procedures known from the literature (see examples I to XIV).

As already mentioned in the introduction, the compounds of the general formula I and their physiologically acceptable salts have valuable pharmacological properties, especially the inhibitory effect on signal transmission mediated by the epidermal growth factor receptor (e. Epidermal Growth Factor receptor, EGF-R), whereby this can achieved, for example, by inhibition of ligand binding, receptor dimerization or with the tyrosine kinase itself. In addition, signal transmission can also be blocked on downstream components.

The biological properties of the new compounds were tested as follows:

Inhibition of EGF-R-mediated signal transmission can be demonstrated, for example, with cells that express human EGF-R and whose survival and proliferation depend on stimulation with EGF, or TGF-alpha. Here, an interleukin-3 (IL-3)-dependent mouse cell line genetically engineered to express functional human EGF-R was used. Proliferation of these cells known as F/L-HERc can therefore be stimulated with murine IL-3 or with EGF (see von Rüden, T. et al. in EMBO J. 7, 2749-2756 (1988) and Pierce, J.H. et al. in Science 239, 628-631 (1988)).

The FDC-P1 cell line, the preparation of which was described by Dexter, T.M., served as the starting material for F/L-HERc cells. et al. in J. Exp. Honey. 152, 1036-1047 (1980). Alternatively, however, other growth factor-dependent cells can also be used (see, for example, Pierce, J.H. et al. in Science 239, 628-631 (1988), Shibuya, H. et al. in Cell 70, 57 -67 (1992) and Alexander, W. S. et al in EMBO J. 10, 3683-3691 (1991)). Recombinant retroviruses were used to express the human EGF-R cDNA (see Ullrich, A. et al. in Nature 309, 418-425 (1984)) as described by von Rüiden, T. et al., in EMBO J. 7, 2749-2756 (1988), except that the LKSSN retrovirus vector was used for EGF-R cDNA expression (see Miller, A.D. et al. in BioTeknigues 7, 980-990 (1989)) and the GP+E86 line ( see Markowitz, D. et al., J. Virol. 62, 1120-1124 (1988)).

The test was conducted as follows:

F/L-HERc cells were grown in 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 with 5% CO2. To test the inhibitory effect of the compounds according to the invention, 1.5x10 cells per well were cultured in the above medium in triplicates in plates with 96 wells (200 μl), whereby cell proliferation was stimulated with EGF (20 ng/ml) or with mouse IL -3. As a source of IL-3, culture residues of the X63/0 mIL-3 cell line served (see Karasuyama, H. et al. in Eur. J. Immunol. 18, 97-104 (1988)). The compounds according to the invention were dissolved in 100% dimethylsulfoxide (DMSO) and were added to the cultures in different dilutions, with the maximum DMSO concentration being 1%. Cultures were incubated for 48 hours at 37°C.

To determine the inhibitory action of the compounds according to the invention, the relative number of cells was measured with a cell titer kit 96™, for the aqueous non-radioactive cell proliferation assay (Promega) in units of O.D. The relative number of cells was calculated as a percentage of the control (F/LHERc cells without inhibitor) and the concentration of the active substance that inhibits cell proliferation by 50% (IC50) was determined. The following results were obtained:

[image]

The compounds of the general formula I according to the invention thus inhibit signal transmission mediated by tyrosine kinases, as demonstrated by the example of human EGF-receptors, and they can therefore be used to treat pathophysiological processes caused by excessive tyrosine kinase function. These are, for example, benign or malignant tumors, especially tumors of epithelial and neuroepithelial origin, metastasis as well as abnormal proliferation of vascular endothelial cells (neoangiogenesis).

The compounds according to the invention can also be used for the prevention and treatment of diseases of the respiratory tract and lungs, which are associated with increased or altered production of mucus, which is caused by stimulation with tyrosine kinases, such as in inflammatory diseases of the respiratory tract, such as chronic bronchitis , chronic obstructive bronchitis, asthma, broncho-ectasia, allergic or non-allergic rhinitis or sinusitis, cystic fibrosis, α1-antitrypsin deficiency, or in cough, pulmonary emphysema, pulmonary fibrosis and hyper-reactive airways.

These compounds are also suitable for the treatment of diseases of the gastrointestinal tract and bile ducts and gall bladder, which are associated with the disturbed action of tyrosine kinases, which can be encountered, for example, in chronic inflammatory changes, such as cholecystitis, Crohn's disease, ulcerative colitis, and ulcers in the gastrointestinal tract or in diseases of the gastrointestinal tract that are associated with increased secretions, such as M. Menetrir's disease, secretory adenoma and protein loss syndrome, and furthermore, also for the treatment of nasal polyps as well as polyps of the gastrointestinal tract of different genesis, such as hairy or adenomatous colon polyps, but also polyps from the polyposis coli family, in intestinal polyps in the scope of Gardner's syndrome, in polyps in the entire gastrointestinal tract in Peutz-Jeghers syndrome, in inflammatory pseudopolyps, juvenile polyps, in Colitis cystica profunda and in pneumatosis cγstoides intestinales.

In addition, the compounds of the general formula I and their physiologically acceptable salts can be used for the treatment of kidney diseases, especially in cystic changes of the kidney, such as renal cysts, for the treatment of renal cysts that may be of idiopathic origin or occur within a syndrome, such as in tuberculous sclerosis, in von-Hippel-Lindau syndrome, in nephronophthisis and spongy kidneys, as well as in other diseases caused by abnormal tyrosine kinase function, such as epidermal hyperproliferation (psoriasis), inflammatory processes, diseases of the immune system, hyperproliferation of hematopoietic cells, etc.

Due to their biological properties, the compounds according to the invention can be used alone or in combination with other pharmacologically effective compounds, for example in tumor therapy, in monotherapy or in combination with other anti-tumor therapeutics, for example in combination with topoisomerase inhibitors (e.g. etoposide ), mitosis inhibitors (e.g. vinblastine), with compounds that react with nucleic acids (e.g. cis-platinum, cyclophosphamide, adriamycin), hormone antagonists (e.g. tamoxifen), inhibitors of metabolic processes (e.g. 5-FU, etc.), cytokines (eg interferons), antibodies, etc. For the treatment of respiratory diseases, these compounds can be used alone or in combination with other therapeutics of the respiratory tract, such as, for example, secretolytics, broncholytics and/or substances that have an anti-inflammatory effect. For the treatment of diseases in the gastrointestinal tract, these compounds can also be used alone or in combination with substances that act on motility or secretion or that have an anti-inflammatory effect. These combinations can be given simultaneously or sequentially.

These compounds can be given alone or in combination with other active substances intravenously, subcutaneously, intramuscularly, intrarectally, intraperitoneally, intranasally, by inhalation or transdermally or orally, aerosol formulations being particularly suitable for inhalation.

The compounds according to the invention are used for pharmaceutical application as a rule for warm-blooded vertebrates, especially for humans, in doses of 0.01-100 mg/kg of body weight, preferably of 0.1-15 mg/kg. For application, they are formulated with one or more of the usual inert carriers and/or diluents, e.g., corn starch, lactose, glucose, 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 with fatty substances such as hard fat or with suitable mixtures thereof in the form of conventional galenic preparations such as tablets, dragees, capsules, powders, suspensions, solutions , spray, or suppositories.

The following examples are provided to further explain the invention, and are not intended to limit it in any way.

PREPARATION OF STARTING CONNECTIONS

Examples

4-[(3-chloro-4-fluoro-phenyl)amino]-6-cyclopentylmethoxy-7-(2-bromo-ethoxyl-quinazoline)

K 3.50 g of 4-[(3-chloro-4-fluoro-phenyl)amino]-6-cyclo-pentylmethoxy-7-hydroxy-quinazoline and 6.89 ml of 1,2-dibromo-ethane in 40 ml of N, 4.84 g of potassium carbonate is added to N-dimethylformamide. The reaction mixture is stirred in a nitrogen atmosphere for 1.5 hours at 80°C. When cooled to room temperature, the reaction mixture was filtered and the filtrate was concentrated in vacuo. The oily brown residue was cooled in an ice bath and stirred with a little methanol, whereupon a yellowish solid crystallized. The precipitate is filtered off with suction, washed with a little cold methanol and dried in a vacuum desiccator. Yield: 2.60 g (58% of theoretical),

Rf value: 0.82 (silica gel, methylene chloride/methanol 9:1) Mass spectrum (ESI+): m/z = 494, 496, 498 [M+H]+.

Analogous to example I, the following compounds were 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). Rf value: 0.72 (silica gel, methylene chloride/methanol/concentrated aqueous ammonia solution = 90:10:0.1).

Mass spectrum (ESI-): m/z = 464, 466, 468 [M-H]-.

(2) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-cyclopentyloxy-7-(2-bromo-ethoxy)-quinazoline

Rf value: 0.65 (silica gel, methylene chloride/methanol/concentrated, aqueous ammonia solution = 90:10:0.1)

Mass spectrum (ESI-): m/z = 478, 480, 482 [M-H]-

(3) 4-[(3-chloro-4-fluoro-phenyl)amino]-7-cyclobutyloxy-6-(3-bromo-propyloxy)-quinazoline

(The reaction is carried out in acetonitrile as a solvent). Rf value: 0.62 (silica gel, methylene chloride/methanol 9:1)

Mass spectrum (ESI-): m/z = 478, 480, 482 [M-H]-

(4) 4-[(3-chloro-4-fluoro-phenyl)amino]-7-cyclopropylmethoxy-6-(3-bromo-propyloxy)-quinazoline

(The reaction is carried out in acetonitrile as a solvent). Rf value: 0.74 (silica gel, methylene chloride/methanol 9:1)

Mass spectrum (ESI-): m/z = 478, 480, 482 [M-H]-

(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 a base). Rf 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 a base). Melting point: 255° C

Mass spectrum (ESI+): m/z = 402, 404 [M+H]+

(8) 4-[(3-chloro-4-fluorophenyl)amino]-6-(3-hydroxy-propyloxy)-7-cyclobutyloxy-quinazoline

Rf value: 0.50 (silica gel, methylene chloride/methanol = 90:10)

Mass spectrum (ESI+): m/z = 418, 420 [M+H]+

(9) 4-[(3-chloro-4-fluorophenyl)amino]-6-(3-hydroxy-propyl-oxy)-7-cyclopropylmethoxy-quinazoline

Rf value: 0.21 (silica gel, methylene chloride/methanol = 95:5)

Mass spectrum (ESI+): m/z = 418, 420 [M+H]+

(10) 4-[(3-chloro-4-fluorophenyl)amino]-6-(2-bromo-ethoxy)-7-cyclopentyloxy-quinazoline

Rf value: 0.67 (silica gel, methylene chloride/methanol 90:10)

Mass spectrum (ESI+): m/z = 480, 482, 484 [M+H]+

(11) 4-[(3-chloro-4-fluorophenyl)amino]-6-(2-bromo-ethoxy)-7-cyclopropylmethoxy-quinazoline

Rf value: 0.68 (silica gel, methylene chloride/methanol = 90:10)

Mass spectrum (ESI+): m/z = 466, 468, 470 [M+H]+

(12) 4-[(3-chloro-4-fluorophenyl)amino]-6-cyclopropylmethoxy-7-(3-hydroxy-propyloxy)-quinazoline

Rf value: 0.53 (silica gel, methylene chloride/methanol = 90:10)

Mass spectrum (ESI + ): m/z = 418, 420 [M+H]+

(13) 4-[(3-chloro-4-fluorophenyl)amino]-6-{4-hydroxy-butyl-oxy)-7-cyclopentyloxy-quinazoline

Rf value: 0.46 (silica gel, ethyl acetate)

(14) 4-[(3-chloro-4-fluorophenyl)amino]-6-(2-bromo-ethoxy)-7-((R)-tetrahydrofuran-3-yloxy)-quinazoline

Rf value: 0.37 (silica gel, methylene chloride/methanol = 9:1)

Mass spectrum (ESI-): m/z = 480, 482, 484 [M-H]-

(15) 4-[(3-chloro-4-fluorophenyl)amino]-6-(2-bromo-ethoxy)-7-[(R)-(tetrahydrofuran-2-yl)methoxy]-quinazoline

Mass spectrum (ESI-): m/z - 494, 496, 498 [M-H]-

(16) 4-[(3-chloro-4-fluorophenyl)amino]-1-(2-bromo-ethoxy)-6-[(S)-(tetrahydrofuran-2-yl)methoxy]-quinazoline

Mass spectrum (ESI-): m/z = 494, 496, 498 [M-H]-

Example II

4-[(3-chloro-4-fluoro-phenyl)amino]-6-cyclopentylmethoxy-7-hydroxy-quinazoline

4.99 g of 4-[(3-chloro-4-fluoro-phenyl)amino]-6-cyclopentyl-methoxy-7-methylcarbonyloxy-quinazoline is suspended in 80 ml of methanol and mixed with 1.80 ml of concentrated aqueous ammonia solution . The reaction mixture was stirred overnight at room temperature. For processing, 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 is 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 under vacuum. Yield: 3.59 g (80% of theoretical), Rf value: 0.48 (silica gel, methylene chloride/methanol/concentrated, aqueous ammonia = 90:10:0.1) Mass spectrum (ESI+): m/z = 388, 340 [M+H]+

Analogous to example II, the following compounds were obtained:

(1) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-cyclopropylmethoxy-7-hydroxy-quinazoline

Rf value: 0.56 (silica gel, methylene chloride/methanol 9:1)

Mass spectrum (ESI-): m/z = 358, 360 [M-H]-

(2) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-cyclopentyloxy-7-hydroxy-quinazoline

Rf value: 0.53 (silica gel, methylene chloride/methanol/concentrated, 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

Rf value: 0.54 (silica gel, methylene chloride/methanol/concentrated, 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 caustic soda in ethanol as a solvent).

Rf value: 0.23 (silica gel, ethyl acetate) Mass spectrum (ESI+): m/z = 346, 348 [M+H]+

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

Rf value: 0.57 (silica gel, methylene chloride/methanol = 9:1)

Mass spectrum (ESI+): m/z = 376, 378 [M+H]+

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

Rf value: 0.42 (silica gel, methylene chloride/methanol = 9:1)

Example III

4-[(3-chloro-4-fluoro-phenyl)amino]-6-cyclopentylmethoxy-7-methylcarbonyloxy-quinazoline

4.03 g of 4-chloro-6-cyclopentylmethoxy-7-methylcarbonyl-oxy-quinazoline is suspended in 70 ml of isopropanol and mixed with 1.95 g of 3-chloro-4-fluoro-aniline. The reaction mixture is refluxed for two hours under a nitrogen atmosphere. When cooled to room temperature, the resulting light-colored precipitate is filtered off with suction, washed with a little isopropanol and air-dried.

Yield: 4.99 g (92% of theoretical), Rf value: 0.80 (silica gel, methylene chloride/methanol/concentrated, aqueous ammonia = 90:10:0.1) Mass spectrum (ESI+): m/z = 430, 432 [M+H]+

Analogous to example II, the following compounds were obtained:

(1) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-cyclopropylmethoxy-7-methylcarbonyloxy-quinazoline

Rf 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

Rf value: 0.73 (silica gel, methylene chloride/methanol/concentrated, 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

Rf value: 0.76 (silica gel, methylene chloride/methanol/concentrated, 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

Rf value: 0.50 (silica gel, ethyl acetate) Mass spectrum (ESI+): m/z - 388, 390 [M+H]+

(5) 4-[(R)-(1-phenyl-ethyl)amino]-6-hydroxy-7-methoxy-quinazoline

(The acetoxy protecting group is already split off under the reaction conditions) .

Rf value: 0.46 (silica gel, ethyl acetate) Mass spectrum (ESI+): m/z = 296 [M+H]+

(6) 6-benzyloxy-4-[(3-chloro-4-fluorophenyl)amino]-7-cyclo-pentyloxy-quinazoline

(Pyridine is added as an auxiliary base). Rf value: 0.51 (silica gel, methylene chloride/methanol = 95:5)

Mass spectrum (ESI+): m/z = 464, 466 [M+H]+

(7) 4-[(3-chloro-4-fluorophenyl)amino]-7-methylcarbonyloxy-6-((S)-tetrahydrofuran-3-yloxy)-kyriazoline

Rf value: 0.67 (silica gel, methylene chloride/methanol = 9:1)

Mass spectrum (ESI-): m/z = 416, 418 [M-H]-

(8) 4-[(3-chloro-4-fluorophenyl)amino]-7-methylcarbonyloxy-6-[(S)-(tetrahydrofuran-2-yl)methoxy]-quinazoline hydrochloride

Melting point: 274-276°C Mass spectrum (ESI+): m/z = 432, 434 [M+H] +

Example IV

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

3.80 g of 4-hydroxy-6-cyclopentylmethoxy-7-methyl-carbonyloxy-quinazoline are suspended in 90 ml of thionyl chloride and heated in a nitrogen atmosphere to the boiling point. After adding four drops of N,N-dimethylformamide, the reaction mixture is heated under reflux for two hours. When it cools down to room temperature, the excess thionyl chloride is distilled off in a water jet vacuum. The brown residue is mixed with 30 ml of toluene. The solvent is distilled off, leaving behind 4.30 g of a gray-brown solid, which is further converted without further purification. Rf value: 0.89 (silica gel, methylene chloride/methanol/concentrated, aqueous ammonia solution = 90:10:0.1) Analogous to example IV, the following compounds were obtained:

(1) 4-chloro-6-cyclopropylmethoxy-7-methylcarbonyloxy-quinazoline

Rf value: 0.84 (silica gel, methylene chloride/methanol = 9:1)

(2) 4-chloro-6-cyclopentyloxy-7-methylcarbonyloxy-quinazoline

Rf value: 0.69 (silica gel, methylene chloride/methanol/concentrated, aqueous ammonia solution = 90:10:0.1)

(3) 6-benzyloxy-4-chloro-7-methylcarbonyloxy-quinazoline

Rf value: 0.77 (silica gel, methylene chloride/methanol/concentrated, aqueous ammonia solution = 90:10:0.1)

(4) 6-benzyloxy-4-chloro-7-cyclopentyloxy-quinazoline

Rf value: 0.91 (silica gel, methylene chloride/methanol = 9:1)

(5) 4-chloro-7-methylcarbonyloxy-6-((S)-tetrahydrofuran-3-yloxy)-quinazoline

Rf value: 0.83 (silica gel, methylene chloride/methanol = 9:1)

(6) 4-chloro-7-methylcarbonyloxy-6-[(S)-(tetrahydrofuran-2-yl)methoxy]-quinazoline

Rf value: 0.48 (silica gel, cyclohexane/ethyl acetate = 1:1)

Example V

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

4.30 g of 4,7-dihydroxy-6-cyclopentylmethoxy-quinazoline in 100 ml of pyridine is heated under a nitrogen atmosphere to 80°C. 1.80 ml of acetic anhydride is added to the dark brown suspension. The reaction mixture is stirred for three hours at 80°C, during which everything dissolves. When cooled to room temperature, the reaction mixture is poured onto approx. 800 ml of ice water. The resulting precipitate is sucked off and thoroughly washed with water. The light gray solid was dried in a vacuum desiccator. Yield: 3.82 g (77% of theoretical), Rf value: 0.49 (silica gel, methylene chloride/methanol = 9:1) Mass spectrum (ESI-): m/z = 301 [M-H]-

Analogous to example V, the following compounds were obtained:

(1) 4-hydroxy-6-cyclopropylmethoxy-7-methylcarbonyloxy-quinazoline

Rf value: 0.53 (silica gel, methylene chloride/methanol = 9:1)

Mass spectrum (ESI-): m/z = 273 [M-H]-

(2) 4-hydroxy-6-cyclopentyloxy-7-methylcarbonyloxy-quinazoline

Melting point: 209-212°C Mass spectrum (ESI-): m/z = 287 [M-H]-

(3) 6-benzyloxy-4-hydroxy-7-methylcarbonyloxy-quinazoline

Rf value: 0.48 (silica gel, methylene chloride/methanol/concentrated, aqueous ammonia solution = 90:10:0.1)

Mass spectrum (ESI-): m/z - 309 [M-H]-

(4) 4-hydroxy-7-methylcarbonyloxy-6-((S)-tetrahydrofuran-3-yloxy)-quinazoline

Rf value: 0.62 (ready-made reverse-phase TLC plates (E. Merck), acetonitrile/water/trifluoroacetic acid = 50:50:1) Mass spectrum (ESI+): m/z = 291 [M+H] +

(5) 4-hydroxy-7-methylcarbonyloxy-6-[(S)-(tetrahydrofuran-2-yl)methoxy]-quinazoline

Rf value: 0.50 (silica gel, methylene chloride/methanol = 9:1)

Mass spectrum (ESI+): m/z - 305 [M+H]+

Example VI

4,7-dihydroxy-6-cyclopentylmethoxy-quinazoline

5.76 g of 2-amino-5-cyclopentylmethoxy-4-hydroxy-benzoic acid and 6.52 g of formamidine acetate in 140 ml of ethanol are heated for approx. three hours under reflux. For processing, the reaction mixture is concentrated to approx. 100 ml and mixed with 300 ml of ice water, whereby a gray precipitate is separated. The precipitate is suctioned off, washed with water and dried in a vacuum desiccator.

Yield: 4.57 g (77% of theoretical), Rf value: 0.25 (silica gel, methylene chloride/methanol = 95:5) Mass spectrum (ESI-): m/z = 259 [M-H]-

Analogous to example VI, the following compounds were obtained:

(1) 4,7-dihydroxy-6-cyclopropylmethoxy-quinazoline

Rf value: 0.45 (silica gel, methylene chloride/methanol/concentrated, aqueous ammonia solution = 90:10:0.1)

Mass spectrum (ESI-): m/z = 231 [M-H]-

(2) 4,7-dihydroxy-6-cyclopentyloxy-quinazoline

Rf value: 0.42 (silica gel, methylene chloride/methanol/concentrated, aqueous ammonia solution = 90:10:0.1)

Mass spectrum (EI): m/z = 246 [M]+

(3) 6-benzyloxy-4,7-dihydroxy-quinazoline

Rf value: 0.44 (silica gel, methylene chloride/methanol/concentrated, aqueous ammonia solution = 90:10:0.1)

Mass spectrum (ESI-): m/z = 267 [M-H]-

(4) 6-benzyloxy-7-cyclopentyloxy-4-hydroxy-quinazoline

Melting point: 221-223°C Mass spectrum (ESI+): m/z = 337 [M+H] +

(5) 4, 7-dihydroxy-6-((S)-tetrahydrofuran-3-yloxy)-quinazoline

Rf value: 0.69 (ready-made reverse phase TLC plate (E. Merck), acetonitrile/water/trifluoroacetic acid = 50:50:1)

Mass spectrum (ESI-): m/z = 247 [M-H]-

(6) 4,7-dihydroxy-6-[(S)-(tetrahydrofuran-2-yl)methoxy]-quinazoline

Rf value: 0.56 (silica gel, methylene chloride/methanol = 9:1)

Mass spectrum (ESI-): m/z = 261 [M-H]-

Example VII

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

6.50 g of 5-cyclopentylmethoxy-4-hydroxy-2-nitro-benzoic acid is dissolved in 130 ml of methanol, 2.00 g of Raney nickel is mixed and hydrided under a hydrogen pressure of 50 psi for approximately three hours at room temperature, until the calculated amount of hydrogen is consumed. The catalyst is filtered off and washed with hot methanol. The filtrate is concentrated in vacuo. The remaining brownish solid is further converted without further purification.

Yield: 5.79 g (100% of theoretical), Rf value: 0.67 (silica gel, methylene chloride/methanol = 9:1) Mass spectrum (ESI-): m/z = 250 [M-H]-

Analogous to example VII, the following compounds were obtained:

(1) 2-amino-5-cyclopropylmethoxy-4-hydroxy-benzoic acid

Rf value: 0.51 (silica gel, methylene chloride/methanol/concentrated, aqueous ammonia solution = 90:10:0.1)

Mass spectrum (ESI-): m/z = 222 [M-H]-

(2) 2-amino-5-cyclopentyloxy-4-hydroxy-benzoic acid

Rf value: 0.38 (silica gel, methylene chloride/methanol/concentrated, aqueous ammonia solution = 90:10:0.1)

Mass spectrum (ESI+): m/z = 238 [M+H]+

(3) 2-amino-5-benzyloxy-4-hydroxy-benzoic acid

Rf value: 0.52 (silica gel, methylene chloride/methanol/concentrated, aqueous ammonia solution = 90:10:0.1)

Mass spectrum (ESI-): m/z = 258 [M-H]-

(4) Cyclopentyl 2-amino-5-benzyloxy-4-cyclopentyloxy-benzoate

(The reaction was carried out in a 1:1 mixture of methanol and tetrahydrofuran).

Rf value: 0.84 (silica gel, ethyl acetate/cyclohexane = 1:1) Mass spectrum (ESI+): m/z = 396 [M+H] +

(5) 2-amino-4-hydroxy-5-((S)-tetrahydrofuran-3-yloxy)-benzoic acid

Rf value: 0.70 (ready-made reverse phase TLC plate (E. Merck), acetonitrile/water/trifluoroacetic acid = 50:50:1) Mass spectrum (ESI-): m/z = 238 [M-H]-

(6) 2-amino-4-hydroxy-5-[(S)-(tetrahydrofuran-2-yl)-methoxy]-benzoic acid

Rf value: 0.59 (ready-made reverse phase TLC plate (E. Merck), acetonitrile/water/trifluoroacetic acid = 50:50:1) Mass spectrum (ESI-): m/z = 252 [M-H]-

Example VIII

5-cyclopentylmethoxy-4-hydroxy-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 in an ice bath under a nitrogen atmosphere. Then 3.90 g of sodium is added in the meals. The reaction mixture is stirred for 30 minutes while cooling in an ice bath, then briefly heated to 35-40°C and then stirred for another three hours while cooling in an ice bath. Then the ice bath is removed and the reaction mixture is stirred overnight at room temperature. The dark brown to reddish reaction solution is poured onto approx. 800 ml of acetone, whereby a dark brown precipitate is separated. The precipitate is suctioned off, washed with acetone, dissolved in 300-400 ml of water and adjusted to approximately pH 2 with 60 ml of 2 N 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 residue in the flask was dissolved in 800 ml of methylene chloride and purified over a silica gel column with methylene chloride/methanol (9:1). A brown oil is obtained, which is brought to crystallization by mixing with water and cooling in an ice bath. The resulting brownish precipitate is suctioned off, washed with a little water and dried in a vacuum desiccator.

Yield: 9.55 g (47% of theoretical), Rf value: 0.67 (silica gel, toluene/dioxane/ethanol/glacial acetic acid = 90:10:10:6) Mass spectrum (ESI-): m/ z = 280 [M-H]-

Analogous to example VIII, the following compounds were obtained:

(1) 5-cyclopropylmethoxy-4-hydroxy-2-nitro-benzoic acid

Rf value: 0.61 (silica gel, toluene/dioxane/ethanol/glacial acetic acid = 90:10:10:6)

Mass spectrum (ESI-): m/z = 252 [M-H]-

(2) 5-cyclopentyloxy-4-hydroxy-2-nitro-benzoic acid

Rf value: 0.62 (silica gel, toluene/dioxane/ethanol/glacial acetic acid = 90:10:10:6)

Mass spectrum (ESI-): m/z - 266 [M-H]-

(3) 5-benzyloxy-4-hydroxy-2-nitro-benzoic acid

Melting point: 176-178°C

Mass spectrum (ESI-): m/z = 288 [M-H]-

(4) 4-hydroxy-2-nitro-5-((S)-tetrahydrofuran-3-yloxy)-benzoic acid

Rf value: 0.58 (ready-made reverse phase TLC plate (E. Merck), acetonitrile/water/trifluoroacetic acid -50:50:1) Mass spectrum (ESI-): m/z = 268 [M-H]-

(5) 4-hydroxy-2-nitro-5-[(S)-(tetrahydrofuran-2-yl)-methoxy]-benzoic acid

Rf value: 0.53 (ready-made reverse phase TLC plate (E. Merck), acetonitrile/water/trifluoroacetic acid = 50:50:1) Mass spectrum (ESI-): m/z = 282 [M-H]-

Example IX

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

To 50.00 g of glycine ethyl ester hydrochloride in 100 ml of saturated potassium carbonate solution, add 100.00 g of sodium carbonate while cooling. The resulting mass is extracted several times with a total of approx. 600 ml of diethyl ether. The combined ether extracts are dried over sodium sulfate and concentrated to dryness. 28.60 g of glycine ethyl ester remains. It is mixed with 26.00 ml of isobutylene oxide and 40 ml of absolute ethanol and heated for 6 hours in a Roth bomb at 90°C. When it cools down to room temperature, the reaction mixture is concentrated, after which a dark seed oil remains. Yield: 45.80 g (73% of theoretical), mass spectrum (ESI + ): m/z = 176 [M+H] +

Example X

4-methylamino-dihydrofuran-2-one

2.00 g of 4-(N-benzyl-N-methyl-amino)-dihydrofuran-2-one in 25 ml of methanol is hydrogenated in the presence of 250 mg of palladium (10% on activated carbon) under a hydrogen pressure of 50 psi, approx. two hours at room temperature, until the calculated amount of hydrogen is consumed. For treatment, the catalyst is filtered off and the filtrate is concentrated in a vacuum. A colorless oil remains, which is immediately used for further conversion without further cleaning. Yield: 1.20 g

Rf value: 0.13 (silica gel, ethyl acetate) Mass spectrum (ESI+): m/z = 116 [M+H] +

Example XI

4-(N-benzyl-N-methyl-amino)-dihydrofuran-2-one

23.20 ml of N-methylbenzylamine is added to 15.00 g of 5H-furan-2-one in 150 ml of methylene chloride. The reaction mixture is stirred approx. 48 hours at room temperature. For processing, the reaction mixture is concentrated and chromatographed in portions on a silica gel column with ethyl acetate/petroleum ether (3:1) as eluent. The desired product is obtained as a yellowish oil.

Yield: 19.77 g (54% of theoretical), Rf 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, 10 ml of trifluoroacetic acid was added dropwise while stirring. The reaction mixture is heated to approx. 40°C. After 20 hours of stirring at room temperature, another 3 ml of trifluoroacetic acid was added. Since the reaction barely progresses even after a further three hours of stirring at room temperature, the reaction mixture is heated to 50°C. After four hours, the conversion is complete and the excess trifluoroacetic acid is distilled off on a rotary evaporator. The residue is mixed with water and concentrated, and basified with aqueous ammonia. The resulting light brown precipitate is filtered off with suction, washed with plenty of water and dried in a desiccator. The resulting product contains trifluoroacetic acid. Yield: 5.82 g Rf value: 0.61 (silica gel, methylene chloride/methanol = 9:1) Mass spectrum (ESI+): m/z = 360, 362 [M+H]+

Analogous to example XII, the following compounds were obtained:

(1) 4-[(3-chloro-4-fluoro-phenyl)amino]-7-cyclopropylmethoxy-6-hydroxy-quinazoline

Rf value: 0.65 (silica gel, methylene chloride/methanol = 9:1)

Mass spectrum (ESI+): m/z = 360, 362 [M+H]+

(2) 4-[(3-chloro-4-fluoro-phenyl)amino]-7-cyclopentylmethoxy-6-hydroxy-quinazoline

Rf value: 0.65 (silica gel, methylene chloride/methanol = 9:1)

Mass spectrum (ESI+): m/z = 374, 376 [M+H]+

(3) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-hydroxy-7-((R)-tetrahydrofuran-3-yloxy)-quinazoline

Rf value: 0.32 (silica gel, methylene chloride/methanol = 9:1)

(4) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-hydroxy-7-[(R)-(tetrahydrofuran-3-yl)-methoxy)-quinazoline

Mass spectrum (ESI-): m/z = 388, 390 [M+H]-

Example XIII

6-benzyloxy-4-4[(3-chloro-4-fluoro-phenyl)amino]-7-cyclo-butyloxy-quinazoline

7.50 g of potassium carbonate and 4, 50 g of cyclobutyl ester of methanesulfonic acid. The reaction mixture is stirred for two hours at 80°C. Then 2.00 g of cyclobutyl ester of methanesulfonic acid and 3.00 g of potassium carbonate are added once more and the mixture is stirred over the weekend at 60°C. Since the conversion is still not complete, 3.50 g of methanesulfonic acid cyclobutyl ester and 5.00 g of potassium carbonate are added again. After further stirring for 20 hours at 80°C, the conversion is almost complete. For work-up, 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, whereby a brownish precipitate forms. It is suctioned off, washed with methanol and dried in a desiccator. Yield: 5.10 g (64% of theory), Rf value: 0.69 (silica gel, methylene chloride/methanol = 9:1) Mass spectrum (ESI-): m/z = 448, 450 [M-H]-

Analogous to example XIII, the following compounds were obtained:

(1) 6-benzyloxy-4-[(3-chloro-4-fluoro-phenyl)amino]-7-cyclo-propylmethoxy-quinazoline

(Bromo-methylcyclopropane was used). Rf value: 0.72 (silica gel, methylene chloride/methanol = 9:1)

Mass spectrum (ESI-): m/z = 448, 450 [M-H]-

(2) 6-benzyloxy-4-[(3-chloro-4-fluoro-phenyl)amino]-7-cyclo-pentylmethoxy-quinazoline

(Bromo-cyclopentane was used). Rf value: 0.78 (silica gel, methylene chloride/methanol = 9:1)

Mass spectrum (ESI+): m/z = 464, 466 [M-H]+

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-dimethylformamide and mixed with 6.97 ml of diisopropylethylamine. Then, while cooling in an ice bath for 30 minutes, 5.91 ml of tert.butyl ester of bromoacetic acid is added. The cooling bath was removed and the reaction mixture was stirred overnight at room temperature. For processing, the reaction mixture is concentrated in a vacuum. The residue in the flask is dissolved in 50 ml of water and saturated with 15 g of sodium chloride. The aqueous solution is extracted several times with ethyl acetate. The combined extracts are washed with saturated sodium chloride solution, dried over magnesium sulfate and concentrated in vacuo to leave a yellowish oil. Yield: 7.36 g (97% of theoretical), Rf value: 0.46 (silica gel, ethyl acetate/methanol = 9:1) Mass spectrum (ESI+): m/z = 190 [M+H]+

Analogous to example XIV, the following compounds were obtained:

(1) (R)-(2-hydroxy-propylamino)-acetic acid-tert-butyl ester

Rf value: 0.46 (silica gel, ethyl acetate/methanol = 9:1)

Mass spectrum (ESI+): m/z = 190 [M+H]+

(2) tert-butyl (1,1-dimethyl-2-hydroxy-ethylamino)-acetate

Mass spectrum (ESI+): m/z = 204 [M+H]+

Rf value: 0.47 (silica gel, methylene chloride/methanol/conc. aqueous ammonia solution = 90:10:0.1)

Example XV

4-[(3-chloro-4-fluorophenyl)amino]-6-(3-methanesulfonyloxy-propyloxy)-7-cyclobutyloxy-quinazoline

This compound was obtained by the reaction of 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(3-hydroxy-propyloxy)-7-cyclobutyloxy-quinazoline with methanesulfonic acid chloride in methylene chloride in the presence of diisopropylethylamine at room temperature . Rf value: 0.37 (silica gel, methylene chloride/methanol = 95:5) Mass spectrum (ESI-): m/z = 494, 496 [M-H]-

Analogous to example XV, the following compounds were obtained:

(1) 4-[(3-chloro-4-fluorophenyl)amino]-6-(3-methanesulfonyloxy-propyloxy)-7-cyclopropylmethoxy-quinazoline

Rf value: 0.65 (silica gel, methylene chloride/methanol = 90:10)

Mass spectrum (ESI-): m/z = 494, 496 [M-H]-

(2) 4-[(3-chloro-4-fluorophenyl)amino]-6-cyclopropylmethoxy-7-(3-methanesulfonyloxy-propyloxy)-quinazoline

Rf value: 0.73 (silica gel, methylene chloride/methanol = 90:10)

Mass spectrum (ESI+): m/z = 496, 498 [M+H]+

(3) 4-[(3-chloro-4-fluorophenyl)amino]-6-(4-methanesulfonyloxy-butyloxy)-7-cyclopentyloxy-quinazoline

Rf value: 0.76 (silica gel, methylene chloride/methanol = 90:10)

Mass spectrum (ESI+): m/z = 524, 526 [M+H]+

Example XVI

4-[(3-chloro-4-fluorophenyl)-amino]-6-hydroxy-7-cyclopropyl-methoxy-quinazoline

This compound was obtained by hydrogenation of 6-benzyloxy-4-[(3-chloro-4-fluorophenyl)amino]-7-cyclopropylmethoxy-quinazoline in the presence of 10% Pd/C in a mixture of methylene chloride, ethanol and conc. hydrochloric acid. (500:210:3,5) in the Parr apparatus.

Utilization: 73% of the theoretical

Mass spectrum (ESI+): m/z = 360, 362 [M+H]+

Example XVII

Cyclopentyl-5-benzyloxy-4-cyclopentyloxy-2-nitro-benzoate

This compound was obtained by the reaction of 5-benzyloxy-4-hydroxy-2-nitro-benzoic acid with 2.2 equivalents of bromocyclopentane in the presence of potassium carbonate as an auxiliary base in dimethyl sulfoxide at room temperature. Utilization: 87% of the theoretical. Rf value: 0.92 (silica gel, ethyl acetate/cyclohexane = 1:1) Mass spectrum (ESI+): m/z = 426 [M+H]+

Example XVIII

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

5.03 ml of diethyl azodicarboxylate was added dropwise to a solution of 8.00 g of 4-[(3-chloro-4-fluorophenyl)amino]-6-benzyloxy-7-hydroxy-quinazoline (see WO 0055141 Al) and 2 .42 ml of (S)-(+)-3-hydroxy-tetrahydrofuran and 7.95 g of triphenyl-phosphine in 160 ml of tetrahydrofuran. The reaction mixture was stirred overnight at room temperature and then evaporated on a rotary evaporator. The residue in the flask was purified by silica gel column chromatography with methylene chloride/ethyl acetate (gradient from 2:1 to 1:2) as eluent.

Yield: 7.34 g (78% of theoretical)

Melting point: 165-168°C

Mass spectrum (ESI + ): m/z = 466, 468 [M+H] +

The following compounds were obtained analogously to example XVIII:

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

Mass spectrum (ESI+): m/z = 480, 482 [M+H]+

Rf value: 0.38 (silica gel, methylene chloride/methanol = 15:1)

(2) 4-[(3-chloro-4-fluorophenyl)amino]-7-(2-bromo-ethoxy)-6-((S)-tetrahydrofuran-3-yloxy)-quinazoline

Rf value: 0.35 (silica gel, methylene chloride/methanol = 20:1)

PREPARATION OF END JOINTS

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-cyclopentyl-methoxy-7-(2-bromo-ethoxy)-quinazoline and 341 mg (2-hydroxy-2-methyl-propylamino) -acetic acid-ethyl ester is dissolved in 20 ml of acetonitrile and mixed with 50 mg of sodium iodide, 275 mg of potassium carbonate and 0.70 ml of diisopropylethylamine. The reaction mixture is heated for approx. 90 hours under reflux. When cooled to room temperature, the reaction mixture was filtered and the filtrate was concentrated in vacuo. The residue in the flask is chromatographed over a column of silica gel with petroleum ether/acetate (50:50, then 0:100) as eluant. The cyclized product is obtained as a beige solid.

Utilization: 62 mg (23% of theoretical),

Rf value: 0.29 (silica gel, ethyl acetate)

Mass spectrum (ESI-): m/z = 541, 543 [M-H]-

Analogous to example 1, the following compounds were obtained:

(1) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-cyclopropylmethoxy-7-[2-(2,2-dimethyl-6-oxo-morpholin-4-yl)-ethoxy]- quinazoline

Rf value: 0.58 (silica gel, methylene chloride/methanol = 9:1)

Mass spectrum (ESI-): m/z = 513, 515 [M-H]-

(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 [M-H]-

(3) 4-[(3-chloro-4-fluoro-phenyl)amino]-7-cyclopropylmethoxy-6-[3-(2,2-dimethyl-6-oxo-morpholin-4-yl)-propyloxy]- quinazoline

Melting point: 200-202°C Mass spectrum (ESI-): m/z = 527, 529 [M-H]-

(4) 4-[(3-chloro-4-fluorophenyl)amino]-6-[3-(2, 2-dimethyl-6-oxo-morpholin-4-yl)-propyloxy]-7-methoxy-quinazoline

Melting point: 222-224°C Mass spectrum (ESI-): m/z = 487, 489 [M-H]-

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-fluoro-phenyl)amino]-6-cyclopropyl-methoxy-7-(2-bromo-ethoxy)-quinazoline and 400 mg of 4-methylamino-dihydrofuran-2-one in 20 ml of acetonitrile is mixed with 240 mg of potassium carbonate and 70 mg of sodium iodide and heated under reflux for 24 hours. When cooled to room temperature, the reaction mixture is filtered and the filtrate is concentrated in vacuo. The residue in the flask is chromatographed on a column of silica gel with methylene chloride/methanol/concentrated aqueous ammonia (97:3:0.05) as eluant. The title compound was obtained as a light beige solid. Yield: 70 mg (22% of theoretical), Rf value: 0.47 (silica gel, methylene chloride/methanol/concentrated, aqueous ammonia solution = 90:10:0.1) Mass spectrum (ESI+): m/z = 501 , 503 [M+H]+

Analogous to example 2, the following compounds were obtained:

(1) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-cyclopentyloxy-7-{2-[N-(2-oxo-tetrahydrofuran-4-yl)-N-methyl-amino] -ethoxy}-quinazoline

Rf value: 0.42 (silica gel, methylene chloride/methanol/concentrated, aqueous ammonia solution = 90:10:0.1)

Mass spectrum (ESI+): m/z = 515, 517 [M+H]+

(2) 4-[(3-chloro-4-fluorophenyl)amino]-6-{3-[N-(2-oxo-tetra-hydrofuran-4-yl)-N-methyl-amino]-propyloxy}- 7-cyclo-butyloxy-quinazoline

Melting point: 147.5-151°C Mass spectrum (ESI+): m/z = 515, 517 [M+H] +

Example 3

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

K 380 mg 4-[(3-bromo-phenyl)amino]-6-(2-N-[(tert-butyl-oxycarbonyl)methyl]-N-((S)-2-hydroxy-propyl)-amino- ethoxy)-7-methoxy-quinazoline in 8 ml of acetonitrile, 90 μl of methanesulfonic acid is added. The reaction mixture is heated for approx. three hours under reflux, then another equivalent of methanesulfonic acid is added and further heated under reflux until the reaction is complete. For processing, the reaction mixture is diluted with acetic ester and washed with a saturated solution of sodium hydrogencarbonate and with a saturated solution of sodium chloride. The organic phase is dried over magnesium sulfate and concentrated in vacuo. The residue in the flask is stirred with diethyl ether and suction. The title layer is obtained as a white solid. Yield: 280 mg (85% of theoretical), Melting point: 190°C Mass spectrum (ESI-): m/z = 485, 487 [M-H]-

Analogous to example 3, the following compounds were 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 [M-H]-

(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).

Rf value: 0.33 (silica gel, ethyl acetate) Mass spectrum (ESI-): m/z = 473, 475 [M-H]-

(4) 4-[(R)-(1-phenyl-ethyl)amino]-6-[3-((S)-6-methyl-2-oxo-morpholin-4-yl)-propyloxy]-7- methoxy-quinazoline

(The reaction is carried out with trifluoroacetic acid in acetonitrile). Rf value: 0.41 (silica gel, ethyl acetate/methanol = 9:1) Mass spectrum (ESI-): m/z = 449 [M-H]-

(5) 4-[(R)-(1-phenyl-ethyl)amino]-6-[2-((S)-6-methyl-2-oxo-morpholin-4-yl)-ethoxy]-7- methoxy-quinazoline

(The reaction is carried out with trifluoroacetic acid in acetonitrile).

Rf value: 0.49 (silica gel, ethyl acetate/methanol/concentrated, aqueous ammonia solution = 9:1:0.1) Mass spectrum (ESI-): m/z = 435 [M-H]-

(6) 4-[(3-chloro-4-fluorophenyl)amino]-6-[3-{(R)-6-methyl-2-oxo-morpholin-4-yl)-propyloxy]-7-cyclobutyloxy- quinazoline

(The reaction is carried out with trifluoroacetic acid in acetonitrile).

Melting point: 185.5-189.5°C Mass spectrum (ESI+): m/z = 515, 517 [M+H]+

(7) 4-[(3-chloro-4-fluorophenyl) amino]-6-[3-(5,5-dimethyl-2-oxo-morpholin-4-yl)-propyloxy]-7-cyclobutyloxy-quinazoline

(The reaction is carried out with trifluoroacetic acid in acetonitrile). Melting point: 214-216°C

Mass spectrum (ESI-): m/z = 527, 529 [M-H]-

(8) 4-[(3-chloro-4-fluorophenyl)amino]-6-[3-((R)-6-methyl-2-oxo-morpholin-4-yl)-propyloxy]-7-cyclopropylmethoxy- quinazoline

(The reaction is carried out with trifluoroacetic acid in acetonitrile). Melting point: 160.5-163°C Mass spectrum (ESI+): m/z = 515, 517 [M+H]+

(9) 4-[(3-chloro-4-fluorophenyl)amino]-6-[3-((S)-6-methyl-2-oxo-morpholin-4-yl)-propyloxy]-7-cyclopropylmethoxy- quinazoline

(The reaction is carried out with trifluoroacetic acid in acetonitrile).

Melting point: 160-162°C Mass spectrum (ESI+): m/z = 515, 517 [M+H]+

(10) 4-[(3-chloro-4-fluorophenyl)amino]-6-[2-((S)-6-methyl-2-oxo-morpholin-4-yl)-ethoxy]-7-cyclopentyloxy- quinazoline

(The reaction is carried out with trifluoroacetic acid in acetonitrile).

Rf value: 0.31 (silica gel, ethyl acetate) Mass spectrum (ESI+): m/z = 515, 517 [M+H]+

(11) 4-[(3-chloro-4-fluorophenyl)amino]-6-[2-((R)-6-methyl-2-oxo-morpholin-4-yl)-ethoxy]-7-cyclopentyloxy- quinazoline

(The reaction is carried out with trifluoroacetic acid in acetonitrile).

Melting point: 176-178°C Mass spectrum (ESI+): m/z = 515, 517 [M+H]+

(12) 4-[{3-chloro-4-fluorophenyl)amino]-6-[2-((S)-6-methyl-2-oxo-morpholin-4-yl)-ethoxy]-7-cyclopropylmethoxy- quinazoline

(The reaction is carried out with trifluoroacetic acid in acetonitrile).

Rf value: 0.37 (silica gel, ethyl acetate) Mass spectrum (ESI+): m/z = 501, 503 [M+H] +

(13) 4-[(3-chloro-4-fluorophenyl)amino]-6-[2-((R)-6-methyl-2-oxo-morpholin-4-yl)-ethoxy]-7-cyclopropylmethoxy- quinazoline

(The reaction is carried out with trifluoroacetic acid in acetonitrile).

Rf value: 0.37 (silica gel, ethyl acetate) Mass spectrum (ESI+): m/z - 501, 503 [M+H]+

(14) 4-[(3-chloro-4-fluorophenyl)amino]-6-cyclopropylmethoxy-7-[2-((5)-6-methyl-2-oxo-morpholin-4-yl)-ethoxy]- quinazoline

(The reaction is carried out with trifluoroacetic acid in acetonitrile).

Rf value: 0.48 (silica gel, ethyl acetate/methanol = 9:1) Mass spectrum (ESI+): m/z = 501, 503 [M+H]+

(15) 4-[(3-chloro-4-fluorophenyl)amino]-6-cyclopropylmethoxy-7-[2-((R)-6-methyl-2-oxo-morpholin-4-yl)-ethoxy]- quinazoline

(The reaction is carried out with trifluoroacetic acid in acetonitrile).

Mass spectrum (ESI+): m/z = 501, 503 [M+H]+

(16) 4-[(3-chloro-4-fluorophenyl)amino]-6-cyclopropylmethoxy-7-[3-((R)-6-methyl-2-oxo-morpholin-4-yl)-propyloxy]- quinazoline

(The reaction is carried out with trifluoroacetic acid in acetonitrile).

Rf value: 0.67 (silica gel, ethyl acetate/methanol = 9:1) Mass spectrum (ESI-): m/z = 513, 515 [M-H]-

(17) 4-[(3-chloro-4-fluorophenyl)amino]-6-cyclopropylmethoxy-7-[3-((S)-6-methyl-2-oxo-morpholin-4-yl)-propyloxy]- quinazoline

(The reaction is carried out with trifluoroacetic acid in acetonitrile).

Rf value: 0.67 (silica gel, ethyl acetate/methanol = 9:1) Mass spectrum (ESI-): m/z = 513, 515 [M-H]-

(18) 4-[(3-chloro-4-fluorophenyl)amino]-6-[2-(2,2-dimethyl-6-oxo-morpholin-4-yl)-ethoxy]-7-cyclopentyloxy-quinazoline

(The reaction is carried out with trifluoroacetic acid in acetonitrile).

Rf value: 0.56 (silica gel, ethyl acetate) Mass spectrum (ESI+): m/z = 529, 531 [M+H]+

(19) 4-[(3-chloro-4-fluorophenyl)amino]-6-cyclopentyloxy-7-[2-((S)-6-methyl-2-oxo-morpholin-4-yl)-ethoxy]- quinazoline

(The reaction is carried out with trifluoroacetic acid in acetonitrile).

Rf value: 0.60 (silica gel, ethyl acetate/methanol = 9:1) Mass spectrum (ESI+): m/z = 515, 517 [M+H]+

(20) 4-[(3-chloro-4-fluorophenyl)amino]-6-cyclopentyloxy-7-[2-((R)-6-methyl-2-oxo-morpholin-4-yl)-ethoxy]- quinazoline

(The reaction is carried out with trifluoroacetic acid in acetonitrile). Mass spectrum (ESI+): m/z = 515, 517 [M+H]+

(21) 4-[(3-chloro-4-fluorophenyl)amino]-6-[4-((S)-6-methyl-2-oxo-morpholin-4-yl)-butyloxy]-7-cyclopentyloxy- quinazoline

(The reaction is carried out with trifluoroacetic acid in acetonitrile).

Rf value: 0.51 (silica gel, ethyl acetate) Mass spectrum (ESI+): m/z = 543, 545 [M+H]+

(22) 4-[(3-chloro-4-fluorophenyl)amino]-6-[4-((R)-6-methyl-2-oxo-morpholin-4-yl)-butyloxy]-7-cyclopentyloxy- quinazoline

(The reaction is carried out with trifluoroacetic acid in acetonitrile). Mass spectrum (ESI + ): m/z = 543, 545 [M+H]+

(23) 4-[(3-chloro-4-fluorophenyl)amino]-6-[3-((S)-6-methyl-2-oxo-morpholin-4-yl)-propyloxy]-7-methoxy- quinazoline

(The reaction is carried out with trifluoroacetic acid in acetonitrile). Melting point: 183-186°C Mass spectrum (ESI+): m/z = 475, 477 [M+H]+

(24) 4-[(3-chloro-4-fluorophenyl)amino]-6-[3-(5,5-dimethyl-2-oxo-morpholin-4-yl)-propyloxy]-7-methoxy-quinazoline

(The reaction is carried out with trifluoroacetic acid in acetonitrile).

Rf value: 0.43 (silica gel, ethyl acetate) Mass spectrum (ESI-): m/z = 487, 489 [M-H]-

(25) 4-[(3-chloro-4-fluorophenyl)amino]-6-[2-((S)-6-methyl-2-oxo-morpholin-4-yl)-ethoxy]-7-methoxy- quinazoline

(The reaction is carried out with trifluoroacetic acid in acetonitrile). Melting point: 212-213°C Mass spectrum (ESI+): m/z = 461, 463 [M+H]+

(26) 4-[(3-chloro-4-fluorophenyl)amino]-6-{2-[N-(carboxy-methyl)-N-((S)-2-hydroxy-propyl)-amino]-ethoxy }-7-methoxy-quinazoline

(By-product from preparation 3(25)).

Melting point: 187-190°C Mass spectrum (ESI+): m/z = 479, 481 [M+H]+

(27) 4-[(3-chloro-4-fluorophenyl)amino]-6-[2-(2,2-dimethyl-6-oxo-morpholin-4-yl)-ethoxy]-7-methoxy-quinazoline

(The reaction is carried out with trifluoroacetic acid in acetonitrile).

Melting point: 229-232°C Mass spectrum (ESI-): m/z = 473, 475 [M-H]-

(28) 4-[(3-chloro-4-fluorophenyl)amino]-6-[2-(2,2-dimethyl-6-oxo-morpholin-4-yl)-ethoxy]-7-((R) -tetrahydrofuran-3-yloxy)-quinazoline

(The reaction is carried out with trifluoroacetic acid in acetonitrile).

Melting point: 195-196°C Mass spectrum (ESI+): m/z = 531, 533 [M+H] +

(29) 4-[(3-chloro-4-fluorophenyl)amino]-6-[2-(2,2-dimethyl-6-oxo-morpholin-4-yl)-ethoxy]-7-[(R) -(tetrahydrofuran-2-yl)methoxy]-quinazoline

(The reaction is carried out with trifluoroacetic acid in acetonitrile).

Melting point: 184°C Mass spectrum (ESI+): n/z = 545, 547 [M+H]+

(30) 4-[(3-chloro-4-fluorophenyl)amino]-7-[2-(2,2-dimethyl-6-oxo-morpholin-4-yl)-ethoxy]-6-((S) -tetrahydrofuran-3-yloxy)-quinazoline

Melting point: 202-205°C Mass spectrum (ESI+): m/z = 531, 533 [M+H]+

(31) 4-[(3-chloro-4-fluorophenyl)amino]-7-[2-(2,2-dimethyl-6-oxo-morpholin-4-yl)-ethoxy]-6-[(S) -(tetrahydrofuran-2-yl)methoxy]-quinazoline

Melting point: 182°C Mass spectrum (ESI+): m/z = 545, 547 [M+H]+

Example 4

4-[(3-bromo-phenyl)amino]-6-(2-N-[(tert-butyloxycarbonyl)-methyl]-N-((S)-2-hydroxy-propyl)-amino-ethoxy)-7 -methoxy-quinazoline

K 650 mg 4-[(3-bromo-phenyl)amino]-6-(2-bromo-ethoxy)-7-methoxy-quinazoline and 1.10 g (S)-(2-hydroxy-propylamino)-acetic acid -tert.butyl ester in 15 ml of acetonitrile, 0.25 ml of diisopropylethylamine is added. The reaction mixture was stirred overnight at 50°C. Since no reaction could be demonstrated, the reaction mixture was concentrated, mixed with 20 ml of N,N-dimethylformamide and stirred for eight hours at 60°C. Then the temperature is raised to 80°C. After a further eight hours, the reaction is complete. The reaction mixture is concentrated and chromatographed over a column of silica gel with acetic ester as a flow agent. The desired product is obtained as a white solid. Yield: 410 mg (51% of theoretical), Rf value: 0.27 (silica gel, ethyl acetate) Mass spectrum (ESI-): m/z = 559, 561 [M-H]-

Analogous to example 4, the following compounds were obtained:

(1) 4-[(3-bromo-phenyl)amino]-6-(2-N-[(tert.butyloxy-carbonyl)-methyl]-N-((R)-2-hydroxy-propyl)-amino -ethoxy)-7-methoxy-quinazoline

Melting point: 130°C Mass spectrum (ESI-): m/z = 559, 561 [M-H]-

(2) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(2-N-[(tert.butyl-oxycarbonyl)methyl]-N-((R)-2-hydroxy-propyl) )-amino-ethoxy)-7-methoxy-quinazoline

(The reaction is carried out in N,N-dimethylformamide).

Rf value: 0.40 (silica gel, ethyl acetate/petroleum ether = 4:1)

(3) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(3-N-[(tert.butyl-oxycarbonyl)methyl]-N-((R)-2-hydroxy-propyl) )-amino-propyloxy)-7-methoxy-quinazoline

(The reaction is carried out in N,N-dimethylformamide). Rf value: 0.37 (silica gel, ethyl acetate/petroleum ether = 4:1)

Mass spectrum (ESI-): m/z = 547, 549 [M-H]-

(4) 4-[(R)-(1-phenyl-ethyl)amino]-6-(3-N-[(tert.butyloxy-carbonyl)methyl]-N-((S)-2-hydroxy-propyl) )-amino-propyloxy)-7-methoxy-quinazoline

(The reaction is carried out in N,N-dimethylformamide). Rf value: 0.65 (silica gel, ethyl acetate/methanol = 9:1)

Mass spectrum (EI): m/z = 524 [M]+

(5) 4-[(R)-(1-phenyl-ethyl)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). Rf value: 0.57 (silica gel, ethyl acetate/methanol/concentrated, aqueous ammonia solution = 9:1:0.1)

(6) 4-[(3-chloro-4-fluorophenyl)amino]-6-(3-{N-[(tert-butyl-oxycarbonyl)methyl]-N-((R)-2-hydroxy-propyl) -amino}-propyloxy)-7-cyclobutyloxy-quinazoline

Rf value: 0.31 (silica gel, methylene chloride/methanol = 95:5)

(7) 4-[(3-chloro-4-fluorophenyl)amino]-6-(3-{N-[(tert-butyl-oxycarbonyl)methyl]-N-(1,1-dimethyl-2-hydroxy- ethyl)-amino}-propyloxy)-7-cyclobutyloxy-quinazoline

Rf value: 0.29 (silica gel, methylene chloride/methanol = 95:5) Mass spectrum (ESI+): m/z = 603, 605 [M+H] +

(8) 4-[(3-chloro-4-fluorophenyl)amino]-6-(3-{N-[(tert-butyl-oxycarbonyl)methyl]-N-((R)-2-hydroxy-propyl) -amino}-propyloxy)-7-cyclopropylmethoxy-quinazoline

Rf value: 0.37 (silica gel, methylene chloride/methanol = 95:5)

(9) 4-[(3-chloro-4-fluorophenyl)amino]-6-(3-{N-[(tert-butyl-oxycarbonyl)methyl]-N-((S)-2-hydroxy-propyl) -amino}-propyloxy)-7-cyclopropylmethoxy-quinazoline

Rf value: 0.50 (silica gel, ethyl acetate)

(10) 4-[(3-chloro-4-fluorophenyl)amino]-6-(2-{N-[(tert-butyl-oxycarbonyl)methyl]-N-((S)-2-hydroxy-propyl) -amino}-ethoxy)-7-cyclopentyloxy-quinazoline

Rf value: 0.54 (silica gel, ethyl acetate/cyclohexane = 9:1)

(11) 4-[(3-chloro-4-fluorophenyl)amino]-6-(2-{N-[(tert-butyl-oxycarbonyl)methyl]-N-((R)-2-hydroxy-propyl) -amino}-ethoxy)-7-cyclopentyloxy-quinazoline

Rf value: 0.66 (silica gel, ethyl acetate)

(12) 4-[(3-chloro-4-fluorophenyl)amino}-6-(2-{N-[(tert-butyl-oxycarbonyl)methyl]-N-((S)-2-hydroxy-propyl) -amino}-ethoxy}-7-cyclopropylmethoxy-quinazoline Rf value: 0.60 (silica gel, ethyl acetate)

(13) 4-[(3-chloro-4-fluorophenyl)amino]-6-(2-{N-[(tert-butyl-oxycarbonyl)methyl]-N-((R)-2-hydroxy-propyl} -amino}-ethoxy)-7-cyclopropylmethoxy-quinazoline

Rf value: 0.60 (silica gel, ethyl acetate)

(14) 4-[(3-chloro-4-fluorophenyl)amino]-6-cyclopropylmethoxy-7-(2-{N-[(tert-butyloxycarbonyl)methyl]-N-((S)-2-hydroxy- propyl)-amino}-ethoxy)-quinazoline

Rf value: 0.30 (silica gel, ethyl acetate)

(15) 4-[(3-chloro-4-fluorophenyl)amino]-6-cyclopropylmethoxy-7-(2-{N-[(tert-butyloxycarbonyl)methyl]-N-((R)-2-hydroxy- propyl)-amino}-ethoxy}-quinazoline

Rf value: 0.30 (silica gel, ethyl acetate)

(16) 4-[(3-chloro-4-fluorophenyl)amino]-6-cyclopropylmethoxy-7-(3-{N-[(tert-butyloxycarbonyl)methyl]-N-((R)-2-hydroxy- propyl )-amino}-propyloxy)-quinazoline

Rf value: 0.35 (silica gel, ethyl acetate)

(17) 4-[(3-chloro-4-fluorophenyl)amino]-6-cyclopropylmethoxy-7-(3-{N-[(tert-butyloxycarbonyl)methyl]-N-((S)-2-hydroxy- propyl)-amino]-propyloxy])-quinazoline

Rf value: 0.35 (silica gel, ethyl acetate)

(18) 4-[(3-chloro-4-fluorophenyl)amino]-6-(2-{N-[(ethoxy-carbonyl)methyl]-N-(2-hydroxy-2-methyl-propyl)-amino }-ethoxy)-7-cyclopentyloxy-quinazoline

Rf value: 0.64 (silica gel, methylene chloride/methanol = 9:1) Mass spectrum (ESI+): m/z = 575, 577 [M+H] +

(19) 4-[(3-chloro-4-fluorophenyl) amino]-6-cyclopentyloxy-7-(2-fN-[ (tert-butyloxycarbonyl)methyl]-N-((S)-2-hydroxy-propyl) )-amino}-ethoxy)-quinazoline

Rf value: 0.51 (silica gel, ethyl acetate)

(20) 4-[(3-chloro-4-fluorophenyl)amino]-6-cyclopentyloxy-7-(2-{N-t(tert-butyloxycarbonyl)methyl]-N-((R)-2-hydroxy-propyl) -amino}-ethoxy)-quinazoline

Rf value: 0.51 (silica gel, ethyl acetate)

(21) 4-[(3-chloro-4-fluorophenyl)amino]-6-(4-{N-[(tert-butyl-oxycarbonyl)methyl]-N-((S)-2-hydroxy-propyl) -amino}-butyloxy)-7-cyclopentyloxy-quinazoline

Rf value: 0.61 (silica gel, ethyl acetate)

(22) 4-[(3-chloro-4-fluorophenyl)amino]-6-(4-{N-[(tert-butyl-oxycarbonyl)methyl]-N-((R)-2-hydroxy-propyl} -amino}-butyloxy)-7-cyclopentyloxy-quinazoline

Rf value: 0.61 (silica gel, ethyl acetate)

(23) 4-[(3-chloro-4-fluorophenyl)amino]-6-(3-{N-[(tert-butyl-oxycarbonyl)methyl]-N-((S)-2-hydroxy-propyl) -amino}-propyloxy}-7-methoxy-quinazoline

Rf value: 0.46 (silica gel, ethyl acetate) Mass spectrum (ESI-): m/z = 547, 549 [M-H]-

(24) 4-[(3-chloro-4-fluorophenyl)amino]-6-(3-{N-[(tert-butyl-oxycarbonyl)methyl]-H-(1,1-dimethyl-2-hydroxy- ethyl)-amino(-propyloxy)-7-methoxy-quinazoline Mass spectrum (ESI+): m/z = 563, 565 [M+H]+

(25) 4-[(3-chloro-4-fluorophenyl)amino]-6-(2-{N-[(tert-butyl-oxycarbonyl)methyl]-N-((S)-2-hydroxy-propyl) -amino}-ethoxy)-7-methoxy-quinazoline

Rf value: 0.66 (silica gel, ethyl acetate/methanol = 9:1) Mass spectrum (ESI+): m/z = 535, 537 [M+H]+

(26) 4-[(3-chloro-4-fluorophenyl)amino]-6-(2-{N-[(ethoxy-carbonyl)methyl]-N-(2-hydroxy-2-methyl-propyl)-amino }-ethoxy)-7-methoxy-quinazoline

(It is formed as a mixture with a compound that has already cyclized). Rf value: 0.44 (silica gel, ethyl acetate)

Mass spectrum (ESI+): m/z = 521, 523 [M+H] +

(27) 4-[(3-chloro-4-fluorophenyl)amino]-6-(2-{N-[(ethoxy-carbonyl)methyl]-N-(2-hydroxy-2-methyl-propyl)-amino }-ethoxy)-7-((R)-tetrahydrofuran-3-yloxy)-quinazoline

(It is formed as a mixture with a compound that has already cyclized). Rf value: 0.30 (silica gel, methylene chloride/methanol = 9:1)

(28) 4-[(3-chloro-4-fluorophenyl)amino]-6-(2-{N-[(ethoxy-carbonyl)methyl]-N-(2-hydroxy-2-methyl-propyl)-amino }-ethoxy)-7-[(R)-(tetrahydrofuran-2-yl)methoxy]quinazoline

Mass spectrum (ESI-): m/z - 589, 591 [M-H]-

(29) 4-[(3-chloro-4-fluorophenyl)amino]-7-(2-{N-[(ethoxy-carbonyl)methyl]-N-(2-hydroxy-2-methyl-propyl)-amino }-ethoxy)-6-((S)-tetrahydrofuran-3-yloxy)-quinazoline

Rf value: 0.16 (silica gel, methylene chloride/methanol = 20:1)

(30) 4-[(3-chloro-4-fluorophenyl)amino]-7-(2-{N-[(ethoxy-carbonyl)methyl]-N-(2-hydroxy-2-methyl-propyl)-amino )-ethoxy)-6-E(S)-(tetrahydrofuran-2-yl)methoxy]-quinazoline

Rf value: 0.68 (silica gel, ethyl acetate/methanol = 15:1)

Analogous to the previous examples and in accordance with procedures known from the literature, the following compounds can be produced:

(1) 4-[(3-chloro-4-fluoro-phenyl)amino]-7-[2-(6-methyl-2-oxo-morpholin-4-yl)-ethoxy]-6-methoxy-quinazoline

(2) 4-[(3-chloro-4-fluoro-phenyl)amino]-7-[3-(6-methyl-2-oxo-morpholin-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-oxo-morpholin-4-yl)-ethoxy]-7-methoxy- quinazoline

(7) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-[3-(3-methyl-2-oxo-morpholin-4-yl)-propyloxy]-7-methoxy-quinazoline

(8) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-[2-(3-methyl-2-oxo-morpholin-4-yl)-ethoxy]-7-methoxy-quinazoline

(9) 4-[(R)-(1-phenyl-ethyl)amino]-6-[3-((R)-6-methyl-2-oxo-morpholin-4-yl)-propyloxy]-7- methoxy-quinazoline

(10) 4-[(R)-(1-phenyl-ethyl)amino]-6-[2-((R)-6-methyl-2-oxo-morpholin-4-yl)-ethoxy]-7- methoxy-quinazoline

(11) 4-[(3-chloro-4-fluorophenyl)amino]-7-[4-(6-methyl-2-oxo-morpholin-4-yl)-butyloxy]-6-methoxy-quinazoline

(12) 4-[(3-chloro-4-fluorophenyl)amino]-7-[3-(6-methyl-2-oxo-morpholin-4-yl)-propyloxy]-6-methoxy-quinazoline

(13) 4-[(3-chloro-4-fluorophenyl)amino]-6-[4-(6-methyl-2-oxo-morpholin-4-yl)-butyloxy]-7-methoxy-quinazoline

(14) 4-[(3-chloro-4-fluorophenyl)amino]-6-[2-(6-methyl-2-oxo-morpholin-4-yl)-ethoxy]-7-(tetrahydrofuran-3-yloxy) )-quinazoline

(15) 4-[(3-chloro-4-fluorophenyl)amino]-6-[2-(6-methyl-2-oxo-morpholin-4-yl)-ethoxy]-7-(tetrahydropyran-3-yloxy )-quinazoline

(16) 4-[(3-chloro-4-fluorophenyl)amino]-6-[2-(6-methyl-2-oxo-morpholin-4-yl)-ethoxy]-7-(tetrahydropyran-4-yloxy )-quinazoline

(17) 4-[(3-chloro-4-fluorophenyl)amino]-6-[2-(6-methyl-2-oxo-morpholin-4-yl)-ethoxy]-7-(tetrahydrofuran-2-yl -methoxy)-quinazoline

(18) 4-[(3-chloro-4-fluorophenyl)amino]-6-[2-(6-methyl-2-oxo-morpholin-4-yl)-ethoxy]-7-(tetrahydropyran-4-yl -methoxy)-quinazoline

(19) 4-[(3-chloro-4-fluorophenyl)amino]-6-[2-(6/6-dimethyl-2-oxo-morpholin-4-yl)-ethoxy]-7-(tetrahydrofuran-3 -yloxy)-quinazoline

(20) 4-[(3-chloro-4-fluorophenyl)amino]-6-[3-(6,6-dimethyl-2-oxo-morpholin-4-yl)-propyloxy]-7-(tetrahydrofuran-3 -yloxy)-quinazoline

(21) 4-[(3-chloro-4-fluorophenyl)amino]-6-[4-(6,6-dimethyl-2-oxo-morpholin-4-yl}-butyloxy]-7-(tetrahydrofuran-3 -yloxy)-quinazoline

(22) 4-[(3-chloro-4-fluorophenyl)amino]-6-[2-(6,6-dimethyl-2-oxo-morpholin-4-yl)-ethoxy]-7-{tetrahydrofuran-2 -ylmethoxy)-quinazoline

(23) 4-[(3-chloro-4-fluorophenyl)amino]-6-[3-(6, 6-dimethyl-2-oxo-morpholin-4-yl)-propyloxy]-7-(tetrahydrofuran-2 -ylmethoxy)-quinazoline

(24) 4-[(3-chloro-4-fluorophenyl)amino]-6-[4-(6,6-dimethyl-2-oxo-morpholin-4-yl)-butyloxy]-7-(tetrahydrofuran-2 -ylmethoxy)-quinazoline

(25) 4-[(3-chloro-4-fluorophenyl)amino]-7-[2-(6-methyl-2-oxo-morpholin-4-yl)-ethoxy]-6-(tetrahydrofuran-3-yloxy )-quinazoline

(26) 4-[(3-chloro-4-fluorophenyl)amino]-7-[2-(6-methyl-2-oxo-morpholin-4-yl)-ethoxy]-6-(tetrahydropyran-3-yloxy )-quinazoline

(27) 4-[(3-chloro-4-fluorophenyl)amino]-7-[2-(6-methyl-2-oxo-morpholin-4-yl)-ethoxy]-6-(tetrahydropyran-4-yloxy )-quinazoline

(28) 4-[(3-chloro-4-fluorophenyl)amino]-7-[2-(6-methyl-2-oxo-morpholin-4-yl)-ethoxy]-6-(tetrahydrofuran-2-yl -methoxy)-quinazoline

(29) 4-[(3-chloro-4-fluorophenyl)amino]-7-[2-(6-methyl-2-oxo-morpholin-4-yl)-ethoxy]-6-(tetrahydropyran-4-yl -methoxy)-quinazoline

(30) 4-[(3-chloro-4-fluorophenyl)amino]-7-[2-(6,6-dimethyl-2-oxo-morpholin-4-yl)-ethoxy]-6-(tetrahydrofuran-3 -yloxy)-quinazoline

(31) 4-[(3-chloro-4-fluorophenyl)amino]-7-[3-(6,6-dimethyl-2-oxo-morpholin-4-yl)-propyloxy]-6-(tetrahydrofuran-3 -yloxy)-quinazoline

(32) 4-[(3-chloro-4-fluorophenyl)amino]-7-[4-(6,6-dimethyl-2-oxo-morpholin-4-yl)-butyloxy]-6-(tetrahydrofuran-3 -yloxy)-quinazoline

(33) 4-[(3-chloro-4-fluorophenyl)amino]-7-[2-(6,6-dimethyl-2-oxo-morpholin-4-yl)-ethoxy]-6-(tetrahydrofuran-2 -ylmethoxy)-quinazoline

(34) 4-[(3-chloro-4-fluorophenyl)amino]-7-[3-(6,6-dimethyl-2-oxo-morpholin-4-yl)-propyloxy]-6-(tetrahydrofuran-2 -ylmethoxy)-quinazoline

(35) 4-[(3-chloro-4-fluorophenyl)amino]-7-[4-(6,6-dimethyl-2-oxo-morpholin-4-yl)-butyloxy]-6-(tetrahydrofuran-2 -ylmethoxy)-quinazoline

Example 5

Dragees with 75 mg of active substance

1 tablet core contains:

active substance 75.0 mg

calcium phosphate 93.0 mg

corn starch 35.5 mg

polyvinylpyrrolidone 10.0 mg

hydroxypropylmethylcellulose 15.0 mg

magnesium stearate 1.5 mg

230.0 mg

Preparation

The active substance is mixed with calcium phosphate, corn starch, polyvinylpyrrolidone, hydroxypropyl-methylcellulose and half the stated amount of magnesium stearate. Tablets with a diameter of approx. 13 mm and these are then passed through a suitable sieve of mesh size 1.5 mm and mixed with the remaining amount of magnesium stearate. This granulate is crushed on a tableting machine into tablets of the desired shape. Core mass: 230 mg Stamp: 9 mm, convex

The dragee cores produced in this way are coated with a film consisting mainly of hydroxypropylmethylcellulose. Finished and film-coated dragees are polished with beeswax.

Dragee mass: 245 mg.

Example 6

Tablets containing 100 mg of active substance

Composition

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

Preparation process

The active substance, milk sugar and starch are mixed and uniformly moistened with an aqueous solution of polyvinyl-pyrrolidone. The wet mass is sieved (sieve size 2.0 mm) and dried in a dryer with a moving belt at 50°C, sieved again (sieve size 1.5 mm) and lubricant is added to the mixture. The finished mixture is pressed into tablets.

Tablet mass: 220 mg

Diameter: 10 mm, biplanar, bevelled on both sides and notched on one side.

Example 7

Tablets containing 150 mg of active substance

Composition

1 tablet contains:

active substance 50.0 mg

powdered lactose 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

Preparation

The active substance is mixed with lactose, corn starch and silicic acid and moistened with a 20% aqueous solution of polyvinylpyrrolidone and sieved through a sieve with a mesh size of 1.5 mm. The granules are dried at 45°C, sieved again through the same sieve and mixed with the specified amount of magnesium stearate. Tablets are pressed from this mixture.

Tablet mass: 300 mg Stamp: 10 mm, flat

Example 8

Capsules in hard gelatin containing 150 mg of active substance

1 capsule contains:

active substance 50.0 mg

corn starch (dried) approx. 80.0 mg

lactose (powder) approx. 87.0 mg

magnesium stearate 3.0 mg

approx. 420.0 mg

Preparation

The active substance is mixed with additives, sifted through a 0.75 mm sieve and homogeneously mixed in a suitable device. The finished mixture is packed in hard gelatin capsules of size 1. Capsule filling: approx. 320 mg

Capsule shell: hard gelatin capsules size 1.

Example 9

Suppositories containing 150 mg of active substance

1 suppository contains:

active substance 150.0 mg

polyethylene glycol 1550 150.0 mg

polyethylene glycol 6000 460.0 mg

polyoxyethylene sorbitan monostearate 840.0 mg

2000.0 mg

Preparation

The mass for making suppositories is melted and the active substance is homogeneously mixed into it. The melt is poured into the cooling molds.

Example 10

Suspensions containing 50 mg of active substance

100 ml of suspension contains:

active substance 1.0 mg

On carboxymethylcellulose salt 0.10 g

methyl p-hydroxybenzoate 0.05 g

propyl p-hydroxybenzoate 0.01 g

glucose 10.00 g

glycerin 5.00 g

70% sorbitol solution 20.00 g

spice 0.30 g

dest. water ad 100 ml

Preparation

Dest. the water is heated to 70°C. Methyl and propyl p-hydroxybenzoate, as well as glycerin and Na salt of carboxymethylcellulose are dissolved in it with stirring. The solution is cooled to room temperature and the active substance is homogeneously dispersed in it with stirring. Sugar, sorbitol solution and spice are added and dissolved, and the suspension is deaerated with stirring to remove air.

5 ml of suspension contains 50 mg of active substance.

Example 11

Ampoules containing 10 mg of active substance

Composition:

active substance 10.0 mg 0.01

N hydrochloric acid q.s.

double distilled water ad 2.0 ml

Preparation

The active substance is dissolved in the required amount of 0.01 N HCl, made isotonic with table salt, sterile filtered and filled into ampoules of 2 ml.

Example 12

Ampoules containing 50 mg of active substance

Composition:

active substance 50.0 mg

0.01 N hydrochloric acid q.s.

double distilled water ad 10.0 ml

Preparation

The active substance is dissolved in the required amount of 0.01 N HCl, adjusted to isotonicity with table salt, sterile filtered and filled into ampoules of 10 ml.

Example 13

Capsules for powder inhalation with 5 mg of active substance

1 capsule contains

active substance 5.0 mg

lactose for inhalation 15.0 mg

20.0 mg

Preparation

The active substance is mixed with lactose for inhalation. The mixture is packed into capsules on a capsule making machine (weight of an empty capsule approx. 50 mg).

Capsule mass: 70.0 mg

Capsule size: 3

Example 14

Inhalation solution for manual atomizer with 2.5 mg of active substance

One spray activation contains:

active substance 2,500 mg

benzalkonium chloride 0.001 mg

1N hydrochloric acid q.s.

ethanol/water (50/50) ad 15,000 mg

Preparation

The active substance and benzalkonium chloride are dissolved in ethanol/water (50/50). The pH value of the solution is adjusted with 1N hydrochloric acid. The resulting solution is filtered and filled in suitable containers for use in a manual atomizer (cartridges).

Container content: 4.5 g.

Claims (12)

1. Bicyclic heterocycles of the general formula [image] indicated by that Ra represents a benzyl or 1-phenylethyl group or a phenyl group substituted with radicals R1 and R2, where R1 is hydrogen, fluorine, chlorine or bromine atom, methyl, trifluoromethyl, cyano or ethynyl group and R2 is hydrogen or a fluorine atom, one of the radicals Rb and Rc represents the group R3-(CH2)m-O-, and the other of the radicals Rb or Rc is methoxy, cyclobutyloxy, cyclopentyloxy, cyclopropylmethoxy, cyclobutylmethoxy, cyclopentylmethoxy, tetrahydrofuran-3-yloxy, tetrahydropyran-3-yloxy, tetrahydropyran-4-yloxy, tetrahydrofuranylmethoxy or tetrahydropyranylmethoxy group, where R3 represents N-(2-oxo-tetrahydrofuran-4-yl)-methyl-amino or N-(2-oxo-tetrahydrofuran-4-yl)-ethylamino group, group R4-O-CO-CH2-N-CH2CH2-OH which is substituted on the methylene groups with one or two methyl or ethyl groups, in which R4 represents a hydrogen atom or a C1-4-alkyl group, or a 2-oxo-morpholin-4-yl group which is substituted with one or two methyl or ethyl groups, and m is the number 2 or 3, provided that the following compounds are excluded: 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 and 4-[(3-bromo-phenyl)amino]-6-{2-[N-(2-oxo-tetrahydrofuran-4-yl)-N-methyl-amino]-ethoxy}-7-methoxy-quinazoline, their tautomers, stereoisomers and their salts. 2. Compounds of general formula I according to claim 1, characterized in that Ra is a benzyl or 1-phenylethyl group or a phenyl group substituted with radicals R1 and R2, where R1 is hydrogen, fluorine, chlorine or bromine atom, methyl, trifluoromethyl, cyano or ethynyl group and R2 is hydrogen or a fluorine atom, one of the radicals Rb and Rc is the group R3-(CH2)m-O-, and the other of the radicals Rb and Rc is methoxy, cyclobutyloxy, cyclopentyloxy, cyclopropylmethoxy, cyclobutylmethoxy, cyclopentylmethoxy, tetrahydrofuran-3-yloxy, tetrahydropyran-3-yloxy, tetrahydropyran- 4-yloxy, tetrahydro-furanylmethoxy or tetrahydropyranylmethoxy group, where R3 represents the N-(2-oxo-tetrahydrofuran-4-yl)-methyl-amino or N-(2-oxo-tetrahydrofuran-4-yl)-ethylamino group, the group R4-O-CO-CH2-N-CH2CH2- OH which is substituted on the methylene groups with one or two methyl or ethyl groups, where R4 is a hydrogen atom or a C1-4-alkyl group, or a 2-oxo-morpholin-4-yl group which is substituted with one or two methyl or ethyl groups, and m is the number 2, 3 or 4, provided that connections are excluded: 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-oxo-morpholin-4-yl)ethoxy]-7-methoxy-quinazoline, 4-[(3-bromo-phenyl)amino]-6-[2-(5,5-dimethyl-2-oxo-morpholin-4-yl)ethoxy]-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-[2-(6,6-dimethyl-2-oxo-morpholin-4-yl)-ethoxy]-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-[2-(6,6-dimethyl-2-oxo-morpholin-4-yl)-ethoxy]-7-cyclobutyloxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-[2-(6,6-dimethyl-2-oxo-morpholin-4-yl)-ethoxy]-7-cyclopentyloxy-quinazoline, 4-t(3-chloro-4-fluoro-phenyl)amino]-6-[2-(6,6-dimethyl-2-oxo-morpholin-4-yl)-ethoxy]-7-cyclopropylmethoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl]amino]-6-[2-(6,6-dimethyl-2-oxo-morpholin-4-yl)-ethoxy]-7-cyclopentylmethoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{2-[N-(2-oxo-tetrahydrofuran-4-yl)-N-methyl-amino]-ethoxy}-7-methoxy -quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{2-[N-(2-oxo-tetrahydrofuran-4-yl)-N-methyl-amino]-ethoxy}-7-cyclopentyloxy -quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{2-[N-(2-oxo-tetrahydrofuran-4-yl)-N-methyl-amino]-ethoxy}-7-cyclopentyl -methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-[3-(6,6-dimethyl-2-oxo-morpholin-4-yl)-propyloxy]-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-[3-(6,6-dimethyl-2-oxo-morpholin-4-yl)-propyloxy]-7-cyclopentyloxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-[3-(6,6-dimethyl-2-oxo-morpholin-4-yl)-propyloxy]-7-cyclopentylmethoxy-quinazoline, (R)-4-[(1-phenyl-ethyl)amino]-6-[3-(6,6-dimethyl-2-oxo-morpholin-4-yl)-propyloxy]-7-cyclopentyloxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-7-[2-(6,6-dimethyl-2-oxo-morpholin-4-yl)-ethoxy]-6-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-7-[2-(6, 6-dimethyl-2-oxo-morpholin-4-yl)-ethoxy]-6-cyclobutyloxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-7-[2-(6,6-dimethyl-2-oxo-morpholin-4-yl)-ethoxy]-6-cyclopentyloxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-7-[2-(6,6-dimethyl-2-oxo-morpholin-4-yl)-ethoxy]-6-cyclopropylmethoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl]amino]-7-[2-(6,6-dimethyl-2-oxo-morpholin-4-yl)-ethoxy]-6-cyclopentylmethoxy-quinazoline, 4 -[(3-chloro-4-fluoro-phenyl)amino]-7-{2-[N-(2-oxo-tetrahydrofuran-4-yl)-N-methyl-amino]-ethoxy}-6-methoxy- quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-7-{2-[N-(2-oxo-tetrahydrofuran-4-yl)-N-methyl-amino]-ethoxy}-6-cyclopentyloxy -quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-7-{2-[N-(2-oxo-tetrahydrofuran-4-yl)-N-methyl-amino]-ethoxy}-6-cyclopentyl -methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-7-[3-(6,6-dimethyl-2-oxo-morpholin-4-yl)-propyloxy]-6-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-7-[3-(6,6-dimethyl-2-oxo-morpholin-4-yl)-propyloxy]-6-cyclopentyloxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-7-[3-(6,6-dimethyl-2-oxo-morpholin-4-yl)-propyloxy]-6-cyclopentylmethoxy-quinazoline and (R)-4-[(1-phenyl-ethyl)amino]-7-[3-(6,6-dimethyl-2-oxo-morpholin-4-yl)-propyloxy]-6-cyclopentyloxy-quinazoline, their tautomers, stereoisomers and their salts. 3. Compounds of the general formula I according to claim 1, characterized in that Ra is a 1-phenylethyl group or a phenyl group substituted with radicals R1 and R2, where R1i represents fluorine, chlorine or bromine atom, methyl or ethynyl group and R2 is hydrogen or a fluorine atom, one of the radicals Rb and Rc is the group R3-(CH2)m-O-, and the other of the radicals Rb and Rc is methoxy, cyclobutyloxy, cyclopentyloxy, cyclopropylmethoxy, cyclobutylmethoxy, cyclopentylmethoxy, tetrahydrofuran-3-yloxy, tetrahydropyran-3-yloxy, tetrahydropyran- 4-yloxy, tetrahydrofuran-ylmethoxy or tetrahydropyranylmethoxy group, where R3 is the group N-(2-oxo-tetrahydrofuran-4-yl)-methylamino, the group R4-O-CO-CH2-N-CH2CH2-OH which is substituted on the methylene groups with one or two methyl groups, where R4 is a C1-4-alkyl group, or a 2-oxo-morpholin-4-yl group substituted with one or two methyl groups, and m is the number 2, 3 or 4, provided that connections are excluded: 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-me toxy-quinazoline, 4-[(3-bromo-phenyl)amino]-6-[2-(3-methyl-2~oxo-morpholin-4-yl)ethoxy]-7-methoxy-quinazoline, 4-[(3-bromo-phenyl)amino]-6-[2-(5,5-dimethyl-2-oxo-morpholin-4-yl)ethoxy]-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-[2-(6,6-dimethyl-2-oxo-morpholin-4-yl)-ethoxy]-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-[2-(6,6-dimethyl-2-oxo-morpholin-4-yl)-ethoxy]-7-cyclobutyloxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-[2-(6,6-dimethyl-2-oxo-morpholin-4-yl)-ethoxy]-7-cyclopentyloxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-[2-(6,6-dimethyl-2-oxo-morpholin-4-yl)-ethoxy]-7-cyclopropylmethoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl]amino]-6-[2-(6,6-dimethyl-2-oxo-morpholin-4-yl)-ethoxy]-7-cyclopentylmethoxy-quinazoline, 4 -[(3-chloro-4-fluoro-phenyl)amino]-6-{2-[N-(2-oxo-tetrahydrofuran-4-yl)-N-methyl-amino]-ethoxy}-7- methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{2-[N-(2-oxo-tetrahydrofuran-4-yl)-N-methyl-amino]-ethoxy}-7-cyclopentyloxy -quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{2-[N-(2-oxo-tetrahydrofuran-4-yl)-N-methyl-amino]-ethoxy}-7-cyclopentyl -methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-[3-(6, 6-dimethyl-2-oxo-morpholin-4-yl)-propyloxy]-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-[3-(6,6-dimethyl-2-oxo-morpholin-4-yl)-propyloxy]-7-cyclopentyloxy- : quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-[3-(6,6-dimethyl-2-oxo-morpholin-4-yl)-propyloxy]-7-cyclopentylmethoxy-quinazoline, (R)-4-[(1-phenyl-ethyl)amino]-6-[3-(6, 6-dimethyl-2-oxo-morpholin-4-yl)-propyloxy]-7-cyclopentyloxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-7-[2-(6,6-dimethyl-2-oxo-morpholin-4-yl)-ethoxy]-6-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-7-[2-(6,6-dimethyl-2-oxo-morpholin-4-yl)-ethoxy]-6-cyclobutyloxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-7-[2-(6,6-dimethyl-2-oxo-morpholin-4-yl)-ethoxy]-6-cyclopentyloxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-7-[2-(6,6-dimethyl-2-oxo-morpholin-4-yl)-ethoxy]-6-cyclopropylmethoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl]amino]-7-[2-(6,6-dimethyl-2-oxo-morpholin-4-yl)-ethoxy]-6-cyclopentylmethoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-7-{2-[N-(2-oxo-tetrahydrofuran-4-yl)-N-methyl-amino]-ethoxy}-6-methoxy -quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-7-{2-[N-(2-oxo-tetrahydrofuran-4-yl)-N-methyl-amino]-ethoxy}-6-cyclopentyloxy -quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-7-{2-[N-(2-oxo-tetrahydrofuran-4-yl)-N-methyl-amino]-ethoxy}-6-cyclopentyl -methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-7-[3-(6,6-dimethyl-2-oxo-morpholine-4-1)-propyloxy]-6-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-7-[3-(6,6-dimethyl-2-oxo-morpholin-4-yl)-propyloxy]-6-cyclopentyloxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-7-[3-(6,6-dimethyl-2-oxo-morpholin-4-yl)-propyloxy]-6-cyclopentylmethoxy-quinazoline and (R)-4-[(1-phenyl-ethyl)amino]-7-[3-(6,6-dimethyl-2-oxo-morpholin-4-yl)-propyloxy]-6-cyclopentyloxy-quinazoline, their tautomers, stereoisomers and their salts. 4. Compounds of general formula I according to claim 1, characterized in that Ra is a 1-phenylethyl group or a phenyl group substituted with radicals R1 and R2, where R1 represents a fluorine, chlorine or bromine atom, and R2 is hydrogen or a fluorine atom, one of the radicals Rb or Rc is the group R3-(CH2)m-O-, and the other of the radicals Rb or Rc is methoxy, cyclobutyloxy, cyclopentyloxy, cyclopropylmethoxy, cyclobutylmethoxy, cyclopentylmethoxy, tetrahydrofuran-3-yloxy, tetrahydropyran-3-yloxy, tetrahydropyran- 4-yloxy, tetrahydrofuran-ylmethoxy or tetrahydropyranylmethoxy group, where R3 represents the group N-(2-oxo-tetrahydrofuran-4-yl)-methylamino or 2-oxo-morpholin-4-yl group which is substituted with one or two methyl groups, and m is the number 2, 3 or 4, provided that connections are excluded: 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-(3-methyl-2-oxo-morpholin-4-yl)-ethoxy]-7-methoxy-quinazoline, 4-[(3-bromo-phenyl)amino]-6-[2-(5,5-dimethyl-2-oxo-morpholin-4-yl)ethoxy]-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-[2-(6,6-dimethyl-2-oxo-morpholin-4-yl)-ethoxy]-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-[2-(6,6-dimethyl-2-oxo-morpholin-4-yl)-ethoxy]-7-cyclobutyloxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-[2-(6,6-dimethyl-2-oxo-morpholin-4-yl)-ethoxy]-7-cyclopentyloxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-[2-(6,6-dimethyl-2-oxo-morpholin-4-yl)-ethoxy]-7-cyclopropylmethoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl]amino]-6-[2-(6,6-dimethyl-2-oxo-morpholin-4-yl)-ethoxy]-7-cyclopentylmethoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{2-[N-(2-oxo-tetrahydrofuran-4-yl)-N-methyl-amino]-ethoxy}-7-methoxy -quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{2-[N-(2-oxo-tetrahydrofuran-4-yl)-N-methyl-amino]-ethoxy}-7-cyclopentyl -oxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{2-[N-(2-oxo-tetrahydrofuran-4-yl)-N-methyl-amino]-ethoxy}-7-cyclopentyl -methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-[3-(6, 6-dimethyl-2-oxo-morpholin-4-yl)-propyloxy]-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-[3-(6,6-dimethyl-2-oxo-morpholin-4-yl)-propyloxy]-7-cyclopentyloxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-[3-(6,6-dimethyl-2-oxo-morpholin-4-yl)-propyloxy]-7-cyclopentylmethoxy-quinazoline, (R)-4-[(1-phenyl-ethyl)amino]-6-[3-(6,6-dimethyl-2-oxo-morpholin-4-yl)-propyloxy]-7-cyclopentyloxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-7-[2-(6,6-dimethyl-2-oxo-morpholin-4-yl)-ethoxy]-6-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-7-[2-(6,6-dimethyl-2-oxo-morpholin-4-yl)-ethoxy]-6-cyclobutyloxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-7-[2-(6,6-dimethyl-2-oxo-morpholin-4-yl)-ethoxy]-6-cyclopentyloxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-7-[2-(6,6-dimethyl-2-oxo-morpholin-4-yl)-ethoxy]-6-cyclopropylmethoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl]amino]-7-[2-(6,6-dimethyl-2-oxo-morpholin-4-yl)-ethoxy]-6-cyclopentylmethoxy-quinazoline, 4 -[(3-chloro-4-fluoro-phenyl)amino]-7-{2-[N-(2-oxo-tetra-hydrofuran-4-yl)-N-methyl-amino]-ethoxy}-6- methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-7-{2-[N-(2-oxo-tetra-hydrofuran-4-yl)-N-methyl-amino]-ethoxy}-6 -cyclopentyloxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-7-{2-[N-(2-oxo-tetra-hydrofuran-4-yl)-N-methyl-amino]-ethoxy}-6 -cyclopentyl-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-7-[3-(6,6-dimethyl-2-oxo-morpholin-4-yl)-propyloxy]-6-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-7-[3-(6,6-dimethyl-2-oxo-morpholin-4-yl)-propyloxy]-6-cyclopentyloxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-7-[3-(6,6-dimethyl-2-oxo-morpholin-4-yl)-propyloxy]-6-cyclopentylmethoxy-quinazoline and (R)-4-[(1-phenyl-ethyl)amino]-7-[3-(6,6-dimethyl-2-oxo-morpholin-4-yl)-propyloxy]-6-cyclopentyloxy-quinazoline, their tautomers, stereoisomers and their salts. 5. Compounds of general formula I according to claim 1, characterized in that Ra represents 1-phenylethyl, 3-bromophenyl or 3-chloro-4-fluorophenyl group, Rb is the group R3-(CH2)m-O- in which R3 represents a 2-oxo-morpholin-4-yl group which is substituted with one or two methyl groups, and m is the number 2 or 3, and Rc is a methoxy, cyclobutyloxy, cyclopentyloxy, cyclopropylmethoxy, tetrahydrofuran-3-yloxy or tetrahydrofuranylmethoxy group, provided 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-oxo-morpholin-4-yl)ethoxy]-7-methoxy-quinazoline, 4-[(3-bromo-phenyl)amino]-6-[2-(5,5-dimethyl-2-oxo-morpholin-4-yl)ethoxy]-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-[2-(6,6-dimethyl-2-oxo-morpholin-4-yl)-ethoxy]-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-[2-(6, 6-dimethyl-2-oxo-morpholin-4-yl)-ethoxy]-7-cyclobutyloxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-[2-(6,6-dimethyl-2-oxo-morpholin-4-yl)-ethoxy]-7-cyclopropylmethoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-[3-(6,6-dimethyl-2-oxo-morpholin-4-yl)-propyloxy]-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-[3-(6,6-dimethyl-2-oxo-morpholin-4-yl)-ethoxy]-7-cyclopentyloxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-[3-(6,6-dimethyl-2-oxo-morpholin-4-yl)-propyloxy]-7-cyclopentyloxy-quinazoline, and (R)-4-[(1-phenyl-ethyl)amino]-6-[3-(6,6-dimethyl-2-oxo-morpholin-4-yl)-propyloxy]-7-cyclopentyloxy-quinazoline, their tautomers, stereoisomers and their salts. 6. Compounds of general formula I according to claim 1, characterized in that Ra represents a 3-chloro-4-fluoro-phenyl group, Rb is a cyclopentyloxy, cyclopropylmethoxy, cyclopentylmethoxy, tetrahydrofuran-3-yloxy or tetrahydrofuranylmethoxy group and Rc is the group R3-(CH2)m-O- in which R3 represents a 2-oxo-morpholin-4-yl group which is substituted with one or two methyl groups, and m is the number 2, provided that connections are excluded: 4-[(3-chloro-4-fluoro-phenyl)amino]-6-cyclopentyloxy-7-[2-(6,6-dimethyl-2-oxo-morpholin-4-yl)-ethoxy]-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-7-[2-(6,6-dimethyl-2-oxo-morpholin-4-yl)-ethoxy]-6-cyclopentyloxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-7-[2-(6,6-dimethyl-2-oxo-morpholin-4-yl)-ethoxy]-6-cyclopropylmethoxy-quinazoline, and 4-[(3-chloro-4-fluoro-phenyl]amino]-7-[2-(6,6-dimethyl-2-oxo-morpholin-4-yl)-ethoxy]-6-cyclopentylmethoxy-quinazoline, their tautomers, stereoisomers and their salts. 7. Compounds of the general formula I according to claim 1, characterized in that they are: (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]- quinazoline, (5) 4-[(3-chloro-4-fluoro-phenyl)amino]-7-cyclopropylmethoxy-6-[3-(2,2-dimethyl-6-oxo-morpholin-4-yl)-propyloxy]- quinazoline, (6) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-cyclopropylmethoxy-7-{2-[N-(2-oxotetrahydrofuran-4-yl)-N-methyl-amino]-ethoxy }-quinazoline, (7) 4-[(3-bromo-phenyl)amino]-6-[2-((S)-6-methyl-2-oxo-morpholin-4-yl)-ethoxy]-7-methoxy-quinazoline, (8) 4-[(3-bromo-phenyl)amino]-6-[2-((R)-6-methyl-2-oxo-morpholin-4-yl)-ethoxy]-7-methoxy-quinazoline, (9) 4-[(3-chloro-4-fluoro-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-[3-((R)-6-methyl-2-oxo-morpholin-4-yl)-propyloxy]-7- methoxy-quinazoline, (11) 4-[(R)-(1-phenyl-ethyl)amino]-6-[3-((S)-6-methyl-2-oxo-morpholin-4-yl)-propyloxy]-7- methoxy-quinazoline, (12) 4-[(R)-(1-phenyl-ethyl)amino]-6-[2-((S)-6-methyl-2-oxo-morpholin-4-yl)-ethoxy]-7- methoxy-quinazoline, i (13) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-[3-((S)-6-methyl-2-oxo-morpholin-4-yl)-ethoxy]-7- methoxy-quinazoline, their tautomers, stereoisomers and their salts. 8. Physiologically tolerable salts of compounds according to at least one claim 1 to 7, characterized in that they are salts with inorganic or organic acids or bases. 9. Pharmaceutical preparations, characterized in that they contain at least one compound according to claims 1 to 7 or a physiologically tolerable salt according to claim 8 together with one or more inert carriers and/or diluents. 10. The use of a compound according to at least one claim 1 to 8, characterized in that it is used for the production of a pharmaceutical preparation suitable for the treatment of benign or malignant tumors, for the prevention and treatment of respiratory and lung diseases, for the treatment of polyps, gastrointestinal diseases tract, bile ducts and gall bladder, as well as kidneys and skin. 11. A method for the preparation of a pharmaceutical preparation according to claim 9, characterized in that the compound according to any of claims 1 to 8 is mixed into one or more inert carriers and/or diluents by a non-chemical method. 12. Process for the preparation of compounds of general formula I according to claims 1 to 8, characterized in that a) a compound of the general formula [image] where Ra is defined as in claims 1 to 7, one of the radicals Rb' or Rc' is a methoxy, cyclobutyl-oxy, cyclopentyloxy, cyclopropylmethoxy, cyclobutyl-methoxy or cyclopentylmethoxy group, and the other of the radicals Rb' or Rc' is a group Z1-(CH2)m-O-, in which m is defined as in claims 1 to 7, i Z1 is a leaving group, it reacts with a compound of the general formula H-R3(III) where R3 is defined as in claims 1 to 7, or b) compound of general formula IV, [image] which, if necessary, is formed in the reaction mixture, in which formula IV Ra is defined as in claims 1 to 7, one of the radicals Rb" and Rc" is a methoxy, cyclo-butyloxy, cyclopentyloxy, cyclopropylmethoxy, cyclo-butylmethoxy or cyclopentylmethoxy group, and the other of the radicals Rb" and Rc" is a group R3'-(CH2)m-O-, in which m is defined as in claims 1 to 7, i R3' is the group R4-O-CO-CH2-N-CH2CH2-OH which is substituted on the methylene groups with one or two methyl or ethyl groups, where R4 represents a hydrogen atom or a C1-4-alkyl group, is cyclized, and if necessary, all protecting groups used during the above reactions are cleaved off again, and/or if desired, the thus obtained compound of the general formula I is separated into its stereoisomers, and/or the thus obtained compound of the general formula I is translated into its salts, especially for pharmaceutical use, into its physiologically acceptable salts.