RS52279B - Bicyclic heterocycles, medicaments containing these compounds, their use, and methods for the production thereof - Google Patents

Abstract

Compounds of the general formula I, in which Ra represents a 1-phenylethyl group or a phenyl group substituted by the radicals R1 and R2, where R1 represents a fluorine, chlorine or bromine atom and R2 represents a hydrogen or fluorine atom, one of the radicals Rb or Rc is R3 - (CH2)m - O - group and the second of the radical Rb or Rc is methoxy -, cyclobutyloxy cyclopentyloxy -, cyclopropylmethoxy -, cyclobutylmethoxy -, cyclopentylmethoxy -, tetrahydrofuran-3-yloxy -, tetrahydropyran-3-yloxy -, tetrahydropyran-4-yloxy-, tetrahydrofuranylmethoxy- or tetrahydropyranylmethoxy- group, wherein R3 represents N-(2-oxo-tetrahydrofuran-4-yl)-methylamino-group or 2-oxo-morpholin-4-yl-group which is substituted with one or two methyl groups and m represents the number 2, 3 or 4, with the order that the compounds 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 - morpholine - 4 - yl) ethoxy] - 7 - methoxy - quinazoline,4 - $(3 - chloro - 4 - fluoro - phenyl) amino] - 6 - $2 - (6,6 - dimethyl - 2 - oxo - morpholine - 4 - yl) - ethoxy] - 7 - methoxy - quinazoline,4 - $(3 - chloro - 4 - fluoro - phenyl) amino] - 6 - $2 - (6,6 - dimethyl - 2 - oxo - morpholine - 4 - yl) - ethoxy] - 7 - cyclobutyloxy - quinazoline,4 - $(3 - chloro - 4 - fluoro - phenyl) amino] - 6 - $2 - (6,6 - dimethyl - 2 - oxo - morpholine - 4 - yl) - ethoxy] - 7 - cyclopentyloxy - quinazoline,4 - $(3 - chloro - 4 - fluoro - phenyl) amino] - 6 - $2 - (6,6 - dimethyl - 2 - oxo - morph olin - 4 - yl) - ethoxy] - 7 - cyclopropylmethoxy - quinazoline,4 - $(3 - chloro - 4 - fluoro - phenyl] amino] - 6 - $2 - (6,6 - dimethyl - 2 - oxo - morpholine - 4-yl)-ethoxy]-7-cyclopentylmethoxy-quinazoline,4-$(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 - cyclopentylmethoxy - quinazoline,4 - $ (3 - chloro - 4 - fluoro - phenyl) amino] - 6 - $3 - (6,6 - dimethyl - 2 - oxo - morpholine - 4 - yl) - propyloxy] - 7 - methoxy - quinazoline,4 - $(3 - chloro - 4 - fluoro - phenyl)amino] - 6 - $3 - (6,6 - dimethyl - 2 - oxo - morpholine - 4 - yl) - propyloxy] - 7 - cyclopentyloxy - quinazoline,4 - $(3 - chloro - 4 - fluo

Description

The present invention relates to bicyclic heterocyclic compounds of the general formula

to their tautomers, their stereoisomers and their salts, and especially their physiologically acceptable salts with inorganic or organic acids or bases, which have pharmacologically valuable properties, and in particular the inhibitory effect on the transduction (transmission) of signals by means of tyrosine kinases, to their application for the treatment of diseases, especially tumors, lung and respiratory tract diseases, and to their production.

In the above general formula I

Ra is a benzyl - or 1-phenylethyl - group or a phenyl - group which is substituted with the radicals Rj and R2, wherein

Represents a hydrogen, fluorine, chlorine or bromine atom, methyl -, trifluoromethyl -, cyano - or ethynyl - group and

R2 represents a hydrogen or fluorine atom,

one of the Rb or Rc radicals is R3 - (CH^m - 0 - group and the other of the Rb or Rc radicals is methoxy -,

cyclobutyloxy-, cyclopentyloxy-, cyclopropylmethoxy-, cyclobutylmethoxy-, cyclopentylmethoxy-, tetrahydrofuran-3-yloxy-, tetrahydropyran-3-yloxy-, tetrahydropyran•4-yloxy-, tetrahydrofuranylmethoxy- or tetrahydropyranylmethoxy- group, wherein

R3 represents N - (2-oxo-tetrahydrofuran-4-yl)-methylamino - or - N -(2-oxo-tetrahydrofuran-4-yl)-ethylamino - group,

R4- O - CO - CH2- N - CH2CH2- OH - a group in which the methylene groups are substituted with one or two methyl - or ethyl - groups, in which

R4 represents a hydrogen atom or Ci. 4 - alkyl - group,

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

m represents the number 2, 3 or 4,

with the stipulation that compounds are excluded

4 - [ (3 - chloro - 4 - fluoro ■ phenyl)amino] - 6 - cyclopentyloxy - 7 - (2 - {N - (2 - hydroxy - 2 - methyl - prop -1 - yl) - N - [(ethoxycarbon) - methyl] - amino} - ethoxy) - quinazoline, 4 - [(3 - chloro - 4 - fluoro - phenyl)amino] - 6 - dclopentyloxy - 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, their stereoisomers and their salts.

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

Preferably a benzyl - or 1 - phenylethyl - group or a phenyl - group which is substituted with radicals R x i R 2 , wherein

Ri represents a hydrogen, fluorine, chlorine or bromine atom, methyl -, trifluoromethyl cyano - or ethynyl - group and R2 represents a hydrogen or fluorine atom,

one of the radicals Rbili Rcje R3-(CH^m - 0 - group and the other of the radicals Rb or Rcje methoxy -, cyclobutyloxy -, declopentyloxy -, chloropropylmethoxy -, cyclobutylmethoxy -, cyclopentylmethoxy -, tetrahydrofuran - 3 - yloxy -, tetrahydropyran - 3 - yloxy -, tetrahydropyran - 4 - yloxy -, tetrahydrofuranylmethoxy - or tetrahydropyranylmethoxy - - group, whereby

R3 represents N - (2-oxo-tetrahydrofuran-4-yl)-methylamino - or N - (2-oxo-tetrahydrofuran-4-yl)-ethylamino - group,

R4- 0 - CO - CH2- N - CH2CH2- OH - a group in which the methylene - groups are substituted 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 represents the number 2, 3 or 4,

with the stipulation that compounds are excluded

4 - [ (3 - chloro - 4 - fluoro - fearl)amino] - 6 - chlorpentyloxy - 7 - (2 - {N - (2 - hydroxy - 2 - methyl - prop -1 - yl) - N - [(ethoxycarbonyl) - methyl] - amino} - ethoxy) - quinazoline, 4 - [(3 - chloro - 4 - fluoro - phenyl)amino] - 6 - chlorpentyloxy - 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 - morpholine - 4 - yl)ethoxy] - 7 - methoxy - quinazoline, 4 - [ (3 - bromo - phenyl)amino] - 6 - [2 - (5,5 - dimethyl - 2 - oxo - morpholine - 4 - yl)ethoxy] - 7 - methoxy - quinazoline, 4 - [ (3 - chloro - 4 - fluoro - phenyl)amino] - 6 - [2 - (6,6 - dimethyl - 2 - oxo - morpholine - 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 - morpholine - 4 - yl) - ethoxy] - 7 - dclopentyloxy - quinazoline, 4 - [ (3 - chloro - 4 - fluoro - phenyl) amino] - 6 - [2 - (6,6 - dimethyl - 2 - oxo - morpholine - 4 - yl) - ethoxy] - 7 - dclopropylmethoxy - quinazoline, 4 - [ (3 - chloro - 4 - fluoro - phenyl)amino] - 6 - [2 - (6,6 - dimethyl - 2 - oxo - morpholin - 4 - yl) - ethoxy] - 7 ■ dclopenitlmethoxy - quinazoline, 4 - [(3 - chloro - 4 - fluoro - phenyl)arnino] - 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 - chlorpentyloxy - quinazoline, 4 - [(3 - chloro - 4 - fluoro - phenyl)amino] - 6 - {2 - [N - (2 - oxo - tetrahydrofuran - 4 - yl) - N - methyl - amino] - ethoxy} - 7 - dclopentylmethoxy - 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] - propyloxy] - 7 - dclopentyloxy - quinazoline, 4 - [ (3 - chloro - 4 - fluoro - phenyl) amino] - 6 - [3 - (6,6 - dimethyl - 2 - oxo - morpholin - 4 - yl) - propyloxy] - 7 - dclopentylmethoxy - quinazoline, (R) - 4 - [ (1 - phenyl - ethyl) amino] - 6 - [3 - (6,6 - dimethyl - 2 - oxo-morpholine - 4 - yl) - propyloxy] - 7 - dclopentyloxy - 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 - clobutyloxy - quinazoline, 4 - [ (3 - chloro - 4 - fluoro - phenyl) amino] - 7 - [2 - (6,6 - dimethyl - 2 - oxo - morpholin - 4 - yl) - ethoxy] - 6 - clopentyloxy - quinazoline, 4 - [0 - chloro - 4 - fluoro - phenyl)amino] - 7 - [2 - (6.6 - dimethyl - 2 - oxo - morpholin - 4 - yl) - ethoxy] - 6 - dclopropylmethoxy - quinazoline, 4 - [ (3 - chloro ■ 4 - fluoro - phenyl]amino] - 7 - [2 - (6,6 - dimethyl - 2 - oxo - morpholin - 4 - yl) - ethoxy] - 6 - dclophenylmethoxy - 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 - diclopentyloxy - quinazoline, 4 - [ (3 - chloro - 4 - fluoro - phenyl) amino] - 7 - {2 - [N - (2 - oxo - tetrahydrofuran - 4 - yl) - N - methyl - arnino] - ethoxy} - 6 - dclopenitlmethoxy - quinazoline, 4 - [(3 - chloro - 4 - fluoro - phenyl)amino] - 7 - [3 - (6,6 - dimethyl - 2 - oxo - morpholine - 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 - diclopentyloxy - quinazoline, 4 - [ (3 - chloro - 4 - fluoro - phenyl)amino] - 7 - [3 - (6,6 - dimethyl - 2 - oxo - morpholine - 4 - yl) - propyloxy] - 6 - dclopentylmethoxy - quinazoline and

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

and especially those in which

Represents 1 - phenylethyl - group or phenyl - group which is substituted with radicals Rii R& wherein

Represents a fluorine, chlorine or bromine atom, a methyl or ethynyl group and

R2 represents a hydrogen or fluorine atom,

one of the radicals Rbili Rcje R3- (CH^m- 0 - group and the other of the radicals Rbili Rcje methoxy -, riclobutyloxy -, diclopentyloxy -, dicyclopropylmethoxy -, diclobutylmethoxy -, diclopentylmethoxy -, tetrahydrofuran-3-yloxy -, tetrahydropyran-3-yloxy -, tetrahydropyran-4-yloxy -, tetrahydrofuranylmethoxy - or tetrahydropyranylmethoxy - group, whereby

R3 represents N-(2-oxo-tetrahydrofuran-4-yl)-methylamino - group,

R4- O - CO - CH2- N - CH2CH2- OH - a group in which methylene groups are substituted with one or two methyl groups, in which

R4 represents Ci. 4 - alka - group,

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

m represents the number 2, 3 or 4,

with the stipulation that compounds are excluded

4- [(3- chloro- 4- fluoro- phenyl) amino] - 6- chlorpentyloxy- 7- (2- {N- (2 - hydroxy - 2 - methyl - prop - 1 - yl) - N - [(ethoxycarbonyl) - methyl] - amino} - ethoxy) - quinazoline,

4 - [(3 - chloro - 4 - fluoro - phenyl)amino] - 6 - chlorpentyloxy - 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 - [0 - bromo - phenyl)amino] - 6 - [2 - (3 - methyl - 2 - oxo - morpholine - 4 - yl)ethoxy] - 7 - methoxy - quinazoline, 4 - [0 - bromo - phenyl)ainino] - 6 - [2 - (5,5 - dimethyl - 2 - oxo - morpholine - 4 - yl)ethoxy] - 7 - methoxy - quinazoline, 4 - [ (3 - chloro - 4 - fluoro - phenU)amino] - 6 - [2 - (6,6 - dimethyl - 2 - oxo - morpholine - 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 -

? dclopentyloxy - quinazoline,

4 - [(3 - chloro - 4 - fluoro - phenyl)amino] - 6 - [2 - (6,6 - dimethyl - 2 - oxo - morpholin - 4 - yl) - ethoxy] - 7 - dclopropylmethoxy - quinazoline, 4 - [(3 - chloro - 4 - fluoro - phenyl)amino] - 6 - [2 - (6,6 - dimethyl - 2 - oxo - morpholin - 4 - yl) - ethoxy] - 7 - dclopenitlmethoxy - 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 - diclopentyloxy - quinazoline, 4 - [ (3 - chloro - 4 - fluoro - phenyl) amino] - 6 - {2 - [N - (2 - oxo - tetrahydrofuran - 4 - yl) - N - methyl - amino] - ethoxy} - 7 - diclopentylmethoxy - 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 - chlorpentyloxy - quinazoline, 4 - [(3 - chloro - 4 - fluoro - phenyl)amino] - 6 - [3 - (6,6 - dimethyl - 2 - oxo - morpholin - 4 - yl) - propyloxy] - 7 - dclopentylmethoxy - quinazoline, (R) - 4 - [(1 - phenyl - ethyl)amino] - 6 - [3 - (6,6 - dimethyl - 2 - oxo - morpholin - 4 - U) - propyloxy] - 7 - dclopentyloxy - 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 - dclobutyloxy - quinazoline, 4 - [(3 - chloro - 4 - fluoro - phenyl)amino] - 7 - [2 - (6,6 - dimethyl - 2 - oxo - morpholin - 4 - yl) - ethoxy] - 6 - chlorpentyloxy - quinazoline, 4 - [(3 - chloro - 4 - fluoro - phenyl)amino] - 7 - [2 - (6,6 - dimethyl - 2 - oxo - morpholin - 4 - yl) - ethoxy] - 6 - diclopropylmethoxy - quinazoline, 4 - [(3 - chloro - 4 - fluoro - phenyl)amino] - 7 - [2 - (6,6 - dimethyl - 2 - oxo - morpholin - 4 - yl) - ethoxy] - 6 - diclopenitlmethoxy - quinazoline, 4 - [(3 - chloro - 4 - fluoro - phenyl)amino] - 7 - {2 - [N - (2 - oxo - tetrahydrofuran - 4 - yl) - N - methyl - amino] - 4 - [(3 - chloro-4 - fluoro-phenyl)amino] - 7 - {2 -[N - (2 - oxo - tetrahydrofuran - 4 - yl) - N - methyl - amino] - ethoxy} - 6 - diclopentyloxy - quinazoline, 4 - [(3 - chloro - 4 - fluoro - phenyl)amino] - 7 - {2 - [N - (2 - oxo - tetrahydrofuran - 4 - yl) - N - methyl - amino] - ethoxy} - 6 - dclopentylmethoxy - quinazoline, 4 - [(3 - chloro - 4 - fluoro - phenyDamino] - 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 - morpholine - 4 - yl) - propyloxy] - 6 - chlorpentyloxy - quinazoline, 4 - [(3 - chloro - 4 - fluoro - phenyl)amino] - 7 - [3 - (6,6 - dimethyl - 2 - oxo - morpholine - 4 - yl) - propyloxy] - 6 - chlorpentylmethoxy - quinazoline and

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

their tautomers, their stereoisomers and their salts.

Particularly preferred are those compounds of general formula I in which

It represents a 1-phenylethyl group or a phenyl group substituted with radicals Ri and R2, where

Represents a fluorine, chlorine or bromine atom and

R2 represents a hydrogen or fluorine atom,

one of the radicals Rbili Rc is the R3 - (CH2)m- O - group and the other of the radicals Rbili Rc is methoxy -, diclobutyloxy -, diclopentyloxy -, diclopropylmethoxy -, diclobutylmethoxy -, diclopentylmethoxy -, tetrahydrofuran - 3 - yloxy -, tetrahydropyran - 3 - yloxy -, tetrahydropyran - 4 - yloxy -,

tetrahydrofuranylmethoxy - or tetrahydropyranylmethoxy - group, wherein

R3 represents an N-(2-oxo-tetrahydrofuran-4-yl)-methylamino group or a 2-oxo-morpholin-4-yl group substituted with one or two methyl groups and

m represents the number 2, 3 or 4,

with the stipulation that compounds are excluded

4 - [(3 - chloro - 4 - fluoro - phenyl)amino] - 6 - chlorpentyloxy - 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 - diclobutyloxy - quinazoline, 4 - [ (3 - chloro - 4 - fluoro - phenyl) amino] - 6 - [2 - (6,6 - dimethyl - 2 - oxo - morpholin - 4 - yl) - ethoxy] - ethoxy] - 7 - chlorpentyloxy - quinazoline, 4 - [ (3 - chloro - 4 - fluoro - phenyl) amino] - 6 - [2 - (6,6 - dimethyl - 2 - oxo - morpholin - 4 - yl) - ethoxy] - 7 - diclopropylmethoxy - quinazoline, 4 - [ (3 - chloro - 4 - fluoro - phenyl) amino] - 6 - [2 - (6,6 - dimethyl - 2 - oxo - morpholin - 4 - yl) - ethoxy] yl) - ethoxy] - 7 - dclopentylmethoxy - quinazoline, 4 - [(3 - chloro - 4 - fluoro - femflamamino] - 6 - {2 - [N - (2 - oxo - tetrahydrofuran - 4 - yl) - N - methyl - arnino] - ethoxy} - 7 - methoxy - quinazoline, 4 - [ (3 - chloro - 4 - fluoro - phenyl) amino] - 6 - {2 - [N - (2 - oxo - tetrahydrofuran - 4 - yl) - N - methyl - arnino] - ethoxy} - 7 - diclopentyloxy - quinazoline, 4 - [ (3 - chloro - 4 - fluoro - phenyl) amino] - 6 - {2 - [N - (2 - oxo - tetrahydrofuran - 4 - yl) - N - methyl - arnino] - ethoxy} - 7 - diclopentylmethoxy - 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 - phenu)amino] - 6 - [3 - (6,6 - dimethyl - 2 - oxo - morpholin - 4 - yl) - propyloxy] - 7 - chlorpentyloxy - quinazoline, 4 - [(3 - chlorine - 4 - fluoro - fem)amino] - 6 - [3 - (6,6 - dimethyl - 2 - oxo - morpholin - 4 - yl) - propyloxy] - 7 - dclopenitlmethoxy - quinazoline, (R) - 4 - [(1 - phenyl - ethyl)amino] - 6 - [3 - (6,6 - dimethyl - 2 - oxo - morpholin - 4 - yl) - propyloxy] - 7 - dclopentyloxy - 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] yl) - ethoxy] - 6 - dclobutyloxy - quinazoline, 4 - [(3 - chloro - 4 - fluoro - ephiul)arnino] - 7 - [2 - (6,6 - dimethyl - 2 - oxo - morpholin - 4 - yl) - ethoxy] - 6 - dclopentyloxy - quinazoline, 4 - [(3 - chloro - 4 - fluoro - phenyl)amino] - 7 - [2 - (6,6 - dimethyl - 2 - oxo - morpholine) - 4 - yl) - ethoxy] - 6 - diclopropylmethoxy - quinazoline, 4 - [ (3 - chloro - 4 - fluoro - phenyl]amino] - 7 - [2 - (6,6 - dimethyl - 2 - oxo - morpholin - 4 - yl) - ethoxy] - 6 - diclophenylmethoxy - 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 - diclopentyloxy - quinazoline, 4 - [ (3 - chloro - 4 - fluoro) - phenyl) amino] - 7 - {2 - [N - (2 - oxo - tetrahydrofuran - 4 - yl) - N - methyl - amino] - ethoxy} - 6 - dclopenitlmethoxy - quinazoline, 4 - [(3 - chloro - 4 - fluoro - phenyDamino] - 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 - chlorpentyloxy - quinazoline, 4 - [ (3 - chloro - 4 - fluoro - phenu)arnino] - 7 - [3 - (6,6 - dimethyl - 2 - oxo - morpholin - 4 - yl) - propyloxy] - 6 - dclopenitlmethoxy - quinazoline and

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

their tautomers, their stereoisomers and their salts.

Those compounds of general formula I in which

Preferably 1 - phenylethyl -, 3- bromophenyl - or 3 - chloro - 4 - fluorophenyl - group,

Rbje R3- (CH^m- 0 - group in which

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

and Rcje methoxy -, cyclobutyloxy -, cyclopentyloxy -, cyclopropylmethoxy -, tetrahydrofuran-3-yloxy - or tetrahydrofuranylmethoxy - group, with the stipulation that compounds are excluded

4 - [(3 - bromo - phenyl)arnino] - 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 - chlorine - 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 - [2 - (6,6 - dimethyl - 2 - oxo - morpholin - 4 - yl) - ethoxy] - 7 - chlorpentyloxy - quinazoline, 4 - [(3 - chloro - 4 - fluoro - phenyl)amino] - 6 - [3 - (6,6 - dimethyl - 2 - oxo - morpholin - 4 - yl) - propyloxy] - 7 - diclopentoxy - quinazoline and

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

their tautomers, their stereoisomers and their salts.

Those compounds of general formula I in which

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

Rbje chlorpentyloxy-, chlorpropylmethoxy-, chlorpentylmethoxy-, tetrahydrofuran-3-yloxy- or

tetraludrofuranil - methoxy group and

Rc is R3 - (CH2)m - 0 - a group in which

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

m represents the number 2,

with the stipulation that compounds are excluded

4 - [0 - chloro- 4 - fluoro - phenyl)arnino] - 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) - morpholine - 4 - yl)-ethoxy]-6-diclophenylmethoxy-quinazoline,

their tautomers, their stereoisomers and their salts.

The following compounds are cited as examples of extremely advantageous compounds:

(1) 4 - [(3 - chloro - 4 - fluoro - phenyl)amino] - 6 - dclopentylmethoxy - 7 - [2 - (2,2 - dimethyl - 6 - oxo - morpholin - 4 - yl) - ethoxy] - quinazoline, (2) 4 - [(3 - chloro - 4 - fluoro - ferdl)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 - morpholine - 4 - U) - ethoxy] - quinazoline, (4) 4 - [(3 - chloro - 4 - fluoro - phenyl)amino] - 7 - dclobutyloxy - 6 - [3 - (2,2 - dimethyl - 6 - oxo - morpholin - 4 - yl) - propyloxy] - quinazoline, \ pj4 --nior - 1 - nuor - iemy arnino j - 1-cuuopropiimeioXi - o -\ o -?, & - uuucui - o - onau - morpholin-4-yl)-propyloxy]-quinazoline, (6) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-cyclopropylmethoxy - 7-{2 ■ [N-(2-oxo-tetrahydrofuran - 4-yl)-N-methyl - amino]-ethoxy}-quinazoline, (7) 4 - [(3 - bromo - phenyl) amino] - 6 - [2 - ((£) - 6 - methyl - 2 - oxo - morpholin - 4 - yl) - ethoxy] - 7 - ethoxy -

quinazoline,

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

quinazoline,

(9) 4 - [(3 - chloro - 4 - fluoro - phenyl)arnino] - 6 - [2 - ((# - 6 - methyl - 2 - oxo - morpholin - 4 - yl) - ethoxy] - 7 -

methoxyquinazoline,

(10) 4-[(3-chloro-4-fluoro-ferral)amino]-6-[3-((Rj-6-methyl-2-oxo-morpholin-4-yl)-propyloxy]-

7-methoxy-quinazoline,

(11) 4-[(#-(1 - phenyl - ethyl)amino]-6-[3-((5)-6-methyl - 2-oxo-morpholin-4-yl)-propyloxy]-7-methoxy-quinazoline, (12) 4 - [(#-(1 - phenyl - ethyl)amino] - 6 - [2 - (CS) - 6 - methyl - 2 - oxo - morpholin-4-yl) - ethoxy] - 7 -

methoxyquinazoline and

(13) 4 - [ (3 - chloro - 4 - fluoro - phenu) amino] - 6 - [2 - (($ - 6 - methyl - 2 - oxo - morpholin - 4 - yl) - ethoxy] - 7 -

methoxyquinazoline,

their tautomers, their stereoisomers and their salts.

Compounds of general formula I are obtained, for example, according to the following procedures:

a) Reaction of compounds of the general formula

in which

Rather, defined the same as above,

one of the radicals Rb' or Rc' represents a methoxy -, cyclobutyloxy -, cyclopentyloxy -, cyclopropylmethoxy -, cyclobutylmethoxy - or cyclopentylmethoxy - group and

the second of the radicals Rb' or Rc' represents the Z\- (CH2)m - O - group, in which

m is defined the same as previously stated i

It has a starting group, such as a halogen atom, or a sulfonyloxy group, such as a chlorine atom or

bromine, methanesulfonyloxy - or p - toluenesulfonyloxy - group,

with a compound of the general formula

in which

R3 is defined the same as above.

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

b) by sliding compounds of the following general formula, which are eventually formed in the reaction mixture

in which

Rather, defined the same as above,

one of the radicals Rb" or Rc" represents a methoxy -, cyclobutyloxy -, cyclopentyloxy -, cyclopropylmethoxy -, cyclobutylmethoxy - or cyclopentylmethoxy - group and

the second of the radicals Rb" or Rc" represents the R3 - (CH^m- 0 - group, in which

m is defined the same as previously stated i

Rs' is R4- O - CO - CH2- N - CH2CH2- OH - a group in which the methylene - groups are substituted with one or two methyl - or ethyl - groups, in which

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

The reaction is carried out, if necessary, in a solvent or solvent mixture, such as methylene chloride, acetonitrile, dimethylformamide, dimethylsulfoxide, sulfolane, benzene, toluene, chlorobenzene, tetrahydrofuran, benzene/tetrahydrofuran or dioxane, suitably in the presence of an acid that does not contain water, such as trifluoroacetic acid, methanesulfonic acid or sulfuric acid or in the presence of a water absorbing agent, for example in the presence of isobutyl ester of chloro formic acid, thionyl chloride, trimethylchlorosilane, phosphorus trichloride, phosphorus pentoxide, N, N' - (lidclohexylcarboxUimide, N, N' - di(^ohexylcarbodiimide/N - hydroxysuccinimide or 1 - hydroxy - benztriazole, N, N' - carbonyldiimidazole or triphem^sphine/carbon tetrachloride, at temperatures between - 20 and 200 °C, and primarily at temperatures between -10 and 160 °C.

In the previously described reactions, possibly present reactive groups, such as hydroxy -, carboxy - or imino - groups, can be protected during the reaction with usual protective groups that are separated again after the reaction.

For example, trimethylsilyl -, acetyl -, benzoyl •, methyl -, ethyl -, tert. butyl -, trityl -, benzyl - or tetrahydropyranyl - group,

as a protective radical for the carboxy group trimethylsilyl -, methyl -, ethyl -, tert. butyl -, benzyl - or tetrahydropyranyl - group i

as a protective radical for the imino - group formyl -, acetyl -, trifluoroacetyl ethoxycarbonyl -, tert. butoxycarbonyl -, benzyloxycarbonyl -, benzyl -, methoxybenzyl ■ or 2,4-dimethoxybenzyl - group.

The final separation of the possibly used protective radical is carried out, for example, hydrolytically in an aqueous solvent solution, e.g. water, isopropanol/water, acetic acid/water, tetrahydrofuran/water or dioxane/water, in the presence of an acid, such as trifluoroacetic acid, sodium acid or sulfuric acid or in the presence of an alkaline base, such as sodium hydroxide or potassium hydroxide or aprotic bases, e.g. in the presence of iodotrimethylsilane, at temperatures between 0 and 120 °C, a

primarily at temperatures between 10 and 100 °C.

Separation of benzyl -, methoxybenzyl - or benzyloxycarbonyl radicals is carried out, for example, hydrogenolytically,

for example with hydrogen in the presence of a catalyst, such as palladium/charcoal, in a suitable solvent, such as

are methanol, ethanol, ethyl acetate or glacial acetic acid, if necessary with the addition of an acid, such as sonic acid, at temperatures between 0 and 100 °C, and preferably at room temperatures between 20 and 60 °C, and under a hydrogen pressure of 1 to 7 bar, and preferably from 3 to 5 bar. Separation 2.4 -

cimethoxybenzyl radical is primarily performed in trifluoroacetic acid in the presence of anisole.

Separation of tert. butyl - or tert. butyloxycarbonyl - radical is primarily carried out by treatment with an acid, such as trifluoroacetic acid or sonic acid, or by treatment with iodotrimethylsilane, if necessary, with the use of a solvent, such as methylene chloride, dioxane, methanol or diethyl ether.

Separation of the trifluoroacetyl radical is primarily carried out by treatment with an acid, such as sonic acid,

in the presence of a solvent, such as acetic acid, at temperatures between 50 and 120 °C or by treating

with sodium hydroxide, if necessary, in the presence of a solvent, such as tetrahydrofuran, at

temperatures between 0 and 50 °C.

Further, the obtained compounds of the general formula I, which were already listed above, can be separated into

its enantiomers and/or diastereomers. Thus, for example, cis - /trans mixtures can be separated into

their cis- and trans-isomers, while compounds with at least one optically active carbon atom can

be separated into its enantiomers.

Thus, for example, the aforementioned cis - /trans - doe can be separated by chromatography into their cis - and trans - isomers, while the resulting compounds of general formula I, which appear in racemates, can be separated into their optical antipodes by procedures known per se (see Allinger N.L and Eliel E.L in 'Topics in Stereochemistry', Vol. 6, Wiley Interscience, 1971)), and compounds of general formula I with at least 2 asymmetric carbon atoms, due to their different physicochemical properties, can be separated using methods known per se, eg chromatography and/or fractional crystallization into their diastereomers, which, if they appear in racemic form, can finally be separated into their enantiomers.

Separation of enantiomers is primarily carried out by columnar separation into chiral phases or by recrystallization from an optically active solvent or by reaction with an optically active substance that forms salts or derivatives with the racemic compound, such as e.g. esters or amides, and especially with acids and their active derivatives or their alcohols, and the separation of the salt mixture containing diastereomers is carried out, for example, on the basis of their different solubilities, whereby free antipodes can be released from pure diastereomeric salts or derivatives under the action of a suitable agent. Particularly notable, optically active acids are e.g. D - and L - forms of tartaric acid or dibenzoyl tartaric acid, di - o - tolyl tartaric acid, malic acid, mandelic acid, camphor sulphonic acid, glutamic acid, aspartic acid or quinic acid. An optically active alcohol is, for example, (+)- or (-)-menthol, and an optically active acyl radical in amides is, for example, (+)- or (-)-menthyloxycarbonyl.

Furthermore, the obtained compounds of the general formula I can be translated into their salts, and especially into their physiologically acceptable salts for pharmaceutical use with inorganic or organic acids. Acids here come into consideration, for example, sodium acid, hydrobromic acid, sulfuric acid,

methanesulfonic acid, phosphoric acid, fumaric acid, glyburic acid, lactic acid,

citric acid, tartaric acid or maleic acid.

In addition, the thus obtained new compounds of the general formula I if they contain carboxy-, hydroxyphosphoryl -,

sulfo-or 5-tetrazolyl - group, can, if desired, finally be translated into their salts with

inorganic or organic bases, and especially in their physiologically acceptable salts for pharmaceutical use. As bases here, for example, sodium hydroxide, potassium hydroxide, arginine,

cyclohexylamine, ethanolamine, ctiethanolamine and triethanolamine.

The compounds of the general formula U to IV used as starting materials are partially known from the literature or are obtained by means of procedures known from the literature as such (see Examples I to

XIV).

As already stated above, the compounds of the general formula I according to the invention and their physiological

acceptable salts have valuable pharmacological properties, and in particular an inhibitory effect on transduction

signals through the Epidermal Growth Factor - receptor (EGF - R), whereby this is done, for example,

by inhibition of ligand binding, receptor dimerization or tyrosine kinase itself. In addition, it is also possible to block the transmission of signals to components located below.

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

Inhibition of signal transmission through EGF-R can be proven, for example. by 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 murine cell line was used, which had been genetically engineered to functionally express human EGF-R. Proliferation of these cells, which were termed F/L-HERc cells, could therefore be stimulated either by murine IL-3 or by EGF (see von Riiden, T. et al. in EMBO J. Z, 2749-2756 (1988) and Pierce, J.H. et al., in Science 232,628-631 (1988)).

The starting material for F/L - HERc cells was the cell line FDC - Pi, the preparation of which was described by von Dexter, T.M. et al. in J. Exp. Med. 152,1036-1047 (1980). Alternatively, other growth factor-dependent cells may be used (see for example Pierce, J.H. et al. in Science 239,628-631

(1988), Shibuwa, H. et al. in Cell ZQ, 57-67 (1992) and Alexander, W.S. et al. in EMBO J. 10_, 3683 - 3691

(1991)). For the expression of the human EGF-R cDNA (see Ullrich, A. et al. in Nature 3Q9_, 418-425 (1984)) recombinant retroviruses were used, as described in von Riiden, T. et al., EMBO J. Z. 2749-2756 (1988), with the difference that a retroviral vector was used for the expression of the EGF-R cDNA. LXSN (see Miller, AD. et al. in BioTechniques Z, 980-990 (1989)) and that the GP+E86 line served as the packaging cell (see Markowitz, D. et al. in J. Virol. 62,1120-1124 (1988)).

The test was performed as follows:

F/L - HERc cells were cultured in RPMI/1640 medium (BioVThittaker) 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 activity of the compounds according to the invention, 1.5 x 10<4> cells per well were cultured in

in triplicate in 96-well plates in the above medium (200 µl), proliferation

cells were stimulated with either EGF (20 ng/ml) or murine IL-3. As a source of IL-3, purified supernatants from X63/0 mIL-3 cell line cultures served as a source (see Karasuvama, 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 concentrations, with the maximum concentration of DMSO being 1%. Cultures were incubated for 48 hours at 37 °C.

To determine the inhibitory activity of the compounds according to the invention, the relative number of cells was measured with the Cell Titer 96 TM Aaueous Non-Radioactive Cell Proliferation Assay (Promega) in O.D. units. The relative number of cells was calculated as a percentage of the control (F/LHERc cells without inhibitor) and of the concentration of the active substance that inhibited cell proliferation by 50% (IC50). The following results were obtained:

This showed that the compounds according to the invention of the general formula I inhibit signal transduction by means of tyrosine kinases, as shown on the example of human EGF - receptors, and thus that they are applicable for the course of pathophysiological processes caused by the excessive function of tyrosine kinases.

These are, for example, benign or malignant tumors, especially tumors of epithelial and neuroepithelial origin, metastases, as well as abnormal proliferation of vascular endothelial cells (neoangiogenesis).

The compounds according to the invention are also applicable for the prevention and treatment of diseases of the airways and lungs, which are accompanied by increased or altered production of mucus, which is caused by the stimulation of tyrosine kinases, such as e.g. in inflammatory diseases of the respiratory tract, such as chronic bronchitis, chronic obstructive bronchitis, asthma, bronchiectasis, allergic or non-allergic rhinitis or sinusitis, cystic fibrosis, deficiency (lack of) al-antitrypsin, or in cough, pulmonary emphysema, pulmonary fibrosis and hyperreactive airways.

These compounds are also suitable for the treatment of disorders of the gastrointestinal tract and bile ducts and gall bladder, which are caused by impaired activity of tyrosine kinases, which may occur, e.g. in chronic inflammatory changes such as cholecystitis, Crohn's disease, ulcerative colitis and ulcers in the gastrointestinal tract or such as those that appear in disorders of the gastrointestinal tract that are caused by increased secretion, such as Menetrier - this disease, secreting adenoma and protein loss syndrome,

and also for the treatment of nasal polyps, as well as polyps of the gastrointestinal tract of different genesis, e.g. such as villous or adenomatous colon polyps, but also polyps that are common in polyposis coli, intestinal polyps that occur in Gardner's syndrome, in polyps in the entire gastrointestinal tract in Feutz-Jeghers syndrome, in inflammatory pseudopolyps, in juvenile polyps, in colitis cvstica profunda and in pneumatosis cvstoides intestinales.

In addition, the compounds of the general formula I and their physiologically acceptable salts can be used for the treatment of kidney diseases, and especially distic changes, such as, for example. in kidney stones, for the treatment of kidney stones with idiopathic genesis or those occurring in connection with diseases such as in the case of sclerosis of the renal tubules in von - Hippel - Lindau - this syndrome, in nephronophthisis and spongy kidneys, as well as in other diseases caused by disturbed tyrosine kinase function, such as, for example, 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 active compounds, for example, in tumor therapy they can be used in monotherapy or in combination with other anti-tumor treatments, for example in combination with topoisomerase inhibitors (e.g. etoposide), mitosis inhibitors (e.g. vinblastine), with compounds that interact with nucleic acids (e.g. ds-platinum, cyclophosphamide, adriamiden), hormone antagonists (e.g. tamoxifen), inhibitors of metabolic processes (e.g. 5-FU, etc.), cytokines (e.g. interferons), antibodies, etc. For the treatment of respiratory tract diseases, these compounds can be used alone or in combination with other respiratory tract products, such as e.g. secretolytic, broncholytic and/or anti-inflammatory substances. For the treatment of disorders in the area of the gastrointestinal tract, these compounds can possibly be administered alone or in combination with substances that affect motility or secretion or that have an anti-inflammatory effect. These combinations can be given either simultaneously or one after the other.

Application of these compounds, either alone or in combination with other active substances, can be done intravenously, subcutaneously, intramuscularly, intrarectally, intraperitoneally, intranasally, by inhalation or transdermally or orally, with aerosol formulations particularly suitable for inhalation.

In the case of pharmaceutical application, the compounds according to the invention are as a rule given to warm-blooded vertebrates, and especially to humans, in doses of 0.01-100 mg/kg of body weight, and primarily of 0.1-15 mg/kg. For administration, said compounds may be formulated with one or more conventional inert carriers and/or diluents, e.g. with corn starch, lactose, sucrose, microcrystalline cellulose, magnesium stearate, polyvinylpyrrolidone, pyrrolidone, citric acid, tartaric acid, water, water/ethanol, water/glycerin, water/sorbitol, water/polyethylene glycol, propylene glycol, stearyl alcohol, carboxymethyl cellulose or fatty substances, such as paraffin or with suitable mixtures thereof in conventional galenic preparations, such as are tablets, dragees, capsules, powders, suspensions, solutions, sprays or suppositories.

The following examples are intended to explain the subject invention in more detail, but it is not limited to them:

Obtaining starting compounds

Examples

4- f(3-chloro-4-fluoro-phenynaminol-6-dclopen^ethoxy-7-(2-bromo-ethoxy)- quinazoline

4.84 g of potassium carbonate were added to 3.50 g of 4-[(3-chloro-4-fluoro-phenyl)amino]-6-diclopentylmethoxy-7-hydroxy-quinazoline and 6.89 ml of 1,2-dibromomethane in 40 ml of N,N-dimethylformamide. The reaction mixture was stirred under a nitrogen atmosphere for 1.5 hours at 80 °C. After cooling to room temperature, the reaction mixture was filtered and the filtrate was concentrated in vacuo. It's an oily, brown residue

cooled in an ice bath and washed with a little methanol to crystallize a yellowish solid

matter. The precipitate was suctioned off, washed again with cold methanol and dried in a vacuum desiccator.

Yield: 2.60 g (58% of theory),

Rf - value 0.82 (silica gel, methylene chloride/methanol 9:1)

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

Analogously to Example I, the following compounds are obtained:

(1) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-cyclopropylmethoxy-7-(2-bromo-ethoxy)-quinazoline

(the reaction is carried out in acetonitrile as a solvent)

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 solution of ammonia-90: 10:0.1)

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

(3) 4-[(3-chloro-4-fluoro-phenyl)amino]-7-diclobutyloxy-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-O-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 - etU) arnino] - 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)arnino] - 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 - fluoro - phenyl)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 - fluoro - phenyl)amino] - 6 - (3 - hydroxy - propyloxy) - 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 - fluoro - phenyl)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 - fluoro - phenylamino] - 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 - fluoro - phenyl)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 - fluoro - phenU)amino] - 6 - (4 - hydroxy - butyloxy) - 7 - cyclopentyloxy - quinazoline Rf - value 0.46 (silica gel, ethyl acetate) (14) 4 - [(3 - chloro - 4 - fluoro - phenyl)amino] - 6 - (2 - bromo - ethoxy) - 7 - ((# - 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 - fluoro - phenyl)amino] - 6 - (2 - bromo - ethoxy) - 7 - [(# - (tetrahydrofuran - 2 - yl)methoxy)] - quinazoline Mass spectrum (ESI •): m/z - 494,496,498 [M - H] - (16) 4 - [(3 - chloro - 4 - fluoro - phenyl)amino] - 7 - (2 - bromo - ethoxy) - 6 - [(5) - (tetoamdrofuran - 2 - yl) methoxy)] - quinazoline

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

Example n

4 - T(3 - chlorine - 4 ■ fluorine - femDaminol - 6 - dclononylmethoxy - 7 - hydroxy - quinazoline

4.99 g of 4-[(3-chloro-4-fluoro-phenyl)amino]-6-diclopentylmethoxy-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. In order to process the reacton, the mixture is

diluted with 500 ml of methylene chloride, washed with water and saturated sodium chloride solution,

it was dried over magnesium sulfate and concentrated. 4.30 g of a brown solid was obtained.

The crude product is mixed with tert. with butylmethylether, it was suctioned off, it was washed again with a little tert. butylmethylether

and dried at room temperature.

Yield: 3.59 g (80% of theory),

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

Mass spectrum (ESI<+>): m/z-388,340 [M + H]<+>

Analogous to Example II, the following compounds are 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 solution of ammonia-90 : 10:0.1)

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

(3) 6-benzyloxy-4-[0-chloro-4-fluoro-phenyl)amino]-7-hydroxy-quinazoline

Rf - value 0.54 (silica geL methylene chloride/methanol/concentrated, aqueous solution of ammonia-90: 10:0.1)

Mass spectrum (ESI<+>): m/z-396,398 [M + H]<+>

(4) 4-[(3-bromo-phenyl)amino]-6-hydroxy-7-methoxy-quinazoline (the reaction is carried out with sodium hydroxide in ethanol as a solvent)

Rf - value 0.23 (silica gel, ethyl acetate)

Mass spectrum (ESI<+>): m/z = 346,348 [M + H]<+>

(5) 4-[(3-chloro-4-fluoro-phenyl)aniino]-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 - fluoro - phenyl) amino] - 7 - hydroxy - 6 - [(5) - (tetrahydrofuran - 2 - yl) methoxy] - quinazoline

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

Example m

4 - T(3 - chloro - 4 - fluoro - phenyDaminol - 6 - aclopentylmetho ka - 7 - methylcarbonyloxy - quinazoline

4.03 g of 4-chloro-6-diclopentylmethoxy-7-methylcarbonyloxy-quinazoline was suspended in 70 ml of isopropanol and mixed with 1.95 g of 3-chloro-4-fluoro-aniline. The reaction mixture was refluxed for two hours under a nitrogen atmosphere. After cooling to room temperature, the resulting light precipitate was filtered off with suction, washed again with a little isopropanol and air-dried.

Yield: 4.99 g (92% of theory),

Rf - value 0.80 (silica gel, methylene chloride/methanol/concentrated, aqueous ammonia solution = 90: 10:0.1)

Mass spectrum (ESI<+>): m/z - 430,432 [M + H]<+>

Analogously to Example II, the following compounds are obtained:

(1) 4-[(3-chloro-4 - fluorophenu)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)arnino] - 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 - fem)arnino] - 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)arnino] - 6 - hydroxy - 7 - methoxy - quinazoline (the acetoxy - protective group has already separated 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 - fluoro - phenyl) amino] - 7 - cyclopentyloxy - quinazoline

(acetoxy - the protecting group has already separated under the reaction conditions)

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 - fluoro - phenyl)amino] - 7 - methylcarbonyloxy - 6 - ((5) - tetrahydrofuran - 3 - yloxy) - quinazoline

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 - fluoro - phenyl)amino] - 7 - methylcarbonyloxy - 6 - [(5) - (tetrahydrofuran - 2 - yl) methoxy] - quinazoline - hydrochloride

Melting point: 274 - 276°C

Mass spectrum (ESI<4>): m/z- 432,434 [M + H]<+>

Example IV

4-Chloro-6-cMonenylmethoxy-7-methylcarbonyloxy-quinazoline

3.80 g of 4-hydroxy-6-dclopenylmethoxy-7-methylcarbonyloxy-quinazoline was suspended in 90 ml

of thionyl chloride and heated to boiling under a nitrogen atmosphere. After adding four drops of N, N-

dimethylformamide reaction mixture was refluxed for another two hours. After cooling to room temperature

excess thionyl chloride was distilled off in a vacuum apparatus with a jet pump. The brown precipitate is mixed

with 30 ml of toluene. The solvent was distilled off and 4.30 g of a gray-brown solid remained, which was

reacted without further purification.

Rf - value 0.89 (silica gel, methylene chloride/methanol/concentrated, aqueous solution of ammonia-90: 10:0.1)

Analogous to Example rV, the following compounds are 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 solution of ammonia-90: 10:0.1)

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

Rf - value 0.77 (silica gel, methylene chloride/methanolAconcentrated, 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-((5)-tetrahydrofuran-3-yloxy)-quinazoline Rf - value 0.83 (silica gel, ethyl acetate/methanol -9:1)

(6) 4 - chloro - 7 - methylcarbonyloxy - 6 - [(.S) - (tetrahydrofuran - 2 - yl) methoxy] - quinazoline Rf - value 0.48 (silica gel, dichlorohexane/ethyl acetate -1:1)

Example V

4 - hydroxy - 6 - dclopentylmethoxy - 7 ■ methylcarbonyloxy - quinazoline

4.30 g of 4,7-dihydroxy-6-diclopentylmethoxy-quinazoline in 100 ml of pyridine was heated under a nitrogen atmosphere to 80 °C. 1.80 ml of acetic anhydride was added to the dark brown suspension. The reaction mixture was stirred for three hours at 80 °C, during which a complete solution was formed. After cooling to room temperature, the reaction mixture was poured with about 800 ml of ice water. The precipitate obtained was vacuumed and thoroughly washed again with water. The light gray solid was dried in a vacuum desiccator. Yield: 3.82 g (77% of theory),

Rf - value 0.49 (silica gel, methylene chloride/methanol -9:1)

Mass spectrum (ESI): m/z - 301 [M - H]'

Analogously to Example V, the following compounds are 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 - ((f) - tetrahydrofuran - 3 - yloxy) - quinazoline Rf-value 0.62 (Reversed Phase DC- prepared plate (E. Merck), acetonitrile/water/trifluoroacetic acid - 50:50:1)

Mass spectrum (ESI+): m/z - 291 [M + H]+

5) 4-hydroxy-7-methylcarbonyloxy-6-[(£)-(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 - dihydrokai - 6 - dclopenitlmethoxy - quinazoline

5.76 g of 2-amino-5-diclopentylmethoxy-4-hydroxy-benzoic acid and 6.52 g of formamidine acetate in 140 ml of ethanol were refluxed for about three hours. In order to process the reaction, the mixture was concentrated to about 100 ml and diluted with 300 ml of ice water, whereby a gray precipitate was obtained. The precipitate was filtered off, washed again with water and dried in a vacuum dryer.

Yield: 4.57g (77% of theory),

Rf - value 0.25 (silica gel, methylene chloride/methanol - 95:5)

Mass spectrum (ESI -): m/z - 259 [M - H] -

Analogously to Example VI, the following compounds are 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 - ((f5 - (tethiahydrofuran - 3 - yloxy) - quinazoline

Rf - value 0.68 (Reversed Phase DC - prepared plate (E. Merck), acetomtril/water/trifluoroacetic acid - 50:50:1)

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

(6) 4,7-dihydroxy-6-[(5)-(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-oclopentylmethoxy-4-hydroxy-benzoic acid

6.50 g of 5-diclopentylmethoxy-4-hydroxy-2-nitro-benzoic acid was dissolved in 130 mL

of methanol, was mixed with 2.00 g of Raney nickel and hydrated under 50 psi hydrogen pressure for about three hours

at room temperature, until it has received the calculated amount of hydrogen. The catalyst was filtered out and

washing with warm methanol was performed again. The filtrate was concentrated in vacuo. It was obtained

a brownish solid, which reacted further without further purification.

Yield: 5.79 g (100% 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 are 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 038 (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 solution of ammonia-90: 10:0.1)

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

(4) cyclopentyl ester of 2-amino-5-benzyloxy-4-cyclopentyloxy-benzoic acid

(the reaction is carried out in a mixture of methanol and tetrahydrofuran in a ratio of 1:1)

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-((5)-(tetrahydrofuran-3-yloxy)-benzoic acid

Rf - value 0.70 (Reversed Phase DC-prepared plate (E. Merck), acetonitrile/water/trifluoride

acetic acid-50:50:1)

Mass spectrum (ESI"): m/z-238 [M-H]-

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

Rf - value 0.59 (Reversed Phase DC-prepared plate (E. Merck), acetonitrile/water/trifluoride

acetic acid - 50:50:1)

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

Example of VUJ

5-Cyclopentylmethoxy-4-hydroxy-2-nitrobenzoic acid

15.37 g of 4,5-methylenedioxy-2-nitro-benzoic acid and 51.84 mldclo<p>entylmethanol were dissolved in

100 ml of dimethylsulfoxide and cooled under a nitrogen atmosphere in an ice bath. Now it's piece by piece

added 3.90 g of sodium. The reaction mixture was stirred for 30 minutes with cooling in an ice bath,

and then it was briefly heated to 35-40 °C and finally it was stirred for the next three hours while cooling in ice

the bathroom. Finally, the ice bath was removed and the reaction mixture was stirred at room temperature

temperature. The dark brown-reddish reaction solution was poured with 800 ml of acetone,

whereby a dark brown precipitate was obtained. The precipitate was filtered off, washed again with acetone, dissolved in

300-400 ml of water and with 60 ml of 2 N sodium acid, the pH value is adjusted to about 2. The aqueous solution is more

extracted twice with methylene chloride. The combined extracts were washed with saturated sodium chloride solution

chloride, were dried over sodium sulfate and concentrated. There is a dark brown, oily residue in the container

dissolved in 800 ml of methylene chloride and purified over silica gel packing with methylene

chloride/methanol (9:1). A brown oil was obtained, which crystallized by mixing with water,

with cooling in an ice bath. The resulting brown precipitate was filtered off with suction, washed again with a little water and dried

is in a vacuum dryer.

Yield: 9.55 g (47% of theory),

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 Vm, the following compounds are 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 (Reversed Phase DC - prepared 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 (Reversed Phase DC - prepared plate (E. Merck), acetotritril/water/trifluoroacetic acid - 50:50:1)

Mass spectrum (ESI'): m/z - 282 [M - H]'

Example<g>

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

100.00 g of saturated sodium carbonate solution was added to 50.00 g of glycine ethyl ester - hydrochloride in 100 ml of saturated potassium carbonate solution while cooling. The obtained mass was extracted several times with a total of about 600 ml of diethyl ether. The combined ether extracts were dried over sodium sulfate and concentrated to dryness. 28.60 g of glycine ethyl ester remained. This was mixed with 26.00 ml of isobutylene oxide and 40 ml of absolute ethanol and heated in a Roth bomb for six hours at 90 °C. After cooling to room temperature, the reaction mixture was concentrated, leaving a thin oil. Yield: 45.80g (73% of theory),

Mass spectrum (ESI<+>): m/z -176 [M + H]<+>

Example X

* - r^tilfM™™ - flhydro - furan - 2 - on

2.00 g of 4 - (N - benzyl - N - methyl - amino) - dihydrofuran - 2 - one in 25 ml of methanol was hydrogenated in the presence of 250 mg of palladium (10% - ni on activated carbon) under a hydrogen pressure of 50 psi for about two

hours at room temperature, until the calculated amount of hydrogen was received. The catalyst was filtered out of the treatment tub and the filtrate was concentrated in a vacuum. A colorless oil was obtained, which reacted further without additional purification.

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)-dimethyl-furan-2-one

23.20 ml of N-methylbenzylarnine was added to 15.00 g of 5/7-furan-2-one in 150 ml of methylene chloride. The reaction mixture was stirred for about 48 hours at room temperature. To work up the reaction, the mixture was concentrated and fractionally chromatographed through a column of silica gel with ethyl acetate/petroleum ether (3:1) as eluent. The desired product was obtained as a yellowish solid.

Yield: 19.77 g (54% of theory),

Rf. value 0.67 (silica gel, ethyl acetate)

Mass spectrum (ESI<+>): m/z - 228 [M+Na]<+>

Example Xn

4 - T f3 - chloro - 4 - fluoro - phenflamino] - 7 - dclobutyloxy - 6 - hydroxy - quinazoline

To 5.60 g of 6-benzyloxy-4-[(3-chloro-4-fluoro-phenyl)amino]-7-dclobutyloxy-quinazoline, 10 ml of trifluoroacetic acid was added drop by drop while stirring. In doing so, the reaction mixture was heated to about 40 °C. After 20 hours of stirring at room temperature, another 3 ml of trifluoroacetic acid was added. Since the reaction barely took place even after three hours at room temperature, the reaction mixture was heated to 50 °C. After four hours the reaction was completely finished and the excess trifluoroacetic acid was further distilled off with a rotary evaporator. The residue was mixed with water and made alkaline with concentrated aqueous ammonia solution. The resulting light brown precipitate was filtered off with suction, washed again with distilled water and dried in a desiccator. The resulting product still contained 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 are improved:

(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 - ((# - tetrahydrofuran - 3 - yloxy) - quinazoline Rf - value 032 (silica gel, methylene chloride / methanol -9:1) (4) 4 - [ (3 - chloro - 4 - fluoro - phenyl)amino] - 6 - hydroxy - 7 - [ (# - (tetrahydrofuran - 2 - yl)methoxy] - quinazoline

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

Example Xni

6 - benzyloxy - 4 - f (3 - chloro - 4 - fluoro - phenyl ffa mino] - 7 - dclobuitloxy - quinazoline

7.50 g of potassium carbonate and 4.50 g of methanesulfonic acid cyclobutyl ester were added to 7.00 g of 6-benzyloxy-4-[(3-chloro-4-fluoro-phenyl)amino]-7-hydroxy-quinazoline in 60 ml of N,N-dimethylformamide. The reaction mixture was stirred for two hours at 80 °C. Then 2.00 g of methanesulfonic acid dichlorobutyl ester and 3.00 g of potassium carbonate were added again and the mixture was stirred over the weekend at 60 °C. Since the reaction was still not complete, 3.50 g of methanesulfonic acid cyclobutyl ester and 5.00 g of potassium carbonate were added again. After another 20 hours at 80 °C, the reaction is complete. To work up the reaction, the mixture was mixed with 300 ml of ethyl acetate and washed with water and saturated sodium chloride solution. The organic phase was dried over magnesium sulfate and concentrated. The residue was mixed with methanol to give a brownish precipitate. It was vacuumed, washed again with methanol and dried in a dryer.

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 are obtained:

(1) 6-benzyloxy-4-[(3-chloro-4-fluoro-phenyl)amino]-7-dichloropropylmethoxy-quinazoline (bromomethylcyclopropane added)

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 - chlorpentyloxy - quinazoline (bromo chlorpentane was added)

Rf - value 0.78 (silica gel, methylene chloride/methanol -9:1)

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

Example XIV

Terc. butyl ester (Si-(2-hydroxy-<p>rorylamino))-acetic acid

15.00 g of (5)-(+)-1-amino-2-propanol was dissolved in 100 ml of N,N-dimethylformamide and mixed with 6.97 ml of diisopropylethylamine. Then, with cooling in an ice bath, 5.91 ml of tert was added dropwise. butyl ester of bromoacetic acid for 30 minutes. The ice bath was removed and the reaction mixture was stirred overnight at room temperature. In order to process the reaction mixture, the mixture was concentrated in a vacuum. The residue in the container was dissolved in 50 ml of water and saturated with 15 g of sodium chloride. The aqueous solution was extracted several times with ethyl acetate. The combined extracts were 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 theory),

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 are obtained:

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

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

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

(2) Terc. butyl ester - (1,1 - dimethyl - 2 - hydroxy - ethylamino) - acetic acid

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

Rf - value 0.47 (silica gel, methylene chloride/methanol/concentrated aqueous ammonia solution - 90: 10:0.1)

Example XV

4 - fft - chlorine - 4 - fluor - phennaminol - 6 - ( 3 - methanesufonyloxy - propyloxy) - 7 - dclobutyloxy - quinazoline

The compound was obtained by the reaction of 4 - [ (3 - chloro - 4 - fluoro - phenyl)amino] - 6 - (3 - hydroxy - propyloxy) - 7 - dclobutyloxy - quinazoline with methanesulfonic acid chloride in methylene chloride in the presence of dinopropylethylamine 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 are obtained:

(1) 4-[(3-chloro - 4 - fluoro - phenyl)amino] - 6 - (3 - methane sulfonyloxy - 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 - fluoro - phenyl)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 - fluoro - femDamino] - 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-fluoro-ferrinamino]-6-hydroxy ■ 7-riMoornylmethoxy-quinazoline

The compound was obtained by hydrogenation of 6-benzyloxy-4-[(3-chloro-4-fluoro-phenyl)amino]-7-cyclopropylmethoxy-quinazoline in the presence of 10% Pd/C in a mixture of methylene chloride, ethanol and conc. of sodium acid (500:210:3.5) in Parr - this apparatus.

Yield: 73% of theoretical

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

Example XVII

Cyclonethyl ester of 5-benzyloxy-4-cyclopentyloxy-2-nitro-benzoic acid

The compound was obtained by the reaction of 5-benzyloxy-4-hydroxy-2-nitro-benzoic acid with 2,2

equivalents of bromo cyclopentane in the presence of potassium carbonate as an auxiliary base in dimethylsulfoxide at

room temperature.

Yield: 87% of theoretical

Rf - value 0.92 (silica gel, ethyl acetate/cyclohexane-1:1)

Mass spectrum (ESI<+>): m/z-426 [M+H]<+>

Example XVm

4-r(3-chloro-4-fluoro-phendiamino]-6-benzyloxy-7-(( R 1 -tetrahydrofuran-3-yloxy)-quinazoline

In a solution of 8.00 g of 4-[(3-chloro-4-fluoro-phenyl)amino]-6-benzyloxy-7-hydroxy-quinazoline (see WO 0055141 A1) and 2.42 ml of (5)-(+)-3-hydroxy-tetrahydrofuran and 7.95 g of triphenylphosphine in 160 ml

5.03 ml of diethyl ester of azodicarboxylic acid was added dropwise to tetrahydrofuran. It is a reactive mixture

stirred overnight at room temperature and finally concentrated with a rotadone evaporator.

vessel 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 theory),

Melting point: 165-168°C

Mass spectrum (ESI+): m/z = 466.468 [M + H]+

Analogous to Example XVIII, the following compounds are obtained:

(1) 4 - [(3 - chloro - 4 - fluoro - phenyl) amino] - 6 - benzyloxy - 7 - [(# - (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 - fluoro - phenylamino] - 7 - (2 - bromo - ethoxy) - 6 - ((5) - tetrahydrofuran - 3 - yloxy) -

quinazoline

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

Obtaining final compounds

Examples

4 - T(3 - chloro - 4 - fluoro - phenylDaminol - 6 - cyclonenthylmethoxy - 7 - \ 2 - (2.2 - dimethyl - 6 - oxo - morpholine - 4 -

(1)-ethoxy-quinazoline

250 mg of 4-[(3-chloro-4-fluoro-phenyl)amino]-6-diclopentylmethoxy-7-(2-bromo-ethoxy)-quinazoline and 341 mg of (2-hydroxy-2-methyl-propylamino)-acetic acid ethyl ester were 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 was refluxed for about 90 hours. After cooling to room temperature, the reaction mixture was filtered and the filtrate was concentrated in vacuo. The rest is

chromatographed through a silica gel column with petroleum ether/ethyl acetate (50:50, later 0:100) as eluent. The cdclized product was obtained in the form of a beige solid.

Yield: 62 mg (23% of theory),

Rf - value: 0.29 (silica gel, ethyl acetate)

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

Analogous to Example 1, the following compounds are obtained:

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

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 - fer^)arnino] - 7 - diclobutyloxy - 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-fluoro-phenyl)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 - ff3 - chloro - 4 - fluoro - phenyl pfarnino] - 6 - dchlorohydronylmethoxy - 7 ■ ( 2 - TN - (2 - oxo - tetrahydrofuran- 4 ■

iD -N-methyl-aminol-ethoxy)-quinazoline

300 mg of 4-[(3-chloro-4-fluoro-phenyl)amino]-6-cyclopropylmethoxy-7-(2-bromo-ethoxy)-quinazoline and 400 mg of 4-methylamino-dihydrofuran-2-one in 20 ml of acetonitrile were mixed with 240 mg of potassium

carbonate and 70 mg of sodium iodide and refluxed for 24 hours. After cooling to room temperature

the reaction mixture was filtered and the filtrate was concentrated in vacuo. The residue was chromatographed through a column

with silica gel with methylene chloride/methanol A concentrated, aqueous ammonia solution (97:

3:0.05). The compound according to the invention was obtained in the form of a light solid substance.

Yield: 70 mg (22% of theory),

Rf- value 0.47 (silica gel, methylene chloride/methanol/concentrated, aqueous solution of ammonia-90: 10:0.1)

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

Analogous to Example 2, the following compounds are obtained:

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

Rf - value 0.42 (silica gel, methylene chloride/methanol/concentrated, aqueous solution of ammonia-90: 10:0.1) Mass spectrum (ESI<+>): m/z-515.517 [M + H]<+>(2) 4 - [ (3 - chloro - 4 - fluoro - phenyl) amino] - 6 - {3 - [N - (2 - oxo - tetrahydrofuran - 4 - yl) - N - methyl -

amino]-propyloxy}-7-diclobutyloxy-quinazoline

Melting point: 1473-151°C

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

Example 3

4 - T(3 - bromo - phenflaminol - 6 - \ 2 - f ( 5) - 6 - methyl - 2 - oxo - morpholine ■ 4 - yl) - ethoxyl - 7 - methoxy -

quinazoline

90 µl of methanesulfonic acid was added to 380 mg of 4-[(3-bromo-phenU)amino]-6-(2-N-[(tert.butyloxycarbonyl)methyl]-N-((5)-2-hydroxy-propyl)-amino-ethoxy)-7-methoxy-quinazoline in 8 ml of acetonitrile. The reaction mixture was refluxed for about three hours, then another equivalent of methanesulfonic acid was added and refluxing was continued until the reaction was complete.

the reaction mixture was diluted with ethyl acetate and washed with saturated sodium chloride solution

bicarbonate and saturated sodium chloride solution. The organic phase is dried over magnesium

sulfate and concentrated in a vacuum. The residue was mixed with diethyl ether and filtered off with suction. It was obtained

the compound according to the invention in the form of a white solid.

Yield: 280 mg (85% of theory),

Melting point: 190 °C

Mass spectrum (ESI-): m/z-485,487 [M-H]'

Analogous to Example 3, the following compounds are obtained:

(1) 4-[(3-bromo-phenyl)amino]-6-[2-((#-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-phenU)amino]-6-[2-((#-6-methyl - 2-oxo-morpholin-4-yl)-ethoxy] - 7 -

methoxy-quinazoline (the reaction was 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-((#-6-methyl - 2-oxo-morpholin-4-yl)-propyloxy]-

7-methoxy-quinazoline (the reaction was 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 - [(# - (1 - phenyl - ethyl)amino] - 6 - [3 - ((5) - 6 - methyl - 2 - oxo - morpholin - 4 - yl) - propyloxy] - 7 - methoxy - quinazoline (the reaction was 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 - [(# - (1 - phenyl - ethyl)amino] - 6 - [2 - (( S) - 6 - methyl - 2 - oxo - morpholin - 4 - yl) - ethoxy] - 7 - methoxy - quinazoline (the reaction was 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-fluoro-phenyl)amino]-6-[3-(C$-6-methyl-2-oxo-morpholin-4-yl)-propyloxy]-

7 - dclobutyloxy - quinazoline (the reaction was 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 - fluoro - feml)amino] - 6 - [3 - (5,5 - dimethyl - 2 - oxo - morpholine - 4 - yl) - propyloxy] - 7 - dclobutyloxy - quinazoline (the reaction was 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 - fluoro - phenyl)amino] - 6 - [3 - ((# - 6 - methyl - 2 - oxo - morpholin - 4 - yl) - propyloxy] - 7 - cyclopropylmethoxy - quinazoline (the reaction was 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-fluoro-phenyl)amino]-6-[3-US)-6-methyl-2-oxo-morpholin-4-yl)-propyloxy]-7-cyclopropylmethoxy-quinazoline (the reaction was 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 - fluoro - phenyl)amino] - 6 - [2 - ((5 - 6 - methyl - 2 - oxo - morpholin - 4 - yl) - ethoxy] - 7 -

dclopentyloxy - quinazoline (the reaction was 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 - fluoro - phenyl)amino] - 6 - [2 - ((# - 6 - methyl - 2 - oxo - morpholin - 4 - yl) - ethoxy] - 7 - cyclopentyloxy - quinazoline (the reaction was 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 - fluoro - phenyl)amino] - 6 - [2 - US) - 6 - methyl • 2 - oxo - morpholin - 4 - yl) - ethoxy] - 7 - cyclopropylmethoxy - quinazoline (the reaction was 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 - fluoro - phenyl)amino] - 6 - [2 - ((# - 6 - methyl - 2 - oxo - morpholin - 4 - yl) - ethoxy] - 7 - cyclopropylmethoxy - quinazoline (the reaction was 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 - fluoro - phenyl) amino] - 6 - cyclopropylmethoxy - 7 - [2 - (( S) - 6 - methyl - 2 - oxo - morpholin - 4 - yl) - ethoxy] - quinazoline (the reaction was performed 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 - fluoro - phenyl) amino] - 6 - cyclopropylmethoxy - 7 - [2 - (( # - 6 - methyl - 2 - oxo -morpholin - 4 - yl) - ethoxy] - quinazoline (the reaction was carried out with trifluoroacetic acid in acetonitrile) Mass spectrum: (ESI<+>): m/z - 501,503 [M + H]<+>(16) 4 - [(3 - chloro - 4 - fluoro - phenyl) amino] - 6 - cyclopropylmethoxy - 7 - [3 - ((# - 6 - methyl - 2 - oxo - morpholin - 4 - yl) - propyloxy] - quinazoline (the reaction was carried out with trifluoroacetic acid in acetonitrile)

Rf - value 0.67 (silica gel, ethyl acetate/methanol -9:1)

Mass spectrum (ESI'): m/z - 531,515 [M - H] -

(17)4- [(3 - chloro - 4 - fluoro - phenyDamino] - 6 - cyclopropylmethoxy - 7 - [3 - ((5) - 6 - methyl - 2 - oxo - morpholin - 4 - yl) - propyloxy] - quinazoline (the reaction was 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 - fluoro - phenylamino] - 6 - [2 - (2,2 - dimethyl - 6 - oxo - morpholin - 4 - yl) - ethoxy] - 7 - cyclopentyloxy - quinazoline (the reaction was 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 - fluoro - phenu)amino] - 6 - cyclopentyloxy - 7 - [2 - ((5) - 6 - methyl - 2 - oxo - morpholine -

4- yl) - ethoxy] - quinazoline (the reaction was 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 - fluoro - phenyl)amino] - 6 - cyclopentyloxy - 7 - [2 - ((# - 6 - methyl - 2 - oxo - morpholine -

4-yl)-ethoxy]-quinazoline (the reaction was carried out with trifluoroacetic acid in acetonitrile)

Mass spectrum (ESI<+>): m/z-515,517 [M+H]<+>(21) 4 - [ (3 - chloro - 4 - fluoro - phenu) amino] - 6 - [4 - ((5) - 6 - methyl - 2 - oxo - morpholin - 4 - yl) - butyloxy] - 7 - cyclopentyloxy - quinazoline (the reaction was 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 - fluoro - phenyl)amino] - 6 - [4 - ((# - 6 - methyl - 2 - oxo - morpholin - 4 - yl) - butyloxy] - 7 - cyclopentyloxy - quinazoline (reaction was performed with trifluoroacetic acid in acetonitrile) Mass spectrum (ESI<+>): m/z = 543,545 [M + H]<+>(23) 4 - [(3 - chloro - 4 - fluoro - femOamino] - 6 - [3 - (( S) - 6 - methyl - 2 - oxo - morpholin - 4 - yl) - propyloxy] -

7 - methoxy - quinazoline (the reaction was 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 - fluoro - phenyl) amino] - 6 - [3 - (5,5 - dimethyl - 2 - oxo - morpholin - 4 - yl) - propyloxy] - 7 - methoxy - quinazoline (the reaction was 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 - fluoro - phenyl) amino] - 6 - [2 - ((5) - 6 - methyl - 2 - oxo - morpholin - 4 - yl) - ethoxy] - 7 - methoxy - quinazoline (the reaction was 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 - fluoro - phenyl)amino] - 6 - {2 - [N - (carboxymethyl) - N - ((5) - 2 - hydroxy - propyl) - amino] - ethoxy} - 7 - methoxy - quinazoline (by-product in obtaining 3 (25))

Melting point: 187 - 190°C

Mass spectrum: (ESI<+>): m/z - 479,481 [M + H]<+>(27) 4 - [(3 - chloro - 4 - fluoro - ferul)arnino] - 6 - [2 - (2,2 - dimethyl - 6 - oxo - morpholin - 4 - yl) - ethoxy] - 7 -

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

((R)- tetratodrofuran-3-yloxy) - quinazoline (the reaction was 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 - fluoro - phenyl)amino] - 6 - [2 - (2,2 - dimethyl - 6 - oxo - morpholin - 4 - yl) - ethoxy] - 7 -

[(R) • tetrahydrofuran-2-yl)-methoxy]-quinazoline (the reaction was carried out with trifluoroacetic acid in acetonitrile)

Melting point: 184°C

Mass spectrum (ESI<+>): m/z - 545,547 [M + H]<+>(30) 4 - [(3 - chloro - 4 - fluoro - phenyl)arnino] - 7 - [2 - (2,2 - dimethyl - 6 - oxo - morpholin - 4 - yl) - ethoxy] - 6 -

((5)-tetrahydrofuran-3-yloxy)-quinazoline

Melting point: 202 - 205°C

Mass spectrum (ESI<+>): m/z - 531,533 [M + H]<+>

(31) 4 - [(3 - chloro - 4 - fluoro - phenyl)amino] - 7 - [2 - (2,2 - dimethyl - 6 - oxo - morpholin - 4 - yl) - ethoxy] - 6 -

[(5)-tetrahydrofuran-2-yl)methoxy]-quinazoline

Melting point: 182°C

Mass spectrum (ESI + ): m/z - 545.547 [M + H] +

Example 4

4 - [(3 - bromo - femDaminol - 6 - ( 2 - f N - rftert. butylocacarbornDimethyl) - N - (( Si - 2 - hydroxy - propyl) -

amino} - ethoxy) - 7 - methoxy - quinazoline

In 650 mg of 4 - [(3 - bromo - phenyl)amino] - 6 - (2 - bromo - ethoxy) - 7 - methoxy - quinazoline and 1.10 g of tert. butyl ester (S) - (2 - hydroxy - propylamino) - acetic acid in 15 ml of acetonitrile, 0.25 ml of diisopropylethylamine was added. The reaction mixture was stirred overnight at 50 °C. Since no reaction could be observed, the reaction mixture was concentrated, mixed with 20 ml of N,N-dimethylformamide and stirred for eight hours at 60 °C. Finally, the temperature was raised to 80 °C. After the next eight hours, the reaction was completely completed. The reaction mixture was concentrated and chromatographed through a silica gel column with ethyl acetate as eluent. The desired product was obtained as a white solid. Yield: 410 mg (51% of theory),

Rf - value 0.27 (silica gel, ethyl acetate)

Mass spectrum (ESI"): m/z - 559,561 [M - H] -

Analogous to Example 4, the following compounds are obtained:

(1) 4 - [0 - bromo - feml)amino] - 6 - (2 - {N - [(tert. butyloxycarbonyl) - methyl] - N - ((# - 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. butylcacarbonyl)methyl] - N - ((# - 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.butyloxycarbonyl)methyl]-N-((#-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 - [(# - (1 - phenyl - ethyl)amino] - 6 - (3 - {N - [(tert. butyloxycarbonyl)methyl] - N - ((£) - 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 (ED: m/z-524 [M]<+>

(5) 4-[(#-(1 - phenyl - ethyl)amino]-6-(2-{N-[(tert. butyloxycarbonyl)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-fluoro-phenyl)amino]-6-(3-{N-[ (tert.butyloxycarbonyl)methyl]-N-(( £)-2-hydroxy-propyl)-amino}-propyloxy)-7-dclobutyloxy-quinazoline

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

(7) 4 - [(3 - chloro - 4 - fluoro - phenyl)amino] - 6 - (3 - {N - [(tert. butyloxycarboiw)methyl] - N - (1,1 - dimethyl -

2 - hydroxy - ethyl) - ainino} - propyloxy) - 7 - dclobutyloxy - 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 - fluoro - phenyl)amino] - 6 - (3 - {N - [(tert. butyloxycarbonyl)methyl] - N - ((# - 2 - hydroxy - propyl) - amino} - propyloxy) - 7 - cyclopropylmethoxy - quinazoline

Rf-value 037 (silica gel, methylene chloride/methanol - 95:5)

(9) 4 - [(3 - chloro - 4 - fluoro - phenyl)amino] - 6 - (3 - {N - [ (tert. butyloxycarbonyl)methyl] - N - ((5) - 2 - hydroxy - propyl) - amino} - propyloxy) - 7 • cyclopropylmethoxy - quinazoline

Rf - value 0.50 (silica gel, ethyl acetate)

(10) 4 - [(3 - chloro - 4 - fluoro - phenyl)amino] - 6 - (2 - {N - [(tert. butyloxycarbonyl)methyl] - N - (CS) - 2 - hydroxy - propyl) - amino} - ethoxy) - 7 - cyclopentyloxy - quinazoline

Rf-value 0.54 (silica gel, ethyl acetate/dichlorohexane -9:1)

(11) 4 - [(3 - chloro - 4 - fluoro - phenylamino] - 6 - (2 - {N - [ (tert. butyloxycarbonyl)methyl] - N - ((# - 2 - hydroxy - propyl) - amino} - ethoxy) - 7 - chlorpentyloxy - quinazoline

Rf - value 0.66 (silica gel, ethyl acetate)

(12) 4 - [(3 - chloro - 4 - fluoro - phenyl)amino] - 6 - (2 - {N - [(tert. butyloxycarbonyl)methyl] - N - ((S) - 2 - hydroxy - propyl) - amino} - ethoxy) - 7 - cyclopropylmethoxy - quinazoline

Rf - value 0.60 (silica gel, ethyl acetate)

(13) 4 - [(3 - chloro- 4 - fluoro-phenyl)amino] - 6 - (2 - {N - [(tert. butyloxycarboniOmethyl] - N - ((# - 2 - hydroxy - propyl) - amino} - ethoxy) - 7 - cyclopropylmethoxy - quinazoline

Rf - value 0.60 (silica gel, ethyl acetate)

(14) 4 - [(3 - chloro-4 - fluoro-phenyl)amino] - 6 - cyclopropylmethoxy - 7 - (2 - {N - [(tert. butyloxycarbonyl)methyl] - N - ((5) - 2 - hydroxy - propyl) - amino} - ethoxy) - quinazoline Rf - value 0.30 (silica gel, ethyl acetate) (15) 4-[(3-chloro-4-fluoro-phenu)amino]-6-cyclopropylmethoxy-7- (2- {N-[(tert. butyloxycarboniOmethyl] - N - (( £) - 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. butyloxycarboniOmethyl] - N - ((# - 2 - hydroxy - propyl) - amino} - propyloxy) - quinazoline Rf. value 0.35 (silica gel, ethyl acetate) (17) 4 - [(3 - chloro - 4 - fluoro - phenylamino] - 6 - cyclopropylmethoxy - 7 - (3 - {N - [(tert.butyloxycarbonyl)methyl] - N - ((5) - 2 - hydroxy - propyl) - amino} - propyloxy) - quinazoline Rf - value 0.35 (silica gel, ethyl acetate) (18) 4 - [(3 - chloro - 4 - fluoro - phenyl)ainino] - 6 - (2 - {N - [(ethoxycarbonyl)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 -fluoro - phenyl)amino] - 6 - chlorpentyloxy - 7 - (2 - {N - [(tert. butyloxycarboniOmethyl] - N - ((5) -2-hydroxy - propyl) - amino} - ethoxy) - quinazoline Rf - value 0.51 (silica gel, ethyl acetate) (20) 4 - [ (3 - chloro - 4 - fluoro - phenyl)amino] - 6 - cyclopentyloxy - 7 - (2 - {N - [(tert. butyloxycarboniOmethyl] - N - (($ - 2 - hydroxy - propyl) - amino} - ethoxy) - quinazoline Rf-value 0.51 (silica gel, ethyl acetate) (21) 4 - [(3 - chloro - 4 - fluoro - phenyl)amino] - 6 - (4 - {N - [(tert. butyloxycarbonylOmethyl] - N - (($ - 2 - hydroxy - propyl) - amino} - butyloxy) - 7 - cyclopentyloxy - quinazoline

Rf - value 0.61 (silica gel, ethyl acetate)

(22) 4 - [(3 - chloro - 4 - fluoro - phenyl)amino] - 6 - (4 - {N - [(tert. butyloxycarboniOmethyl] - N - ((# - 2 - hydroxy - propiO - amino} - butyloxy) - 7 - cyclopentyloxy - quinazoline)

Rf - value 0.61 (silica gel, ethyl acetate)

23

Rf - value 0.46 (silica gel, ethyl acetate)

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

24

Mass spectrum (ESI<+>): m/z - 563,565 [M + H]<+>

(25) 4 - [(3 - chloro - 4 - fluoro - feml)araino] - 6 - (2 - {N - [(tert. butyloxycarboniOmethyl] -N - (C5J - 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 - [0 - chloro- 4 - fluoro - phenyl)amino] - 6 - (2 - {N - [(ethoxycarboniOmethyl] - N - (2 - hydroxy - 2 - methyl - propyl) - amino} - ethoxy) - 7 - methoxy - quinazoline

(appears as a mixture with an already cyclized substance)

Rf - value 0.44 (silica gel, ethyl acetate)

Mass spectrum (ESI + ): m/z - 521.523 [M + H] +

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

(appears as a mixture with an already cyclized substance)

Rf - value 0.30 (silica gel, methylene chloride/methanol -9:1)

(28) 4 - [(3 - chloro - 4 - fluoro - phenylamino] - 6 - (2 - {N - [(ethoxycarbonyl)methyl] - N - (2 - hydroxy - 2 -methyl - propyl)-arnino}-ethoxy)-7-[( R )-tetrahydrofuran-2-U) methoxy]-quinazoline

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

29

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

(30) 4 - [(3 - chloro - 4 - fluoro - phenyl)amino] - 7 - (2 - {N - [(ethoxycarboniOmethyl] - N - (2 - hydroxy - 2 - methyl - propyl) - amino} - ethoxy) - 6 - [( S) - tetrahydrofuran - 2 - yl) - methoxy - quinazoline Rf - value 0.68 (silica gel, ethyl acetate/methanol -15:1)

Analogous to the Examples and other methods known from the literature, the following compounds are obtained: (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 - morpholine - 4 - yl) - propyloxy] - 6 - methoxy - quinazoline(3) 4 - [(3 - chloro - 4 - fluoro - phenylamino] - 6 - [2 - ((S) - 6 - methyl - 2 - oxo - morpholine - 4 - yl) - ethoxy] - 7 - methoxy - quinazoline (4) 4 - [ 0 - chloro - 4 - fluoro - phenyl) ainino] - 6 - [3 - ((5) - 6 - methyl - 2 - oxo - morpholine - 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) - propyloxy] - ethoxy] - 7 - methoxy - quinazoline (7) 4 - [(3 - chloro -4- fluoro - phenyOamino] - 6 - [3 - (3 - methyl - 2 - oxo - morpholin -4- yl) - propyloxy] - 7 - methoxy - quinazoline (8) 4 - [ (3 - chloro - 4 - fluoro - phenu) amino] - 6 - [2 - (3 - methyl - 2 - oxo - morpholin -4-yl) - yl) - ethoxy] - 7 - methoxy - quinazoline (9) 4 - [(R) - (1 - phenyl - ethylOamino] - 6 - [3 - ((# - 6 - methyl - 2 - oxo - morpholin - 4 - yl) - propyloxy] - 7 - methoxy - quinazoline(10) 4 - [ ( Rj - (1 - phenyl - ethyl)amino] - 6 - [2 - ((# - 6 - methyl - 2 - oxo - morpholine - 4 - yl) - ethoxy] - 7 - methoxy - quinazoline (11) 4 - [ (3 - chloro - 4 - fluoro - phenyl)amino] - 7 - [4 - ( 6 - methyl - 2 - oxo - morpholin - 4 - yl) - butyloxy] - 6 - methoxy - quinazoline (12) 4 - [(3 - chloro - 4 - fluoro - phenyl)amino] - 7 - [3 - (6 - methyl - 2 - oxo - morpholine - 4 - yl) - propyloxy] - 6 - methoxy - quinazoline (13) 4 - [(3 - chloro - 4 - fluoro - pheryl)airino] - 6 - [4 - (6 - methyl - 2 - oxo - morpholin - 4 - yl) - butyloxy] - 7 - methoxy - quinazoline (14) 4 - [ (3 - chloro - 4 - fluoro - phenyl) amino] - 6 - [2 - (6 - methyl - 2 - oxo - morpholine - 4 - yl) - ethoxy] - 7 -

(tetramdrofuran - 3 - yloxy) - quinazoline

(15) 4 - [ (3 - chloro - 4 - fluoro - phenyl) amino] - 6 - [2 - (6 - methyl - 2 - oxo - morpholin - 4 - yl) - ethoxy] ■ 7 -

(tetrahydropyran - 3 - yloxy) - quinazoline

(16) 4 - [ (3 - chloro - 4 - fluoro - phenyl) amino] - 6 - [2 - (6 - methyl - 2 - oxo - morpholin - 4 - yl) - ethoxy] - 7 -

(tetrahydropyran-4-yloxy) - quinazoline

(17) 4 - [ 0 - chloro - 4 - fluoro - phenyl) amino] - 6 - [2 - (6 - methyl - 2 - oxo - morpholin - 4 - yl) - ethoxy] - 7 -

(tetrahydrofuran - 2 - ylmethoxy) - quinazoline

(18) 4 - [(3 - chloro - 4 - fluoro - phenyl)amino] - 6 - [2 - (6 - methyl - 2 - oxo - morpholin - 4 - yl) - ethoxy] - 7 -

(tetrahydropyran - 4 - ylmethoxy) - quinazoline

(19) 4 - [ (3 - chloro - 4 - fluoro - phenyl) amino] - 6 - [2 - (6,6 - dimethyl - 2 - oxo - morpholin - 4 - yl) - ethoxy] - 7 -

(tetrahydrofuran - 3 - yloxy) - quinazoline

(20) 4 - [(3 - chloro - 4 - fluoro - phenyl) amino] - 6 - [3- (6,6 - dimethyl - 2 - oxo - morpholin - 4 - yl) - propyloxy] -

7 - (tetrahydrofuran - 3 - yloxy) - quinazoline

(21) 4 - [(3 - chloro - 4 - fluoro - phenyl) - 6 - [4 - (6,6 - dimethyl - 2 - oxo - morpholin - 4 - yl) - butyloxy] - 7 -

(tetramdroturane - 3 - yloxy) - quinazoline

(22) 4 - [(3 - chloro - 4 - fluoro - fer^)amino] - 6 - [2 - (6,6 - dimethyl - 2 - oxo - morpholin - 4 - yl) - ethoxy] - 7 -

(tetrahydrofuran - 2-ylmethoxy) - quinazoline

(23) 4 - [(3 - chloro - 4 - fluoro - phenyl)arnino] - 6 - [3 - (6,6 - dimethyl - 2 - oxo - morpholin - 4 - yl) - propyloxy] -

7 - (tetrahydrofuran - 2 - ylmethoxy) - quinazoline

(24) 4 - [(3 - chloro - 4 - fluoro - phenyl)arnino] - 6 - [4 - (6,6 - dimethyl - 2 - oxo - morpholin - 4 - yl) - butyloxy] - 7 -

(tetrahydrofuran - 2 - ylmethoxy) - quinazoline

(25) 4 - [ (3 - chloro - 4 - fluoro - phenyl) amino] - 7 - [2 - (6 - methyl - 2 - oxo - morpholin - 4 - yl) - ethoxy] - 6 -

(tetrahydrofuran - 3 - yloxy) - quinazoline

(26) 4 - [ (3 - chloro - 4 - fluoro - phenyl)amino] - 7 - [2 - (6 - methyl - 2 - oxo - morpholin - 4 - yl) - ethoxy] - 6 -

(tetrahydropyran - 3 - yloxy) - quinazoline

(27) 4 - [ (3 - chloro - 4 - fluoro - phenyl) amino] - 7 - [2 - (6 - methyl - 2 - oxo - morpholin - 4 - yl) - ethoxy] - 6 -

(tetrahydropyran - 4 - yloxy) - quinazoline

(28) 4 - [ (3 - chloro - 4 - fluoro - phenyl) amino] - 7 - [2 - (6 - methyl ■ 2 - oxo - morpholin - 4 - yl) - ethoxy] - 6 -

(tetrahydrofuran - 2-ylmethoxy) - quinazoline

(29) 4 - [ (3 - chloro - 4 - fluoro - phenyl) amino] - 7 - [2 - (6 - methyl - 2 - oxo - morpholin - 4 - yl) - ethoxy] - 6 -

(tetrahydropyran-4-ylmethoxy) - quinazoline

(30) 4 - [ (3 - chloro - 4 - fluoro - phenyl) amino] - 7 - [2 - (6,6 - dimethyl - 2 - oxo - morpholin - 4 - yl) - ethoxy] - 6 -

(tetrahydrofuran - 3 - yloxy) - quinazoline

(31) 4 - [(3 - chloro - 4 - fluoro - phenyl)amino] - 7 - [3 - (6,6 - dimethyl - 2 - oxo - morpholin - 4 - yl) - propyloxy] -

6 - (tetrahydrofuran - 3 - yloxy) - quinazoline

(32) 4 - [(3 - chloro - 4 - fluoro - phenyl)airino] - 7 - [4 - (6,6 - dimethyl - 2 - oxo - morpholin - 4 - yl) - butyloxy] - 6 -

(tetrahydrofuran - 3 - yloxy) - quinazoline

(33) 4 - [ (3 - chloro - 4 - fluoro - phenyl) amino] - 7 - [2 - (6,6 - dimethyl - 2 - oxo - morpholin - 4 - yl) ■ ethoxy] - 6 -

(tetrahydrofuran - 2 - ylmethoxy) - quinazoline

(34) 4 - [(3 - chloro - 4 - fluoro - phenyl)amino] - 7 - [3 - (6,6 - dimethyl - 2 - oxo - morpholin - 4 - yl) - propyloxy] -

6 - (tetrahydrofuran - 2 - ylmethoxy) - quinazoline

(35) 4 - [(3 - chloro - 4 - fluoro - phenyl)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 dragee contains:

Obtaining:

The active substance is mixed with calcium phosphate, cornstarch, poUvMpyrrolidone, hydroxypropylmethylcellulose and half of the stated amount of magnesium stearate. On the machine for

tableting, blanks with a diameter of about 13 mm were made, which were then pushed through a sieve with openings of 1.5 mm on a suitable machine and mixed with the remaining amount of magnesium stearate. This granulate was pressed on a tableting machine into tablets of the desired shape.

core weight: 230 mg

mold: 9 mm, convex

The dragee cores made in this way were coated with a film consisting essentially of hydroxypropylmethylcellulose. Finished dragees coated with a film are polished with beeswax, dragee weight: 245 mg.

Example 6

Tablets with 100 mg of active substance

Composition:

1 tablet contains:

Procedure for obtaining

The active substance, lactose and starch are mixed and simultaneously moistened with an aqueous solution of potivinylpyrrolidone. After sieving the wet mass (sieve opening of 2.0 mm) and drying in a dryer with

shelves at 50 °C, sieving was carried out again (1.5 mm sieve opening) and a means for

lubrication. The mixture that was prepared for compression was then processed into tablets,

tablet weight: 220 mg

diameter: 10 mm, biplanar with a facet on both sides and with a partial notch on one side.

Example 7

Tablets with 150 mg of active substance

Composition:

1 tablet contains:

Refutation;

The active substance mixed with lactose, corn starch and syllium acid is moistened

with a 20% aqueous solution of polyvinylpyrrolidone and passed through a sieve with openings of 1.5 mm.

The granulate, which was dried at 45 °C, was once again pushed through the same sieve and mixed with the

amount of magnesium stearate. Tablets were pressed from this mixture.

tablet weight: 300 mg

mold: 10 mm, flat

Example 8

Capsules made of hard gelatin with 150 mg of active substance

1 capsule contains:

Rebuttal:

The active substance is mixed with auxiliary substances, it is sieved through a sieve with openings of 0.75 mm.

and mixed in a suitable device until the end of homogenization.

Hard gelatin capsules of size 1 were filled with the beaten final mixture.

capsule filling: about 320 mg

capsule shell: hard gelatin capsule, size 1.

Example 9

Su<p>ositoriie with 150 mg of active substance

1 suppository contains:

Rebuttal:

After melting the mass for suppositories, the active substance was homogeneously distributed in it and melted

the mass was poured into cooled molds.

Example 10

Suspension with 50 mg of active substance

100 ml of suspension contains:

Winners:

The water supply is heated to 70 °C. Methyl- and propyl-ester p-

hydroxybenzoic acid, as well as glycerin and sodium salt of carboxymethylcellulose. Then this is it

cooled to room temperature, the active substance was added with mixing and dispersed homogeneously.

After adding and dissolving sugar, sorbitol solution and aroma, the suspension was evacuated with stirring

to remove air.

5 ml of suspension contains 50 mg of active substance.

Example 11

Ampoules with 10 mg of active substance

Composition:

It is difficult;

The active substance was dissolved in the required amount of 0.01 N HCl, the isotonicity was adjusted with table salt, it was sterile filtered and ampoules of 2 ml were filled with it.

Examples

Amnules with 50 mg of active substance

Composition:

Pppijianje;

The active substance was dissolved in the required amount of 0.01N HC1, its isotonicity was adjusted with Itzuhinja salt, it was sterile filtered and ampoules of 10 ml were filled with it.

Example 13

Capsules for inhaling powder with 5 mg of active substance

1 capsule contains:

Obtaining:

The active substance is mixed with lactose intended for inhalation. Capsules were filled with that mixture on the encapsulation machine (the weight of an empty capsule is about 50 mg),

capsule weight: 70.0 mg

capsule size: 3

Example 14

Ttofgtgftr »a ;nhf*frffljv «?a 2.5 mg of active substance for hand weeders

1 spray stroke contains:

Rebuttal:

The active substance and benzalkonium chloride were dissolved in ethanol/water (50/50). The pH value of the solution was adjusted with 1N sodium acid. The solution obtained in this way was filtered and filled with it in a suitable vessel

(cartridge) for hand sprayers.

mass with which the container is filled: 43 g

Claims (9)

1. Compounds of general formula I, in which Represents a 1-phenylethyl group or a phenyl group substituted with R1 R2 radicals, whereby Ri represents a fluorine, chlorine or bromine atom and R2 represents a hydrogen or fluorine atom, one of the radicals Rbili Rcje R3-(CH2)m - O - group and the other of the radicals Rbili Rcje methoxy -, diclobutyloxy -, diclopentyloxy -, diclopropylmethoxy -, diclobutylmethoxy -, diclopentylmethoxy -, tetrahydrofuran-3-yloxy -, tetrahydropyran-3-yloxy -, tetrahydropyran-4-yloxy -, tetrahydrofuranylmethoxy - or tetrahydropyranylmethoxy - group, whereby R3 represents N-(2-oxo-tetrahydrofuran-4-yl)-methylamino-group or 2-oxo-morpholin-4-yl-group which is substituted with one or two methyl - groups i m represents the number 2, 3 or 4, with the stipulation that compounds are excluded 4 - [(3 - chloro - 4 - fluoro - phenylamino] - 6 - chlorpentyloxy - 7 - [2 - (6,6 - dimethyl - 2 - oxo - morpholin - 4 - yl) - ethoxy] - quinazoline, 4 - [(3 - bromo - phenylamino] - 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 - morpholine - 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 - dclobutyloxy - quinazoline, 4 - [(3 - chloro - 4 - fluoro - phenyl)amino] - 6 - [2 - (6,6 - dimethyl - 2 - oxo - morpholin - 4 - yl) - ethoxy] - 7 - chlorpentyloxy - 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 - phenylamino] - 6 - [2 - (6,6 - dimethyl - 2 - oxo - morpholin - 4 - yl) - ethoxy] - 7 - dclopentylmethoxy - 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 - phenylamino] - 6 - {2 - [N - (2 - oxo - tetrahydrofuran - 4 - yl) - N - methyl - amino] - ethoxy} - 7 - chlorpentyloxy - quinazoline, 4 - [ (3 - chloro - 4 - fluoro - phenyl) amino] - 6 - {2 - [N - (2 - oxo - tetrahydrofuran - 4 - yl) - N - methyl - amino ] - ethoxy} - 7 - diclopenitlmethoxy - quinazoline, 4 - [(3 - chloro - 4 - fluoro - phenyl)arnino] - 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 - dclopentylmethoxy - quinazoline, (R) - 4 - [(1 - phenyl - ethyl)amino] - 6 - [3 - (6,6 - dimethyl - 2 - oxo - morpholin - 4 - yl) - propyloxy] - propyloxy] - 7 - chlorpentyloxy - 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 - dclobutyloxy - quinazoline, 4 - [(3 - chloro - 4 - fluoro - phenyl)amino] - 7 - [2 - (6,6 - dimethyl - 2 - oxo - morpholin - 4 - yl) - ethoxy] - 6 - chlorpentyloxy - 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 - diclopenitlmethoxy - 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 - phenuamino] - 7 - {2 - [N - (2 - oxo - tetrahydrofuran - 4 - u) - 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 - cyclopentylmethoxy - 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, their stereoisomers and their salts. 2. Compounds of general formula I according to claim 1, in which Preferably 1 - phenylethyl -, 3 - bromophenyl - or 3 - chloro - 4 - fluorophenyl - group, Rbje R3- (CH2)m- 0 - a group in which R3 is a 2-oxo-morpholin-4-yl group substituted with one or two methyl groups and m is 2 or 3, and Rcje methoxy -, dichlorobutyloxy -, dichloropentyloxy -, dichloropropylmethoxy -, tetrahydrofuran-3-yloxy - or tetrahydrofuranylmethoxy - group, with the stipulation that compounds are excluded 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 - morpholine - 4 - yl)ethoxy] - 7 - methoxy - quinazoline, 4 - [(3 - bromo - phenyl)amino] - 6 - [2 - (5,5 - dimethyl - 2 - oxo - morpholine - 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 - dclobutyloxy - 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 - [2 - (6,6 - dimethyl - 2 - oxo - morpholin - 4 - yl) - ethoxy] - 7 - chlorpentyloxy - quinazoline, 4 - [ (3 - chloro - 4 - fluoro - phenyl)amino] - 6 - [3 - (6,6 - dimethyl - 2 - oxo - morpholin - 4 - yl) - propyloxy] - 7 - cyclopentoxy - quinazoline and (R) - 4 - [(1 - phenyl - ethyl)amino] - 6 - [3 - (6,6 - dimethyl - 2 - oxo - morpholin - 4 - yl) - propyloxy] - 7 - chlorpentyloxy - quinazoline, their tautomers, their stereoisomers and their salts. 3. Compounds of general formula I, according to claim 1, in which Rather 3 - chloro - 4 - fluoro - phenyl - group, Rb is a cyclopentyloxy-, cyclopropylmethoxy-, cyclopentylmethoxy-, tetrahydrofuran-3-yloxy- or tetrahydrofuranyl-methoxy group and Rc is R3 - (CH2)m - 0 - a group in which R3 is a 2-oxo-morpholin-4-yl group substituted with one or two methyl groups and m is 2, with the stipulation that compounds 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 - phenylamino] - 7 - [2 - (6,6 - dimethyl - 2 - oxo - morpholin - 4 - yl) - ethoxy] - 6 - cyclopentylmethoxy - quinazoline, their tautomers, their stereoisomers and their salts. 4. The following compounds of general formula I according to claim 1: (1) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-cyclopentylmethoxy-7-[2-(2,2-dimethyl-6-oxo-morpholin-4-yl)-ethoxy]-quinazoline, (2) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-cyclopentyloxy-7 - {2 - [N - (2 - oxo - tetrahydrofuran - 4 - yl) - N - methyl - amino] - ethoxy} - quinazoline, (3) 4 - [(3 - chloro - 4 - fluoro - phenyl)amino] - 6 - cyclopropylmethoxy - 7 - [2 - (2,2 - dimethyl - 6 - oxo - morpholin - 4 - yl) - ethoxy] - quinazoline, (4) 4 - [(3 - chloro - 4 - fluoro - phenyl)amino] - 7 - dclobutyloxy - 6 - [3 - (2,2 - dimethyl - 6 - oxo - morpholin - 4 - yl) - propyloxy] - quinazoline, (5) 4 - [(3 - chloro - 4 - fluoro - phenyl)amino] - 7 - dclopropylmethoxy - 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 - oxo - tetrahydrofuran - 4 - yl) - N - methyl - amino] - ethoxy} - quinazoline, (7) 4 - [(3 - bromo - phenyl) amino] - 6 - [2 - ((5) - 6 - methyl - 2 - oxo - morpholine - 4 - 11) - ethoxy] - 7 - ethoxy - 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 - (( Rj - 6 - methyl - 2 - oxo - morpholin - 4 - ethoxy) yl) - ethoxy] - 7 - methoxy - quinazoline, (10) 4 - [(3 - chloro - 4 - fluoro - phenyl)amino] - 6 - [3 - (( £) - 6 - methyl - 2 - oxo - morpholin - 4 - yl) - propyloxy] - 7 - methoxy - quinazoline, (11) 4 - [(# - (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 - (($ - 6 - methyl - 2 - oxo - morpholin - 4 - yl) - ethyloxy] - 7 - methoxy - quinazoline and (13) 4 - [0 - chloro - 4 - fluoro - phenyl)amino] - 6 - [2 - ((S) - 6 - methyl - 2 - oxo - morpholin - 4 - yl) - ethoxy] - 7 - methoxy - quinazoline, their tautomers, their stereoisomers and their salts. 5. Physiologically acceptable salts of compounds according to claims 1 to 4 with inorganic or organic acids or bases. 6. Pharmaceutical compositions containing a compound according to one of claims 1 to 4 or a physiologically acceptable salt according to claim 5, possibly with one or more inert carriers and/or diluents. 7. Application of the compound according to one of the claims 1 to 5 for obtaining a pharmaceutical composition suitable for the treatment of benign or malignant tumors, for the prevention or treatment of diseases of the respiratory tract and lungs, for the treatment of polyps, for the treatment of diseases of the gastrointestinal tract, diseases of the bile ducts and gall bladder, as well as of the kidneys and skin. 8. A method for obtaining a pharmaceutical composition according to claim 6, characterized in that the compound according to one of claims 1 to 5 is formulated non-chemically with one or more inert carriers and/or diluents. 9. Process for obtaining the compound of the general formula I according to claims 1 to 5, characterized in that a) the compound of the general formula in which Preferably defined as in claims 1 to 4, one of the radicals Rb' or Rc' represents a methoxy -, dichlorobutyloxy -, dicyclo<p>enthyloxy -, dichloropropylmethoxy -, cyclobutylmethoxy - or diclophenylmethoxy - group and the second of the radicals Rb' or Rc' represents the Zi - (CH2)m- 0 - group, in which m is defined the same as in claims 1 to 4 i Z is the starting group, reacts with a compound of the general formula in which R3 is defined as in claims 1 to 4, or b) the compound of the following general formula is cyclized, which is eventually formed in the reaction mixture in which Preferably defined as in claims 1 to 4, one of the radicals Rb" or Rc" represents methoxy -, diclobutyloxy -, diclopentyloxy -, dicyclopropylmethoxy -, cyclobutylmethoxy - or diclopentylmethoxy - group and the second of the radicals Rb" or Rc" represents the R3<*>- (CH2)m - 0 - group, in which m is defined the same as in claims 1 to 4 i R3<*>is R* - O - CO - CH2- N - CH2CH2- OH - a group in which the methylene - groups are substituted with one or two methyl - or ethyl - groups, in which R4 represents a hydrogen atom or a C1.4-alkyl group, and if necessary, the protective radical used in the previously described reactions and/or is separated again 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, and especially into its physiologically acceptable salts for pharmaceutical use.