EA005679B1

EA005679B1 - Bicyclic heterocycles, medicaments containing these compounds, their use, and methods for the production thereof

Info

Publication number: EA005679B1
Application number: EA200300219A
Authority: EA
Inventors: Франк Химмельсбах; Эльке Лангкопф; Биргит Юнг; Штефан Блех; Флавио Золька
Original assignee: Бёрингер Ингельхайм Фарма Гмбх Унд Ко. Кг
Priority date: 2000-08-26
Filing date: 2001-08-18
Publication date: 2005-04-28
Also published as: JP2004507529A; SK287747B6; KR100862873B1; EE05269B1; KR20030024914A; AU8769401A; HUP0300819A2; MY126132A; YU14003A; IL154602A0; BR0113519A; BG107559A; CZ302567B6; AU2001287694B2; RS52279B; NO20030870L; WO2002018351A1; DE10042058A1; NO324866B1; JP4834282B2

Abstract

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

Description

The present invention relates to bicyclic heterocycles of the General formula

N

their tautomers, their stereoisomers and their salts, primarily their physiologically acceptable salts with inorganic or organic acids or bases, which have valuable pharmacological properties, primarily inhibitory effect on tyrosine kinase-mediated signaling, their use for the treatment of various diseases, especially tumor diseases , pulmonary diseases and diseases of the pulmonary tract, and the way they are received.

In the above General formula I, the substituents have the following meanings:

TO _but denotes a benzyl or 1-phenylethyl group or substituted by Κι and K residues ₂ phenyl group, with Κ _one represents a hydrogen atom, fluorine, chlorine or bromine, methyl, trifluoromethyl, cyano or ethynyl group, and

TO ₂ represents a hydrogen atom or fluorine, and one of the substituents K _s or to _with denotes k ₃ - (CH ₂ ) _t -O-group, and another of the substituents K _s or R, represents a methoxy, cyclobutyloxy, cyclopentyloxy, cyclopropylmethoxy, tsiklobutilmetoksi-, tsiklopentilmetoksi-, tetrahydrofuran-3-iloksi-, tetrahydropyran-3-iloksi-, tetrahydropyran-4iloksi-, tetragidrofuranilmetoksi- or tetragidropiranilmetoksigruppu, wherein

TO ₃ is an H- (2-oxotetrahydrofuran-4-yl) methylamino or N- (2oxotetrahydrofuran-4-yl) ethylamino group substituted on the methylene groups with one or two methyl or ethyl groups; a K group. ₂ - \ - CH ₂ CH ₂ -O11, where K _four denotes a hydrogen atom or C _1-4 an alkyl group, or is a 2-oxomorpholin-4-yl group substituted by one or two methyl or ethyl groups, and t is 2, 3 or 4, with the exception of the following compounds:

4 - [(3-chloro-4-fluorophenyl) amino] -6-cyclopentyloxy-7- (2 - {^ (2-hydroxy-2-methylprop-1-yl) ^ [(ethoxycarbonyl) methyl] amino} ethoxy) quinazoline,

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

4 - [(3-bromophenyl) amino] -6- [2- (6,6-dimethyl-2-oxomorpholin-4-yl) ethoxy] -7-methoxy-quinazoline and

4 - [(3-bromophenyl) amino] -6- {2- [H- (2-oxotetrahydrofuran-4-yl) ^ - methylamino] ethoxy} -7 methoxyquinazoline.

Preferred compounds of the above general formula I include compounds in which

TO _but denotes a benzyl or 1-phenylethyl group or substituted by residues K _one and K ₂ phenyl group, with K _one represents a hydrogen atom, fluorine, chlorine or bromine, methyl, trifluoromethyl, cyano or ethynyl group, and K ₂ represents a hydrogen atom or fluorine, and one of the substituents K _s or K, denotes K ₃ - (CH ₂ ) _t -O-group, and another of the substituents K _s or R, represents a methoxy, cyclobutyloxy, cyclopentyloxy, cyclopropylmethoxy, tsiklobutilmetoksi-, tsiklopentilmetoksi-, tetrahydrofuran-3-iloksi-, tetrahydropyran-3-iloksi-, tetrahydropyran-4iloksi-, tetragidrofuranilmetoksi- or tetragidropiranilmetoksigruppu, wherein

TO ₃ represents the no. (2-oxotetrahydrofuran-4-yl) methylamino or N - [- (2oxotetrahydrofuran-4-yl) ethylamino group substituted on the methylene groups with one or two methyl or ethyl groups K4-O-CO-CH ₂ - \ - CH ₂ CH ₂ -O11, where denotes a hydrogen atom or _1-4 an alkyl group, or is a 2-oxomorpholin-4-yl group substituted by one or two methyl or ethyl groups, and t is 2, 3 or 4, with the exception of the following compounds:

4 - [(3-chloro-4-fluorophenyl) amino] -6-cyclopentyloxy-7- (2- {No. (2-hydroxy-2-methylprop-1-yl) ^ [(ethoxycarbonyl) methyl] amino} ethoxy) quinazoline,

4 - [(3-bromophenyl) amino] -6- [2- (6,6-dimethyl-2-oxomorpholin-4-yl) ethoxy] -7-methoxy-quinazoline, 4 - [(3-bromophenyl) amino] -6 - {2- | L- (2-oxotetrahydrofuran-4-yl) ^ - methylamino] ethoxy} -7methoxyquinazoline,

4 - [(3-bromophenyl) amino] -6- (2- {No. (2-hydroxy-2-methylprop-1-yl) -N [(ethoxycarbonyl) methyl] amino} ethoxy) -7-methoxyquinazoline,

4 - [(3-bromophenyl) amino] -6- [2- (3-methyl-2-oxomorpholin-4-yl) ethoxy] -7-methoxyquinazoline,

4 - [(3-bromophenyl) amino] -6- [2- (5,5-dimethyl-2-oxomorpholin-4-yl) ethoxy] -7-methoxy-quinazoline,

- 1 005679

4 - [(3-chloro-4-fluorophenyl) amino] -6- [2- (6,6-dimethyl-2-oxomorpholin-4-yl) ethoxy] -7-methoxyquinazoline,

4 - [(3-chloro-4-fluorophenyl) amino] -6- [2- (6,6-dimethyl-2-oxomorpholin-4-yl) ethoxy] -7-cyclobutyloxyquinazoline,

4 - [(3-chloro-4-fluorophenyl) amino] -6- [2- (6,6-dimethyl-2-oxomorpholin-4-yl) ethoxy] -7-cyclopentyloxyquinazoline,

4 - [(3-chloro-4-fluorophenyl) amino] -6- [2- (6,6-dimethyl-2-oxomorpholin-4-yl) ethoxy] -7-cyclopropylmethoxyquinazoline,

4 - [(3-chloro-4-fluorophenyl] amino] -6- [2- (6,6-dimethyl-2-oxomorpholin-4-yl) ethoxy] -7-cyclopentylmethoxyquinazoline,

4 - [(3-chloro-4-fluorophenyl) amino] -6- {2- [L- (2-oxotetrahydrofuran-4-yl) -M-methylamino] ethoxy} -7 methoxyquinazoline,

4 - [(3-chloro-4-fluorophenyl) amino] -6- {2- [L- (2-oxotetrahydrofuran-4-yl) -M-methylamino] ethoxy} -7 cyclopentyloxyquinazoline,

4 - [(3-chloro-4-fluorophenyl) amino] -6- {2- [L- (2-oxotetrahydrofuran-4-yl) -M-methylamino] ethoxy} -7 cyclopentylmethoxyquinazoline,

4 - [(3-chloro-4-fluorophenyl) amino] -6- [3- (6,6-dimethyl-2-oxomorpholin-4-yl) propyloxy] -7-methoxyquinazoline,

4 - [(3-chloro-4-fluorophenyl) amino] -6- [3- (6,6-dimethyl-2-oxomorpholin-4-yl) propyloxy] -7-cyclopentyloxyquinazoline,

4 - [(3-chloro-4-fluorophenyl) amino] -6- [3- (6,6-dimethyl-2-oxomorpholin-4-yl) propyloxy] -7-cyclopentylmethoxyquinazoline, (H) -4 - [( 1-phenylethyl) amino] -6- [3- (6,6-dimethyl-2-oxomorpholin-4-yl) propyloxy] -7-cyclopentyloxyquinazoline,

4 - [(3-chloro-4-fluorophenyl) amino] -7- [2- (6,6-dimethyl-2-oxomorpholin-4-yl) ethoxy] -6-methoxyquinazoline,

4 - [(3-chloro-4-fluorophenyl) amino] -7- [2- (6,6-dimethyl-2-oxomorpholin-4-yl) ethoxy] -6-cyclobutyloxyquinazoline,

4 - [(3-chloro-4-fluorophenyl) amino] -7- [2- (6,6-dimethyl-2-oxomorpholin-4-yl) ethoxy] -6-cyclopentyloxyquinazoline,

4 - [(3-chloro-4-fluorophenyl) amino] -7- [2- (6,6-dimethyl-2-oxomorpholin-4-yl) ethoxy] -6-cyclopropylmethoxyquinazoline,

4 - [(3-chloro-4-fluorophenyl] amino] -7- [2- (6,6-dimethyl-2-oxomorpholin-4-yl) ethoxy] -6-cyclopentylmethoxyquinazoline,

4 - [(3-chloro-4-fluorophenyl) amino] -7- {2- [L- (2-oxotetrahydrofuran-4-yl) -M-methylamino] ethoxy} -6 methoxyquinazoline,

4 - [(3-chloro-4-fluorophenyl) amino] -7- {2- [L- (2-oxotetrahydrofuran-4-yl) -M-methylamino] ethoxy} -6 cyclopentyloxyquinazoline,

4 - [(3-chloro-4-fluorophenyl) amino] -7- {2- [L- (2-oxotetrahydrofuran-4-yl) -M-methylamino] ethoxy} -6cyclopentylmethoxyquinazoline,

4 - [(3-chloro-4-fluorophenyl) amino] -7- [3- (6,6-dimethyl-2-oxomorpholin-4-yl) propyloxy] -6-methoxyquinazoline,

4 - [(3-chloro-4-fluorophenyl) amino] -7- [3- (6,6-dimethyl-2-oxomorpholin-4-yl) propyloxy] -6-cyclopentyloxyquinazoline,

4 - [(3-chloro-4-fluorophenyl) amino] -7- [3- (6,6-dimethyl-2-oxomorpholin-4-yl) propyloxy] -6-cyclopentylmethoxyquinazoline and (H) -4 - [( 1-phenylethyl) amino] -7- [3- (6,6-dimethyl-2-oxomorpholin-4-yl) propyloxy] -6-cyclopentyloxyquinazoline, especially preferred are compounds in which Na represents a 1-phenylethyl group or is substituted by residues H _one and H ₂ phenyl group, while

H _one represents a fluorine, chlorine or bromine atom, a methyl or ethinyl group, and

H ₂ represents a hydrogen atom or fluorine, and one of the substituents K + or H _with is H3 (CH ₂ ) _t -O-group, and another of the substituents K + or H _with denotes a methoxy, cyclobutyloxy, cyclopentyloxy, cyclopropylmethoxy, tsiklobutilmetoksi-, tsiklopentilmetoksi-, tetrahydrofuran-3-iloksi-, tetrahydropyran-3-iloksi-, tetrahydropyran-4-iloksi-, tetragidrofuranilmetoksi- or tetragidropiranilmetoksigruppu, wherein

H ₃ represents N- (2-oxotetrahydrofuran-4-yl) methylamino group, substituted on methylene groups by one or two methyl groups, group I _four -O-CO-CH ₂ -Y-CH ₂ CH ₂ -ON where

H _four denotes C _1-4 an alkyl group or is a 2-oxomorpholin-4-yl group substituted by one or two methyl groups, and t is 2, 3 or 4, with the exception of the following compounds:

- 2 005679

4 - [(3-chloro-4-fluorophenyl) amino] -6-cyclopentyloxy-7- (2- {L- (2-hydroxy-2-methylprop-1-yl) -M [(ethoxycarbonyl) methyl] amino} ethoxy) quinazoline,

4 - [(3-bromophenyl) amino] -6- [2- (6,6-dimethyl-2-oxomorpholin-4-yl) ethoxy] -7-methoxy-quinazoline,

4 - [(3-bromophenyl) amino] -6- {2- [L- (2-oxotetrahydrofuran-4-yl) -M-methylamino] ethoxy} -7 methoxynazoline,

4 - [(3-bromophenyl) amino] -6- (2- {Н- (2-hydroxy-2-methylprop-1 -yl) -Y - [(ethoxycarbonyl) methyl] amino} ethoxy) -7-methoxy-quinazoline

4 - [(3-chloro-4-fluorophenyl) amino] -6- [3- (6,6-dimethyl-2-oxomorpholin-4-yl) propyloxy] -7-cyclopentylmethoxyquinazoline, (K) -4 - [( 1-phenylethyl) amino] -6- [3- (6,6-dimethyl-2-oxomorpholin-4-yl) propyloxy] -7-cyclopentyloxyquinazoline,

4 - [(3-chloro-4-fluorophenyl) amino] -7- [3- (6,6-dimethyl-2-oxomorpholin-4-yl) propyloxy] -6-cyclopentylmethoxyquinazoline and (K) -4 - [( 1-phenylethyl) amino] -7- [3- (6,6-dimethyl-2-oxomorpholin-4-yl) propyloxy] -6-cyclopentyloxyquinazoline, their tautomers, their stereoisomers and their salts.

More preferred compounds of general formula I include compounds in which K _but denotes a 1-phenylethyl group or substituted by residues U and K ₂ phenyl group, while

- 3 005679

TO! represents a fluorine, chlorine or bromine atom, and

TO ₂ represents a hydrogen atom or fluorine, and one of the substituents K _s or to _with denotes k ₃ - (CH ₂ ) _t O-group, and another of the substituents K _s or to _with denotes a methoxy, cyclobutyloxy, cyclopentyloxy, cyclopropylmethoxy, tsiklobutilmetoksi-, tsiklopentilmetoksi-, tetrahydrofuran-3-iloksi-, tetrahydropyran-3-iloksi-, tetrahydropyran-4-iloksi-, tetragidrofuranilmetoksi- or tetragidropiranilmetoksigruppu, wherein

TO ₃ denotes the M- (2-oxotetrahydrofuran-4-yl) methylamino group or a 2-oxomorpholin-4-yl group substituted by one or two methyl groups, and t is the number 2, 3 or 4, with the exception of the following compounds: 4 - [(3- chloro-4-fluorophenyl) amino] -6-cyclopentyloxy-7- [2- (6,6-dimethyl-2-oxomorpholine-4yl) ethoxy] quinazoline,

4 - [(3-bromophenyl) amino] -6- [2- (6,6-dimethyl-2-oxomorpholin-4-yl) ethoxy] -7-methoxy-quinazoline, 4 - [(3-bromophenyl) amino] -6 - {2- [M- (2-oxotetrahydrofuran-4-yl) -Y-methylamino] ethoxy} -7-methoxy-quinazoline,

4 - [(3-bromophenyl) amino] -6- [2- (3-methyl-2-oxomorpholin-4-yl) ethoxy] -7-methoxyquinazoline, 4 - [(3-bromophenyl) amino] -6- [ 2- (5,5-dimethyl-2-oxomorpholin-4-yl) ethoxy] -7-methoxyquinazoline, 4 - [(3-chloro-4-fluorophenyl) amino] -6- [2- (6,6-dimethyl -2-oxomorpholin-4-yl) ethoxy] -7-methoxyquinazoline,

4 - [(3-chloro-4-fluorophenyl) amino] -6- {2- [M- (2-oxotetrahydrofuran-4-yl) -Y-methylamino] ethoxy} -methoxyquinazoline,

4 - [(3-chloro-4-fluorophenyl) amino] -6- {2- [M- (2-oxotetrahydrofuran-4-yl) -Y-methylamino] ethoxy} -7 cyclopentyloxyquinazoline,

4 - [(3-chloro-4-fluorophenyl) amino] -6- {2- [M- (2-oxotetrahydrofuran-4-yl) -Y-methylamino] ethoxy} -7 cyclopentylmethoxyquinazoline,

4 - [(3-chloro-4-fluorophenyl) amino] -7- {2- [M- (2-oxotetrahydrofuran-4-yl) -Y-methylamino] ethoxy} -6 methoxyquinazoline,

4 - [(3-chloro-4-fluorophenyl) amino] -7- {2- [M- (2-oxotetrahydrofuran-4-yl) -Y-methylamino] ethoxy} -6 cyclopentyloxyquinazoline,

4 - [(3-chloro-4-fluorophenyl) amino] -7- {2- | M- (2-oxotetrahydrofuran-4-yl) -Y-methylamino] ethoxy} -6 cyclopentylmethoxyquinazoline,

4 - [(3-chloro-4-fluorophenyl) amino] -7- [3- (6,6-dimethyl-2-oxomorpholin-4-yl) propyloxy] -6-cyclopentylmethoxyquinazoline and

- 4 005679 (K) -4 - [(1-phenylethyl) amino] -7- [3- (6,6-dimethyl-2-oxomorpholin-4-yl) propyloxy] -6-cyclopentyloxyquinazoline, their tautomers, their stereoisomers and their salts.

Particularly preferred compounds of general formula I include compounds in which K _but denotes a 1-phenylethyl, 3-bromophenyl or 3-chloro-4-fluorophenyl group, K _s denotes k ₃ (CH2) _t -O-group, where

I ₃ is a 2-oxomorpholin-4 substituted by one or two methyl groups, and t is 2 or 3, and _with means a methoxy, cyclobutyloxy, cyclopentyloxy, cyclopropylmethoxy, tetrahydrofuran-3-yloxy or tetrahydrofuranmethoxy group, with the exception of the following compounds:

4 - [(3-chloro-4-fluorophenyl) amino] -6- [3- (6,6-dimethyl-2-oxomorpholin-4-yl) propyloxy] -7-cyclopentyloxyquinazoline and (K) -4 - [( 1-phenylethyl) amino] -6- [3- (6,6-dimethyl-2-oxomorpholin-4-yl) propyloxy] -7-cyclopentyloxyquinazoline, their tautomers, their stereoisomers and their salts.

Particularly preferred compounds of general formula I also include compounds in which

TO _but stands for H-chloro-4-fluorophenyl group, K _s denotes a cyclopentyloxy, cyclopropylmethoxy, cyclopentylmethoxy, tetrahydrofuran-3-yloxy or tetrahydrofuranmethoxy group and K _with denotes k ₃ - (CH ₂ ) _t -O-group, where

TO ₃ is a 2-oxomorpholin-4-substituted group substituted by one or two methyl groups, and t is the number 2, with the exception of the following compounds:

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

4 - [(3-chloro-4-fluorophenyl) amino] -7- [2- (6,6-dimethyl-2-oxomorpholin-4-yl) ethoxy] -6-cyclopropylmethoxyquinazoline and

4 - [(3-chloro-4-fluorophenyl) amino] -7- [2- (6,6-dimethyl-2-oxomorpholin-4-yl) ethoxy] -6-cyclopentylmethoxyquinazoline, their tautomers, their stereoisomers and their salts .

As an example of the most preferred compounds should include the following:

(1) 4 - [(3-chloro-4-fluorophenyl) amino] -6-cyclopentylmethoxy-7- [2- (2,2-dimethyl-6-oxomorpholine-4yl) ethoxy] quinazoline, (2) 4- [ (3-chloro-4-fluorophenyl) amino] -6-cyclopentyloxy-7- {2- [M- (2-oxotetrahydrofuran-4-yl) -Ymethylamino] ethoxy} quinazoline, (3) 4 - [(3-chloro -4-fluorophenyl) amino] -6-cyclopropylmethoxy-7- [2- (2,2-dimethyl-6-oxomorpholine-4yl) ethoxy] quinazoline, (4) 4 - [(3-chloro-4-fluorophenyl) amino ] -7-cyclobutyloxy-6- [3- (2,2-dimethyl-6-oxomorpholin-4-yl) propyloxy] quinazoline, (5) 4 - [(3-chloro-4-fluorophenyl) amino] -7- cyclopropylmethoxy-6- [3- (2,2-dimethyl-6-oxomorpholine-4yl) propyloxy] quinazoline, (6) 4 - [(3-chloro-4-fluorophenyl) amino] -6-cyc lopropylmethoxy-7- {2- [N- (2-oxotetrahydrofuran-4-yl) N-methylamino] ethoxy} quinazoline, (7) 4 - [(3-bromophenyl) amino] -6- [2 - (8) -6-methyl-2-oxomorpholin-4-yl) ethoxy] -7-methoxyquinazoline, (8) 4 - [(3-bromophenyl) amino] -6- [2 - ((K) -6-methyl-2- oxomorpholin-4-yl) ethoxy] -7-methoxyquinazoline, (9) 4 - [(3-chloro-4-fluorophenyl) amino] -6- [2 - (K) -6-methyl-2-oxomorpholine-4 -il) ethoxy] -7-methoxyquinazoline,

- 5 005679 (10) 4 - [(3-chloro-4-fluorophenyl) amino] -6- [3 - ((K) -6-methyl-2-oxomorpholin-4-yl) propyloxy] -7-metho- xyquinazoline, (11) 4 - [(K) - (1-phenylethyl) amino] -6- [3 - ((8) -6-methyl-2-oxomorpholin-4-yl) propyloxy] -7-methoxy-quinazoline , (12) 4 - [(K) - (1-phenylethyl) amino] -6- [2 - ((8) -6-methyl-2-oxomorpholin-4-yl) ethoxy] -7-methoxyquinazoline and (13 ) 4 - [(3-chloro-4-fluorophenyl) amino] -6- [2 - ((8) -6-methyl-2-oxomorpholin-4-yl) ethoxy] -7-methoxy-naphtha, their tautomers, their stereoisomers and their salts.

Compounds of general formula I can be prepared, for example, by the following methods. a) In this embodiment, the compound of the general formula

wherein

TO _but has the above meanings, one of the substituents Кь 'or КС denotes a methoxy, cyclobutyloxy, cyclopentyloxy, cyclopropylmethoxy, cyclobutylmethoxy or cyclopentylmethoxy group, and the other of the substituents K _s 'or COP means 21- (CH ₂ ) _t -O-group, where t has the above values and

Zι represents a leaving group, such as a halogen atom or a sulfonyloxy group, for example a chlorine or bromine atom, a methanesulfonyloxy or η-toluenesulfonyloxy group, is reacted with a compound of the formula

N - K ₃ , (Iii) in which K ₃ has the above values.

This reaction is optionally carried out in a solvent or mixture of solvents, for example, in methylene chloride, acetonitrile, dimethylformamide, dimethyl sulfoxide, sulfolane, benzene, toluene, chlorobenzene, toluhydrofuran, benzene / tarahydrofuran or dioxane; while such organic bases can simultaneously serve as a solvent, or in the presence of an inorganic base such as sodium carbonate or potassium carbonate, preferably at a temperature of from -20 to 200 ° C, preferably at a temperature of from 0 to 150 ° C.

b) In this variant, cyclization of a compound of the general formula that is formed under certain conditions is provided

N

wherein

Ka has the above values, one of the substituents Кь or КС 'denotes a methoxy, cyclobutyloxy, cyclopentyloxy, cyclopropylmethoxy, cyclobutylmethoxy or cyclopentylmethoxy group, and the other of the substituents K _s or KS 'means K3' - (CH ₂ ) _t -O-group, where t has the above values and

TO ₃ represents a K4-O-CO-CH group substituted by methylene groups with one or two metal or ethyl groups ₂ -Y-CH ₂ CH ₂ -OH in which K4 represents a hydrogen atom or C1 _-four alkyl group.

This reaction is optionally carried out in a solvent or mixture of solvents, for example, in methylene chloride, acetonitrile, dimethylformamide, dimethyl sulfoxide, sulfolane, benzene, toluene, chlorobenzene, tetrahydrofuran, benzene / tetrahydrofuran or dioxane, preferably in the presence of anhydrous acid, trifluoroethylene, preferably in the presence of anhydrous acid, trifluorohydrofuran, trifluorooxane, teflourax, I, I, I, I, I, I, I, I, I, I, I, I, I, I, I, I, I, I) myself, I, I, I, I, I) will have not already, I, I, I, I) not like this, I, I, I not have been), I, I, I not already have you, but not in a way that you, I, have been one. sulfuric acid, or in the presence of a dehydrating agent, for example in the presence of isobutyl chloroformate, thionyl chloride, trimethylchlorosilane, trichloride yes, phosphorus, phosphorus pentoxide, Ν, Ν'-dicyclohexylcarbodiimide, Ν, Ν'-dicyclohexylcarbodiimide, hydroxysuccinimide or 1 hydroxybenzotriazole, Ν, Ν'-carbonyldiimidazole or triphenylphosphine, a set of 17 17 15 15 17 at a temperature of from -10 to 160 ° C.

- 6 005679

When carrying out the reactions described above, under certain conditions, reactive groups, such as hydroxy, carboxy or imino groups, can be protected for the duration of the reaction with the usual protective groups and can be removed again after the reaction.

As an example of a protective group for a hydroxy group, one can mention a trimethylsilyl, acetyl, benzoyl, methyl, ethyl, tert-butyl, trityl, benzyl or tetrahydropyranyl group; as an example of a protective group for a carboxy group, one can mention trimethylsilyl, methyl, ethyl, tert-butyl, benzyl or a tetrahydropyranyl group, and as an example of a protective group for an amino group, there can be mentioned formyl, acetyl, trifluoroacetyl, ethoxycarbonyl, tert-butoxycarbonyl, benzyl oxycarbonyl, benzyl, methoxybenzyl or 2,4-dimethoxybenzyl group.

If necessary, the subsequent cleavage of the used protecting group is carried out, for example, by hydrolyzing in an aqueous solvent, for example in water, isopropanol / water, acetic acid / water, tetrahydrofuran / water or dioxane / water, in the presence of an acid, such as trifluoroacetic acid, hydrochloric acid or sulfuric acid, or in the presence of an alkaline base, such as sodium hydroxide or potassium hydroxide, or aprotic, for example in the presence of iodotrimethylsilane, at a temperature of from 0 to 120 ° C, preferably at mperature from 10 to 100 ° C.

However, the benzyl, methoxybenzyl or benzyloxycarbonyl group is cleaved, for example, by hydrogenolysis, in particular, using hydrogen in the presence of a catalyst, such as palladium on carbon, in a suitable solvent, such as methanol, ethanol, ethyl acetate or glacial acetic acid acid, optionally with the addition of an acid, such as hydrochloric acid, at a temperature of from 0 to 100 ° C, preferably, however, at close to room temperatures of 20 to 60 ° C, and at a hydrogen pressure of 1 to 7 bar, but preferably from 3 to 5 bar. The 2,4-dimethoxybenzyl group is preferably cleaved, however, in trifluoroacetic acid in the presence of anisole.

The tert-butyl or tert-butyloxycarbonyl group is preferably cleaved by treatment with an acid, such as trifluoroacetic acid or hydrochloric acid, or by treatment with iodotrimethylsilane, optionally with a solvent, such as methylene chloride, dioxane, methanol or diethyl ether.

The trifluoroacetyl group is preferably cleaved off by treatment with an acid, such as hydrochloric acid, optionally in the presence of a solvent, such as acetic acid, at a temperature of from 50 to 120 ° C, or by treatment with caustic soda, optionally in the presence of a solvent, such as tetrahydrofuran, at a temperature of from 0 to 50 ° C.

In addition, the compounds of general formula I can be separated, as mentioned above, into their enantiomers and / or diastereomers. For example, cis / trans mixtures can be separated into their separate cis and trans isomers, and compounds with at least one optically active carbon atom can be divided into their enantiomers.

So, in particular, the obtained cis / trans mixtures can be separated by chromatography into their individual cis and trans isomers, the compounds of general formula I, which are formed as racemates, can be separated by known methods (see L.Shideg B.L. and Е1те1 Е.Ь., Τορίεκ ίη §1 geosjetMgu. t. 6, publishing house \ UPeu 1n1s5s1se (1971) into their optical antipodes, and compounds of general formula I with at least 2 asymmetric carbon atoms can be divided on the basis of their differences physical and chemical properties according to known methods, for example, chromatography and / or fraction ionirovannoy crystallization, their diastereomers which during their formation in racemic form may be separated in the following, as described above, into the enantiomers.

The separation into enantiomers is preferably carried out by column separation on chiral phases, either 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 esters or amides, primarily by interaction with acids and their activated derivatives or alcohols, and separation of the resulting mixture of diastereomeric salts or derivatives, for example, based on differences in their solution Bridges, while free pure antipodes can be released from pure diastereomeric salts or derivatives by exposure to an agent suitable for this purpose. As an example of the most commonly used optically active acids for the above purposes, one can mention Ό- and-forms of tartaric acid, dibenzoyl tartaric acid, di-tolyl tartric acid, malic acid, mandelic acid, camphorsulfonic acid, glutamic acid, aspartic acid or quinic acid . An example of an optically active alcohol is (+) - or (-) - menthol, and as an example of an optically active acyl moiety in amides, you can call the (+) - or (-) - menthyloxycarbonyl moiety.

In addition, the compounds of the formula I obtained can be converted into their salts, primarily into their physiologically acceptable salts suitable for pharmaceutical use, with inorganic or organic acids. Examples of suitable acids include hydrochloric acid, hydrobromic acid, sulfuric acid, methanesulfonic acid, phosphoric acid.

- 7 005679 acid, fumaric acid, succinic acid, lactic acid, citric acid, tartaric acid or maleic acid.

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

The compounds of the general formulas P-PG are used as starting materials, they are known from the literature, or they are obtained by methods known from the literature (see examples 1-KSU).

The compounds of general formula I according to the invention and their physiologically acceptable salts possess, as already mentioned above, valuable pharmacological properties, primarily inhibiting effect on the receptor-mediated epidermal growth factor (ECP-K) signaling, which may be caused, for example, by inhibiting the binding ligands, receptor dimerization, or tyrosine kinase itself. In addition, signaling may also be blocked by components located at a deeper level.

The biological properties of the new compounds were investigated by the method described below.

Inhibition of receptor-mediated ECP-K signaling can be confirmed, for example, on cells that express the human ECP-K receptor, and whose survival and proliferation depends on stimulation by the ECP factor, respectively, on the TSR-α factor. For this purpose, an interleukin-3 (GE-3 dependent) cell line of murine origin was used, which was genetically modified to express the functional human ECP-K receptor. Therefore, the proliferation of cells designated as P / B-HEXC can be stimulated either by using mouse 1B-3 or by using the ECP factor (see Kyjep T. et al., EMBO B 7, pp. 2749-2756 (1988), also Yegs GN. et al., 8c1epse 239, pp. 628-631 (1988)).

The starting material for cells R / B-NEXC served cell line RES-P _one , the receipt of which is described in Eehtier TM and others in 1. Exp. May 152, ss. 1036-1047 (1980). In another embodiment, other growth factor dependent cells can also be used (see, for example, Pilegs 1. N. et al., Cluster 239, pp. 628-631 (1988), 8Bioua N. et al., Ce11 70, pp 57-67 (1992), as well as Alexander Aig., Et al., EMBO B 10, pp. 3683-3691 (1991)). For the expression of the human receptor cDNA, ECP-K (see A. A. et al., No. 3098, pp. 418-425 (1984)), the retroviruses described in νοη described in Kiép T. et al., EMBO, 1 were used by recombination. 7, ss. 27492756 (1988), with the difference that for the expression of the ECP-K receptor cDNA, the ров8Ν retroviral vector was used (see M111E AE et al., VyuTsyshciez 7, pp. 980-990 (1989)), and as a package cells of the CP + E86 line were served (see Magkosh12. and others, B U1go1. 62, pp. 1120-1124 (1988)).

The experiment was carried out as follows.

Cells R / B-NEXs were cultured at 37 ° C in an atmosphere with 5% CO ₂ in the CRM1 / 1640 environment (firm Βίο Ayyakeg), supplemented with 10% fetal calf serum (FTS, firm Voeigtzeg Mappietz), 2 mM glutamine (firm ViAyaykeg), standard antibiotics and 20 ng / ml of human factor ECP (firm Rgotaeda). To study the inhibitory activity of the compounds of the invention, the cells were triply cultured in the medium of the above composition (200 μl) in 96-well plates at a rate of 1.5-10 cells per well, while cell proliferation was stimulated by either ECP factor (20 ng / ml), or murine 1B-3. The source of 1B-3 was the supernatants of the culture media in which cells of the X63 / 0 t1B-3 line were cultured (see Kagaziuat N. et al., Eig. B. 1 ttipo1. 18, pp. 97-104 (1988)). The compounds according to the invention were dissolved in 100% dimethyl sulfoxide (DMSO) and added to the cultures at various dilutions, the maximum concentration of DMSO being 1%. Cultures were incubated for 48 hours at 37 ° C.

The inhibitory activity of the compounds according to the invention was determined by measuring the relative cell number in units of optical density (OD) using a non-radioactive cell proliferation assay for Ce11 Tceg 96 A () „eois Ms-CayuasIx'e Ce11 Progaugayyop Azzaw (firm Rgotheda) for this purpose. The relative number of cells was calculated as a percentage relative to the control (cells R / B-HEX without an inhibitor) and determined the concentration of the active substance at which cell proliferation is inhibited by 50% (1C ₅₀ ). The following results were obtained:

Compound Inhibition of ESR-dependent proliferation (from example №) 1C ₅₀ [nM] one 59 1 (1) 29 1 (2) 29 2 (1) 36

- 8 005679

From the above results, it follows that the compounds of the general formula I proposed in the invention inhibit tyrosine kinase-mediated signaling, as illustrated by the example of human ECE receptor, and therefore suitable for the treatment of pathophysiological processes caused by tyrosine kinase hyperfunction. Examples of such processes include the formation of benign and malignant tumors, especially tumors of epithelial and neuroepithelial origin, metastasis, as well as abnormal proliferation of vascular endothelial cells (neoangiogenesis).

The compounds according to the invention are also suitable for the prophylaxis and treatment of diseases of the respiratory tract and lungs associated with excessive or altered mucus formation caused by stimulation of tyrosine kinases, for example, for inflammatory diseases of the respiratory tract, such as chronic bronchitis, chronic obstructive bronchitis, asthma, bronchiectasis, allergic or non-allergic rhinitis or sinusitis, cystic fibrosis, αΐ-antitrypsin deficiency or coughing, emphysema, pulmonary fibrosis and increased reactivity respiratory tract.

The compounds according to the invention are further suitable for the treatment of diseases of the gastrointestinal tract, as well as the bile ducts and gallbladder, associated with impaired tyrosine kinase activity, as is the case, for example, in chronic inflammatory changes, such as cholecystitis, Crohn's disease, ulcerative colitis and ulcers in the gastrointestinal tract, or as is the case for diseases of the gastrointestinal tract associated with hypersecretion, such as Menetria’s disease, adenoma of the secretory glands and protein loss syndrome, and in addition for the treatment of nasal polyps and gastrointestinal polyps of various origins, such as villous or adenomatous colon polyps, as well as polyps for congenital familial intestinal polyposis, intestinal polyps for Gardner syndrome, polyps throughout the gastrointestinal tract for syndrome Peitz-Jeghers, pseudopolyps, juvenile polyps, cystic colitis (Coli 18 suits rtoeiib) and cystic intestinal pneumatosis.

The compounds of general formula I and their physiologically acceptable salts can also be used for the treatment of kidney diseases, especially for cystic changes, such as, for example, in cystic kidneys, for the treatment of kidney cysts, which can be idiopathic or observed in various syndromes, for example, in tuberous sclerosis, in Hippel-Lindau disease, in nephronophthiasis and spongy (spongy) kidney, as well as other diseases caused by aberrant tyrosine kinase function, such as, for example, the epidermal hyperproliferator ation (psoriasis), inflammatory processes, diseases of the immune system, hyperproliferation of hematopoietic cells, etc.

Owing to their biological properties, the compounds according to the invention can be used individually or in combination with other pharmacologically active compounds, for example, for the therapeutic treatment of tumors with monotherapy or in combination with other anticancer therapeutic agents, for example in combination with topoisomerase inhibitors (for example etoposide), with antimitotic agents (for example, vinblastine), with nucleic acid-interacting compounds (for example, cis-platinum, cyclophosphamide , adriamycin), with hormone antagonists (for example, tamoxifen), with inhibitors of metabolic processes (for example, 5Ei, etc.), with cytokines (for example, interferons), with antibodies, etc. For the treatment of diseases of the respiratory tract, these compounds can be used individually or in combination with other drugs intended for the treatment of the respiratory tract, such as, for example, having expectorant, bronchodilator and / or inflammatory-suppressant action of substances. For the treatment of diseases in the gastrointestinal tract, these compounds can also be administered individually or in combination with substances that affect peristalsis or secretion or suppress inflammatory processes. In such combinations, the active substances can be administered either simultaneously or sequentially.

The compounds according to the invention, individually or in combination with other active ingredients, can be administered intravenously, subcutaneously, intramuscularly, rectally, intraperitoneally, nasally, by inhalation or percutaneously or orally, and aerosol preparations are suitable for inhalation.

For pharmaceutical use, the compounds according to the invention are administered, as a rule, to warm-blooded vertebrate animals, especially to humans, in doses of from 0.01 to 100 mg / kg body weight, preferably from 0, to ΐ5 mg / kg. For the preparation of drugs such compounds are processed together with one or more conventional inert carriers and / or diluents, such as corn starch, lactose, cane sugar, microcrystalline cellulose, magnesium stearate, polyvinylpyrrolidone, citric acid, tartaric acid, water, water / ethanol, water / glycerin, water / sorbitol, water / polyethylene glycol, propylene glycol, stearyl alcohol, carboxymethylcellulose, or fat-containing substances, such as hardened minutes fat or suitable mixtures thereof in conventional galenic preparations such as tablets, dragees, capsules, powders, suspensions, solutions, sprays or suppositories.

Below the invention is illustrated by examples, not limiting its scope.

Getting the original connections

- 9 005679

Example 1. 4 - [(3-chloro-4-fluorophenyl) amino] -6-cyclopentylmethoxy-7- (2-bromoethoxy) quinazoline

4.84 g are added to 3.50 g of 4 - [(3-chloro-4-fluorophenyl) amino] -6-cyclopentylmethoxy-7-hydroxyquinazoline and 6.89 ml of 1,2-dibromoethane in 40 ml of д, Ν-dimethylformamide potassium carbonate. The reaction mixture is stirred for 1.5 hours under nitrogen at 80 ° C. After cooling to room temperature, the reaction mixture is filtered and the filtrate is concentrated in vacuo. The oily brown residue is cooled in an ice bath and triturated with a small amount of methanol, a yellowish solid crystallizes out. The precipitate is suction filtered, then washed with cold methanol and dried in a vacuum desiccator.

Output: 2.60 g (58% of theory),

P (value: 0.82 (silica gel, methylene chloride / methanol 9: 1), mass spectrum (E81 ⁺ ): t / ζ = 494, 496, 498 [M + H] ⁺ .

Analogously to example 1, the following compounds are obtained:

(1) 4 - [(3-chloro-4-fluorophenyl) amino] -6-cyclopropylmethoxy-7- (2-bromoethoxy) quinazoline (the reaction is carried out in acetonitrile as a solvent):

^ (- value: 0.72 (silica gel, methylene chloride / methanol / concentrated aqueous ammonia in the ratio 90: 10: 0.1), mass spectrum (E8G): t / ζ = 464, 466, 468 [M – H] ^- ;

(2) 4 - [(3-chloro-4-fluorophenyl) amino] -6-cyclopentyloxy-7- (2-bromoethoxy) quinazoline:

Purpose: 0.65 (silica gel, methylene chloride / methanol / concentrated aqueous ammonia in the ratio of 90: 10: 0.1), mass spectrum (Е8Г): t / ζ = 478, 480, 482 [M-H] ^- ;

(3) 4 - [(3-chloro-4-fluorophenyl) amino] -7-cyclobutyloxy-6- (3-bromopropyloxy) quinazoline (the reaction is carried out in acetonitrile as a solvent):

^ (- value: 0.62 (silica gel, methylene chloride / methanol in the ratio 9: 1), mass spectrum (E8G) ^: t / ζ = 478, 480, 482 [M – H] ^- ;

(4) 4 - [(3-chloro-4-fluorophenyl) amino] -7-cyclopropylmethoxy-6- (3-bromopropyloxy) quinazoline (the reaction is carried out in acetonitrile as a solvent):

H (-value: 0.74 (silica gel, methylene chloride / methanol in the ratio 9: 1) mass spectrum (E8G): t / ζ = 478, 480, 482 [M – H] ^- ;

(5) 4 - [(3-bromophenyl) amino] -6- (2-bromoethoxy) -7-methoxy-quinazoline: melting point: 244 ° C, mass spectrum (E81 ⁺ ): t / ζ = 452, 454, 456 [M + H] ⁺ ;

(6) 4 - [(H) - (1-Phenylethyl) amino] -6- (3-bromopropyloxy) -7-methoxy-quinazoline (the reaction is carried out in the presence of potassium tert-butylate as base):

Purpose: 0.60 (silica gel, ethyl acetate / methanol in a ratio of 9: 1);

(7) 4 - [(H) - (1-phenylethyl) amino] -6- (2-bromoethoxy) -7-methoxy-quinazoline (the reaction is carried out in the presence of potassium tert-butylate as base):

melting point: 255 ° С, mass spectrum (Е81 ⁺ ): t / ζ = 402, 404 [M + H] ⁺ ;

(8) 4 - [(3-chloro-4-fluorophenyl) amino] -6- (3-hydroxypropyloxy) -7-cyclobutyloxyquinazoline:

H- value: 0.50 (silica gel, methylene chloride / methanol in the ratio 90:10), mass spectrum (Е81 ⁺ ): t / ζ = 418, 420 [M + H] ⁺ ;

(9) 4 - [(3-chloro-4-fluorophenyl) amino] -6- (3-hydroxypropyloxy) -7-cyclopropylmethoxyquinazoline:

Purpose: 0.21 (silica gel, methylene chloride / methanol 95: 5), mass spectrum (E81 ⁺ ): t / ζ = 418, 420 [M + H] ⁺ ;

(10) 4 - [(3-chloro-4-fluorophenyl) amino] -6- (2-bromoethoxy) -7-cyclopentyloxyquinazoline:

Purpose: 0.67 (silica gel, methylene chloride / methanol 90:10), mass spectrum (E81 ⁺ ): t / ζ = 480, 482, 484 [M + H] ⁺ ;

(11) 4 - [(3-chloro-4-fluorophenyl) amino] -6- (2-bromoethoxy) -7-cyclopropylmethoxyquinazoline:

H (value: 0.68 (silica gel, methylene chloride / methanol in the ratio 90:10), mass spectrum (E81 ⁺ ): t / ζ = 466, 468, 470 [M + H] ⁺ ;

(12) 4 - [(3-chloro-4-fluorophenyl) amino] -6-cyclopropylmethoxy-7- (3-hydroxypropyloxy) quinazoline:

Purpose: 0.53 (silica gel, methylene chloride / methanol in the ratio of 90:10), mass spectrum (E81 ⁺ ): t / ζ = 418, 420 [M + H] ⁺ ;

(13) 4 - [(3-chloro-4-fluorophenyl) amino] -6- (4-hydroxybutyloxy) -7-cyclopentyloxy-quinazoline:

Purpose: 0.46 (silica gel, ethyl acetate);

(14) 4 - [(3-chloro-4-fluorophenyl) amino] -6- (2-bromoethoxy) -7 - ((H) -tetrahydrofuran-3-yloxy) quinazoline: Use: 0.37 (silica gel, methylene chloride / methanol in a ratio of 9: 1), mass spectrum (E8G): t / ζ = 480, 482, 484 [M – H] ^- ;

(15) 4 - [(3-chloro-4-fluorophenyl) amino] -6- (2-bromoethoxy) -7 - [(H) - (tetrahydrofuran-2-yl) methoxy] quinazoline:

mass spectrum (E8G): t / ζ = 494, 496, 498 [M – H] ^- ;

- 10 005679 (16) 4 - [(3-chloro-4-fluorophenyl) amino] -7- (2-bromoethoxy) -6 - [(8) - (tetrahydrofuran-2-yl) methoxy] quinazoline:

mass spectrum (E8T): t / ζ = 494, 496, 498 [M – H] ^- .

Example 2. 4 - [(3-chloro-4-fluorophenyl) amino] -6-cyclopentylmethoxy-7-hydroxyquinazoline.

4.99 g of 4 - [(3-chloro-4-fluorophenyl) amino] -6-cyclopentylmethoxy-7-methylcarbonyloxyquinazoline is suspended in 80 ml of methanol and mixed with 1.80 ml of concentrated aqueous ammonia solution. The reaction mixture is stirred overnight at room temperature. For processing, the reaction mixture is diluted with 500 ml of methylene chloride, washed with water and saturated sodium chloride solution, dried over magnesium sulfate, and concentrated. In this way, 4.30 g of a brownish solid is obtained. The crude product is stirred with t-butyl methyl ether, suction filtered, then washed with a small amount of tert-butyl methyl ether and dried in vacuo at room temperature.

Output: 3.59 g (80% of theory),

TO _g value: 0.48 (silica gel, methylene chloride / methanol / concentrated aqueous ammonia solution in a ratio of 90: 10: 0.1), mass spectrum (Е§1 ⁺ ): t / ζ = 388, 340 [M + H] ⁺ .

Analogously to example 2, the following compounds are obtained:

(1) 4 - [(3-chloro-4-fluorophenyl) amino] -6-cyclopropylmethoxy-7-hydroxy-quinazoline:

Yar -value: 0.56 (silica gel, methylene chloride / methanol in the ratio 9: 1), mass spectrum (Е8Т): t / ζ = 358, 360 [M – H] ^- ;

(2) 4 - [(3-chloro-4-fluorophenyl) amino] -6-cyclopentyloxy-7-hydroxy-quinazoline:

Kg value: 0.53 (silica gel, methylene chloride / methanol / concentrated aqueous ammonia solution in a ratio of 90: 10: 0.1), mass spectrum (Е§1 ⁺ ): t / ζ = 374, 376 [M + H] ⁺ ;

(3) 6-benzyloxy-4 - [(3-chloro-4-fluorophenyl) amino] -7-hydroxyquinazoline:

K-value: 0.54 (silica gel, methylene chloride / methanol / concentrated aqueous ammonia solution in a ratio of 90: 10: 0.1), mass spectrum (Е§1 ⁺ ): t / ζ = 396, 398 [M + H] ⁺ ;

(4) 4 - [(3-bromophenyl) amino] -6-hydroxy-7-methoxy-quinazoline (the reaction is carried out in the presence of sodium hydroxide in ethanol as a solvent):

K-value: 0.23 (silica gel, ethyl acetate), mass spectrum (E§1 ⁺ ): t / ζ = 346, 348 [M + H] ⁺ ;

(5) 4 - [(3-chloro-4-fluorophenyl) amino] -7-hydroxy-6 - ((8) -tetrahydrofuran-3-yloxy) quinazoline:

K-value: 0.57 (silica gel, methylene chloride / methanol in the ratio 9: 1), mass spectrum (Е§1 ⁺ ): t / ζ = 376, 378 [M + H] ⁺ ;

(6) 4 - [(3-chloro-4-fluorophenyl) amino] -7-hydroxy-6 - [(8) - (tetrahydrofuran-2-yl) methoxy] quinazoline: K-value: 0.42 (silica gel, methylene chloride / methanol (9: 1).

Example 3. 4 - [(3-chloro-4-fluorophenyl) amino] -6-cyclopentylmethoxy-7-methylcarbonyloxyquinazoline

4.03 g of 4-chloro-6-cyclopentylmethoxy-7-methylcarbonyloxyquinazoline is suspended in 70 ml of isopropanol and mixed with 1.95 g of 3-chloro-4-fluoroaniline. The reaction mixture is refluxed for two hours under a nitrogen atmosphere. After cooling to room temperature, the resulting bright precipitate is suction filtered, then washed with a small amount of isopropanol and dried in air.

Yield: 4.99 g (92% of theory),

K-value: 0.80 (silica gel, methylene chloride / methanol / concentrated aqueous ammonia solution in a ratio of 90: 10: 0.1), mass spectrum (Е§1 ⁺ ): t / ζ = 430, 432 [M + H] ⁺ .

Analogously to example III, the following compounds are obtained:

(1) 4 - [(3-chloro-4-fluorophenyl) amino] -6-cyclopropylmethoxy-7-methylcarbonyloxyquinazoline:

K-value: 0.86 (silica gel, methylene chloride / methanol 9: 1), mass spectrum (Е§1 ⁺ ): t / ζ = 402, 404 [M + H] ⁺ ;

(2) 4 - [(3-chloro-4-fluorophenyl) amino] -6-cyclopentyloxy-7-methylcarbonyloxyquinazoline:

K-value: 0.73 (silica gel, methylene chloride / methanol / concentrated aqueous ammonia solution in a ratio of 90: 10: 0.1), mass spectrum (Е§1 ⁺ ): t / ζ = 416, 418 [M + H] ⁺ ;

(3) 6-benzyloxy-4 - [(3-chloro-4-fluorophenyl) amino] -7-methylcarbonyloxyquinazoline:

K-value: 0.76 (silica gel, methylene chloride / methanol / concentrated aqueous ammonia solution in a ratio of 90: 10: 0.1), mass spectrum (Е§1 ⁺ ): t / ζ = 438, 440 [M + H] ⁺ ;

(4) 4 - [(3-bromophenyl) amino] -6-methylcarbonyloxy-7-methoxyquinazoline:

K-value: 0.50 (silica gel, ethyl acetate), mass spectrum (E§1 ⁺ ): t / ζ = 388, 390 [M + H] ⁺ ;

- 11 005679 (5) 4 - [(B) - (1-phenylethyl) amino] -6-hydroxy-7-methoxy-quinazoline (the acetoxy protecting group is cleaved under the reaction conditions):

^ (- value: 0.46 (silica gel, ethyl acetate), mass spectrum (E§1 ⁺ ): t / ζ = 296 [M + H] ⁺ ;

(6) 6-benzyloxy-4 - [(3-chloro-4-fluorophenyl) amino] -7-cyclopentyloxyquinazoline (pyridine is added as an auxiliary base):

B-value: 0.51 (silica gel, methylene chloride / methanol in the ratio 95: 5), mass spectrum (Е§1 ⁺ ): t / ζ = 464, 466 [M + H] ⁺ ;

(7) 4 - [(3-chloro-4-fluorophenyl) amino] -7-methylcarbonyloxy-6 - ((8) -tetrahydrofuran-3-yloxy) quinazoline:

B-value: 0.67 (silica gel, methylene chloride / methanol in the ratio 9: 1), mass spectrum (E8G): t / ζ = 416, 418 [M – H] ^- ;

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

melting point: 274-276 ° C, mass spectrum (E 1 1 ⁺ ): t / ζ = 432, 434 [M + H] ⁺ .

Example 4. 4-chloro-6-cyclopentylmethoxy-7-methylcarbonyloxyquinazoline

3.80 g of 4-hydroxy-6-cyclopentylmethoxy-7-methylcarbonyloxyquinazoline is suspended in 90 ml of thionyl chloride and heated to boiling under a nitrogen atmosphere. After adding four drops of Ν, Ν dimethylformamide, the reaction mixture is refluxed for another two hours. After cooling to room temperature, the excess thionyl chloride is distilled off in a vacuum created by a water-jet pump. The brown residue is stirred with 30 ml of toluene. After distilling off the solvent, 4.30 g of a gray-brown solid remains, which is used without further purification in the subsequent reaction.

B - value: 0.89 (silica gel, methylene chloride / methanol / concentrated aqueous ammonia in the ratio 90: 10: 0.1).

Analogously to example 4 receive the following compounds:

(1) 4-chloro-6-cyclopropylmethoxy-7-methylcarbonyloxyquinazoline:

B - value: 0.84 (silica gel, methylene chloride / methanol in the ratio 9: 1);

(2) 4-chloro-6-cyclopentyloxy-7-methylcarbonyloxyquinazoline:

B - value: 0,69 (silica gel, methylene chloride / methanol / concentrated aqueous ammonia in the ratio of 90: 10: 0.1);

(3) 6-benzyloxy-4-chloro-7-methylcarbonyloxyquinazoline:

B - value: 0.77 (silica gel, methylene chloride / methanol / concentrated aqueous ammonia in the ratio 90: 10: 0.1);

(4) 6-benzyloxy-4-chloro-7-cyclopentyloxyquinazoline:

B - value: 0.91 (silica gel, methylene chloride / methanol in the ratio 9: 1);

(5) 4-chloro-7-methylcarbonyloxy-6 - ((8) -tetrahydrofuran-3-yloxy) quinazoline:

B - value: 0.83 (silica gel, ethyl acetate / methanol in the ratio 9: 1);

(6) 4-chloro-7-methylcarbonyloxy-6 - [(8) - (tetrahydrofuran-2-yl) methoxy] quinazoline:

B - value: 0.48 (silica gel, cyclohexane / ethyl acetate in the ratio 1: 1).

Example 5. 4-hydroxy-6-cyclopentylmethoxy-7-methylcarbonyloxyquinazoline.

4.30 g of 4,7-dihydroxy-6-cyclopentylmethoxyquinazoline in 100 ml of pyridine is heated under nitrogen to 80 ° C. Next, 1.80 ml of acetic anhydride is added to the dark brown suspension. The reaction mixture is stirred for three hours at 80 ° C, and a solution is completely formed. After cooling to room temperature, the reaction mixture is poured onto about 800 ml of an ice-water mixture. The precipitate formed is suction filtered and washed thoroughly with water. The resulting light gray solid is dried in a vacuum desiccator.

Yield: 3.82 g (77% of theory),

B-value: 0.49 (silica gel, methylene chloride / methanol in the ratio 9: 1), mass spectrum (E8G): t / ζ = 301 [M – H] ^- .

Analogously to example V, the following compounds are obtained:

(1) 4-hydroxy-6-cyclopropylmethoxy-7-methylcarbonyloxyquinazoline:

B-value: 0.53 (silica gel, methylene chloride / methanol in the ratio 9: 1), mass spectrum (E8G): t / ζ = 273 [M – H] ^- ;

(2) 4-hydroxy-6-cyclopentyloxy-7-methylcarbonyloxyquinazoline, melting point: 209-212 ° C, mass spectrum (E8G): t / ζ = 287 [M-H] ^- ;

(3) 6-benzyloxy-4-hydroxy-7-methylcarbonyloxyquinazoline:

B - value: 0.48 (silica gel, methylene chloride / methanol / concentrated aqueous ammonia solution in a ratio of 90: 10: 0.1), mass spectrum (E8G): t / ζ = 309 [M – H] ^- ;

- 12 005679 (4) 4-hydroxy-7-methylcarbonyloxy-6 - ((8) -tetrahydrofuran-3-yloxy) quinazoline:

Yu - value: 0.62 (reversed-phase TLC plate (E. Megsk), acetonitrile / water / trifluoroacetic acid in the ratio 50: 50: 1), mass spectrum (E81 ⁺ ): t / ζ = 291 [M + H] ⁺ ;

(5) 4-hydroxy-7-methylcarbonyloxy-6 - [(8) - (tetrahydrofuran-2-yl) methoxy] quinazoline:

^ (- value: 0.50 (silica gel, methylene chloride / methanol in the ratio 9: 1), mass spectrum (Е81 ⁺ ): t / ζ = 305 [M + H] ⁺ .

Example 6. 4,7-dihydroxy-6-cyclopentylmethoxyquinazoline.

5.76 g of 2-amino-5-cyclopentylmethoxy-4-hydroxybenzoic acid and 6.52 g of formamidine acetate in 140 ml of ethanol are heated under reflux for about three hours. For processing, the reaction mixture is concentrated to a volume of 100 ml and mixed with 300 ml of a mixture of ice-water and a gray precipitate is formed. This precipitate is suction filtered, washed with water and dried in a vacuum desiccator.

Yield: 4.57 g (77% of theory),

AT _£ - value: 0.25 (silica gel, methylene chloride / methanol in the ratio 95: 5), mass spectrum (Е8Г): t / ζ = 259 [M – H] ^- ;

Analogously to example 6 receive the following compounds:

(1) 4,7-dihydroxy-6-cyclopropylmethoxyquinazoline:

- value: 0.45 (silica gel, methylene chloride / methanol / concentrated aqueous ammonia solution in a ratio of 90: 10: 0.1), mass spectrum (Е8Г): t / ζ = 231 [M-H] ^- ;

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

Yu - value: 0.42 (silica gel, methylene chloride / methanol / concentrated aqueous ammonia solution in a ratio of 90: 10: 0.1), mass spectrum (Е1): t / ζ = 246 [M];

(3) 6-benzyloxy-4,7-dihydroxyquinazoline,

Yu - value: 0.44 (silica gel, methylene chloride / methanol / concentrated aqueous ammonia solution in a ratio of 90: 10: 0.1), mass spectrum (E8G): t / ζ = 267 [M – H] ^- ;

(4) 6-benzyloxy-7-cyclopentyloxy-4-hydroxyquinazoline:

melting point: 221-223 ° C, mass spectrum (E81): t / ζ = 337 [M + H];

(5) 4,7-dihydroxy-6 - ((8) -tetrahydrofuran-3-yloxy) quinazoline:

Yu - value: 0.69 (finished plate for reverse phase TLC (E. Megsk), acetonitrile / water / trifluoroacetic acid in the ratio 50: 50: 1), mass spectrum (Е8Г): t / ζ = 247 [ Mn] ^- ;

(6) 4,7-dihydroxy-6 - [(8) - (tetrahydrofuran-2-yl) methoxy] quinazoline: U-value: 0.56 (silica gel, methylene chloride / methanol in a ratio of 9: 1), mass spectrum (E8G): t / ζ = 261 [M – H] ^- .

Example 7. 2-Amino-5-cyclopentylmethoxy-4-hydroxybenzoic acid

6.50 g of 5-cyclopentylmethoxy-4-hydroxy-2-nitrobenzoic acid is dissolved in 130 ml of methanol, mixed with 2.00 g of Raney nickel and hydrogenated at room temperature under hydrogen pressure of 50 psi for about three hours absorption of the calculated amount of hydrogen. After that, the catalyst is filtered off and washed with hot methanol. The filtrate is concentrated in vacuo. The result is a brownish solid, which is used without further purification in the subsequent reaction.

Output: 5.79 g (100% of theory),

S-value: 0.67 (silica gel, methylene chloride / methanol 9: 1), mass spectrum (E8G): t / ζ = 250 [M – H] ^- .

Analogously to example 7 receive the following compounds:

(1) 2-amino-5-cyclopropylmethoxy-4-hydroxybenzoic acid:

U-value: 0.51 (silica gel, methylene chloride / methanol / concentrated aqueous ammonia solution in a ratio of 90: 10: 0.1), mass spectrum (E8G): t / ζ = 222 [M-H] ^- ;

(2) 2-amino-5-cyclopentyloxy-4-hydroxybenzoic acid:

U-value: 0.38 (silica gel, methylene chloride / methanol / concentrated aqueous ammonia solution in a ratio of 90: 10: 0.1), mass spectrum (E81 ⁺ ): t / ζ = 238 [M + H] ⁺ ;

(3) 2-amino-5-benzyloxy-4-hydroxybenzoic acid:

U-value: 0.52 (silica gel, methylene chloride / methanol / concentrated aqueous ammonia solution in a ratio of 90: 10: 0.1), mass spectrum (E8G): t / ζ = 258 [M-H] ^- ;

- 13 005679 ratio of acid (4) cyclopentyl ester of 2-amino-5-benzyloxy-4-cyclopentyloxybenzoic acid (the reaction is carried out in a mixture of methanol and tetrahydrofuran in a ratio of 1: 1):

^ {- value: 0.84 (silica gel, ethyl acetate / cyclohexane in the ratio 1: 1), mass spectrum (E8G): t / ζ = 396 [M + H] ⁺ ;

(5) 2-amino-4-hydroxy-5 - ((8) -tetrahydrofuran-3-yloxy) benzoic acid:

K ^ -value: 0,70 (reversed phase TLC plate (E. Megsk), acetonitrile / water / trifluoroacetic acid in the ratio 50: 50: 1), mass spectrum (E8G): t / ζ = 238 [Mn] ^- ;

(6) 2-amino-4-hydroxy-5 - [(8) - (tetrahydrofuran-2-yl) methoxy] benzoic acid:

K-value: 0.59 (reversed-phase TLC finished plate (E. Megsk), acetonitrile / water / trifluoroacetic acid in a ratio of 50: 50: 1), mass spectrum (Е8Ц: t / ζ = 252 [M -H] ^- .

Example 8. 5-Cyclopentylmethoxy-4-hydroxy-2-nitrobenzoic acid.

15.37 g of 4,5-metzlendzox-2-nctrobenzoic acid and 51.84 ml of cyclopenzylmethanol are dissolved in 100 ml of dimethyl sulfoxide and cooled under nitrogen in an ice bath. 3.90 g of sodium are then added in portions. The reaction mixture is stirred for 30 minutes while cooling in an ice bath, then briefly heated to 35-40 ° C and then stirred for another three hours while cooling in an ice bath. The ice bath is then removed and the reaction mixture is stirred overnight at room temperature. The dark brown reaction solution is poured into about 800 ml of acetone, and a dark brown precipitate forms. This precipitate is suction filtered, washed with acetone, dissolved in 300-400 ml of water and the pH is adjusted to about 2 by adding 60 ml of 2N. of hydrochloric acid. The aqueous solution is extracted several times with methylene chloride. The combined extracts are washed with a saturated solution of sodium chloride, dried over sodium sulfate and concentrated. The dark brown oily residue on the bottom of the flask is dissolved in 800 ml of methylene chloride and purified through silica gel cap using methylene chloride / methanol (9: 1 ratio). In this way, a brown oil is obtained which is crystallized by stirring with water while cooling in an ice bath. The brownish precipitate formed is suction filtered, washed with a small amount of water and dried in a vacuum desiccator.

Yield: 9.55 g (47% of theory),

-Value: 0.67 (silica gel, toluene / dioxane / ethanol / ice acetic 90: 10: 10: 6), mass spectrum (E8G): t / ζ = 280 [M – H] ^- .

Analogously to example 8 receive the following compounds:

(1) 5-cyclopropylmethoxy-4-hydroxy-2-nitrobenzoic acid:

Purpose: 0.61 (silica gel, toluene / dioxane / ethanol / ice acetic 90: 10: 10: 6), mass spectrum (Е8Г): t / ζ = 252 [M-H] ^- ;

(2) 5-cyclopentyloxy-4-hydroxy-2-nitrobenzoic acid:

K-value: 0.62 (silica gel, toluene / dioxane / ethanol / glacial acetic 90: 10: 10: 6), mass spectrum (E8G): t / ζ = 266 [M-H] ^- ;

(3) 5-benzyloxy-4-hydroxy-2-nitrobenzoic acid: melting point: 176-178 ° C, mass spectrum (E8G): t / = 288 [M-H] ^- ;

(4) 4-hydroxy-2-nitro-5 - ((8) -tetrahydrofuran-3-yloxy) benzoic acid:

K-value: 0.58 (ready-made plate for TLC with reversed phase (company E. Megsk), acetonitrile / water / trifluoroacetic acid in the ratio 50: 50: 1), mass spectrum (Е8Г): t / ζ = 268 [ Mn] ^- ;

(5) 4-hydroxy-2-nitro-5 - [(8) - (tetrahydrofuran-2-yl) methoxy] benzoic acid:

K-value: 0.53 (ready-made plate for TLC with reversed phase (company E. Megsk), acetonitrile / water / trifluoroacetic acid in the ratio 50: 50: 1), mass spectrum (Е8Г): t / ζ = 282 [ Mn] ^- .

Example 9. (2-Hydroxy-2-methylpropylamino) acetic acid ethyl ester.

To 50.00 g of glycine ethyl ester hydrochloride in 100 ml of a saturated solution of potassium carbonate, 100.00 g of sodium carbonate are added with cooling. The resulting mass is extracted several times with diethyl ether, a total of about 600 ml. The combined ether extracts are dried over sodium sulfate and concentrated to dryness. As a result, 28.60 g of glycine ethyl ester remains. This product is mixed with 26.00 ml of isobutylene oxide and 40 ml of absolute ethanol, then heated in a high-pressure vessel Rota to 90 ° C and maintained at this temperature for six hours. After cooling to room temperature, the reaction mixture is concentrated, resulting in a liquid oil as a residue.

Output: 45.80 g (73% of theory), acid to acid ratio

- 14 005679 mass spectrum (E81 ⁺ ): t / ζ = 176 [M + H] ⁺ .

Example 10. 4-Methylamino dihydrofuran-2-one.

2.00 g of 4- (N-benzyl-N-methylamino) dihydrofuran-2-one in 25 ml of methanol is hydrogenated at room temperature in the presence of 250 mg of palladium (10% on activated carbon) under a hydrogen pressure of 50 psig. an inch for about two hours before absorbing the calculated amount of hydrogen. For processing, the catalyst is filtered off and the filtrate is concentrated in vacuo. As a result, a colorless oil is formed as a residue, which is directly used in the subsequent reaction without further purification.

Yield: 1.20 g,

Yag - value: 0.13 (silica gel, ethyl acetate), mass spectrum (E81 ⁺ ): t / ζ = 116 [M + H] ⁺ .

Example 11. 4- (M-benzyl-N-methylamino) dihydrofuran-2-one.

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

Yield: 19.77 g (54% of theory),

I-value: 0.67 (silica gel, ethyl acetate), mass spectrum (E81 ⁺ ): t / ζ = 228 | Μ + Ν; · ι | '.

Example 12. 4 - [(3-chloro-4-fluorophenyl ') amino] -7-cyclobutyloxy-6-hydroxyquinazoline.

To 5.60 g of 6-benzyloxy-4 - [(3-chloro-4-fluorophenyl) amino] -7-cyclobutyloxyquinazoline, 10 ml of trifluoroacetic acid are added dropwise with stirring. When this reaction mixture is heated to about 40 ° C. After stirring for 20 hours at room temperature, 3 ml of trifluoroacetic acid are added again. Since, however, and after stirring for the next three hours at room temperature, the interaction between the reactants is practically absent, the reaction mixture is heated to 50 ° C. After four hours, after which the interaction is complete, the excess trifluoroacetic acid is almost completely distilled off on a rotary evaporator. The residue is mixed with water and the pH is adjusted to alkaline by addition of concentrated aqueous ammonia. The resulting light brown precipitate is separated by vacuum filtration, washed with plenty of water and dried in a desiccator. The product thus obtained still contains trifluoroacetic acid.

Output: 5.82 g, value: 0.61 (silica gel, methylene chloride / methanol 9: 1), mass spectrum (E81 ⁺ ): t / ζ = 360, 362 [M + H] ⁺ .

Analogously to example XII receive the following compounds:

(1) 4 - [(3-chloro-4-fluorophenyl) amino] -7-cyclopropylmethoxy-6-hydroxy-quinazoline:

^ {- value: 0.65 (silica gel, methylene chloride / methanol in the ratio 9: 1), mass spectrum (Е8Д): t / ζ = 360, 362 [M + H] ⁺ ;

(2) 4 - [(3-chloro-4-fluorophenyl) amino] -7-cyclopentyloxy-6-hydroxy-quinazoline:

- value: 0.65 (silica gel, methylene chloride / methanol in the ratio 9: 1), mass spectrum (Е8Д): t / ζ = 374, 376 [M + H] ⁺ ;

(3) 4 - [(3-chloro-4-fluorophenyl) amino] -6-hydroxy-7 - ((I) -tetrahydrofuran-3-yloxy) quinazoline: I-value: 0.32 (silica gel, methylene chloride / methanol in the ratio of 9: 1);

(4) 4 - [(3-chloro-4-fluorophenyl) amino] -6-hydroxy-7 - [(I) - (tetrahydrofuran-2-yl) methoxy] quinazoline: mass spectrum (E8G): t / = 388, 390 [M – H] ^- .

Example 13. 6-benzyloxy-4 - [(3-chloro-4-fluorophenyl) amino] -7-cyclobutyloxyquinazoline.

To 7.00 g of 6-benzyloxy-4 - [(3-chloro-4-fluorophenyl) amino] -7-hydroxyquinazoline in 60 ml of Ν, dimethylformamide, add 7.50 g of potassium carbonate and 4.50 g of methanesulfonic acid cyclobutyl ether. The reaction mixture is stirred for two hours at 80 ° C. Then, 2.00 g of methanesulfonic acid cyclobutyl ester and 3.00 g of potassium carbonate are added again and the mixture is stirred at 60 ° C over the weekend. Since, however, after this period of time, the interaction between the reagents is still not completed, 3.50 g of methanesulfonic acid cyclobutyl ester and 5.00 g of potassium carbonate are added again. After the next 20 hours, during which the mixture was kept at 80 ° C, the interaction was almost complete. For processing, the reaction mixture is mixed with 300 ml of ethyl acetate and washed with water and saturated sodium chloride solution. The organic phase is dried over magnesium sulphate and concentrated. The residue is stirred with methanol, a brownish precipitate is formed. This precipitate is separated by vacuum filtration, washed with methanol and dried in a desiccator.

Output: 5.10 g (64% of theory), ^ {- value: 0.69 (silica gel, methylene chloride / methanol in the ratio 9: 1), mass spectrum (E8G): t / ζ = 448, 450 [M -H] ^- .

- 15 005679

Analogously to example 13 receive the following compounds:

(1) 6-benzyloxy-4 - [(3-chloro-4-fluorophenyl) amino] -7-cyclopropylmethoxyquinazoline (using bromomethylcyclopropane):

K-value: 0.72 (silica gel, methylene chloride / methanol in the ratio 9: 1), mass spectrum (E8G): t / ζ = 448, 450 [M – H] ^- ;

(2) 6-benzyloxy-4 - [(3-chloro-4-fluorophenyl) amino] -7-cyclopentyloxyquinazoline (using bromocyclopentane):

K-value: 0.78 (silica gel, methylene chloride / methanol in the ratio 9: 1), mass spectrum (Е8Й): t / ζ = 464, 466 [M + H] ⁺ .

Example 14. (8) - (2-Hydroxypropylamino) acetic acid tert-butyl ester.

15.00 g (8) - (+) - 1-amino-2-propanol is dissolved in 100 ml of,-dimethylformamide and mixed with 6.97 ml of diisopropylethylamine. Then, while cooling in an ice bath, 5.91 ml of bromoacetic acid tert-butyl ester are added dropwise over 30 minutes. The cooling bath is removed and the reaction mixture is stirred overnight at room temperature. For processing, the reaction mixture is concentrated in vacuo. The residue at the bottom of the flask is dissolved in 50 ml of water and saturated with 15 g of sodium chloride. The aqueous solution is extracted several times with ethyl acetate. The combined extracts are washed with a saturated solution of sodium chloride, dried over magnesium sulphate and concentrated in vacuo to give a yellowish oil as a residue.

Output: 7.36 g (97% of theory),

K-value: 0.46 (silica gel, ethyl acetate / methanol in a ratio of 9: 1), mass spectrum (E8J): t / ζ = 190 [M + H] ⁺ .

Analogously to example 14, the following compounds are obtained:

(1) (K) - (2-hydroxypropylamino) acetic acid tert-butyl ester:

K -value: 0.46 (silica gel, ethyl acetate / methanol 9: 1), mass spectrum (E8J): t / ζ = 190 [M + H] ⁺ ;

(2) (1,1-Dimethyl-2-hydroxyethylamino) acetic acid tert-butyl ester:

mass spectrum (E8J): t / = 204 [M + H] ⁺ , ^ (- value: 0.47 (silica gel, methylene chloride / methanol / conc. aqueous ammonia solution in a ratio of 90: 10: 0.1).

Example 15. 4- [(3-chloro-4-fluorophenyl) amino] -6- (3-methanesulfonyloxypropyloxy) -7-cyclobutyloxy-quinazoline.

The title compound is obtained by reacting 4 - [(3-chloro-4-fluorophenyl) amino] -6- (3-hydroxypropyloxy) -7-cyclobutyloxyquinazoline with methanesulfonic acid chloride in methylene chloride in the presence of diisopropylethylamine at room temperature.

K-value: 0.37 (silica gel, methylene chloride / methanol in the ratio 95: 5), mass spectrum (E8G): t / ζ = 494, 496 [M – H] ^- .

Analogously to example 15 receive the following compounds:

(1) 4 - [(3-chloro-4-fluorophenyl) amino] -6- (3-methanesulfonyloxypropyloxy) -7-cyclopropylmethoxyquinazoline:

K-value: 0.65 (silica gel, methylene chloride / methanol in the ratio 90:10), mass spectrum (E8G): t / ζ = 494, 496 [M – H] ^- ;

(2) 4 - [(3-chloro-4-fluorophenyl) amino] -6-cyclopropylmethoxy-7- (3-methanesulfonyloxypropyloxy) quinazoline:

K-value: 0.73 (silica gel, methylene chloride / methanol in the ratio 90:10), mass spectrum (Е8Й): t / ζ = 496, 498 [M + H] ⁺ ;

(3) 4 - [(3-chloro-4-fluorophenyl) amino] -6- (4-methanesulfonyloxybutyloxy) -7-cyclopentyloxyquinazoline

K-value: 0.76 (silica gel, methylene chloride / methanol in the ratio 90:10) mass spectrum (Е8Й): t / ζ = 524, 526 [M + H] ⁺ .

Example 16. 4 - [(3-chloro-4-fluorophenyl) amino] -6-hydroxy-7-cyclopropylmethoxyquinazoline.

The title compound is prepared by hydrogenation of 6-benzyloxy-4 - [(3-chloro-4fluorophenyl) amino] -7-cyclopropylmethoxyquinazoline in the presence of 10% Rb / C in a mixture of methylene chloride, ethanol and conc. hydrochloric acid (in the ratio 500: 210: 3.5) in the Parr apparatus.

Output: 73% of theory, mass spectrum (E8J): t / ζ = 360, 362 [M + H] ⁺ .

Example 17. Cyclopentyl ester of 5-benzyloxy-4-cyclopentyloxy-2-nitrobenzoic acid.

The title compound is obtained by reacting 5-benzyloxy-4-hydroxy-2-nitrobenzoic acid with 2.2 equivalents of bromocyclopentane in the presence of potassium carbonate as an auxiliary base in dimethyl sulfoxide at room temperature.

Output: 87% of theory,

K-value: 0.92 (silica gel, ethyl acetate / cyclohexane in a 1: 1 ratio), mass spectrum (E8J): t / ζ = 426 [M + H] ⁺ .

- 16 005679

Example 18. 4 - [(3-chloro-4-fluorophenyl) amino] -6-benzyloxy-7 - ((H) -tetrahydrofuran-3-yloxy) quinazoline.

To a solution of 8.00 g of 4 - [(3-chloro-4-fluorophenyl) amino] -6-benzyloxy-7-hydroxyquinazoline (see AO 00/55141 A1), 2.42 ml (5) - (+) - 3-hydroxytetrahydrofuran and 7.95 g of triphenylphosphine in 160 ml of tetrahydrofuran are added dropwise 5.03 ml of diethyl azodicarboxylic ester. The reaction mixture is stirred overnight at room temperature and then concentrated on a rotary evaporator. The residue on the bottom of the flask was purified by chromatography on a silica gel column using 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 (E 1 1 ⁺ ): t / ζ = 466, 468 [M + H] ⁺ .

Analogously to example 18, the following compounds are obtained:

(1) 4 - [(3-chloro-4-fluorophenyl) amino] -6-benzyloxy-7 - [(H) - (tetrahydrofuran-2-yl) methoxy] quinazoline: mass spectrum (E1 ⁺ ): t / ζ - 480, 482 [M + H] ⁺ ,

Appointment: 0,38 (silica gel, methylene chloride / methanol in the ratio 15: 1);

(2) 4 - [(3-chloro-4-fluorophenyl) amino] -7- (2-bromoethoxy) -6 - ((8) -tetrahydrofuran-3-yloxy) quinazoline:

Appointment: 0,35 (silica gel, methylene chloride / methanol in the ratio 20: 1).

Obtaining final compounds

Example 1 4 - [(3-chloro-4-fluorophenyl) amino] -6-cyclopentylmethoxy-7- [2- (2,2-dimethyl-6-oxomorpholin-4-yl) ethoxy] quinazoline

250 mg of 4 - [(3-chloro-4-fluorophenyl) amino] -6-cyclopentylmethoxy-7- (2-bromoethoxy) quinazoline and 341 mg of (2-hydroxy-2-methylpropylamino) acetic acid ethyl ester are dissolved in 20 ml of acetonitrile and mixed with 50 mg of sodium iodide, 275 mg of potassium carbonate and 0.70 ml of diisopropylethylamine. The reaction mixture is heated to reflux for about 90 hours. After cooling to room temperature, the reaction mixture is filtered and the filtrate is concentrated in vacuo. The residue on the bottom of the flask is chromatographed on a silica gel column using petroleum ether / ethyl acetate (50/50 and then 0: 100) as eluent. In this way, the cyclized product is obtained in the form of a beige solid.

Yield: 62 mg (23% of theory),

H-value: 0.29 (silica gel, ethyl acetate), mass spectrum (E8T): t / ζ = 541, 543 [M-H] ^- .

Analogously to example 1, the following compounds are obtained:

(1) 4 - [(3-chloro-4-fluorophenyl) amino] -6-cyclopropylmethoxy-7- [2- (2,2-dimethyl-6-oxomorpholine-4yl) ethoxy] quinazoline:

H _g value: 0.58 (silica gel, methylene chloride / methanol in the ratio 9: 1), mass spectrum (E8T): t / ζ = 513, 515 [M – H] ^- ;

(2) 4 - [(3-chloro-4-fluorophenyl) amino] -7-cyclobutyloxy-6- [3- (2,2-dimethyl-6-oxomorpholin-4-yl) propyloxy] quinazoline:

melting point: 212-214 ° C, mass spectrum (E8T): t / ζ = 527, 529 [M – H] ^- ;

(3) 4 - [(3-chloro-4-fluorophenyl) amino] -7-cyclopropylmethoxy-6- [3- (2,2-dimethyl-6-oxomorpholine-4yl) propyloxy] quinazoline:

melting point: 200-202 ° С, mass spectrum (Е8Т): t / ζ = 527, 529 [М-Н] ^- ;

(4) 4 - [(3-chloro-4-fluorophenyl) amino] -6- [3- (2,2-dimethyl-6-oxomorpholin-4-yl) propyloxy] -7-methoxyquinazoline:

melting point: 222-224 ° С, mass spectrum (Е8Т): t / ζ = 487, 489 [M-H] ^- .

Example 2. 4 - [(3-chloro-4-fluorophenyl) amino] -6-cyclopropylmethoxy-7- {2- [N- (2-oxotetrahydrofuran-4-yl) -Y-methylamino] ethoxy} quinazoline.

300 mg of 4 - [(3-chloro-4-fluorophenyl) amino] -6-cyclopropylmethoxy-7- (2-bromoethoxy) quinazoline and 400 mg of 4-methylamino dihydrofuran-2-one in 20 ml of acetonitrile are 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 is filtered and the filtrate is concentrated in vacuo. The residue on the bottom of the flask is chromatographed on a silica gel column using methylene chloride / methanol / concentrated aqueous ammonia (ratio 97: 3: 0.05) as eluent. The title compound is obtained as a light beige solid.

Yield: 70 mg (22% of theory),

Purpose: 0.47 (silica gel, methylene chloride / methanol / concentrated aqueous ammonia solution in a ratio of 90: 10: 0.1), mass spectrum (Е§1 ⁺ ): t / ζ = 501, 503 [M + H] ⁺ .

Analogously to example 2, the following compounds are obtained:

- 17 005679 (1) 4 - [(3-chloro-4-fluorophenyl) amino] -6-cyclopentyloxy-7- {2- [M- (2-oxotetrahydrofuran-4-yl) -Ymethylamino] ethoxy} quinazoline:

^ {- value: 0.42 (silica gel, methylene chloride / methanol / concentrated aqueous ammonia in the ratio of 90: 10: 0.1), mass spectrum (E81 ⁺ ): t / ζ = 515, 517 [M + H] ⁺ ;

(2) 4 - [(3-chloro-4-fluorophenyl) amino] -6- {3- [M- (2-oxotetrahydrofuran-4-yl) -Y-methylamino] propyloxy} -7-cyclobutyloxyquinazoline:

melting point: 147.5-151 ° С, mass spectrum (Е81 ⁺ ): t / ζ = 515, 517 [M + H] ⁺ .

Example 3. 4 - [(3-bromophenyl) amino] -6- [2 - ((8) -6-methyl-2-oxomorpholin-4-yl) ethoxy] -7-methoxyquinazoline.

K 380 mg 4 - [(3-bromophenyl) amino] -6- (2- {S - [(tert-butyloxycarbonyl) methyl] -H - ((8) -2-hydroxypropyl) amino} ethoxy) -7-methoxy-quinazoline 90 μl of methanesulfonic acid is added to 8 ml of acetonitrile. The reaction mixture is heated under reflux for about three hours, after which one equivalent of methanesulfonic acid is added again and refluxing is continued until the reaction is complete. For processing, the reaction mixture is diluted with ethyl acetate and washed with saturated sodium bicarbonate solution and saturated sodium chloride solution. The organic phase is dried over magnesium sulfate and concentrated in vacuo. The residue at the bottom of the flask is stirred with diethyl ether and suction filtered. In this way, the title compound is obtained as a white solid.

Output: 280 mg (85% of theory), melting point: 190 ° C, mass spectrum (E8T): t / ζ = 485, 487 [M – H] ^- .

Analogously to example 3, the following compounds are obtained:

(1) 4 - [(3-bromophenyl) amino] -6- [2 - ((K) -6-methyl-2-oxomorpholin-4-yl) ethoxy] -7-methoxyquinazoline: melting point: 193 ° C, mass spectrum (E81 ⁺ ): t / ζ = 487, 489 [M + H] ⁺ ;

(2) 4 - [(3-chloro-4-fluorophenyl) amino] -6- [2 - ((K) -6-methyl-2-oxomorpholin-4-yl) ethoxy] -7-methoxyquinazoline (the reaction is carried out with trifluoroacetic acid in acetonitrile):

melting point: 208 ° С, mass spectrum (Е8Т): t / = 459, 461 [М-Н] ^- ;

(3) 4 - [(3-chloro-4-fluorophenyl) amino] -6- [3 - ((K) -6-methyl-2-oxomorpholin-4-yl) propyloxy] -7-methoxyquinazoline (the reaction is carried out with trifluoroacetic acid in acetonitrile):

K-value: 0.33 (silica gel, ethyl acetate), mass spectrum (E8P): t / ζ = 473, 475 [M-H] ^- ;

(4) 4 - [(K) - (1-phenylethyl) amino] -6- [3 - ((8) -6-methyl-2-oxomorpholin-4-yl) propyloxy] -7-methoxyquinazoline (the reaction is carried out with trifluoroacetic acid in acetonitrile):

K-value: 0.41 (silica gel, ethyl acetate / methanol in a ratio of 9: 1), mass spectrum (Е8Т): t / ζ = 449 [M – H] ^- ;

(5) 4 - [(K) - (1-phenylethyl) amino] -6- [2 - ((8) -6-methyl-2-oxomorpholin-4-yl) ethoxy] -7-methoxyquinazoline (the reaction is carried out with trifluoroacetic acid in acetonitrile),

K-value: 0.49 (silica gel, ethyl acetate / methanol / concentrated aqueous ammonia solution in a ratio of 9: 1: 0.1), mass spectrum (E8T): t / ζ = 435 [M-H] ^- ;

(6) 4 - [(3-chloro-4-fluorophenyl) amino] -6- [3 - ((K) -6-methyl-2-oxomorpholin-4-yl) propyloxy] -7-cyclobutyloxyquinazoline (the reaction is carried out with trifluoroacetic acid in acetonitrile):

melting point: 185.5-189.5 ° С, mass spectrum (Е81 ⁺ ): t / ζ = 515, 517 [M + H] ⁺ ;

(7) 4 - [(3-chloro-4-fluorophenyl) amino] -6- [3- (5,5-dimethyl-2-oxomorpholin-4-yl) propyloxy] -7-cyclobutyloxyquinazoline (reaction is carried out with trifluoroacetic acid in acetonitrile):

melting point: 214-216 ° C, mass spectrum (E8T): t / ζ = 527, 529 [M – H] ^- ;

(8) 4 - [(3-chloro-4-fluorophenyl) amino] -6- [3 - ((K) -6-methyl-2-oxomorpholin-4-yl) propyloxy] -7-cyclopropylmethoxyquinazoline (the reaction is carried out with trifluoroacetic acid in acetonitrile):

melting point: 160.5-163 ° С, mass spectrum (Е81 ⁺ ): t / ζ = 515, 517 [M + H] ⁺ ;

(9) 4 - [(3-chloro-4-fluorophenyl) amino] -6- [3 - ((8) -6-methyl-2-oxomorpholin-4-yl) propyloxy] -7-cyclopropylmethoxyquinazoline (the reaction is carried out with trifluoroacetic acid in acetonitrile):

melting point: 160-162 ° С, mass spectrum (Е81 ⁺ ): t / ζ = 515, 517 [M + H] ⁺ ;

(10) 4 - [(3-chloro-4-fluorophenyl) amino] -6- [2 - ((8) -6-methyl-2-oxomorpholin-4-yl) ethoxy] -7-cyclopentyloxyquinazoline (the reaction is carried out with trifluoroacetic acid in acetonitrile):

K-value: 0.31 (silica gel, ethyl acetate), mass spectrum (E81 ⁺ ): t / ζ = 515, 517 [M + H] ⁺ ;

- 18 005679 (11) 4 - [(3-chloro-4-fluorophenyl) amino] -6- [2 - ((K) -6-methyl-2-oxomorpholin-4-yl) ethoxy] -7-cyclopentyloxyquinazoline ( the reaction is carried out with trifluoroacetic acid in acetonitrile):

melting point: 176-178 ° С, mass spectrum (Е8Е): t / ζ = 515, 517 [M + H] ⁺ ;

(12) 4 - [(3-chloro-4-fluorophenyl) amino] -6- [2 - ((8) -6-methyl-2-oxomorpholin-4-yl) ethoxy] -7-cyclopropylmethoxyquinazoline (the reaction is carried out with trifluoroacetic acid in acetonitrile):

K-value: 0.37 (silica gel, ethyl acetate), mass spectrum (Е8Е): t / ζ = 501, 503 [M + H] ⁺ ;

(13) 4 - [(3-chloro-4-fluorophenyl) amino] -6- [2 - ((K) -6-methyl-2-oxomorpholin-4-yl) ethoxy] -7-cyclopropylmethoxyquinazoline (the reaction is carried out with trifluoroacetic acid in acetonitrile):

(14) 4 - [(3-chloro-4-fluorophenyl) amino] -6-cyclopropylmethoxy-7- [2 - ((8) -6-methyl-2-oxomorpholine-4yl) ethoxy] quinazoline (the reaction is carried out with trifluoroacetic acid in acetonitrile):

K-value: 0.48 (silica gel, ethyl acetate / methanol in a ratio of 9: 1), mass spectrum (Е8Е): t / ζ = 501, 503 [M + H] ⁺ ;

(15) 4 - [(3-chloro-4-fluorophenyl) amino] -6-cyclopropylmethoxy-7- [2 - ((K) -6-methyl-2-oxomorpholine-4yl) ethoxy] quinazoline (the reaction is carried out with trifluoroacetic acid in acetonitrile):

mass spectrum (Е8Е): t / ζ = 501, 503 [M + H] ⁺ ;

(16) 4 - [(3-chloro-4-fluorophenyl) amino] -6-cyclopropylmethoxy-7- [3 - ((K) -6-methyl-2-oxomorpholine-4yl) propyloxy] quinazoline (the reaction is carried out with trifluoroacetic acid in acetonitrile):

K-value: 0.67 (silica gel, ethyl acetate / methanol in a ratio of 9: 1), mass spectrum (E8G): t / ζ = 513, 515 [M – H] ^- ;

(17) 4 - [(3-chloro-4-fluorophenyl) amino] -6-cyclopropylmethoxy-7- [3 - ((8) -6-methyl-2-oxomorpholine-4yl) propyloxy] quinazoline (the reaction is carried out with trifluoroacetic acid in acetonitrile):

(18) 4 - [(3-chloro-4-fluorophenyl) amino] -6- [2- (2,2-dimethyl-6-oxomorpholin-4-yl) ethoxy] -7-cyclopentyloxyquinazoline (reaction is carried out with trifluoroacetic acid in acetonitrile):

K-value: 0.56 (silica gel, ethyl acetate), mass spectrum (Е8Е): t / ζ = 529, 531 [M + H] ⁺ ;

(19) 4 - [(3-chloro-4-fluorophenyl) amino] -6-cyclopentyloxy-7- [2 - ((8) -6-methyl-2-oxomorpholine-4yl) ethoxy] quinazoline (the reaction is carried out with trifluoroacetic acid in acetonitrile):

K-value: 0.60 (silica gel, ethyl acetate / methanol 9: 1), mass spectrum (E81 ⁺ ): t / ζ = 515, 517 [M + H] ⁺ ;

(20) 4 - [(3-chloro-4-fluorophenyl) amino] -6-cyclopentyloxy-7- [2 - ((K) -6-methyl-2-oxomorpholine-4yl) ethoxy] quinazoline (the reaction is carried out with trifluoroacetic acid in acetonitrile):

mass spectrum (EM '): t / = 515, 517 [M + H] ⁺ ;

(21) 4 - [(3-chloro-4-fluorophenyl) amino] -6- [4 - ((8) -6-methyl-2-oxomorpholin-4-yl) butyloxy] -7-cyclopentyloxyquinazoline (the reaction is carried out with trifluoroacetic acid in acetonitrile):

K-value: 0.51 (silica gel, ethyl acetate), mass spectrum (EM ⁺ ): t / ζ = 543, 545 [M + H] ⁺ ;

(22) 4 - [(3-chloro-4-fluorophenyl) amino] -6- [4 - ((K) -6-methyl-2-oxomorpholin-4-yl) butyloxy] -7-cyclopentyloxyquinazoline (the reaction is carried out with trifluoroacetic acid in acetonitrile):

mass spectrum (EM ⁺ ): t / ζ = 543, 545 [M + H] ⁺ ;

(23) 4 - [(3-chloro-4-fluorophenyl) amino] -6- [3 - ((8) -6-methyl-2-oxomorpholin-4-yl) propyloxy] -7-methoxyquinazoline (the reaction is carried out with trifluoroacetic acid in acetonitrile):

melting point: 183-186 ° C, mass spectrum (EM ⁺ ): t / ζ = 475, 477 [M + H] ⁺ ;

(24) 4 - [(3-chloro-4-fluorophenyl) amino] -6- [3- (5,5-dimethyl-2-oxomorpholin-4-yl) propyloxy] -7-methoxyquinazoline (reaction is carried out with trifluoroacetic acid in acetonitrile):

K-value: 0.43 (silica gel, ethyl acetate), mass spectrum (EM ^- ): t / ζ = 487, 489 [M – H] ^- ;

(25) 4 - [(3-chloro-4-fluorophenyl) amino] -6- [2 - ((8) -6-methyl-2-oxomorpholin-4-yl) ethoxy] -7-methoxyquinazoline (the reaction is carried out with trifluoroacetic acid in acetonitrile):

melting point: 212-213 ° С, mass spectrum (I eat ⁺ ): t / ζ - 461, 463 [M + H] ⁺ ;

(26) 4 - [(3-chloro-4-fluorophenyl) amino] -6- {2- [L- (carboxymethyl) -M - ((8) -2-hydroxypropyl) amino] ethoxy} -7-methoxyquinazoline ( by-product in the preparation of compound 3 (25)):

melting point: 187-190 ° С, mass spectrum (Е81 ⁺ ): t / ζ = 479, 481 [M + H] ⁺ ;

- 19 005679 (27) 4 - [(3-chloro-4-fluorophenyl) amino] -6- [2- (2,2-dimethyl-6-oxomorpholin-4-yl) ethoxy] -7-methoxyquinazoline (the reaction is carried out with trifluoroacetic acid in acetonitrile):

melting point: 229-232 ° C, mass spectrum (E8T): t / ζ = 473, 475 [M – H] ^- ;

(28) 4 - [(3-chloro-4-fluorophenyl) amino] -6- [2- (2,2-dimethyl-6-oxomorpholin-4-yl) ethoxy] -7 - ((H) -tetrahydrofuran- 3-yloxy) quinazoline (the reaction is carried out with triperoxonane acid in acetonitrile):

melting point: 195-196 ° С mass spectrum (Е81 ⁺ ): t / ζ = 531, 533 [M + H] ⁺ ;

(29) 4 - [(3-chloro-4-fluorophenyl) amino] -6- [2- (2,2-dimethyl-6-oxomorpholin-4-yl) ethoxy] -7 - [(H) - (tetrahydrofuran -2-yl) methoxy] quinazoline (the reaction is carried out with trifluoroacetic acid in acetonitrile):

melting point: 184 ° С, mass spectrum (Е81 ⁺ ): t / ζ = 545, 547 [M + H] ⁺ ;

(30) 4 - [(3-chloro-4-fluorophenyl) amino] -7- [2- (2,2-dimethyl-6-oxomorpholin-4-yl) ethoxy] -6 - ((8) -tetrahydrofuran- 3-yloxy) quinazoline:

melting point: 202-205 ° С, mass spectrum (Е81 ⁺ ): t / ζ = 531, 533 [M + H] ⁺ ;

(31) 4 - [(3-chloro-4-fluorophenyl) amino] -7- [2- (2,2-dimethyl-6-oxomorpholin-4-yl) ethoxy] -6 - [(8) - (tetrahydrofuran -2-yl) methoxy] quinazoline:

melting point: 182 ° С, mass spectrum (Е81 ⁺ ): t / ζ = 545, 547 [M + H] ⁺ .

Example 4. 4 - [(3-bromophenyl) amino1-6- (2- {No. [(tert-butyloxycarbonyl) methyl] -L - ((8) -2-hydroxypropyl) amino) ethoxy) -7-methoxyquinazoline.

To 650 mg of 4 - [(3-bromophenyl) amino] -6- (2-bromoethoxy) -7-methoxyquinazoline and 1.10 g of tert-butyl ether (8) - (2-hydroxypropylamino) acetic acid in 15 ml of acetonitrile are added 0.25 ml of diisopropylethylamine. The reaction mixture is stirred over night at 50 ° C. Since no reaction is observed, the reaction mixture is concentrated, mixed with 20 ml of Ν, dimethylformamide and stirred for eight hours at 60 ° C. After that, the temperature is raised to 80 ° C. After the next eight hours, the interaction is complete. The reaction mixture is concentrated and chromatographed on a silica gel column using ethyl acetate as eluant. In this way, get the target product in the form of a white solid.

Yield: 410 mg (51% of theory),

Purpose: 0.27 (silica gel, ethyl acetate), mass spectrum (Е8Т): t / ζ = 559, 561 [M-H] ^- .

Analogously to example 4 receive the following compounds:

(1) 4 - [(3-bromophenyl) amino] -6- (2- {No. [(tert-butyloxycarbonyl) methyl] -L - ((H) -2-hydroxypropyl) amino} ethoxy) -7-methoxyquinazoline:

melting point: 130 ° C, mass spectrum (E8T): t / = 559, 561 [M – H] ^- ;

(2) 4 - [(3-chloro-4-fluorophenyl) amino] -6- (2- {No. [(tert-butyloxycarbonyl) methyl] -H - ((H) -2-hydroxypropyl) amino} ethoxy) - 7-methoxyquinazoline (the reaction is carried out in, Ν-dimethylformamide):

Purpose: 0.40 (silica gel, ethyl acetate / petroleum ether 4: 1);

(3) 4 - [(3-chloro-4-fluorophenyl) amino] -6- (3- {No. [(tert-butyloxycarbonyl) methyl] -H - ((H) -2-hydroxypropyl) amino} propyloxy) - 7-methoxyquinazoline (the reaction is carried out in, Ν-dimethylformamide):

Purpose: 0.37 (silica gel, ethyl acetate / petroleum ether in the ratio 4: 1), mass spectrum (Е8Т): t / ζ = 547, 549 [M – H] ^- ;

(4) 4 - [(H) - (1-phenylethyl) amino] -6- (3- {No. [(tert-butyloxycarbonyl) methyl] -L - ((8) -2-hydroxypropyl) amino} propyloxy) - 7-methoxyquinazoline (the reaction is carried out in, Ν-dimethylformamide):

Purpose: 0.65 (silica gel, ethyl acetate / methanol in a ratio of 9: 1), mass spectrum (Е1): t / ζ = 524 [M];

(5) 4 - [(H) - (1-phenylethyl) amino] -6- (2- {No. [(tert-butyloxycarbonyl) methyl] -L - ((8) -2-hydroxypropyl) amino} ethoxy) - 7-methoxyquinazoline (the reaction is carried out in, Ν-dimethylformamide):

Purpose: 0.57 (silica gel, ethyl acetate / methanol / concentrated aqueous ammonia solution in a ratio of 9: 1: 0.1);

(6) 4 - [(3-chloro-4-fluorophenyl) amino] -6- (3- {No. [(tert-butyloxycarbonyl) methyl] - L - ((H) -2-hydroxypropyl) amino} propyloxy) - 7-cyclobutyloxyquinazoline:

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

(7) 4 - [(3-chloro-4-fluorophenyl) amino] -6- (3 - {No. [(tert-butyloxycarbonyl) methyl] - L- (1,1-dimethyl-2-hydroxyethyl) amino} propyloxy) - 7-cyclobutyloxyquinazoline:

H _g Value: 0.29 (silica gel, methylene chloride / methanol 95: 5), mass spectrum (E81 ⁺ ): t / ζ = 603, 605 [M + H] ⁺ ;

- 20 005679 (8) 4 - [(3-chloro-4-fluorophenyl) amino] -6- (3- {No. [(tert-butyloxycarbonyl) methyl] -N ((K) -2-hydroxypropyl) amino} propyloxy ) -7-cyclopropylmethoxyquinazoline:

TO _g value: 0.37 (silica gel, methylene chloride / methanol in a ratio of 95: 5);

(9) 4 - [(3-chloro-4-fluorophenyl) amino] -6- (3- {No. [(tert-butyloxycarbonyl) methyl] -N ((8) -2-hydroxypropyl) amino} propyloxy) -7 -cyclopropylmethoxyquinazoline:

TO _g value: 0.50 (silica gel, ethyl acetate);

(10) 4 - [(3-chloro-4-fluorophenyl) amino] -6- (2- {No. [(tert-butyloxycarbonyl) methyl] -N ((8) -2-hydroxypropyl) amino} ethoxy) -7 -cyclopentyloxyquinazoline:

K-value: 0.54 (silica gel, ethyl acetate / cyclohexane in a ratio of 9: 1);

(11) 4 - [(3-chloro-4-fluorophenyl) amino] -6- (2- {No. [(tert-butyloxycarbonyl) methyl] -N ((K) -2-hydroxypropyl) amino} ethoxy) -7 -cyclopentyloxyquinazoline;

TO _g value: 0.66 (silica gel, ethyl acetate):

(12) 4 - [(3-chloro-4-fluorophenyl) amino] -6- (2- {No. [(tert-butyloxycarbonyl) methyl] -N ((8) -2-hydroxypropyl) amino} ethoxy) -7 -cyclopropylmethoxyquinazoline:

TO _g value: 0.60 (silica gel, ethyl acetate);

(13) 4 - [(3-chloro-4-fluorophenyl) amino] -6- (2- {No. [(tert-butyloxycarbonyl) methyl] -N ((K) -2-hydroxypropyl) amino} ethoxy) -7 -cyclopropylmethoxyquinazoline:

K-value: 0.60 (silica gel, ethyl acetate);

(14) 4 - [(3-chloro-4-fluorophenyl) amino] -6-cyclopropylmethoxy-7- (2- {No. [(tert-butyloxycarbonyl) methyl] -N ((8) -2-hydroxypropyl) amino} ethoxy) quinazolin:

Kg value: 0.30 (silica gel, ethyl acetate);

(15) 4 - [(3-chloro-4-fluorophenyl) amino] -6-cyclopropylmethoxy-7- (2- {No. [(tert-butyloxycarbonyl) methyl] -№ (K) -2-hydroxypropyl) amino} ethoxy) quinazolin:

KG-value: 0.30 (silica gel, ethyl acetate);

(16) 4 - [(3-chloro-4-fluorophenyl) amino] -6-cyclopropylmethoxy-7- (3- {No. [(tert-butyloxycarbonyl) methyl] -N ((K) -2-hydroxypropyl) amino} propyloxy) quinazoline:

TO _g value: 0.35 (silica gel, ethyl acetate);

(17) 4 - [(3-chloro-4-fluorophenyl) amino] -6-cyclopropylmethoxy-7- (3- {No. [(tert-butyloxycarbonyl) methyl] -N ((8) -2-hydroxypropyl) amino} propyloxy]) quinazoline:

K-value: 0.35 (silica gel, ethyl acetate);

(18) 4 - [(3-chloro-4-fluorophenyl) amino] -6- (2- {No. [(ethoxycarbonyl) methyl] -N (2-hydroxy-2-methylpropyl) amino} ethoxy) -7-cyclopentyloxyquinazoline :

K (-value: 0.64 (silica gel, methylene chloride / methanol 9: 1), mass spectrum (Ε8Ι ^one ): t / ζ = 575, 577 [M + H] ⁺ ;

(19) 4 - [(3-chloro-4-fluorophenyl) amino] -6-cyclopentyloxy-7- (2- {No. [(tert-butyloxycarbonyl) methyl] No. ((8) -2-hydroxypropyl) amino} ethoxy a) quinazolin:

Kg value: 0.51 (silica gel, ethyl acetate);

(20) 4 - [(3-chloro-4-fluorophenyl) amino] -6-cyclopentyloxy-7- (2- {No. [(tert-butyloxycarbonyl) methyl] No. ((K) -2-hydroxypropyl) amino} ethoxy a) quinazolin:

TO _g value: 0.51 (silica gel, ethyl acetate);

(21) 4 - [(3-chloro-4-fluorophenyl) amino] -6- (4- {No. [(tert-butyloxycarbonyl) methyl] -N ((8) -2-hydroxypropyl) amino} -butyloxy) - 7-cyclopentyloxyquinazoline:

KG-value: 0.61 (silica gel, ethyl acetate);

(22) 4 - [(3-chloro-4-fluorophenyl) amino] -6- (4- {No. [(tert-butyloxycarbonyl) methyl] -N ((K) -2-hydroxypropyl) amino} -butyloxy) - 7-cyclopentyloxyquinazoline:

KG value: 0.61 (silica gel, ethyl acetate);

(23) 4 - [(3-chloro-4-fluorophenyl) amino] -6- (3- {No. [(tert-butyloxycarbonyl) methyl] -N ((8) -2-hydroxypropyl) amino} propyloxy) -7 - methoxyquinazoline:

TO _R -value: 0.46 (silica gel, ethyl acetate), mass spectrum (Ε8Ι ^- ): t / ζ = 547, 549 [M – H] ^- ;

(24) 4 - [(3-chloro-4-fluorophenyl) amino] -6- (3- {No. [(tert-butyloxycarbonyl) methyl] -N (1,1-dimethyl-2 hydroxyethyl) amino} propyloxy) -7 - methoxyquinazoline:

mass spectrum (Ε8Ι ⁺ ): t / ζ = 563, 565 [M + H] ⁺ ;

(25) 4 - [(3-chloro-4-fluorophenyl) amino] -6- (2- {No. [(tert-butyloxycarbonyl) methyl] -N ((8) -2-hydroxypropyl) amino} ethoxy) -7 - methoxyquinazoline:

K-value: 0.66 (silica gel, ethyl acetate / methanol 9: 1), mass spectrum (Ε8 ⁺ ): t / ζ = 535, 537 [M + H] ⁺ ;

(26) 4 - [(3-chloro-4-fluorophenyl) amino] -6- (2- {No. [(ethoxycarbonyl) methyl] -N (2-hydroxy-2-methylpropyl) amino} ethoxy) -7-methoxy-quinazoline (in the form of a mixture with an already cyclized substance):

TO _R value: 0.44 (silica gel, ethyl acetate), mass spectrum (Ε8Ι ⁺ ): t / ζ = 521, 523 [M + H] ⁺ ;

- 21 005679 (27) 4 - [(3-chloro-4-fluorophenyl) amino] -6- (2- {Н - [(ethoxycarbonyl) methyl] -H- (2-hydroxy-2-methylpropyl) amino} ethoxy ) -7 - ((K) -tetrahydrofuran-3-yloxy) quinazoline (in the form of a mixture with an already cyclized substance):

K-value: 0.30 (silica gel, methylene chloride / methanol in a ratio of 9: 1);

(28) 4 - [(3-chloro-4-fluorophenyl) amino] -6- (2- {S - [(ethoxycarbonyl) methyl] -M- (2-hydroxy-2-methylpropyl) amino} ethoxy) -7 - [(K) - (tetrahydrofuran-2-yl) methoxy] quinazoline:

mass spectrum (E8G): t / = 589, 591 [M – H] ^- ;

(29) 4 - [(3-chloro-4-fluorophenyl) amino] -7- (2- {Ы - [(ethoxycarbonyl) methyl] -M- (2-hydroxy-2-methylpropyl) amino} ethoxy) -6 - ((8) -tetrahydrofuran-3-yloxy) quinazoline:

Purpose: 0.16 (silica gel, methylene chloride / methanol in a ratio of 20: 1);

(30) 4 - [(3-chloro-4-fluorophenyl) amino] -7- (2- {Ы - [(ethoxycarbonyl) methyl] -M- (2-hydroxy-2-methylpropyl) amino} ethoxy) -6 - [(8) - (tetrahydrofuran-2-yl) methoxy] quinazoline:

K-value: 0.68 (silica gel, ethyl acetate / methanol in a ratio of 15: 1).

Similarly to the above examples and other methods known from the literature, the following compounds can also be obtained:

(1) 4 - [(3-chloro-4-fluorophenyl) amino] -7- [2- (6-methyl-2-oxomorpholin-4-yl) ethoxy] -6-methoxyquinazoline, (2) 4 - [( 3-chloro-4-fluorophenyl) amino] -7- [3- (6-methyl-2-oxomorpholin-4-yl) propyloxy] -6-methoxyquinazoline, (3) 4 - [(3-chloro-4-fluorophenyl ) amino] -6- [2 - ((8) -6-methyl-2-oxomorpholin-4-yl) ethoxy] -7-methoxyquinazoline, (4) 4 - [(3-chloro-4-fluorophenyl) amino] -6- [3 - ((8) -6-methyl-2-oxomorpholin-4-yl) propyloxy] -7-methoxyquinazoline, (5) 4 - [(3-chloro-4-fluorophenyl) amino] -6- [3- (5,5-dimethyl-2-oxomorpholin-4-yl) propyloxy] -7-methoxy-quinazoline, (6) 4 - [(3-chloro-4-fluorophenyl) amino] -6- [2- (5 , 5-dimethyl-2-oxomorpholin-4-yl) ethoxy] -7-methoxy-quinazoline, (7) 4 - [(3-chloro-4-ft rphenyl) amino] -6- [3- (3-methyl-2-oxomorpholin-4-yl) propyloxy] -7-methoxyquinazoline, (8) 4 - [(3-chloro-4-fluorophenyl) amino] -6- [2- (3-methyl-2-oxomorpholin-4-yl) ethoxy] -7-methoxyquinazoline, (9) 4 - [(K.) - (1-phenylethyl) amino] -6- [3 - ((K ) -6-methyl-2-oxomorpholin-4-yl) propyloxy] -7-methoxyquinazoline, (10) 4 - [(K) - (1-phenylethyl) amino] -6- [2 - (K) -6 -methyl-2-oxomorpholin-4-yl) ethoxy] -7-methoxy-quinazoline, (11) 4 - [(3-chloro-4-fluorophenyl) amino] -7- [4- (6-methyl-2-oxomorpholine- 4-yl) butyloxy] -6-methoxyquinazoline, (12) 4 - [(3-chloro-4-fluorophenyl) amino] -7- [3- (6-methyl-2-oxomorpholin-4-yl) propyloxy] - 6-methoxyquinazoline, (13) 4 - [(3-chloro-4-fluorophenyl) amino] -6- [4- (6th) Tyl-2-oxomorpholin-4-yl) butyloxy] -7-methoxyquinazoline, (14) 4 - [(3-chloro-4-fluorophenyl) amino] -6- [2- (6-methyl-2-oxomorpholine-4 -yl) ethoxy] -7- (tetrahydrofuran-3-yloxy) -quinazoline, (15) 4 - [(3-chloro-4-fluorophenyl) amino] -6- [2- (6-methyl-2-oxomorpholin-4 -yl) ethoxy] -7- (tetrahydropyran-3-yloxy) -quinazoline, (16) 4 - [(3-chloro-4-fluorophenyl) amino] -6- [2- (6-methyl-2-oxomorpholin-4 -yl) ethoxy] -7- (tetrahydropyran-4-yloxy) quinazoline, (17) 4 - [(3-chloro-4-fluorophenyl) amino] -6- [2- (6-methyl-2-oxomorpholin-4 -yl) ethoxy] -7- (tetrahydrofuran-2-ylmethoxy) quinazoline, (18) 4 - [(3-chloro-4-fluorophenyl) amino] -6- [2- (6-methyl-2-oxomorpholine-4 -il) ethoxy] -7- (tetragi ropyran-4-ylmethoxy) quinazoline, (19) 4 - [(3-chloro-4-fluorophenyl) amino] -6- [2- (6,6-dimethyl-2-oxomorpholin-4-yl) ethoxy] -7 - (tegrahydrofuran 3-yloxy) quinazoline, (20) 4 - [(3-chloro-4-fluorophenyl) amino] -6- [3- (6,6-dimethyl-2-oxomorpholin-4-yl) propyloxy] -7 - (tetrahydrofuran-3-yloxy) quinazoline, (21) 4 - [(3-chloro-4-fluorophenyl) amino] -6- [4- (6,6-dimethyl-2-oxomorpholin-4-yl) butyloxy] -7- (tetrahydrofuran-3-yloxy) quinazoline, (22) 4 - [(3-chloro-4-fluorophenyl) amino] -6- [2- (6,6-dimethyl-2-oxomorpholin-4-yl) ethoxy] -7- (tetrahydrofuran-2-ylmethoxy) -quinazoline, (23) 4 - [(3-chloro-4-fluorophenyl) amino] -6- [3- (6,6-dimethyl-2-oxomorpholin-4-yl) propyloxy] -7- (tetr agidrofuran-2-ylmethoxy) quinazoline,

- 22 005679 (24) 4 - [(3-chloro-4-fluorophenyl) amino] -6- [4- (6,6-dimethyl-2-oxomorpholin-4-yl) butyloxy] -7- (tetrahydrofuran-2 -ylmethoxy) quinazoline, (25) 4 - [(3-chloro-4-fluorophenyl) amino] -7- [2- (6-methyl-2-oxomorpholin-4-yl) ethoxy] -6- (tetrahydrofuran-3yloxy ) quinazoline, (26) 4 - [(3-chloro-4-fluorophenyl) amino] -7- [2- (6-methyl-2-oxomorpholin-4-yl) ethoxy] -6- (tetrahydropyran-3yloxy) quinazoline , (27) 4 - [(3-chloro-4-fluorophenyl) amino] -7- [2- (6-methyl-2-oxomorpholin-4-yl) ethoxy] -6- (tetrahydropyran-4yloxy) quinazoline, ( 28) 4 - [(3-chloro-4-fluorophenyl) amino] -7- [2- (6-methyl-2-oxomorpholin-4-yl) ethoxy] -6- (tetrahydrofuran-2ylmethoxy) quinazoline, (29) 4 - [(3-chloro-4- torphenyl) amino] -7- [2- (6-methyl-2-oxomorpholin-4-yl) ethoxy] -6- (tetrahydropyran-4ylmethoxy) quinazoline, (30) 4 - [(3-chloro-4-fluorophenyl) amino] -7- [2- (6,6-dimethyl-2-oxomorpholin-4-yl) ethoxy] -6- (tetrahydrofuran 3-yloxy) quinazoline, (31) 4- [(3-chloro-4-fluorophenyl) amino] -7- [3 - (6,6-dimethyl-2-oxomorpholin-4-yl) propyloxy] -6- (tetrahydrofuran-3-yloxy) quinazoline, (32) 4 - [(3-chloro-4- fluorophenyl) amino] -7- [4- (6,6-dimethyl-2-oxomorpholin-4-yl) butyloxy] -6- (tetrahydrofuran-3-yloxy) quinazoline, (33) 4 - [(3-chloro 4-fluorophenyl) amino] -7- [2- (6,6-dimethyl-2-oxomorpholin-4-yl) ethoxy] -6- (tetrahydrofuran-2-ylmethoxy) quinazoline, (34) 4 - [(3-chloro 4 ft orphenyl) amino] -7- [3- (6,6-dimethyl-2-oxomorpholin-4-yl) propyloxy] -6- (tetrahydrofuran-2-ylmethoxy) quinazoline, (35) 4 - [(3-chloro 4-fluorophenyl) amino] -7- [4- (6,6-dimethyl-2-oxomorpholin-4-yl) butyloxy] -6- (tetrahydrofuran-2-ylmethoxy) quinazoline.

Example 5. Bean with the content of the active substance 75 mg The composition is based on 1 core dragee: Active substance 75.0 mg Calcium phosphate 93.0 mg Corn starch 35.5 mg Polyvinylpyrrolidone 10.0 mg Hydroxypropyl methylcellulose 15.0 mg Magnesium stearate 1.5 mg 230.0 mg

Receiving:

The active ingredient is mixed with calcium phosphate, corn starch, polyvinylpyrrolidone, hydroxypropylmethylcellulose and half of the specified amount of magnesium stearate. From the mixture obtained, a tabletting machine produces pressed products with a diameter of approximately 13 mm, which are rubbed on a suitable machine through a sieve with a mesh size of 1.5 mm and mixed with the remaining amount of magnesium stearate. From this granulate, tablets of a given shape are pressed on a tabletting machine.

Kernel mass: 230 mg,

Punch: diameter 9 mm, with concave working surface.

The dragee cores obtained in this way are coated mainly consisting of hydroxypropyl methylcellulose. Finished coated tablets are polished with beeswax.

Pill weight: 245 mg.

Example 6. Tablets with an active substance content of 100 mg

The composition is based on 1 tablet:

Active ingredient 100.0 mg

Lactose 80.0 mg

Corn Starch 34.0 mg

Polyvinylpyrrolidone 4.0 mg

Magnesium stearate 2.0 mg

220.0 mg Preparation:

The active ingredient is mixed with lactose and starch and evenly moistened with an aqueous solution of polyvinylpyrrolidone. After squeezing the wet mass through a sieve (cell size 2.0 mm) and drying in a lattice drying oven at 50 ° C, the product is re-sieved through a sieve (cell size 1.5 mm) and the lubricant is mixed. The mixture, ready to pressing, is processed into tablets.

Tablet weight: 220 mg.

Tablet diameter: 10 mm, bipartite with a double-sided facet and a dividing notch on one side.

- 23 005679

Example 7. Tablets with an active substance 150 mg The composition is based on 1 tablet: Active substance 150.0 mg Lactose, powder 89.0 mg Corn starch 40.0 mg Colloidal silicic acid 10.0 mg Polyvinylpyrrolidone 10.0 mg Magnesium stearate 1.0 mg 300.0 mg

Receiving:

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

Tablet weight: 300 mg.

Punch: diameter 10 mm, with a flat working surface.

Example 8. Hard Gel capsules with an active ingredient content of 150 mg Composition per 1 capsule:

Active ingredient Corn starch, dried Lactose, powdered magnesium stearate 150.0 mg approximately 180.0 mg approximately 87.0 mg 3.0 mg approximately 420.0 mg

Receiving:

The active substance is mixed with auxiliary substances, sieved through a sieve with a mesh size of 0.75 mm and mixed to homogeneity in an appropriate apparatus. The resulting mixture is packaged in solid-gelatin capsules of size 1.

Capsule content weight: about 320 mg.

Capsule shell: size 1 hard gelatin capsule.

Example 9. Suppositories with an active substance content of 150 mg

The composition is based on 1 candle:

Active ingredient Polyethylene glycol 1500 Polyethylene glycol 6000 Polyoxyethylene sorbitan monostearate 150.0 mg 550.0 mg 460.0 mg 840.0 mg 2000.0 mg

Receiving:

After the mass for suppositories has been melted, the active substance is dispersed homogeneously in it and the molten mass is poured into previously cooled forms.

Example 10. Suspension with an active substance content of 50 mg

The composition is based on 100 ml of suspension:

1.00 g

0.10 g

0.05 g

0.01 g

10.00 g

5.00 g

20.00 g

0.30 g to 100 ml

Active ingredient №1-carboxymethylcellulose salt

P-hydroxybenzoic acid methyl ester p-hydroxybenzoic acid propyl ester Cane sugar

Glycerol

Sorbitol solution, 70%

Flavoring

Distilled water

Receiving:

Distilled water is heated to 70 ° C. Then, under stirring, dissolve the methyl and propyl esters of p-hydroxybenzoic acid, as well as glycerol and sodium carboxymethylcellulose. The solution is cooled to room temperature, the active substance is added with stirring and dispersed to homogeneity. After adding and dissolving sugar, sorbitol solution and flavoring, the suspension is evacuated with vacuum to remove air from it.

In 5 ml of suspension, the content of active ingredient is 50 mg. Example 11. Ampoules with an active substance content of 10 mg. Composition:

Active substance

0.01n. hydrochloric acid

Double distilled water

10.0 mg

84

up to 2.0 ml

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Receiving:

The active substance is dissolved in the required amount of 0.01 n. HC1, the solution is brought to isotonic by adding salt, sterilized by filtration and packaged in 2 ml ampoules.

Example 12. Ampoules with an active substance content of 50 mg

Composition:

Active ingredient 0.01 n. hydrochloric acid Double-distilled water 50.0 mg δ.ς. up to 10.0 ml

The active substance is dissolved in the required amount of 0.01 n. HC1, the solution is brought to isotonic by adding salt, sterilized by filtration and packaged in 10-ml ampoules.

Example 13. Capsules for powder inhalation with the content of the active substance 5 mg Composition per 1 capsule:

Active ingredient Lactose for inhalation 5.0 mg 15.0 mg 20.0 mg

Receiving:

The active ingredient is mixed with lactose for inhalation. The resulting mixture was filled into capsules (empty capsule weight about 50 mg) in a capsule filling machine.

Capsule weight: 70.0 mg.

Capsule size: 3.

Example 14. Solution for inhalation, containing 2.5 mg of active ingredient, for a manual inhaler

The composition is based on one portion, issued by a single click on the head of the inhaler:

Active ingredient Benzalkonium chloride 1 n. hydrochloric acid Ethanol / water (50:50) Preparation: 2,500 mg 0,001 mg Ts.8. up to 15,000 mg

The active ingredient and benzalkoniykhridid dissolved in ethanol / water (50:50 ratio). The pH value of the solution is set to neutral by adding 1N. of hydrochloric acid. The resulting solution is filtered and packaged in replaceable cartridges (cartridges) intended for a manual inhaler.

Mass content of the can: 4.5 g

Claims

CLAIM

1. Bicyclic heterocycles of the general formula

N in which

K _a denotes a benzyl or 1-phenylethyl group or a phenyl group substituted by K ₁ and K ₂ residues, wherein

K1 represents a hydrogen, fluorine, chlorine or bromine atom, a methyl, trifluoromethyl, cyano or ethynyl group, and

R2 represents hydrogen or fluorine, and one of the substituents K _i or K _with K ₃ denotes - (CH ₂₎ _m -O-group and the other of the substituents K _c or K _c denotes a methoxy, cyclobutyloxy, cyclopentyloxy, cyclopropylmethoxy-, cyclobutylmethoxy-, cyclopentylmethoxy-, tetrahydrofuran-3-yloxy-, tetrahydropyran-3-yloxy-, tetrahydropyran-4-yloxy-, tetrahydrofuranylmethoxy, or tetrahydropyranylmethoxy group, with

K ₃ represents X- (2-oxotetrahydrofuran-4-yl) methylamino or N- (2oxotetrahydrofuran-4-yl) ethylamino group substituted on the methylene groups with one or two methyl or ethyl groups of Cd-O-CO-CH ₂ - % CH ₂ CH ₂ —OH, where K4 denotes a hydrogen atom or a C _1-4 alkyl group, or is a 2-oxomorpholine-4-yl group substituted by one or two methyl or ethyl groups, and t is 2, 3 or 4 With the exception of the following compounds:

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4 - [(3-chloro-4-fluorophenyl) amino] -6-cyclopentyloxy-7- (2- {No. (2-hydroxy-2-methylprop-1-yl) -N [(ethoxycarbonyl) methyl] amino} ethoxy a) quinazoline,

4 - [(3-bromophenyl) amino] -6- [2- (6,6-dimethyl-2-oxomorpholin-4-yl) ethoxy] -7-methoxy-quinazoline and 4 - [(3-bromophenyl) amino] -6 - {2-Shch- (2-oxotetrahydrofuran-4-yl) -Methylamino] ethoxy} -7methoxyquinazoline, their tautomers, their stereoisomers and their salts.

2. Compounds of general formula I according to claim 1, in which B _a denotes a benzyl or 1-phenylethyl group or a phenyl group substituted by residues B1 and B2, wherein

B1 represents a hydrogen atom, fluorine, chlorine or bromine, a methyl, trifluoromethyl, cyano or ethynyl group, and

B2 represents a hydrogen or fluorine atom, and one of the substituents of B or B represents _a IN ₃ - (CH ₂₎ _m -O-group and the other substituents of B or B denotes a methoxy, cyclobutyloxy, cyclopentyloxy, cyclopropylmethoxy , cyclobutylmethoxy, cyclopentylmethoxy, tetrahydrofuran-3-yloxy, tetrahydropyran-3-yloxy, tetrahydropyran-4yloxy, tetrahydrofuranmethoxy, or tetrahydropyranylmethoxy,

B represents the No. (2-oxotetrahydrofuran-4-yl) methylamino or N- (2oxotetrahydrofuran-4-yl) ethylamino group substituted on the methylene groups with one or two methyl or ethyl groups of the B-O-CO-CH ₂ -CH group ₂ CH ₂ -OH, where

B4 represents a hydrogen atom or a C1-4 alkyl group, or is a 2-oxomorpholine-4-ilen group substituted by one or two methyl or ethyl groups, and t is 2, 3 or 4, with the exception of the following compounds:

4 - [(3-bromophenyl) amino] -6- [2- (6,6-dimethyl-2-oxomorpholin-4-yl) ethoxy] -7-methoxy-quinazoline, 4 - [(3-bromophenyl) amino] -6 - {2-Sch- (2-oxotetrahydrofuran-4-yl) -№ methylamino] ethoxy} -7 methoxy-quinazoline,

4 - [(3-chloro-4-fluorophenyl) amino] -6- {2-Sch- (2-oxotetrahydrofuran-4-yl) -Methylamino] ethoxy} -7-methoxyquinazoline,

4 - [(3-chloro-4-fluorophenyl) amino] -6- {2-Sch- (2-oxotetrahydrofuran-4-yl) -Methylamino] ethoxy} -7 cyclopentyloxyquinazoline,

4 - [(3-chloro-4-fluorophenyl) amino] -6- {2-Sch- (2-oxotetrahydrofuran-4-yl) -Methylamino] ethoxy} -7 cyclopentylmethoxyquinazoline,

4 - [(3-chloro-4-fluorophenyl) amino] -6- [3 - (6,6-dimethyl-2-oxomorpholin-4-yl) propyloxy] -7-methoxyquinazoline,

4 - [(3-chloro-4-fluorophenyl) amino] -6- [3 - (6,6-dimethyl-2-oxomorpholin-4-yl) propyloxy] -7-cyclopentyloxyquinazoline,

4 - [(3-chloro-4-fluorophenyl) amino] -6- [3 - (6,6-dimethyl-2-oxomorpholin-4-yl) propyloxy] -7-cyclopentylmethoxyquinazoline, (B) -4 - [( 1-phenylethyl) amino] -6- [3- (6,6-dimethyl-2-oxomorpholin-4-yl) propyloxy] -7-cyclopentyloxyquinazoline,

- 26 005679

4 - [(3-chloro-4-fluorophenyl) amino] -7- {2-Sch- (2-oxotetrahydrofuran-4-yl) -Y-methylamino] ethoxy} -6 methoxyquinazoline,

4 - [(3-chloro-4-fluorophenyl) amino] -7- {2-L- (2-oxotetrahydrofuran-4-yl) -Y-methylamino] ethoxy} -6 cyclopentyloxyquinazoline,

4 - [(3-chloro-4-fluorophenyl) amino] -7- {2-Sch- (2-oxotetrahydrofuran-4-yl) -Y-methylamino] ethoxy} -6 cyclopentylmethoxyquinazoline,

4 - [(3-chloro-4-fluorophenyl) amino] -7- [3 - (6,6-dimethyl-2-oxomorpholin-4-yl) propyloxy] -6-methoxyquinazoline,

4 - [(3-chloro-4-fluorophenyl) amino] -7- [3 - (6,6-dimethyl-2-oxomorpholin-4-yl) propyloxy] -6-cyclopentyloxyquinazoline,

4 - [(3-chloro-4-fluorophenyl) amino] -7- [3 - (6,6-dimethyl-2-oxomorpholin-4-yl) propyloxy] -6-cyclopentylmethoxyquinazoline and (K) -4 - [( 1-phenylethyl) amino] -7- [3- (6,6-dimethyl-2-oxomorpholin-4-yl) propyloxy] -6-cyclopentyloxyquinazoline, their tautomers, their stereoisomers and their salts.

3. Compounds of General formula I according to claim 1, in which

K _a denotes a 1-phenylethyl group or a phenyl group substituted by K ₁ and K ₂ residues, wherein

K ₁ is a fluorine, chlorine or bromine atom, a methyl or ethynyl group, and

K ₂ represents a hydrogen or fluorine atom, and one of the substituents Kb or Kc represents K3- (CH2) t-O- group, and the other of the substituents Kb or Kc denotes methoxy, cyclobutyloxy, cyclopentyloxy, cyclopropylmethoxy, cyclobutylmethoxy- , cyclopentylmethoxy-, tetrahydrofuran-3-yloxy-, tetrahydropyran-3-yloxy-, tetrahydropyran-4yloxy-, tetrahydrofuranmethoxy- or tetrahydropyranylmethoxy group, while

K ₃ is the No. (2-oxotetrahydrofuran-4-yl) methylamino group substituted on the methylene groups with one or two methyl groups, the K ₄ —O — CO — CH ₂ —Y — CH ₂ CH ₂ —OH group, where

K ₄ is a C _1-4 alkyl group, or a 2-oxomorpholin-4-yl group substituted by one or two methyl groups, and t is 2, 3 or 4, with the exception of the following compounds:

4 - [(3-chloro-4-fluorophenyl) amino] -6-cyclopentyloxy-7- (2-Shch- (2-hydroxy-2-methylprop-1-yl) -Y [(ethoxycarbonyl) methyl] amino} ethoxy a) quinazoline,

4 - [(3-bromophenyl) amino] -6- [2- (6,6-dimethyl-2-oxomorpholin-4-yl) ethoxy] -7-methoxy-quinazoline, 4 - [(3-bromophenyl) amino] -6 - {2-Shch- (2-oxotetrahydrofuran-4-yl) -Y-methylamino] ethoxy} -7-methoxyquinazoline,

4 - [(3-bromophenyl) amino] -6- (2-Shch- (2-hydroxy-2-methylprop-1-yl) -Y - [(ethoxycarbonyl) methyl] amino} ethoxy) -7-methoxyquinazoline,

4 - [(3-chloro-4-fluorophenyl) amino] -6- [2- (6,6-dimethyl-2-oxomorpholin-4-yl) ethoxy] -7-cyclopentylmethoxyquinazoline,

4 - [(3-chloro-4-fluorophenyl) amino] -6- {2-Sch- (2-oxotetrahydrofuran-4-yl) -Y-methylamino] ethoxy} -7 methoxyquinazoline,

- 27 005679

4 - [(3-chloro-4-fluorophenyl) amino] -6- [3 - (6,6-dimethyl-2-oxomorpholin-4-yl) propyloxy] -7-cyclopentylmethoxyquinazoline, (Я) -4 - [( 1-phenylethyl) amino] -6- [3- (6,6-dimethyl-2-oxomorpholin-4-yl) propyloxy] -7-cyclopentyloxyquinazoline,

4 - [(3-chloro-4-fluorophenyl) amino] -7- [2- (6,6-dimethyl-2-oxomorpholin-4-yl) ethoxy] -6-cyclopentylmethoxyquinazoline,

4 - [(3-chloro-4-fluorophenyl) amino] -7- {2-Shch- (2-oxotetrahydrofuran-4-yl) -Methylamino] ethoxy} -6 methoxyquinazoline,

4 - [(3-chloro-4-fluorophenyl) amino] -7- {2-Shch- (2-oxotetrahydrofuran-4-yl) -Methylamino] ethoxy} -6 cyclopentyloxyquinazoline,

4 - [(3-chloro-4-fluorophenyl) amino] -7- {2-Sch- (2-oxotetrahydrofuran-4-yl) -Methylamino] ethoxy} -6 cyclopentylmethoxyquinazoline,

4 - [(3-chloro-4-fluorophenyl) amino] -7- [3 - (6,6-dimethyl-2-oxomorpholin-4-yl) propyloxy] -6-cyclopentylmethoxyquinazoline and (I) -4 - [( 1-phenylethyl) amino] -7- [3- (6,6-dimethyl-2-oxomorpholin-4-yl) propyloxy] -6 cyclopentyloxyquinazoline, their tautomers, their stereoisomers and their salts.

4. Compounds of General formula I according to claim 1, in which

I _a denotes a 1-phenylethyl group or substituted residues I ₁ and I ₂ phenyl group, while

I ₁ is a fluorine, chlorine or bromine atom and

I ₂ represents a hydrogen or fluorine atom, and one of substituents _L or I _I I ₃ represents - (CH ₂₎ _m -O-group and the other of the substituents or I _b I _c denotes a methoxy, cyclobutyloxy, cyclopentyloxy , cyclopropylmethoxy-, cyclobutylmethoxy-, cyclopentylmethoxy-, tetrahydrofuran-3-yloxy-, tetrahydropyran-3-yloxy-, tetrahydropyran-4yloxy-, tetrahydrofuranylmethoxy- or tetrahydropyranylmethoxy, with

I ₃ is the no. (2-oxotetrahydrofuran-4-yl) methylamino group or the 2-oxomorpholin-4-ilen group substituted by one or two methyl groups, and t is the number 2, 3 or 4, with the exception of the following compounds:

- 28 005679

4 - [(3-chloro-4-fluorophenyl) amino] -6- [3 - (6,6-dimethyl-2-oxomorpholin-4-yl) propyloxy] -7-cyclo pentylmethoxyquinazoline, (S) -4- [ (1-Phenylethyl) amino] -6- [3- (6,6-dimethyl-2-oxomorpholin-4-yl) propyloxy] -7-cyclopentyloxyquinazoline,

4 - [(3-chloro-4-fluorophenyl) amino] -7- {2- [M- (2-oxotetrahydrofuran-4-yl) -Y-methylamino] ethoxy} -6 cyclopentylmethoxyquinazoline,

4 - [(3-chloro-4-fluorophenyl) amino] -7- [3 - (6,6-dimethyl-2-oxomorpholin-4-yl) propyloxy] -6-cyclopentylmethoxyquinazoline and (U) -4 - [( 1-phenylethyl) amino] -7- [3- (6,6-dimethyl-2-oxomorpholin-4-yl) propyloxy] -6 cyclopentyloxyquinazoline, their tautomers, their stereoisomers and their salts.

5. Compounds of General formula I according to claim 1, in which

Yu denotes a 1-phenylethyl, 3-bromophenyl or 3-chloro-4-fluorophenyl group,

The _s represents Yu ₃ - (CH ₂₎ _m -O-group wherein

S ₃ is a 2-oxomorpholine-4-substituted group with one or two methyl groups, and t is 2 or 3, and

Yus denotes a methoxy, cyclobutyloxy, cyclopentyloxy, cyclopropylmethoxy, tetrahydrofuran-3-yloxy or tetrahydrofuranylmethoxy group, with the exception of the following compounds:

- 29 005679

4 - [(3-chloro-4-fluorophenyl) amino] -6- [3 - (6,6-dimethyl-2-oxomorpholin-4-yl) propyloxy] -7-cyclopentyloxyquinazoline and (K) -4 - [( 1-phenylethyl) amino] -6- [3- (6,6-dimethyl-2-oxomorpholin-4-yl) propyloxy] -7 cyclopentyloxyquinazoline, their tautomers, their stereoisomers and their salts.

6. Compounds of General formula I according to claim 1, in which

B represents a 3-chloro-4-fluorophenyl group,

K stands for cyclopentyloxy, cyclopropylmethoxy, cyclopentylmethoxy, tetrahydrofuran-3yloxy or tetrahydrofuranmethoxy and

K _with denotes K ₃ - (CH ₂ ) _t -O-group, where

K ₃ is a 2-oxomorpholine-4-substituted group substituted by one or two methyl groups, and t is 2, except for the following compounds:

7. Compounds of General formula I according to claim 1 from the group including:

(1) 4 - [(3-chloro-4-fluorophenyl) amino] -6-cyclopentylmethoxy-7- [2- (2,2-dimethyl-6-oxomorpholine-4yl) ethoxy] quinazoline, (2) 4- [ (3-chloro-4-fluorophenyl) amino] -6-cyclopentyloxy-7- {2-Sch- (2-oxotetrahydrofuran-4-yl) -N methylamino] ethoxy} quinazoline, (3) 4 - [(3-chloro -4-fluorophenyl) amino] -6-cyclopropylmethoxy-7- [2- (2,2-dimethyl-6-oxomorpholine-4yl) ethoxy] quinazoline, (4) 4 - [(3-chloro-4-fluorophenyl) amino ] -7-cyclobutyloxy-6- [3- (2,2-dimethyl-6-oxomorpholin-4-yl) propyloxy] quinazoline, (5) 4 - [(3-chloro-4-fluorophenyl) amino] -7- cyclopropylmethoxy-6- [3- (2,2-dimethyl-6-oxomorpholine-4yl) propyloxy] quinazoline, (6) 4 - [(3-chloro-4-fluorophenyl) amino] -6-cyc lopropylmethoxy-7- {2-Sch- (2-oxotetrahydrofuran-4-yl) No. methylamino] ethoxy} quinazoline, (7) 4 - [(3-bromophenyl) amino] -6- [2 - (8) -6 -methyl-2-oxomorpholin-4-yl) ethoxy] -7-methoxy-quinazoline, (8) 4 - [(3-bromophenyl) amino] -6- [2 - ((K) -6-methyl-2-oxomorpholine- 4-yl) ethoxy] -7-methoxyquinazoline, (9) 4 - [(3-chloro-4-fluorophenyl) amino] -6- [2 - (K) -6-methyl-2-oxomorpholin-4-yl ) ethoxy] -7-methoxyquinazoline, (10) 4 - [(3-chloro-4-fluorophenyl) amino] -6- [3 - ((K) -6-methyl-2-oxomorpholin-4-yl) propyloxy] -7-methoxyquinazoline, (11) 4 - [(K) - (1-phenylethyl) amino] -6- [3 - ((8) -6-methyl-2-oxomorpholin-4-yl) propyloxy] -7- methoxyquinazoline, (12) 4 - [(K) - (1-phenylethyl) amino] -6- [2 - ((8) -6-meth L-2-oxomorpholin-4-yl) ethoxy] -7-methoxy-quinazoline and (13) 4 - [(3-chloro-4-fluorophenyl) amino] -6- [2 - ((8) -6-methyl-2 -oxomorpholin-4-yl) ethoxy] -7-methoxy-quinazoline, their tautomers, their stereoisomers and their salts.

8. Physiologically acceptable salts of the compounds according to any one of claims 1 to 7 with inorganic or organic acids or bases.

9. A drug containing a compound according to any one of claims 1 to 7 or a physiologically acceptable salt according to claim 8, as well as optionally one or more inert carriers and / or diluents.

10. The use of a compound according to any one of claims 1 to 8 to obtain a drug suitable for the treatment of benign or malignant tumors, for the prevention and treatment of diseases of the respiratory tract and lungs, for the treatment of polyps, diseases of the gastrointestinal tract, bile duct and gall bladder, as well as the kidneys and skin.

11. The method of obtaining a medicinal product according to claim 9, characterized in that the compound according to any one of claims 1 to 8 is processed in a non-chemical manner together with one or more inert carriers and / or diluents.

12. The method of obtaining compounds of General formula I according to any one of claims 1 to 8, characterized in that

a) compound of general formula

N in which

H _a has the meanings indicated in claims 1–7 and one of the substituents _Hb ′ or H _c ′ denotes a methoxy, cyclobutyloxy, cyclopentyloxy, cyclopropylmethoxy, cyclobutylmethoxy or cyclopentylmethoxy group, and the other of the substituents _Hb ′ or H _c 'means 7! - (CH ₂ ) _t -O-group, where t has the values specified in paragraphs 1-7, and

Ζι is a leaving group, is reacted with a compound of general formula

H-H3 (III), in which H ₃ has the values specified in claims 1-7, and / or the compound of general formula I thus obtained is divided into its stereoisomers, and / or the compound of general formula I thus obtained is converted into its salt first of all, in its physiologically acceptable salts suitable for pharmaceutical use.

13. The method of producing compounds of general formula I according to any one of paragraphs.1-8, characterized in that the compound of general formula formed under certain conditions in the reaction mixture obtained according to paragraph 12

N ^E \ /

Wherein N is at values indicated in claims 1-7 and one of the substituents Hb or _Hc denotes a methoxy, cyclobutyloxy, cyclopentyloxy, cyclopropylmethoxy, or tsiklobutilmetoksi- tsiklopentilmetoksigruppu and the other of the substituents H _L or H _with H denotes ₃ '- (CH ₂ ) _t -O-group, where t has the values specified in claims 1-7, and

H ₃ 'is a Cz-O-CO-CH ₂ A-CH ₂ CH ₂ -OH group substituted by methylene groups with one or two methyl or ethyl groups, in which

H4 denotes a hydrogen atom or a C1-4 alkyl group, cyclizes and then, if necessary, clears the protective group used in the above reactions and, or if necessary, the compound of the general formula I obtained in this way, is separated into its stereoisomers, and / or thus obtained. The compound of general formula I is converted to its salts, primarily to its physiologically acceptable salts suitable for pharmaceutical use.