SK287747B6 - 4-Aminoquinazolines, method for producing thereof and pharmaceutical compositions containing them - Google Patents

Abstract

Described are bicyclic heterocycles of the general formula (I), 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; pharmaceutical compositions containing them and method for producing thereof.

Description

Technical field

The present invention relates to 4-aminoquinazoles, a process for their preparation, pharmaceutical compositions containing them.

BACKGROUND OF THE INVENTION

4-Aminoquinazoline are described in WO 98/13354 as VEGF inhibitors, for example for the treatment of cancer and rheumatoid arthritis. In their application, systemic side effects often occur, which are largely due to their resistance to cleavage by plasma enzymes.

SUMMARY OF THE INVENTION

The present invention relates to 4-aminoquinazoles of the general formula

and their salts, in particular their physiologically acceptable salts with inorganic or organic acids or bases, having valuable pharmacological properties, in particular the inhibitory effect of tyrosine kinase-mediated signal transduction, their use in the treatment of diseases, in particular cancer, lung and respiratory diseases, and their manufacture .

In the above general formula (I)

R ^a is 1-phenylethyl group or a phenyl group substituted with groups R ¹ and R ^2, wherein R ¹ is F, Cl or Br and R ² is a hydrogen or fluorine atom, one of R ^b and R ^c is R ³ - (CH _{2) m} O-, and the remaining of R ^b and R ^c is methoxy, cyclobutyloxy, cyclopentyloxy, cyclopropylmethoxy, cyclobutylmethoxy, cyclopentylmethoxy, tetrahydrofuran-3-yloxy, tetrahydropyran-3-yloxy, tetrahydropyran-4-yloxy-, tetrahydrofuranylmethoxy- or tetrahydropyranylmethoxy group, wherein:

R ³ is N - (2-oxo-tetrahydrofuran-4-yl) -methylamino or 2-oxo-morpholin-4-yl substituted with one or two methyl groups and m is 2, 3 or 4, provided that they are excluded the following compounds:

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

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

4 - [(3-Bromo-phenylamino) -6- [2- (3-methyl-2-oxo-morpholin-4-yl) -ethoxy] -7-methoxy-quinazoline,

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

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

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

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

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

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

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

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

4 - [(3-chloro-4-fluoro-phenyl) amino] -6- {2 - [/ V- (2-oxo-tetrahydrofuran-4-yl) -N-methylamino] -ethoxy} -7 cyclopentylmethoxy-quinazoline,

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

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

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

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

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

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

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

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

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

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

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

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

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

4 - [(3-chloro-4-fluoro-phenyl) amino] -7- [3- (6,6-dimethyl-2-oxo-morpholin-4-yl) -propyloxy] -6-cyclopentylmethoxy-quinazoline and ( R) -4 - [(1-Phenyl-ethyl) amino] -7- [3- (6,6-dimethyl-2-oxo-morpholin-4-yl) -propyloxy] -6-cyclopentyloxy-quinazoline, their tautomers, stereoisomers and salts thereof.

Particularly preferred compounds of formula (I) are those in which

R ^a is 1-phenylethyl, 3-bromophenyl or 3-chloro-4-fluorophenyl,

R ^b represents a group R ³ - (CH ₂ ) _m -O- in which

R ³ is 2-oxo-morpholin-4-yl radical substituted by one or two methyl groups and m represents the number 2 or 3, and

R ^c is methoxy, cyclobutyloxy-, cyclopentyloxy-, cyclopropylmethoxy-, tetrahydrofuran-3-yloxy- or tetrahydrofuranylmethoxy, provided that the following compounds are excluded:

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

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

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

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

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

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

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

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

4 - [(3-chloro-4-fluoro-phenyl)] amino] -6- [3- (6,6-dimethyl-2-oxo-morpholin-4-yl) -propyloxy] -7-cyclopentyloxy-quinazoline and ( R - 4 - [(1-Phenyl-ethyl) amino] -6- [3- (6,6-dimethyl-2-oxo-morpholin-4-yl) -propyloxy] -7-cyclopentyloxy-quinazoline, their tautomers, stereoisomers and salts thereof.

Particularly preferred compounds of formula (I) are also those in which

R ^a represents a 3-chloro-4-fluoro-phenyl group,

R ^b is cyclopentyloxy-, cyclopropylmethoxy-, cyclopentylmethoxy-, tetrahydrofuran-3-yloxy- or tetrahydrofuranylmethoxy and R ^c is a group R ³ - (CH ₂ ) _m -O- in which

R ³ represents a 2-oxo-morpholin-4-yl group substituted with one or two methyl groups and m represents the number 2, provided that the following compounds are excluded:

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

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

4 - [(3-chloro-4-fluoro-phenyl) amino] -7- [2- (6,6-dimethyl-2-oxo-morpholin-4-yl) -ethoxy] -6-cyclopentylmethoxy-quinazoline; tautomers, stereoisomers and salts thereof.

As particularly preferred compounds, the following are exemplified:

(1) 4 - [(3-chloro-4-fluoro-phenyl) amino] -7-cyclobutyloxy-6- [3- (2,2-dimethyl-6-oxo-morpholin-4-yl) -propyloxy] - quinazoline, (2) 4 - [(3-chloro-4-fluoro-phenyl) amino] -7-cyclopropylmethoxy-6- [3- (2,2-dimethyl-6-oxo-morpholin-4-yl) -propyloxy (3) 4 - [(3-chloro-4-fluoro-phenyl) amino] -6-cyclopropylmethoxy-7- {2- [N - (2-oxo-tetrahydro-furan-4-yl) -] - N-methyl-amino-ethoxy} -quinazoline, (4) 4 - [(3-bromo-phenyl) amino] -6- [2 - ((S) -6-methyl-2-oxo-morpholin-4-yl) -ethoxy] -7-methoxy-quinazoline, (S) 4 - [(3-bromo-phenyl) amino] -6- [2 - ((R) -6-methyl-2-oxo-morpholin-4-yl) -ethoxy] -7-methoxy-quinazoline, (6) 4 - [(3-chloro-4-fluorophenyl) amino] -6- [2 - ((R) -6-methyl-2-oxo-morpholine- (7) 4 - [(3-chloro-4-fluorophenyl) amino] -6- [3 - ((R) -6-methyl-4-yl) -ethoxy] -7-methoxy- (8) 4 - [(R) - (1-Phenyl-ethyl) amino] -6- [3- (2-oxo-morpholin-4-yl) -propyloxy] -7-methoxy-quinazoline ((S) -6-methyl-2-oxo-morpholin-4-yl) -propyloxy] -7-methoxy-quinazoline, (9) 4 - [(R) - (1-phenyl-ethyl) amino] - 6- [2 - ((5j-6-methyl-2-oxo-morpholin-4-yl) -ethoxy] -7-methoxy-quinazoline and (10) 4 - [(3-chloro-4-fluoro-phenyl) amino] -6- [2 - ((5,6-methyl-2-oxo-morpholin-4-yl) -ethoxy] -7 -methoxy-quinazoline, their tautomers, their stereoisomers and their salts.

Compounds of formula (I) may be prepared, for example, as follows: a) Reaction of a compound of formula

, (II) in which

R "is as defined above, one of R or R ^{bl C |} represents methoxy, cyclobutyloxy-, cyclopentyloxy-, cyclopropylmethoxy-, cyclobutylmethoxy- or cyclopentylmethoxy and the remainder of the groups R ^b 'or R ^C '^; represents a group Z '- (CH 2) _{n 1} -O-, wherein m is as defined above and

Z ¹ represents a leaving group such as a halogen atom or a sulfonyloxy group such as a chlorine or bromine atom, a methanesulfonyloxy group or a p-toluenesulfonyloxy group, with a compound of the general formula

HR ³ (III), in which R ³ is guaranteed earlier.

The reaction is optionally carried out in a solvent or solvent mixture such as methylene chloride, acetonitrile, dimethylformamide, dimethylsulfoxide, sulfolane, benzene, toluene, chlorobenzene, tetrahydrofuran, benzene / tetrahydrofuran or dioxane suitably in the presence of a tertiary organic base such as triethyl amine or triethylamine; diisopropylamine, wherein the organic base may also serve as a solvent or in the presence of an inorganic base such as sodium carbonate or potassium carbonate at a temperature in the range of -20 to 200 ° C, more preferably at a temperature in the range of 0 to 150 ° C .

b) Cyclization of a compound which may be formed in the reaction mixture of the general formula (IV)

in which

R ^a is as defined above, one of R ^b or R ^c is methoxy, cyclobutyloxy, cyclopentyloxy, cyclopropylmethoxy, cyclobutylmethoxy or cyclopentylmethoxy and the remainder of R ^b or R ^c is R ³ '- (CH ₂ ) _m -O-, wherein m is as defined above and

R ³ 'represents a group R ⁴ -O-CO-CH 2 -N-CH 2 CH 2 -OH substituted on methylene groups by one or two methyl or ethyl groups in which R ⁴ represents a hydrogen atom or a C 1-4 -alkyl group.

Alternatively, the reaction is carried out in a solvent or solvent mixture such as methylene chloride, acetonitrile, dimethylformamide, dimethylsulfoxide, sulfolane, benzene, toluene, chlorobenzene, tetrahydrofuran, benzene / tetrahydrofuran or dioxane suitably in the presence of anhydrous acid such as trifluoroacetic acid, methanesulfonic acid, sulfuric acid or in the presence of a dehydrating agent, for example, in the presence of isobutyl chloroformate, thionyl chloride, trimethylchlorosilane, phosphorus trichloride, phosphorus pentoxide, N, N'-dicyclohexylcarbodiimide, N, N'-dicyclohexylcarbodiimide or N, N-dihydroxide; N, N'-carbonyldiimidazole or triphenylphosphine / tetra-chlorohydrocarbon, at a temperature in the range of -20 to 200 ° C, more preferably at a temperature in the range of -10 to 160 ° C.

In the reactions described, optionally reactive groups such as hydroxy, carboxy or imino groups may be protected during the reaction by conventional protecting groups which are cleaved again after the reaction.

Suitable hydroxyl groups for the hydroxy group are trimethylsilyl, acetyl, benzoyl, methyl, ethyl, tert-butyl, trityl, benzyl or tetrahydropyranyl, as carboxy protecting groups trimethylsilyl, methyl, ethyl, Zerobutyl, benzyl or tetrahydropyranyl imino groups are formyl, acetyl, trifluoroacetyl, ethoxycarbonyl, tert-butoxycarbonyl, benzyloxycarbonyl, benzyl, methoxybenzyl or 2,4-dimethoxybenzyl.

Any subsequent cleavage of the protecting group used is carried out, for example, hydrolytically in an aqueous solvent, for example water, isopropanol / water, acetic acid / water, tetrahydrofuran / water or dioxane / water, in the presence of an acid such as trifluoroacetic acid, hydrochloric acid or acid. 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 temperatures ranging from 0 to 120 ° C, more preferably at temperatures ranging from 10 to 100 ° C.

The cleavage of the benzyl, methoxybenzyl or benzyloxycarbonyl group is, however, carried out, for example, hydrogenolytically, for example with hydrogen in the presence of a catalyst such as palladium / carbon in a suitable solvent such as methanol, ethanol, ethyl acetate or glacial acetic acid. temperatures in the range of from 0 to 100 ° C, more preferably at temperatures in the range of from 20 to 60 ° C, and at a hydrogen pressure of from 0.1 to 0.7 MPa (from 1 to 7 bar), more preferably from 0.3 up to 0.5 MPa (from 3 to 5 bar). The cleavage of the 2,4-dimethoxybenzyl group, however, is preferably carried out in trifluoroacetic acid in the presence of anisole.

Cleavage of the tert-butyl or the tert-butyloxycarbonyl group is preferably carried out by treatment with acids such as trifluoroacetic acid or hydrochloric acid or with iodotrimethylsilane, optionally using a solvent such as methylene chloride, dioxane, methanol or diethyl ether.

The cleavage of the trifluoroacetyl group is more preferably carried out by treatment with an acid such as hydrochloric acid optionally in the presence of a solvent such as acetic acid at temperatures ranging from 50 to 120 ° C or with sodium hydroxide optionally in the presence of a solvent such as tetrahydrofuran at temperatures ranging from 0 to 50 ° C

Furthermore, the compounds of formula (I) obtained above may be separated into their enantiomers and / or diastereomers. Thus, for example, cis-itrans mixtures can be separated into their cis and trans isomers, and compounds having at least one optically active carbon atom into their enantiomers.

Thus, for example, it is possible to separate the cis -trans mixtures obtained by chromatography into their cis and trans isomers, and to obtain the compounds of formula (I) present in racemic form according to generally known methods (see Allinger NL and Eliel EL in "Topics in Stereochemistry", Volume 6, Wiley

Interscience, 1971) into their optical antipodes and compounds of formula (I) containing at least two asymmetric carbon atoms can be separated, by their physicochemical differences by generally known methods, for example by chromatography and / or fractional crystallization, into their diastereomers, formed in racemic form, they can then be resolved as enantiomers.

The separation of enantiomers is preferably carried out by column separation on chiral phases or by recrystallization from an optically active solvent or by reaction with an optically active substance, in particular acids and their activated derivatives or alcohols, which forms salts or derivatives such as esters or amides with the racemic compound. a diastereomeric mixture of salts or derivatives obtained in the process, for example on account of their different solubilities, whereby free antipodes can be released from the pure diastereomeric salts or derivatives by suitable means. Particularly common optically active acids are, for example, the D- and L-forms of tartaric acid or dibenzoyltartaric acid, di-o-tolyltartaric acid, malic acid, mandelic acid, camphorsulfonic acid, glutamic acid, aspartic acid or quinolinic acid. Suitable optically active alcohol is, for example, (+) - or (-) - menthol and, as optically active acyl group in amides, for example, is (+) - or (-) - mentyloxycarbonyl.

Furthermore, the compounds of formula (I) obtained can be converted by their inorganic or organic acids into their salts, in particular for pharmaceutical use, into their physiologically acceptable salts. Suitable acids for this purpose are, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, methanesulfonic acid, phosphoric acid, fumaric acid, succinic acid, lactic acid, citric acid, tartaric acid or maleic acid.

In addition, the novel compounds of the formula (I) thus obtained, if they contain a carboxy, hydroxyphosphoryl, sulfo or 5-tetrazolyl group, can optionally be converted, by inorganic or organic bases, into their salts, in particular to physiologically acceptable salts for pharmaceutical use. . Suitable bases here are, for example, sodium hydroxide, potassium hydroxide, arginine, cyclohexylamine, ethanolamine, diethanolamine and triethanolamine.

The compounds of formulas (II) to (IV) used as starting materials are partly known from the literature or are obtained in a manner known from the literature (see Examples I to XIV).

As already mentioned, the compounds of the formula (I) and their physiologically acceptable salts have valuable pharmacological properties, in particular an inhibitory effect on the signal transduction mediated by the Epidermal Growth Factor Receptor (EGF-R), which may be caused, for example, by inhibition of ligand binding. , receptor dimerization or tyrosine kinase alone.

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

Inhibition of EGF-R-mediated signal transduction can be demonstrated, for example, by cells that express human EGF-R and whose survival and proliferation depend on stimulation via EGF or TGF-alpha. Here, an interleukin-3- (IL-3) dependent cell line was used that was genetically altered to functionally express human EGF-R. Proliferation of these F / F-HERc named cells can therefore be stimulated either through mouse IF-3 or through EGF (see von Riiden, T. et al. In EMBO J, 7, 2749-2756 (1988) and Pierce, JH et al. in Science 239: 628-631 (1988).

The starting material for the F / L-HERc cells was the cell line ^FDC-P1 whose preparation has been described by Dexter, TM, et al, J. Exp. Med. 152, 1036-1047 (1980). Alternatively, other growth factor-dependent cells may be used (see, e.g., Pierce, JH et al. In Science 239, 628-631 (1988); Shibuya, H. et al. In Cell 70, 57-67 (1992) and Alexander, WS et al. in EMBO J. 10, 3683-3691 (1991) Recombinant retroviruses were used to express human EGF-R cDNA (see Ullrich, A. et al. in Nature 309, 418-425 (1984) as described in von. Ruden, T. et al. In EMBO J, 7, 2749-2756 (1988), except that the retroviral vector LXSN was used to express EGF-R cDNA (see Miller, AD et al. In BioTechniques 7, 980-990 (1989)). and the GP + E86 line served as the envelope cell (see Markowitz, D. et al., J. Virol. 62, 1120-1124 (1988)).

The test was performed as follows:

F / L-HERc cells were cultured in RPMI / 1640 Medium (BioWhittaker) supplemented with 10% fetal bovine serum (FCS, Boehringer Mannheim), 2 mM glutamine (BioWhittaker), standard antibiotic and 20 ng / ml human EGF (Promega) , at 37 ° C and 5% CO ₂ . To determine the inhibitory activity of the compounds of the invention, 1.5 x 10 ⁴ cells per well were cultured in triplicate in a 96-well plate in the indicated medium (200 μΐ), with cell proliferation stimulated with either EGF (20 ng / ml) or IL-3 mice. Excess cultures of the X63 / 0 mIL-3 cell line served as a source for IL-3 (see Karasuyama, H. et al., Eur. J. Immunol. 18, 97-104 (1988). Compounds of the invention were dissolved in 100% - dimethylsulfoxide (DMSO) and added at various dilutions to the cultures at a maximum DMSO concentration of 1% The cultures were incubated for 48 hours at 37 ° C.

To determine the inhibitory activity of the compounds of the invention, the relative cell number was measured using Cell Titer 96 ™ AQ _ue111 with Non-Radioactive Cell Proliferation Assay (Promega) in OD units. The relative cell number was calculated as percentage of control (F / LHERc cells without inhibitor). the active compound concentration which inhibits cell proliferation by 50% (IC _50). The following results were obtained here:

compound Inhibition of EGF-dependent proliferation (example #) IC ₅₀ [nM] 1 59 1 (1) 29 1 (2) 29 2 (1) 36

The compounds of the formula I inhibit the signal transduction by tyrosine kinase as shown in the example of the human EGF receptor and are therefore useful for the treatment of pathophysiological processes which are induced by the increased activity of tyrosine kinases. These are, for example, benign or malignant tumors, in particular tumors of epithelial and neuroepithelial origin, metastases, as well as abnormal proliferation of vascular endothelial cells (neoangiogenesis).

The compounds of the invention are also useful for the prevention and treatment of respiratory and lung diseases characterized by increased or altered mucus production caused by tyrosine kinase stimulation, such as in inflammatory respiratory diseases such as chronic bronchitis, chronic obstructive bronchitis, asthma, bronchiectasis, allergic or non-allergic rhinitis or sinusitis, cystic fibrosis, al-antitrypsin deficiency, or cough, pulmonary emphysema, pulmonary fibrosis and hyperreactive respiratory tract.

The compounds are also useful in the treatment of gastric and biliary tract and gall bladder diseases caused by impaired tyrosine kinase activity, such as found in chronic inflammatory changes such as cholecystitis, M. Crohn, Colitis ulcerosa, and gastric ulcers. intestinal tract or as they occur in diseases of the gastrointestinal tract characterized by increased secretion such as M. Ménétrier, secreted adenomas and protein loss syndromes, as well as for the treatment of nasal polyps as well as polyps in the gastrointestinal tract of various development such as villous or adenomatous colon polyps, but also polyps of the familial Polyposis coli, in intestinal polyps under Gardnero syndrome, in polyps of the whole gastric-intestinal tract in PeutzJeghers syndrome, in inflammatory pseudopolyps, in juvenile polyps, in Colitis cystica profúumata and stinales.

In addition, it is possible to use the compounds of formula (I) and their physiologically acceptable salts for the treatment of kidney diseases, in particular cystic changes such as those of the kidney cysts, for the treatment of kidney cysts, which may be idiopathic or syndromed such as in tuberous sclerosis, von-Hippel-Lindau syndrome, nephtonoflisis and meoloma kidney, as well as other diseases caused by aberrant tyrosine kinase function, such as epidermal hyperproliferation (Psoriasis), inflammatory processes, diseases of the immune system, etc.

Based on biological properties, the compounds of the invention may be used alone or in combination with other pharmacologically active compounds, for example for the treatment of cancer in monotherapy or in combination with other anti-cancer therapeutics, for example in combination with topoisomerase inhibitors (e.g. Etoposide), mitosis inhibitors (e.g. Vinblastin) ), compounds interacting with nucleic acids (e.g. cis-Platin, Cyclophosphamide, Adriamycin), hormonal antagonists (e.g. Tamoxifen), inhibitors of metabolic processes (e.g. 5-FU, etc.), cytokines (e.g. Interferonen), and antibodies, etc. For the treatment of airway diseases, these compounds may be used alone or in combination with other airway therapeutics such as secretory, broncholytic and / or anti-inflammatory agents. For the treatment of diseases in the area of the gastrointestinal tract, it is also possible to use these compounds alone or in combination with agents affecting mobility or secretion or with anti-inflammatory agents. These combinations may be administered either concurrently or sequentially.

Administration of these compounds, either alone or in combination with other active agents, can be carried out either intravenously, subcutaneously, intramuscularly, intrarectally, intraperitoneally, intranasally, by inhalation or transdermally or orally, with aerosol formulations being particularly suitable for inhalation.

For pharmaceutical application, the compounds of the invention are generally used in warm-blooded vertebrate animals, in particular in humans, at a dosage of from 0.01 to 100 mg / kg body weight, more preferably from 0.1 to 15 mg / kg. For dosing, these compounds are mixed with one or more conventional inert carriers and / or diluents, for example, corn starch, milk sugar, cane sugar, microcrystalline cellulose, magnesium stearate, polyvinylpyrrolidone, citric acid, tartaric acid, water, water / water / water / water / water / glycerin, water / sorbitol, water / polyethylene glycol, propylene glycol, stearyl alcohol, carboxymethylcellulose or a fatty substance such as hardened fat or with suitable mixtures thereof in conventional galenical preparations such as tablets, dragees, capsules, powders, suspensions, solutions, sprays suppositories.

The following examples are intended to further illustrate the present invention without limiting it.

DETAILED DESCRIPTION OF THE INVENTION

Production of starting materials:

Preparation 1

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

To 3.50 g of 4 - [(3-chloro-4-fluoro-phenyl) amino] -6-cyclopentylmethoxy-7-hydroxy-quinazoline and 6.89 ml of 1,2-dibromomethane in 40 ml of N, N-dimethylformamide are added. 4.84 g of potassium carbonate was added. The reaction mixture was stirred under a nitrogen atmosphere at 80 ° C for 1.5 hours. After cooling to room temperature, the reaction mixture was filtered and the filtrate was concentrated in vacuo. The oily brown residue was cooled in an ice bath and triturated with a little methanol to crystallize a yellowish solid. The precipitate was filtered off with suction, washed with cold methanol and dried in a vacuum desiccator.

Yield: 2.60 g (58% of theory)

_{R f} value: 0.82 (silica gel, methylene chloride / methanol 9: 1)

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

Analogous to Preparation 1, the following compounds were obtained:

(1) 4 - [(3-Chloro-4-fluoro-phenyl) amino] -6-cyclopropylmethoxy-7- (2-bromo-ethoxy) -quinazoline (reaction was performed in acetonitrile as solvent)

Rf value: 0.72 (silica gel, methylene chloride / methanol / concentrated aqueous ammonia solution = 90: 10: 0.1) Mass spectrum (ESP): m / z = 464, 466, 468 [MH] - (2) 4- [ (3-chloro-4-fluoro-phenyl) amino] -6-cyclopentyloxy-7- (2-bromo-ethoxy) -quinazoline

Rf value: 0.65 (silica gel, methylene chloride / methanol / concentrated aqueous ammonia solution = 90: 10: 0.1) Mass spectrum (ESI -): m / z = 478, 480, 482 [MH] - (3) 4- [(3-Chloro-4-fluoro-phenyl) amino] -7-cyclobutyloxy-6- (3-bromo-propyloxy) -quinazoline (reaction was carried out in acetonitrile as solvent)

Rf value: 0.62 (silica gel, methylene chloride / methanol 9: 1)

Mass Spectrum (ESI -): m / z = 478, 480, 482 [MH] - (4) 4 - [(3-Chloro-4-fluoro-phenyl) amino] -7-cyclopropylmethoxy-6- (3-bromo) -propyloxy) -quinazoline (the reaction was carried out in acetonitrile as solvent)

Rf: 0.74 (silica gel, methylene chloride / methanol 9: 1)

Mass Spectrum (ESI): m / z = 478, 480, 482 [M-H] - (5) 4 - [(3-Bromo-phenyl) amino] -6- (2-bromo-ethoxy) -7-methoxy-quinazoline

Mp 244 ° C

Mass Spectrum (ESI ⁺ ): m / z = 452, 454, 456 [M + H] ⁺ (6) 4 - [(R) - (1-Phenyl-ethyl) amino] -6- (3-bromo-propyloxy) ) -7-methoxy-quinazoline (reaction was carried out with potassium tert-butylate as base)

Rf value: 0.60 (silica gel, acetate / methanol 9: 1) (7) 4 - [(R) - (1-phenyl-ethyl) amino] -6- (2-bromoethoxy) -7-methoxy- quinazoline (the reaction was carried out with potassium tert-butylate as the base)

M.p .: 255 ° C

Mass Spectrum (ESI ⁺ ): m / z = 402, 404 [M + H] ⁺ (8) 4 - [(3-Chloro-4-fluoro-phenyl) amino] -6- (3-hydroxy-propyloxy) - 7-cyclobutyloxy-quinazoline

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

Mass Spectrum (ESI ⁺ ): m / z = 418, 420 [M + H] ⁺ (9) 4 - [(3-Chloro-4-fluoro-phenyl) amino] -6- (3-hydroxy-propyloxy) - 7-cyclopropylmethoxy-quinazoline

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

Mass Spectrum (ESI ⁺ ): m / z = 418, 420 [M + H] ⁺ (10) 4 - [(3-Chloro-4-fluoro-phenyl) amino] -6- (2-bromoethoxy) - 7-cyclopentyloxy-quinazoline

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

Mass Spectrum (ESI ⁺ ): m / z = 480, 482, 484 [M + H] ⁺ (11) 4 - [(3-Chloro-4-fluoro-phenyl) amino] -6- (2-bromo-ethoxy) ) -7-cyclopropylmethoxy-quinazoline

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

Mass Spectrum (ESI ⁺ ): m / z = 466, 468, 470 [M + H] ⁺ (12) 4 - [(3-Chloro-4-fluoro-phenyl) amino] -6-cyclopropylmethoxy-7- (3) -hydroxy-propyloxy) -quinazoline Rf value: 0.53 (silica gel, methylene chloride / methanol = 90: 10)

Mass Spectrum (ESI ⁺ ): m / z = 418, 420 [M + H] ⁺ (13) 4 - [(3-Chloro-4-fluoro-phenyl) amino] -6- (4-hydroxy-butyloxy) - 7-cyclopentyloxy-quinazoline

Rf value: 0.46 (silica gel, acetate) (14) 4 - [(3-Chloro-4-fluorophenyl) amino] -6- (2-bromoethoxy) -7 - ((R) - tetrahydrofuran-3-yloxy) -quinazoline Rf value: 0.37 (silica gel, methylene chloride / methanol = 9: 1)

Mass Spectrum (ESE): m / z = 480, 482, 484 [MH] - (15) 4 - [(3-Chloro-4-fluoro-phenyl) amino] -6- (2-bromo-ethoxy) -7 - [(R) - (tetrahydrofuran-2-yl) -methoxy] -quinazoline Mass spectrum (ESE): m / z = 494, 496, 498 [MH] - (16) 4 - [(3-Chloro-4-) Fluoro-phenyl) amino] -7- (2-bromo-ethoxy) -6 - [(S) - (tetrahydrofuran-2-yl) -methoxy] -quinazoline Mass spectrum (ESI): m / z = 494, 496, 498 [MH] -

Preparation 2

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

4.99 g of 4 - [(3-chloro-4-fluoro-phenyl) amino] -6-cyclopentylmethoxy-7-methylcarbonyloxy-quinazoline was suspended in 80 ml of methanol and treated with 1.80 ml of concentrated aqueous ammonia solution. . The reaction mixture was stirred overnight at room temperature. To work up the reaction mixture, the reaction mixture was diluted with 500 ml of methylene chloride, washed with water and saturated sodium chloride solution, dried over magnesium sulfate and concentrated. 4.30 g of a brownish solid was obtained. The crude product was mixed with tert-butyl methyl ether, filtered off with suction and washed with a small amount of tert-butyl methyl ether and dried in vacuo at room temperature.

Yield: 3.59 g (80% of theory)

Rf value: 0.48 (silica gel, methylene chloride / methanol / concentrated aqueous ammonia solution = 9: 10: 0.1) Mass spectrum (ESI ⁺ ): m / z = 388, 340 [M + H] ⁺

Analogously to Preparation 2, the following compounds were obtained:

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

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

Mass Spectrum (ESE): m / z = 358,360 [M-H] (2) 4 - [(3-Chloro-4-fluoro-phenyl) amino] -6-cyclopentyloxy-7-hydroxy-quinazoline

Rf value: 0.53 (silica gel, methylene chloride / methanol / concentrated aqueous ammonia solution = 90: 10: 0.1) Mass spectrum (ESI ⁺ ): m / z = 374, 376 [M + H] ⁺ (3) 6- benzyloxy-4 - [(3-chloro-4-fluoro-phenyl) amino] -7-hydroxy-quinazoline

Rf value: 0.54 (silica gel, methylene chloride / methanol / concentrated aqueous ammonia solution = 90: 10: 0.1) Mass spectrum (ESI ⁺ ): ni / z = 396, 398 [M + H] ⁺ (4) 4- [(3-Bromo-phenyl) amino] -6-hydroxy-7-methoxy-quinazoline (reaction was carried out with sodium hydroxide in ethanol as solvent)

Rf value: 0.23 (silica gel, acetate)

Mass Spectrum (ESI ⁺ ): m / z = 346, 348 [M + H] ⁺ (5) 4 - [(3-Chloro-4-fluoro-phenyl) amino] -7-hydroxy-6 - ((5) tetrahydrofuran-3-yloxy) -quinazoline

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

Mass Spectrum (ESI ⁺ ): m / z = 376, 378 [M + H] ⁺ (6) 4 - [(3-Chloro-4-fluoro-phenyl) amino] -7-hydroxy-6 - [(5) - (tetrahydrofuran-2-yl) methoxy] -quinazoline

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

Preparation

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

4.03 g of 4-chloro-6-cyclopentylmethoxy-7-methylcarbonyloxyquinazoline were suspended in 70 ml of isopropanol and mixed with 1.95 g of 3-chloro-4-fluoroaniline. The reaction mixture was heated under reflux under nitrogen atmosphere for two hours. After cooling to room temperature, the resulting light precipitate was aspirated, washed with a small amount of isopropanol and air dried.

Yield: 4.99 g (92% of theory)

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

In analogy to Preparation 3, the following compounds were obtained:

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

Rf value: 0.86 (silica gel, methylene chloride / methanol = 9: 1)

Mass Spectrum (ESI ⁺ ): m / z = 402, 404 [M + H] ⁺ (2) 4 - [(3-Chloro-4-fluoro-phenyl) amino] -6-cyclopentyloxy-7-methylcarbonyloxy-chazoline

Rf value: 0.73 (silica gel, methylene chloride / methanol / concentrated aqueous ammonia solution = 90: 10: 0.1) Mass spectrum (ESI ⁺ ): m / z = 416, 419 [M + H] ⁺ (3) 6-Benzyloxy-4 - [(3-chloro-4-fluoro-phenyl) amino] -7-methylcarbonyloxy-quinazoline

Rf value: 0.76 (silica gel, methylene chloride / methanol / concentrated aqueous ammonia solution = 90: 10: 0.1) Mass spectrum (ESI ⁺ ): m / z = 388, 390 [M + H] ⁺ (4) 4 - [(3-Bromo-phenyl) amino] -6-methylcarbonyloxy-7-methoxy-quinazoline

_{R f} value: 0.50 (silica gel, ethyl)

Mass Spectrum (ESI ⁺ ) m / z = 346, 348 [M + H] ⁺ (S) 4 - [(R) - (1-Phenyl-ethyl) amino] -6-hydroxy-7-methoxy-quinazoline (the acetoxy protecting group was removed under the reaction conditions)

Rf value: 0.46 (silica gel, acetate)

Mass Spectrum (ESI ⁺ ): m / z = 296 [M + H] ⁺ (6) 6-Benzyloxy-4 - [(3-chloro-4-fluoro-phenyl) amino] -7-cyclopentyloxy-quinazoline (as auxiliary) base added pyridine)

Rf value: 0.51 (silica gel, methylene chloride / methanol = 95: 5)

Mass Spectrum (ESI ⁺ ): m / z = 464, 466 [M + H] ⁺ (7) 4 - [(3-Chloro-4-fluoro-phenyl) amino] -7-methylcarbonyloxy-6 - ((S) -tetrahydrofuran-3-yloxy) -quinazoline Rf value: 0.67 (silica gel, methylene chloride / methanol = 9: 1)

Mass Spectrum (ESI): m / z = 416, 418 [MH] (8) 4 - [(3-Chloro-4-fluoro-phenyl) amino] -7-methylcarbonyloxy-6 - [(5) - (tetrahydrofuran- 2-yl) -methoxy] -chraznaoline hydrochloride

Melting point: 274-276 ° C

Mass spectrum (ESI ⁺ ): m / z = 432, 434 [M + H] < ⁺ > ^.

Preparation 4

4-Chloro-6-cyclopentylmethoxy-7-methylcarbonyloxy-quinazoline

3.80 g of 4-hydroxy-6-cyclopentylmethoxy-7-methylcarbonyloxy-quinazoline were suspended in 90 ml of thionyl chloride and heated to boiling under nitrogen. After addition of four drops of N, N -dimethylformamide, the reaction mixture was heated at reflux for two hours. After cooling to room temperature, the excess thionyl chloride was distilled off in a water pump vacuum. The brown residue was mixed with 30 ml of toluene. The solvent was distilled off to give 4.30 g of an off-brown solid which was reacted further without further purification.

Rf value: 0.89 (silica gel, methylene chloride / methanol / concentrated aqueous ammonia solution = 90: 10: 0.1) Analogously to Preparation 4, the following compounds were obtained:

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

Rf value: 0.84 (silica gel, methylene chloride / methanol 9: 1) (2) 4-Chloro-6-cyclopentyloxy-7-methylcarbonyloxy-quinazoline

Rf value: 0.69 (silica gel, methylene chloride / methanol / concentrated aqueous ammonia solution = 90: 10: 0.1) (3) 6-Benzyloxy-4-chloro-7-methylcarbonyloxy-quinazoline

Rf value: 0.77 (silica gel, methylene chloride / methanol / concentrated aqueous ammonia = 90: 10: 0.1) (4) 6-Benzyloxy-4-chloro-7-cyclopentyloxy-quinazoline

Rf value: 0.91 (silica gel, methylene chloride / methanol = 9: 1) (5) 4-Chloro-7-methylcarbonyloxy-6 - ((S) -tetrahydrofuran-3-yloxy) -quinazoline

Rf value: 0.83 (silica gel, acetate / methanol = 9: 1) (6) 4-Chloro-7-methylcarbonyloxy-6 - [(S) - (tetrahydrofuran-2-ylmethoxy) -quinazoline

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

Preparation

4-Hydroxy-6-cyclopentylmethoxy-7-methylcarbonyloxy-quinazoline

4.30 g of 4,7-dihydroxy-6-cyclopentylmethoxyquinazoline were heated in 80 ml of pyridine at 80 ° C under nitrogen. 1.80 ml of acetic anhydride was added to the dark brown suspension. The reaction mixture was stirred at 80 ° C for three hours to give a complete solution. After cooling to room temperature, the reaction mixture was poured into approximately 800 mL of ice water. The resulting precipitate was aspirated and washed thoroughly with water. The light gray solid was dried in a vacuum desiccator.

Yield: 3.82 g (77% of theory)

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

Mass Spectrum (ESP): m / z = 301 [M-H] < - >

In analogy to Preparation 5, the following compounds were obtained:

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

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

Mass Spectrum (ESI -): m / z = 273 [M-H] - (2) 4-Hydroxy-6-cyclopentyloxy-7-methylcarbonyloxy-quinazoline

Mp 209-212 ° C

Mass Spectrum (ESI +): m / z = 287 [M-H] - (3) 6-Benzyloxy-4-hydroxy-7-methylcarbonyloxy-quinazoline

Rf value: 0.48 (silica gel, methylene chloride / methanol / concentrated aqueous ammonia solution = 90: 10: 0.1) Mass spectrum (ESI +): m / z = 309 [MH] - (4) 4-Hydroxy-7-methylcarbonyloxy 6 - ((5) -tetrahydrofuran-3-yloxy) -quinazoline

Rf value: 0.62 (DC-ready reversed phase board (E. Merck), acetonitrile-water / trifluoroacetic acid = 50: 50: 1)

Mass Spectrum (ESP): m / z = 291 [M + H] ⁺ (S) 4-Hydroxy-7-methylcarbonyloxy-6 - [(S) - (tetrahydrofuran-2-yl) methoxy] quinazoline

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

Mass spectrum (ESP): m / z = 305 [M + H] < ⁺ > ^.

Preparation 6

4,7-Dihydroxy-6-cyclopentylmethoxy-quinazoline

5.76 g of 2-amino-5-cyclopentylmethoxy-4-hydroxybenzoic acid and 6.52 g of formamidine acetate were heated in refluxing 140 ml of ethanol for approximately three hours. Upon work-up, the reaction mixture was concentrated to approximately 100 ml and 300 ml of ice water were added thereto, whereupon a gray precipitate precipitated. The precipitate was suction filtered, washed with water and dried in a vacuum desiccator.

Yield: 4.57 g (77% of theory)

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

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

In analogy to Preparation 6, the following compounds were obtained:

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

Rf value: 0.45 (silica gel, methylene chloride / methanol / concentrated aqueous ammonia solution = 90: 10: 0.1) Mass spectrum (ESI -): m / z = 231 [MH] - (2) 4.7- Dihydroxy -6-cyclopentyloxyquinazoline

_{R f} value: 0.42 (silica gel, methylene chloride / methanol / concentrated aqueous ammonia = 9: 10: 0.1) Mass spectrum (EI): m / z = 246 [M] ⁺ (3) 6-Benzyloxy-4 , 7-dihydroxy-quinazoline

Rf value: 0.44 (silica gel, methylene chloride / methanol / concentrated aqueous ammonia solution = 90: 10: 0.1) Mass spectrum (ESI '): m / z = 367 [MH] (4) 6-Benzyloxy-7-cyclopentyloxy -4-hydroxy-quinazoline

Melting point: 221-223 ° C

Mass Spectrum (ESI ⁺ ): m / z = 337 [M + H] ⁺ (S) 4,7-Dihydroxy-6 - ((S) -tetrahydrofuran-3-yloxy) -quinazoline

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

Mass Spectrum (ESI): m / z = 247 [M-H] (6) 4,7-Dihydroxy-6 - [(S) - (tetrahydrofuran-2-yl) methoxy] quinazoline

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

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

Preparation 7

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

6.50 g of 5-cyclopentylmethoxy-4-hydroxy-2-nitro-benzoic acid was dissolved in 130 ml of methanol, mixed with 2.00 g of Raney nickel and hydrogenated at 50 psi hydrogen for about three hours at room temperature. (50 psi) until the calculated amount of hydrogen was received. The catalyst was filtered off and washed with hot methanol. The filtrate was concentrated in vacuo. A brownish solid formed which was allowed to react further without further purification.

Yield: 5.79 g (100% of theory)

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

Mass Spectrum (ESI): m / z = 250 [M-H] -

In analogy to Preparation 7, the following compounds were obtained:

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

Rf value: 0.51 (silica gel, methylene chloride / methanol / concentrated aqueous ammonia solution = 90: 10: 0.1) Mass spectrum (ESI '): m / z = 222 [MH] (2) 2-Amino-5- acid cyclopentyloxy-4-hydroxy-benzoic acid

Rf value: 0.38 (silica gel, methylene chloride / methanolConcentrated aqueous ammonia solution = 90: 10: 0.1) Mass spectrum (ESI ⁺ ): m / z = 238 [M + H] ⁺ (3) 2-Amino-5 acid benzyloxy-4-hydroxy-benzoic acid

Rf value: 0.52 (silica gel, methylene chloride / methanol / concentrated aqueous ammonia solution = 90: 10: 0.1) Mass spectrum (ESI '): m / z = 258 [MH] - (4) 2-Amino-cyclopentyl ester 5-benzyloxy-4-cyclopentyloxy-benzoic (the reaction was carried out in a 1: 1 mixture of methanol and tetrahydrofuran)

Rf value: 0.84 (silica gel, acetate / cyclohexane = 1: 1)

Mass Spectrum (ESI ⁺ ): m / z = 396 [M + H] ⁺ (5) 2-Amino-4-hydroxy-5 - ((S) -tetrahydrofuran-3-yloxy) benzoic acid

Rf value: 0.70 (DC-ready reversed phase plate (E. Merck), acetonitrile / water / trifluoroacetic acid = 50: 50: 1)

Mass Spectrum (ESI): m / z = 238 [M-H] - (6) 2-Amino-4-hydroxy-5 - [(S) - (tetrahydrofuran-2-yl) methoxy] -benzoic acid

Rf value: 0.59 (DC-ready reversed phase plate (E. Merck), acetonitrile / water / trifluoroacetic acid = 50: 50: 1)

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

Preparation

5-Cyclopentylmethoxy-4-hydroxy-2-nitro-benzoic acid

15.37 g of 4,5-methylenedioxy-2-nitro-benzoic acid and 51.84 ml of cyclopentyl-methanol were dissolved in

100 ml of dimethylsulfoxide and cooled under an nitrogen atmosphere in an ice bath. 3.90 g of sodium were added in portions. The reaction mixture was stirred under cooling with an ice bath for 30 minutes, then briefly warmed to 35-40 ° C and stirred for an additional three hours under cooling with an ice bath. Subsequently, the ice bath was removed and the reaction mixture was stirred overnight at room temperature. The dark brown-red reaction solution was poured into approximately 800 mL acetone, whereupon a dark brown precipitate precipitated. The precipitate was filtered off with suction, washed with acetone, dissolved in 300 to 400 ml of water and the pH was adjusted to approximately 2 with 60 ml of 2N hydrochloric acid. The aqueous solution was extracted several times with methylene chloride. The combined extracts were washed with saturated sodium chloride solution, dried over sodium sulfate and concentrated. The dark brown, oily residue in the flask was dissolved in 800 mL of methylene chloride and purified through a silica gel pad with methylene chloride / methanol (9: 1). A brown oil was obtained which, after dilution with water, was crystallized by cooling in an ice bath. The resulting brownish precipitate was suction filtered, washed with a little water and dried in a vacuum desiccator.

Yield: 9.55 g (47% of theory)

Rf value: 0.67 (silica gel, toluene / dioxane / ethanol / glacial acetic acid = 90: 10: 10: 6)

Mass Spectrum (ESI -): m / z = 280 [M-H] -

In analogy to Preparation 8, the following compounds were obtained:

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

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

Mass spectrum (ESI -): m / z = 252 [M-H] - (2) 5-Cyclopentyloxy-4-hydroxy-2-nitro-benzoic acid

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

Mass Spectrum (ESI -): m / z = 266 [M-H] (3) 5-Benzyloxy-4-hydroxy-2-nitro-benzoic acid

Melting point: 176-178 ° C

Mass Spectrum (ESI '): m / z = 288 [M-H] - (4) 4-Hydroxy-2-nitro-5 - ((S) -tetrahydrofuran-3-yloxy) -benzoic acid

Rf value: 0.58 (DC-ready reversed phase plate (E. Merck), acetonitrile / water / trifluoroacetic acid = 50: 50: 1)

Mass Spectrum (ESI '): m / z = 268 [M-H] - (5) 4-Hydroxy-2-nitro-5 - [(S) - (tetrahydrofuran-2-yl) methoxy] -benzoic acid

Rf value: 0.53 (DC-ready reversed phase plate (E. Merck), acetonitrile / water / trifluoroacetic acid = 50: 50: 1)

Mass Spectrum (ESI ’): m / z = 282 [M-H]’

Preparation 9

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

To 50.00 g of glycine ethyl ester hydrochloride in 100 ml of saturated potassium carbonate solution was added 100.00 g of sodium carbonate while cooling. The resulting mass was extracted several times with a total of approximately 600 mL of diethyl ether. The combined ether extracts were dried over sodium sulfate and concentrated to dryness. 28.60 g of glycine ethyl ester was formed. This was mixed with 26.00 mL of isobutylene oxide and 40 mL of absolute ethanol and heated at 90 ° C for six hours in a Roth autoclave. After cooling to room temperature, the reaction mixture was concentrated to give a thin oil.

Yield: 45.8 g (73% of theory)

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

Preparation 10

4-methylamino-dihydro-furan-2-one

2.00 g of 4- (N-benzyl- N -methyl-amino) -dihydro-furan-2-one in 25 ml of methanol was hydrogenated for about two hours at room temperature in the presence of 250 mg of palladium (10%). on activated carbon) at 50 psi of hydrogen until the calculated amount of hydrogen was received. On working up, the catalyst was filtered off and the filtrate was concentrated in vacuo. A colorless oil was formed which reacted immediately without further purification.

Yield: 1.20 g

Rf value: 0.13 (silica gel, acetate)

Mass spectrum (ESI ⁺ ): m / z = 116 [M + H] < ⁺ > ^.

Preparation 11

4 (A-Benzyl-N-methyl-amino) -dihydro-furan-2-one

To 15.00 g of 5H-furan-2-one in 150 ml of methylene chloride was added 23.20 ml of N-methylbenzylamine. The reaction mixture was stirred for about 48 hours at room temperature. Upon working up, the reaction mixture was concentrated and chromatographed in portions over a silica gel column with acetate / petroleum ether (3: 1) as the mobile phase. The desired product was obtained as a yellowish oil.

Yield: 19.77 g (54% of theory)

Rf value: 0.67 (silica gel, acetate)

Mass spectrum (ESI ⁺ ): m / z = 228 [M + Na] ^< ^{+ >.}

Preparation 12

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

To 5.60 g of 6-benzyloxy-4 - [(3-chloro-4-fluoro-phenyl) amino] -7-cyclobutyloxy-quinazoline, 10 ml of trifluoroacetic acid was added dropwise with stirring. The reaction mixture was heated to about 40 ° C. After stirring at room temperature for 20 hours, 3 ml of trifluoroacetic acid were added once more. After the reaction has almost not progressed at room temperature for an additional three hours of stirring, the reaction mixture is heated to 50 ° C. After four hours, the reaction was complete and excess trifluoroacetic acid was distilled off on a large scale rotary evaporator. The residue was mixed with water and made alkaline with a concentrated aqueous ammonia solution. The resulting pale brown precipitate was aspirated, washed with plenty of water and dried in a desiccator. The product obtained still contained trifluoroacetic acid.

Yield: 5.82 g

Rf value: 0.61 (silica gel, methylene chloride / methanol = 9: 1)

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

In analogy to Preparation 12, the following compounds were obtained:

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

_{R f} value: 0.65 (silica gel, methylene chloride / methanol = 9: 1)

Mass Spectrum (ESI ⁺ ): m / z = 360, 362 [M + H] ⁺ (2) 4 - [(3-Chloro-4-fluoro-phenyl) -amino] -7-cyclopentyloxy-6-hydroxy-quinazoline

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

Mass Spectrum (ESI ⁺ ): m / z = 374, 376 [M + H] ⁺ (3) 4 - [(3-Chloro-4-fluoro-phenyl) amino] -6-hydroxy-7 - ((7? ) -tetrahydrofuran-3-yloxy) -quinazoline

Rf value: 0.32 (silica gel, methylene chloride / methanol = 9: 1) (4) 4 - [(3-Chloro-4-fluorophenyl) amino] -6-hydroxy-7 - [(R) - ( tetrahydrofuran-2-yl) methoxy] -quinazoline

Mass Spectrum (ESI): m / z = 388.390 [M-H] '

Preparation 13

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

To 7.00 g of 6-benzyloxy-4 - [(3-chloro-4-fluoro-phenyl) amino] -7-hydroxy-quinazoline in 60 ml of N, N-dimethylformamide was added 7.50 g of potassium carbonate and 4, 50 g of methanesulfonic acid cyclobutyl ester. The reaction mixture was stirred at 80 ° C for two hours. Then 2.00 g of methanesulfonic acid cyclobutyl ester and 3.00 g of potassium carbonate were added and the reaction mixture was stirred at 60 ° C over the weekend. Since the reaction was not complete, 3.50 g of methanesulfonic acid cyclobutyl ester and 5.00 g of potassium carbonate were added once more. After an additional 20 hours at 80 ° C, the reaction was almost complete. For work-up, the reaction mixture was mixed with 300 ml of acetate and washed with water and saturated sodium chloride solution. The organic phase was dried over magnesium sulfate and concentrated. The residue was mixed with methanol to give a brownish precipitate. This was aspirated, washed with methanol and dried in a desiccator.

Yield: 5.10 g (64% of theory)

Rf value: 0.69 (silica gel, methylene chloride / methanol = 9: 1)

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

In analogy to Preparation 13, the following compounds were obtained:

(1) 6-Benzyloxy-4 - [(3-chloro-4-fluoro-phenyl) amino] -7-cyclopropylmethoxy-quinazoline (bromomethylcyclopropane was used)

Rf value: 0.72 (silica gel, methylene chloride / methanol = 9: 1)

Mass spectrum (EST): m / z = 448, 450 [MH] - (2) 6-Benzyloxy-4 - [(3-chloro-4-fluoro-phenyl) amino] -7-cyclopentyloxy-quinazoline (bromocyclopentane was used) )

_{R f} value: 0.78 (silica gel, methylene chloride / methanol = 9: 1)

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

Preparation 14

(S) - (2-Hydroxy-propylamino) -acetic acid tert-butyl ester

15.00 g of (S) - (+) - 1-amino-2-propanol were dissolved in 100 ml of N, N-dimethylformamide and mixed with

6.97 ml of diisopropylethylamine. Then, 5.91 ml of tert-butyl bromoacetate was added dropwise over 30 minutes while cooling in an ice bath. The cooling bath was removed and the reaction mixture was stirred overnight at room temperature. For working up, the reaction mixture was concentrated in vacuo. The residue in the flask was dissolved in 50 ml of water and saturated with 15 g of sodium chloride. The aqueous solution was extracted several times with acetate. The combined extracts were washed with saturated brine, dried over magnesium sulfate and concentrated in vacuo to give a yellowish oil.

Yield: 7.36 g (97% of theory)

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

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

Analogously to Preparation 14, the following compounds were obtained:

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

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

Mass Spectrum (ESI ⁺ ): m / z = 190 [M + H] ⁺ (2) ((1,1-Dimethyl-2-hydroxy-ethylamino) -acetic acid tert-butyl ester)

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

Rf value: 0.47 (silica gel, methylene chloride / methanol / concentrated aqueous ammonia solution = 90: 10: 0.1) Preparation 15

4 - [(3-chloro-4-fluoro-phenyl) amino] -6- (3-methanesulfonyloxy-propoxy) -7-cyclobutyloxy-quinazoline

The compound was obtained by reacting 4 - [(3-chloro-4-fluoro-phenyl) amino] -6- (3-hydroxy-propyloxy) -7-cyclobutyloxy-quinazoline with methanesulfonic acid chloride in methylene chloride in the presence of diisopropylethylamine at room temperature.

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

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

In analogy to Preparation 15, the following compounds were obtained:

(1) 4 - [(3-Chloro-4-fluoro-phenyl) amino] -6- (3-methanesulfonyloxy-propyloxy) -7-cyclopropylmethoxy-quinazoline Rf: 0.65 (silica gel, methylene chloride / methanol = 90: 10 )

Mass Spectrum (ESI): m / z = 494, 496 [MH] - (2) 4 - [(3-Chloro-4-fluoro-phenyl) amino] -6-cyclopropylmethoxy-7- (3-methanesulfonyloxy-propyloxy) -quinazoline Rf value: 0.73 (silica gel, methylene chloride / methanol = 90: 10)

Mass Spectrum (ESI ⁺ ): m / z = 496, 498 [M + H] ⁺ (3) 4 - [(3-Chloro-4-fluorophenyl) amino] -6- (4-methanesulfonyloxy-butyloxy) -7- cyclopentyloxy-quinazoline Rf value: 0.76 (silica gel, methylene chloride / methanol = 90: 10)

Mass spectrum (ESI ⁺ ): m / z = 524.526 [M + H] ⁺

Preparation 16

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

The compound was obtained by hydrogenation of 6-benzyloxy-4 - [(3-chloro-4-fluoro-phenyl) -amino] -7-cyclopropylmethoxy-quinazoline in the presence of 1% Pd / C in a mixture of methylene chloride, ethanol and concentrated hydrochloric acid ( 500: 210: 3.5) in the Parr apparatus.

Yield: 73%

Mass spectrum (ESI ⁺ ): m / z = 360.362 [M + H] < ⁺ > ^.

Preparation 17

5-Benzyloxy-4-cyclopentyloxy-2-nitro-benzoic acid cyclopentylester

The compound was obtained by reacting 5-benzyloxy-4-hydroxy-2-nitro-benzoic acid with 2.2 equivalents of bromocyclopentane in the presence of potassium carbonate as an auxiliary base in dimethylsulfoxide at room temperature.

Yield: 87%

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

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

Preparation 18

4 - [(3-chloro-4-fluoro-phenyl) amino] -6-benzyloxy-7 - ((/?) - tetrahydrofuran-3-yloxy) -quinazoline

To a solution consisting of 8.00 g of 4 - [(3-chloro-4-fluorophenyl) amino] -6-benzyloxy-7-hydroxy-quinazoline (see WO 0055141 A1) and 2.42 ml of (S) - ( + - - 3-Hydroxy-tetrahydrofuran and 7.95 g of triphenylphosphine in 160 ml of tetrahydrofuran were added dropwise to 5.03 ml of diethyl azodicarboxylic acid ester. The reaction mixture was stirred overnight at room temperature and then concentrated in a rotary evaporator. The residue in the flask was purified by silica gel column chromatography using a methylene chloride / acetate mixture (gradient from 2: 1 to 1: 2) as the mobile phase.

Yield: 7.34 g (78% of theory)

Melting point: 165-168 ° C

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

In analogy to Preparation 18, the following compounds were obtained:

(1) 4 - [(3-Chloro-4-fluoro-phenyl) amino] -6-benzyloxy-7 - [(R) - (tetrahydrofuran-2-yl) methoxy] -chazoline Mass spectrum (ESI ⁺ ) : m / z = 480, 482 [M + H] < ⁺ > ^.

_{R f} value: 0.38 (silica gel, methylene chloride / methanol = 15: 1) (2) 4 - [(3-chloro-4-fluoro-phenyl) amino] -7- (2-bromo-ethoxy) -6- ((S) -tetrahydrofuran-3-yloxy) -quinazoline Rf value: 0.35 (silica gel, methylene chloride / methanol = 20: 1)

Production of final compounds

Example 1

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

250 mg of 4 - [(3-chloro-4-fluoro-phenyl) amino] -6-cyclopentylmethoxy-7- (2-bromoethoxy) -quinazoline and 341 mg of (2-hydroxy-2-methyl-propylamino) -acetic acid ethyl ester are added. was dissolved in 20 ml of acetonitrile and mixed with 50 mg of sodium iodide, 275 mg of potassium carbonate and 0.70 ml of diisopropylethylamine. The reaction mixture was heated to reflux for about 90 hours. After cooling to room temperature, the reaction mixture was filtered and the filtrate was concentrated in vacuo. The residue in the flask was chromatographed over a silica gel column using petroleum ether / acetate (50:50, later 0: 100) as the mobile phase. The cyclized product was obtained as a beige-colored solid.

Yield: 62 mg (23% of theory)

Rf: 0.29 (silica gel, acetate)

Mass spectrum (ESI): m / z = 541.543 [M-H] -

In analogy to Example 1, the following compounds were obtained:

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

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

Mass Spectrum (ESI): m / z = 513, 515 [MH] (2) 4 - [(3-Chloro-4-fluoro-phenyl) amino] -7-cyclobutyloxy-6- [3- (2,2- dimethyl-6-oxo-morpholin-4-yl) propyloxy] quinazoline

Mp .: 212-214 ° C

Mass Spectrum (ESI): m / z = 527,529 [MH] - (3) 4 - [(3-Chloro-4-fluoro-phenyl) amino] -7-cyclopropylmethoxy-6- [3- (2,2) dimethyl-6-oxo-morpholin-4-yl) propyloxy] quinazoline

Melting point: 200-202 ° C

Mass Spectrum (ESI): m / z = 527,529 [MH] - (4) 4 - [(3-Chloro-4-fluorophenyl) amino] -6- [3- (2,2-dimethyl-6)] oxo-morpholin-4-yl) propyloxy] -7-methoxy-quinazoline

Melting point: 222-224 ° C

Mass spectrum (EST): m / z = 487.489 [M-H] -

Example 2

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

300 mg of 4 - [(3-chloro-4-fluoro-phenyl) amino] -6-cyclopropylmethoxy-7- (2-bromoethoxy) -quinazoline and 400 mg of 4-methylaminopyridofuran-2-one in 20 ml of acetonitrile were mixed with 240 ml of potassium carbonate and 70 mg of sodium iodide were heated under reflux for 24 hours. After cooling to room temperature, the reaction mixture was filtered and the filtrate was concentrated in vacuo. The residue in the flask was chromatographed through a silica gel column using methylene chloride / methanol / concentrated aqueous ammonia (97: 3: 0.05) as the mobile phase. The title compound was obtained as a light beige-colored solid.

Yield: 70 mg (22% of theory)

_{R f} value: 0.47 (silica gel, methylene chloride / methanol / concentrated aqueous ammonia = 90: 10: 0.1) Mass spectrum (ESI ^+): m / z = 501, 503 [M + H] ⁺

In analogy to Example 2, the following compounds were obtained:

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

Rf value: 0.42 (silica gel, methylene chloride / methanol / concentrated, aqueous ammonia = 90: 10: 0.1)) Mass spectrum (ESI ⁺ ): m / z = 515, 517 [M + H] ⁺ (2) 4 - [(3-chloro-4-fluoro-phenyl) amino] -6- {3 - [/ V- (2-oxo-tetrahydrofuran-4-yl) - / V-methyl-amino] propyloxy} -7 -cyklobutyloxy-quinazoline

Melting point: 147.5-151 ° C

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

Example 3

4 - [(3-Bromo-phenyl) amino] -6- [2 - ((5) -6-methyl-2-oxo-morpholin-4-yl) -ethoxy] -7-methoxy-quinazoline

To 380 mg of 4 - [(3-bromo-phenyl) amino] -6- (2- {N - [(tert-butyloxycarbonyl) methyl] - N - ((5 -2-hydroxy-propyl) -amino} -) of ethoxy) -7-methoxy-quinazoline in 8 ml of acetonitrile was added 90 μΐ of methanesulfonic acid, and the reaction mixture was heated at reflux for about 3 hours, followed by the addition of methanesulfonic acid equivalent again and heated under reflux until the reaction was complete. For work-up, the reaction mixture was diluted with acetate and washed with saturated sodium bicarbonate solution and saturated sodium chloride solution, the organic phase was dried over magnesium sulfate and concentrated in vacuo, and the residue in the flask was stirred with diethyl ether and sucked off. solid.

Yield: 280 mg (85% of theory)

Mp .: 190 ° C

Mass Spectrum (EST): m / z = 485, 487 [M-H] < - >

In analogy to Example 3, the following compounds were obtained:

(1) 4 - [(3-Bromo-phenyl) amino] -6- [2 - ((R, 6-methyl-2-oxo-morpholin-4-yl) -ethoxy] -7-methoxy-quinazoline Mp .: 193 ° C

Mass Spectrum (ESI ⁺ ): m / z = 487, 489 [M + H] ⁺ (2) 4 - [(3-Chloro-4-fluoro-phenyl) amino] -6- [2 - ((R)) -6-methyl-2-oxo-morpholin-4-yl) -ethoxy] -7-methoxy-quinazoline (the reaction was carried out with trifluoroacetic acid in acetonitrile)

Mp .: 208 ° C

MS (ESI +): m / z = 459, 461 [MH] + (3) 4 - [(3-chloro-4-fluoro-phenyl) amino] -6- [3 - _((7?) -6 -methyl-2-oxo-morpholin-4-yl) -propyloxy] -7-methoxy-quinazoline (the reaction was carried out with trifluoroacetic acid in acetonitrile)

Rf value: 0.33 (silica gel, acetate)

Mass Spectrum (ESI): m / z = 473, 475 [MH] - (4) 4 - [(R) - (1-Phenylethyl) amino] -6- [3 - ((S) -6-methyl- 2-oxo-morpholin-4-yl) -propyloxy] -7-methoxy-quinazoline (reaction was carried out with trifluoroacetic acid in acetonitrile)

Rf value: 0.41 (silica gel, acetate / methanol = 9: 1)

Mass Spectrum (ESE): m / z = 449 [MH] - (S) 4 - [(R) - (1-Phenylethyl) amino] -6- [2 - ((S) -6-methyl-2- oxo-morpholin-4-yl) ethoxy] -7-methoxy-quinazoline (reaction was carried out with trifluoroacetic acid in acetonitrile)

_{R f} value: 0.49 (silica gel, ethyl / methanol / concentrated aqueous ammonia = 9: 1: 0.1)

Mass Spectrum (ESE): m / z = 435 [MH] - (6) 4 - [(3-Chloro-4-fluorophenyl) amino] -6- [3 - ((R) -6-methyl- 2-oxo-morpholin-4-yl) -propyloxy] -7-cyclobutyloxy-quinazoline (the reaction was carried out with trifluoroacetic acid in acetonitrile)

Mp: 185.5-189.5 ° C

Mass Spectrum (ESI ⁺ ): m / z = 515, 517 [M + H] ⁺ (7) 4 - [(3-Chloro-4-fluoro-phenyl) amino] -6- [3- (5,5- dimethyl-2-oxo-morpholin-4-yl) -propyloxy] -7-cyclobutyloxy-quinazoline (the reaction was carried out with trifluoroacetic acid in acetonitrile)

Melting point: 214-216 ° C

Mass Spectrum (ESI +): m / z = 527, 529 [MH] (8) 4 - [(3-Chloro-4-fluoro-phenyl) amino] -6- [3 - ((R) -6-methyl) -2-oxo-morpholin-4-yl) -propyloxy] -7-cyclopropylmethoxy-quinazoline (the reaction was carried out with trifluoroacetic acid in acetonitrile)

Melting point: 160.5-163 ° C

Mass Spectrum (ESI ⁺ ): m / z = 515, 517 [M + H] ⁺ (9) 4 - [(3-Chloro-4-fluoro-phenyl) amino] -6- [3 - ((S) - 6-methyl-2-oxo-morpholin-4-yl) -propyloxy] -7-cyclopropylmethoxy-quinazoline (the reaction was carried out with trifluoroacetic acid in acetonitrile)

Melting point: 160-162 ° C

Mass Spectrum (ESI ⁺ ): m / z = 515, 517 [M + H] ⁺ (10) 4 - [(3-Chloro-4-fluoro-phenyl) amino] -6- [2 - ((S) - 6-methyl-2-oxo-morpholin-4-yl) -ethoxy] -7-cyclopentyloxy-quinazoline (the reaction was carried out with trifluoroacetic acid in acetonitrile)

_{R f} value: 0.31 (silica gel, ethyl)

Mass Spectrum (ESI ⁺ ): m / z = 515, 517 [M + H] ⁺ (11) 4 - [(3-Chloro-4-fluoro-phenyl) amino] -6- [2 - ((R) - 6-methyl-2-oxo-morpholin-4-yl) -ethoxy] -7-cyclopentyloxy-quinazoline (the reaction was carried out with trifluoroacetic acid in acetonitrile)

Melting point: 176-178 ° C

Mass Spectrum (ESI ⁺ ): m / z = 515, 517 [M + H] ⁺ (12) 4 - [(3-Chloro-4-fluoro-phenyl) amino] -6- [2 - ((5) - 6-methyl-2-oxo-morpholin-4-yl) -ethoxy] -7-cyclopropylmethoxy-quinazoline (the reaction was carried out with trifluoroacetic acid in acetonitrile)

Rf: 0.37 (silica gel, acetate)

Mass Spectrum (ESI ⁺ ): m / z = 501, 503 [M + H] ⁺ (13) 4 - [(3-Chloro-4-fluoro-phenyl) amino] -6- [2 - ((A) - 6-methyl-2-oxo-morpholin-4-yl) -ethoxy] -7-cyclopropylmethoxy-quinazoline (the reaction was carried out with trifluoroacetic acid in acetonitrile)

Rf: 0.37 (silica gel, acetate)

Mass Spectrum (ESI ⁺ ): m / z = 501, 503 [M + H] ⁺ (14) 4 - [(3-Chloro-4-fluoro-phenyl) -amino] -6-cyclopropylmethoxy-7- [2- ( (5) -6-methyl-2-oxo-morpholin-4-yl) -ethoxy] -quinazoline (the reaction was carried out with trifluoroacetic acid in acetonitrile)

Rf: 0.48 (silica gel, acetate / methanol = 9: 1)

Mass Spectrum (ESI ⁺ ): m / z = 501, 503 [M + H] ⁺ (15) 4 - [(3-Chloro-4-fluoro-phenyl) -amino] -6-cyclopropylmethoxy-7- [2- ( (R) -6-methyl-2-oxo-morpholin-4-yl) -ethoxy] -quinazoline (the reaction was carried out with trifluoroacetic acid in acetonitrile)

Mass Spectrum (ESI ⁺ ): m / z = 501, 503 [M + H] ⁺ (16) 4 - [(3-Chloro-4-fluoro-phenyl) -amino] -6-cyclopropylmethoxy-7- [3- ( (R) -6-Methyl-2-oxo-morpholin-4-yl) -propyloxy] -quinazoline (the reaction was carried out with trifluoroacetic acid in acetonitrile)

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

Mass Spectrum (ESE): m / z = 513,515 [MH] (17) 4 - [(3-Chloro-4-fluoro-phenyl) amino] -6-cyclopropylmethoxy-7- [3 - ((S / -) 6-methyl-2-oxo-morpholin-4-yl) -propyloxy] -quinazoline (the reaction was carried out with trifluoroacetic acid in acetonitrile)

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

Mass Spectrum (ESI): m / z = 513,515 [MH] - (18) 4 - [(3-Chloro-4-fluoro-phenyl) amino] -6- [2- (2,2-dimethyl-6)] -oxo-morpholin-4-yl) -ethoxy] -7-cyclopentyloxy-quinazoline (the reaction was carried out with trifluoroacetic acid in acetonitrile)

Rf value: 0.56 (silica gel, acetate)

Mass Spectrum (ESI ⁺ ): m / z = 529,531 [M + H] ⁺ (19) 4 - [(3-Chloro-4-fluoro-phenyl) amino] -6-cyclopentyloxy-7- [2- ( (5) -6-methyl-2-oxo-morpholin-4-yl) -ethoxy] -quinazoline (the reaction was carried out with trifluoroacetic acid in acetonitrile)

Rf value: 0.60 (silica gel, acetate / methanol = 9: 1)

Mass Spectrum (ESI ⁺ ): m / z = 515, 517 [M + H] ⁺ (20) 4 - [(3-Chloro-4-fluoro-phenyl) amino] -6-cyclopentyloxy-7- [2- ( (R) -6-Methyl-2-oxo-morpholin-4-yl) -ethoxy] -quinazoline (reaction was carried out with trifluoroacetic acid in acetonitrile)

Mass Spectrum (ESI ⁺ ): m / z = 515, 517 [M + H] + (21) 4 - [(3-Chloro-4-fluoro-phenyl) amino] -6- [4 - ((S) - 6-methyl-2-oxo-morpholin-4-yl) -butyloxy] -7-cyclopentyloxy-quinazoline (the reaction was carried out with trifluoroacetic acid in acetonitrile)

Rf value: 0.51 (silica gel, acetate)

Mass Spectrum (ESI ⁺ ): m / z = 543, 545 [M + H] ⁺ (22) 4 - [(3-Chloro-4-fluoro-phenyl) amino] -6- [4 - ((R) - 6-methyl-2-oxo-morpholin-4-yl) -butyloxy] -7-cyclopentyloxy-quinazoline (the reaction was carried out with trifluoroacetic acid in acetonitrile)

Mass Spectrum (ESI ⁺ ): m / z = 543, 545 [M + H] ⁺ (23) 4 - [(3-Chloro-4-fluoro-phenyl) amino] -6- [3 - ((S) - 6-methyl-2-oxo-morpholin-4-yl) -propyloxy] -7-methoxy-quinazoline (the reaction was carried out with trifluoroacetic acid in acetonitrile)

Mp: 183-186 ° C

Mass Spectrum (ESI ⁺ ): m / z = 475, 477 [M + H] ⁺ (24) 4 - [(3-Chloro-4-fluoro-phenyl) amino] -6- [3- (5,5- dimethyl-2-oxo-morpholin-4-yl) -propyloxy] -7-methoxy-quinazoline (the reaction was carried out with trifluoroacetic acid in acetonitrile)

_{R f} value: 0.43 (silica gel, ethyl)

Mass Spectrum (ESI -): m / z = 487, 489 [MH] - (25) 4 - [(3-Chloro-4-fluoro-phenyl) amino] -6- [2 - ((S) -6-) methyl-2-oxo-morpholin-4-yl) -ethoxy] -7-methoxy-quinazoline (the reaction was carried out with trifluoroacetic acid in acetonitrile)

Mp .: 212-213 ° C

Mass Spectrum (ESI ⁺ ): m / z = 461, 463 [M + H] ⁺ (2S) 4 - [(3-Chloro-4-fluorophenyl) amino] -6- {2 - [N - (carboxymethyl)] - N - ((S) -2-hydroxy-propyl) -amino] -ethoxy} -7-methoxy-quinazoline (by-product of production 3 (25))

Mp 187-190 ° C

Mass Spectrum (ESI ⁺ ): m / z = 479, 481 [M + H] ⁺ (27) 4 - [(3-Chloro-4-fluoro-phenyl) amino] -6- [2- (2,2- dimethyl-6-oxo-morpholin-4-yl) -ethoxy] -7-methoxy-quinazoline (the reaction was carried out with trifluoroacetic acid in acetonitrile)

Melting point: 229-232 ° C

Mass spectrum (EST): m / z = 473, 475 [MH] - (28) 4 - [(3-Chloro-4-fluoro-phenyl) amino] -6- [2- (2,2-dimethyl-6)] -oxo-morpholin-4-yl) -ethoxy] -7 - ((R) -tetrahydrofuran-3-yloxy) -quinazoline (the reaction was carried out with trifluoroacetic acid in acetonitrile)

M.p .: 195-196 ° C

Mass Spectrum (ESI ⁺ ): m / z = 531, 533 [M + H] ⁺ (29) 4 - [(3-Chloro-4-fluoro-phenyl) amino] -6- [2- (2,2- dimethyl-6-oxo-morpholin-4-yl) -ethoxy] -7 - [(R) -tetrahydrofuran-2-yl) methoxy] -quinazoline (reaction was carried out with trifluoroacetic acid in acetonitrile)

Melting point: 184 ° C

Mass Spectrum (ESI ⁺ ): m / z = 545, 547 [M + H] ⁺ (30) 4 - [(3-Chloro-4-fluoro-phenyl) amino] -7- [2- (2,2- dimethyl-6-oxo-morpholin-4-yl) -ethoxy] -6 - ((5) -tetrahydrofuran-3-yloxy) -quinazoline

Melting point: 202-205 ° C

Mass Spectrum (ESI ⁺ ): m / z = 531, 533 [M + H] ⁺ (31) 4 - [(3-Chloro-4-fluoro-phenyl) amino] -7- [2- (2,2- dimethyl-6-oxo-morpholin-4-yl) ethoxy] -6 - [(S) - (tetrahydrofuran-2-yl) methoxy] quinazoline

Melting point: 182 ° C

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

Example 4

4 - [(3-Bromo-phenyl) amino] -6- (2- {Λ '- [(tert-butyloxycarbonyl) methyl] - N - ((S-2-hydroxy-propyl) -amino} -ethoxy) - 7-methoxy-quinazoline

650 mg of 4 - [(3-bromo-phenyl) amino] -6- (2-bromo-ethoxy) -7-methoxy-quinazoline and 1.10 g of (S) - (2-hydroxy-propylamino) tert -butyl ester Acetic acid in 15 ml of acetonitrile was added 0.25 ml of diisopropylethylamine. The reaction mixture was stirred at 50 ° C overnight. Since no reaction was evident, the reaction mixture was concentrated and mixed with 20 ml of N, N-dimethyl form du and stirred at 60 ° C for eight hours. Subsequently, the temperature was raised to 80 ° C. After another eight hours, the reaction was complete. The reaction mixture was concentrated and chromatographed through a silica gel column with acetate as the mobile phase. The desired product was obtained as a white solid. Yield: 410 mg (51% of theory)

Rf: 0.27 (silica gel, acetate)

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

In analogy to Example 4, the following compounds were obtained:

(1) 4 - [(3-Bromo-phenyl) amino] -6- (2- {N - [(N-t-butyloxycarbonyl) methyl] - N - ((R) -2-hydroxypropyl) amino} ethoxy) -7-methoxy-quinazoline

Melting point: 130 ° C

Mass spectrum (EST): m / z = 559,561 [MH] - (2) 4 - [(3-Chloro-4-fluorophenyl) amino] -6- (2- {N - [(tert-butyloxycarbonyl) methyl] - N - ((R) -2-hydroxy-propyl) -amino} -ethoxy) -7-methoxy-quinazoline (the reaction was carried out in N, N-dimethylformamide)

Rf value: 0.40 (silica gel, acetate / petroleum ether = 4: 1) (3) 4 - [(3-Chloro-4-fluorophenyl) amino] -6- (3- {A - [(tert-butyloxycarbonyl)) methyl] - N - ((R) -2-hydroxy-propyl) -amino} -propyloxy) -7-methoxy-quinazoline (the reaction was carried out in N, N-dimethylformamide)

Rf: 0.37 (silica gel, acetate / petroleum ether = 4: 1)

Mass Spectrum (ESI): m / z = 547, 549 [MH] - (4) 4 - [(R) - (1-Phenyl-ethyl) amino] -6- (3 - {- V - [(/) tert-butyloxycarbonyl) methyl] - N - ((η 2 -hydroxy-propyl) -amino} -propyloxy) -7-methoxy-quinazoline (the reaction was carried out in N, N-dimethylformamide)

_{R f} value: 0.65 (silica gel, ethyl / methanol = 9: 1)

Mass Spectrum (EI): m / z = 524 [M] ⁺ (S) 4 - [(R) - (1-Phenyl-ethyl) amino] -6- (2- {N - [(tert-butyloxycarbonyl) methyl] ] - N - ((5 / -2-hydroxy-propyl) -amino} -ethoxy) -7-methoxy-quinazoline (reaction was carried out in N, N-dimethylformamide)

Rf value: 0.57 (silica gel, acetate / methanol / concentrated, aqueous ammonia = 9: 1: 0.1) (6) 4 - [(3-Chloro-4-fluorophenyl) amino] -6- (3) - {A - [(te / tert-butyloxycarbonyl) methyl] -N - ((/? / - 2-hydroxy-propyl) amino} propyloxy) -7-cyclobutyloxy-quinazoline

Rf value: 0.31 (silica gel, methylene chloride / methanol = 95: 5) (7) 4 - [(3-Chloro-4-fluoro-phenyl) amino] -6- (3- {¥ - [(tert-butyloxycarbonyl) methyl] - N - (1,1-dimethyl-2-hydroxy-ethyl) -amino} -propyloxy) -7-cyclobutyloxy-quinazoline

Rf value: 0.29 (silica gel, methylene chloride / methanol = 95: 5)

Mass Spectrum (ESI ⁺ ): m / z = 603, 605 [M + H] ⁺ (8) 4 - [(3-Chloro-4-fluoro-phenyl) amino] -6- (3- {7H - [( tert-butyloxycarbonyl) methyl] -7V - ((R) -2-hydroxy-propyl) amino} propyloxy) -7-cyclopropylmethoxy-quinazoline

Rf value: 0.37 (silica gel, methylene chloride / methanol = 95: 5) (9) 4 - [(3-Chloro-4-fluorophenyl) amino] -6- (3- {N - [(tert-butyloxycarbonyl)) methyl] -N - ((5) -2-hydroxy-propyl) amino} propyloxy) -7-cyclopropylmethoxy-quinazoline

Rf value: 0.50 (silica, acetate) (10) 4 - [(3-Chloro-4-fluoro-phenyl) amino] -6- (2- {N - [(tert-butyloxycarbonyl) methyl] -A- ( (S) -2-Hydroxy-propyl) -amino} -ethoxy) -7-cyclopentyloxy-quinazoline

Rf value: 0.54 (silica gel, acetate / cyclohexane = 9: 1) (11) 4 - [(3-Chloro-4-fluoro-phenyl) amino] -6- (2- {N - [(tert-butyloxycarbonyl)) methyl] - N - ((R) -2-hydroxy-propyl) -amino} -ethoxy) -7-cyclopentyloxy-quinazoline

Rf value: 0.66 (silica gel, acetate) (12) 4 - [(3-Chloro-4-fluoro-phenyl) amino] -6- (2- {N - [(tert-butyloxycarbonyl) methyl] -A- ( (S) -2-hydroxy-propyl) -amino} ethoxy) -7-cyclopropylmethoxy-quinazoline

R f value: 0.60 (silica gel, acetate) (13) 4 - [(3-Chloro-4-fluoro-phenyl) amino] -6- (2- {N - [(tert-butyloxycarbonyl) methyl] -A- ( (R) -2-Hydroxy-propyl) -amino} -ethoxy) -7-cyclopropylmethoxy-quinazoline

Rf value: 0.60 (silica gel, acetate) (14) 4 - [(3-Chloro-4-fluorophenyl) amino] -6-cyclopropylmethoxy-7- (2- {N - [(tert -butyloxycarbonyl) ) methyl] -N - ((S) -2-hydroxy-propyl) -amino} ethoxy) -quinazoline

Rf value: 0.30 (silica gel, acetate) (15) 4 - [(3-Chloro-4-fluorophenyl) amino] -6-cyclopropylmethoxy-7- (2- {A - [(tert-butyloxycarbonyl)) methyl] -N - ((R) -2-hydroxy-propyl) -amino} ethoxy) -quinazoline

Rf value: 0.30 (silica gel, acetate) (16) 4 - [(3-Chloro-4-fluoro-phenyl) amino] -6-cyclopropyimethoxy-7- (3- {N - [(tert-butyloxycarbonyl) ) methyl] -N - ((R) -2-hydroxy-propyl) amino} propyloxy) -quinazoline

Rf value: 0.35 (silica, acetate) (17) 4 - [(3-Chloro-4-fluorophenyl) amino] -6-cyclopropylmethoxy-7- (3- {N - [(tert-butyloxycarbonyl) ) methyl] -N - ((S) -2-hydroxy-propyl) amino} propyloxy) -quinazoline

Rf value: 0.35 (silica gel, acetate) (18) 4 - [(3-Chloro-4-fluorophenyl) amino] -6- (2- {N - [(ethoxycarbonyl) methyl] -N- (2-) hydroxy-2-methyl-propyl) amino} -ethoxy) -7-cyclopentyloxy-quinazoline

Rf value: 0.64 (silica gel, methylene chloride / methanol = 9: 1)

Mass Spectrum (ESI ⁺ ): m / z = 575, 577 [M + H] ⁺ (19) 4 - [(3-Chloro-4-fluoro-phenyl) amino] -6-cyclopentyloxy-7- (2- { Y - [(/ t-butyloxy-carbonyl) -methyl] -7'7 - ((5) -2-hydroxy-propyl) -amino} ethoxy) -quinazoline

_{R f} value: 0.51 (silica gel, ethyl) (20) 4 - [(3-chloro-4-fluoro-phenyl) amino] -6-cyclopentyloxy-7- (2 - {/ V - [(tert-butoxy carbonyl) methyl] ^-N - ((/?) - 2-hydroxy-propyl) -amino} ethoxy) -quinazoline

Rf value: 0.51 (silica gel, acetate) (21) 4 - [(3-Chloro-4-fluorophenyl) amino] -6- (4 - {N - [(tert -butyloxycarbonyl) methyl] -] N - ((S) -2-Hydroxy-propyl) -amino} -butyloxy) -7-cyclopentyloxy-quinazoline

Rf value: 0.61 (silica gel, acetate) (22) 4 - [(3-Chloro-4-fluorophenyl) amino] -6- (4 - {N - [(tert -butyloxycarbonyl) methyl] -7H - ((/?) - 2-hydroxy-propyl) amino} butyloxy) -7-cyclopentyloxy-quinazoline

Rf value: 0.61 (silica gel, acetate) (23) 4 - [(3-Chloro-4-fluoro-phenyl) amino] -6- (3 - {N - [(tert -butyloxycarbonyl) methyl] -7H - ((S) -2-Hydroxy-propyl) -amino} -propyloxy) -7-methoxy-quinazoline

Rf: 0.46 (silica gel, acetate)

Mass spectrum (ESP): m / z = 547, 549 [MH] - (24) 4 - [(3-Chloro-4-fluoro-phenyl) amino] -6- (3 - {N - [(tert) butyloxycarbonyl) methyl] - / V- (l, l-dimethyl-2-hydroxy-ethyl) -amino} propyloxy) -7-methoxy-quinazoline

Mass Spectrum (ESI ⁺ ): m / z = 563, 565 [M + H] ⁺ (2S) 4 - [(3-Chloro-4-fluoro-phenyl) amino] -6- (2- {A - [( tert-butyloxycarbonyl) methyl] - N - ((S) -2-hydroxy-propyl) -amino} -ethoxy) -7-methoxy-quinazoline

Rf value: 0.66 (silica gel, acetate / methanol = 9: 1)

Mass Spectrum (ESI ⁺ ): m / z = 535, 537 [M + H] ⁺ (2S) 4 - [(3-Chloro-4-fluoro-phenyl) amino] -6- (2 - {N - [-] - (ethoxycarbonyl) methyl] - N - (2-hydroxy-2-methyl-propyl) -amino} -ethoxy) -7-methoxy-quinazoline (exists in a mixture with an already cyclized substance)

Rf: 0.44 (silica gel, acetate)

Mass Spectrum (ESI ⁺ ): m / z = 521,523 [M + H] ⁺ (27) 4 - [(3-Chloro-4-fluoro-phenyl) amino] -6- (2- {7H - [( ethoxycarbonyl) methyl] -N- (2-hydroxy-2-methyl-propyl) -amino} -ethoxy) -7 - ((R) -tetrahydro-furan-3-yloxy) -quinazoline (exists in admixture with an already cyclized substance)

Rf value: 0.30 (silica gel, methylene chloride / methanol = 9: 1) (28) 4 - [(3-Chloro-4-fluorophenyl) amino] -6- (2 - {N - [(ethoxycarbonyl) methyl] N - (2-hydroxy-2-methyl-propyl) -amino} -ethoxy) -7 - [(R) - (tetrahydrofuran-2-yl) methoxy] quinazoline

Mass Spectrum (ESI -): m / z = 589, 591 [MH] - (29) 4 - [(3-Chloro-4-fluoro-phenyl) amino] -7- (2- {N - [(ethoxycarbonyl) ) methyl] -N- ^f - (2-hydroxy-2-methyl-propyl) -amino} ethoxy) -6 - ((5) -tetrahydrofuran-3-yloxy) -quinazoline

Rf value: 0.16 (silica gel, methylene chloride / methanol = 20: 1) (30) 4 - [(3-Chloro-4-fluoro-phenyl) amino] -7- (2 - {N - [(ethoxycarbonyl)] methyl] -jY- (2-hydroxy-2-methyl-propyl) -amino} ethoxy) -6 - [(S) - (tetrahydrofuran-2-yl) methoxy] -quinazoline

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

By analogy to the above examples and other literature methods, the following compounds can be prepared:

(1) 4 - [(3-chloro-4-fluoro-phenyl) amino] -7- [2- (6-methyl-2-oxo-morpholin-4-yl) -ethoxy] -6-methoxy-quinazoline ( 2) 4 - [(3-chloro-4-fluoro-phenyl) amino] -7- [3- (6-methyl-2-oxo-morpholin-4-yl) -propyloxy] -6-methoxy-quinazoline (3) 4 - [(3-chloro-4-fluoro-phenyl) amino] -6- [2 - ((S) -6-methyl-2-oxo-morpholin-4-yl) -ethoxy] -7-methoxy- quinazoline (4) 4 - [(3-chloro-4-fluoro-phenyl) amino] -6- [3 - ((S) -6-methyl-2-oxo-morpholin-4-yl) -propyloxy] -7 -methoxy-quinazoline (5) 4 - [(3-chloro-4-fluoro-phenyl) amino] -6- [3- (5,5-dimethyl-2-oxo-morpholin-4-yl) -propyloxy] - 7-Methoxy-quinazoline (6) 4 - [(3-chloro-4-fluoro-phenyl) amino] -6- [2- (5,5-dimethyl-2-oxo-morpholin-4-yl) -ethoxy] -7-Methoxy-quinazoline (7) 4 - [(3-chloro-4-fluoro-phenyl) amino] -6- [3- (3-methyl-2-oxo-morpholin-4-yl) -propyloxy] - 7-Methoxy-quinazoline (8) 4 - [(3-chloro-4-fluoro-phenyl) amino] -6- [2- (3-methyl-2-oxo-morpholin-4-yl) -ethoxy] -7 (9) 4 - [(R) - (1-phenyl-ethyl) amino] -6- [3 - ((R) -6-methyl-2-oxo-morpholin-4-yl) -methoxy-quinazoline] -propyloxy] -7-methoxy-quinazoline (10) 4 - [(R) - (1-phenyl-ethyl) amino] -6- [2 - ((R) -6-m) ethyl-2-oxo-morpholin-4-yl) -ethoxy] -7-methoxy-quinazoline (11) 4 - [(3-chloro-4-fluoro-phenyl) amino] -7- [4- (6-methyl) 2-oxo-morpholin-4-yl) -butyloxy] -6-methoxy-quinazoline (12) 4 - [(3-chloro-4-fluoro-phenyl) amino] -7- [3- (6-methyl- 2-Oxo-morpholin-4-yl) -propyloxy] -6-methoxy-quinazoline (13) 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- [4- (6-methyl-2) (14) 4 - [(3-Chloro-4-fluoro-phenyl) -amino] -6- [2- (6-methyl-2-) -oxo-morpholin-4-yl) -butyloxy] -7-methoxy-quinazoline oxo-morpholin-4-yl) -ethoxy] -7- (tetrahydrofuran-3-yloxy) -quinazoline (15) 4 - [(3-chloro-4-fluorophenyl) amino] -6- [2- (6) -methyl-2-oxo-morpholin-4-yl) -ethoxy] -7- (tetrahydropyran-3-yloxy) -quinazoline (16) 4 - [(3-chloro-4-fluoro-phenyl) amino] -6- [2- (6-Methyl-2-oxo-morpholin-4-yl) -ethoxy] -7- (tetrahydropyran-4-yloxy) -quinazoline (17) 4 - [(3-chloro-4-fluoro-phenyl)] amino] -6- [2- (6-methyl-2-oxo-morpholin-4-yl) -ethoxy] -7- (tetrahydrofuran-2-ylmethoxy) -quinazoline (18) 4 - [(3-chloro-4) -fluoro-phenyl) amino] -6- [2- (6-methyl-2-oxo-morpholin-4-yl) -ethoxy] -7- (tetrahydropyran-4-ylmethoxy) -quinazoline (19) 4 - [( 3 chloro-4-fluoro-phenyl) amino] -6- [2- (6,6-dimethyl-2-oxo-morpholin-4-yl) -ethoxy] -7- (tetrahydrofuran-3-yloxy) -quinazoline (20 4 - [(3-chloro-4-fluoro-phenyl) amino] -6- [3- (6,6-dimethyl-2-oxo-morpholin-4-yl) -propyl-oxy] -7- (tetrahydrofuran) -3-yloxy) -quinazoline (21) 4 - [(3-chloro-4-fluoro-phenyl) amino] -6- [4- (6,6-dimethyl-2-oxo-morpholin-4-yl) - butyloxy] -7- (tetrahydrofuran-3-yloxy) -quinazoline (22) 4 - [(3-chloro-4-fluorophenyl) amino] -6- [2- (6,6-dimethyl-2-oxo) Morpholin-4-yl) -ethoxy] -7- (tetrahydrofuran-2-ylmethoxy) -quinazoline (23) 4 - [(3-chloro-4-fluorophenyl) amino] -6- [3- (6,6) -Dimethyl-2-oxo-morpholin-4-yl) -propyloxy] -7- (tetrahydrofuran-2-ylmethoxy) -quinazoline (24) 4 - [(3-chloro-4-fluoro-phenyl) amino] - 6- [4- (6,6-Dimethyl-2-oxo-morpholin-4-yl) -butyloxy] -7- (tetrahydrofuran-2-ylmethoxy) -quinazoline (2S) 4 - [(3-chloro-4- Fluoro-phenyl) amino] -7- [2- (6-methyl-2-oxo-morpholin-4-yl) -ethoxy] -6- (tetrahydrofuran-3-yloxy) -quinazoline (26) 4 - [(3) -chloro-4-fluoro-phenyl) amino] -7- [2- (6-methyl-2-oxo-morpholin-4-yl) -ethoxy] -6- (tetrahydropyran-3) -yloxy) -quinazoline (2 S) 4 - [(3-chloro-4-fluoro-phenyl) amino] -7- [2- (6-methyl-2-oxo-morpholin-4-yl) -ethoxy] -6 - (tetrahydropyran-4-yloxy) -quinazoline (2 S) 4 - [(3-chloro-4-fluorophenyl) amino] -7- [2- (6-methyl-2-oxo-morpholin-4-yl)] -ethoxy] -6- (tetrahydrofuran-2-ylmethoxy) -quinazoline (29) 4 - [(3-chloro-4-fluoro-phenyl) amino] -7- [2- (6-methyl-2-oxo-morpholine) -4-yl) ethoxy] -6- (tetrahydropyran-4-ylmethoxy) quinazoline (30) 4 - [(3-chloro-4-fluorophenyl) amino] -7- [2- (6,6- dimethyl-2-oxo-morpholin-4-yl) -ethoxy] -6- (tetrahydrofuran-3-yloxy) -quinazoline (31) 4 - [(3-chloro-4-fluoro-phenyl) amino] -7- [ 3- (6,6-Dimethyl-2-oxo-morpholin-4-yl) -propyloxy] -6- (tetrahydrofuran-3-yloxy) -quinazoline (32) 4 - [(3-chloro-4-fluoro) -phenyl) amino] -7- [4- (6,6-dimethyl-2-oxo-morpholin-4-yl) -butyloxy] -6- (tetrahydrofuran-3-yloxy) -quinazoline (33) 4 - [( 3-chloro-4-fluoro-phenyl) amino] -7- [2- (6,6-dimethyl-2-oxo-morpholin-4-yl) -ethoxy] -6- (tetrahydrofuran-2-ylmethoxy) quinazoline (34) 4 - [(3-chloro-4-fluoro-phenyl) amino] -7- [3- (6,6-dimethyl-2-oxo-morpholin-4-yl) -propyloxy] -6- (tetrahydrofuran-2-ylmethoxy) -quinazoline (35) 4 - [(3-chloro-4-fluoro-phenyl) amino] -7- [4- (6,6-dimethyl-2-oxo-morpholine- 4-yl) butyloxy] -6- (tetrahydrofuran-2-ylmethoxy) quinazoline

Example 5

Dragees containing 75 mg of active ingredient dragee contains:

Active Substance 75.0 mg Calcium phosphate 93.0 mg Corn starch 35.5 mg Polyvinylpyrrolidone 10.0 mg Hydroxypropylmethylcellulose 15.0 mg Magnesium stearate 1.5 mg

230.0 mg

Production

The active ingredient was mixed with calcium phosphate, corn starch, polyvinylpyrrolidone, hydroxypropyl methylcellulose and half of the amount of magnesium stearate. Moldings with a diameter of approximately 13 mm were made on a tabletting machine, which were spread on a suitable machine through a 1.5 mm mesh sieve and mixed with the remaining amount of magnesium stearate. This granulate was pressed on a tabletting machine into tablets of the desired shape.

Core weight: 230 mg

Punch: 9 mm, domed

The dragee cores thus produced were coated with a film consisting essentially of hydroxypropylmethylcellulose. The finished film-coated dragees were polished with beeswax.

Weight dragees: 245 mg.

Example 6

Tablets of 100 mg of the active substance

Ingredients:

tablet contains:

Active Substance 100.0 mg Milk Sugar 80.0 mg Corn Starch 34.0 mg Polyvinylpyrrolidone 4.0 mg Magnesium stearate 2.0 mg

220.0 mg

Method of production

The active ingredient, milk sugar and starch were mixed and uniformly moistened with an aqueous solution of polyvinylpyrrolidone. After sieving the moist mass (2.0 mm mesh distance) and drying in a grid oven at 50 ° C, it was sieved again (1.5 mm mesh distance) and grease was added. The ready-to-mix mixture was formulated into tablets.

Tablet weight: 220 mg

Diameter: 10 mm, biplanes with double-sided edges and partial one-side vaulting.

Example 7

Tablets of 150 mg of the active substance

Ingredients:

tablet contains:

Active Substance 150.0 mg Milk Sugar Powder 89.0 mg Corn Starch 40.0 mg Colloidal Silicic acid 10.0 mg Polyvinylpyrrolidone 10.0 mg Magnesium stearate 1.0 mg

300.0 mg

Production

The active ingredient mixed with milk sugar, corn starch and silicic acid was moistened with a 20% aqueous solution of polyvinylpyrrolidone and shaken through a sieve with a mesh width of 1.5 mm.

The granulate dried at 45 ° C was sieved again through the same sieve and mixed with a given amount of magnesium stearate. Tablets were compressed from this mixture.

Tablet weight: 300 mg

Punch: 10 mm, flat

Example 8

Hard gelatin capsule with 150 mg of active substance The capsule contains:

active substance 150.0 mg Corn starch, dry around 180.0 mg milk powdered around 87.0 mg magnesium stearate 3.0 mg around 420.0 mg

Production

The active ingredient was mixed with excipients, passed through a sieve with a mesh gap of 0.75 mm and mixed homogeneously in a suitable apparatus.

The final blend was filled into hard gelatin size 1 capsules.

Capsule filling: approx. 320 mg

Capsule shell: Hard gelatin capsule size 1

Example 9

Supository with 150 mg of active ingredient suppository contains:

Active substance 150.0 mg polyethylene glycol 1500 550.0 mg polyethylene glycol 6000 460.0 mg polyoxyethylene sorbitan monostearate 840.0 mg

2000.0 mg

Production

After melting the suppository mass, the active ingredient was dispersed homogeneously therein and the melt was cast into chilled molds.

Example 10

Suspension with 50 mg of the active substance

100 ml of suspension contains:

active substance 1.00 g carboxymethylcellulose, sodium salt 0.10 g p-hydroxybenzoic acid methyl ester 0.05 g p-hydroxybenzoic acid propyl ester 0.01 g cane sugar 10.00 g glycerin 5.00 g sorbitol solution, 70% 20.00 g aroma 0.30 g distilled water ad 100 ml

Production

Distilled water was heated to 70 ° C. Methyl and propyl p-hydroxybenzoate as well as glycerol and sodium carboxymethylcellulose were dissolved therein with stirring. It was cooled to room temperature and the active ingredient was added with stirring and dispersed homogeneously. After addition and dissolution of the sugar, sorbitol solution and aroma, the suspension was evacuated with stirring.

ml of suspension contained 50 mg of active ingredient.

Example 11

Ampoules with 10 mg of active substance

Ingredients:

active substance

0,0IN hydrochloric acid bidistilled

10.00 mg if necessary ad 2.0 ml

Production

The active ingredient was dissolved in the required amount of 0.0IN HCl, made isotonic with sodium chloride, sterile filtered and filled into 2 ml ampoules.

Example 12

Ampoules with 50 mg of active substance

Ingredients:

active ingredient 50.00 mg

0.01N hydrochloric acid as needed water bidistilled to 10.0 ml

Production

The active ingredient was dissolved in the required amount of 0.0 IN HCl, made isotonic with sodium chloride, sterile filtered and filled into 10 ml ampoules.

Example 13

Capsule for inhalation of powder with 5 mg of active substance The capsule contains the active substance of 5.00 mg lactose for inhalation purposes 15.0 mg

20.0 mg

Production

The active ingredient was mixed with lactose for inhalation purposes. The mixture was filled on a capsule filling machine into capsules (empty capsule weight approximately 50 mg).

Capsule weight: 70.00 mg

Capsule size: 3

Example 14

Inhalation solution for manual nebulizer with 2.5 mg active substance dose contains:

active substance 2,500 mg benzalkonium chloride 0,001 mg 1N-hydrochloric acid ethanol / water (50/50) ad 15,000 mg

Production

The active ingredient and benzalkonium chloride were dissolved in ethanol / water (50/50). The pH of the solution was adjusted with 1N-hydrochloric acid. The adjusted solution was filtered and filled into cartridges for manual sprayers.

Cartridge filling weight: 4.5 g

Claims (7)

PATENT CLAIMS A 4-aminoquinazoline of the formula (I) ^R and H ⁵ wherein: R ^a is 1-phenylethyl group or a phenyl group substituted with groups R ¹ and R ^2, wherein R ¹ is F, Cl or Br and R ² is a hydrogen or fluorine atom, one of R ^b and R ^c is R ³ - (CH ₂ ) _r -O- and consisting of R ^b or R ^c is methoxy-, cyclobutyloxy-, cyclopentyloxy-, cyclopropylmethoxy-, cyclobutylmethoxy-, cyclopentylmethoxy-, tetrahydrofuran-3-yloxy-, tetrahydropyran-3-yloxy -, tetrahydropyran-4-yloxy-, tetrahydrofuranylmethoxy- or tetrahydropyranylmethoxy, wherein: R ³ is N - (2-oxo-tetrahydrofuran-4-yl) -methylamino or 2-oxo-morpholin-4-yl substituted with one or two methyl groups and m is 2, 3 or 4, provided that they are excluded the following compounds: 4 - [(3-chloro-4-fluoro-phenyl) amino] -6-cyclopentyloxy-7- [2- (6,6-dimethyl-2-oxo-morpholin-4-yl) ethoxy] -quinazoline, 4 - [(3-bromo-phenyl) amino] -6- [2- (6,6-dimethyl-2-oxo-morpholin-4-yl) -ethoxy] -7-methoxy-quinazoline, 4 - [(3-bromo-phenyl) amino] -6- {2- (N- (2-oxo-tetrahydrofuran-4-yl) -N-methylamino] -ethoxy} -7-methoxy-quinazoline, 4 - [(3-bromo-phenyl) amino] -6- [2- (3-methyl-2-oxo-morpholin-4-yl) -ethoxy] -7-methoxy-quinazoline, 4 - [(3-bromo-phenyl) amino] -6- [2- (5,5-dimethyl-2-oxo-morpholin-4-yl) -ethoxy] -7-methoxy-quinazoline, 4 - [(3-chloro-4-fluoro-phenyl) amino] -6- [2- (6,6-dimethyl-2-oxo-morpholin-4-yl) -ethoxy] -7-methoxy-quinazoline, 4 - [(3-chloro-4-fluoro-phenyl) amino] -6- [2- (6,6-dimethyl-2-oxo-morpholin-4-yl) -ethoxy] -7-cyclobutyloxy-quinazoline, 4 - [(3-chloro-4-fluoro-phenyl) amino] -6- [2- (6,6-dimethyl-2-oxo-morpholin-4-yl) -ethoxy] -7-cyclopentyloxy-quinazoline, 4 - [(3-chloro-4-fluoro-phenyl) amino] -6- [2- (6,6-dimethyl-2-oxo-morpholin-4-yl) -ethoxy] -7-cyclopropylmethoxy-quinazoline, 4 - [(3-chloro-4-fluoro-phenyl] amino] -6- [2- (6,6-dimethyl-2-oxo-morpholin-4-yl) -ethoxy] -7-cyclopentylmethoxy-quinazoline, 4 - [(3-chloro-4-fluoro-phenyl) amino] -6- {2- [N- (2-oxo-tetrahydrofuran-4-yl) -V-methyl-amino] -ethoxy} -7-methoxy quinazoline 4 - [(3-chloro-4-fluoro-phenyl) amino] -6- {2- [N- (2-oxo-tetrahydrofuran-4-yl) -N-methylamino] -ethoxy} -7-cyclopentyloxy quinazoline 4 - [(3-chloro-4-fluoro-phenyl) amino] -6- {2- [N- (2-oxo-tetrahydrofuran-4-yl) -N-methylamino] -ethoxy} -7-cyclopentylmethoxy quinazoline 4 - [(3-chloro-4-fluoro-phenyl) amino] -6- [3- (6,6-dimethyl-2-oxo-morpholin-4-yl) -propyloxy] -7-methoxy-quinazoline, 4 - [(3-chloro-4-fluoro-phenyl) amino] -6- [3- (6,6-dimethyl-2-oxo-morpholin-4-yl) -propyloxy] -7-cyclopentyloxy-quinazoline, 4 - [(3-chloro-4-fluoro-phenyl) amino] -6- [3- (6,6-dimethyl-2-oxo-morpholin-4-yl) -propyloxy] -7-cyclopentylmethoxy-quinazoline, ( R) -4 - [(l-phenyl-ethyl) amino] -6- [3- (6,6-dimethyl-2-oxo-morpholin-4-yl) propyloxy] -7-cyclopentyloxy-quinazoline, 4 - [(3-chloro-4-fluoro-phenyl) amino] -7- [2- (6,6-dimethyl-2-oxo-morpholin-4-yl) -ethoxy] -6-methoxy-quinazoline, 4 - [(3-chloro-4-fluoro-phenyl) amino] -7- [2- (6,6-dimethyl-2-oxo-morpholin-4-yl) -ethoxy] -6-cyclo-butoxy-quinazoline . 4 - [(3-chloro-4-fluoro-phenyl) amino] -7- [2- (6,6-dimethyl-2-oxo-morpholin-4-yl) -ethoxy] -6-cyclopentyloxy-quinazoline . 4 - [(3-chloro-4-fluoro-phenyl) amino] -7- [2- (6,6-dimethyl-2-oxo-morpholin-4-yl) -ethoxy] -6-cyclopropyl-quinazolin-propylmetoxy . 4 - [(3-chloro-4-fluoro-phenyl) amino] -7- [2- (6,6-dimethyl-2-oxo-morpholin-4-yl) -ethoxy] -6-cyclopropyl-quinazolin-pentylmetoxy . 4 - [(3-chloro-4-fluoro-phenyl) amino] -7- {2 - [/ V- (2-oxo-tetrahydrofuran-4-yl) -7V-methyl-amino] -ethoxy} -6- methoxy-quinazoline, 4 - [(3-chloro-4-fluoro-phenyl) amino] -7- {2- [N- (2-oxo-tetrahydrofuran-4-yl) - / V-methyl-amino] -ethoxy} -6- cyclopentyloxy-quinazoline, 4 - [(3-chloro-4-fluoro-phenyl) amino] -7- {2- [7v ^{I '-} (2-oxo-tetrahydrofuráan-4-yl) -N-methylamino] -ethoxy} -6 cyclopentylmethoxy-quinazoline, 4 - [(3-chloro-4-fluoro-phenyl) amino] -7- [3- (6,6-dimethyl-2-oxo-morpholin-4-yl) propyloxy] -6-methoxy-quinazoline, 4 - [(3-chloro-4-fluoro-phenyl) amino] -7- [3- (6,6-dimethyl-2-oxo-morpholin-4-yl) propyloxy] -6-cyclopentyloxy-quinazoline, 4 - [(3-chloro-4-fluoro-phenyl) amino] -7- [3- (6,6-dimethyl-2-oxo-morpholin-4-yl) -propyloxy] -6-cyclopentylmethoxy-quinazoline and ( 7?) - 4 - [(l-phenyl-ethyl) amino] -7- [3- (6,6-dimethyl-2-oxo-morpholin-4-yl) propyloxy] -6-cyclopentyloxy-quinazoline . The 4-aminoquinazoline of formula (I) according to claim 1, wherein R ^a is 1-phenylethyl, 3-bromophenyl or 3-chloro-4-fluorophenyl, R ^b represents a group R ³ - (CH ₂ ) _m -O- in which R ³ is 2-oxo-morpholin-4-yl substituted with one or two methyl groups and m is 2 or 3, and R ^c is methoxy-, cyclobutyloxy-, cyclopentyloxy-, cyclopropylmethoxy-, tetrahydrofuran-3-yloxy- or tetrahydrofuranylmethoxy , provided that the following compounds are excluded: 4 - [(3-bromo-phenyl) amino] -6- [2- (6,6-dimethyl-2-oxo-morpholin-4-yl) -ethoxy] -7-methoxy-quinazoline, 4 - [(3-bromo-phenyl) amino] -6- [2- (3-methyl-2-oxo-morpholin-4-yl) -ethoxy] -7-methoxy-quinazoline, 4 - [(3-bromo-phenyl) amino] -6- [2- (5,5-dimethyl-2-oxo-morphobin-4-yl) -ethoxy] -7-methoxy-quinazoline, 4 - [(3-chloro-4-fluoro-phenyl) amino] -6- [2- (6,6-dimethyl-2-oxo-morpholin-4-yl) -ethoxy] -7-methoxy-quinazoline, 4 - [(3-chloro-4-fluoro-phenyl) amino] -6- [2- (6,6-dimethyl-2-oxo-morpholin-4-yl) -ethoxy] -7-cyclo-butoxy-quinazoline . 4 - [(3-chloro-4-fluoro-phenyl) amino] -6- [2- (6,6-dimethyl-2-oxo-morpholin-4-yl) -ethoxy] -7-cyclopropyl-quinazolin-propylmetoxy . 4 - [(3-chloro-4-fluoro-phenyl) amino] -6- [3- (6,6-dimethyl-2-oxo-morpholin-4-yl) propyloxy] -7-methoxy-quinazoline, 4 - [(3-chloro-4-fluoro-phenyl) amino] -6- [2- (6,6-dimethyl-2-oxo-morpholin-4-yl) -ethoxy] -7-cyclopentyloxy-quinazoline 4 - [(3-chloro-4-fluoro-phenyl) amino] -6- [3- (6,6-dimethyl-2-oxo-morpholin-4-yl) -propyloxy] -7-cyclopentyloxy-quinazoline and ( 7?) - 4 - [(l-phenyl-ethyl) amino] -6- [3- (6,6-dimethyl-2-oxo-morpholin-4-yl) propyloxy] -7-cyclopentyloxy-quinazoline . The 4-aminoquinazoline of formula (I) according to claim 1, wherein R ^a is 3-chloro-4-fluoro-phenyl, R ^b is cyclopentyloxy-, cyclopropylmethoxy-, cyclopentylmethoxy-, tetrahydrofuran-3-yloxy- or tetrahydrofuranylmethoxy and R ^c is a group R ³ - (CH ₂ ) _m -O- in which R ³ represents a 2-oxo-morpholin-4-yl group substituted with one or two methyl groups and m represents the number 2, provided that the following compounds are excluded: 4 - [(3-chloro-4-fluoro-phenyl) amino] -6-cyclopentyloxy-7- [2- (6,6-dimethyl-2-oxo-morpholin-4-yl) -ethoxy] -quinazoline, 4 - [(3-chloro-4-fluoro-phenyl) amino] -7- [2- (6,6-dimethyl-2-oxo-morpholin-4-yl) -ethoxy] -6-cyclopentyloxy-quinazoline . 4 - [(3-chloro-4-fluoro-phenyl) amino] -7- [2- (6,6-dimethyl-2-oxo-morpholin-4-yl) -ethoxy] -6-cyclopropyl-quinazolin-propylmetoxy and 4 - [(3-chloro-4-fluoro-phenyl) amino] -7- [2- (6,6-dimethyl-2-oxo-morpholin-4-yl) -ethoxy] -6-cyclopentylmethoxy-quinazoline . The 4-aminoquinazoline of formula (I) according to claim 1, selected from the group consisting of: (1) 4 - [(3-chloro-4-fluoro-phenyl) amino] -6-cyclopentylmethoxy-7- [2- (2,2-dimethyl-6-oxo-morpholin-4-yl) -ethoxy] - quinazoline, (2) 4 - [(3-chloro-4-fluoro-phenyl) amino] -6-cyclopentyloxy-7- {2- [N- (2-oxo-tetrahydro-furan-4-yl) -N] - (3) 4 - [(3-chloro-4-fluoro-phenyl) amino] -6-cyclopropylmethoxy-7- [2- (2,2-dimethyl-6-oxo-methyl) amino] -ethoxy} -quinazoline (4) 4 - [(3-chloro-4-fluoro-phenyl) amino] -7-cyclobutyloxy-6- [3- (2,2-dimethyl-6-) morpholin-4-yl) -ethoxy] -quinazoline oxo-morpholin-4-yl) -propyloxy] -quinazoline, (S) 4 - [(3-chloro-4-fluoro-phenyl) amino] -7-cyclopropylmethoxy-6- [3- (2,2-dimethyl- (6) 4 - [(3-Chloro-4-fluoro-phenyl) -amino] -6-cyclopropylmethoxy-7- {2 - [(N) - (6-oxo-morpholin-4-yl) -propyloxy] -quinazoline (7) 4 - [(3-Bromo-phenyl) amino] -6- [2 - ((5) 2-oxo-tetrahydro-furan-4-yl) -N-methyl-amino] -ethoxy} -quinazoline 6-Methyl-2-oxo-morpholin-4-yl) -ethoxy] -7-methoxy-quinazoline, (8) 4 - [(3-bromo-phenyl) amino] -6- [2 - ((R) (9) 4 - [(3-Chloro-4-fluoro-phenyl) -amino] -6- [2- (6-methyl-2-oxo-morpholin-4-yl) -ethoxy] -7-methoxy-quinazoline (R) -6-methyl 1-2- oxo-morpholin-4-yl) -ethoxy] -7-methoxy-quinazoline, (10) 4 - [(3-chloro-4-fluoro-phenyl) amino] -6- [3 - ((R) -) - (11) 4 - [(R) - (1-Phenyl-ethyl) amino] -6- [3- (6-methyl-2-oxomorpholin-4-yl) -propyloxy] -7-methoxy-quinazoline ((S) -6-methyl-2-oxo-morpholin-4-yl) -propyloxy] -7-methoxy-quinazoline, (12) 4 - [(R) - (1-phenyl-ethyl) amino] -6 - [2 - ((S-6-methyl-2-oxo-morpholin-4-yl) -ethoxy] -7-methoxy-quinazoline and (13) 4 - [(3-chloro-4-fluoro-phenyl) amino] - ] -6- [2 - ((5) -6-methyl-2-oxo-morpholin-4-yl) -ethoxy] -7-methoxy-quinazoline. Physiologically acceptable salts of 4-aminoquinazoline according to any one of claims 1 to 4 with inorganic or organic acids or bases. A pharmaceutical composition comprising 4-aminoquinazoline according to any one of claims 1 to 4 or a physiologically acceptable salt thereof according to claim 5, optionally together with one or more inert carriers and / or diluents. A process for the preparation of 4-aminoquinazoles of formula (I) according to any one of claims 1 to 5, characterized in that: a) to a compound of formula (II), (II) wherein: R ^a is as defined in claims 1 to 4, one of R ^{b 1} or R ^{c 1} represents methoxy, cyclobutyloxy-, cyclopentyloxy-, cyclopropylmethoxy-, cyclobutylmethoxy- or cyclopentylmethoxy and the rest of the groups R ^{b |} or R ^C1 represents a group Z '- (CH 2) _m -O-, wherein m is as defined in claims 1 to 4, and Z ¹ is a leaving group, acts by a compound of formula HR ³ (III), wherein R ³ is as defined in claims 1 to 4, or b) cyclizing the compound which may be formed in the reaction mixture of formula (IV) wherein R ^a is as defined in claims 1 to 4, one of R ^b or R ^c being methoxy, cyclobutyloxy, cyclopentyloxy, cyclopropylmethoxy, cyclobutylmethoxy or cyclopentylmethoxy and the remainder of R ^b or R ^c being R ³ '- (CH ₂ ) _m -O-, wherein m is as defined in claims 1 to 4, and R ³ 'represents a group R ⁴ -O-CO-CH ₂ -N-CH ₂ CH ₂ -OH substituted on the methylene groups by one or two methyl or ethyl groups in which R ⁴ represents a hydrogen atom or a C _1-4 -alkyl group and, if necessary, the protecting group used is cleaved in one of the reactions described.