EP1322645A2

EP1322645A2 - Quinazolines, medicaments, which contain these compounds and which are effective as tyrosine kinase inhibitors, their use, and methods for the production thereof

Info

Publication number: EP1322645A2
Application number: EP01978279A
Authority: EP
Inventors: Frank Himmelsbach; Elke Langkopf; Birgit Jung; Stefan Blech; Flavio Solca
Original assignee: Boehringer Ingelheim Pharma GmbH and Co KG
Current assignee: Boehringer Ingelheim Pharma GmbH and Co KG
Priority date: 2000-08-26
Filing date: 2001-08-18
Publication date: 2003-07-02
Also published as: AU2002210444A1; MXPA03001484A; WO2002018375A1; DE10042064A1; CA2417955A1; JP2004507537A

Abstract

The invention relates to quinazolines of general formula (I), in which Ra, Rb and n are defined as referred to in Claim No. 1, to their tautomers, their stereoisomers, and to their salts, particularly their physiologically compatible salts with inorganic or organic acids or bases, which have valuable pharmacological properties, in particular, an inhibitive effect on the signal transduction imparted by tyrosine kinases. The invention also relates to the use of said quinazolines for treating diseases, especially tumor diseases, disorders of the lung and of the respiratory tract, and to the production thereof.

Description

CHINAZOLINE, MEDICINAL PRODUCTS CONTAINING THESE COMPOUNDS AS TYROSINKINASE INHIBITORS, THE USE THEREOF AND METHOD FOR THE PRODUCTION THEREOF

The present invention relates to quinazolines of the general formula

their tautomers, their stereoisomers and their salts, in particular their physiologically tolerable salts with inorganic or organic acids or bases, which have valuable pharmacological properties, in particular an inhibitory effect on signal transduction mediated by tyrosine kinases, their use for the treatment of diseases, in particular tumor diseases , diseases of the lungs and respiratory tract and their production.

In the above general formula I means

R _{a is} a benzyl or 1-phenylethyl group or a phenyl group substituted by the radicals R- _L and R ₂ , where

R- _{L represents} a hydrogen, fluorine, chlorine or bromine atom, a methyl, trifluoromethyl, cyan or ethynyl group and R _{2 represents} a hydrogen or fluorine atom,

R _{b is} a -N (CH ₂ CO ₂ R ₃ ) ₂ group, where

R _{3 represents} a hydrogen atom, a methyl or ethyl group, an R ₄ O-CO-CH ₂ -N-CH ₂ -CH ₂ -OH group optionally substituted on the methylene groups by 1 or 2 methyl or ethyl groups, where

R _{4 represents} a hydrogen atom or a C _1-4 alkyl group,

a 2-oxomorpholin-4-yl group which can be substituted by 1 or 2 methyl or ethyl groups, or

an N- (2-oxo-tetrahydrofuran-4-yl) methylamino group and

n is an integer from 2 to 4,

Preferred compounds of the general formula I above are those with the exception of the compound

4- [(3-bromophenyl) amino] -7- [3- (2-oxomorpholin-4-yl) propyloxy] - 6- t (vinylcarbonyl) amino] -quinazoline,

their tautomers, their stereoisomers and their salts.

Particularly preferred compounds are the compounds of the general formula I mentioned above in which

R _{a is} a 1-phenylethyl group or a phenyl group substituted by the radicals R _x and R ₂ , where

R _{x represents} a fluorine, chlorine or bromine atom, a methyl or ethinyl group and R _{2 represents} a hydrogen or fluorine atom,

R _{b is} a 2-oxomorpholin-4-yl group which is substituted by 1 or 2 methyl or ethyl groups, or

an N- (2-oxo-tetrahydrofuran-4-yl) methylamino group and

n is an integer from the range from 2 to 4, their tautomers, their stereoisomers and their salts.

Very particularly preferred compounds are the compounds of the general formula I above, in which

R _{a is} a 1-phenylethyl or 3-chloro-4-fluorophenyl group,

R _{b is} a 2 -oxo-morpholin-4-yl group which is substituted by 1 or 2 methyl groups, and

n is an integer from the range from 2 to 4,

their tautomers, their stereoisomers and their salts.

Examples of the following particularly preferred compounds of the general formula I are mentioned:

(1) 4- [(R) - (1-phenylethyl) amino] -7- [2- (2, 2-dimethyl-6-oxomorpholin-4-yl) ethoxy] -6- [( vinylcarbonyl) amino] -quinazoline,

(2) 4- [(3-chloro-4-fluorophenyl) amino] -7- [3- ((S) -6-methyl-

2-oxo-morpholin-4-yl) propyloxy] -6- [(vinylcarbonyl) mino] - quinazoline,

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

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

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

2-oxo-morpholin-4-yl) ethoxy] -6- [(vinylcarbonyl) amino] quinazoline,

(7) 4- [(3-chloro-4-fluorophenyl) amino] -7- [2- ((S) -6-methyl-

2-oxo-morpholin-4-yl) ethoxy] -6- [(vinylcarbonyl) amino] quinazoline,

(8) 4- [(3-chloro-4-fluoro-phenyl) amino] -7- [4- ((S) -3-methyl-2-oxo-morpholin-4-yl) butyloxy] -6- [(vinylcarbonyl) amino] - quinazoline and

(9) 4- [(3-chloro-4-fluorophenyl) amino] -7- [4- ((R) -6-methyl-

2-oxo-morpholin-4-yl) butyloxy] -6- [(vinylcarbonyl) amino] - quinazoline,

their tautomers, their stereoisomers and their salts.

The compounds of the general formula I can be prepared, for example, by the following processes:

a) implementation of a compound of the general formula

in the

R _a , R _b and n are defined as mentioned at the beginning, with a

Compound of the general formula

CO - CH = CH,, (III)

in the Z- _{L represents} a leaving group such as a halogen atom, for example a chlorine or bromine atom, a vinylcarbonyloxy group or a hydroxyl group.

The reaction is optionally carried out in a solvent or solvent mixture such as methylene chloride, dimethylformamide, acetonitrile, toluene, chlorobenzene, tetrahydrofuran, methylene chloride / tetrahydrofuran or dioxane, if appropriate in the presence of an inorganic or organic base and, if appropriate, in the presence of a dehydrating agent at temperatures between -80 and 150 ° C, preferably at temperatures between -60 and 80 ° C.

With a compound of general formula III in which Z _{x represents} a leaving group, the reaction is optionally carried out in a solvent or solvent mixture such as methylene chloride, dimethylformamide, acetonitrile, toluene, chlorobenzene, tetrahydrofuran, methylene chloride / tetrahydrofuran or dioxane in the presence of a tertiary organic base such as triethylamine or N-ethyl-diisopropylamine (Hünig base), these organic bases can also serve as solvents at the same time, or in the presence of an inorganic base such as sodium carbonate, potassium carbonate or sodium hydroxide preferably at temperatures between -80 and 150 ° C, preferably at temperatures between -60 and 80 ° C.

With a compound of the general formula III in which Z _{x represents} a hydroxy group, the reaction is preferably carried out in the presence of a dehydrating agent, for example in the presence of isobutyl chloroformate, thionyl chloride, trimethylchlorosilane, phosphorus trichloride, phosphorus pentoxide, hexamethyldisilazane, N, N ' -Dicyclohexylcarbodiimid, N, N '-Dicyclohexyl-carbodiimide / N-hydroxysuccinimide or 1-hydroxy-benzotriazole and optionally additionally in the presence of 4-dimethylamino-pyridine, N, N' -carbonyldiimidazole or triphenylphosphine / tetra-chlorocarbon as appropriate in a carbon Methylene chloride, tetrahydrofuran, dioxane, toluene, chlorobenzene, dimethyl sulfoxide, ethylene glycol diethyl ether or sulfolane and optionally in the presence of a reaction accelerator such as 4-dimethylaminopyridine at temperatures between -80 and 150 ° C, but preferably at temperatures between -60 and 80 ° C.

However, the reaction is carried out particularly advantageously with acrylic acid and acrylic acid chloride in the presence of triethylamine.

In the reactions described above, any reactive groups present, such as hydroxyl, carboxy or imino groups, can be protected during the reaction by customary protective groups, which are split off again after the reaction.

For example, the trimethylsilyl, acetyl, benzoyl, methyl, ethyl, tert-butyl, trityl, benzyl or tetrahydropyranyl group comes as a protective radical for a hydroxyl group,

as protective residues for a carboxy group, the trimethylsilyl, methyl, ethyl, tert-butyl, benzyl or tetrahydropyranyl group and

as protective residues for an imino group, the formyl, acetyl, trifluoroacetyl, ethoxycarbonyl, tert. butoxycarbonyl, benzyloxycarbonyl, benzyl, methoxybenzyl or 2,4-ethoxybenzyl group are considered.

The subsequent subsequent splitting off of a protective radical used takes place, for example, hydrolytically in an aqueous solvent, for example in water, isopropanol / water, acetic acid / water, tetrahydrofuran / water or dioxane / water, in the presence of an acid such as trifluoroacetic acid, hydrochloric acid or sulfuric acid or in the presence of an alkali base such as sodium hydroxide or potassium hydroxide or aprotic, for example in Presence of iodotrimethylsilane, at temperatures between 0 and 120 ° C, preferably at temperatures between 10 and 100 ° C.

However, a benzyl, methoxybenzyl or benzyloxycarbonyl radical is split off, for example by hydrogenolysis, e.g. 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, optionally with the addition of an acid such as hydrochloric acid at temperatures between 0 and 100 ° C, but preferably at room temperatures between 20 and 60 ° C, and at a hydrogen pressure of 1 to 7 bar, but preferably from 3 to 5 bar. However, a 2,4-dimethoxybenzyl radical is preferably cleaved in trifluoroacetic acid in the presence of anisole.

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

A trifluoroacetyl radical is preferably split off by treatment with an acid such as hydrochloric acid, if appropriate in the presence of a solvent such as acetic acid at temperatures between 50 and 120 ° C. or by treatment with sodium hydroxide solution optionally in the presence of a solvent such as tetrahydrofuran at temperatures between 0 and 50 ° C.

Furthermore, the compounds of general formula I obtained, as already mentioned at the beginning, can be separated into their enantiomers and / or diastereomers. For example, ice / trans mixtures can be separated into their ice and trans isomers, and compounds with at least one optically active carbon atom can be separated into their enantiomers. For example, the cis / trans mixtures obtained can be chromatographed into their eis and trans isomers, the compounds of general formula I obtained which occur in racemates, according to methods known per se (see Allinger NL and Eliel EL in "Topics in Stereochemistry", Vol. 6, Wiley Interscience, 1971)) in their optical antipodes and compounds of general formula I with at least 2 asymmetric carbon atoms due to their physicochemical differences according to methods known per se, for example by chromatography and / or fractional Separate crystallization into their diastereomers, which, if they occur in racemic form, can then be separated into the enantiomers as mentioned above.

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 a salt or derivative such as e.g. Optically active substance which forms esters or amides, in particular acids and their activated derivatives or alcohols, and separation of the diastereomeric salt mixture or derivative obtained in this way, e.g. due to different solubilities, it being possible for the free antipodes to be released from the pure diastereomeric salts or derivatives by the action of suitable agents. Particularly common, optically active acids are e.g. 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 quinic acid. For example, (+) - or (-) menthol comes as optically active alcohol and as optically active

Acyl radical in amides, for example, (+) or (-) menthyloxycarbonyl into consideration.

Furthermore, the compounds of the formula I obtained can be converted into their salts, in particular for pharmaceutical use into their physiologically tolerable salts with inorganic or organic acids. Come as acids 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.

Some of the compounds of general formulas II to III used as starting materials are known from the literature or can be obtained by processes known per se from the literature (see Examples I to X).

As already mentioned at the beginning, the compounds of the general formula I according to the invention and their physiologically tolerated salts have valuable pharmacological properties, in particular an inhibitory effect on the signal transduction mediated by the epidermal growth factor receptor (EGF-R), this being achieved, for example, by inhibiting the Ligand binding, the receptor dimerization or the tyrosine kinase itself can be effected. It is also possible that the signal transmission on further downstream components may be blocked.

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

The inhibition of EGF-R-mediated signal transmission can be demonstrated, for example, with cells which express human EGF-R and whose survival and proliferation depend on stimulation by EGF or TGF-alpha. An interleukin-3 (IL-3) -dependent cell line of murine origin was used here which has been genetically modified in such a way that it expresses functional human EGF-R. The proliferation of these cells called F / L-HERc can therefore be stimulated either by murine IL-3 or by EGF (see von Rüden, T. et al. In EMBO J. 2, 2749-2756 (1988) and Pierce, JH et al. in Science 2__9_, 628-631 (1988)). The FDC-Pi _^ cell line was used as the starting material for the F / L-HERc cells. Their production by Dexter, TM et al. in J. Exp. Med. 152, 1036-1047 (1980). Alternatively, however, other growth factor-dependent cells can also be used (see, for example, Pierce, JH et al. In Science 2.3.2, 628-631 (1988), Shibuya, H. et al. In Cell 2JQ_, 57-67 ( 1992) and Alexander, WS et al. In EMBO J. Lu, 3683-3691 (1991)). Recombinant retroviruses were used to express the human EGF-R cDNA (see Ullrich, A. et al. In Nature 309, 418-425 (1984)), as described in von Rüden, T. et al. , EMBO J. 2, 2749-2756 (1988), with the difference that the retroviral vector LXSN (see Miller, AD et al. In BioTechniques 2, 980-990 (1989)) is used to express the EGF-R cDNA and the line GP + Ξ86 (see Markowitz, D. et al. in J. Virol. £ 2, 1120-1124 (1988)) served as the packaging cell.

The test was carried out as follows:

F / L-HERc cells were in RPMI / 1640 medium (BioWhittaker), supplemented with 10% fetal bovine serum (FCS, Boehringer Mannheim), 2 mM glutamine (BioWhittaker), standard antibiotics and 20 ng / ml human EGF (Promega), at 37 ° C and 5% CO ₂ cultivated. To investigate the inhibitory activity of the compounds according to the invention, 1.5 × 10 ⁴ cells per well were cultured in triplicates in 96-well plates in the above medium (200 μl), the proliferation of the cells either using EGF (20 ng / ml ) or murine IL-3 was stimulated. Culture supernatants from the cell line X63 / 0 mIL-3 served as the source for IL-3 (see Karasuyama, H. et al. In Eur. J. Immunol.

18., 97-104 (1988)). The compounds according to the invention were dissolved in 100% dimethyl sulfoxide (DMSO) and added to the cultures in various dilutions, the maximum DMSO concentration being 1%. The cultures were incubated at 37 ° C for 48 hours. To determine the inhibitory activity of the compounds according to the invention, the relative cell number was determined using the Cell

Titer 96 ™ AQ _uθ ous Non-Radioactive Cell Proliferation Assay (Promega) measured in OD units. The relative cell number was calculated as a percentage of the control (F / LHERc cells without inhibitor) and the active substance concentration which inhibits the proliferation of the cells by 50% (IC5 ₀ ) was derived. The following results were obtained:

The compounds of the general formula I according to the invention thus inhibit signal transduction by tyrosine kinases, as has been shown using the example of the human EGF receptor, and are therefore useful for the treatment of pathophysiological processes which are caused by overactive tyrosine kinases. These are e.g. benign or malignant tumors, in particular tumors of epithelial and neuroepithelial origin, metastasis and the 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 associated with increased or altered mucus production caused by stimulation of tyrosine kinases such as e.g. for inflammatory diseases of the respiratory tract such as chronic bronchitis, chronic obstructive bronchitis, asthma, bronchiectasis, allergic or non-allergic rhinitis or sinusitis, cystic fibrosis, l-antitrypsin deficiency, or for cough, pulmonary emphysema, pulmonary fibrosis and hyperreactive respiratory tract.

The compounds are also suitable for the treatment of diseases of the gastrointestinal tract and bile ducts and - bladder that is associated with impaired activity of the tyrosine kinases, such as those found in chronic inflammatory changes, such as cholecystitis, Crohn's disease, ulcerative colitis, and ulcers in the gastrointestinal tract or as in gastrointestinal disorders Tracts that are associated with increased secretion, such as M. Menetrier, secreting adenomas and protein loss syndromes,

furthermore for the treatment of nasal polyps as well as of polyps of the gastrointestinal tract of different genesis such as e.g. villous or adenomatous polyps of the large intestine, but also of polyps in familial polyposis coli, in intestinal polyps as part of the Gardner syndrome, in polyps in the entire gastrointestinal tract in Peutz-Jeghers syndrome, in inflammatory pseudopolypes, in juvenile polyps , with colitis cystica profunda and with Pneumatosis cystoides intestinales.

In addition, the compounds of the general formula I and their physiologically tolerable salts for the treatment of kidney diseases, in particular in the case of cystic changes such as in cystic kidneys, for the treatment of kidney cysts which may be of idiopathic origin or occur in the context of syndromes such as e.g. in tuberous sclerosis, in von Hippel-Lindau syndrome, in nephronophthisis and marrow sponge kidney as well as other diseases which are caused by aberrant function of tyrosine kinases, e.g. epidermal hyperproliferation (psoriasis), inflammatory processes, diseases of the immune system, hyperproliferation of hematopoietic cells etc.

Because of their biological properties, the compounds according to the invention can be used alone or in combination with other pharmacologically active compounds, for example in tumor therapy in monotherapy or in combination with other anti-tumor therapeutic agents, for example in combination with topoisomerase inhibitors (for example etoposide) , Mitosis inhibitors (e.g. vinblastine), with nucleic acid interacting compounds (e.g. cis-platinum, cyclophosphamide, adriamycin), hormone antagonists (e.g. tamoxifen), inhibitors of metabolic processes (e.g. 5-FU etc), cytokines (e.g. interferons), antibodies etc. For the treatment of respiratory diseases these compounds are used alone or in combination with other respiratory therapeutic agents such as secretolytic, broncholytic and / or anti-inflammatory substances. For the treatment of disorders of the gastrointestinal tract, these compounds may also be used alone or in combination with moti- litäts- or secretion influencing or inflammatory ^■ inhibiting substances are given. These combinations can be administered either simultaneously or sequentially.

The use of these compounds either alone or in

Combination with other active substances can take place intravenously, subcutaneously, intramuscularly, intrarectally, intraperitoneally, intranasally, by inhalation or transdermally or orally, aerosol formulations being particularly suitable for> inhalation.

In pharmaceutical use, the compounds according to the invention are generally used in warm-blooded vertebrates, in particular in humans, in doses of 0.01-100 mg / kg body weight, preferably 0.1-15 mg / kg. For administration, these are mixed with one or more conventional inert carriers and / or diluents, e.g. with corn starch, milk sugar, cane sugar, microcrystalline cellulose, magnesium stearate, polyvinylpyrrolidone, citric acid, tartaric acid, water, water / ethanol, water / glycerin, water / - sorbitol, water / polyethylene glycol, propylene glycol, stearyl alcohol, carboxymethyl cellulose or fat-containing substances such as hard fat their suitable mixtures are incorporated into conventional pharmaceutical preparations such as tablets, dragees, capsules, powders, suspensions, solutions, sprays or suppositories.

The following examples are intended to illustrate the present invention without restricting it: Preparation of the starting compounds:

Example I

6-amino-4- [(3-chloro-4-fluorophenyl) amino] -7- [3- (2, -2-dimethyl-

6-oxo-morpholin-4-yl) propyloxy! -quinazoline

308 mg of 4- [(3-chloro-4-fluorophenyl) amino] -7- [3- (2,2-dimethyl-6-oxomorpholin-4-yl) propyloxy] -6-nitro-quinazoline and 145 mg of iron powder are suspended in 15 ml of ethanol and heated to boiling. The suspension is mixed with 0.38 ml of glacial acetic acid and 0.30 ml of water in the heat. The reduction is complete after about 1.5 hours. For working up, the solvent is distilled off in vacuo on a rotary evaporator. The residue is taken up with methylene chloride, a few smaller chunks of ice are added and 2 ml of 4N. atrone lye made alkaline. The organic phase is separated off and the dark aqueous phase is extracted with methylene chloride / methanol (95: 5). The combined organic phases are dried over magnesium sulfate and concentrated. The raw product is implemented without further purification. Yield: .267 mg (92% of theory), R _f r value: 0.32 (silica gel, methylene chloride / methanol = 95: 5) mass spectrum (ESI-): m / z = 472, 474 [MH] ^"

The following compounds are obtained analogously to Example I:

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

R _f value: 0.47 (silica gel, methylene chloride / methanol / concentrated aqueous ammonia solution = 90: 10: 0.1) mass spectrum (ESI ^" ): m / z = 458, 460 [MH] ^"

(2) 6-Amino-4- [(R) - (1-phenyl-ethyl) amino] -7- [2- (2, 2-dimethyl-

6-oxo-morpholin-4-yl) ethoxy] quinazoline

R _f value: 0.23 (silica gel, methylene chloride / methanol = 95: 5) Mass spectrum (ESI ^" ): m / z = 434 [MH] ^"

(3) 6-amino-4- [(3-chloro-4-fluoro-phenyl) amino] -7- [3- ((S) -6-methyl-2-oxo-morpholin-4-yl) -propyloxy] -quinazoline R _f -value: 0.31 (silica gel, methylene chloride / methanol = 95: 5) mass spectrum (ESI ⁺ ): m / z = 460, 462 [M + H] ⁺

(4) 6-Amino-4- [(R) - (1-phenyl-ethyl) amino] -7- (2- {N, N-bis [(methoxycarbonyl) methyl] amino} ethoxy) - quinazoline R _f value: 0.22 (silica gel, methylene chloride / methanol = 95: 5) mass spectrum (ESI ⁺ ): m / z = 468 [M + H] ⁺

(5) 6-Amino-4- [(3-chloro-4-fluorophenyl) amino] -7- [3- ((R) -6-methyl-2-oxo-morpholin-4-yl) -propyloxy] -quinazoline R _f -value: 0.31 (silica gel, methylene chloride / methanol = 95: 5) mass spectrum (ESI ^" ): m / z = 458, 460 [MH] ^"

(6) 6-Amino-4- [(3-chloro-4-fluorophenyl) amino] -7- [2- ((R) -6-methyl-2-oxo-morpholin-4-yl) -ethoxy] -quinazoline R _f value: 0.23 (silica gel, methylene chloride / methanol = 95: 5) mass spectrum (ESI ^" ): m / z = 444, 446 [MH] ^"

(7) 6-Amino-4- [(3-chloro-4-fluorophenyl) amino] -7- [2- ((S) -6-methyl-2-oxo-morpholin-4-yl) -ethoxy] -quinazoline R _f value: 0.23 (silica gel, methylene chloride / methanol = 95: 5) mass spectrum (ESI ^" ): m / z = 444, 446 [MH] ^"

(8) 6-Amino-4- [(3-chloro-4-fluorophenyl) amino] -7- [4- ((S) -3-methyl-2-oxo-morpholin-4-yl) -butyloxy] -quinazoline R _f value: 0.59 (silica gel, methylene chloride / methanol / concentrated, aqueous ammonia solution = 90: 10: 0.1) mass spectrum (ESI ^" ) -, m / z = 472, 474 [MH] ^"

(9) 6-Amino-4- [(3-chloro-4-fluorophenyl) amino] -7- (2- {N- [(tert-butyloxycarbonyl) methyl] -N- (1,1-dimethyl -2-hydroxy-ethyl) amino} ethoxy) quinazoline R _f value: 0.50 (silica gel, methylene chloride / methanol = 9: 1) mass spectrum (ESI-): m / z = 532, 534 [MH] ^"

Example II

4- [(3-chloro-4-fluorophenyl) amino] -7- [3- (2, 2-dimethyl-6-oxomorpholin-4-yl) propyloxy! -6-nitro-chi namli n

152 mg of 4- [(3-chloro-4-fluorophenyl) amino] -7- (3-methanesulfonyloxypropyloxy) -6-nitro-quinazoline and 0.21 ml of diisopropylethylamine in 10 ml of acetonitrile are added to 500 mg Potassium carbonate and 100 mg sodium iodide. Then 561 mg (2-hydroxy-2-methyl-propylamino) ethyl acetate are added and the reaction mixture is heated under reflux for about seven hours. For working up, the reaction mixture is concentrated. The residue is stirred with plenty of ethyl acetate, washed with a little cold water and saturated sodium chloride solution, dried over magnesium sulfate and concentrated. Since a mixture of open-chain and already cyclized product is evidently formed, the resinous residue is refluxed with 0.08 ml of acetyl chloride in 40 ml of ethanol for about 30 minutes. The mixture is then concentrated and toluene is added to the residue. The solvent is distilled off and the flask residue is suspended in methylene chloride, mixed with a little ice water and made alkaline with 1 ml of 4N sodium hydroxide solution. The organic phase is separated off, dried over magnesium sulfate and concentrated. The residue is chromatographed on a silica gel column using methylene chloride / methanol (98: 2). The desired product is stirred with a little ter. Butyl methyl ether, suction filtered and dried. The lactone is obtained as a yellowish solid. Yield: 129 mg (24% of theory), R _f value: 0.32 (silica gel, ethyl acetate) mass spectrum (ESI ^" ): m / z = 502, 504 [MH] ^"

The following compounds are obtained analogously to Example II: (1) 4- [(3-chloro-4-fluorophenyl) amino] -7- [2- (2, 2-dimethyl-6-oxo-morpholin-4-yl) ethoxy] -6-nitro- quinazoline (the cyclized product is formed immediately, post-treatment is therefore avoided) R _f value: 0.38 (silica gel, ethyl acetate)

Mass spectrum (ESI ^" ): m / z = 488, 490 _, [MH] ^"

(2) 4- [(R) - (1-phenylethyl) amino] -7- [2- (2, 2-dimethyl-6-oxomorpholin-4-yl) ethoxy] -6-nitro- quinazoline (the product mixture initially obtained is converted into the cyclized product by post-treatment with p-toluenesulfonic acid in toluene)

R _f value: 0.45 (silica gel, methylene chloride / methanol = 95: 5)

Mass spectrum (ESI ^" ): m / z = 464 [MH] ^"

(3) 4- [(3-chloro-4-fluorophenyl) amino] -7- [3- ((S) -6-methyl-

2-oxo-morpholin-4-yl) -propyloxy] -6-nitro-quinazoline (The cyclized product is formed immediately, so the after-treatment is avoided) R _f value: 0.37 (silica gel, methylene chloride / methanol = 95: 5 ) Mass spectrum (ESI ^" ): m / z = 488, 490 [MH] ^"

(4) 4- [(R) - (1-phenylethyl) amino] -7- (2- {N, N-bis [(methoxycarbonyl) methyl] amino} ethoxy) -6-nitro- quinazoline (The reaction is carried out in N, N-dimethylformamide. The aftertreatment is dispensed with)

R _f value: 0.31 (silica gel, methylene chloride / methanol = 95: 5) mass spectrum (ESI ^" ): m / z = 496 [MH] ^"

(5) 4- [(3-chloro-4-fluorophenyl) amino] -7- [4- ((S) -3-methyl-

2-oxo-morpholin-4-yl) -butyloxy] -6-nitro-quinazoline (no after-treatment is carried out. The starting material (S) -2- (2-hydroxyethylamino) propionic acid ethyl ester is obtained by reacting ( R) -2- (trifluoromethylsulfonyloxy) propionic acid ethyl ester obtained with 2-aminoethanol in methylene chloride) R _f value: 0. 73 (silica gel, methylene chloride / methanol = 9: 1) mass spectrum (ESI ^" ): m / z = 502, 504 [MH] ^"

(6) 4- [(3-Chloro-4-fluorophenyl) amino] -7- (2- {N- [(tert-butyloxycarbonyl) ethyl] -N- (1,1-dimethyl-2-hydroxy -ethyl) - amino} -ethoxy) -6-nitro-quinazoline R _f value: 0.46 (silica gel, ethyl acetate)

(7) 4- [(3-chloro-4-fluoro-phenyl) amino] -7- (3- {N- [(tert-butyloxycarbonyl) methyl] -N- (1,1-dimethyl-2-hydroxy -ethyl) - amino} -propyloxy) -β-nitro-quinazoline

R _f value: 0.31 (silica gel, methylene chloride / methanol = 95: 5) mass spectrum (ESI-): m / z = 576, 578 [MH] ^"

(8) 4- [(3-chloro-4-fluorophenyl) amino] -7- {2- [N- (2-oxotetrahydrofuran-4-yl) -N-methylamino] ethoxy} - 6-nitroquinazoline

(The preparation of the starting material 4-methylamino-2-oxotetrahydrofuran has already been described elsewhere: WO 0055141 AI)

Melting point: 214-215.5 ° C

Mass spectrum (ESI ⁺ ): m / z = 476, 478 [M + H] ⁺

(9) 4- [(3-Chloro-4-fluorophenyl) amino] -7- (4- {N- [(tert-butyloxycarbonyl) ethyl] -N- (1,1-dimethyl-2-hydroxy -ethyl) - amino} -butyloxy) -6-nitro-quinazoline R _f value: 0.44 (silica gel, ethyl acetate) mass spectrum (ESI ^" ): m / z = 590, 592 [MH] ^"

(10) 4- [(3-chloro-4-fluoro-phenyl) amino] -7- (4- {N- [(tert-butyloxycarbonyl) methyl] -N- ((R) -2-hydroxy-prop -l-yl) -amino} - butyloxy) -6-nitro-quinazoline

Rf value: 0.33 (silica gel, methylene chloride / methanol = 95: 5) Mass spectrum (ESI ⁺ ): m / z = 578, 580 [M + H] ⁺

(11) 4- [(3-Chloro-4-fluorophenyl) amino] -7- (4- {N- [(tert-butyloxycarbonyl) methyl] -N- ((S) -2-hydroxy-prop -l-yl) -amino} - butyloxy) -6-nitro-quinazoline

R _f value: 0.33 (silica gel, methylene chloride / methanol = 95: 5) mass spectrum (ESI ⁺ ): m / z = 578, 580 [M + H] ⁺

(12) 4- [(3-chloro-4-fluorophenyl) amino] -7- (4- {N- [(ethoxycarbonyl) methyl] -N- (2-hydroxy-2-methyl-prop-l- yl) - amino} -butyloxy) -6-nitro-quinazoline R _f value: 0.40 (silica gel, methylene chloride / methanol = 95: 5)

(13) 4- [(3-chloro-4-fluorophenyl) amino] -7- {3- [N- (2-oxotetrahydrofuran-4-yl) -N-methylamino] propyloxy} - 6-nitroquinazoline

R _f value: 0.23 (silica gel, methylene chloride / methanol = 95: 5) mass spectrum (ESI ⁺ ): m / z = 490, 492 [M + H] ⁺

Example III

4- [(3-chloro-4-fluorophenyl) amino] -7- (3-methanesulfonyloxy-ropyloxy) -6-nitro-quinazoline

4.60 g of 4- [(3-chloro-4-fluorophenyl) amino] -7- (3-hydroxy-propyloxy) -6-nitro-quinazoline and 4.29 ml of diisopropylethylamine in 150 ml of methylene chloride are stirred at room temperature 0.96 ml of methanesulfonic acid chloride was added dropwise. The reaction mixture is stirred for about 30 minutes at room temperature, then another 0.1 ml of methanesulfonic acid chloride is added. After about an hour, the reaction is complete and ice water is added to the cloudy reaction solution. A thick, yellowish precipitate is formed, which is filtered off, washed with a little methylene chloride and water and dried in a desiccator. Yield: 5.06 g (92% of theory), R _f value: 0.43 (silica gel, methylene chloride / methanol = 95: 5) mass spectrum (ESI ^" ): m / z = 469, 471 [MH] ^"

The following compounds are obtained analogously to Example III:

(1) 4- [(3-chloro-4-fluorophenyl) amino] -7- (2-methanesulfonyloxyethoxy) -6-nitroquinazoline

R _f value: 0.53 (silica gel, methylene chloride / methanol / concentrated aqueous ammonia solution = 90: 10: 1) mass spectrum (ESI ^" ): m / z = 455, 457 [MH] ^"

(2) 4- [(R) - (1-phenylethyl) amino] -7- (2-methanesulfonyloxyethoxy) -6-nitroquinazoline

R _f value: 0.45 (silica gel, methylene chloride / methanol = 95: 5) mass spectrum (ESI ^" ): m / z = 431 [MH] ^"

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

R _f value: 0.82 (silica gel, methylene chloride / methanol = 9: 1) mass spectrum (ESI ^" ): m / z = 483, 485 [MH] ^"

Example IV

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

To 21.30 g of 4- [(3-chloro-4-fluorophenyl) amino] -7- [3- (tetrahydropyran-2-yloxy) propyloxy] -6-nitro-quinazoline in 200 ml of methanol are 3.00 ml concentrated hydrochloric acid dropped. A yellow precipitate falls out. The suspension is stirred at 50 ° C for about 3.5 hours. For working up, the methanol is distilled off in vacuo on a rotary evaporator. The residue is mixed with ethyl acetate and a little ice water and made alkaline with sodium hydroxide solution. The organic phase is washed with water and saturated sodium chloride solution and remains overnight at room temperature, a yellow precipitate being formed. This is suctioned off, washed with ethyl acetate and dried. The filtrate is concentrated and the evaporation residue recrystallized from ethyl acetate. The crystals obtained in this way are combined with the precipitate which has been suctioned off and recrystallized again from ethyl acetate. The desired product is obtained in the form of pale yellow crystals.

Yield: 4.60 g (40% of theory),

Melting point: 224-227 ° C

Mass spectrum (ESI ^" ): m / z = 391, 393 [MH] ^"

The following compounds are obtained analogously to Example IV:

(1) 4- [(3-chloro-4-fluorophenyl) amino] -7- (2-hydroxyethoxy) - 6-nitroquinazoline

R _f value: 0.46 (silica gel, methylene chloride / methanol / concentrated aqueous ammonia solution = 90: 10: 1)

Mass spectrum (ESI ^" ): m / z = 377, 379 [MH] ^"

(2) 4- [(R) - (1-phenyl-ethyl) amino] -7- (2-hydroxy-ethoxy) -

6-nitro-quinazoline Melting point: 192-194 ° C

Mass spectrum (ESI ^" ): m / z = 353 [MH] ^"

(3) 4- [(3-chloro-4-fluorophenyl) amino] -7- (4-hydroxybutyloxy) - 6-nitroquinazoline R _f value: 0.70 (silica gel, methylene chloride / methanol = 9: 1) Mass spectrum (ESI ^" ): m / z = 405, 407 [MH] ^"

Example V

4- [(3-chloro-4-fluorophenyl) amino] -7- [2- (tetrahydropyran-2-yloxy) ethoxy! -6-nitro-chinaτ: olin

3.64 g of sodium hydride (60% strength) are added in portions to 13.00 g of 2- (tetrahydropyran-2-yloxy) ethanol in 250 ml of tetrahydrofuran while cooling with an ice bath. The reaction mixture is then warmed to about 30-40 ° C. in a water bath and stirred for a further 15 minutes. Then it is cooled again in an ice bath and mixed with 15.60 g of 4- [(3-chloro-4-fluorophenyl) amino] -7-fluoro-6-nitro- quinazoline in 50 ml of tetrahydrofuran. The reaction mixture immediately turns dark red. After 10 minutes the ice bath is removed and the reaction mixture is stirred for one hour at room temperature. Then a total of 1.00 g of sodium hydride is again added and stirring is continued for a further 1.5 hours at 50 ° C. until the reaction is complete. For working up, about 200 ml of tetrahydrofuran are distilled off on a rotary evaporator. The residue is poured into 1 liter of ice water and neutralized with citric acid. The aqueous phase is extracted thoroughly with ethyl acetate. The combined organic phases are washed with 250 ml of semi-saturated sodium chloride solution, dried over magnesium sulfate and concentrated. A yellowish precipitate is formed, which is suctioned off and dried in a desiccator. The mother liquor is concentrated again. The solid yellowish flask residue is triturated with te.rt.butyl methyl ether, suction filtered and also dried in a desiccator. Yield: 18.93 g (88% of theory), R _f value: 0.60 (silica gel, petroleum ether / ethyl acetate = 1: 2) mass spectrum (ESI ^" ): m / z = 461, 463 [MH] ^"

The following compounds are obtained analogously to Example V:

(1) 4- [(3-Chloro-4-fluorophenyl) amino] -7- [3- (tetrahydropyran-2-yloxy) propyloxy] -6-nitro-quinazoline

R _f value: 0.37 (silica gel, cyclohexane / ethyl acetate = 1: 1) mass spectrum (ESI ^" ): m / z = 475, 477 [MH] ^"

(2) 4- [(R) - (1-phenylethyl) amino] -7- [2- (tetrahydropyran- 2-yloxy) ethoxy] -6-nitroquinazoline

R _f value: 0.12 (silica gel, cyclohexane / ethyl acetate = 1: 1) mass spectrum (ESI ^" ): m / z = 437 [MH] ^"

(3) 4- [(3-Chloro-4-fluorophenyl) amino] -7- [4- (tetrahydropyran- 2-yloxy) butyloxy] -6-nitro-quinazoline (The reaction is carried out with

Potassium ert.butylate carried out in N, N-dimethylformamide)

R _f value: 0.38 (silica gel, petroleum ether / ethyl acetate = 1: 1) Mass spectrum (ESI ^" ): m / z = 489, 491 [MH] ^"

Example VI

(2-Hydroxy-2-methyl-propylaminoacetic acid ethyl ester

100.00 g of sodium carbonate are added with cooling to 50.00 g of glycine ethyl ester hydrochloride in 100 ml of saturated potassium carbonate solution. The resulting mass is extracted several times with a total of about 600 ml of diethyl ether. The combined ether extracts are dried over sodium sulfate and the

Dry evaporated. There remain 28.60 g of glycine ethyl ester. This is mixed with 26.00 ml of isobutylene oxide and 40 ml of absolute ethanol and heated in a Roth bomb at 90 ° C for six hours. After cooling to room temperature, the reaction mixture is concentrated, leaving a thin oil.

Yield: 45.80 g (73% of theory), mass spectrum (ESI ⁺ ): m / z = 176 [M + H] ⁺

It's a VTT

() - (2-Hydroxy-propylamino) -esen ethyl acetate To 5.00 g of (S) - (+) -l-aminopropan-2-ol and 11.32 ml diisopropylethylamine in 40 ml acetonitrile are cooled with ice bath within 3.88 ml of ethyl bromoacetate in 10 ml of acetonitrile was added dropwise for 20 minutes. The reaction mixture is allowed to warm to room temperature overnight. For working up, the reaction solution is concentrated. The oily flask residue is dissolved in about 15 ml of water and extracted first with tert-butyl methyl ether, then with ethyl acetate. The extracts are washed with water and saturated sodium chloride solution, dried over magnesium sulfate and concentrated. The light oil thus obtained is reacted further without further purification. Yield: 1.53 g (27% of theory), R _f value: 0.55 (silica gel, methylene chloride / methanol = 9: 1) mass spectrum (ESI ⁺ ): m / z = 162 [M + H] ⁺ The following compounds are obtained analogously to Example VII:

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

(The reaction is carried out in N, N-dimethylformamide) R _f value: 0.46 (silica gel, ethyl acetate / methanol = 9: 1) mass spectrum (ESI ⁺ ): m / z = 190 [M + H] ⁺

(2) (S) - (2-Hydroxy-propylamino) -acetic acid- ert.butyl ester

(3) (2-Hydroxy-l, 1-dimethyl-ethylamino) acetic acid, butyl ester (the reaction is carried out in N, N-dimethylformamide) R _f value: 0.47 (silica gel, methylene chloride / methanol / concentrated, aqueous) Ammonia solution = 90: 10: 0.1) mass spectrum (ESI ⁺ ): m / z = 204 [M + H] ⁺

Example VIII

4- \ (R) - (1 ~ phenyl-ethyl) amino] -6-nitro-7-fluoro-quinazoline

A solution of 74 ml of (R) -1-phenyl-ethylamine in 100 ml of dioxane is added dropwise to 108.8 g of 4-chloro-6-nitro-7-fluoro-quinazoline in 800 ml of methylene chloride while cooling with an ice bath. The reaction mixture is stirred at room temperature overnight. For working up, it is shaken out with water. The organic phase is dried over magnesium sulfate and concentrated. The residue is purified by chromatography on a silica gel column using petroleum ether / ethyl acetate (1: 1) as the eluent.

Yield 52.90 g (35% of theory), melting point: 203 ° C.

jp-ig iel TY 4 - [(3-Chloro-4-fluorophenyl) amino] - 7 - [3 - ((R) - 6-methyl -2-oxo-orpholin-4-yl) propyloxy! -6 nl tro-quinazoline

285 mg 4- [(3-chloro-4-fluoro-phenyl) amino] -7- (3- {N- [(tert-butyloxycarbonyl) methyl] -N- ((R) -2-hydroxypropyl) - amino} -propyl-oxy) -6-nitro-quinazoline in 5 ml of acetonitrile are mixed with 0.50 ml of trifluoroacetic acid and heated under reflux for about two hours. The reaction solution is concentrated and the residue is taken up in methylene chloride. The solution is made alkaline with ice-bath cooling with saturated potassium carbonate solution. The aqueous phase is extracted with methylene chloride / methanol (95: 5). The combined organic phases are washed with water, dried over magnesium sulfate and concentrated. The yellowish, resinous crude product is reacted further without further purification. Yield: 254 mg

R _f value: 0.37 (silica gel, methylene chloride / methanol = 95: 5) mass spectrum (ESI ^" ): m / z = 488, 490 [MH] ^"

The following compounds are obtained analogously to Example IX:

(1) 4- [(3-chloro-4-fluorophenyl) amino] -7- [2- ((R) -6-methyl -

2-oxo-morpholin-4-yl) -ethoxy] -6-nitro-quinazoline R _f value: 0.17 (silica gel, ethyl acetate) mass spectrum (ESI ^" ): m / z = 474, 476 [MH] ^"

(2) 4- [(3-chloro-4-fluorophenyl) amino] -7- [2- ((S) -6-methyl- '

2-oxo-morpholin-4-yl) -ethoxy] -6-nitro-quinazoline R _f value: 0.18 (silica gel, ethyl acetate) mass spectrum (ESI ^" ): m / z = 474, 476 [MH] ^"

(3) 4- [(3-chloro-4-fluorophenyl) amino] -7- [3- (5, 5-dimethyl-2-oxo-morpholin-4-yl) propyloxy] -6-nitro- quinazoline R _f value: 0.33 (silica gel, methylene chloride / methanol = 95: 5) mass spectrum (ESI ^" ): m / z = 502, 504 [MH] ^" (4) 4- [(3-chloro-4-fluorophenyl) amino] -7- [4- (5, 5-dimethyl-2-oxo-morpholin-4-yl) butyloxy] -6-nitro- quinazoline R _f value: 0.34 (silica gel, methylene chloride / methanol = 95: 5) mass spectrum (ESI-): m / z = 516, 518 [MH] ^"

(5) 4- [(3-chloro-4-fluorophenyl) amino] -7- [4- ((R) -6-methyl-2-oxo-morpholin-4-yl) butyloxy] -6- nitro-quinazoline R _f value: 0.20 (silica gel, ethyl acetate)

Mass spectrum (ESI ^" ): m / z = 502, 504 [MH] ^"

(6) 4- [(3-chloro-4-fluoro-phenyl) amino] -7- [4- ((S) -6-methyl-2-oxo-morpholin-4-yl) butyloxy] -6- nitro-quinazoline R _f value: 0.21 (silica gel, ethyl acetate)

Mass spectrum (ESI ^" ): m / z = 502, 504 [MH] ^"

(7) 4- [(3-chloro-4-fluorophenyl) amino] -7- [4- {2, 2-dimethyl-6-oxo-morpholin-4-yl) butyloxy] -6-nitro- quinazoline melting point: 194-197 ° C

Mass spectrum (ESI ⁺ ): m / z = 518, 520 [M + H] ⁺

Example X

4- [(3-chloro-4-fluorophenyl) amino] -7- (3- {N- [(tert.butyloxycarbonyl) methyl] -N- ((R) -2-hydroxypropyl) amino} -propyloxy) -6-nitro-quinazoline

To 1.00 g of 4- [(3-chloro-4-fluorophenyl) amino] -7- (3-methanesulfonyloxypropyloxy) -6-nitroquinazoline and 1.21 g of (R) - (2-hydroxy) -propylamino) -essigsaure- ert.butylester in 10 ml acetonitrile 0.42 ml triethylamine, 415 mg potassium carbonate and 200 mg sodium iodide. The reaction mixture is refluxed for about ten hours. For working up, the inorganic salts are filtered off and washed with ethyl acetate. The filtrate is concentrated, the flask residue is taken up in ethyl acetate and washed with water. The organic see phase is washed with saturated sodium chloride solution, dried over magnesium sulfate and concentrated. The crude product is purified by chromatography on a silica gel column using methylene chloride / methanol (98: 2) eluent. Yield: 480 mg (40% of theory),

R _f value: 0.37 (silica gel, methylene chloride / methanol = 95: 5) mass spectrum (ESI ^" ): m / z = 562, 564 [MH] ^"

The following compounds are obtained analogously to Example X:

(1) 4- [(3-chloro-4-fluoro-phenyl) amino] -7- (2- {N- [(tert-butyloxycarbonyl) methyl] -N- ((R) -2-hydroxypropyl) -amino} -ethoxy) -6-nitro-quinazoline

R _f value: 0.33 (silica gel, methylene chloride / methanol = 95: 5) mass spectrum (ESI ^" ): m / z = 548, 550 [MH] ^"

(2) 4- [(3-chloro-4-fluoro-phenyl) amino] -7- (2- {N- [(tert-butyloxycarbonyl) methyl] -N- ((S) -2-hydroxypropyl) -amino} -ethoxy) -6-nitro-quinazoline R _f value: 0.43 (silica gel, ethyl acetate)

Example XI

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

The substance is obtained in 65% yield by hydrogenation of 4- [(3-chloro-4-fluorophenyl) amino] -7- [3- (5, 5-dimethyl-2-oxomorpholin-4-yl) - propyloxy] -6-nitro-quinazoline in tetrahydrofuran in the presence of Raney nickel in a Parr apparatus at a hydrogen partial pressure of 50 psi.

R _f value: 0.17 (silica gel, methylene chloride / methanol = 95: 5) mass spectrum (ESI ⁺ ): m / z = 474, 476 [M + H] ⁺

The following compounds are obtained analogously to Example XI: (1) 6-Amino-4- [(3-chloro-4-fluorophenyl) amino] -7- {2- [N- (2-oxotetrahydrofuran-4-yl) -N-methylamino] -ethoxy} -quinazoline R _f value: 0.27 (silica gel, methylene chloride / methanol = 9: 1) mass spectrum (ESI ⁺ ): m / z = 446, 448 [M + H] ⁺

(2) 6-Amino-4- [(3-chloro-4-fluoro-phenyl) amino] -7- [4- (5,5-dimethyl-2-oxomorpholin-4-yl) butyloxy] - quinazoline R _f value: 0.22 (silica gel, methylene chloride / methanol = 95: 5) mass spectrum (ESI ⁺ ): m / z = 488, 490 [M + H] ⁺

(3) 6-Amino-4- [(3-chloro-4-fluorophenyl) amino] -7- [4- ((R) -6-methyl-2-oxo-morpholin-4-yl) butyloxy ] -quinazoline R _f value: 0.16 (silica gel, methylene chloride / methanol = 95: 5) mass spectrum (ESI ^" ): m / z = 472, 474 [MH] ^"

(4) 6-Amino-4- [(3-chloro-4-fluoro-phenyl) amino] -7- [4- ((S) -6-methyl-2-oxo-morpholin-4-yl) butyloxy ] -quinazoline

Melting point: 134-139 ° C

Mass spectrum (ESI ^" ): m / z = 472, 474 [MH] ^"

(5) 6-Amino-4- [(3-chloro-4-fluoro-phenyl) amino] -7- [4- (2,2-dimethyl-6-oxomorpholin-4-yl) butyloxy] - quinazoline R _f value: 0.26 (silica gel, methylene chloride / methanol = 95: 5) mass spectrum (ESI ⁺ ): m / z = 488, 490 [M + H] ⁺

(6) 6-Amino-4- [(3-chloro-4-fluorophenyl) amino] -7- {3- [N- (2-oxotetrahydrofuran-4-yl) -N-methylamino] -propyloxy} -quinazoline mass spectrum (ESI ^" ): m / z = 458, 460 [MH] ^"

Making the end connections:

Step Example! 1

4- [(3-chloro-4-fluorophenyl) amino] -7- [3- (2, 2-dimethyl-6-oxo-orpho! In-4-yl) propyloxy! -6- f (vinylcarbonyl isminnl -chi ir.a 7.nl in 0.47 ml of triethylamine are added to 101 mg of acrylic acid in 5 ml of tetrahydrofuran under a nitrogen atmosphere. This mixture is cooled to about -50 ° C. in a dry ice / acetone cooling bath and 119 mg of acrylic acid chloride in 3 ml of tetrahydrofuran are added, a colorless precipitate being formed. The suspension is stirred at this temperature for about an hour. Then 240 mg of 6-amino-4- [(3-chloro-4-fluorophenyl) amino] -7- [3- (2, 2-dimethyl-6-oxo-morpholin-4-yl) propyloxy] -quinazoline added dropwise in 7 ml of tetrahydrofuran at -55 ° C. The reaction mixture is allowed to slowly warm to -30 ° C. in the cooling bath. After about an hour, the dry ice / acetone cooling bath is replaced with an ice / sodium chloride cooling bath. The reaction mixture is allowed to warm to 0 ° C. As soon as the reaction is complete, the reaction is mixed with water and methylene chloride and made alkaline with sodium hydroxide solution. The separated aqueous phase is extracted again with methylene chloride and a little methanol. The combined organic extracts are washed with water, dried and concentrated. There remains a yellow resin, which as a silica gel column with methylene chloride / methanol (98: 2)

Eluent is chromatographed. The desired product is stirred with a little ter. Butyl methyl ether, the finely crystalline

The precipitate is filtered off, washed with tert-butyl methyl ether and dried at 50 ° C in a vacuum. Yield: 160 mg (60% of theory),

R _f value: 0.42 (silica gel, methylene chloride / methanol = 95: 5) mass spectrum (ESI ^" ): m / z = 526, 528 [MH] ^"

The following compounds are obtained analogously to Example 1:

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

Melting point: 182.5-184 ° C mass spectrum (ESI ^" ): m / z = 512, 514 [MH] ^" (2) 4 - [(R) - (1-phenylethyl) amino] -7- [2 - (2, 2-dimethyl-6-oxomorpholin-4-yl) ethoxy] -6- [( vinylcarbonyl) amino] -quinazoline R _f value: 0.30 (silica gel, methylene chloride / methanol = 95: 5) mass spectrum (ESI ^" ): m / z = 488 [MH] ^"

(3) 4- [(3-chloro-4-fluorophenyl) amino] -7- [3- ((S) -6-methyl-

2-oxo-morpholin-4-yl) propyloxy] -6- [(vinylcarbonyl) amino] quinazoline

R _f value: 0.38 (silica gel, methylene chloride / methanol = 95: 5) mass spectrum (ESI ^" ): m / z = 512, 514 [MH] ^"

(4) 4- [(R) - (1-phenylethyl) amino] -7- (2- {N, N-bis [(methoxycarbonyl) methyl] amino} ethoxy) -6- [( vinylcarbonyl) amino] -quinazoline R _f value: 0.40 (silica gel, methylene chloride / methanol = 95: 5) mass spectrum (EI): m / z = 521 [M] ⁺

(5) 4- [(3-chloro-4-fluorophenyl) amino] -7- [3- ((R) -6-methyl-

2-oxo-morpholine ~ 4-yl) propyloxy] -6- [(vinylcarbonyl) amino] - quinazoline R _f value: 0.38 (silica gel, methylene chloride / methanol = 95: 5)

Mass spectrum (ESI ^" ): m / z = 512, 514 [MH] ^"

(6) 4- [(3-chloro-4-fluorophenyl) amino] -7- [2- ((R) -6-methyl-

2-oxo-morpholin-4-yl) ethoxy] -6- [(vinylcarbonyl) amino] quinazoline

R _f value: 0.32 (silica gel, methylene chloride / methanol = 95: 5) mass spectrum (ESI ^" ): m / z = 498, 500 [MH] ^"

(7) 4- [(3-Chloro-4-fluorophenyl) amino] -7- [2- ((S) -6-methyl-2-oxo-morpholin-4-yl) ethoxy] -6- [(vinylcarbonyl) amino] - quinazoline

R _f value: 0.32 (silica gel, methylene chloride / methanol = 95: 5)

Mass spectrum (ESI ^" ): m / z = 498, 500 [MH] ^" (8) 4- [(3-chloro-4-fluorophenyl) amino] -7- [4- ((S) -3-methyl-

2-oxo-morpholin-4-yl) butyloxy] -6- [(vinylcarbonyl) amino] quinazoline

R _f value: 0.63 (silica gel, methylene chloride / methanol / concentrated aqueous ammonia solution = 90: 10: 0.1)

Mass spectrum (ESI ^" ): m / z = 526, 528 [MH] ^"

(9) 4- [(3-Chloro-4-fluorophenyl) amino] -7- (2- {N- [(tert-butyloxycarbonyl) methyl] -N- (1,1-dimethyl-2-hydroxy -ethyl) - amino} -ethoxy) -6- [(vinylcarbonyl) amino] -quinazoline

R _f value: 0.22 (silica gel, methylene chloride / methanol = 95: 5)

(10) 4- [(3-Chloro-4-fluorophenyl) amino] -7- [3- (5, 5-dimethyl-2-oxo-morpholin-4-yl) propyloxy] -6- [( vinylcarbonyl) amino] - quinazoline

R _f value: 0.25 (silica gel, methylene chloride / methanol = 95: 5) mass spectrum (ESI ^" ): m / z = 526, 528 [MH] ^"

(11) 4- [(3-chloro-4-fluorophenyl) amino] -7- {2- [N- (2-oxotetrahydrofuran-4-yl) -N-methylamino] ethoxy} - 6

[(vinylcarbonyl) amino] quinazoline

Melting point: 195-199 ° C

Mass spectrum (ESI ⁺ ): m / z = 500, 502 [M + H] ⁺ >

(12) 4- [(3-chloro-4-fluorophenyl) amino] -7- [4- (5, 5-dimethyl-2-oxo-morpholin-4-yl) butyloxy] -6- [( vinylcarbonyl) amino] - quinazoline

R _f value: 0.33 (silica gel, methylene chloride / methanol = 95: 5) mass spectrum (ESI ⁺ ): m / z = 564, 566 [M + Na] +

(13) 4- [(3-chloro-4-fluoro-phenyl) amino] -7- [4- ((R) -6-methyl-2-oxo-morpholin-4-yl) butyloxy] -6- [(vinylcarbonyl) amino] - quinazoline

R _f value: 0.30 (silica gel, methylene chloride / methanol = 95: 5) mass spectrum (ESI ⁺ ) .- m / z = 550, 552 [M + Na] ⁺ (14) 4- [(3-chloro-4-fluorophenyl) amino] -7- [4- ((S) -6-methyl-2 - oxo-morpholin-4-yl) butyloxy] -6- [(vinylcarbonyl) amino] - quinazoline

Mass spectrum (ESI ^" ): m / z = 526, 528 [MH] ^"

(15) 4- [(3-chloro-4-fluorophenyl) amino] -7- [4- (2, 2-dimethyl-6-oxo-morpholin-4-yl) butyloxy] -6- [( vinylcarbonyl) amino] - quinazoline

Melting point: 110-112 ° C mass spectrum (ESI ^" ): m / z = 540, 542 [MH] ^"

(16) 4- [(3-chloro-4-fluorophenyl) amino] -7- {3- [N- (2-oxotetrahydrofuran-4-yl) -N-methylamino] propyloxy} - 6

[(vinylcarbonyl) amino] -quinazoline R _f value: 0.22 (silica gel, methylene chloride / methanol = 95: 5) mass spectrum (ESI ⁺ ): m / z = 514, 516 [M + H] ⁺

Example 2

4- [(3-chloro-4-fluorophenyl) amino] -7- [2- (5, 5-dimethyl-2-oxomorpholin-4-yl) ethoxy! -6- \ (vinylcarbonyl) amino! -quinazoline The substance is obtained by treating 4- [(3-chloro-4-fluorophenyl) amino] -7- (2- {N- [(tert -butyloxycarbonyl) methyl] -N- (1,1- dimethyl-2-hydroxy-ethyl) -amino} -ethoxy) -6- [(vinylcarbonyl) amino] -quinazoline with trifluoroacetic acid 'in acetonitrile under reflux.

R _f value: 0.29 (silica gel, methylene chloride / methanol = 95: 5) mass spectrum (ESI ⁺ ): m / z = 514, 516 [M + H] ⁺

The following compounds can be prepared analogously to the examples above and other processes known from the literature:

(1) 4- [(3-Chloro-4-fluoro-phenyl) amino] -7- [3- (5, 5-dimethyl-2-oxo-morpholin-4-yl) propyloxy] -6- [( vinylcarbonyl) amino] - quinazoline (2) 4- [(3-chloro-4-fluoro-phenyl) amino] -7- [2- (5, 5-dimethyl-2-oxomorpholin-4-yl) ethoxy] -6- [( vinylcarbonyl) amino] - quinazoline

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

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

(5) 4- [(3-bromophenyl) amino] -7- [3- ((S) -6-methyl-2-oxo-morpholin-4-yl) propyloxy] -6- [( vinylcarbonyl) amino] quinazoline

(6) 4- [(3-bromophenyl) amino] -7- [3- ((R) -6-methyl-2-oxo-morpholin-4-yl) propyloxy] -6- [( vinylcarbonyl) amino] quinazoline

(7) 4- [(3-methylphenyl) amino] -7- [2- ((S) -6-methyl-2-oxo-morpholin-4-yl) ethoxy] -6- [( vinylcarbonyl) amino] quinazoline

(8) 4- [(3-methylphenyl) amino] -7- [2- ((R) -6-methyl-2-oxo-morpholin-4-yl) ethoxy] -6- [( vinylcarbonyl) amino] quinazoline

(9) 4- [(3-Chloro-4-fluorophenyl) amino] -7- {2- [N- (2-oxotetrahydrofuran-4-yl) -N-methylamino] ethoxy } -6- [(vinylcarbonyl) amino] quinazoline

(10) 4- [(3-Chloro-4-fluorophenyl) amino] -7- {3- [N- (2-oxotetrahydrofur ₍ an-4-yl) -N-methylamino] -propyloxy} -6- [(vinylcarbonyl) amino] quinazoline

Example 3

Coated tablets with 75 mg Wi rksubstan ?,

1 coated tablet contains: Active substance 75.0 mg

Calcium phosphate 93.0 mg

Corn starch 35.5 mg

Polyvinylpyrrolidone 10.0 mg hydroxypropylmethyl cellulose 15.0 mg

Magnesium stearate 1.5 mg

230.0 mg

Production: The active substance is mixed with calcium phosphate, corn starch, polyvinylpyrrolidone, hydroxypropylmethyl cellulose and half of the stated amount of magnesium stearate. Pressings with a diameter of approx. 13 mm are produced on a tabletting machine, these are rubbed on a suitable machine through a sieve with a 1.5 mm mesh size and mixed with the remaining amount of magnesium stearate. This granulate is pressed on a tablet machine into tablets of the desired shape.

• Core weight: 230 mg stamp: 9 mm, curved

The dragee cores thus produced are coated with a film consisting essentially of hydroxypropylmethyl cellulose. The finished film coated tablets are polished with beeswax. ^: Coated weight: 245 mg.

Example 4

Tablets with 100 mg active subshan ?:

Composition: 1 tablet contains:

Active substance 100.0 mg

Milk sugar 80.0 mg corn starch 34.0 mg

Polyvinyl pyrrolidone 4.0 mg

Magnesium stearate 2.0 mg 220.0 mg

Manufacturing process:

Active ingredient, milk sugar and starch are mixed and moistened uniformly with an aqueous solution of the polyvinylpyrrolidone. After screening the moist mass (2.0 mm mesh size) and drying in a rack drying cabinet at 50 ° C, sieving is again carried out (1.5 mm mesh size) and the lubricant is added. The ready-to-press mixture is processed into tablets. Tablet weight: 220 mg

Diameter: 10 mm, biplane with facet on both sides and partial notch on one side.

Example 5

Tablets with 150 mg of active substance

Composition:

1 tablet contains: active substance 150.0 mg

Milk sugar powder 89.0 mg

Corn starch 40.0 mg

Colloidal silica 10.0 mg

Polyvinylpyrrolidone 10.0 mg magnesium stearate 1.0 mg

300.0 mg

production:

The active substance mixed with milk sugar, corn starch and silica is moistened with a 20% aqueous polyvinylpyrrolidone solution and passed through a sieve with a mesh size of 1.5 mm.

The granulate dried at 45 ° C is again through the same

Grated sieve and mixed with the specified amount of magnesium stearate. Tablets are pressed from the mixture. Tablet weight: 300 mg stamp: 10 mm, flat In game 6

Hard gelatin capsules with 150 mg of active substance

1 capsule contains:

Active ingredient 150.0 mg

Cornstarch dr. approximately 180.0 mg

Milk sugar powder approx. 87.0 mg magnesium stearate 3.0 mg approx. 420.0 mg

production:

The active ingredient is mixed with the excipients, passed through a sieve with a mesh size of 0.75 mm and mixed homogeneously in a suitable device.

The final mix is filled into size 1 hard gelatin capsules.

Capsule filling: approx. 320 mg capsule shell: hard gelatin capsule size 1.

Example 7

Suppositories with 150 mg of active substance>

1 suppository contains:

Active ingredient 150.0 mg

Polyethylene glycol 1500 550.0 mg

Polyethylene glycol 6000 460.0 mg Polyoxyethylene sorbitan monostearate 840 _r 0 mg

2,000.0 mg

production:

After the suppository mass has melted, the active ingredient is homogeneously distributed therein and the melt is poured into pre-cooled molds. For example _.

Suspension with 50 mg of active substance

100 ml suspension contain:

Active ingredient 1.00 g

Carboxymethylcellulose Na salt 0.10 g methyl p-hydroxybenzoate 0.05 g propyl p-hydroxybenzoate 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

H position:

Dest. Water is heated to 70 ° C. P-Hydroxybenzoic acid methyl ester and propyl ester as well as glycerol and carboxymethyl cellulose sodium salt are dissolved therein with stirring. It is cooled to room temperature and the active ingredient is added with stirring and dispersed homogeneously. According were to admit and ^■ dissolving the sugar, the sorbitol solution and the flavoring, the suspension is evacuated with stirring for deaeration.

5 ml of suspension contain 50 mg of active ingredient.

Example] 2.

Ampoules with 10 mg of active substance

Composition:

Active ingredient 10.0 mg

0.01 N hydrochloric acid s. q.

Aqua bidest ad 2.0 ml

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

Example 1H

Ampoules with 50 mg of active substance

Composition: active ingredient 50.0 mg

0.01 N hydrochloric acid s.q. Aqua bidest to 10.0 ml

manufacture; The active substance is dissolved in the required amount of 0.01N HCl, made isotonic with sodium chloride, sterile filtered and filled into 10 ml ampoules.

Example 11

Capsules for powder inhalation with 5 mg of active substance

1 capsule contains:

Active substance 5.0 mg

Lactose for inhalation purposes 15.0 mg

20.0 mg

manufacture; The active substance is mixed with lactose for inhalation purposes. The mixture is filled into capsules on a capsule machine (weight of the empty capsule approx. 50 mg).

Capsule weight: 70.0 mg capsule size = 3 Example 12

Inhalation solution for hand-held nebulizers with 2.5 mg active substance

1 hub includes:

Active substance 2.500 mg

Benzalkonium chloride 0.001 mg IN hydrochloric acid q.s. Ethanol / water (50/50) ad 15,000 mg

production:

The active substance and benzalkonium chloride are dissolved in ethanol / water (50/50). The pH of the solution is adjusted with 1N hydrochloric acid. The adjusted solution is filtered and filled into containers (cartridges) suitable for the hand-held nebuliser.

Filling mass of the container: 4.5 g

Claims

claims

1. Quinazolines of the general formula

in the

R _{a is} a benzyl or 1-phenylethyl group or a phenyl group substituted by the radicals R _x and R ₂ , where

R _{x represents} a hydrogen, fluorine, chlorine or bromine atom, a methyl, trifluoromethyl, cyan or ethinyl group and R _{2 represents} a hydrogen or fluorine atom,

R _{b is} a -N (CH ₂ CO ₂ R ₃ ) ₂ group, where

R _{3 represents} a hydrogen atom, a methyl or ethyl group,

an R ₄ O-CO-CH ₂ -N-CH ₂ -CH ₂ -OH group optionally substituted on the methylene groups by 1 or 2 methyl or ethyl groups, where

R _{4 represents} a hydrogen atom or a C 1-4 alkyl group,

a 2 -oxo-morpholin-4-yl group which can be substituted by 1 or 2 methyl or ethyl groups, or

an N- (2-oxo-tetrahydrofuran-4-yl) methylamino group and

2. Compounds of general formula I according to claim 1, in which

R _{a is} a benzyl or 1-phenylethyl group or a phenyl group substituted by the radicals R-_ and R ₂ , where

R _{b is} a -N (CH ₂ CO ₂ R ₃ ) ₂ group, where

R _{3 represents} a hydrogen atom, a methyl or ethyl group,

R _{4 represents} a hydrogen atom or a C 1-4 alkyl group,

an N- (2-oxo-tetrahydrofuran-4-yl) methylamino group and

n is an integer from the range from 2 to 4,

except for the connection

4- [(3-bromophenyl) amino] -7- [3- (2-oxo-morpholin-4-yl) propyloxy] - 6- [(vinylcarbonyl) amino] -quinazoline,

their tautomers, their stereoisomers and their salts.

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

R _{a is} a 1-phenylethyl group or a phenyl group substituted by the radicals R and R ₂ , where

R _] , a fluorine, chlorine or bromine atom, a methyl or ethinyl group and R _{2 represent} a hydrogen or fluorine atom,

an N- (2-oxo-tetrahydrofuran-4-yl) methylamino group and

n is an integer from the range from 2 to 4,

their tautomers, their stereoisomers, and their salts.

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

R _{a is} a 1-phenylethyl or 3-chloro-4-fluorophenyl group,

R _{b is} a 2-oxomorpholin-4-yl group which is substituted by 1 or 2 methyl or ethyl groups, and

n is an integer from the range from 2 to 4,

their tautomers, their stereoisomers and their salts.

5. The following compounds of general formula I according to claim 1:

(1) 4- [(R) - (1-phenylethyl) amino] -7- [2- (2, 2-dimethyl-6-oxomorpholin-4-yl) ethoxy] -6- [( vinylcarbonyl) amino] -quinazoline, (2) 4- [(3-chloro-4-fluoro-phenyl) amino] -7- [3- ((S) -6-methyl -

2-oxo-morpholin-4-yl) propyloxy] -6- [(vinylcarbonyl) amino] quinazoline,

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

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

(6) 4- [(3-chloro-4-fluorophenyl) amino] -7- [2- ((R) -6-methyl-

2-oxo-morpholin-4-yl) ethoxy] -6- [(vinylcarbonyl) amino] quinazoline,

(7) 4- [(3-chloro-4-fluorophenyl) amino] -7- [2- ((S) -6-methyl -

2-oxo-morpholin-4-yl) ethoxy] -6- [(vinylcarbonyl) amino] quinazoline,

(8) 4- [(3-chloro-4-fluorophenyl) amino] -7- [4- ((S) -3 -methyl-

2-oxo-morpholin-4-yl) butyloxy] -6- [(vinylcarbonyl) amino] quinazoline and

(9) 4- [(3-chloro-4-fluorophenyl) amino] -7- [4- ((R) -6-methyl -

2-oxo-morpholin-4-yl) butyloxy] -6- [(vinylcarbonyl) amino] - quinazoline,

their tautomers, their stereoisomers and their salts.

6. Physiologically acceptable salts of the compounds according to at least one of claims 1 to 5 with inorganic or organic acids or bases.

7. Medicament containing a compound according to at least one of claims 1 to 5 or a physiologically acceptable salt according to claim 6 in addition to optionally one or more inert carriers and / or diluents.

8. Use of a compound according to at least one of claims 1 to 6 for the manufacture of a medicament for the treatment of benign or malignant tumors, for the prevention and • treatment of diseases of the respiratory tract and lungs, for the treatment of polyps, of diseases of the stomach. Intestinal tract, the bile ducts and bladder as well as the kidney and skin are suitable.

9. A method for producing a medicament according to claim

7, characterized in that a compound according to at least one of claims 1 to 7 is incorporated into one or more inert carriers and / or diluents in a non-chemical way.

10. A process for preparing the compounds of the general formula ^• I according to claims 1 to 6, characterized in that

a) a compound of the general formula

in the R _a , R _b and n are as defined in claims 1 to 5, with a compound of the general formula

Z _x - CO - CH = CH ₂ , (III)

in the

Z _{x represents} a leaving group, is implemented and

if necessary, a protective residue used in the implementations described above is split off again and / or

if desired, a compound of the general formula I thus obtained is separated into its stereoisomers and / or

a compound of the general formula I thus obtained is converted into its salts, in particular for its pharmaceutical use into its physiologically tolerable salts.