SK287573B6 - Quinazoline derivatives, method for production thereof, pharmaceutical preparation containing said compounds and their use - Google Patents

Abstract

Ouinazoline derivatives of the general formula (I), their tautomers, stereoisomers and salts, especially their physiologically acceptable salts with inorganic or organic acids, which have valuable pharmacological properties, especially an inhibiting effect upon signal transduction caused by tyrosine kinase; the process for their preparation and their use in the treatment of diseases, especially of tumoral diseases, diseases of the lung and the respiratory tract.

Description

The invention relates to quinazoline derivatives having valuable pharmacological properties, in particular the tyrosine kinase-mediated inhibitory effect of signal transduction, their use in the treatment of diseases, in particular cancer, lung and airway diseases. The invention further relates to processes for their preparation and pharmaceutical compositions containing them.

BACKGROUND OF THE INVENTION

WO 01/77104, DE 199 11 366, DE 199 08 567, WO 00/55141 and WO 00/78735 include bicyclic heterocycles having a tyrosine kinase inhibitory effect, which are useful in the treatment of cancer.

US 6,127,374 discloses 4-anilino-quinazolines which, by virtue of their tyrosine kinase inhibitory activity, are useful in the treatment of cancer.

WO 99/06396 discloses irreversible tyrosine kinase inhibitors having a bicyclic heteroaromatic nucleus containing two to four nitrogen atoms.

WO 97/38983 discloses irreversible tyrosine kinase inhibitors having a quinazoline core which is considered useful in the treatment of cancer, atherosclerosis, restenosis, endometriosis and psoriasis.

SUMMARY OF THE INVENTION

The present invention provides quinazoline derivatives of formula (I)

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

In the above general formula (I)

R ^a represents a benzyl, 1-phenylethyl or 3-chloro-4-fluorophenyl group,

R ^b is dimethylamino a

R ^c is tetrahydrofuran-3-yl-oxy-, tetrahydrofuran-2-yl-methoxy-, tetrahydrofuran-3-yl-methoxy-, tetrahydropyran-4-yl-oxy or tetrahydropyran-4-yl-methoxy.

Particularly preferred compounds of formula (I) are those wherein:

R ^a represents a 3-chloro-4-fluorophenyl group,

R ^b is dimethylamino a

R ^c is tetrahydrofuran-3-yl-methoxy- or tetrahydropyran-4-yl-methoxy, their tautomers, stereoisomers and salts.

Examples of particularly preferred compounds of formula (I) include:

(a) 4 - [(3-chloro-4-fluorophenyl) amino] -6 - {[4- (N, _N -dimethylamino) -1-oxo-2-buten-1-yl] amino} - 7 - ((R) -tetrahydrofuran-3-yloxy) -quinazoline, (b) 4 - [(3-chloro-4-fluorophenyl) amino] -6 - {[4- (N ', N-dimethylamino)] (1) - (2-buten-1-yl) -amino} -7 - ((S) -tetrahydrofuran-3-yloxy) -quinazoline, (c) 4 - [(3-chloro-4-fluorophenyl) amino] -6 - {[4- (N, N-dimethylamino) -1-oxo-2-buten-1-yl] -amino} -7- (tetrahydropyran-4-yloxy) -quinazoline, (d) 4- [ (3-Chloro-4-fluorophenyl) amino] -6 - {[4- (7H, N-dimethylamino) -1-iso-2-buten-1-yl] amino} -7 - [(tetrahydrofuran-2- yl) methoxy) N-quinazoline, (e) 4 - [(3-chloro-4-fluorophenyl) amino] -6 - {[4- (N, N-dimethylamino) -1-oxo-2-butene-1] -yl] -amino} -7 - [(tetrahydrofuran-3-ylmethoxy) -quinazoline, (f) 4 - [(3-chloro-4-fluorophenyl) amino] -6 - {[4- (7V, v / v)] dimethylamino) -1-oxo-2-buten-1-yl] amino} -7 - [(S) - (tetrahydrofuran-2-yl) methoxy] quinazoline, their tautomers, stereoisomers and salts thereof.

An especially preferred quinazoline derivative is (b) 4 - [(3-chloro-4-fluorophenyl) amino] -6 - {[4- (N, N-dimethylamino) -1-oxo-2-buten-1-yl] -amino} -7 - ((S) -tetrahydrofuran-3-yloxy) -quinazoline, its tautomers, stereoisomers and salts thereof.

The compounds of formula (I) may be prepared, for example, as follows:

a) Reaction of a compound of formula (II)

(II) in which:

R ^a and R ^c are determined with a compound of formula (III)

(III) in which:

R ^b is dimethylamino a

Z ¹ represents a leaving group such as a halogen atom, for example a chlorine or bromine atom, or a hydroxy group.

The reaction is optionally carried out in a solvent or solvent mixture such as methylene chloride, dimethylformamide, benzene, toluene, chlorobenzene, tetrahydrofuran, benzene / tetrahydrofuran or dioxane optionally in the presence of an inorganic or organic base and optionally in the presence of a dehydrating agent most preferably at a temperature ranging from -50 to 150 ° C, more preferably at a temperature in the range of -20 to 80 ° C.

The reaction with a compound of formula (III) wherein Z ¹ is a leaving group is optionally carried out in a solvent or solvent mixture such as methylene chloride, dimethylformamide, benzene, toluene, chlorobenzene, tetrahydrofuran, benzene / tetrahydrofuran or dioxane, more preferably in the presence of tertiary. an organic base such as triethylamine, pyridine or 4-dimethylaminopyridine in the presence of N-ethyl-diisopropylamine (Hiinig base), which organic bases may also serve as a solvent or in the presence of an inorganic base such as sodium carbonate, potassium carbonate or sodium hydroxide solution most preferably at a temperature in the range of -50 to 150 ° C, more preferably at a temperature in the range of -20 to 80 ° C.

The reaction with a compound of formula (III) in which Z ¹ is hydroxy 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'-dicyclohexyl. N, N -dicyclohexylcarbodiimide N -hydroxysuccinimide, 1-hydroxybenztriazole, N, N'-carbonyldiimidazole or triphenylphosphine / carbon tetrachloride, preferably in a solvent such as methylene chloride, dimethylformamide, tetrahydrofuran, dioxane, toluene, chloroethane, toluene, dimethyl sulfoxide, ethylene glycol diethyl ether or sulfolane and optionally in the presence of a reaction accelerator such as 4-dimethylaminopyridine at a temperature in the range of -50 to 150 ° C, more preferably at a temperature in the range of -20 to 80 ° C.

b) Reaction of a compound of formula (IV)

in which

R ^a and R ^c are determined and (iv),

Z ² represents a leaving group such as a halogen atom, a substituted hydroxy group or a substituted sulfonyloxy group such as a chlorine or bromine atom, a methanesulfonyloxy group or a p-toluenesulfonyloxy group, with a compound of formula (V)

HR ^b (V), wherein R ^b is as defined.

The reaction is optionally carried out in a solvent such as isopropanol, butanol, tetrahydrofuran, dioxane, toluene, chlorobenzene, dimethylformamide, dimethylsulfoxide, methylene chloride, ethylene glycol monomethyl ether, ethylene glycol diethyl ether or sulfolane, or a mixture of such solvents, optionally in the presence of an organic solvent, sodium or potassium hydroxide, a tertiary organic base such as triethylamine or N-ethyl-diisopropylamine (Hunig's base), these organic bases may also serve as a solvent and optionally in the presence of a reaction accelerator such as an alkali halide at a temperature ranging from - 20 to 150 ° C, more preferably at a temperature in the range of -10 to 100 ° C. However, the reaction may also be carried out without solvent or in excess of the compound of formula (V) used.

In the reactions described, the secondary amino groups attached to the quinazoline of formula (II) or (IV) may be protected during the reaction by conventional protecting groups which will be cleaved again after the reaction is complete. Suitable protecting groups are formyl, acetyl, trifluoroacetyl, ethoxycarbonyl, tert-butoxycarbonyl, benzyloxycarbonyl, benzyl, methoxybenzyl or 2,4-dimethoxybenzyl.

Alternatively, the subsequent cleavage of the protecting group used is carried out, for example, hydrolytically in an aqueous solvent such as 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 aproticly, 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, by hydrogenolysis, for example by means of 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. at 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 (1 to 7 bar), more preferably from 0.3 up to 0.5 MPa (3 to 5 bar). The 2,4-dimethoxybenzyl group is, however, more preferably cleaved in trifluoroacetic acid in the presence of anisole.

The cleavage of the tert-butyl or tert-butyloxycarbonyl group is preferably carried out by treatment with an acid 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 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, it is possible to separate cis-trans mixtures into their cis and trans isomers, and compounds with at least one optically active carbon atom into their enantiomers.

Thus, for example, it is possible to separate the obtained cis-and trans-mixtures by chromatography into their cis- and trans-isomers, the obtained compounds of formula (I) which occur in racemic form according to generally known methods (see Allinger NL and Eliel EL in "Topics in Stereochemistry", Vol. 6, Wiley Interscience, 1971) to their optical antipodes and compounds of formula (I) containing at least two asymmetric carbon atoms can be separated based on their physico-chemical differences by generally known methods, e.g. and / or by fractional crystallization, into their diastereomers, those formed in racemic form can subsequently be resolved, as mentioned, into 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 optically active substances, in particular acids and their activated derivatives or alcohols, which form salts or derivatives such as esters or amides with the racemic compound and the diastereomeric mixture of salts or derivatives obtained in this way, 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 quinic 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.

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

For example, the starting compound of formula (II) is obtained, for example, by reacting the 7-fluoro-6-nitro compound appropriately substituted in the 4-position with the corresponding alcoholate and subsequently reducing the thus obtained nitro compound or starting compound of formula III. an amine of formula (V) known from the literature or a starting compound of formula (IV) is obtained by acylating a compound of formula (II) with a suitable crotonic acid derivative.

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. In addition, it is possible for signal transmission to be blocked on the outermost component.

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

Blocking of human EGF-receptor kinase was determined using cytoplasmic tyrosine kinase domains (methionine 664 to alanine 1186 based on the sequence published in Nature 309 (1984), 418). For this purpose, the protein was expressed in Sf9 insect cells as a GST-fusion protein using the rod virus expression system.

Enzyme activity measurements were performed in the presence or absence of test compounds in serial dilutions. The substrate used was a pEY (4: 1) polymer from SIGMA. Biotinated pEY (bio-pEY) was added as Tracer-substrate. Each 100 μΐ reaction solution contained 10 μΐ inhibitor in 50% DMSO, 20 μΐ substrate solution (200 mM HEPES pH 7.4, 50 mM magnesium acetate, 2.5 mg / ml poly (EY), 5 pg / ml bio -pEY) and 20 μΐ of the prepared enzyme. The enzyme reaction was triggered by the addition of a 50 μΐ solution containing 100 μΜ ATP in 10 mM magnesium chloride. The dilution of the prepared enzyme was adjusted so that the incorporation of phosphate into the bio-pEY was linear with respect to the time and amount of the enzyme. The prepared enzyme was diluted in 20 mM HEPES pH 7.4, 1 mM EDTA, 130 mM sodium chloride, 0.05% Triton X-100, 1 mM DTT and 10% glycerin.

Enzymatic assays were performed at room temperature for 30 minutes and terminated by the addition of 50 μΐ of stop solution (250 mM EDTA in 20 mM HEPES pH 7.4). 100 μΐ was plated on a streptavidin-coated microtiter plate and incubated for 60 minutes at room temperature. The plate was then washed with 200 μΐ wash solution (50 mM Tris, 0.05% Tween 20). After addition of 100 μΐ HRPO-boosted anti-PY antibody (PY20H Anti-PTyr: HRP from Transduction Laboratories, 250 ng / ml), it was incubated for 60 minutes. The microtiter plate was then washed three times with 200 μΐ of wash solution each. 100 μΐ of TMB-peroxidase solution (A: B = 1: 1, Kirkegaard Perry Laboratories) was then added to the samples. After 10 minutes, the reaction was discontinued. Extinction was determined at an optical density of 450 nm using an ELISA reader. All points were set three times.

The data was adjusted using an iterative calculation using a sigmoidal curve analysis program (Graph Pad Prism Version 3.0) with variable Hill-Pitch. All data were released iterative correlation coefficient greater than 0.9 and the value of the upper and lower curves have a factor of 5. Opening of the curve was derived from the concentration of the active compound that inhibits the activity of EGF-receptor by 50% (IC ₅ o).

The following results were obtained:

Compound (Example #) Inhibition of EGF-receptor kinase IC ₅₀ [nM] 1 0.7 1 (2) 0.6 1 (3) 4.0 1 (5) 3.0 1 (10) 0.5 1 (22) 1.0 1 (32) 0.3 1 (33) 0.5 1 (34) 0.4

The compounds of the invention of formula (I) inhibit this tyrosine kinase-mediated signal transduction, 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 present 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 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 diseases of the gastrointestinal tract and of the bile duct and gall bladder 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 that are characterized by increased secretion, such as M. Ménétrier, secreted adenomas and protein loss syndromes.

In addition, it is possible to use the compounds of formula (I) and their physiologically acceptable salts for the treatment of other diseases caused by the aberrant tyrosine kinase function, such as epidermal hyperproliferation (Psoriasis), inflammatory processes, diseases of the immune system, hyperproliferation of hematopoietic cells, etc.

Based on biological properties, the compounds of the invention may be used alone or in combination with other pharmacologically active compounds, for example in tumor therapy in monotherapy or in combination with other antitumor therapeutics, for example in combination with topoisomerase inhibitors (e.g. Etoposide), mitosis inhibitors (e.g. Vinblastin) ), with compounds interacting with nucleic acids (eg czs-Platin, Cyclo-phosphamide, Adriamycin), with hormone antagonists (eg Tamoxifen), with inhibitors of metabolic processes (eg 5-FU etc.), with cytokines (eg Interferonen) , 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. It is also possible to use these compounds alone or in combination with agents affecting motility or secretion for the treatment of diseases of the gastrointestinal tract. 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, 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 are formulated together 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

3-methylamino-tetrahydrofuran

3.43 g of lithium aluminum hydride were added in portions to 50 ml of tetrahydrofuran while cooling in an ice bath. Subsequently, a solution containing 5.00 g of 3 - [(benzyloxycarbonyl) amino] tetrahydrofuran in 20 ml of tetrahydrofuran was added dropwise, maintaining the temperature below 10 ° C. After 10 minutes, the cooling bath was removed and the reaction mixture was heated to reflux for about 3 hours. For working up, 3.7 ml of water, 3.7 ml of 15% sodium hydroxide, and 3 ml of water were carefully added dropwise to the reaction mixture while cooling in an ice bath. Subsequently, a small amount of tetrahydrofuran was added and stirred for 15 minutes. The precipitated aluminum hydroxide slurry was aspirated and washed with a total of 150 ml of tetrahydrofuran. The filtrate was concentrated on a rotary evaporator. The residue was a colorless oil which was used without further purification.

Mass spectrum (ESI ⁺ ): m / z = 102 [M + H] < ⁺ > ^.

Rf value: 0.20 (silica gel, methylene chloride / methanol = 9: 1)

Preparation 2

- [(Benzyloxycarbonyl) amino] tetrahydrofuran

12.36 ml of tetrahydrofuran-3-carboxylic acid and 27.84 ml of diphenylphosphoryl azide in 500 ml of dioxane were mixed with 41.91 g of benzyl alcohol and 35.81 ml of triethylamine. The reaction mixture was heated at 100 ° C for approximately seven hours. After cooling to room temperature, the reaction mixture was concentrated on a rotary evaporator. The residue was mixed with 500 ml of methylene chloride and washed twice with 100 ml of 1 N sodium hydroxide each time. The organic phase was dried over magnesium sulfate and concentrated. The crude product was purified by chromatography on a silica gel column with cyclohexane / acetate (from 3: 1 to 1: 2) as the mobile phase.

Yield: 15.60 g (55% of theory) Mass spectrum (ESE): m / z = 220 [M-H] - Rf: 0.78 (silica gel, methylene chloride / methanol = 9: 1)

Preparation

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

A mixture of 12.80 g of 4 - [(3-chloro-4-fluorophenyl) amino] -6-nitro-7 - ((R) -tetrahydrofuran-3-yloxy) quinazoline, 200 ml of ethanol, 100 ml water and 17.20 ml of glacial acetic acid were heated to reflux. A total of 7.00 g of iron powder was then added in portions. The reaction mixture was heated at reflux for about an hour and then cooled to room temperature overnight. Upon working up, the reaction mixture was concentrated on a rotary evaporator. The residue was mixed with methylene chloride / methanol (9: 1), treated with 20 ml of concentrated ammonia solution and filtered through a pad of silica gel. Subsequently, a large amount of methylene chloride / methanol (9: 1) was washed and the combined filtrates were concentrated. The residue was slurried in diethyl ether and aspirated.

Yield: 8.59 g (73% of theory) Mass spectrum (ESP): m / z = 373, 375 [M-H] - Rf: 0.27 (silica gel, acetate / methanol = 9: 1)

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

(1) 6-Amino-4 - [(3-chloro-4-fluorophenyl) amino] -7 - ((S) -tetrahydrofuran-3-yloxy) quinazoline Mass spectrum (ESI): m / z = 373, 375 [ MH]

Rf value: 0.27 (silica gel, acetate / methanol = 9: 1) (2) 6-Amino-4 - [(3-chloro-4-fluorophenyl) amino] -7- (tetrahydropyran-4-yloxy) quinazoline Mass spectrum (ESE): m / z = 387, 389 [MH] -

Rf value: 0.20 (silica gel, acetate) (3) 6-Amino-4 - [(3-chloro-4-fluorophenyl) amino] -7 - [(tetrahydrofuran-2-yl) methoxy] quinazoline Mass spectrum (ESE) ): m / z = 387.389 [MH] -

Rf value: 0.55 (silica gel, acetate / methanol = 9: 1) (4) 6-Amino-4 - [(3-chloro-4-fluorophenyl) amino] -7 - [(tetrahydrofuran-3-yl) methoxy] quinazoline Mass Spec (ESP): m / z = 387.389 [MH] -

Rf value: 0.40 (silica gel, acetate / methanol = 9: 1)

Preparation 4

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

To a solution of 10.80 g of (R) -3-hydroxy-tetrahydrofuran in 100 ml of N, N-dimethylformamide was added portionwise 13.80 g of potassium tert -butyrate while cooling in an ice bath. The reaction mixture was stirred for about one hour, then 10.40 g of 4 - [(3-chloro-4-fluorophenyl) amino] -6-nitro-7-fluoroquinazoline was added portionwise. Subsequently, the cooling bath was removed and the dark red reaction mixture was stirred for two hours at room temperature. Upon working up, the reaction mixture was poured into approximately 500 ml of water and neutralized with 2N hydrochloric acid. The precipitated yellowish precipitate was aspirated and dried in a circulating oven at 70 ° C.

Yield: 12.80 g

Mp 244 ° C

Mass Spec (ESP): m / z = 403, 405 [M-H] -

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

(1) 4 - [(3-Chloro-4-fluorophenyl) amino] -6-nitro-7 - ((S) -tetrahydrofuran-3-yloxy) quinazoline Mass spectrum (ESI): m / z = 403, 405 [ MH]

Rf value: 0.45 (silica gel, acetate) (2) 4 - [(3-Chloro-4-fluorophenyl) amino] -6-nitro-7- (tetrahydropyran-4-yloxy) quinazoline Mass spectrum (ESE): m m / z = 417.419 [MH] -

Rf value: 0.42 (silica gel, acetate) (3) 4 - [(3-Chloro-4-fluorophenyl) amino] -6-nitro-7 - [(tetrahydro-furan-2-yl) methoxy] quinazoline Mass spectrum (ESE) : m / z = 417.419 [MH] -

Rf value: 0.47 (silica gel, acetate) (4) 4 - [(3-Chloro-4-fluorophenyl) amino] -6-nitro-7 - [(tetrahydrofuran-3-yl) methoxy] quinazoline Mass spectrum (ESI ') ): m / z = 417.419 [MH] -

Rf value: 0.41 (silica gel, acetate) (S) 4 - [(3-Chloro-4-fluorophenyl) amino] -6-nitro-7 - [(tetrahydropyran-4-yl) methoxy] quinazoline Mass spectrum (ESI ⁺ ): m / z = 433.435 [M + H] ⁺

Rf value: 0.79 (silica gel, acetate / methanol = 9: 1) (6) 4 - [(3-Chloro-4-fluorophenyl) amino] -6-nitro-7 - [(7 R) -tetrahydrofuran-2- yl) methoxy] quinazoline Mass spectrum (ESI): m / z = 419, 421 [M + H] ⁺

Rf value: 0.44 (silica gel, acetate) (7) 4 - [(3-Chloro-4-fluorophenyl) amino] -6-nitro-7 - [(S) -tetrahydro-furan-2-yl) methoxy] -quinazoline Mass spectrum (ESI ⁺ ): m / z = 419, 421 [M + H] ⁺

Rf: 0.44 (silica gel, acetate)

Preparation 5 (R) -N7 - [(Tetrahydrofuran-2-yl) methyl] -N-methyl-amine

21.10 g of (R) -N '- [(tetrahydrofuran-2-yl) methyl] -N'-benzyl- N -methyl-amine (crude product from Preparation 4) was dissolved in 200 ml of methanol and hydrogenated at room temperature in the presence of 4.00 g of palladium on charcoal (10% Pd) until hydrogen uptake is complete. On working up, the catalyst was filtered off and the filtrate was concentrated on a rotary evaporator. A thin, yellowish oil was formed which reacted immediately without further purification. Yield: 8.60 g (73% of theory) Mass spectrum (ESI ⁺ ): m / z = 116 [M + H] ⁺

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

(1) (S) -N - [(T-tetrahydrofuran-2-yl) methyl] - N -methyl-amine Mass spectrum (ESI ⁺ ): m / z = 116 [M + H] ⁺ (2) A - [(T-tetrahydropyran-4-yl) methyl] -N-methyl-amine Mass spectrum (ESI ⁺ ): m / z = 130 [M + H] ⁺

Preparation 6 (R) -N - [(Tetrahydro-furan-2-yl) methyl] -N-benzyl-N-methyl-amine

A solution consisting of 24.60 g of (R) -tetrahydrofuran-2-carboxylic acid N-benzyl-N-methyl-amide in 90 ml of tetrahydrofuran was added dropwise to 17.00 g of lithium aluminum hydride in 150 ml of tetrahydrofuran. The reaction mixture was boiled under reflux for two hours. For working-up, it was cooled to 0 ° C in an ice bath, mixed with 20 ml of water and 10 ml of 15N sodium hydroxide solution and stirred for 20 minutes. Subsequently, it was filtered through a pad of magnesium sulfate and washed with a total of approximately 500 ml of tetrahydrofuran. The filtrate was concentrated in vacuo to a yellowish oil which was further reacted without further purification.

Yield: 21.10 g (92% of theory)

Mass spectrum (ESI ⁺ ): m / z = 206 [M + H] < ⁺ > ^.

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

(1) (S) - N - [(Tetrahydrofuran-2-yl) methyl] -A ^L benzyl-N-methylamine

_{R f} value: 0.20 (silica gel, ethyl / methanol = 9: 1) (2) _l A - [(tetrahydropyran-4-yl) methyl] - / ^{V-benzyl-a-methyl-amine} MS (ESI ⁺ ): m / z = 220 [M + H] < ⁺ > ^.

Preparation of (R) -tetrahydrofuran-2-carboxylic acid N-benzyl-N-methyl-amide

To a solution consisting of 20.00 ml of (R) -tetrahydrofuran-2-carboxylic acid in 200 ml of tetrahydrofuran was added 25.30 g of N-benzyl-N-methylamine. Then, in portions with cooling in an ice bath was added a total of 67.10 g of O- (benzotriazol-l-yl) -N / A ^/ ', / V', / V-tetrametyluróniumtetrafluoroboritanu and the mixture is then stirred for about 48 hours at room temperature. The resulting precipitate was filtered off with suction, the filtrate was concentrated, mixed with water and filtered again. The filtrate obtained was basified with sodium bicarbonate solution and extracted with acetate. The combined acetate extracts were washed with water and saturated sodium chloride solution, dried over magnesium sulfate and concentrated. The residue was a yellowish oil which was further reacted without further purification.

Yield: 24.60 g (54% of theory)

Mass Spectrum (ESI ⁺ ): m / z = 220 [M + H] ⁺ R f value: 0.62 (silica gel, acetate)

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

(1) (S) -Tetrahydrofuran-2-carboxylic acid N-benzyl-N-methyl-amide

Mass spectrum (ESI ⁺ ): m / z = 242 [M + Na] ⁺ R f value: 0.62 (silica gel, acetate) (2) tetrahydropyran-4-carboxylic acid N -benzyl- N -methyl-amide (Amide bond) by 1,1'-carbonyldiimidazole in tetrahydrofuran.)

Mass spectrum (ESI ⁺ ): m / z = 256 [M + Na] ^< ^{+ >.}

Rf value: 0.45 (silica gel, acetate)

Preparation

6-amino-4 - [(3-chloro-4-fluorophenyl) amino] -7 - [(tetrahydropyran-4-yl) methoxy] -quinazoline

22.80 g of 4 - [(3-chloro-4-fluorophenyl) amino] -6-nitro-7 - [(tetrahydropyran-4-yl) methoxy] quinazoline in 300 ml of tetrahydrofuran was hydrogenated in the presence of 3.50 g platinum dioxide at room temperature until the calculated amount of hydrogen was absorbed. The catalyst was filtered off and the filtrate was concentrated to dryness on a rotary evaporator. The residue was mixed with diethyl ether, sucked off, washed with diethyl ether and dried at room temperature. Yield: 19.95 g (93% of theory) Mass spectrum (ESI ⁺ ): m / z = 403, 405 [M + H] ⁺

221 °

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

(1) 6-Amino-4 - [(3-chloro-4-fluorophenyl) amino] -7 - [(7 R) -tetrahydrofuran-2-yl) methoxy] quinazoline Mass spectrum (ESI ⁺ ): m / z = 389.391 [M + H] ⁺

Rf value: 0.11 (silica gel, acetate) (2) 6-Amino-4 - [(3-chloro-4-fluorophenyl) amino] -7 - [(S) -tetrahydrofuran-2-yl) methoxy] quinazoline Mass spectrum (ESI ⁺ ): m / z = 389, 391 [M + H] ⁺

Rf value: 0.33 (silica gel, acetate / methanol = 9: 1)

Production of final compounds

Example 1

4 - [(3-chloro-4-fluorophenyl) amino] -6 - {(4- [N- (2-methoxy-ethyl) -7V-methyl-amino] -l-oxo-2-buten-l-yl } amino) -7-cyclopropylmethoxy-quinazoline

To a solution of 4.50 g of bromocrotonic acid in 60 ml of methylene chloride was added dropwise 4.70 ml of oxalyl chloride. Subsequently, one drop of Λ / Ν-dimethylformamide was added. After about 30 minutes, the evolution of gas was complete and the reaction mixture was concentrated on a rotary evaporator. The crude bromocrotonic chloride was mixed with 30 ml of methylene chloride and added dropwise to a solution consisting of 7.00 g of 4 - [(3-chloro-4-fluorophenyl) amino] -6-amino-7-cyclopropylmethoxyquinazoline and 10 ml. 20 ml of Hunig's base in 150 ml of tetrahydrofuran. The reaction mixture was further stirred while cooling in an ice bath for about 1.5 hours and further at room temperature for 2 hours. Then 5.20 g of N- (2-methoxy-ethyl) - N -methyl-amine was added and the reaction mixture was stirred overnight at room temperature. Upon processing, the mixture was diluted with methylene chloride and washed thoroughly with water. The organic phase was dried over magnesium sulfate and concentrated. The crude product was purified by chromatography on a silica gel column with acetate followed by an acetate / methanol (19: 1) mixture as the mobile phase.

Yield: 5.07 g (51% of theory)

Mass spectrum (ESI -): m / z = 512, 514 [M-H] -

Rf value: 0.25 (silica gel, acetate / methanol = 9: 1)

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

(1) 4 - [(3-Chloro-4-fluorophenyl) amino] -6 - {[4- (N, N-dimethylamino) -1-oxo-2-buten-1-yl] amino} -7 -cyklobutyloxy-quinazoline

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

Rf value: 0.09 (silica gel, acetate / methanol = 9: 1) (2) 4 - [(3-Chloro-4-fluorophenyl) amino] -6 - {[4- (N, N-dimethylamino) -1] - oxo-2-buten-l-yl] amino} -7-cyclopentyloxy-quinazoline

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

Rf value: 0.11 (silica gel, acetate / methanol = 9: 1) (3) 4 - [(R) - (1-Phenyl-ethyl) amino] -6 - {[4- (A, A-bis- (2-Methoxy-ethyl) -amino) -1-iso-2-buten-1-yl] amino} -7-cyclopropylmethoxy-quinazoline

Mass Spectrum (ESF): m / z = 532 [M-H] < - >

Rf value: 0.40 (silica gel, acetate / methanol = 9: 1) (4) 4 - [(R) - (1-Phenyl-ethyl) amino] -6- ({4- [N - (2-methoxy) -ethyl-N-ethyl-amino] -1-iso-2-buten-1-yl} amino) -7-cyclopropylmethoxy-quinazoline

Mass spectrum (ESF): m / z = 502 [M-H] -

Rf value: 0.20 (silica gel, acetate / methanol = 9: 1) (5) 4 - [(R) - (1-Phenyl-ethyl) amino] -6 - ({4- [N - (2-methoxy) ethyl) -N-methyl-amino] -l-oxo-2-buten-l-yl} amino) -7-cyclopropylmethoxy-quinazoline

Mass spectrum (ESF): m / z = 488 [M-H] -

Rf value: 0.25 (silica gel, acetate / methanol = 9: 1) (6) 4 - [(R) - (1-Phenyl-ethyl) amino] -6 - ([4- [N- (tetrahydropyran-4-)]) yl) -A-methyl-amino] -1-iso-2-buten-1-yl} amino) -7-cyclopropylmethoxy-quinazoline

Mass Spectrum (ESF): m / z = 514 [M-H] < - >

Rf value: 0.15 (silica gel, acetate / methanol = 9: 1) (7) 4 - [(R) - (1-Phenyl-ethyl) amino] -6 - ({4- [N - (tetrahydrofuran-3- yl) -A-methyl-amino] -1-iso-2-buten-1-yl} amino) -7-cyclopropylmethoxy-quinazoline

Mass Spectrum (ESI): m / z = 500 [M-H] -

Rf value: 0.18 (silica gel, acetate / methanol = 9: 1) (8) 4 - [(3-Chloro-4-fluorophenyl) amino] -6 - [(4- {A - [(tetrahydrofuran-3-yl) ) methyl] -N-methylamino} -l-oxo-2-buten

-1-yl) amino] -7-cyclopropylmethoxy-quinazoline

Mass spectrum (ESF): m / z = 538, 540 [M-H] -

Rf value: 0.27 (silica gel, acetate / methanol = 9: 1) (9) 4 - [(3-Chloro-4-fluorophenyl) amino] -6 - {[4- (A, A-dimethylamino) -1] -οχο-2-buten-1-yl] amino} -7 - ((R) - (tetrahydrofuran-3-yloxy) quinazoline

Mass Spectrum (ESI ⁺ ): m / z = 486, 488 [M + H] ⁺ (10) 4 - [(3-Chloro-4-fluorophenyl) amino] -6 - {[4- (N, N-dimethylamino) 1-Oxo-2-buten-1-yl] -amino} -7 - ((S) - (tetrahydrofuran-3-yloxy) -quinazoline

Mass spectrum (ESI ⁺ ): m / z = 486, 488 [M + H] < ⁺ > ^.

Rf value: 0.45 (silica gel, methylene chloride / methanol = 5: 1) (11) 4 - [(3-Chloro-4-fluorophenyl) amino] -6 - {[4- (N, N-dimethylamino) -1 - oxo-2-buten-1-yl] -amino} -7- (tetrahydropyran-4-yloxy) -quinazoline

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

Rf value: 0.55 (silica gel, methylene chloride / methanol = 5: 1) (12) 4 - [(3-Chloro-4-fluorophenyl) amino] -6 - {[4- (N, ^N' -dimethylamino) -1] -οχο-2-buten-1-yl] amino} -7 - [(tetrahydrofuran-2-yl) methoxy] quinazoline

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

Rf value: 0.60 (silica gel, methylene chloride / methanol = 5: 1) (13) 4 - [(3-Chloro-4-fluorophenyl) amino] -6 - {[4- (N, N-dimethylamino)] - 1-οχο-2-buten-1-yl] -amino} -7 - [(tetrahydrofuran-3-yl) methoxy] quinazoline

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

Rf value: 0.50 (silica gel, methylene chloride / methanol = 5: 1) (14) 4 - [(3-Chloro-4-fluorophenyl) amino] -6 - {[4- (7V, A-diethylamino) -1] -οχο-2-buten-1-yl] -amino} -7 - [(tetrahydrofuran-3-yl) methoxy] -quinazoline

Mass spectrum (ESI): m / z = 528, 530 [M + H] < ⁺ > ^.

Rf value: 0.31 (silica gel, acetate / methanol = 9: 1) (15) 4 - [(R) - (1-Phenyl-ethyl) amino] -6 - {[4- (N, N-dimethylamino) ) -l-oxo-2-buten-l-yl] amino} -7-cyclopropylmethoxy-quinazoline

Mass spectrum (ESI ⁺ ): m / z = 446 [M + H] < ⁺ > ^.

R f value: 0.11 (silica gel, acetate / methanol = 9: 1) (16) 4 - [(3-Chloro-4-fluorophenyl) amino] -6- ({4- (N, N-bis- (2- methoxy-ethyl) amino] -1-iso-2-buten-1-yl} amino) -7 - [(tetrahydrofuran-2-yl) methoxy] quinazoline

Mass spectrum (ESI ⁺ ): m / z = 588, 590 [M + H] < ⁺ > ^.

Rf value: 0.55 (silica gel, methylene chloride / methanol = 9: 1) (17) 4 - [(3-Chloro-4-fluorophenyl) amino] -6 - {[4- (morpholin-4-yl) -1] - oxo-2-buten-l-yl] amino} -7 - [(tetrahydrofuran-2-yl) methoxy] -quinazoline

Mass spectrum (ESI ⁺ ): m / z = 542, 544 [M + H] < ⁺ > ^.

Rf value: 0.55 (silica gel, methylene chloride / methanol = 9: 1) (18) 4 - [(3-Chloro-4-fluorophenyl) amino] -6- ({4 - [N - (2-methoxy-ethyl) (N-Methyl-amino] -1-iso-2-buten-1-yl} amino) -? cyclopentyloxy-quinazoline

Mass spectrum (ESI): m / z = 528, 530 [M + H] < ⁺ > ^.

Rf value: 0.25 (silica gel, acetate / methanol = 9: 1) (19) 4 - [(3-Chloro-4-fluorophenyl) amino] -6 - [(4 - {(R) - N - [] (tetrahydrofuran-2-yl) methyl] - N -methyl-amino} -1-oxo-2-buten-1-yl) amino] -7-cyclopropylmethoxy-quinazoline

Mass spectrum (ESI ⁺ ): m / z = 540.542 [M + H] ⁺

Mp .: 149-153 ° C (20) 4 - [(3-Chloro-4-fluorophenyl) amino] -6 - [(4 - {(S ') - N - [(tetrahydrofuran-2-yl) methyl] 1 - [N-methylamino} -1-oxo-2-buten-1-yl) amino] -7-cyclopropylmethoxy-quinazoline

Mass spectrum (ESI ⁺ ): m / z = 540.542 [M + H] ⁺

Rf value: 0.29 (silica gel, acetate / methanol = 9: 1) (21) 4 - [(R) - (1-Phenyl-ethyl) amino] -6 - {[4 - (N, N -) dimethylamino) -1-iso-2-buten-1-yl] -amino} -7-cyclopentyloxy-quinazoline

Mass spectrum (ESI ⁺ ): m / z = 560 [M + H] < ⁺ > ^.

Rf value: 0.17 (silica gel, acetate / methanol = 9: 1) (22) 4 - [(3-Chloro-4-fluorophenyl) amino] -6 - {[4- (N-cyclopropyl-N-methyl- amino) -l-oxo-2-buten-l-yl] amino} -7-cyclopentyloxy-quinazoline

Mass Spectrum (ESI -): m / z = 508, 510 [M-H] -

Melting point: 140 ° C (23) 4 - [(3-Chloro-4-fluorophenyl) amino] -6 - {[4- (N-cyclopropyl-N-methyl-amino) -1-iso-2-butene] -1-yl] amino} -7-cyclopropylmethoxy-quinazoline

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

Rf value: 0.42 (silica gel, acetate / methanol = 9: 1) (24) 4 - [(3-Chloro-4-fluorophenyl) amino] -6 - [(4- {N - [(tetrahydropyran-4-yl)] - ) methyl] - N -methyl-amino} -1-oxo-2-

-buten-1-yl) amino] -7-cyclopropylmethoxy-quinazoline

Mass spectrum (ESI ⁺ ): m / z = 554, 556 [M + H] < ⁺ > ^.

Melting point: 141 ° C (25) 4 - [(R) - (1-Phenyl-ethyl) amino] -6 - [(4- {N - [(tetrahydropyran-4-yl) methyl] -A-methyl- amino} -1-oxo-2-buten-1-yl) amino] -7-cyclopropylmethoxy-quinazoline

Mass spectrum (ESI ⁺ ): m / z = 530 [M + H] < ⁺ > ^.

Rf value: 0.32 (silica gel, acetate / methanol / concentrated aqueous ammonia = 90: 10: 0.5) (26) 4 - [(3-Chloro-4-fluorophenyl) amino] -6 - [(4- { (R) - N - [(tetrahydrofuran-2-yl) methyl] - N -methyl-amino} -1-oxo-2-buten-1-yl) amino] -7-cyclopentyloxy-quinazole

Mass spectrum (ESI ⁺ ): m / z = 554, 556 [M + H] < ⁺ > ^.

Melting point: 117-121 ° C (27) 4 - [(3-Chloro-4-fluorophenyl) amino] -6 - [(4 - {(S) -A - [(tetrahydrofuran-2-yl) methyl] - N-Methylamino} -1-oxo-2-buten-1-yl) amino] -7-cyclopentyloxy-quinazoline

Mass spectrum (ESI ⁺ ): m / z = 554, 556 [M + H] < ⁺ > ^.

Rf value: 0.32 (silica gel, acetate / methanol / concentrated aqueous ammonia = 90: 10: 0.5) (28) 4 - [(3-Chloro-4-fluorophenyl) amino] -6 - {[4- ( A, A-dimethylamino) -l-oxo-2-buten-l-yl] amino} -7 - [(tetrahydropyran-4-yl) methoxy] -quinazoline

Mass spectrum (ESI ⁺ ): m / z = 514, 516 [M + H] < ⁺ > ^.

Rf value: 0.19 (silica gel, methylene chloride / methanol / concentrated aqueous ammonia = 95: 5: 0.05) (29) 4 - [(3-Chloro-4-fluorophenyl) amino] -6 - {[4- ( Morpholin-4-yl) -1-oxo-2-buten-1-yl] amino} -7 - [(tetrahydropyran-4-yl) methoxy] quinazoline

Mass spectrum (EST): m / z = 554.556 [M-H] -

Melting point: 174 ° C (30) 4 - [(3-Chloro-4-fluorophenyl) amino] -6 - ({4- [N, N-bis- (2-methoxy-ethyl) -amino] -1- οχο-2-buten-1-yl} amino) -7 - [(tetrahydropyran-4-yl) methoxy] quinazoline

Mass spectrum (ESI ⁺ ): m / z = 602, 604 [M + H] < ⁺ > ^.

Melting point: 100 to 102 ° C (31) 4 - [(3-Chloro-4-fluorophenyl) amino] -6 - {[4- (N, N-dimethylamino) -1-oxo-2-butene-1- yl] amino} -7 - [(7?) - (tetrahydrofuran-2-yl) methoxy] -quinazoline

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

Melting point: 110 to 112 ° C (32) 4 - [(3-Chloro-4-fluorophenyl) amino] -6 - {[4- (N, N-dimethylamino) -1-iso-2-butene-1 - yl] amino} -7 - [(S) - (tetrahydrofuran-2-yl) methoxy] quinazoline

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

Rf value: 0.23 (silica gel, acetate / methanol / concentrated aqueous ammonia = 90: 10: 0.1) (33) 4 - [(3-Chloro-4-fluorophenyl) amino] -6 - {[4- ( N-Ethyl-N-methyl-amino) 1-oxo-2-buten-1-yl] amino} -7 - [(S) - (tetrahydrofuran-3-yl) oxy] quinazoline

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

Melting point: 154-157 DEG C. (34) 4 - [(3-chloro-4-ŕluórfenyl) amino] -6 - {[4- ^(N, -izopropyl- / V-methyl-amino) l-oxo-2 buten-l-yl] amino} -7 - [(5) - (tetrahydrofuran-3-yl) oxy] -quinazoline

Mass spectrum (ESI ⁺ ): m / z = 514, 516 [M + H] < ⁺ > ^.

Rf value: 0.34 (silica gel, acetate / methanol / concentrated aqueous ammonia = 90: 10: 1) (35) 4 - [(3-Chloro-4-fluorophenyl) amino] -6 - {[4- (morpholine- 4-yl) -1-oxo-2-buten-1-yl] amino} -7 - [(S) - (tetrahydrofuran-3-yl) oxy] quinazoline

Mass spectrum (ESI ⁺ ): m / z = 528, 530 [M + H] < ⁺ > ^.

Melting point: 184-185 ° C (36) 4 - [(3-Chloro-4-fluorophenyl) amino] -6 - {[4- (N-isopropyl-N-methylamino) 1-oxo-2-butene -l-yl] amino} -7-cyclopentyloxy-quinazoline

Mass spectrum (ESI ⁺ ): m / z = 512.514 [M + H] ⁺

Rf value: 0.53 (silica gel, acetate / methanol / concentrated aqueous ammonia = 90: 10: 0.5) (37) 4 - [(3-Chloro-4-fluorophenyl) amino] -6 - {[4- ( N ¹ -ethyl- N -methyl-amino) 1-oxo-2-buten-1-yl] amino} -7 - [(S) - (tetrahydro-furan-2-yl) methoxy] -quinazoline

Mass Spectrum (ESE): m / z = 512.514 [M-H] -

Rf value: 0.15 (silica gel, acetate / methanol / concentrated aqueous ammonia = 90: 10: 1) (38) 4 - [(3-Chloro-4-fluorophenyl) amino] -6 - {[4 - (V)] , N-diethylamino) -l-oxo-2-buten-l-yl] amino} -7 - [(S) - (tetrahydrofuran-2-yl) methoxy] -quinazoline

Mass Spectrum (ESE): m / z = 526.528 [M-H] -

Rf value: 0.27 (silica gel, methylene chloride / methanol = 9: 1) (39) 4 - [(3-Chloro-4-fluorophenyl) amino] -6 - {[4- (N-isopropyl- N -methyl- amino) 1- (2-buten-1-yl) amino} -7 - [(S) - (tetrahydrofuran-2-yl) methoxy] quinazoline

Mass spectrum (ESI ⁺ ): m / z = 528, 530 [M + H] < ⁺ > ^.

Rf value: 0.31 (silica gel, methylene chloride / methanol = 9: 1)

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

(1) 4-Benzylamino-6 - {[4- (N, N-diethylamino) -1-iso-2-buten-1-yl] amino} -7-cyclopropylmethoxyquinazoline (2) 4- [ (3-Chloro-4-fluorophenyl) amino] -6 - [(4 - {N - [(tetrahydropyran-4-yl) methyl] -N-methylamino} -1-oxo-2-butene-1- yl) amino] -7-cyclopropylmethoxyquinazoline (3) 4 - [(3-Chloro-4-fluorophenyl) amino] -6 - {[4- (N, N-dimethylamino) -1-iso-2-butene] -1-yl] -amino} -7 - [(tetrahydropyran-4-yl) methoxy] -quinazoline (4) 4 - [(R) - (1-Phenyl-ethyl) amino] -6 - [(4- N - [(tetrahydrofuran-2-yl) methyl] - N -methyl-amino} -1-oxo-2-buten-1-yl) amino] -7-cyclopropylmethoxy-quinazoline (5) 4 - [(/ (R) - (1-Phenyl-ethyl) amino] -6 - {[4- (N, N-dimethylamino) -1-iso-2-buten-1-yl] -amino} -7 - [(tetrahydrofuran- 2-yl) methoxy] -quinazoline (6) 4 - [(/?) - (1-phenylethyl) amino] -6- (4-} _[I, V, A-bis (2-methoxyethyl) -amino] -1-iso-2-buten-1-yl} amino) -7 - [(tetrahydrofuran-2-yl) methoxy] quinazoline (7) 4 - [(R) - (1-phenyl) - ethyl) amino] -6 - {[4- (morpholin-4-yl) -1-iso-2-buten-1-yl] amino} -7 - [(tetrahydrofuran-2-yl) methoxy] quinazoline

Example 2

Dragees with 75 mg of active substance dragee core contains: active substance calcium phosphate maize starch polyvinylpyrrolidone hydroxypropylmethylcellulose magnesium stearate

75.0 mg

93.0 mg

35.5 mg

10.0 mg

15.0 mg _L5mg 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 produced on a tabletting machine, which were spread on a suitable machine through a sieve with a mesh size

1.5 mm 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 3

Tablets of 100 mg of active substance The tablet contains:

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

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, biplanar with bevelled edges on both sides and partial one-side vaulting.

Example 4

Tablets of 150 mg of the active substance

Ingredients:

tablet contains:

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

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 the indicated amount of magnesium stearate. Tablets were compressed from this mixture.

Tablet weight: 300 mg

Punch: 10 mm, flat

Example 5

Hard gelatin capsule with 150 mg of active substance 1 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 6

Supository with 150 mg of active ingredient 1 suppository contains: active ingredient polyethylene glycol 1500 polyethylene glycol 6000

150.0 mg

550.0 mg

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 7

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 8

Ampoules with 10 mg of active substance

Ingredients:

active substance 10.0 mg

0.01 N hydrochloric acid water bidistilled to 2.0 ml as needed

Production

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

Example 9

Ampoules with 50 mg of active substance

Ingredients:

active substance 50.0 mg

0.01 N hydrochloric acid water bidistilled to 10.0 ml as needed

Production

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

Example 10

Capsule for inhalation of powder with 5 mg of active substance The capsule contains:

active substance 5.0 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 11

Inhalation solution for manual nebulizer with 2.5 mg active ingredient stroke 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 suitable for manual sprayers.

Cartridge filling weight: 4.5 g

PATENT CLAIMS

Claims (8)

Quinazoline derivatives of the general formula (I) (I), in which R ^a is 1-phenylethyl or 3-chloro-4-fluorophenyl, R ^b is dimethylamino a R ^c is tetrahydrofuran-3-yl-oxy-, tetrahydrofuran-2-yl-methoxy-, tetrahydrofuran-3-yl-methoxy-, tetrahydropyran-4-yl-oxy or tetrahydropyran-4-yl-methoxy, their tautomers, stereoisomers and salts. Quinazoline derivatives of the general formula (I) according to claim 1, in which R ^a represents a 3-chloro-4-fluorophenyl group a R ^c is tetrahydrofuran-3-yl-oxy- or tetrahydropyran-4-yl-oxy, tautomers, stereoisomers and salts thereof. The quinazoline derivatives of formula (I) according to claim 1, which are the following compounds: a) 4 - [(3-chloro-4-fluorophenyl) amino] -6 - {[4- (N, N-dimethylamino) -1-oxo-2-buten-1-yl] amino} -7- ( (R) -Tetrahydro-furan-3-yloxy) -quinazoline, b) 4 - [(3-chloro-4-fluorophenyl) amino] -6 - {[4- (N, N-dimethylamino) -1-oxo-2-buten-1-yl] amino} -7- ( (5) -tetrahydrofuran-3-yloxy) -quinazoline, c) 4 - [(3-chloro-4-fluorophenyl) amino] -6 - {[4- (N, N-dimethylamino) -1-iso-2-buten-1-yl] amino} -7- ( tetrahydropyran-4-yloxy) -quinazoline, d) 4 - [(3-chloro-4-fluorophenyl) amino] -6 - {[4- (N, N-dimethylamino) -1-oxo-2-buten-1-yl] amino} -7- [(tetrahydrofuran-2-yl) methoxy]] quinazoline, e) 4 - [(3-chloro-4-fluorophenyl) amino] -6 - {[4- (N, N ^- dimethylamino) -1-oxo-2-buten-1-yl] amino} -7- [(tetrahydrofuran-3-yl) methoxy] -quinazoline, f) 4 - [(3-chloro-4-fluorophenyl) amino] -6 - {[4- (N, N-dimethylamino) -1-oxo-2-buten-1-yl] amino} -7- [ (S) - (tetrahydrofuran-2-yl) methoxy] quinazoline, their tautomers, stereoisomers and salts thereof. The quinazoline derivative of the general formula (I) according to claim 1, which is (b) 4 - [(3-chloro-4-fluorophenyl) amino] -6 - {[4- (N, N -dimethylamino) -1 -one] -2-buten-1-yl] -amino} -7 - ((S) -tetrahydrofuran-3-yloxy) -quinazoline, its tautomers, stereoisomers and salts thereof. Physiologically acceptable salts of quinazoline derivatives according to any one of claims 1 to 4 with inorganic or organic acids or bases. A pharmaceutical composition comprising a quinazoline derivative according to any one of claims 1 to 4 or a physiologically acceptable salt according to claim 5, optionally together with one or more inert carriers and / or diluents. Use of quinazoline derivatives according to any one of claims 1 to 5 for the manufacture of a medicament for the treatment of malignant or malignant tumors, for the prevention and treatment of diseases of the respiratory tract and lung as well as for the treatment of diseases of the gastrointestinal tract, bile ducts and gallbladder. A process for the preparation of quinazoline derivatives of the general formula (I) according to any one of claims 1 to 4, characterized in that: