NO325672B1 - Quinazoline derivatives, drugs containing these compounds, their use in the manufacture of drugs, and the method of preparation thereof - Google Patents

Description

The subject matter of the present invention are quinazoline derivatives with the general formula

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

In the above general formula I means

Ra a benzyl, 1-phenylethyl or 3-chloro-4-fluorophenyl group,

Rb a dimethylamino group and

Rc a tetrahydrofuran-3-yl-oxy-, tetrahydrofuran-2-yl-methoxy-, tetrahydrofuran-3-yl-methoxy-, tetrahydropyran-4-yl-oxy- or

tetrahydropyran-4-yl-methoxy group,

their tautomers, their stereoisomers and their salts.

Particularly preferred compounds of the general formula I are those in which

Ra means a 1-phenylethyl or 3-chloro-4-fluorophenyl group,

Rc a tetrahydrofuran-3-yl-oxy- or tetrahydropyran-4-yl-methoxy group,

their tautomers, their stereoisomers and their salts.

For example, the following particularly preferred compounds with the general formula I are mentioned: (a) 4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2 -buten-1 -yl]amino}-7-((fl)-tetrahydrofuran-3-yloxy)-quinazoline, (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, (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-(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-butene- 1-yl]amino}-7-[(tetrahydrofuran-3-yl)methoxy]-quinazoline, and (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, their stereoisomers and their salts.

The compounds with the general formula I can, for example, be prepared by the following method:

a) Reaction of a compound with the general formula

in which

Ra and Rc are defined as initially mentioned, with a compound of the general formula

in which

Rb is defined as initially mentioned and

Z1 is a leaving group such as a halogen atom, e.g. a chlorine or bromine atom, or a hydroxy group.

The reaction is optionally carried out in a solvent or a 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 water-extracting agent, suitably at temperatures between -50 and 150°C, preferably at temperatures between -20 and 80°C,.

With a compound of the general formula III, in which Zi is a leaving 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, conveniently in the presence of a tertiary organic base such as triethylamine, pyridine or 4-dimethylaminopyridine, in the presence of N-ethyl-diisopropylamine (Honig base), during which these organic bases can also serve as a solvent, or in the presence of an inorganic base such as sodium carbonate, potassium carbonate or caustic soda, suitable at temperatures between -50 and 150°C, preferably at temperatures between -20 and 80°C.

With a compound of the general formula III in which Z 1 is a hydroxy group, the reaction is preferably carried out in the presence of a water-extracting agent, e.g. in the presence of chloroformate isobutyl ester, thionyl chloride, trimethylchlorosilane, phosphorus trichloride, phosphorus pentoxide, hexamethyldisilazane, N,N'-dicyclohexylcarbodiimide, N,N'-dicyclohexylcarbodiimide/N-hydroxysuccinimide, 1-hydroxy-benztriazole, N,N'-carbonyldiimidazole or triphenylphosphine/ tetrachloromethane, suitably in a solvent such as methylene chloride, tetrahydrofuran, dioxane, toluene, chlorobenzene, dimethylformamide, dimethyl sulfoxide, ethylene glycol diethyl ether or sulfolane and optionally in the presence of a reaction accelerator such as 4-dimethylaminopyridine at temperatures between -50 and 150°C, but preferably at temperatures between -20 and 80°C.

b) Reaction of a compound with the general formula

in which

Ra and Rc are defined as initially mentioned, and

Z2 is a leaving group such as a halogen atom, a substituted hydroxy or sulfonyloxy group, such as a chlorine or bromine atom, a methanesulfonyloxy or p-toluenesulfonyloxy group, with a compound of the general formula

in which Rb is defined as initially mentioned.

The reaction is conveniently carried out in a solvent such as isopropanol, butanol, tetrahydrofuran, dioxane, toluene, chlorobenzene, dimethylformamide, dimethyl sulfoxide, methylene chloride, ethylene glycol monomethyl ether, ethylene glycol diethyl ether or sulfolane or their mixtures, possibly in the presence of an inorganic or tertiary organic base, e.g. sodium carbonate or potassium hydroxide, a tertiary organic base, e.g. triethylamine or N-ethyl-diisopropylamine (Hunig base), during which these organic bases can simultaneously also serve as a solvent, and possibly in the presence of a reaction accelerator such as an alkali halide at temperatures between -20 and 150°C, but preferably at temperatures between - 10 and 100°C. However, the reaction can also be carried out without a solvent or in an excess of the compound of the general formula V used.

In the previously described reaction, the secondary amino group bound to the quinazoline of the general formula II or IV can be protected during the reaction with normal protecting groups, which are cleaved off again after the reaction. Examples of protection residues include the formyl, acetyl, trifluoroacetyl, ethoxycarbonyl, tert.butoxycarbonyl, benzyloxycarbonyl, benzyl, methoxybenzyl or 2,4-dimethoxybenzyl group.

The possibly subsequent cleavage of an applied protective residue takes place, for example, hydrolytically in an aqueous solvent, e.g. 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, e.g. in the presence of iodotrimethylsilane at temperatures between 0 and 120°C, preferably at temperatures between 10 and 100°C.

However, the cleavage of a benzyl, methoxybenzyl or benzyloxycarbonyl residue takes place, for example, hydrogenolytically, e.g. with hydrogen in the presence of a catalyst such as palladium/carbon in a suitable solvent such as methanol, ethanol, acetic acid ethyl ester or glacial acetic acid, optionally with the addition of an acid such as hydrochloric acid at temperatures between 0 and 100°C, preferably however at room temperature between 20 and 60° C, and at a hydrogen pressure of 1 to 7 bar, preferably however of 3 to 5 bar. However, the cleavage of a 2,4-dimethoxybenzyl residue takes place preferably in trifluoroacetic acid in the presence of anisole.

The cleavage of a tert-butyl or tert-butyloxycarbonyl residue preferably takes place 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.

The cleavage of a trifluoroacetyl residue preferably takes place by treatment with an acid such as hydrochloric acid, optionally in the presence of a solvent such as acetic acid at temperatures between 50 and 120°C, or by treatment with caustic soda, optionally in the presence of a solvent such as tetrahydrofuran at temperatures between 0 and 50°C.

Furthermore, the obtained compounds with the general formula I, as was already mentioned at the outset, can be resolved into their enantiomers and/or diastereomers. Thus, for example, cisVtrans mixtures can be split into their cis and trans isomers, and compounds with at least one optically active carbon atom split into their enantiomers.

Thus, for example, the obtained cisVtrans mixtures can be separated by chromatography into their cis- and trans-isomers, the obtained compounds with the general formula I, which occur in racemates, by methods known per se (see Allinger N. L. and Eliel E. L. in "Topics in Stereochemistry", vol. 6, Wiley Interscience, 1971)) in their optical antipodes, and compounds of the general formula I with at least 2 asymmetric carbon atoms due to their physico-chemical differences by methods known per se, e.g. .ex. by chromatography and/or fractional crystallization, into their diastereomers, which, if formed in racemic form, can then be separated as above into the enantiomers.

The enantiomer separation preferably takes place by column separation on chiral phases or by recrystallization from an optically active solvent or by reaction with an optically active substance that forms salts or derivatives such as e.g. esters or amides with the racemic compound, especially acids and their activated derivatives or alcohols, and separation of the diastereomeric salt mixture or derivative thus obtained, e.g. due to different solubilities, during which the free antipodes can be released from the pure diastereomeric salts or derivatives under the action of a suitable agent. Particularly applicable, 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, camphorsulphonic acid, glutamic acid, aspartic acid or quinic acid. As an optically active alcohol, for example (+)- or (-)-menthol and as an optically active acyl residue in amides, for example (+)- or (-)-menthyloxycarbonyl come into consideration.

In addition, the obtained compounds of formula I can be transferred in their salts, particularly for pharmaceutical use in their physiologically tolerable salts with inorganic or organic acids. Examples of acids for this are 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 with the general formulas II to V used as starting materials are partially known from the literature, or they are obtained by methods known per se from the literature.

For example, a starting compound with the general formula II is obtained by reacting a similarly substituted 7-fluoro-6-nitro compound in the 4-position with a corresponding alcoholate and subsequent reduction of the thus obtained nitro compound or

a starting compound with the general formula III, for example by reacting a suitable bromocrotonic acid derivative with an amine known from the literature with the general formula V or

a starting compound of the general formula IV by acylation of a compound of the general formula II with a suitable crotonic acid derivative.

As already mentioned at the outset, the compounds of the general formula I and their physiologically tolerable salts show valuable pharmacological properties, in particular an inhibitory effect on the signal transduction effected by the Epidermal Growth Factor receptor (EGF-R), whereby this can be effected, for example, by inhibiting the ligand binding , the receptor dimerization or the tyrosine kinase itself. In addition, it is possible to block the signal transmission on more distant components.

The biological properties of the new compounds were tested as follows: The inhibition of the human EGF receptor kinase was determined using the cytoplasmic tyrosine kinase domain (methionine 664 to alanine 1186 based on the sequence published in Nature 309 (1984), 418). For this, the protein was expressed in Sf9 insect cells as a GST fusion protein using the Baculovirus expression system.

The measurement of the enzyme activity was carried out in the presence or absence of test compounds in serial dilutions. The polymer pEY (4:1) from SIGMA was used as substrate. Biotinylated pEY (bio-pEY) was added as a tracer substrate. Each 100 µl reaction solution contained 10 µl of the inhibitor in 50% DMSO, 20 µl of the substrate solution (200 mM HEPES pH 7.4, 50 mM magnesium acetate, 2.5 mg/ml poly(EY), 5 µg/ml bio- pEY) and 20 µl enzyme preparation. The enzyme reaction was started by adding 50 µl of a 100 µM ATP solution in 10 mM magnesium chloride. The dilution of the enzyme preparation was adjusted so that the phosphate incorporation into bio-pEY was linear with respect to time and enzyme quantity. The enzyme preparation 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% glycerol.

The enzyme measurements were carried out at room temperature over a period of 30 minutes and terminated by the addition of 50 µl of a stop solution (250 mM EDTA in 20 mM HEPES pH 7.4). 100 µl was brought onto a streptavidin-coated microtiter plate and incubated for 60 minutes at room temperature. Then the plate was washed with 200 µl of a washing solution (50 mM Tris, 0.05% Tween 20). After addition of 100 µl of an HRPO-labeled 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 µl wax solution each time. The samples were then mixed with 100 µl of a TMB peroxidase solution (A:B = 1:1, Kirkegaard Perry Laboratories). After 10 minutes the reaction was stopped. Extinction was measured at OD450nm with an ELISA reader. All data points were determined as triplicates.

The data were fitted by an iterative calculation using a sigmoid curve analysis program (Graph Pad Prism Version 3.0) with variable Hill slope. All released iteration data showed a correlation coefficient of over 0.9 and the upper and lower values of the curves showed a spread of at least a factor of 5. From the curves, the active substance concentration that inhibits the activity of EGF receptor kinase by 50% (IC50) was derived.

The following results were obtained:

The compounds according to the invention with the general formula I thus inhibit the signal transduction with tyrosine kinases, as was shown, for example, for the human EGF receptor, and are therefore applicable in the production of drugs for the treatment of pathophysiological processes, which arise from too strong a function of tyrosine kinases. It is e.g. benign or malignant tumors, especially tumors of epithelial and neuroepithelial origin, metastasis as well as abnormal proliferation of vascular endothelial cells (neoangiogenesis).

Due to their biological properties, the compounds according to the invention can be used alone or in combination with other pharmacologically active compounds, for example in tumor therapy in monotherapy or in combination with other anti-tumor therapeutics, for example in combination with topoisomerase inhibitors (e.g. etoposide ), mitosis inhibitors (e.g. vinblastine), with compounds that interact with nucleic acids (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.

The use of these compounds either alone or in combination with other active substances can take place intravenously, subcutaneously, intramuscularly, intraperitoneally, intranasally, by inhalation or transdermally or orally, whereby aerosol formulations in particular are suitable for inhalation.

In the pharmaceutical application, the compounds according to the invention are usually used on warm-blooded vertebrates, especially on humans, in dosages of 0.01-

100 mg/kg body weight, preferably at 0.1-15 mg/kg. For administration, these are incorporated with one or more usual 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/glycerol, water/sorbitol, water/polyethylene glycol, propylene glycol, stearyl alcohol, carboxymethyl cellulose or fatty substances such as hard fat or their suitable

mixtures in common galenic preparations such as tablets, dragees, capsules, powders, suspensions, solutions, sprays or suppositories.

The following examples shall illustrate the present invention in more detail:

Preparation of the output compounds:

Example I

3- Methylamino-tetrahydrofuran

3.43 g of lithium aluminum hydride are added in portions under ice bath cooling to 50 ml of tetrahydrofuran. Then a solution of 5.00 g of 3-[(benzyloxycarbonyl)amino]-tetrahydrofuran in 20 ml of tetrahydrofuran is added dropwise, during which the temperature remains below 10 °C. After 10 minutes, the cooling bath is removed, and the reaction mixture is heated approx. three hours under reflux. For work-up, the reaction mixture is carefully mixed dropwise with 3.7 ml of water, 3.7 ml of 15% caustic soda and once to 3 ml of water under ice bath cooling. Then some tetrahydrofuran is added and stirred for a further 15 minutes. The precipitated aluminum hydroxide sludge is filtered off and washed with a total of 150 ml of tetrahydrofuran. The filtrate is evaporated on a rotary evaporator. A colorless oil is left behind, which is converted without further purification.

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

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

Example II

3- r(Benzyloxycarbonyl)aminol-tetrahydrofuran

12.36 ml of tetrahydrofuran-3-carboxylic acid and 27.84 ml of diphenylphosphoryl azide in 500 ml of dioxane are mixed with 41.91 g of benzyl alcohol and 35.81 ml of triethylamine. The reaction mixture becomes heated for about seven hours at 100 °C. After cooling to room temperature, the reaction mixture is evaporated on a rotary evaporator. The residue is taken up in 500 ml of methylene chloride and washed twice with 100 ml of 1 N caustic soda each time. The organic phase is dried over magnesium sulfate and evaporated.

The crude product is purified chromatographically over a silica gel column with cyclohexane/acetic ester (3:1 to 1:2) as eluent.

Yield: 15.60 g (55% of theoretical)

Mass spectrum (ESI ): m/z = 220 [M-H]"

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

Example III

e- amino^- rO- chloro-^ fluorophenvDaminol^- fffD- tetrahydrofuran- a- vloxv^- quinazoline A mixture of 12.80 g of 4-[(3-chloro-4-fluorophenyl)amino]-6-nitro-7 -(((fl)-tetrahydrofuran-3-yloxy)-quinazoline, 200 ml of ethanol, 100 ml of water and 17.20 ml of glacial acetic acid are heated to reflux temperature. Now a total of 7.00 g of iron powder is added in portions. The reaction mixture is heated approx. four hours under reflux and then cooled overnight to room temperature. For work-up, the reaction mixture is evaporated on a rotary evaporator. The residue is taken up in methylene chloride/methanol (9:1), mixed with 20 ml of concentrated ammonia solution and filtered over a layer of silica gel. It is washed with plenty of methylene chloride/methanol (9:1), and the combined filtrates are evaporated. The residue is stirred with diethyl ether and filtered off.

Yield: 8.59 g (73% of theoretical)

Mass spectrum (ESr): m/z = 373, 375 [M-H]"

Rf value: 0.27 (silica gel, acetic acid/methanol = 9:1)

Analogous to Example III, the following compounds are obtained: (1) 6-amino-4-[(3-chloro-4-fluorophenyl)amino]-7-((S)-tetrahydrofuran-3-yloxy)-quinazoline Mass spectrum (ESr): m/z = 373, 375 [M-H]"

Rf value: 0.27 (silica gel, acetic acid/methanol = 9:1)

(2) 6-amino-4-[(3-chloro-4-fluorophenyl)amino]-7-(tetrahydropyran-4-yloxy)-quinazoline Mass spectrum (ESr): m/z = 387, 389 [M-H]"

Rf value: 0.20 (silica gel, acetic acid)

(3) 6-amino-4-[(3-chloro-4-fluorophenyl)am Mass spectrum (ESI ): m/z = 387, 389 [M-H]"

Rf value: 0.55 (silica gel, acetic acid/methanol = 9:1)

(4) 6-amino-4-[(3-chloro-4-fluorophenyl)amino]-7-[(tetrahydrofuran-3-yl)methoxy]-quinazoline Mass spectrum (ESI ): m/z = 387, 389 [M-H ]"

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

Example IV

To a solution of 10.80 g of (R)-3-hydroxy-tetrahydrofuran in 100 ml of N,N-dimethylformamide, 13.80 g of potassium tetrabutylate are added in portions while cooling in an ice bath. The reaction mixture is stirred approx. one hour, then 10.40 g of 4-[(3-chloro-4-fluorophenyl)amino]-6-nitro-7-fluoroquinazoline are added in portions. The cooling bath is then removed and the deep red reaction mixture is stirred for two hours at room temperature. For work-up, the reaction mixture is completely in approx. 500 ml of water and neutralized with 2 N hydrochloric acid. The precipitated yellowish precipitate is filtered off and dried in a circulation drying cabinet at 70°C.

Yield: 12.80 g

Melting point: 244°C

Mass spectrum (ESI): m/z = 403, 405 [M-H]"

Analogously to Example IV, the following compounds are obtained: (1) 4-[(3-chloro-4-fluorophenyl)amino]-6-nitro-7-((S)-tetrahydrofuran-3-yloxy)-quinazoline Mass spectrum (ESI ): m/z = 403, 405 [M-H]"

Rf value: 0.45 (silica gel, acetic acid)

(2) 4-[(3-chloro-4-fluorophenyl)amino]-6-nitro-7-(tetrahydropyran-4-yloxy)-quinazoline Mass spectrum (ESI"): m/z = 417, 419 [M-H]"

Rf value: 0.42 (silica gel, acetic acid)

(3) 4-[(3-chloro-4-fluorophenyl)amino]-6-nitro-7-[(tetrahydrofuran-2-yl)methoxy]-quinazoline

Mass spectrum (ESI"): m/z = 417, 419 [M-H]"

Rf value: 0.47 (silica gel, acetic acid)

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

Mass spectrum (ESI ): m/z = 417, 419 [M-H]"

Rf value: 0.41 (silica gel, acetic acid)

(5) 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, acetic acid/methanol = 9:1)

(6) 4-[(3-chloro-4-fluorophenyl)amino]-6-nitro-7-[(fl)-(tetrahydrofuran-2-yl)methoxy]-quinazoline

Mass spectrum (ESr): m/z = 419, 421 [M+Hf

Rf value: 0.44 (silica gel, acetic acid)

(7) 4-[(3-chloro-4-fluorophenyl)amino]-6-nitro-7-[(S)-(tetrahydrofuran-2-yl)methoxy]-quinazoline

Mass spectrum (ESr): m/z = 419, 421 [M+H]<+>

Rf value: 0.44 (silica gel, acetic acid)

Example V

(/ 7)- N- r( tetrahydrofuran- 2- methylvn- N- metvl- amine

21.10 g of (f?)-N-[(tetrahydrofuran-2-yl)methyl]-N-benzyl-N-methyl-amine (crude product from Example VI) is dissolved in 200 ml of methanol and hydrogenated in the presence of 4, 00 g of palladium on activated carbon (10% Pd) at room temperature until the hydrogen uptake has ended. For processing, the catalyst is filtered off and the filtrate is evaporated on a rotary evaporator. A thin, yellowish oil is left behind, which is converted without further purification

further.

Yield: 8.60 g (73% of theoretical)

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

Analogous to Example V, the following compounds are obtained:

(1) (S)-N-[(tetrahydrofuran-2-yl)methyl]-N-methyl-amine

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

(2) N-[(tetrahydropyran-4-yl)methyl]-N-methylamine

Mass spectrum (ESr): m/z = 130 [M+H]<+>

Example VI

f/ 7>- N- r( tetrahydrofuran- 2- vhmetvll- N- benzvl- N- metvl- amine

A solution of 24.60 g of (fl)-tetrahydrofuran-2-carboxylic acid-N-benzyl-N-methyl-amide in 90 ml of tetrahydrofuran is added dropwise to 17.00 g of lithium aluminum hydride in 150 ml of tetrahydrofuran. The reaction mixture is refluxed for two hours. For processing, it is cooled in an ice bath to 0°C, mixed with 20 ml of water and 10 ml of 15N caustic soda and stirred for a further 20 minutes. It is then filtered through a layer of magnesium sulphate and washed with a total of approx. 500 ml of tetrahydrofuran. The filtrate is evaporated in vacuo, during which a yellowish oil remains, which is reacted further without further purification.

Yield: 21.10 g (92% of theoretical)

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

Analogous to Example VI, the following compounds are obtained:

(1) (S)-N-[(tetrahydrofuran-2-yl)methyl]-N-benzyl-N-methyl-amine

Rf value: 0.20 (silica gel, acetic acid/methanol = 9:1)

(2) N-[(tetrahydropyran-4-yl)methyl]-N-benzyl-N-methyl-amine

Mass spectrum (ESr): m/z = 220 [M+H]<+>

Example VII

( ff )- tetrahydrofuran- 2- carboxylic acid- N- benzyl- N- methyl- amicl

25.30 g of N-benzyl-N-methylamine are added to a solution of 20.00 ml of (fl)-tetrahydrofuran-2-carboxylic acid in 200 ml of tetrahydrofuran. Subsequently, a total of 67.10 g of 0-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate is added in portions under ice-bath cooling, and the reaction mixture is then stirred for approx. 48 h at room temperature. The formed precipitate is filtered off, the filtrate evaporated, mixed with water and filtered again. The filtrate obtained is made alkaline with sodium bicarbonate solution and extracted with acetic acid. The combined acetate extracts are washed with water and saturated sodium chloride solution, dried over magnesium sulfate and evaporated. A yellowish oil remains, which is converted further without further purification.

Yield: 24.60 g (54% of theoretical)

Mass spectrum (ESI<+>): m/z = 220 [M+H]<+>

Rf value: 0.62 (silica gel, acetic acid)

Analogous to Example VII, the following compounds are obtained:

(1) (S)-tetrahydrofuran-2-carboxylic acid-N-benzyl-N-methyl-amide Mass spectrum (ESr): m/z = 242 [M+Na]<+>

Rf value: 0.62 (silica gel, acetic acid)

(2) Tetrahydropyran-4-carboxylic acid-N-benzyl-N-methyl-amide

(The amide coupling performed with 1,1'-carbonyldiimidazole in tetrahydrofuran.)

Mass spectrum (ESr): m/z = 256 [M+Na]<+>

Rf value: 0.45 (silica gel, acetic acid)

Example VIII

6- amino- 4- r( 3- chloro- 4- fluorophenyl) amino1- 7- r( tetrahydrofuran- 4- nmethoxysv1- quinazoline 22.80 g 4-[(3-chloro-4-fluorophenyl)amino]-6- nitro-7-[(tetrahydropyran-4-yl)methoxy]-quinazoline becomes the hydrogen in 300 ml of tetrahydrofuran in the presence of 3.50 g of platinum dioxide at room temperature until the calculated amount of hydrogen is taken up. The catalyst becomes

filtered off and the filtrate evaporated to dryness on a rotary evaporator. The residue is stirred with diethyl ether, filtered off, washed with diethyl ether and dried at room temperature.

Yield: 19.95 g (93% of theoretical)

Mass spectrum (ESr): m/z = 403, 405 [M+H]<+>

melting point: 221 °C

Analogous to Example VIII, the following compounds are obtained: (1) 6-amino-4-[(3-chloro-4-fluorophenyl)amino]-7-[(fl)-(tetrahydrofuran-2-yl)methoxy]-quinazoline

Mass spectrum (ESI<+>): m/z = 389, 391 [M+H]<+>

Rf value: 0.11 (silica gel, acetic acid)

(2) 6-amino-4-[(3-chloro-4-fluorophenyl)amino]-7-[(S)-(tetrahydrofuran-2-yl)methoxy]-quinazoline

Mass spectrum (ESr): m/z = 389, 391 [M+H]<+>

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

Making end connections:

Reference Example 1

4-[(3-chloro-4-fluorophenyl)amino]-6-({4-[N-(2-methoxy-ethyl)-N-methyl-amino]-1-oxo-2-buten-1-vl ) amino)- 7- cvclopropvlmethoxysvquinazoline

4.70 ml of oxalyl chloride are added dropwise to a solution of 4.50 g of bromocrotonic acid in 60 ml of methylene chloride. A drop of N,N-dimethylformamide is then added. After approx. After 30 minutes, gas evolution has ended and the reaction mixture is evaporated on a rotary evaporator. The crude bromocrotonic acid chloride is taken up in 30 ml of methylene chloride and, under ice-bath cooling, added dropwise to a solution of 7.00 g of 4-[(3-chloro-4-fluorophenyl)amino]-6-amino-7-cyclopropylmethoxyquinazoline and 10, 20 ml Honey base in 150 ml tetrahydrofuran. The reaction mixture is stirred approx. 1.5 hours under ice bath cooling and a further two hours at room temperature. Now 5.20 g of N-(2-methoxyethyl)-N-methylamine are added, and the reaction mixture is stirred overnight at room temperature. For processing, it is diluted with methylene chloride and washed thoroughly with water. The organic phase is dried over magnesium sulfate and evaporated. The crude product is purified chromatographically over a silica gel column with ethyl acetate followed by ethyl acetate/methanol (19:1) as eluent.

Yield: 5.07 g (51% of theoretical)

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

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

Analogous to reference Example 1, the following compounds are obtained:

(1) 4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-buten-1-yl]amino}-7-( (f)-tetrahydrofuran-3-yloxy)-quinazoline

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

(2) 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)

(3) 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 (ESr): m/z = 500, 502 [M+H]<+>

Rf value: 0.55 (silica gel, methylene chloride/methanol = 5:1)

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

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

Rf value: 0.60 (silica gel, methylene chloride/methanol = 5:1)

(5) 4-[(3-chloro-4-fluophrenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-buten-1-yl]amino}-7-[ (tetrahydrofuran-3-yl)methoxy]quinazoline

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

Rf value: 0.50 (silica gel, methylene chloride/methanol = 5:1)

(6) 4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-buten-1-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/con. aqueous ammonia = 95:5:0.05)

(7) 4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-buten-1-yl]amino}-7-[ (f)-(tetrahydrofuran-2-yl)methoxy]-quinazoline

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

melting point: 110-112°C

(8) 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

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

Rf value: 0.23 (silica gel, acetate/methanol/con. aqueous ammonia = 90:10:0.1)

Analogous to the previous examples and other methods known from the literature, the following compounds can also be prepared: (1) 4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo -2-buten-1 -yl]amino}-7-[(tetrahydropyran-4-yl)methoxy]-quinazoline (2) 4-[(fl)-(1-phenyl-ethyl)amino]-6-{[ 4-(N,N-dimethylamino)-1-oxo-2-buten-1-ylamino}-7-[(tetrahydrofuran-2-yl)methoxy]-quinazoline

Example 2

Drasiés with 75 mg active substance

1 Dragee core contains:

Manufacturing:

The active substance is mixed with calcium phosphate, corn starch, polyvinylpyrrolidone, hydroxypropylmethylcellulose and half of the specified amount of magnesium stearate. On a tableting machine, tablets with a cross section of approx. 13 mm prepared, these are shredded on a suitable machine with a sieve of 1.5 mm mesh size and mixed with the residual amount of magnesium stearate. This granule is pressed onto a

tableting machine for tablets of the desired shape.

The dragée cores produced in this way are coated with a film which essentially consists of hydroxypropylmethylcellulose. The finished film dressings are glossed with beeswax.

Example 3

Tablets with 100 mg active substance

Composition:

1 tablet contains:

Method of production:

Active ingredient, milk sugar and starch are mixed and evenly moistened with an aqueous solution of polyvinylpyrrolidone. After sieving the moist mass (2.0 mm mesh size) and drying in a Horden drying cabinet at 50°C, it is sieved again (1.5 mm mesh size) and the lubricant is mixed. The press-ready mixture is processed into tablets.

Example 4

Tablets with 150 mg active substance

Composition:

1 tablet contains:

Manufacturing:

The active substance mixed with milk sugar, corn starch and silicic acid 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 shredded once more with the same sieve and mixed with the specified amount of magnesium stearate. Tablets are pressed from the mixture.

Example 5

Hardoelatin capsules with 150 mg active substance

1 capsule contains:

Manufacturing:

The active substance is combined with the excipients when added through a sieve with a mesh size of 0.75 mm and mixed homogeneously in a suitable device.

The final mixture is in filled hard gelatin capsules of size 1.

Capsule filling: approx. 320 mg

Capsule shell: Hard gelatin capsule size 1.

Example 6

Suppositories with 150 mo of active substance

1 suppository contains:

Manufacturing:

After melting the suppository mass, the active ingredient is distributed homogeneously therein and the mixture is poured into pre-cooled molds.

Example 7

Suspension with 50 mg active substance

100 ml suspension contains:

Manufacturing:

Dest. water is heated to 70°C. This dissolves while stirring

p-Hydroxybenzoic acid methyl ester and -propyl ester as well as glycerol and carboxymethyl cellulose sodium salt. It is cooled to room temperature and the active ingredient added while stirring and dispersed homogeneously. After adding and dissolving the sugar, the sorbitol solution and the aroma, the suspension is placed under vacuum for venting while stirring.

5 ml of suspension contains 50 mg of active ingredient.

Example 8

Ampoules with 10 mg active substance Composition:

Manufacturing:

The active substance is 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 active substance

Composition:

Manufacturing:

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

Example 10

Capsules for powder inhalation with 5 mg active substance

1 capsule contains:

Manufacturing:

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

Capsule weight: 70.0 mg

Capsule size: 3

Example 11

Inhalation solution for hand atomizer with 2.5 mg of active substance

1 shock contains:

Manufacture<g>:

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

Filling mass in the container: 4.5 g

Claims (9)

1. Quinazoline derivatives of the general formula in which Ra means a 1-phenylethyl or 3-chloro-4-fluorophenyl group, Rb a dimethylamino group and Rc a tetrahydrofuran-3-yl-oxy-, tetrahydrofuran-2-yl-methoxy-, tetrahydrofuran-3-yl-methoxy-, tetrahydropyran-4-yl-oxy- or tetrahydropyran-4-yl-methoxy group, their tautomers, their stereoisomers and their salts. 2. Compounds of the general formula I according to claim 1, in which Ra means a 3-chloro-4-fluorophenyl group and Rc a tetrahydrofuran-3-yl-oxy or tetrahydropyran-4-yl-methoxy group, their tautomers, their stereoisomers and their salts. 3. The following compounds with the general formula I according to claim 1: (a) 4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2 -buten-1 -yl]amino}-7-((fl)-tetrahydrofuran-3-yloxy)-quinazoline, (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, (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-(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-butene- 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, their stereoisomers and their salts. 4. The following compound of the general formula I according to claim 3: (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, 5. Physiologically acceptable salts of the compounds according to at least one of claims 1 to 4 with inorganic or organic acids or bases. 6. Medicinal product containing a compound of general formula I according to at least one of claims 1 to 4 or a physiologically acceptable salt according to claim 5 next to possibly one or more inert carrier substances and/or diluents. 7. Use of a compound according to at least one of claims 1 to 5 for the production of a medicinal product, which is suitable for the treatment of benign or malignant tumours. 8. Process for producing a medicinal product according to claim 6, characterized in that a compound of general formula I according to at least one of claims 1 to 5 is incorporated non-chemically into one or more inert carriers and/or diluents. 9. Process for preparing the compounds of the general formula I according to claims 1 to 5, characterized in that a) a compound of the general formula in which Ra and Rc are defined as in claims 1 to 5, are reacted with a compound of the general formula in which Rb is defined as in claims 1 to 5, and Z: is a leaving group or a hydroxy group, or b) a compound of the general formula in which Ra and Rc are defined as in claims 1 to 5, and Z2 is a leaving group, reacts with a compound of the general formula wherein Rb is defined as in claims 1 to 5, and if necessary, a protective residue used in the reaction described above is cleaved off again, and/or if desired, a thus obtained compound of the general formula I is split into its stereoisomers, and/or a thus obtained compound of the general formula I is transferred in its salts, especially for the pharmaceutical use in its physiologically acceptable salts.