EP1641767A2

EP1641767A2 - Bicyclic heterocycles, drugs containing said compounds, the use thereof and method for preparing the same

Info

Publication number: EP1641767A2
Application number: EP04739543A
Authority: EP
Inventors: Frank Himmelsbach; Rainer Soyka; Birgit Jung
Original assignee: Boehringer Ingelheim International GmbH; Boehringer Ingelheim Pharma GmbH and Co KG
Current assignee: Boehringer Ingelheim International GmbH; Boehringer Ingelheim Pharma GmbH and Co KG
Priority date: 2003-06-06
Filing date: 2004-06-02
Publication date: 2006-04-05
Also published as: UY28347A1; JP2006527176A; TW200510341A; DE10326186A1; US20100267718A1; US20060264450A1; WO2004108664A3; US20050014772A1; WO2004108664A2; CA2526995A1; AR044604A1; PE20050227A1; CL2004001409A1; US7196091B2

Abstract

The invention relates to the bicyclic heterocycles of general formula (I), wherein R<a>, R<b>, R<c>, R<d>, X and n are defined as in claim 1, to their tautomers, stereoisomers, mixtures and salts thereof, especially the physiologically acceptable salts thereof with inorganic or organic acids. The inventive compounds have valuable pharmacological properties, especially they inhibit tyrosinkinase-mediated signal transduction. The invention also relates to the use of said compounds for treating diseases, especially tumor diseases and benign prostatic hyperplasia (BPH), diseases of the lung and respiratory tracts, and to the production of these compounds.

Description

Bicyclic heterocycles, medicaments containing these compounds, their use and processes for their preparation

The present invention relates to bicyclic heterocycles of the general formula

their tautomers, their stereoisomers, their mixtures and their salts, in particular their physiologically acceptable salts with inorganic or organic acids, which have valuable pharmacological properties, in particular an inhibitory effect on tyrosine kinase-mediated signal transduction, their use for the treatment of diseases, especially of tumor diseases and benign prostatic hyperplasia (BPH), lung and respiratory diseases and their production.

In the above general formula I mean

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

R ^{b is} a phenyl or 1-phenylethyl group in which the phenyl is in each case substituted by the radicals R ¹ to R ³ , wherein

R ¹ and R ² , which may be the same or different, each represents a hydrogen, fluorine, chlorine, bromine or iodine atom,

a Cι _-4 alkyl, hydroxy, Cι _-4 alkoxy, C ₂ - ₃ -alkenyl or C _2-3 -alkynyl, a phenyloxy or phenylmethoxy group, wherein the phenyl portion of the aforementioned groups is optionally substituted by a fluorine or chlorine atom, or

a pyridyloxy or pyridinylmethoxy group, wherein the pyridinyl moiety of the abovementioned groups is optionally substituted by a methyl or trifluoromethyl group,

a substituted by 1 to 3 fluorine atoms methyl or methoxy group or

a cyano, nitro or amino group, and

R ^{3 is} a hydrogen, fluorine, chlorine or bromine atom or

represent a methyl or trifluoromethyl group,

R ^c is a (2-hydroxyethyl) amino-group in which the carbon skeleton of the (2-hydroxyethyl) portion optionally _-3 alkyl substituted by one or two Cι,

a N- (2-hydroxyethyl) -N- (Cι. ₃ alkyl) amino group in which the carbon skeleton of the (2-hydroxyethyl) _-3 -TeiIs alkyl is optionally substituted by one or two Cι, or

an optionally by one or two Cι _-3 alkyl substituted 2-oxo-oxazolidin-3-yl group,

R ^{d is} a hydrogen atom,

a hydroxy group,

a -C. _3- alkyloxy group, a C ₂ . ₄ alkyloxy group which is substituted by a radical R ⁴ , wherein

R ^{4 is} a hydroxy, C _1-3 alkyloxy, C ₃ -6-cycloalkyloxy, A ino, Cι. _3- alkylamino, di (C ₃ -alkyl) amino, bis (2-methoxyethyl) amino, pyrrolidin-1-yl, piperidin-1-yl, homopiperidin-1-yl , Morpholin-4-yl, homomorpholin-4-yl, 2-oxa-5-azabicyclo [2.2.1] hept-5-yl, 3-oxa-8-aza-bicyclo [3.2.1] oct-8-yl, 8-oxa-3-azabicyclo [3.2.1] oct-3-yl, piperazin-1-yl, 4-methyl- ₃ -piperazin-1-yl,

Homopiperazin-1-yl or 4-Cι _-3 alkyl-homopiperazin-1-yl group, whilst the abovementioned pyrrolidinyl, piperidinyl, piperazinyl and morpholinyl _-3 alkyl groups may each be substituted by one or two Cι,

a C ₃ -Cycloalkyloxy or C ₃ -Cycloalkyl-C 1-3 -alkyloxy group,

a tetrahydrofuran-3-yloxy, tetrahydropyran-3-yloxy or tetrahydropyran-4-yloxy group, or

a tetrahydrofuranyl-C _1-3 -alkyloxy or tetrahydropyranyl-C _1-3 -alkyloxy group,

X is a methine group substituted by a cyano group or a nitrogen atom

and

n is the number 2, 3 or 4,

Unless otherwise stated, the abovementioned alkyl groups may be straight-chain or branched,

their tautomers, their stereoisomers, their mixtures and their salts.

Preferred compounds of the above general formula I are those in which

R ^{a is} a hydrogen atom, R ^{b is} a 3-bromophenyl, 3,4-difluorophenyl, 3-chloro-4-fluorophenyl or a 3-ethynylphenyl group,

R ^G is a (2-hydroxypropyl) amino or N- (2-hydroxypropyl) -N- (Cι _-3 alkyl) amino group,

amino- N- (2-HydroxybutyI) or N- (2-hydroxybutyl) -N- (Cι _-3 -alkyl) -amino group,

a (2-hydroxy-2-methyl-propyl) amino or N- (2-hydroxy-2-methyl-propyl) -N- (Cι _-3 alkyl) amino group,

an N- (2-hydroxy-2-ethyl-butyl) amino or N- (2-hydroxy-2-ethyl-butyl) -N- (C _1-3 alkyl) -amino group, or

a 2-oxo-5-methyl-oxazolidin-3-yl, 2-oxo-5-ethyl-oxazolidin-3-yl, 2-oxo-5,5-dimethyl-oxazolidin-3-yl or 2-oxo oxo-5,5-diethyl-oxazolidin-3-yl group,

R ^{d is} a hydrogen atom,

a methoxy, ethyloxy or 2-methoxyethyloxy group,

a cyclobutyloxy, cyclopentyloxy or cyclohexyloxy group,

a cyclopropylmethoxy, cyclobutylmethoxy, cyclopentylmethoxy or cyclohexylmethoxy group,

a tetrahydrofuranylmethoxy or tetrahydropyranylmethoxy group,

X is a nitrogen atom, and

n is the number 2 or 3,

their tautomers, their stereoisomers, their mixtures and their salts.

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

R ^{a is} a hydrogen atom,

R ^{b is} a 3-chloro-4-fluoro-phenyl group or 3-ethynylphenyl group,

R ° is a (2-hydroxypropyl) amino group,

an N- (2-hydroxypropyl) -N-methylamino or N- (2-hydroxypropyl) -N-ethylamino group,

a (2-hydroxy-2-methyl-propyl) amino group,

an N- (2-hydroxy-2-methyl-propyl) -N-methyl-amino or N- (2-hydroxy-2-methyl-propyl) -N-ethyl-amino group, or

a 2-oxo-5-methyl-oxazolidin-3-yl or 2-oxo-5,5-dimethyl-oxazolidin-3-yl group,

R ^{d is} a methoxy, ethyloxy or 2-methoxyethyloxy group,

X is a nitrogen atom,

and

n is the number 2, their tautomers, their stereoisomers, their mixtures and their salts.

For example, the following particularly preferred compounds of general formula I may be mentioned:

(a) (S) -4 - [(3-Chloro-4-fluoro-phenyl) -amino] -6- [2- (2-oxo-5-methyl-oxazolidin-3-yl) -ethyloxy] -7-methoxy -quinazoline

(b) (S) -4 - [(3-Chloro-4-fluorophenyl) amino] -6- {2 - [(2-hydroxypropyl) amino] ethyloxy} -7-methoxy-quinazoline

(c) 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- {2 - [(2-hydroxy-2-methyl-propyl) -amino] -ethyloxy} -7-methoxy-quinazoline

(d) 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- [2- (2-oxo-5,5-dimethyl-oxazolidin-3-yl) -ethyloxy] -7-methoxy-quinazoline

and their salts.

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

a) reaction of a compound of the general formula

in the R ^a , R ^b , R ^d and X are as defined above, with a compound of the general formula

Z ¹ - (CH ₂ ) _n - R ^c (III),

in the

R ^α and n are defined as mentioned above and Z ^{1 represents} a leaving group such as a halogen atom, for example a chlorine or bromine atom, a sulfonyloxy group such as a methanesulfonyloxy or p-toluenesulfonyloxy or a hydroxy group. The reaction is conveniently carried out in a solvent such as ethanol, isopropanol, acetonitrile, toluene, tetrahydrofuran, dioxane, dimethylformamide, dimethyl sulfoxide or N-methylpyrrolidinone, optionally in the presence of a base such as potassium carbonate or N-ethyl-diisopropylamine, at temperatures between 20 ° C and 160 ° C.

With a compound of general formula III, in which Z ^{1 represents} a hydroxy group, the reaction is carried out in the presence of a dehydrating agent, preferably in the presence of a phosphine and an azodicarboxylic acid derivative, for example triphenylphosphine / diethyl azodicarboxylate, conveniently in a solvent such as methylene chloride, acetonitrile, tetrahydrofuran, Dioxane, toluene or Ethylenglycoldiethylether at temperatures between -50 and 150 ° C, but preferably at temperatures between -20 and 80 ° C performed.

b) For the preparation of compounds of general formula I in which X represents a nitrogen atom:

Reaction of a compound of the general formula

in which R °, R ^d and n are as defined above, with a halogenating agent, for example an acid halide such as thionyl chloride, thionyl bromide, phosphorus trichloride, phosphorus pentachloride or phosphorus oxychloride to form an intermediate of the general formula (V),

in which R °, R ^d and n are defined as mentioned above and Z ^{2 represents} a halogen atom such as a chlorine or bromine atom,

and subsequent reaction with a compound of the general formula

R ^a - NH - R ^b (VI),

in which R ^a and R are defined as mentioned above.

The reaction with the halogenating agent is optionally carried out in a solvent such as methylene chloride, chloroform, acetonitrile or toluene and optionally in the presence of a base such as N, N-diethylaniline or N-ethyl-diisopropylamine at temperatures between 20 ° C and 160 ° C. Preferably, however, the reaction is carried out with thionyl chloride and catalytic amounts of dimethylformamide at the boiling temperature of the reaction mixture. The reaction of the compound of the general formula (V) with a compound of the general formula (VI) is conveniently carried out in a solvent such as ethanol, isopropanol, acetonitrile, dioxane or dimethylformamide, optionally in the presence of a base such as potassium carbonate or N-ethyl-diisopropylamine Temperatures between 20 ° C and 160 ° C.

c) reaction of a compound of the general formula

in which R ^a , R ^b , R ^d , X and n are defined as mentioned above, and Z ^{3 represents} a leaving group such as a halogen atom, for example a chlorine or bromine atom, a sulphonyloxy group such as a methanesulphonyloxy or p-toluenesulphonyloxy group,

with a compound of the general formula

H - R ^c (VIII),

in the R ^c is defined as mentioned above.

The reaction is conveniently carried out in a solvent such as ethanol,

Isopropanol, acetonitrile, toluene, tetrahydrofuran, dioxane, dimethylformamide,

Dimethylsulfoxide or N-methylpyrrolidinone, optionally in the presence of a base such as

Potassium carbonate or N-ethyl-diisopropylamine, at temperatures between 20 ° C and

160 ° C.

If, according to the invention, a compound of the general formula I is obtained in which R ^{c is} optionally substituted by one or two C 1. _3- alkyl substituted 2-oxo-oxazolidin-3-yl group, it can be converted by hydrolysis, for example by hydrolysis in the presence of an alkali metal hydroxide such as lithium hydroxide, sodium hydroxide or potassium hydroxide, in a R ° a (2 Represents hydroxyethyl) amino group, in which the carbon skeleton of the (2-hydroxyethyl) part is optionally substituted by one or two Cι- alkyl groups, and / or

a compound of the general formula I in which R ° represents a (2-hydroxyethyl) amino group in which the carbon skeleton of the (2-hydroxyethyl) part optionally _-3 alkyl substituted by one or two Cι, this can by reaction with a derivative of carbonic acid, for example, phosgene, N, N ^'- are diphenyl carbonic acid, converted carbonyldiimidazole or in a compound in which R ° is an optionally by one or two Cι _-3 alkyl substituted 2-oxo-oxazolidin-3-yl group, and / or

a compound of the general formula I which contains an amino, alkylamino or imino group, this can be converted into a corresponding alkyl compound of the general formula I by means of alkylation or reductive alkylation, for example by formaldehyde or acetaldehyde and sodium triacetoxyborohydride.

Compounds of the general formula I in which R ^a , R, R and n are defined as mentioned above, X is a nitrogen atom and R ° is a (2-hydroxyethyl) amino group in which the carbon skeleton of the (2-hydroxyethyl) part is optionally substituted by one or two Cι _-3 alkyl groups, is, are useful as starting compounds for preparing the corresponding quinazoline derivative of the general formula

in which R ^a, R ^b, R ^d and n are as hereinbefore defined and R ^e and R ^f independently represent hydrogen atoms or Cι _-3 alkyl groups. Such compounds are described in WO 02/18351. The structure of the 2-oxomorpholine ring is carried out by reacting said starting compounds with reactive acetic acid derivatives, for example with an α-haloacetic ester, such as α-bromoacetic acid methyl ester.

The preparation of the compounds of general formula (IX) is carried out by reacting said starting compounds conveniently in one Solvents such as acetonitrile, toluene, tetrahydrofuran, dioxane, dimethylformamide, dimethyl sulfoxide or N-methylpyrrolidinone, if appropriate in the presence of a base such as potassium carbonate or N-ethyl-diisopropylamine, at temperatures between 20 ° C and 160 ° C, preferably at temperatures between 0 and 50 ° C, and then heating expediently in a solvent such as toluene, dioxane, N-methylpyrrolidinone, methyl ethyl ketone, diethyl ketone or n-butyl acetate or mixtures thereof to 80-180 ° C, preferably 100-150 ° C.

In the reactions described above, optionally present reactive groups such as hydroxyl, amino, alkylamino or imino groups can be protected during the reaction by conventional protecting groups, which are cleaved again after the reaction.

For example, come as a protective group for a hydroxy group, the trimethylsilyl, acetyl, trityl, benzyl or tetrahydropyranyl group into consideration.

Suitable protecting groups for an amino, alkylamino or imino group are, for example, the formyl, acetyl, trifluoroacetyl, ethoxycarbonyl, tert-butoxycarbonyl, benzyloxycarbonyl, benzyl, methoxybenzyl or 2,4-dimethoxybenzyl groups.

The optional subsequent cleavage of a protective moiety used is carried out, 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 metal 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.

The cleavage of a benzyl, methoxybenzyl or Benzyloxycarbonyirestes, however, for example hydrogenolytically, for example with hydrogen in the presence of a catalyst such as palladium / carbon in a suitable solvent such as methanol, ethanol, ethyl acetate or glacial acetic acid, 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, the cleavage of a 2,4-dimethoxy-benzyl radical is preferably carried out in trifluoroacetic acid in the presence of anisole.

The removal of a tert-butyl or tert-Butyloxycarbonylrestes 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 Trifluoracetylrestes 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 sodium hydroxide, optionally in the presence of a solvent such as tetrahydrofuran or methanol at temperatures between 0 and 50 ° C. ,

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

Thus, for example, the resulting cis / trans mixtures can be chromatographed into their cis and trans isomers, the compounds of general formula I which are obtained in racemates can be prepared by 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 having at least 2 asymmetric carbon atoms due to their physicochemical differences according to methods known per se, eg by chromatography and / or fractionated crystallization, into their diastereomers, which, if they are obtained 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 reacting with a, with the racemic compound salts or derivatives such as esters or amides forming optically active substance, in particular acids and their activated derivatives or alcohols, and Separation of the thus obtained diastereomeric salt mixture or derivative, for example due to different solubilities, wherein from the pure diastereomeric salts or derivatives, the free antipodes can be released by the action of suitable agents. Particularly common optically active acids are, for example, the D- and L-forms of tartaric acid or dibenzoyltartaric acid, di-O-toluen-tartaric acid, malic acid, mandelic acid, camphorsulphonic acid, glutamic acid, aspartic acid or quinic acid. Examples of optically active alcohols are (+) - or (-) - menthol and, for example, (+) - or (-) - menthyloxycarbonyl as the optically active acyl radical in amides.

Furthermore, the resulting compounds of the formula I can be converted into their salts, in particular for the pharmaceutical application in their physiologically acceptable salts with inorganic or organic acids. Examples of suitable acids are 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 the general formulas II to VIII used as starting materials are known from the literature or can be obtained by methods known from the literature (see Examples I to XVI), if appropriate with additional introduction of protective radicals. For example, the starting compounds for the novel compounds of general formula I in which X is a nitrogen atom and R ^c represents an optionally substituted by one or two Cι _-3 alkyl 2-oxo-oxazolidin-3-yl group, according to the following synthesis scheme accessible :

wherein R ^d and Z ³ are as hereinbefore defined and R ¹⁰ and R ^11, which may be identical or different, represent hydrogen atoms or Cι _-3 alkyl groups. Instead of those mentioned as a contactor group in the 3-position of the 3,4-dihydro-4-oxo-quinazoline radical

Benzyl group, other protecting groups such as 4-methoxybenzyl, 2,4- Dimethoxybenzyl, methoxymethyl, benzyloxymethyl, (2-methoxyethyl) oxymethyl, (2-trimethylsilylethyl) oxymethyl or the pivaloyloxymethyl group.

As already mentioned, 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) Inhibition of ligand binding, the receptor dimerization or the tyrosine kinase itself can be effected. In addition, it is possible that the signal transmission is blocked at further downstream components.

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

The inhibition of the human EGF receptor kinase was determined with the aid of 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 profein using the baculovirus expression system.

The measurement of enzyme activity was carried out in the presence or absence of the test compounds in serial dilutions. The polymer pEY (4: 1) from SIGMA was used as a 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 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 μ \ enzyme preparation. The enzyme reaction was started by adding 50 L of a 100 / M ATP solution in 10 mM magnesium chloride. The dilution of the enzyme preparation was adjusted so that the phosphate incorporation into the bio-pEY was linear with respect to time and amount of enzyme. The enzyme preparation was diluted in 20 mM HEPES pH 7.4, 1 mM EDTA, 130 mM saline, 0.05% Triton X-100, 1 mM DTT and 10% glycerol. The enzyme assays were carried out at room temperature for a period of 30 minutes and terminated by adding 50 μl of a challenge solution (250 mM EDTA in 20 mM HEPES pH 7.4). 100 .mu.l were placed on a streptavidin-coated microtiter plate and incubated for 60 minutes at room temperature. Thereafter, 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-PTyπHRP from Transduction Laboratories, 250 ng / ml) was incubated for 60 minutes. Thereafter, the microtiter plate was washed three times with 200 μ \ wash solution. The samples were then spiked with 100 μl of a TMB peroxidase solution (A: B = 1: 1, Kirkegaard Perry Laboratories). After 10 minutes, the reaction was stopped. The absorbance was measured at OD ₄₅ _nm with an ELISA reader. All data points were determined as triplicates.

The data was fit by means of an iterative calculation using a sigmoid curve analysis program (Graph Pad Prism Version 3.0) with variable hill slope. All shared iteration data showed a correlation coefficient of about 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 concentration of active substance has been derived, which inhibits the activity of EGF receptor kinase by 50% (IC ₅₀ ). The novel compounds have IC ₅ o values of below 10 uM.

The compounds of the general formula I according to the invention thus inhibit the signal transduction by tyrosine kinases, as shown by the example of the human EGF receptor, and are therefore useful for the treatment of pathophysiological processes which are caused by hyperfunction of 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 present invention are also useful for the prevention and treatment of respiratory and pulmonary diseases associated with increased or altered mucus production caused by stimulation of tyrosine kinases, such as in respiratory tract inflammatory diseases such as acute bronchitis, chronic bronchitis, chronic obstructive bronchitis (COPD), asthma, bronchiectasis, allergic or non-allergic rhinitis or sinusitis, cystic fibrosis, α1-antitrypsin deficiency, or for cough, pulmonary emphysema, pulmonary fibrosis, and hyperreactive airways.

The compounds are also useful in the treatment of inflammatory diseases of the gastrointestinal tract and the bile ducts and bladder associated with impaired activity of the tyrosine kinases, e.g. in acute or chronic inflammatory changes, such as cholecystitis, Crohn's disease, ulcerative colitis, and ulcers or polyposis in the gastrointestinal tract or as they occur in diseases of the gastrointestinal tract, which are associated with increased secretion such as M. Menetrier, secreting adenomas and protein loss syndromes,

in addition, for the treatment of inflammatory diseases of the joints, such as rheumatoid arthritis, inflammatory diseases of the skin, eyes, in inflammatory pseudopolyps, in colitis cystica profunda or in pneumatosis cystoides intestinales.

Preferred areas of application are inflammatory diseases of the respiratory organs or of the intestine, such as chronic bronchitis (COPD), chronic sinusitis, asthma, Crohn's disease, ulcerative colitis or polyposis of the intestine.

Particularly preferred indications are inflammatory diseases of the respiratory tract or the lungs, such as chronic bronchitis (COPD) or asthma.

In addition, the compounds of general formula I and their physiologically acceptable salts can be used for the treatment of other diseases caused by aberrant function of tyrosine kinases, such as epidermal hyperproliferation (psoriasis), benign prostate hyperplasia (BPH), inflammatory processes, diseases of the immune system, Hyperproliferation of hematopoietic cells, the treatment of nasal polyps, etc .. Due to their biological properties, the compounds of 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 (eg etoposide), mitotic inhibitors (eg, vinblastine), nucleic acid-interacting compounds (eg, cisplatin, cyclophosphamide, adriamycin), hormone antagonists (eg, tamoxifen), inhibitors of metabolic processes (eg, 5-FU, etc.), cytokines (eg, interferons), antibodies, etc. For the treatment of respiratory diseases, these compounds alone or in combination with other respiratory therapies, such as secretolytic (eg Ambroxol, N-acetylcysteine), broncholytic (eg tiotropium or ipratropium or fenoterol, salmeterol, salbutamol) and / or anti-inflammatory (eg theophylline or glucocorticoids) active substances be used. For the treatment of diseases in the region of the gastrointestinal tract, these compounds can also be given alone or in combination with motility or secretion-influencing substances. These combinations can be administered either simultaneously or sequentially.

The use of these compounds, either alone or in combination with other active substances, may be intravenous, subcutaneous, intramuscular, intraperitoneal, intranasal, by inhalation or transdermally or orally, in particular aerosol formulations being suitable for inhalation.

In the pharmaceutical application, the compounds according to the invention are generally used in warm-blooded vertebrates, in particular in humans, in dosages of 0.001-100 mg / kg body weight, preferably at 0.1-15 mg / kg. For administration, these are with one or more conventional inert carriers and / or diluents, for example with corn starch, lactose, 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 conventional incorporated galenic preparations such as tablets, dragees, capsules, powders, suspensions, solutions, sprays or suppositories.

The inventive compounds of the general formula I in which R ° is a (2-hydroxyethyl) amino-group in which the carbon skeleton of the (2-hydroxyethyl) portion is optionally substituted by one or two Cι _-3 alkyl group, are, also for the preparation of corresponding 2-oxo-morpholin-4-yl derivatives, as described for example in WO 00/55141 or WO 02/18351. For example, the compound of Example 2 with methyl bromoacetate can be prepared (S) -4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- [2- (6-methyl-2-oxo-morpholin-4-yl ) ethyloxy] -7-methoxy-quinazoline (see method example A).

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

Preparation of the starting compounds:

Example I

cr ^φ cςr 3-Benzyl-3,4-dihydro-4-oxo-6-acetyloxy-7-methoxy-quinazoline

169 g of 3,4-dihydro-4-oxo-6-acetyloxy-7-methoxy-quinazoline, 118.8 ml of benzyl bromide and 138.2 g of potassium carbonate are heated in 1600 ml of acetone for 8 hours at 35-40 ° C. The mixture is stirred for 15 hours at room temperature and then treated with 2000 ml of water. The suspension is cooled to 0 ° C, the precipitate is filtered off with suction, washed with 400 ml of water and 400 ml of tert-butyl methyl ether and dried at 50 ° C. The solid is dissolved in 4000 ml of methylene chloride, filtered and concentrated. The residue is suspended in tert-butyl methyl ether, filtered off with suction and dried at 50.degree. Yield: 203 g (86% of theory) R _f value: 0.80 (silica gel, methylene chloride / ethanol = 9: 1) Mass spectrum (ESI ⁺ ): m / z = 325 [M + H] ⁺ Example II

3-benzyl-3,4-dihydro-4-oxo-6-hydroxy-7-methoxy-quinazolin

Method A:

168.5 g of 6-hydroxy-7-methoxy-benzo [d] [1,3] oxazin-4-one are dissolved in 1200 ml of toluene and 74.7 ml of benzylamine are added. The mixture is refluxed for 15 hours and then cooled to room temperature. The precipitate is filtered off and washed with tert-butyl methyl ether. Yield 124 g (72% of theory)

Method B:

200 g of 3-benzyl-3,4-dihydro-4-oxo-6-acetyloxy-7-methoxy-quinazoline are suspended in 200 ml of water and, 1000 ml of ethanol. 300 ml of 10N sodium hydroxide solution are added at room temperature and the mixture is heated to 30 ° C. for 1 hour. After

Add 172 ml of acetic acid and 2000 ml of water, the mixture for 20 hours

Room temperature stirred. The precipitate is filtered off with suction, washed with water and acetone and dried at 60.degree. Yield: 172.2 g (98% of theory)

R _f value: 0.25 (silica gel, methylene chloride / ethanol = 19: 1)

Mass Spectrum (ESI ⁺ ): m / z = 283 [M + H] ⁺

example

(S) -3-Benzyl-3,4-dihydro-4-oxo-6- [2- (2-oxo-5-methyl-oxazolidin-3-yl) -ethyloxy] -7-methoxy-quinazoline Method A

12.34 g of (S) -3-benzyl-3,4-dihydro-4-oxo-6- {2 - [(2-hydroxypropyl) amino] ethyloxy} -7-methoxy-quinazoline and 8.1 g of N, N'-carbonyldiimidazole be in 120 ml

Suspended tetrahydrofuran and stirred at room temperature for 2 hours. The

Solvent is stripped off and the residue is dissolved in 250 ml of water. The

Solution is cooled to 2 ° C, the precipitate is filtered off with suction and from a

Recrystallized mixture of ethyl acetate and diisopropyl ether and dried at 40 ° C.

Yield: 11.4 g (87% of theory)

Method B

12.13 g of (S) -5-methyl-oxazolidin-2-one are dissolved in 200 ml of N-methylpyrrolidone and 13.46 g of potassium tert-butoxide are added. After 30 minutes, 34.48 g of 3-benzyl-3,4-dihydro-4-oxo-6- (2-chloro-ethyloxy) -7-methoxy-quinazoline are added and the mixture is heated to 65 ° C for 7.5 hours. After addition of water, the precipitate is filtered off with suction and washed with water. The solid is purified by column chromatography on silica gel with methylene chloride / ethanol (50: 1). The product-containing fractions are collected, combined, concentrated, the residue recrystallized from ethyl acetate and dried at 40 ° C. Yield: 25.5 g (62% of theory)

Method C

2.82 g of 3-benzyl-3,4-dihydro-4-oxo-6-hydroxy-7-methoxyquinazoline, 1.8 g of (S) -3- (2-

Chloroethyl) ~ 5-methyl-oxazolidin-2-one and 2.07 g of potassium carbonate are heated to 70-75 ° C in 30 ml of dimethylformamide for 7.5 hours. The mixture is mixed with 90 ml

Added water and cooled to 0 ° C. The precipitate is filtered off with suction, washed with water and dried.

Yield: 2.2 g (53% of theory)

Analogously to Method C, the title compound can also be obtained by using (S) -3- [2- (4-toluenesulfonyloxy) ethyl] -5-methyl-oxazolidin-2-one as the alkylating agent.

R, value: 0.63 (silica gel, methylene chloride / ethanol = 19: 1)

Mass spectrum (ESI ⁺ ): m / z = 410 [M + H] ⁺ Example IV

(S) -3,4-Dihydro-4-oxo-6- [2- (2-oxo-5-methyl-oxazolidin-3-yl) -ethyloxy] -7-methoxy-quinazoline

Method A:

27 g of (S) -3-benzyl-3,4-dihydro-4-oxo-6- [2- (2-oxo-5-methyl-oxazolidin-3-yl) -ethyloxy] -7-methoxy-quinazoline are added a pressure of 50 psi and a temperature of 50 ° C with 2 g of palladium on activated carbon (10% Pd) in 200 ml of acetic acid hydrogenated for 17 hours. The catalyst is filtered off and the solvent is removed. The residue is recrystallized from ethyl acetate and dried at 50.degree. Yield: 17.5 g (83% of theory)

Method B:

1 g (S) -3,4-dihydro-4-oxo-6- {2 - [(2-hydroxypropyl) amino] ethyloxy} -7-methoxy-quinazoline and 0.81 g of N, N ^{'-carbonyldiimidazole} in 20 ml of Tetrahydrofuran heated under reflux for 4 hours. The mixture is mixed with 40 ml of water and cooled to 0 ° C. The precipitate is filtered off with suction, washed with water and dried at 50.degree. Yield: 0.9 g (82% of theory)

Rr value: 0.45 (silica gel, methylene chloride / ethanol = 9: 1) mass spectrum (ESI ⁺ ): m / z = 320 [M + H] ⁺

Example V

6-hydroxy-7-methoxybenzo [d] [1,3] oxazin-4-one

1 g of 2-amino-5-hydroxy-4-methoxybenzoic acid (prepared by reaction of methyl 2-nitro-4,5-dimethoxybenzoate with potassium hydroxide solution to give 2-nitro-5-hydroxy-4- methoxy-benzoic acid potassium salt and subsequent catalytic hydrogenation in

Presence of palladium on charcoal) and 20 ml of triethyl orthoformate are heated at 100 ° C for 2.5 hours. After cooling to room temperature, the

The precipitate was filtered off with suction and washed with diethyl ether.

Yield: 0.97 g (93% of theory)

R _f value: 0.86 (silica gel, methylene chloride / methanol / acetic acid = 90: 10: 1)

Mass spectrum (ESI ⁺ ): m / z = 194 [M + H] ⁺

Example VI

3-Benzyl-3,4-dihydro-4-oxo-6- (2-chloro-ethyloxy) -7-methoxy-quinazoline 98.8 g of 3-benzyl-3,4-dihydro-4-oxo-6-hydroxy-7 Methoxy-quinazoline, 96.5 g of toluene-4-sulfonic acid (2-chloro-ethyl) ester and 96.7 g of potassium carbonate are heated to 40-45 ° C in 500 ml of dimethylformamide for 24 hours. After addition of 1400 ml of water, the precipitate is filtered off with suction, washed with water and tert-butyl methyl ether and dried at 50 ° C. Yield: 119 g (98% of theory) Rr value: 0.45 (silica gel, methylene chloride / ethanol = 19: 1) mass spectrum (ESI ⁺ ): m / z = 345, 347 [M + H] ⁺

Example VII

(S) -3-Benzyl-3,4-dihydro-4-oxo-6- {2 - [(2-hydroxypropyl) amino] ethyloxy} -7-methoxy-quinazoline 23 g of 3-benzyl-3,4-dihydro 4-Oxo-6- (2-chloro-ethyloxy) -7-methoxy-quinazoline and 21.1 g of sodium carbonate are heated to 135-140 ° C in 50 ml of N-methylpyrrolidone. To this mixture is added dropwise within 25 minutes 15 g of (S) -1-amino-2-propanol dissolved in 100 ml of N-methyl-pyrrolidine. The mixture is heated to 135-140 ° C for 2 hours, then cooled to room temperature and filtered. The solvent is distilled off and the residue is purified by column chromatography on silica gel with methylene chloride / methanol (9: 1). The product-containing fractions are collected, combined and concentrated. The residue is dissolved in ethyl acetate and the product is precipitated by addition of tert-butyl methyl ether. The precipitate is filtered off with suction and dried. Yield: 22 g (85% of theory) Rr value: 0.15 (silica gel, methylene chloride / methanol = 9: 1) mass spectrum (ESl ⁺ ): m / z = 384 [M + H] ⁺

Example Vlil

(S) -3-Benzyl-3,4-dihydro-4-oxo-6- {2- [N- (2-hydroxypropyl) -N-benzyl-amino] -ethyloxy} -7-methoxy-quinazoline 3.45 g 3 Benzyl 3,4-dihydro-4-oxo-6- (2-chloro-ethyloxy) -7-methoxy-quinazoline, 1.98 g

(S) -1-Benzylamino-propan-2-ol, 2.12 g of sodium carbonate and 1.45 g of sodium iodide are heated to 125 ° C in 20 ml of N-methylpyrrolidone for 4 hours. After addition of 70 ml of water, 30 ml of diisopropyl ether and 30 ml of ethyl acetate, the precipitate is filtered off with suction, washed with water and dried at 70 ° C. The crude product is dissolved in 25 ml of ethyl acetate in the heat, treated with activated charcoal and filtered. The filtrate is mixed with 80 ml of diisopropyl ether and cooled to 0 ° C. The precipitate is filtered off with suction and dried at 50.degree.

Yield: 1.95 g (41% of theory)

Rr value: 0.30 (silica gel, methylene chloride / ethanol = 19: 1) mass spectrum (ESI ⁺ ): m / z = 474 [M + H] ⁺ Example IX

(S) -3,4-Dihydro-4-oxo-6- {2 - [(2-hydroxypropyl) amino] ethyloxy} -7-methoxy-quinazoline 5.8 g of (S) -3-benzyl-3,4-dihydro 4-Oxo-6- {2- [N- (2-hydroxypropyl) -N-benzylamino] ethyloxy} -7-methoxy-quinazoline are dissolved in 50 ml of acetic acid at 50 psi and 60 ° C in the presence of 0.6 g of palladium on activated carbon (10% Pd) hydrogenated for 8 hours. The catalyst is filtered off and the solvent is removed. The residue is purified by column chromatography on silica gel with methylene chloride / ethanol / conc. aqueous ammonia = 90: 10: 2 purified. The product-containing fractions are collected, combined and concentrated. The residue is recrystallized from ethanol and dried at 60.degree. Yield: 1.54 g (43% of theory)

Rr value: 0.20 (silica gel, methylene chloride / ethanol / concentrated aqueous ammonia = 90: 10: 2)

Mass spectrum (ESI ⁺ ): m / z = 294 [M + H] ⁺

Example X

(S) -5-methyl-oxazolidin-2-one

Prepared by reaction of (S) -1-amino-2-propanol with carbonic diphenyl ester in toluene and subsequent fractional distillation. Mass spectrum (ESI ⁺ ): m / z = 102 [M + H] ⁺

Example XI

(S) -3- (2-chloro-ethyl) -5-methyl-oxazolidin-2-one 10.11 g of (S) -5-methyl-oxazolidin-2-one are dissolved in 150 ml of dimethylformamide. To this are added 11.22 g of potassium tert-butoxide and 22.07 g of toluene-4-sulfonic acid (2-chloroethyl) ester and heated to 110 ° C. for 2 hours. The solvent is distilled off and the residue is mixed with 150 ml of water. The aqueous phase is extracted twice with 200 ml of ethyl acetate. The organic phase is washed with 100 ml of brine. The solvent is removed and the residue is purified by column chromatography on silica gel with methylene chloride / ethanol (50: 1). The product-containing fractions are collected, combined and concentrated. Yield: 6.1 g (37% of theory) Rr value: 0.40 (silica gel, methylene chloride / ethanol = 49: 1) Mass spectrum (ESI ⁺ ): m / z = 164, 166 [M + H] ⁺

Example XII

(S) -N- (2-hydroxypropyl) -N- [2- (benzyloxy) ethyl] benzylamine

10.4 g of (S) -1-benzylamino-propan-2-ol, 7.56 ml of 2- (benzyloxy) -ethylbromide, 8.71 g of potassium carbonate and 100 ml of acetonitrile are stirred at 60 ° C. for 2.5 days. 0.7 ml of 2- (benzyloxy) ethyl bromide and 0.8 g of potassium carbonate are also added and the mixture is stirred at 80 ° C. for a further 8 hours. The reaction mixture is concentrated, the residue is partitioned between ethyl acetate and water and the organic phase is washed with water and saturated brine, dried and concentrated. 16.8 g of the residue are purified by chromatography on a silica gel column with methylene chloride / methanol. Yield: 10.4 g (62% of theory) R _f value: 0.54 (silica gel, methylene chloride / methanol = 95: 5) Mass spectrum (ESI ⁺ ): m / z = 300 [M + H] ⁺ Example XIII

(S) -N- (2-hydroxypropyl) -N- [2- (benzyloxy) ethyl] -amine

5.0 g of (S) -N- (2-hydroxypropyl) -N- [2- (benzyloxy) ethyl] benzylamine in 50 ml of ethanol at room temperature for 2 hours in the presence of 1 g of palladium on activated carbon

(10% Pd) hydrogenated. It is filtered off from the catalyst and concentrated to dryness.

Yield: 3.49 g (100% of theory)

Rr value: 0.30 (silica gel, methylene chloride / methanol = 9: 1)

Mass spectrum (ESI ⁺ ): m / z = 210 [M + H] ⁺

Example XIV

(S) -3- [2- (benzyloxy) ethyl] -5-methyl-oxazolidin-2-one

3.375 g (S) -N- (2-hydroxypropyl) -N- [2- (benzyloxy) ethyl] amine and 2.615 g of N, N ^'- carbonyldiimidazole are stirred for 3 hours at room temperature in 35 ml of tetrahydrofuran. There are still 0.523 g of N, N ^{'-carbonyldiimidazole} was added and stirred for a further 2 hours. After addition of 0.5 ml of water is stirred for 2.5 days. Thereafter, 5 ml of 1 M sodium hydroxide solution are added, stirred for 1.5 hours, then added 3 ml of 1 M sodium hydroxide solution and stirred for another hour. The reaction mixture is concentrated, and the residue is partitioned between ethyl acetate and water. The organic phase is washed with 1M hydrochloric acid, water and brine, dried and concentrated to dryness. Yield: 3.2 g (84% of theory) Rr value: 0.72 (silica gel, methylene chloride / methanol = 95: 5) Mass spectrum (ESI ⁺ ): m / z = 236 [M + H] ⁺ Example XV

(S) -3- (2-hydroxyethyl) -5-methyl-oxazolidin-2-one

3.2 g of (S) -3- [2- (benzyloxy) ethyl] -5-methyl-oxazolidin-2-one are dissolved in 35 ml of ethyl acetate at room temperature for 1.5 hours in the presence of 0.7 g of palladium on activated carbon

Yield: 1.93 g (98% of theory)

Rr value: 0.24 (silica gel, methylene chloride / methanol = 95: 5)

Mass spectrum (ESI ⁺ ): m / z = 146 [M + H] ⁺

Example XVI

(S) -3- [2- (4-ToIuolsulfonyloxy) ethyl] -5-methyl-oxazolidin-2-one

To 1.9 g of (S) -3- (2-hydroxyethyl) -5-methyl-oxazolidin-2-one in 5 ml of pyridine are added under ice-cooling 2.5 g of 4-toluenesulfonyl chloride, stirred for 2 hours under ice-cooling and for a further hour at room temperature. The reaction mixture is poured onto a mixture of 50 ml of ice-water and 6 ml of concentrated hydrochloric acid, 70 ml of ethyl acetate are added and stirred. The organic phase is separated, washed with water and brine, dried and concentrated. Yield: 2.8 g (72% of theory)

Rr value: 0.44 (silica gel, ethyl acetate / cyclohexane = 7: 3) mass spectrum (ESI ⁺ ): m / z = 300 [M + H

Preparation of the end compounds: example 1

(S) -4 - [(3-Chloro-4-fluoro-phenyl) -amino] -6- [2- (2-oxo-5-methyl-oxazolidin-3-yl) -ethyloxy] -7-methoxy-quinazoline 1 g (S) -3,4-dihydro-4-oxo-6- [2- (2-oxo-5-methyl-oxazolidin-3-yl) -ethyloxy] -7-methoxy-quinazoline, 15 ml of thionyl chloride and 0.1 ml Dimethylformamide are refluxed for 2 hours. The solvent is removed and the residue is dissolved twice in 20 ml of toluene and concentrated again to dryness. The residue is dissolved in isopropanol and 1 g of 3-chloro-4-fluoroaniline and 0.82 g of Hünig base are added. The mixture is refluxed for 2 hours. After cooling to

0 ° C and addition of 30 ml of water, the precipitate is filtered off with suction, washed with 50% aqueous isopropanol and dried at 50 ° C.

Yield: 0.9 g (64% of theory)

Rr value: 0.27 (silica gel, methylene chloride / ethanol = 19: 1) mass spectrum (ESI ⁺ ): m / z = 447/449 [M + H] ⁺

Example 2

(S) -4 - [(3-Chloro-4-fluorophenyl) amino] -6- {2 - [(2-hydroxypropyl) amino] ethyloxy} -7-methoxy-quinazoline

0.8 g of (S) -4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- [2- (2-oxo-5-methyl-oxazolidin-3-yl) -ethyloxy] -7-methoxy quinazoline and 0.2 g of lithium hydroxide are dissolved in a mixture of 20 ml of isopropanol and 5 ml of water. The mixture is refluxed for 8 hours, concentrated to 10 ml and cooled to 0 ° C. After adding 10 ml of diisopropyl ether, the precipitate is filtered off with suction, washed with water and dried at 50 ° C. Yield: 0.6 g (79% of theory)

Rr value: 0.38 (silica gel, methylene chloride / methanol / concentrated aqueous ammonia = 90: 10: 1)

Mass Spectrum (ESI ⁺ ): m / z = 421/423 [M + Hf

Example 3

(S) -4 - [(3-Chloro-4-fluorophenyl) amino] -6- {2- [N- (2-hydroxypropyl) -N-methylamino] ethyloxy} -7-methoxy-quinazoline

A mixture of 210 mg of (S) -4 - [(3-chloro-4-fluorophenyl) amino] -6- {2 - [(2-hydroxypropyl) amino] ethyloxy} -7-methoxyquinazoline, 0.26 ml N-ethyl-diisopropylamine and 4 ml of tetrahydrofuran are stirred for 30 minutes at room temperature. Subsequently, 94 μ \ 37% aqueous formalin solution and 318 mg

Sodium triacetoxyborohydride and stirred overnight at room temperature.

The reaction mixture is mixed with 10% potassium carbonate solution and with

Extracted vinegar. The organic phase is washed with water and brine, dried and concentrated. Yield: 100 mg (46% of theory)

Rr value: 0.42 (silica gel, methylene chloride / methanol / concentrated aqueous ammonia logo CNRS logo INIST

60: 10: 1)

Mass spectrum (ESI ⁺ ): m / z = 435, 437 [M + H] ⁺

Analogously to Example 3, the following compounds are obtained:

(1) (S) -4 - [(3-Chloro-4-fluoro-phenyl) -amino] -6- {2- [N- (2-hydroxypropyl) -N-ethyl-amino] -ethyloxy} -7-methoxy -quinazoline

Rr value: 0.60 (silica gel, methylene chloride / methanol / concentrated aqueous ammonia logo CNRS logo INIST

60: 10: 1)

Mass spectrum (ESI ⁺ ): m / z = 449, 451 [M + H] ⁺

(2) 4 - [(3-Chloro-4-fluoro-phenyl) -amino] -6- {2- [- (2-hydroxy-2-methyl-propyl) -N-methyl-amino-1-yloxy} -7 -methoxy-chanazole in

Rr value: 0.40 (silica gel, methylene chloride / methanol / concentrated aqueous ammonia = 70: 10: 1)

Mass spectrum (ESI ⁺ ): m / z = 449, 451 [M + H] ⁺

(3) 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- {2- [N- (2-hydroxy-2-methyl-propyl) -N-ethyl-amino] -ethyloxy} -7 methoxy-quinazoline

Rr value: 0.44 (silica gel, methylene chloride / methanol / concentrated aqueous ammonia logo CNRS logo INIST

70: 10: 1)

Mass Spectrum (ESI ⁺ ): m / z = 463, 465 [M + H] ⁺

Example 4

4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- {2 - [(2-hydroxy-2-methyl-propyl) -amino] -ethyloxy} -7-methoxy-chiazolazine

A mixture of 4.8 g of 4 - [(3-chloro-4-fluorophenyl) amino] -6- (2-chloroethyloxy) -7-methoxy-quinazoline (R f value: 0.38, (silica gel, methylene chloride / ethanol = 19 : 1) prepared by reacting 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6-hydroxy-7-methoxy-quinazoline with benzenesulfonic acid (2-chloroethyl) ester in dimethylformamide

45 ° C in the presence of potassium carbonate), 2.23 g of 2-hydroxy-2-methyl-propylamine, 3.33 g of sodium carbonate and 25 ml of dimethylformamide are stirred at 60 ° C for 3 days. The reaction mixture is partitioned between ethyl acetate and water, the organic phase is washed with water and brine, dried and concentrated. Of the

Residue is by chromatography on a silica gel column

Methyienchlorid / methanol / conc. cleaned aqueous ammonia.

Yield: 1.1 g (20% of theory) R _f value: 0.58 (silica gel, methylene chloride / methanol / concentrated aqueous ammonia

60: 10: 1)

Mass spectrum (ESI ⁺ ): m / z = 435, 437 [M + H] ⁺

Example 5

4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- [2- (2-oxo-5,5-dimethyl-oxazolidin-3-yl) -ethyloxy] -7-methoxy-quinazoline

To 217 mg of 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- {2 - [(2-hydroxy-2-methyl-propyl) -amino] -ethyloxy} -7-methoxy-quinazoline in 4 ml Tetrahydrofuran is added to 89 mg of N, N'-carbonyldiimidazole and left at room temperature for 18 hours and a further 6

Stirred at 70 ° C for hours. After addition of another 40 mg of N, N ^{'-carbonyldiimidazole} is stirred again at 70 ° C for 3 hours. The reaction mixture is cooled in an ice bath, the precipitate is filtered off with suction, washed with a little tetrahydrofuran and dried.

Yield: 70 mg (30% of theory)

Rr value: 0.50 (silica gel, methylene chloride / methanol / concentrated aqueous ammonia logo CNRS logo INIST

70: 10: 1)

Mass spectrum (ESI ⁺ ): m / z = 461, 463 [M + H] ⁺

The following compound is obtained analogously to Example 5:

(1) (S) -4 - [(3-Chloro-4-fluoro-phenyl) -amino] -6- [2- (2-oxo-5-methyl-oxazolidin-3-yl) -ethyloxy] -7-methoxy -quinazoline

Rr value: 0.65 (silica gel, methylene chloride / ethanol = 9: 1) mass spectrum (ESI ⁺ ): m / z = 447/449 [M + H] ⁺

Analogously to the abovementioned examples and other processes known from the literature, the following compounds can also be prepared:

Example 6

Dragees with 75 mg active substance

Zusammensetzunq:

1 drag core contains:

Active substance 75.0 mg

Calcium phosphate 93.0 mg

Cornstarch 35.5 mg

Polyvinylpyrrolidone 10.0 mg

Hydroxypropylmethylcellulose 15.0 mg

Magnesium stearate 1.5 mg

230.0 mg

production:

The active substance is mixed with calcium phosphate, corn starch, polyvinylpyrrolidone, hydroxypropylmethylcellulose and half of the stated amount of magnesium stearate. On a tabletting machine, compacts with a diameter of about 13 mm are produced, which are ground on a suitable machine through a sieve with a 1.5 mm mesh size and mixed with the remaining amount of magnesium. Stearate mixed. This granulate is pressed on a tabletting machine into tablets of the desired shape.

Core weight: 230 mg

Stamp: 9 mm, curved

The Drageekeme thus prepared are coated with a film consisting essentially of hydroxypropylmethylcellulose. The finished film dragees are shined with beeswax.

Dragee weight: 245 mg.

Example 7

Tablets with 100 mg active substance

Composition:

1 tablet contains:

Active substance 100.0 mg lactose 80.0 mg

Corn starch 34.0 mg

Polyvinylpyrrolidone 4.0 mg

Magnesium stearate 2.0 mg

220.0 mg

Herstellunαverfahren:

Active ingredient, lactose and starch are mixed and uniformly moistened with an aqueous solution of polyvinylpyrrolidone. After sieving the moist mass (2.0 mm mesh size) and drying in a tray drying oven at 50 ° C is again sieved (1.5 mm mesh) and the lubricant mixed. The ready-to-use mixture is processed into tablets.

Tablet weight: 220 mg Diameter: 10 mm, biplan with facet on both sides and one-sided part notch.

Example 8

Tablets with 150 mg active substance

Composition: 1 tablet contains: active substance 150.0 mg

Lactose powdered 89.0 mg cornstarch 40.0 mg

Colloidal silicic acid 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 silicic acid is moistened with a 20% strength aqueous solution of polyvinylpyrrolidone and filtered through a sieve

1.5 mm mesh hit.

The granules dried at 45 ° C are again rubbed through the same sieve and mixed with the stated amount of magnesium stearate. Out of the mix

Pressed tablets.

Tablet weight: 300 mg. Stamp: 10 mm, flat

Example 9

Hard gelatine capsules with 150 mg active substance

Composition: 1 capsule contains:

Active ingredient 150.0 mg

Corn starch drink. about 180.0 mg

Lactose 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 of 0.75 mm mesh size and mixed homogeneously in a suitable device. The final mixture is filled into size 1 hard gelatin capsules. Capsule filling: approx. 320 mg

Capsule shell: hard gelatin capsule size 1.

Example 10

Suppositories with 150 mg active substance

Composition: 1 suppository contains:

Active ingredient 150.0 mg

Polyethylene glycol 1500 550.0 mg

Polyethylene glycol 6000 460.0 mg

Polyoxyethylene sorbitan monostearate 840.0 mg 2000.0 mg

production:

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

Example 11

Suspension with 50 mg active substance Composition:

100 ml suspension contain:

Active ingredient 1.00 g carboxymethylcellulose Na 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

Glycerine 5.00 g sorbitol solution 70% 20.00 g

Aroma 0.30 g

Water dist. ad 100.00 ml

Preparation: Distilled water is heated to 70 ° C. Herein, p-hydroxybenzoic acid methyl ester and propyl ester and also glycerol and carboxymethylcellulose sodium salt are dissolved with stirring. It is cooled to room temperature and added with stirring, the active ingredient and dispersed homogeneously. After addition and dissolution of the sugar, the sorbitol solution and the aroma, the suspension is evacuated to vent with stirring.

5 ml of suspension contain 50 mg of active ingredient.

Example 12

Ampoules with 10 mg active substance

Composition:

Active ingredient 10.0 mg 0.01 n hydrochloric acid s.q.

Aqua bidest ad 2.0 ml

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

Example 13

Ampoules with 50 mg active substance

Composition:

Active ingredient 50.0 mg 0.01 n hydrochloric acid s.q.

Aqua bidest ad 10.0 ml

production:

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

Example 14

Capsules for powder inhalation with 5 mg active substance

1 capsule contains:

Active substance 5.0 mg

Lactose for inhalation 15.0 mg 20.0 mg

production:

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 15

Inhalation solution for handheld nebulizers with 2.5 mg active substance

1 hub contains:

Active substance 2,500 mg

Benzalkonium chloride 0.001 mg

1 N 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 1 N hydrochloric acid. The adjusted solution is filtered and filled into containers suitable for the hand nebulizer (cartridges).

Fill weight of the container: 4.5 g

Process Example A

(S) -4 - [(3-Chloro-4-fluoro-phenyl) -amino] -6- [2- (6-methyl-2-oxomorpholin-4-yl) -ethyloxy] -7-methoxy-quinazoline

425 g of (S) -4 - [(3-chloro-4-fluorophenyl) amino] -6- {2 - [(2-hydroxypropyl) amino] ethyloxy} -7-methoxyquinazoline and 210 ml of N-ethyl Di-isopropylamine are dissolved in 640 ml of N-methylpyrrolidone. After addition of 105 ml of methyl bromoacetate, the mixture is stirred for 1 hour at 20-25 ° C. After addition of 8500 ml of n-butyl acetate and 4300 ml of water, the phases are separated and the organic phase is washed with 4300 ml of water. The organic phase is concentrated at 200 mbar to 50% of the original volume and 4300 ml of n-butyl acetate are added. The Mixture is heated for 40 hours at 120-130 ° C, filtered and concentrated at 200 mbar to a volume of 2000 ml. After cooling to -10 ° C, the precipitate is filtered off with suction, washed with 800 ml of n-butyl acetate and dried at 50 ° C. The crude product is recrystallized twice from methyl ethyl ketone (3750 and 5100 ml). Yield: 170 g (36% of theory) Mass Spectrum (ESI ⁺ ): m / z = 461/463 [M + Hf

Claims

claims

1. Bicyclic heterocycles of the general formula

in which

R ^{a represents} a hydrogen atom or a C _1-3 -alkyl group,

R ^{b is} a phenyl or 1-phenylethyl group in which the phenyl nucleus is substituted in each case by the radicals R ¹ to R ³ , wherein

a Cι _-4 alkyl, hydroxy, Cι _-4 alkoxy, C _2-3 -alkenyl or C _2-3 -alkynyl,

a phenyloxy or phenylmethoxy group, wherein the phenyl portion of the aforementioned groups is optionally substituted by a fluorine or chlorine atom, or

a substituted by 1 to 3 fluorine atoms methyl or methoxy group or

a cyano, nitro or amino group, and R ^{3 is} a hydrogen, fluorine, chlorine or bromine atom or

represent a methyl or trifluoromethyl group,

R ^{c is} a (2-hydroxyethyl) amino group in which the carbon skeleton of the (2-hydroxyethyl) part is optionally substituted by one or two C _1-3 -alkyl groups,

an N- (2-hydroxyethyl) -N- (Cι _-3 -alkyl) -amino group in which the carbon skeleton of the (2-hydroxyethyl) part is optionally substituted by one or two C _1-3 alkyl groups, or

R ^{d is} a hydrogen atom,

a hydroxy group,

a d _-3 -alkyloxy group,

a C _2-4 alkyloxy group substituted by a radical R ⁴ , wherein

R ι is a hydroxy, Cι _-3 alkyloxy-, C _3-6 cycloalkyloxy, amino, amino- C _1-3 alkyl,

Di- (Cι _-3 alkyl) amino, bis- (2-methoxyethyl) -amino, pyrrolidin-1-yl, piperidin-1-yl, homopiperidin-1-yl, morpholin-4-yl- , Homomorpholin-4-yl, 2-oxa-5-azabicyclo [2.2.1] hept-5-yl, 3-oxa-8-azabicyclo [3.2.1] oct-8-yl, 8-oxa-3-azabicyclo [3.2.1] oct-3-yl, piperazin-1-yl, 4-C. _3- Alkyl-piperazin-1-yl, homopiperazin-1-yl or 4-Cι- _3- alkyl-homopiperazin-1-ylgruppe, wherein the above-mentioned pyrrolidinyl, piperidinyl, piperazinyl and Morpholinylgruppen each by a or two Cι _-3 alkyl groups may be substituted, a C ₃ . ₇ cycloalkyloxy or C _{_3-7} cycloalkyl-Cι- alkyloxy group _3,

a tetrahydrofuranyl-C 1 -alkyloxy or tetrahydropyranyl-C 1 -alkyloxy group,

X is a methine group substituted by a cyano group or a nitrogen atom

and

n is the number 2, 3 or 4,

their tautomers, their stereoisomers, their mixtures and their salts.

2. bicyclic heterocycles of the general formula I according to claim 1, in which

R ^{a is} a hydrogen atom,

R ^{b is} a 3-bromophenyl, 3,4-difluorophenyl, 3-chloro-4-fluorophenyl or a 3-ethynylphenyl group,

R ° is a (2-hydroxypropyl) amino or N- (2-hydroxypropyl) -N- (C _1-3 -alkyl) -amino group,

an N- (2-hydroxybutyl) amino or N- (2-hydroxybutyl) -N- (C _1-3 -alkyl) amino group,

a (2-hydroxy-2-methyl-propyl) amino or N- (2-hydroxy-2-methyl-propyl) -N- (Cι _-3 alkyl) amino group, an N- (2-hydroxy-2-ethyl-butyl) amino or N- (2-hydroxy-2-ethyl-butyl) -N- (Cι _-3 alkyl) - amino group, or

a 2-oxo-5-methyl-oxazolidin-3-yl, 2-oxo-5-ethyl-oxazolidin-3-yl, 2-oxo-5,5-dimethyl-oxazolidin-3-yl or 2- oxo-5,5-diethyl-oxazolidin-3-yl group,

R ^{d is} a hydrogen atom,

a methoxy, ethyloxy or 2-methoxyethyloxy group,

a cyclobutyloxy, cyclopentyloxy or cyclohexyloxy group,

a tetrahydrofuranylmethoxy or tetrahydropyranylmethoxy group,

X is a nitrogen atom,

and

n is the number 2 or 3,

their tautomers, their stereoisomers, their mixtures and their salts.

3. bicyclic heterocycles of the general formula I according to claim 1, in which

R ^{a is} a hydrogen atom, R ^{b is} a 3-chloro-4-fluoro-phenyl group or 3-ethynylphenyl group, ^"

R ^{c is} a (2-hydroxypropyl) amino group,

a (2-hydroxy-2-methyl-propyl) amino group,

a 2-oxo-5-methyl-oxazolidin-3-yl or 2-oxo-5,5-dimethyl-oxazolidin-3-yl group,

R ^{d is} a methoxy, ethyloxy or 2-methoxyethyloxy group,

X is a nitrogen atom,

and

n is the number 2,

their tautomers, their stereoisomers, their mixtures and their salts.

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

(e) (S) -4 - [(3-Chloro-4-fluoro-phenyl) amino] -6- [2- (2-oxo-5-methyl-oxazolidin-3-yl) -ethyloxy] -7-methoxy -quinazoline

(f) (S) -4 - [(3-Chloro-4-fluorophenyl) amino] -6- {2 - [(2-hydroxypropyl) amino] ethyloxy} -7-methoxy-quinazoline (g) 4 - [(3-Chloro-4-fluoro-phenyl) -amino] -6- {2 - [(2-hydroxy-2-methyl-propyl) -amino] -ethyloxy} -7-methoxy-quinazoline

(h) 4 - [(3-Chloro-4-fluoro-phenyl) -amino] -6- [2- (2-oxo-5,5-dimethyl-oxazolidin-3-yl) -ethyloxy] -7-methoxy-quinazoline

and their salts.

5. Physiologically acceptable salts of the compounds according to at least one of claims 1 to 4 with inorganic or organic acids.

6. A pharmaceutical composition containing a compound according to at least one of claims 1 to 4 or a physiologically acceptable salt according to claim 5 together with optionally one or more inert carriers and / or diluent mittein.

7. Use of a compound according to any one of claims 1 to 5 for the manufacture of a medicament for the treatment of benign or malignant tumors, for the prevention and treatment of respiratory and pulmonary diseases and for the treatment of diseases of the gastrointestinal tract and the bile duct and bladder is suitable.

8. A process for the preparation of a medicament according to claim 6, characterized in that a compound according to at least one of claims 1 to 5 is incorporated into one or more inert carriers and / or diluents by non-chemical means.

9. A process for the preparation of the compounds of general formula I according to claims 1 to 4, characterized in that

a) a compound of the general formula

in the

R ^a , R ^b , R ^d and X are defined as mentioned in claims 1 to 4, with a

Compound of the general formula

Z ¹ - (CH ₂ ) _n - R ^c (III).

in the

R ^c and n are as defined in claims 1 to 4 are defined and Z ^{1 represents} a leaving group or hydroxy group, is reacted or

b) for the preparation of compounds of the general formula I in which X represents a nitrogen atom, a compound of the general formula

in which R ^c , R ^d and n are as defined in claims 1 to 4, with a halogenating agent to give an intermediate compound of general formula (V), in which R °, R ^d and n are defined as defined in claims 1 to 4 and Z ^{2 is} a halogen atom such as a chlorine or bromine atom,

and then with a compound of the general formula

R ^a - NH - R ^D (VI),

in which R ^a and R ^{b are defined} as defined in claims 1 to 4, or is reacted

c) a compound of the general formula

in which R ^a , R, R, X and n are defined as mentioned in claims 1 to 4, and Z ^{3 represents} a leaving group,

with a compound of the general formula

H - R ° (VIII),

in which R ° is defined as defined in claims 1 to 4, is reacted and

if desired, a thus-obtained compound of general formula I in which R ^c is an optionally by one or two C _f - ₃ alkyl substituted 2-oxo oxazolidin-3-yl group is converted by hydrolysis into a compound of general formula I, in which R ^{c is} optionally substituted on the carbon skeleton of the (2-hydroxyethyl) -substituted (2-hydroxyethyl) amino group, and / or

a compound of the general formula I in which R ^{c is} a (2-hydroxyethyl) amino group in which the carbon skeleton of the (2-hydroxyethyl) part is optionally substituted by one or two C ₃ alkyl groups, in a compound is converted, in which R ^{c represents} an optionally substituted by one or two Cι - ₃ - alkyl groups 2-oxo-oxazolidin-3-yl group, and / or

a compound of general formula I thus obtained, which contains an amino, alkylamino or imino group, is converted by means of alkylation or reductive alkylation into a corresponding alkyl compound of general formula I and / or

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

if desired, a compound of 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 the pharmaceutical application into its physiologically tolerated salts.

10. A process for the preparation of quinazoline derivatives of the general formula

in which R ^a , R ^b , R ^d and n are defined as defined in claims 1 to 4 and R ^e and R ^f independently represent hydrogen atoms or C-ι _-3 alkyl groups, characterized in that a compound of general formula I in which R ^a , R ^b , R ^d and n are as defined in claims 1 to 4, X is a nitrogen atom and R ^{c is} a (2-hydroxyethyl) amino group in which the carbon skeleton of the (2- Hydroxyethyl) part optionally by one or two C. _3- alkyl groups, is reacted with a reactive acetic acid derivatives.