EP1966189A1

EP1966189A1 - Bicyclic heterocycles, medicaments containing said compounds, use thereof, and method for the production thereof

Info

Publication number: EP1966189A1
Application number: EP06819573A
Authority: EP
Inventors: Frank Himmelsbach; Marco Santagostino; Birgit Jung; Rainer Soyka
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: 2005-12-12
Filing date: 2006-11-17
Publication date: 2008-09-10
Also published as: IL191988A0; JP2009518450A; AR058286A1; WO2007068552A1; BRPI0619603A2; TW200730508A; CA2631813A1; KR20080077009A; US20070135463A1; AU2006326157A1

Abstract

The invention relates to bicyclic heterocycles of general formula (I), the tautomers thereof, the mixtures and salts thereof, especially the physiologically acceptable salts thereof comprising inorganic or organic acids, which have valuable pharmaceutical properties, particularly an inhibitive effect on signal transduction mediated by tyrosine kinases, the use thereof for treating diseases, especially tumor diseases and benign prostatic hyperplasia (BPH), lung diseases, and respiratory tract diseases, and the production thereof.

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)

R ^{a is} a hydrogen atom,

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

R ^{c is} a radical selected from the group consisting of 1-methoxycarbonyl-piperidin-4-yl, i-ethyloxycarbonyl-piperidin-4-yl, 1-trifluoroacetyl-piperidin-4-yl, cis-4

(Methoxycarbonylamino) -cyclohex-i-yl, trans-4- (methoxycarbonylamino) -cyclohex-1-yl, cis-4- (ethyloxycarbonylamino) -cyclohex-1-yl, trans-4- (ethyloxycarbonylamino) -cyclohex 1 -yl, cis-4- (thfluoroacetylamino) -cyclohex-1-yl, trans-4- (trifluoroacetylamino) -J-cyclohex-i-yl, cis-4- (N-methoxycarbonyl-N-methyl-amino) - cyclohex-1-yl, trans-4- (N-methoxycarbonyl-N-methyl-amino) -cyclohex-1-yl, cis-4- (N -ethyloxycarbonyl-N-methyl-amino-1-cyclohex-i-yl , trans-4- (N-ethyloxycarbonyl-N-methyl-amino) -cyclohex-1-yl, cis-4- (N-trifluoroacetyl-N-methyl-amino) -cyclohex-1-yl, trans- 4- (N-trifluoroacetyl-N-methyl-amino) -cyclohex-1-yl, cis-4-phthalimido-cyclohex-1-yl and trans ^ -phthalimido-cyclohex-i-yl, preferably a radical from the group consisting of 1-methoxycarbonyl-piperidin-4-yl, 1-ethyloxycarbonyl-piperidin-4-yl, cis-4- (methoxycarbonylamino) -cyclohex-i-yl, trans-4- (methoxycarbonylamino) - cyclohex-1 -yl, cis-4- (ethyloxycarbonylamino) -cyclohex-1-yl, trans-4- (ethyloxycarbonylamino) cyclohex-1-yl, cis-4- (N-methoxycarbonyl-N-methyl) amino) -cyclohex-1-yl, trans-4- (N-methoxycarbonyl-N-methyl-amino-1-cyclohex-i-yl, cis-4- (N-ethyloxycarbonyl-N-methyl-amino) -cyclohex- 1-yl, trans-4- (N -ethyloxycarbonyl-N-methyl-amino) -cyclohex-1-yl, cis-4-phthalimido-cyclohex-i-yl and trans-4-Pht halimido-cyclohex-1-yl group,

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

optionally in the form of their tautomers, their racemates, their enantiomers, their diastereomers and their mixtures, and optionally their pharmacologically acceptable acid addition salts, solvates and hydrates, preferably their tautomers, their racemates, their enantiomers, their diastereomers and their mixtures, and optionally their pharmacologically acceptable acid addition salts.

The compounds of the 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 and R ^{d are} as defined above, with a compound of the general formula

in the

R ^c is defined as mentioned above and Z ^{1 represents} a leaving group such as a halogen atom, for example a chlorine or bromine atom, a sulphonyloxy group such as a methanesulfonyloxy or p-toluenesulfonyloxy group 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 in the range of 20 ⁰ C to 160 ⁰ C, preferably at temperatures in the range of 80 ° C to 140 ⁰ C. With a compound of general formula (III) in which Z ^{1 represents} a hydroxy group, the reaction in the presence of a dehydrating agent, preferably in Presence of a phosphine and a Azodicarbonsäurederivates such as triphenylphosphine / Azodicarbonsäurediethylester, conveniently in a solvent such as methylene chloride, acetonitrile, tetrahydrofuran, dioxane, toluene or Ethylenglycoldiethylether at temperatures in the range of -50 to 150 ° C, but preferably at temperatures in the range of -20 to 80 ° C, performed.

b) Reaction of a compound of the general formula (IV)

in which R ^c and R ^{d 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 compound of the general formula (V),

in which R ^c and R are defined as mentioned above and Z represents a halogen atom, such as a chlorine or bromine atom,

and subsequent reaction with a compound of general formula (VI)

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

in which R ^a and R ^b 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 in the range of 20 ⁰ C to 160 ⁰ C, preferably carried out from 40 ° C to 120 ⁰ C. Preferably, however, the reaction is carried out with thionyl chloride and catalytic amounts of dimethylformamide at the boiling temperature of the reaction mixture. Also preferred is the Reaction with phosphorus oxychloride in the presence of triethylamine with acetonitrile as solvent at the boiling point 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 in the range of 20 ⁰ C and 160 ⁰ C, preferably from 60 ° C to 120 ⁰ C. Preferably, however, the reaction is carried out in isopropanol at the boiling point of the reaction mixture. A further preferred variant consists of further reacting the solution of general formula (V) obtained after reaction with phosphorus oxychloride in the presence of triethylamine with acetonitrile as solvent with a solution of the compound of general formula (VI), preferably at a temperature between 20-80 ° C.

c) for the preparation of compounds of the general formula (I) in which R ^{c is} a 1-methoxycarbonyl-piperidin-4-yl, 1-ethyloxycarbonyl-piperidin-4-yl, 1-trifluoroacetyl-piperidin-4-yl , cis -4- (methoxycarbonylamino) -cyclohex-1-yl, trans-4-

(Methoxycarbonylamino) -cyclohex-i -yl, cis-4- (ethyloxycarbonylamino) -cyclohex-1-yl, trans-4- (ethyloxycarbonylamino) -cyclohex-1-yl, cis-4- (trifluoroacetylamino) cyclohex 1 -yl, trans-4- (trifluoroacetylamino) -cyclohex-1-yl, cis-4- (N-

Methoxycarbonyl-N-methyl-amino) -cyclohex-1-yl, trans-4- (N-methoxycarbonyl-N-methyl-amino) -cyclohex-1-yl, cis-4- (N-ethyloxycarbonyl-N- methyl-amino) -cyclohex-1-yl, trans-4- (N -ethyloxycarbonyl-N-methyl-amino) -cyclohex-1-yl, cis-4- (N-trifluoroacetyl-N-methyl-amino) -cyclohex-1-yl, trans-4- (N-trifluoroacetyl-N-methyl-amino) -cyclohex-1-yl group, reaction of a compound of general formula (VII)

in which R ^a , R ^b and R ^d are defined as mentioned above, and R ^{c is} a piperidin-4-yl, cis-4-amino-cyclohex-1-yl, trans-4-amino-cyclohex-1 - represents yl, cis-4- (methylamino) -cyclohex-1-yl or trans-4- (methylamino) -cyclohex-1-yl group,

with a corresponding acylating agent such as methyl chloroformate, ethyl chloroformate, pyrocarbonic acid dimethyl ester, Pyrokohlensäure- diethyl ester, trifluoroacetic anhydride or methyl trifluoroacetate.

The reaction is conveniently carried out in a solvent such as methylene chloride, acetonitrile, toluene, tetrahydrofuran, dioxane, dimethylformamide, dimethyl sulfoxide or N-methylpyrrolidinone, preferably in tetrahydrofuran or dioxane, optionally in the presence of a base such as potassium carbonate, sodium hydroxide or N-ethyl-diisopropylamine, at temperatures in the range from -20 ⁰ C to 80 ⁰ C, preferably from 0 ⁰ C to 40 ⁰ C. With methyl trifluoroacetate, the reaction can also be carried out in methanol.

d) For the preparation of compounds of the general formula (I) in which R ^{c is} a cis-4-phthalimido-cyclohex-i -yl or trans-4-phthalimido-cyclohex-1-yl group, reaction of a compound of general formula (VIII)

^RR

in which R ^a , R ^b and R ^d are defined as mentioned above, and R ^{c represents} a cis-4-aminocyclohex-1-yl or trans-4-amino-cyclohex-i-yl group,

with phthalic anhydride or another reactive derivative of phthalic acid. The reaction is conveniently carried out in a solvent such as acetic acid, 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, in a temperature range of 60 ⁰ C to 160 ⁰ C, preferably from 80 ° C to 120 ⁰ C.

Preferably, however, the reaction is carried out in acetic acid at temperatures between 80 ° C to 120 ° C.

Compounds of the general formula (I) in which R ^a , R ^b , R ^c and R ^d are defined as mentioned above, are also suitable as starting compounds for the preparation of corresponding quinazoline derivatives of the general formula (VII)

wherein R ^a , R ^b , R ^c and R ^{d are} as defined above. such

Compounds are described in WO 03/082290. The cleavage of the acyl groups in the radical R ^c takes place here under acidic or alkaline conditions, in the case of the phthalimido group, preferably with hydrazine, methylamine or ethanolamine.

The obtained compounds of the general formula (I) can be separated into their diastereomers. Thus, for example, cis / trans mixtures can be separated into their cis and trans isomers, for example by chromatography.

Furthermore, the compounds of the formula (I) obtained can be converted into their salts, in particular for the pharmaceutical application, into their physiologically tolerated salts with inorganic or organic acids. As acids for this example, hydrochloric acid, Hydrobromic acid, sulfuric acid, methanesulfonic acid, phosphoric acid, fumaric acid, succinic acid, lactic acid, citric acid, tartaric acid or maleic acid into consideration.

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 processes known from the literature (see Examples I to X), if appropriate with additional introduction of protective radicals.

The compounds of the general formula (I) according to the invention and their physiologically tolerable salts have valuable pharmacological properties, in particular an inhibitory effect on the signal transduction mediated by the epidermal growth factor receptor (EGF-R), which is inhibited, for example, by inhibition of ligand binding 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 are 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 protein 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 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 the bio-pEY was linear in terms of 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 performed at room temperature for a period of 30 minutes and terminated by addition of 50 μl of a stop solution (250 mM EDTA in 20 mM HEPES pH 7.4). 100 μl was 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-PTyr: HRP from Transduction Laboratories, 250 ng / ml) was incubated for 60 minutes. Thereafter, the microtiter plate was washed three times with 200 ul of washing 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 OD45o _πm with an ELISA reader. All data points were determined as triplicates.

The data were fit by means of an iterative calculation using a sigmoid curve analysis program (Graph Päd Prism Version 3.0) with variable hill slope. All released iteration data had one

Correlation coefficients of above 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 drug concentration was derived, which inhibits the activity of the EGF receptor kinase to 50% (IC50). The compounds according to the invention have IC 50 values of less than 100 μM.

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, for example, benign or malignant tumors, in particular Tumors of epithelial and neuroepithelial origin, metastasis and abnormal proliferation of vascular endothelial cells (neoangiogenesis).

The compounds of the 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, e.g. in inflammatory diseases

Respiratory tracts 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 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. The compounds are also contemplated for the treatment of CNS and spinal cord injuries.

Preferred areas of application include 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 secretolytically (e.g., ambroxol, N-acetylcysteine), broncholytic (e.g., tiotropium or ipratropium or fenoterol, salmeterol, salbutamol) and / or anti-inflammatory (e.g., theophylline or

Glucocorticoids) are 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 common pharmaceutical preparations such as tablets, dragees, capsules, powders, suspensions, solutions, sprays or suppositories incorporated.

The compounds of the general formula (I) according to the invention are also suitable for the preparation of derivatives, as described, for example, in WO 03/082290. For example, the compound of Example 1 can be reacted with sodium hydroxide solution or potassium hydroxide solution to give 4 - [(3-chloro-4-fluorophenyl) amino] -6- (piperidin-4-yloxy) -7-methoxyquinazoline (see Process Example A ).

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

Preparation of the starting compounds:

Example I

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 ⁰ C. The mixture is stirred for 15 hours at room temperature and then mixed with 2000 ml of water. The suspension is cooled to 0 ⁰ C, the precipitate is filtered off with suction, washed with 400 ml of water and 400 ml tert-butyl methyl ether and dried at 50 ⁰ C. The solid is dissolved in 4000 ml of methylene chloride, filtered and concentrated. The residue is suspended in tert-butyl methyl ether, suction filtered and dried at 50 ⁰ C. Yield: 203 g (86% of theory)

Rf value: 0.80 (silica gel, methylene chloride / ethanol = 9: 1) Mass spectrum (ESI ⁺ ): m / z = 325 [M + H] ⁺

Analogously to Example I can be obtained:

(1) 3-Benzyl-3,4-dihydro-4-oxo-6-acetyloxy-7-ethyloxy-quinazoline

(2) 3-Benzyl-3,4-dihydro-4-oxo-6-acetyloxy-quinazoline

(3) 3-Benzyl-3,4-dihydro-4-oxo-6-acetyloxy-7- (2-methoxyethyloxy) quinazoline

Example Il

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

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 ⁰ C for 1 hour. After addition of 172 ml of acetic acid and 2000 ml of water, the mixture is stirred for 20 hours at room temperature. The precipitate is filtered off with suction, washed with water and acetone and dried at 60 ⁰ C. Yield: 172.2 g (98% of theory) Rf value: 0.25 (silica gel, methylene chloride / ethanol = 19: 1) Mass spectrum (ESI ⁺ ): m / z = 283 [M + H] ⁺

Analogously to Example II can be obtained:

(1) 3-Benzyl-3,4-dihydro-4-oxo-6-hydroxy-7-ethyloxy-quinazoline

(2) 3-Benzyl-3,4-dihydro-4-oxo-6-hydroxyquinazoline

(3) 3-Benzyl-3,4-dihydro-4-oxo-6-hydroxy-7- (2-methoxyethyloxy) quinazoline

example

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

1 g of 2-amino-5-hydroxy-4-methoxy-benzoic acid (prepared by reacting 2-nitro-4,5-dimethoxy-benzoic acid methyl ester with potassium hydroxide solution to give 2-nitro-5-hydroxy-4-methoxybenzoic acid Potassium salt and subsequent catalytic hydrogenation in the presence of palladium on activated carbon) and 20 ml of triethyl orthoformate are heated at 100 ^° C. for 2.5 hours. After cooling to room temperature, the precipitate is filtered off with suction and washed with diethyl ether. Yield: 0.97 g (93% of theory)

Rf value: 0.86 (silica gel, methylene chloride / methanol / acetic acid = 90: 10: 1) Mass spectrum (ESI ⁺ ): m / z = 194 [M + H] ⁺

Analogously to Example III can be obtained:

(1) 6-hydroxy-7-ethyloxybenzo [d] [1,3] oxazin-4-one

(2) 6-hydroxybenzo [d] [1,3] oxazin-4-one

(3) 6-Hydroxy-7- (2-methoxyethyloxy) benzo [d] [1,3] oxazin-4-one

Example IV

cis-1- (methanesulfonyloxy) -4- (N-methanesulfonyl-N-methyl-amino) -cyclohexane

Prepared by reaction of cis-i-hydroxy ^ -methylamino-cyclohexane with methanesulfonyl chloride in tetrahydrofuran in the presence of triethylamine. Mass spectrum (ESI ⁺ ): m / z = 286 [M + H] ⁺

Analogously to Example IV can be obtained:

Example V

3-Benzyl-3,4-dihydro-4-oxo-6- (1-ethyloxycarbonyl-piperidin-4-yloxy) -7-methoxy-quinazoline

Prepared by reaction of 56.46 g of 3-benzyl-3,4-dihydro-4-oxo-6-hydroxy-7-methoxy-quinazoline and 62.82 g of i-ethyloxycarbonyl-4-methanesulfonyloxy-piperidine

Presence of 41, 46 g of potassium carbonate in 500 ml of N-methyl-pyrrolidinone at 100-

120 ⁰ C.

Mass Spectrum (ESI ⁺ ): m / z = 438 [M + H] ⁺

Analogously to Example V can be obtained:

Example VI

3,4-dihydro-4-oxo-6- (1-ethyloxycarbonyl-piperidin-4-yloxy) -7-methoxy-quinazoline

A mixture of 58.5 g of 3-benzyl-3,4-dihydro-4-oxo-6- (1-ethyloxycarbonyl-piperidin-4-yloxy) -7-methoxy-quinazoline and 600 ml of glacial acetic acid in the presence of 6 g of palladium Activated carbon (10% Pd) hydrogenated for 3 hours at 80 ⁰ C and a hydrogen pressure of 50 psi. The catalyst is filtered off, the filtrate is concentrated to 100 ml and treated with 600 ml of tert-butyl methyl ether. The precipitate is filtered off with suction and dried. Yield: 46 g (99% of theory) Rf value: 0.26 (silica gel, methylene chloride / ethanol = 19: 1) Mass spectrum (ESI ⁺ ): m / z = 348 [M + H] ⁺ Analogously to Example VI can be obtained:

Example VII

4-chloro-6- (1-trifluoroacetyl-piperidin-4-yloxy) quinazoline hydrochloride

5.3 g of 3,4-dihydro-4-oxo-6- (1-trifluoroacetyl-piperidin-4-yloxy) quinazoline in 25 ml of acetonitrile are mixed with 25 ml of thionyl chloride and a few drops of dimethylformamide. The mixture is refluxed for 2 hours, concentrated in vacuo, treated with toluene and concentrated again. By alkaline workup and the free base can be obtained. R _f value: 0.92 (silica gel, ethyl acetate)

Analogously to Example VII can be obtained:

By alkaline workup, the free bases of the above-mentioned compounds can also be obtained.

Example VIII

cis-1-hydroxy-4- (N-tert-butyloxycarbonyl-N-methyl-amino) -cyclohexane

Prepared by reaction of cis-i-hydroxy-4-methylamino-cyclohexane with pyrocarbonic di-tert-butyl ester in ethyl acetate at room temperature. Mass spectrum (ESI ⁺ ): m / z = 230 [M + H] ⁺

Analogously to Example VIII can be obtained:

Example IX

3-Benzyl-3,4-dihydro-4-oxo-6- (cis-4-methylamino-cyclohexan-1-yloxy) -7-methoxy-quinazoline

Obtainable by treatment of 3-benzyl-3,4-dihydro-4-oxo-6- {cis-4- [N- (tert-butyloxycarbonyl) -N-methyl-amino] -cyclohexan-1-yloxy} -7- methoxy quinazoline with hydrochloric acid or trifluoroacetic acid at room temperature. Upon cleavage of the tert-butyloxycarbonyl radical with ethanolic or isopropanolic hydrochloric acid, the hydrochloride is isolated. Mass spectrum (ESI ⁺ ): m / z = 394 [M + H] ⁺

Analogously to Example IX can be obtained:

Example X

3-Benzyl-3,4-dihydro-4-oxo-6- (cis-4- {N - [(morpholin-4-yl) carbonyl] -N-methylamino} -cyclohexan-1-ylxy) -7-methoxy -quinazoline

Obtainable by reaction of 3-benzyl-3,4-dihydro-4-oxo-6- (cis-4-methylamino-cyclohexan-1-yloxy) -7-methoxyquinazoline in acetonitrile with (morpholin-4-yl) - carbonyl chloride in the presence of N-ethyl-diisopropylamine. Mass spectrum (ESI ⁺ ): m / z = 507 [M + H] ⁺

Analogously to Example X can be obtained:

Preparation of the end compounds:

example 1

4 - [(3-Chloro-4-fluoro-phenyl) -amino] -6- (1-ethyloxycarbonyl-piperidin-4-yloxy) -7-methoxy-quinazoline

24 g of 3,4-dihydro-4-oxo-6- (1-ethyloxycarbonyl-piperidin-4-yloxy) -7-methoxy-quinazoline, 75 ml of thionyl chloride and 0.1 ml of dimethylformamide are refluxed for 2 hours. The volatile components of the reaction mixture are stripped off on a rotary evaporator and the residue is combined with 350 ml of isopropanol and 23.29 g of 3-chloro-4-fluoroaniline. The mixture is submerged for 2.5 hours Reflux heated. Thereafter, 350 ml of water are added and cooled. The solid is filtered off with suction and washed with water and isopropanol. The solid is suspended in 400 ml of methanol, made alkaline with concentrated aqueous ammonia. The mixture is mixed with ice water and the solid filtered off with suction and dried at 70 ⁰ C. Yield: 29 g (88% of theory) Rf value: 0.36 (silica gel, methylene chloride / ethanol = 19: 1) Mass spectrum (ESI ⁺ ): m / z = 475, 477 [M + H] ⁺

Analogously to Example 1, the following compound is obtained:

(1) 4 - [(3-Ethynylphenyl) amino] -6- (1-ethyloxycarbonyl-piperidin-4-yloxy) -7-methoxy-quinazoline hydrochloride

Mass spectrum (ESI ⁺ ): m / z = 447 [M + H] ⁺

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

Example 2

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

Core weight: 230 mg

Stamp: 9 mm, curved

The coated dragee cores are coated with a film consisting essentially of hydroxypropylmethylcellulose. The finished film dragees are shined with beeswax.

Dragee weight: 245 mg.

Example 3

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

Production process: Active ingredient, lactose and starch are mixed and uniformly moistened with an aqueous solution of polyvinylpyrrolidone. After sieving the wet mass (2.0 mm mesh size) and drying in a rack oven at 50 ⁰ C is re-screened (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 4

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 silica is moistened with a 20% strength aqueous solution of polyvinylpyrrolidone and beaten through a sieve with a mesh size of 1.5 mm.

The granules dried at 45 ° C are again rubbed through the same sieve and mixed with the stated amount of magnesium stearate. From the mixture tablets are pressed.

Tablet weight: 300 mg

Stamp: 10 mm, flat

Example 5

Hard gelatine capsules with 150 mg active substance

Composition: 1 capsule contains:

Active ingredient 150.0 mg corn starch drink. about 180.0 mg

Milk sugar powder approx. 87.0 mg

Magnesium stearate 3.0 mg approx. 420.0 mg

production:

The active ingredient is mixed with the excipients, passed through a sieve 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 gelatine capsule size 1. Example 6

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 7

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

Glycerol 5.00 g

Sorbitol solution 70% 20.00 g Aroma 0.30 g

Water dest.ad 100.00 ml production:

Distilled water is heated to 70 ⁰ C. Herein, p-hydroxybenzoic acid methyl ester and propyl ester and glycerol and carboxymethyl cellulose 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 8

Ampoules with 10 mg active substance

Composition:

Active ingredient 10.0 mg

0.01 n hydrochloric acid s.g.

Agua bidest ad 2.0 ml

production:

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

Example 9

Ampoules with 50 mg active substance

Composition:

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

Agua 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 10

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 11

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 g.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

4 - [(3-chloro-4-fluoro-phenyl) amino] -6- (piperidin-4-yloxy) -7-methoxy-quinazoline

14.3 g of 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- (1-ethyloxycarbonyl-piperidin-4-yloxy) -7-methoxy-quinazoline and 15 g of potassium hydroxide are placed in 250 ml of isopropanol for 48 hours Reflux heated. The reaction mixture is concentrated in vacuo to about 50 ml and then treated with ice-water. The solid is filtered off with suction and recrystallized from ethyl acetate and tert-butyl methyl ether. Yield: 9.6 g (79% of theory)

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

Analogously to process example A, the following can be obtained:

Method Example B

4 - [(3-Chloro-4-fluoro-phenyl) -amino] -6- (1-methanesulfonyl-piperidin-4-yloxy) -7-ethoxy-quinazoline

The title compound can be prepared from 4-chloro-6- (1-methylsulfonyl-piperidin-4-yloxy) -7-ethoxy-quinazoline hydrochloride (Example VII (25)) by reaction with 3-chloro-4-fluoroaniline in isopropanol at reflux temperature. The work-up is carried out as described in Example 1.

Analogously to process example B, it is possible to obtain:

Process Example C

4 - [(3-Chloro-4-fluoro-phenyl) -amino] -6- (cis-4-amino-cyclohexan-1-yloxy) -7-methoxy-quinazoline The title compound can be prepared from 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- (cis-4-phthalimidocyclohexan-1-yloxy) -7-methoxy-quinazoline (Example 1 (17)) Treatment with methylamine or ethanolamine can be obtained.

Analogously to process example C, it is possible to obtain:

Claims

claims

1. Bicyclic Heterocycles of the General Formula (I)

wherein R ^{a is} a hydrogen atom,

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

R ^{c is} a radical selected from the group consisting of 1-methoxycarbonyl-piperidin-4-yl, 1-ethyloxycarbonyl-piperidin-4-yl, 1-trifluoroacetyl-piperidin-4-yl, cis-4- (methoxycarbonylamino) cyclohex-1-yl, trans-4-

(Methoxycarbonylamino) -cyclohex-i-yl, cis-4- (ethyloxycarbonylamino) -cyclohex-1-yl, trans-4- (ethyloxycarbonylamino) -cyclohex-1-yl, cis-4- (trifluoroacetylamino) -cyclohex -1-yl, trans-4- (trifluoroacetylamino) -cyclohex-1-yl, cis-4- (N-methoxycarbonyl-N-methyl-amino) -cyclohex-1-yl, trans-4- (N - methoxycarbonyl-N-methyl-amino) -cyclohex-1-yl, cis-4- (N-ethyloxycarbonyl-

N-methyl-amino) -cyclohex-1-yl, trans-4- (N -ethyloxycarbonyl-N-methyl-amino) -cyclohex-1-yl, cis-4- (N-trifluoroacetyl-N-methyl) amino) -cyclohex-1-yl, trans-4- (N-trifluoroacetyl-N-methyl-amino) -cyclohex-1-yl, cis-4-phthalimido-cyclohex-1-yl and trans-4- phthalimido-cyclohex-1-yl group,

R ^{d is} a hydrogen atom, a methoxy, ethyloxy or 2-methoxyethyloxy group, optionally in the form of their tautomers, their racemates, their enantiomers, their diastereomers and their mixtures, and optionally their pharmacologically acceptable acid addition salts, solvates and hydrates.

2. bicyclic heterocycles of the general formula (I) according to claim 1, wherein

R ^a , R ^b and R ^d may be as defined, and

R ^{c is} a radical selected from the group consisting of 1-methoxycarbonyl-piperidin-4-yl, 1-ethyloxycarbonyl-piperidin-4-yl, cis-4- (methoxycarbonylamino) -cyclohex-i-yl, trans-4 - (methoxycarbonylamino) - cyclohex-1-yl, cis-4- (ethyloxycarbonylamino) -cyclohex-1-yl, trans-4- (ethyloxycarbonylamino) -cyclohex-i-yl, cis-4- (N-methoxycarbonyl -N-methyl-amino) -cyclohex-1-yl, trans-4- (N-methoxycarbonyl-N-methyl-amino) -cyclohex-

1 -yl, cis -4- (N -ethyloxycarbonyl-N-methyl-amino) -cyclohex-1-yl, trans-4- (N -ethyloxycarbonyl-N-methyl-amino-1-cyclohex-i-yl, cis-4-phthalimido-cyclohex-1-yl and trans-4-phthalimido-cyclohex-i-yl group.

3. Physiologically acceptable salts of the compounds according to any one of claims 1 or 2 with inorganic or organic acids.

4. A pharmaceutical composition containing a compound according to any one of claims 1 to 2 or a physiologically acceptable salt according to claim

3 next to optionally one or more inert carriers and / or diluents.

5. Use of a compound according to any one of claims 1 to 3 for the manufacture of a medicament for the treatment of benign or malignant tumors, for the prevention and treatment of respiratory and lung diseases and for the treatment of diseases of the gastrointestinal tract and the bile duct and bladder is suitable.

6. A process for the preparation of the compounds of general formula I according to claims 1 or 2, characterized in that

a) a compound of general formula (II)

wherein,

R ^a , R and R are as defined in claims 1 to 2, with a compound of the general formula

Z ¹ - R ^c

wherein R 5C ^{c is} as defined in claims 1 to 2, and

Z ^{1 represents} a leaving group or hydroxy group, is reacted, or

b) a compound of the general formula (IV)

wherein R ^c and R are as defined in the claims, with a halogenating agent to an intermediate of the general

Formula (V),

wherein R ^c and R ^{d are} as defined in the claims and Z ^{2 is} a halogen atom,

and subsequently with a compound of general formula (VI)

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

wherein R ^a and R ^{b are} as defined in the claims.

7. A process for the preparation of the compounds of general formula (I) according to claims 1 or 2, characterized in that

R ^a , R ^b and R ^{d are} as defined in the claims, and

R ^{c is} a radical selected from the group consisting of a 1-methoxycarbonyl-piperidin-4-yl, 1-ethyloxycarbonyl-piperidin-4-yl, 1-trifluoroacetyl-piperidin-4-yl, cis-4- (methoxycarbonylamino ) -cyclohex-1-yl, trans-4- (methoxycarbonylamino) -cyclohex-i-yl, cis-4- (ethyloxycarbonylamino) -cyclohex-1-yl, trans-4- (ethyloxycarbonylamino) -cyclohex-1 -yl, cis-4- (trifluoroacetylamino) -cyclohex-i-yl, trans-4- (trifluoroacetylamino) -cyclohex-1-yl, cis-4- (N-methoxycarbonyl-N-methyl-amino) - cyclohex-1-yl, trans-4- (N-methoxycarbonyl-N-methyl-amino) -cyclohex-1-yl, cis-4- (N -ethyloxycarbonyl-N-methyl-amino) -cyclohex-1 yl, trans-4- (N-ethyloxycarbonyl-N-methyl) amino) -cyclohex-1-yl, cis-4- (N-trifluoroacetyl-N-methyl-amino) -cyclohex-1-yl and trans-4- (N-trifluoroacetyl-N-methyl-amino) -cyclohex -1 -yl group, means

a compound of general formula (VII)

wherein,

R ^a , R ^b and R ^{d are} as defined in the claims, and

R ^{c is} a radical selected from the group consisting of piperidin-4-yl, cis-4-amino-cyclohex-1-yl, trans-4-amino-cyclohex-1-yl, cis-4- (methylamino) cyclohex-1-yl and trans-4- (methylamino) cyclohex-1-yl,

is reacted with a corresponding acylating agent.

8. A process for the preparation of the compounds of general formula (I) according to claims 1 or 2, characterized in that

R> a ^a , π R> b and R are as defined in claims 1 or 2, and

R ^{c represents} a cis-4-phthalimido-cyclohex-1-yl or trans-4-phthalimido-cyclohex-1-yl group, and

a compound of the general formula (VIII)

wherein,

R ^a , R ^b and R ^{d are} as defined in claims 1 or 2, and R ^{c represents} a cis-4-amino-cyclohex-1-yl or trans-4-amino-cyclohex-1-yl group,

is reacted with phthalic anhydride or another reactive derivative of phthalic acid.

9. A process for the preparation of the compounds of general formula (VII) according to claim 7, characterized in that

a compound of general formula (I) according to claims 1 or 2, to quinazoline derivatives of general formula (VII) is reacted.