Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
  • C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
  • C07D239/72—Quinazolines; Hydrogenated quinazolines
  • C07D239/86—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in position 4
  • C07D239/94—Nitrogen atoms
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
  • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
  • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P11/00—Drugs for disorders of the respiratory system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
  • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
  • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
  • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings

Definitions

• Bicyclic heterocycles medicaments containing these compounds, their use and processes for their preparation
• the present invention relates to bicyclic heterocycles of the general formula
• R a represents a 3-chloro-2-fluoro-phenyl, 3-chloro-4-fluoro-phenyl or 3-ethynylphenyl group,
• R b is a tetrahydrofuran-3-yl, tetrahydropyran-3-yl or tetrahydropyran-4-yl group, and
• R c is a tetrahydrofuran-3-yl, tetrahydropyran-3-yl or tetrahydropyran-4-yl 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:
• R a and R c are defined as mentioned above, with a compound of the general formula
• R b 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 sulfonyloxy group such as a methanesulfonyloxy or p-toluenesulfonyloxy or a hydroxy group.
• 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.
• reaction is conveniently carried out in a solvent such as ethanol, isopropanol, acetonitrile, toluene, tetrahydrofuran, dioxane, dimethylformamide, dimethyl sulfoxide or N-methylpyrrolidinone, if appropriate in the presence of a base as potassium carbonate or N-ethyl-diisopropylamine, at temperatures ranging from 20 0 C to 160 0 C, preferably at temperatures ranging from 40 ° C to 120 0 C.
• a solvent such as ethanol, isopropanol, acetonitrile, toluene, tetrahydrofuran, dioxane, dimethylformamide, dimethyl sulfoxide or N-methylpyrrolidinone
• the reaction is carried out in the presence of a dehydrating agent, preferably in the presence of a phosphine and an azodicarboxylic acid derivative such as triphenylphosphine / Azodicarbonklarediethylester, conveniently in a solvent such as methylene chloride, acetonitrile, tetrahydrofuran, dioxane, toluene or Ethylenglycoldiethylether at temperatures in the range of -50 to 150 0 C, but preferably at temperatures in the range of 0 to 80 0 C performed.
• a dehydrating agent preferably in the presence of a phosphine and an azodicarboxylic acid derivative such as triphenylphosphine / Azodicarbonklathylester
• a solvent such as methylene chloride, acetonitrile, tetrahydrofuran, dioxane, toluene or Ethylenglycoldieth
• R a and R b are as defined above, with a compound of the general formula
• R c and Z 1 are defined as mentioned above.
• reaction is conveniently carried out in a solvent such as ethanol, isopropanol, acetonitrile, toluene, tetrahydrofuran, dioxane, dimethylformamide, dimethyl sulfoxide or N-methylpyrrolidinone, if appropriate in the presence of a base as potassium carbonate or N-ethyl-diisopropylamine, at temperatures ranging from 20 0 C to 160 0 C, preferably at temperatures ranging from 40 ° C to 120 0 C.
• a solvent such as ethanol, isopropanol, acetonitrile, toluene, tetrahydrofuran, dioxane, dimethylformamide, dimethyl sulfoxide or N-methylpyrrolidinone
• the reaction is carried out in the presence of a dehydrating agent, preferably in the presence of a phosphine and an azodicarboxylic acid derivative such as triphenylphosphine / Azodicarbonklarediethylester, conveniently in a solvent such as methylene chloride, acetonitrile, tetrahydrofuran, dioxane, toluene or Ethylenglycoldiethylether at temperatures in the range of -50 to 150 0 C, but preferably at temperatures in the range of 0 to 80 0 C performed.
• a dehydrating agent preferably in the presence of a phosphine and an azodicarboxylic acid derivative such as triphenylphosphine / Azodicarbonklathylester
• a solvent such as methylene chloride, acetonitrile, tetrahydrofuran, dioxane, toluene or Ethylenglycoldieth
• R a is as defined above, with a compound of the general formula
• Z 1 is defined as mentioned above and R d represents a tetrahydrofuran-3-yl, tetrahydropyran-3-yl or tetrahydropyran-4-yl group.
• reaction is conveniently carried out in a solvent such as ethanol, isopropanol, acetonitrile, toluene, tetrahydrofuran, dioxane, dimethylformamide, dimethyl sulfoxide or N-methylpyrrolidinone, if appropriate in the presence of a base as potassium carbonate or N-ethyl-diisopropylamine, at temperatures ranging from 20 0 C to 160 0 C, preferably at temperatures ranging from 40 ° C to 120 0 C.
• a solvent such as ethanol, isopropanol, acetonitrile, toluene, tetrahydrofuran, dioxane, dimethylformamide, dimethyl sulfoxide or N-methylpyrrolidinone
• the reaction is carried out in the presence of a dehydrating agent, preferably in the presence of a phosphine and an azodicarboxylic acid derivative such as triphenylphosphine / Azodicarbonklarediethylester, conveniently in a solvent such as methylene chloride, acetonitrile, tetrahydrofuran, dioxane, toluene or Ethylenglycoldiethylether at temperatures in the range of -50 to 150 0 C, but preferably at temperatures in the range of 0 to 80 0 C performed.
• a dehydrating agent preferably in the presence of a phosphine and an azodicarboxylic acid derivative such as triphenylphosphine / Azodicarbonklathylester
• a solvent such as methylene chloride, acetonitrile, tetrahydrofuran, dioxane, toluene or Ethylenglycoldieth
• 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 (IX),
• R b and R c 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 (X)
• 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.
• the reaction is carried out with thionyl chloride and catalytic amounts of dimethylformamide at the boiling temperature of the reaction mixture, wherein the reaction can also be carried out with the addition of acetonitrile as the solvent.
• reaction of the compound of general formula (IX) with a compound of general formula (X) 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 ° C and 160 ° C, preferably from 60 0 C to 120 ° C. Preferably, however, the reaction is carried out in isopropanol at the boiling temperature of the reaction mixture.
• a solvent such as ethanol, isopropanol, acetonitrile, dioxane or dimethylformamide
• a base such as potassium carbonate or N-ethyl-diisopropylamine
• the obtained compounds of the general formula (I) can be separated into their diastereomers, for example by chromatographic methods.
• 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.
• 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.
• 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.
• EGF-R epidermal growth factor receptor
• 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).
• 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 ⁇ l reaction solution contained 10 ⁇ l of the inhibitor in 50% DMSO, 20 ⁇ l of the substrate solution (200 mM HEPES pH 7.4, 50 mM magnesium acetate, 2.5 mg / ml poly (EY), 5 ⁇ g / ml bio-pEY) and 20 ⁇ l enzyme preparation.
• the enzyme reaction was made by adding 50 ⁇ l of a 100 ⁇ M ATP solution started 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 ⁇ l of a stop solution (250 mM EDTA in 20 mM HEPES pH 7.4). 100 ⁇ l was placed on a streptavidin-coated microtiter plate and incubated for 60 minutes at room temperature. Thereafter, the plate was washed with 200 ⁇ l of a washing solution (50 mM Tris, 0.05% Tween 20). After addition of 100 ⁇ l of an HRPO-labeled anti-PY antibody (PY20H anti-PTyr: HRP from Transduction Laboratories, 250 ng / ml) was incubated for 60 minutes.
• a stop solution 250 mM EDTA in 20 mM HEPES pH 7.4
• 100 ⁇ l was placed on a streptavidin-coated microtiter plate and incubated for 60 minutes at room temperature. Thereafter, the plate was washed with 200 ⁇ l of a washing solution (
• microtiter plate was washed three times with 200 ul of washing solution.
• 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 iterative data had a correlation coefficient 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 by 50% (IC50) , The compounds according to the invention have IC 50 values of less than 100 ⁇ M.
• 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.
• pathophysiological processes which are caused by hyperfunction of tyrosine kinases.
• tyrosine kinases 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 nasal polyps
• cystic fibrosis ⁇ 1-antitrypsin deficiency
• hyperreactive airways 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,
• 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.
• COPD chronic bronchitis
• Particularly preferred indications are inflammatory diseases of the respiratory tract or the lungs, such as chronic bronchitis (COPD) or asthma or nasal polyps.
• the compounds of general formula (I) and their physiologically acceptable salts may be used for the treatment of other diseases caused by aberrant function of tyrosine kinases, e.g. epidermal hyperproliferation (psoriasis), benign prostatic hyperplasia (BPH), inflammatory processes, diseases of the immune system, hyperproliferation of hematopoietic cells, etc ..
• tyrosine kinases e.g. epidermal hyperproliferation (psoriasis), benign prostatic hyperplasia (BPH), inflammatory processes, diseases of the immune system, hyperproliferation of hematopoietic cells, etc .
• 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.
• 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.
• these compounds alone or in combination with other respiratory therapies, such as secretolytically (e.g., ambroxol, N-acetylcysteine), broncholytically (e.g., tiotropium or ipratropium or fenoterol, salmeterol, salbutamol) and / or anti-inflammatory (e.g., theophylline or glucocorticoids) substances.
• secretolytically e.g., ambroxol, N-acetylcysteine
• broncholytically e.g., tiotropium or ipratropium or fenoterol, salmeterol, salbutamol
• anti-inflammatory e.g., theophylline or glucocorticoids
• 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.
• these are administered with one or more conventional inert carriers and / or diluents, e.g.
• lactose cane sugar, microcrystalline cellulose, magnesium stearate, polyvinylpyrrolidone, citric acid, tartaric acid, water, water / ethanol, water / glycerin, water / sorbitol, water / polyethylene glycol, propylene glycol, stearyl alcohol, carboxymethyl cellulose or fatty substances such as hard fat or their suitable mixtures in usual galenic preparations such as tablets, dragees, capsules, powders, suspensions, solutions, sprays or suppositories incorporated.
• composition 1 Drageekern contains: Active substance 75.0 mg
• the active substance is mixed with calcium phosphate, corn starch, polyvinylpyrrolidone, hydroxypropylmethylcellulose and half of the stated amount of magnesium stearate.
• 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.
• coated dragee cores are coated with a film consisting essentially of hydroxypropylmethylcellulose.
• the finished film dragees are shined with beeswax.
• Composition 1 tablet contains:
• Active ingredient, lactose and starch are mixed and uniformly moistened with an aqueous solution of polyvinylpyrrolidone. After screening of the moist mass (2.0 mm mesh size) and drying in a rack oven at 50 0 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.
• Composition 1 tablet contains:
• 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.
• Composition 1 capsule contains:
• 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.
• Composition 1 suppository contains:
• Polyethylene glycol 1500 550.0 mg
• the active ingredient is distributed homogeneously therein and the melt is poured into pre-cooled molds.
• Carboxymethylcellulose Na salt 0.10 g p-hydroxybenzoic acid methyl ester 0.05 g p-hydroxybenzoic acid propyl ester 0.01 g
• Distilled water is heated to 70 0 C.
• 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.
• 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.
• Active ingredient 50.0 mg 0.01 n hydrochloric acid s.g.
• 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.
• 1 capsule contains:
• 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).
• 1 hub contains:
• 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).

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• 2007
  • 2007-02-20 WO PCT/EP2007/051589 patent/WO2007101782A1/de active Application Filing
  • 2007-02-20 JP JP2008557710A patent/JP2009529511A/ja active Pending
  • 2007-02-20 CA CA002643363A patent/CA2643363A1/en not_active Abandoned
  • 2007-02-20 US US12/281,190 patent/US20090306105A1/en not_active Abandoned
  • 2007-02-20 EP EP07704659A patent/EP1996561A1/de not_active Withdrawn

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