EP1315705A1 - Bicyclische heterocyclen, diese verbindungen enthaltende arzneimittel, deren verwendung und vefahren zu ihrer herstellung - Google Patents

Bicyclische heterocyclen, diese verbindungen enthaltende arzneimittel, deren verwendung und vefahren zu ihrer herstellung

Info

Publication number
EP1315705A1
EP1315705A1 EP01967285A EP01967285A EP1315705A1 EP 1315705 A1 EP1315705 A1 EP 1315705A1 EP 01967285 A EP01967285 A EP 01967285A EP 01967285 A EP01967285 A EP 01967285A EP 1315705 A1 EP1315705 A1 EP 1315705A1
Authority
EP
European Patent Office
Prior art keywords
amino
quinazoline
chloro
fluorophenyl
ethoxy
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
EP01967285A
Other languages
German (de)
English (en)
French (fr)
Inventor
Frank Himmelsbach
Elke Langkopf
Birgit Jung
Stefan Blech
Flavio Solca
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Boehringer Ingelheim Pharma GmbH and Co KG
Original Assignee
Boehringer Ingelheim Zentrale GmbH
CH Boehringer Sohn AG and Co KG
Boehringer Ingelheim Pharma GmbH and Co KG
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Boehringer Ingelheim Zentrale GmbH, CH Boehringer Sohn AG and Co KG, Boehringer Ingelheim Pharma GmbH and Co KG filed Critical Boehringer Ingelheim Zentrale GmbH
Publication of EP1315705A1 publication Critical patent/EP1315705A1/de
Ceased legal-status Critical Current

Links

Classifications

    • 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
    • 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
    • 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
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
    • 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
    • A61P11/08—Bronchodilators
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/16—Otologicals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/04—Antineoplastic agents specific for metastasis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/08—Antiallergic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings

Definitions

  • Bicyclic heterocycles pharmaceutical compositions containing these compounds, their use and process for their preparation
  • the present invention relates to bicyclic heterocycles of the general formula
  • R a is a benzyl or 1-phenylethyl group or a phenyl group substituted by the radicals R ⁇ and R 2 , where
  • R x represents a hydrogen, fluorine, chlorine or bromine atom, a methyl, trifluoromethyl, cyan or ethynyl group and R 2 represents a hydrogen or fluorine atom,
  • one of the radicals R b or R c is an R 3 - (CH 2 ) m -0 group and the other of the radicals R b or R c is a methoxy, cyclobutyloxy, cyclopenty-1oxy, Cyc1oprop 1met oxy-, Cyc1obuty1methoxy- , Cyc1openyl methoxy-, tetrahydrofuran-3-yloxy-, tetrahydropyran-3- yloxy, tetrahydropyran-4-yloxy, tetrahydrofuranylmethoxy or tetrahydropyranylmethoxy group, where
  • R 3 is an N- (2-oxo-tetrahydrofuran-4-yl) methylamino or N- (2-oxo-tetrahydrofuran-4-yl) ethylamino group,
  • R 4 represents a hydrogen atom or a C 1-4 alkyl group
  • n represents the number 2, 3 or 4,
  • R a is a benzyl or 1-phenylethyl group or a phenyl group substituted by the radicals R x and R 2 , where
  • R x represents a hydrogen, fluorine, chlorine or bromine atom, a methyl, trifluoromethyl, cyan or ethynyl group and R 2 represents a hydrogen or fluorine atom,
  • one of the radicals R b or R c is an R 3 ⁇ (CH 2 ) m -O group and the other of the radicals R b or R c is a methoxy, cyclobutyloxy, cyclopentyloxy, cyclopropylmethoxy, cyclobutylmethoxy, cyclopentyl ethoxy , Tetrahydrofuran-3-yloxy-,
  • R 3 is an N- (2-oxo-tetrahydrofuran-4-yl) methyl ino- or N- (2-oxo-tetrahydrofuran-4-yl) ethylamino group,
  • R 4 is a hydrogen atom or a C 1 . 4 represents alkyl group
  • n represents the number 2, 3 or 4,
  • R a represents a 1-phenylethyl group or a phenyl group substituted by the radicals R x and R 2 , where R is a fluorine, chlorine or bromine atom, a methyl or
  • R 2 represents a hydrogen or fluorine atom
  • one of the radicals R b or R c is an R 3 - (CH 2 ) m -0 group and the other of the radicals R b or R 0 is a methoxy, cyclobutyloxy, cyclopentyloxy, cyclopropylmethoxy, cyclobutylmethoxy, cyclopentylmethoxy -, Tetrahydrofuran-3-yloxy, tetrahydropyran-3-yloxy, tetrahydropyran-4-yloxy, tetrahydrofuranylmethoxy or tetrahydropyranylmethoxy group, where
  • R 3 is an N- (2-0xo-tetrahydrofuran-4-yl) methylamino group
  • R 4 represents a C 1 _ 4 alkyl group
  • R a represents a 1-phenylethyl group or a phenyl group substituted by the radicals R x and R 2 , where.
  • R a is a fluorine, chlorine or bromine atom
  • R 2 represents a hydrogen or fluorine atom
  • one of the radicals R b or R c is an R 3 - (CH 2 ) m -O group and the other of the radicals R b or R c is a methoxy, cyclobutyloxy, cyclopentyloxy, cyclopropylmethoxy, cyclobutylmethoxy, cyclo- pentylmethoxy, tetrahydrofuran-3-yloxy, tetrahydropyran-3-yloxy, tetrahydropyran-4-yloxy, tetrahydrofuranylmethoxy or tetrahydropyranylmethoxy group, where
  • R 3 is an N- (2-oxo-tetrahydrofuran-4-yl) methylamino group or a 2-oxo-morpholin-4-yl group substituted by one or two methyl groups and
  • n represents the number 2, 3 or 4,
  • R a is a 1-phenylethyl, 3-bromophenyl or 3-chloro-4-fluorophenyl group
  • R b is an R 3 - (CH 2 ) m -0 group in which
  • R 3 represents a 2-oxomorpholin-4-yl group substituted by one or two methyl groups and m represents the number 2 or 3,
  • R c is a methoxy, cyclobutyloxy, cyclopentoxy, cyclopropylmethoxy, tetrahydrofuran-3-yloxy or tetrahydrofuranylmethoxy group with the proviso that the compounds
  • R a is a 3-chloro-4-fluorophenyl group
  • R b is a cyclopentyloxy, cyclopropylmethoxy, cyclopentylmethoxy, tetrahydrofuran-3-yloxy or tetrahydrofuranylmethoxy group and
  • R c is an R 3 - (CH 2 ) m -0 group in which
  • R 3 is a 2-oxomorpholin-4-yl group substituted by one or two methyl groups and
  • the compounds of the general formula I can be prepared, for example, by the following processes: a) implementation of a compound of the general formula
  • R a is defined as mentioned at the outset, one of the radicals R b 'or R c ' is a methoxy, cyclobutyloxy,
  • R b 'or R c ' represents a Z x - (CH 2 ) ra -O group in which
  • Z x denotes a leaving group such as a halogen atom or a sulfonyloxy group such as a chlorine or bromine atom, a methanesulfonyloxy or p-toluenesulfonyloxy group,
  • R 3 is defined as mentioned at the beginning.
  • the reaction is optionally carried out in a solvent or mixture of solvents such as methylene chloride, acetonitrile, dirthylformamide, dimethyl sulfoxide, sulfolane, benzene, toluene, chlorobenzene, tetrahydrofuran, benzene / tetrahydrofuran or dioxane in the presence of a tertiary organic base such as triethylamine or N-ethyl -diisopropylamine, these organic bases also being used as can serve medium, or in the presence of an inorganic base such as sodium carbonate or potassium carbonate, conveniently at temperatures between -20 and 200 ° C, preferably at temperatures between 0 and 150 ° C.
  • solvent or mixture of solvents such as methylene chloride, acetonitrile, dirthylformamide, dimethyl sulfoxide, sulfolane, benzene, toluene, chlorobenzen
  • R a is as defined at the outset, one of the radicals R b “or R c " represents a methoxy, cyclobutyloxy, cyclopentyloxy, cyclopropylmethoxy, cyclobutylmethoxy or cyclopentylmethoxy group and the other of the radicals R b “or R c " represents an R 3 '- (CH 2 ) m -0 group in which
  • n is defined as mentioned at the beginning and R 3 'is a substituted on the methylene groups by one or two methyl or ethyl groups
  • R 4 is -0-CO-CH 2 -N-CH 2 CH 2 -OH group in which
  • R 4 represents a hydrogen atom or a C 1 _ 4 alkyl group.
  • the reaction is optionally carried out in a solvent or solvent mixture such as methylene chloride, acetonitrile, dimethylformamide, dimethyl sulfoxide, sulfolane, benzene, toluene, chlorobenzene, tetrahydrofuran, benzene / tetrahydrofuran or dioxane in the presence of an anhydrous acid such as trifluoroacetic acid, methanesulfonic acid or sulfuric acid or in the presence of a dehydrating agent, for example in the presence of isobutyl chloroformate, thionyl chloride, trimethylchlorosilane, phosphorus trichloride, phosphorus pentoxide, N, N'-dicyclohexylcarbodiimide, N, N '-dicyclohexylcarbodimide / N-hydroxysuccinimide, n-triazole, or 1-hydroxyl-niazole, n-
  • any reactive groups present such as hydroxyl, carboxy or imino groups, can be protected during the reaction by customary protective groups, which are split off again after the reaction.
  • the trimethylsilyl, acetyl, benzoyl, methyl, ethyl, tert-butyl, trityl, benzyl or tetrahydropyranyl group comes as a protective radical for a hydroxyl group
  • the formyl, acetyl, trifluoroacetyl, ethoxycarbonyl, tert.butoxycarbonyl, benzyloxycarbonyl, benzyl, methoxybenzyl or 2,4-dimethoxybenzyl group are considered.
  • the subsequent subsequent splitting off of a protective residue used takes place, for example, hydrolytically in an aqueous solvent, e.g. in water, isopropanol / water, acetic acid / water, tetrahydrofuran / water or dioxane / water, in the presence of an acid such as trifluoroacetic acid, hydrochloric acid or sulfuric acid or in the presence of an alkali base such as
  • Sodium hydroxide or potassium hydroxide or aprotic for example in Presence of iodotrimethylsilane, at temperatures between 0 and 120 ° C, preferably at temperatures between 10 and. 100 ° C.
  • a benzyl, methoxybenzyl or benzyloxycarbonyl radical is split off, for example by hydrogenolysis, e.g. 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, if appropriate - with 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.
  • a 2,4-dimethoxybenzyl radical is preferably cleaved in trifluoroacetic acid in the presence of anisole.
  • a tert-butyl or tert-butyloxycarbonyl radical is preferably cleaved off by treatment with an acid such as trifluoroacetic acid or hydrochloric acid or by treatment with iodotrimethylsilane, optionally using a
  • Solvents such as methylene chloride, dioxane, methanol or
  • a trifluoroacetyl radical is preferably split off by treatment with an acid such as hydrochloric acid, if appropriate in the presence of a solvent such as acetic acid at temperatures between 50 and 120 ° C. or by treatment with sodium hydroxide solution optionally in the presence of a solvent such as tetrahydrofuran at temperatures between 0 and 50 ° C.
  • the compounds of general formula I obtained can be separated into their enantiomers and / or diastereomers.
  • cis / trans mixtures can be separated into their ice and trans isomers, and compounds with at least one optically active carbon atom can be separated into their enantiomers.
  • the cis / trans mixtures obtained can be chromatographed into their eis and trans isomers, the compounds of general formula I obtained which occur in racemates, according to methods known per se (see Allinger NL and Eliel EL in "Topics in Stereochemistry", Vol.
  • the separation of enantiomers is preferably carried out by column separation on chiral phases or by recrystallization from an optically active solvent or by reaction with a salt or derivative such as e.g. Optically active substance which forms esters or amides, in particular acids and their activated derivatives or alcohols, and separation of the diastereomeric salt mixture or derivative thus obtained, e.g. due to different solubilities, it being possible for the free antipodes to be released from the pure diastereomeric salts or derivatives by the action of suitable agents.
  • a salt or derivative such as e.g. Optically active substance which forms esters or amides, in particular acids and their activated derivatives or alcohols
  • optically active alcohols are (+) or (-) menthol and optically active acyl radicals in amides are, for example, (+) or (-) menthyloxycarbonyl.
  • the compounds of formula I obtained in their salts, in particular for pharmaceutical use in their physiologically compatible salts with inorganic or organic acids are converted.
  • suitable acids for this are hydrochloric acid, hydrobromic acid, sulfuric acid, methanesulfonic acid, phosphoric acid, fumaric acid, succinic acid, lactic acid, citric acid, tartaric acid or maleic acid.
  • the new compounds of the formula I obtained in this way if they contain a carboxy, hydroxyphosphoryl, sulfo or 5-tetrazolyl group, can, if desired, subsequently be converted into their salts with inorganic or organic bases, in particular for pharmaceutical use in their physiologically tolerable salts , convict.
  • Suitable bases are, for example, sodium hydroxide, potassium hydroxide, arginine, cyclohexylamine, ethanolamine, diethanolamine and triethanolamine.
  • 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), this being achieved, for example, by inhibiting the Ligand binding, the receptor dimerization or the tyrosine kinase itself can be effected. It is also possible that the signal transmission on further downstream components may be blocked.
  • EGF-R epidermal growth factor receptor
  • the biological properties of the new compounds were tested as follows: The inhibition of EGF-R-mediated signal transmission can be demonstrated, for example, with cells which express human EGF-R and whose survival and proliferation depend on stimulation by EGF or TGF-alpha.
  • An interleukin-3 (IL-3) -dependent cell line of murine origin was used here, which has been genetically modified in such a way that it expresses functional human EGF-R.
  • the proliferation of these cells called F / L-HERc can therefore be stimulated either by murine IL-3 or by EGF (see von Rüden, T. et al. In EMBO J. 2, 2749-2756 (1988) and Pierce, JH et al. in Science, Sept. 23, 628-631 (1988)).
  • other growth factor-dependent cells can also be used (see, for example, Pierce, JH et al. In Science 223., 628-631 (1988), Shibuya, H. et al. In Cell IQ., 57-67 (1992) and Alexander, WS et al. in EMBO J. Lu, 3683-3691 (1991)).
  • Recombinant retroviruses were used to express the human EGF-R cDNA (see Ullrich, A. et al.
  • F / L-HERc cells were in RPMl / 1640 medium (BioWhittaker), supplemented with 10% fetal bovine serum (FCS, Boehringer Mannheim), 2 mM glutamine (BioWhittaker), standard antibiotics and 20 ng / ml human EGF (Promega), at 37 ° C and 5% CO 2 cultivated fourth.
  • FCS fetal bovine serum
  • FCS Boehringer Mannheim
  • 2 mM glutamine BioWhittaker
  • standard antibiotics 20 ng / ml human EGF (Promega)
  • 20 ng / ml human EGF Promega
  • the relative cell number was determined using the Cell
  • the compounds of the general formula I according to the invention thus inhibit signal transduction by tyrosine kinases, as has been shown using the example of the human EGF receptor, and are therefore useful for the treatment of pathophysiological processes caused by overactive tyrosine kinases become.
  • tyrosine kinases as has been shown using the example of the human EGF receptor, and are therefore useful for the treatment of pathophysiological processes caused by overactive tyrosine kinases become.
  • tyrosine kinases are, for example, 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 invention are also useful for the prevention and treatment of respiratory and lung diseases associated with increased or altered mucus production caused by stimulation of tyrosine kinases such as e.g. for inflammatory diseases of the respiratory tract such as chronic bronchitis, chronic obstructive bronchitis, asthma, bronchiectasis, allergic or non-allergic rhinitis or sinusitis, cystic
  • the compounds are also suitable for the treatment of diseases of the gastrointestinal tract and the bile ducts and bladder which are associated with impaired activity of the tyrosine kinases, such as e.g. in chronic inflammatory
  • Changes can be found, such as cholecystitis, Crohn's disease, ulcerative colitis, and ulcers in the gastrointestinal tract or how they occur in diseases of the gastrointestinal tract that are associated with increased secretion, such as M. Menetrier, secreting Adenomas and protein loss syndromes,
  • nasal polyps as well as polyps of the gastrointestinal tract of different origins such as villous or adenomatous polyps of the colon, but also of polyps in familial polyposis coli, in intestinal polyps as part of the Gardner syndrome, in polyps in the entire gastrointestinal tract at Peutz -Jeghers syndrome, with inflammatory pseudopolyps, with juvenile polyps, with colitis cystica profunda and with Pneumatosis cystoides intestinales.
  • kidney diseases in particular in the case of cystic changes such as in cystic kidneys
  • kidney cysts which may be of idiopathic origin or occur in the context of syndromes, for example in tuberous sclerosis von Hippel-Lindau syndrome, which uses nephronophthisis and marrow sponge kidney as well as other diseases caused by aberrant function of tyrosine kinases, such as epidermal hyperproliferation (psoriasis), inflammatory processes, diseases of the immune system, hyperproliferation of hematopoietic cells etc.
  • psoriasis epidermal hyperproliferation
  • inflammatory processes diseases of the immune system
  • hyperproliferation of hematopoietic cells etc.
  • the compounds according to the invention can be used alone or in combination with other pharmacologically active compounds, for example in tumor therapy in monotherapy or in combination with other anti-tumor therapeutic agents, for example in combination with topoisomerase inhibitors (for example etoposide), mitotic inhibitors (e.g. vinblastine), with
  • nucleic acids e.g. cis-platinum, cyclophosphamide, adriamycin
  • hormone antagonists e.g. tamoxifen
  • inhibitors of metabolic processes e.g. 5-FU etc
  • cytokines e.g. interferons
  • antibodies etc.
  • These compounds can be used to treat respiratory diseases used alone or in combination with other respiratory therapies, such as secretolytic, broncholytic and / or anti-inflammatory substances.
  • these compounds can also be given alone or in combination with substances which influence motility or secretion or which have anti-inflammatory effects. These combinations can be administered either simultaneously or sequentially.
  • These compounds can be used either alone or in combination with other active compounds, intravenously, subcutaneously, intramuscularly, intrarectally, intraperitoneally, intranasally, by inhalation or transdermally or orally, aerosol formulations in particular being suitable for inhalation.
  • the compounds according to the invention are generally used in warm-blooded vertebrates, in particular in humans, in doses of 0.01-100 mg / kg body weight, preferably 0.1-15 mg / kg.
  • these are mixed with one or more conventional inert carriers and / or diluents, e.g. with corn starch, milk sugar, cane sugar, microcrystalline cellulose, magnesium stearate, polyvinylpyrrolidone, citric acid, tartaric acid, water, water / ethanol, water / glycerin, water / sorbitol, water / polyethylene glycol, propylene glycol, stearyl alcohol ,.
  • Carboxymethyl cellulose or fatty substances such as hard fat or their suitable mixtures are incorporated into conventional pharmaceutical preparations such as tablets, dragees, capsules, powders, suspensions, solutions, sprays or suppositories.
  • Cyclopentylmethanol are dissolved in 100 ml of dimethyl sulfoxide and cooled in an ice bath under a nitrogen atmosphere. 3.90 g of sodium are now added in portions. The reaction mixture is stirred for 30 minutes with ice bath cooling, then briefly warmed to 35-40 ° C. and then stirred for a further three hours with ice bath cooling. The ice bath is then removed and the reaction mixture is stirred at room temperature overnight. The dark brown-red reaction solution is poured onto about 800 ml of acetone, whereby a dark brown precipitate precipitates. The precipitate is filtered off, washed with acetone, dissolved in 300-400 ml of water and adjusted to about pH 2 with 60 ml of 2N hydrochloric acid.
  • the compound is obtained by hydrogenation of 6-benzyloxy-4- [(3-chloro-4-fluorophenyl) amino] -7-cylcopropylmethoxy-quinazoline
  • reaction mixture is refluxed for about three hours, then another equivalent of methanesulfonic acid is added and the reflux is continued until the reaction is complete.
  • the reaction mixture is diluted with ethyl acetate and washed with saturated sodium bicarbonate solution and saturated sodium chloride solution.
  • the organic phase is dried over magnesium sulfate and concentrated in vacuo.
  • the flask residue is stirred with diethyl ether and suction filtered.
  • the title compound is obtained as a white solid. Yield: 280 mg (85% of theory), melting point: 190 ° C.
  • 1 coated tablet contains:
  • the active substance is mixed with calcium phosphate, corn starch,
  • the dragee cores thus produced are coated with a film consisting essentially of hydroxypropylmethyl cellulose.
  • the finished film coated tablets are polished with beeswax. Drage weight: 245 mg.
  • 1 tablet contains: active substance 100.0 mg
  • Active ingredient, milk sugar and starch are mixed and moistened uniformly with an aqueous solution of the polyvinylpyrrolidone. After screening the moist mass (2.0 mm mesh size) and drying in a rack drying cabinet at 50 ° C, sieving is again carried out (1.5 mm mesh size) and the lubricant is added. The ready-to-press mixture is processed into tablets. Tablet weight: 220 mg
  • Diameter 10 mm, biplane with facet on both sides and partial notch on one side.
  • 1 tablet contains: active substance 150.0 mg
  • the active substance mixed with milk sugar, corn starch and silica is moistened with a 20% aqueous polyvinylpyrrolidone solution and passed 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 specified amount of magnesium stearate. Tablets are pressed from the mixture.
  • 1 capsule contains: Active ingredient 150.0 mg corn starch dr. approx.180.0 mg powdered milk sugar approx.87.0 mg magnesium stearate 3,0 mg approx.420.0 mg
  • the active ingredient is mixed with the excipients, passed through a sieve with a mesh size of 0.75 mm and mixed homogeneously in a suitable device.
  • the final mix is filled into size 1 hard gelatin capsules.
  • Capsule filling approx. 320 mg capsule shell: hard gelatin capsule size 1.
  • 1 suppository contains: active ingredient 150.0 mg
  • Polyethylene glycol 1500 550.0 mg
  • Carboxymethylcellulose Na salt 0.10 g methyl p-hydroxybenzoate 0.05 g propyl p-hydroxybenzoate 0.01 g cane sugar 10.00 g
  • Dest. Water is heated to 70 ° C. P-Hydroxybenzoic acid methyl ester and propyl ester as well as glycerol and carboxymethyl cellulose sodium salt are dissolved therein with stirring. It is cooled to room temperature and the active ingredient is added with stirring and dispersed homogeneously. After adding and dissolving the sugar, the sorbitol solution and the aroma, the suspension is evacuated with stirring for deaeration. 5 ml of suspension contain 50 mg of active ingredient.
  • composition Active ingredient 10.0 mg
  • the active substance is dissolved in the required amount of 0.01N HCl, made isotonic with sodium chloride, sterile filtered and filled into 2 ml ampoules.
  • the active substance is dissolved in the required amount of 0.01N 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 includes:
  • the active substance and benzalkonium chloride are dissolved in ethanol / water (50/50).
  • the pH of the solution is adjusted with IN hydrochloric acid.
  • the resulting solution is filtered and filled into suitable containers for hand-held nebulisers ⁇ (cartridges).

Landscapes

  • Health & Medical Sciences (AREA)
  • Organic Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • Public Health (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • General Chemical & Material Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Pulmonology (AREA)
  • Oncology (AREA)
  • Immunology (AREA)
  • Dermatology (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Urology & Nephrology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
EP01967285A 2000-08-26 2001-08-18 Bicyclische heterocyclen, diese verbindungen enthaltende arzneimittel, deren verwendung und vefahren zu ihrer herstellung Ceased EP1315705A1 (de)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
DE10042058 2000-08-26
DE10042058A DE10042058A1 (de) 2000-08-26 2000-08-26 Bicyclische Heterocyclen, diese Verbindungen enthaltende Arzneimittel, deren Verwendung und Verfahren zu ihrer Herstellung
PCT/EP2001/009532 WO2002018351A1 (de) 2000-08-26 2001-08-18 Bicyclische heterocyclen, diese verbindungen enthaltende arzneimittel, deren verwendung und vefahren zu ihrer herstellung

Publications (1)

Publication Number Publication Date
EP1315705A1 true EP1315705A1 (de) 2003-06-04

Family

ID=7653945

Family Applications (1)

Application Number Title Priority Date Filing Date
EP01967285A Ceased EP1315705A1 (de) 2000-08-26 2001-08-18 Bicyclische heterocyclen, diese verbindungen enthaltende arzneimittel, deren verwendung und vefahren zu ihrer herstellung

Country Status (30)

Country Link
EP (1) EP1315705A1 (cs)
JP (1) JP4834282B2 (cs)
KR (1) KR100862873B1 (cs)
CN (1) CN100404517C (cs)
AR (1) AR033562A1 (cs)
AU (2) AU2001287694B2 (cs)
BG (1) BG107559A (cs)
BR (1) BR0113519A (cs)
CA (1) CA2417897C (cs)
CZ (1) CZ302567B6 (cs)
DE (1) DE10042058A1 (cs)
EA (1) EA005679B1 (cs)
EC (1) ECSP034464A (cs)
EE (1) EE05269B1 (cs)
HR (1) HRP20030138A2 (cs)
HU (1) HUP0300819A3 (cs)
IL (2) IL154602A0 (cs)
ME (1) MEP58708A (cs)
MX (1) MXPA03001483A (cs)
MY (1) MY126132A (cs)
NO (1) NO324866B1 (cs)
NZ (1) NZ524668A (cs)
PL (1) PL360248A1 (cs)
RS (1) RS52279B (cs)
SK (1) SK287747B6 (cs)
TW (1) TWI294422B (cs)
UA (1) UA73004C2 (cs)
UY (1) UY26903A1 (cs)
WO (1) WO2002018351A1 (cs)
ZA (1) ZA200300991B (cs)

Families Citing this family (41)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
HK1044769B (zh) 1999-06-21 2005-02-25 贝林格尔英格海姆法玛两合公司 雙環雜環化合物，含有該化合物的藥物組合物，該化合物的用途及其製備方法
DE10042059A1 (de) * 2000-08-26 2002-03-07 Boehringer Ingelheim Pharma Bicyclische Heterocyclen, diese Verbindungen enthaltende Arzneimittel, deren Verwendung und Verfahren zu ihrer Herstellung
US7019012B2 (en) 2000-12-20 2006-03-28 Boehringer Ingelheim International Pharma Gmbh & Co. Kg Quinazoline derivatives and pharmaceutical compositions containing them
TW200813014A (en) 2002-03-28 2008-03-16 Astrazeneca Ab Quinazoline derivatives
AU2003226705B2 (en) * 2002-03-30 2008-11-06 Boehringer Ingelheim Pharma Gmbh & Co. Kg 4-(N-phenylamino)-quinazolines / quinolines as tyrosine kinase inhibitors
US6924285B2 (en) 2002-03-30 2005-08-02 Boehringer Ingelheim Pharma Gmbh & Co. Bicyclic heterocyclic compounds, pharmaceutical compositions containing these compounds, their use and process for preparing them
DE10214412A1 (de) * 2002-03-30 2003-10-09 Boehringer Ingelheim Pharma Bicyclische Heterocyclen, diese Verbindungen enthaltende Arzneimittel, deren Verwendung und Verfahren zu ihrer Herstellung
EP1521747B1 (en) 2002-07-15 2018-09-05 Symphony Evolution, Inc. Receptor-type kinase modulators and methods of use
DE10326186A1 (de) * 2003-06-06 2004-12-23 Boehringer Ingelheim Pharma Gmbh & Co. Kg Bicyclische Heterocyclen, diese Verbindungen enthaltende Arzneimittel, deren Verwendung und Verfahren zu ihrer Herstellung
DE10334226A1 (de) * 2003-07-28 2005-02-17 Boehringer Ingelheim Pharma Gmbh & Co. Kg Verwendung von Tyrosinkinase-Inhibitoren zur Behandlung inflammatorischer Prozesse
GB0317665D0 (en) 2003-07-29 2003-09-03 Astrazeneca Ab Qinazoline derivatives
AU2004272348B2 (en) 2003-09-16 2008-09-04 Astrazeneca Ab Quinazoline derivatives as tyrosine kinase inhibitors
DE602004004553T2 (de) 2003-09-19 2007-10-25 Astrazeneca Ab Chinazolinderivate
ATE520403T1 (de) 2003-09-26 2011-09-15 Exelixis Inc N-ä3-fluoro-4-(ä6-(methyloxy)-7-ä(3-morpholin-4 ylpropyl)oxyüquinolin-4-ylüoxy)phenylü-n'-(4- fluorophenyl)cyclopropane-1,1-dicarboxamid zur behandlung von krebs
DE10345875A1 (de) * 2003-09-30 2005-04-21 Boehringer Ingelheim Pharma Bicyclische Heterocyclen, diese Verbindungen enthaltende Arzneimittel, deren Vewendung und Verfahren zu ihrer Herstellung
US7456189B2 (en) 2003-09-30 2008-11-25 Boehringer Ingelheim International Gmbh Bicyclic heterocycles, medicaments containing these compounds, their use and processes for their preparation
DE10350717A1 (de) * 2003-10-30 2005-06-02 Boehringer Ingelheim Pharma Gmbh & Co. Kg Verwendung von Tyrosinkinase-Inhibitoren zur Behandlung inflammatorischer Prozesse
US20060035893A1 (en) 2004-08-07 2006-02-16 Boehringer Ingelheim International Gmbh Pharmaceutical compositions for treatment of respiratory and gastrointestinal disorders
PE20060777A1 (es) 2004-12-24 2006-10-06 Boehringer Ingelheim Int Derivados de indolinona para el tratamiento o la prevencion de enfermedades fibroticas
JP5054544B2 (ja) 2005-02-26 2012-10-24 アストラゼネカ アクチボラグ チロシンキナーゼ阻害剤としてのキナゾリン誘導体
KR100673775B1 (ko) * 2005-04-08 2007-01-24 엘지전자 주식회사 냉장고용 홈바
US20100234371A1 (en) * 2005-08-22 2010-09-16 Frank Himmelsbach Bicyclic heterocycles, pharmaceutical compositions containing these compounds, the use thereof and processes for the preparation thereof
JP5688877B2 (ja) 2005-11-11 2015-03-25 ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング 癌疾患の治療用キナゾリン誘導体
CA2643363A1 (en) * 2006-03-09 2007-09-13 Boehringer Ingelheim International Gmbh Bicyclic heterocycles, medicaments containing these compounds, their use and process for preparing them
PL2068880T3 (pl) 2006-09-18 2012-09-28 Boehringer Ingelheim Int Sposób leczenia raka z mutacjami EGFR
EP1921070A1 (de) 2006-11-10 2008-05-14 Boehringer Ingelheim Pharma GmbH & Co. KG Bicyclische Heterocyclen, diese Verbindungen enthaltende Arzneimittel, deren Verwendung und Verfahren zu ihrer Herstelllung
EP2118075A1 (de) 2007-02-06 2009-11-18 Boehringer Ingelheim International GmbH Bicyclische heterocyclen, diese verbindungen enthaltende arzneimittel, deren verwendung und verfahren zu ihrer herstellung
HRP20120869T1 (hr) 2008-02-07 2012-11-30 Boehringer Ingelheim International Gmbh Spirocikliäśki heterocikli, lijekovi koji sadrže te spojeve, njihova uporaba te postupak njihove proizvodnje
WO2009138781A1 (en) 2008-05-13 2009-11-19 Astrazeneca Ab Fumarate salt of 4- (3-chloro-2-fluoroanilino) -7-methoxy-6- { [1- (n-methylcarbamoylmethyl) piperidin- 4-yl] oxy}quinazoline
JP5539351B2 (ja) 2008-08-08 2014-07-02 ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング シクロヘキシルオキシ置換ヘテロ環、これらの化合物を含有する医薬、およびそれらを生成するための方法
CN106083714B (zh) 2009-01-16 2019-11-26 埃克塞里艾克西斯公司 N-(4-{[6,7-双(甲基氧基)喹啉-4-基]氧基}苯基)-n′-(4-氟苯基)环丙烷-1,1-二甲酰胺苹果酸盐及其结晶型
SI2451445T1 (sl) 2009-07-06 2019-07-31 Boehringer Ingelheim International Gmbh Postopek za sušenje BIBW2992, njegovih soli in trdnih farmacevtskih formulacij, ki obsegajo to aktivno sestavino
UA108618C2 (uk) 2009-08-07 2015-05-25 Застосування c-met-модуляторів в комбінації з темозоломідом та/або променевою терапією для лікування раку
KR101317809B1 (ko) 2011-06-07 2013-10-16 한미약품 주식회사 암세포의 성장을 억제하는 아마이드 유도체 및 비금속염 활택제를 포함하는 약학 조성물
KR20140096571A (ko) 2013-01-28 2014-08-06 한미약품 주식회사 1-(4-(4-(3,4-디클로로-2-플루오로페닐아미노)-7-메톡시퀴나졸린-6-일옥시)피페리딘-1-일)프로프-2-엔-1-온의 제조방법
ES2642201T3 (es) 2013-03-06 2017-11-15 Astrazeneca Ab Inhibidores de quinazolina de formas mutantes de activación del receptor del factor de crecimiento epidérmico
US9242965B2 (en) 2013-12-31 2016-01-26 Boehringer Ingelheim International Gmbh Process for the manufacture of (E)-4-N,N-dialkylamino crotonic acid in HX salt form and use thereof for synthesis of EGFR tyrosine kinase inhibitors
KR20160138084A (ko) * 2014-04-04 2016-12-02 하. 룬드벡 아크티에셀스카브 Pde1 저해제인 할로겐화된 퀴나졸린-thf-아민
US20170176028A1 (en) 2015-12-18 2017-06-22 Lg Electronics Inc. Air conditioner
JP7265985B2 (ja) 2016-11-17 2023-04-27 ボード オブ リージェンツ，ザ ユニバーシティ オブ テキサス システム Ｅｇｆｒまたはｈｅｒ２のエクソン２０変異を有するがん細胞に対する抗腫瘍活性を有する化合物
CN112321814B (zh) * 2020-12-30 2021-03-23 广州初曲科技有限公司 一种吉非替尼艾地苯醌轭合物的制备及用途

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000055141A1 (en) * 1999-03-15 2000-09-21 Boehringer Ingelheim Pharma Kg Bicyclic heterocycles, pharmaceutical compositions containing these compounds, and processes for preparing them

Family Cites Families (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB9508538D0 (en) * 1995-04-27 1995-06-14 Zeneca Ltd Quinazoline derivatives
GB9624482D0 (en) * 1995-12-18 1997-01-15 Zeneca Phaema S A Chemical compounds
CA2242425C (en) * 1996-02-13 2006-07-18 Zeneca Limited Quinazoline derivatives as vegf inhibitors
GB9603095D0 (en) * 1996-02-14 1996-04-10 Zeneca Ltd Quinazoline derivatives
US6291455B1 (en) * 1996-03-05 2001-09-18 Zeneca Limited 4-anilinoquinazoline derivatives
RO121900B1 (ro) * 1996-04-12 2008-07-30 Warner-Lambert Company Compuşi inhibitori, ireversibili, ai tirozin kinazelor, compoziţie farmaceutică care îi conţine şi utilizarea acestora
GB9718972D0 (en) * 1996-09-25 1997-11-12 Zeneca Ltd Chemical compounds

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000055141A1 (en) * 1999-03-15 2000-09-21 Boehringer Ingelheim Pharma Kg Bicyclic heterocycles, pharmaceutical compositions containing these compounds, and processes for preparing them

Also Published As

Publication number Publication date
AU8769401A (en) 2002-03-13
JP2004507529A (ja) 2004-03-11
ECSP034464A (es) 2003-03-31
EE200300077A (et) 2004-12-15
PL360248A1 (en) 2004-09-06
WO2002018351A1 (de) 2002-03-07
UY26903A1 (es) 2002-03-22
AU2001287694B2 (en) 2007-09-06
CA2417897C (en) 2009-03-31
MY126132A (en) 2006-09-29
CZ302567B6 (cs) 2011-07-13
HUP0300819A2 (hu) 2003-09-29
BG107559A (bg) 2003-10-31
CA2417897A1 (en) 2003-01-30
JP4834282B2 (ja) 2011-12-14
ZA200300991B (en) 2004-04-16
AR033562A1 (es) 2003-12-26
KR20030024914A (ko) 2003-03-26
BR0113519A (pt) 2003-07-01
RS52279B (en) 2012-10-31
NO20030870D0 (no) 2003-02-25
EA200300219A1 (ru) 2003-08-28
NO20030870L (no) 2003-02-25
NO324866B1 (no) 2007-12-17
HRP20030138A2 (en) 2005-04-30
IL154602A (en) 2008-07-08
DE10042058A1 (de) 2002-03-07
CN100404517C (zh) 2008-07-23
EE05269B1 (et) 2010-02-15
IL154602A0 (en) 2003-09-17
UA73004C2 (uk) 2005-05-16
NZ524668A (en) 2006-06-30
CN1449390A (zh) 2003-10-15
YU14003A (sh) 2006-01-16
MXPA03001483A (es) 2003-06-06
TWI294422B (en) 2008-03-11
EA005679B1 (ru) 2005-04-28
HK1057557A1 (zh) 2004-04-08
MEP58708A (en) 2011-05-10
SK2312003A3 (en) 2003-10-07
SK287747B6 (sk) 2011-08-04
HUP0300819A3 (en) 2008-03-28
KR100862873B1 (ko) 2008-10-15

Similar Documents

Publication Publication Date Title
EP1315705A1 (de) Bicyclische heterocyclen, diese verbindungen enthaltende arzneimittel, deren verwendung und vefahren zu ihrer herstellung
EP1315718B1 (de) Bicyclische heterocyclen, diese verbindungen enthaltende arzneimittel, deren verwendung und verfahren zu ihrer herstellung
EP1315720B1 (de) Bicyclische heterocyclen, diese verbindungen enthaltende arzneimittel, deren verwendung und verfahren zu ihrer herstellung
EP1731511B1 (de) Bicyclische Heterocyclen, diese Verbindungen enthaltende Arzneimittel, deren Verwendung und Verfahren zu ihrer Herstellung
DE60022866T2 (de) Bizyklische heterozyklen, diese verbindungen enthaltende zusammenstellungen und verfahren zu deren herstellung
EP1345910B9 (de) Chinazolinderivate, diese verbindungen enthaltende arzneimittel, deren verwendung und verfahren zu ihrer herstellung
EP1280798B1 (de) Bicyclische heterocyclen, diese verbindungen enthaltende arzneimittel, deren verwendung und verfahren zu ihrer herstellung
WO2002018373A1 (de) Chinazolin derivate, diese verbindungen enthaltende arzneimittel, deren verwendung und verfahren zu ihrer herstellung
WO2002018370A1 (de) Bicyclische heterocyclen, diese verbindungen enthaltende arzneimittel, deren verwendung und verfahren zu ihrer herstellung
DE10326186A1 (de) Bicyclische Heterocyclen, diese Verbindungen enthaltende Arzneimittel, deren Verwendung und Verfahren zu ihrer Herstellung
EP1322645A2 (de) Chinazoline, diese verbindungen enthaltende als tyrosinkinase inhibitoren wirksame arzneimittel, deren verwendung und verfahren zu ihrer herstellung
DE10017539A1 (de) Bicyclische Heterocyclen, diese Verbingungen enthaltende Arzneimittel, deren Verwendung und Verfahren zu ihrer Herstellung
DE19908567A1 (de) Bicyclische Heterocyclen, diese Verbindungen enthaltende Arzneimittel, deren Verwendung und Verfahren zu ihrer Herstellung
DE19911366A1 (de) Bicyclische Heterocyclen, diese Verbindungen enthaltende Arzneimittel, deren Verwendung und Verfahren zu ihrer Herstellung
DE19928281A1 (de) Bicyclische Heterocyclen, diese Verbindungen enthaltende Arzneimittel, deren Verwendung und Verfahren zu ihrer Herstellung
DE19954816A1 (de) Bicyclische Heterocyclen, diese Verbindungen enthaltende Arzneimittel, deren Verwendung und Verfahren zu ihrer Herstellung
DE10023085A1 (de) Bicyclische Heterocyclen, diese Verbindungen enthaltende Arzneimittel, deren Verwendung und Verfahren zu ihrer Herstellung

Legal Events

Date Code Title Description
PUAI Public reference made under article 153(3) epc to a published international application that has entered the european phase

Free format text: ORIGINAL CODE: 0009012

17P Request for examination filed

Effective date: 20030326

AK Designated contracting states

Designated state(s): AT BE CH CY DE DK ES FI FR GB GR IE IT LI LU MC NL PT SE TR

AX Request for extension of the european patent

Extension state: AL LT LV MK RO SI

RAP1 Party data changed (applicant data changed or rights of an application transferred)

Owner name: BOEHRINGER INGELHEIM PHARMA GMBH & CO.KG

RIN1 Information on inventor provided before grant (corrected)

Inventor name: SOLCA, FLAVIO

Inventor name: BLECH, STEFAN

Inventor name: JUNG, BIRGIT

Inventor name: LANGKOPF, ELKE

Inventor name: HIMMELSBACH, FRANK

17Q First examination report despatched

Effective date: 20050621

REG Reference to a national code

Ref country code: DE

Ref legal event code: R003

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: THE APPLICATION HAS BEEN REFUSED

18R Application refused

Effective date: 20140626