EP1641767A2 - Heterocycles bicycliques, medicaments contenant ces composes, leur utilisation et procede pour leur production - Google Patents

Heterocycles bicycliques, medicaments contenant ces composes, leur utilisation et procede pour leur production

Info

Publication number
EP1641767A2
EP1641767A2 EP04739543A EP04739543A EP1641767A2 EP 1641767 A2 EP1641767 A2 EP 1641767A2 EP 04739543 A EP04739543 A EP 04739543A EP 04739543 A EP04739543 A EP 04739543A EP 1641767 A2 EP1641767 A2 EP 1641767A2
Authority
EP
European Patent Office
Prior art keywords
group
amino
general formula
compound
methyl
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.)
Withdrawn
Application number
EP04739543A
Other languages
German (de)
English (en)
Inventor
Frank Himmelsbach
Rainer Soyka
Birgit Jung
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 International GmbH
Boehringer Ingelheim Pharma GmbH and Co KG
Original Assignee
Boehringer Ingelheim International GmbH
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 International GmbH, Boehringer Ingelheim Pharma GmbH and Co KG filed Critical Boehringer Ingelheim International GmbH
Publication of EP1641767A2 publication Critical patent/EP1641767A2/fr
Withdrawn legal-status Critical Current

Links

Classifications

    • 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
    • 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
    • A61P1/16—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
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/02—Drugs for disorders of the urinary system of urine or of the urinary tract, e.g. urine acidifiers
    • 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
    • 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

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 hydrogen atom or a C 1 -alkyl group
  • R b is a phenyl or 1-phenylethyl group in which the phenyl is in each case substituted by the radicals R 1 to R 3 , wherein
  • R 1 and R 2 which may be the same or different, each represents a hydrogen, fluorine, chlorine, bromine or iodine atom,
  • a C ⁇ -4 alkyl hydroxy, C ⁇ -4 alkoxy, C 2 - 3 -alkenyl or C 2-3 -alkynyl, a phenyloxy or phenylmethoxy group, wherein the phenyl portion of the aforementioned groups is optionally substituted by a fluorine or chlorine atom, or
  • a pyridyloxy or pyridinylmethoxy group wherein the pyridinyl moiety of the abovementioned groups is optionally substituted by a methyl or trifluoromethyl group,
  • R 3 is a hydrogen, fluorine, chlorine or bromine atom or
  • R c is a (2-hydroxyethyl) amino-group in which the carbon skeleton of the (2-hydroxyethyl) portion optionally -3 alkyl substituted by one or two C ⁇ ,
  • R d is a hydrogen atom
  • R 4 is a hydroxy, C 1-3 alkyloxy, C 3 -6-cycloalkyloxy, A ino, C ⁇ . 3- alkylamino, di (C 3 -alkyl) amino, bis (2-methoxyethyl) amino, pyrrolidin-1-yl, piperidin-1-yl, homopiperidin-1-yl , Morpholin-4-yl, homomorpholin-4-yl, 2-oxa-5-azabicyclo [2.2.1] hept-5-yl, 3-oxa-8-aza-bicyclo [3.2.1] oct-8-yl, 8-oxa-3-azabicyclo [3.2.1] oct-3-yl, piperazin-1-yl, 4-methyl- 3 -piperazin-1-yl,
  • Homopiperazin-1-yl or 4-C ⁇ -3 alkyl-homopiperazin-1-yl group whilst the abovementioned pyrrolidinyl, piperidinyl, piperazinyl and morpholinyl -3 alkyl groups may each be substituted by one or two C ⁇ ,
  • X is a methine group substituted by a cyano group or a nitrogen atom
  • n is the number 2, 3 or 4,
  • alkyl groups may be straight-chain or branched
  • R a is a hydrogen atom
  • R b is a 3-bromophenyl, 3,4-difluorophenyl, 3-chloro-4-fluorophenyl or a 3-ethynylphenyl group
  • R G is a (2-hydroxypropyl) amino or N- (2-hydroxypropyl) -N- (C ⁇ -3 alkyl) amino group
  • R d is a hydrogen atom
  • X is a nitrogen atom
  • n is the number 2 or 3
  • R a is a hydrogen atom
  • R b is a 3-chloro-4-fluoro-phenyl group or 3-ethynylphenyl group
  • R ° is a (2-hydroxypropyl) amino group
  • R d is a methoxy, ethyloxy or 2-methoxyethyloxy group
  • X is a nitrogen atom
  • n is the number 2, their tautomers, their stereoisomers, their mixtures and their salts.
  • the compounds of general formula I can be prepared, for example, by the following processes:
  • R ⁇ and n are defined as mentioned above and Z 1 represents a leaving group such as a halogen atom, for example a chlorine or bromine atom, a sulfonyloxy group such as a methanesulfonyloxy or p-toluenesulfonyloxy or a hydroxy group.
  • 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, optionally in the presence of a base such as potassium carbonate or N-ethyl-diisopropylamine, at temperatures between 20 ° C and 160 ° C.
  • 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, for example triphenylphosphine / diethyl azodicarboxylate, conveniently in a solvent such as methylene chloride, acetonitrile, tetrahydrofuran, Dioxane, toluene or Ethylenglycoldiethylether at temperatures between -50 and 150 ° C, but preferably at temperatures between -20 and 80 ° C performed.
  • a dehydrating agent preferably in the presence of a phosphine and an azodicarboxylic acid derivative, for example triphenylphosphine / diethyl azodicarboxylate
  • a solvent such as methylene chloride, acetonitrile, tetrahydrofuran, Dioxane, toluene or Ethylenglycoldiethylether at
  • R °, R d and n are as defined above, with a halogenating agent, for example an acid halide such as thionyl chloride, thionyl bromide, phosphorus trichloride, phosphorus pentachloride or phosphorus oxychloride to form an intermediate of the general formula (V),
  • a halogenating agent for example an acid halide such as thionyl chloride, thionyl bromide, phosphorus trichloride, phosphorus pentachloride or phosphorus oxychloride
  • R °, R d and n are defined as mentioned above and Z 2 represents a halogen atom such as a chlorine or bromine atom,
  • the reaction with the halogenating agent is optionally carried out in a solvent such as methylene chloride, chloroform, acetonitrile or toluene and optionally in the presence of a base such as N, N-diethylaniline or N-ethyl-diisopropylamine at temperatures between 20 ° C and 160 ° C.
  • a solvent such as methylene chloride, chloroform, acetonitrile or toluene
  • a base such as N, N-diethylaniline or N-ethyl-diisopropylamine at temperatures between 20 ° C and 160 ° C.
  • the reaction is carried out with thionyl chloride and catalytic amounts of dimethylformamide at the boiling temperature of the reaction mixture.
  • reaction of the compound of the general formula (V) with a compound of the general formula (VI) is conveniently carried out in a solvent such as ethanol, isopropanol, acetonitrile, dioxane or dimethylformamide, optionally in the presence of a base such as potassium carbonate or N-ethyl-diisopropylamine Temperatures between 20 ° C and 160 ° C.
  • a solvent such as ethanol, isopropanol, acetonitrile, dioxane or dimethylformamide
  • R a , R b , R d , X and n are defined as mentioned above, and Z 3 represents a leaving group such as a halogen atom, for example a chlorine or bromine atom, a sulphonyloxy group such as a methanesulphonyloxy or p-toluenesulphonyloxy group,
  • reaction is conveniently carried out in a solvent such as ethanol,
  • a compound of the general formula I in which R c is optionally substituted by one or two C 1.
  • 3- alkyl substituted 2-oxo-oxazolidin-3-yl group it can be converted by hydrolysis, for example by hydrolysis in the presence of an alkali metal hydroxide such as lithium hydroxide, sodium hydroxide or potassium hydroxide, in a R ° a (2 Represents hydroxyethyl) amino group, in which the carbon skeleton of the (2-hydroxyethyl) part is optionally substituted by one or two C ⁇ - alkyl groups, and / or
  • R ° represents a (2-hydroxyethyl) amino group in which the carbon skeleton of the (2-hydroxyethyl) part optionally -3 alkyl substituted by one or two C ⁇
  • this can by reaction with a derivative of carbonic acid, for example, phosgene, N, N '- are diphenyl carbonic acid, converted carbonyldiimidazole or in a compound in which R ° is an optionally by one or two C ⁇ -3 alkyl substituted 2-oxo-oxazolidin-3-yl group, and / or
  • a compound of the general formula I which contains an amino, alkylamino or imino group this can be converted into a corresponding alkyl compound of the general formula I by means of alkylation or reductive alkylation, for example by formaldehyde or acetaldehyde and sodium triacetoxyborohydride.
  • R a, R b, R d and n are as hereinbefore defined and R e and R f independently represent hydrogen atoms or C ⁇ -3 alkyl groups.
  • R a, R b, R d and n are as hereinbefore defined and R e and R f independently represent hydrogen atoms or C ⁇ -3 alkyl groups.
  • R e and R f independently represent hydrogen atoms or C ⁇ -3 alkyl groups.
  • the preparation of the compounds of general formula (IX) is carried out by reacting said starting compounds conveniently in one Solvents such as acetonitrile, toluene, tetrahydrofuran, dioxane, dimethylformamide, dimethyl sulfoxide or N-methylpyrrolidinone, if appropriate in the presence of a base such as potassium carbonate or N-ethyl-diisopropylamine, at temperatures between 20 ° C and 160 ° C, preferably at temperatures between 0 and 50 ° C, and then heating expediently in a solvent such as toluene, dioxane, N-methylpyrrolidinone, methyl ethyl ketone, diethyl ketone or n-butyl acetate or mixtures thereof to 80-180 ° C, preferably 100-150 ° C.
  • Solvents such as acetonitrile, toluene, tetrahydrofuran, dioxane,
  • optionally present reactive groups such as hydroxyl, amino, alkylamino or imino groups can be protected during the reaction by conventional protecting groups, which are cleaved again after the reaction.
  • Suitable protecting groups for an amino, alkylamino or imino group are, for example, the formyl, acetyl, trifluoroacetyl, ethoxycarbonyl, tert-butoxycarbonyl, benzyloxycarbonyl, benzyl, methoxybenzyl or 2,4-dimethoxybenzyl groups.
  • the optional subsequent cleavage of a protective moiety used is carried out, for example, hydrolytically in an aqueous solvent, e.g. in water, isopropanol / water, acetic acid / water, tetrahydrofuran / water or dioxane / water, in the presence of an acid such as trifluoroacetic acid, hydrochloric acid or sulfuric acid or in the presence of an alkali metal base such as sodium hydroxide or potassium hydroxide or aprotic, e.g. in the presence of iodotrimethylsilane, at temperatures between 0 and 120 ° C, preferably at temperatures between 10 and 100 ° C.
  • an aqueous solvent e.g. in water, isopropanol / water, acetic acid / water, tetrahydrofuran / water or dioxane / water
  • an acid such as trifluoroacetic acid, hydrochloric acid or sulfuric acid
  • cleavage of a benzyl, methoxybenzyl or Benzyloxycarbonyirestes for example hydrogenolytically, for example with hydrogen in the presence of a catalyst such as palladium / carbon in a suitable solvent such as methanol, ethanol, ethyl acetate or glacial acetic acid, optionally with the addition of an acid such as hydrochloric acid at temperatures between 0 and 100 ° C, but preferably at room temperatures between 20 and 60 ° C, and at a hydrogen pressure of 1 to 7 bar, but preferably from 3 to 5 bar.
  • cleavage of a 2,4-dimethoxy-benzyl radical is preferably carried out in trifluoroacetic acid in the presence of anisole.
  • a tert-butyl or tert-Butyloxycarbonylrestes preferably takes place by treatment with an acid such as trifluoroacetic acid or hydrochloric acid or by treatment with iodotrimethylsilane optionally using a solvent such as methylene chloride, dioxane, methanol or diethyl ether.
  • an acid such as trifluoroacetic acid or hydrochloric acid
  • iodotrimethylsilane optionally using a solvent such as methylene chloride, dioxane, methanol or diethyl ether.
  • Trifluoracetylrestes preferably takes place by treatment with an acid such as hydrochloric acid optionally in the presence of a solvent such as acetic acid at temperatures between 50 and 120 ° C or by treatment with sodium hydroxide, optionally in the presence of a solvent such as tetrahydrofuran or methanol at temperatures between 0 and 50 ° C. ,
  • the compounds of general formula I obtained can be separated into their enantiomers and / or diastereomers.
  • cis / trans mixtures can be separated into their cis and trans isomers, and compounds having at least one optically active carbon atom can be resolved into their enantiomers.
  • the resulting cis / trans mixtures can be chromatographed into their cis and trans isomers, the compounds of general formula I which are obtained in racemates can be prepared by methods known per se (see Allinger NL and Eliel EL in "Topics in Stereochemistry", Vol. 6, Wiley Interscience, 1971)) in their optical antipodes and compounds of general formula I having at least 2 asymmetric carbon atoms due to their physicochemical differences according to methods known per se, eg by chromatography and / or fractionated crystallization, into their diastereomers, which, if they are obtained in racemic form, can then be separated into the enantiomers as mentioned above.
  • the separation of enantiomers is preferably carried out by column separation on chiral phases or by recrystallization from an optically active solvent or by reacting with a, with the racemic compound salts or derivatives such as esters or amides forming optically active substance, in particular acids and their activated derivatives or alcohols, and Separation of the thus obtained diastereomeric salt mixture or derivative, for example due to different solubilities, wherein from the pure diastereomeric salts or derivatives, the free antipodes can be released by the action of suitable agents.
  • optically active acids are, for example, the D- and L-forms of tartaric acid or dibenzoyltartaric acid, di-O-toluen-tartaric acid, malic acid, mandelic acid, camphorsulphonic acid, glutamic acid, aspartic acid or quinic acid.
  • optically active alcohols are (+) - or (-) - menthol and, for example, (+) - or (-) - menthyloxycarbonyl as the optically active acyl radical in amides.
  • the resulting compounds of the formula I can be converted into their salts, in particular for the pharmaceutical application in their physiologically acceptable salts with inorganic or organic acids.
  • suitable acids are hydrochloric acid, hydrobromic acid, sulfuric acid, methanesulfonic acid, phosphoric acid, fumaric acid, succinic acid, lactic acid, citric acid, tartaric acid or maleic acid.
  • R d and Z 3 are as hereinbefore defined and R 10 and R 11, which may be identical or different, represent hydrogen atoms or C ⁇ -3 alkyl groups. Instead of those mentioned as a contactor group in the 3-position of the 3,4-dihydro-4-oxo-quinazoline radical
  • Benzyl group other protecting groups such as 4-methoxybenzyl, 2,4- Dimethoxybenzyl, methoxymethyl, benzyloxymethyl, (2-methoxyethyl) oxymethyl, (2-trimethylsilylethyl) oxymethyl or the pivaloyloxymethyl group.
  • the compounds of the general formula I according to the invention and their physiologically tolerated salts have valuable pharmacological properties, in particular an inhibitory effect on the signal transduction mediated by the epidermal growth factor receptor (EGF-R) Inhibition of ligand binding, the receptor dimerization or the tyrosine kinase itself can be effected. In addition, it is possible that the signal transmission is blocked at further downstream components.
  • 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 profein using the baculovirus expression system.
  • the measurement of enzyme activity was carried out in the presence or absence of the test compounds in serial dilutions.
  • the polymer pEY (4: 1) from SIGMA was used as a substrate.
  • Biotinylated pEY (bio-pEY) was added as a tracer substrate.
  • Each 100 ⁇ L reaction solution contained 10 ⁇ L of the inhibitor in 50% DMSO, 20 ⁇ L 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 ⁇ ⁇ enzyme preparation.
  • the enzyme reaction was started by adding 50 L of a 100 / M ATP solution in 10 mM magnesium chloride.
  • the dilution of the enzyme preparation was adjusted so that the phosphate incorporation into the bio-pEY was linear with respect to time and amount of enzyme.
  • the enzyme preparation was diluted in 20 mM HEPES pH 7.4, 1 mM EDTA, 130 mM saline, 0.05% Triton X-100, 1 mM DTT and 10% glycerol.
  • the enzyme assays were carried out at room temperature for a period of 30 minutes and terminated by adding 50 ⁇ l of a challenge solution (250 mM EDTA in 20 mM HEPES pH 7.4). 100 .mu.l were placed on a streptavidin-coated microtiter plate and incubated for 60 minutes at room temperature.
  • the data was fit by means of an iterative calculation using a sigmoid curve analysis program (Graph Pad Prism Version 3.0) with variable hill slope. All shared iteration data showed a correlation coefficient of about 0.9, and the upper and lower values of the curves showed a spread of at least a factor of 5. From the curves, the concentration of active substance has been derived, which inhibits the activity of EGF receptor kinase by 50% (IC 50 ). The novel compounds have IC 5 o values of below 10 uM.
  • the compounds of the general formula I according to the invention thus inhibit the signal transduction by tyrosine kinases, as shown by the example of the human EGF receptor, and are therefore useful for the treatment of pathophysiological processes which are caused by hyperfunction of tyrosine kinases.
  • tyrosine kinases e.g. benign or malignant tumors, in particular tumors of epithelial and neuroepithelial origin, metastasis and the abnormal proliferation of vascular endothelial cells (neoangiogenesis).
  • the compounds of the present invention are also useful for the prevention and treatment of respiratory and pulmonary diseases associated with increased or altered mucus production caused by stimulation of tyrosine kinases, such as in respiratory tract inflammatory diseases such as acute bronchitis, chronic bronchitis, chronic obstructive bronchitis (COPD), asthma, bronchiectasis, allergic or non-allergic rhinitis or sinusitis, cystic fibrosis, ⁇ 1-antitrypsin deficiency, or for cough, pulmonary emphysema, pulmonary fibrosis, and hyperreactive airways.
  • respiratory tract inflammatory diseases such as acute bronchitis, chronic bronchitis, chronic obstructive bronchitis (COPD), asthma, bronchiectasis, allergic or non-allergic rhinitis or sinusitis, cystic fibrosis, ⁇ 1-antitrypsin deficiency, or for cough, pulmonary em
  • 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.
  • COPD chronic bronchitis
  • Particularly preferred indications are inflammatory diseases of the respiratory tract or the lungs, such as chronic bronchitis (COPD) or asthma.
  • COPD chronic bronchitis
  • 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 ..
  • 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 ..
  • 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 secretolytic (eg Ambroxol, N-acetylcysteine), broncholytic (eg tiotropium or ipratropium or fenoterol, salmeterol, salbutamol) and / or anti-inflammatory (eg theophylline or glucocorticoids) active substances be used.
  • secretolytic eg Ambroxol, N-acetylcysteine
  • broncholytic eg tiotropium or ipratropium or fenoterol, salmeterol, salbutamol
  • anti-inflammatory eg 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 with one or more conventional inert carriers and / or diluents, for example with corn starch, lactose, cane sugar, microcrystalline cellulose, magnesium stearate, polyvinylpyrrolidone, citric acid, tartaric acid, water, water / ethanol, water / glycerol, water / sorbitol, water / Polyethylene glycol, propylene glycol, stearyl alcohol, carboxymethyl cellulose or fatty substances such as hard fat or their suitable mixtures in conventional incorporated galenic preparations such as tablets, dragees, capsules, powders, suspensions, solutions, sprays or suppositories.
  • inventive compounds of the general formula I in which R ° is a (2-hydroxyethyl) amino-group in which the carbon skeleton of the (2-hydroxyethyl) portion is optionally substituted by one or two C ⁇ -3 alkyl group are, also for the preparation of corresponding 2-oxo-morpholin-4-yl derivatives, as described for example in WO 00/55141 or WO 02/18351.
  • the compound of Example 2 with methyl bromoacetate can be prepared (S) -4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- [2- (6-methyl-2-oxo-morpholin-4-yl ) ethyloxy] -7-methoxy-quinazoline (see method example A).
  • Solvent is stripped off and the residue is dissolved in 250 ml of water.
  • Chloroethyl) ⁇ 5-methyl-oxazolidin-2-one and 2.07 g of potassium carbonate are heated to 70-75 ° C in 30 ml of dimethylformamide for 7.5 hours.
  • the mixture is mixed with 90 ml
  • the title compound can also be obtained by using (S) -3- [2- (4-toluenesulfonyloxy) ethyl] -5-methyl-oxazolidin-2-one as the alkylating agent.
  • the precipitate was filtered off with suction and washed with diethyl ether.
  • the reaction mixture is mixed with 10% potassium carbonate solution and with
  • Residue is by chromatography on a silica gel column
  • 1 drag core contains:
  • the active substance is mixed with calcium phosphate, corn starch, polyvinylpyrrolidone, hydroxypropylmethylcellulose and half of the stated amount of magnesium stearate.
  • a tabletting machine compacts with a diameter of about 13 mm are produced, which are ground on a suitable machine through a sieve with a 1.5 mm mesh size and mixed with the remaining amount of magnesium. Stearate mixed. This granulate is pressed on a tabletting machine into tablets of the desired shape.
  • the Drageekeme thus prepared are coated with a film consisting essentially of hydroxypropylmethylcellulose.
  • the finished film dragees are shined with beeswax.
  • 1 tablet contains:
  • Active ingredient, lactose and starch are mixed and uniformly moistened with an aqueous solution of polyvinylpyrrolidone. After sieving the moist mass (2.0 mm mesh size) and drying in a tray drying oven at 50 ° C is again sieved (1.5 mm mesh) and the lubricant mixed. The ready-to-use mixture is processed into tablets.
  • Tablet weight 220 mg Diameter: 10 mm, biplan with facet on both sides and one-sided part notch.
  • Composition 1 tablet contains: active substance 150.0 mg
  • the active substance mixed with milk sugar, corn starch and silicic acid is moistened with a 20% strength aqueous solution of polyvinylpyrrolidone and filtered through a sieve
  • Composition 1 capsule contains:
  • Corn starch drink about 180.0 mg
  • the active ingredient is mixed with the excipients, passed through a sieve of 0.75 mm mesh size and mixed homogeneously in a suitable device.
  • the final mixture is filled into size 1 hard gelatin capsules. Capsule filling: approx. 320 mg
  • Capsule shell hard gelatin capsule size 1.
  • 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.
  • 5 ml of suspension contain 50 mg of active ingredient.
  • Active ingredient 10.0 mg 0.01 n hydrochloric acid s.q.
  • the active ingredient is dissolved in the required amount 0.01 N HCl, made isotonic with sodium chloride, sterile filtered and filled into 2 ml ampoules.
  • Active ingredient 50.0 mg 0.01 n hydrochloric acid s.q.
  • 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).

Abstract

L'invention concerne des hétérocycles bicycliques de formule générale (I), dans laquelle R<a>, R<b>, R<c>, R<d>, X et n ont la signification indiquée dans la revendication 1, leurs tautomères, leurs stéréoisomères, leurs mélanges et leurs sels, notamment leurs sels physiologiquement tolérables comportant des acides inorganiques et organiques, qui présentent des propriétés pharmacologiques intéressantes, notamment un effet inhibiteur sur la transduction de signaux médiée par les tyrosine kinases. Elle concerne également leur utilisation pour le traitement de maladies, notamment de maladies tumorales et de l'hyperplasie bénigne de la prostate (BPH), de maladies pulmonaires et de maladies des voies respiratoires, ainsi que la production desdits composés.
EP04739543A 2003-06-06 2004-06-02 Heterocycles bicycliques, medicaments contenant ces composes, leur utilisation et procede pour leur production Withdrawn EP1641767A2 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE10326186A DE10326186A1 (de) 2003-06-06 2003-06-06 Bicyclische Heterocyclen, diese Verbindungen enthaltende Arzneimittel, deren Verwendung und Verfahren zu ihrer Herstellung
PCT/EP2004/005965 WO2004108664A2 (fr) 2003-06-06 2004-06-02 Heterocycles bicycliques, medicaments contenant ces composes, leur utilisation et procede pour leur production

Publications (1)

Publication Number Publication Date
EP1641767A2 true EP1641767A2 (fr) 2006-04-05

Family

ID=33482765

Family Applications (1)

Application Number Title Priority Date Filing Date
EP04739543A Withdrawn EP1641767A2 (fr) 2003-06-06 2004-06-02 Heterocycles bicycliques, medicaments contenant ces composes, leur utilisation et procede pour leur production

Country Status (11)

Country Link
US (3) US7196091B2 (fr)
EP (1) EP1641767A2 (fr)
JP (1) JP2006527176A (fr)
AR (1) AR044604A1 (fr)
CA (1) CA2526995A1 (fr)
CL (1) CL2004001409A1 (fr)
DE (1) DE10326186A1 (fr)
PE (1) PE20050227A1 (fr)
TW (1) TW200510341A (fr)
UY (1) UY28347A1 (fr)
WO (1) WO2004108664A2 (fr)

Families Citing this family (19)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EE04748B1 (et) 1999-06-21 2006-12-15 Boehringer Ingelheim Pharma Kg Bitsüklilised heterotsüklilised ühendid, neid ühendeid sisaldavad ravimid, nende kasutamine ja meetodid nende valmistamiseks
US7019012B2 (en) * 2000-12-20 2006-03-28 Boehringer Ingelheim International Pharma Gmbh & Co. Kg Quinazoline derivatives and pharmaceutical compositions containing them
DE10204462A1 (de) * 2002-02-05 2003-08-07 Boehringer Ingelheim Pharma Verwendung von Tyrosinkinase-Inhibitoren zur Behandlung inflammatorischer Prozesse
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
DE10221018A1 (de) * 2002-05-11 2003-11-27 Boehringer Ingelheim Pharma Verwendung von Hemmern der EGFR-vermittelten Signaltransduktion zur Behandlung von gutartiger Prostatahyperplasie (BPH)/Prostatahypertrophie
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
US20050096332A1 (en) * 2003-10-30 2005-05-05 Boehringer Ingelheim International Gmbh Use of tyrosine kinase inhibitors for the treatment of inflammatory processes
CA2627590A1 (fr) * 2005-07-04 2007-01-11 Boehringer Ingelheim International Gmbh Procede pour produire des derives de quinazolinone
WO2007054550A1 (fr) 2005-11-11 2007-05-18 Boehringer Ingelheim International Gmbh Derives de quinazoline pour le traitement des affections cancereuses
WO2007101782A1 (fr) * 2006-03-09 2007-09-13 Boehringer Ingelheim International Gmbh Heterocycles bicycliques, medicaments contenant ces composes, leur utilisation et leur procede de fabrication
DK2068880T3 (da) 2006-09-18 2012-07-23 Boehringer Ingelheim Int Fremgangsmåde til behandling af cancer, der huser EGFR-mutationer
EP1921070A1 (fr) * 2006-11-10 2008-05-14 Boehringer Ingelheim Pharma GmbH & Co. KG heterocycles bicycliques, medicaments á base de ces composes, leur usage et procédé pour leur preparation
WO2008095847A1 (fr) * 2007-02-06 2008-08-14 Boehringer Ingelheim International Gmbh Hétérocycles bicycliques, agents pharmaceutiques contenant ces composés, leur utilisation et leur procédé de préparation
WO2009098061A1 (fr) 2008-02-07 2009-08-13 Boehringer Ingelheim International Gmbh Hétérocycles spirocycliques, médicaments contenant ces composés, leur utilisation et procédé pour les produire
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
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
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
CN105399689B (zh) * 2015-12-03 2017-03-01 中国人民解放军***南京总医院 一种新型喹唑啉衍生物lu1503及其制备方法和应用
CN105418517B (zh) * 2015-12-03 2017-03-22 中国人民解放军***南京总医院 一种新型喹唑啉衍生物lu1509及其制备方法和应用

Family Cites Families (6)

* 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
EP0824525B1 (fr) * 1995-04-27 2001-06-13 AstraZeneca AB Derives de quinazoline
DE19911509A1 (de) * 1999-03-15 2000-09-21 Boehringer Ingelheim Pharma Bicyclische Heterocyclen, diese Verbindungen enthaltende Arzneimittel, deren Verwendung und Verfahren zu ihrer Herstellung
AU779695B2 (en) * 2000-04-07 2005-02-10 Astrazeneca Ab Quinazoline compounds
DE10042058A1 (de) * 2000-08-26 2002-03-07 Boehringer Ingelheim Pharma Bicyclische Heterocyclen, diese Verbindungen enthaltende Arzneimittel, deren Verwendung und Verfahren zu ihrer Herstellung
US6656946B2 (en) 2000-08-26 2003-12-02 Boehringer Ingelheim Pharma Kg Aminoquinazolines which inhibit signal transduction mediated by tyrosine kinases

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO2004108664A2 *

Also Published As

Publication number Publication date
AR044604A1 (es) 2005-09-21
TW200510341A (en) 2005-03-16
US20050014772A1 (en) 2005-01-20
US20060264450A1 (en) 2006-11-23
JP2006527176A (ja) 2006-11-30
CL2004001409A1 (es) 2005-05-06
WO2004108664A3 (fr) 2005-05-26
US20100267718A1 (en) 2010-10-21
WO2004108664A2 (fr) 2004-12-16
PE20050227A1 (es) 2005-05-18
DE10326186A1 (de) 2004-12-23
UY28347A1 (es) 2005-01-31
US7196091B2 (en) 2007-03-27
CA2526995A1 (fr) 2004-12-16

Similar Documents

Publication Publication Date Title
EP1345910B9 (fr) Derives de la quinazoline, medicaments contenant ces composes, leur utilisation et leur procede de fabrication
EP1731511B1 (fr) Heterocycles bicycliques, medicaments contenant ces composés, leur utilisation et procédés permettant de les préparer
EP1315718B1 (fr) Heterocycles bicycliques, medicaments contenant lesdits composes, leur utilisation et procedes permettant de les produire
EP1597240B1 (fr) Heterocycles bicycliques, medicaments les contenant, leur utilisation et leurs procedes de production
EP1641767A2 (fr) Heterocycles bicycliques, medicaments contenant ces composes, leur utilisation et procede pour leur production
EP1315720B1 (fr) Heterocycles bicycliques, medicaments contenant lesdits composes, leur utilisation et procedes permettant de les produire
WO2007068552A1 (fr) Heterocycles bicycliques, medicaments contenant ces composes, utilisation et procede de fabrication de ceux-ci
WO2003082290A1 (fr) 4-(n-phenylamino)-quinazolines / quinolines en tant qu&#39;inhibiteurs de la tyrosine kinase
DE10042058A1 (de) Bicyclische Heterocyclen, diese Verbindungen enthaltende Arzneimittel, deren Verwendung und Verfahren zu ihrer Herstellung
DE10042060A1 (de) Bicyclische Heterocyclen, diese Verbindungen enthaltende Arzneimittel, deren Verwendung und Verfahren zu ihrer Herstellung
US20070185081A1 (en) Bicyclic heterocylces, pharmaceutical compositions containing these compounds, their use and processes for preparing them
DE10217689A1 (de) Bicyclische Heterocyclen, diese Verbindungen enthaltende Arzneimittel, ihre Verwendung und Verfahren zu ihrer Herstellung
EP1921070A1 (fr) heterocycles bicycliques, medicaments á base de ces composes, leur usage et procédé pour leur preparation
DE10042061A1 (de) Bicyclische Heterocyclen,diese Verbindungen enthaltende Arzneimittel, deren Verwendung und Verfahren zu ihrer Herstellung
WO2007023073A2 (fr) Heterocycles bicycliques, produits pharmaceutiques contenant ces composes, leur utilisation et procede pour les preparer
EP2118075A1 (fr) Hétérocycles bicycliques, agents pharmaceutiques contenant ces composés, leur utilisation et leur procédé de préparation
DE10214412A1 (de) Bicyclische Heterocyclen, diese Verbindungen enthaltende Arzneimittel, deren Verwendung und Verfahren zu ihrer Herstellung
DE10042064A1 (de) Chinazoline, 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
WO2005033096A1 (fr) Derives de quinoleine et de quinazoline, medicaments contenant ces composes, utilisation et procede de production de ceux-ci
WO2007101782A1 (fr) Heterocycles bicycliques, medicaments contenant ces composes, leur utilisation et leur procede de fabrication
EP1956010A1 (fr) Hétérocycles bicycliques, médicament contenant cette composition, son utilisation et son procédé de fabrication
DE10231711A1 (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

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: 20060109

AK Designated contracting states

Kind code of ref document: A2

Designated state(s): AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HU IE IT LI LU MC NL PL PT RO SE SI SK TR

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

Owner name: BOEHRINGER INGELHEIM INTERNATIONAL GMBH

Owner name: BOEHRINGER INGELHEIM PHARMA GMBH & CO.KG

DAX Request for extension of the european patent (deleted)
17Q First examination report despatched

Effective date: 20100917

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

Free format text: STATUS: THE APPLICATION IS DEEMED TO BE WITHDRAWN

18D Application deemed to be withdrawn

Effective date: 20110118