EP1608659A1 - Derives de benzofuro-1,4-diazepin-2-one - Google Patents

Derives de benzofuro-1,4-diazepin-2-one

Info

Publication number
EP1608659A1
EP1608659A1 EP04719947A EP04719947A EP1608659A1 EP 1608659 A1 EP1608659 A1 EP 1608659A1 EP 04719947 A EP04719947 A EP 04719947A EP 04719947 A EP04719947 A EP 04719947A EP 1608659 A1 EP1608659 A1 EP 1608659A1
Authority
EP
European Patent Office
Prior art keywords
formula
compounds
bromine
chlorine
hydrogen
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Withdrawn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
EP04719947A
Other languages
German (de)
English (en)
Inventor
Rüdiger Fischer
Bernd Kalthof
Rudi Grützmann
Elisabeth Woltering
Beatrix Stelte-Ludwig
Martina Wuttke
Pablo Jesus Hernandez Blasco
Carmelo Pina Gadea
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.)
Bayer AG
Original Assignee
Bayer Healthcare AG
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 Bayer Healthcare AG filed Critical Bayer Healthcare AG
Publication of EP1608659A1 publication Critical patent/EP1608659A1/fr
Withdrawn legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems
    • 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
    • A61P17/06—Antipsoriatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis

Definitions

  • the present invention relates to new benzofuro-l, 4-diazepin-2-one derivatives, 3 processes for their preparation and their use as P2X receptor antagonists for the production of medicaments for the treatment and / or prophylaxis of diseases, in particular arteriosclerosis, restenosis and other inflammatory diseases.
  • Atherosclerosis is a multifactorial disease that affects many different factors. Inflammatory processes play a central role here, in which inflammation-inducing cytokines such as CD40L and IFN ⁇ are involved [P. Libby, Nature 420 (6917): 868-74 (2002)].
  • the purinergic receptor P2X 4 belongs to the P2X family. So far, six different P2X receptors have been described in humans. These are calcium-permeable channels that can be activated by ATP [F. Virgilio et al., Blood 91 (3): 587-600 (2001); RA North, A. Surprenant, Annu. Rev. Pharmacol. Toxicol. 40: 563-80 (2000)].
  • the P2X channel is highly expressed in highly vascularized organs and vessels [K. Yamamoto et al., Circ. Res. 87 (5): 385-91 (2000)].
  • the P2X 4 receptor is also expressed on human monocytes. When human monocytes were incubated with CD40L and IFN ⁇ , a five-fold increase in P2X expression was observed. Also in the vascular wall of the rabbit aorta after damage by balloon angioplasty and cholesterol feeding [TJ. Pulvirenti et al., J. Neurocytol.
  • the present invention relates to compounds of the general formula (I)
  • R 2 is hydrogen, halogen, nitro, cyano or a group of the formula -C (0) -OR, -C (O) - NR 4 R 5 , -S0 2 -OR 3 or -S0 2 -NR 4 R 5 , wherein
  • R, R and R independently of one another represent hydrogen or (CC ⁇ ⁇ alkyl
  • R 1 is hydrogen
  • R halogen, nitro, cyano or a group of the formula -C (0) -OR J , -C (0) -NR 4 4 ⁇ R> 5 D , -S0 2 -OR or -S0 2 -NR 4 R 5 , wherein
  • R, R and R independently of one another represent hydrogen or (C r C6) -alkyl
  • the compounds of the invention may also be in the form of their salts, solvates and solvates of their salts.
  • the substituents generally have the following meaning:
  • (-C-Cfi) -alkyl and (C r C) -alkyl stand for a straight-chain or branched alkyl radical having 1 to 6 or 1 to 4 carbon atoms.
  • a straight-chain or branched alkyl radical having 1 to 4 carbon atoms is preferred.
  • the following may be mentioned as examples and preferably: methyl, ethyl, n-propyl, isopropyl and tert-butyl.
  • Halogen in the context of the invention includes fluorine, chlorine, bromine and iodine. Chlorine or bromine are preferred.
  • the compounds according to the invention can exist in stereoisomeric forms which either behave like image and mirror image (enantiomers) or do not behave like image and mirror image (diastereomers).
  • the invention relates both to the enantiomers or diastereomers and to their respective mixtures.
  • the racemic forms can be separated into the stereoisomerically uniform constituents in a known manner.
  • the compounds according to the invention can also be present as salts.
  • physiologically acceptable salts are preferred.
  • Physiologically acceptable salts can be salts of the compounds according to the invention with inorganic or organic acids.
  • Salts with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid or sulfuric acid, or salts with organic carboxylic or sulfonic acids such as acetic acid, propionic acid, maleic acid, fumaric acid, malic acid, citric acid, tartaric acid, lactic acid, benzoic acid, or methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid are preferred , Toluenesulfonic acid or naphthalenedisulfonic acid.
  • Physiologically acceptable salts can also be salts of the compounds according to the invention with bases, such as metal or ammonium salts.
  • bases such as metal or ammonium salts.
  • alkali metal salts for example sodium or potassium salts
  • alkaline earth metal salts for example magnesium or calcium salts
  • ammonium salts which are derived from ammonia or organic amines, for example ethylamine, di- or triethylamine, ethyldiisopropylamine, monoethanolamine, di - or triethanolamine, dicyclohexylamine, dimethylaminoethanol, dibenzylamine, N-methylmorpholine, dihydroabietylamine, 1-ephenamine, N-methylpiperidine, arginine, lysine, ethylenediamine or 2-phenylethylamine.
  • the compounds according to the invention and their salts can also be present in the form of their solvates, in particular in the form of their hydrates.
  • R 2 is hydrogen, chlorine, bromine, nitro, cyano or a group of the formula -C (0) -OR 3 or -C (0) -NR 4 R 5 , wherein
  • R 3 , R 4 and R 5 independently of one another represent hydrogen or (-CC 4 ) -alkyl
  • R 1 is hydrogen
  • R 2 is chlorine, bromine, nitro, cyano or a group of the formula -C (0) -OR 3 or -C (0) -NR 4 R 5 , wherein
  • R 3 , R 4 and R 5 independently of one another represent hydrogen or (-CC) alkyl
  • R is hydrogen, chlorine, bromine, nitro or cyano
  • R 1 is hydrogen
  • X 1 represents a suitable leaving group such as chlorine, bromine or iodine
  • X 2 and X 3 are the same or different and represent a suitable leaving group such as chlorine, bromine or iodine,
  • Inert organic solvents which do not change under the reaction conditions are suitable as solvents for process step (II) + (HI) -> (IV).
  • halogenated hydrocarbons such as dichloromethane, trichloromethane, carbon tetrachloride, trichloroethane, tetrachloroethane, 1,2-dichloroethane or trichlorethylene, ethers such as diethyl ether, dioxane, tetrahydrofuran, glycol dimethyl ether or diethylene glycol dimethyl ether, hydrocarbons, toluene, xylolane, hydrocarbons such as benzene, xylolane, hexanol, toluene, xylolane, hexanol, tolene, xanol, hexanol, tolene, xylolohexanol, tolene, xylolohexan
  • the usual inorganic or organic bases are suitable as bases for process step (II) + (HI) -> • (IV).
  • bases preferably include alkali or alkaline earth carbonates such as sodium, potassium or calcium carbonate, alkali hydrides such as sodium hydride, amides such as lithium bis (trimethylsilyl) amide or lithium diisopropylamide, or organic amines such as pyridine, 4-NN-dimethylaminopyridine, 4-pyrrolidinopyridine , Triethylamine, ethyldiisopropylamine, N-methylmorpholine, N-methylpiperidine, l, 5-diazabicyclo [4.3.0] non-5-ene (DB ⁇ ) or 1,8-diazabicyclo- [5.4.0] undec-7-ene (DBU). Triethylamine is particularly preferred.
  • the base is used here in an amount of 1 to 5 mol, preferably in an amount of 1 to 2 mol, based on 1 mol of the compound of the formula (II).
  • the reaction generally takes place in a temperature range from 0 ° C. to + 150 ° C., preferably in a temperature range from + 20 ° C. to + 100 ° C.
  • the implementation can with normal, increased or be carried out at reduced pressure (for example from 0.5 to 5 bar). Generally one works at normal pressure.
  • Inert organic solvents which do not change under the reaction conditions are likewise suitable as solvents for process step (TV) - (V).
  • These include halogenated hydrocarbons such as dichloromethane, trichloromethane, tetrachloromethane, trichloroethane, tetrachloroethane, 1,2-dichloroethane or trichlorethylene, ethers such as diethyl ether, dioxane, tetrahydrofoftirane, glycol dimethyl ether or dietliylene glycol dimethyl ether, alcohols such as methanol, ethanol, isopropanol, ethanol, ethanol, ethanol, ethanol, ethanol, ethanol, ethanol, ethanol, ethanol, methanol, ethanol n-butanol or tert-butanol, hydrocarbons such as benzene, xylene, toluene, hexane, cyclohex
  • the usual inorganic or organic bases are suitable as base for process step (IN) - »(V).
  • These preferably include alkali or alkaline earth carbonates such as sodium, potassium or calcium carbonate, alkali hydroxides such as lithium, sodium or potassium hydroxide, alkali alcoholates such as sodium or potassium methoxide, sodium or potassium ethoxide or potassium tert-butoxide, alkali hydrides such as sodium hydride , Amides such as lithium bis (trimethylsilyl) amide or lithium diisopropylamide, or organic amines such as pyridine, 4-N, N-dimethylamino-pyridine, 4-pyrrölidinopyridine, triethylamine, ethyldiisopropylamine, N-methylmorpholine, N-methylpiperidine, l, 5- Diazabicyclo [4.3.0] non-5-ene (DB ⁇ ) or 1,8-diazabicyclo [5.4.0] undec-7-ene (D
  • the base is used in an amount of 0.5 to 5 mol, preferably in an amount of 1 to 2 mol, based on 1 mol of the compound of the formula (TV).
  • the reaction generally takes place in a temperature range from 0 ° C. to + 120 ° C., preferably in a temperature range from + 20 ° C. to + 100 ° C.
  • the reaction can be carried out at normal, elevated or reduced pressure (e.g. from 0.5 to 5 bar). Generally one works at normal pressure.
  • Suitable solvents for process step (V) + (VI) -> (VII) are all inert solvents which do not change under the reaction conditions. These include halogenated hydrocarbons such as dichloromethane, trichloromethane, carbon tetrachloride, trichloroethane, tetrachloroethane, 1,2-dichloroethane or trichlorethylene, ethers such as diethyl ether, dioxane, tetrahydrofuran, glycol dimethyl ether or diethylene glycol dimethyl ether, hydrocarbons such as benzene, xololane, hydrocarbons such as benzene, xolohexane, hydrocarbons such as benzene, xolohexanol, hexanol, tolene, xololane, hydrocarbons, such as benzene, xololane, hexanol, tolene, x
  • Suitable bases for process step (V) + " (VI) -> (VII) are the customary inorganic or organic bases. These preferably include alkali or alkaline earth metal carbonates and hydrogen carbonates such as sodium, potassium or calcium carbonate and sodium carbonate.
  • alkali hydrides such as sodium hydride
  • amides such as lithium bis (trimethylsilyl) amide or lithium diisopropylamide
  • organic amines such as pyridine, 4-N, N-dimethylaminopyridine, 4-pyrrolidinopyridine, triethylamine, ethyldiisopropylamine, N-methylmorpholine, N-methylpiperidine , l, 5-diazabicyclo [4.3.0] non-5-ene (DB ⁇ ) or l, 8-diazabicyclo [5.4.0] undec-7-ene (DBU), particularly preferred is sodium hydrogen carbonate.
  • alkali hydrides such as sodium hydride
  • amides such as lithium bis (trimethylsilyl) amide or lithium diisopropylamide
  • organic amines such as pyridine, 4-N, N-dimethylaminopyridine, 4-pyrrolidinopyridine, triethylamine, eth
  • the base is used in an amount of 1 to 10 mol, preferably in an amount of 1 to 5 mol, based on 1 mol of the compound of the formula (V).
  • the reaction generally takes place in a temperature range from -20 ° C to + 50 ° C, preferably in a temperature range from -20 ° C to + 20 ° C.
  • the reaction can be carried out at normal, elevated or reduced pressure (e.g. from 0.5 to 5 bar). Generally one works at normal pressure.
  • Suitable solvents for process step (VII) ⁇ (I) are all inert solvents which do not change under the reaction conditions. These include halohydrocarbons such as dichloromethane, trichloromethane, tetrachloromethane, trichloroethane, tetrachloroethane, 1,2-dichloroethane or trichlorethylene, ethers such as diethyl ether, dioxane, tetrahydrofuran, glycol dimethyl ether or diethylene glycol dimethyl ether, or hydrocarbons such as benzene, xylene, toluene, hexane, cyclohexane or petroleum fractions. It is also possible to use mixtures of the solvents mentioned. Dioxane is preferred.
  • the compounds according to the invention have an unforeseeable, valuable pharmacological spectrum of activity and are therefore suitable for use as medicaments for the treatment and / or prophylaxis of diseases in humans and animals.
  • the compounds according to the invention act as antagonists of the P2X receptor.
  • the compounds according to the invention can be used alone or in combination with other medicaments for the treatment and / or prophylaxis of inflammatory diseases.
  • they are suitable for the treatment of chronic inflammatory diseases of the vascular intima such as arteriosclerosis and restenosis, inflammatory diseases of the central nervous system such as multiple sclerosis and pain, inflammatory diseases of the connective tissue such as rheumatoid arthritis, chronic polyarthritis, panniculitis and tendinitis, and disease Bechterew, from inflammatory skin diseases such as psoriasis, psoriasis and neurodermatitis, from chronic inflammatory bowel diseases such as enteritis, enterocolitis, Crohn's disease and ulcerative colitis, from inflammatory diseases of the small airways and from myositis and endocarditis.
  • the compounds of the invention can be used alone or in combination with others if necessary
  • Active substances preferably from the group of CETP inhibitors, antidiabetics, antioxidants, thyroid hormones and / or thyroid mimetics, inhibitors of HMG-CoA reductase, inhibitors of HMG-CoA reductase gene expression, squalene synthase inhibitors, ACAT inhibitors, Cholesterol absorption inhibitors, fibrates, MTP inhibitors, trigyceride depressants, nicotinic acid and derivatives, antiplatelet agents, anticoagulants, calcium antagonists, ACE inhibitors, angiotensin II receptor antagonists, beta-blockers and steroidal and non-steroidal drugs are administered.
  • the present invention further relates to medicaments which contain at least one compound according to the invention, preferably together with one or more pharmacologically acceptable auxiliaries or excipients, and to their use for the purposes mentioned above.
  • the compounds according to the invention can act systemically and / or locally.
  • they can be applied in a suitable manner, e.g. oral, parenteral, pulmonary, nasal, sublingual, lingual, buccal, rectal, dermal, transdermal, conjunctival, otic or as an implant or stent.
  • Oral application is preferred.
  • the active substances can be administered in suitable administration forms for these administration routes.
  • suitable administration forms for oral administration, state-of-the-art functional, fast and / or modified application forms that deliver the active ingredient are suitable, e.g. Tablets (non-coated and coated tablets, e.g. with enteric coatings), capsules, dragees, granules, pellets, powders, emulsions, suspensions and solutions.
  • the parenteral application can be bypassing a resorption step (e.g. intravenous, intraarterial, intracardial, intraspinal or intralumbal) or by switching on absorption (e.g. intramuscular, subcutaneous, intracutaneous or intraperitoneal).
  • Suitable forms of application for parenteral administration include: Injection and infusion preparations in the form of solutions, suspensions, emulsions, lyophilisates and sterile powders.
  • L inhalation drug forms including powder inhalers, nebulizers
  • nasal drops / solutions sprays, lingual, sublingual or buccal tablets or capsules to be applied
  • suppositories e.g., suppositories, ear and eye preparations
  • vaginal capsules e.g., aqueous suspensions (lotions, shake mixes), lipophilic suspensions , Ointments, creams, milk, pastes, powder, implants or stents.
  • the active compounds can be converted into the administration forms mentioned in a manner known per se. This is done using inert, non-toxic, pharmaceutically suitable excipients. These include carriers (e.g. microcrystalline cellulose), solvents (e.g. liquid polyethylene glycols), emulsifiers (e.g. sodium dodecyl sulfate), dispersants (e.g. polyvinylpyrrolidone), synthetic and / or natural biopolymers (e.g. albumin), stabilizers (e.g. antioxidants such as ascorbic acid), colorants (e.g. inorganic pigments such as iron oxides) or flavorings and / or odors.
  • carriers e.g. microcrystalline cellulose
  • solvents e.g. liquid polyethylene glycols
  • emulsifiers e.g. sodium dodecyl sulfate
  • dispersants e.g. polyvinylpyrrolidone
  • synthetic and / or natural biopolymers
  • the amount is about 0.001 to 100 mg kg, preferably about 0.005 to 30 mg / kg body weight.
  • Device type MS Micromass ZQ
  • Device type HPLC Waters Alliance 2790; Column: Uptisphere C 18, 50 mm x 2.0 mm, 3.0 ⁇ m; Eluent B: acetonitrile + 0.05% formic acid, eluent A: water + 0.05% formic acid; Gradient: 0.0 min 5% B ⁇ 2.0 min 40% B ⁇ 4.5 min 90% B ⁇ 5.5 min 90% B; Oven: 45 ° C; Flow: 0.0 min 0.75 ml / min - »4.5 min 0.75 ml / min ⁇ 5.5 min 1.25 ml / min; UV detection: 210 nm.
  • the P2X receptor is a ligand-activated ion channel. Binding of the agonist ATP leads to activation of the P2X receptor, opening of the ion channel and influx of extracellular calcium into the cell. This calcium influx is measured using the calcium-sensitive photoprotein aequorin.
  • a recombinant CHO cell line Choinese hamster ovary cells with constitutive expression of the human P2X 4 receptor and of apoaequorin was produced.
  • the CHO cells are sown 1-2 days beforehand on microtiter plates in 96-, 384- or 1536-well format, depending on the used microtiter plate format with 5000 (96 format), 2000 (384- Format) or 500 (1536 format) cells per well.
  • the cell culture medium is removed and the cells are incubated for 4 hours in physiological saline (Tyrode buffer) with 5 ⁇ g / ml coelenterazine. Test substances are added 5 minutes before the actual experiment.
  • ATP is then added in a concentration of 1-2 ⁇ M and the ATP-induced calcium signal is measured in a luminometer as aequorin luminescence.
  • Substances with antagonistic activity at the P2X receptor can inhibit the ATP-induced calcium signal either by interference with the binding of ATP to the P2X 4 receptor, by preventing the opening of the channel or by blocking the influx of calcium through the opened channel.
  • Embodiments 1-3 show ICsn values of 0.5, 2 and 0.6 ⁇ M in this test.
  • ROS oxygen radical formation
  • the assay is performed in Hank's Balanced Salt Solution (HBSS) to which 10 mM glucose is added.
  • Monocytes are e.g. isolated using the "Becton Dickinson Vacutainer System” as described by the manufacturer and suspended in HBSS.
  • HRPO Horse Radish Peroxidase
  • luminol 50 ⁇ M final concentration
  • HRPO 10 U / ml final concentration
  • Test batch ATP (100 ⁇ M final concentration) added. The final volume in the test batch is 200 ul. Immediately after adding ATP, the ROS formation is monitored with a microplate lumino meter over a period of 120 seconds.
  • Monocytes are isolated from blood using standard methods. The chemotaxis of the monocytes is observed in a Transwell system [CC Bleul et al., J. Exp. Med. 184: 1101-1109 (1996)].
  • the membrane used (3 ⁇ m pore size, polyethylene terephthalate, Falcon) is first coated with fibronectin. 10 5 monocytes in RPMI 1640 medium are added to the upper chamber.
  • the lower chamber contains varying concentrations of stimulus or constant stimulus concentration (500 ⁇ M ATP or 10 nM MCP-1) and varying concentrations of the test substance.
  • the substances to be examined are in both chambers.
  • the test mixture is incubated for 3 h at 37 ° C. and 5% CO 2 [W. Falk et al., J. Immunol. Methods 38: 239-247 (1980)]. After the incubation, the cells that have migrated to the lower chamber are determined.
  • the compounds according to the invention can be converted into pharmaceutical preparations as follows:
  • Example 1 100 mg of the compound from Example 1, 50 mg lactose (monohydrate), 50 mg corn starch (native), 10 mg polyvinylpyrrolidone (PVP 25) and 2 mg magnesium stearate.
  • a single dose of 100 mg of the compound according to the invention corresponds to 10 ml of oral suspension.
  • Rhodigel is suspended in ethanol, the active ingredient is added to the suspension. The water is added with stirring. The swelling of the Rhodigel is stopped for about 6 hours.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Engineering & Computer Science (AREA)
  • Public Health (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Urology & Nephrology (AREA)
  • Vascular Medicine (AREA)
  • Cardiology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Pain & Pain Management (AREA)
  • Rheumatology (AREA)
  • Dermatology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)

Abstract

La présente invention concerne de nouveaux dérivés de benzofuro-1,4-diazépin-2-one, leur procédé de production et leur utilisation comme antagoniste du récepteur P2X4 pour la production de médicaments destinés au traitement et/ou à la prophylaxie de maladies, notamment d'artériosclérose, de resténose et autres maladies inflammatoires.
EP04719947A 2003-03-24 2004-03-12 Derives de benzofuro-1,4-diazepin-2-one Withdrawn EP1608659A1 (fr)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
DE10312969A DE10312969A1 (de) 2003-03-24 2003-03-24 Benzofuro-1,4-diazepin-2-on-Derivate
DE10312969 2003-03-24
PCT/EP2004/002580 WO2004085440A1 (fr) 2003-03-24 2004-03-12 Derives de benzofuro-1,4-diazepin-2-one

Publications (1)

Publication Number Publication Date
EP1608659A1 true EP1608659A1 (fr) 2005-12-28

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EP (1) EP1608659A1 (fr)
JP (1) JP2006521308A (fr)
CA (1) CA2519987A1 (fr)
DE (1) DE10312969A1 (fr)
WO (1) WO2004085440A1 (fr)

Families Citing this family (20)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2009057281A (ja) * 2005-12-19 2009-03-19 Nippon Chemiphar Co Ltd Ｐ２ｘ４受容体拮抗剤
JP2009062278A (ja) * 2005-12-29 2009-03-26 Nippon Chemiphar Co Ltd Ｐ２ｘ４受容体拮抗剤
WO2008020651A1 (fr) * 2006-08-17 2008-02-21 Kyushu University, National University Corporation antagoniste de récepteur P2X4
CN101541768A (zh) * 2006-08-25 2009-09-23 日本化学医药株式会社 P2x4受体拮抗剂
EP2184278A4 (fr) * 2007-08-10 2011-08-03 Nippon Chemiphar Co Antagoniste de récepteur p2x4
CN102395577B (zh) * 2009-02-16 2014-04-23 日本化学医药株式会社 二氮杂*二酮衍生物
EP2597088B1 (fr) 2010-07-13 2017-11-01 Nippon Chemiphar Co., Ltd. Antagoniste des récepteurs p2x4
US8673915B2 (en) 2010-07-29 2014-03-18 Nippon Chemiphar Co., Ltd. P 2×4 receptor antagonist
CA2810150C (fr) 2010-08-03 2018-06-05 Nippon Chemiphar Co., Ltd. Antagoniste du recepteur p2x4
CA2819997C (fr) 2010-11-05 2019-06-25 Kyushu University Agent preventif ou therapeutique de la douleur associee au zona en phase aigue
CA2840336C (fr) * 2011-05-25 2020-06-30 Kyushu University Agent prophylactique ou therapeutique pour la douleur neuropathique associee au syndrome de guillain-barre
EP2803662B1 (fr) * 2012-01-13 2017-03-01 Nippon Chemiphar Co., Ltd. Antagoniste des récepteurs p2x4
EP2814474B1 (fr) 2012-02-15 2020-11-18 The United States of America, as Represented By the Secretery, Department of Health and Human Services Procédés de traitement et de prévention de maladies et de troubles du système nerveux central
US10150744B2 (en) 2013-07-12 2018-12-11 Nippon Chemiphar Co., Ltd P2X4 receptor antagonist
JP6357475B2 (ja) 2013-07-12 2018-07-11 日本ケミファ株式会社 Ｐ２ｘ４受容体拮抗剤
WO2015088565A1 (fr) * 2013-12-13 2015-06-18 Sunovion Pharmaceuticals Inc. Composés modulateurs du récepteur p2x4 et leurs procédés d'utilisation
AU2017255086B2 (en) * 2016-04-28 2023-04-27 Kyushu University, National University Corporation Medicament for treatment of multiple sclerosis
US10695355B2 (en) 2017-03-30 2020-06-30 University Of Connecticut Methods for pharmacologic treatment of stroke
AU2020439775A1 (en) * 2020-03-30 2022-11-03 Nippon Chemiphar Co., Ltd. Medicament for use in preventing or treating irritable bowel syndrome or inflammatory bowel disease
WO2023239767A2 (fr) * 2022-06-07 2023-12-14 University Of Connecticut Compositions et méthodes pour le traitement pharmacologique d'un accident vasculaire cérébral et d'une lésion d'ischémie-reperfusion myocardique

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
TW219896B (fr) * 1988-07-07 1994-02-01 Duphar Int Res
ATE336492T1 (de) * 2000-01-14 2006-09-15 Us Gov Health & Human Serv Methonocarbacycloalkylanaloga von nucleosiden

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO2004085440A1 *

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