EP0788503A1 - Nouveaux derives de quinoxalinedione, leur preparation et leur utilisation dans des medicaments - Google Patents

Nouveaux derives de quinoxalinedione, leur preparation et leur utilisation dans des medicaments

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Publication number
EP0788503A1
EP0788503A1 EP95935834A EP95935834A EP0788503A1 EP 0788503 A1 EP0788503 A1 EP 0788503A1 EP 95935834 A EP95935834 A EP 95935834A EP 95935834 A EP95935834 A EP 95935834A EP 0788503 A1 EP0788503 A1 EP 0788503A1
Authority
EP
European Patent Office
Prior art keywords
alkyl
hydrogen
acid
trifluoromethyl
nitrogen atom
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Withdrawn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
EP95935834A
Other languages
German (de)
English (en)
Inventor
Andreas Huth
Martin Krüger
Eckhard Ottow
Dieter Seidelmann
Graham Hugh Jones
Herbert Schneider
Lechoslaw Turski
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 Pharma AG
Original Assignee
Schering 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 Schering AG filed Critical Schering AG
Publication of EP0788503A1 publication Critical patent/EP0788503A1/fr
Withdrawn legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6558—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system
    • C07F9/65583—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system each of the hetero rings containing nitrogen as ring hetero atom
    • 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
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/08—Antiepileptics; Anticonvulsants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P39/00—General protective or antinoxious agents
    • A61P39/02—Antidotes
    • 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
    • C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
    • C07D241/36—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings condensed with carbocyclic rings or ring systems
    • C07D241/38—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings condensed with carbocyclic rings or ring systems with only hydrogen or carbon atoms directly attached to the ring nitrogen atoms
    • C07D241/40—Benzopyrazines
    • C07D241/44—Benzopyrazines with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the hetero ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/28—Phosphorus compounds with one or more P—C bonds
    • C07F9/38—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)]
    • C07F9/40—Esters thereof
    • C07F9/4003—Esters thereof the acid moiety containing a substituent or a structure which is considered as characteristic
    • C07F9/4006—Esters of acyclic acids which can have further substituents on alkyl
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/553—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having one nitrogen atom as the only ring hetero atom
    • C07F9/576—Six-membered rings
    • C07F9/58—Pyridine rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/645—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having two nitrogen atoms as the only ring hetero atoms
    • C07F9/6509—Six-membered rings
    • C07F9/650952—Six-membered rings having the nitrogen atoms in the positions 1 and 4
    • C07F9/650994—Six-membered rings having the nitrogen atoms in the positions 1 and 4 condensed with carbocyclic rings or carbocyclic ring systems

Definitions

  • the invention relates to quinoxalinedione derivatives, their preparation and use in medicaments.
  • quinoxaline derivatives have affinity for the quisqualate receptors and, because of their affinity, are suitable as medicaments for the treatment of diseases of the central nervous system.
  • R 5 , R 6 , R 7 and R 8 are identical or different and are hydrogen C 1 -6- alkyl, CF 3 , nitro,
  • R 2 is hydrogen or - (CH 2 ) q -R 3 ,
  • R 3 is hydrogen, hydroxy, C 1-6 alkoxy or NR 15 R 16 ,
  • n, m and q each 0, 1, 2 or 3
  • R 11 is H, C 1 -6 alkyl, phenyl,
  • R 12 , R 13 and R 18 are hydrogen or C 1 -4 -alkyl
  • R 14 is H or optionally substituted 1-3 times by halogen C 1 -6 alkyl
  • X and Y are the same or different and denote hydroxy, C 1 -6- alkoxy, C 1 -4 -alkyl or NR 21 R 22 , R 15 and R 16 , R 21 and R 22 are the same or different and are hydrogen.
  • C 1 -4 -alkyl, aryl or together with the nitrogen atom form a 5-7-membered saturated heterocycle which can contain and be substituted by another oxygen, sulfur or nitrogen atom or form an unsaturated 5-membered heterocycle which Can contain 3 N atoms and can be substituted,
  • R 19 and R 20 are identical or different and form hydrogen, C 1 -4 -alkyl or together with the nitrogen atom a saturated 5-7-membered heterocycle which may contain a further oxygen, sulfur or nitrogen atom, and their isomers or Salts, at least one of the substituents R 5 , R 6 , R 7 or R 8 being aryl or hetaryl.
  • the compounds of general formula I also include the possible tautomeric forms and include the E or Z isomers or, if a chiral center is present, the racemates or enantiomers.
  • the substituents are preferably in the 6- and / or 7-position.
  • Alkyl is in each case to be understood as a straight-chain or branched alkyl radical, such as, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec. Butyl, pentyl, isopentyl, hexyl, C 1 -4 -alkyl radicals being preferred.
  • Halogen is to be understood as fluorine, chlorine, bromine and iodine.
  • the Aryirest R 5 , R 6 , R 7 or R 8 has 6-12 carbon atoms such as naphthyl, biphenyl or especially phenyl and can be substituted one or more times.
  • Hetaryl is to be understood as meaning optionally substituted 5- or 6-membered heteroaromatics with 1-3 nitrogen, oxygen and / or sulfur atoms, which can contain a fused-on benzene ring, such as thiophene, furan, oxazole, thiazole or pyridine, pyrimidine, pyrazine, Pyridazine, triazine, quinoline, isoquinoline.
  • Halogen or C 1 -4 -alkoxy, nitro, trifluoromethyl, C 1-4 -alkyl, NR 23 R 24 or SR 25 can occur as substituents one or more times, the meaning of NR 23 R 24 being the radical NR 15 R 16 and the meaning of R 25 corresponds to the radical R 14 .
  • the heteroaromatic can be linked to the quinoxaline in any position, but not via an N atom. If R 15 and R 16 , R 21 and R 22 , R 19 and R 20 form a saturated heterocycle together with the nitrogen atom, piperidine is for example. Pyrrolidine, morpholine, thiomorpholine, hexahydroazepine or piperazine are meant.
  • Heterocycle for example imidazole, pyrazole, pyrrole and triazole.
  • the physiologically tolerated salts of organic and inorganic bases are suitable as salts, such as the readily soluble alkali and alkaline earth metal salts and salts with N-methyl-glucamine, dimethyl-glucamine, ethyl-glucamine, lysine, 1,6-hexadiamine ,
  • physiologically compatible salts of organic and inorganic acids are suitable, such as HCl, H 2 SO 4 , phosphoric acid, citric acid. Tartaric acid etc.
  • the compounds of the formula I and their physiologically tolerable salts can be used as medicaments because of their affinity for the AMPA receptors.
  • the compounds according to the invention are suitable for the treatment of diseases which are caused by hyperactivity of excitatory amino acids such as, for example, glutamate or aspartate. Since the new compounds act as antagonists of excitatory amino acids and show a high specific affinity for the AMPA receptors by using the radiolabelled specific agonist (RS) a-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA) from displace the AMPA receptors, they are particularly suitable for the treatment of diseases which are influenced by the receptors of excitatory amino acids, in particular the AMPA receptor.
  • RS radiolabelled specific agonist
  • AMPA a-amino-3-hydroxy-5-methyl-4-isoxazole propionate
  • the compounds can be used for the treatment of neurological and psychiatric disorders which are triggered by overstimulation of the AMPA receptor.
  • Neurological diseases that can be treated functionally and preventively include, for example, neurodegenerative disorders such as Parkinson's disease, Alzheimer's disease, Huntington's disease, amyotrophic lateral sclerosis and olivopontocerebellar degeneration.
  • the compounds can be used to prevent post-ischemic cell death, cell death after brain trauma, in the event of a stroke. Hypoxia, anoxia and Hypogiycaemia and for the treatment of senile dementia, AIDS dementia, neurological symptoms associated with HIV infections. Multi-infarct dementia as well as epilepsy and muscle spasticity can be used.
  • Psychiatric disorders include anxiety, schizophrenia, migraines, pain, as well as the treatment of sleep disorders and withdrawal symptoms after drug abuse such as alcohol, cocaine, benzodiazepine or opiate withdrawal.
  • the compounds can also be used in the prevention of tolerance development during long-term treatment with sedative drugs such as benzodiazepines. Find barbiturates and morphine.
  • the compounds can be used as anesthetics (anesthetic), anti-pain medication or antiemetics.
  • the compounds according to the invention are brought into the form of a pharmaceutical preparation which, in addition to the active substance for enteral or parenteral administration, has suitable pharmaceutical, organic or inorganic inert carrier materials, such as, for example, water, gelatin, gum arabic,
  • the pharmaceutical preparations can be in solid form, for example as tablets. Dragees, suppositories, capsules or in liquid form, for example as solutions, suspensions or emulsions. If necessary, they also contain auxiliary substances such as preservatives, stabilizers, wetting agents or emulsifiers, salts for changing the osmotic pressure or buffers.
  • Injection solutions or suspensions in particular aqueous solutions of the active compounds in polyhydroxyethoxyated castor oil, are particularly suitable for parenteral use.
  • Surfactant auxiliaries such as salts of bile acids or animal or vegetable phospholipids, but also mixtures thereof and liposomes or their components can also be used as carrier systems.
  • Tablets are particularly suitable for oral use.
  • Dragees or capsules with talc and / or hydrocarbon carriers or binders, such as lactose, corn or potato starch, are suitable. It can also be used in liquid form, for example as juice, to which a sweetener may be added.
  • the dosage of the active ingredients can vary depending on the route of administration, age and weight of the patient, type and severity of the disease to be treated and similar factors.
  • the daily Dose is 0.5-1000 mg, preferably 50-200 mg, whereby the dose can be given as a single dose to be administered or divided into 2 or more daily doses.
  • the compound of the invention is prepared by methods known per se.
  • compounds of formula I can be obtained by using a compound of formula II
  • R 1 to R 8 have the meaning given above, cyclized with oxalic acid or reactive oxalic acid derivatives and, if desired, then saponifying the ester group or esterifying or amidating the acid group or introducing a tetrazole group or separating the isomers or forming the salts.
  • R 1 has the above meaning and R 5 ' , R 6' , R 7 ' and R 8' are a leaving group or R 5 , R 6 , R 7 or R 8 , a leaving group is replaced by aryl or hetaryl and then the Nitro group reduced to the amino group in the usual way.
  • the cyclization to compounds of formula I is carried out in a known manner with oxalic acid in a single stage in an acidic medium or with a reactive oxalic acid derivative in one or two stages.
  • the two-stage process should preferably be considered, in which the diamine with an oxalic acid derivative such as oxal ester half-chloride or reactive oxalic acid imidazolide derivatives in polar solvents such as cyclic or acyclic ethers or halogenated hydrocarbons, for example tetrahydrofuran, diethyl ether or methylene chloride or in water according to Schotten Baumann in the presence of a base such as organic Amines, for example triethylamine, pyridine, Hünig base or dimethylaminopyridine or also soda or sodium hydroxide solution.
  • the subsequent cyclization can be carried out in a basic or acidic manner, but preferably in an acidic environment, and solubilizers such as alcohol or
  • Suitable bases for the two-stage process are also alkali metal hydrides such as NaH, which are used in inert solvents such as hydrocarbons or ethers.
  • Halogens such as fluorine, chlorine, bromine, iodine or O-mesylate, O-tosylate are escape groups in the preparation of compounds of the formula II.
  • the nucleophilic substitution for the introduction of the aryl or hetaryl residues is carried out under the catalysis of transition metal complexes such as Pd (O), e.g. Palladium tetrakistriphenylphosphine or Pd (2+) e.g.
  • Palladium-bis-tri-o-tolylphosphine dichloride or nickel (O) may be carried out according to methods known from the literature in the presence of a base and is activated by an activating electron-withdrawing group such as e.g. Nitro, cyano, trifluoromethyl preferably favored in the o-position.
  • an activating electron-withdrawing group such as e.g. Nitro, cyano, trifluoromethyl preferably favored in the o-position.
  • Suitable nucleophiles are, for example, aryl or hetarylboronic acids or boranes or organotin compounds, organozinc compounds or also Grignard compounds.
  • the reaction can be carried out in polar solvents such as dimethylformamide, dimethylacetamide, acetonitrile, in hydrocarbons such as toluene or in ethers such as tetrahydrofuran, dimethoxyethane or diethyl ether.
  • Suitable bases are inorganic bases such as alkali or alkaline earth metal hydroxides or carbonates or organic bases such as cyclic, alicyclic and aromatic amines, such as pyridine, triethylamine, DBU, Hunig base.
  • the optionally subsequent saponification of an ester group can be carried out in a basic or, preferably, acidic manner by hydrolysing at elevated temperature to the boiling point of the reaction mixture in the presence of acids such as highly concentrated aqueous hydrochloric acid, if appropriate in solvents such as trifluoroacetic acid or alcohols.
  • acids such as highly concentrated aqueous hydrochloric acid, if appropriate in solvents such as trifluoroacetic acid or alcohols.
  • Phosphonic acid esters are preferred by heating in highly concentrated aqueous Acids such as concentrated hydrochloric acid, optionally with the addition of an alcohol or by treatment with trimethylsilyl halide in inert solvents such as acetonitrile and subsequent treatment with water.
  • esterification of the carboxylic acid or phosphonic acid takes place in a manner known per se with the corresponding alcohol with acid catalysis or in the presence of an activated acid derivative.
  • suitable acid derivatives are acid chloride, imidazolide or anhydride.
  • the esterification can be achieved by reaction with orthoesters, if appropriate with the addition of catalysts such as p-toluenesulfonic acid.
  • amidation takes place on the free acids or on their reactive derivatives such as acid chlorides, mixed anhydrides, imidazolides or azides by reaction with the corresponding amines at room temperature.
  • the tetrazole can be introduced by reacting the corresponding nitrile with an azide, e.g. Trimethylsilyl azide. Hydrogen nitric acid or sodium azide, optionally with the addition of a proton source such as e.g. Ammonium chloride or triethylammonium chloride in polar solvents such as dimethylformamide. Dimethylacetamide or N-methylpyrrolidone at temperatures up to the boiling point of the solvent.
  • an azide e.g. Trimethylsilyl azide.
  • Hydrogen nitric acid or sodium azide optionally with the addition of a proton source such as e.g. Ammonium chloride or triethylammonium chloride in polar solvents such as dimethylformamide. Dimethylacetamide or N-methylpyrrolidone at temperatures up to the boiling point of the solvent.
  • the isomer mixtures can be separated into the enantiomers or E / Z isomers by customary methods such as, for example, crystallization, chromatography or salt formation.
  • the salts are prepared in a customary manner by adding a solution of the compound of the formula I with the equivalent amount or an excess of a base or acid, which is optionally in solution. added and the precipitate is separated off or the solution is worked up in the usual way.
  • the collected aqueous phase is acidified to pH 1 with 4N hydrochloric acid and extracted three times with 100 ml of ethyl acetate.
  • the organic phase is washed with water, dried, filtered and concentrated. 6.85 g (68% of theory) of N- (2-nitro-4-trifluoromethyl-5-chlorophenyl) aminomethanephosphonic acid with a melting point of 207.3 ° C. are obtained.
  • N- (2-nitro-4-trifluoromethyl-5-chlorophenyl) aminomethanephosphonic acid 1.67 g of N- (2-nitro-4-trifluoromethyl-5-chlorophenyl) aminomethanephosphonic acid are mixed with 190 mg of p-toluenesulfonic acid in 25 ml of triethyl orthoformate and heated to a bath temperature of 150 ° C. for 3 hours. After evaporation in vacuo, it is taken up in 25 ml of water and extracted three times with 25 ml of ethyl acetate. The collected ethyl acetate phase is washed once with water, dried, filtered and concentrated. 2 g (> 100% of theory) of diethyl N- (2-nitro-4-trifluoromethyl-5-chlorophenyl) aminomethanephosphonate are obtained.
  • N [(6-Tnfluoromethyl-7- (pyrid-3-yl) -1,2,3,4-tetrahydroquinoxaline-2,3-dione) -1yl] methanephosphonic acid diethyl ester N - [(6-Trifluoromethyl-7- (4-methoxyphenyi) -1,2.3,4-tetrahydroquinoxaline-2,3-dione) -1yl] methanephosphonic acid diethyl ester.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Molecular Biology (AREA)
  • Biochemistry (AREA)
  • Medicinal Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Engineering & Computer Science (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Chemical & Material Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Biomedical Technology (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Psychiatry (AREA)
  • Pain & Pain Management (AREA)
  • Hospice & Palliative Care (AREA)
  • Toxicology (AREA)
  • Pulmonology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne de nouveaux dérivés de quinoxalinedione (I), leur préparation et leur utilisation dans des médicaments.
EP95935834A 1994-10-25 1995-10-25 Nouveaux derives de quinoxalinedione, leur preparation et leur utilisation dans des medicaments Withdrawn EP0788503A1 (fr)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
DE4439492 1994-10-25
DE4439492A DE4439492A1 (de) 1994-10-25 1994-10-25 Neue Chinoxalindionderivate, deren Herstellung und Verwendung in Arzneimitteln
PCT/DE1995/001517 WO1996012724A1 (fr) 1994-10-25 1995-10-25 Nouveaux derives de quinoxalinedione, leur preparation et leur utilisation dans des medicaments

Publications (1)

Publication Number Publication Date
EP0788503A1 true EP0788503A1 (fr) 1997-08-13

Family

ID=6532530

Family Applications (1)

Application Number Title Priority Date Filing Date
EP95935834A Withdrawn EP0788503A1 (fr) 1994-10-25 1995-10-25 Nouveaux derives de quinoxalinedione, leur preparation et leur utilisation dans des medicaments

Country Status (6)

Country Link
US (1) US6143733A (fr)
EP (1) EP0788503A1 (fr)
JP (1) JPH10507459A (fr)
CA (1) CA2203656A1 (fr)
DE (1) DE4439492A1 (fr)
WO (1) WO1996012724A1 (fr)

Families Citing this family (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6057304A (en) * 1992-10-26 2000-05-02 Schering Aktiengesellschaft Quinoxaline-phosphonic acid derivatives
US5631373A (en) * 1993-11-05 1997-05-20 State Of Oregon, Acting By And Through The Oregon State Board Of Higher Education, Acting For And On Behalf Of The Oregon Health Sciences University And The University Of Oregon, Eugene Oregon Alkyl, azido, alkoxy, and fluoro-substituted and fused quinoxalinediones
GB9419318D0 (en) * 1994-09-24 1994-11-09 Pfizer Ltd Therapeutic agents
DE19519979A1 (de) * 1995-05-24 1996-11-28 Schering Ag Neue Chinoxalindionderivate, deren Herstellung und Verwendung in Arzneimitteln
DE19545251A1 (de) * 1995-11-24 1997-05-28 Schering Ag Neue Chinoxalindionderivate, deren Herstellung und Verwendung in Arzneimitteln
GB9605027D0 (en) * 1996-03-09 1996-05-08 Pfizer Ltd Quinoxalinediones
US6153650A (en) * 1996-10-23 2000-11-28 Warner-Lambert Company Substituted gamma aminobutyric acids as pharmaceutical agents
DE19737446A1 (de) * 1997-08-22 1999-02-25 Schering Ag Verfahren zur Herstellung von Phosphonsäurederivaten
WO2000001376A2 (fr) * 1998-07-02 2000-01-13 Eisai Co., Ltd Compositions pharmaceutiques et leur utilisation
CN1298704C (zh) 2000-01-24 2007-02-07 神经研究公司 具有神经营养活性的靛红衍生物
TW200403066A (en) * 2002-04-30 2004-03-01 Novartis Ag New uses of substituted aminoalkanephosphonic acids
US20060148841A1 (en) * 2004-02-26 2006-07-06 Lundeen James E Pharmaceutical composition comprising combination of non-alkaloid and alkaloid-based component for treating skeletal muscle spasm
WO2010053757A1 (fr) * 2008-10-29 2010-05-14 Gilead Palo Alto, Inc. Inhibiteurs, à base de 2-oxoquinoxaline, des canaux sodiques tardifs

Family Cites Families (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS5586482A (en) * 1978-12-25 1980-06-30 Narita Katsumi Vague operation absorbing machine of safe ball receiving instrument for pinball machine
JPS59120941A (ja) * 1982-12-28 1984-07-12 Fujitsu Ltd 透過型センサ
JPS62129746A (ja) * 1985-11-30 1987-06-12 Nippon Kokan Kk <Nkk> エッジピンホール検出装置
DK142388A (da) * 1987-03-17 1988-09-18 Diagnostic Systems Inc Fremgangsmaade og apparat til detektering af analyter i fluidumproever, navnlig glucose i legemesvaesker
DK69790D0 (da) * 1990-03-16 1990-03-16 Novo Nordisk As Heterocykliske forbindelser, deres fremstilling af anvendelse
PT101004B (pt) * 1991-10-26 1999-10-29 Schering Ag Derivados da quinoxalina, processo para a sua preparacao e composicoes farmaceuticas que os contem
DE4217952A1 (de) * 1992-05-30 1993-12-02 Basf Ag Chinoxalin-2,3(1H,4H)-dione
IL109397A0 (en) * 1993-04-28 1994-07-31 Schering Ag Quinoxalinedione derivatives, processes for the preparation thereof and pharmaceutical compositions containing the same

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO9612724A1 *

Also Published As

Publication number Publication date
JPH10507459A (ja) 1998-07-21
CA2203656A1 (fr) 1996-05-02
DE4439492A1 (de) 1996-05-02
US6143733A (en) 2000-11-07
WO1996012724A1 (fr) 1996-05-02

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