WO1999000384A1 - Nouveaux derives de dione de quinoxaline, leur preparation et leur utilisation dans des medicaments - Google Patents

Nouveaux derives de dione de quinoxaline, leur preparation et leur utilisation dans des medicaments Download PDF

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Publication number
WO1999000384A1
WO1999000384A1 PCT/DE1998/001821 DE9801821W WO9900384A1 WO 1999000384 A1 WO1999000384 A1 WO 1999000384A1 DE 9801821 W DE9801821 W DE 9801821W WO 9900384 A1 WO9900384 A1 WO 9900384A1
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WO
WIPO (PCT)
Prior art keywords
trifluoromethyl
compounds
tetrahydro
formula
hydrogen
Prior art date
Application number
PCT/DE1998/001821
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German (de)
English (en)
Inventor
Andreas Huth
Eckhard Ottow
Ingrid Schumann
Martin Krüger
Original Assignee
Schering Aktiengesellschaft
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 Aktiengesellschaft filed Critical Schering Aktiengesellschaft
Priority to AU90614/98A priority Critical patent/AU9061498A/en
Priority to EP98942480A priority patent/EP0993461A1/fr
Priority to JP50521699A priority patent/JP2002506450A/ja
Publication of WO1999000384A1 publication Critical patent/WO1999000384A1/fr

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Classifications

    • 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
    • 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
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • 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
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • 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
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs
    • 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
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
    • 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
    • A61P25/20—Hypnotics; Sedatives
    • 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
    • A61P25/22—Anxiolytics
    • 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
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
    • 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

Definitions

  • the invention relates to quinoxalinedione derivatives, their preparation and use in medicaments.
  • quinoxaline derivatives have affinity for the quisqualate receptors and, because of the affinity, are suitable as medicaments for the treatment of diseases of the central nervous system.
  • 1-carboxylic acid quinoxaline derivatives are known to be very sparingly soluble and, because of their poor dissolving behavior, cannot be used as medicaments.
  • the compounds according to the invention not only have excellent affinity for the AMPA receptor, but are also distinguished by very good solubility in water.
  • the compounds according to the invention have the formula I.
  • R 1 - (CH 2 ) n -CR 2 H- (CH2) mZ and R5 and R6 are the same or different and are hydrogen, NO2, halogen, cyano or optionally halogenated C 1-8 alkyl,
  • R 2 is hydrogen or - (CH2> q -R 3
  • R 3 is hydrogen, hydroxy, C-
  • n, m and q each 0, 1, 2 or 3
  • R 3 and R9 together with the nitrogen atom mean pyrrolidine, morpholine, thiomorpholine, piperazine or hexahydroazepine, which can be substituted by C-
  • R 1 6 OH, C- ⁇ e alkoxy or NR 1 2 R 1 3
  • R 1 1, R 1 2 unc j R 1 3 are the same or different and form hydrogen, C 1-4 alkyl, phenyl or together with the nitrogen atom a 5-7 membered saturated heterocycle, which is another oxygen, sulfur or nitrogen atom can contain and be substituted
  • the compounds of the general formula I also include the possible tautomeric forms or, if a chiral center is present, the racemates or enantiomers.
  • the substituents R ⁇ , R6 and R 7 can be in any position, preferably in the 6- and 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, tert. Butyl, pentyl, isopentyl, hexyl, with C-1.4 alkyl radicals being preferred.
  • alkyl radical is halogenated, it can be present one to more times or perhalogenated and in particular means CF3.
  • Halogen is to be understood as fluorine, chlorine, bromine and iodine.
  • R " O and R ⁇ 'R ⁇ 2 and R ⁇ 3 form a saturated heterocycle together with the nitrogen atom, this means, for example, pyrrolidine, morpholine, thiomorpholine, piperidine, hexahydroazepine or piperazine.
  • the heterocycles can -substituted with C 1-4 alkyl or a phenyl, benzyl or benzoyl radical which is optionally substituted with halogen, for example N-methylpiperazine, 2,6-dimethylmorpholine or phenylpiperazine.
  • the physiologically compatible salts of organic and inorganic bases are suitable as salts, for example the readily soluble alkali and alkaline earth metal salts and the salts with N-methylglucamine, dimethylglucamine, ethylglucamine, lysine, 1, 6- Hexadiamine, ethanolamine, glucosamine, sarcosine, serinol, tris-hydroxymethylamino-methane, aminopropanediol, sovak base, 1-amino-2,3,4-butanetriol.
  • physiologically compatible salts of organic and inorganic acids such as HCI, H2SO4, phosphoric acid, citric acid, tartaric acid and others are suitable.
  • the compounds of the formula I and their physiologically tolerable salts can be used as medicaments because of their affinity for the AM PA receptors.
  • the compounds according to the invention are suitable for the treatment of diseases caused by hyperactivity excitatory amino acids such as 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 to 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 AM PA 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.
  • the 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 for the prevention of post-ischemic cell death, cell death after brain trauma, stroke, hypoxia, anoxia and hypoglycemia 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 become.
  • 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 find use in the prevention of tolerance development during long-term treatment with sedative drugs such as benzodiazepines, barbiturates and morphine.
  • the compounds can be used as anesthetics (anesthetic), anti-pain medication or antiemetics.
  • mice weighing 1 8-22 g were kept under controlled conditions (6 0 0 -1 8 0 0 o'clock light / dark rhythm, with free access to food and water) and their assignment to groups was randomized.
  • the groups consisted of 5 - 1 6 animals. The animals were observed between 8 ° and 13 °.
  • AMPA was injected into the left ventricle by freely moving mice.
  • the applicator consisted of a cannula with a stainless steel device that limits the depth of the injection to 3.2 mm.
  • the applicator was connected to an injection pump.
  • the injection needle was inserted perpendicular to the surface of the skull according to the coordinates of Montemurro and Dukelow.
  • the animals were observed for up to 180 seconds until clonic or tonic cramps occurred.
  • the clonic movements that lasted longer than 5 seconds were counted as convulsions.
  • the beginning of the clonic cramps was used as the end point for the determination of the cramp threshold.
  • the dose required to increase or decrease the seizure threshold by 50% (THRD50) was determined in 4-5 experiments.
  • the THRD50 and confidence limits were determined in a regression analysis.
  • Treatment with the compounds according to the invention prevents or delays the cell damage and functional disorders which occur as a result of the disease and reduces the symptoms which arise as a result.
  • the indications can be shown by conventional pharmacological tests.
  • a pharmaceutical preparation which, in addition to the active ingredient for enteral or parenteral administration, has suitable pharmaceutical, organic or inorganic inert carrier materials, such as, for example, water, gelatin, gum arabic, lactose, starch , Magnesium stearate, talc, vegetable oils, polyalkylene glycols etc. contains.
  • the pharmaceutical preparations can be in solid form, for example as tablets, dragées, 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 polyhydroxyethoxylated 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, coated tablets or capsules with talc and / or hydrocarbon carriers or binders, such as lactose, corn or potato starch, are particularly suitable for oral use. 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, and the dose can be given as a single dose to be administered once or divided into 2 or more daily doses.
  • the compound of the invention is prepared by methods known per se.
  • compounds of the formula I are obtained by
  • R 2 'R 5 , R * ⁇ R 7 , n and m have the above meaning and Z' has the meaning of Z or -C ⁇ N, cyclized with oxalic acid or reactive oxalic acid derivatives or
  • m, - (e j have the above significance, if desired, hydrolyzed and then esterified carboxyl or amidated or the isomers are separated or forms, the salts.
  • R 1 'R 1 or (CH2) n-CR 2 - ( CH 2) rrf CsN and R 5 ', R 6 'and R 7 ' represent a leaving group or R ⁇ , R6 or R 7 , substituted a leaving group and the nitro group is reduced and cyclized analogously to process variant a) with oxalic acid or reactive oxalic acid derivatives.
  • 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 subsequent cyclization can be carried out in a basic or acidic manner, but preferably in an acidic environment, and solubilizers such as alcohol or acetonitrile can be added to the reaction mixture.
  • 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, O-triflate or O-nonaflate are suitable as escape groups of the compounds of the formula III.
  • the nucleophilic substitution with amines is carried out at the lowest possible temperature, preferably at room temperature. An excess of amine is not a disadvantage.
  • the amine can also be used as a solvent. Suitable solvents are ethers such as tetrahydrofuran or hydrocarbons such as toluene or halogenated hydrocarbons such as methylene chloride.
  • alkenyl compounds takes place with the catalysis of transition metal complexes such as Pd (0), e.g.
  • Palladium tetrakistriphenylphosphine or Pd ⁇ 2 + such as palladium-bis-tri-o-tolylphosphine dichloride or nickel (O) according to methods known from the literature, if appropriate in the presence of a base and is preferably activated by an activating electron-withdrawing group such as nitro, cyano, trifluoromethyl Favored position.
  • the corresponding boronic acids are, for example, nucleophiles. or - boranes or organotin compounds, organozinc compounds, Grignard compounds or the alkenyls as such are suitable.
  • 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, carbonates or acetates or organic bases such as cyclic, alicyclic and aromatic amines such as pyridine, triethylamine, DBU, Hunig base, optionally with the addition of water.
  • Any subsequent oxidative cleavage of the alkenyl compounds to the aldehyde can be carried out using methods known from the literature. Ozonation in solvents such as e.g. halogenated hydrocarbons or alcohols or mixtures thereof at temperatures from -78 ° C to room temperature.
  • solvents such as e.g. halogenated hydrocarbons or alcohols or mixtures thereof at temperatures from -78 ° C to room temperature.
  • the ozonide which forms is reductively cleaved to form the aldehyde by trapping with thiourea, trialkylphosphites or, preferably, with triarylphosphines.
  • the aldehyde can be chain extended by e.g. by Petersonolefinitation, or by Wittig or Wittig-Homer reaction initially produces an appropriate enol ether.
  • the aldehyde with the previously generated anion e.g. an appropriately substituted phosphonium salt or phosphonic acid ester in solvents such as toluene, tetrahydrofuran, diethyl ether or dimethoxyethane.
  • bases are e.g. Alkali hydrides, alkali amides, alkali alcoholates such as potassium tert-butoxide, alkali or alkaline earth carbonates or hydroxides, optionally in the presence of phase transfer catalysts such as e.g.
  • Crown ethers or organic bases such as triethylamine, diisopropylethylamine or diazabicycloundecane, if appropriate in the presence of salts such as lithium bromide, are suitable.
  • the corresponding enol ether can then be cleaved by acid.
  • the aldehydes can be reduced to the corresponding alcohols by methods known from the literature.
  • the reduction is preferably carried out with complex metal hydrides such as sodium boranate in solvents such as alcohol.
  • the hydroxyl group can be converted into escape groups such as chloride, bromide, iodide, triflate, mesylate or tosylate by methods known from the literature and by various processes. It is preferably converted into the chloride or tosylate with tosyl chloride in the presence of bases such as, for example, triethylamine, ethyldiisopropylamine or dimethylaminopyridine in solvents such as halogenated hydrocarbons or ethers.
  • bases such as, for example, triethylamine, ethyldiisopropylamine or dimethylaminopyridine in solvents such as halogenated hydrocarbons or ethers.
  • nucleophilic substitution is carried out by nucleophiles such as amines in solvents such as alcohols, halogenated hydrocarbons or ketones or without solvents, optionally with the addition of a base such as alkali or alkaline earth metal hydroxide or carbonate or else organic bases such as e.g. Triethylamine, ethyldiisopropylamine or
  • the nitro group is reduced in the customary manner catalytically or by reduction with iron powder in acetic acid at elevated temperature or else with sodium sulfide and ammonium hydroxide in alcohol.
  • the reduction of the alkenyl group takes place in the usual way catalytically and then usually takes place together with the reduction of the nitro group.
  • the optionally subsequent saponification of an ester group or the saponification of a nitrile 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, optionally in solvents such as trifluoroacetic acid or alcohols.
  • esterification of the carboxylic 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 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 amidation can also be carried out directly from the ester by reaction with an amine in the presence of trimethyl aluminum.
  • 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 the 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, and removing the precipitate or working up the solution in the customary manner.
  • the starting materials are produced by processes known from the literature.
  • the residue is taken up in 100 ml of ethanol, mixed with 100 ml of 1N hydrochloric acid and heated to a bath temperature of 110 ° C. for 2 h.
  • the ethanol is then drawn off and extracted three times with 100 ml of ethyl acetate each time.
  • the organic phase is washed with water, dried, filtered and concentrated.
  • the residue is covered with silica gel

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

Abstract

L'invention concerne des composés de la formule (I), ainsi que leur préparation et leur utilisation dans des médicaments.
PCT/DE1998/001821 1997-06-27 1998-06-26 Nouveaux derives de dione de quinoxaline, leur preparation et leur utilisation dans des medicaments WO1999000384A1 (fr)

Priority Applications (3)

Application Number Priority Date Filing Date Title
AU90614/98A AU9061498A (en) 1997-06-27 1998-06-26 New quinoxaline dione derivatives, the production thereof and use of the same inmedicaments
EP98942480A EP0993461A1 (fr) 1997-06-27 1998-06-26 Nouveaux derives de dione de quinoxaline, leur preparation et leur utilisation dans des medicaments
JP50521699A JP2002506450A (ja) 1997-06-27 1998-06-26 Ａｍｐａ受容体アンタゴニストとしてのキノキサリンジオン誘導体

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE19728326.8 1997-06-27
DE19728326A DE19728326A1 (de) 1997-06-27 1997-06-27 Neue Chinoxalindionderivate, deren Herstellung und Verwendung in Arzneimitteln

Publications (1)

Publication Number Publication Date
WO1999000384A1 true WO1999000384A1 (fr) 1999-01-07

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Application Number Title Priority Date Filing Date
PCT/DE1998/001821 WO1999000384A1 (fr) 1997-06-27 1998-06-26 Nouveaux derives de dione de quinoxaline, leur preparation et leur utilisation dans des medicaments

Country Status (5)

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EP (1) EP0993461A1 (fr)
JP (1) JP2002506450A (fr)
AU (1) AU9061498A (fr)
DE (1) DE19728326A1 (fr)
WO (1) WO1999000384A1 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11034669B2 (en) 2018-11-30 2021-06-15 Nuvation Bio Inc. Pyrrole and pyrazole compounds and methods of use thereof

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7892755B2 (en) * 2004-08-30 2011-02-22 Takeda Pharmaceutical Company Limited Screening method

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1993008173A1 (fr) * 1991-10-26 1993-04-29 Schering Aktiengesellschaft Derives de quinoxaline ayant une affinite pour les recepteurs de quisqualate
DE4314592A1 (de) * 1993-04-28 1994-11-03 Schering Ag Benzo(f)chinoxalindionderivate, deren Herstellung und Verwendung in Arzneimitteln
WO1994025469A1 (fr) * 1993-04-28 1994-11-10 Schering Aktiengesellschaft Nouveaux derives de quinoxalinedione, leur fabrication et leur utilisation dans des medicaments
WO1996010023A1 (fr) * 1994-09-27 1996-04-04 Yamanouchi Pharmaceutical Co., Ltd. Derive de 1,2,3,4-tetrahydroquinoxalindione

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1993008173A1 (fr) * 1991-10-26 1993-04-29 Schering Aktiengesellschaft Derives de quinoxaline ayant une affinite pour les recepteurs de quisqualate
DE4314592A1 (de) * 1993-04-28 1994-11-03 Schering Ag Benzo(f)chinoxalindionderivate, deren Herstellung und Verwendung in Arzneimitteln
WO1994025469A1 (fr) * 1993-04-28 1994-11-10 Schering Aktiengesellschaft Nouveaux derives de quinoxalinedione, leur fabrication et leur utilisation dans des medicaments
WO1996010023A1 (fr) * 1994-09-27 1996-04-04 Yamanouchi Pharmaceutical Co., Ltd. Derive de 1,2,3,4-tetrahydroquinoxalindione

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11034669B2 (en) 2018-11-30 2021-06-15 Nuvation Bio Inc. Pyrrole and pyrazole compounds and methods of use thereof

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JP2002506450A (ja) 2002-02-26
AU9061498A (en) 1999-01-19
DE19728326A1 (de) 1999-01-07
EP0993461A1 (fr) 2000-04-19

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