WO1993020077A1 - Derive de quinoxalinone fondue et composition pharmaceutique le contenant - Google Patents

Derive de quinoxalinone fondue et composition pharmaceutique le contenant Download PDF

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Publication number
WO1993020077A1
WO1993020077A1 PCT/JP1993/000357 JP9300357W WO9320077A1 WO 1993020077 A1 WO1993020077 A1 WO 1993020077A1 JP 9300357 W JP9300357 W JP 9300357W WO 9320077 A1 WO9320077 A1 WO 9320077A1
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WO
WIPO (PCT)
Prior art keywords
group
quinoxaline
imidazolyl
compound
nitro
Prior art date
Application number
PCT/JP1993/000357
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English (en)
Japanese (ja)
Inventor
Shuichi Sakamoto
Jun-Ya Ohmori
Masao Sasamata
Masamichi Okada
Kazyuki Hidaka
Original Assignee
Yamanouchi Pharmaceutical Co., Ltd.
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 Yamanouchi Pharmaceutical Co., Ltd. filed Critical Yamanouchi Pharmaceutical Co., Ltd.
Publication of WO1993020077A1 publication Critical patent/WO1993020077A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

Definitions

  • the present invention relates to a fused quinoxalinone derivative and a pharmaceutical composition thereof.
  • the present invention relates to a fused quinoxalinone derivative having glutamate receptor antagonism, particularly NMD A-glycin receptor antagonism and Z or n 0 n-NMD A receptor antagonism, a tautomer thereof, and a pharmaceutical product thereof. And a hydrate thereof, and a pharmaceutical composition containing these.
  • amino acids such as L-glucamic acid and L-aspartic acid are central nervous system transmitters. Accumulation of these excitatory amino acids and continued excessive stimulation of the nerves are observed after Huntington's chorea, Parkinson's disease, epilepsy, senile dementia, and cerebral ischemia, anoxia, hypoglycemia Neurodegeneration is said to lead to mental and motor dysfunction.
  • drugs capable of regulating the abnormal action of these excitatory amino acids have been considered to be useful for treating neurodegenerative and psychiatric disorders.
  • excitatory amino acids The action of excitatory amino acids is exerted via specific receptors located at postsynaptic or presynaptic sites. Such receptors are currently subdivided into three groups based on electrophysiological and neurochemical evidence.
  • L-Glutamate and L-aspartate activate the above receptors and transmit excitement. Applying excessive amounts of NMDA, AMPA, and kainate to nerves causes neuropathy.
  • 2-Amino-5-phosphonovaleric acid or 2-amino-7-phosphonohepnoic acid a selective antagonist of the NMD A receptor, is used in experimental animal models of NMD A-induced neuropathy, epilepsy, and cerebral ischemia Pharmaceutical and Experimental Therapeutics, 250, 100 (1 989); J. Pharmacology and Experimental Therapeutics, 240, 737 (1 987); Science. 226, 850 (1 984) ) o
  • the NMD A receptor has been reported to work allosterically by the glycine receptor.
  • the European Journal of Pharmacology, 126, 303 (1 986)], HA, an antagonist of the glycine receptor, 966 has also been reported to be effective in laboratory animal models of cerebral ischemia (American Neuroscience Society 1989).
  • NBQX (2,3-dihydroxy-6-nitro-6-sulfamoylbenzo (f) quinoxalin), a selective AMP A receptor antagonist, is also effective in experimental animal models of cerebral ischemia. It has been reported [Science, _ ⁇ _ 47, 571 (1990)]. No selective antagonist of kainate receptor or metabotropic glutamate receptor has been reported so far.
  • the present inventors have synthesized various novel compounds for the purpose of providing a compound having glutamate receptor antagonism and conducted screening under the above-mentioned state of the art.
  • A) a fused quinoxalinone derivative represented by the formula (I), a tautomer thereof, a pharmaceutically acceptable salt thereof, or a hydrate thereof having excellent glutamate receptor antagonistic activity;
  • they have found that they have NMD A-glycine receptor antagonism and n 0 n-NMD A receptor antagonism (AMP A receptor antagonism and Z or kainate receptor antagonism), leading to the present invention.
  • R 1 nitro group or trifluoromethyl group c
  • R 7 mono or di-lower alkylamino group, or imidazolyl group.
  • R 8 a lower alkyl group or a cycloalkyl group.
  • one of the objects of the present invention is to provide a compound represented by the above general formula (I), a tautomer thereof, a pharmaceutically acceptable salt thereof, or a hydrate thereof.
  • Another object of the present invention is to provide a pharmaceutical composition containing a compound represented by the above general formula (I), a tautomer thereof, a pharmaceutically acceptable salt thereof, or a hydrate thereof. It is in.
  • the compound of the present invention includes two substituents: a 5-membered heterocyclic group containing 2 to 3 nitrogen atoms such as an imidazolyl group, and a nitro or trifluoromethyl group on the benzene ring of quinoxaline. It is a novel compound having a chemical structural characteristic in that it is a substituted imidazo- or triazoloquinoxalinone derivative.
  • the compounds of the present invention are pharmacologically characterized in that they have excellent NMD A-glycine receptor antagonistic activity and Z or non-NMD A receptor antagonistic activity (AMP A receptor antagonistic activity and / or kainate receptor antagonistic activity). Has features.
  • the compound having no substitution group of both a nitrogen-containing heterocyclic group and a nitro group or a trifluoromethyl group such as the compound of the present invention is referred to as EP04.
  • the compound of Example 2 of No. 05883 was confirmed as a comparative compound, almost no activity was observed, confirming the characteristics of the compound of the present invention in terms of chemical structure.
  • the “lower alkyl group” specifically includes, for example, a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a sec-butyl group, a tert-butyl group, a pentyl group, an isobutyl group Pentyl group, neopentyl group, tert-pentyl group, 1-methylbutyl group, 2-methylbutyl group, 1,2-dimethylpropyl group, hexyl group, isohexyl group, 1-methylpentyl group, 2-methylpentyl group, 3-methylpentyl group, 1,1-dimethylbutyl group, 1,2-dimethylbutyl group, 2,2-dimethylbutyl group, 1,3-dimethylbutyl group, 2,3-dimethylbutyl group, 3,3-dimethylbutyl Group, 1-ethylbut
  • a methyl group, Echiru group, d -C 4 alkyl groups such as isopropyl group, butyl group, especially methyl group, Echiru groups, C such as a propyl group, a -C 3 alkyl group is preferred.
  • the “lower alkylene group” represented by B includes methylene group, ethylene group, methylmethylene group, trimethylene group, 1-methylethylene group, 2-methylethylene group, tetramethylene group, 1-methyltrimethylene group, 2- Methyltrimethylene group, 3-methyltrimethylene group, 1-ethylethylene group, 2-ethylethylene group, 1,2-dimethylethylene group, propylmethylene group, pentamethylene group, 1-methyltetramethylene group, 2-methyltetramethylene group, 3-methyltetramethylene group, 4-methyltetramethylene group, 1-ethyltrimethylene group, 2-ethyltrimethylene group, 3-ethyltrimethylene group, 1,1-dimethyltrimethylene group, 2, 2-dimethyltrimethylene group, 3,3-dimethyltrimethylene group, hexamethylene group, 1-methylpentamethyl Down group, 2-methyl pentamethylene, 3-Mechirupen Tamechiren group, 4-methyl pentamethylene group, 5-M
  • the “mono- or di-lower alkylamino group J” means a group in which one or two hydrogen atoms of an amino group are substituted with the above “lower alkyl group_!”.
  • a methylamino group or an ethylamino group A monoalkylamino group substituted by a linear or branched lower alkyl group such as a mino group, a propylamino group, an isopropylamino group, a butylamino group, an isobutylamino group, a pentylamino group, an isopentylamino group, a hexylamino group; Symmetric dialkylamino groups, di-substituted by linear or branched lower alkyl groups such as dimethylamino, getylamino, dipropylamino, diisopropylamino, dibutylamino, dipentylamino, dihexylamino, etc.,
  • an amino group mono- or di-substituted with a lower alkyl group having 1 to 3 carbon atoms such as a methylamino group, an ethylamino group, a dimethylamino group, a dimethylamino group, a methylethylamino group, a methylpropylamino group, is preferred.
  • a lower alkanoylamino lower alkyl group j is
  • “Lower alkyl group” refers to a group in which any hydrogen atom of the "lower alkyl group” is replaced by a lower alkylaminoylamino group, specifically, for example, formylaminomethyl, forminoleaminoethyl, formylaminopropyl, 1- Honolemilaminomethylethyl group, formylaminobutyl group, 2-formylaminomethylpropyl group, formylaminopentyl group, holmi Laminohexyl, acetylaminomethyl, acetylaminoethyl, acetylaminopropyl, 1-acetylaminomethylethyl, acetylaminobutyl, 2-acetylaminomethylpropyl, Propionylaminomethyl group, propionylaminoethyl group, propionylaminopropyl group, butyrylaminomethyl group, butyrylamino
  • cycloalkyl group examples include those having 3 to 8 carbon atoms, specifically, a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group, a cyclooctyl group, Among them, a cycloalkyl group having 5 to 7 carbon atoms is preferable.
  • the “5-membered heterocyclic group containing 2 to 3 nitrogen atoms” include imidabryl group, imidabrinyl group, imidazolidinyl group, pyrazolyl group, birazolinyl group, birazolidinyl group, 1,2,4-triazolyl group 1,3,4—triazolyl group, 1,2,3—tozolyl group, etc., and these groups are quinoxalic via their nitrogen atoms. In the benzene ring. Of these, an imidazolyl group, a 1,2,4-triazolyl group, and particularly an imidabril group are preferred.
  • nitrogen-containing heterocyclic groups may be substituted with one or two lower alkyl groups or lower alkanoylamino lower alkyl groups.
  • the compound of the present invention has tautomers based on the quinoxalinone skeleton. Also, depending on the type of the substituent, there is optical isomerism (optical activity, racemate, diastereomer).
  • the present invention includes an isolated form or a mixture of these isomers.
  • the present compound may be isolated as a hydrate, a solvate with a solvent such as ethanol, or a polymorph as a product, and these compounds are included in the present invention.
  • the compound (I) forms a salt with an acid and a base.
  • the present invention also includes pharmaceutically acceptable salts of the compound (I).
  • the salt with an acid include hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid and the like.
  • salts with bases include inorganic bases such as sodium, potassium, lithium, magnesium, calcium, and aluminum, and organic bases such as methylamine, ethylamine, ethylamine, imidazole, lysine, and ordinine.
  • organic bases such as methylamine, ethylamine, ethylamine, imidazole, lysine, and ordinine.
  • particularly preferred compounds are those in which AN-is an imidazolyl group or a 1,2,4-triazolyl group,
  • the compound of the present invention can be synthesized by various methods utilizing the characteristics of the basic skeleton and the substituent.
  • the typical production method is illustrated below.
  • Examples of the active carbonyl compound include carbonyldiimidable, phosgene, bromophosgene, and disuccinimidyl carbonate.
  • the reaction is usually carried out by heating and stirring in a solvent such as dimethylformamide, dimethylsulfoxide, di-alpha-benzene, or nitrobenzene.
  • a solvent such as dimethylformamide, dimethylsulfoxide, di-alpha-benzene, or nitrobenzene.
  • the compound (I) of the present invention is obtained by heating and stirring the condensed quinoxaline 1-4 (5H) one compound (17) and a corresponding amount of the nitrogen-containing ring compound ( ⁇ ) in an inert solvent.
  • an inert solvent used in these methods include dimethylformamide, chloroform, benzene, toluene and the like.
  • the reaction product obtained by each of the above production methods is isolated and purified as a free compound, a salt thereof, a hydrate or various solvates.
  • the salt can be produced by subjecting it to a usual salt formation reaction.
  • Isolation and purification are performed by applying ordinary chemical operations such as extraction, concentration, distillation, crystallization, filtration, recrystallization, and various types of chromatography.
  • Industrial applicability such as extraction, concentration, distillation, crystallization, filtration, recrystallization, and various types of chromatography.
  • the compound of the present invention has a strong affinity for NMD A-glycine receptor and Z or non-NMD A receptor, particularly AMPA receptor, and is one-D of n 0 n-NMD A receptor. It also has affinity for kainate receptors.
  • the compound of the present invention further exhibits a potent audiogenic seizure inhibitory action in DBAZ2 mice and a potent neuroprotective action in sand rats.
  • AMP A receptor binding activity [ 3 H] —AMP A binding inhibitory activity is, for example, that of the compound of Example 6.
  • the K i value was 20 nM.
  • Example 6 the compound of Example 6 was treated with DBA /
  • the compound of Example 5 is 60 minutes, 70 minutes after 5 minutes of ischemia,
  • NMD A- measurement of the effect of glycine receptor ([3 H] MK-80 1 binding inhibitory activity):
  • test compound was suspended in a 0.5% methylcellulose solution and administered intraperitoneally 15 minutes before sound stimulation.
  • the efficacy was evaluated by the presence or absence of seizures, and the minimum effective dose (MED) was determined.
  • MED minimum effective dose
  • the bilateral common carotid artery was occluded for 5 minutes under halothane anesthesia while the rats were kept warm to avoid hypothermia, and the animals were allowed to recover from anesthesia.
  • the brain was removed and sectioned, and the degree of neuronal damage in the hippocampal CAI was examined histologically.
  • test drug was suspended in 0.5% methylcellulose solution or dissolved in physiological saline and administered intraperitoneally. At 60 minutes, 70 minutes, and 85 minutes after reopening, administration of 3 OmgZkg was performed once.
  • reaction buffer 50 mM Tris HC1, 5 mM EGTA pH 7.1
  • Wistar male rat cerebral cortex membrane preparation 5 nM [ 3 H] Kainate
  • the compound was incubated at 0 ° C. for 60 minutes.
  • the reaction was stopped by sucking and filtering the reaction solution with a glass filter.
  • the scintillation cocktail was added to the glass filter, and the non-specific binding measured by) 3 counter was determined in the presence of 0.6 mM glutamic acid, and the specific binding was determined by subtracting the non-specific binding from the total binding. .
  • the compounds of the present invention show excellent glutamate receptor antagonism, particularly NMDA-glycine receptor and Z or n 0 n-NMDA receptor (AMP A receptor and Z or Has an antagonistic effect on adenosine receptor), an inhibitory effect on audiogenic seizures, and a protective effect on neurons or neurons.
  • AMP A receptor and Z or Has an antagonistic effect on adenosine receptor an inhibitory effect on audiogenic seizures
  • a protective effect on neurons or neurons ⁇ ⁇ , Prevention of cerebral hemorrhage, cerebral ischemia, cerebral infarction, cardiac arrest, anoxia, etc. It is useful as a psychotropic drug for the prevention and / or treatment of psychiatric disorders such as Huntington's chorea, Parkinson's disease, epilepsy, Alzheimer's disease, senile dementia, depression and anxiety.
  • compositions containing one or more of compound (I), a tautomer thereof, a pharmacologically acceptable salt thereof, or a hydrate thereof as an active ingredient are usually used for formulation. It is prepared using a carrier, an excipient, and other additives.
  • Pharmaceutical carriers and excipients may be solid or liquid, such as lactose, magnesium stearate, starch, talc, gelatin, agar, pectin, gum arabic, olive oil, sesame oil, and cocoa butter. , Ethylene glycol and the like and other commonly used ones.
  • Administration is oral, such as tablets, pills, capsules, granules, powders, and liquids, or parenteral, such as injections such as intravenous and intramuscular injections, suppositories, transdermal agents, and narrowing agents. Either form may be used, and it may be performed systemically or locally.
  • the dosage varies depending on age, body weight, symptoms, therapeutic effect, administration method, treatment time, etc., but is usually 1 to 100 mg / day, preferably 50 to 200 mg / day for an adult. Orally in the range of 1 mg to several times a day or in the range of 1 mg to 50 mg per day per adult, once or several times a day per adult Or, it is administered intravenously for 1 hour to 24 hours a day. Of course, as described above, since the dose varies under various conditions, a smaller dose or amount than the above dose range may be sufficient.
  • the obtained crude crystals are washed with ethyl acetate and dried under reduced pressure.
  • NNC 1 4-Monochloro-8-fluoro-1-methyl-7-nitro [1,24] triazolo [4,3-a] quinoxaline
  • the reaction mixture was diluted with a mixed solvent of chloroform and ethyl acetate, washed successively with water and saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure.
  • To the obtained residue were added 468 mg of imidazole and 8 ml of N, N-dimethylformamide, and the mixture was added to 100 mg.
  • the mixture was heated with C for 2 hours and stirred. After the reaction mixture was cooled, it was concentrated under reduced pressure, and the obtained residue was extracted by adding a mixed solvent of water and ethyl monoethyl acetate. The organic layer was separated, washed successively with water and saturated brine, dried over sodium sulfate, and concentrated under reduced pressure.
  • Elemental element analysis analysis value (as C 16 H 14 N 5 F 30 ⁇ 0.5 H 2 ⁇ )
  • D-mannitol 10 Omg (1.0 Take 80 Onil in water, add 5 g of the compound of the present invention, 21 g of citric acid and 10 g of D-mannitol sequentially to dissolve, and add water to make 100 ml. This solution is aseptically filtered, filled into brown vials at a volume of 10 ml each, and lyophilized to give a ready-to-use solution.

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  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

On présente un dérivé de quinoxalinone fondue, un de ses isomères tautomères, un de ses sels ou de ses hydrates pharmaceutiquement acceptable, et une composition pharmaceutique pouvant les contenir. Ce dérivé, qui présente un antagonisme pour le récepteur du glutamate et se révèle utile comme anti-ischémique et psychotrope, répond à la formule générale (I), où α représente un groupe hétérocyclique pentagonal contenant deux ou trois atomes d'azote, R représente nitro ou trifluorométhyle, X représente (a), (b), (c) ou (d) et R?2, R3, R4, R5 et R6¿ peuvent être identiques ou différents et représenter chacun hydrogène ou alkyle inférieur pouvant être substitué par mono- ou di(alkyle inférieur)amino.
PCT/JP1993/000357 1992-04-03 1993-03-25 Derive de quinoxalinone fondue et composition pharmaceutique le contenant WO1993020077A1 (fr)

Applications Claiming Priority (6)

Application Number Priority Date Filing Date Title
JP4/110770 1992-04-03
JP11077092 1992-04-03
JP4/134245 1992-04-27
JP13424592 1992-04-27
JP33507792 1992-11-20
JP4/335077 1992-11-20

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Cited By (15)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1994021639A1 (fr) * 1993-03-19 1994-09-29 Novo Nordisk A/S DERIVES DE [1,2,4] TRIAZOLO [4,3-a] QUINOXALINE, LEUR PREPARATION ET LEUR UTILISATION
WO1994022447A1 (fr) * 1993-03-31 1994-10-13 Basf Aktiengesellschaft Imidazo-quinoxalinones pour le traitement de maladies du systeme nerveux central
WO1994026737A1 (fr) * 1993-05-12 1994-11-24 Yamanouchi Pharmaceutical Co., Ltd. Derive d'imidazolylquinoxalinedione et composition pharmaceutique le contenant
WO1995012594A1 (fr) * 1993-11-05 1995-05-11 Rhone-Poulenc Rorer S.A. 7H-IMIDAZO(1,2-a)PYRAZINE-8-ONE ANTAGONISTES DU RECEPTEUR NMDA
WO1995021842A1 (fr) * 1994-02-11 1995-08-17 Novo Nordisk A/S Composes heterocycliques, leur preparation et leur utilisation
FR2722789A1 (fr) * 1994-07-20 1996-01-26 Rhone Poulenc Rorer Sa Derives d'acide imidazo (1,2-a)indeno(1,2-e) pyrazine-2-carboxylique, leur preparation et les medicaments les contenant
WO1996008493A1 (fr) * 1994-09-16 1996-03-21 Novo Nordisk A/S Derives de la [1,2,4]triazolo[4,3-a]quinoxalinone, leur preparation et utilisation
WO1996008492A1 (fr) * 1994-09-16 1996-03-21 Novo Nordisk A/S DERIVES DE LA [1,2,4]TRIAZOLO[4,3-a]QUINOXALINONE, LEUR PREPARATION ET UTILISATION
WO1996010572A1 (fr) * 1994-09-30 1996-04-11 Basf Aktiengesellschaft Nouvelles imidazoloquinoxalinones heterocycliques substituees, leur preparation et leur utilisation
WO1997034896A1 (fr) * 1996-03-22 1997-09-25 Basf Aktiengesellschaft Nouvelles imidazolo-quinoxalinones heterocycliquement substituees, leur preparation et leur utilisation
DE10012373A1 (de) * 2000-03-14 2001-09-20 Dresden Arzneimittel Verwendung von Pyrido[3,2-e]-pyrazinonen als Inhibitoren der Phosphodiesterase 5 zur Therapie von erektiler Dysfunktion
US6465465B1 (en) 2000-03-14 2002-10-15 Arzneimittelwerk Dresden Gmbh Process for the treatment of erectile dysfunction and product therefor
WO2008072779A1 (fr) * 2006-12-13 2008-06-19 Aska Pharmaceutical Co., Ltd. Dérivé de quinoxaline
JP2015517549A (ja) * 2012-05-21 2015-06-22 ドマン・テラプーティック グループｉｉの代謝型グルタミン酸受容体のアロステリックモジュレーターとしての、置換ピラゾロキナゾリノンおよびピロロキナゾリノン
WO2016199943A1 (fr) * 2015-06-11 2016-12-15 Takeda Pharmaceutical Company Limited Composés hétérocycliques

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US4780464A (en) * 1986-12-08 1988-10-25 Warner-Lambert Company (1,2,4)triazolo(4,3-a)quinoxaline-4-amines

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JPS5823693A (ja) * 1981-07-16 1983-02-12 ユ−エスヴイ−・フア−マシユ−テイカル・コ−ポレ−シヨン イミダゾキノキザリン化合物類
US4780464A (en) * 1986-12-08 1988-10-25 Warner-Lambert Company (1,2,4)triazolo(4,3-a)quinoxaline-4-amines

Cited By (26)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AU685783B2 (en) * 1993-03-19 1998-01-29 Novo Nordisk A/S (1,2,4) triazolo (4,3-a) quinoxaline derivatives, their preparation and use
WO1994021639A1 (fr) * 1993-03-19 1994-09-29 Novo Nordisk A/S DERIVES DE [1,2,4] TRIAZOLO [4,3-a] QUINOXALINE, LEUR PREPARATION ET LEUR UTILISATION
WO1994022447A1 (fr) * 1993-03-31 1994-10-13 Basf Aktiengesellschaft Imidazo-quinoxalinones pour le traitement de maladies du systeme nerveux central
WO1994026737A1 (fr) * 1993-05-12 1994-11-24 Yamanouchi Pharmaceutical Co., Ltd. Derive d'imidazolylquinoxalinedione et composition pharmaceutique le contenant
WO1995012594A1 (fr) * 1993-11-05 1995-05-11 Rhone-Poulenc Rorer S.A. 7H-IMIDAZO(1,2-a)PYRAZINE-8-ONE ANTAGONISTES DU RECEPTEUR NMDA
FR2711993A1 (fr) * 1993-11-05 1995-05-12 Rhone Poulenc Rorer Sa Médicaments contenant des dérivés de 7H-imidazol[1,2-a]pyrazine-8-one, les nouveaux composés et leur préparation.
WO1995021842A1 (fr) * 1994-02-11 1995-08-17 Novo Nordisk A/S Composes heterocycliques, leur preparation et leur utilisation
FR2722789A1 (fr) * 1994-07-20 1996-01-26 Rhone Poulenc Rorer Sa Derives d'acide imidazo (1,2-a)indeno(1,2-e) pyrazine-2-carboxylique, leur preparation et les medicaments les contenant
US5726175A (en) * 1994-07-20 1998-03-10 Rhone-Poulenc Rorer S.A. Imidazo 1,2-A!indeno 1,2-E!pyrazine-2-carboxylic acid derivatives, preparation thereof and drugs containing same
WO1996002544A1 (fr) * 1994-07-20 1996-02-01 Rhone-Poulenc Rorer S.A. DERIVES D'ACIDE IMIDAZO[1,2-a]INDENO[1,2-e]PYRAZINE-2-CARBOXYLIQUE, LEUR PREPARATION ET LES MEDICAMENTS LES CONTENANT
WO1996008492A1 (fr) * 1994-09-16 1996-03-21 Novo Nordisk A/S DERIVES DE LA [1,2,4]TRIAZOLO[4,3-a]QUINOXALINONE, LEUR PREPARATION ET UTILISATION
WO1996008493A1 (fr) * 1994-09-16 1996-03-21 Novo Nordisk A/S Derives de la [1,2,4]triazolo[4,3-a]quinoxalinone, leur preparation et utilisation
US6001832A (en) * 1994-09-16 1999-12-14 Novo Nordiskals [1,2,4]triazolo[4,3-a]quinoxalinone derivatives, their preparation and use
US6121265A (en) * 1994-09-30 2000-09-19 Basf Aktiengesellschaft Heterocyclic substituted imidazoloquinoxalinones, their preparation and their use
CN1046518C (zh) * 1994-09-30 1999-11-17 巴斯福股份公司 新型的带杂环取代基的咪唑并喹喔啉酮及其制备方法和应用
WO1996010572A1 (fr) * 1994-09-30 1996-04-11 Basf Aktiengesellschaft Nouvelles imidazoloquinoxalinones heterocycliques substituees, leur preparation et leur utilisation
WO1997034896A1 (fr) * 1996-03-22 1997-09-25 Basf Aktiengesellschaft Nouvelles imidazolo-quinoxalinones heterocycliquement substituees, leur preparation et leur utilisation
DE10012373A1 (de) * 2000-03-14 2001-09-20 Dresden Arzneimittel Verwendung von Pyrido[3,2-e]-pyrazinonen als Inhibitoren der Phosphodiesterase 5 zur Therapie von erektiler Dysfunktion
US6465465B1 (en) 2000-03-14 2002-10-15 Arzneimittelwerk Dresden Gmbh Process for the treatment of erectile dysfunction and product therefor
WO2008072779A1 (fr) * 2006-12-13 2008-06-19 Aska Pharmaceutical Co., Ltd. Dérivé de quinoxaline
US8299080B2 (en) 2006-12-13 2012-10-30 Aska Pharmaceutical Co., Ltd. Substituted imidazo[1,5-A] quinoxalines as a PDE9 inhibitor
JP5578786B2 (ja) * 2006-12-13 2014-08-27 あすか製薬株式会社 キノキサリン誘導体
US8829000B2 (en) 2006-12-13 2014-09-09 Aska Pharmaceutical Co., Ltd. Substituted imidazo[1,5-A]quinoxalines as phosphodiesterase 9 inhibitors
US9040536B2 (en) 2006-12-13 2015-05-26 Aska Pharmaceutical Co., Ltd. Substituted pyrrolo[1,2-a]quinoxalines as PDE9 inhibitors
JP2015517549A (ja) * 2012-05-21 2015-06-22 ドマン・テラプーティック グループｉｉの代謝型グルタミン酸受容体のアロステリックモジュレーターとしての、置換ピラゾロキナゾリノンおよびピロロキナゾリノン
WO2016199943A1 (fr) * 2015-06-11 2016-12-15 Takeda Pharmaceutical Company Limited Composés hétérocycliques

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