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WO1992011245A1 - Derives 2-acylamido de 3,4-dihydro-3-oxo-quinoxaline possedant une activite pharmaceutique - Google Patents

Derives 2-acylamido de 3,4-dihydro-3-oxo-quinoxaline possedant une activite pharmaceutique Download PDF

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Publication number
WO1992011245A1
WO1992011245A1 PCT/US1991/008586 US9108586W WO9211245A1 WO 1992011245 A1 WO1992011245 A1 WO 1992011245A1 US 9108586 W US9108586 W US 9108586W WO 9211245 A1 WO9211245 A1 WO 9211245A1
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Prior art keywords
compound
oxo
dihydro
dichloro
preparation
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PCT/US1991/008586
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English (en)
Inventor
Sheryl Jeanne Hays
Graham Johnson
Leonard Joseph Lescosky
Thomas Charles Malone
Perry Michael Novak
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Warner-Lambert Company
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Publication of WO1992011245A1 publication Critical patent/WO1992011245A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C233/00—Carboxylic acid amides
    • C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C233/12—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by halogen atoms or by nitro or nitroso groups
    • C07C233/15—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by halogen atoms or by nitro or nitroso groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by a carbon atom of a six-membered aromatic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C251/00—Compounds containing nitrogen atoms doubly-bound to a carbon skeleton
    • C07C251/32—Oximes
    • C07C251/34—Oximes with oxygen atoms of oxyimino groups bound to hydrogen atoms or to carbon atoms of unsubstituted hydrocarbon radicals
    • C07C251/36—Oximes with oxygen atoms of oxyimino groups bound to hydrogen atoms or to carbon atoms of unsubstituted hydrocarbon radicals with the carbon atoms of the oxyimino groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C251/38—Oximes with oxygen atoms of oxyimino groups bound to hydrogen atoms or to carbon atoms of unsubstituted hydrocarbon radicals with the carbon atoms of the oxyimino groups bound to hydrogen atoms or to acyclic carbon atoms to carbon atoms of a saturated carbon skeleton
    • 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
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/10—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing aromatic rings

Definitions

  • the present invention relates to novel
  • the compounds of the present invention are active as mediators of excitatory amino acid receptors.
  • Such activity is useful in the treatment of neurodegenerative disorders including cerebrovascular disorders as well as in the treatment of
  • NMDA N-methyl-D-aspartate
  • anoxia such as from drowning, pulmonary surgery and cerebral trauma.
  • U.S. Patent Number 4,181,724 discloses certain acids and esters of quinoxalinone compounds useful for asthma, eczema, or urticaria in animals.
  • Publication No. 010,426 disclose more specifically substitutions on acids and esters of quinoxalinone compounds that are useful as antivirals, especially against influenza viruses.
  • the further preparation of these compounds is as in Japanese application
  • Quaternary ammonium salts of certain acids of quinoxalinone compounds are also disclosed as antivirals in U.S. 4,252,954.
  • Amido derivatives of quinoxalinones are substituents of
  • alkylarylsulfonylureas for use in hypoglycemia in
  • the present invention provides compounds of the formula
  • Y is oxygen or sulfur
  • R 1 , R 2 , R 11 , and R 12 are independently hydrogen, lower alkyl, halogen, trifluoromethyl, cyano, nitro, methylthio, lower alkenyl, lower alkynyl, SO 2 NH 2 , S(O) 1-2 R wherein R is hydrogen or lower alkyl, OCF 3 , or two of R 1 , R 2 , R 11 , and R 12 can be taken together to form a carbocyclic ring of six carbons, or can be taken together to form a heterocyclic or heteroaryl ring wherein the heteroatom is oxygen, sulfur, or nitrogen, and wherein the carbon on the carbocyclic ring is optionally further substituted by one of R 1 , R 2 , R 11 , or R 12 ;
  • R 3 and R 4 are independently
  • alkenyl of from three to twenty carbons, preferably three to twelve carbons;
  • alkynyl of from three to twenty carbons, preferably three to twelve carbons;
  • the preferred compounds of the present invention include but are not limited to the compounds of
  • R 2 and R 11 are chloro, Y is oxygen, and X is NHS(O) 2 CH 3 , NHS (O) 2 phenyl, or NHS (O) 2 (CH 2 ) 4 H.
  • the more preferred compounds of the present invention are 6,7-dichloro-3,4-dihydro-3-oxo-N-[phenylsulfonyl]-2-quinoxalinecarboxamide and
  • the present invention also includes a
  • cerebral infarction cerebral vasospasm
  • hypoglycemia cardiac arrest
  • status epilepticus cerebral trauma
  • schizophrenia, epilepsy neurodegenerative disorders. Parkinson's disease, Alzheimer's disease, or
  • Huntington's disease comprising a therapeutically effective amount of a compound of Formula I together with a pharmaceutically acceptable carrier.
  • the present invention also includes a method for treating cerebrovascular disorders which comprises administering to a patient in need thereof the above pharmaceutical composition in unit dosage form.
  • the present invention also includes a method for treating disorders responsive to the blockade of glutamic and aspartic acid receptors comprising administering to a patient in need thereof a
  • composition in unit dosage form is provided.
  • the invention also includes a method for treating cerebral ischemia, cerebral infarction, cerebral vasospasm, hypoglycemia, cardiac arrest, status epilepticus, cerebral trauma, schizophrenia, epilepsy, neurodegenerative disorders, Parkinson's disease, Alzheimer's disease, or Huntington's disease
  • the invention also includes a method for treating stroke in patients in need thereof which comprises administering to a patient in need thereof a
  • composition in unit dosage form is provided.
  • the invention also includes using as an
  • the invention further includes processes for the preparation of compounds of Formula I wherein one of the novel intermediates of the Formula II' wherein R 6 is hydrogen are treated to obtain selected
  • the invention still further includes novel intermediates useful in the processes.
  • the novel intermediate of the present invention is a pure compound of the formula (II')
  • R 1 and R 11 are as defined above with the proviso that R' 2 and R' 12 are independently hydrogen or halogen with the proviso that at least one of R' 2 and R' 12 are halogen, and R 6 is as defined herein.
  • a novel intermediate of the present invention is also a compound of the Formula V
  • R 1 , R 2 , R 11 , and R 12 are as defined above and Alk 1-6 is lower alkyl.
  • An additional novel intermediate of the present invention is a compound of the Formula (IV) wherein R 1 , R 2 , R 11 , R 12 , and Alk 1-6 are as defined above.
  • the present invention is a process for the preparation of a compound of the Formula (L)
  • R 1 , R 2 , R 11 , R 12 , X, and Y are as defined above.
  • the present invention is a process which comprises
  • R 1 , R 2 , R 11 , and R 12 are as defined above and Alk 1-6 is lower alkyl.
  • Loweralkyl means a straight chained or branched chain of from one to four carbon atoms including but not limited to methyl, ethyl, propyl, butyl.
  • Loweralkenyl means a group from two to
  • Loweralkynyl means a group from two to
  • propynyl is the preferred group.
  • Cycloalkylloweralkyl means cycloalkyl of from three to six carbon atoms and lower alkyl as above, meaning for example, cyclopropylmethyl,
  • cyclobutylmethyl cyclopentylmethyl
  • cyclopropylmethyl is the preferred group.
  • Loweralkoxy means a group of from one to four carbon atoms, for example, but not limited to methoxy, ethoxy, propoxy; methoxy is the preferred group.
  • Halogen is fluorine, chlorine, bromine, or iodine; fluorine, chlorine and bromine are the
  • Arylloweralkyl means aryl as defined above and alkyl as defined above, for example, benzyl, 2-phenylethyl, 3-phenylpropyl; preferred groups are benzyl and the benzyl or phenyl is as substituted above.
  • Arylloweralkenyl means aryl as defined above and alkenyl as defined above, for example,
  • Monoloweralkylamino means a group containing from one to four carbon atoms, for example, but not limited to methylamino, ethylamino, n- or i-(propylamino or butylamino).
  • Diloweralkylamino means a group containing from one to four carbon atoms in each lower alkyl group, for example, but not limited to dimethylamino,
  • diethylamino di-(n-propyl)-amino, di-(n-butyl) -amino, or may represent a fused ring, for example piperidine.
  • Heteroaryl means a 5- or 6-membered monocyclic, bicyclic, or fused bicyclic heteroaryl.
  • the monocycle or fused bicyclic aromatic ring contains at least 1 to 4 heteroatoms in at least one ring, such as nitrogen, oxygen, or sulfur or a combination thereof.
  • Such a heteroaryl group includes, for example, thienyl, benzothienyl, furanyl, benzofuranyl, pyridyl,
  • such a heteroaryl may be a 2- or 3-thienyl; which may further be substituted by, for example, a 2-, 3-, or 4-pyridyl ring; 2- or 3-furanyl; 2-, or 3-, or 4-pyridyl or -pyridyl-N-oxide; 2-, 4-, or 5-pyrimidinyl; 3- or 4-pyridazinyl; 2-pyrazinyl; 2-pyrazinyl-N-oxide; 2- or 3-pyrrolyl; 3-, 4-, or 5-pyrazolyl; 2-, 4-, or 5-oxazolyl; 2-, 4-, or
  • 5-(1,2,4,-)triazolyl 4- or 5- (1,2,3-) triazolyl; 2-, 4-, or 5-imidazolyl; 2-, 3-, 4-, 5-, 6-, or 7-indolyl; 2-, 3-, 4-, 5-, 6-, 7-, or 8-quinolinyl; 1-, 3-, 4-, 5-, 6-, 7-, or 8-isoquinolinyl; 2-, 4-, 5-, 6-, or 7-benzothiazolyl; 2-, 3-, 4-, 5-, 6-, or aryl,
  • Heterocycle means piperidine, piperazine,
  • N-piperidine and N-piperazine which may be further substituted by phenyl.
  • the compounds of the present invention contain asymmetric carbon atoms.
  • the instant invention includes the individual diastereomers and enantiomers, which may be prepared or isolated by methods known to those skilled in the art.
  • Selected compounds of the present invention can exist also as syn and anti forms and are also the present invention.
  • Any resulting racemate can be resolved into the optical antipodes by known methods, for example by separation of the diastereomeric salts thereof, with an optically active acid, and liberating the optically active amine compound by treatment with a base.
  • Racemic compounds of the present invention can thus be resolved into their optical antipodes e.g., by
  • the compounds of the instant invention may also be resolved by the formation of diastereomeric amides or amides by reaction the compounds of the instant invention with an optically active activated carboxylic acid such as that derived from (+) or (-) phenylalanine, (+) or (-) phenylglycine, (+) or (-) -camphanic acid or by the formation of diastereomeric carbamates by reaction of the compounds of the instant invention with an optically active activated carboxylic acid such as that derived from (+) or (-) phenylalanine, (+) or (-) phenylglycine, (+) or (-) -camphanic acid or by the formation of diastereomeric carbamates by reaction of the compounds of the instant invention with an optically active activated carboxylic acid such as that derived from (+) or (-) phenylalanine, (+) or (-) phenylglycine, (+) or (-) -camphanic acid or by the formation of diastere
  • Salts of the compounds of the invention are preferably pharmaceutically acceptable salts.
  • the compounds of the invention are basic amines from which acid addition salts of pharmaceutically acceptable inorganic or organic acids such as strong mineral acids, for example, hydrohalic, e.g., hydrochloric or hydrobromic acid; sulfuric, phosphoric or nitric acid; aliphatic or aromatic carboxylic or sulfonic acids, e.g., acetic, propionic, succinic, glycolic, lactic, malic, tartaric, gluconic, citric, ascorbic, maleic, fumaric, pyruvic, pamoic, nicotinic, methanesulfonic, ethanesulfonic, hydroxyethanesulfonic, benzenesulfonic, p-toluenesulfonic, or napthlenesulfonic acid can be prepared.
  • Selected compounds of the invention are also acids from which base salts may be prepared.
  • hydrates of compounds of the invention are also the present invention.
  • the compounds of the instant invention exhibit valuable pharmacological properties by selectively blocking the N-methyl-D-aspartate sensitive excitatory amino acid receptors in mammals.
  • the compounds are thus useful for treating diseases responsive to excitatory amino acid blockade in mammals.
  • Such disorders include but are not limited to cerebral ischemia or cerebral infarction resulting from a range of conditions such as thromboembolic or hemorrhagic stroke, cerebral vasospasm, hypoglycemia, cardiac arrest, status epilepticus, perinatal
  • neurodegenerative disorders such as Parkinson's disease, Alzheimer's disease or Huntington's disease, Olivo-pontocerebellar atrophy, spinal cord injury, and poisoning by exogenous NMDA poisons (e.g., some forms of lathyrism).
  • NMDA poisons e.g., some forms of lathyrism.
  • Further uses are as analgesics and anesthetics, particularly for use in surgical
  • the effects are demonstrable in in vitro tests or in vivo animal tests using mammals or tissues or enzyme preparations thereof, e.g., mice, rats, or monkeys.
  • the compounds are administered to patients enterally or parenterally, for example, orally, transdermally, subcutaneously, intravenously, or intraperitoneally.
  • Forms include but are not limited to gelatin capsules, or aqueous suspensions or solutions.
  • the applied in vivo dosage may range between about 0.01 to 100 mg/kg, preferably between about 0.05 and 50 mg/kg, most preferably between about 0.1 and 10 mg/kg.
  • NR 6 HSO 2 R 3 , NR 6 NHCO 2 R 3 or NR 6 CO 2 R 3 and R 11 , R 12 , and R 1 , R 2 , R 3 , R 4 , R 5 , and R 6 are as previously defined and are illustrated in Schemes A and B.
  • Scheme D consists of treating the compounds of Formula A with chloroethylmalonate, chloromethylmalonate, or the like in a solvent such as benzene or toluene or the like to provide the compounds of the Formula B.
  • the compounds of the Formula B are then treated with sodium ethoxide in ethanol or sodium methoxide in methanol to provide the compounds of the Formula C.
  • the compounds of the Formula C are further reacted with phosphorous trichloride or phosphorous tribromide in a solvent such as tetrahydrofuran, dioxane, or the like to provide the compounds of the Formula D.
  • Scheme E shows a preparation for compounds of the Formula I which consists of treating the compounds of the Formula VI with sodium nitrite, potassium nitrite, or the like in an acetic acid/tetrahydrofuran/water solvent mixture to provide the compounds of the
  • the compounds of the Formula II' 1 are subjected to saponification using KOH in water/iPrOH or the like to give the compounds ofFormula II' 2 .
  • NR 6 COR 5 NR 6 CO 2 R 3 , NR 6 NHSO 2 R 3 , NR%HCO 2 R 3 , wherein R 1 , R 2 , R 11 , R 12 , R 3 , R 4 , R 5 , and R 6 are as defined above, are prepared by the method of Schemes A-E above.
  • Scheme A consists of treating a carboxylic acid of the general structure (II) with a coupling reagent in an inert solvent to produce an activated carboxylic acid derivative.
  • the resulting activated carboxylic acid derivative is reacted with a variety of nitrogen nucleophiles to produce amides of the general
  • Suitable coupling agents for this purpose include, for example, such reagents as thionyl chloride, acetic anhydride, oxalyl chloride/ DMF, carbonyldiimidazole, DCC, and diphenylphosphoryl azide, preferably carbonyldiimidazole.
  • activated carboxylic acid derivative is meant an acid
  • Such acid derivatives include, for example, acid chlorides, acid bromides, anhydrides, and mixed anhydrides.
  • inert solvent is meant a nonprotic solvent such as, for example, methylene chloride, chloroform, carbon tetrachloride, ethyl acetate, tetrahydrofuran, and dimethylformamide.
  • Formula Via is deprotected with trimethylsilyl iodide or a combination of trimethylsilyl chloride and sodium iodide if the protecting ether is a methoxy group.
  • the allyloxy group is removed using Wilkinson' s catalyst to afford compounds of Formula Vila.
  • the base salts may be generated from compounds of Formula I by reaction of the latter with one
  • the compounds of Formula I may be recovered from the base salt by reaction of the salt with an aqueous solution of a suitable acid such as hydrobromic, hydrochloric, or acetic acid.
  • a suitable acid such as hydrobromic, hydrochloric, or acetic acid.
  • Suitable bases for forming base salts of the compounds of this invention include amines such as triethylamine or dibutylamine, or alkali metal bases and alkaline earth metal bases.
  • amines such as triethylamine or dibutylamine
  • alkali metal bases and alkaline earth metal bases are the hydroxides of lithium, sodium, potassium, magnesium, or calcium.
  • Suitable acids for forming acid salts of the compounds of this invention containing a basic group include, but are not necessarily limited to acetic, benzoic, benzenesulfonic, tartaric, hydrobromic, hydrochloric, citric, fumaric, gluconic, glucuronic, glutamic, lactic, malic, maleic, methanesulfonic, pamoic, salicylic, stearic, succinic, sulfuric, and tartaric acids.
  • the acid addition salts are formed by procedures well known in the art.
  • the compounds of this invention may exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol and the like.
  • the solvated forms are considered equivalent to the unsolvated forms for the purposes of this invention.
  • the compounds of the present invention can be administered in a wide variety of oral and parenteral dosage forms . It will be obvious to those skilled in the art that the following dosage forms may comprise as the active component, either a compound of
  • compositions from the compounds of the present invention can be either solid or liquid.
  • Solid form preparations include powders, tablets, pills, capsules, cachets,
  • a solid carrier can be one or more substances which may also act as diluents, flavoring agents, solubilizers, lubricants, suspending agents, binders, preservatives, tablet disintegrating agents, or an encapsulating material.
  • the carrier is a finely divided solid which is in a mixture with the finely divided active component.
  • the active component is mixed with the carrier having the necessary binding properties in suitable proportions and compacted in the shape and size desired.
  • the powders and tablets preferably contain from five or ten to about seventy percent of the active compound.
  • Suitable carriers are magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, a low melting wax, cocoa butter, and the like.
  • the term "preparation" is intended to include the formulation of the active compound with encapsulating material as a carrier providing a capsule in which the active component, with or without carriers, is surrounded by a carrier, which is thus in association with it.
  • cachets and lozenges are included. Tablets, powders, capsules, pills, cachets, and lozenges can be used as solid dosage forms suitable for oral administration.
  • a low melting wax such as a mixture of fatty acid glycerides or cocoa butter
  • the active component is dispersed homogeneously therein, as by stirring.
  • the molten homogeneous mixture is then poured into convenient sized molds, allowed to cool, and thereby to solidify.
  • Liquid form preparations include solutions, suspensions, and emulsions, for example, water or water propylene glycol solutions.
  • parenteral injection liquid preparations can be formulated in solution in aqueous polyethylene glycol solution.
  • Aqueous solutions suitable for oral use can be prepared by dissolving the active component in water and adding suitable colorants, flavors, stabilizing and thickening agents, as desired.
  • Aqueous suspensions suitable for oral use can be made by dispersing the finely divided active component in water with viscous material, such as natural or synthetic gums, resins, methylcellulose, sodium carboxymethylcellulose, and other well-known viscous material, such as natural or synthetic gums, resins, methylcellulose, sodium carboxymethylcellulose, and other well-known viscous material, such as natural or synthetic gums, resins, methylcellulose, sodium carboxymethylcellulose, and other well-known
  • solid form preparations which are intended to be converted, shortly before use, to liquid form preparations for oral administration.
  • Such liquid forms include solutions, suspensions, and emulsions. These preparations may contain, in
  • sweeteners such as sweeteners, dispersants, thickeners, solubilizing agents, and the like.
  • the pharmaceutical preparation is preferably in unit dosage form.
  • the preparation is subdivided into unit doses containing appropriate quantities of the active component.
  • the unit dosage form can be a packaged preparation, the package containing discrete quantities of preparation, such as packeted tablets, capsules, and powders in vials or ampoules.
  • the unit dosage form can be a
  • capsule tablet, cachet, or lozenge itself, or it can be the appropriate number of any of these in packaged form.
  • the quantity of active component in a unit dose preparation may be varied or adjusted from 1 mg to 1000 mg preferably 10 mg to 100 mg according to the particular application and the potency of the active component.
  • the composition can, if desired, also contain other compatible therapeutic agents.
  • the compounds of this invention are extremely useful in the treatment of central nervous system disorders related to their biological activity.
  • the compounds of this invention may accordingly be
  • excitatory amino acid dependent psychosis excitatory amino acid dependent anorexia
  • excitatory amino acid dependent ischemia excitatory amino acid dependent convulsions
  • excitatory amino acid dependent migraine excitatory amino acid dependent migraine
  • Suitable dosage ranges are 0.1 to 1000 mg daily, 10 to 400 mg daily, and especially 30 to 100 mg daily, dependent as usual upon the exact mode of
  • carbonyldiimidazole is dissolved in 250 mL dry DMF. To this is added 0.029 mole of a suitably substituted 2-oxo-quinoxoline-3-carboxylate. This solution is heated at 80°C for 2 hours under nitrogen, then dry DMF to make 300 mL is added and the solution cooled to 25°C.
  • reaction is stirred at 25°C for 1 to 5 days. When a solid remained after the mixing of the solutions, the reaction is refluxed for 1 to 8 hours to go to
  • reaction is worked up by pouring into a mixture of 300 g each of ice and concentrated HC1.
  • the precipitated solid is washed with water.
  • the crude product is dissolved in hot DMF and precipitated with the addition of water. After cooling the solid is filtered, washed with cold DMF, water, heptane, then dried for 24 hours at 140°C under vacuum to yield the product as a yellow powder.
  • acetonitrile, diethyl ether, or methanol is substituted for DMF as the washing solvent.
  • O-alkylhydroxylamine hydrochloride or O-alkylarylhydroxylamine hydrochloride This is stirred at 25°C for 1 hour.
  • Solution B To Solution B is added 60 mL of Solution A as described for Method A. The reaction is stirred at 25°C for 1 to 5 days. The reaction is poured into a mixture of 300 g each of ice and 3N HCl. The solid is washed with 50 mL 5% NaHCO 3 , 50 mL water, 50 mL acetonitrile, and 50 mL diethylether. The product is dried at 140°C under vacuum. In some cases the product is recrystallized from DMF/water or is
  • Solution B To Solution B is added 60 mL of Solution A as described for Method A. The reaction is stirred at 25°C for 1 to 5 days or stirred at 25°C for 18 hours and then heated to 80°C for 1 to 4 hours.
  • the reaction is stirred at 25°C for 1 to 5 days or stirred at 25°C for 18 hours and then heated to 80°C for 1 to 4 hours.
  • reaction is poured into a mixture of 300 g each of ice and 3N HCl.
  • the solid is washed with 50 mL 5% NaHCO 3 , 50 mL water, 50 mL acetonitrile, and 50 mL
  • diethylether The product is dried at 140°C under vacuum. In some cases the product is recrystallized from DMF/water or is triturated by washing with hot acetonitrile or ethanol.
  • trimethylsilyl iodide was added. The reaction was stirred at 25°C for 18 hours. The reaction was poured into 5% sodium bisulfite and stirred for 10 minutes. The two layers were filtered to produce a crude solid. The solid was dissolved in a minimum of DMF, stirred over charcoal and filtered through a Celite pad. The bright yellow solution was diluted with EtOH so that the composition of the solution was approximately EtOH/DMF (2:1). Water was added to the point of cloudiness, the solution was cooled to 5°C and
  • Solution B To a suspension of sodium hydride (1.5 g, 38.6 mmol) (60% dispersion in mineral oil) in dry DMF (20 mL) is added benzenesulfonylhydrazide (6.65 g, 38.6 mmol). The reaction is stirred at 25°C for 1 hour and a solution containing 7.72 mmol of the reagent prepared as described in General
  • Preparation 1 Solution A is added to Solution B. This solution is stirred at 90°C for 24 hours and then is poured into water (500 mL). The solution is made acidic with 6N HCl to pH 2. The solid is collected and recrystallized twice from hot DMF/water, washed with acetonitrile, followed by diethylether, and then dried at 137°C under vacuum to give the title compound (1.44 g, 45% yield) as a yellow solid; m.p. 283°C. Elemental analysis calculated for C 15 H 10 N 4 O 4 Cl 2 S:
  • Solution B To a suspension of sodium hydride
  • Preparation 1 Solution A is added to Solution B. The reaction is stirred at 25°C for 24 hours and the solution is poured into water (500 mL). The solution is made acidic with 6N HC1 to pH 2. The solid is collected and taken up in hot DMF. The DMF solution is treated with charcoal and filtered. The solution is cooled and diluted with an equal volume of water. The yellow solid is collected, washed with
  • Solution B To a suspension of sodium hydride (0.93 g, 23.2 mmol) (60% dispersion in mineral oil) in dry DMF (20 mL) is added 1-piperidinecarboxamide (2.97 g, 23.2 mmol). The solution is stirred at 60°C for 0.5 hours. A solution containing 0.00772 mol of the reagent prepared as described in General
  • Solution B To a suspension of sodium hydride
  • Preparation 19a the product from Preparation 18a (10.0 g, 31.2 mmol) is converted to the title compound as a yellow solid (9.49 g, 87%) .
  • Preparation 27a the product from Preparation 23a (8.00 g, 25.3 mmol) is converted to the title compound as a yellow solid (2.11 g, 33%); m.p. 196-198°C.
  • the compounds of the present invention have activity as antagonists at the strychnine insensitive glycine receptor which is located on the NMDA receptor complex.
  • the compounds of the present invention are NMDA receptor antagonists.
  • the compounds of the present invention have activity as AMPA and kainate receptor antagonists.
  • compounds of the invention exhibit valuable biological properties because of these excitatory amino acid antagonizing properties.
  • the glycine binding assay is performed as described by W. Frost White, et al. Journal of
  • Selected compounds having the Formula I of the present invention are tested in the glycine binding assay and provide the following data expressed as % inhibition at the dose expressed as molar
  • the AMPA binding assay may also be performed to provide an activity profile for the compounds of the present invention.
  • the kainate binding assay is performed as described by T. Honore et al, Neuroscience Letters 1986;65:47-52.
  • the compounds of Formula I and their pharmacologically acceptable acid addition salts are effective agents in the prophylaxis and/or therapeutic treatment of disorders responsive to agents which block NMDA receptors, thus forming a further aspect of the present invention in like manner.

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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention se rapporte à de nouveaux dérivés 2-acylamido de 3,4-dihydro-3-oxo-quinoxaline utilisés comme agents pharmaceutiques, à leurs procédés de production, à des compositions pharmaceutiques et à des procédés thérapeutiques les mettant en application. Les composés décrits par l'invention possèdent une activité de médiateurs de récepteurs d'acides aminés excitatoires et, de ce fait, ont une utilité thérapeutique dans le traitement d'un grand nombre de troubles neurodégénératifs, y compris les troubles cérébrovasculaires tels que les attaques.
PCT/US1991/008586 1990-12-20 1991-11-22 Derives 2-acylamido de 3,4-dihydro-3-oxo-quinoxaline possedant une activite pharmaceutique WO1992011245A1 (fr)

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US63113990A 1990-12-20 1990-12-20
US631,139 1990-12-20

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WO1992011245A1 true WO1992011245A1 (fr) 1992-07-09

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PCT/US1991/008586 WO1992011245A1 (fr) 1990-12-20 1991-11-22 Derives 2-acylamido de 3,4-dihydro-3-oxo-quinoxaline possedant une activite pharmaceutique

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AU (1) AU9049391A (fr)
IE (1) IE914452A1 (fr)
MX (1) MX9102701A (fr)
PT (1) PT99899A (fr)
WO (1) WO1992011245A1 (fr)
ZA (1) ZA9110018B (fr)

Cited By (19)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2707643A1 (fr) * 1993-07-16 1995-01-20 Rhone Poulenc Rorer Sa Dérivés d'imidazo[1,2-a]pyrazine-4-one, leur préparation et les médicaments les contenant.
WO1995012417A1 (fr) * 1993-11-05 1995-05-11 Acea Pharmaceuticals, Inc. Quinoxalinediones condensees et substituees par alkyle, azido, alcoxy et fluoro et leur utilisation comme antagonistes du recepteur de la glycine
US5514680A (en) * 1992-06-22 1996-05-07 The 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 Glycine receptor antagonists and the use thereof
WO1999011632A1 (fr) * 1997-09-01 1999-03-11 Kyorin Pharmaceutical Co., Ltd. Derives d'acide quinoxalinecarboxylique disubstitues en position 6,7-asymetrique, sels d'addition de ces derives, et procedes de preparation de ces derives et de ces sels
AU718748B2 (en) * 1995-01-27 2000-04-20 Cocensys, Inc. AZA and AZA (N-oxy) analogs of glycine/NMDA receptor antagonists
WO2000050420A1 (fr) * 1999-02-26 2000-08-31 Kyorin Pharmaceutical Co., Ltd. Derives d'acide 7-heteroquinoxaline carboxilique 6-substitue et leurs sels d'addition, procedes de preparation de ces derives et de leurs sels d'addition
US6417189B1 (en) 1999-11-12 2002-07-09 Gpi Nil Holdings, Inc. AZA compounds, pharmaceutical compositions and methods of use
WO2003010146A1 (fr) * 2001-07-20 2003-02-06 Neuro3D Composes derives de quinoleine et quinoxaline, preparation et utilisations
DE10153345A1 (de) * 2001-10-29 2003-05-08 Gruenenthal Gmbh Substituierte 1H-Chinoxalin-2-on-Verbindungen und substituierte 4-Aryl- und 4-Heteroarylcyclohexan-Verbindungen
WO2005056547A3 (fr) * 2003-12-04 2005-09-22 Vertex Pharma Quinoxalines utiles comme inhibiteurs des proteines kinases
US6974823B2 (en) 1999-12-21 2005-12-13 Gpi Nil Holdindgs, Inc. Hydantoin derivative compounds, pharmaceutical compositions, and methods of using same
US7078424B2 (en) 1998-06-03 2006-07-18 Gpi Nil Holdings, Inc. N-linked sulfonamides of N-heterocyclic carboxylic acids or carboxylic acid isosteres
US7153883B2 (en) 1998-06-03 2006-12-26 Gpi Nil Holdings Inc. Carboxylic acids and carboxylic acid isosteres of N-heterocyclic compounds
US7253169B2 (en) 1999-11-12 2007-08-07 Gliamed, Inc. Aza compounds, pharmaceutical compositions and methods of use
CN100424080C (zh) * 2003-08-28 2008-10-08 阿斯利康(瑞典)有限公司 作为嗜中性白细胞弹性蛋白酶抑制剂的喹喔啉衍生物及它们的用途
WO2009070644A1 (fr) * 2007-11-30 2009-06-04 Smithkline Beecham Corporation Inhibiteurs de prolyl hydroxylases
WO2009073497A3 (fr) * 2007-11-30 2010-11-11 Glaxosmithkline Llc Inhibiteurs des prolyl hydroxylases
US8889683B2 (en) * 2010-09-27 2014-11-18 Merck Sharp & Dohme Corp. Substituted quinoxalines as inhibitors of fatty acid binding protein
RU2744429C1 (ru) * 2020-05-02 2021-03-09 Андрей Александрович Иващенко Противо-РНК вирусное, в том числе противокоронавирусное средство - замещенный хиноксалин, фармацевтическая композиция и применения

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AU674613B2 (en) * 1993-09-28 1997-01-02 Otsuka Pharmaceutical Co., Ltd. Quinoxaline derivative as antidiabetic agent

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EP0008864A1 (fr) * 1978-08-15 1980-03-19 FISONS plc Dérivés de la pyridopyrazine et de la quinoxaline, procédés pour leur préparation, et compositions pharmaceutiques les contenant
EP0010426A1 (fr) * 1978-10-20 1980-04-30 Eli Lilly And Company Compositions pharmaceutiques à base des 3,4-dihydro-3-oxo-2-quinoxalines, de telles quinoxalines et procédés pour leur production
US4252954A (en) * 1979-10-25 1981-02-24 Eli Lilly And Company Salts of dihalo-3,4-dihydro-3-oxo-2-quinoxaline carboxylic acids and hindered amines

Patent Citations (4)

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EP0008864A1 (fr) * 1978-08-15 1980-03-19 FISONS plc Dérivés de la pyridopyrazine et de la quinoxaline, procédés pour leur préparation, et compositions pharmaceutiques les contenant
EP0010426A1 (fr) * 1978-10-20 1980-04-30 Eli Lilly And Company Compositions pharmaceutiques à base des 3,4-dihydro-3-oxo-2-quinoxalines, de telles quinoxalines et procédés pour leur production
US4264600A (en) * 1978-10-20 1981-04-28 Eli Lilly And Company Treatment of influenza with 2-estersubstituted-3,4-dihydro-3-oxoquinoxalines
US4252954A (en) * 1979-10-25 1981-02-24 Eli Lilly And Company Salts of dihalo-3,4-dihydro-3-oxo-2-quinoxaline carboxylic acids and hindered amines

Cited By (31)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5622952A (en) * 1992-06-22 1997-04-22 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 Glycine receptor antagonists and the use thereof
US5514680A (en) * 1992-06-22 1996-05-07 The 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 Glycine receptor antagonists and the use thereof
US5620979A (en) * 1992-06-22 1997-04-15 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 Glycine receptor antagonists and the use thereof
WO1995002601A1 (fr) * 1993-07-16 1995-01-26 Rhone-Poulenc Rorer S.A. DERIVES D'IMIDAZO[1,2-a]PYRAZIN-4-ONE, LEUR PREPARATION ET LES MEDICAMENTS LES CONTENANT
FR2707643A1 (fr) * 1993-07-16 1995-01-20 Rhone Poulenc Rorer Sa Dérivés d'imidazo[1,2-a]pyrazine-4-one, leur préparation et les médicaments les contenant.
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
US5977107A (en) * 1993-11-05 1999-11-02 Cocensys, Inc. Alkyl, azido, alkoxy, and fluoro-substituted and fused quinoxalinediones and the use thereof as glycine receptor antagonists
WO1995012417A1 (fr) * 1993-11-05 1995-05-11 Acea Pharmaceuticals, Inc. Quinoxalinediones condensees et substituees par alkyle, azido, alcoxy et fluoro et leur utilisation comme antagonistes du recepteur de la glycine
US6147075A (en) * 1993-11-05 2000-11-14 Cocensys, Inc. Alkyl, azido, alkoxy and fluoro-substituted and fused quinoxalinediones and the use thereof as glycine receptor antagonist
US6251903B1 (en) 1993-11-05 2001-06-26 Cocensys, Inc. Alkyl, azido, alkoxy, and fluoro-substituted and fused quinoxalinediones and the use thereof as glycine receptor antagonist
AU718748B2 (en) * 1995-01-27 2000-04-20 Cocensys, Inc. AZA and AZA (N-oxy) analogs of glycine/NMDA receptor antagonists
KR100588247B1 (ko) * 1997-09-01 2006-06-13 교린 세이야꾸 가부시키 가이샤 6,7-비대칭 이치환된 퀴녹살린카복실산 유도체와 이의부가염 및 이들의 제조방법
WO1999011632A1 (fr) * 1997-09-01 1999-03-11 Kyorin Pharmaceutical Co., Ltd. Derives d'acide quinoxalinecarboxylique disubstitues en position 6,7-asymetrique, sels d'addition de ces derives, et procedes de preparation de ces derives et de ces sels
US6348461B1 (en) * 1997-09-01 2002-02-19 Kyorin Pharmaceutical Co., Ltd. 6,7-asymmetrically disubstituted quinoxalinecarboxylic acid derivatives, addition salts thereof, and processes for the preparation of both
US7078424B2 (en) 1998-06-03 2006-07-18 Gpi Nil Holdings, Inc. N-linked sulfonamides of N-heterocyclic carboxylic acids or carboxylic acid isosteres
US7459473B2 (en) 1998-06-03 2008-12-02 Glia Med, Inc. N-linked sulfonamides of N-heterocyclic carboxylic acids or carboxylic acid isosteres
US7153883B2 (en) 1998-06-03 2006-12-26 Gpi Nil Holdings Inc. Carboxylic acids and carboxylic acid isosteres of N-heterocyclic compounds
WO2000050420A1 (fr) * 1999-02-26 2000-08-31 Kyorin Pharmaceutical Co., Ltd. Derives d'acide 7-heteroquinoxaline carboxilique 6-substitue et leurs sels d'addition, procedes de preparation de ces derives et de leurs sels d'addition
US6632813B1 (en) 1999-02-26 2003-10-14 Kyorin Pharmaceutical Co., Ltd. 6-subtituted-7-heteroquinoxalinecarboxylic acid derivatives and addition salts thereof and processes for the preparation of both
US7253169B2 (en) 1999-11-12 2007-08-07 Gliamed, Inc. Aza compounds, pharmaceutical compositions and methods of use
US6417189B1 (en) 1999-11-12 2002-07-09 Gpi Nil Holdings, Inc. AZA compounds, pharmaceutical compositions and methods of use
US6974823B2 (en) 1999-12-21 2005-12-13 Gpi Nil Holdindgs, Inc. Hydantoin derivative compounds, pharmaceutical compositions, and methods of using same
WO2003010146A1 (fr) * 2001-07-20 2003-02-06 Neuro3D Composes derives de quinoleine et quinoxaline, preparation et utilisations
DE10153345A1 (de) * 2001-10-29 2003-05-08 Gruenenthal Gmbh Substituierte 1H-Chinoxalin-2-on-Verbindungen und substituierte 4-Aryl- und 4-Heteroarylcyclohexan-Verbindungen
CN100424080C (zh) * 2003-08-28 2008-10-08 阿斯利康(瑞典)有限公司 作为嗜中性白细胞弹性蛋白酶抑制剂的喹喔啉衍生物及它们的用途
WO2005056547A3 (fr) * 2003-12-04 2005-09-22 Vertex Pharma Quinoxalines utiles comme inhibiteurs des proteines kinases
US7592340B2 (en) 2003-12-04 2009-09-22 Vertex Pharmaceuticals Incorporated Quinoxalines useful as inhibitors of protein kinases
WO2009070644A1 (fr) * 2007-11-30 2009-06-04 Smithkline Beecham Corporation Inhibiteurs de prolyl hydroxylases
WO2009073497A3 (fr) * 2007-11-30 2010-11-11 Glaxosmithkline Llc Inhibiteurs des prolyl hydroxylases
US8889683B2 (en) * 2010-09-27 2014-11-18 Merck Sharp & Dohme Corp. Substituted quinoxalines as inhibitors of fatty acid binding protein
RU2744429C1 (ru) * 2020-05-02 2021-03-09 Андрей Александрович Иващенко Противо-РНК вирусное, в том числе противокоронавирусное средство - замещенный хиноксалин, фармацевтическая композиция и применения

Also Published As

Publication number Publication date
AU9049391A (en) 1992-07-22
IE914452A1 (en) 1992-07-01
MX9102701A (es) 1992-06-01
PT99899A (pt) 1993-01-29
ZA9110018B (en) 1993-06-21

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