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WO1994026737A1 - Derive d'imidazolylquinoxalinedione et composition pharmaceutique le contenant - Google Patents

Derive d'imidazolylquinoxalinedione et composition pharmaceutique le contenant Download PDF

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Publication number
WO1994026737A1
WO1994026737A1 PCT/JP1994/000758 JP9400758W WO9426737A1 WO 1994026737 A1 WO1994026737 A1 WO 1994026737A1 JP 9400758 W JP9400758 W JP 9400758W WO 9426737 A1 WO9426737 A1 WO 9426737A1
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WIPO (PCT)
Prior art keywords
group
lower alkyl
imidazole
acid
reduced pressure
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PCT/JP1994/000758
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English (en)
Japanese (ja)
Inventor
Shuichi Sakamoto
Jun-Ichi Shishikura
Masahiro Iwata
Masamichi Okada
Masao Sasamata
Original Assignee
Yamanouchi Pharmaceutical Co., Ltd.
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Priority to AU66903/94A priority Critical patent/AU6690394A/en
Publication of WO1994026737A1 publication Critical patent/WO1994026737A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/56—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
    • C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles

Definitions

  • the present invention relates to imidazolylquinoxalinedione derivatives and pharmaceutical compositions thereof.
  • the present invention relates to an imidazolylquinoxalinedione derivative having a glutamate receptor antagonistic action, in particular, an anti-kainic acid neurocytotoxic action, an audiogenic seizure inhibitory action and a neuroprotective action, and a pharmaceutically acceptable salt thereof. And a pharmaceutical composition containing them.
  • Amino acids such as L-glutamic acid and L-aspartic acid are known to be mediators of the central nervous system. If these excitatory amino acids accumulate extracellularly and continue to stimulate the nerves excessively, Huntington's chorea, Parkinson's disease, epilepsy, Alzheimer's disease, senile dementia, and cerebral ischemia, hypoxia, low It is said to lead to neurodegeneration or mental and motor dysfunction observed after blood sugar status
  • drugs capable of regulating the abnormal action of these excitatory amino acids have been considered to be useful for treating neurodegenerative and psychiatric disorders.
  • NMD A N-methyl-D-aspartate receptor
  • NMD A-induced neuropathy, epilepsy and cerebral ischemia has been tested in NMD A-induced neuropathy, epilepsy and cerebral ischemia It has been reported to be effective in animal models (J. Pharmacology and Experimental Therapeutics, 250, 100 (1989): J. Pharmacology and Experimental Therapeutics, 240, 737 (1987): Science, 226, 850 (1984)).
  • the NMD A receptor has been reported to work in an allosteric manner via the glycine receptor (EJP, -126, 303 (1986)), and HA-966, an antagonist of the glycine receptor, is still present. It has been reported to be effective in experimental animal models of cerebral ischemia (American Neuroscience Society 1989).
  • NBQX 6-nitro7-sulfamoylbenzo [f] quinoxaline
  • a selective AMP A receptor antagonist has also been reported to be effective in experimental animal models of cerebral ischemia. (Science, 247, 571 (1990)). On the other hand, no selective antagonists of kainate receptor and metabotropic glutamate receptor have been reported so far. Disclosure of the invention
  • An object of the present invention is to provide a compound having a diketoquinoxaline-based glutamate receptor antagonistic action, and particularly having an anti-kainic acid neurotoxicity action, an audiogenic spasm inhibitory action, and a neuroprotective action. Is what you do.
  • Several diketoquinoxaline derivatives having NMDA-glycine receptor antagonistic activity and / or AMP A receptor antagonistic activity have been reported (JP-A-63-83074, No. 6 3 ⁇ 2 5 8 4 6 6; Japanese Unexamined Patent Application Publication No. HEI 1—15 3680; Japanese Unexamined Patent Application Publication No. HEI 2—4 857 8 No.
  • the compound of the present invention is imidazolyl via a linking group of 0, S and N heteroatoms.
  • the structure of the quinoxalinedione skeleton connected to a substituted or unsubstituted hydrocarbon chain represented by R 3 —A—, a substituted or unsubstituted carbocyclic ring, or a substituted or unsubstituted heterocyclic ring It is a novel compound having even better pharmacological activity.
  • the present invention provides a compound represented by the general formula (I):
  • R 1 hydrogen atom or lower alkyl group
  • R 2 hydrogen atom or hydroxyl group
  • X group — 0—, — NR 4 — or —S (0) R 4 a hydrogen atom or a lower alkyl group
  • n 0, 1 or 2
  • R 3 1) a lower alkyl group
  • the present invention relates to an imidazolylquinoxalinedione derivative represented by the formula or a pharmaceutically acceptable salt thereof.
  • the present invention also relates to a pharmaceutical composition
  • a pharmaceutical composition comprising an imidazolyl quinoxalindione derivative represented by the above general formula (I) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
  • the “lower alkyl group” specifically, 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 isopentyl group , Neopentyl, tert-pentyl, 1-methylbutyl, 2-methylbutyl, 1,2-dimethylpropyl, hexyl, isohexyl, 1-methylpentyl, 2-methylpentyl, 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- Dimethylbuty 1-ethylbutyl group, 2-ethylbutyl group, 1,2,2-trimethyl
  • the “lower alkylene group” represented by A includes methylene group, ethylene group, methylmethylene group, trimethylene group, 1-methylethylene group, 2-methylethylene group, tetramethylene group, 1-methyltrimethylene group, 2-methyl Trimethylene 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-ethylethylmethylene group, 3-ethyltrimethylene group, 1,1-dimethyltrimethylene group, 2,2- Dimethyltrimethylene group, 3,3-dimethyltrimethylene group, hexamethylene group, 1-methylpentame Carbon atoms such as styrene, 2-methylpentamethylene, 3-methylpentamethylene, 4-methylpentamethylene,
  • the ⁇ optionally substituted phenyl group, cycloalkyl group, or monocyclic or bicyclic heterocyclic group having N and / or S as a hetero atom '' is a phenyl group, a substituted phenyl group.
  • cycloalkyl group substituted cycloalkyl group, monocyclic or bicyclic heterocyclic group having N and S or S as a hetero atom, monocyclic or bicyclic heterocyclic group having substituted N and / or S as a hetero atom
  • Cyclic heterocyclic group means all Among them, the cycloalkyl group is preferably a cycloalkyl group 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 Groups.
  • the monocyclic or bicyclic heterocyclic group having N and Z or S as a hetero atom include, for example, a pyrrolyl group, a pyrrolinyl group, an imidazolyl group, an imidazolinyl group, a virazolyl group, a virazolinyl group, and a triazolyl group.
  • a pyrrolyl group a pyrrolinyl group
  • an imidazolyl group an imidazolinyl group
  • a virazolyl group a virazolinyl group
  • a triazolyl group a triazolyl group.
  • 5- or 6-membered monocyclic heterocyclic group containing only 1 to 4 nitrogen atoms thiazolyl group A 5- to 6-membered monocyclic heterocyclic group containing 1 to 4 nitrogen and sulfur atoms such as isothiazolyl group, thiadiazolyl group, dithiazolyl group, dithiazolinyl group, thiazinyl group, thiadiazinyl group, dithiazinyl group, chenyl group , Dithiolyl, thiopyranyl, dichenyl, trithenyl, etc.
  • phenyl ring, cycloalkyl ring, monocyclic or bicyclic heterocycle having N and S or hetero atoms as hetero atoms may have one or more substituents at any positions.
  • substituents include a phenyl ring, a cycloalkyl ring and a heterocyclic ring in the art.
  • Any known substituents on the mouth ring may be used, and in particular, halogen atoms; lower alkyl groups, halogeno lower alkyl groups, carboxy lower alkyl groups, lower alkoxy groups, lower alkoxy groups, lower alkyl groups, and lower amino alkyl groups.
  • Substituted or unsubstituted lower alkyl groups such as mono- or di-lower alkylamino lower alkyl groups; substituents of hydroxyl groups such as hydroxyl group and lower alkoxy group; substitution of carboxy groups such as carboxy group and lower alkoxycarbonyl group Group; a cyano group; a nitro group; a substituent of an amino group such as an amino group, a mono- or di-lower alkylamino group; or a monocyclic or bicyclic heterocyclic group having N as a hetero atom is preferable. Examples thereof include a substituent.
  • halogen atom includes a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom
  • lower alkyl group includes the specific groups described above.
  • Halogeno lower alkyl group means a group in which any one or two or more hydrogen atoms of the lower alkyl group are substituted with a halogen atom.
  • a halogen atom is exemplified by a fluorine atom, a fluoromethyl group, a difluoromethyl group Trifluoromethyl group, 2,2,2-trifluoroethyl group and the like.
  • the "lower alkoxy group” includes methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyl (amyl) oxy, isopentyl And the like.
  • a “lower alkoxycarbonyl group” is a group in which these “lower alkoxy groups” are esterified by replacing OH of a carboxy group (eg, a methoxycarbonyl group, an ethoxycarbonyl group). Etc.).
  • “Mono or di-lower alkylamino group” is one of the amino groups or A group in which two hydrogen atoms are mono- or di-substituted with a specific group of the lower alkyl group, specifically, for example, a methylamino group, an ethylamino group, a propylamino group, an isopropylamino group, a butylamino group, Mono-lower alkylamino such as isobutylamino, sec-butylamino, tert-butylamino, pentylamino, isopentylamino, hexylamino, isohexylamino, dimethylamino, getylamino, dipropylamino And asymmetric di-lower alkylamino groups such as a symmetric di-lower alkylamino group such as a group, disopropylamino group and dibutylamino group, an ethylmethyl
  • Carboxy lower alkyl group “lower alkoxycarbonyl lower alkyl group”, “amino lower alkyl group”, “mono or di lower alkylamino lower alkyl group” means that any hydrogen atom of the lower alkyl group is carboxy.
  • a lower alkoxycarboxy group, an amino group, or a group substituted with the mono- or di-lower alkylamino group is ⁇ carboxy lower alkyl group '' such as carboxymethyl group
  • Examples of the ⁇ lower alkoxycarbonyl lower alkyl group '' include carboxyethyl, carboxypropyl, carboxybutyl, and the like, and methoxycarbonylmethyl, ethoxycarbonylmethyl, methoxycarbonylethyl, ethoxycarbonylethyl, Methoxycarbonyl A propyl group, an ethoxycarbonylpropyl group, a methoxycarbonylbutyl group, an ethoxycarbonylbutyl group, and the like, and the “amino lower alkyl group” are an aminomethyl group, an aminoethyl group, an aminopropyl group, an aminobutyl group, and the like.
  • Lower alkylamino lower alkyl group "and Examples include methylaminomethyl, ethylaminomethyl, dimethylaminomethyl, ethylaminomethyl, methylaminoethyl, ethylaminoethyl, dimethylaminoethyl, and dimethylaminoethyl. And methylaminopropyl group, ethylaminopropyl group, propylaminopropyl group, dimethylaminopropyl group, getylaminopropyl group, dipropylaminopropyl group and the like.
  • Examples of the “monocyclic or bicyclic heterocyclic group having N as a heteroatom” include all the heterocyclic groups having only a nitrogen atom among the above-mentioned heterocyclic groups, and particularly, an imidazolyl group and a triazolyl group. And a tetrazolyl group.
  • the “monocyclic or bicyclic heterocyclic group having N as a hetero atom” as a substituent is particularly preferably a group bonded via a ring carbon atom.
  • the compound (I) of the present invention forms a salt with an acid. Further, depending on the type of the substituent, a salt with a base may be formed.
  • the present invention also includes pharmaceutically acceptable salts of compound (I), and examples of such salts include inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, and phosphoric acid.
  • Formic acid acetic acid, propionic acid, succinic acid, valeric acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, citric acid, tartaric acid, carbonic acid, picric acid, methanesulfonic acid
  • Acid addition salts with organic acids such as ethanesulfonic acid, glutamic acid, and aspartic acid
  • inorganic bases such as sodium, potassium, magnesium, calcium, and aluminum, such as methylamine, ethylamine, dimethylamine, getylamine, Trimethylamine, triethylamine, monoethanolamine, diethanolamine, triethanolamine, cyclohexylamine
  • organic bases such as lysine and lysine, and ammonium salts.
  • the compound of the present invention has a tautomer based on a diketoquinoxaline structure. Also, depending on the type of the substituent, there are optical isomers (optically active isomers, diastereomers, etc.). The present invention includes a separated form of these isomers and a mixture thereof.
  • the compound of the present invention may be isolated as various solvates such as hydrates and ethanol solvates and crystalline polymorphic substances, and the present invention includes all of these substances.
  • R 3 is a halogen atom, a lower alkyl group, a halogeno lower alkyl group, a carboxy lower alkyl group, a lower alcohol, Oxycarbonyl lower alkyl group, amino lower alkyl group, mono or di lower alkyl amino lower alkyl group, hydroxyl group, lower alkoxy group, carboxy group, lower alkoxycarbonyl group, cyano group, nitro group, amino group, A phenyl group which may be substituted with one or more substituents selected from the group consisting of a mono- or di-lower alkylamino group, and a monocyclic or bicyclic heterocyclic group having N as a hetero atom Compounds.
  • preferred compounds include the compounds described in Examples, and particularly preferred examples include the following.
  • the compound of the present invention can be produced by a method represented by the following reaction formula.
  • R 1 , R 2 , R 3 , X and A have the above-mentioned meaning, and Y means a halogen atom.
  • the compound (I) of the present invention can be obtained by reacting a halogen compound ( ⁇ ) in an amount corresponding to the reaction with an imidazole compound ( ⁇ ) while stirring. Although the reaction proceeds without solvent, it is usually heated in a solvent such as dimethylformamide (DMF), dimethylsulfoxide (DMSO), acetonitrile, acetone, tetrahydrofuran (THF) or the like. Done. To promote the reaction, a base such as caustic soda, caustic potash, potassium carbonate or a copper salt may be added.
  • a solvent such as dimethylformamide (DMF), dimethylsulfoxide (DMSO), acetonitrile, acetone, tetrahydrofuran (THF) or the like.
  • a base such as caustic soda, caustic potash, potassium carbonate or a copper salt may be added.
  • the compound of the general formula (la) in the compound of the present invention is obtained by reacting the diamino compound (W) with an equivalent to excess amount of oxalic acid or a reactive derivative (V) thereof at room temperature to under heating, preferably under heating to reflux. Can be reacted.
  • the reactive derivative of oxalic acid include salts, esters, hydrates, anhydrides, and acid halides. This reaction is usually performed in water or an alcohol solvent. To promote the reaction, it is preferred to add an acid such as hydrochloric acid.
  • R 1 , R 3 , X and A have the above-mentioned meanings, and t Bu means a tert-butyl group.
  • This production method is an alternative to the second production method, and comprises adding a tert-butylamine compound (VI) and an equivalent or excess amount of oxalic acid or a reactive derivative thereof in water or an alcohol solvent under an acidic condition from room temperature to a heated condition.
  • the reaction can be carried out while stirring.
  • the reactive derivative of oxalic acid is as described above.
  • R 1 , R 3 , X and A have the above-mentioned meaning, and R 5 represents an ester-forming group.
  • the compound (Ia) of the present invention is a lower alkoxalylamino compound (W)
  • W can be produced by reductive cyclization of Is not particularly limited as long as herein ester forming group for R 5 is an ester-forming group that does not inhibit the cyclization by reaction, typically a methyl group, those lower alkyl groups such as Echiru group used.
  • the reaction can be carried out, for example, by a conventional catalytic reduction method in which hydrogen gas is used at least three times the amount of the compound (W) in the presence of a catalyst such as Raney nickel or palladium-carbon (Pd-C), such as iron chloride or activated carbon.
  • the reaction can be carried out by a reduction method using hydrazine or a hydrate thereof in the presence of a catalyst prepared from Raney nickel or the like.
  • Present compound (lb) is a lower alkoxy hexa Lil amino compound (W) palladium one-carbon, platinum oxide (P t 0 2), Irijiumu - carbon
  • (Ir-C) can be obtained by a conventional catalytic reduction method in which twice the amount of hydrogen gas is allowed to act in the presence of a catalyst such as (Ir-C). It can also be added.
  • R 1 , R 2 , X and A have the above-mentioned meanings, and B is a bond or an optionally substituted phenylene group, cycloalkanediyl group, or N and or S is a heteroatom
  • the compound (Ic) of the present invention having at least one carboxy group as a substituent is a corresponding ester It can be produced by hydrolyzing compound (H).
  • ester-forming group of R 6 is not particularly limited as long as it forms an ester as well as the lower alkyl group constituting the compound of the present invention and gives the corresponding carboxylic acid by this hydrolysis.
  • Hydrolysis may be carried out by any of acid hydrolysis in the presence of an acid such as hydrochloric acid and alkylation in the presence of a base such as sodium hydroxide. Can be.
  • the compound (I e) having at least one tetrazolyl group in the compound of the present invention when the corresponding nitrile compound (I d) is used as a raw material, may be used in an amount corresponding to the reaction or an excess amount of hydrogen azide or azide. It can be produced by reacting a metal azide, such as sodium azide, tin azide compound, gayzide azide compound and aluminum azide compound, usually under heating.
  • a metal azide such as sodium azide, tin azide compound, gayzide azide compound and aluminum azide compound
  • the reaction is usually carried out in an organic solvent such as DMF.However, N-methylpyrrolidone is used as a solubilizing agent, or an amine such as ammonium chloride such as ammonium chloride or trimethylamine or triethylamine, or an amine or a salt thereof is added. Solubility can also be improved.
  • the compound of the present invention can also be produced by applying various conventional methods, particularly the methods described in Reference Examples and modifications thereof in consideration of the features of the structure in addition to the above-mentioned production methods.
  • a compound in which X is -0- or _S- is a compound in which the corresponding halide is replaced with a hydroxy or mercapto compound, such as sodium hydride.
  • the reaction can be carried out at room temperature or under heating in the presence of a base by conventional etherification or thioetherification.
  • the compound in which X is -N- is used to convert the corresponding amine and the corresponding halide or sulfonate from room temperature to heating in the presence of a base such as potassium carbonate or triethylamine, if necessary. It can be produced by applying a so-called N-alkylation ordinary method for reacting with the above.
  • Compounds having a mono- or di-lower alkylamino group or a mono- or di-lower alkylamino lower alkyl group as a substituent can be produced by the same N-alkylation using the corresponding primary or secondary amino compound as a raw material.
  • compounds in which X is —SO— or 1 S 0 2 — can be used to convert the corresponding sulfide (—S—) or sulfonyl (—SO—) compound into an organic peracid such as m-chloroperbenzoic acid. It can be produced by conventional oxidation by treating with an oxidizing agent such as hydrogen peroxide or nitric acid.
  • Compounds having a lower alkoxycarbonyl group as a substituent can be prepared by reacting a reactive derivative thereof such as a corresponding carboxylic acid diacid halide with a reactive derivative thereof such as a lower alkanol or a lower alkyl halide.
  • a reactive derivative thereof such as a corresponding carboxylic acid diacid halide
  • a reactive derivative thereof such as a lower alkanol or a lower alkyl halide.
  • the compound of the present invention thus produced is isolated and purified as a free compound, a salt thereof, a hydrate, various solvates and the like.
  • the pharmaceutically acceptable salt of the compound (I) of the present invention can also be produced by subjecting the compound to a conventional salt formation reaction.
  • Isolation and purification are performed by applying ordinary chemical operations such as extraction, fractional crystallization, and various types of fractional chromatography.
  • the optical isomer can be obtained by selecting an appropriate starting compound or by a racemic resolution method of a racemic compound (for example, a method of leading to a diastereomer salt with a general optically active base and performing optical fractionation). Can lead to stereochemically pure isomers.
  • the compound of the present invention has an affinity for AMPA receptor, but has a strong anti-kainic acid neurotoxicity in rat fetal hippocampal neuronal primary culture system regardless of the degree of affinity for AMPA receptor. Showed an effect. In rat fetal hippocampus primary cultures, the kainate-binding site of the AMPA kainate receptor is thought to play an important role in inducing neuronal necrosis [J. Neuroscience, 10, 693 (1990)]. Furthermore, the compound of the present invention strongly suppressed late neuronal necrosis in the hippocampus of murine rats. In addition, the platform of the present invention also showed strong suppression of audiogenic convulsions in DBAZ2 mice.
  • the compound of the present invention is effective for hunting-ton's chorea, Parkinson's disease, epilepsy, Alzheimer's disease, senile dementia, cerebral ischemia, cerebral ischemia, and oxygen deficiency based on these effects, particularly the potent anti-kainic acid neurocytotoxic effect It is a particularly useful drug for protecting cells during temporary cardiac arrest, preventing hypoglycemia and post-convulsive neurodegeneration or mental and motor dysfunction.
  • the activity of the compound of the present invention for inhibiting the binding to the AMP A receptor was expressed at a concentration of 10 nM to 100 M.
  • the hippocampus was excised from the rat brain on days 18-20 of the embryo and treated with papain and DNase I to disperse the cells.
  • the cells were suspended in MEM containing 10% serum, and seeded on a 48-well plate previously treated with poly-1-Lysine at a concentration of 4 ⁇ 10 5 cellZcnf. After 24 hours, the medium was replaced with a serum-free medium. The medium was exchanged twice / week. Cells cultured for 6 days or more were subjected to the following experiment.
  • Neurotoxicity was expressed as the activity of lactate dehydratase released into the culture medium due to cell death. 300; in a serum-free medium containing kainic acid Using the compound exposed for 24 hours as a control, each compound was allowed to act on nerve cells for 24 hours simultaneously with 300 ⁇ ⁇ ⁇ of kainate, and the inhibitory effect of each compound on nerve cell death caused by kainate was evaluated.
  • the compound of Example 37 had an IC 5 .
  • the value of 0.20 / ⁇ showed an excellent effect.
  • mice 21 1-28-day-old male mice (10 mice) were placed in a soundproof box, and 1 2 kHz,
  • a 12 OdB sound stimulus was applied for 1 minute or until the mouse developed rigid convulsions.
  • the test compound was suspended in a 0.5% methylcellulose solution or dissolved in saline, and administered intraperitoneally 15 minutes before sound stimulation.
  • the efficacy was evaluated based on the presence or absence of seizures, and the minimum effective dose (MED) was determined.
  • MED minimum effective dose
  • Example 3 suppressed the convulsive seizure by 0.3 ⁇ 13 ⁇ 4.
  • the brain was removed and sectioned, and the degree of neuronal damage in hippocampal CA 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. 3 Evaluation method
  • Example 23 of the present invention had a score of 1 in the degree of damage.
  • compositions containing one or more of the compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof as an active ingredient can be used as a carrier for commonly used pharmaceutical preparations. Tablets, powders, fine granules, granules, capsules, pills, liquids, injections, suppositories, etc., and orally or parenterally. .
  • the dosage is determined as appropriate depending on the individual case, taking into account the symptoms, age of the subject to be administered, gender, body weight, etc., but it is usually l-1000 mg, preferably 50-200 mg per adult daily. Orally once or several times daily in the range of lmg to 50 mg / day for adults, once or several times daily, or It is continuously administered intravenously for 1 hour to 24 hours a day. Of course, as described above, the dose varies under various conditions, so that a dose smaller than the above dose range may be sufficient.
  • the one or more active substances include at least one inert diluent, such as lactose, mannitol, glucose, hydroxypropylcellulose, microcrystalline cellulose, starch, polyvinylpyrrolidone.
  • the metasilicate is mixed with magnesium aluminate.
  • the composition is prepared according to the usual methods, using additives other than inert diluents, such as magnesium stearate.
  • Tablets or pills may be coated with a film of a gastric or enteric substance such as sucrose, gelatin, hydroxypropylcellulose, or hydroxypropylmethylcellulose phthalate, if necessary.
  • Liquid compositions for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, elixirs and the like, and commonly used inert diluents such as purified water , Including ethanol.
  • This composition may contain, in addition to the inert diluent, solubilizing or dissolving aids, auxiliary agents such as wetting agents and suspending agents, sweeteners, flavoring agents, fragrances, and preservatives. .
  • Injections for parenteral administration include sterile aqueous or non-aqueous solutions, suspensions, and emulsions.
  • aqueous diluents and suspension diluents include distilled water for injection and physiological saline.
  • diluents for non-water-soluble solutions and suspensions for example, propylene glycol, polyethylene glycol, vegetable oils such as olive oil, alcohols such as ethanol, polysorbate 80 (trade name) And so on.
  • Such compositions may further comprise additives such as tonicity agents, preservatives, wetting agents, emulsifiers, dispersants, stabilizers (eg, lactose), solubilizing or solubilizing aids. Good.
  • the reaction mixture was concentrated under reduced pressure, neutralized with saturated aqueous sodium hydrogen carbonate, and extracted with ethyl acetate. The organic layer was separated, washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure.
  • N- [5-Fluoro-4 -— [(4-ethoxycarbonylphenyl) oxy] —2-ditrophenyl] oxamic acid 2.00 g (4.5 mmol) and 0.80 g (0.98 mraol) of 4-methylimidazole were heated under reflux for 3 hours. After cooling, the reaction mixture was diluted with chloroform, washed with water and saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure.
  • reaction mixture was concentrated, purified with HP-20 resin, and purified with 4- [6— (1H-imidazole-1-11) -12,3 (1H, 4H) -quinoxalinedione-7- Oxyphthalic acid 36 Omg (64%) was obtained.
  • the reaction mixture was concentrated under reduced pressure, and the obtained residue was diluted with water, purified with HP-20 (Mitsubishi Kasei), and purified with 6- (1H-imidazole-11-yl) -17- [1-methyl). Tetrazole-5-yl) thio] —2,3 (1 H, 4 H) monoquinoxalinedione (183 mg, 59%) was obtained.
  • reaction mixture was concentrated under reduced pressure, and the obtained residue was diluted with water, purified with HP-20 (Mitsubishi Chemical), and purified with 6- (1H-imidazolone 1-yl) 17-[(5-methyl- 1,3,4-Thiadiazol-2-yl) thio] —2,3 (1H, 4H) —quinoxalinedion 2 15 mg (24%) was obtained.
  • Example 2 The same reaction as in Example 19 was carried out using 121 mg of sodium hydride, 52 mg of 4-ethoxycarbonylimidazolone 2-thiol, 22 mg of THF, and 10 m of DMF, and purified with HP-20. 2 — [[2,3-Dioxo—7— (1H—imidazo-1-yl) —1,2,3,4-tetrahydro-6_quinoxalinyl] thio] —1H—imidazole-4 There were obtained 25.2 mg (19%) of the acid hydrochloride.
  • Example 2 1 [[2,3-Dioxo—7— (1H—imidazo-1-yl) —1,2,3,4-tetrahydro-6_quinoxalinyl] thio] —1H—imidazole-4 There were obtained 25.2 mg (19%) of the acid hydrochloride.
  • Example 2 1 [[2,3-Dioxo—7— (1H—imidazo-1-yl) —1,2,
  • Example 26 After concentration under reduced pressure, the same treatment as in Example 13 was carried out using 5 ⁇ 31 hydrochloric acid 5 and 0.95 g of oxalic acid, followed by treatment with 4-[[7- (1H-imidazoyl-1-yl)]. 1.27 g (65%) of 1,2,3-dioxo-1,2,3,4-tetrahydroquinoxaline-6-yl] oxy] butyric acid hydrochloride was obtained.
  • Example 26 Example 26
  • a mixture of 465 mg (1.04 marl ol), DMF 2 Or, sodium azide 678 mg, and ammonium chloride 556 mg was stirred for 5 hours on a 120 ° C. oil bath. After cooling, the reaction mixture was diluted with water, the pH was adjusted to 2 by adding 3N hydrochloric acid, and the precipitated compound was collected by filtration.
  • N- [5-(1H-imidazole-1-1yl)-4-[(4-methoxycarbonylphenyl) methoxy]-2-ditrophenyl] ethyl ethyl oxamate 6 45 mg (1.
  • a mixture of 38 mraol), THF 60, methanol 120 ⁇ , 3 lmg of iron chloride (BI), 1 drop of water and 53 mg of activated carbon was refluxed under heating for 30 minutes.
  • hydrazine monohydrate 0.6 was added dropwise, and the mixture was refluxed for 20 hours while heating. After cooling, the reaction mixture was filtered and concentrated under reduced pressure.
  • Table 1 shows the structures and physicochemical properties of the compounds obtained in the examples.

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Abstract

Sont décrits un dérivé d'imidazolylquinoxalinedione représenté par la formule générale (I), et utile comme antagoniste des récepteurs du glutamate, ainsi que son sel pharmaceutiquement acceptable, et une composition pharmaceutique le contenant comme principe actif. Dans ladite formule, R1 représente un groupe hydrogène ou alkyle inférieur; R2 représente un groupe hydrogène ou hydroxy; X représente un groupe -O-, -NR4- ou bien -S(O)¿n-; R?4 représente un groupe hydrogène ou alkyle inférieur; n vaut 0, 1 ou 2; A représente une liaison directe ou un groupe alkylène inférieur; et R3 représente (1) un groupe alkyle inférieur, (2) carboxy, ou (3) phényle, cycloalkyle ou bien hétérocyclique mono- ou bicyclique dans lequel le ou les hétéroatomes est ou sont N et/ou S, chacun d'eux pouvant être substitué.
PCT/JP1994/000758 1993-05-12 1994-05-11 Derive d'imidazolylquinoxalinedione et composition pharmaceutique le contenant WO1994026737A1 (fr)

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Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1997046555A1 (fr) * 1996-06-06 1997-12-11 Yamanouchi Pharmaceutical Co., Ltd. Derives de quinoxalinedione a substitution imidazole
US6015800A (en) * 1997-09-03 2000-01-18 Warner-Lambert Company Substituted quinoxaline-2-ones as glutamate 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
US6599942B1 (en) 1999-03-29 2003-07-29 Novartis Ag Thyromimetic organic compounds
US6790978B2 (en) 1999-03-29 2004-09-14 Novartis Ag Thyromimetic organic compounds
US6794406B2 (en) 2000-12-27 2004-09-21 Bayer Aktiengesellschaft Indole derivatives
WO2005030716A1 (fr) * 2003-09-25 2005-04-07 Wyeth Acides ou esters d'indoles-2-carboxylique heterocyclique ou aryloxy, -thio ou -amino substitues en tant que pai-1

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1993020077A1 (fr) * 1992-04-03 1993-10-14 Yamanouchi Pharmaceutical Co., Ltd. Derive de quinoxalinone fondue et composition pharmaceutique le contenant

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1993020077A1 (fr) * 1992-04-03 1993-10-14 Yamanouchi Pharmaceutical Co., Ltd. Derive de quinoxalinone fondue et composition pharmaceutique le contenant

Cited By (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1997046555A1 (fr) * 1996-06-06 1997-12-11 Yamanouchi Pharmaceutical Co., Ltd. Derives de quinoxalinedione a substitution imidazole
US6121264A (en) * 1996-06-06 2000-09-19 Yamanouchi Pharmaceutical Co., Ltd. Imidazole-substituted quinoxalinedione derivatives
US6015800A (en) * 1997-09-03 2000-01-18 Warner-Lambert Company Substituted quinoxaline-2-ones as glutamate 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
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
US6599942B1 (en) 1999-03-29 2003-07-29 Novartis Ag Thyromimetic organic compounds
US6689896B2 (en) 1999-03-29 2004-02-10 Novartis Ag Thyromimetic organic compounds
US6790978B2 (en) 1999-03-29 2004-09-14 Novartis Ag Thyromimetic organic compounds
US6794406B2 (en) 2000-12-27 2004-09-21 Bayer Aktiengesellschaft Indole derivatives
WO2005030716A1 (fr) * 2003-09-25 2005-04-07 Wyeth Acides ou esters d'indoles-2-carboxylique heterocyclique ou aryloxy, -thio ou -amino substitues en tant que pai-1
JP2007506772A (ja) * 2003-09-25 2007-03-22 ワイス Ｐａｉ−１としてのヘテロサイクリックまたはアリールオキシ、−チオまたは−アミノ置換インドール−２−カルボン酸またはエステル
US7332521B2 (en) 2003-09-25 2008-02-19 Wyeth Substituted indoles

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