1,2,3,4-TETRAHYDROQUINOXALINEDIONE DERIVATIVES AND USE AS GLUTAMATE RECEPTOR ANTAGONISTS

Abstract: A 1,2,3,4-tetrahydroquinoxalinedione derivative represented by the following formula (I) or salt thereof, an NMDA-glycine receptor and/or AMPA receptor antagonist or kainic acid neurotoxicity inhibitor containing the derivative or salt. In addition, a pharmaceutical composition comprising said compound and a pharmaceutically acceptable carrier. wherein symbols in the above formula represent the following meanings, respectively: X: N, CH, R: an imidazolyl group or a di-lower alkylamino group, R 1 : (1) a halogen atom, a nitro group, a cyano group, a carboxyl group, an amino group, a mono- or di-lower alkylamino group, a lower alkanoyl group, a lower alkylthio group, a lower alkylsulfinyl group, a lower alkylsulfonyl group or a carbamoyl group, (2) a lower alkyl group or lower alkoxyl group which may be substituted by a halogen atom, a carboxyl group or an aryl group, (3) a phenyloxy group which may be substituted by a lower alkoxycarbonyl group or a carboxyl group, R 2 : a hydroxyl group, a lower alkoxyl group, an amino group or a mono- or di-lower alkylamino group, A: a lower alkylene group which may be substituted or a group represented by the formula -O-B-, and B: a lower alkylene group, with the proviso that the case wherein R represents an imidazolyl group, R 1 represents a cyano group, A represents an ethylene group and R 2 represents a hydroxyl group is excluded.

Description: Technical Field The present invention relates to quinoxalinedione compounds which have glutamate receptor antagonizing action, high affinity with AMPA receptors which are non-NMDA receptors, potent inhibitory action against kainic acid neurotoxicity, audiogenic seizure inhibitory action, and high solubility. Background Art Amino acids such as L-glutamic acid and L-aspartic acid are known to be central nervous system neurotransmitters. It is said that extracellular accumulation of these excitatory amino acids and their continuous or excessive stimulation of the nerves lead to Huntington chorea, Parkinson disease, epilepsy, Alzheimer disease, senile dementia or neurodegeneration or deficiency in mental and motor functions observed after the condition of cerebral ischemia, oxygen deficiency or hypoglycemia. It has come to be considered that a regulator of the abnormal activity of an excitatory amino acid is useful for the therapeutic treatment of neurodegeneration or psychic diseases. Excitatory amino acids exhibit their action through glutamate receptors which are specific receptors existing at postsynapse or presynapse. At present, such receptors can be classified into three groups based on electrophysiological and neurochemical studies. 1) NMDA (N-methyl-D-aspartate) receptor 2) non-NMDA receptor a) AMPA [2-amino-3-(3-hydroxy-5-methyl-4-isoxazolyl)propionic acid] receptor b) kainate receptor 3) metabotropic glutamate receptor The compound according to the present invertion has glutamate receptor antagonizing action and inhibitory action against kainic acid neurotoxicity and is useful as an anti-ischemia or as an psychotropic. L-glutamic acid or L-aspartic acid activates the above-described glutamate receptors and transmits excitation. When an excess amount of NMDA, AMPA or kainic acid is caused to act on the neuron, neuronal death occurs. It is reported that 2-amino-5-phosphonovalerianic acid or 2-amino-7-phosphonoheptanic acid which is a selective antagonist against the NMDA receptor is effective for experimental animal models suffering from neuropathy, epilepsy or cerebral ischemia ( J. Pharmacology and Experimental Therpeutics , 250 , 100(1989); J. Pharmacology and Experimental Therapeutics, 240, 737(1987); or Science, 226, 850(1984)). It is reported that NMDA receptor functions are allosterically regulated by a glycine receptor (Eur.J.Pharmacol. 126 ), 303(1986)) , while it is reported that HA-966 which is an antagonist against the glycine receptor is effective in experimental animal models suffering from cerebral ischemia (Annual meeting of Society for Neuroscience, 1989). It is also reported that NBQX (6-nitro-7-sulfamoylbenzo[f]quinoxaline) which is a selective antagonist against the AMPA receptor is also effective in experimental animal models suffering from cerebral ischemia ( Science , 247 , 571(1990)). On the other hand, it has been shown that all the non-NMDA receptors subjected to cloning have affinity with kainic acid and it is suggested that among these receptors, a receptor having low affinity with kainic acid (the AMPA/kainate receptor) has a relation with neuronal death at the time of ischemia such as cerebral infarction (P.C. May and P.M. Robison, J. Neurochem., 60, 1171-1174 (1933)). This AMPA/kainate receptor has high affinity with AMPA but the binding sites of AMPA and kainic acid are not known. It is however reported that AMPA and kainic acid exhibit different electrophysiologic responses against the AMPA/kainate receptor. It is reported that in a neuronal toxicity test using a neuronal culture system, kainic acid itself causes marked neuronal cell death, while the action of AMPA alone is weak (P.C. May and P.M. Robison, J. Neurochem., 60, 1171-1174 (1993)). Accordingly, there is a possibility that neuronal death caused by excessive excitation by glutamic acid at the time of ischemia is intensely suppressed by a compound having inhibitory action against kainic acid toxicity in the neuronal culture system. There are several reports on diketoquinoxaline derivatives having an NMDA-glycine receptor antagonizing action and/or AMPA receptor antagonizing action (an unexamined published Japanese patent application ( kokai ) No. 63-83074, an unexamined published Japanese patent application (kokai) No. 63-258466, an unexamined published Japanese patent application ( kokai ) No. 1-153680, an unexamined published Japanese patent application ( kokai ) No. 2-48578, an unexamined published Japanese patent application ( kokai ) No. 2-221263, an unexamined published Japanese patent application ( kokai ) No. 2-221264, an international patent publication WO92/07847 and an international patent publication WO93/08173). WO-A-9308173 and WO-A-9425467 disclose quinoxalinedione AMPA receptor binders which may be 1-substituted by carboxyalkyl and substituted on the aryl ring by various groups including imidazolyl. EP-A-0556393 discloses 6-cyano-7-(1-imidazolyl)-1-[2-carboxyethyl) -quinoxaline-2,3-dione and similar compounds as AMPA receptor antagonists. Disclosure of the Invention The compounds of the present invention have, as will be described hereinafter in detail, an antagonizing action against quinoxaline-based glutamate receptor, high affinity for the AMPA receptor which is a non-NMDA receptor, intense inhibitory action against kainic acid neurotoxicity and audiogenic seizure depressant action, and also have high solubility. The present invention provides a 1,2,3,4-tetrahydroquinoxalinedione derivative of formula (I) or a tautomer thereof or a salt or hydrate or solvate of said derivative or tautomer : wherein R is an imidazolyl group and R 1 is a nitro or benzyloxy group. These compounds of the present invention are glutamate receptor antagonists, more specifically, they have NMDA-glycine receptor antagonising action and/or AMPA receptor antaginizing action, or inhibitory activity of kainate-induced neurotoxicity and are useful for anti-ischemia or as psychotropics. The present invention further provides a pharmaceutical composition which comprises a compound of the invention and a pharmceutically acceptable carrier, preferably such a composition which is for AMPA receptor antagonism. Particularly preferred compounds are: 2-[2,3-dioxo-7-(1H-imidazol-1-yl)-6-nitro-1,2,3,4-tetrahydroquinoxalin-1-yl]acetic acid or salt thereof; and 2-[6-benzyloxy-2,3-dioxo-7-(1H-imidazol-1-yl)-1,2,3,4-tetrahydroquinoxalin-1-yl]acetic acid or salt thereof. The derivative (I) of the present invention has a tautomer based on the diketoquinoxaline skeleton, and this is included in the present invention. The compounds of the present invention can be salts with acid or base. Examples of salt with an acid include acid addition salts with an inorganic acid, for example, mineral acid such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid or phosphoric acid and those with an organic acid such as formic acid, acetic acid, propionic 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, ethanesulfonic acid or glutamic acid. Examples of salt with a base include salts with a an inorganic base such as sodium, potassium, magnesium, calcium or aluminum, salts with an organic base such as methylamine, ethylamine or ethanolamine, salts with a basic amino acid such as lysine, arginine or ornithine, and ammonium salts. In addition, the compounds of the present invention can be hydrates or solvates (e.g. with ethanol) and can show polymorphism. (Preparation Methods) The compoundsof the present invention can be prepared in accordance with the process shown by the following reaction scheme, wherein X is CH; A is CH 2 ; R and R 1 are as defined above; Y is halogen and Y 1 is halogen other than fluorine; R 1' is hydrogen or R 1 ; R 3 is a C 1 - C 6 alkyl group; Z 1 and Z 2 are independently hydrogen or R 3 COCO- with the proviso that they are not both hydrogen; Y and R are at the 7-position; and R 1 and R 1' are at the 6-position; and R 2 is a hydroxyl or C 1 -C 6 alkoxy or amino or mono- or di-C 1 -C 6 alkylamino group. Illustrative examples of the C 1 -C 6 alkyl include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl (amyl), isopentyl, neopentyl, tert-pentyl, 1-methylbutyl, 2-methylbutyl, 1,2-dimethylpropyl, hexyl, isohexyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl, 3,3-dimethylbutyl, 1-ethylbutyl, 2-ethylbutyl, 1,1,2-trimethylpropyl, 1,2,2-trimethylpropyl, 1-ethyl-1-methylpropyl, 1-ethyl-2-methylpropyl and the like. Preferred is an alkyl group having 1 to 3 carbon atoms. The term "mono- or di-C 1 -C 6 alkylamino group" as used herein means an amino group substituted by one or two lower alkyl groups exemplified above. The illustrative examples include mono-lower alkylamino groups such as methylamino, ethylamino, propylamino, isopropylamino, butylamino, isobutylamino, sec-butylamino, tert-butylamino, pentyl(amyl)amino, isopentylamino, neopentylamino and tert-pentylamino group; and di-lower alkylamino groups such as dimethylamino, ethylmethylamino, diethylamino, dipropylamino, diisopropylamino, dibutylamino and diisobutylamino groups. Among them, amino, methylamino, ethylamino, dimethylamino and diethylamino groups are preferred. Examples of the C 1 - C 6 alkoxy group include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy (amyloxy), isopentyloxy, tert-pentyloxy, neopentyloxy, 2-methylbutoxy, 1,2-dimethylpropoxy, 1-ethylpropoxy and hexyloxy groups. Among then, methoxy, ethoxy, propoxy and isopropoxy groups are preferred. Above compounds IV, IX and X where R 2 is other than hydroxyl are also according to the invention. In the above reaction scheme, examples of the halogen atom include fluorine, chlorine, bromine and iodine atoms. When the compound has OH as R 2 , a compound protected with a protective group for a carboxyl group can be used. Examples of the protected carboxyl group and its equivalent include esters, amides and orthoesters; and also the derivatives exemplified in " Protective Groups in Organic Synthesis, 2nd ed., edited by T.W. Greene and P.G. M. Wuts, John Wiley & Sons, INC., Chapter 5 (1990)". Method 1 A compound (I) or (IV) of the present invention can be obtained by reacting a halogen compound (II) and an imidazole (III) in an amount corresponding to the reaction at -10°C to 150°C, preferably at 20°C to 120°C in a solvent or without solvent under stirring. The reaction is generally carried out under heating in a solvent such as dimethylformamide (DMF), dimethylsulfoxide (DMSO), acetonitrile, acetone or tetrahydrofuran (THF). To accelerate the reaction, a base such as sodium hydroxide or potassium hydroxide, or a copper salt may be added. The compound (I) of the present invention can also be obtained by subjecting the compound (IV) to deprotection or R 2 removal reaction in a manner known in the art. The deprotection or R 2 removal reaction can be carried out in accordance with the method shown in the above-described book edited by T.W. Greene, et al. or in a manner known in the art. For example, hydrolysis can be employed. Examples of hydrolysis include acid hydrolysis carried out in the presence of hydrochloric acid or the like and alkali saponification carried out in the presence of a base such as sodium hydroxide. Method 2 A compound (I) or (X) of the present invention can be obtained by the following process: (1) A nitroaniline or nitroaminopyridine compound (V) is reduced, whereby a diamine compound (VI) is obtained. (2) The diamine compound (VI) is reacted with an oxalate halide (VII), whereby an amide compound (VIII) and a mixture thereof are obtained. (3) The amide compound (VIII) and a mixture thereof are subjected to ring-closure reaction, whereby a quinoxalinedione compound (IX) or (X) is obtained. (4) The quinoxalinedione compound (IX) is subjected to known aromatic substitution reaction, whereby a substituted quinoxalinedione compound (X) is obtained. (5) Deprotection or R 2 removal reaction is carried out in accordance with the method 1. The representative processes for the aforementioned steps (1) to (4) are described below. Examples of the reduction reaction in (1) include catalytic reduction using, for example, Raney nickel or palladium-carbon in a manner known in the art; and metal reduction using iron powder or zinc dust. Examples of the amidation reaction in (2) include the reaction between the diamine compound (VI) and an oxalate halide (VII) in an amount corresponding to the reaction in a solvent of chloroform or THF at -10°C to 60°C, preferably 0°C to room temperature. It is preferred to add an alkali such as triethylamine in order to accelerate the reaction The ring-closure reaction in (3) is carried out, for example, by heating the amide compound (VIII) and a mixture thereof in the above-described solvent or by heating in the presence of an acid catalyst such as hydrochloric acid. Examples of the aromatic substitution reaction in (4) in the case where R 1' of the compound (IX) represents a hydrogen atom include the method of reacting nitric acid or salt thereof with quinoxalinedione compound (IX) in sulfuric acid acetic anhydride-acetic acid, or sulfuric acid-acetic anhydride-acetic acid; and the method of causing reaction between the quinoxalinedione compound and nitronium tetrafluoroborate in an organic solvent such as sulfolane or acetonitrile at 0°C or under heating. Method 3 The compound (I) or (X) of the present invention can be obtained by the following process: a) A nitroanilide compound is reduced as described in (2) of method 2, whereby an aminoanilide compound (XII) is obtained. b) The aminoanilide compound (XII) is subjected to ring-closure reaction as described in (3) of method 2, whereby a quinoxalinedione compound (IX) or (X) is obtained. The subsequent process to obtain the compound (I) of the present invention is performed in accordance with the second preparation process. The compound having a nitro group as R 1 can be obtained, for example, by subjecting the quinoxalinedione compound (IX) wherein R 1 is a hydrogen atom to nitration reaction in accordance with (4) of method 2. The invention compound so prepared is isolated and purified as a free compound or its salt. Isolation and purification are carried out by ordinary chemical operation such as extraction, concentration, evaporation, crystallization, filtration, recrystallization, various kinds of chromatography, or the like. The compound of the present invention has high affinity with the AMPA receptor and exhibited potent activities in the inhibitory action against kainic acid, neurotoxicity and anticonvulsant effect for audiogenic seizure in DBA/2 mouse. Accordingly, based on this action, the compound of the present invention is a particularly useful pharmaceutical as a psychotropic for the prevention and treatment of Huntington chorea, Parkinson disease, epilepsy, Alzheimer disease or senile dementia; and also as an anti-ischemia agent for the prevention and treatment of cell death caused by cerebral ischemia, oxygen deficiency or temporary cardiac arrest, neurodegeneration observed after hypoglycemia or seizure, and deficiency of mental and motor function. Testing method Inhibitory activity against binding with [ 3 H]-AMPA, kainic acid neurotoxicity and audiogenic seizure were confirmed as follows: 1) Measurement of inhibitory activity against the binding of [ 3 H]-AMPA: On ice water, 0.5 ml in total of a reaction liquid containing about 45 nM [ 3 H]-AMPA [2-amino-3-(3-hydroxy-5-methyl-4-isoxazolyl)propionic acid], about 300 mg of a sample of a rat cerebral membrane and a test compound was reacted for 45 minutes. The amount of [ 3 H]-AMPA bound to the AMPA receptor was measured by the filtration method. A portion substituted by 10 µM quisqualic acid in the total bound amount was taken as the specific binding amount. Evaluation of the test compound was carried out by determining the binding inhibition ratio against the specific binding. As a result, for example, the Ki value of the compound of Example 1 was 0.73 µM and that of the compound of Example 19 was 0.070 µM, which are potent. 2) Measurement of inhibitory activity against kainic acid neurotoxicity: Inhibitory action of the invention compound against kainic acid neurotoxicity was investigated using the primary culture system of the hippocampal neuron of a fetal rat. (1) Incubation conditions The hippocamp was cut out from the brain of the 18 to 20-day-old fetal rat and was subjected to enzyme treatment with papain and DNase I to disperse the cells. The cells so obtained were floated on MEM containing 10% serum and then were inoculated on a 48-well plate treated in advance with poly-L-lysine in a concentration of 4 × 10 5 cell/cm 2 . Twenty four hours later, the serum was replaced by a serum-free medium. The medium replacement was carried out twice a week. The cells which were cultivated for at least 6 days were provided for the following test. (2) Inhibition against kainic acid neurotoxicity Neurotoxicity was expressed by activity of lactate dehydrogenase released in the culture medium by the cell death. As a control, neurons which were exposed to a serum-free medium containing 300 µM kainic acid for 24 hours were used. Each compound, together with 300 µM kainic acid, was allowed to act on the neuron for 24 hours and inhibitory action of each compound against neuronal death caused by kainic acid was evaluated. As the result, for example, the compound of Example 1 had IC 50 of 0.8 µM and the compound of Example 19 had IC 50 of 0.48 µM, which are potent. 3) Measurement of audiogenic seizure inhibitory action in DBA/2 mouse Ten male 21 to 28-day-old mice were exposed to auditory stimulation by sound of 12 kHz and 120 dB in a sound proof box for one minute or until they suffered tonic seizure. The test compound was suspended in a 0.5% methylcellulose solution or dissolved in physiological saline and the resulting suspension or solution was intraperitoneally administered 15 minutes before the stimulation by sound. The drug efficacy was evaluated by presence or absence of the appearance of seizure aid the minimum effective dose (MED) was determined. As a result, the compound of Example 1 and the compound of Example 19 suppressed audiogenic seizure in amounts of 3 mg/kg and 1 mg/kg, respectively. 4) Measurement of solubility Preparation of Buffer: To a 0.1M aqueous solution of potassium dihydrogenphosphate, a 0.1M aqueous solution of sodium dihydrogenphosphate was added, whereby buffers having pH of 5, 6, 7 and 8 were prepared, respectively. Measurement of Solubility: About 5 mg portions of the invention compound were weighed precisely in four glass test tubes and 0.1 ml phosphate buffers having pH 5, 6, 7 and 8 were added, respectively, followed by thorough shaking. The value obtained in accordance with the following equation was taken as the solubility. Solubility (mg/ml) of the invention compound = weighed value (mg) of the invention compound Volume (ml) of phosphate buffer used for dissolution of invention compound The results are shown in Table 1. The compound of the invention showed high solubility even at the neutral point or in the vicinity of neutral point. Accordingly, the compound of the present invention can be easily formulated into an oral preparation such as tablets and capsules or a parenteral preparation such as injection so that it is a markedly useful compound. In addition, the compound of the present invention has high and therefore excellent solubility in blood even on clinical administration and does not precipitate easily in the organs, so that is has high utility. pH 5 pH 6 pH 7 pH 8 Example 1 2489 (µg/ml) 2621 3641 5130 A pharmaceutical preparation containing one or more compounds of the present invention as an effective ingredient is prepared using a carrier or excipient and other additives ordinarily used for the formulation. The carrier or excipient for pharmaceutical preparations may be either solid or liquid, such as lactose, magnesium stearate, starch, talc, gelatin, agar, pectin, gum arabic, olive oil, sesame oil, cacao butter and ethylene glycol and other conventional carriers or excipients. As a solid composition for oral administration according to the present invention, tablets, powders, granules or the like may be used. In such a solid composition, one or more active substances are mixed with at least one inert diluent such as lactose, mannitol glucose, hydroxypropylcellulose, microcrystalline cellulose, starch, polyvinyl pyrrolidone or aluminum magnesium metasilicate. The composition may contain an additive other than the inactive diluent, for example, a lubricant such as magnesium stearate, disintegrator such as calcium cellulose glycolate, stabilizer such as lactose, or solubilizing agent or solubilizing assistant such as glutamic acid or aspartic acid. The tablet or pill may be coated with a film made of a gastric or enteric substance such as sucrose, gelatin, hydroxypropylcellulose or hydroxypropylmethylcellulose phthalate. Examples of liquid composition for oral administration include a pharmaceutically acceptable emulsion, solution, suspension, syrup or elixir and contain a generally employed inactive diluent such as purified water or ethanol. In addition to the inactive diluent, the liquid composition may also contain an adjuvant such as solubilizing agent or solubilizing assistant, wetting agent or suspending agent, a sweetener, a flavoring agent, an aroma or an antiseptic. Examples of injections for parenteral administration include sterile aqueous or nonaqueous solution, suspension and emulsion. As a diluent for aqueous solution or suspension, injection-grade distilled water and physiological saline are included. Examples of the diluent for nonaqueous solution or suspension include propylene glycol, polyethylene glycol, vegetable oil such as olive oil, alcohol such as ethanol and "Polysorbate 80" (trade name). Such a composition may further contain an additive such as an isotonicity agent, antiseptic, wetting agent, emulsifying agent, dispersing agent, stabilizing agent (e.g., lactose), or solubilizing agent or solubilizing assistant. They are sterilized, for example, by filtration through a bacteria-retaining filter, incorporation of an insecticide, or irradiation. The injection can also be obtained by first preparing a sterile solid composition and then dissolving it in sterile water or sterile injection-graded solvent upon use. Administration may be carried out in any form such as oral administration by tablets, pills, capsules, granules, powders or liquid; or parenteral administration by injections such as intravenous injection or intramuscular injection, suppositories or transdermal administration. The dose is determined appropriately according to each case in consideration of the symptoms, age and sex of the patient to be treated. The general dose ranges from 1 to 1000 mg/day, preferably 50 to 200 mg/day, per adult once a day or in several portions in the case of oral administration, or 1 mg to 500 mg a day per adult once a day or in several portions in the case of intravenous administration or in the case of continuous intravenous administration within a range of 1 hour/day to 24 hours/day. As described above, the dose may vary depending on various conditions, and doses smaller than the above ranges may sometimes be sufficient. Examples Hereinafter, the present invention will be described in further detail by way of Examples. It should however borne in mind that the present invention is not limited to or by the following Examples. Example 1 1) To a mixture of 13.96 g of a glycine ethyl ester hydrochloride, 30 ml of THF, 10.11 g of triethylamine and 30 ml of DMF, 15.91 g of 2,4-difluoronitrobenzene was added, followed by heating under reflux for 3 hours under an argon gas stream. After cooling of the reaction mixture and dilution with ethyl acetate, the insoluble matter precipitated was removed by filtration. The filtrate was concentrated under reduced pressure. The resulting residue was dissolved in ethyl acetate, washed successively with water and brine, and then dried over anhydrous sodium sulfate, followed by concentration under reduced pressure. The resulting residue was recrystallized from ethanol to give 17.32 g (71.5%) of N-(2-nitro-5-fluorophenyl)glycine ethyl ester. Mass analysis (m/z): 242 (M + )Nuclear magnetic resonance spectrum (CDCl 3 , TMS internal standard): δ: 1.33 (3H, t, J=6.5Hz), 4.04 (2H, d, J=4.9Hz), 4.31 (2H, q, J=6.5Hz), 6.34 (1H, dd, J=2.4, 11.0Hz), 6.44 (1H, m), 8.25 (1H, dd, J=6.1, 9.7Hz), 8.55 (1H, s). 2) A mixture of 6.52 g of N-(2-nitro-5-fluorophenyl)glycine ethyl ester, 100 ml of THF, 50 ml of methanol and 500 mg of 10% palladium-carbon was stirred in a hydrogen gas atmosphere, whereby the nitro group was reduced. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. To the resulting residue, 200 ml of chloroform and 7.54 ml of triethylamine were added to dissolve the former in the latter. While stirring, a 30 ml chloroform solution of 7.35 g of ethyl chloroglyoxylate was added dropwise to the resulting mixture under an argon gas stream under ice cooling. After the dropwise addition, stirring was carried out for 1 hour at room temperature, followed by dilution with chloroform. The diluted solution was washed successively with water, a saturated aqueous solution of sodium bicarbonate, a saturated aqueous solution of ammonium chloride and brine, and was dried over anhydrous sodium sulfate, followed by concentration under reduced pressure. To the resulting residue, 150 ml of ethanol and 1 ml of concentrated hydrochloric acid were added, followed by heating under reflux for 1 hour. After cooling, the resulting crystals were collected by filtration and dried under reduced pressure to give 5.80 g (80%) of ethyl 2-(7-fluoro-2,3-dioxo-1,2,3,4-tetrahydroquinoxalin-1-yl)acetate. Mass analysis (m/z): 266 (M + )Nuclear magnetic resonance spectrum (DMSO-d 6 , TMS internal standard): δ: 1.22 (3H, t, J=7.3Hz), 4.17 (2H, q, J=7.3Hz), 4.95 (2H, s), 7.70 (1H, m), 7.22 (1H, dd, J=5.4, 8.8Hz), 7.36 (1H, dd, J=2.4, 11.2Hz), 12.20 (1H, s) 3) To 15 ml of concentrated sulfuric acid, below 0°C, 1.20 g of ethyl 2-(7-fluoro-2,3-dioxo-1,2,3,4-tetrahydroquinoxalin-1-yl)acetate were added to dissolve the latter in the former. While stirring, 0.21 ml of fuming nitric acid (d=1.52) was added dropwise to the resulting solution and they were stirred at the same temperature for 30 minutes. The reaction mixture was poured into ice water. The crystals so precipitated were collected by filtration, washed with water and then dried under reduced pressure to give 1.35 g (96%) of ethyl 2-(7-fluoro-6-nitro-2,3-dioxo-1,2,3,4-tetrahydroquinoxalin-1-yl)acetate. Mass analysis (m/z): 312 (M + + 1)Nuclear magnetic resonance spectrum (DMSO-d 6 , TMS internal standard): δ: 1.24 (3H, t, J=7.3Hz), 4.18 (2H, q, J=7.3Hz), 5.02 (2H, s), 7.74 (1H, d, J=13.5Hz), 7.95 (1H, d, J=7.3Hz), 12.4 (1H, s). 4) A mixture of 928 mg of ethyl 2-(2,3-dioxo-7-fluoro-6-nitro-1,2,3,4-tetrahydroquinoxalin-1-yl)acetate, 450 mg of imidazole and 10 ml of DMF was stirred at 120°C for 6 hours. After cooling, the reaction mixture was poured into ice water. The resulting crystals were collected by filtration, washed with water and then dried under reduced pressure. The resulting compound was added to 5 ml of a 1N aqueous solution of sodium hydroxide at room temperature, followed by stirring for 15 minutes to hydrolyze the ester. The reaction mixture was adjusted to about pH 3.5 with 1N hydrochloric acid. The crystals so precipitated were collected by filtration, washed with water and then dried under reduced pressure to give 473 mg (40%) of 2-[2,3-dioxo-7-1H-imidazol-1-yl)-6-nitro-1,2,3,4-tetrahydroquinoxalin-1-yl)acetic acid•1 hydrochloride•1.2 hydrate. Melting point: 225°C (decomposition) Elemental analysis for C 13 H 9 N 5 O 6 . HCl . 1.2H 2 O C(%) H(%) N(%) Cl(%) Calculated 40.11 3.21 17.99 9.11 Found 40.01 3.11 17.86 9.02 Mass analysis (m/z): 332 (M + + 1) Nuclear magnetic resonance spectrum (DMSO-d 6 TMS internal standard): δ: 4.89 (2H, s), 7.88 (1H, s), 8.01 (1H, s), 8.08 (1H, s), 8.28 (1H, s), 9.43 (1H, s), 12.89 (1H,s), 13.1-14.2 (1H, bs). Reference Example 1 1) To a mixture of 6.86 g of 2,4-difluoro-5-nitrobenzonitrile, 22.67 g of triethylamine, 40 ml of DMF and 40 ml of THF, 5.20 g of glycine ethyl ester hydrochloride was added under ice-cooling, followed by stirring at the same temperature for 4 hours. To the reaction mixture, water was added and the reaction product was extracted with chloroform. The extract was washed successively with water and brine, dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The resulting residue was purified by chromatography on a silica gel column (eluent: hexane:ethyl acetate = 80:20) to give 4.85 g (49%) of N-(4-cyano-5-fluoro-2-nitrophenyl)glycine ethyl ester. Nuclear magnetic resonance spectrum (CDCl 3 , TMS internal standard): δ: 1.22-1.48 (3H, m), 4.08 (2H, d, J=5.3Hz), 4.19-4.50 (2H, m), 6.46 (1H, d, J=11.3Hz), 8.57 (1H, d, J=6.7Hz), 8.80-9.05 (1H, br). 2) A mixture of 2.50 g of N-(4-cyano-5-fluoro-2-nitrophenyl)glycine ethyl ester, 0.67 g of imidazole, 7.40 g of pyridine and 40 ml of DMSO was stirred at 80°C for 4 hours. After the addition of water, the reaction product was extracted with chloroform. The extract was washed successively with water and brine, dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The resulting residue was purified by chromatography on a silica gel column (eluent: chloroform:methanol = 95:5) to give 2.82 g (92%) of N-[4-cyano-5-(1H-imidazol-1-yl)-2-nitrophenyl]glycine ethyl ester. Nuclear magnetic resonance spectrum (DMSO-d 6 , TMS internal standard): δ: 1.15-1.26 (3H, m), 4.10-4.21 (2H, m), 4.45 (2H, d, J=5.5Hz), 7.15-7.22 (2H, m), 7.68-7.73 (1H, m), 8.17 (1H, s), 8.75 (1H, s), 8.85-8.94 (1H, m). 3) A mixture of 2.00 g of N-[4-cyano-5-(1H-imidazol-1-yl)-2-nitrophenyl]glycine ethyl ester, 40 ml of THF, 8 ml of methanol and 200 mg of 10% palladium-carbon was stirred under a hydrogen gas atmosphere to reduce the nitro group. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. Then, 50 ml. of chloroform and 4.43 ml of triethylamine were added to the resulting residue, followed by the dropwise addition of 1.69 ml of ethyl chloroglyoxylate under ice-cooling. After stirring at room temperature for 20 hours, the reaction mixture was diluted with chloroform. The diluted mixture was washed with brine, dried over anhydrous sodium sulfate and then concentrated under reduced pressure. Then, 60 ml of ethanol and 0.5 ml of concentrated hydrochloric acid were added to the resulting residue, followed by heating under reflux for 3 hours. After cooling, the crystals so formed were collected by filtration and dried under reduced pressure to give 1.07 g (50%) of ethyl 2-[6-cyano-2,3-dioxo-7-(1H-imidazol-1-yl)-1,2,3,4-tetrahydroquinoxalin-1-yl]acetate. Nuclear magnetic resonance spectrum (DMSO-d 6 , TMS internal standard): δ: 1.15-1.25 (3H, m), 4.10-4.20 (2H, m), 4.99 (2H, s), 7.84 (1H, s), 7.90 (1H, s), 8.04 (1H, s), 8.16 (1H, s), 9.47 (1H, s), 12.83 (1H, s). 4) To 6 ml of a 1N aqueous solution of sodium hydroxide, 672 mg of ethyl 2-[6-cyano-2,3-dioxo-7-(1H-imidazol-1-yl)-1,2,3,4-tetrahydroquinoxalin-1-yl]acetate was added at room temperature, followed by stirring for one hour to hydrolyze the ester. The reaction mixture was adjusted to about pH 1 with 1N hydrochloric acid. The crystals so precipitated were collected by filtration, washed with water and then dried under reduced pressure to give 417 mg (62%) of 2-[6-cyano-2,3-dioxo-7-(1H-imidazol-1-yl)-1,2,3,4-tetrahydroquinoxalin-1-yl]acetic acid•1.7 hydrate. Melting point: 283-285°C (decomposition)Nuclear magnetic resonance spectrum (DMSO-d 6 , TMS internal standard) : δ: 4.95 (2H, s), 7.17 (1H, s), 7.62 (2H, s), 7.74 (1H, s), 8.06 (1H, s), 12.54 (1H, s), 13.2-13.4 (1H, br). In a similar manner to Reference Example 1 the compound of Example 2 was obtained. Example 2 1) By using 4.41 g of benzyl 2,4-difluoro-5-nitrophenyl ether, 5.05 g of triethylamine, 30 ml of DMF, 30 ml of THF and 2.32 g of glycine ethyl ester hydrochloride, 454 mg (8%) of N-(4-benzyloxy-5-fluoro-2-nitrophenyl)glycine ethyl ester was obtained. Nuclear magnetic resonance spectrum (CDCl 3 , TMS internal standard): δ: 1.32 (3H, t, J=7.3Hz), 4.03 (2H, d, J=5.5Hz), 4.25-4.33 (2H, m), 5.09 (2H, s), 6.44 (1H, d, J=12.2Hz), 7.30-7.48 (5H, m), 7.99 (1H, d, J=8.5Hz), 8.40 (1H, br). 2) By using 448 mg of N-(4-benzyloxy-5-fluoro-2-nitrophenyl)glycine ethyl ester, 350 mg of imidazole and 2 ml of DMF, 331 mg (65%) of N-[4-benzyloxy-5-(1H-imidazol-1-yl)-2-nitrophenyl]glycine ethyl ester was obtained. Nuclear magnetic resonance spectrum (CDCl 3 , TMS internal standard): δ: 1.32 (3H, t, J=7.3Hz), 4.08 (2H, d, J=5.5Hz), 4.25-4.34 (2H, m), 5.09 (2H, s), 6.63 (1H, s), 7.20 (1H, s), 7.25-7.40 (6H, m), 7.92 (1H, s), 8.00 (1H, s), 8.31-8.37 (1H, m). 3) By using 100 mg of N-[4-benzyloxy-5-(1H-imidazol-1-yl)-2-nitrophenyl]glycine ethyl ester, 70 mg (66%) of ethyl 2-[6-benzyloxy-2,3-dioxo-7-(1H-imidazol-1-yl)-1,2,3,4-tetrahydroquinoxalin-1-yl]acetate was obtained. Nuclear magnetic resonance spectrum (DMSO-d 6 , TMS internal standard): δ: 1.08-1.33 (3H, m), 4.16 (2H, q, J=7.3Hz), 4.95 (2H, s), 5.19 (2H, s), 7.15-7.52 (6H, n), 7.75-7.92 (2H, m), 7.94-8.08 (1H, m), 9.36-9.48 (1H, m), 12.47 (1H, s). 4) By using 134 mg of ethyl 2-[6-benzyloxy-2,3-dioxo-7-(1H-imidazol-1-yl)-1,2,3,4-tetrahydroquinoxalin-1-yl)acetate, 86 mg (62%) of 2-[6-benzyloxy-2,3-dioxo-7-(1H-imidazol-l-yl)-1,2,3,4-tetrahydroquinoxalin-1-yl]acetic acid•0.5 hydrochloride•1.4 hydrate was obtained. Melting point: 275°C (decomposition)Mass analysis (m/z): 393 (M + + 1)Nuclear magnetic resonance spectrum (DMSO-d 6 , TMS internal standard): δ: 4.88 (2H, s), 5.17 (2H, s), 7.13 (1H, s), 7.30-7.48 (6H, m), 7.64 (1H, s), 7.74 (1H, s), 8.66 (1H, s), 12.32 (1H, s). Example 3 A mixture of 2.94 g of ethyl 2-[7-fluoro-2,3-dioxo-6-nitro-1,2,3,4-tetrahydroquinoxalin-1-yl]acetate, 1.36 g of imidazole and 20 ml of DMF was stirred under heating at 120°C for 3 hours. After cooling, the reaction mixture was poured into ice water. The crystals so precipitated were collected by filtration, washed with water and dried under reduced pressure to give 3.45 g (99%) of ethyl 2-[2,3-dioxo-7-(1H-imidazol-1-yl)-6-nitro-1,2,3,4-tetrahydroquinoxalin-1-yl]acetate•0.65 hydrate. Melting point: 159-160°C (decomposition) Example 4 1) A mixture of 5.85 g (20 mmol) of ethyl 2-([5-(1H-imidazol-1-yl)-2-nitrophenyl]amino) acetate, 250 ml of THF and 1.5 g of 10% palladium-carbon was stirred at room temperature under a hydrogen gas atmosphere. After the reduction of the nitro group, the catalyst was removed by filtration. To the filtrate, 11.3 ml of triethylamine was added. Under ice-cooling, a mixture of 11 g of ethyl chloroglyoxylate and 30 ml of THF was added dropwise to the resulting mixture, followed by stirring. After the dropwise addition, the reaction mixture was heated to room temperature and stirred overnight. The insoluble matter so formed was removed by filtration. The filtrate was concentrated under reduced pressure. To the residue, 150 ml of ethanol was added, followed by heating under reflux for 5 hours under an argon gas atmosphere. After cooling, the precipitate so formed was collected by filtration, washed with ethanol and dried under reduced pressure to give 3.94 g (60%) of ethyl 2-[2,3-dioxo-7-(1H-imidazol-l-yl)-1,2,3,4-tetrahydroquinoxalin-1-yl]acetate. Mass analysis (m/z): 314 (M + )Nuclear magnetic resonance spectrum (DMSO-d 6 , TMS internal standard): δ: 1.22 (3H, t, J=7.0Hz), 4.18 (2H, q, J=7.0Hz), 5.06 (2H, s), 7.41 (1H, d, J=8.6Hz), 7.60 (1H, d-d, J=2.5, 8.6Hz), 7.65 (1H, s), 7.77 (1H, d, J=25Hz), 8.13 (1H, s), 9.24 (1H, s), 12.47 (1H, s) 2) At a temperature of 0°C or less, 3.63 g of ethyl 2-[2,3-dioxo-7-(1H-imidazol-1-yl)-1,2,3,4-tetrahydroquinoxalin-1-yl]acetate was dissolved in 15 ml of fuming nitric acid under stirring. The resulting solution was heated to room temperature, stirred for one hour, and poured into ice water, followed by adjustment to about pH 2.0 with an aqueous solution of sodium hydroxide. The resulting insoluble matter was removed by filtration. To tie filtrate, an aqueous solution of sodium hydroxide was added to adjust the pH of the resulting liquid to about pH 6.5. The resulting insoluble matter was collected by filtration, washed with water and dried under reduced pressure to give 1.07 g (26%, purity: about 95% (HPLC)) of ethyl 2-[2,3-dioxo-7-(1H-imidazol-1-yl)-6-nitro-1,2,3,4-tetrahydroquinoxalin-1-yl]acetate. 3) A mixture of 2.12 g of ethyl 2-[2,3-dioxo-7-(1H-imidazol-1-yl)-6-nitro-1,2,3,4-tetrahydroquinoxalin-1-yl]acetate and 13 ml of a 1N aqueous solution of sodium hydroxide was stirred at room temperature under an argon gas atmosphere. After the reaction, 0.5 ml of concentrated hydrochloric acid and a proper amount of 1N hydrochloric acid were added to the reaction mixture to adjust the pH to about 3.0. The crystals so precipitated were collected by filtration, washed with 1N hydrochloric acid and dried under reduced pressure. The resulting crude crystals were recrystallized from 1N hydrochloric acid to give 1.90 g (84%) of 2-[2,3-dioxo-7-(1H-imidazol-1-yl)-6-nitro-1,2,3,4-tetrahydroquinoxalin-1-yl]acetic acid•1 hydrochloride•1 hydrate. Melting point: 248-250°C (decomposition)Mass analysis (m/z): 331 (M + )Nuclear magnetic resonance spectrum (DMSO-d 6 , TMS internal standard): δ: 4.90 (2H, s), 7.89 (1H, s), 8.03 (1H, s), 8.09 (1H, s), 8.33 (1H, s), 9.48 (1H, s), 12.96 (1H, s). Example 5 To 66 ml of a 1N aqueous solution of sodium hydroxide, 8.5 g of the compound of Example 3 was added gradually under ice-cooling to dissolve the latter in the former. To the resulting solution, 44 ml of a 1N aqueous solution of hydrochloric acid was added gradually under ice-cooling. The crystals so precipitated were collected by filtration and dried to give 6.8 g of 2-[2,3-dioxo-7-(1H-imidazol-1-yl)-6-nitro-1,2,3,4-tetrahydroquinoxalin-1-yl]acetic acid in the form of crystals. Elemental analysis for C 13 H 9 N 5 O 6 ·0.2H 2 O C(%) H(%) N(%) Calculated 46.63 2.83 20.92 Found 46.51 2.91 21.00 Nuclear magnetic resonance spectrum (DMSO-d 6 , TMS internal standard): δ: 4.95 (2H, s), 7.10 (1H, s), 7.40 (1H, s), 7.73 (1H, s), 7.88 (1H, s), 8.00 (1H, s), 12.58 (1H, s), 13.4 (1H, brs). Example 6 To 6 ml of aqueous ammonia, 100 mg of ethyl 2-[2,3-dioxo-7-(1H-imidazol-1-yl)-6-nitro-1,2,3,4-tetrahydroquinoxalin-1-yl]acetate was added at -5°C, followed by stirring at 0°C for 3 hours and concentration under reduced pressure. The concentrate was washed with water and dried under reduced pressure to give 90 mg (89%) of 2-[2,3-dioxo-7-(1H-imidazol-1-yl)-6-nitro-1,2,3,4-tetrahydroquinoxalin-1-yl]acetamide•0.5 ammonia•1.3 hydrate. Melting point: 245°C (decomposition) Mass analysis (m/z): 331 (M + + 1) Nuclear magnetic resonance spectrum (DMSO-d 6 , TMS internal standard): δ: 4.77 (2H, s), 6.3-6.9 (1H, br), 7.07 1H, s), 7.22-7.33 (2H, m), 7.36 (1H, s), 7.64 (1H, s), 7.80-7.87 (2H, m). The chemical structural formulae of the compounds obtained in the Examples are shown in Table 2. Formulation Example A formulation example of the invention compound as a pharmaceutical preparation is shown below. A lyophilized preparation in one vial Compound of Example 1 50 mg (0.5%) Citric acid 210 mg (2.1%) D-mannitol 100 mg (1.0%) 10 ml In 800 ml of water, 5 g of the compound of Example 1, 21 g of citric acid and 10 g of D-mannitol were added successively to dissolve the latter in the former. Water was added to make a total amount of 1000 ml. After sterile filtration, a 10 ml portion of the solution was filled in a brown vial, followed by lyophilization to obtain a dissolution-upon-use type injection.

Claims: A 1,2,3,4-tetrahydroquinoxalinedione derivative of formula (I) or a tautomer thereof or a salt or hydrate or solvate of said derivative or tautomer: wherein R is an imidazolyl group, and R 1 is a nitro or benzyloxy group. A compound according to claim 1 wherein R 1 is a nitro group. A compound according to claim 2 wherein R is a 1-imidazolyl group. A compound according to claim 1 which is 2-[2,3-dioxo-7-(1H-imidazol-1-yl)-6-nitro-1,2,3,4-tetrahydro-quinoxalin-1-yl)acetic acid or a salt thereof. A compound according to claim 1 which is 2-[6-benzyloxy-2,3-dioxo-7-(1H-imidazol-1-yl)-1,2,3,4-tetrahydroquinoxalin-1-yl] acetic acid or a salt thereof. A pharmaceutical composition comprising a compound according to any preceding claim and pharmaceutically acceptable carrier. A pharmaceutical composition according to claim 6 which is for AMPA receptor antagonism. The use of a compound according to any of claims 1 to 5 for the preparation of an AMPA receptor antagonist medicament. An intermediate for a compound according to any of claims 1 to 3, said intermediate being a 1,2,3,4-tetrahydroquinoxalinedione derivative of formula (II) or a tautomer thereof or a salt or hydrate or solvate of said derivative or tautomer: wherein R is an imidazolyl group, and R 1 is a nitro or benzyloxy group, and R 2 is an amino or a mono- or di-(C 1 -C 6 alkyl) amino or a C 1 -C 6 alkoxy group.

Inventors: FUJII MITSUO, INAMI HIROSHI, OKADA MASAMICHI, SAKAMOTO SHUICHI, SASAMATA MASAO, SHISHIKURA JUN-ICHI, TSUKAMOTO SHIN-ICHI, FUJII, MITSUO, INAMI, HIROSHI, OKADA, MASAMICHI, SAKAMOTO, SHUICHI, SASAMATA, MASAO, SHISHIKURA, JUN-ICHI, TSUKAMOTO, SHIN-ICHI
Applicants: YAMANOUCHI PHARMA CO LTD, YAMANOUCHI PHARMACEUTICAL CO. LTD.
Application year: 1995
Main classification: C07D403
IPC codes: C07D403, C07D471, C07D241, A61P25, A61K31, C07D521