1-SUBSTITUTED ALKYL-1, 2-DIHYDRO-2-PYRAZINONE DERIVATIVES

Abstract: Compounds of formula (I) wherein R is hydroxyl, halogen, lower alkanoyloxy, R₄-­ carbamoyloxy, arylthio, 1-methyltetrazole-5-yl-thio, 1-­ imidazolyl, morpholino, in which R₄ is lower alkyl or aryl, R₅ is hydrogen, lower alkyl or aryl, R₆ is hydrogen, lower alkyl, hydroxy-lower alkyl, aryl, aryl-lower alkanoyl, arylcarbonyl, arylsulfonyl or thienyl-lower alkanoyl, A and A₁ are lower alkylene, m is an integer of from 4 to 6, n is the integer 2 or 3; R₁ is alkyl aryl-lower alkyl or aryl; and R₂ and R₃ are each lower alkyl or together constitute tetramethylene; and pharmacologically acceptable non-toxic salts thereof; wherein aryl means phenyl unsubstututed or substituted by C 1-3 alkyl, halogen, nitro or lower alkoxyl; have an inhibitory action on platelet aggregation, vasodilating activity and/or inhibitory action on lipoperoxide generation.

Description: This invention relates to novel 1-substituted alkyl-2-dihydro pyrazine derivatives and 1-substituted alkyl-2-hexahydro quinoxaline derivatives, which are pharmaceuticals useful for improvement in circulation and metabolic disorder having activities of platelet aggregation inhibition, vasodilation and/or anti-lipoperoxide generation. Recently, not a little number of compounds having platelet aggregation inhibitory activities have been reported. Amongst these, however, only compounds having pyrazine ring as the main structural element such as tetramethyl pyrazine (16th Heterocyclic chemistry Symposium (Osaka) p. 65-68 (1984) and a 2-higher-fatty acid acyloxymethyl pyrazine (Japan. Pat. Unexam. Publ. No. 59-­ 219269) have been known. It is of great importance to find excellent pharmaceuticals having stronger inhibitory activities for platelet aggregation in order to use these in the therapy of circulation and metabolic disorders. We have found that 1-substituted alkyl-2-dihydro pyra­ zinone derivatives and 1-substituted alkyl-2-hexahydro quino­ quixaline derivatives revealed an inhibitory action on platelet aggregation, vasodilation activity and/or anti-lipoperoxide generation, and are expected to have an excellent pharmaceut­ ical action. In the present invention, a compound of the formula wherein R is hydroxyl, halogen, lower alkanoyloxy, R₄-carbamoyloxy, arylthio, 1-methyltetrazole-5-yl-thio, 1-imidazolyl, morpholino, in which R₄ is lower alkyl or aryl, R₅ is hydrogen, lower alkyl or aryl, R₆ is hydrogen, lower alkyl, hydroxy-lower alkyl, aryl, aryl-lower alkanoyl, arylcarbonyl, arylsulfonyl or thienyl-­ lower alkanoyl, A and A₁ are lower alkylene, m is integer of 4-6, n is integer of 2-3, the above aryl is phenyl optionally substituted by C₁ - ₃ lower alkyl, halogen, nitro or lower alkoxy, R₁ is alkyl, phenyl-lower alkyl optionally having substituent, R₂ and R₃ are each lower alkyl, or in together constitute tetramethylene, or salt thereof is provided. The compound [1] can be provided as a salt thereof. The salts are pharmacologically acceptable non-toxic salts thereof. Examples of salts are salt of inorganic acid such as hydrochloride, sulfate or phosphate, and organic acid such as acetate, propionate, butyrate, glycolate, gluconate, malate, tartate, succinate, mandelate, aspartete, glutarate, methane­ sulfonate or toluenesulfonate. Other known salts can be included. The compound [1] can be produced by the following processes. [A] A compound [1] wherein R is hydroxyl of the formula [1a] wherein R₁: R₂: R₃ and A have the same meanings hereinbefore: The above compound [1a] can be produced by reacting a compound of the formula [2] wherein R₁, R₂ and R₃ have the same meanings hereinbefore, with a hydroxyalkyl halide of the formula X - A - OH wherein X is halogen and A has the same meaning hereinabove, in an organic solvent. In the compound [2] hereinabove, R₁ is alkyl, phenyl optionally having substituent, or phenyl-lower alkyl optionally having substituent. The above alkyl means saturated or unsatu­ rated alkyl of C 1-20 which may optionally be branched. Examples are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, t-butyl, pentyl, isopentyl, hexyl, heptyl, octyl, nonyl, decylc, undecyl, docecyl, tridecyl, tetradecyl, penta­ decyl or hexadecyl. A phenyl optionally having substituent is phenyl or phenyl substituted by lower alkyl of C 1-3 , halogen, nitro or lower alkoxy. A phenyl-lower alkyl optionally having substituent is phenyl optionally substituted by lower alkyl of C 1-3 , halogen, nitro or lower alkoxy, in which lower alkyl means methyl, 2-ethyl, 1-ethyl, 3-propyl or 1-propyl. Example thereof is benzyl, p-chlorobenzyl, 2-phenylethyl or 1-phenyl­ ethyl. In the compound [2] hereinabove, R₂ and R₃ are each lower alkyl, or are in together constitute tetramethylene. The lower alkyl can be methyl, ethyl or propyl. The compound [2] wherein R₂ and R₃ in together constitute tetramethylene, can be designated as 2-hydroxy-3-substituted-hexahydro quino­ xaline. Among the compound [2], in which especially R₂ and R₃ are lower alkyl, i.e. 2-hydroxy-3-substituted-5,6-dilower alkylpyrazine, some compounds have been known, however of course unknown compounds are included. These compounds can be produced by a process or its improved method disclosed in J. Am. Chem. Soc., 71: 78-81 (1949) and ibid. 74: 1580-1588 (1952). Novel compounds thereof can also be produced according to the methods described in the above references. The compound [2] wherein R₂ and R₃ in together constitute tetramethylene, i.e. 2-hydroxy-3-substituted-hexahydro quinoxaline derivatives, can be produced by the process found by the present inventors, in which reacting an α-amino acidamide except glycine with 1,2-­ cyclohexanedione in alkaline medium. A group A in the above hydroxylalkyl halide is lower alkylene. Example of lower alkylene is methylene, ethylene, methylmethylene, propylene, 1-methylethylene, 1,1-dimethyl-­ methylene or 1-ethylmethylene, in which ethylene is preferable. A group X in the above hydroxyalkyl halide is halogen such as chlorine or bromine, and in general chlorine is prefer­ able. Preferable compound is ethylene chlorohydrine. A reaction of the compound [2] with hydroxyalkyl halide proceeds in an organic solvent such as butanol. The above reaction proceeds preferably in an aqueous alkali such as hydroxy alkali, and preferably if possible under heating. Isolation of a product [1a] can be performed by adding water in the reaction mixture and extracting with water immiscible organic solvent. [B] A compound [1] wherein R is lower alkanoyloxy (herein­ after designates as compound [1b] ): A compound [1b] can be produced by acylatingthe above compound [1a] with lower fatty acid or its reactive derivative. Example of lower fatty acid is a fatty acid of C 1-6 , which is optionally branched, such as acetic acid, propionic acid, butyric acid, isobutyric acid, sec-butyric acid, valeric acid, isovaleric acid or hexanoic acid. Example of reactive derivative is a known acylating agent for hydroxyl, such as acid halide, acid anhydride, mixed anhydride or active ester. A lower fatty acid per se can be acylated in the presence of a condensation reagent such as N,N-dicyclohexyl carbodiimide (DCC). In the above reactions, co-produced acid can be removed in the presence of acid-binder like a known tertiary organic amine such as pyridine or triethylamine. A product [1b] can be isolated by pouring the reaction mixture into diluted aqueous alkali and extracting with water immiscible organic solvent therefrom. [C] A compound [1] wherein R is R₄-carbamoyloxy (herein­ after designates as a compound [1c] ): A compound [1c] can be produced by reacting the above compound [1a] with lower alkyl isocyanate or aryl isocyanate. A lower alkyl in the above lower alkyl carbamoyloxy means alkyl of C 1-6 which is optionally branched, and an aryl in the above aryl carbamoyloxy means a phenyl which is option­ ally substituted by lower alkyl of C 1-3 , halogen, nitro or lower alkoxy. A reaction of the compound [1a] and isocyanate compound proceeds in an organic solvent such as pyridine. Isolation of the product [1c] can be made by removing a solvent from the reaction mixture and extracting a residue with an inert organic solvent in an aqueous medium, or precipitating the product [1c] by adding solvent such as ether. [D] A compound [1] wherein R is halogen, of the formula [1d] wherein X is halogen, A, R₁, R₂ and R₃ have the same meanings hereinbefore: A compound [1d] can be produced by halogenating the compound [1a] hereinbefore with halogenating agent. Example of the said halogenating agent is a known halo­ genating agent. The said product [1d] can derive to a compound [1e] and [1f] hereinbelow, and in the said reaction, known chlorination reagent or bromination reagent can be used. Conventional chlorination reagent such as SOCl₂, PCl₅ or POCl₃ can be applied. Haloganation reaction can be made, in general, in an inert organic solvent such as chloroform. Reaction proceeds at room temperature. Isolation of the product [1d] can be made by adding water immiscible organic solvent such as chloroform, washing with diluted aqueous alkali, dehydrating the organic layer and removing off the solvent therefrom. The compound [1d] can be used without purifying such as by silica-gel column chromatography when the said compound is made to derive into the compounds [1e] and [1f]. [E] A compound [1 ] wherein R is arylthio or 1-methyltetra­ zole-5-yl-thio (hereinafter designates as a compound [1e] ): A compound [1e] can be produced by reacting the above compound [1d] with alkaline metal salt of arylmercaptan or alkaline metal salt of 1-melthyl-5-mercaptotetrazole in an organic solvent. A n aryl in the above arylthio means a phenyl which is optionally substituted by lower alkyl of C 1-3 , halogen, nitro or lower alkoxy. Example of the above alkaline salts of arylmercaptane or 1-methyl-5-mercaptotetrazole is sodium salt or potassium salt. A reaction of the above compound [1d] and the said alkaline metal salt of mercapto compound proceeds, in general, in an organic solvent such as dimethyl formamide (DMF). Isolation of the product [1e] can be made by removing off the reaction solvent and extracting the residue with water immisci­ ble organic solvent in the presence of diluted aqueous alkali. [F] A compound [1] wherein R is a group except hydroxyl, halogen, lower alkanoyloxy, R₄-carbamoyloxy, arylthio and 1-methyltetrazole-5-yl-thio (hereinafter designates as a compound [1f]): A compound [1f] can be produced by reacting a compound [1d] with an amine of the formula R′ - H wherein R′ is 1-imidazolyl, morpholino, and R₁, R₂, R₃, R₅, R₆, A, A₁, m and n have the same meanings hereinabove. A ring in the above wherein m is integer of 4 - 6, means pyrrolidine, piperidine or hexamethyleneimine ring. R₅ means hydrogen, lower alkyl or aryl. A position of these groups may be any position in the ring hereinabove except at position-1. The above alkyl means an alkyl of C 1-6 which may be branched. An aryl hereinabove means a phenyl which may optionally be substituted by lower alkyl of C 1-3 , halogen, nitro or lower alkoxy. A group R₆ in the above means hydrogen, lower alkyl, hydroxy-lower alkyl, aryl, aryl-­ lower alkanoyl, arylcarbonyl, arylsulfonyl or thienyl-lower alkanoyl. Example of the above alkyl is an alkyl of C 1-4 which may optionally be branched, such as methyl, 2-ethyl, 1-ethyl, propyl, isopropyl or 1-methyethyl. Example of aryl is phenyl which may optionally be substituted by lower alkyl of C 1-3 , halogen, nitro or lower alkoxy, such as phenyl, tolyl, xylyl, p(m or o)-nitrophenyl, p(m or o)-fluorophenyl, 2,4(2,3-, 3,4- 2,5-, 3,5- or 2,6-)-dichlorophenyl, p(m or o)-nitrophenyl, p(m or o)-methoxyphenyl, 2,3(2,4-, 3,4- 2,5-, 3,5- or 2,6-)-­ dimethoxyphenyl. The above lower alkanoyl may optionally be branched, and is an alkanoyl of C 2-4 , such as acetyl, propionyl, butyryl, isobutyrl or sec-butyryl. A ring in wherein n is integer or 2 - 3, hereinbefore means piperazine or homopiperazine ring. A term A, means lower alkylene such as methylene, ethylene, methylmethylene, propylene, 1-methyl­ ethylene or 1-ethylmethylene and preferable example is methylene and ethylene. An aryl hereinabove means phenyl which may optionally be substituted by lower alkyl of C 1-3 , halogen, nitro or lower alkoxy. Example thereof has been illustrated hereinbefore. Accordingly examples of amine are 1-imidazole, morpholine, pyrrolidine, piperidine, 4-methylpiperazine, 4-ethylpiperazine, 4-butylpiperazine, 4-(2-hydroxyethyl)-piperazine, 4-phenyl-­ piperazine, 4-(o-chlorophenyl)-piperazine, 4-(o-methoxyphenyl)-­ piperazine, 4-(phenylacetyl)-piperazine, 4-benzoyl-piperazine, 4-(p-chlorobenzoyl)-piperazine, 4-(p-nitrobenzoyl)-piperazine, 4-(p-methoxybenzoyl)-piperazine, 4-(2,3-dimethoxybenzoyl)-­ piperazine, 4-(2,4-dimethoxybenzoyl)-piperazine, 4-(3,4-di­ methoxybenzoyl)-piperazine, 4-(3,4,5-trimethoxybenzoyl)-­ piperazine, 4-bernzenesulfonyl-piperazine, 4-(p-chlorobenzene­ sulfonyl)-piperazine, 4-(2-thienylacetyl)-piperazine, 4-benzyl-piperazine, 4-(p-methylbenzyl)-piperazine, 4-(p-­ chlorobenzyl)-piperazine, 4-(m-chlorobenzyl)-piperazine, 4-(o-­ chlorobenzyl)-piperazine, 4-(2,4-dichlorobenzyl)-piperazine, 4-(p-fluorobenzyl)-piperazine, 4-(p-nitrobenzyl)-piperazine, 4-(p-methoxybenzyl)-piperazine, 4-benzyl-homopiperazine, 4-(p-methylbenzyl)-homopiperazine, 4-(p-chlorobenzyl)-homo­ piperazine, 4-(p-fluorobenzyl)-homopiperazine, 4-(p-nitro­ benzyl)-homopiperazine or 4-(p-methoxybenzyl)-homopiperazine. A reaction of the compound [1d] and the amine hereinabove can conventionally be proceeded in an inert organic solvent such as benzene under heating. In the reaction hydrogen halogenide is generated so that the said reaction is proceeded in the presence of acid binder, for example known tertiary organic amine such as triethylamine. The compound [1f] can be isolated by pouring a reaction mixture into diluted aqueous alkali and extracting with water immiscible organic solvent such as benzene or chloroform. [G] A compound [1] wherein R is in which R₆ is aryl-lower alkanoyl, arylcarbonyl, arylsulfonylor thienyl-lower alkanoyl (hereinafter designates as a compound [1g]: A compound [1g] can be produced by a process [F] hereinbefore, but is also produced by means of another method in which a compound [1f′] of the formula wherein R₁, R₂, R₃ and A have the same meanings hereinbefore, is acylated by organic acid or a reactive derivative thereof. The above organic acid is aryl-lower fatty acid, aryl­ carboxylic acid, arylsulfonic acid or thienyl-lower fatty acid, in which aryl means a phenyl optionally substituted by lower alkyl of C 1-3 , halogen, nitro or lower alkoxy, and lower fatty acid means a fatty acid optionally having branched chain of C 1-4 , for example acetic acid, propionic acid, butyric acid, isobutyric acid or sec-butyric acid. Examples of organic acid are phenyl acetic acid, benzoic acid, p-chlorobenzoic acid, p-nitrobenzoic acid, p-methoxybenzoic acid, 2,3-dimethoxy benzoic acid, 2,4-dimethoxybenzoic acid, 3,4-dimethoxybenzoic acid, 3,4,5-trimethoxybenzoic acid, benzenesulfonic acid, p-toluenesulfonic acid and 2-thienylacetic acid. Example of a reactive derivative is a known acylating agent for amino group, for example acid halide, acid anhydride, mixed anhydride or activated ester. Also organic acid per se can be acylated in the presence of condensation agent such as DCC. In the reac­ tion in acid is coproduced, the reaction may proceed in the presence of an acid binder, for example known tertiary organic amine such as pyridine or triethylamine. Acylating reaction is proceeded in a conventional organic solvent. A produced compound [1g] can be isolated by pouring the reaction mixture into diluted aqueous alkali and extracting with water immisci­ ble organic solvent. The thus obtained compound [1] is purified, if req­ uired, by column chromatography using silica-gel, activated alumina or adsorption resin with elution solvent such as chlo­ roform-methanol or benzene-ethyl acetate. A compound [1] is in general produced in the form of free base, but it can be produced in the form of a conven­ tional salt thereof. For example, a hydrochloride can be pre­ pared by dissolving a compound [1] in a lower alcohol such as methanol or ethanol, adding a slightly excess-molar amount of hydrochloric acid, and isolating the precipitated material, or if not precipitated, by adding ether therein to precipitate. A molar ratio of hydrochloric acid may be altered according to a kind of the compound [1]. Examples of the compound [1] of the present inven­ tion are illustrated in Table 1. [Effect of the invention] Pharmacological actions of the present compound [1] are illustrated hereinbelow. All the compounds [1] used in the pharmacological tests are applied in the form of hydro­ chloride. (1) Platelet aggregation inhibition: Sample solution containing a compound [1] (final concentration 500 or 100 µM) is added in rabbit platelet plasma added with 1/10 volume of 3.8% sodium citrate and incu­ bated at 37°C for 3 minutes. A platelet activation factor (PAF, final concentration 10-50 ng/ml) or collagen (final con­ centration 2.5 µg/ml) as an aggregating agent are added thereto, and platelet aggregation activity is measured by aggrigometer. Result of assays on PAF induced aggregation is shown in Table 2, and that of collagen induced aggregation is shown in Table 3, in which showing clear platelet aggregation inhibitory activities of the compound [1] of the present invention. (2) Vasodilation activity: Dog, pretreated with morphine 81.5 mg/kg, sc), is anesthesized with urethane 8450 mg/kg, iv) and α-chloralos (45 mg/kg, iv), and fixed at dosal position. Right femoral arterial blood is introduced into a left femoral artery via perfusion pump, and Sterling's resistance is connected in the exosomatic circulation system to perfuse in a left back limb at constant pressure. Perfusion pressure is set on a valve slightly higher than that of an average blood pressure of the animal. Sample (100 µg) dissolved in physiological saline is administered into a right femoral artery, and changes of blood flow is measured. Vasodilation activity is determined as a specific activity by setting the increased ratio of blood flow as 100% when papaverin 30 µg is administered intra arterially. Result is shown in Table 4 in which the compound [1] of the present invention has clear vasodilation activity. (3) Antioxidant activity: Antioxidant activity is determined according to a method of Stocks et al. [Clin. Sci. Mol. Med., 47: 215 (1974)]. Rat cerebrum is added in ice-cooled 40 mM phosphate saline buffer solution (PBS) (pH 7.4, buffer 4 ml per cerebrum 1 g), homogenized and centrifuged (1000 X g, 4 °C, 10 min.) to obtain supernatant solution. The supernatant solution is diluted for 5 times with the above ice-cooled PBS solution, and to a 0.9 ml thereof is added the sample of compound [1] (0.1 ml, final concentration 100 µM) dissolved in ethanol, incubated at 37 °C for 15 minutes, added 35% perchloric acid (0.2 ml), ice-cooled to stop the reaction and centrifuged (1300 X g, 4 °C, 10 min.). Thiobarbituric acid (5 g/lit. of 50% acetic acid, 0.5 ml) is added to the supernatant solution (1 ml), heatd at 100°C for 30 minutes and ice-cooled to measure absorbancy at 532 nm. The thus formed amount of lipoperoxide is expressed as an amount of malondialdehyde. Result is shown in Table 5 in which a compound [1] of the present invention has an inhibitory action for lipoperoxide generation. As explained hereinabove, a compound [1] of the present invention or its salt has an inhibitory action for platelet aggregation, vasodilating activity and/or inhibitory action lipoperoxide generation, and is useful as pharmaceuticals for improvement on circulation and metabolic disorder. [Examples] Following examples illustrated the present invention but are not construed as limiting. In the examples, Rf value of silica-gel thin layer chromatography (TLC) is a value measured, if not specified, by using the following carrier and developing solvent. Carrier: silica-gel, Kieselgel 60 F₂₅₄ (Merck) Developper: chloroform - methanol (20 : 1) Physical properties of the compound [1] obtained in the following examples are illustrated in Table 27. Example 1 1-(2-hydroxyethyl)-3,5,6-trimethyl-2-oxo-1,2-­ dihydropyrazine (compound 026): 2-hydroxy-3,5,6-trimethylpyrazine (13.8 g, 0.1 M) and 5N-NaOH (100 ml, 0.5 M) were added to t-butanol (200 ml). Ethylene chlorohydrin (40.3 g, 0.5 M) was added therein and stirred at 60 °C for 2 hours. Water was added to the reaction mixture, extracted 10 times with chloroform (100 ml), dried the extract with anhydrous magnesium sulfate and concentrated in vacuo. Residue was charged on a column of silica-gel (Wako Pure Chem. Co., C-200) and eluted with chloroform-methanol (300 : 1) to obtain the product. (14.4 g, Yield: 79.1%) dihydrochloride: m.p.: 140 - 144°C. Examples 2-9 1-(2-substituted ethyl)-3,5,6-trimethyl-2-oxo-1,2-­ dihydropyrazine: Thionylchloride (0.86 ml, 12mM) in chloroform (0.5 ml) was added dropwise under ice-cooling to the compound 026 (1.82 g, 10 mM) suspended in chloroform (5 ml) and stirred at room temperature for 3 hours to chlorinate. Reaction mixture was poured into diluted aqueous Na₂CO₃, extracted 3 times with chloroform, dried the extract with anhydrous sodium sulfate, and concentrated in vacuo. Base (20mM) and triethylamine (2.8 ml, 20 mM) were added to the obtained chlorinated compound dissolved in benzene (60 ml) and refluxed. Reaction mixture was washed with diluted aqueous Na₂CO₃ and an aqueous layer was extracted 2 times with benzene. Combined benzene layer, which was dried with anhyd­ rous sodium sulfate, was concentrated in vacuo. Residue was chromatographed on a silica-gel (80 g) column using elution solvent of chloroform-methanol to obtain the compounds in Table 6. Kind of base, reflux time and ratio of chloroform-meth­ anol mixture are shown in Table 6. Examples 10-11 1-(2-substituted thioethyl)-3,5,6-trimethyl-2-oxo-­ 1,2-dihydropyrazine: A compound 026 (0.91 g, 5 mM) was chlorinated with thionylchloride according to the same method in Examples 2-9. The thus obtained chlorinated compound was dissolved in dime­ thylformamide (DMF, 10 ml), added sodium mercaptane (5 mM) and stirred at room temperature for 2 days. DMF was removed off in vacuo. Diluted aqueous K₂CO₃ solution was added to the residue, extracted with chloroform, dried by adding anhydrous sodium sulfate and concentrated in vacuo. Residue was chromato­ graphed on a silica-gel (C-200, 50 g) column eluted with benzene­ ethyl acetate (5 : 1) to obtain the product in Table 7. A kind of mercaptane is illustrated in Table 7. Example 12 1,4-bis [2-(3,5,6-trimethyl-2-oxo-1,2-dihydropyrazine-­ 1-yl)ethyl ] -piperazine (compound 101): Chloroform (3 ml) solution of thionylchloride (4.3 ml, 60 mM)was added dropwise under ice-cooling to a compound 026 (9.10 g, 50 mM) suspended in chloroform (15 ml). After stir­ ring at room temperature for 3 hours, reaction mixture was poured into diluted aqueous K₂CO₃ and extracted with chloroform (200 ml). Chloroform layer was dried with anhydrous magnesium sulfate and concentrated in vacuo. Residue was dissolved in benzene (300 ml), added piperazine (2.15 g) and triethylamine (0.3 ml, 50mM) and refluxed for 3 hours. Reaction mixture was washed with diluted aqueous K₂CO₃ and extracted the aqueous layer with chloroform. Chloroform layer was dried with anhyd­ rous magnesium sulfate and concentrated in vacuo. Residue was charged on a column of silica-gel (C-200, 180 g), and eluted with chloroform-methanol (100 : 1) to obtain the compound 101. (7.60 g, Yield: 73.2%) Example 13 1-(2-pyperazinoethyl)-3,5,6-trimethyl-1,2-dihydro pyrazine (compound 642): In example 12, piperazine (17.2 g, 0.2 M) and triethyl­ amine (28 ml, 0.2 M) were used and the other conditions were repeated according to the example 12 to obtain the compound 642 (5.52 g, Yield: 44.2%) which showed lower Rf value as compared with the compound 101. Example 14 1-(2-hydroxyethyl)-3-phenyl-5,6-dimethyl-2-oxo-­ 1,2-dihydropyrazine (compound 109): Ethylene chlorohydrin (20.2 g, 0.25 M) was added to 2-hydroxy-3-phenyl-5,6-dimethyl-pyrazine (10.0 g, 50 mM) and 5N-NaOH (50 ml) dissolved in t-butanol (150 ml) and stirred at 60°C for 2.5 hours. Water was added to the reaction mixture, extracted with chloroform, dried with anhydrous sodium sulfate and concentrated in vacuo. Residue was charged on a column of silica-gel (C-200, 130 g) packed with chloroform and eluted with chloroform-methanol (100 : 1) to obtain the compound 109. (8.73 g, Yield: 71.5%) Example 15 1-(2-chloroethyl)-3-phenyl-5,6-dimethyl-2-oxo-­ 1,2-dihydropyrazine (compound 612): Thionylchloride (0.42 ml, 6.0 mM) was added dropwise under ice-cooling to a compound 109 (1.22 g, 50 mM) dissolved in chloroform (10 ml) and stirred at room temperature for 3 hours. Chloroform was added to the reaction mixture, washed with diluted aqueous K₂CO₃ and further extracted the aqueous layer with chloroform. Chloroform layer was combined, dried with anhydrous magnesium sulfate and concentrated in vacuo. Residue was charged on a column of silica-gel (C-200, 25 g), and eluted with chloroform to obtain the compound 612. (0.59 g, Yield: 42.7%) Examples 16-17 1-(2-substituted ethyl)-3-phenyl-5,6-dimethyl-2-oxo-­ 1,2-dihydropyrazine: Base (5 mM) and triethylamine (0.70 ml, 5 mM) were added to a compound 612 (0.66 g, 2.5 mM) dissolved in benzene (15 ml) and refluxed. Reaction mixture was washed with diluted aqueous K₂CO₃, further extracted the aqueous layer with benzene. Benzene layer was combined, dried with anhydrous sodium sulfate and concentrated in vacuo. Residue was charged on a column of silica-gel (C-200, 65 g) and eluted with chloroform-methanol to obtain the compounds in Table 8. A kind of base, reflux time and ratio of chloroform-­ methanol mixture are shown in Table 8. Example 18 1-(2-hydroxyethyl)-3-benzyl-5,6-dimethyl-2-oxo-­ 1,2-dihydropyrazine (compound 112): Ethylene chlorohydrin (4.03 g, 50 mM) was added to 2-hydroxy-3-benzyl-5,6-dimethyl-pyrazine (2.14 g, 10 mM) and 5N-NaOH (10 ml) dissolved in t-butanol (30 ml), and stirred at 60°C for 2.5 hours. Water (100 ml) was added to the reaction mixture, extracted 3 times with chloroform, dried the extract with anhydrous magnesium sulfate and concentrated in vacuo. Residue was charged on a column of silica-gel (C-200, 25 g) and eluted with chloroform-methanol (100 : 1) to obtain the compound 122. (2.22 g, Yield: 86.0%) Example 19 1-(2-chloroethyl)-3-benzyl-5,6-dimethyl-2-oxo-­ 1,2-dihydropyrazine (compound 613): Thionylchloride (0.42 ml, 6.0 mM) was added dropwise to a compound 112 (1.29 g, 5 mM) dissolved in chloroform (6 ml) under ice-cooling and stirred at room temperature for 5 hours. Chloroform (70 ml) was added to the reaction mixture, washed with diluted aqueous K₂CO₃ and further extracted twice the aqueous layer with chloroform. Chloroform layer was combined, dried with anhydrous magnesium sulfate and concentrated in vacuo. Residue was charged on a column of silica-gel (C-200, 25 g), packed with chloroform, and eluted with chloroform to obtain the compound 613. (1.00 g, Yield: 87.5%) Examples 20-23 1-(2-substituted ethyl)-3-benzyl-5,6-dimethyl-2-oxo-­ 1,2-dihydropyrazine : Base (6.0 mM) and triethylamine (0.84 ml, 6.0 mM) were added to a compound 613 (0.83 g, 3.0 mM) dissolved in benzene (15 ml) and refluxed. Reaction mixture was washed with diluted aqueous K₂CO₃, further extracted the aqueous layer with benzene. Benzene layer was combined, dried with anhydrous sodium sulfate and concentrated in vacuo. Residue was charged on a column of silica-gel (C-200, 65 g) packed with chloroform and eluted with chloroform-methanol to obtain the compounds in Table 9. A kind of base, reflux time and ratio of chloroform-­ methanol mixture are shown in Table 9. Examples 24-28 1-(2-hydroxyethyl)-3-alkyl-5,6-dimethyl-2-oxo-­ 1,2-dihydropyrazine : Aqueous 5N-NaOH (10 ml, 50 mM), t-butanol (30 ml) and ethylene chlorohydrin (50 mM) were added to 2-hydroxy-3-alkyl-­ 5,6-dimethyl-pyrazine (10 mM) and stirred at 60 °C. Water was added to the reaction mixture, extracted 3 times with chloro­ form, dried with anhydrous magnesium sulfate and concentrated in vacuo. Residue was charged on a column of silica-gel (C-­ 200, 120 g) and eluted with chloroform-methanol to obtain the compounds (hydroxy ethyl form) in Table 10. A kind of 2-hydroxy-3-alkyl-5,6-dimethyl-pyrazine indi­ cated as a group R₁, its amount used, reaction time in hour, and ratio of mixture of chloroform-methanol are illustrated in Table 10. Examples 29-46 1-(2-substituted ethyl)-3-alkyl-5,6-trimethyl-­ 2-oxo-1,2-dihydropyrazine: Thionylchloride (0.34 ml) was added dropwise under ice-­ cooling to the hydroxy ethyl form of compound (4 mM), obtained in Examples 24-28, dissolved in chloroform (5 ml) and stirred at room temperature for 1 hour. Chloroform was added to the reaction mixture, washed with diluted aqueous K₂CO₃, further extracted twice the aqueous layer with chloroform. Chloroform layer was combined, dried with anhydrous magnesium sulfate and concentrated in vacuo. Benzene (30ml), triethylamine (1.12 ml) and base (8 mM) were added to the residue and refluxed. Chloro­ form (100-120 ml) was added to the reaction mixture and washed with diluted aqueous K₂CO₃. Aqueous layer was extracted twice with chloroform. Chloroform layer was combined, dried with anhydrous magnesium sulfate and concentrated in vacuo. Residue was charged on a column of silica-gel (C-200, 60 g) and eluted with chloroform-methanol to obtain the compounds shown in Table 11. Kind of starting material (hydroxy ethyl form), base, reflux time and ratio of chloroform-methanol mixture are shown in Table 11. Examples 47-49 1-(2-hydroxyethyl)-3-alkyl-5,6-dimethyl-2-oxo-­ 1,2,5,6,7,8-hexahydroquinoxaline: Aqueous 5N-NaOH (10 ml, 50 mM), t-butanol (30 ml) and ethylene chlorohydrin (50 mM) were added to 2-hydroxy-3-alkyl-­ 5,6,7,8-tetrahydroquinoxaline (10 mM) and stirred at 60 °C. Water was added to the reaction mixture, extracted with chloro­ form, dried with anhydrous magnesium sulfate and concentrated in vacuo. Residue was charged on a column of silica-gel (C-­ 200) and eluted with chloroform-methanol to obtain the compounds (hydroxy ethyl form) in Table 12. A kind of 2-hydroxy-3-alkyl-5,6,7,8-tetrahydroquinoxaline indicated as a group R₁, its amount used, reaction time in hour, and ratio of mixture of chloroform-methanol are illustrated in Table 12. Examples 50-62 1-(2-substituted ethyl)-3-alkyl-2-oxo-­ 1,2,5,6,7,8-hexahydroquinoxaline: Thionylchloride (0.34 ml) was added dropwise under ice-­ cooling to the hydroxy ethyl form of compound (4 mM), obtained in Examples 47-49, dissolved in chloroform and stirred at room temperature for 1 hour. Chloroform was added to the reaction mixture, washed with diluted aqueous K₂CO₃, further extracted the aqueous layer with chloroform. Chloroform layer was com­ bined, dried with anhydrous magnesium sulfate and concentrated in vacuo. Benzene (30ml), triethylamine (1.12 ml, 8mM) and base (8 mM) were added to the reactionmixture and refluxed. Chloro­ form (100 ml) was added to the reaction mixture, washed with diluted aqueous K₂CO₃, then extracted the aqeous layer with chloroform. Chloroform layer was combined, dried with anhyd­ rous magnesium sulfate and concentrated in vacuo. Residue was charged on a column of silica-gel (C-200, 70 g) and eluted with chloroform-methanol to obtain the compounds shown in Table 13. Kind of starting material (hydroxy ethyl form), base, reflux time and ratio of chloroform-methanol mixture are shown in Table 13. Examples 63-68 1-(2-hydroxyethyl)-3-alkyl-5,6-diethyl-2-oxo-­ 1,2-dihydropyrazine : Aqueous 5N-NaOH (10 ml, 50 mM), t-butanol (30 ml) and ethylene chlorohydrin (50 mM) were added to 2-hydroxy-3-alkyl-­ 5,6-diethyl-pyrazine (10 mM) and stirred at 60°C. Water was added to the reaction mixture, extracted with chloroform, dried with anhydrous sodium sulfate and concentrated in vacuo. Residue was charged on a column silica-gel (C-200) packed with chloroform and eluted with chloroform-methanol to obtain the compounds in Table 14. A kind of 2-hydroxy-3-alkyl-5,6-diethyl-pyrazine indicated as a group R₁, its amount used, reaction time in hour, an amount of silica-gel and ratio of mixture of chloroform-methanol are illustrated in Table 14. Examples 69-101 1-(2-substituted ethyl)-3-alkyl-5,6-diethyl-­ 2-oxo-1,2-dihydropyrazine: Thionylchloride (0.34 ml) was added dropwise under ice-­ cooling to the hydroxy ethyl form of compound (4 mM), obtained in Examples 63-68, dissolved in chloroform (5 ml) and stirred at room temperature for 1 hour. Chloroform was added to the reaction mixture, washed with diluted aqueous K₂CO₃, further extracted twice the aqueous layer with chloroform. Chloroform layer was combined, dried with anhydrous magnesium sulfate and concentrated in vacuo. Benzene (30ml), triethylamine (1.12 ml, 8 mM) and base (8 mM) were added to the residue and refluxed. Chloroform (100 ml) was added to the reaction mixture and washed with diluted aqueous K₂CO₃. Further aqueous layer was extracted with chloroform. Chloroform layer was combined, dried with anhydrous magnesium sulfate and concentrated in vacuo. Residue was charged on a column of silica-gel (C-200, 60 g) packed with chloroform, and eluted with chloroform-methanol to obtain the compounds shown in Table 15. A kind of starting material (hydroxy ethyl form), base, reflux time and ratio of chloroform-methanol mixture are shown in Table 15. Example 102 1-(2-hydroxyethyl)-3-ethyl-5,6-dimethyl-2-oxo-­ 1,2-dihydropyrazine (compound 630): Ethylene chlorohydrin (32.21 g, 0.4 M) was added to 2-hydroxy-3-ethyl-5,6-dimethyl-pyrazine (12.16 g, 80 mM) and 5N-NaOH (80 ml) dissolved in t-butanol (240 ml), and stirred at 60 °C for 3 hours. Diluted aqueous K₂CO₃ was added to the reaction mixture, extracted with chloroform, and further ext­ racted twice the aqueous layer with chloroform. Combined chloroform layer was dried with anhydrous magnesium sulfate and concentrated in vacuo. Residue was charged on a column of silica-gel (C-200, 250 g) packed with chloroform and eluted with chloroform-methanol (from 200 : 1 to 50 : 1) to obtain the compound 630. (12.31 g, Yield: 78.5%) Examples 103-110 1-(2-substituted ethyl)-3-ethyl-5,6-dimethyl-­ 2-oxo-1,2-dihydropyrazine: Thionylchloride (0.43 ml) was added dropwise under ice-­ cooling to the compound (0.98 g, 5 mM) dissolved in chloroform (5 ml) and stirred at room temperature for 1 hour. Chloroform (50 ml) was added to the reaction mixture, washed with diluted aqueous K₂CO₃, further extracted twice the aqueous layer with chloroform (50 ml). Chloroform layer was combined, dried with anhydrous magnesium sulfate and concentrated in vacuo. Benzene (30ml), triethylamine (1.40 ml) and base (10 mM) were added to the residue and refluxed. Chloroform (100 ml) was added to the reaction mixture and washed with diluted aqueous K₂CO₃. Further aqueous layer was extracted twice with chloroform (50 ml). Chloroform layer was combined, dried with anhydrous magnesium sulfate and concentrated in vacuo. Residue was charged on a column of silica-gel (C-200, 70 g) packed with chloroform, and eluted with chloroform-methanol to obtain the compounds shown in Table 16. A kind of base, reflux time and ratio of chloroform-­ methanol mixture are shown in Table 16. Example 111 1-(2-hydroxyethyl)-3-benzyl-5,6-diethyl-2-oxo-­ 1,2-dihydropyrazine (compound 640): Ethylene chlorohydrin (20.15 g, 0.25 M) was added to 2-hydroxy-3-benzyl-5,6-diethyl-pyrazine (12.10 g, 50 mM) and 5N-NaOH (50 ml) dissolved in t-butanol (150 ml), and stirred at 60°C for 3 hours. A t-butanol kwas distilled off in vacuo, added water thereto and extracted 3 times with chloroform. Extract was dried with anhydrous magnesium sulfate and concent­ rated in vacuo. Residue was charged on a column of silica-gel (C-200, 230 g) packed with chloroform and eluted with chloro­ form-methanol (100 : 1) to obtain the compound 640. (12.31 g, Yield: 58.7%) Examples 112-122 1-(2-substituted ethyl)-3-benzyl-5,6-dimethyl-­ 2-oxo-1,2-dihydropyrazine: Thionylchloride (0.34 ml) was added dropwise under ice-­ cooling to the compound 640 (1.15 g, 4.0 mM) dissolved in chlo­ roform (5 ml) and stirred at room temperature for 1 hour. Chloroform (100 ml) was added to the reaction mixture, washed with diluted aqueous K₂CO₃, further extracted twice the aqueous layer with chloroform (30 ml). Chloroform layer was combined, dried with anhydrous sodium sulfate and concentrated in vacuo. Triethylamine (1.12 ml, 8 mM) and base (8 mM) were added to the residue dissolved in benzene (30 ml) and refluxed. The reaction mixture was washed with diluted aqueous K₂CO₃. Aqueous layer was extracted twice with benzene. Benzen layer was combined, dried with anhydrous sodium sulfate and concentrated in vacuo. Residue was charged on a column of silica-gel (C-200, 60 g) and eluted with chloroform-methanol to obtain the compounds shown in Table 17. Kind of base, reflux time and a ratio of chloroform-­ methanol mixture are shown in Table 17. Example 123 1-(2-hydroxyethyl)-3-p-chlorobenzyl-5,6-dimethyl-­ 2-oxo-1,2-dihydropyrazine (compound 641): Ethylene chlorohydrin (16.11 g, 0.20 M) was added to 2-hydroxy-3-p-chlorobenzyl-5,6-dimethyl-pyrazine (11.06 g, 40 mM) dissolved in aqueous 5N-NaOH (40 ml) and t-butanol (120 ml), and stirred at 60°C for 3 hours. A t-butanol was distil­ led off in vacuo. Diluted aqueous K₂CO₃ was added to the residue, extracted three times with chloroform, dried with anhydrous sodium sulfate and concentrated in vacuo. Residue was charged on a column of silica-gel (C-200, 300 g) packed with chloroform and eluted with chloroform-methanol (100 : 1) to obtain the compound 641. (9.73 g, Yield: 75.9%) Example 124 1-(2-chloroethyl)-3-p-chlorobenzyl-5,6-diethyl-2-oxo-­ 1,2-dihydropyrazine (compound 647): Thionylchloride (1.20 ml) was added dropwise to compound 641 (4.16 g, 13 mM) dissolved in chloroform (20 ml) under ice-­ cooling and stirred at room temperature for 1.5 hours. Diluted aqueous K₂CO₃ was added to the reaction mixture, extracted with chloroform, dried with anhydrous sodium sulfate and concentrated in vacuo to obtain the compound 647. (4.27 g, Yield: 96.9%) Examples 125-129 1-(2-substituted ethyl)-3-p-chlorobenzyl-5,6-diethyl-­ 2-oxo-1,2-dihydropyrazine : Base (6 mM) and triethylamine were added to chloroethyl compound 649 1.023 g, 3 mM) dissolved in benzene (30 ml) and refluxed. Reaction mixture was poured into diluted aqueous K₂CO₃, waqshed and extracted the aqueous layer with benzene. Benzene layer was combined, dried with anhydrous sodium sulfate and concentrated in vacuo. Residue was charged on a column of silica-gel (C-200, 65 g) packed with chloroform and eluted with chloroform-methanol to obtain the compounds in Table 18. A kind of base, reflux time and ratio of chloroform-­ methanol mixture are shown in Table 18. Examples 130-138 1-(2-hydroxyethyl)-3-alkyl-2-oxo-­ 1,2,5,6,7,8-hexahydroquinoxaline: Ethylene chlorohydrin (4.03 g, 50 mM) was added to 2-hydroxy-3-alkyl-5,6,7,8-tetrahydro quinoxaline (10 mM) dis­ solved in aqueous 5N-NaOH (10 ml, 50 mM) and t-butanol (30 ml) and stirred at 60°C for 4 hours. Water was added to the reac­ tion mixture, extracted with chloroform, dried with anhydrous sodium sulfate and concentrated in vacuo. Residue was charged on a column of silica-gel (C-200) packed with chloroform and eluted to obtain the compounds (hydroxy ethyl form) in Table 19. A kind of 2-hydroxy-3-alkyl-5,6,7,8-tetrahydro quinoxa­ line indicated as a group R₁, its amount used, amount of sili­ ca-gel used in column chromatography and a kind of elution solvent are illustrated in Table 19. Examples 139-214 1-(2-substituted ethyl)-3-alkyl-2-oxo-­ 1,2,5,6,7,8-hexahydroquinoxaline: Thionylchloride (1.3 equivalent) was added dropwise under ice-cooling to the hydroxy ethyl form of compound (3-5 mM), obtained in Examples 130-138, dissolved in chloroform (3-­ 5 ml) and stirred at roomtemperature for 1 hour. Diluted aque­ ous K₂CO₃ was added to the reaction mixture, extracted 3 times with chloroform (50 ml), dried with anhydrous sodium sulfate, and concentrated in vacuo. Benzene (30ml), triethylamine (2 eq.) and base (2 eq.) were added to the residue and refluxed. Reaction mixture was poured into diluted aqueous K₂CO₃, then ext­ racted with several times with benzene. Extract was dried with anhydrous sodium sulfate and concentrated in vacuo. Residue was charged on a column of silica-gel (C-200, 60 g) and eluted with chloroform-methanol (200 : 1) to obtain the compounds shown in Table 20. Kind of starting material (hydroxy ethyl form), amount of used thereof, base and reflux time are shownin Table 20. Example 215 1-(2-piperazinyl ethyl)-3-ethyl-5,6-dimethyl-­ 2-oxo-1,2-dihydropyrazine: Thionylchloride (6.6 ml) was added dropwise under ice-­ cooling to the compound 630 (18.72 g, 70 mM) dissolved in chloro­ form (70 ml) and stirred at room temperature for 1 hour. Diluted aqueous K₂CO₃ was added to the reaction mixture and extracted with chloroform. Extract was dried with anhydrous magnesium sulfate and concentrated in vacuo. Triethylamine (19.6 ml, 0.14 M) and anhydrous piperazine (64.4 g, 0.75 M) were added to the residue dissolved in benzene (420 ml) and refluxed for 3 hours. Reaction mixture was washed with diluted aqueous K₂CO₃. Further aqueous layer was extracted with benzene. Benzene layer was combined, dried with anhydrous magnesium sulfate and concentrated in vacuo. Residue was charged on a column of silica-gel (C-200, 375 g) packed with chloroform and eluted with chloroform-methanol (10 : 1) to obtain the compound 454. (13.66 g, Yield: 73.9%) Examples 216-226 1- [2-(4′-arylpiperazinyl) ethyl] -3-ethyl-5,6-­ dimethyl-2-oxo-1,2-dihydropyrazine: (a) Acid chloride method: Triethylamine (0.84 ml, 6 mM) was added to a compound 454 (0.81 g, 3 mM) dissolved in chloroform (10 ml), and acid chloride (3 mM) was added thereto under ice-cooling. Diluted aqueous K₂CO₃ was added to the reaction mixture and extracted 3 times with chloroform. Combined chloroform layer was dried with anhydrous sodium sulfate and concentrated in vacuo. Residue was charged on a column of silica-gel (C-200, 80 g) packed with chloroform and eluted with chloroform-methanol to obtain the compounds shown in Table 21. (b) Mixed anhydride method: Triethyamine (0.70 ml) was added to the carboxylic acid (5 mM) dissolved in tetrahydrofuran (10 ml). After pivaloyl chloride (0.61 g, 5 mM) was added dropwise thereto at -5°C and stirred for 30 minutes, a chloroform sollution of compound 454 (1.06 g, 4 mM) was added dropwise. Reaction was continued under gradually increasing up to room temperature. Reaction mixture was treated as same as of the above (a) to obtain the product shown in Table 21. Acyaltion method, acylating agent used, reaction time and a ratio of mixture of chloroform-methanol were shown in Table 21. Example 227 1-(2-hydroxyethyl)-3-benzyl-2-oxo-­ 1,2,5,6,7,8-hexahydroquinoxaline (compound 643): Ethylene chlorohydrin (16.10 g, 0.2 M) was added to 2-hydroxy-3-benzyl-5,6,7,8-tetrahydro quinoxaline (9.60 g, 40 mM) dissolved in diluted aqueous 5N-NaOH (40 ml) and t-butanol (120 ml), and stirred at 60 °C for 3 hours. A t-butanol was distilled off in vacuo. The residue was extracted 3 times with chloroform, dried with anhydrous sodium sulfate and concentrated in vacuo. Residue was charged on a column of silica-gel (C-­ 200, 220 g) packed with chloroform, and eluted with chloroform -methanol (200 : 1) to obtain the compound 643. (10.90 g, Yield: 83.8%) Example 228 1-(2-chloroethyl)-3-benzyl-2-oxo-­ 1,2,5,6,7,8-hexahydroquinoxaline (compound 644): Thionylchloride (2.96 ml, 1.3 eq.) was added dropwise under ice-cooling to the compound 643 (9.09 g, 32 mM) dissolved in chloroform (30 ml) and stirred at room temperature for 2 hours. Diluted aqueous K₂CO₃ was added to the reaction mixture, extracted twice with chloroform, dried with anhydrous sodium sulfate and concentrated in vacuo. Residue was charged on a column of silica-gel (C-200, 100 g) packed with chloroform and eluted with chloroform to obtain the compound 644. (7.55 g, Yield: 78.0%) Examples 229-234 1-(2-substituted ehtyl)-3-benzyl-2-oxo-­ 1,2,5,6,7,8-hexahydroquinoxaline: Base (7 mM) and triethylamine (0.98 ml) were added to a compound 644 (1.05 g, 3.5 mM) dissolved in benzene (30 ml), and refluxed. Reaction mixture was washed with diluted aqueous K₂CO₃ and extracted the aqueous layer with benzene. Combined benzene layer was dried with anhydrous sodium sulfate and concentrated in vacuo. Residue was charged on a column of silica-gel (C-200, 65 g) packed with chloroform and eluted with chloroform-methanol to obtain the compounds shown in Table 22. A kind of base, reflux time and ratio of chloroform-­ methanol mixture are shown in Table 22. Example 235 1-(2-hydroxyethyl)-3-(2-phenylethyl)-2-oxo-­ 1,2,5,6,7,8-hexahydroquinoxaline (compound 645): Ethylene chlorohydrin (9.0 g) was added to 2-hydroxy-3-­ (2-phenylethyl)-5,6,7,8-tetrahydro quinoxaline (5.59 g, 22 mM) dissolved in aqueous 5N-NaOH and t-butanol (60 ml), and stirred at 60 °C for 3 hours. A t-butanol was distilled off in vacuo, added water to the residue and extracted 3 times with chloroform. Extract was dried with anhydrous sodium sulfate and concentrated in vacuo. Residue was charged on a column of silica-gel (C-­ 200, 170 g) packed with chloroform, and eluted with chloroform-­ methanol (200 : 1) to obtain the compound 645. (6.73 g, Yield: 90.9%) Example 236 1-(2-chloroethyl)-3-(2-phenylethyl)-2-oxo-­ 1,2,5,6,7,8-hexahydroquinoxaline (compound 647): Thionylchloride (2.05 ml) was added dropwise under ice-­ cooling to the compound 645 (6.49 g, 22.1 mM) dissolved in chloro­ form (25 ml) and stirred at room temperature for 2 hours. Diluted aqueous K₂CO₃ was added to the reaction mixture and extracted twice with chloroform. Extract was dried with anhydrous sodium sulfate and concentrated in vacuo to obtain the compound 647, which was further used without purification for the forthcoming reaction. Examples 237-241 1-(2-substituted ethyl)-3-(2-phenylethyl)-2-oxo-­ 1,2,5,6,7,8-hexahydroquinoxaline: Base (7 mM) and triethylamine (0.98 ml) were added to a compound 647 (1.11 g, 3.5 mM) dissolved in benzene (30 ml), and refluxed. Reaction mixture was washed with diluted aqueous K₂CO₃ and extracted the aqueous layer with benzene. Combined benzene layer was dried with anhydrous sodium sulfate and concentrated in vacuo. Residue was charged on a column of silica-gel (C-200, 65 g) packed with chloroform and eluted with chloroform-methanol to obtain the compounds shown in Table 23. A kind of base, reflux time and ratio of chloroform-­ methanol mixture are shown in Table 23. Example 242 1-(2-hydroxyethyl)-3-ethyl-2-oxo-­ 1,2,5,6,7,8-hexahydroquinoxaline (compound 646): Ethylene chlorohydrin (20.2 g, 0.25 M) was added to 2-hydroxy-3-ethyl-5,6,7,8-tetrahydro quinoxaline (8.90 g, 50 mM) dissolved in diluted aqueous 5N-NaOH (50 ml) and t-butanol (150 ml), and stirred at 60°C for 3 hours. A t-butanol was distilled off in vacuo. Water was added to the residue, which was extrac­ ted 3 times with chloroform, dried with anhydrous sodium sulfate and concentrated in vacuo. Residue was charged on a column of silica-gel (C-200, 170 g) packed with chloroform, and eluted with chloroform-methanol (100 : 1) to obtain the compound 646. (9.30 g, Yield: 83.8%) Examples 243-248 1-(2-substituted ethyl)-3-ethyl-2-oxo-­ 1,2,5,6,7,8-hexahydroquinoxaline: Thionylchloride (0.47 ml) was added dropwise under ice-­ cooling to the compound 646 (1.11 g, 5 mM) dissolved in chloroform (4 ml) and stirred at room temperature for 1 hour. Diluted aqueous K₂CO₃ was added to the reaction mixture and extracted with chloroform. Extract was dried with anhydrous sodium sulfate and concentrated in vacuo. Benzene (30 ml), triethylamine (1.4 ml) and base (10 mM) were added to a residue and refluxed. Reaction mixture was poured into diluted aqueous K₂CO₃ and extracted with benzene. Extract was dried with anhydrous sodium sulfate and concent­ rated in vacuo. Residue was charged on a column of silica-gel (C-200, 65 g) packed with chloroform and eluted with chloroform-­ methanol to obtain the compounds shown in Table 24. A kind of base, reflux time and ratio of chloroform-­ methanol mixture are shown in Table 24. Example 249 1-(2-acetoxyethyl)-3,5,6-trimethyl-­ 2-oxo-1,2-dihydropyrazine (compound 061): Acetic anhydride (2 ml) was added to a compound 026 (0.91 g, 5 mM) dissolved in pyridine (10 ml) under ice-cooling and stirred at room temperature for 1.5 hour. Reaction mixture was concentrated in vacuo and diluted aqueous K₂CO₃ was added thereto extracted 3 times with chloroform. Extract was dried with anhydrous magnesium sulfate and concentrated in vacuo. Residue was charged on a column of silica-gel (Florisil, 60 g) packed with benzene and eluted with benzene-ethyl acetate (5 : 1) to obtain the compound 061. (0.58 g, Yield: 51.8%) Example 250 1-(2-phenylthioethyl)-3-propyl-2-oxo-­ 1,2,5,6,7,8-hexahydroquinoxaline (compound 615): Thionylchloride (0.47 ml) was added dropwise under ice-­ cooling to the compound 614 (1.18 g, 5 mM, hydroxyethyl form) obtained in Example 47 dissolved in chloroform (5 ml) and stirred at room temperature for 1 hour. Chloroform was added to a reac­ tion mixture, washed with diluted aqueous K₂CO₃ and extracted with chloroform. Combined chloroform layer was dried with anhydrous magnesium sulfate and concentrated in vacuo. Sodium thiophenolate (0.66 g) was added to a residue dissolved in DMF (20 ml) and stirred at room temperature for 2 days. DMF was distilled off in vacuo, added diluted aqueous K₂CO₃ to the residue and extracted with chloroform. Extract was dried with anhydrous sodium sulfate and concentrated in vacuo. Residue was charged on a column of silica-gel (C-200, 50 g) and eluted with benzene-ethyl acetate (5 : 1) to obtain the compound 615. (1.32 g, Yield: 80.7%) Referential example 1 2-hydroxy-3-ethyl-5,6,7,8-tetrahydroquinoxaline: 1,2-cyclohexanedione (6.72 g, 60 mM) was added at once to a methanol solution (100 ml) of α-aminobutylamide (5.1 g, 50 mM) at -30 °C, and aqueous 12.5 N-NaOH (5 ml) was added dropwise thereto. Reaction mixture was stirred at -30°C for 30 minutes, stopped the cooling and stirred at room temperature for 3 hours. Conc. hydrochloric acid (6.25 ml) was added to the reaction mixture under ice-cooling, furhther added sodium bicarbonate (5 g) after 10 minutes and distilled off methanol in vacuo. Residue was extracted with chloroform, washed the extracxt with water, dried with anhydrous sodium sulfate and concentrated in vacuo. Residue was washed with acetone and recrystallized from acetone to obtain the product as colorless crystals. (5.3 g. Yield: 60%), m.p.: 152 - 153 °C. NMR (CDCl₃) δ (ppm): 1.25 (t, 3H, -CH₂ CH ₃), 1.7-1.9 (m, 4H, 6-H₂, 7-H₂), 2.5-2.8 (m, 4H, 5-H₂, 8-H₂), 2.80 (q, 2H, -CH₂ CH₃), 13.06 (br. s, 1H, 0H) Mass (CI): 179 (M⁺ + 1) Referential example 2 2-hydroxy-3-propyl-5,6,7,8-tetrahydroquinoxaline: 1,2-cyclohexanedione (5.4 g, 48 mM) was added at once to a methanol solution (80 ml) of norvalineamide hydrochloride (6.1 g, 40 mM) at -30 °C, and aqueous 12.5 N-NaOH (8 ml) was added dropwise thereto. Reaction mixture was stirred at -30°C for 30 minutes, stopped the cooling and stirred at room tempe­ rature for 3 hours. Conc. hydrochloric acid (10 ml) was added to the reaction mixture under ice-cooling, further added sodium bicarbonate (8 g) after 10 minutes and distilled off methanol in vacuo. Residue was extracted with chloroform, washed the extracxt with water, dried with anhydrous sodium sulfate and concentrated in vacuo. Residue was washed with acetone and recrystallized from acetone to obtain the product as colorless crystals. (3.8 g. Yield: 50%) m.p.: 131 - 133°C. NMR (CDCl₃)δ (ppm): 1.00 (t, 3H, -CH₂CH₂ CH ₃), 1.55-1.90 (m, 4H, 6-H, -CH₂CH₂CH₃, 6-H₂, 7-H₂), 2.67-2.83 (m, 6H, -CH₂ CH₂CH₃, 5-H₂, 6-H₂), 13.09 (br. s, 1H, 0H) Mass (CI): 193 (M⁺ + 1) Referential examples 3-13 : 2-hydroxy-3-alkyl-5,6,7,8-tetrahydroquinoxaline: 1,2-cyclohexanedione (6.72 g, 60 mM) was added at once to a methanol solution (100 ml) of α-amino acidamide hydro­ chloride (50 mM) at -30 °C, and aqueous 12 N-NaOH (10 ml) was added dropwise thereto. Reaction mixture was stirred for 30 minutes, stopped the cooling and stirred at room temperature for 5 hours. Conc. hydrochloric acid (12.5 ml) was added to the reaction mixture under ice-cooling, furhther added sodium bi­ carbonate (10 g) after 10 minutes and distilled off methanol in vacuo. Residue was extracted with chloroform, washed the extracxt with water, dried with anhydrous sodium sulfate and concentrated in vacuo. Residue was washed with acetone and recrystallized from acetone to obtain the product shown in Table 25. A kind of product, yield (weight and %) and physical properties are shown in Table 25. Referential example 14 2-hydroxy-3-benzyl-5,6,7,8-tetrahydroquinoxaline: A methanol (30 ml) solution of 1,2-cyclohexanedione (13.44 g, 0.12 M) was added to phenylalanineamide hydrochloride (20.05 g, 0.1 M) dissolved in methanol (200 ml) under cooling below -30 °C, and aqueous 12.5 N-NaOH (20 ml) was added drop­ wise thereto. Reaction mixture was stirred under - 30 °C for 30 minutes, stopped the cooling and stirred at room temperature for 3 hours. Conc. hydrochloric acid (25 ml) was added to the reaction mixture under ice-cooling, furhther added sodium bicarbonate (15 g) after 10 minutes stirring and distilled off methanol in vacuo. Residue, which was added with water, was extracted 3 times with chloroform, washed the extracxt with water, dried with anhydrous magnesium sulfate and concentrated in vacuo. Residue was washed with acetone and recrystallized from acetone to obtain the product. (19.7 g. Yield: 82.1%) NMR (CDCl₃, TMS) δ (ppm): 1.6-2.0 (m, 4H), 2.4-2.7 (m, 4H), 4.02 (s, 2H), 7.0-7.4 (m, 5H) Mass (CI): 241 (M⁺ + 1) Referential example 15 2-hydroxy-3-(phenylethyl)-5,6,7,8-tetrahydro­ quinoxaline: A methanol (20 ml) solution of 1,2-cyclohexanedione (5.38 g) was added to a methanol suspention (100 ml) of α-­ amino-(3-phenyl)-butylamide hydrochloride (8.58 g, 40 mM) at below -30 °C, and aqueous 12.5 N-NaOH (8 ml) was added dropwise thereto. Reaction mixture was stirred at below -30 °C for 30 minutes, stopped the cooling and stirred at room temperature for 6 hours. Conc. hydrochloric acid (8 ml) was added to the reaction mixture under ice-cooling, furhther added sodium bicarbonate (6.0 g) after 10 minutes stirring and distilled off methanol in vacuo. Residue, which was added with water, was extracted 3 times with chloroform, washed the extracxt with water, dried with anhydrous sodium sulfate and concentrated in vacuo. Residue was washed with acetone and recrystallized from acetone to obtain the product. (6.79 g. Yield: 66.8%) NMR (CDCl₃, TMS) δ (ppm): 1.6-2.0 (m, 4H), 2.5-2.8 (m, 4H), 3.06 (s, 2H x 2), 7.1-7.3 (s, 5H), 12.9 (br. s, 1H) Mass (CI): 255 (M⁺ + 1) Referential examples 16-23 : 2-hydroxy-3-alkyl-5,6-diethylpyrazine: α-amino acidamide (0.20 M) and 3,4-hexane (22.8 g, 0.20 M) were added to triethylamine (200 ml), stirred at room temp­ erature for 30 minutes and refluxed for 15 hours. Triethyamine was distilled off in vacuo, dissolved a residue in chloroform and washed with diluted aqueous K₂CO₃. Chloroform layer was dried with anhydrous sodium sulfate and concentrated in vacuo. Residue was recrystallized from acetone to obtain the products shown in Table 26. Product, yield (weight and %) and physical properties are shown in Table 26.

Claims: 1. A compound of the formula (I): wherein R is hydroxyl, halogen, lower alkanoyloxy, R₄ -­ carbamoyloxy, arylthio, 1-methyltetrazole-5-yl-thio, 1-­ imidazolyl, morpholino, in which R₄ is lower alkyl or aryl, R₅ is hydrogen, lower alkyl or aryl, R₆ is hydrogen, lower alkyl, hydroxy-lower alkyl, aryl, aryl-lower alkanoyl, arylcarbonyl, arylsulfonyl or thienyl-lower alkanoyl, A and A₁ are lower alkylene, m is an integer of from 4 to 6, n is the integer 2 or 3; R₁ is alkyl, aryl-lower alkyl or aryl; and R₂ and R₃ are each lower alkyl or together constitute tetramethylene; and pharmacologically acceptable non-toxic salts thereof; wherein aryl means phenyl unsubstituted or substituted by C1-3 alkyl, halogen, nitro or lower alkoxy. 2. A compound according to claim 1, wherein R₁ is methyl, ethyl, phenyl, benzyl, p-chlorobenzyl or 2-phenylethyl. 3. A compound according to claim 1 or 2, wherein R₂ and R₃ are both methyl or are both ethyl. 4. A compound according to any one of the preceding claims, wherein A is -CH₂CH₂-. 5. A process for the preparation of a compound of formula (I) as defined in claim 1 wherein R is hydroxyl, or a pharmacologically acceptable non-toxic salt thereof, which process comprises reacting a compound of the formula (2) wherein R₁, R₂ and R₃ are as defined in claim 1, with a hydroxyalkyl halide of the formula: X-A-OH wherein X is halogen and A is as defined in claim 1, in an organic solvent and, if desired, converting the resultant compound of formula (I) wherein R is hydroxyl into a pharmacologically acceptable non-toxic salt thereof. 6. A process for the preparation of a compound of formula (I) as defined in claim 1 wherein R is lower alkanoyloxy, or a pharmacologically acceptable non-toxic salt thereof, which process comprises acylating a compound of formula (I) as defined in claim 1 wherein R is hydroxyl such as to convert the said hydroxyl into a lower alkanoyloxy group and, if desired, converting the resultant compound of formula (I) wherein R is lower alkanoyloxy into a pharmacologically acceptable non-toxic salt thereof. 7. A process for the preparation of a compound of formula (I) as defined in claim 1 wherein R is R₄-­ carbamoyloxy, R₄ being as defined in claim 1, or a pharmacologically acceptable non-toxic salt thereof, which process comprises reacting a compound of formula (I) as defined in claim 1 wherein R is hydroxyl with a lower alkyl isocyanate or aryl isocyanate and, if desired, converting the resultant compound of formula (I) wherein R is R₄-­ carbamoyloxy into a pharmacologically acceptable non-toxic salt thereof. 8. A process for the preparation of a compound of formula (I) as defined in claim 1 wherein R is halogen, or a pharmacologically acceptable non-toxic salt thereof, which process comprises halogenating a compound of formula (I) as defined in claim 1 wherein R is hydroxyl and, if desired, converting the resultant compound of formula (I) wherein R is halogen into a pharmacologically acceptable non-toxic salt thereof. 9. A process for the preparation of a compound of formula (I) as defined in claim 1 wherein R is arylthio or 1-methyltetrazole-5-yl-thio or a pharmacologically acceptable non-toxic salt thereof, which process comprises reacting a compound of formula (I) as defined in claim 1 wherein R is halogen with an alkali or alkaline earth metal salt of arylmercaptan or of 1-methyl-5-mercaptotetrazole in an organic solvent and, if desired, converting the resultant compound of formula (I) wherein R is arylthio or 1-methyl­ tetrazole-5-yl-thio into a pharmacologically acceptable non-­ toxic salt thereof. 10. A process for the preparation of a compound of formula (I) as defined in claim 1 except R is not hydroxyl, halogen, lower alkanoyloxy, R₄-carbamoyloxy, arylthio or 1-methyltetrazole-5-yl-thio, or a pharmacologically acceptable non-toxic salt thereof, which process comprises reacting a compound of formula (I) as defined in claim 1 wherein R is halogen with an amine of the formula R′ -H wherein R′ is 1-imidazolyl, morpholino, wherein R₁, R₂, R₃, R₅, R₆, A, A₁, m and n are as defined in claim 1 and, if desired, converting the resultant compound of formula (I) into a pharmacologically acceptable non-toxic salt thereof. 11. A process for the preparation of a compound of formula (I) as defined in claim 1 wherein R is in which R₆ is aryl-lower alkanoyl, arylcarbonyl, arylsulfonyl or thienyl-lower alkanoyl, or a pharmacologically acceptable non-toxic salt thereof, which process comprises arylating a compound (1f′) of the formula wherein R₁, R₂, R₃ and A are as defined above, such as to convert the piperazinyl group thereof into a group of formula- - R₆ and, if desired, converting the resultant compound of formula (I) into a pharmacologically acceptable non-toxic salt thereof. 12. A pharmaceutical composition comprising as active ingredient a compound of formula (I) as defined in claim 1 or a pharmacologically acceptable non-toxic salt thereof, together with a pharmaceutically acceptable carrier or diluent.

Inventors: HAYASHI, EIICHI, SHIBATA, KENSUKE, SUZUKI, YUKIO, YASO, MASAO
Applicants: TOYO JOZO KABUSHIKI KAISHA
Application year: 1987
Main classification: C07D241
IPC codes: C07D521, A61K31, A61P7, C07D401, A61P3, A61P9, C07D241, C07D409, C07D243, C07D247, C07D403, C07D333