JPH06135946A - Pyrazine derivative - Google Patents

Abstract

PURPOSE:To obtain a new compound useful for preventing and treating autoimmune disease such as rheumatism, etc., arteriosclerosis, ischemic heart disease, cerebral disorder, nephritis, etc., having inhibitory action superoxide and anti- proteinuria action. CONSTITUTION:A compound of formula I (R<1> is lower alkoxy; B is N O, N; R<3> is lower alkyl ; A is lower alkylene; R<2> is N-containing 5to 13-membered ring monocyclic or heterocyclic residue, X-R', amino, etc.; X is O or S(O)m: (m) is 0-2; R<4> is lower alkyl, phenyl, etc.) such as 3-isobutyl-5-methoxy-6-(1,2,4- triazol-3-yl)thiomethyl-1,2-dihydropyrazin-2-on-4-oxide. The compound of formula I is obtained by reacting a compound of formula II (Y is halogen, lower alkanesulfonyloxy, etc.; R<7> is phenyl lower alkoxy) with a compound of the formula R<2a>H (R<2a> is phthalimide, etc.) and reducing the reaction product.

Description

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION The present invention relates to a novel pyrazine derivative.

[0002]

DISCLOSURE OF THE INVENTION The pyrazine derivative of the present invention is a novel compound not described in the literature and is represented by the following general formula (1).

[0003]

[Chemical 2] [In the formula, R ¹ represents a lower alkoxy group. B is a group N → O
Alternatively, it represents a nitrogen atom. R ³ represents a lower alkyl group. A
Represents a lower alkylene group. R ² is a 5- to 13-membered saturated or unsaturated monocyclic, dicyclic or tricyclic heterocyclic residue having 1 to 4 nitrogen atoms (wherein the heterocycle is substituted with an oxo group). may also be), group ^{-X-R 4,} an amino group or a group -NH
COR ⁶ is shown. Here, X is an oxygen atom or S (0) m
(M is 0, 1 or 2). R ⁴ is a phenyl group which may have a substituent selected from the group consisting of a hydroxyl group, a phenyl lower alkoxy group and a halogen atom on the phenyl ring, or a nitrogen atom, an oxygen atom or a sulfur atom. 5- to 10-membered unsaturated monocyclic or binomial heterocyclic residue having 1 to 3 groups (the heterocyclic ring may be substituted with a lower alkyl group or a phenyl group) ) Is shown. R ⁶ is a lower alkyl group, a phenyl group which may have a lower alkyl group which may have 1 to 3 halogen atoms on the phenyl ring, or a phenyl group which may have a lower alkoxy group as a substituent on the phenyl ring. A lower alkenyl group is shown. The pyrazine derivative represented by the general formula (1) and a salt thereof have, for example, an inhibitory effect on superoxide (O ₂ ⁻ ) released by stimulation from guinea pig macrophages, an antiproteinuria effect on Masugi nephritis, and the like. , As a preventive and therapeutic agent for diseases and cases involving the above superoxide radical, for example, autoimmune diseases such as rheumatism, arteriosclerosis, ischemic heart disease, ischemic brain injury, liver failure, renal failure, and nephritis It is useful as a preventive and therapeutic agent in various clinical fields.

More specifically, each group represented by the above general formula (1) is as follows.

Examples of the lower alkoxy group include linear or branched chain alkoxy groups having 1 to 6 carbon atoms such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, tert-butoxy, pentyloxy and hexyloxy groups. it can.

Examples of the lower alkyl group include methyl,
Ethyl, propyl, isopropyl, butyl, tert-
Examples thereof include linear or branched alkyl groups having 1 to 6 carbon atoms such as butyl, pentyl and hexyl groups.

Examples of the lower alkylene group include methylene, ethylene, trimethylene, 2-methyltrimethylene, 2,2-dimethyltrimethylene, 1-methyltrimethylene, methylmethylene, ethylmethylene, tetramethylene, pentamethylene and hexamethylene. Number of carbon atoms such as 1
Examples of the straight-chain or branched-chain alkylene group of ~ 6 can be mentioned.

Examples of the phenyl group which may have a substituent selected from the group consisting of a hydroxyl group, a phenyl lower alkoxy group and a halogen atom on the phenyl ring include, for example, phenyl, 2-methoxyphenyl, 3-methoxyphenyl, 4 -Methoxyphenyl, 2-ethoxyphenyl, 3
-Ethoxyphenyl, 4-ethoxyphenyl, 3-isopropoxyphenyl, 4-hexyloxyphenyl,
3,4-dimethoxyphenyl, 2,5-dimethoxyphenyl, 3,4,5-trimethoxyphenyl, 4-benzyloxyphenyl, 2- (2-phenylethoxy) phenyl, 3- (3-phenylpropoxy) phenyl, 4-
(4-phenylbutoxy) phenyl, 2- (5-phenylpentyloxy) phenyl, 3- (6-phenylhexyloxy) phenyl, 2-hydroxyphenyl, 3-
Hydroxyphenyl, 4-hydroxyphenyl, 2,3
-Dihydroxyphenyl, 3,4-dihydroxyphenyl, 3,5-dihydroxyphenyl, 3,4,5-trihydroxyphenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2
-Bromophenyl, 3-bromophenyl, 4-bromophenyl, 2-iodophenyl, 3-iodophenyl, 4
-Iodophenyl, 3,4-dichlorophenyl, 3,5
-Dichlorophenyl, 2,6-dichlorophenyl, 2,
3-dichlorophenyl, 2,4-dichlorophenyl,
3,4-difluorophenyl, 3,5-dibromophenyl, 3,4,5-trichlorophenyl, 2-methoxy-
As a substituent on the phenyl ring such as 3-chlorophenyl and 3,5-di-tert-butoxy-4-hydroxyphenyl group, a hydroxyl group, a linear or branched alkoxy group having 1 to 6 carbon atoms in the alkoxy moiety. And a phenyl group that may have 1 to 3 groups selected from the group consisting of halogen atoms.

Examples of the phenyl group which may have a lower alkyl group which may have 1 to 3 halogen atoms on the phenyl ring include, for example, phenyl, 2-methylphenyl, 3-methylphenyl, 4-methylphenyl and 2 -Ethylphenyl, 3-ethylphenyl, 4-ethylphenyl, 3-isopropylphenyl, 4-hexylphenyl, 3,4-dimethylphenyl, 3,4,5-trimethylphenyl, 4-trifluoromethylphenyl, 3-chloro Methylphenyl, 2-dibromomethylphenyl, 4
-(2,2,2-trifluoroethyl) phenyl, 3-
One halogen atom is present on the phenyl ring such as (3-chloropropyl) phenyl, 2- (4-fluorobutyl) phenyl, 4- (5-chloropentyl) phenyl, 4- (5,6-dichlorohexyl) phenyl group. 1 to 3 linear or branched alkyl groups having 1 to 6 carbon atoms which may have 3 to 3 carbon atoms
The phenyl group which may have one can be illustrated.

Examples of the phenyl lower alkenyl group which may have a lower alkoxy group as a substituent on the phenyl ring include styryl, 3-phenyl-2-propenyl, 3-phenyl-1-propenyl and 4-phenyl-3.
-Butenyl, 4-phenyl-2-butenyl, 4-phenyl-1-butenyl, 5-phenyl-4-pentenyl, 5
-Phenyl-3-pentenyl, 5-phenyl-2-pentenyl, 5-phenyl-1-pentenyl, 1-methyl-
3-phenyl-2-butenyl, 1-methylstyryl, 2
-, 3- or 4-methoxystyryl, 3- (4-ethoxyphenyl) -2-propenyl, 3- (3-propoxyphenyl) -1-propenyl, 4- (4-butoxyphenyl) -3-butenyl, 5 -(2-pentyloxyphenyl) -4-pentenyl, 2-methyl- (3-hexyloxy) styryl, 3,4-dimethoxystyryl,
2 carbon atoms having a phenyl group which may have 1 to 3 linear or branched alkoxy groups having 1 to 6 carbon atoms as a substituent on the phenyl ring such as 3,4,5-trimethoxystyryl group Examples of the straight-chain or branched-chain alkenyl group of ~ 6 can be mentioned.

Examples of the saturated or unsaturated monocyclic, dicyclic or tricyclic heterocyclic residue having 5 to 13 membered ring having 1 to 4 nitrogen atoms include, for example, pyrrolidinyl, piperidinyl, piberazinyl, pyridyl and quinolyl. , 1,4-dihydroquinolyl, pyrazinyl, pyrimidyl, pyridazinyl, pyrrolyl, carbostyril, 3,4-dihydrocarbostyril, 1,2,3,4-tetrahydroquinolyl, indolyl, isoindolyl, indolinyl, benzimidazolyl, imidazolidinyl, Isoquinolyl, quinazolidinyl, quinoxalinyl, cinnolinyl, phthalazinyl, isoindolinyl, pyrazolyl, imidazolyl, pyrazolidinyl, 1H-indazolyl, isoindolinyl, 2-
Imidazolinyl, 2-pyrrolinyl, pyranyl, pyrazolidinyl, 2-pyrazolinyl, quinuclidinyl, 1,2,
3,4-tetrahydroquinoxalinyl, 1,2,4-triazolyl, 1,3,4-triazolyl, 7-azaindolyl, carbazolyl, 1,2,3,4-tetrazolyl, 1,2,3,5- A tetrazolyl group etc. can be illustrated.

The above heterocycle substituted with an oxo group includes
For example, phthalimide, 4-oxopiperidinyl, 2-oxoindolyl, 4-oxo-1,4-dihydroquinolyl, 1-oxopyridyl, 2-oxopyridyl, 2-oxobenzimidazolyl, 4-oxopyridyl group, etc. The heterocycle substituted with an oxo group can be exemplified.

Examples of the unsaturated monocyclic or binomial heterocyclic residue of 5 to 10 membered ring having 1 to 3 groups selected from the group consisting of nitrogen atom, oxygen atom or sulfur atom include, for example, 1 ，
2,3-benzotriazolyl, 1,3,4-thiadiazolyl, 1,2,4-triazolyl, 1,3,4-triazolyl, 1,3,4-oxadiazolyl, pyridyl, thienyl, quinolyl, 1,4 -Dihydroquinolyl, benzothiazolyl, pyrazinyl, pyrimidyl, pyridazinyl,
Pyrolyl, carbostyril, 3,4-dihydrocarbostyril, 1,2,3,4-tetrahydroquinolyl, indolyl, isoindolyl, indolinyl, benzimidazolyl, benzoxazolyl, imidazolidinyl, isoquinolyl, quinazolidinyl, quinoxalinyl, cinnolinyl, phthalazinyl, Chromanil, isoindolinyl,
Isochromanyl, pyrazolyl, imidazolyl, pyrazolidinyl, benzofuryl, benzothienyl, 4H-chromenyl, 1H-indazolyl, thienyl, isoindolinyl, 2-imidazolinyl, 2-pyrrolinyl, furyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyranyl, pyrazolidinyl, 2-pyrazolidinyl, 2-pyrazolidinyl. , 1,4-benzoxazinyl, 3,4-dihydro-
2H-1,4-benzoxazinyl, 3,4-dihydro-2H-1,4-benzothiazinyl, 1,4-benzothiazinyl, 1,2,3,4-tetrahydroquinoxalinyl, 1,3 -Dithia-2,4-dihydronaphthalenyl,
A 1,4-dithianaphthalenyl group etc. can be illustrated.

Examples of the heterocyclic residue substituted with a lower alkyl group or a phenyl group include 4-phenyl-1,4
-Dihydroquinolyl, 2-phenylpyridyl, 6-methylbenzothiazolyl, 3-phenyl-3,4-dihydro-2H-1,4-benzothiazinyl, 1-methyl-4,
5-diphenylimidazolyl, 2-methylbenzothiazolyl, 3-phenyl-3,4-dihydro-2H-1,4
-Benzoxazinyl, 2-phenylbenzimidazolyl, 2-phenylbenzothiazolyl, 2-phenylbenzoxazolyl, 3,4-dimethylquinolyl, 4-phenylpyridyl, 2-ethylbenzoxazolyl, 2- Propylbenzimidazolyl, 2-butylbenzothiazolyl, 6-pentylcarbostyryl, 7-hexylcarbostyryl, 4-methylpyrazolyl, 2-methylpyridyl, 4-methylpyridyl, 2-ethylpyrrolyl, 5-methylindolyl, 5- Ethyl-1H-indanyl, 6-
Methylbenzimidazolyl, 6,7,8-trimethylquinolyl, 3-methylfuryl, 2-methylthienyl, 2-
Phenylindolyl, 4,5-diphenylimidazolyl, 5-methyl-1,3,4-oxadiazolyl, 5-
1 to 3 carbon atoms such as methyl-1,3,4-thiadiazolyl group
6 is a linear or branched alkyl group or phenyl group of 1 to
The said heterocyclic group substituted by 3 can be illustrated.

Examples of the phenyl lower alkoxy group include benzyloxy, 2-phenylethoxy, 1-phenylethoxy, 3-phenylpropoxy, 4-phenylbutoxy, 1,1-dimethyl-2-phenylethoxy and 5
Examples thereof include a phenylalkoxy group in which the alkoxy moiety such as -phenylpentyloxy, 6-phenylhexyloxy, 2-methyl-3-phenylpropoxy group is a linear or branched alkoxy group having 1 to 6 carbon atoms.

The halogen atom is, for example, a fluorine atom,
Examples thereof include chlorine atom, bromine atom and iodine atom.

The compound of the present invention represented by the above-mentioned general formula (1) can be produced by various methods, and a preferable example thereof is the method shown below.

[0018]

[Chemical 3] [In the Formula, R < ¹ >, R < ³ >, A and B are the same as the above. R ^2a represents the R ² other than the group —NHCOR ⁶ (R ⁶ is the same as the above). Y represents a halogen atom, a lower alkanesulfonyloxy group, an arylsulfonyloxy group or an aralkylsulfonyloxy group. R ⁷ represents a phenyl lower alkoxy group which may have a lower alkoxy group on the phenyl ring. ] Compound (2) or (2a) and compound (3)
The reaction with is generally carried out in a suitable inert solvent in the presence or absence of a basic compound. Examples of the inert solvent used include aromatic hydrocarbons such as benzene, toluene and xylene, ethers such as tetrahydrofuran, dioxane and diethylene glycol dimethyl ether, halogenated hydrocarbons such as dichloromethane, chloroform and carbon tetrachloride, methanol and ethanol. , Lower alcohols such as isopropanol, butanol, tert-butanol, acetic acid, ethyl acetate, acetone, acetonitrile, pyridine, dimethylsulfoxide, dimethylformamide, hexamethylphosphoric triamide, and mixed solvents thereof. Examples of the basic compound include carbonates such as sodium carbonate, potassium carbonate, sodium hydrogen carbonate and potassium hydrogen carbonate, metal hydroxides such as sodium hydroxide and potassium hydroxide, sodium hydride, potassium, sodium, sodium amide, Metal alcoholates such as sodium methylate and sodium ethylate, pyridine, N-ethyldiisopropylamine, dimethylaminopyridine, triethylamine, 1,5-diazabicyclo [4.3.0] nonene-5.
(DBN), 1,8-diazabicyclo [5.4.0] undecene-7 (DBU), 1,4-diazabicyclo [2.2.2. Examples thereof include organic bases such as octane (DABCO). The use ratio of the compound (2) or (2a) and the compound (3) is not particularly limited and may be appropriately selected within a wide range, but the latter is at least about equimolar amount, preferably equimolar to the former. It is preferable to use about 2-fold molar amount. The reaction is generally carried out at about 200 ° C to about 0 ° C to 170 ° C, and the reaction is generally completed in about 30 minutes to 30 hours. An alkali metal halogen compound such as sodium iodide or potassium iodide may be added to the reaction system.

R ^2a is a phthalimido group or a group --X--R ⁴
(Wherein R ⁴ is the same as above, X represents S (0) m, and m is 0.) In the case of the compound (3), an alkali metal salt of the compound (3) , That is, the formula

[0020]

[Chemical 4] Or a compound represented by the general formula R ⁴ XM (M represents an alkali metal atom such as potassium or sodium. R ⁴ and X are the same as above) and the compound (2)
Alternatively, by reacting the compound (2a) with the compound (2) under the same conditions as in the reaction of the compound (3), the corresponding R ^2a is a phthalimide group or a group —X—R ⁴
(R ⁴ and X are the same as the above), and the compound (4) or the compound (1a) can be obtained.

When R ^2a is a compound (3) showing an indolyl group or a 7-azaindolyl group, the compound (3) and the compound (2) or the compound (2a) are reacted under the reaction conditions shown below. By reacting, the corresponding R
^2a is 3-indolyl group or 7-azaindole-3-
It can be led to compound (4) or compound (1a) which is an yl group. That is, the compound (2) or the compound (2a) and the compound (3) or a salt thereof, preferably a salt thereof,
Compound (4) or compound (1a) by reacting
Is obtained. Examples of the salt of the compound (3) include alkali metal salts of lithium, sodium, potassium and the like, MgX ¹ (X
¹ represents a halogen atom), SnR ⁸ (R ⁸ represents a lower alkyl group), ZnX ¹ (X ¹ is the same as the above), and the like. Preferred salts include alkali metal salts such as lithium, sodium and potassium, ZnX ^{1 and the} like.
This reaction is usually performed in a suitable solvent. As the solvent used here, aromatic hydrocarbons such as benzene, toluene and xylene, ethers such as diethyl ether, tetrahydrofuran, dioxane and diethylene glycol dimethyl ether, halogenated hydrocarbons such as chloroform, dichloromethane and carbon tetrachloride. Etc. can be mentioned. The reaction is completed usually at -30 to 150 ° C, preferably at 0 to 100 ° C in about 10 minutes to 50 hours. The amount of the compound (3) used is at least equimolar, preferably equimolar to 5 times the molar amount of the compound (2) or the compound (2a).

The reaction for converting the compound (4) into the compound (1a) is carried out, for example, by reducing the compound (4) (method A). This reduction reaction can be carried out, for example, by catalytic hydrogenation in the presence of a catalyst in a suitable solvent. As the solvent used, for example, water, acetic acid, alcohols such as methanol, ethanol and isopropanol, hydrocarbons such as hexane and cyclohexane, ethers such as dioxane, tetrahydrofuran, diethyl ether, ethylene glycol dimethyl ether, ethyl acetate, acetic acid. Examples thereof include esters such as methyl, aprotic polar solvents such as dimethylformamide, and mixed solvents thereof. Examples of the catalyst used include palladium, palladium-black, palladium-carbon, platinum, platinum oxide, copper chromite, Raney nickel and the like. The amount of the catalyst used is generally 0.
The amount is preferably about 02 to 1 times. The reaction temperature is usually −
It is preferable that the temperature is about 20 to 100 ° C., preferably about 0 to 80 ° C., the hydrogen pressure is usually 1 to 10 atm, and the reaction is generally completed in about 0.5 to 20 hours.

The reaction for converting the compound (4) to the compound (1a) is carried out in the presence of the above-mentioned reduction reaction solvent and catalyst with an ammonium salt such as ammonium formate at room temperature to 150 ° C., preferably room temperature to 100 ° C. It can also be carried out by reacting for 1 to 10 hours (method B). The amount of the catalyst used may be the same as that of the above reduction reaction. The ammonium salt is used in an amount of at least equimolar, preferably equimolar to 10 times the molar amount of the compound (4).

The reaction for converting the compound (4) to the compound (1a) can also be carried out using an oxidizing agent (C
Law). Examples of the oxidizing agent used include benzoquinones such as 2,3-dichloro-5,6-dicyanobenzoquinone and chloranil (2,3,5,6-tetrachlorobenzoquinone), N-bromosuccinimide, N-chlorosuccinic acid. N-halogenated succinimides such as imide,
Examples thereof include triphenylmethylboron tetrafluorate and ceric ammonium nitrate. The amount of the oxidizing agent used is not particularly limited and may be appropriately selected from a wide range, but is usually 1 to 1 with respect to the compound (4).
It is preferable to use about 5-fold molar amount, preferably about 1- to 2-fold molar amount. As the solvent, for example, dioxane, tetrahydrofuran, methoxyethanol, ethers such as dimethoxyethane, benzene, toluene, xylene, aromatic hydrocarbons such as cumene, dichloromethane, dichloroethane, chloroform, halogenated hydrocarbons such as carbon tetrachloride, Examples thereof include alcohols such as butanol, amyl alcohol and hexanol, polar protic solvents such as water and acetic acid, polar aprotic solvents such as acetonitrile, dimethylformamide, dimethyl sulfoxide and hexamethylphosphoric triamide, and mixed solvents thereof. The reaction is usually completed at about room temperature to about 150 ° C., preferably about room temperature to about 100 ° C., in about 1 to 20 hours.

Further, the reaction for converting the compound (4) into the compound (1a) can be carried out in the presence of an acid in a suitable solvent. Examples of the acid used here include mineral acids such as sulfuric acid and organic acids such as methanesulfonic acid and trifluoroacetic acid. The amount of such an acid used is usually a large excess amount, preferably 10 to 20 times the molar amount of the compound (4). Examples of the solvent include ethers such as dioxane, tetrahydrofuran, methoxyethanol and dimethoxyethane, aromatic hydrocarbons such as benzene, toluene and xylene, halogenated hydrocarbons such as dichloromethane, dichloroethane, chloroform and carbon tetrachloride. It can be illustrated. The reaction is usually 0 to 100 ° C., preferably 0 to 7
It finishes in about 1 minute to 5 hours at around 0 ° C.

In the reaction for converting the compound (4) to the compound (1a), when B is a group N → O in the compound (4) when the compound (4) is reacted by the above method A or D, the group is simultaneously reduced. In some cases, the compound (1a) may be a compound in which B is a nitrogen atom.

In the reaction for converting the compound (4) in which R ^2a represents the group —X—R ⁴ (X represents S (0) m) to the compound (1a), the above-mentioned Method C and Method D are applied. Is particularly preferable.

In the reaction formula-1, the lower alkanesulfonyloxy group is specifically, methanesulfonyloxy, ethanesulfonyloxy, isopropanesulfonyloxy, propanesulfonyloxy, butanesulfonyloxy, tert-butanesulfonyloxy, pentanesulfone. Examples thereof include a dioxy group and a hexanesulfonyloxy group. Specific examples of the arylsulfonyloxy group include phenylsulfonyloxy, 4-methylphenylsulfonyloxy, 2-methylphenylsulfonyloxy, 4-nitrophenylsulfonyloxy and 4 Examples include substituted or unsubstituted arylsulfonyloxy groups such as -methoxyphenylsulfonyloxy, 3-chlorophenylsulfonyloxy, and α-naphthylphenylsulfonyloxy groups. Specific examples of the aralkylsulfonyloxy group include benzylsulfonyloxy, 2-phenylethylsulfonyloxy, 4-phenylbutylsulfonyloxy, 4-methylbenzylsulfonyloxy, 2-methylbenzylsulfonyloxy, 4-nitrobenzylsulfonyloxy. , 4-methoxybenzylsulfonyloxy, 3-chlorobenzylsulfonyloxy,
Examples thereof include a substituted or unsubstituted aralkylsulfonyloxy group such as an α-naphthylmethylsulfonyloxy group.

As the phenyl lower alkoxy group which may have a lower alkoxy group on the phenyl ring, benzyloxy, 2-phenylethoxy, 1-phenylethoxy, 3-phenylpropoxy, 4-phenylbutoxy,
1,1-dimethyl-2-phenylethoxy, 5-phenylpentyloxy, 6-phenylhexyloxy, 2-
Methyl-3-phenylpropoxy, 4-methoxybenzyloxy, 3,4-dimethoxybenzyloxy, 3,
4,5-trimethoxybenzyloxy, 1- (3-methoxyphenyl) ethoxy, 2- (2-methoxyphenyl) ethoxy, 3- (2-ethoxyphenyl) propoxy, 4- (4-ethoxyphenyl) butoxy, 5 -(3
-Ethoxyphenyl) pentyloxy, 6- (4-isopropoxyphenyl) hexyloxy, 1,1-dimethyl-2- (4-hexyloxyphenyl) ethoxy, 2
-Methyl-3- (3,4-dimethoxyphenyl) propoxy, 2- (3,4-dimethoxyphenyl) ethoxy,
2- (3,4-diethoxyphenyl) ethoxy, 2-
(3,4,5-trimethoxyphenyl) ethoxy, 1-
Carbon of an alkoxy moiety which may have 1 to 3 linear or branched alkoxy groups having 1 to 6 carbon atoms on the phenyl ring such as (2,5-dimethoxyphenyl) ethoxy, trityloxy and diphenylmethoxy groups. A straight-chain or branched-chain alkoxy group having a number of 1 to 6, wherein the phenyl group is 1 to 3;
Examples of the phenylalkoxy group are individually substituted. Among them, especially benzyloxy, 1-phenylethoxy, 4-methoxybenzyloxy, 1- (3-methoxyphenyl)
1-position of the above-mentioned substituted or unsubstituted phenyl group at the 1-position of the alkyl moiety such as ethoxy, 1- (2,5-dimethoxyphenyl) ethoxy, trityloxy and diphenylmethoxy group.
A 3-substituted phenyl lower alkoxy group is preferred.

[0030]

[Chemical 5] IN FORMULA, R < ¹ >, R < ² >, R < ³ >, R < ⁷ > AND A ARE THE SAME AS THE ABOVE-MENTIONED. ]
The reaction for converting the compound (1b) or (1g) to the compound (1c) is the same as the reaction formula -1 for converting the compound (4) into the compound (1a).
Can be carried out under the same conditions as in Method A in the reaction leading to, but in the case of a palladium catalyst, acetic acid,
It is preferable to add an acid such as hydrochloric acid. Further, a trivalent phosphorus compound such as trimethyl phosphite, triethyl phosphite and tri-n-butyl phosphine can also be used.

[0031]

[Chemical 6] [In the formula, R ¹ , R ³ , A, B and R ⁶ are the same as defined above. The reaction of the compound (1d) with the compound (5) is carried out according to a usual amide bond forming reaction. The amide bond-forming reaction is carried out by various known methods, for example, (a) mixed acid anhydride method, for example, by reacting carboxylic acid (5) with a halocarboxylic acid alkyl ester to obtain a mixed acid anhydride, and then adding an amine (1
Method of reacting d); (b) active ester method, for example, carboxylic acid (5) with p-nitrophenyl ester, N-
A method in which an active ester such as hydroxysuccinimide ester, 1-hydroxybenzotriazole ester, etc. is reacted with an amine (1d); (c) a carbodiimide method; A method of condensing in the presence of an activator such as carbonyldiimidazole; (d) another method, for example, carboxylic acid (5) is converted to a carboxylic acid anhydride with a dehydrating agent such as acetic anhydride, and then amine (1d) is added thereto.
, A method of reacting an amine (1d) with an ester of carboxylic acid (5) and a lower alcohol at high pressure and high temperature, an acid halide of carboxylic acid (5), that is, a carboxylic acid halide with amine (1d). It can be carried out by a reaction method or the like. Further, a method of activating the carboxylic acid (5) with a phosphorus compound such as triphenylphosphine or diethylchlorophosphate and reacting it with an amine (1d), and further activating the carboxylic acid (5) with an acetylene compound such as trimethylsilylethoxyacetylene. Turned into
A method of reacting this with an amine (1d) can also be used.

In the mixed acid anhydride method shown in (a) above, the mixed acid anhydride used is obtained by the usual Schotten-Baumann reaction, and this is usually reacted with the amine (1d) without isolation. According to
To produce the compound. The Schotten-Baumann reaction is carried out in the presence of a basic compound. As the basic compound used, a compound commonly used in the Schotten-Baumann reaction is used, and examples thereof include triethylamine, trimethylamine, pyridine, dimethylaniline, N-methylmorpholine, 4-dimethylaminopyridine, DBN and DBU.
Examples include organic bases such as DABCO and inorganic bases such as potassium carbonate, sodium carbonate, potassium hydrogen carbonate, sodium hydrogen carbonate and the like. The reaction is carried out at about -20 to 100 ° C, preferably 0 to 50 ° C for about 5 minutes to 10 hours, preferably about 5 minutes to 2 hours. The reaction between the obtained mixed acid anhydride and the amine (1d) is about -20 to 150.
It takes about 5 minutes to 10 hours, preferably about 5 minutes to 5 hours at 0 ° C, preferably 10 to 50 ° C. The mixed acid anhydride is generally a solvent commonly used in this kind of mixed acid anhydride method, specifically, methylene chloride, chloroform, dichloroethane, and other halogenated hydrocarbons, benzene, toluene, xylene, and other aromatic hydrocarbons. , Diethyl ether, dioxane, diisopropyl ether,
Ethers such as tetrahydrofuran and dimethoxyethane, esters such as methyl acetate and ethyl acetate, 1,1,
It is carried out in a suitable solvent or a mixed solvent such as an aprotic polar solvent such as 3,3-tetramethylurea, N, N-dimethylformamide, dimethylsulfoxide and hexamethylphosphoric triamide, or in the absence thereof. Examples of the halocarboxylic acid alkyl ester used in the production of the above mixed acid anhydride include methyl chloroformate, methyl bromoformate, ethyl chloroformate, ethyl bromoformate, isobutyl chloroformate and the like. The halocarboxylic acid alkyl ester is generally used in at least an equimolar amount, preferably about 1 to 1.5 times the molar amount of the amine (1d).
The amount of carboxylic acid (5) used is usually amine (1d).
To at least an equimolar amount, preferably about 1-1.5
It is preferable that the amount is twice the molar amount.

In the active ester method shown in (b) above, for example, when N-hydroxysuccinimide ester is used, the reaction is not affected in the presence or absence of a basic compound in a suitable solvent. Done below. A condensation agent such as dicyclohexylcarbodiimide, carbonyldiimidazole, 1-ethyl-3- (3'-dimethylaminopropyl) carbodiimide, etc. may be added to the reaction system of the reaction. Here, as the basic compound, any of the basic compounds used in the Schotten-Baumann reaction can be used, and in addition to them, sodium acetate,
Sodium benzoate, sodium formate, potassium acetate,
It is also possible to use carboxylic acid alkali metal salts such as lithium benzoate and cesium acetate, and alkali metal halide salts such as potassium fluoride and cesium fluoride. As the solvent, specifically, methylene chloride, chloroform, halogenated hydrocarbons such as dichloroethane, benzene, toluene, aromatic hydrocarbons such as xylene, diethyl ether, dioxane, tetrahydrofuran, ethers such as dimethoxyethane, Examples thereof include esters such as methyl acetate and ethyl acetate, aprotic polar solvents such as N, N-dimethylformamide, dimethylsulfoxide, and hexamethylphosphoric triamide, and mixed solvents thereof. The reaction is performed at 0 to 150 ° C, preferably 10 to 100 ° C for 5
It ends in 30 hours. The ratio of the amine (1d) and the N-hydroxysuccinimide ester used is the same as that of the compound (5).
To at least equimolar, preferably equimolar to 2
It is desirable that the amount is twice the molar amount.

The amine (1d) and the carboxylic acid (5) are combined with triphenylphosphine, triphenylphosphine-2,2'-dipyridyl disulfide, diethyl chlorophosphate, diphenylphosphinyl chloride, phenyl N-phenylphosphoramide. Compound (1e) can also be obtained by reacting a phosphorus compound such as chloridate, diethyl cyanophosphate, and bis (2-oxo-3-oxazolidinyl) phosphinic chloride in the presence of a condensing agent. As the basic compound used here, known compounds can be widely used, and examples thereof include sodium hydroxide and potassium hydroxide in addition to the basic compound used in the Schotten-Baumann reaction. Examples of the solvent include, in addition to the solvent used in the mixed acid anhydride method, for example, pyridine, acetone, acetonitrile and the like, or a mixed solvent of two or more of the above solvents. The reaction is usually performed at about -20 to 150 ° C, preferably at about 0 to 100 ° C, and generally the reaction is completed in 5 minutes to 30 hours. The amount of the condensing agent and the carboxylic acid (5) used is at least about equimolar, preferably about equimolar to about 2 times the molar amount of the amine (1d).

The compound (1e) can also be obtained by reacting the amine (1d) with the carboxylic acid (5) in the presence of a condensing agent. The reaction is carried out in a suitable solvent in the presence or absence of a catalyst. Examples of the solvent used here include halogenated hydrocarbons such as dichloromethane, dichloroethane, chloroform and carbon tetrachloride, acetonitrile, dimethylformamide and the like. Examples of the catalyst used include organic bases such as dimethylaminopyridine and 4-piperidinopyridine, salts such as pyridinium tosylate, camphorsulfonic acid, and mercury oxide. Examples of the condensing agent include acetylene compounds such as trimethylsilylethoxyacetylene. The condensing agent is usually equimolar to the amine (1d).
It is preferable to use a 10-fold molar amount, preferably a 2- to 6-fold molar amount. The carboxylic acid (5) is usually used in an amount of at least about equimolar to the amine (1d), preferably about equimolar to 2 times the molar amount. The reaction is usually carried out at about 0 to 150 ° C., preferably at room temperature to about 100 ° C., and generally the reaction is completed in about 1 to 10 hours.

When the method of reacting the carboxylic acid halide with the amine (1d) shown in (d) above is adopted, the reaction is carried out in the presence of a dehydrohalogenating agent in a suitable solvent. As the dehydrohalogenating agent, a usual basic compound is used. As the basic compound, widely known compounds can be used, and examples thereof include sodium hydroxide, potassium hydroxide, sodium hydride and potassium hydride, in addition to the basic compound used in the Schotten-Baumann reaction. As the solvent, other than the solvent used in the mixed acid anhydride method, for example, alcohols such as methanol, ethanol, propanol, butanol, 3-methoxy-1-butanol, ethyl cellosolve, and methyl cellosolve, pyridine, acetone, atonitrile, etc. These mixed solvent etc. can be mentioned. The use ratio of the amine (1d) and the carboxylic acid halide is not particularly limited and is appropriately selected within a wide range, but the latter is usually used in at least an equimolar amount, preferably an equimolar to 5 times molar amount with respect to the former. Is good. The reaction is usually carried out at about -20 to 180 ° C, preferably about 0 to 150 ° C, and generally about 5
The reaction is completed in minutes to 30 hours.

In the above, the carboxylic acid halide is produced, for example, by reacting the carboxylic acid (5) with a halogenating agent in the absence of a solvent or in the presence of a solvent. As the solvent, any solvent that does not adversely affect the reaction can be used,
Examples thereof include aromatic hydrocarbons such as benzene, toluene and xylene, halogenated hydrocarbons such as chloroform, methylene chloride and carbon tetrachloride, ethers such as dioxane, tetrahydrofuran and diethyl ether, dimethylformamide and dimethylsulfoxide. . As the halogenating agent, an ordinary halogenating agent that changes a hydroxyl group of a carboxy group into a halogen can be used, and examples thereof include thionyl chloride, phosphorus oxychloride, phosphorus oxybromide, phosphorus pentachloride,
Examples include phosphorus pentabromide and the like. The proportion of the carboxylic acid (5) and the halogenating agent used is not particularly limited and may be appropriately selected. When carrying out the reaction, the latter is usually at least equimolar to the former,
Preferably, a 2- to 4-fold molar amount is used. The reaction temperature (and reaction time) is not particularly limited, but is usually room temperature to 100.
C., preferably 50 to 80.degree. C., for 30 minutes to 6 hours.

[0038]

[Chemical 7] [In the Formula, R < ¹ >, R < ³ >, A and B are the same as the above. The reaction for converting the compound (1f) to the compound (1d) can be carried out by reacting the compound (1f) with hydrazine in a suitable solvent or by hydrolysis. As the solvent used for the reaction with hydrazine, in addition to water, any of the same solvents as those used for the reaction between the compound (1d) of the reaction formula-3 and the compound (5) can be used. The reaction is usually carried out at room temperature to about 120 ° C, preferably about 0 to 100 ° C, and is generally completed in about 0.5 to 5 hours. The amount of hydrazine used is at least about equimolar, preferably about equimolar to 5 times the molar amount of the compound (1f).

The above hydrolysis can be carried out in a suitable solvent or without solvent in the presence of an acid or a basic compound. Examples of the solvent used include water, lower alcohols such as methanol, ethanol and isopropanol, ketones such as acetone and methyl ethyl ketone, ethers such as dioxane, tetrahydrofuran and ethylene glycol dimethyl ether, fatty acids such as acetic acid and formic acid, and mixtures thereof. A solvent etc. can be mentioned. Examples of the acid include mineral acids such as hydrochloric acid, sulfuric acid and hydrobromic acid, organic acids such as formic acid, acetic acid and aromatic sulfonic acid, and examples of the basic compound include sodium carbonate and potassium carbonate. Examples thereof include metal carbonates and metal hydroxides such as sodium hydroxide, potassium hydroxide and calcium hydroxide. The reaction normally proceeds suitably at room temperature to 200 ° C, preferably at room temperature to 150 ° C, and is generally completed in about 10 minutes to 25 hours.

[0040]

[Chemical 8] [In the formula, R ¹ , R ³ , R ⁷ , A, B, M and Y are the same as defined above. The reaction for converting the compound (4a) to the compound (6) is the same as the reaction of the compound (1f) in the above Reaction Formula-4 to the compound (1d).
Is carried out under the same conditions as the reaction leading to. Compound (6)
The reaction for converting compound (1f) into compound (1f) is carried out under the same conditions as the reaction for converting compound (4) into compound (1a) in the aforementioned Reaction formula-1. The reaction between the compound (2) and the compound (8) is carried out under the same conditions as the reaction between the compound (2) and the compound (3) in the reaction formula-1.

Various methods can be applied to the reaction for converting the compound (7) into the compound (6), for example, catalytic hydrogenation in a suitable solvent in the presence of a catalyst. As the solvent used, for example, water, acetic acid, methanol, ethanol, alcohols such as isopropanol, hexane, hydrocarbons such as cyclohexane, ethers such as diethylene glycol dimethyl ether, dioxane, tetrahydrofuran, diethyl ether, ethyl acetate, Examples thereof include esters such as methyl acetate, aprotic polar solvents such as dimethylformamide, and mixed solvents thereof. Examples of the catalyst used include palladium, palladium-black, palladium-carbon, platinum,
Platinum oxide, copper chromite, Raney nickel, etc. are used. The amount of the catalyst used is generally 0.02 to 1 times the amount of the raw material compound. The reaction temperature is usually -20 ° C to 100 ° C, preferably 0 ° C to 70 ° C, the hydrogen pressure is usually 1 to 10 atm, and the reaction is generally completed in about 0.5 to 20 hours.

Although the above reduction reaction conditions can be used, the reduction method using a hydrogenation reducing agent is preferably used.
Examples of the hydrogenation-reducing agent used include lithium aluminum hydride, sodium borohydride, and civolane, and the amount used is usually at least equimolar, preferably equimolar to 10 times the amount of the compound (7). It is in the molar range. This reduction reaction is usually performed using a suitable solvent such as water, methanol, ethanol, lower alcohols such as isopropanol, tetrahydrofuran, diethyl ether, ethers such as diglyme, dimethyl sulfoxide, dimethylformamide or a mixed solvent thereof, etc. It is carried out at about −60 to 50 ° C., preferably −30 ° C. to room temperature, for about 10 minutes to 5 hours. In addition,
When lithium aluminum hydride or diborane is used as the reducing agent, it is preferable to use an anhydrous solvent such as diethyl ether, tetrahydrofuran or diglyme.

[0043]

[Chemical 9] IN FORMULA, R < ¹ >, R < ³ >, R < ⁶ >, R <^7> , A AND B ARE THE SAME AS THE ABOVE-MENTIONED. The reaction between the compound (6) and the compound (5) is carried out under the same conditions as the reaction between the compound (1d) and the compound (5) in the above Reaction Formula-3. The reaction for converting the compound (4b) into the compound (1e) is carried out under the same conditions as the reaction for converting the compound (4) into the compound (1a) in the aforementioned Reaction scheme-1. When using a compound (5) in which R ⁶ represents a phenyl lower alkenyl group which may have a lower alkoxy group as a substituent on the phenyl ring, it can be carried out under various conditions. It is particularly preferable to use the method D and the method D.

The compound (4) used as an intermediate can also be produced by the method shown in the following reaction scheme-7.

[0045]

[Chemical 10] [In formula, R < ¹ >, R < ³ >, R < ⁴ >, R < ⁷ > and B are the same as the above. ]
The reaction for leading the compound (4c) to the compound (4d) and the reaction for leading the compound (4d) to the compound (4e) are carried out by oxidizing the starting compound. This oxidation reaction is carried out in the presence of an oxidizing agent in a suitable solvent. Examples of the solvent used here include water, formic acid, acetic acid, organic acids such as trifluoroacetic acid, alcohols such as methanol and ethanol, halogenated hydrocarbons such as chloroform and dichloromethane, and mixed solvents thereof. . Examples of the oxidizing agent used include formic acid, peracetic acid, pertrifluoroacetic acid, perbenzoic acid, m-chloroperbenzoic acid, o-
Peracids such as carboxyperbenzoic acid, hydrogen peroxide, sodium metaperiodate, dichromic acid, sodium dichromate,
Dichromate such as potassium dichromate, permanganate,
Examples thereof include permanganates such as potassium permanganate and sodium permanganate, and lead salts such as lead tetraacetate. The oxidizing agent is usually used in an amount of at least equimolar, preferably equimolar to 2 times the molar amount of the raw material compound. The above reaction is usually performed at -10 to 40 ° C, preferably -10 ° C to around room temperature, and is completed in about 1 to 10 hours.

The reaction for converting the compound (4c) to the compound (4e) can be carried out under the same conditions as the reaction for converting the compound (4c) to the compound (4d), but the amount of the oxidizing agent used is changed to the starting material. However, it is preferable that the molar ratio is 2 to 4 times.

The compound (1) in which R ⁴ is a phenyl group having at least one phenyl lower alkoxy group on the phenyl ring can be converted into the compound (1) in the reaction formula-1 under the reaction conditions. It can be reduced under the same conditions as in Method A to give a compound (1) in which the corresponding R ⁴ is a phenyl group having at least one hydroxyl group on the phenyl ring.

Of the compounds of the present invention represented by the general formula (1), the compound having a basic group can be easily converted into an acid addition salt by reacting with a pharmaceutically acceptable acid. Examples of the acid include inorganic acids such as hydrochloric acid, sulfuric acid, phosphoric acid, hydrobromic acid, oxalic acid, acetic acid, succinic acid, malonic acid, methanesulfonic acid, maleic acid, fumaric acid, malic acid, tartaric acid, and citric acid. , Organic acids such as benzoic acid.

Further, among the compounds of the present invention represented by the general formula (1), the compound having an acidic group can be easily converted into a salt by reacting with a pharmaceutically acceptable basic compound. Examples of the basic compound include sodium hydroxide, potassium hydroxide, calcium hydroxide, sodium carbonate, potassium hydrogen carbonate and the like.

The target compound of each step thus obtained can be easily isolated and purified by a conventional separation means. Examples of the separating means include a solvent extraction method,
Examples include dilution method, recrystallization method, column chromatography, preparative thin layer chromatography and the like.

The compounds of the present invention also include optical isomers and stereoisomers.

The compound of the general formula (1) is usually used in the form of a general pharmaceutical preparation. The preparation is prepared using diluents or excipients such as fillers, fillers, binders, moisturizers, disintegrants, surfactants and lubricants which are usually used. Various forms of this pharmaceutical preparation can be selected according to the therapeutic purpose, and typical examples thereof include tablets, pills, powders, solutions, suspensions, emulsions, granules, capsules, suppositories, and injections ( Liquid preparations, suspensions, etc.) and the like. In the case of molding in the form of tablets, those conventionally known in this field can be widely used as carriers, for example, lactose, sucrose, sodium chloride,
Excipients such as glucose, urea, starch, calcium carbonate, kaolin, crystalline cellulose, silicic acid, water, ethanol, propanol, simple syrup, glucose solution, starch solution, gelatin solution, carboxymethylcellulose, shellac, methylcellulose, potassium phosphate , Binders such as polyvinylpyrrolidone, dry starch, sodium alginate, agar powder, laminaran powder, sodium hydrogen carbonate, calcium carbonate, polyoxyethylene sorbitan fatty acid esters, sodium lauryl sulfate, stearic acid monoglyceride, starch, disintegrants such as lactose , White sugar,
Disintegration inhibitors such as stearin, cocoa butter, hydrogenated oils, quaternary ammonium bases, absorption enhancers such as sodium lauryl sulfate, humectants such as glycerin and starch, starch, lactose, kaolin, bentonite, colloidal silicic acid, etc. Examples thereof include adsorbents, purified talc, stearates, boric acid powder, and lubricants such as polyethylene glycol. Further, the tablet may be a tablet coated with a usual coating, if necessary, such as a sugar-coated tablet, a gelatin-coated tablet, an enteric-coated tablet, a film-coated tablet, a double tablet, or a multilayer tablet. In the case of molding in the form of pills, those conventionally known in this field can be widely used as carriers, for example, grapes, lactose, starch, cocoa butter, hydrogenated vegetable oils, excipients such as kaolin and talc, and gum arabic powder. , Tragacanth powder, a binder such as gelatin and ethanol, a disintegrating agent such as laminaranthantene, and the like. In the case of molding in the form of suppositories, conventionally known carriers can be widely used, and examples thereof include polyethylene glycol, cocoa butter, higher alcohols, esters of higher alcohols, gelatin, and semisynthetic glycerides. When prepared as an injection, the solution and suspension are preferably sterilized and isotonic with blood, and when formed into the form of these solutions, emulsions and suspensions, they are used as diluents. Any of those commonly used in the field can be used, and examples thereof include water, ethyl alcohol, propylene glycol, ethoxylated isostearyl alcohol, polyoxylated isostearyl alcohol, and polyoxyethylene sorbitan fatty acid esters. In this case, a sufficient amount of salt, glucose or glycerin to prepare an isotonic solution may be contained in the pharmaceutical preparation, and a usual solubilizing agent, buffer, soothing agent, etc. may be added. May be. Further, if necessary, a coloring agent, a preservative, a flavoring agent, a flavoring agent, a sweetening agent, and other pharmaceuticals may be contained in the pharmaceutical preparation.

The amount of the compound of the general formula (1) contained in the above-mentioned pharmaceutical preparation is not particularly limited and may be appropriately selected within a wide range.
It is 0% by weight.

The administration method of the above-mentioned pharmaceutical preparation is not particularly limited, and it is determined according to various preparation forms, patient's age, sex and other conditions, degree of disease and the like. For example, tablets, pills, solutions, suspensions, emulsions, granules and capsules are orally administered. In the case of an injection, it may be administered alone or mixed with a normal replenisher such as glucose or amino acid, and then intravenously administered. Further, if necessary, it may be administered intramuscularly, intracutaneously, subcutaneously or intraperitoneally. In the case of suppositories, it will be administered rectally.

The dose of the above-mentioned pharmaceutical preparation is appropriately selected according to the usage, the age of the patient, the sex and other conditions, the degree of disease, etc. About 0.5 to 30 mg per Kg is recommended. In addition, the active ingredient in the dosage unit form is about 10 to 1
It is recommended to contain 000 mg.

[0056]

[Examples] Reference examples, examples, formulation examples and pharmacological test results are listed below. Reference Example 1 6-Bromomethyl-3-isobutyl-5-methoxy-2
1.65 g of 4- (4-methoxybenzyloxy) pyrazine 4-oxide and 0.65 g of 4-chlorothiophenol
0.64 ml of DBU to 50 ml of isopropanol
And stir at room temperature for 3 hours. After evaporating the solvent, the obtained residue was subjected to silica gel column chromatography (eluent:
Purify with n-hexane: acetic acid = 2: 1 to give 6- (4
-Chlorophenylthio) methyl-3-isobutyl-5-
1.32 g of methoxy-2- (4-methoxybenzyloxy) pyrazine 4-oxide was obtained. Colorless viscous oil ¹ H-NMR (250 MHz, CDCl ₃ ) δ ppm;
0.90 (6H, d, J = 7Hz), 2.10-2.3
8 (1H, m), 2.76 (2H, d, J = 7Hz),
3.82 (3H, s), 4.01 (3H, s), 4.1
3 (2H, s), 5.12 (2H, s), 6.89 (2
H, d, J = 7 Hz), 7.21-7.45 (6H,
m). Reference Example 2 To a solution of 2-benzyloxy-6-iodomethyl-3-isobutyl-5-methoxypyrazine 4-oxide (6.42 g) in dry dimethylformamide (150 ml) was added potassium phthalimide (2.96 g), and the mixture was stirred at room temperature for 2 hours.
The reaction solution is transferred to ice water and extracted with ethyl acetate. The ethyl acetate extract is washed with saturated saline solution three times and then dried over magnesium sulfate. After evaporating the solvent, the obtained residue was purified by silica gel column chromatography (eluent: dichloromethane: methanol = 40: 1) to give 6-phthalimidomethyl-3-isobutyl-5-methoxy-2-benzyloxy. 1.11 g of pyrazine 4-oxide was obtained. White powder ¹ H-NMR (250 MHz, CDCl ₃ ) δ ppm;
0.91 (6H, d, J = 7Hz), 2.10-2.2
8 (1H, m), 2.77 (2H, d, J = 7Hz),
4.16 (3H, s), 4.95 (2H, s), 5.0
4 (2H, s), 7.05-7.20 (5H, m),
7.72-7.82 (2H, m), 7.82-7.93
(2H, m). Reference Example 3 7-azaindole 0.85 g and 2-benzyloxy-6-iodomethyl-3-isobutyl-5-methoxypyrazine 4-oxide 1.50 g anhydrous toluene 30 ml
0.73 g of potassium t-butoxide was added to the solution under ice cooling, and the mixture was stirred at room temperature for 1 hour. Water is added to the reaction solution and the mixture is extracted with ethyl acetate. After drying over magnesium sulfate, the solvent is distilled off. The obtained residue was purified by silica gel column chromatography (eluent: 70% ethyl acetate-n-hexane) and recrystallized from ethanol to give 1.03 g of 6-.
(7-azaindol-3-yl) methyl-2-benzyloxy-3-isobutyl-5-methoxypyrazine 4-
Oxide was obtained. mp: 147.5-149 ° C, white powder. Reference Example 4 6- (4-chlorophenylthio) methyl-3-isobutyl-5-methoxy-2- (4-methoxybenzyloxy) pyrazine 4-oxide 0.85 g was added to a solution of dry dichloromethane in 30 ml of m-chloro under ice cooling. Perbenzoic acid 0.
Add 31 g and stir at the same temperature for 2 hours. The reaction solution is washed with a sodium thiosulfate aqueous solution and a saturated sodium hydrogen carbonate aqueous solution in this order, and then dried over magnesium sulfate.
The solvent was distilled off, and the resulting residue was subjected to silica gel column chromatography (eluent; n-hexane; ethyl acetate =
2: 1) and 0.52 g of 6- (4-chlorophenylsulfinyl) methyl-3-isobutyl-5-
Methoxy-2- (4-methoxybenzyloxy) pyrazine 4-oxide was obtained. White powder ¹ H-NMR (250 MHz, CDCl ₃ ) δ ppm;
0.90 (6H, d, J = 7Hz), 2.11-2.2
9 (1H, m), 2.76 (2H, d, J = 7Hz),
3.82 (3H, s), 4.01 (3H, s), 4.1
3 (2H, s), 5.12 (2H, s), 6.89 (2
H, d, J = 7 Hz), 7.21 to 7.53 (6H,
m). Reference Example 5 6- (Benzothiazol-2-ylthio) methyl-3-
Isobutyl-5-methoxy-2- (4-methoxybenzyloxy) pyrazyl 4-oxide 1.52 g acetic acid 60
0.48 g of potassium permanganate is added to the ml solution, and the mixture is stirred at room temperature for 5 hours. The reaction solution is diluted with water and extracted with ethyl acetate. The ethyl acetate extract is washed 3 times with saturated brine, washed with saturated aqueous sodium hydrogen carbonate solution, and dried over magnesium sulfate. The solvent was evaporated and the obtained residue was purified by silica gel column chromatography (eluent; n-hexane: acetic acid = 2: 1) to give 1.14 g of 6- (benzothiazol-2-ylsulfonyl) methyl. -3-Isobutyl-5-methoxy-2- (4-methoxybenzyloxy) pyrazine 4-oxide was obtained. White powder ¹ H-NMR (250 MHz, CDCl ₃ ) δ ppm;
0.87 (6H, d, J = 7Hz), 2.06-2.2
5 (1H, m), 2.72 (2H, d, J = 7Hz),
3.80 (3H, s), 4.18 (3H, s), 4.3
5 (2H, s), 4.93 (2H, s), 6.80 (2
H, d, J = 9 Hz), 6.94 (2H, d, J = 9H)
z), 7.55-7.71 (2H, m), 7.95-
8.05 (1H, m), 8.24-8.33 (1H,
m). Reference Example 6 6-Iodomethyl-3-isobutyl-5-methoxy-2
-Sodium azide 1 in a solution of 43 mg of benzyloxypyrazine 4-oxide in 1 ml of dry dimethylformamide
Add 0 mg and stir at room temperature for 2.5 hours. After diluting with ethyl acetate, wash with saturated saline three times. After drying over magnesium sulfate, the solvent was evaporated under reduced pressure to give 34 mg of 6-azidomethyl-2-benzyloxy-3-isobutyl-5-.
Methoxypyrazine 4-oxide was obtained. Pale yellow powdery ¹ H-NMR (250 MHz, CDCl ₃ ) δ ppm;
0.95 (6H, d, J = 7Hz), 2.14-2.3
5 (1H, m), 2.84 (2H, d, J = 7Hz),
4.06 (3H, s), 4.34 (2H, s), 5.4
0 (2H, s), 7.31-7.49 (5H, m).

Using the appropriate starting materials, the following compounds were obtained in the same manner as in the above Reference Example. 6-azidomethyl-2-
(4-Methoxybenzyloxy) -3-isobutyl-5
-Methoxypyrazine 4-oxide was obtained. White powder ¹ H-NMR (250 MHz, CDCl ₃ ) δ ppm;
0.93 (6H, d, J = 7Hz), 2.11-2.3
2 (1H, m), 2.81 (2H, d, J = 7Hz),
3.82 (3H, s), 4.05 (3H, s), 4.3
5 (2H, s), 5.33 (2H, s), 6.91 (2
H, d, J = 9Hz), 7.37 (2H, d, J = 9H)
z). Reference example 7 To a solution of 6-aminomethyl-2-benzyloxy-3-isobutyl-5-methoxypyrazine 4-oxide (0.76 g) in dry pyridine (20 ml) was added acetic anhydride (0.24 ml), and the mixture was allowed to stand at room temperature for 1 hour. After distilling off the solvent under reduced pressure, the obtained residue was dissolved in dichloromethane, and a cupric sulfate aqueous solution was added.
The extract is washed with saturated brine and dried over magnesium sulfate. After the solvent was distilled off, the crude crystals were washed with diethyl ether to give a 0.2.
76 g of 6-acetamidomethyl-2-benzyloxy-3-isobutyl-5-methoxypyrazine 4-oxide were obtained. White powder ¹ H-NMR (250 MHz, CDCl ₃ ) δ ppm;
0.96 (6H, d, J = 7Hz), 2.03 (3H,
s), 2.17-2.31 (1H, m), 2.83 (2)
H, d, J = 7 Hz), 4.05 (3H, s), 4.4
8 (2H, d, J = 5Hz), 5.38 (2H, s),
6.16 (1H, brs), 7.30-7.44 (5
H, m).

The compounds shown in Tables 1 to 5 were obtained in the same manner as in Reference Example 1 above using appropriate starting materials.

[0059]

[Table 1]

[0060]

[Table 2]

[0061]

[Table 3]

[0062]

[Table 4]

[0063]

[Table 5] NMR1) ¹ H-NMR (250 MHz, CDCl ₃ ) δppm;
0.95 (6H, d, J = 7Hz), 2.24 (1H,
sept, J = 7 Hz), 2.84 (2H, d, J = 7)
Hz), 5.14 (2H, s), 5.40 (2H, s)
s), 6.49 (1H, t, J = 3Hz), 6.95
(1H, dd, J = 9Hz, 3Hz), 7.1-7.5
(8H, m), 8.15 (1H, brs). NMR2) ¹ H-NMR (250 MHz, CDCl ₃ ) δppm;
0.90 (6H, d, J = 7Hz), 2.09-2.2
9 (1H, m), 2.79 (2H, d, J = 7Hz),
3.96 (3H, s), 5.08 (2H, s), 5.5
7 (2H, s), 7.19-7.26 (1H, m),
7.30-7.48 (7H, m), 7.95-8.05
(1H, m). NMR3) ¹ H-NMR (250 MHz, CDCl ₃ ) δppm;
0.94 (6H, d, J = 7Hz), 2.24 (1H,
sept, J = 7 Hz), 2.84 (2H, d, J = 7)
Hz), 4.04 (3H, s), 5.02 (2H,
s), 5.04 (2H, s), 5.38 (2H, s),
6.9-7.0 (4H, m), 7.3-7.4 (10
H, m). NMR4) ¹ H-NMR (250 MHz, CDCl ₃ ) δppm;
0.94 (6H, d, J = 7Hz), 1.35-1.5
0 (2H, m), 1.50-1.62 (4H, m),
2.17-2.36 (1H, m), 2.40-2.58
(4H, m), 2.83 (2H, d, J = 7Hz),
3.56 (2H, s), 4.04 (3H, s), 5.3
9 (2H, s), 7.30-7.50 (5H, m). NMR5) ¹ H-NMR (250 MHz, CDCl ₃ ) δppm;
0.93 (6H, d, J = 7Hz), 2.21 (1H,
sept, J = 7 Hz), 2.81 (2H, d, J = 7)
Hz), 3.98 (3H, s), 5.12 (2H,
s), 5.32 (2H, s), 6.96 (1H, d, J
= 1 Hz), 7.06 (1H, d, J = 1 Hz), 7.
3-7.4 (5H, m), 7.61 (1H, s). NMR6) ¹ H-NMR (250 MHz, CDCl ₃ ) δppm;
0.91 (6H, d, J = 7Hz), 2.10-2.3
1 (1H, m), 2.77 (2H, d, J = 7Hz),
3.78 (3H, s), 4.11 (3H, s), 4.7
0 (2H, s), 5.20 (2H, s), 6.79-
6.89 (2H, m), 7.27-7.50 (3H,
m), 7.43 (1H, t, J = 7Hz), 7.77
(1H, d, J = 7Hz), 7.89 (1H, d, J =
7 Hz). NMR7) ¹ H-NMR (250 MHz, CDCl ₃ ) δppm;
0.95 (6H, d, J = 7Hz), 1.78 (2H,
s), 2.14-2.35 (1H, m), 2.83 (2)
H, d, J = 7 Hz), 3.90 (2H, s), 4.0
3 (3H, s), 4.40 (2H, s), 7.29-
7.48 (5H, m). NMR8) ¹ H-NMR (250 MHz, DMSO-d ₆ ) δpp
m; 0.80 (6H, d, J = 7Hz), 1.95-
2.12 (1H, m), 2.63 (2H, d, J = 7H
z), 3.64 (3H, s), 3.99 (3H, s),
4.87 (2H, s), 4.98 (2H, s), 6.5
7 (2H, d, J = 9Hz), 7.00 (2H, d, J
= 9 Hz), 7.87-8.01 (4H, m). NMR9) ¹ H-NMR (250 MHz, CDCl ₃ ) δppm;
0.93 (6H, d, J = 7Hz), 1.83 (2H,
s), 2.11-2.32 (1H, m), 2.80 (2
H, d, J = 7 Hz), 3.81 (3H, s), 3.9
0 (2H, s), 4.03 (3H, s), 5.33 (2
H, s), 6.91 (2H, d, J = 9 Hz), 7.3
5 (2H, d, J = 9 Hz).

The compounds shown in Tables 6 to 7 were obtained in the same manner as in Reference Example 7 above using appropriate starting materials.

[0065]

[Table 6]

[0066]

[Table 7] NMR10) ¹ H-NMR (250 MHz, CDCl ₃ ) δppm;
0.96 (6H, d, J = 7Hz), 2.15-2.3
5 (1H, m), 2.84 (2H, d, J = 7Hz),
4.10 (3H, s), 4.71 (2H, d, J = 5H
z), 5.38 (2H, s), 6.96 (1H, br)
s), 7.27-7.40 (5H, m), 7.40-
7.60 (3H, m), 7.77 (2H, d, J = 7H
z). NMR11) ¹ H-NMR (250 MHz, CDCl ₃ ) δppm;
0.96 (6H, d, J = 7Hz), 2.15-2.3
2 (1H, m), 2.85 (2H, d, J = 7Hz),
4.11 (3H, s), 4.71 (2H, d, J = 5H
z), 5.39 (2H, s), 6.98 (1H, br)
s), 7.27-7.48 (5H, m), 7.72 (2)
H, d, J = 9 Hz), 7.85 (2H, d, J = 9H)
z). NMR12) ¹ H-NMR (250 MHz, CDCl ₃ ) δppm;
0.93 (6H, d, J = 7Hz), 2.15-2.3
1 (1H, m), 2.81 (2H, d, J = 7Hz),
3.75 (3H, s), 4.09 (3H, s), 4.6
4 (2H, d, J = 5Hz), 5.33 (2H, s),
6.38 (1H, brs), 6.45 (1H, d, J =
16 Hz), 6.89 (2H, d, J = 9 Hz), 7.
33-7.45 (5H, m), 7.47-7.59 (2
H, m), 7.69 (1H, d, J = 16 Hz). NMR13) ¹ H-NMR (250 MHz, CDCl ₃ ) δppm;
0.93 (6H, d, J = 7Hz), 2.12-2.3
0 (1H, m), 2.80 (2H, d, J = 7Hz),
3.76 (3H, s), 3.91 (3H, s), 3.9
2 (3H, s), 4.08 (3H, s), 4.64 (2
H, d, J = 5 Hz), 5.30 (2H, s), 5.3
3 (2H, s), 6.34 (1H, brs), 6.36
(1H, d, J = 16Hz), 6.86-6.97 (3
H, m), 7.06-7.20 (2H, m), 7.35.
(2H, d, J = 9 Hz), 7.63 (1H, d, J =
16 Hz).

Example 1 0.20 g of 3-mercapto-1,2,4-triazole
0.15 g of sodium ethylate is added to a solution of 0.44 g of 6-bromomethyl-3-isobutyl-5-methoxy-1,2-dihydropyrazin-2-one 4-oxide in 15 ml of absolute ethanol, and the mixture is stirred at room temperature for 13 hours. . The precipitated crystals are collected by filtration, washed with water and dried. Recrystallized from ethanol to give 0.34 g of 3-isobutyl-5-
Methoxy-6- (1,2,4-triazol-3-yl) thiomethyl-1,2-dihydropyrazin-2-one 4-oxide was obtained. mp: 184.5-186 ° C., colorless needles. Example 2 1-to a solution of 6- (7-azaindol-3-yl) methyl-2-benzyloxy-3-isobutyl-5-methoxypyrazine 4-oxide (1.00 g) in 40 ml of ethanol.
0.10 g of 0% palladium-carbon is added, and the mixture is stirred under a hydrogen gas atmosphere at room temperature and 1 atm for 5 hours. The catalyst is filtered off,
The filtrate was concentrated under reduced pressure, and the obtained residue was recrystallized from methanol-dichloromethane to give 0.51 g of 6- (7-azaindol-3-yl) methyl-3-isobutyl-5-.
Methoxy-1,2-dihydropyrazin-2-one 4-oxide was obtained. mp: 222.5 ° C (decomposition), white powder. Example 3 6- (4-chlorophenylsulfinyl) methyl-3-
0.82 g of ceric ammonium nitrate was added to a 20 ml solution of acetic acid-water (9: 1) containing 0.52 g of isobutyl-5-methoxy-2- (4-methoxybenzyloxy) pyrazine 4-oxide, and the mixture was stirred at room temperature for 2 hours. Stir for hours. The reaction solution is diluted with water and then extracted with ethyl acetate. The ethyl acetate extract is washed 3 times with saturated aqueous sodium chloride solution and then with saturated aqueous sodium hydrogen carbonate solution, and dried over magnesium sulfate. The solvent was distilled off, and the resulting residue was subjected to silica gel column chromatography (eluent; dichloromethane: methanol = 2).
0: 1) and 0.19 g 6- (4-chlorophenylsulfinyl) methyl-3-isobutyl-5-
Methoxy-1,2-dihydropyrazin-2-one 4-oxide was obtained. mp: 172.5-174 ° C (decomposition), white powder. Example 4 6- (3,4-dimethoxycinnamoylamino) methyl-3-isobutyl-5-methoxy-2- (4-methoxybenzyloxy) pyrazine 4-oxide 0.75 g in dichloromethane 15 ml solution was treated with trifluoroacetic acid 1. 5m
1 is added and left for 2 minutes at room temperature. After evaporating the solvent at room temperature under reduced pressure, the obtained residue is dissolved in ethyl acetate and washed with a saturated aqueous sodium hydrogen carbonate solution. After drying over magnesium sulfate, the solvent was distilled off, and the obtained residue was purified by silica gel column chromatography (eluent; dichloromethane: methanol = 40: 1) and recrystallized from ethyl acetate-diethyl ether to give a 0.2. 30 g of 6- (3,4-dimethoxycinnamoylamino) methyl-3-isobutyl-5
-Methoxy-1,2-dihydropyrazin-2-one 4-
Oxide was obtained. mp: 205.5-206.5 ° C, colorless needles. Example 5 6-phthalimidomethyl-3-isobutyl-5-methoxy-2-benzyloxypyrazine 4-oxide 1.79
g ethanol 60 ml and dimethylformamide 50
0.18 g of 10% palladium-carbon is added to the mixed solution of ml, and the mixture is stirred at 60 ° C. for 5 hours under a hydrogen gas atmosphere. After removing the catalyst by filtration, the filtrate was concentrated under reduced pressure, and the obtained residue was recrystallized from methanol to give 1.29 g of 3-isobutyl-.
5-Methoxy-6-phthalimidomethyl-1,2-dihydropyrazin-2-one was obtained. mp: 185-186 ° C, colorless scale-like. Example 6 6- (Benzothiazol-2-ylsulfonyl) methyl-3-isobutyl-5-methoxy-2- (4-methoxybenzyloxy) pyrazine 4-oxide 0.83 g in dichloromethane 25 ml solution trifluoroacetic acid 1.23.
Add ml and stir at room temperature for 2 hours. The solvent was distilled off under reduced pressure at room temperature, and the obtained residue was washed with water and dried to give 0.60 g.
To give 6- (benzothiazol-2-ylsulfonyl) methyl-3-isobutyl-5-methoxy-1,2-dihydropyrazin-2-one. mp: 172-173 ° C (decomposition), colorless needles. Example 7 Hydrazine hydrate 0.15 was added to a suspension of 0.82 g of 3-isobutyl-5-methoxy-6-phthalimidomethyl-1,2-dihydropyrazin-2-one in 20 ml of methanol.
Add ml and heat to reflux for 6 hours. The solvent is distilled off under reduced pressure, and the obtained residue is triturated with dichloromethane. After removing the insoluble matter by filtration, the filtrate is concentrated under reduced pressure. The obtained residue was recrystallized from ethyl acetate to give 0.12 g of 6
-Aminomethyl-3-isobutyl-5-methoxy-1,
2-Dihydropyrazin-2-one is obtained. mp: 161-162 ° C (decomposition), pale yellow scaly.

The compounds shown in Tables 8 to 16 are obtained in the same manner as in Examples 1 to 4 by using appropriate starting materials.

[0069]

[Table 8]

[0070]

[Table 9]

[0071]

[Table 10]

[0072]

[Table 11]

[0073]

[Table 12]

[0074]

[Table 13]

[0075]

[Table 14]

[0076]

[Table 15]

[0077]

[Table 16] Using the appropriate starting materials as in Examples 2-4, Table 1
7 and the compounds shown in Table 18 are obtained.

[0078]

[Table 17]

[0079]

[Table 18] NMR14) ¹ H-NMR (250 MHz, DMSO-d ₆ ) δpp
m; 0.88 (6H, d, J = 7Hz), 2.03-
2.25 (1H, m), 2.71 (2H, d, J = 7H
z), 3.81 (3H, s), 5.20 (2H, s),
7.68-7.80 (2H, m), 8.21-8.40
(2H, m). NMR15) ¹ H-NMR (250 MHz, CDCl ₃ ) δppm;
1.02 (6H, d, J = 7Hz), 2.20-2.3
8 (1H, m), 2.83 (2H, d, J = 7Hz),
4.10 (3H, s), 4.55 (2H, d, J = 5H
z), 6.40 (1H, d, J = 16Hz), 7.07
(1H, brs), 7.32-7.40 (3H, m),
7.41-7.51 (2H, m), 7.67 (1H,
d, J = 16 Hz). The compound of the present invention, citric acid, lactose, dicalcium phosphate, pron F-68 and sodium lauryl sulfate were mixed.

No. Sifted with 60 screen, polyvinylpyrrolidone, carbowax 1500
Wet granulation with an alcoholic solution consisting of Carbowax 6000 and Carbowax 6000. Add alcohol as needed,
The powder was made into a pekato mass. Add cornstarch,
Mixing was continued until uniform particles were formed. No. 10
It was passed through a screen, put in a toilet, and dried in an oven at 100 ° C for 12 to 14 hours. The dried particles were 16
After screening with a screen, dry sodium lauryl sulphate and dry magnesium stearate were added, mixed and compression molded into the desired shape on a tablet machine.

The core was treated with varnish and talc was sprinkled to prevent moisture absorption. An undercoat layer was coated around the core. The varnish was applied a sufficient number of times for internal use. Further subbing layers and smooth coatings were applied in order to make the tablets completely round and smooth. Color coating was applied until the desired shade was obtained. After drying, the coated tablets were polished to prepare tablets of uniform gloss. Test compound 1.3-isobutyl-5-methoxy-6- (4-hydroxyphenoxy) methyl-1,2-dihydropyrazine-
2-one 4-oxide 2.3-isobutyl-5-methoxy-6- (5-indolyloxy) methyl-1,2-dihydropyrazine-2-
On 4-oxide 3.3-isobutyl-5-methoxy-6- (1,2,3
-Benzotriazol-1-yloxy) methyl-1,
2-dihydropyrazin-2-one 4-oxide 4.3-isobutyl-5-methoxy-6- (1-imidazolyl) methyl-1,2-dihydropyrazin-2-one 4-oxide 5.3-isobutyl-5 -Methoxy-6- (9-carbazolyl) methyl-1,2-dihydropyrazin-2-one 4-oxide. 6.3-Isobutyl-5-methoxy-6-phthalimidomethyl-1,2-dihydropyrazin-2-one 4-oxide 7.3-isobutyl-5-methoxy-6-phthalimidomethyl-1,2-dihydropyrazine- 2-one 8.3-isobutyl-5-methoxy-6- (1-piperidinyl) methyl-1,2-dihydropyrazin-2-one 4-oxide 9.3-isobutyl-5-methoxy-6- (4- Chlorophenylthio) methyl-1,2-dihydropyrazine-2
-One 4-oxide 10.3-isobutyl-5-methoxy-6- (benzoxazol-2-ylthio) methyl-1,2-dihydropyrazin-2-one 4-oxide 11.3-isobutyl-5-methoxy- 6- (5-Methyl-1,3,4-thiadiazol-2-ylthio) methyl-1,2-dihydropyrazin-2-one 4-oxide 12.3-isobutyl-5-methoxy-6- (1,2 ，
4-Triazol-3-ylthio) methyl-1,2-dihydropyrazin-2-one 4-oxide 13.3-isobutyl-5-methoxy-6- (benzimidazol-2-ylthio) methyl-1,2-dihydro Pyrazin-2-one 4-oxide 14.3-isobutyl-5-methoxy-6- (pyrimidin-2-ylthio) methyl-1,2-dihydropyrazin-2-one 4-oxide 15.3-isobutyl-5- Methoxy-6- (5-methyl-1,3,4-oxadiazol-2-ylthio) methyl-1,2-dihydropyrazin-2-one 4-oxide 16.3-isobutyl-5-methoxy-6- (4,5-
Diphenyl-2-imidazolylthio) methyl-1,2-
Dihydropyrazin-2-one 4-oxide 17.3-isobutyl-5-methoxy-6- (4-chlorophenylsulfinyl) methyl-1,2-dihydropyrazin-2-one 4-oxide 18.3-isobutyl-5- Methoxy-6- (benzothiazol-2-ylsulfonyl) methyl-1,2-dihydropyrazin-2-one 19.3-isobutyl-5-methoxy-6-benzoylaminomethyl-1,2-dihydropyrazine-2- On 4
-Oxide 20.3-isobutyl-5-methoxy-6- (4-trifluoromethylbenzoylamino) methyl-1,2-dihydropyrazin-2-one 4-oxide 21.3-isobutyl-5-methoxy-6- Acetylaminomethyl-1,2-dihydropyrazin-2-one 4-
Oxide 22.3-isobutyl-5-methoxy-6- (3,4-
Dimethoxycinnamylamino) methyl-1,2-dihydropyrazin-2-one 4-oxide 23.3-isobutyl-5, methoxy-6- (7-azaindol-3-yl) methyl-1,2-dihydropyrazine 2-On-4-oxide Pharmacological Test Example 1 Effect Test on O ₂ ⁻ Released by Stimulation from Guinea Pig Peritoneal Macrophages Guinea pig peritoneal macrophages were intraperitoneally administered with 15 ml of mineral oil, and collected 96 hours after intraperitoneal injection.

O ₂ was measured by the cytochrome C reduction method [T. Mztsumoto, K, Takeshige and S.M. Minami, Biochemical a
nd Biophysical Research C
Communications, 88 (3), 974-9
79 (1979)]. That is,
Macrophages were added to 1 ml of 80 μM cytochrome solution so that the final concentration was 2 × 10 ^6, and the test compound or water (control group) was further added, followed by preincubation at 37 ° C. for 1 minute. O ₂ ^- as a stimulator, a final concentration of 10 to FMLP (formylmethionyl leucyl phenylalanine)
^It was added so as to be ^-7, and further reacted for 1 minute. During this period, the difference in absorbance at OD ₅₅₀ was measured and the ratio of the control group was calculated.
It was calculated the IC _50.

The results are shown in Table 19.

[0084]

[Table 19] Pharmacological test example 2 Effect on H ₂ O ₂ production from peritoneal neutrophils 1% casein solution was injected into the abdominal cavity of SD rats to give 16
The abdominal cavity was washed for an hour to obtain neutrophils. Neutrophils were washed with Hank's solution.

Sodium azide 1 mM, sodium chloride 140 mM, potassium chloride 5 mM, magnesium chloride 1
mM, calcium chloride 1 mM, glucose 5.5 mM,
Phenol red 0.28 mM, HRP (Horse
Radish peroxidase) 8.5 U / m
1, HEPES (N- (2-hydroxyethyl) piperazine-N'-2-ethanesulfonic acid) 10 mM (pH
7.0), rat neutrophils 10 ⁶ / ml and FMLP2 ×
The test compound was added to the reaction solution containing 10 ⁻⁶ M to prepare 3
Incubated at 7 ° C for 1 hour. 1 at 2000 rpm
After centrifuging for 0 minutes, 1 ml of the supernatant was taken and 10 μl of 1N sodium hydroxide aqueous solution was added.

It was measured at OD ₆₁₀ with a spectrophotometer. The IC ₅₀ was calculated by taking the ratio with the control group. The results are shown in Table 20.
Shown in.

[0087]

[Table 20]

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁵ Identification code Internal reference number FI Technical indication location A61K 31/495 ACS 9360-4C ACV 9360-4C ADD 9360-4C C07D 401/12 241 8829-4C 401 / 14 8829-4C 403/12 8829-4C 403/14 8829-4C 413/12 241 8829-4C 413/14 8829-4C 417/12 241 9051-4C 417/14 9051-4C 471/04 104 Z 8829- 4C // (C07D 401/12 215: 00 7019-4C 241: 00) 8615-4C (C07D 413/12 241: 00 8615-4C 263: 00) 9283-4C (C07D 413/12 241: 00 8615-4C 271: 00) 9283-4C (C07D 417/12 241: 00 8615-4C 277: 00) 9051-4C (C07D 417/12 241: 00 8615-4C 285: 00) 9284-4C (72) Inventor Toshiki Miyazaki 35 (72) Inventor Nakano at 12 Toiwahama, Okuwashima, Narato-cho, Tokushima Prefecture Yoshimasa 2 of 37 Higashino, Kasagi, Aizumi-cho, Itano-gun, Tokushima Prefecture

Claims (1)

[Claims] 1. A general formula: [In the formula, R ¹ represents a lower alkoxy group. B is a group N → O
Alternatively, it represents a nitrogen atom. R ³ represents a lower alkyl group. A
Represents a lower alkylene group. R ² is a 5- to 13-membered saturated or unsaturated monocyclic, dicyclic or tricyclic heterocyclic residue having 1 to 4 nitrogen atoms (wherein the heterocycle is substituted with an oxo group). may also be), group ^{-X-R 4,} an amino group or a group -NH
COR ⁶ is shown. Here, X is an oxygen atom or S (0) m
(M is 0, 1 or 2). R ⁴ is a phenyl group which may have a substituent selected from the group consisting of a hydroxyl group, a phenyl lower alkoxy group and a halogen atom on the phenyl ring, or a nitrogen atom, an oxygen atom or a sulfur atom. 5- to 10-membered unsaturated monocyclic or binomial heterocyclic residue having 1 to 3 groups (the heterocyclic ring may be substituted with a lower alkyl group or a phenyl group) ) Is shown. R ⁶ is a lower alkyl group, a phenyl group which may have a lower alkyl group which may have 1 to 3 halogen atoms on the phenyl ring, or a phenyl group which may have a lower alkoxy group as a substituent on the phenyl ring. A lower alkenyl group is shown. ] The pyrazine derivative represented by these, or its salt.