JPH01135775A - Pyrazine derivative and pharmaceutical preparation - Google Patents

Abstract

NEW MATERIAL:A pyrazine derivative of formula I [X is H, cyano, alkoxy; R1 is H, halogen; R2 is H, halogen, alkyl, cyano, naphthylmethyl, substituted benzyl (with halogen, alkyl or amino), carboxyl, alkyloxycarbonyl]. EXAMPLE:2,3-Diphenyl-5-(o-chlorobenzyl)pyrazine. USE:Anticoagulant, anti-inflammatory. PREPARATION:For example, a benzyl derivative of formula II is heated together with 1,2-diamine derivative of formula III in an organic solvent such as ethanol and the resultant a dihydropyrazine derivative of formula IV is heated together with sulfur at 100-180 deg.C to give a pyrazine derivative of formula I where both R1 and R2 are H.

Description

DETAILED DESCRIPTION OF THE INVENTION [Industrial Field of Application] The present invention relates to novel pyrazine derivatives and pharmaceutical formulations containing the same.

Since the pyrazine derivatives of the present invention have a strong platelet aggregation inhibiting effect, they are effective in preventing diseases caused by platelet aggregation, such as thrombosis. Furthermore, compounds having a cyclooxygenase inhibitory effect are generally known to have an anti-inflammatory effect, and since the pyrazine derivative of the present invention has the above-mentioned inhibitory effect, it can also be used as an anti-inflammatory agent.

[Problems to be solved by conventional technology and invention]

Various substances are known to have antiplatelet aggregation effects, but
The effect is weak, and it is hoped that an improved drug will emerge. In addition, thromboses such as myocardial infarction and cerebral thrombosis have become a large proportion of adult diseases in recent years.
There is a strong desire for the emergence of antithrombotic agents that can effectively prevent this.

Various pyrazine derivatives are conventionally known, and for example, 2,3-diphenylpyrazine is described in Journal on Heterocyclic Chemistry, Vol. 21, pp. 103-106. However, it has not been known so far that these pyrazine derivatives have an anti-platelet aggregation inhibitory effect.

The present inventors synthesized many novel pyrazine derivatives and conducted intensive research on their pharmacological activities. As a result, they discovered that certain pyrazine derivatives have excellent platelet aggregation inhibiting and anti-inflammatory effects, and completed the present invention. I let it happen.

Therefore, it is an object of the present invention to provide novel pyrazine derivatives.

A further object of the present invention is to provide a platelet aggregation inhibitor and an anti-inflammatory agent containing a pyrazine derivative as an active ingredient.

[Means for solving the problems] In order to achieve the above object, the present invention has the following configuration.

1, Formula (wherein X is a hydrogen atom 1. Represents a cyano group or a lower alkoxy group, R1 represents a hydrogen atom or a halogen atom,
R1 represents a hydrogen atom, a halogen atom, a lower alkyl group, a cyano group, a naphthylmethyl group, a substituted benzyl group having a halogen atom or a lower alkylamino group as a substituent, a carboxyl group, or a lower alkyloxycarbonyl group. ) pyrazine derivatives.

2. A platelet aggregation inhibitor and an anti-inflammatory agent containing a pyrazine derivative having the general formula (I).

According to the present invention, a novel pyrazine derivative having the above formula (1) is provided.

In the formula (I), X represents a hydrogen atom, a cyano group, or a lower alkoxy group (eg, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy).

R is a hydrogen atom or a halogen atom (for example, chlorine).

Bromine, fluorine atoms).

h is a hydrogen atom, a halogen atom (for example, chlorine, bromine, or fluorine atom), or a lower alkyl group (for example, methyl).

ethyl, propyl, isopropyl, butyl, isobutyl), cyano group, naphthylmethyl group, carboxyl group, lower alkyloxycarbonyl group (e.g. methoxycarbonyl, ethoxycarbonyl).

(propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl) or formula (n) (wherein R3 is a halogen atom (e.g. chlorine, bromine, fluorine atom) or a lower alkylamino group (e.g. methylamino, ethylamino, propyl (amino, isopropylamine, butylamino, inbutylamino).

In the pyrazine derivative (I), a compound in which R+ and lh are both hydrogen atoms is obtained by combining a benzyl derivative having the formula (wherein X has the same meaning as above) and a 1,2-diamine derivative (IV) in an appropriate manner. It is produced by heating a dihydropyrazine derivative (V) (in the formula, X has the same meaning as described above) which can be heated in an organic solvent (for example, ethanol) with sulfur at 100 to 180°C.

In the pyrazine derivative (I), a compound in which R1 is a hydrogen atom, R2 is a naphthylmethyl group, and a substituted benzyl group having a halogen atom or a lower alkylamino group as a substituent is a compound in which the dihydropyrazine derivative (V) is combined with nat aldehyde and as a substituent. It is produced by reacting a substituted benzaldehyde having a halogen atom or a lower alkylamino group.

Further, in the above formula (1), the pyrazine derivative in which R1 is a hydrogen atom or a halogen atom, and R is a halogen atom, the pyrazine derivative (1) in which R, it is a hydrogen atom, is mixed with permaleic acid (Perma 1 eic ac
id) to obtain a mono- or di-N-oxide, which is then halogenated with phosphorus oxyhalide to obtain a 2,3-diphenyl-4 (or 4,5-) halogenated pyrazine derivative. can be manufactured.

Further, in the above formula (I), the pyrazine derivative in which R3 is a hydrogen atom and R2 is a cyano group, a carboxyl group, or a lower alkyloxycarbonyl group is the above-mentioned 2,3-diphenyl-4-chloropyrazine derivative (Vl) (in the formula X
has the same meaning as described above) and potassium cyanide in the presence of a palladium catalyst (for example, tetrakis(triphenylphosphine)palladium), yields (1) in which R2 has a cyano group.

By alkaline hydrolysis of this compound, R
(I) in which 2 has a carboxyl group is obtained, and by further alkyl esterification, (1) in which R1 is a lower alkyloxycarbonyl group is obtained.

Since the pyrazine derivative of the present invention has the effect of inhibiting platelet aggregation, it can be effectively used as a platelet aggregation inhibitor to prevent cerebral thrombosis and the like. Furthermore, the pyrazine derivative of the present invention has a cyclooxygenase inhibitory effect and can also be used as an anti-inflammatory agent.

The dosage is generally about 30 to 600 μl per day for adults, and if necessary, it is preferably administered in 1 to 3 divided doses.

The method of administration can take any form suitable for administration;
Oral administration is particularly desirable, but intravenous injection is also possible.

The compound of the present invention may be formulated into tablets, powders, capsules, or granules either alone or mixed with pharmaceutical carriers or excipients in a conventional manner. Examples of carriers or excipients include calcium carbonate, calcium phosphate, starch, sucrose, lactose, talc, magnesium stearate, and the like. In addition to the above-mentioned solid formulations, the compounds of the present invention can also be used in oily suspensions,
It can also be made into a liquid preparation such as syrup.

The compound of the present invention can also be stabilized by inclusion with cyclodextrin.

Next, the present invention will be explained in more detail with reference to Examples and pharmacological test examples.

Example 1 2.3-diphenyl-5,6-cyhydrovirazine 2.5
7g.

1.40 g of 0-chlorobenzaldehyde and 0.672 g of potassium hydroxide were dissolved in 20rIIi of methanol and reacted under heating under reflux for 1 hour. Methanol was removed from the reaction mixture by distillation under reduced pressure, and 50 d of water was added to the residue, which was extracted three times with ethyl acetate. Wash the extracted organic layer with water,
After drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure.

The obtained extraction residue was subjected to silica gel column chromatography, and a crude product was obtained from the fraction eluted with 8:1 of hexane and ethyl acetate. The crude product was recrystallized from methanol and hot water to give 2,3-diphenyl-5 as colorless prism crystals.
-(0-chlorobenzyl)pyrazine 2.633g (7
4χ) was obtained. The melting point is 112-114'C, and the physical property data of Honjima support the structure of the following formula (■).

Elemental analysis value: CC23HI, CllNz) Calculated value: C, 77, 41: H, 4, 80; N, 7.
85 actual measurement value: C, 77, 13i H, 4, 81;
N, 7.83MASS (+++/z): 356
(Molecular ion peak) 'H-NMR (CD (/! 3
) δ (ppm): 4.42 (2H, s) 8.47 (1
8,s) Example 2 2.3-diphenyl-5,6-dihydropyrazine (2,
57g) and m-chlorobenzaldehyde (1.40g)
Using the same procedure as in Example 1, the melting point was 58-59°.
3.338 g (94χ) of 2°3-diphenyl-5-(tochlorobenzyl)pyrazine was obtained as colorless prism crystals of C (recrystallized from methanol and water). The physical property data of the main island supports the structure of formula (■) below.

Elemental analysis value' (Cz3H1?CINt) Calculated value
: C, 77, 41i H, 4, 80, N, 7.85
Actual value: e, ? 7.35; H, 4,75;
N, 7.80MASS (m/z): 356 (
molecular ion peak) + H-NMR (CDCl 3')
δ (ppm): 4.18 (2H, s), 8.40 (I
H,s) Example 3 2.3-diphenyl-5,6-dihydropyrazine (2,
57g) and ρ-chlorobenzaldehyde (1.40g)
Using the same procedure as in Example 1, the melting point was 105 to 10.
3.358 g (94x) of 2,3-diphenyl-5-(p-chlorobenzyl)pyrazine was obtained as colorless prism crystals at 6°C (recrystallized from isoprobil alcohol).

The physical property data of the main island supports the structure of formula (IX) below.

Elemental analysis value: CC23HI”tCI2Nt) Calculated value
: C,? ? ,41,H,4,80;N,
7.85 Actual value: C, 77,54; H, 4,8
0: N, 7.86MASS (m/z): 35
6 (molecular ion peak) 'H-NMR (CDCIl
s) δ (ppm): 4.20 (2H, s), 8.4
0(IH,s) Example 4 2.3-diphenyl-5,6-dihydropyrazine (2,
57 g) and p-bromobenzaldehyde (1.85 g)
using a melting point of 100 to 10 by the same operation as in Example 1.
2 as colorless needles at 1°C (recrystallized from methanol)
．． 3.87 g (97x) of 3-diphenyl-5-(p-bromobenzyl)pyrazine was obtained. The physical property data of the main island supports the structure of formula (X) below.

Elemental analysis value: CCtxHlqB rN2) Calculated value
: C, 68,83, H, 4,27; N, 6.9
8 Actual measurement value: C, 68, 84; H, 4, 24;
N, 6.97MASS (m/z): 401 (
molecular ion peak)'H-NMR (CDi 3) δ(p
pm): 4.23 (2H, s), 8.48 (
IH,s) Below Margin Example 5 2.3-diphenyl-5,6-cyhydropyrazine (2,
57g) and p-dimethylaminobenzaldehyde (1,
49g), and the melting point was 80 by the same operation as in Example 1.
3.36 g (92χ) of 2,3-diphenyl-5-(p-dimethylaminobenzyl)pyrazine was obtained as colorless prism crystals at ~82°C (recrystallized from methanol and water). Physical property data of ice crystals supports the structure of formula (XI) below.

Elemental analysis value: CCzsHtsNs) Calculated value: C, 82, 16; H, 6, 34; N
, 11.50 Actual value: C, 82, 14; H,
6,30; N, 11.50 gates ^SS (m/z): 3
65 (molecular ion peak)') l-NMR (CDCf
z) δ (ppm): 2.8B (6B, s), 4.12 (
2H,s) 8.40(IH,s) Below Margin Example 6 2.3-diphenyl-5,6-cyhydrovirazine (2,
57 g) and 1-nataldehyde (1,56 g), the same procedure as in Example 1 was performed to obtain a melting point of 91-92°C (methanol).

3.30 g of 2,3-diphenyl-5-(1-naphthyl)methylpyrazine as colorless prism crystals (recrystallized from water)
(89χ) was obtained. The physical property data of ice crystals is expressed by the following formula (XI
) supports the structure.

Elemental analysis value: (C2?H2°N,) Calculated value: C,87,06, H,5,41,N,
7.52 Actual measurement value: C, 86,96; H, 5,4
3; N, ? , 50MASS (m/z): 37
2 (molecular ion peak)' H-NMR (CDCl
3) δ (ppm): 4.70 (2H, s), 8
．． 30 (IH, s) or less Margin Example 7 2.3-bis(p-methoxyphenyl)pyrazine 1.4
- Dioxide (1.80 g, 5.6n+M) was mixed with phosphorus oxychloride (20d) and reacted under heating under reflux for 1 hour.

After cooling, the reaction mixture was poured into ice water, made basic with potassium carbonate, extracted with methylene chloride, and the solvent was distilled off to obtain a pale yellow extraction residue. The residue was subjected to silica gel column chromatography (Wakoge j! C-2
00.32 g, a mixed solution of benzene-A co Ht). 1.50 g (78x) of 2,3-bis(p-methoxyphenyl)-5,6-dichloropyrazine was obtained as the first eluate.

Recrystallization from hexane gave 2°3-bis(p-methoxyphenyl)-5,6-dichloropyrazine as colorless needles. Melting point: 120-121°C. Physical property data of ice crystals supports the structure of the formula (X I[).

Elemental analysis value: (CI a Hl 4 Cf 2 N
20□) Calculated value: C, 59,85; H, 3,9
1; N, 7.76 Actual value: C, 60,02;
H, 3, 88, N, 7.79MASS (m/z)
:360 (molecular ion peak)'H-NMR (CD
Cjl! δ (ppm): 3.77 (6H, s)
, 6.83 (411, d.

J=7.511z), 7.43(4H,d.

Example 8 2.3-bis(p-methoxyphenyl)virazine tinoxide (3.92 g, 12.7 d) was mixed in 20 ml of phosphorus oxychloride and reacted under heating under reflux for 30 minutes. Ta. After cooling, the reaction mixture was poured into ice water and then made basic with potassium carbonate to precipitate a yellow-orange solid.

This was collected by filtration and subjected to silica gel column chromatography.
(Wakoge II C-200, 70g solvent: hexane-methylene chloride = 1:l) gives 2.3-bis(
p-methoxydiphenyl)-5-chloropyrazine 2.82
g (76K) was obtained.

Melting point: 127-128°C (pale yellow prismatic crystals, recrystallized from ethanol). The physical property data of ice crystals is the following formula (XIV)
support the structure of

Elemental analysis value: (CtsH+5CffiNxOz) Calculated value: C, 66, 17, H, 4, '63, N,
8.57 Actual measurement value: C, 65,91; H, 4,
63; N, 8.60MASS (m/z): 32
6 (molecular ion beak)'H-NMR (CDCj!s
) δ (ppm): 3.7? (6B, s), 6
．． 77 (4H, d.

J=7Hz), 7.33(21(,d,J=7Hz),
7.37 (2H, d, J=7)1z).

8.42 (IH,s) Example 9 2.3-bis(p-methoxyphenyl)-5-chloropyrazine (3.27g, 10mM), potassium cyanide (975■, 15mM), tetrakis(triphenylphosphine)palladium (580mg, 0.5m
M) in anhydrous DMF (50d) under an argon atmosphere.
Heat to reflux for an hour. The solvent was distilled off under reduced pressure, and water (100 d
1) was added, extracted with methylene chloride, and the solvent was distilled off to obtain a dark brown sticky substance. This was subjected to medium pressure silica gel column chromatography 11 (column: Kiese lg
e 4260, 230-400 mesh, manufactured by Merck & Co., 20 mm x 200 mm, solvent hexane-AcoE
t=4-1), 2.66 g (84χ) of 2,3-bis(p-methoxyphenyl)-5-cyanopyrazine was obtained. Melting point: 110-112°C (pale yellow needles, recrystallized from methanol). The physical property data of ice crystals is expressed by the following formula (X V
) supports the structure.

* UVILOG ALPC-100 (Oyo Spectroscopic Instruments Co., Ltd.) Elemental analysis value: (CI* Hls N x
O□) Calculated value: C, 71,91, H, 4,76;
N, 13.24 Actual measurement value: C,? 1.89,
H, 4,63; N, 13.27MASS (m/z
): 317 (Molecular Ion Beak) / 'H-NMR (
CDCl 3) δ (ppm): 3.77 (6H, s)
, 6.80 (4H, dJ=9Hz), 7.43 (21+
, d, J=9Hz), 7.45(2H, d, J=9Hz
)8.70(IH,5)IR(KBr)co+-': 2260(CEN)Example 10 2.3-bis(p-methoxyphenyl)-5-cyanopyrazine (2.0g, 6.3mM) Methanol (4
0m), 1.2 to 4-dioxane (30mf) mixture
After adding 0% sodium hydroxide solution, the mixture is heated under reflux for 4 hours. The solvent was distilled off under reduced pressure, neutralized by adding 5% hydrochloric acid solution, extracted with methylene chloride, and the solvent was distilled off to obtain a crude product. The crude product was recrystallized from ethanol to obtain 2.07 g (95χ) of 2.3-bis(p-methoxyphenyl)pyrazine-5-carboxylic acid as colorless needle crystals.

Melting point 234-235℃0 The physical property data of this product is expressed by the following formula (X
VI).

Elemental analysis value: (C+wHI&Nzo-) Calculated value:
C, 67,85; H, 4,8Q; N, 8.33
Actual value: C, 67, 69; H, 4, 85, N,
8.34MASS (m/z): 336 (Molecular Ion Beak) IR (KBr) cm-': 1690 Example 1
1 2.3-bis(p-methoxyphenyl)pyrazine-5-
Carboxylic acid (336 mg, 1 mM) in methanol (5
After adding concentrated sulfuric acid (0.1d) to the (iffi) solution, the mixture is heated under reflux for 3 hours.

The solvent was distilled off under reduced pressure, water (15 ml.) was added, and the mixture was neutralized with potassium carbonate, extracted with methylene chloride, and the solvent was distilled off to obtain a crude product. The crude product was recrystallized from methanol to obtain 320 µ (91 χ) of 2,3-bis(p-methoxyphenyl)pyrazine-5-carboxylic acid methyl ester as colorless needle crystals. Melting point 140-141°C
0 The physical property data of this product support the structure of the following formula (X■).

Elemental analysis value; (C8°H + 5NtOa) Calculated value:
C, 6B, 56; H, 5, 18; N, 8.00
Actual measurements: C, 6B, 40; H, 5, 11;
N, 7.93MASS (II/Z): 350
(Molecular ion peak)'+! -NMR (CDCl3)
δ (ppm): 3.77 (6H, s), 3.97
(3H, s) 6.78 (4H, d, J-9Hz).

7.43 (48, d, J = 9 Hz) 9.12 (IH, s) Pharmacological test example [platelet aggregation inhibitory effect] After collecting 1710 volumes of 3.8χ sodium citrate blood from a rabbit carotid artery, the blood was centrifuged, Plasma rich in platelets (P
RP: 5×10′ pieces/μ2) is obtained.

Put 200 μl of the PRP and 25 μl of saline into a cuvette, set it on an alibometer, heat it at 37°C for 2 minutes, and add 1.25 μl of an ethanol solution of the pyrazine derivative to be tested.
After incubating for 3 minutes, arachidonic acid solution or collagen solution, which is an agent for inducing platelet aggregation, was added and platelet aggregation was measured using an alibometer [Hematotracer ■].
: Niko Bioscience ■]. The 50% inhibitory concentrations for platelet aggregation induced by arachidonic acid (801xM) or collagen (15 μs/m) are shown in Table 1. Acetylsalicylic acid was used as a comparative example.

As shown in Table 1, the pyrazine derivatives of the present invention were found to have significant antiplatelet aggregation activity. Furthermore, it was confirmed that pyrazine derivatives according to the present invention not shown in Table 1 also have similar activities. In addition, the 50% inhibitory concentration in the table refers to the aggregation ability of platelets when the pyrazine derivative according to the present invention is not introduced.
In this case, it means the concentration of the pyrazine derivative solution required to suppress the aggregation ability of the platelets to 50% by introducing the pyrazine derivative.

Table 1 Anti-platelet aggregation activity [cyclooxygenase inhibition effect] Using a cannula from the rabbit carotid artery, 9 volumes of blood per 1 volume of 3.8x sodium citrate solution was collected into a centrifuge tube. Obtain platelet-rich plasma by centrifugation. After adding 1/10 volume of 77 mM εDTA solution to the platelet-rich plasma and mixing well, centrifugation is performed at 2500 rpm for 10 minutes at room temperature. Discard the supernatant and wash solution (sodium chloride 1341
1IM, trisaminomethane 15mM, EDTA 1
5mM D-glucose dissolved in distilled water and adjusted to pH 7.4 with 1N hydrogen chloride) Approximately 3 rtdl
Resuspend the platelets at 2000 revolutions/min at room temperature for 10
Centrifuge for minutes. Discard the supernatant and remove the precipitated platelets.
Resuspend in IB8.0 1/15M phosphate buffer and adjust platelet count to 6-8 x 10'/μl.

The washed platelets thus obtained are used as a cyclooxygenase enzyme source.

3 μg of arachidonic acid and 0.2 μC1 (1 Hg) of l 4 C-labeled arachidonic acid (toluene solution) were placed in a test tube with a covalent tube, and a mixture of propylene glycol/ethanol (
Add one drop of 1:3 volume) and evaporate the ethanol and toluene under nitrogen gas. Add 50μ of sample solution here! In addition, 500μ of washed platelets! Add and react at 37°C for 3 minutes.

While cooling on ice, add 3 drops of 0.5N hydrogen chloride to bring the pn to 2~
Make it 3. Add 2 d of ethyl acetate, shake and extract for 10 minutes, and centrifuge at 2500 rpm for 10 minutes at 4°C.

Transfer the supernatant to a flask and concentrate, then reduce the residue to 100μ! A thin silica gel plate (60F25 manufactured by Merck & Co., Ltd.) was dissolved in ethanol.
Spot Venus on 4).

Developing solvent (chloroform/methanol/acetic acid/water = 90
: 8 : 1 : 0.8), the sum of the radioactivities of prostaglandin Eg, prostaglandin D2 and HHT was measured using a radiochromatography scanner to determine the inhibitory activity. The results are shown in Table 2. Furthermore, pyrazine derivatives according to the present invention which are not shown in Table 2 also have similar activity f! It has been certified.

Margin table 2 below. Cyclooxygenase inhibitory activity [Elephant, sexual toxicity] An acute toxicity test was conducted by oral administration using ICR male mice (5 weeks old). L of the pyrazine derivative of the present invention
D. The values were all over 300 μ/kg, confirming high safety.

〔Effect of the invention〕

According to the present invention, novel pyrazine derivatives and pharmaceutical formulations containing the same are provided.

The above-mentioned compounds of the present invention significantly inhibit platelet aggregation induced by arachidonic acid or collagen, so that diseases caused by platelet aggregation, particularly myocardial infarction, ischemic attack after cerebral hemorrhage, cerebral infarction, etc., are associated with platelet aggregation. It can be used as a prophylactic agent for thrombosis.

Furthermore, since the above-mentioned compound of the present invention has a cyclooxygenase inhibitory effect, it can also be used as an anti-inflammatory agent.

Claims (3)

[Claims] (1) General formula (I) ▲Mathematical formulas, chemical formulas, tables, etc.▼(I) (In the formula, X represents a hydrogen atom, a cyano group, or a lower alkoxy group, R_1 represents a hydrogen atom or a halogen atom,
R_2 is a hydrogen atom, a halogen atom, a lower alkyl group, a cyano group, a naphthylmethyl group, a substituted benzyl group having a halogen atom or a lower alkylamino group as a substituent,
Indicates a carboxyl group or lower alkyloxycarbonyl group. ) pyrazine derivatives. (2) General formula (I) ▲Mathematical formulas, chemical formulas, tables, etc.▼(I) (In the formula, X represents a hydrogen atom, a cyano group, or a lower alkoxy group, R_1 represents a hydrogen atom or a halogen atom,
R_2 is a hydrogen atom, a halogen atom, a lower alkyl group, a cyano group, a naphthylmethyl group, a substituted benzyl group having a halogen atom or a lower alkylamino group as a substituent,
Indicates a carboxyl group or lower alkyloxycarbonyl group. ) A platelet aggregation inhibitor containing a pyrazine derivative. (3) General formula (I) ▲Mathematical formulas, chemical formulas, tables, etc.▼(I) (In the formula, X represents a hydrogen atom, a cyano group, or a lower alkoxy group, R_1 represents a hydrogen atom or a halogen atom,
R_2 is a hydrogen atom, a halogen atom, a lower alkyl group, a cyano group, a naphthylmethyl group, a substituted benzyl group having a halogen atom or a lower alkylamino group as a substituent,
Indicates a carboxyl group or lower alkyloxycarbonyl group. ) An anti-inflammatory agent containing a pyrazine derivative having