JPH0374372A - Pyrazine derivative and platelet agglutination inhibiting agent or antiinflammatory agent containing the same - Google Patents

Abstract

NEW MATERIAL:A pyrazine derivative of formula I (X is H, halogen, cyano, lower alkyl, lower alkylamino, di lower alkylamino or lower alkoxy; the ring A is group of formula II or III). EXAMPLE:2,3-Bis (p-methoxyphenyl) benzo [g] quinoxaline. USE:A platelet agglutination-inhibiting agent or antiinflammatory agent. PREPARATION:A benzyl derivative of formula II is thermally reacted with a 1,2-diamine derivative of formula III is a suitable organic solvent to prepare a dihydropyrazine derivative of formula IV, which is heated together with sulfer at 100-180 deg.C to provide the compound of formula I.

Description

DETAILED DESCRIPTION OF THE INVENTION [Industrial Application Field] The present invention relates to a novel pyrazine derivative and a platelet aggregation inhibitor or anti-inflammatory agent 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.

[Prior Art and Problems to be Solved by the Invention] Various pyrazine derivatives having antiplatelet aggregation effects are known, but there is a desire for the emergence of more improved drugs. In addition, thrombosis such as myocardial infarction and cerebral thrombosis has recently become a large proportion of adult diseases, and there is a strong desire for an antithrombotic agent that can effectively prevent this. Furthermore, existing anti-inflammatory drugs, such as aspirin and indomethacin, have a damaging effect on the gastric mucosa, which poses a problem as a side effect.

The present inventors have synthesized many novel pyrazine derivatives and have conducted intensive research on their pharmacological activities. As a result, certain pyrazine derivatives have excellent platelet aggregation inhibitory effects and anti-inflammatory effects, and are also known to have harmful effects on the gastric mucosa. They discovered that the effect was small and completed the present invention.

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 problems]

In order to achieve this object, the present invention has the following configuration.

1) General formula (I) (wherein X represents a hydrogen atom, a halogen atom, a cyano group, a lower alkyl group, a lower alkylamino group, a di-lower alkylamino group, or a lower alkoxy group, and ring A is the formula %) A pyrazine derivative having ( ) ).

2) A platelet aggregation inhibitor containing the pyrazine derivative according to item 1 above.

3) An anti-inflammatory agent containing the pyrazine derivative described in item 1 above.

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

The pyrazine derivatives having the general formula (I) of the present invention include a benzyl derivative having the formula (II) (in the formula, X has the same meaning as described above) and a 1,2-diamine derivative (m) 2N (in the formula, the ring A dihydropyrazine derivative (IV) (wherein X and the ring have the same meaning as above) obtained by heating A has the same meaning as above in a suitable organic solvent (e.g. ethanol). 100-1 with sulfur
Manufactured by heating at 80°C.

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 30-600 mg per adult daily dose;
It is preferable to administer the drug in 1 to 3 divided doses if necessary.

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.

(Left below) Example 1 Synthesis of 2.3-bis(p-methoxyphenyl)benzo[g]quinoxaline Anisyl (1,350g, 5mmoR), 2,3-
Diaminonaphthalene (0,79g, 5mmof1)
A solution of M e OH (50 ml) was heated to reflux for 8 hours. After cooling, the precipitated crystals were collected by filtration, and the obtained crystals were subjected to medium pressure silica gel chromatography (column: Kiesel
gel [io.

230-400 mesh, manufactured by Merck, 20mm
200m+.

When attached to solvent hexane:ethyl acetate-1=1), 2.
3-bis(p-methoxyphenyl)benzo[g]quinoxaline (1.40 g, 71%) was obtained. Melting point 185~
1.87°C (pale yellow needle crystals, recrystallized from MeCN).

Calculated value for elemental analysis value C26H2oN202: C
,79,5B, H,5,14; N, 7.14 Experimental value: C,79,63,H,5,L4. N, 7.2
9Mass: m/z 392 (M)'H-
nmr (CDC, lJ 3/TMS): δ3.80 (
S, 6H), 6.87 (d, J=9Hz, 4H), 7.
50 (+n, 211), 7.53 (d.

J-9Hz, 4)1), 8.05(dd, J-B
and 3Hz, 2H), 8.67(s, 2H)p
p.m.

Example 2 Synthesis of 2.3-bis(p-methoxyphenyl)benzo(f)quinoxaline Anisyl (1,350 g, 5 mmail), 1
．． 2-diaminonaphthalene (0.79 g, 5 mmo
M e OH solution of ρ)] O solution (50 ml) was heated under reflux for 8 hours. After cooling, the precipitated crystals were collected by filtration, and the obtained crystals were subjected to medium pressure silica gel chromatography (column: Kieselgel 80°2
30-400 mesh, manufactured by Merck, 20 mm x 200
m mouth.

When attached to solvent hexane:ethyl acetate=1:1), 2.
3-bis(p-methoxyphenyl)benzo(f)quinoxaline (0.52 g, 27%) was obtained. Melting point 165~
166°C (colorless needle crystals, recrystallized from MeOH).

Calculated value for elemental analysis value C26H2oN202: C
,79,58,H,5,14,N, 7.14 Experimental value:
C, 79, 72, H, 5, 04, N, 7.27 Ma
ss: mHz 392 (M")'H-nmr
(CDCj) 3/TMS): δ3.77 (s, 8H)
, 8.80 (d, J=9Hz, 4H), 7.53 (d,
J-9Hz, 4t(), 7.63(dj-9Hz, 2H
), 7.87 (m, 3H), 7.97 (s.

2H), 9.28 (m, LH) ppm.

Pharmacological test example 1 Platelet aggregation inhibitory effect After collecting 1,710 volumes of 3.8% sodium citrate blood from the rabbit carotid artery, the blood was centrifuged and platelet-rich plasma (P
RP: 5x105 pieces/μQ).

Put 200 μQ of the PRP and 25 μQ of saline into a cuvette, set it in an alibometer, and heat it at 37°C for 2 minutes.
After adding μQ and incubating for 3 minutes, an 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 (80 μM) or collagen (15 μg/ml) 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 means that the platelet aggregation ability is 100% 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.

1 2 Pharmacological Test Example 2 Cyclooxygenase Inhibition Effect Using a cannula, collect 9 volumes of blood per 1 volume of 3.8% sodium citrate solution into a centrifuge tube from the rabbit carotid artery. Obtain platelet-rich plasma by centrifugation. Add 1/10 volume of 77 mM EDTA solution to platelet-rich plasma, mix well, and centrifuge at 2500 rpm for 10 minutes at room temperature. Discard the supernatant and wash solution (sodium chloride 13
4mM, Trisamifugu 2F15 5+nM was dissolved in distilled water and diluted with 1N hydrogen chloride.I)87
．． 4) Resuspend the platelets in approximately 3 ml and centrifuge at 2000 rpm for 10 minutes at room temperature. Discard the supernatant, resuspend the precipitated platelets in 1/15M phosphate buffer, pH 8.0, and reduce the number of platelets to 6 to 8 x 10/.
Adjust to μQ.

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

Place 3 μg of arachidonic acid and 0.2 μCi (1 g) of 14C-labeled arachidonic acid (toluene solution) in a test tube with a stopper, and add propylene glycol/ethanol mixed acid (1 g) to a test tube with a stopper.
3 volumes) and evaporate the ethanol and toluene under nitrogen gas. Add 50 μg of the sample solution, further add 500 μQ of washed platelets, and react at 37° C. for 3 minutes.

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

After transferring the supernatant to a flask and concentrating, the residue was dissolved in 100μQ ethanol and placed on a thin silica gel plate (Merck, 60F).
254), spot the entire amount.

Developing solvent (chloroform/methanol/acetic acid/water-90
: 8 : 1 : 0.8), and the sum of the radioactivities of prostaglandin E2, prostaglandin D2 and HHT was measured using a radiochromatography scanner to determine the inhibitory activity. The results are shown in Table 2.

In addition, it was confirmed that pyrazine derivatives according to the present invention not shown in Table 2 also have similar activities.

Table 2 Cyclooxygenase inhibitory activity Pharmacological test example 3 Gastric mucosal damage effect of pyrazine derivative of the present invention Experimental group Control group (5% Tween 80) n-4
Indomethacin 30a+g/kg n −
4 Aspirin 100 mg/kg n = 4 Compound of Example 2 30 n+g/kg n -5 Experimental Method Rats fasted for 24 hours (Wjstar-imamic
The test substance was orally administered to hi), and the mice were exsanguinated to death 3.5 hours later. The pylorus and cardia of the stomach were ligated, 1% formaldehyde (LOML) was injected into the stomach, the stomach was removed, 5 6 incisions were made, and the number of ulcers formed on the stomach wall was counted under a stereomicroscope. Incidentally, ulcers whose length was 0.5 m or more were counted.

The results are shown in Tables 3 and 4 and FIG.

Table 3 Examination of the gastric mucosal damaging effect of pyrazine derivatives Table 4
When testing the number of ulcers*, a significant difference was observed with aspirin at a risk rate of 5% or less.

A significant difference was observed below.

(Left below) Acute 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
The D5o values were all 300 mg/kg or higher, 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 suppress platelet aggregation induced by arachidonic acid or collagen. It can be used as a prophylactic agent for related 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.

Furthermore, the compound of the present invention causes less damage to the gastric mucosa than anti-inflammatory agents such as indomethacin and aspirin.

[Brief explanation of drawings]

FIG. 1 is a graph showing the number of gastric ulcers when each drug was administered.

Claims (1)

[Claims] 1) General formula (I) ▲ Numerical formulas, chemical formulas, tables, etc. ▼ (I) (In the formula, X is a hydrogen atom, a halogen atom, a cyano group, a lower alkyl group, a lower alkylamino group, a A pyrazine derivative that represents a lower alkylamino group or a lower alkoxy group, and ring A has the following formula: 2) A platelet aggregation inhibitor containing the pyrazine derivative according to claim 1. 3) An anti-inflammatory agent containing the pyrazine derivative according to claim 1.