JPS61212522A - Platelet coagulation inhibitor - Google Patents

Abstract

PURPOSE:To provide the titled inhibitor containing a pyrazine derivative and effective also for the prevention of cancer metastasis. CONSTITUTION:The objective platelet coagulation inhibitor can be produced by using the compound of formula as an active component. It is useful as a preventive for diseases caused by the coagulation of platelet, i.e. thrombosis, metastasis of cancer, etc. Dose: 30-600mg daily, if necessary in 1-3 divided doses. It is administered preferably by oral administration, however, it can be administered also by intravenous injection. It is used in the form of tablet, powder, capsule, granule, etc., using a carrier or diluent such as calcium carbonate, calcium phosphate, starch, sucrose, lactose, talc, magnesium stearate, etc. It may be used as a liquid medicine such as suspension in oil, syrup, etc., or may be stabilized by including the compound with cyclodextrin.

Description

Detailed Description of the Invention (5) Background of the Invention Technical Field The present invention relates to a platelet aggregation inhibitor. The piratine derivative represented by the formula (I) used in the present invention has a strong platelet aggregation inhibitory effect fjI:v. Therefore, it is effective in preventing diseases caused by platelet aggregation, such as thrombosis. Furthermore, it is known that platelet aggregation is also involved in cancer metastasis, and the platelet aggregation inhibitor of the present invention also has a preventive effect on cancer metastasis.

Prior Art Various substances having antiplatelet aggregation effects are known, but
The effect is weak, and it is hoped that a drug with improved effects 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 an antithrombotic agent that prevents this tV effect. Although the substance represented by the above general formula (1), which is an active ingredient of the platelet aggregation inhibitor of the present invention, is a known substance, it is not yet known to have a platelet aggregation inhibitory effect.

■0 Purpose of the Invention The present inventors synthesized piratin derivatives and conducted extensive research on their pharmacological activities. As a result, they discovered that the piratin derivatives used in the present invention have an excellent platelet aggregation inhibiting effect. She was able to give birth to a child.

Therefore, an object of the present invention is to provide a potent platelet aggregation inhibitor containing a pyratine derivative represented by the above formula (I). The piratene derivatives used in the present invention have a strong platelet aggregation inhibitory effect, and are useful as preventive agents for diseases caused by platelet aggregation, such as hematocytosis and cancer metastasis.

The present invention, which achieves this object, is a platelet aggregation inhibitor containing a piratin derivative represented by general formula (1). In the present invention, the term "platelet aggregation inhibitor" refers to a preparation that has the effect of inhibiting platelet aggregation.

■0 Detailed Description of the Invention The pitchin yeast conductor used as an active ingredient or one of the active ingredients in the present invention is described, for example, in the document r Het.
eroc7cles J (Volume 22, No. 2317-2
321, published in 1984).

The piratine derivative used in the present invention is effective for diseases caused by platelet aggregation, but is particularly used as a cerebral thrombosis agent or a tr/metastasis preventive agent, and the dosage is generally about 30 to 600 μl per day for adults. and 1 if necessary
It is best to administer in ~3 doses. The method of administration can be any form suitable for administration, particularly oral administration is preferred, but intravenous injection is also possible.

The compound used in 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, salt, lactose, Merck, magnesium stearate, and the like. In addition to the above-mentioned solid preparations, the present invention can also be made into liquid preparations such as oily suspensions, syrups, and liquids.

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

Next, examples and test examples will be shown to explain the present invention. I will explain it in a more different way.

Examples include the literature r Heterocycles
2,3-diphenyl-5-
Methylpyrazine was synthesized.

Test Example Platelet Aggregation Inhibition Effect 3.9 volumes of blood were collected from a rabbit carotid artery using a syringe containing 8 sodium citrate solution (1 volume). The blood is centrifuged to obtain platelet-rich plasma (PRP: 7
x105 pieces/μt).

The PRP268 μt was placed in a cupette, heated for 2 minutes in a 37°C constant temperature bath, 2 μtft of an ethanol solution of the piratin derivative to be tested was added, and incubated for 3 minutes. Then, an arachidonic acid bath solution or a collagen solution, which is an aggregation-inducing agent for platelets, was added and the platelets were incubated. Aggregation is determined by Born's nephelometric method [for example, Journal og Physioloso (J,
Physiol, Vol. 168, p. 178, published in 1968). arachidonic acid (
50 micromol), collagen (10 μf/ld)
Table 1 shows the 50% inhibitory concentration for platelet aggregation induced by acetylsalicylic acid as a comparative example.

As a result of the test, significant anti-platelet aggregation activity was found as shown in Table 1 below. In addition, the 50th inhibition concentration in the table refers to the pyratine derivative used in the present invention. When the aggregation ability of platelets without introduction is taken as 100%, it means the concentration of piratin derivative f@ solution required to suppress the aggregation ability of platelets to 50% after introduction of the piratin derivative.

Table 1 Anti-blood platelet agglutination activity Acute toxicity An acute toxicity test was conducted by oral administration using ICE male mice (5 weeks old). L of the compound used in the present invention
Both Dso values are 4001! q/ is 9 or more,
High safety was confirmed.

■6 Effects of invention The present invention provides a powerful platelet aggregation inhibitor.

The pyratine derivative used in the present invention is arachidone@
Alternatively, since the platelet aggregation effect induced by collagen is significantly suppressed, the present invention can be used to treat diseases caused by platelet aggregation, particularly thrombosis involving platelet aggregation such as myocardial infarction, ischemic attack after cerebral hemorrhage, and cerebral infarction. It can be used as a preventive agent. Furthermore, since platelet aggregation is involved in cancer metastasis, the present invention can also be used as an agent for preventing cancer metastasis.

Claims (1)

[Claims] (1) Platelet aggregation inhibitor containing a piratin derivative represented by the general formula (I) ▲There are mathematical formulas, chemical formulas, tables, etc.▼(I).