Agent inhibition of platelet aggregation


(57) Abstract:

2-Semicarbazone 1,2-naphthoquinone is used as an agent for inhibiting platelet aggregation. The drug after administration of 10 mg/kg/day to rats significantly inhibits platelet aggregation caused by ADP or thrombin. table 1.

This invention relates to new uses of derivatives of beta-naphthoquinone, and their salts.

Special patent medicine 954 M describes the use of medicines derived beta-naphthoquinone. In this patent, these derivatives are described as having hemostatic properties and vitamin properties.

It is known that platelets interact with coagulation factors and components of the walls of blood vessels and play a major role, on the one hand, favorable to maintain the integrity of blood vessels in hemostasis and, on the other hand, adverse, causing thrombosis and the development of atherosclerose.

Continuing the study of the above-mentioned derivatives of beta-naphthoquinone, quite unexpectedly, the applicant has found that these latter possess significant inhibitory activity against platelet aggregation.

Thus, this application concerns a new note is NH-CO-CH3or hydroxyl, and their additive salts of pharmaceutically acceptable mineral or organic acids, for receiving the medicines, allowing to inhibit platelet aggregation.

Additive salts with pharmaceutically acceptable mineral or organic acids can be, for example, salts formed with hydrochloric acid, hydrogen bromide, idestam hydrogen, nitric, sulfuric, phosphoric, propionic, formic, benzoic, maleic, fumaric, succinic, tartaric, citric, oxalic, glyoxalase, aspartic acids, alkanesulfonyl, such as ethane-sulfonic acids and arylsulfonate, such as benzosulfimide.

Among the derivatives of beta-naphthoquinone General formula (1) include, in particular:

the compound of formula (1), where R is the group-NH-CO-NH2and its additive salts with pharmaceutically acceptable mineral or organic acids;

the compound of formula (1), where R is the group-NH-CO-CH3and its additive salts with pharmaceutically acceptable mineral or organic acids;

the compound of formula (1), where R is oxygraph and its additive salts with pharmaceutically acceptable mineral or org to obtain drugs, allowing to inhibit platelet aggregation, can be distinguished, in particular, 2-semicarbazone 1,2-naphthoquinone, better known under the international name of naftazone. In the experimental part of this product is marked with the international abbreviation DCI.

High inhibiting platelet aggregation activity, illustrated below in the experimental part, derived beta-naphthoquinone of formula (1) described above, as well as their additive salts with pharmaceutically acceptable mineral or organic acids can be used, for example, in the treatment or prevention of arterial thrombolytic complications (cerebrovascular disorders, myocardial infarction) or diseases of the veins (phlebitis) and all cardiovascular diseases associated with atherosclerosis (particularly the brain), in the treatment and prevention of ischemic complications in the treatment of trombotsitnoy disorders.

The usual dose, changing depending on the product, treat the patient and the disease may be, for example, a dose of from 1 mg to 100 mg per day, introduced through the mouth or injected. At least one of these compounds can be in pharmaceutical compositions as an active start.

E is Oh, commonly used in medicine, as, for example, tablets, coated tablets, gelatin pills, capsules, granules, suppositories, drugs or injections; they are obtained in the usual way. One or more active principles can be put into the excipients usually used in pharmaceutical compositions, such as talc, gum Arabic, lactose, starch, magnesium stearate, cocoa butter, aqueous or non-aqueous media, animal or vegetable fats, various wetting, dispersing agents, emulsifiers, preservatives.

Methods of obtaining derivatives of beta-naphthoquinone of formula (1) and their salts are described in the technical literature. In particular, we can cite the methods described in the special patent on a medicine 924 M or in the French patent 2103504.

The following are non-limiting examples of the nature of pharmaceutical compositions that may be used in carrying out the invention.

Example 1. Received the tablets of the following composition:

Naftazone 10 mg

Excipient in sufficient quantity for one of the finished tablets 150 mg

(Example excipient: lactose, starch, talc, magnesium stearate).

Example 2. Was received injection of the following composition:

Naftazone is Casona in 200 ml of acetic anhydride. After heating for 10 h at 140oC, and then cooling, filtration, extraction of the precipitate with chloroform, evaporation to dryness, the absorption of ethanol, treatment with activated carbon, filtration and slow crystallization gain of 5.1 g of product corresponding to the formula (1), where R = -NH-CO-CH3(microcrystalline powder, ochre-yellow, so pl. = 137 - 138oC).

Pharmacological studies.

1 - Inhibition of platelet aggregation. Currently, many compounds can inhibit platelet function, but only two aspirin and ticlopidine have recognized activity: inhibition of platelet aggregation outside of a living organism (ex vivo).

Therefore, naftazone emanated compared with ticlopidine and aspirin out of the living organism on the rat and, in another case, in vitro on platelet rats and humans.

In the test tube. Platelet aggregation in humans and rats, tanned from their plasma induced by adenosine diphosphate (ADP) or thrombin, in the presence of different concentrations of naftazone (10-4M to 10-8M) significantly and statically decreased significantly. The reduction was 70 - 20% for concentrations of naftazone respectively from 10-4M to 10-6M.

the following sequential injection of 10 mg/kg/day of naftazone, the inhibition of platelet aggregation caused by ADP or thrombin, was substantial and statistically significant (table).

The results of the aggregation induced by thrombin or ADP, expressed in percent optical transmittance (average C. O.). The number of one and the same column bearing the same letters differ statistically significantly (at least p < 0,05) according to the method of aggregation Newman-Keuls.

Thus, the results show that in these experimental conditions naftazone inhibits platelet aggregation caused by ADP or thrombin. This inhibition demonstrated in vitro in human platelets and platelets of rats, confirmed outside of a living organism in rats. In addition, this effect is equivalent to the action of ticlopidine and aspirin at the same conditions.

S. O. = Standard otklonenie

Application 2-semicarbazone 1,2-naphthoquinone as an agent that allows you to inhibit platelet aggregation.


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