HK1076034B - Novel association of an antithrombotic agent with aspirin and use thereof for the manufacture of a medicament for treating atherothrombotic diseases - Google Patents

Description

New combination of an antithrombotic agent with aspirin and use thereof for the preparation of a medicament for the treatment of atherothrombotic diseases

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The present invention relates to novel combinations of an antithrombotic agent with aspirin and pharmaceutical compositions containing them.

More specifically, the present invention relates to combinations of TP receptor antagonists with aspirin.

Thromboxane A₂(TXA₂) Is an unstable metabolite of arachidonic acid, which is involved in the pathogenesis of various blood circulation diseases. Thromboxane A₂Not only are potent platelet activators, but also potent vasoconstrictors, which have cell proliferation and pro-adhesion properties.

TXA₂With other metabolites of arachidonic acid, e.g. endoperoxides (PGH)₂) HETE and isoprostaglandin (isoprostane) exert their effects through a co-receptor known as the TP receptor.

A great deal of research has recently been conducted on the prevention of thromboxane A₂Excessive circulating diseases are generated. It has been found that: among the antagonists, those described in patent specification EP 648741 are potent and selective TP receptor antagonists, effective for administration by the oral route and long duration of action.

More specifically, it has been found that: compounds (a) of formula (I) in racemic form or in optically pure isomeric form and their pharmaceutically acceptable salts are potent antithrombotic agents:

the compounds selectively inhibit platelet aggregation caused by TP receptor activation after administration by the oral route, and furthermore have anti-atherosclerotic properties.

We have now found that: the combination of compound a with aspirin surprisingly allows a synergistic effect in terms of antithrombotic activity to be obtained.

The combination of certain anti-platelet aggregation agents, such as dipyridamole, with aspirin has been described in the literature to have an additive effect, and has proven to be very beneficial in preventing cerebrovascular events.

Combinations of other anti-platelet aggregation agents with aspirin have been described in the literature. Due to the fact that: these anti-agglutinating agents act on the platelet aggregation pathway (e.g., purinergic pathway, ADP), unlike aspirin, which acts through the arachidonic acid metabolic pathway, so an additive effect of the activity of these compounds is expected to be observed.

The combinations to which the invention relates are completely different: both compound a and aspirin act on the arachidonic acid metabolic pathway: the former converts arachidonic acid into endoperoxide (PGH) by irreversible inhibition₂) By combating certain metabolites of arachidonic acid, such as thromboxane A₂The activities of isoprostaglandin and endoperoxide play a role.

It has surprisingly been found that: the combination of compound a with aspirin allows to obtain a large synergy in activity, which could not be foreseen by the teachings of any literature.

This synergistic effect has been demonstrated in arterial thrombosis tests performed in guinea pigs. During the test it was shown that: the antithrombotic activity of compound a was enhanced in the presence of aspirin and increased in a very large and completely unpredictable manner.

In the combination of the present invention, compound (a) and aspirin may be present in the form of a pharmaceutically acceptable salt.

Among the addition salts of compound (a), there may be mentioned, without limitation, addition salts with pharmaceutically acceptable bases, such as sodium, potassium, tert-butylamine, and diethylamine salts, and the like.

The sodium salt is preferably used.

Among the aspirin addition salts, mention may be made, without limitation, of addition salts with pharmaceutically acceptable acids, such as acetate, benzoate, fumarate, maleate, citrate, tartrate, lysine salts, and the like.

In the combinations of the invention, the compound (A) preferably has the absolute configuration (R).

The invention also relates to pharmaceutical compositions comprising compound (a) in combination with aspirin, and one or more suitable, inert, non-toxic excipients, where appropriate in the form of pharmaceutically acceptable salts.

In the pharmaceutical compositions of the present invention, more specifically mention may be made of those suitable for oral, parenteral or nasal administration, such as tablets or dragees, sublingual tablets, gelatin capsules, lozenges, suppositories, creams, ointments, dermal gels and the like.

The dosage may vary depending on the nature and severity of the condition, the route of administration, and the age and weight of the patient.

In the composition of the present invention, the amount of the active ingredient is 1 to 300mg of compound (a), 100 to 1000mg of aspirin.

Thus, the compositions of the present invention are useful in the treatment of atherosclerotic thrombotic diseases (atherothrombotic inflammation) associated with TP receptor activation and/or metabolite formation, and in the treatment of the consequences of such diseases. These conditions include, but are not limited to, stable or unstable angina, diseases with endothelial or vascular dysfunction such as hypertension, diabetes, heart failure, cardiovascular or cerebrovascular diseases, or thromboembolic diseases, especially those associated with atherosclerosis.

The combination of the invention has been studied and its synergistic effect has been confirmed in an arterial thrombosis test carried out in guinea pigs.

The assay is based on a model originally described by Roux et al (Thromb Haemost 71: 252-. Guinea pigs were anesthetized with ketamine + xylazine (90+12) mg/kg intramuscular injection. A catheter was inserted into the trachea and the animal was kept breathing spontaneously. A catheter is inserted into the jugular vein so that the test compound can be administered intravenously. The common carotid artery was isolated and a doppler probe was mounted so that arterial blood flow could be measured. After stabilization, arterial wall lesions were made by using a clip at the distal end of the doppler probe. After the manufacturing injury, blood flow is reduced. When the flow reaches zero, the artery is shaken slightly, which can restore the flow. The thrombosis process continues, again resulting in a reduction and cessation of flow. Accordingly, the thrombosis phenomenon resulted in a decrease in Circulating Flow Rate (CFR), which was observed over a period of 20 minutes. After this period, animals were treated with or without compound (a) and observed for CFR again for 20 minutes. The experiment was performed in control animals or in animals treated with aspirin (2mg/kg) by the intravenous route.

The study was performed with the sodium salt of the (R) isomer of compound (a).

The results show that: 10. + -.1 CFR/20 min was observed in untreated animals. Administration of compound (a) by the intravenous route can reduce CFR in a dose-dependent manner; significant effects (5 + -2 CFR/20 min) were obtained from the 0.3mg/kg dose. Almost complete inhibition (2. + -. 2CFR/20 min) was obtained with a dose of 1 mg/kg.

In aspirin treated animals, 8 ± 1CFR/20 min was observed; this value was not different from the value obtained in the control animals.

Compound (a) can reduce CFR in a dose-dependent manner by administering by intravenous route to an animal that has been treated with aspirin; in this case, a significant effect (5. + -. 1CFR/20 min) can be obtained from a dose of 0.01mg/kg, and an almost complete inhibitory effect (2. + -. 1CFR/20 min) can be obtained with a dose of 0.1 mg/kg.

These results demonstrate for the first time the potent antithrombotic activity of compound (a), which is effective from a 0.3mg/kg dose.

Furthermore, the antithrombotic activity of compound (a) is enhanced and increased by at least 30-fold in the presence of a dose of aspirin that does not produce an antithrombotic effect. In fact, the effect was observed from the 0.01mg/kg dose, which indicates that: when both active ingredients are administered simultaneously, there is a very large synergy.

Claims (8)

1. Used for treating thromboxane A₂Combination of a compound of formula (I) or one of its pharmaceutically acceptable salts and aspirin or one of its pharmaceutically acceptable salts, for atherosclerotic thrombotic diseases associated with prostaglandin endoperoxide receptor activation and/or metabolite formation:

2. combination according to claim 1, characterized in that the compound of formula (I) is in the form of an optical isomer of the R configuration.

3. Combination according to claim 1 or claim 2, characterized in that the compound of formula (I) is in the form of the sodium salt.

4. Used for treating thromboxane A₂Pharmaceutical composition for atherosclerotic thrombotic disorders associated with prostaglandin endoperoxide receptor activation and/or metabolite formation, comprising as active ingredient a combination of a compound of formula (I), optionally in optically active isomeric form, or one of its pharmaceutically acceptable salts, and aspirin, or one of its pharmaceutically acceptable salts, in combination with one or more pharmaceutically acceptable inert excipients or carriers

5. Pharmaceutical composition according to claim 4, characterized in that the compound of formula (I) is in the form of an optical isomer of the R configuration.

6. Pharmaceutical composition according to claim 4 or claim 5, characterized in that the compound of formula (I) is in the form of the sodium salt.

7. Pharmaceutical composition according to claim 4 or claim 5, characterized in that the amount of active ingredient is from 1 to 300mg of compound of formula (I), aspirin 10 to 1000mg, respectively.

8. Use of a pharmaceutical composition according to any one of claims 4 to 7 for the preparation of a medicament for the treatment of thromboxane A₂Atherosclerotic thrombotic disease associated with prostaglandin endoperoxide receptor activation and/or metabolite formation.