Anti-thrombotic compounds

Abstract

New compounds, namely, (7aS,2′S)-2-oxoclopidogrel and its pharmaceutically acceptable salts thereof are disclosed for treatment or prophylaxis of thrombo-embolism and / or cardiovascular diseases.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS[0001]The present application claims priority to Indian Patent Application No. 1848 / MUM / 2011, filed Jun. 27, 2011, the entire disclosure of which is incorporated by reference herein.TECHNICAL FIELD OF INVENTION[0002]The present invention relates to anti-thrombotic compounds, specifically substantially pure isomer of an intermediate metabolite of clopidogrel, namely, (7aS,2′S)-2-oxoclopidogrel and its pharmaceutically acceptable salts thereof. The present invention also relates to a method of ameliorating the drawbacks of the anti-platelet drug, clopidogrel, said method comprises administration of isolated substantially pure isomer of (7aS,2′S)-2-oxoclopidogrel in its free or pharmaceutically acceptable salt form for alleviating the symptoms of thrombosis and / or embolism by inhibiting blood platelet aggregation.BACKGROUND OF THE INVENTION[0003]Conditions resulting from thrombotic or thromboembolic events are the leading causes of illness and dea...

AI Technical Summary

Benefits of technology

[0020]Thus in an aspect, the present invention provides isomerically enriched & substantially pure isolated (7aS,2′S)-2-oxo-clopidogrel {chemical Name: Methyl (7aS,2′S)-2-(2-chlorophenyl)-2-(2,4,5,6,7,7a-hexahydrothieno[3,2-c]-5-pyridin-2-one)acetate} and its pharmaceutically acceptable salts for pharmaceutical application. The compound of the present invention is substantially stable to manufacture in substantially pure state and also for the manufacture of drug products (formulations) for long term storage and pharmaceutical use. The compound of the present invention is substantially free of other isomers for example, compound of Formula VI, and Formula VII, apart from isomer of Formula IIB. Substantially free herein means the levels of these compounds individually or cumulatively are less than 10%, preferably less than, 5%, more preferably less than 3%, still more preferably, less than 1.0%.

[0024]In preferred embodiments of this aspect of the present invention, the method achieves a therapeutic effect substantially greater to that observed following the administration of a substantially higher dose of clopidogrel due to the elimination of unwanted metabolic products and other isomers in the administration of clopidogrel.

[0029]According to a fourth aspect of the present invention, there is provided a method for minimizing inter individual platelet reactivity variability and metabolic loading in the treatment and / or prophylaxis of thrombosis and / or embolisms observed following administration of a dose of clopidogrel said method comprising administering substantially pure (7aS,2′S)-2-oxoclopidogrel or its pharmaceutically acceptable salt to a patient in need thereof.

Problems solved by technology

Conditions resulting from thrombotic or thromboembolic events are the leading causes of illness and death in adults in western civilization.

Unregulated activation of the hemostatic system has the potential to cause thrombosis and embolism, which can reduce blood flow to critical organs like the brain and myocardium.

These thrombi often form in leg veins and can break off and embolize to the pulmonary circulation.

These arterial thrombi may readily dislodge from the arterial wall and embolize to distant sites to cause temporary or permanent ischemia.

This is particularly common in the cerebral and retinal circulation and may lead to transient neurologic dysfunction (transient ischemic attacks) including temporary monocular blindness (amaurosis fugax) or strokes.

However, clopidogrel has several potential limitations.

Third, almost all clinical trials involving clopidogrel reveal that therapeutic levels of platelet inhibition are not achieved in a majority of patients because of large inter-individual variability in response to clopidogrel treatment.

Treatment of patients with a recently approved drug, namely, prasugrel rendered them susceptible to bleeding episodes, which may be life threatening, restricting its application in patients having a body weight of less than 60 kg and age of more than 75 years.

Therefore there are unmet medical needs, which are not being offered by the current therapy options such as clopidogrel and prasugrel.

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