Substituted quinazolines

Abstract

This invention relates to the discovery of 3- and 5-substituted analogues of the selective platelet lowering agent anagrelide with reduced potential for cardiovascular side-effects which should lead to improved patient compliance and safety in the treatment of myeloproliferative diseases. More specifically, the present invention relates to certain imidazoquinazoline derivatives which have utility as platelet lowering agents in humans. The compounds of the present invention function by inhibiting megakaryocytopoeisis and hence the formation of blood platelets.

Description

[0001]This application is a continuation of U.S. patent application Ser. No. 11 / 946,572, filed Nov. 28, 2007, which claims priority to U.S. Provisional Application Ser. No. 60 / 861,458 filed Nov. 28, 2006. The disclosures of which are herein incorporated by reference in their entirety.FIELD OF THE INVENTION[0002]This invention relates to the discovery of 3- and 5-substituted analogues of the selective platelet lowering agent anagrelide with reduced potential for cardiovascular side-effects which should lead to improved patient compliance and safety in the treatment of myeloproliferative diseases. More specifically, the present invention relates to certain imidazoquinazoline derivatives which have utility as platelet lowering agents in humans. The compounds of the present invention function by inhibiting megakaryocytopoeisis and hence the formation of blood platelets.BACKGROUND OF THE INVENTION[0003]Anagrelide hydrochloride (Agrylin®, Xagrid®) is a novel orally administered imidazoqui...

AI Technical Summary

Benefits of technology

The present invention relates to an improved anagrelide compound that has better pharmacokinetics and tolerability than the original compound. The new compound has lower PDE III inhibitory activity and is more effective in treating patients with various medical conditions. The compound has a unique structure that prevents certain metabolites from being formed, which can improve its safety and effectiveness. The invention also includes a method for making the new compound and pharmaceutical compositions containing it. Overall, the new compound has better properties and can be used to treat more patients with fewer side effects.

Problems solved by technology

However, in the treatment of a so-called silent disease (i.e., asymptomatic) such as ET, the cardiovascular side-effects of palpitations and tachycardia associated with anagrelide limit its utility and a significant proportion of patients—reportedly between 25 and 50%—fail to tolerate the drug during long term treatment.

While initially this property may appear to be beneficial in essential thrombocythemia patients predisposed to greater thrombotic risk, such anti-platelet effects, in excess, could have haemorrhagic consequences and on balance may not be desirable.

The PDE III mediated cardiovascular side-effects associated with anagrelide treatment mean that many patients have to be switched to the only significant alternative therapy, namely that with hydroxyurea.

While anagrelide offers some selectivity in its mechanism of action, the limitations to its use are those associated with cardiovascular effects resulting from its secondary pharmacology and contributed largely by the active metabolite of anagrelide, 3-hydroxyanagrelide.

The metabolism of anagrelide generally proceeds extremely rapidly, resulting in a less than ideal pharmacokinetic profile of the drug.

This, combined with the side-effects profile, can lead to poor patient compliance.

Furthermore, anagrelide undergoes a large first pass effect (>50%) leading to considerable intersubject variation in achieved exposures and, therefore, potentially variable drug response.

Overall, this may result in the need for careful dose titration in patients being treated with anagrelide.

However, this disclosure does not appreciate the entirely separate anti-megakaryocytic potential (reducing platelet numbers) which could be associated with some analogues.

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