Design and Synthesis of Differentially Substituted Chiral Aminomethyl Piperidine Derivatives as Potential Antithrombotics

Abstract

Arterial thrombosis is the acute complication that develops on the chronic lesions of atherosclerosis and causes heart attack and stroke, today the most common causes of mortality in developed countries. On the basis of current estimates from the American Heart Association, more than 60 million people in the United States alone have one or more forms of cardiovascular disease, and a high proportion of these individuals are at increased risk of arterial thrombosis. The participation of platelets in atherogenesis and the subsequent formation of occlusive thrombi depend on platelets’ adhesive properties and the ability to respond to stimuli with rapid activation. By understanding the multifaceted mechanisms involved in platelet interactions with vascular surfaces and aggregation, new approaches can be tailored to selectively inhibit the pathways most relevant to the pathological aspects of atherothrombosis. The present study embodiment is an integrated approach towards designing and synthesis of various amino acids derived, constrained lactam scaffolds bearing carboxylate functionality. Our reticently diagnosed chiral cyclic diamines on amide coupling with the above said carboxylate moieties furnished compounds with interesting platelet adhesion inhibitory activities through the marked attenuation of platelet-collagen adhesion. First Chapter, Chapter-1a, entitled ‘Platelets in atherothrombosis: Triggers, targets and treatments for thrombosis’ reviews the haemostasis phenomenon along with the centrality of the platelet in atherothrombosis and briefly looks at the efficacy of antiplatelet agents in preventing and treating cardiovascular disease. The Chapter provides an elaborative explanation of different platelet receptors agonists and antagonists and their role in primary haemostasis. Chapter-1b, ‘Basis of Work’ reviews the antiplatelet activity of N-heterocyclic carboxamides with a basic group. The chapter also explains the interest behind the designing of cyclic diamine scaffold, essentiality and influence of the 3-functional group and the importance of the chiral centre at the 3-position of the piperidine ring of the basic diamine part. Chapter-2 narrates our efforts towards the detailed account of the work which has been carried out for the design and synthesis of chiral 3-aminomethylpiperidine and more lipohilic, rigid bispidine derivatives of N-substituted pyroglutamic acids. This chapter also describes the exploratory work to further assess the amendment of piperidine ring 3- substituent of the cyclic diamines and modification of carboxamide linkage in the search of enhanced activity results. Chapter-3 encompasses the synthesis of N-substituted oxazolidine & thiazolidine carboxamides with selectively protected chiral 3-aminomethyl piperidine moiety. Taking account of the importance of ring sizes of the lactam on biological potency, we incorporated the synthesis of N-substituted 6-membered lactams and their carboxamide derivatives in this part. Alkylation of pyroglutamates has found to be essential in order to expand the range of glutamate analogues and to study their biological properties. Therefore Chapter- 4 describes our efforts to utilise the C-4 position of N-aryl pyroglutamic acid followed by the synthesis of corresponding pyroglutamides. Chapter-5 compiles the chapter wise activity results for all the molecules and discusses the SAR results. We are so proud to proclaim that the compound, S-007-867 thus prepared as a part of this study seems to be a potential candidate as an antithrombotic drug due to its specific inference with collagen mediated platelet adhesion and activation. Further, the compound S-010-1639 exhibited its anti-platelet efficacy through dual mechanism inhibited both collagen as well as U46619 induced platelet aggregation.