Síntese de análogos estruturais de aminoguanidinoidrazonas planejadas como protótipos de fármacos anti-hipertensivos e protetores contra infarto do miocárdio e nova metodologia para formação de ligação C-N em meio aquoso

Abstract

The Systemic Arterial Hypertension (SAH) has a high prevalence and low rates of control and its major complication infarction. In the center of the genesis of these diseases are found the Advanced Glycation Endproducts (AGEs), whose first inhibitor described was the aminoguanidine. Amongst the therapeutic arsenal available for treating hypertension are the guanidines agonists of α2-adrenergic receptors of central action. Given the high prevalence of hypertension and high mortality rates associated with complications of the disease, this work proposes the synthesis of aminoguanidinehydrazones (AGH) with potential application for the treatment of hypertension and at another time, the creation of rigid molecular frameworks for these flexible AGHs that allow the obtention of prototypes that, retaining the anti-hypertensive activity, are useful for prevention of damage caused by ischemic heart disease. It was synthesized 20 AGHs with different aromatic substituents, which yields ranged from about 70 to 90%, using classical methods of condensation between aminoguanidine and different aromatic aldehydes, being described here for the first time the antihypertensive activity for one of them, the compound 234, also known as LQM01. Among the synthesized AGHs, four were selected to serve as the basis for the synthesis of rigid analogs, and 25 different substances were obtained with yields ranging around 40 to 90% using a variety of synthetic strategies. Of these 25 substances, 13 are new, there are no reports in the literature of its synthesis and / or pharmacological activities. In a second step, this paper also proposes a new methodology development study for the reaction of carbon-nitrogen bond formation in aqueous medium catalyzed by copper in order to contribute to the arsenal of currently available reactions for arylation of primary amines and amides, with a reaction that is easy to perform, inexpensive and environmentally friendly. Two new methods were developed, one allowing the arylation of primary amines and other the arylation of primary and secondary amides and certain heterocyclic amines, both supplemented with TPGS using water as solvent and glucose as a reducing agent. In the arylation of primary amines model we bring here 34 examples of reactions, including different aliphatic and aromatic amines and aromatic and heteroaromatic halides with yields ranging around 50 to 90%. We also bring 34 examples of reactions with the catalyst system to arylation of amides, including reactions with aromatic and aliphatic amides, a lactam, aryl and heteroaryl halides, and also some heterocyclic amines with yields ranging around 60 to 90%. This work allowed two important contributions, one in the field of Medicinal Chemistry, with the synthesis of novel derivatives rigid molecular frameworks of AGHs with potential application in cardiovascular disease and other contribution in the field of Synthetic Organic Chemistry, with the development of new methodologies for C-N bond formation in an aqueous medium and with the use of sustainable additives.