Preparación de bisheteroarilos mediante metodología radicalaria intramolecular. Obtención y estudio farmacológico de nuevos análogos de paracetamol no hepatotóxicos

Resumen

Biaryls and heterocyclic aryl derivatives are a valuable synthetic scaffold for the obtaining of compouds with biological and medical interest. However, the preparation of these kind of compounds is challenging and synthetic procedures available are limited, but their synthesis via a intramolecular heteroaryl radical addition to arenes would represent a straightforward pathway to access to bisaryls. In this thesis, an new method for the preparation of bipyridines has been developed, consisting on the intramolecular addition of pyridyl radicals onto another pyridine interconnected by a linker containing a sulfonamide, using transition-metal free methodology and in the presence of tris(trimethylsilyl)silane (TTMSS) and azobisisobutironitrile (AIBN), obtaining aminobipyridines and/or bipyridin sultams. Following with the bis (hetero)arylation process via a radical pathway, the ß-carboline core was chosen as a good candidate to expand our methodology, preparing 1-Pyridin-3-yl-ß-carboline derivatives from a pyridine sulfonamide, through a heterobiarylsultam intermediate, by a facile method oriented to generation of molecular diversity by means of the substitution with different nucleophiles. In the section dedicated to Medical Chemistry, a new series of analgesics based on the structure of paracetamol have been developed. The structural modifications consisted on the insertion of a saccharin moiety onto the methyl group of paracetamol and subsequent ring opening of the saccharine heterocyclic moiety, supplying the corresponding N-substituted amides. Biological studies showed that the resulting compounds improved the in vivo analgesic profile of paracetamol, while the hepatotoxicity was considerably decreased. Finally, in this thesis the results obtaining during the predoctoral stay at the University of Hamburg are reported, consisting on the development of new luminol derivatives substituted in position C7 with different electron-withdrawing (EWG) or electron-donating (EDG) groups with the aim to obtain more information about the chemiluminescence mechanisms and the effect of the substituents.