1,8-Naphthyridines V. Novel N-substituted 5-amino-N,N-diethyl-9-isopropyl [1,2,4]triazolo[4,3-a] [1,8]naphthyridine-6-carboxamides, as potent anti-inflammatory and/or analgesic agents completely devoid of acute gastrolesivity

Most N,N-disubstituted 5-amino-N,N-diethyl-9-isopropyl [1,2,4]triazolo[4,3-a] [1,8]naphthyridine-6- carboxamides 9 (compounds 9a, c–i) and the N-monosubstituted one 8c were obtained by treating with excess amine the corresponding 5-chloroderivative 7a, which was in turn prepared by cyclocondensation of the 2,4-dichloro-N,N-diethyl-1,8-naphthyridine-3-carboxamide (4a) with isobutyrohydrazide. Compounds 8a,b and 9b,j–m were obtained according with the methods shown in Scheme 1. The above now synthesized compounds, along with the previously described 8d and 8e, were tested for their anti-inflammatory, analgesic and antipyretic properties, and most compounds also for their effect on spontaneous mice locomotor activity and their acute gastrolesivity in rats. Several compounds showed potent anti-inflammatory and/or analgesic activities, and all the compounds tested proved to be completely lacking in acute gastrolesivity. In many cases compounds 8 and 9 produced hypothermic effect, usually at high doses. On the whole, the N-monosubstituted 5-aminoderivatives 8 appeared to be more potent anti-inflammatory agents than the corresponding N,N-disubstituted 9, whereas these latter compounds exhibited higher analgesic activity.