Synthesis and structure elucidation of 2,3,5,6,7,8-hexahydro1-H-[1,2,4]triazolo[1,2-a]pyridazine-1-thione, 3,3-disubstituted and 2-substituted derivatives and evaluation of their inhibitory activity against inducible nitric oxide synthase

The 3-monosubstituted 2,3,5,6,7,8-hexahydro-1H-[1,2,4]triazolo[1,2-a]pyridazine-1-thiones 3 (R1, R3 = H) were recently reported to possess inhibitory activity against inducible nitric oxide synthase in a cell based assay (Schulz et al. 2013). The 3,3-disubstituted 2,3,5,6,7,8-hexahydro-1H-[1,2,4]triazolo[1,2-a]pyridazine-1-thiones 3 and 4 (R2, R3 ≠ H) were synthesized by cyclocondensation of the hexahydropyridazine-1-carbothioamides 1 with ketones. In order to access the 3,3-unsubstituted 2,3,5,6,7,8-hexahydro-1H-[1,2,4]triazolo[1,2-a]pyridazine-1-thiones, the unsubstituted parent system of these compounds, several synthetic routes were studied. By these methods the desired heterocyclic system 2a as well as new a-anellated and N-substutited hexahydropyridazines were obtained. The biological evaluation of the title compounds confirmed the previously made finding that an aromatic moiety in position 3 of the substance is important for an inducible nitric oxide synthase (iNOS) inhibitory activity.