Investigations on 5,6,7,8-tetrahydro-[1,2,4]triazolo[1,2-]pyridazin-1-amines and related compounds: synthesis, chemical behaviour, structure elucidation and iNOS inhibitory activity.

The present work reports on the preparation of the hitherto unknown title compounds with various synthetic routes described. The initially pursued concept of S-N exchange with varioius 1-substituted 3-methylsulfanyl-5,6,7,8-tetrahydro-1 -[1,2,4]triazolo[1,2- ]pyridazines by using nitrogen nucleophiles was only marginally successful. The reactions proceeded slowly and the yields were low, mainly because of the pronounced formation of 5,6,7,8-tetrahydro-[1,2,4]triazolo[1,2- ]pyridazin-1-imines by oxidation of the heterocyclic amines initially formed. The integration of the synthesis of 3-acylsulfanyl analogues with the more reactive leaving groups also failed. On the other hand, the cyclization of the hydrohalides of hexahydropyridazine-1-carboximidamide with aromatic aldehydes and some low molecular weight ketones gives significantly better results in the synthesis of the title compounds . The use of the hydrochloride proved to be advantageous in comparison to the hydroiodide because the yields were significantly better and the imines formed at the same time only to a small extent. In addition, the starting compound can be prepared in a single-step synthesis in very good yield from hexahydropyridazine hydrochloride and cyanamide. The cyclization of -phenylhexahydropyridazine-1-carboximidamide hydrochloride with substituted benzaldehydes gives the 3-aryl-substituted 2-phenyl-2,3,5,6,7,8-hexahydro -[1,2,4]triazolo[1,2- ] pyridazin-1-imines . In the context with the study of the reaction of hexahydropyridazine-1-carboximidamide hydroiodide with cyclohexanone, the hexahydropyridazine-1-carboxamide was specifically synthesized. This can be reacted with aromatic aldehydes to give the 5,6,7,8-tetrahydro-1 -[1,2,4]triazolo[1,2- ]pyridazin-1-ones in very good yields. The results of the biological testing of representatives of the synthesized 5,6,7,8-tetrahydro-[1,2,4] triazolo[1,2-a]pyridazine-1-amines show, in comparison to the already examined thions and 3-methylsulfanyl derivatives significantly less inducible nitric oxide synthase (iNOS) inhibitory activity.