Investigations on 5,6,7,8-tetrahydro-[1,2,4]triazolo[1,2-<i>a</i>]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 <b>5,</b> 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 <i>H</i> -[1,2,4]triazolo[1,2- <i>a</i> ]pyridazines <b>4</b> 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- <i>a</i> ]pyridazin-1-imines <b>7</b> by oxidation of the heterocyclic amines <b>5</b> 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 <b>5</b>. The use of the hydrochloride <b>6b</b> proved to be advantageous in comparison to the hydroiodide <b>6a</b> because the yields were significantly better and the imines <b>7</b> formed at the same time only to a small extent. In addition, the starting compound <b>6b</b> can be prepared in a single-step synthesis in very good yield from hexahydropyridazine hydrochloride <b>1</b> and cyanamide. The cyclization of <i>N'</i> -phenylhexahydropyridazine-1-carboximidamide hydrochloride <b>6c</b> with substituted benzaldehydes gives the 3-aryl-substituted 2-phenyl-2,3,5,6,7,8-hexahydro <i>-1H</i> -[1,2,4]triazolo[1,2- <i>a</i> ] pyridazin-1-imines <b>8</b>. In the context with the study of the reaction of hexahydropyridazine-1-carboximidamide hydroiodide <b>6a</b> with cyclohexanone, the hexahydropyridazine-1-carboxamide <b>9</b> was specifically synthesized. This can be reacted with aromatic aldehydes to give the 5,6,7,8-tetrahydro-1 <i>H</i> -[1,2,4]triazolo[1,2- <i>a</i> ]pyridazin-1-ones <b>10</b> 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 <b>5</b> show, in comparison to the already examined thions <b>3</b> and 3-methylsulfanyl derivatives <b>4,</b> significantly less inducible nitric oxide synthase (iNOS) inhibitory activity.