本工作报告了迄今为止未知的标题化合物5的制备,其中描述了各种合成路线。最初使用氮亲核体与varioius1-取代的3-甲硫基-5,6,7,8-四氢-1H-[1,2,4]三唑并[1,2-a]吡啶嗪4进行S-N交换的概念仅取得了轻微的成功。反应进行缓慢,产率低,主要是因为通过最初形成的杂环胺5的氧化而明显形成5,6,7,8-四氢-[1,2,4]三唑并[1,2-a]哒嗪-1-亚胺7。3-酰基硫基类似物与更具反应性的离去基团的合成整合也失败了。另一方面,六氢吡啶-1-甲脒的氢卤化物与芳族醛和一些低分子量酮的环化在标题化合物5的合成中产生明显更好的结果。与氢碘化物6a相比,盐酸盐6b的使用被证明是有利的,因为产率显著更好,并且亚胺7仅在小程度上同时形成。此外,起始化合物6b可以由盐酸六氢吡啶嗪1和氨基氰在单步合成中以非常好的产率制备。用取代的苯甲醛环化N'-苯基六氢吡嗪-1-甲脒盐酸盐6c得到3-芳基-取代的2-苯基-2,3,5,6,7,8-六氢-1H-[1,2,4]三唑并[1,2-a]吡嗪-1-亚胺8。在研究六氢吡啶-1-甲脒氢碘化物6a与环己酮的反应的背景下,具体合成了六氢吡啶嗪-1-甲酰胺9。这可以与芳族醛反应,以非常好的产率得到5,6,7,8-四氢-1H-[1,2,4]三唑并[1,2-a]哌嗪-1-酮10。合成的5,6,7,8-四氢-[1,2,4]三唑并[1,2-a]哌嗪-1-胺5的代表的生物测试结果表明,与已经检查的硫3和3-甲硫基衍生物4相比,诱导型一氧化氮合酶(iNOS)抑制活性明显较低。
The present work reports on the preparation of the hitherto unknown title compounds 5, 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 H -[1,2,4]triazolo[1,2- a ]pyridazines 4 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- a ]pyridazin-1-imines 7 by oxidation of the heterocyclic amines 5 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 5. The use of the hydrochloride 6b proved to be advantageous in comparison to the hydroiodide 6a because the yields were significantly better and the imines 7 formed at the same time only to a small extent. In addition, the starting compound 6b can be prepared in a single-step synthesis in very good yield from hexahydropyridazine hydrochloride 1 and cyanamide. The cyclization of N\' -phenylhexahydropyridazine-1-carboximidamide hydrochloride 6c with substituted benzaldehydes gives the 3-aryl-substituted 2-phenyl-2,3,5,6,7,8-hexahydro -1H -[1,2,4]triazolo[1,2- a ] pyridazin-1-imines 8. In the context with the study of the reaction of hexahydropyridazine-1-carboximidamide hydroiodide 6a with cyclohexanone, the hexahydropyridazine-1-carboxamide 9 was specifically synthesized. This can be reacted with aromatic aldehydes to give the 5,6,7,8-tetrahydro-1 H -[1,2,4]triazolo[1,2- a ]pyridazin-1-ones 10 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 5 show, in comparison to the already examined thions 3 and 3-methylsulfanyl derivatives 4, significantly less inducible nitric oxide synthase (iNOS) inhibitory activity.