Dannhardt G, Dominiak P, Laufer S
Institut für Pharmazeutische Chemie, Johann Wolfgang Goethe-Universität, Frankfurt am Main.
Arch Pharm (Weinheim). 1991 Mar;324(3):141-8. doi: 10.1002/ardp.19913240303.
The 5-aminoisoxazole 1 is converted via the 4-nitro derivative to the 4,5-diamino compound 4, which cyclises with glyoxal to yield the isoxazolo[4,5-b)pyrazine 5. Decomposition of the isoxazole moiety is always observed in experiments to hydrogenate partially the pyrazine ring and to phenylate the N-atom, respectively. Therefore, the corresponding tetrahydro derivative 6 is prepared from 4 and 1,2-ethandiol ditosylate. Starting with benzohydroxamic acid chloride and a cyanoacetic acid amide the tetrahydro isoxazolo[5,4-e]1,4-diazepinone-4 18 is synthesized. All new compounds are characterized by their spectroscopic data, the reaction mechanisms are discussed. Using the model of the pithed and the anaesthetized rat, resp., the pyrazino- and diazepino-isoxazoles (compounds 5, 6, 13, 18) have less or no hypertensive activity as compared to the corresponding derivatives with fully flexible side chains.
5-氨基异恶唑1通过4-硝基衍生物转化为4,5-二氨基化合物4，4与乙二醛环化生成异恶唑并[4,5-b]吡嗪5。在分别对吡嗪环进行部分氢化和对N原子进行苯基化的实验中，总是会观察到异恶唑部分的分解。因此，相应的四氢衍生物6由4和1,2-乙二醇二对甲苯磺酸酯制备。以苯甲酰羟肟酸氯和氰基乙酰胺为起始原料，合成了四氢异恶唑并[5,4-e]1,4-二氮杂环庚烷-4-酮18。所有新化合物均通过光谱数据进行表征，并对反应机理进行了讨论。分别使用脊髓切断和麻醉大鼠模型，与具有完全柔性侧链的相应衍生物相比，吡嗪并异恶唑和二氮杂环庚并异恶唑（化合物5、6、13、18）具有较低或无高血压活性。
