5-(BETA-AMINOETHYL)AMINOISOXAZOLES WITH HYPERTENSIVE ACTIVITY - SYNTHESIS AND SCREENING OF ISOXAZOLO-PYRAZINES AND ISOXAZOLO-DIAZEPINES

The 5-aminoisoxazole 1 is converted via the 4-nitro derivative to the 4,5-di-amino 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.