Berkowitz P T, Long R A, Dea P, Robins R K, Mathews T R
J Med Chem. 1977 Jan;20(1):134-8. doi: 10.1021/jm00211a028.
Treatment of 6H-1,2,4-oxadiazin-3(2H)-one-5(4H)-thione (2) with hydroxylamine, hydrazine, methylamine, or benzylamine afforded the corresponding N5-substituted 5-amino-6H-1,2,4-oxadiazin-3(2H)-ones 3c-f. Refluxing a dioxane solution of 6H-1,2,4-oxiazine-3,5(2H,4H)-dione (1) with benzylamine or aminodiphenylmethane and hexamethyldisilazane in the presence of ammonium sulfate gave 5-benzylamino-6H-1,2,4-oxadiazin-3(2H)-one (3f) and the corresponding 5-diphenylmethylamino derivative 3g. Reaction of 1 with methyl iodide, benzyl chloride, dihydropyran, dihydrofuran, or benzyloxycarbonyl chloride afforded the corresponding 2-substituted 6H-1,2,4-oxadiazine-3,5(2H,4H)-diones 6a-e. Reaction of 2-methyl-6H-1,2,4-oxadiazine-3,5(2H,4H)-dione (6a) or the corresponding 2-benzyl derivative 6b with phosphorus pentasulfide in dioxane gave 2-methyl-6H-1,2,4-oxadiazin-3(2H)-one-5(4H)-thione (8a) and the corresponding 2-benzyl derivative 8b, respectively. Reaction of 8a with ammonia in dioxane afforded 2-methyl-5-amino-6H-1,2,4-oxadiazin-3(2H)-one (9). The degree of in vitro activity and the presence of antibacterial activity in the urine of animals given 5-amino-6H-1,2,4-oxadiazin-3(2H)-one (3a) by oral route of administration prompted selection of this compound for further study.
用羟胺、肼、甲胺或苄胺处理6H-1,2,4-恶二嗪-3(2H)-酮-5(4H)-硫酮(2)，得到相应的N5-取代的5-氨基-6H-1,2,4-恶二嗪-3(2H)-酮3c-f。在硫酸铵存在下，将6H-1,2,4-恶二嗪-3,5(2H,4H)-二酮(1)的二氧六环溶液与苄胺或氨基二苯甲烷和六甲基二硅氮烷回流，得到5-苄基氨基-6H-1,2,4-恶二嗪-3(2H)-酮(3f)和相应的5-二苯甲基氨基衍生物3g。1与碘甲烷、苄基氯、二氢吡喃、二氢呋喃或苄氧羰基氯反应，得到相应的2-取代的6H-1,2,4-恶二嗪-3,5(2H,4H)-二酮6a-e。2-甲基-6H-1,2,4-恶二嗪-3,5(2H,4H)-二酮(6a)或相应的2-苄基衍生物6b与五硫化二磷在二氧六环中反应，分别得到2-甲基-6H-1,2,4-恶二嗪-3(2H)-酮-5(4H)-硫酮(8a)和相应的2-苄基衍生物8b。8a与氨在二氧六环中反应，得到2-甲基-5-氨基-6H-1,2,4-恶二嗪-3(2H)-酮(9)。通过口服途径给予5-氨基-6H-1,2,4-恶二嗪-3(2H)-酮(3a)的动物尿液中的体外活性程度和抗菌活性的存在促使选择该化合物进行进一步研究。
