Synthesis of potential anticancer agents. Pyrido[4,3-b][1,4]oxazines and pyrido[4,3-b][1,4]thiazines

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Abstract
Hydrolysis of the chloro group of ethyl (6-amino-4-chloro-5-nitropyridin-2-yl)carbamate (3) with formic acid gave the corresponding 4-hydroxypyridine 4. Catalytic hydrogenation of the nitro group of 4 gave the 5-amino-4-hydroxypyridine 5, which was reacted with .alpha.-halo ketones in acetic acid at room temperature to give a series of 3- and 2,3-substituted ethyl (5-amino-2H-pyrido[4,3-b][1,4]oxazin-7-yl)carbamates 8. Treatment of 8 with hot concentrated HCl regenerated the pyridine synthon 5. In the reaction of 3 with thioacetate, the product underwent hydrolysis and air-oxidation to give the corresponding disulfide 6. Simultaneous reduction of both the nitro group and difulside linkage of 6 gave the 5-amino-4-mercaptopyridine 7, which was reacted with .alpha.-halo ketones in acetic acid at room temperature or in a mixture of ethanol and water at reflux to give a series of 3-, 2,3- and 2,2,3-substituted ethyl (5-amino-2H-pyrido[4,3-b][1,4]thiazin-7-yl]carbamates 9. The effects of these pyridooxazines and pyridothiazines on the proliferation and the mitotic index of cultured L1210 [mouse leukemia] cells and on the survival of mice bearing P388 [mouse] leukemia were determined.