4-Cyano-2-oxo-1,2,4-oxadiazolo[2,3-a]quinoxaline 5-N-oxides. New synthetic method and reaction with alcohols. Potential cytotoxic activity

Several quinoxaline 1,4-di-N-oxides have been shown to be efficient and selective cytotoxins for hypoxic cells. We present now a series of 4-cyano-2-oxo-1,2,4-oxadiazolo[2,3-a]quinoxaline 5-N-oxides 2a-2k . They were prepared starting from 3-amino-2-quinoxalinecarbonitrile 1,4-di-N-oxides 1a-1k and 2-chloroethyl isocyanate in dry dioxane at 100–110°. A reaction mechanism is proposed. The treatment of 1a with phenyl isocyanate afforded 2a . Reaction of 2c with silica gel yielded 1c . Compounds 2a-2g were heated in the presence of ethanol and 2-propanol giving the corresponding carbamates 3a-3g and 4a-4g . Compound 2d was already obtained by heating a mixture of 1d and ethyl chloroformiate. Compound 2b was prepared when the carbamate 3b was heated at 150°. Quinoxalines were tested as cytotoxic agents both in oxic and hypoxic cells. The most interesting compounds were 3g and 4g .