Some imidazo-1,2,3,-triazines and their biological relationship to the purines.

Since the time that benzimidazole was recognized to be a structural analogue of adenine, and its antimicrobial action was found to be antagonized competitively by this purine (l), several other antimetabolites of the purines have been described. Thus, carbon atom 8 of the ring system has been replaced by a nitrogen atom to yield analogues of adenine, guanine, and hypoxanthine (2). Likewise, the substituents attached to the ring have been altered in order to achieve such agents as, for example, 2,6diaminopurine, an antimetabolite of adenine (3). We wish to report in this paper the synthesis and biological examination of members of a new series of purine analogues, one member of which is a rather potent competitive antagonist to hypoxanthine when tested in several kinds of microorganisms and in higher animals. Purine analogues in which carbon atom 2 has been exchanged for nitrogen are of interest from a chemical as well as from a biological standpoint, because substances containing the imidazo-1 ,2,3-triazine ring have apparently not been described previously. The development of convenient syntheses for 4-amino-5imidazolecarboxamide (4) and its amidine (5) has permitted the realization of two of these compounds. When the imidazoleamide was treated with nitrous acid, 6-hydroxyimidazo-l , 2,3-triazine was obtained in good yield. Similar operations on the amidine gave 6-aminoimidazo-1,2,3-triazine. The former has been called 2-azahypoxanthine, and the latter 2-azaadenine. The relationship of the two types of compounds may be seen in Fig. 1. 2-Azahypoxanthine was obtained by Stetten and Fox (6), who did not identify it, by reaction of nitrous acid with the amine isolated from a culture of Escherichia cc& grown in the presence of sulfadiazine. 2-Azahypoxanthine was not toxic to a variety of microorganisms but, instead, was able to replace hypoxanthine in the growth of Lactobacillus brevis. This organism showed an exquisite need for purines, in contrast to the behavior of other lactic acid bacteria for which folic acid can replace