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We have prepared 8-amino-9-benzylguanine (1) as a key intermediate in the synthesis of some potential antifilarial agents, i.e. methyl 9-benzylguanine-8-carbamate (2). In view of the close structural similarity between 1 and 8-aminoguanosine (3) a potent inhibitor of purine nucleoside phosphorylase (PNP) with a Ki of 17.0 (mu)M , we initiated a program designed to synthesize and evaluate a series of 8-amino-9-benzylguanine compounds with various substituents on the benzyl group (4), as potential PNP inhibitors. They were designed with the intent of increasing the binding affinity of 8-aminoguanine to the target enzyme by specific modifications at the N-9 position of 8-aminoguanine. The reaction of 2,5-diamino-4-benzylaminopyrimidin-6-one (5) with methoxycarbonyl isothiocyanate (6) gave the intermediate 2-amino-4-benzylamino-5- 1-(3-methoxycarbonyl)thioureido pyrimidin-6-one (7) in good yield. The cyclodesulfurization of 7 with dicyclohexylcarbodiimide (DCC) in N,N-dimethylformamide did not afford the expected 2, but instead led to the formation of methyl 6-amino-4-benzylaminooxazolo 5,4-d pyrimidin-2-carbamate (8) in 87% yield. Treatment of 7 with one equivalent of methyl iodide and potassium carbonate at room temperature furnished 2-amino-4-benzylamino-5- 1-(3-methoxycarbonyl)-S-methyl-pseudothioureido pyrimidin-6-one (9). The synthesis of compound 2 accomplished in an excellent yield either by a novel ring opening of 8 and subsequent reannulation or directly from 9. To explore the scope of this synthetic methodology, a reaction of 5- 1-(3-methoxycarbonyl)thioureido uracil (10) with DCC was performed in methanol at reflux temperature to afford a good yield of 5- 1-(3-methoxycarbonyl)-O-methyl-pseudoureido uracil (11), instead of the expected methyl oxazolo 5,4-d pyrimidin-6-one-2-carbamate (12). On the basis of this interesting finding, and on the premise that 5-functionalized uracils possess very good potential of having biological activity, the reaction of 11, the corresponding uridine and 2'-deoxyuridine analogs with DCC in the presence of water, ethanol, benzylamine, ammonia and ethanethiol have been studied. |
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