Synthesis and antiviral activity of 2,4-diamino-5-cyano-6-[2-(phosphonomethoxy)ethoxy]pyrimidine and related compounds

Synthesis of 2,4-diamino-5-cyano-6-{[(diisopropoxyphosphoryl)methoxy]ethoxy}pyrimidine was based on the formation of the pyrimidine ring by cyclization followed by modification of the side chain by alkylation. The 5-cyano group was also transformed to a 5-formyl and 5-hydroxymethyl group by reduction. As a side product an unexpected dimer was formed. Resulting compounds were converted to the free phosphonic acids by treatment with bromotrimethylsilane followed by hydrolysis. The 5-cyano and 5-formyl derivatives showed pronounced antiretroviral activity, comparable to that of the reference drugs adefovir and tenofovir. (C) 2004 Elsevier Ltd. All rights reserved.