The reaction of thymidine, AZT (Fig. 1, compound 1) and ddCyd (Fig. 1, compound 2) with bis(2,2,2-trichloroethyl) phosphorochloridate gave novel 5 '_ bis(2,2,2-trichloroethyl) phosphates, characterized by spectroscopic and analytical data. Analogous reactions with bis(2,2,2-trifluoroethyl) phosphorochloridate gave the corresponding AZT and ddCyd derivatives. In both of the ddCyd reactions, by-products were isolated and characterized as 05', N4-diphosphorylated materials. It was hoped that the 5 '_ phosphate triesters might act as membrane-soluble pro-drugs of the bio-active free nucleotides of AZT or ddCyd. In fact, all of the 5'·phosphate derivatives of AZT and ddCyd displayed anti-HIV activity in vitro. Surprisingly, the thymidine compound also displayed very slight anti-HIV activity. The striking activity of the AZT and ddCyd derivatives is attributed to the metabolic instability of the substituted trialkyl phosphate moiety.

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Novel phosphate derivatives of the and-HIV nucleoside anulogue AZT have been prepared by phosphorochloridate chemistry. In particular, phosphates carrying ester-containing side-chains are described. These materials arc designed 10 act as membrane-soluble prodrugsof the bio-active free nucleotides. In vitro evaluation revealed the compounds to have a pronounced, selective anliviral activity. In several cases the phosphate derivatives are more seieclive in their aclhl than the parent nucleoside AZT. In particular, this arises from the low toxicity of the phosphate pro-drugs by comparison to AZT. These data support the suggestion thal the phosphate derivatives exert their biological effects via intracellular release of the nuclcotide forms, and suggests that such pro-drug forms may be worthy of further study.