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To investigate the design of prodrugs of antiviral nucleosides for targeting t o the central nervous system, the bis(4-acyloxybenzyl) esters of the 5'-monophosphate of AZT 5 (R = Me, Et, Pr' or Bur) have been prepared. The reaction of the appropriate bis(4-acyloxybenzyl) N,N-diisopropylphosphoramidite 10 (R = Me, Et, Pri or Bur) with AZT in the presence of 1 H-tetrazole, followed by oxidation of the PI'' intermediate with 3-chloroperoxybenzoic acid gave the required triesters 5 in good yield. The lithium salts of the mono(4-acyloxybenzyl) esters of the 5'-phosphate of AZT 7 (R = Me, Et, Pr' or Bur) were prepared by treatment of the triesters 5 with lithium iodide. In the presence of porcine liver carboxyesterase the triesters 5 and diesters 7 decomposed readily t o the 5'-monophosphate of AZT 9. The anti-HIV activities of the triesters 5 and diesters 7 were, with one exception, comparable t o that of AZT, but the greater cytotoxicity of certain compounds in particular types of cell significantly reduced their selectivity indices.

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Ethyl 8-carbamoyl-4-oxo-3,4-dihydroimidazo[5, 1 -4 -172,3,5-tetrazin-3-ylacetate 6a can be prepared by treating 5-diazoimidazole-4-carboxamide 3 with ethyl isocyanatoacetate or by diazotisation of N-( 5-amino-4carbamoylimidazol-1 -ylcarbonyl)glycine ethyl ester 5. Barton radical decarboxylation of the tetrazin-3-ylacetic acid 6b affords temozolomide 1 I (26%) whereas deprotection of the 3-trimethylsilylmethylimidazotetrazine 6g with TBAF in acetonitrile-acetic acid yields 1 in 78% yield. 3-Benzylimidazotetrazinones 10a-c are stable t o hydrogenolytic or oxidative debenzylation reactions.The original synthesis of the antitumour agent temozolomide 1 involved the conversion of 5-aminoimidazole-4-carboxamide hydrochloride 2 into the unstable diazoimidazole 3 which was subsequently treated with methyl isocyanate (MIC) (Scheme This synthesis gave temozolomide in high yield and of a clinical-grade quality without the necessity for further purification. With the requirement for larger supplies of the drug to sustain clinical trials, the use of single solvents (e.g. dichloromethane or ethyl acetate, in which the diazoimidazole was very sparingly soluble) was unsatisfactory and led to long reaction times, typically 2 months on a 100 g scale at 25 "C.

Three new pathways to the antitumor drug temozolomide (4) have been explored via intermediates 3, 6, and 7. The key intermediate 5-amino-1-(N-methylcarbamoyl)imidazole-4-carboxamide (6) has been successfully converted to 4 in 45% yield by employing sodium nitrite in aqueous tartaric acid at 0-5 degrees C. Compound 6 is prepared from nitrophenyl carbamate 14a and methylamine or directly from 5-aminoimidazole-4-carboxamide (13) and either methyl isocyanate or N-methylcarbamoyl chloride. Temozolomide (4) is also prepared from 8-cyano-3-methylimidazo[5,1-d]-1,2,3,5-tetrazin-4(3H)-one (7) by hydrolysis to the hydrochloride salt of 4 in 10 M hydrochloric acid. Compound 7is prepared from either 5-diazoimidazole-4-carbonitrile (28) and methyl isocyanate or by diazotization of 5-amino-1-(N-methylcarbamoyl)imidazole-4-carbonitrile (25). Attempts to cyclize 5-(3-methyltriazen-1-yl)imidazole-4-carboxamide (3) with phosgene or phosgene equivalents were unsuccessful: only 2-azahypoxanthine (11) was isolated.