SYNTHESIS AND BIOLOGICAL EFFECTS OF 9-(3-HYDROXY-2-PHOSPHONOMETHOXYPROPYL) DERIVATIVES OF DEAZAPURINE BASES

Analogs of antiviral 9-(S)-(3-hydroxy-2-phosphonomethoxypropyl)adenine (HPMPA, I), containing modified purine bases 3-deazaadenine XII, 1-de azaadenine XIV, 7-deaza-7-cyanoadenine XXXII and 3-deazaguanine XXXVII I. were prepared by alkylation of the bases with synthon XVII, contain ing preformed structure of the side chain, in the presence of cesium c arbonate. The obtained protected derivatives were deblocked successive ly with sodium methoxide and bromotrimethylsilane to give phosphonic a cids XII, XIV. XXXII and XXXVIII. Compounds XII, XIV and XVI were also prepared from (S)- or (R)-9-(2,3-dihydroxypropyl) derivatives VI, VII and XV by reaction with chloromethanephosphonyl dichloride, isomeriza tion of the arising 2'- and 3'-chloromethanephosphonates and conversio n of the 3'-isomers into the phosphonic acids in alkaline medium. The 3-deaza analog XII was also prepared by ditritylation of VI, reaction with bis(2-propyl) tosyloxymethanephosphonate (XXII), subsequent acid hydrolysis and reaction with bromotrimethylsilane. 3-DeazaHPMPA (XII) is a potent inhibitor of DNA viruses (HSV-1, HSV-2, VZV, CMV) and exhi bits activity against Plasmodium sp.