Analogs of 8-azainosine

Abstract

A convenient synthesis of 8-azapurine ribonucleosides substituted at the 6 position with thio, alkylthio, alkoxy, amino, and alkylamino groups is described. The reaction of 6-(methylthio)-8-azapurine (1) with 2,3,5-tri-O-acetyl-D-ribofuranosyl chloride in the presence of Linde AW-500 molecular sieve gave a 2:1 mixture of 2 and 3, respectively. This mixture was rearranged by heating with molecular sieve in refluxing toluene to give a 6:1 mixture of 2 and 3. Treatment of 2 or 3 with the appropriate nucleophiles at room temperature gave 6-substituted 8-azapurine ribonucleosides (7-substituted 2- or 3-beta-D-ribofuranosyl-3H-1,2,3-triazolo[4,5-d]pyrimidines) 4-13. The thione 11 rearranges to N-beta-D-ribofuranosyl[1,2,3]thiadiazolo[5,4-d]pyrimidin-7-amine (14) in the solid state or in solution. All of these compounds were cytotoxic to H.Ep. No. 2 cells in culture except the parent base, 8-aza-6-(methylthio)purine (1) and the 8-isomers (3,12, and 13). Three of these compounds-8azaadenosine (4), 8-aza-6-(methylthio)purine ribonucleoside (5), and 8-aza-6-(methoxy)purine ribonucleoside (7)-showed borderline activity in the leukemia L1210 system. The thiadiazolopyrimidine (14) showed activity at three dose levels.