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 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 compounds. This mixture was rearranged by heating with molecular sieve in refluxing toluene to give a 6:1 mixture. Treatment of either compound 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-.beta.-D-ribofuranosyl-3H-1,2,3-triazolo[4,5-d]pyrimidines). The thione rearranges to N-.beta.-D-ribofunosyl[1,2,3]thiadiazolo[5,4-d]pyrimidin-7-amine in the solid state or in solution. All of these compounds were cytotoxic to [human laryngeal carcinoma] H.Ep. No. 2 cells in culture except the parent base, 8-aza-6-(methylthio)purine and the 8-isomers. Three of these compounds, 8-azaadenosine, 8-aza-6-(methylthio)purine ribonucleoside and 8-aza-6-(methoxy)purine ribonucleoside, showed borderline activity in the [mouse] leukemia L1210 system. The thiadiazolopyrimidine showed activity at 3 dose levels.