Synthesis and antiviral activity of certain carbamoylpyrrolopyrimidine and pyrazolopyrimidine nucleosides

Following our recent discovery that 9-beta-D-ribofuranosylpurine-6-carboxamide (1) exhibits potent antiviral activity, we were prompted to synthesize certain pyrrolopyrimidine and pyrazolopyrimidine nucleosides containing a carbamoyl function (7a,b and 13). The key precursor, 7-(2,3,5-tri-O-acetyl-beta-D-ribofuranosyl)pyrrolo[2,3-d]pyrimidine-4- carbonitrile (8a), required for the synthesis of 7a was prepared from the corresponding 4-chloro analogue (4a). Reaction of 4a with methanethiol, followed by oxidation, gave the 4-methylsulfonyl derivative (6a), which with NaCN in DMF gave 8a. Alkaline hydrolysis of 8a provided 7a. Similarly, 7b was prepared from 4-chloro-1-(2,3,5-tri-O-acetyl-beta-D-ribofuranosyl)pyrazolo[3,4-d] pyrimidine (4b) via the carbonitrile intermediate 8b. Starting with thioformycin B or 7-chloro-3-(2,3,5-tri-O-acetyl-beta-D-ribofuranosyl)pyrazolo[4,3-d]pyrimidine (10) and following the similar sequence of reactions, we obtained compound 13. The in vitro antiviral studies of these carbamoyl and certain related nucleosides indicated 7a to be a potent antiviral agent against vaccinia virus, whereas 13 was moderately active. 4-Chloro-7-beta-D-ribofuranosylpyrrolo[2,3-d]pyrimidine was found to be one of the most active compounds against RVF, PICH, YF, and SF viruses in culture.