Synthesis and antiviral activity of certain carbamoylpyrrolopyrimidine and pyrazolopyrimidine nucleosides

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Abstract
Following a recent discovery that 9-.beta.-D-ribofuranosylpurine-6-carboxamide (1) exhibits potent antiviral activity, certain pyrrolopyrimidine and pyrazolopyrimidine nucleosides containing a carbamoyl function (7-.beta.-D-ribofuranosylpyrrolo[2,3-d]pyriminidine-4-carboxamide (7a), 1-.beta.-D-ribofuranosylpyrazolo[3,4-d]pyrimindine-4-carboxamide (7b) and 3-.beta.-D-ribofuranosylpyrazolo[4,3-d]pyrimidine-7-carboxamide) were synthesized. 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 analog (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 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 and following the similar sequence of reactions, compound was obtained. The in vitro antiviral studies of these carbamoyl and certain related nucleosides indicated 7a to be a potent antiviral agent against vaccinia virus; 13 was moderately active. 4-Chloro-7-.beta.-D-ribofuranosylpyrrolo[2,3-d]pyrimidine was found to be 1 of the most active compounds against Rift Valley Fever, Pichinde, yellow fever and Sandfly fever viruses in African green monkey kidney Vero cell culture.