Synthesis and Antiproliferative and Antiviral Activity of Carbohydrate-Modified Pyrrolo[2,3-d]pyridazin-7-one Nucleosides

Sugar-modified analogs of 4-amino-1-(β-d-ribofuranosyl)pyrrolo[2,3-d]pyridazin-7-one (1) and 4-amino-3-bromo-1-(β-d-ribofuranosyl)pyrrolo[2,3-d]pyridazin-7-one (3) were prepared in an effort to obtain selective antiviral agents. Treatment of ethyl 3-cyano-1-(2,3,5-tri-O-benzyl-1-β-d-arabinofuranosyl)pyrrole-2-carboxylate (6) with hydrazine afforded 4-amino-1-(2,3,5-tri-O-benzyl-1-β-d-arabinofuranosyl)pyrrolo[2,3-d]pyridazin-7-one (7). Treatment of 7 with bromine afforded 4-amino-3-bromo-1-(2,3,5-tri-O-benzyl-β-d-arabinofuranosyl)pyrrolo[2,3-d]pyridazin-7-one hydrobromide (9). The benzyl ether functions of 7 and 9 were removed with boron trichloride to afford 4-amino-1-(β-d-arabinofuranosyl)pyrrolo[2,3-d]pyridazin-7-one (8) and its 3-bromo analog 10. 4-Amino-1-(2-deoxy-β-d-erythro-pentofuranosyl)pyrrolo[2,3-d]pyridazin-7-one (13) was prepared by the sodium salt condensation of ethyl 3-cyanopyrrole-2-carboxylate (5) with 2-deoxy-3,5-di-O-p-toluoyl-α-d-erythro-pentofuranosyl chloride (11) followed by ring annulation with hydrazine. Deprotection of ethyl 3-cyano-1-(2-deoxy-3,5-di-O-p-toluoyl-β-d-erythro-pentofuranosyl)pyrrole-2-carboxylate (12) using sodium ethoxide furnished ethyl 1-(2-deoxy-β-d-erythro-pentofuranosyl)-3-cyanopyrrole-2-carboxylate (14) which served as the starting material for the preparation of 4-amino-1-(2,3-dideoxy-β-d-glycero-pentofuranosyl)pyrrolo[2,3-d]pyridazin-7-one (20). Selective protection of the 5‘-hydroxyl group of 14 with tert-butyldimethylsilyl chloride followed by a Barton type deoxygenation sequence of the 3‘-hydroxyl groups afforded ethyl 3-cyano-1-[2,3-dideoxy-5-O-tert-butyldimethylsilyl)-β-d-glycero-pentofuranosyl]pyrrole-2-carboxylate (18). Deprotection of 18 with tetra-n-butylammonium fluoride and ring annulation with hydrazine afforded 20. The acyclic analog 4-amino-1-[(1,3-dihydroxy-2-propoxy)methyl]pyrrolo[2,3-d]pyridazin-7-one (24) was prepared via the sodium salt glycosylation of 5 with (1,3-dihydroxy-2-propoxy)methyl bromide (22) followed by a ring annulation with hydrazine. N-Bromosuccinimide treatment of 13, 20, and 25 afforded the 3-bromo derivatives 15, 21, and 25. Evaluation of these compounds in L1210, HFF, and KB cells showed that the sugar-modified analogs all were less cytotoxic than their corresponding ribonucleoside analogs. The compounds also were less active against human cytomegalovirus (HCMV) and herpes simplex virus type 1 (HSV-1). The 3-bromo derivatives were much more active than the 3-unsubstitut