SYNTHESIS AND ANTIPROLIFERATIVE AND ANTIVIRAL ACTIVITY OF CARBOHYDRATE-MODIFIED PYRROLO[2,3-D]PYRIDAZIN-7-ONE NUCLEOSIDES

Sugar-modified analogs of beta-D-ribofuranosyl)pyrrolo[2,3-d]pyridazin -7-one (1) and beta-D-ribofuranosyl)pyrrolo[2,3-d]pyridazin-7-one (3) were prepared in an effort to obtain selective antiviral agents. Treat ment of ethyl yl-1-beta-D-arabinofuranosyl)pyrrole-2-carboxylate (6) w ith hydrazine afforded ta-D-arabinofuranosyl)pyrrol[2,3-d]pyridazin-7- one (7). Treatment of 7 with bromine afforded a-D-arabinofuranosyl)pyr rolo[2,3-d]pyridazin-7-one hydrobromide (9). The benzyl ether function s of 7 and 9 were removed with boron trichloride to afford a-D-arabino furanosyl)pyrrolo[2,3-d]pyridazin-7-one (8) and its 3-bromo analog 10. ythro-pentofuranosyl)pyrrolo[2,3-d]pyridazin-7-one (13) was prepared by the sodium salt condensation of ethyl 3-cyanopyrrole-2-carboxylate (5) with -3,5-di-O-p-toluoyl-alpha-D-erythro-pentofuranosyl chloride ( 11) followed by ring annulation with hydrazine. Deprotection of ethyl -beta-erythro-pentofuranosyl)pyrrole-2-carboxylate (12) using sodium e thoxide furnished ethyl ythro-pentofuranosyl)-3-cyanopyrrole-2-carboxy late (14) which served as the starting material for the preparation of ycero-pentofuranosyl)pyrrolo[2,3-d]pyridazin-7-one (20). Selective pr otection of the 5'-hydroxyl group of 14 with tert-butyldimethylsilyl c hloride followed by a Barton type deoxygenation sequence of the 3'-hyd roxyl groups afforded ethyl eta-D-glycero-pentofuranosyl]pyrrole-2-car boxylate (18). Deprotection of 18 with tetra-n-butylammonium fluoride and ring annulation with hydrazine afforded 20. The acyclic analog oxy -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)methy l bromide (22) followed by a ring annulation with hydrazine. N-Bromosu ccinimide treatment of 13, 20, and 25 afforded the 3-bromo derivatives 15, 21, and 25. Evaluation of these compounds in L1210, HFF, and KB c ells showed that the sugar-modified analogs all were less cytotoxic th an their corresponding ribonucleoside analogs. The compounds also were less active against human cytomegalovirus (HCMV) and herpes simplex v irus type 1 (HSV-1). The 3-bromo derivatives were much more active tha n the 3-unsubstituted analogs in both the cytotoxicity, and antiviral assays. However, there was only modest separation between activity aga inst HCMV and cytotoxicity and there was virtually no selectivity for activity against HSV-1.