| Abstract
| - Sugar-modified analogs of4-amino-1-(β-d-ribofuranosyl)pyrrolo[2,3-d]pyridazin-7-one(1) and4-amino-3-bromo-1-(β-d-ribofuranosyl)pyrrolo[2,3-d]pyridazin-7-one(3) were prepared in aneffort to obtain selective antiviral agents. Treatment of ethyl3-cyano-1-(2,3,5-tri-O-benzyl-1-β-d-arabinofuranosyl)pyrrole-2-carboxylate(6) with hydrazine afforded4-amino-1-(2,3,5-tri-O-benzyl-1-β-d-arabinofuranosyl)pyrrolo[2,3-d]pyridazin-7-one(7). Treatment of 7 withbromineafforded4-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 of7 and 9 were removed with borontrichloride to afford4-amino-1-(β-d-arabinofuranosyl)pyrrolo[2,3-d]pyridazin-7-one(8) and its3-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 ofethyl 3-cyanopyrrole-2-carboxylate(5) with2-deoxy-3,5-di-O-p-toluoyl-α-d-erythro-pentofuranosylchloride (11) followed by ringannulation with hydrazine. Deprotection of ethyl3-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 of4-amino-1-(2,3-dideoxy-β-d-glycero-pentofuranosyl)pyrrolo[2,3-d]pyridazin-7-one (20). Selectiveprotection of the 5‘-hydroxyl group of 14 withtert-butyldimethylsilyl chloride followed by a Barton type deoxygenationsequence of the 3‘-hydroxylgroups afforded ethyl3-cyano-1-[2,3-dideoxy-5-O-tert-butyldimethylsilyl)-β-d-glycero-pentofuranosyl]pyrrole-2-carboxylate (18). Deprotectionof 18 with tetra-n-butylammoniumfluorideand ring annulation with hydrazine afforded 20. Theacyclic analog 4-amino-1-[(1,3-dihydroxy-2-propoxy)methyl]pyrrolo[2,3-d]pyridazin-7-one(24) was prepared via the sodium saltglycosylation of 5 with (1,3-dihydroxy-2-propoxy)methylbromide (22) followed by a ring annulationwith hydrazine. N-Bromosuccinimide treatment of13, 20, and 25 afforded the3-bromoderivatives 15, 21, and 25.Evaluation of these compounds in L1210, HFF, and KB cellsshowedthat the sugar-modified analogs all were less cytotoxic than theircorresponding ribonucleosideanalogs. The compounds also were less active against humancytomegalovirus (HCMV) andherpes simplex virus type 1 (HSV-1). The 3-bromo derivatives weremuch more active thanthe 3-unsubstituted analogs in both the cytotoxicity, and antiviralassays. However, therewas only modest separation between activity against HCMV andcytotoxicity and there wasvirtually no selectivity for activity against HSV-1.
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