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

Journal of Medicinal Chemistry
1997.0

Abstract

Sugar-modified analogs of 4-amino-1-(beta-D-ribofuranosyl)pyrrolo[2,3-d]pyridazin-7-one (1) and 4-amino-3-bromo-1-(beta-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-beta-D-arabinofuranosyl)pyrrole-2- carboxylate (6) with hydrazine afforded 4-amino-1-(2,3,5-tri-O-benzyl-1-beta-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-beta-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-(beta-D-arabinofuranosyl)pyrrolo[2,3-d]pyridazin-7-one (8) and its 3-bromo analog 10. 4-Amino-1-(2-deoxy-beta-D-erythro-pentofuranosyl)pyrrolo[2,3-d]pyrida zin-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-alpha-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-beta-D-erythro-pentofuranosyl)pyrr ole- 2-carboxylate (12) using sodium ethoxide furnished ethyl 1-(2-deoxy-beta-D-erythro-pentofuranosyl)-3-cyanopyrrole-2-carboxy late (14) which served as the starting material for the preparation of 4-amino-1-(2,3-dideoxy-beta-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)-beta-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-unsubstituted analogs in both the cytotoxicity, and antiviral assays. However, there was only modest separation between activity against HCMV and cytotoxicity and there was virtually no selectivity for activity against HSV-1.

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