SYNTHESIS OF RO-1-(BETA-D-RIBOFURANOSYL)NAPHTHO[2,3-D]IMIDAZOLE - A LINEAR DIMENSIONAL ANALOG OF THE ANTIVIRAL AGENT TCRB

Human cytomegalovirus (HCMV) remains a significant clinical problem in neonates and immunocompromised individuals such as those undergoing t ransplantation as well as individuals with acquired immune deficiency syndrome (AIDS). Recently in our laboratory, ,6-trichloro-1-(beta-D-ri bofuranosyl)benzimidazole (TCRB, 1a) and 5,6-dichloro-1-(beta-D-ribofu ranosyl)benzimidazole (BDCRB, 1b) were found to have better activities in cell culture studies against HCMV than the clinically used agents ganciclovir and foscarnet. These benzimidazole compounds appear to act by a unique mechanism. However, as the biological target of TCRB and BDCRB has not been completely identified, o-1-(beta-D-ribofuranosyl)na phthol[2,3-d]imidazole (2) was designed as a linear dimensional analog ue of TCRB for a study on the spatial limitation of the binding site i n the target enzyme. In the synthesis, a convenient route was develope d for the synthesis of 2-substituted 6,7-dichloronaphtho[2,3-d]imidazo les involving a Diels-Alder reaction of 4,5-dichloro-o-quinodimethane (8) as the key step. 6,7-Dichloro-1,4-dihydro-2,3-benzoxathiin 3-oxide (15) was found to be an ideal precursor for the generation of the elu sive intermediate 8. The ribosylation of 6,7-dichloronaphtho[2,3-d]imi dazoles was influenced by the functional group at the 2-position and 6 ,7-dichloro-2-methylthionaphtho[2,3-d]imidazole (3c) was found to smoo thly undergo ribosylation. The 2-methylthio group of the unprotected n ucleoside 25 was converted into a chloro group under mild conditions t o give nucleoside 2 in high yield.