Synthesis of 3',5'-Cyclic Phosphate and Thiophosphate Esters of 2'-C-Methyl Ribonucleosides

2'-C-Methylnucleosides are known to exhibit antiviral activity against Hepatitis C virus. Since the inhibitory activity depends on their intracellular conversion to 5'-triphosphates, dosing as appropriately protected 5'-phosphates or 5'-phosphorothioates appears attractive. For this purpose, four potential pro-drugs of 2'-C-methylguanosine, i.e., 3',5'-cyclic phosphorothioate of 2'-C-methylguanosine and 2'-C,O6-dimethylguanosine, 1 and 2, respectively, the S-[(pivaloyloxy)methyl] ester of 2'-C,O6-dimethylguanosine 3',5'-cyclic phosphorothioate and the O-methyl ester of 2'-C,O6-dimethylguanosine 3',5'-cyclic phosphate, 3 and 4, respectively, have been prepared

5 ',5 '-Phosphodiesters and esterase labile triesters of 2 '-C-methylribonucleosides

Bis(2'-C-methyladenosin-5'-yl) (11), bis(2'-C-methylguanosin-5'-yl) (13), bis(2'-C-methyluridin-5'-yl) (15) and 2'-C-methylguanosin-5'-yl 2'-C-methyluridin-5'-yl (16) phosphodiesters have been prepared as pro-drug candidates for the respective 2'-C-methylribonucleoside 5'-monophosphates, expectedly exhibiting antiviral activity against Hepatitis C virus. Additionally, the bis(2'-C-methyladenosine) diester has been converted to 3-acetyloxymethoxy-2,2-bis(ethoxycarbonyl)propyl (19) or pivaloyloxymethyl (20) triester. The underlying idea is that the 5',5'-phosphodiester is first released by intracellular carboxyesterases and subsequently cleaved to nucleoside and nucleoside 5'-monophosphate by phosphodiesterases