Phosphonate analogues of cyclopropavir phosphates and their E-isomers. Synthesis and antiviral activity

Abstract

Z- and E-Phosphonate analogues 12 and 13 derived from cyclopropavir and the corresponding cyclic phosphonates 14 and 15 were synthesized and their antiviral activity was investigated. The 2,2-bis(hydroxymethylmethylenecyclopropane acetate (17) was transformed to tetrahydropyranyl acetate 18. Deacetylation gave intermediate 19 which was converted to bromide 20. Alkylation with diisopropyl methylphosphonate afforded after protecting group exchange (21 to 22) acetylated phosphonate intermediate 22. Addition of bromine gave the dibromo derivative 16 which was used in the alkylation-elimination procedure with 2-amino-6-chloropurine to give Z- and E-isomers 23 and 24. Hydrolytic dechlorination coupled with removal of all protecting groups gave the guanine phosphonates 12 and 13. Cyclization afforded the cyclic phosphonates 14 and 15. Z-Phosphonate 12 was a potent and non-cytotoxic inhibitor of human and murine cytomegalovirus (HCMV and MCMV) with EC(50) 2.2-2.7 and 0.13 microM, respectively. It was also an effective agent against Epstein-Barr virus (EBV, EC(50) 3.1 microM). The cyclic phosphonate 14 inhibited HCMV (EC(50) 2.4-11.5 microM) and MCMV (EC(50) 0.4 microM) but it was ineffective against EBV. Both phosphonates 12 and 14 were as active against two HCMV Towne strains with mutations in UL97 as they were against wild-type HCMV thereby circumventing resistance due to such mutations. Z-Phosphonate 12 was a moderate inhibitor of replication of herpes simplex virus types 1 and 2 (HSV-1 and HSV-2) but it was a potent agent against varicella zoster virus (VZV, EC(50) 2.9 microM). The cyclic phosphonate 14 lacked significant potency against these viruses. E-isomers 13 and 15 were devoid of antiviral activity.

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Reagents and conditions: (a) 3,4-Dihydro-2H-pyran, MeSO3H, CH2Cl2; (b) NH3, MeOH, Δ; (c) CBr4, Ph3P, NEt3, CH2Cl2; (d) CH3P(O)(i-PrO)2, BuLi, THF; (e) AcCl, CH2Cl2; (f) Pyridine.HBr3, CH2Cl2; (g) 1. B-H, Cs2CO3, DMF, Δ. 2. Chromatography; (h) 80% HCO2H, Δ; (i) 1. Me3SiBr, DMF. 2. NH4OH. 3. Chromatography; (j) N,N′-Dicyclohexyl-4-mopholinecarboxamidine, DCC, pyridine. 2. NH4OH. 3. Dowex 50 (H(+)).