6-[2-(phosphonomethoxy)alkoxy]pyrimidines with antiviral activity

6-Hydroxypyrimidines substituted at positions 2 and 4 by hydrogen, methyl, amino, cyclopropylamino, dimethylamino, methylsulfanyl, or hydroxyl group afford by the reaction with diisopropyl 2-(chloroethoxy)methylphosphonate in the presence of NaH, Cs2CO3, or DBU a mixture of N-1- and O-6-[2-(diisopropylphosphorylmethoxy)ethyl] isomers which were converted to the free phosphonic acids by treatment with bromotrimethylsilane followed by hydrolysis. Analogously, 2,4-diamino-6-hydroxypyrimidine gave on reaction with [(R)- and (S)-2-(diisopropylphosphorylmethoxy)propyl] tosylate, followed by deprotection, the enantiomeric 6-[2-(phosphonomethoxy)propoxylpyrimidines. 2,4-Diamino-6-sulfanylpyrimidine gave, on treatment with diisopropyl 2-(chloroethoxy)methylphosphonate in the presence of NaH and subsequent deprotection, 2,4-diamino-6-1[2-(phosphonomethoxy)ethyl]sulfanyl}pyrimidine. 2-Amino-4-hydroxy-6-[2-(phosphonomethoxy)ethyl]pyrimidine was obtained from the appropriate 2-amino4-chloropyrimidine derivative by alkaline hydrolysis and ester cleavage. Direct alkylation of 2-amino-4,6-dihydroxypyrimidine afforded a mixture of 2-amino-4,6-bis[2-(phosphonomethoxy)ethyl] - and 2-amino-1,4-bis [2-(phosphonomethoxy)ethyl] pyrimidine. None of the N1- [2-(phosphonomethoxy)ethyl] isomers exhibited any antiviral activity against DNA viruses or RNA viruses tested in vitro. On the contrary, the O-6-isomers, namely the compounds derived from 2,4-diamino-, 2-amino-4-hydroxy-, or 2-amino-4-[2-(phosphonomethoxy)ethoxyl-6-hydroxypyrimidine, inhibited the replication of herpes viruses [herpes simplex type 1 (HSV-1) and type 2 (HSV-2), varicella-zoster virus (VZV), and cytomegalovirus (CM-V)1 and retroviruses [Moloney sarcoma virus (MSV) and human immunodeficiency virus type 1 (HIV-1) and type 2 (HIV-2)], their activity being most pronounced against the latter. The antiviral activity was lower if the oxygen at the position 6 was replaced by a sulfur atom, as in 2,4-diamino-6-[2(phosphonomethoxy)ethylsulfanyl] pyrimidine. In analogy to 2V9- [2-(phosphonomethoxy)propyl] 2,6-diaminopurine (PMPDAP), solely the (R)-2,4-diamino-6-[2-(phosphonomethoxy)propoxylpyrimidine exerted antiviral activity, whereas its (S)-enantiomer was essentially inactive.