Synthesis and in Vivo Evaluation of Prodrugs of 9-[2-(Phosphonomethoxy)ethoxy]adenine

Abstract

A number of esters and amides of the anti-HIV nucleotide analogue 9-[2-(phosphonomethoxy)-ethoxy]adenine (1) have been synthesized as potential prodrugs and evaluated for oral bioavailability in mice. Dialkyl esters 17-20 were prepared via a Mitsunobu coupling of alcohols 8-11 with 9-hydroxypurine 12 whereas (acyloxy)alkyl esters 25-33 and bis-[(alkoxycarbonyl)methyl] and bis(amidomethyl) esters 34-39 were obtained by reaction of 1 with a suitable alkylating agent. Phosphonodichloridate chemistry was employed for the preparation of dialkyl and diaryl esters 42-65, and bis(phosphonoamidates) 66 and 67. Following oral administration to mice, most of the dialkyl esters 17-20 were well-absorbed and then converted to the corresponding monoesters, but minimal further metabolism to 1 occurred. Bis[(pivaloyloxy)methyl] ester 25 displayed an oral bioavailability of 30% that was 15-fold higher than the bioavailability observed after dosing of 1. Methyl substitution at the alpha carbon of the bis[(pivaloyloxy)methyl] ester 25 (33) increased the oral bioavailability of 1 to 74%. Some of the diaryl esters also showed improved absorption properties in comparison with that of 1. In particular, the crystalline hydrochloride salt of diphenyl ester 55 was well-absorbed and efficiently converted to the parent compound with an oral bioavailability of 50%. On the basis of these results as well as the physicochemical properties of the prodrugs and their stability in mouse duodenal contents, the hydrochloride salt of diphenyl ester 55 was identified as the preferred prodrug of 1.

Synthesis of Nucleoside Phosphate and Phosphonate Prodrugs

“…Thus, Serafinowska et al reported the synthesis of acyclophosphonate prodrug 538 (259) in 15% yield by treatment of ethyl phosphonate derivative 535 with TMSBr, reaction of the corresponding silyl ester 536 with PCl 5 , and reaction with alanine methyl ester hydrochloride in the presence of triethylamine and NMI (Scheme 167). …”

Alkoxycarbonyloxyethyl Ester Prodrugs of FR900098 with Improved In Vivo Antimalarial Activity

“…Treatment of the aldehyde 2 with O-benzylhydroxylamine gave the oxime, which was then reduced without prior isolation with sodium cyanoborohydride and hydrochloric acid to yield the O-(benzylhydroxylamino)propylphosphonic acid diethyl ester 3 [6]. Acetylation to 4 and subsequent reaction of 4 with trimethylbromosilane [7] and hydrolysis of the re- sulting silylester with water yielded the O-benzyl protected FR900098 5.Phosphonic acid 5 was then coupled with commercially available chloroacetic acid methylester or chloromethyl pivalate, respectively, in DMF in the presence of triethylamine leading to the phosphonic acid diesters 6a and 6b [8]. This method was unsuccessful in the case of 1-chloroethyl pivalate and 1-chloroethyl benzoate.…”

“…This method was unsuccessful in the case of 1-chloroethyl pivalate and 1-chloroethyl benzoate. However, when the phosphonic acid 5 and the chloroalkyl esters [9] were reacted in N, NЈ-dimethyl-N,NЈ-propyleneurea (DMPU) in the presence of triethylamine and sodium iodide, the bis(acyloxy)alkyl esters 6cϪg and 6k were obtained as diastereomeric mixtures [8]. Removal of the protecting groups with hydrogen and 10 % Pd/C in methanol gave the prodrugs 7aϪg and 7k.…”

“…The resulting phosphonic acid monochloride was directly coupled with benzyl alcohol to obtain the monobenzyl ester 8 [11]. Reaction of 8 with the 1-chloro ethyl esters in DMPU in the presence of triethylamine and sodium iodide [8] led to the esters 9a and b as diastereomeric mixtures. The protection groups were removed hydrogenolytically to obtain the mono-pivaloyl prodrug 10a as a powder and the mono-palmitoyl derivative 10b as a waxy substance.…”

Selective Nucleoside Triphosphate Diphosphohydrolase-2 (NTPDase2) Inhibitors: Nucleotide Mimetics Derived from Uridine-5′-carboxamide

“…It has been described that short alkyl chain esters of phosphonates are metabolically quite stable. 56,57 Incubation with rat liver microsomes showed that both compounds, 19a and 19c, were relatively stable toward liver enzymes. Only a very small percentage (<5%) was metabolized under the applied conditions (see Experimental Section), while >95% of the compounds were recovered unchanged.…”