105970-02-3

New oxime-containing acyclic nucleoside phosphonates 9-{2-[(phosphonomethyl)oximino]ethyl}adenine (1), -guanine (2) and 9-{2-[(phosphonomethyl)oximino]propyl}adenine (3) with wide spectrum activity against different types of viruses were synthesized. The key intermediate, diethyl aminooxymethylphosphonate, was obtained by the Mitsunobu reaction. Modified conditions for the by-product separation (without chromatography and distillation) allowed us to obtain 85% yield of the aminooxy intermediate. The impact of DBU and Cs2CO3 on the N9/N7 product ratio for adenine and guanine alkylation was studied. A convenient procedure for aminooxy group detection was found. The synthesized phosphonates were tested and they appeared to display moderate activity against different types of viruses (HIV, herpes viruses in cell cultures, and hepatitis C virus in the replicon system) without toxicity up to 1000 μM.

Under the assistance of β-cyclodextrin, purine was effectively alkylated at N9 together with up to 99% conversion and good to excellent yield using water as the solvent. High regioselectivity-N9/N7 selectivity>99:1 was attributed to the β-cyclodextrin cav

Reaction of 1,3-dichloro-2-propanone (VII) with methylmagnesium chloride, followed by alkaline hydrolysis, afforded 2-methylpropane-1,2,3-triol (VIII) which on treatment with 2,2-dimethoxypropane and subsequent tosylation give 4-(p-toluenesulfonyloxymethyl)-2,2,4-trimethyl-1,3-dioxolane (IXb).Compound IXb was condensed with sodium salt of adenine and the intermediate X was acid-hydrolysed to give 9-(RS)-(2,3-dihydroxy-2-methylpropyl)adenine (XI).Oxidation of XI with sodium periodate led to 9-(2-oxopropyl)adenine (XII). 9-(RS)-(2-Hydroxy-2-hydroxymethyloctyl)adenine (XVI) was obtained analogously from compound VII and hexylmagnesium bromida via triol XIV.Methyl 2-bromomethyl-2-propenoate (XVII) reacted with sodium salt of adenine and the resulting methyl 2-(adenin-9-ylmethyl)-2-propenoate (XVIII) was hydroxylated with sodium perchlorate and osmium tetroxide.The obtained methyl (RS)-2-(adenin-9-ylmethyl)-2,3-dihydroxypropanoate (XIX) was alkali-hydrolysed to give sodium salt of the acid XX.Reduction of ester XIX with sodium borohydride furnished 9-(RS)-(2,3-dihydroxy-2-hydroxymethylpropyl)adenine (XXI). 1-Nonen-3-ol (XXIII), obtained by reaction of propenal with hexylmagnesium bromide, was converted by hydroxylation with osmium tetroxide into nonane-1,2,3-triol (XXIVa) and further into its 1-O-p-toluenesulfonate XXIVb which reacted with 2,2-dimethoxypropane to give 2,2-dimethyl-4-hexyl-5-(p-toluenesulfonyloxymethyl)-1,3-dioxolane (XXV).Compound XXV reacted with adenine and the resulting intermediate XXVI was converted into 9-(RS)-(2,3-dihydroxynonyl)adenine (XXVII) by acid hydrolysis. 9-(3-Methyl-2-buten-1-yl)adenine (XXVIII), obtained by alkylation of sodium salt of adenine with 1-bromo-3-methyl-2-butene, was oxidized with potassium permanganate in an acid medium to give 9-(3-hydroxy-2-oxo-3-methylbutyl)adenine (XXIX).This compound was converted into 9-(RS)-(2,3-dihydroxy-3-methylbutyl)adenine (XXX) by reduction with sodium borohydride. 4-C-Hydroxymethyl-1,2-O-isopropylidene-α-D-xylofuranose (XXXII) reacted with 2,2-dimethoxypropane under formation of 4-C-hydroxymethyl-1,2:3,5-di-O-isopropylidene derivative XXXIIIa whose p-toluenesulfonyl derivative XXXIIIb on treatment with adenine afforded 4-C-(adenin-9-yl)methyl-1,2:3,5-di-O-isopropylidene-α-D-xylofuranose (XXXIV).Acid hydrolysis of this compound, followed by oxidation in an alkaline medium, gave (2S,3R)-4-(adenin-9-yl)-3-hydroxymethyl-2,3-dihydroxybutanoic acid, isolated as its ethyl ester XXXVI.

Analogues of the antivirals (2S)-9-(3-hydroxy-2-phosphonylmethoxypropyl)adenine (Ia) and 9-(2-phosphonylmethoxyethyl)adenine (Ib), modified in the alkyl chain, are described.The phosphonylmethoxyalkyl derivatives were prepared by condensation of sodium alkoxides of hydroxyalkyladenines (or their N-protected derivatives) with dimethyl p-toluenesulfonyloxymethanephosphonate (II) followed by alkaline hydrolysis and reactions with halotrimethylsilane, or by reaction of vicinal dihydroxyalkyl derivatives with chloromethanephosphonyl dichloride (XIV) and subsequent cyclization of the intermediates XV in aqueous alkali.In the second case the pure regioisomers were also obtained from substituted dihydroxy derivatives with one free hydroxyl group.The following compounds were prepared in this way: 3-O-methyl ether IIIc and 3-O-octyl ether IVc, 9-(3-phosphonylmethoxypropyl)- (Vc), 9-(4-phosphonylmethoxybutyl)- (Vf), 9-(5-phosphonylmethoxypentyl) (Vi), 9-(2-phosphonylmethoxypropyl)- (VIc), 9-(1-phosphonylmethoxy-3-hydroxy-2-propyl)- (XIIc), 9-(2-methoxy-3-phosphonylmethoxypropyl)- (XIIIc), erythro-9-(2-phosphonylmethoxy-3,4-dihydroxybutyl)- (VIIc), and threo-9-(4-phosphonylmethoxy-2,3-dihydroxybutyl)adenine (IXc) and its enantiomer (Xc). 9-(2-Phosphonylmethoxy-3,3-dihydroxypropyl)adenine (VIII) was obtained by oxidation of VIIc with sodium periodate, 9-(2-phosphonylmethoxyethoxymethyl)adenine (XIc) by reaction of II with sodium salt of 9-(2-hydroxyethoxymethyl)adenine (XIa). 9-(1,2-Dihydroxy-2-methyl-3-propyl)adenine 1- and 2-phosphonylmethyl ether (XVIb), 9-(3,4-dihydroxybutyl)adenine 3- and 4-phosphonylmethyl ether (XVIIb) and 9-(2,3-dihydroxybutyl)adenine 2- and 3-phosphonylmethyl ether (XVIIIb) were prepared by reaction chloromethanephosphonyl dichloride (XIV) followed by alkaline treatment.Analogous reaction was also employed in the preparation of regioisomerically pure 1-phosphonylmethyl ethers of 9-(1,2-dihydroxy-3-butyl)adenine (XXIV), 9-(1,2-dihydroxy-2-methyl-3-propyl)adenine (XVIb) and 9-(1,2-dihydroxy-3-nonyl)adenine (XXV).Alkylation of adenine with diethyl chloromethoxymethanephosphonate (XXVII) followed by hydrolysis afforded 9-(phosphonylmethoxymethyl)adenine (XXVIIIb). 9-(Phosphonylmethyl)adenine (XLI) was obtained by condensation of adenine with compound II.Conversion of 9-(ω-hydroxyalkyl)adenines into the ω-halogenoalkyl derivatives followed by reaction with trialkyl phosphite and cleavage was used in the preparation of 9-(2-phosphonylethyl)adenine (XXXIVa), 9-(4-phosphonylbutyl)adenine (XXXIVb) and 9-(2-phosphonylethoxymethyl)adenine (XXXIX). 9-(2-Phosphonyl-2-hydroxyethyl)adenine (Lc) and 9-(3-phosphonyl-3-hydroxypropyl)adenine (Lb) were synthesized by treatment of ω-(adenin-9-yl)alkanals with dialkyl phosphite and subsequent cleavage with halogenotrimethylsilane; the same procedure converted 9-(2-oxopropyl)adenine (XLVIIIa) into 9-(2-phosphonyl-2-hydroxypropyl)adenine (La).

α-Methylene-γ-lactones covalently linked to adenine (3), hypoxantine (4), and guanine (5) were synthesized by using the convenient Reformatsky-type reaction between ethyl α-(bromomethyl)acrylate and the proper purine ketones.In vitro cytotoxicity data demonstrated that these compounds were active against L-1210 tissue culture cells with 3 being most potent (ED50 = 0.3 μg/mL).