The pyrimidine acyclonucleoside 5-fluoro-1-[(2-hydroxyethoxy)methyl]uracil (3) was synthesized as part of a program aimed at the development of new 5-fluorouracil derivatives with fewer side effects and a broader margin of safety. Condensation of 5-fluoro-2,4-bis[(trimethylsilyl)oxy]pyrimidine with 2-acetoxyethyl acetoxymethyl ether (6) in the presence of SnCl4 afforded the acetate ester 7, which on deprotection with NaOMe gave 3 in 50-60% overall yield. The 5-bromo and 5-iodo analogues 10 and 11, respectively, were obtained similarly. Reaction of 5-fluoro-4-(methylthio)-2-[(trimethylsilyl)oxy]pyrimidine with 2-acetoxyethyl acetoxymethyl ether and SnCl4, followed by ammonolysis, yielded 5-fluoro-1-[(2-hydroxyethoxy)methyl]cytosine (12). Deamination of 12 with nitrous acid produced 3, thereby confirming that alkylation of 5-fluoro-2,4-bis[(trimethylsilyl)oxy]pyrimidine had occurred at N1. The ID50 of 3 against L1210 mouse leukemia cells in culture was 1.7 x 10(-5) M, as compared with 1 x 10(-6) M for FU. The 5-fluorocytosine analogue 12 was inactive at up to 1 x 10(-4) M, and the other halogenated derivatives 10 and 11 had no effect even at 1 x 10(-3) M. When 3 was given ip in water to P388 leukemic mice at 400 mg/kg (b.i.d. x 4) or 240 mg/kg (q.d. 1-9), a 75% increase in survival was observed relative to untreated controls, and there was no evidence of any host toxicity.
The first chemical synthesis of 2-aminoimidazo[1,2-a]-s-triazin-4-one (8), the corresponding nucleoside and nucleotide, and certain related derivatives of a new class of purine analogues containing a bridgehead nitrogen atom is described. Condensation of 2-amino-4-chloro-6-hydroxy-s-triazine (2) with aminoacetaldehyde dimethyl acetal followed by the ring annulation gave the guanine analogue 8. A similar ring annulation of 4-(2,2-dimethoxyethylamino)-s-triazine-2,6-dione (5) gave imidazo[1,2-a]-s-triazine-4,6-dione (9). Direct glycosylation of the trimethylsilyl derivative of 8 with 1-O-acetyl-2,3,5-tri-O-benzoyl-beta-D-ribofuranose in the presence of stannic chloride, followed by debenzoylation, gave the guanosine analogue 2-amino-8-(beta-D-ribofuranosyl)imidazo[1,2-a]-s-triazin-4-one (12b), which on deamination gave the xanthosine analogue 13. Phosphorylation of 12b gave 2-amino-8-(beta-D-ribofuranosyl)imidazo[1,2-a]-s-triazin-4-one 5'-monophosphate (II). The anomeric configuration has been determined unequivocally by using NMR of the 2',3'-O-isopropylidene derivate 10 and the site of ribosylation has been established by using 13C NMR spectroscopy. These compounds were tested against type 1 herpes, type 13 rhino, and type 3 parainfluenza viruses in tissue culture. Moderate rhinovirus activity was observed for several compounds at nontoxic dosage levels.
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