Antiviral compounds and methods of administration

#1. Field of the Invention

#The present invention relates to novel nucleoside and phosphonoacid lipophilic conjugates and methods of treatment such as treatment of virally infected cells by administering one or more of the conjugates of the invention. Compounds of the invention include phosphonoacid/nucleoside conjugates where the carboxyl group and phosphonyl groups of the phosphonoacid are esterified whereby the compound contains at least one lipophilic group and at least one nucleoside group.

#2. Background

#Method A. A solution of 1-octadecanol (6.0 g, 22 mmol) in a mixture of toluene (240 mL) and Et2O(120 mL) was added dropwise to a stirred, ice-cold solution of 20% phosgene in toluene (26.7 mL, 50 mmol) over 30 minutes. The reaction mixture was allowed to come to room temperature, and stirring was continued under an argon atmosphere for 2 hours. Evaporation at water aspirator pressure followed by trituration with Et2O, suction filtration and drying yielded a waxy white solid (7.12 g, 97%); mp 30-32° C.; IR (KBr): υ 2950-2900, 2850, 1780, 1455, 1375 cm−1; 1H NMR (CDCl3) δ0.7-1.9 (m, 35H, CH3(CH2)16), 4.3(t, 2H, CH2O). Anal. Calcd. for C19H37ClO2: C, 68.52; H, 11.22; Cl, 10.65. Found: C, 68.24; H, 10.98; Cl, 10.23.

#Method B. Solid triphosgene (2.7 g, 9.1 mmol) was added to a stirred solution of 1-octadecanol (5.0 g, 1.8 mmol) and dry pyridine (0.15 g, 1.9 mmol) in dry CCl4 (20 mL) cooled in an ice-salt mixture. After 5 minutes at −15° C., the mixture was allowed to come to room temperature, stirred for 1.5 hours, and finally warmed to 40° C. in a water bath and stirred overnight at room temperature. After filtration of the pyridinium chloride salt, the solvent was evaporated to obtain a colorless gum indistinguishable from the triester obtained by Method A above; yield 6 g (99%)

#The same methods as described for Example 1 were employed using 1-eicosanol to provide the title compound as a waxy white solid from which traces of toluene were not fully removed (95% yield); mp 33-34° C.; TLC: Rƒ 0.49 (silica gel, 98:2 CHCl3-MeOH); IR (KBr): υ 2980-2890-2850, 1780, 1470, 1380, 1300, 1215 cm−1; NMR (CDCl3) δ0.8-1.6 (m, 39H, CH3(CH2)18), 4.3 (t, 2H, CH2O). Anal. Calcd. for C12H41ClO20.1C6H5CH3: H, 70.38; H, 11.40; Cl, 9.57. Found: C, 70.69; H 11.28; Cl, 9.49.