Novel phosphorus-containing prodrugs
A prodrug and pharmaceutical technology, applied in the field of new phosphorus-containing prodrugs, can solve refractory liver cancer and other problems
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Embodiment 1
[0562] Example 1: General Procedure for Phosphoramidate Prodrugs of Drugs Containing Phosphonic Acids:
[0563] A suspension of 5-isobutyl-2-methyl-4-(2-(5-phosphono)furyl)thiazole (200 mg, 0.6 mmol) in 2.5 mL of thionyl chloride was heated at reflux temperature for 4 Hour. The reaction mixture was cooled and evaporated to dryness, then azeotroped with toluene. To a solution of the resulting residue in 4 ml of dichloromethane was added aminoethanol (82 mg, 0.54 mmol) and pyridine (0.5 ml, 6 mmol) in 1 mL of dichloromethane.
[0564] After stirring at 25°C for 4 hours, the reaction was evaporated and co-evaporated with toluene. The crude product was chromatographed eluting with 10% methanol-dichloromethane to afford 52 mg (20.8%) of the less polar isomer and 48 mg (19.2%) of the more polar isomer.
[0565] The following compound was prepared in this way: 1.1: 5-isobutyl-2-methyl-4-{2-[5-(1-phenyl-1,3-propyl)phosphonimino]furyl}thiazole , the less polar isomer. Rf = 0.76 in...
Embodiment 2
[0566] Embodiment 2: Step A:
[0567] At 0°C, a solution of 3-amino-3-phenyl-1-propanol (1 g, 6.6 mmol) and triethylamine (3 ml, 21.8 mmol) in tetrahydrofuran (60 ml) was added dropwise to 4-Nitrophenyl dichlorophosphate in solution in tetrahydrofuran. A white precipitate formed rapidly. The yellow heterogeneous mixture was stirred at 0 °C for 1 h, then slowly warmed to room temperature. After stirring at room temperature for 60 hours, the precipitate was dissolved in water (40ml). The clear yellow solution was concentrated to about 40ml. The resulting mixture was diluted with saturated aqueous sodium bicarbonate and extracted twice with ethyl acetate. The combined organic extracts were washed with saturated aqueous sodium bicarbonate and brine. The aqueous washes were extracted again and the organic extracts were combined. The combined organic extracts were dried over sodium sulfate, concentrated and purified by column chromatography (silica gel, hexane / ethyl acetate) t...
Embodiment 3
[0570] Embodiment 3: Step A:
[0571] Same as step A of embodiment 2. Step B:
[0572] Lithium hydride (15 mg, 1.52 mmol) was added to 9-β-D-arabinofurano-adenine (100 mg, 0.37 mmol) and the rapidly eluting (4-nitrophenoxy)-4- Phenyl-1,3,2-oxazaphosphorin-2-one (250 mg, 0.74 mmol) in solution in dimethylformamide. After 6 hours, the yellow heterogeneous mixture was neutralized with acetic acid. The clear yellow solution was concentrated and the residue was purified by column chromatography (silica gel, methanol / dichloromethane). The isolated product was further purified by preparative TLC and recrystallized from ethanol to afford the prodrug: 18 mg (11% yield).
[0573] The following compound was prepared in this way: 3.15'-O-(2-oxo-4-phenyl-1,3,2-oxazaphosphorin-2-yl)-9-β-D-A Sugar Furanadenine. mp>250. Rf = 0.25 (silica gel, 2 / 8 methanol / dichloromethane). C 19 h 23 N 6 o 6 Theoretical values of P: C: 49.35; H: 5.01; N: 18.17. Found values: C: 49.22; H: 4.89; N...
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