title: Phosphoryloxymethyl carbamates and carbonates--novel water-soluble prodrugs for amines and hindered alcohols.
abstract: Phosphoryloxymethyl carbonates and carbamates of the type R1R2X-CO-O-CH2-O-PO3(-2) (X = O or N) were evaluated as potentially novel water-soluble collapsible prodrugs for alcohols and amines. These were prepared by reaction of alpha-chloromethyl chloroformate with the starting alcohol or amine to give the corresponding alpha-chloromethyl carbonate or carbamate, respectively. Reaction with silver dibenzyl phosphate followed by debenzylation by hydrogenolysis gave the desired products. The aqueous chemical stability of the phosphoryloxymethylcarbonyl derivatives of 2-indanol (3a), beta-(3,4-dimethoxyphenyl)ethylamine (3b), and benzocaine (3c) were evaluated. The aqueous hydrolysis of 3a-3c resulted in regeneration of the parent alcohol or amines. As expected, the hydrolytic behaviors of these derivatives were found to differ from that of simple alkyl and aryl phosphomonoesters. The rates of hydrolysis were extremely rapid, with the dianionic phosphate species possessing a higher reactivity than the monoanionic species. This was attributed to the proximity of the phosphate group to the carbonyl moiety. The carbamate derivatives, 3b and 3c, displayed greater chemical stability compared to the carbonate derivative, 3a. Alkaline phosphatases-mediated hydrolysis of the phosphate ester bond in 3c led to a rapid cascade reaction resulting in regeneration of the parent amine, benzocaine. Although the alcohol derivative described here appeared to be too chemically unstable to be ideal as a prodrug, the derivatives of the amines might have some use. They are expected to be cleaved in vivo by alkaline phosphatases.
authors.affiliation: ABIC Pharmaceutical and Chemical Industries, Netanya, Israel.
authors.forename: M
authors.initials: M
authors.lastname: Safadi
authors.forename: R
authors.initials: R
authors.lastname: Oliyai
authors.forename: V J
authors.initials: VJ
authors.lastname: Stella
mesh_terms: D000438:Alcohols / Q000138:chemical synthesis*; D000469:Alkaline Phosphatase / Q000378:metabolism; D000588:Amines / Q000138:chemical synthesis*; D002219:Carbamates / Q000138:chemical synthesis*; D002254:Carbonates / Q000138:chemical synthesis*; D002851:Chromatography, High Pressure Liquid; D004355:Drug Stability; D005260:Female; D006801:Humans; D006868:Hydrolysis; D007700:Kinetics; D009943:Organophosphorus Compounds / Q000138:chemical synthesis*; D010920:Placenta / Q000201:enzymology; D011247:Pregnancy; D011355:Prodrugs / Q000138:chemical synthesis*; D013056:Spectrophotometry, Ultraviolet
chemical_list: D000438:Alcohols; D000588:Amines; D002219:Carbamates; D002254:Carbonates; D009943:Organophosphorus Compounds; D011355:Prodrugs; D000469:Alkaline Phosphatase