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.

The kinetics and mechanism of the degradation of cyclosporin A have been studied under aqueous acidic conditions. The rate of degradation was found to be specific acid‐catalyzed over the pH range studied (1–4), with isocyclosporin A as the predominant degradation product. Selective reduction of the olefinic bond of the amino acid 2‐N‐methyl‐(R)‐((E)‐2‐butenyl)‐4‐methyl‐l‐threonine (MeBmt) did not affect the overall degradation kinetics and product distribution of cyclosporin A. These observations indicate that the alternative degradation pathway involving intramolecular alkoxy addition to the olefinic bond of amino acid MeBmt apparently does not significantly contribute to the overall degradation kinetics of cyclosporin A in the pH range 1–4. The chemical reactivity of O‐acetyl‐cyclosporin A was examined to probe the governing mechanism for the isomerization of cyclosporin A. Under identical conditions, O‐acetyl‐cyclosporin A showed a much greater chemical stability than cyclosporin A, consistent with a mechanism involving the hydroxyoxazolidine intermediate. The chemical stability of cyclosporin C, which contains two β‐hydroxyl groups, was also examined. The rate and product distribution for the degradation of cyclosporin C suggest that under aqueous acidic conditions it undergoes N,O‐acyl migration solely at the amino acid residue MeBmt. Additionally, the impact of side‐chain bulkiness of amino acid MeBmt was examined by studying the degradation kinetics of a series of cyclosporin A analogs. The apparent rate constants for the isomerization of these analogs were not significantly different from that of cyclosporin A, indicating that the terminal bulkiness of amino acid MeBmt may not play a critical role in controlling the rate and extent of N,O‐acyl migration in cyclosporin A.

Ethyl l-(4-Methoxyphenyl)-6-(benzyloxy)-2-methyl-5methoxy-2,3-dihydro-lff-l,9-diazaphenalene-8-carboxylate (18f). The reaction of iminophosphorane 28 with 4-methoxyphenyl isocyanate under the same conditions described for the preparation of 18 led to 18f:

Reaction of methyl benzoylphenylphosphinate 1 with hydroxylamine gave methyl a-hydroxyiminobenzylphenylphosphinate 2 as a mixture of €and Z isomers with the E isomer predominating. Pure ( E ) -2 when heated gave methyl N-benzoylphenylphosphonamidate 3 as the sole product. In contrast, (Z) -2 when heated gave, as a result of fragmentation, mainly methyl hydrogen phenylphosphonate 4 and benzonitrile, together with methyl N-phenylcarbamoylphenylphosphinate 5 as the minor product; the latter results from Beckmann rearrangement of (2)-2. Analogous behaviour is exhibited by the two geometrical isomers of dimethyl a-hydroxyiminobentylphosphonate 8. The crystal structures of methyl ( E ) -a-hydroxyiminobenzylphenylphosphinate ( E ) -2 and methyl benzoylphenylphosphonamidate 3 are reported.Recently we reported initial results from our study concerning the oxyiminophosphonic functional group. ' Our interest in this

No abstract