Investigation of (Oxodioxolenyl)methyl carbamates as nonchiral bioreversible prodrug moieties for chiral amines.

The preparation of (oxodioxolenyl)methyl carbamates and their evaluation as novel nonchiral prodrug moieties for chiral primary and secondary amino functional drugs are described. 4-(Carbamoylmethyl)-2-oxo-1,3-dioxolene derivatives of 3,4-dimethoxyphenethylamine with 5-methyl, 5-phenyl, and 5-anisyl substitution (5a, 5b, and 5c) on the dioxolenone ring were prepared as model amine prodrugs by a one step process involving displacement of p-nitrophenol from appropriately substituted ring opening of these carbamates led to a cascade reaction resulting in the rapid and quantitative regeneration of the parent amine drug. Aryl substitution did not significantly alter the hydrolysis rates of these dioxolenone carbamates in buffers at pH 1 and 7.

Investigation of N-[(acyloxy) alkyl] ester as a prodrug model for drugs containing the phenyltetrazole moiety.

N-Acyloxyalkylation using 5-phenyltetrazole as a model compound was investigated as a general means of prodrug modification of the tetrazole ring with a view to change the physicochemical properties for improving biomembrane transport. Pivaloxymethylation gave a mixture of 1- and 2- [(pivaloxy)methyl] -5-phenyltetrazole isomers in 1:4 ratio. The structures of the compounds were established by NMR spectroscopy using nuclear Overhauser effect (NOE) difference and heteronuclear multiple bond correlation (HMBC) techniques.

Application site dependent ocular absorption of timolol.

Ocular absorption of timolol in rabbits was studied after topical ocular administration of 3H-timolol in an eyedrop or in silicone cylindrical devices that released timolol at 7.2 micrograms/h. The devices were applied in either the inferior or superior conjunctival sac.

Systemic delivery of timolol after dermal application: Transdermal flux and skin irritation potential in the rat and dog.

Timolol, a beta-adrenergic antagonist, was evaluated for transdermal flux with rat skin in vitro and with the dog in vivo. Skin irritation after dermal application of timolol was assessed in the rat in vivo. Drug flux across rat skin in vitro ranged between 2 and 110 µg cm(-2) hr(-1), dependent on the formulation.

Bisulfite-ion-catalyzed degradation of fluorouracil.

5-Fluorouracil (I) reversibly adds bisulfite ion across its greater than C5 equals C6 smaller than bond to form 5-fluoro-5,6-dihydrouracil-6-sulfonate (II). The pH-independent equilibrium constant for this reaction was calculated to be 560 M-1 at ionic strength 1.00 M at 25 degrees.