(Acyloxy)alkyl carbamates of the type R1R2N-CO-O-CHR3-OCO-R4 are described as novel bioreversible prodrugs for primary and secondary amines. These were prepared either by a one-step reaction involving nucleophilic attack on p-nitrophenyl alpha-(acyloxy)alkyl carbonates with displacement of p-nitrophenol or by reaction of alpha-haloalkyl carbamates with silver or mercury salts of carboxylic acids. Enzymatic hydrolysis of the ester bond in these ester carbamates leads to a cascade reaction resulting in rapid regeneration of the parent amine. Permeability measurements of such nonionic derivatives of atenolol, betaxolol, pindolol, propranolol, and timolol through fuzzy rat skin and rabbit cornea mounted on diffusion cells show that derivatization of the hydrophilic beta-blockers results in several-fold increase in permeation through these biological membranes. However, prodrug modification of the lipophilic beta-blockers leads to little advantage in permeability characteristics.

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 7.4 or in rat plasma, although the hydrolysis rates of 5-phenyl- (1b) and 5-anisyl- 4-methyl-1,3-dioxol-4-en-2-one (1c) in pH 7.4 phosphate buffer were 2-3 fold faster than that of the 5-methyl-substituted analog (1a). Application of this prodrug strategy to the chiral fibrinogen receptor antagonist L-734,217 resulted in a prodrug that gave quantitative reconversion in rat and dog plasma in vitro and oral bioavailability of 23 +/- 6% in dogs for the parent drug.

As a new prodrug approach to norfloxacin (NFLX) we prepared the acetoxyalkyl carbamates of the type NFLX-CO-OCHR-OAc by the reaction of sodium or mercuric acetate on NFLX alpha-chloroalkyl carbamates. These produrgs did not have the bitter taste of NFLX. In vitro, the acetoxyethyl carbamate exhibited activity only against Staphylococcus spp. and was inactive against Gram-negative organisms. However, in the presence of serum and intestinal homogenate, esterase-catalyzed hydrolysis of the ester bond in these modified carbamates led to a cascade reaction resulting in the rapid regeneration of NFLX. At high oral doses of the prodrug, the acetaldehyde produced as a side product in the breakdown of the promoiety caused a slight decrease in alcohol metabolism in a mouse model. The bioavailability of NFLX from the acetoxyethyl carbamate was lower compared to an equivalent dose of NFLX when given as an oral suspension in rhesus monkeys, presumably because of the lower aqueous solubility of the prodrug.

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20 J. Org. Chem. 8.10. Found C, 68.65; H, 8.39.4@-(2,5@,6,6-Tetramet hyl-2-cyclohexenyl)-3( E)-buten-&one (2a,. The ketone 18a (35 mg, 0.09 mmol) in dry THF (3 mL) was added to MeONa (30 mg, 0.57 mmol) dissolved in t-BuOH (6 mL) at 5 OC under N2. The mixture was stirred a t room temperature for 7 h. The usual workup and chromatography (SiOz, benzene-AcOEt (101)) provided 2a (16 mg, 86%) as a colorless oil. The synthetic 2a was homogeneous on VPC 4+3m, 170 "C), and ita IR and NMR spectra were superimposable with those of the authentic sample (Shinetsu). Similarly, 1 and 2b were prepared from 17 and 18b in 84 and 85% yield, respectively. The published spectral data of 1,2a, and 2b were in 1980,45, 20-24 agreement with those of the synthetic sample^.'^ RegistryThe chemistry of aloe-emodin (3) has been explored with a view toward its use as a synthon for the regioepecific synthesis of adriamycin and analogues of it. Routes for satisfactory large-scale monomethyl ether formation at CB (4) and regiospecific introduction of a phenolic oxygen function a t C4 (21) are described. Interesting side reactions were encountered, including an apparent peri 0 to 0 acyl wandering reaction during methylation and a reductive debromination reaction during displacement of an aryl bromide by methanolic methoxide.Aloe-emodin (4) has been converted in six steps to 1,4,5-trihydroxy-2-(2,3-dicarboxypropyl)-9,lO-ant~aquinone (17), a synthon suitable for further regiospecific elaboration into daunomycin-adriamycin analogues. A method for Friedel-Crafts acylation of anthraquinones by reduction to the anthracenone, cyclization, and reoxidation has been developed as a key feature of the synthesis.