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(5-Substituted 2-oxo-1, 3-dioxolen-4-yl) methyl esters were designed as a new type of ampicillin prodrug. These esters were prepared and confirmed to produce higher blood levels of ampicillin than ampicillin trihydrate itself after oral administration to mice. The compounds which produced particularly high blood levels of ampicillin were found to be hydrolyzed readily in blood in vitro. Ampicillin (5-methyl-2-oxo-1, 3-dioxolen-4-yl) methyl ester hydrochloride (KBT-1585) showed the best oral absorbability in mice.

Several 3-formylquinolone derivatives (8a-c) were synthesized to assay the antibacterial activity both in vitro and in vivo. In vitro, all of the compounds 8a-c showed lower activity than that of the corresponding 3-carboxyl compounds 1a-c, and in vivo, they showed higher activity than that of compounds 1a-c. After oral administration of 3-formyl compounds 8a-c to mice, the compounds were rapidly metabolized into 3-carboxyl compounds 1a-c. In particular, the 3-formyl derivative (8a) of norfloxacin (NFLX, 1a) gave a 2-fold higher serum level than that of NFLX and functioned as a prodrug of NFLX.

As a prodrug approach to norfloxacin (NFLX, 2), we have prepared several N-masked NFLXs (1a-f) and studied the cleavage mechanism of the C-N bond of N-masked NFLXs utilizing the following experiments: (1) the oxidation of N-masked NFLXs (1a-f) with m-chloroperbenzoic acid (MCPBA) and their subsequent cleavage to 2 in chloroform at room temperature or at 50 degrees C; (2) the liberation of NFLX from N-masked NFLXs after oral administration in mice. It was found that the chemical oxidative dealkylation of N-masked NFLXs proceeded when anion-stabilizing groups (e.g., CN, COR, COOR) are present on the alpha carbon of the nitrogen atom. In in vivo experiments, N-masked NFLXs having acidic hydrogens on the alpha carbon to the nitrogen atom also liberated NFLX (2) after oral administration.

As a new type of norfloxacin (NFLX) prodrug, N-(5-substituted 2-oxo-1, 3-dioxol-4-yl) methyl NFLXs were designed. These N-masked NFLXs were prepared and confirmed to produce higher NFLX levels in blood than NFLX itself after oral administration to mice. N-(5-Methyl-2-oxo-1, 3-dioxol-4-yl) methyl NFLX was found to be smoothly hydrolyzed in mouse blood in vitro, and when administered orally, gave about 5-fold higher blood levels of NFLX than NFLX itself. Thus, the (5-methyl-2-oxo-1, 3-dioxol-4-yl) methyl group was confirmed to function as an amine-type promoiety.

In order to prepare ampicillin prodrugs conveniently for practical use, a new synthetic method for 6β-aminopenicillanic acid (6-APA) esters as key intermediates of various ampicillin prodrugs has been developed. Acylation of 6-APA esters to ampicillin esters was achieved in good yields by using phenylglycyl chloride hydrochloride in dichloromethane in the presence of sodium bicarbonate and amide, or ammonium bicarbonate alone. KBT-1585, bacampicillin, talampicillin and pivampicillin have been obtained in good yields by this procedure.

The chemical oxidation of N-[(5-methyl-2-oxo-1,3-dioxol-4-yl)methyl] norfloxacin (2) was carried out to afford N-[(4-methyl-5-methylene-2-oxo-1,3-dioxolan-4-yl)oxy]norfloxacin (4). In vitro, 4 exhibited lower activity than that of norfloxacin (NFLX, 1) for both Gram-positive and Gram-negative bacteria. However, in vivo the activity of 4 was higher than that of NFLX. Bioavailability studies in mice showed that 4 liberated a higher concentration of NFLX in plasma than NFLX itself when administered orally. From these data, 4 obtained by the chemical oxidation of 2 functioned as a prodrug of NFLX as well as did 2. The mechanism of the formation of 4 is interpreted in terms of [2,3]-sigmatropic rearrangement.

Several N-(oxoalkyl)norfloxacin derivatives (3a-g) were synthesized and evaluated for antibacterial activity in vitro and in vivo. Most of the compounds exhibited in vitro activity comparable to that of norfloxacin for Gram-positive bacteria, whereas their activity was lower than for Gram-negative bacteria. N-(2-Oxopropyl)norfloxacin (3b) liberated norfloxacin in the blood after oral administration in mice, and the serum level of norfloxacin was about 3-fold higher than that of norfloxacin itself. Thus, 3b showed high antibacterial activity in vivo.

In order to prepare ampicillin prodrugs conveniently for practical use, a new synthetic method for 6β-aminopenicillanic acid (6-APA) esters as key intermediates of various ampicillin prodrugs has been developed. Acylation of 6-APA esters to ampicillin esters was achieved in good yields by using phenylglycyl chloride hydrochloride in dichloromethane in the presence of sodium bicarbonate and amide, or ammonium bicarbonate alone. KBT-1585, bacampicillin, talampicillin and pivampicillin have been obtained in good yields by this procedure.

In order to investigate a new type of promoiety for ampicillin prodrugs, acyloxyallyl esters were prepared and their oral absorbabilities, stabilities and hydrolyzabilities to parent ampicillin were studied. As starting materials for (3-phthalidylidene)ethyl esters, ethylidenephthalide and its derivatives were regiospecifically prepared by a new method using the Wittig reaction. (3-Phthalidylidene)ethyl esters (14a-c) given orally were well absorbed, but (thiophthalidylidene)ethyl ester (14d) and (isocoumarin-4-yl)methyl ester (14e) were poorly absorbed.