Preparation, hydrolysis, and oral absorption of alpha-carboxy esters of carbenicillin.

Twelve alpha-carboxy esters of carbenicillin, a parenteral broad spectrum semisynthetic penicillin, were synthesized and examined as potential oral carbenicillin derivatives. The rates at which the esters were hydrolyzed in vitro to carbenicillin by animal and human tissues were compared and the carbenicillin serum levels arising after oral administration of the esters were measured in squirrel monkeys and human volunteer subjects. The alpha-carboxyphenyl ester of carbenicillin [carfecillin (British Pharmacopoeia approved name), BRL 3475] WAS SELECTED FOR FURTHER STUDY AND IS PRESENTLY UNDERGOING CLInical trial.

Synthesis of 17 beta-hydroxy esters of 4-estren-17 beta-ol-3-one and carbenicillin, ticarcillin, or functionalized oxacillin: potentially useful conjugates for beta-lactamase-based homogeneous immunoassays.

On the basis of the large range of kinetic constants of their substrates, beta-lactamases seem to be interesting enzymes for the development of homogeneous immunoassays. For this purpose, hapten-penicillin or -cephalosporin conjugates have to be prepared. The aim of this work is to couple the anabolizing steroid nandrolone to several penicillins characterized by extremely low K(m) and kcat values: ticarcillin, carbenicillin, and oxacillin. The easy decarboxylation of derivatives of phenylmalonic acid (carbenicillin) and thienylmalonic acid (ticarcillin) imposes the choice of very mild procedures which have been specifically adapted to each substance investigated. 4-Estren-17 beta-ol-3-one hemiphenylmalonate is conjugated to 6-aminopenicillanic acid after 1,1'-carbonyldiimidazole activation, while 4-estren-17 beta-ol-3-one hemi(3-thiophene)malonate is coupled to 6-aminopenicillanic acid after activation using methanesulfonyl chloride. Before conjugation of oxacillin, a carboxylated analogue of its side chain has been prepared. A procedure resorting to tert-butyl ester protection of the carboxyl group present on the isoxazole ring allows the binding of nandrolone to the remaining carboxyl followed, after specific deprotection, by the conjugation to 6-aminopenicillanic acid giving the oxacillin derivative. In this way, conjugates retaining immunological properties of nandrolone and high inhibiting power of beta-lactamases should be obtained.

Synthesis and properties of disodium tetraethyleneglycol-bis-(alpha-carboxybenzylpenicillin).

Disodium tetraethyleneglycol-bis-(alpha-carboxybenzylpenicillin) (TEG-carbenicillin), a tetraethyleneglycol (TEG) diester of carbenicillin, was synthesized to develop a carbenicillin prodrug with enhanced acid stability for oral administration. Antimicrobial activities of TEG-carbenicillin tested against gram-negative Escherichia coli (TG-1) and gram-positive Staphylococcus aureus (ATCC-12228) and Bacillus subtilis (NA-1) were comparable to that of carbenicillin. Stability of the beta-lactam ring of TEG-carbenicillin was determined by iodometry at pH 6.8, pH 4.5, and pH 2.0 at varied time intervals and was compared to that of carbenicillin. In 26 hr, both of the compounds were stable at pH 6.8. At pH 4.5, about 41% of the carbenicillin was decomposed, while TEG-carbenicillin was not appreciably decomposed. At pH 2.0, carbenicillin was decomposed about 61% after 6 hr, while TEG-carbenicillin was decomposed about 21% during the same period.