763. Some preparative uses of benzylpenicillinic ethoxyformic anhydride

Abstract

The mixed anhydride (I), named in the title, which is readily prepared from a salt of benzylpenicillin and ethyl chloroformate, reacts with amines to form amides, with alcohols to form esters, and with thiols for form thiol-esters of the antibiotic. Several of the derivatives so prepared are hydrolysed in aqueous media to liberate free benzylpenicillin, a property that makes them of possible therapeutic interest. ESTERS of benzylpenicillin have attracted relatively little interest in the past largely becausethe first known members, namely, the simple alkyl and aralkyl esters, were devoid of antibacterial activity both in vitro and in man (though not in mice and rats). Carpenter ( J . Amer. Chem. Soc., 1948, 70, 2964), however, found that the dimethylaminoethyl ester (11; X = -O*CH,*CH,*NMe,) exhibited full activity in the plate bioassay, owing, as he showed, to its ready hydrolysis to free penicillin and the amino-alcohol. More recently the important discovery has been made that the dialkylaminoethyl esters, particularly the hydriodide of the diethylamino-homologe (Estopen), are selectively concentrated in inflamed lung tissue : of these, however, only the last mentioned has been tested on human subjects; it gave rise to prolonged effective levels of penicillin in their sputa (Friederiksen and Nielson, XIIth Internat. Congr.

The Chemistry of Chloroformates

“…Their reaction with nucleophiles proceeds readily under mild conditions to give good yields of the expected products. 1. With Alcohols (39,335,359) The preparation of esters by the route shown in the following equation is especially useful in cases where 0 0 0 rJoCOR' + R'OH -R¿OR" + CO, + R'OH the acids are thermally or otherwise unstable. The use of chloroformates as esterification catalysts has been reported (238).…”

Coupling products of amino acids to penicillin V and cephalothin: synthesis and susceptibility to carboxypeptidases and lysosomal enzymes

“…Injection of cephalothin-valine (22), cephalothin-tyrosine (28) or cephalothin-leucine (21) into mice also failed to reveal any significant conversion of these derivatives to microbiologically active substances. Thus, whereas the 48-h sample of urine of mice injected with cephalothin contained microbiologically active substance(s) equivalent to 40% of the injected dose, no detectable activity was Figure 1.…”

“…In Vivo Experiments. Three groups of two mice (NMRI) were injected intraperitoneally with cephalothin, cephalothin-leucine (21), cephalothin-valine (22), or cephalothin-tyrosine (28). The drug was administered as a single dose of 20 mg in physiological saline solution.…”

Penicillins and Cephalosporins

“…that the amino acid is actually isoglutamine. Moreover, benzylpenicillin amide (HoLYSZ and STAVELY, 1950) and the morpholide (BARNDEN et al, 1953) are biologically active; whether the activity is inherent or results from hydrolysis hasn't been proven. TIPPER andSTROMINGER (1965) andTIPPER (1965) propose a closely analogous explanation to that of WISE and PARK but with some differences.…”