Cephalosporin 3-unsubstituted

In these papers, the carboxylic acid to be protected was a stable, unsubstituted compound. Harsh conditions were acceptable for both formation and cleavage of the amide. Typically, a simple secondary amide is very difficult to cleave. As the pKa of the conjugate acid of an amide decreases, the rate of hydrolysis of amides derived from these amines increases. The dimethylamide of a cephalosporin was prepared as follows using 2,2 -dipyridyl disulfide. ... 

Now we turn to a discussion of the influence of a-substitution at C(6) or C(7) on the chemical reactivity of the lactam ring (Table 5.4,B). This substitution has been introduced mainly to improve lactamase stability (see Sect. 5.2.2.2). The insertion of an additional a-substituent at C(6) or C(7) of penicillins or cephalosporins, respectively, has a relatively small effect on the rate of base hydrolysis [82] [83], 6a-Methoxypenicillin is hydrolyzed at a rate that is approximately half that observed for the unsubstituted parent penicillin. This decrease is due mainly to unfavorable steric interaction between the... 

All orally active (3-lactams carry an unsubstituted or modified D-phenylglycine side group in the A-terminus position and therefore should have affinities similar to di- and tripeptides with an A-terminal D-amino acid [14]. The stereoselective transport of (3-lactam antibiotics is of particular interest because the L-isomer of aminocephalosporin failed to be absorbed in vivo to a significant extent [15]. However, a study on d- and L-enantiomers of cephalexin and loracarbef demonstrated the higher affinity of the L-isomer to oligopeptide transporter than the o-isomer (Fig. 5) [16]. Consequently, the apparent low absorption rate of L-isomers of amino cephalosporines does not appear to be due to lack of transport by the peptide transporter, but, more likely, because of the rapid enzymatic... 

The synthesis of 3-unsubstituted cephalosporins demonstrated a gratifying application which accrued from research technology developed for the total synthesis of cephalosporin C. Having at hand a suitable intermediate and a know-how in constructing the cephem system, the Woodward group in Basel decided to prepare cephalocillin. This new substance is, in fact, a hybrid of the cephalosporin and penicillin structures, devoid of a substituent at the 3-position. 

Removal of the ester group afforded the cephalosporin acid (205). 7-Amino- and 7-acylaminocephalosporin esters directly substituted at position 3 with a secondary acyclic amino group or a cyclic secondary amino group were reduced in dry solvents with diborane to yield 3-unsubstituted 3-cephems. The same 3-aminocephalosporins were reacted with an alkyl or aryl Grignard reagent to afford the corresponding 3-alkyl- or 3-aryl-3-cephem esters (U.S. Patent 4,065,618). 

In general, none of the 7(6)-alkylated (acylated) cephalosporins or penicillins reported showed enhanced biological activity relative to their unsubstituted parents. These disappointing results, coupled with the concomitant discovery of cephamycins, led researchers to explore the latter more promising area. Among the earliest methods employed for 7(6)-methoxyl introduction was initial -lactam sulfenylation or halogenation,... 

The results presented in Table III show that any substitution in the 6a-position of penicillin G or penicillin V reduces both enzyme inhibition and antibacterial activity. In contrast, introduction of a 7a-methoxy group into cephalosporins results in antibiotics that are better inhibitors of transpeptidase than their unsubstituted counterparts, although they do not necessarily possess better antibacterial properties (Table III). To test the effect of 6a-substitution in penicillins and 7a-substitution in cephalosporins on the chemical stability of these respective 3-lactams, the relative rates of hydrolysis of the substituted compounds were determined in aqueous solution at pH 10 (Table IV). The results show that 7a-methoxy substitution in cephalosporins has no pronounced effect on the reactivity of the p-lactam, which is in contrast to the three- to fivefold decrease in reactivity found with 6a-methoxy substitution in penicillins G and V. Indelicato and Wilham (1974) have suggested that loss of... 

The addition of a p-hydroxyl substituent to a phenylglycine cephalosporin had little effect on the in vitro activity. In some cases no changes in activity were noted, whereas in other cases slight decreases in activity were seen (Webber and Ott, 1977). Studies by Preston and Wick (1974) and Dunn et al., (1976) suggested, however, that as in the case of amoxicillin, addition of a p-hydroxyl substituent increased oral absorption in mice relative to unsubstituted phenylglycine cephalosporins. The addition of a m-hydroxyl substitutent has been reported (Dunn et al., 1976) to have a negligible effect on the oral absorption of some cephem antibiotics in mice. 

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