Cephalosporins methoxy derivatives

Firestone and Christensen [207] obtained 6a-hydroxypenicillin (107a) and its derivatives through an N-acylimine intermediate (106), but these had a markedly lower activity compared to the 6a-methoxy derivative (100). There is a direct one-step route to 6a-methoxypenicillin sulphox-ides (108) [208], which were converted into cephalosporins via a subse-... 

Anodic oxidation of cephalosporins in methanol-tetrahydrofuran mixtures containing Et4NOTs provides a useful synthesis of the corresponding 2-methoxy derivatives [105]. When ethanol, 2-propanol, or benzyl alcohol are substituted for methanol, the 2-alkoxy derivatives are formed in acceptable yields ... 

The occurrence of deacetoxycephalosporin C (236c) and the 7a-methoxy derivative of cephalosporin C (236f) provide an alternative route to the Morin method [14,74] for the preparation of cephalosporins of clinical usefulness. The side-chain exchange can be solved either using deacylation—reacylation methods [5,193—196] or via a diacyl derivative, successfully introduced for the preparation of cephamycin analogues [1.97]. 

To summarise, cephalosporins are produced by ring expansion of penicillin N to deacetoxycephalosporin C which is then oxidised to deacetylcephalosporin C. In C. acremonium, this last compound is acet-ylated to cephalosporin C. In 5. clavuligerus deacetylcephalosporin C is transcarbamoylated then converted to the 7a-methoxy derivative cephamycin C, probably via a 7a-hydroxy intermediate. Cephalosporin biosynthesis is shown diagramatically in Fig. 8. 

The most important a-alkoxy-a-amino acid compounds are the cephamycins (7-methoxycephalosporins) (1) (5, 271), which are of considerable therapeutic significance by virtue of their activity against Gram negative bacteria. Several methods have been developed for the conversion of penicillins and cephalosporins into their 6-(7-)methoxy derivative (44). 

The appropriate energy content and reactivity of the /8-lactam 0=C-N bond (cf. the problem of 6(7)a-methyl and methoxy substitution and 2-substituted derivatives). Although the molecular orbital calculations on penicillins and cephalosporins [271,272,293] are not enough to yield exact conclusions, it is likely that a parabolic relationship exists between the electron population of the 0=C-N bond and the antimicrobial activity. 

Cefroxadiite. 7-[(Amino-l,4 cyciohexadien-l-yl-acetyl)amino]-3 methoxy 8-oxo-5-thia-l,azabicyclo[4.2.0]-oct-2-ene 2-carboxylic acid 7-[d-2-ami no-2-(1,4-cyclohex-adienyl)acetamidej -3 -methoxy -3 -cephem -4-carboxylic acid CGP-9000 Oraspor. Cl(iH1(NjOsS mol wt 365,41, C 52.59%. H 5.24%, N 11.50%, O 21.89%, S 8.77%. Orally active cephalosporin deriv. Prepn R. Scartazzini, H. 

The 7p amino group is essential for antimicrobial activity (X = H), whereas replacement of the hydrogen at C-7 (X = H) with an alkoxy (X = OR) results in improvement of the antibacterial activity of the cephalosporin. Within specific cephalosporin derivatives, the addition of a 7a methoxy also improves the drugs stability toward p-lactamase. The derivatives where Y = S exhibit greater antibacterial activity than if Y = 0, but the reverse is true when stability toward p-lactamase is considered. The 6a hydrogen is essential for biological activity. Finally, antibacterial activity is improved when Z is a 5-membered heterocycle versus a 6-membered heterocycle. 

Synthesis of the 3-methoxy-7-amino-3-cephem-4-carboxylic acid (149) was of practical importance, since it enabled the Swiss chemists to prepare a number of amide derivatives for biological testing. Thus, for example, acylation of the amino group of the 3-methoxy nucleus (149) with D-phenylglycine or with d-2-( 1,4-cyclohexadienyl)glycine afforded two orally active cephalosporins, CGP 3940 and CGP 9000. 

The in vitro activities of 2-tetrazolylvinylcephalosporin derivatives are shown in Table XXIV. Introduction of a 7a-methoxy group results in a marked decrease in antibacterial activity for both the thienylacetyl and cyanomethylthioacetyl compounds. These results emphasize the importance of the 3 -position in the overall interrelationship of 7a-methoxylated cephalosporins and their antimicrobial activity. 

In addition to these deacylation or transacylation methods, much effort has been directed towards the introduction of a 7a-methoxy substituent into the cephalosporin nucleus. Such methods have also usually been applicable to penicillins. One of the first methods developed made use of the diazo intermediate (211) derived from 7-aminocephalosporanic acid (183). Treatment with bromo-azide yielded a mixture of isomers (212), which with silver tetrafluoroborate and methanol formed (213). Reduction and acylation readily followed. The stereoselective addition of methoxide to... 

Although naturally occurring cephalosporins in which the sulphur atom is replaced by oxygen are not known, mention should be made of the semisynthetic 7-methoxy-l-oxacephalosporin derivative moxalactam (6059-S)... 

The cephalosporin produced by Streptomyces clavuligerus, cephamycin C (203), has also been shown to be derived from the amino acids a-aminoadipic acid, cysteine and valine 288), DL-[1- C]-Cysteine, DL-[3- C]-cysteine, DL-[l- " C]-valine and DL-a-amino-[l- C]-adipic acid all labelled cephamycin C. Acid hydrolysis of cephamycin C, followed by separation of the hydrolysis mixture using an amino acid analyser, indicated that DL-a-amino-[l- C]-adipic acid was specifically incorporated into the acylamino side chain. The 7-methoxy group was shown to be derived from L-[me//i> /- C]-methionine. 

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