Cephalosporin 7-methoxy

Parenterally administered cephalosporins that are metabolically stable and that are resistant to many types of jS-lactamases include eefuroxime, cefamandole, cefotaxime and cefoxitin, which has a 7a-methoxy group at R. Injectable cephalosporins with anti-pseudomonal activity include cefsulodin and cefoperazone. 

In addition, the last of the shown drugs, moxalactam, contains a hydrooxazine ring instead of the dihydrothiazine ring common to all other cephalosporins. A few cephalosporins contain an additional methoxy group at position C7 of aminocephalosporanic acid (cefotetan, cefaclor). 

Cefoxitin and cefotetan, which are cephamicins and differ from other cephalosporins principally in the presence of a methoxy group at position 7 of the cephalosporanic system, which significantly increases their resistibility with respect to beta-lactamases, belong to the second-generation cephalosporins. 

The cephamycins comprise a set of beta lactamase resistant fermentation products that consist of cephalosporins that include a methoxy group on the carbon bearing the amine. These agents were not suitable as drugs in their own right because of their poor biopharmaceutical properties. This was due to the circumstance that the natural products, like the original cephalosporins, occurred as their highly... 

The last procedure is important as it can be used for the synthesis of 6- and 7-methoxy penicillins or cephalosporins which are potent antibiotics against Gramnegative bacteria (Eq. (55))... 

Further, the discovery of 7-a-methoxy cephalosporins [5] from Streptomyces in 1971, carbapenems [6], thienamycin [7], clavulanic acid [8], sulbactum [9] as well as the totally synthetic oxapenems [10], oxacephams [11], and other bicyclic (3-lactams stimulated the search for novel antibiotics. More recent dedicated efforts to find new active molecules and modify the penicillin and cephalosporin structure have resulted in the discovery of simple monocyclic (3-lactams such as norcardicins and monobactams [12, 13]. Yet another dimension has been added to the (3-lactam research with the recent discovery of tricyclic (3-lactam antibiotics called trinems [14]. Thus, (3-lactam antibiotics in general can be classified into several groups based on their structures (Fig. 1). 

Several synthetic procedures for the preparation of C-2-acetoxy- and methoxy-cephalosporins have been reported20). The functionalization at the C-2 position of cephalosporin 15 can be started with the oxidation of the divalent sulfur atom which produces sulfenium cation intermediates, which are precursors of C-2-substituted cephalosporins. The electrochemical conversion of cephalosporins 15 into their C-2-substituted homologs has been realized 2,). For example, the electrochemical acetoxy-lation at the C-2 position of desacetoxycephalosporin 15 is carried out in an AcOH— Ba(OAc)2—(Pt) system to give the C-2-acetoxylated products 24 (R1 = CFL,OPh R2 = Me) in 70% yield (Scheme 2-8). Electromethoxylation at the C-2 position of 15 is performed in a MeOH/CHClj—BuEtjNCl—(Pt) system to give the compounds 25 (R1 = CH2OPh R2 = CH2Ph) in 43% yield. The methoxylated product 25 can lead to the further oxidized product 26 by electrolysis in a H20/CHClj—MgC —(Pt) two-layer system. 

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-... 

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. 

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 ... 

Continuing use of the third-generation cephalosporins and the introduction of p-lactamase inhibitor combinations (clavulanate with amoxycillin or ticarcillin, sulbactam with ampicillin, and tazobactam with piperacillin see section 4.2) resulted in the appearance of plasmids encoding class C P-lactamases. After several unconfirmed reports, the first proof that a class C P-lactamase had been captured on a plasmid came in 1990 when transmissible resistance to a-methoxy and oxyimino-P-lactams was shown to be mediated by an enzyme whose gene was 90% identical to the ampC gene of E. cloacae. They have subsequently been found worldwide. Strains with plasmid-mediated AmpC enzymes are typically resistant to aminopenicillins (ampicillin or amoxycillin), carboxypenicillins (carbenicillin or ticarcillin) and ureidopenicillins (piperacillin). The enzymes also provide resistance to the oxyimino cephalosporins (ceftazidime, cefo-... 

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