Cephalothin derivatives

Most methods used for the preparation of amides and esters of cephalothin (X) gave rise to the isomeric cephalothin derivatives (XV) which have decreased antimicrobial activity... 

Pharmaeokinetie properties of the cephalosporins depend to a considerable extent on their ehemieal nature, e.g. the substituent R. The 3-acetoxymethyl compounds such as cephalothin, cephapirin and cephacetrile are converted in vivo by esterases to the antibaeterially less aetive 3-hydroxymethyl derivatives and are excreted partly as such. The rapid exeretion means that such cephalosporins have a short half-life in the body. Replaeement of the 3-acetoxymethyl group by a variety of groups has rendered other eephalosporins mueh less prone to esterase attack. For example, cephaloridine has an internally eompensated betaine group at position 3 (R ) and is metabolically stable. 

Among the semisynthetic derivatives, cephalothin (9.47) is the most widely used since it is a broad-spectrum antibiotic resistant to lactamase. Its main drawback is that it must be injected. Cefazolin (9.48) and cephaloridine (9.49) are metabolized to a lesser extent cephalexin (9.50, analogs to ampicillin) is orally active and has a much higher acid stability than the penicillins. Cefotaxime (9.51) and moxalactam (9.52) are highly active against meningitis. 

This intermediate, like 6-APA, incorporates a primary amine that can be coupled with a host of side chains. The presence of an additional reactive function, the allylic acetate at the 3 position, provides an additional center that can be modified. The observation that both types of modifications provided unproved antibiotics has resulted in the synthesis of hundreds of analogues. The very few examples discussed below barely scratch the surface in this field. One of the earliest examples of a doubly derivatized 7-ACA derivative, cephalothin (19-1), is stUl widely used as an antibiotic. Acylation of (18-4) with 2-thiophenylacetyl chloride gives the corresponding amide (19-2). Heating that product with pyridine leads to the displacement of the allyl acetate by the basic nitrogen. The resulting product, cephalothin (19-3), is isolated as the internal betaine [23]. 

The polarographic reductions of cephaloridine, cephalothin, and cephalosporin C each yield one wave that is both pH and concentration dependent [126]. The reduction of these compounds and a related derivative, 3-(5-methyl-1,3,4-thiadiazol-2-ylthiomethyl)-7-[2-(3-sydnone)acetamido]-3-cephem-4-carboxylic acid-sodium salt [I], have been described [127]. The reduction of I yields two waves. The first is believed to be the two-electron reductive elimination of the... 

The compound (which had a dihydrothiazine ring fused to the P-lactam core) showed resistance to P-lactamases and was less toxic than benzylpenicillin. The discovery that the basic building block, namely 7-aminocephalosporanic acid (7-ACA), could be synthesised, led to the preparation of numerous cephalosporin derivatives eg cephalothin, cephaloglycin (orally active), cefaclor and cefuroxime (Figure 7). 

The different anhydride and thioanhydride derivatives may be regarded merely as intermediates useful for obtaining amides and esters. The penicillin anhydrides were synthesized long ago [105,106]. Some cephalosporin anhydrides too were described recently [106]. Cephalothin anhydride (72a) was reported to be effective against S. aureus Smith in a dose of 0.24 figlml. Assuming quantitative hydrolysis, the antimicrobial... 

Cephapirin Sodium, Sterile, USP. Cephapirin (Cefa-dyl) is a scmisynthctic 7-ACA derivative released in the United States in 1974. It closely resembles ccphalothin in chemical and phannacokinetic properties. Like cephalothin, cephapirin is unstable in acid and must be administered par-enterally in the form of an aqueous solution of the. sodium salt. It is moderately protein bound (45 to 50%) in plasma and cleared rapidly by the kidneys. Cephapirin and cephalothin arc very similar in antimicrobial spectrum and potency. Conflicting reports concerning the relative tK-currence of pain at the site of injection and thrombophlebitis after intravenous injection of cephapirin and cephalothin are dirTicuIt to as.sess on the basis of available clinical data. 

The NMR spectrum Fig.2 was obtained by preparing a solution of sodium cephalothin in deuterated water. The spectral assignments shown in Fig. 2 have been discussed in detail by DeMarco and Nagarajan. Interpretation and assignment of the absorption and resonance frequencies to the different atomic features of many cephalosporin derivatives has been discussed. ... 

NMR spectroscopy has been the most useful tool in cephalosporin C chemistry. In cephalosporins the carbons are unsaturated or highly substituted with heteroatoms, and the protons are usually widely separated in chemical shift and have simple coupling patterns. Recently, solvent induced chemical shifts, nuclear Overhauser effects, and the anisotropy of the sulfoxide bond have been utilized in chemical studies of cephalosporin C derivatives. Analytical information may be derived from NMR spectra of cephalothin by observing the contribution of the 0-lactam protons, thiophene protons, methylene groups, and methyl protons (from acetate). 

Although cephalosporin C is divisable into a-aminoadipic acid, cysteine, and valine, the actual mechanism whereby Cephalosporium sp. incorporates the three amino acids into cephalosporin C has not been established, Arnstein and Morris isolated 8 (a-aminoadipyl) cysteinyl valine from mycelia of Penicillium chrysogenum and suggested that the tripeptide is a precursor in all penicillin biosynthesis.. This same tripeptide also appears to be found in the intracellular pool of Cephalosporium sp.- The final postulated step in the biosynthesis of penicillin is an acyl transfer reaction, or the production of 6-aminopeni-cillanic acid if precursor is not added. Cephalosporium sp. apparently do not produce sidechain amidases or acyl transferases, and no 7-ACA has been reported found in the fermentation. Thus, to obtain clinically useful antibiotics, chemical manipulation of cephalosporin C is necessary. Synthesis of many 7-acyl derivatives was possible once a practical cleavage reaction made available large amounts of 7-ACA from cephalosporin C. of these derivatives, sodium cephalothin was the first... 

Redstone developed a specific colorimetric assay to determine cephalosporin derivatives containing the acetyl moiety. In this assay the acetoxyl portion of cephalothin is displaced by nicotinamide and the resulting... 

Solvent systems used for paper chromatographic analysis of cephalosporin derivatives and their degradation products are supplied in a review by Betina. 4 Paper and thin layer chromatographic procedures having particular application for cephalothin are given below. 

For quantitation of deacetyl and lactone derivatives in the presence of cephalothin ... 

Cephalosporins such as cephalothin, cephalogly-cin, cephapirin, cephacetrile and cefotaxime share an acetoxymethyl group at the position 3 (Figure 2) and are all metabolically converted to desacetyl derivatives and to the antibacterially inactive lactone of these substances. 

In some related work, the same authors reported on the preparation of C-10 alkoxy derivatives via a 3-methylenecepham intermediate (Ochiai etai, 1972c). First, 2-[4-carboxy-7-(thiophene-2-acetamido)-3-cephem-3-yl-methylthio]-pyridineN-oxide (10) was prepared by displacement of the C-10 acetoxy group in cephalothin sodium salt by 2-pyridinethiol N-... 

Biological tests show that 3-carboxamide (251), compared with cephalothin, displays equal Staphylococcus activity but is less active against other bacteria (Table XXVII). Other 3-carboxamides were prepared from the 3-carboxylic acid chlorides or mixed anhydrides (U.S. Patent 3,953,436). The 3-nitrone derivative was also used to prepare various five-membered heterocyclic rings at C-3 via 1,3-dipolar cycloaddition reaction with various dipolarophiles. In general, these derivatives showed considerable loss in biological activity (Spry, 1975a,b). 

As suggested above, most research during the 1970s was devoted to preparing cephalosporins with an expanded antibacterial spectrum. Even so, several derivatives described during this period with a cephalothin-like bacterial spectrum of activity are worthy of note. 

A carbon analogue of penicillin V (Ic) was resistant to Bacillus cer-eus B l ctamase and moderately active against gram-positive organisms.6 ) Several 2-acetoxymethyl penicillins (2ja,y6 and 2-spirocyclopropyl cephalosporins (3 )65 vere prepared. Various chemical procedures were developed for the 7(6)a-methoxylation of B-lactam antibiotics.66-72 Conversion of penicillins to cephalosporins was achieved by new synthetic routes.73-76 Some [2,3]-fused tricyclic cephem derivatives (4a-c) were synthesized.77,78 Compound displayed significant antibiotic activity.78 Racemic cephalothin, 7-methoxycephalothin, and cefoxitin were obtained by total synthesis of a novel type.79-81 nuclear analogue of a 7-methylcephalosporin (5), prepared by total synthesis, lacked antibiotic activity,82... 

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