Elimination lactam rings

Some penicillins cannot be given orally as their beta-lactam ring is hydrolyzed and inactivated in the stomach by gastric acid. In general intramuscular injections are painful and therefore not advised. The pharmacokinetic behavior of penicillins is further characterized by short elimination half-lives. Renal elimination is prominent. 

Nylon 6 is also a polyamide, but is made from the monomer e-caprolactam, which is a cyclic amide of e-aminocaproic acid. Heat opens the lactam ring to give the amino acid salt, which forms amide bonds with other molecules by eliminating water. 

Despite the strong implications of the thiazepinone rearrangement of penicillins that elimination can occur in the /3-lactam ring, no example of this reaction has been uncovered for monocyclic /8-lactams, even for a leaving group as reactive as chloride. In basic solutions hydrolysis or methanolysis of the /8-lactam ring takes precedence. The only reaction... 

It is known that p-lactamase catalyzes the rapid hydrolysis of the p-lactam ring of penicillins and cepharosporines. The hydrolytic activity of these enzymes eliminates the bacteriocidal action of many p-lactam antibiotics and makes the organism resistant to these molecules. For this reason, the p-lactamase inhibitors have long been regarded as promising targets from a medicinal viewpoint. A comparison between the kinetic characteristics of p-lactamase and penicillin-sensitive enzymes (carboxy-peptidase and transpeptidase) is of interest in this respect. p-Lactamases very efficiently hydrolyze p-lactam in contrast to penicillin-sensitive enzymes [high /e4 in Eq. (9)]. 

Azole approach. The /8-lactam ring in penicillanic acid derivatives can be expanded to a pyrimidine ring. Thus methyl 6/8-phthalimidopenicillanate (506) is transformed by CSI into the corresponding fused pyrimidine (507) with retention of the stereochemistry (78JCS(P1)817). Treatment of penicillanate S-oxides (508) with acyl isocyanates in a similar manner yields fused pyrimidines which subsequently eliminate water from the rearranged sulfoxide (74USP3850933). 

Disposition in the Body. Readily absorbed after oral administration bioavailability almost 100%. Metabolised by demethylation and subsequent deamination to the active metabolites desme-thylchlordiazepoxide and demoxepam. Demoxepam is further metabolised by hydrolysis with cleavage of the lactam ring and by reduction to desmethyldiazepam (nordazepam) followed by hydroxylation to oxazepam (desmethyldiazepam and oxazepam are also pharmacologically active). About 60% of a dose is excreted in the urine and 10 to 20% is eliminated in the faeces less than 1% of a dose is excreted in the urine unchanged, about 6% is excreted as demoxepam, and the remainder as ring-opened derivatives and glucuronide conjugates of oxazepam and other hydroxylated metabolites. 

The lactam derivative dibenz[h/]l 4-oxazepin-ll-(lOH)-one is a primary metabolic product of metabolism and a direct precursor of the urinary hydroxylated metabolites. In rats, the lactam, a dihydro-CR metabolite, an amino alcohol of CR, and an arene oxide are metabolites in CR degradation. In the rat, the major mechanism for elimination is sulfate conjugation and biliary excretion to a limited extent. Phase I metabolism by microsomal mixed fimction oxidases involves reduction of CR to the amino alcohol, oxidation to form the lactam ring, and hydroxylation to form the hydroxylactams. Phase II conjugation reactions sulfate the hydroxylactam intermediates for renal elimination. Amino alcohol intermediates are conjugated with glucuro-nide for biliary secretion. 

The spectrum of the free acid showed no molecular ion. Ions of highest mass, m/e 30 + and 292, probably arose from the free acid by the hydrolytic elimination of acetic acid and sulfur, and acetic acid and carbon dioxide respectively. An intense peak at m/e + + (CO ) supported this conclusion. Peaks at m/e 216 and 215, expected from the fission across the p-lactam ring, were not observed. Three peaks which may be assigned to the side chain and part of the p-lactam ring were m/e 97 (CsD -CH +), m/e 12 + ( -CH-C=0+), and m/e l8l ( -CH -C0-NH-CH=G=0+). Occolowitz concluded that the spectrum arose by ionization of hydrolysis products of the free acid. 

Cephalothin can be determined by means of the colored complex formed on the addition of a ferric reagent to the corresponding hy-droxamic acid produced by treatment with hy-droxylamine. The method used is essentially the same.as the procedure described for penicillins. The ferric hydroxamate procedure is not specific for cephalothin or penicillins. For example, many amides, esters, and anhydrides form hydroxamic acids when reacted with hydroxyl-amine. This type of interference is eliminated by the blank determination wherein cephalothin is rendered incapable of forming hydroxamic acid by use of basic hydrolysis or enzymatic hydrolysis with cephalosporinase. Since cephalothin degradation products having an intact (3-lactam ring react as well as the parent compound, the method measures total 3-lactam content. ... 

A variety of enzymatic mechanisms for antibiotic resistance are known. Hydrolysis of the lactam rings of /3-lactams, cephalosporins, and carbapenams destroys their ability to inhibit transpeptidases that cross-link peptidoglycan in bacterial cell walls. Modification of aminoglycoside antibiotics by acetylation, phosphorylation, or adenylation interferes with their ability to bind to the 16S subunit of the ribosome. Streptogramin activity can be destroyed by acetylation or by an elimination reaction that opens the lactone ring. The enzymes responsible for these detoxification reactions evolved in response to naturally occurring antibiotics, but are easily adapted to modify semisynthetic and completely synthetic antibiotics. For example, only a few point mutations are needed to enhance the ability of TEM /3-lactamases to hydrolyze third-generation cephalosporins such as cefotaxime and ceftazidime. ... 

Imipenem and meropenem have the same mode of antibacterial action as the penicillins and cephalosporins but structurally are carbapenems that have the p-lactam ring. Their clinial uses, routes of elimination, and side affects are considered. 

Farad WS, Pratt RF. Elimination of a good leaving group from the 3 -position of a cephalosporin need not be concerted with P-lactam ring opening TEM-2 P-lactamase-catalysed hydrolysis of pyridine-2-azo-4 -(N, N -dimethylanUine) cephalosporin (PADAC) and of cephaloridine. 1 Am Chem Soc. 1984 106 1489-90. 

Replacement of methoxyl by cyano groups a,) -Ethylenenitriles from enolethers Lactam ring elimination a,/ -Ethylene-) -cyanoketones... 

Hydrogen chloride Lactam ring elimination a,j -Etbylene-j -cyanoketones s. 17, 815... 

---