Ampicillin prodrugs

Use antibacterial, semisynthetic p-lactam antibiotic, derivative of ampicillin (prodrug for ora application)... 

Ampicillin prodrugs moderate i minimal i abnormalities of flora C. difficile correlated with 38... 

In attempts to improve the oral activity of norfloxacin, prodrug techniques have been employed. In an initial approach, the (5-methyl-2-oxo-l,3-diox-4-yl)-methyl group, which had been shown previously to be effective in a novel ampicillin prodrug, was investigated as a promoiety [ 109]. However, although the ester (77) liberates norfloxacin in the presence of mouse blood, after oral administration to mice, it was found that the blood levels of norfloxacin achieved are lower (approximately with respect to Cmax) than those achieved upon oral administration of an equimolar dose of norfloxacin, itself. This observation has been assumed to be due to an instability of this ester prior to absorption rather than an inability to liberate the parent drug after absorption. 

Fig. 5.14. Degradation of the ampicillin prodrug hetacillin (5.42). In an alkaline medium, Pathway a (epimerization at C(6)) is more important than Pathway b (hydrolysis producing... 

Lenampicillin [86273-18-9], antibacterial, semisynthetic -lactam antibiotic, derivative of ampicillin (prodrug for oral application), 145. The key reagent, the substituted vinyl-ene carbonate 144, is prepared by the phosgenation of acetoin 143 [103-111]. 

Price also stated that one of the significant new advances in penicillin research was the use of esters to enhance the oral absorption of ampi-cillin. This area of research has resulted in a number of ampicillin prodrugs, several of which are available clinically in Europe. Bacampicillin was recently approved for clinical use in the United States. This tech-... 

An alternate route to ampicillin not only circumvents the need for 6-APA but also has the advantage of providing a prodrug form of ampicillin as well as the parent compound. Reaction of benzylpenicillin (4) with the acid protecting group, 29, gives the formol ester, 30. Reaction of the product with phosphorus pentachloride leads to the corresponding imino chloride (31). 

Latentiation of ampicillin can also be achieved by tying up the proximate amino and amide functions as an acetone aminal. Inclusion of acetone in the reaction mixture allows 6-APA to be condensed directly with the acid chloride from 24. There is thus obtained directly the prodrug hetacillin (34). Although this compound has little antibiotic activity in its own right, it hydrolyzes to ampicillin in the body. The p-hydroxy derivative amoxycillin (35) shows somewhat better oral activity. A similar sequence using formaldehyde gives metampicillin (36). °... 

Sarpicillin (10) is a double prodrug of ampicillin in that not only is the carboxy group masked as an ester, but a... 

Ampicillin (5) remains the penicillin of choice for many infections because of its oral activity and good potency against Gram-negative bacteria. A number of prodrugs have been examined in attempts to... 

S Ehrnebo, O Nilsson, LO Boreus. Pharmacokinetics of ampicillin and its prodrugs bacampicillin and pivampicillin in man. J Pharm Biopharmacokin 7(5) 429-451, 1979. 

A few well-established prodrugs contain an (acyloxy)methyl or an [(alkoxycarbonyl)oxy]methyl group. Classical examples of the former are two prodrugs of /1-lactam antibiotics, namely pivampicillin (8.50), the (pivaloyloxy)methyl ester of ampicillin, and cefuroxime axetil (8.51), the... 

One of the most popular orally active penicillins in present elinieal use is amoxicillin (12). Its oral effectiveness and broad speetrum of activity against common pathogens as well as its better absorption than its elosest preeedent competitor, ampicillin (14), largely accounts for this. Higher blood and tissue levels of antibiotics is another means of dealing with resistance. In an attempt to achieve yet further improvements in oral bioavailability and hence blood and tissue levels of amoxicillin, the prodrug fumoxicillin (13) is prepared from amoxicillin (12) by treatment with furfural [3]. The imlne moiety is less ba.sie than the primary amine so that the isoelectric point of fumoxicillin is more on the acid side than is that of amoxicillin. 

Hetacillin is a semisynthetic prodrug of ampicillin also inactivated by -lactamases. It is more stable in the gastric acid than ampicillin and amoxicillin and, therefore, is absorbed best. Hetacillin is inactive per se, but after it enters the bloodstream it is metabolized to ampicillin and becomes active. 

Sulbactam is produced by Pfizer. The oral version of sulbactam in combination with ampicillin is called Unasyn Oral, which is the mutual prodrug sultamicillin. Two sulbactam parenteral products are sold, a combination product with ampicillin called Unasyn and a combination with cefoperazone called Sulperazon. In addition, sulbactam is sold alone for parenteral use with any 0-lactain antibiotic as Betainaze. 

Prodrugs are drug substances that are biotransformed in the body to active metabolites and chemotherapeutic agents. Examples include sulfasalazine to sul-fapyridine, phenylbutazone to oxy-phenbutazone, aspirin to salicylate, and heta-cillin to ampicillin. In some cases, such as aspirin (ester) and hetacillin (amide), hydrolysis in water releases the active drug moiety contained within the basic structure of the prodrug. 

Ester prodrugs are employed to enhance membrane permeation and transepithelial transport of hydrophilic drugs by increasing the lipophilicity of the parent compound, resulting in enhanced transmembrane transport by passive diffusion. For example, pivampicillin, a pival-oyloxymethyl ester of ampicillin, is more lipophilic than its parent ampicillin and has demonstrated increased membrane permeation and transepithelial transport in in vivo studies.103... 

Besides Ampicillin, 1-chloroalkyl alkyl carbonates and particularly 1-chloroethyl ethyl carbonate (CEEC), 1-chlo-roethyl isopropyl carbonate (CEIC), 1-chloroethyl cyclohexyl carbonate (CECC) and chloromethyl ethyl carbonate (CEMC), have been proposed to modify numerous compounds. Among the many types of prodrugs patented which require this method, there are examples of ... 

This kind of application was initially developed to produce Bacampicillin, a prodrug from Ampicillin [Scheme 63]. 

SUltamieillin [ban, inn, usan] is a semisynthetic (penicillin) ANTIBIOTIC, a prodrug of ampicillin and sulbactam, joined by a double ester, where the latter is an enzyme inhibitor that is resistant to P-lactamase and inhibits this penicillindegrading enzyme. It can be used clinically as an ANTIBACTERIAL to treat certain infections. 

These three compounds are all prodrugs of ampicillin. In all three examples, the esters used to mask the carboxylic acid group seem rather elaborate and one may ask why a simple methyl ester is not used. The answer is that methyl esters of penicillins are not metabolized in man. Perhaps the bulkiness of the penicillin skeleton being so close to the ester functional group prevents the esterases from binding the penicillin. 

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