Orally active 7-phenylglycyl cephalosporins. Structure-activity studies related to cefatrizine (SK&F 60771).

Abstract

The synthesis of a series of related broad-spectrum 7-phenylglycyl cephalosporins with 3-heterocyclicthiomethyl substituents is described. The effects of benzene-ring hydroxylation and 3-substituent variation on the in vitro antibacterial activity, height and duration of mouse serum levels, and effectiveness in protecting against bacterial infection in the mouse are examined. Included for comparison are cephalexin, cephaloglycin and their ortho-, meta-and para-hydroxy derivatives. The biological properties examined were influenced by the position of the hydroxyl group and by the nature of the 3-substituent. The 7-(p-hydroxyphenylglycyl)-3-heterocyclicthiomethyl analogs were found to produce significantly higher serum levels on oral administration to mice than their unhydroxylated counterparts. This effect was not observed with the 7-(m-hydroxyphenylglycyl)-3-heterocyclicthiomethyl cephalosporins, nor with the p-hydroxyphenylglycyl analog of cephalexin. While m-and p-hydroxylation had little effect on in vitro activity the o-hydroxyphenylglycyl cephalosporins tested had very low antibacterial activities and were not examined further. One derivative, 7-[R-2-amino-2-(4-hydroxyphenyl)acetamido]-3-(1H-1, 2, 3-triazole-4(5)-ylthiomethyl)-3-cephem-4-carboxylic acid (SK&F 60771) was found to have outstanding in vitro and in vivo activities along with oral and subcutaneous serum levels in the mouse that were significantly higher than those obtained with cephalexin. This derivative which has been given the generic name cefatrizine was selected for extensive additional biological evaluation.The criteria used in selecting a cephalosporin antibiotic as a candidate for clinical use require that it exhibit simultaneously a number of desirable chemotherapeutic and pharmacokinetic characteristics. Three of the characteristics examined in our laboratory for evaluating the potential utility of a cephalosporin are the in vitro activity (MIC) against gram-positive and gram-negative bacteria, the effectiveness in protecting small laboratory animals against bacterial infection (PD5O, mouse) and the serum concentrations attained when the cephalosporin is administered orally or by injection. Frequently these characteristics, and others of importance to the successful use of the cephalosporin, can be altered by modifying the chemical structure; but the alterations in biological properties do not necessarily proceed in a parallel direction. For example, recent studies',') demonstrate that in certain cases in vitro activity can be increased against a number of bacteria by substituting an appropriate heterocyclicthiomethyl group for the methyl or acetoxymethyl group at the 3-position of the cephalosporin nucleus. The efficacy of this structural change is illustrated by cefazolin and cefamandole, two injectable cephalosporins with 3-heterocyclicthiomethyl substituents. Both

Kinetics of Cefatrizine Penetration into Gynaecological Tissues after Oral Administration

“…Cefatrizine is a 7-phenyl-glycyl semi synthetic cephalosporin with a thiomethylic heterocyclic substituent in position 3 of the 7-am inocephalosporanic acid nu cleus [1], Cefatrizine has the following chemical structure: 7-[F(-)-2-amino-2-(phydroxyphenyl)acetam ide -] -3 -( 1H -1,2,3 triazole -4(5) -ylthiomethyl) -3 -cephem -4-carboxylic acid (Fig. 1).…”

Characterization of the Oral Absorption of β-Lactam Antibiotics II: Competitive Absorption and Peptide Carrier Specificity

“…11 Specifically, Adibi and Soleimanpour12 demonstrated that the Michaelis constant of glycylglycine is 43.4 mM, whereas the bulkier dipeptide, glycylleucine, has a K, value equal to 26.8 mM in perfused human jejunum. Similarly, Dunn et al 13 reported that the absorption site was even more discriminating to structural differences with para substitution of a hydroxyl group on the 7-phenylglycyl cephalosporins, resulting in a significant increase in absorption over the metu-substituted compound in the mouse.…”

Synthesis and antibacterial activity of 6- and 7- (2-(5-carboxyimidazole-4-carboxamido)phenylacetamido)-penicillins and cephalosporins.

“…In our research for suitable synthetic methods of monoamides, we found that two carbonyl chloride groups of 2 are selectively hydrolyzed by treatment with water at 1040°C to give a novel diimidazopyrazine derivative (3). Since both carbonyl imidazolide moieties in 3 are activated, the compound (3) reacts effectively with two equivalent moles of amines to produce the corresponding monoamides.…”

“…Nucleophilic displacement of the C-3 acetoxy group of 6 and 8 with the appropriate heterocyclic thiols and pyridine derivatives was achieved in the usual manner. 3,4,5) The prepared C-3 analogs (9-13) are presented in Table 1.…”