Synthesis and antimicrobial evaluation of dirithromycin (AS-E 136; LY237216), a new macrolide antibiotic derived from erythromycin

Abstract

Dirithromycin is a 9-N-ll-O-oxazine derivative which is formed by condensation of 9(S)-erythromycylamine with 2-(2-methoxyethoxy)acetaldehyde. Dirithromycin is hydrolyzed, either under acidic conditions or in vivo, to its major active metabolite, 9(S)-erythromycylamine. The antimicrobial spectrum of dirithromycin is similar to that of erythromycin; both antibiotics are active against gram-positive bacteria, Legionella spp., Helicobacter pylori, and Chlamydia trachomatis. Comparable results were obtained for each antibiotic in MIC and MBC determinations and in the potential development of resistance in vitro. The effects of human serum, bacterial growth media, test methodology, and inoculum size on MICs were similar for each antibiotic. In standard mouse protection studies, dirithromycin was more efficacious than erythromycin against experimental infections after subcutaneous administration of antibiotic. These results were consistent with pharmacokinetic studies in rodents, which showed that dirithromycin gave more persistent concentrations of antibiotic in serum and tissues than were achieved with erythromycin. These studies indicate that dirithromycin possesses antimicrobial activity comparable to that of erythromycin in vitro but is more active than erythromycin in vivo, which may be attributable to the persistence of antimicrobial activity in the tissue(s) of the test animals.Erythromycin is an important antimicrobial agent whose role in chemotherapy is well established. It has now assumed even greater importance because of its activity against such increasingly prevalent pathogens as Legionella, Helicobacter (formerly Campylobacter), Mycoplasma, and Chlamydia species (5,25,35). During the past decade, substantial efforts have been devoted to structural modifications of erythromycin in order to improve upon its biological properties (10, 18). Dirithromycin ( Fig. 1) is a novel derivative of erythromycin which was initially discovered at Karl Thomae GmbH (22). Although its spectrum of antimicrobial activity is similar to that of erythromycin, dirithromycin exhibits higher and more prolonged concentrations in tissues than does erythromycin (6). This report describes our initial results of the synthesis and antimicrobial evaluation of dirithromycin.(These results were presented in part at the 28th Interscience Conference on Antimicrobial Agents and Chemotherapy, Los Angeles, Calif., 23 to 26 October 1988 [7a, 7b].) MATERIALS AND METHODS Synthesis of dirithromycin. 9(S)-Erythromycylamine (Fig. 2, compound 7) (18.5 g, 25.2 mmol) and 2-(2-methoxyethoxy) acetaldehyde (Fig. 2, compound 4) (4.4 g, 37 mmol) were dissolved in acetonitrile (55 ml). The reaction mixture was stirred for 18 h and cooled to 0 to 5°C. The solid was filtered, washed with cold acetonitrile, and dried to yield 16.6 g (79%) of dirithromycin (Fig. 2, compound 8). Dirithromycin was recrystallized from ethanol-water by dissolving it (3.0 g) in ethanol (12 ml) at 30°C and slowly adding water (28 ml). The mixture was cooled, and the solid was filter...

Antimicrobial characterization and interrelationships of dirithromycin and epidirithromycin

“…Dirithromycin and epidirithromycin readily interconvert to an equilibrium mixture, and both hydrolyze in vitro and in vivo to their common precursor, 9(S)-erythromycylamine, itself a potent and well-known antibiotic (3,10). All three compounds generally exhibit the same antibacterial activity under standard conditions for testing in vitro susceptibility.…”

“…Table 2 on p. 3860, the assignments for dirithromycin at H-7 should be 1.35/1.25 ppm and for epidirithromycin at H-11 should be 3.68 ppm [11a]). Precipitation of dirithromycin from solution then drives the synthetic reaction toward formation of dirithromycin as the thermodynamically controlled product (3,12). In contrast, with diethyl ether as solvent and a shorter reaction period, epidirithromycin is obtained at approximately 95% purity, with the other 5% consisting of dirithromycin (3%) and unreacted erythromycylamine (2%).…”

“…Epimerization studies. Dirithromycin was prepared in acetonitrile as previously reported (3). Samples of the reaction mixture, including any solid that formed, were collected at various times and analyzed by HPLC.…”

“…Dirithromycin is synthesized by treating erythromycylamine with 2-(2-methoxyethoxy)-acetaldehyde for several hours in organic solvents such as acetonitrile (3,8,11). HPLC analysis of the reaction mixture revealed that epidirithromycin is very rapidly formed as the initial reaction product and that it subsequently epimerizes until an 85:15 equilibrium ratio in favor of dirithromycin is reached within approximately 1 h in solution (Fig.…”

“…It is a semisynthetic derivative of erythromycin that is prepared by first converting erythromycin to 9(S)-erythromycylamine and then condensing this intermediate with 2-(2-methoxyethoxy)-acetaldehyde, thereby creating a 9-N,11-O-oxazine ring system ( Fig. 1) (3,8,11). The stereochemistry of the methoxyethoxymethyl substituent attached to the newly formed oxazine ring has been firmly established as the R configuration by X-ray crystallography (8).…”