Molecular structure of 9-deoxy-11-deoxy-9-11-(imino(2-(2-methoxyethoxy)ethylidene)oxy)-(9S)-erythromycin, a new erythromycin derivative

Luger, Peter; Maier, Roland

doi:10.1007/bf01200526

Cited by 25 publications

(14 citation statements)

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“…The earliest of these modifications was roxithromycin, selected as the candidate with the best therapeutic index from a new series of oxime derivatives synthesized at Roussel-Uclaf (J. F. Chantot Erythromycylamine is an older derivative of erythromycin, formally the result of reductive amination of the C-9 ketone; however, both it and its N-benzylidene derivative gave extremely low levels in blood when administered orally to humans (53). Dirithromycin, a new oxazine formed from erythromycylamine and (2-methoxyethoxy)acetaldehyde, was selected by Boehringer-Ingelheim on the basis of high levels in tissues (52). Formerly designated AS-E 136, it is being developed jointly with Eli Lilly & Co. (formerly LY237216).…”

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confidence: 99%

New directions for macrolide antibiotics: structural modifications and in vitro activity

Kirst

Sides

1989

Antimicrob Agents Chemother

152

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confidence: 99%

New directions for macrolide antibiotics: structural modifications and in vitro activity

Kirst

Sides

1989

Antimicrob Agents Chemother

152

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“…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.…”

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confidence: 99%

“…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). More recently, the various polymorphic, isomorphic, and solvated forms of dirithromycin in the solid state have been described (14).…”

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“…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).…”

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Antimicrobial characterization and interrelationships of dirithromycin and epidirithromycin

Kirst

Creemer

Paschal

et al. 1995

Antimicrob Agents Chemother

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Dirithromycin is the 9-N,11-O-oxazine adduct formed from 9(S)-erythromycylamine and 2-(2-methoxyethoxy)acetaldehyde in which the methoxyethoxymethyl substituent on the oxazine ring possesses the R configuration. Epidirithromycin is its isomer in which the methoxyethoxymethyl substituent has the opposite (S) configuration. Both compounds readily epimerize in solution, reaching an equilibrium ratio of 85:15 in favor of dirithromycin, given sufficient time. The rate of interconversion is dependent upon pH, temperature, and solvent. An enriched sample of epidirithromycin (95% purity) was synthesized by condensing erythromycylamine and 2-(2-methoxyethoxy)acetaldehyde in diethyl ether as the reaction solvent, and the product was fully characterized by nuclear magnetic resonance spectroscopy and high-pressure liquid chromatographic (HPLC) analysis. Both oxazine derivatives readily hydrolyze to erythromycylamine, so all three compounds exhibit the same antibiotic activity in vitro. In order to determine whether dirithromycin itself possesses significant antimicrobial activity without initial hydrolysis to erythromycylamine, inhibition of cell-free ribosomal protein synthesis was measured under conditions which were adapted to minimize hydrolysis, as measured by analytical HPLC in parallel experiments. Under these particular conditions, inhibition of ribosomal protein synthesis by dirithromycin was <10% of the value measured for erythromycylamine.

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“…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).…”

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

Counter

Ensminger

Preston

et al. 1991

Antimicrob Agents Chemother

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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...

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Molecular structure of 9-deoxy-11-deoxy-9-11-(imino(2-(2-methoxyethoxy)ethylidene)oxy)-(9S)-erythromycin, a new erythromycin derivative

Cited by 25 publications

References 4 publications

New directions for macrolide antibiotics: structural modifications and in vitro activity

New directions for macrolide antibiotics: structural modifications and in vitro activity

Antimicrobial characterization and interrelationships of dirithromycin and epidirithromycin

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

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