Erythromycin A derivatives

Cyclic carbonic esters were also prepared, for example, from the cardiac glycoside proscillaridine[257] (where besides CDI the benzyloxycarbonylimidazole was successfully used), ingenol, 2581 the macrolide antibiotic tylosine,[259] and an erythromycin A derivative.12601... 

Asaka, T, Tanikawa, T, Ishii, T., and Kashimura, M. (1998). Preparation of erythromycin A derivatives as bactericides. Patent W09813373. 

Fig. 5. Chemical stractures of erythromycin A derivatives. (Reprinted with permission from Omura et al. [19]. Copyright 1987 American Chemical Society.)...

A cydocarbonate moiety is formed on a macrolide scaffold during the synthesis of an intermediate of erythromycin A derivatives. Erythromycin A is a safe and effective antibiotic for the treatment of Gram-positive pathogens, and, in particular, it is the drug of choice for the treatment of Legionnaires disease. Erythromycin A, how-... 

Clarithromycin is a derivative of erythromycin (macrolide). Advantages over erythromycin include lower frequency of gastrointestinal side-effects and lower dosage frequency. Clarithromycin is administered every 12 hours. As with all macrolides it should be used with caution in patients who are at risk of developing QT interval prolongation caused either by electrolyte imbalances or the concomitant use of other drugs. 

In many cases, biotechnology-derived products may have many components that have biological activity. The aim should be to devise controls that monitor the various components so as to retain a consistent potency and purity. For example, the USP monograph for erythromycin [9] indicates that the principal component is erythromycin A and that the percentage of erythromycin A, erythromycin B, and erythromycin C is not less than 85.0% and not more than 100.5%. Within these parameters, the relative ratios of erythromycins A, B, and C may change. This is not always the case for biotechnology-derived products, however. For example, the USP monograph for amoxicillin [10] allows for only one active component. 

Miller also explored the ASD of glycerol derivatives through an enantioselective acylation process which relies on the use of a pentapeptide-catalyst which incorporates an A-terminal nucleophilic 3-(l-imidazolyl)-(5)-alanine residue [171], Most recently, Miller has probed in detail the role of dihedral angle restriction within a peptide-based catalyst for ferf-alcohol KR [172], site selective acylation of erythromycin A [173], and site selective catalysis of phenyl thionoformate transfer in polyols to allow regioselective Barton-McCombie deoxygenation [174],... 

One of the most famous examples of intramolecular attack of oxygen on the nitriUnm ion intermediate was observed in the Beckmann rearrangement of Erythromycin oxime derivatives and was used in the discovery and synthesis of the commercial macrolide antibiotic Azithromycin 464. In fact, the Beckmann rearrangement of Erythromycin A 9( )-oxime 460 produced only small amounts (5%) of the expected amide 463, along with two isomeric imino ethers (461 and 462) in a fair yield (38 and 43%) (equation 198). 

Cholestatic hepatitis may occur when drug therapy lasts longer than 10 days or repeated courses are prescribed. The hepatitis is characterized by fever, enlarged and tender liver, hyperbilirubinemia, dark urine, eosinophilia, elevated serum bilirubin, and elevated transaminase levels. Hepatitis has been associated with the estolate salt of erythromycin but not with other formulations. Although the hepatitis usually occurs 10 to 20 days after the initiation of therapy, it can occur within hours in a patient who has had such a reaction in the past. The hepatitis is believed to be the result of both a hepatotoxic effect and a hypersensitivity reaction this latter effect is reversible on withdrawal of the drug. Erythromycin and derivatives induce hepatic microsomal enzymes and interfere with the actions of various drugs, including theophylline and carbamazepine. 

Several 2-fluoroerythromycin derivatives have also been prepared by means of electrophilic fluorination with Selectfluor of the enolate of the )S-ketoester fragment (Fig. 45) [121]. Fluorination is stereoselective and leads to the a-fluo-rine compound [122]. Two derivatives of 2-fluoroerythromycin are in clinical development HMR-3562 and HMR-3787). These compounds are promising agents for the treatment of respiratory pathogens resistant to erythromycin A (Fig. 45) [123]. 

In the total synthesis of optically active erythromycin A reported by Woodward and collaborators (87), the bicyclic compound 142 (Fig. 1) was used to produce the two segments Cg-C)5 (143) and Cg-Cg (144) of erythronolide A. These two segments were then combined (-145) and converted into 146). Aldol condensation of a propionate ester derivative with 146 gave the erythronolide A secoacid derivative J 47 (Fig. 2) which was successfully transformed into erythromycin A (149) through a series of chemical transformations where compound 148 was one of the key intermediates. 

A combination of propionate and acetate units is used to produce the 14-membered macrocyclic ring of oleandomycin (Figure 3.62) from Strep-tomyces antibioticus, but otherwise many of the structural features and the stereochemistry of oleandomycin resemble those of erythromycin A. One acetate provides the starter unit, whilst seven propionates, via methylmalonyl-CoA, supply the extension units (Figure 3.62). One methyl group derived... 

Erythromycin A 64 and spinosyns A and D 65a/65b are important macrolides produced by Saccharopolyspora erythraea and Sacch. spinosa, respectively. Compound 65a contains per-O-methylated L-rhamnose and D-forosamine attached O-glycosidically to the aglycone. Gene knockouts in respective strains as well as expression of various sugar cassettes (along with appropriate GT gene(s)) in Sacch. erythraea mutants led to production of many derivatives of 64 and 65a and tylosin [111-114],... 

Like tetracyclines, macrolides are also polyketides that are isolated from bacteria and inhibit protein synthesis in certain bacteria. Erythromycin (A.32) is the original macrolide (Figure A.9). Clarithromycin (Biaxin, A.33) and azithromycin (Zithromax, A.34) are semisynthetic derivatives of erythromycin. 

Oikawa, Y, Nishi, T, Yonemitsu, O, Chiral synthesis of polyketide-derived natural product. Chemical correlation of chiral synthons, derived from D-glucose for the synthesis of erythromycin A, with chemical cleavage products of the natural antibiotic, J. Chem. Soc., Perkin. Trans. 1, 27-33, 1985. 

Aldol reaction of (5)-2-benzyloxypropanal with the lithium enolate of methyl 2-methoxypro-panoate gives a 7 2 1 mixture of /3-hydroxyesters. The major product has been converted into L-cladinose, a saccharide moiety of erythromycin A [332]. The isomeric methyl 3,6-dideoxy-3-C-methylhexofuranosides have been derived from (5)-2-benzyloxypropanal via homoaldol reactions in three steps. 

The C10-C13 segment 24 was prepared from D-ribose (35) (O Scheme 2). In this case, selective protection of the hydroxy groups was realized by isopropylidenation (from 35 to 36). One of the other procedures for conversion of cyclic monosaccharides to acyclic derivatives is nucleophilic addition to the anomeric position in free monosaccharides. Grignard reagent, MeMgl, was added to 36 to provide 37 as the sole product. The subsequent manipulation of 37 to the C10-C13 segment 24, which is not restricted in monosaccharides chemistry, is summarized in O Scheme 2. After the completion of the synthesis of erythronolide A (20), Toshima, Nakata, Tatsuta, Kinoshita, and coworkers achieved the total synthesis of erythromycin A (18) by their own glycosidation method [18,19]. 

Claforan cefotaxime, clarithromycin [ban, inn, usan] (Blaxln Klaricid ) is the 6-0-methyl derivative of erythromycin, a macrolide, and has superior pharmacokinetic properties. It can be used clinically as an oral or parenteral antibacterial to treat a wide variety of infections, including skin, soft tissue and respiratory tract infections. It is usually given to patients who are allergic to penicillin. 

One of the most impressive synthetic achievements with the P-based mediators is the deoxygenation of an erythromycin B derivative towards the industrial synthesis of ABT-229, a potent motilin receptor agonist. Clean... 

Other closely related acyl demycinosyltylosins, such as 3,23,2 -tri-0-acetyl 23-O-demycinosyl 4"-0-isovaleryltylosin (Sch 37644) and its 12,13-epoxy derivative (Sch 38646) [205], showed improved pharmacokinetics but no advantages over erythromycin A against experimental Gram-positive infections in mice (Fig. 33) [206]. 

Chantot, J. F., Case, J. C., Gouin D Ambrieres, S., and Lutz, A. (1983). New ether oxime derivatives of erythromycin A Preparation and antibacterial activities. Presented at 23rd Intersci. Conf. Antimicrob. Agents Chemother. (Las Vegas, NV). Abstr. No. 447. 

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