Erythromycin 2,-esters

Erythromycin esters Mixed Within reference limits or only slightly elevated (up to 1.5 times the upper reference limit) in patients with overt hepatic disease (C31, F2, F8)... 

The data is fitted by multiple regression analysis using a computer. The Free-Wilson equation for the erythromycin esters is shown in equation (3.15). ... 

We generated a CoMFA fit of the erythromycin esters, adding the substituents to the crystal structure of the unsubstituted compound. Only steric fields were significant. Table 3.5 (below) summarizes the statistics. 

Table 3.5 Statistics of the CoMFA analysis of the potency of erythromycin esters, = 28.

Martin YC, Jones PH, Perun TJ, Grundy WE, Bell S, Bower RR, Shipkowitz NL (1972) Chemical modification of erythromycin antibiotics. 4. Structure-activity relations of erythromycin esters. J Med Chem 15 635-638... 

The acid-instabihty of erythromycin makes it susceptible to degradation in the stomach to intramolecular cyclization products lacking antimicrobial activity. Relatively water-insoluble, acid-stable salts, esters, and/or formulations have therefore been employed to protect erythromycin during passage through the stomach, to increase oral bioavakabihty, and to decrease the variabiUty of oral absorption. These various derivatives and formulations also mask the very bitter taste of macroHdes. 

The 11,12-carbonate of erythromycin (32) is an older cycHc ester which had greater stabdity and antibiotic activity by diminishing formation of intramolecular enol ether (27) (136,137). A later analogue, the ll-A/-12-0-cychc carbamate of... 

NMR, 4, 575 Erythritol, 1,4-anhydro-structure, 4, 546 Erythromycin antibacterial veterinary use, 1, 206 as pharmaceutical, 1, 153 synthesis, 1, 480 Erythropterin biosynthesis, 3, 321 occurence, 3, 323 structure, 3, 276 synthesis, 3, 289 Erythropterin, 3,5-dimethyl-methyl ester synthesis, 3, 303 Erythrosine application, 3, 879 Esculetin... 

Lower stereoselectivities arise, however, from the addition of ester enolates to this glyceralde-hyde4. Another highly stereoselective addition is in the synthesis of erythromycin A where a single product results from the addition of lithiated tert-butyl thiopropanoate to the enantiomerically pure aldehyde (2/ ,3/ ,4,S, 6/ ,7/ ,8,S, 9/ ,10.S, 11 / )-7-acetoxy-3,4 9,10-bis(isopropy1-idenedioxy)-11-methoxymethoxy-2,4,6,8,10-pentamethyltridecanal5. 

Oleandomycin, its ester (triacetyloleandomycin) and spiran rdn have a similar range of activity as erythromycin but are less active. Resistance develops only slowly in chnical practice. However, cross-resistance may occur between all four members of this group. 

In some cases enzymes can increase the rate of reaction by up to lO times. Carnell and Roberts (1997) have briefly discussed the scope of biotransformations that are used to make pharmaceuticals like penicillins, cephalosporines, erythromycin, lovastatin, cyclosporin, etc., and for food additives like citric acid, L-glutamate, and L-lysine. A very successful transformation by Zeneca has been that of benzene reduction, with Pseudomonase Putida, to dihydrocatechol and catechol the dihydro derivative is used to produce (+/-) pinitol. Fluorobenzene has been converted to fluorodihydrocatechol, an intermediate for pharmaceuticals. The highly stereo selective Bayer-Villeger reaction has been carried out with genetically engineered S-cerevisvae. Hydrolases have allowed enantioselective, and in some cases regioselective, hydrolysis of racemic esters. 

A complication here, however, is noted with those drugs that exhibit a limited chemical stability in either acidic or alkaline fluids. Since the rate and extent of degradation is directly dependent on the concentration of drug in solution, an attempt is often made to retard dissolution in the fluid where degradation is seen. There are preparations of various salts or esters of drugs (e.g., erythromycin) that do not dissolve in gastric fluid and thus are not degraded there but which dissolve in intestinal fluid prior to absorption. A wide variety of chemical derivatives are used for such purposes. 

In a reaction of CDI with 2 -0,3 -Af-bis(benzyloxycarbonyl)-jV-desmethyl-6-0-methylerythromycin A the corresponding imidazolecarboxylate (K2C03, THF, 36% yield) was formed, which yielded in a further reaction with C6H5CH2OH the 4 -benzyl-oxycarbonic ester of this erythromycin A analogue in 40% yield.12413... 

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... 

Finally, macrocyclization is carried out via protection and deprotection sequences and cyclization of the activated ester 26, and this accomplishes the synthesis of 27 (Scheme 7-6), which, through deprotection and glycosidation, can be converted to erythromycin A, a compound containing a hopelessly complex array of chiral centers.4... 

The macrolides are orally absorbed but they are acid-labile. They therefore need to be administered in acid-resistant capsules or as acid-resistant esters. The macrolides are widely distributed into all fluids except the CNS. Protein binding is about 90%. They are eliminated via biliary excretion with extensive enterohepatic circulation. Elimination half-lives vary from 1.4 h for erythromycin to 40-60 h for azithromycin. 

The general structure of erythromycin is shown with the macrolide ring and the sugars desosamine and cladinose. It is poorly soluble in water (0.1%) but dissolves readily in organic solvents. Solutions are fairly stable at 4°C but lose activity rapidly at 20°C and at acid pH. Erythromycins are usually dispensed as various esters and salts. 

Modification of Chemical Structure of Drug The use of a Hammett linear free-energy relationship to investigate the effects of substituents on the rates of aromatic side-chain reactions such as hydrolysis of esters has been alluded to earlier vis-a-vis attainment of optimum stability [9,10]. Degradation of erythromycin under acidic pH conditions is inhibited by substituting a methoxy group for the C-6 hydroxyl as found for the acid stability of clathromycin, which is 340 times greater than that of erythromycin [70]. 

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. 

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