Tilmicosin preparation

Labeled Compound. Two different C-tilmicosin preparations were used in these studies. One was piperidine labeled C-tilmicosin which was prepared by reacting (2,6 C) 3,5-dimethylpiperidine (California Bionuclear, Sun Valley, CA) with unlabeled desmycosin. This material is designated as Pip- C-tilmicosin. The second was an equimolar mixture of " C-tilmicosin labeled in the macrolide ring (87% of the... 

For characterization of RA in tissues and excreta the following general extraction and purification scheme was developed. Samples were extracted with 80 20 methanol water and the extract was diluted with a volume (usually 0.6 v/v) of 10% aqueous sodium chloride solution. The diluted extract was partitioned at ca. pH 6 with ecu and then adjusted to ca. pH 8. The tilmicosin and metabolites were extracted into 1 1 CCI4/CHCI3 for further purification or evaluation. Thin-layer chromatography (TLC) was conducted wiA silica gel plates developed in 100 15 2 CHCl3 methanol ammonium hydroxide. Autoradiograms were prepared by overlay of the plates with X-ray film. 

Identification of Compound T-2. The metabolism work on liver suggested that Compound T-2 in liver was from the dosing material rather than from metabolism. A quantity of T-2 was isolated from technical tilmicosin by countercurrent partitioning and preparative HPLC on a C-18 reversed phase column. Extensive NMR and MS analyses were conducted. The structure of T-2 that was deduced from this work is that it is a dimeric derivative of tilmicosin. A description of this work is beyond the scope of this paper and will be published later. 

The JECFA has allocated ADIs for erythromycin, spiramycin, tilmicosin, and tylosin, with those values for erythromycin, spiramycin, and tylosin based on microbiological endpoints. The CAC also established MRLs for erythromycin in muscle, liver, kidney, and fat of chickens and turkeys, and in chicken eggs for spiramycin in muscle, liver, kidney, and fat of cattle, pigs, and chickens for tilmicosin in muscle, liver, kidney, fat (or fat/skin) of cattle, sheep, pigs, chickens, and turkeys and MRLs for tylosin in muscle, liver, kidney, fat of cattle, pigs and chickens, and in chicken eggs." Details of residue smdies considered by JECFA are contained in monographs prepared for erythromycin, spiramycin, tilmicosin, " and tylosin. ... 

Reductive amination of the aldehyde group to aminomethyl derivatives has provided another route to potentially useful compounds. An initial report described the synthesis of primary amino derivatives of tylosin and leucomycin along with dimeric structures of each [140]. A group of derivatives of tylosin and demycarosyltylosin (desmycosin) were subsequently synthesized and shown to retain antimicrobial activity [141]. From a more extensive series of compounds prepared by reductive amination of tylosin and related macrolides, 20-deoxo-20-(3,5-dimethylpiperidinyl)desmycosin was selected for further development in veterinary medicine [142]. This compound, under the generic name of tilmicosin (see Fig. 7), is being evaluated for treatment of pneumonia in cattle and pigs [143, 144, 145]. 

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