title: Synthesis and antimicrobial evaluation of 20-deoxo-20-(3,5-dimethylpiperidin-1-yl)desmycosin (tilmicosin, EL-870) and related cyclic amino derivatives.
abstract: A series of 20-deoxo-20-cyclic (alkylamino) derivatives of tylosin, desmycosin, macrocin and lactenocin was prepared by reductive amination of the C-20 aldehyde group. The majority of the compounds were prepared using metal hydrides (sodium cyanoborohydride or sodium borohydride) as the reducing agents and a suitable cyclic alkylamine. Subsequently, a more convenient procedure was developed using formic acid as a reducing agent. The C-20 amino derivatives prepared from desmycosin exhibited good in vitro antimicrobial activity against Pasteurella haemolytica and Pasteurella multocida (MIC range of 0.78 approximately 6.25 micrograms/ml) as well as Mycoplasma species (MIC range of 0.39 approximately 6.25 micrograms/ml). Several derivatives showed excellent oral efficacy against infections caused by P. multocida in chicks. One of these derivatives, 20-deoxo-20-(3,5-dimethylpiperidin-1-yl)desmycosin (tilmicosin or EL-870) was selected for development as a therapeutic agent for pasteurellosis in calves and pigs.
authors.affiliation: Lilly Research Laboratories, Lilly Corporate Center, Eli Lilly and Company, Indianapolis, IN 46285.
authors.forename: M
authors.initials: M
authors.lastname: Debono
authors.forename: K E
authors.initials: KE
authors.lastname: Willard
authors.forename: H A
authors.initials: HA
authors.lastname: Kirst
authors.forename: J A
authors.initials: JA
authors.lastname: Wind
authors.forename: G D
authors.initials: GD
authors.lastname: Crouse
authors.forename: E V
authors.initials: EV
authors.lastname: Tao
authors.forename: J T
authors.initials: JT
authors.lastname: Vicenzi
authors.forename: F T
authors.initials: FT
authors.lastname: Counter
authors.forename: J L
authors.initials: JL
authors.lastname: Ott
authors.forename: E E
authors.initials: EE
authors.lastname: Ose
mesh_terms: D000586:Amination; D000818:Animals; D000900:Anti-Bacterial Agents; D002645:Chickens; D007933:Leucomycins / Q000138:chemical synthesis* / Q000494:pharmacology / Q000627:therapeutic use; D018942:Macrolides; D051379:Mice; D008826:Microbial Sensitivity Tests; D015394:Molecular Structure; D009174:Mycoplasma / Q000187:drug effects; D010084:Oxidation-Reduction; D010325:Pasteurella / Q000187:drug effects; D010326:Pasteurella Infections / Q000188:drug therapy; D013290:Streptococcal Infections / Q000188:drug therapy; D013297:Streptococcus pyogenes; D015645:Tylosin / Q000031:analogs & derivatives*
chemical_list: D000900:Anti-Bacterial Agents; D007933:Leucomycins; D018942:Macrolides; C052319:tilmicosin; D015645:Tylosin