Synthesis and antimicrobial evaluation of 20-deoxo-20-(3,5-dimethylpiperidin-1-yl)desmycosin (tilmicosin, EL-870) and related cyclic amino derivatives.
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.
Debono
M
M
Lilly Research Laboratories, Lilly Corporate Center, Eli Lilly and Company, Indianapolis, IN 46285.
Willard
K E
KE
Kirst
H A
HA
Wind
J A
JA
Crouse
G D
GD
Tao
E V
EV
Vicenzi
J T
JT
Counter
F T
FT
Ott
J L
JL
Ose
E E
EE
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*
D000900:Anti-Bacterial Agents; D007933:Leucomycins; D018942:Macrolides; C052319:tilmicosin; D015645:Tylosin