Synthesis and structure-activity relationships of new 9-N-alkyl derivatives of 9(S)-erythromycylamine.
A series of new 9-N-alkyl derivatives of 9(S)-erythromycylamine has been synthesized by reductive alkylation of erythromycylamine with aliphatic aldehydes and sodium cyanoborohydride. Alternative syntheses employing hydrogenation methods have also been developed. These new 9-N-alkyl derivatives possess excellent antimicrobial activity in vitro and in vivo, especially when administered orally to treat experimental infections in mice. From structure-activity studies, 9-N-(1-propyl)erythromycylamine (LY281389) was selected as the most efficacious derivative. These methods have also been extended to the synthesis of some 9-N,N-dialkyl derivatives of erythromycylamine.
Kirst
H A
HA
Lilly Research Laboratories, Lilly Corporate Center, Indianapolis, Indiana 46285.
Wind
J A
JA
Leeds
J P
JP
Willard
K E
KE
Debono
M
M
Bonjouklian
R
R
Greene
J M
JM
Sullivan
K A
KA
Paschal
J W
JW
Deeter
J B
JB
D000478:Alkylation; D000818:Animals; D001424:Bacterial Infections / Q000188:drug therapy; D055598:Chemical Phenomena; D002621:Chemistry; D004917:Erythromycin / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000627:therapeutic use; D009682:Magnetic Resonance Spectroscopy; D051379:Mice; D015394:Molecular Structure; D051381:Rats; D013203:Staphylococcal Infections / Q000188:drug therapy; D013290:Streptococcal Infections / Q000188:drug therapy; D013329:Structure-Activity Relationship
C066283:9-N-(1-propyl)erythromyclamine; C007626:erythromyclamine; D004917:Erythromycin