3-Quaternary ammonium 1-carba-1-dethiacephems.
A series of structurally unique 1-carba-1-dethiacephems is described. The structural stability of the 1-carba-1-dethiacephem nucleus was essential for the preparation of this series of 3-quaternary ammonium carbacephems. The known p-nitrobenzyl 7 beta-(phenoxyacetamido)- 3-[(trifluoromethyl)sulfonyl]oxy]-1-carba-1-dethia-3-cephem- 4-carboxylate served as both a quaternization substrate as well as a precursor to derivatives such as allyl 7 beta-[[2-[allyloxy)carbonyl]amino-4- thiazoly] (methoxyimino)acetyl]amino]-3-[(trifluoromethyl) sulfonyl] oxy]-1-carba-1-dethia-3-cephem-4-carboxylate. Quaternization of these enol triflates was accomplished either by dissolution in acetonitrile containing the base or by dissolution in the base, with or without warning to 50 degrees C. Bases nucleophilic enough to displace the triflate include a variety of substituted pyridines and N-methylimidazole. Deprotection then produced a very active series of 1-[7 beta-[(2-amino- 4-thiazolyl)(methoxyimino)acetyl]amino]-2-carboxy-8-oxo- 1-azabicyclo[4.2.0]oct-2-en-3-yl] quaternary ammonium hydroxide inner salts. These compounds were extremely potent antibacterials against a broad range of Gram-positive and -negative bacteria including constitutive cephalosporinase producers, such as Enterobacter cloacae. The compounds exhibit similar hydrolysis kinetics and pharmacokinetics to the analogous cephalosporin-3'-quaternary ammonium salts.
Cook
G K
GK
Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana 46285.
McDonald
J H
JH
Alborn
W
W
Boyd
D B
DB
Eudaly
J A
JA
Indelicato
J M
JM
Johnson
R
R
Kasher
J S
JS
Pasini
C E
CE
Preston
D A
DA
D000818:Animals; D002511:Cephalosporins / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology*; D055598:Chemical Phenomena; D002621:Chemistry; D006090:Gram-Negative Bacteria / Q000187:drug effects; D006094:Gram-Positive Bacteria / Q000187:drug effects; D008958:Models, Molecular; D051381:Rats; D013329:Structure-Activity Relationship
D002511:Cephalosporins