Fluoronaphthyridines as antibacterial agents. 6. Synthesis and structure-activity relationships of new chiral 7-(1-, 3-, 4-, and 6-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)naphthyridine analogues of 7-[(1R,4R)-2,5- diazabicyclo[2.2.1]heptan-2-yl]-1-(1,1-dimethylethyl)-6-fluoro-1,4-dihy dro-4-oxo-1,8-naphthyridine-3-carboxylic acid. Influence of the configuration on blood pressure in dogs. A quinolone-class effect.
A series of novel chiral 7-(1-, 3-, 4-, and 6-methyl-[(1R,4R)-2,5- diazabicyclo[2.2.1]heptan-2-yl]-substituted naphthyridines has been prepared with the aim of obtaining good in vitro and in vivo antibacterial agents with a decrease of the pseudoallergic type reaction when compared to that observed with 7[(1R,4R)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-1-(1,1-dimethylethyl )1,4- dihydro-6-fluoro-4-oxo-1,8-naphthyridine-3-carboxylic acid (1a) (BMY 40062). The derivatives 7-[(1R,4R,6S)-6-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl]- 1-(1,1-dimethylethyl)-6-fluro-1,4-dihydro-4-oxo-1,8-naphthyridine- 3-carboxylic acid (41) and 7-[(1R,4R,6S)-6-methyl-2,5-diazabicyclo[2.2.1]heptan-2- yl]-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxy lic acid (49) showed potent in vitro and in vivo antibacterial activity against Gram-positive and Gram-negative bacteria. The derivative 49 displayed a less marked decrease in blood pressure (MAP), compared to that of 1a, after intravenous infusion in dogs and was selected as a potential candidate for preclinical trials.
Remuzon
P
P
Bristol-Myers Squibb Pharmaceutical Research Institute, Marne-la-Vallée, France.
Bouzard
D
D
Guiol
C
C
Jacquet
J P
JP
D000818:Animals; D000890:Anti-Infective Agents / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D001794:Blood Pressure / Q000187:drug effects*; D004285:Dogs; D005260:Female; D024841:Fluoroquinolones; D006090:Gram-Negative Bacteria / Q000187:drug effects; D006094:Gram-Positive Bacteria / Q000187:drug effects; D008297:Male; D051379:Mice; D009287:Naphthyridines / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D015363:Quinolones / Q000494:pharmacology*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D000890:Anti-Infective Agents; D024841:Fluoroquinolones; D009287:Naphthyridines; D015363:Quinolones; C060734:BMY 40062