(FLUOROCYCLOPROPYL)QUINOLONES .2. SYNTHESIS AND STEREOCHEMICAL STRUCTURE-ACTIVITY-RELATIONSHIPS OF CHIRAL [2.4]HEPTAN-5-YL)-1-(2-FLUOROCYCLOPROPYL)QUINOLONE ANTIBACTERIAL AGENTS

A series of novel chiral 7-(7-amino-5-azaspiro[2.4]heptan-5-yl)-8 quin olones were synthesized as a continuation of a research project of 1-( 2-fluorocyclopropyl)quinolones by considering stereochemical and physi cochemical properties of the molecule. Absolute configurations of the 1-(cis-2-fluorocyclopropyl) moiety and the 7-(7-amino-5-azaspiro[2.4]h eptan-5-yl) moiety were determined by X-ray crystallographic analysis. Stereochemical structure-activity relationship studies indicated that 1-[(1R,2S)-2-fluorocyclopropyl] and 7-(7S)-amino-5-azaspiro[2.4]hepta n-5-yl derivatives are more potent against Gram-positive and Gram-nega tive bacteria than the other stereoisomers and -8-chloro-1-[(1R,2S)-2- fluorocyclopropyl]quinolone (33) is the most potent of all stereoisome rs. Pharmacokinetic profiles and physicochemical properties of the sel ected compounds were also examined, and it was found that 33 (DU-6859a ) possesses moderate lipophilicity and good pharmacokinetic profiles.