(Fluorocyclopropyl)quinolones. 2. Synthesis and Stereochemical Structure-Activity Relationships of Chiral 7-(7-Amino-5-azaspiro[2.4]heptan-5-yl)-1-(2-fluorocyclopropyl)quinolone Antibacterial Agents

• Published in: Journal of medicinal chemistry Vol. 37; no. 20; pp. 3344 - 3352
• Main Authors: Kimura, Youichi, Atarashi, Shohgo, Kawakami, Katsuhiro, Sato, Kenichi, Hayakawa, Isao
• Format: Journal Article
• Language: English
• Published: United States American Chemical Society 01-09-1994
• Subjects: Animals; Anti-Infective Agents - chemical synthesis; Anti-Infective Agents - pharmacokinetics; Anti-Infective Agents - pharmacology; Chemical Phenomena; Chemistry, Physical; Crystallography, X-Ray; Fluoroquinolones; Gram-Negative Bacteria - drug effects; Gram-Positive Bacteria - drug effects; Molecular Conformation; Molecular Structure; Quinolones - chemical synthesis; Quinolones - pharmacokinetics; Quinolones - pharmacology; Rats; Spiro Compounds - chemical synthesis; Spiro Compounds - pharmacokinetics; Spiro Compounds - pharmacology; Stereoisomerism; Structure-Activity Relationship
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm00046a019

A series of novel chiral 7-(7-amino-5-azaspiro[2.4]heptan-4-yl)-8-chloro-1-(2-fluo rocyclopropyl)- quinolones were synthesized as a continuation of a research project of 1-(2-fluorocyclopropyl)-quinolones by considering stereochemical and physicochemical properties of the molecule. Absolute configurations of the 1-(cis-2-fluorocyclopropyl) moiety and the 7-(7-amino-5-azaspiro-[2.4]heptan-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]heptan-5-yl] derivatives are more potent against Gram-positive and Gram-negative bacteria than the other stereoisomers and 7-[(7S)-7-amino-5-azaspiro[2.4]-heptan-5-yl]-8-chloro-1-[(1R ,2S)-2- fluorocyclopropyl]quinolone (33) is the most potent of all stereoisomers. Pharmacokinetic profiles and physicochemical properties of the selected compounds were also examined, and it was found that 33 (DU-6859a) possesses moderate lipophilicity and good pharmacokinetic profiles.