(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

J Med Chem. 1994 Sep 30;37(20):3344-52. doi: 10.1021/jm00046a019.

Abstract

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.

Publication types

  • Comparative Study

MeSH terms

  • 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

Substances

  • Anti-Infective Agents
  • Fluoroquinolones
  • Quinolones
  • Spiro Compounds
  • sitafloxacin