Bulky amine analogues of ketoprofen: potent antiinflammatory agents

J Med Chem. 1984 Dec;27(12):1682-90. doi: 10.1021/jm00378a027.

Abstract

Replacement of the carboxyl group of 2-(3-benzoylphenyl)propionic acid (Ketoprofen) with various bulky amines has produced a series of highly active antiinflammatory agents that have reduced intestinal ulcerogenicity and have better therapeutic ratios in the 21-day adjuvant arthritis assay in rats than currently marketed nonsteroidal antiinflammatory drugs. Activity is maintained on reduction of these 2-(3-benzoylphenyl)propyl bulky amines to the corresponding alcohols or methylene analogues, on conversion of the ketone function to a primary amine or oxime, and on introduction of a 4-halo substitutent (Cl or F) on the terminal aromatic ring. Removal of the alpha-CH3 group greatly reduces the antiinflammatory activity of the series. These compounds have been synthesized by the reductive amination of 2-(3-bromophenyl)propionaldehyde with the respective amine followed by lithiation of this product and condensation with the appropriate benzonitrile.

Publication types

  • Comparative Study

MeSH terms

  • Animals
  • Anti-Inflammatory Agents / chemical synthesis*
  • Arthritis, Experimental / drug therapy
  • Chemical Phenomena
  • Chemistry
  • Drug Evaluation, Preclinical
  • Edema / drug therapy
  • Indicators and Reagents
  • Ketoprofen / analogs & derivatives
  • Ketoprofen / chemical synthesis*
  • Ketoprofen / therapeutic use
  • Magnetic Resonance Spectroscopy
  • Male
  • Phenylpropionates / chemical synthesis*
  • Rats
  • Rats, Inbred Strains
  • Structure-Activity Relationship

Substances

  • Anti-Inflammatory Agents
  • Indicators and Reagents
  • Phenylpropionates
  • Ketoprofen