Bulky amine analogs of ketoprofen: potent antiinflammatory agents

• Published in: Journal of medicinal chemistry 1984-12, Vol.27 (12), p.1682-1690
• Main Authors: Schlegel, Donald C, Zenitz, Bernard L, Fellows, Constance A, Laskowski, Stanley C, Behn, D. Craig, Phillips, Donald K, Botton, Irving, Speight, Phyllis T
• Format: Article
• Language: English
• Subjects: Animals; Anti-Inflammatory Agents - chemical synthesis; Arthritis, Experimental - drug therapy; Chemical Phenomena; Chemistry; Drug Evaluation, Preclinical; Edema - drug therapy; Exact sciences and technology; Heterocyclic compounds; Indicators and Reagents; Ketoprofen - analogs & derivatives; Ketoprofen - chemical synthesis; Ketoprofen - therapeutic use; Magnetic Resonance Spectroscopy; Male; Miscellaneous; Organic chemistry; Phenylpropionates - chemical synthesis; Preparations and properties; Rats; Rats, Inbred Strains; Structure-Activity Relationship
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm00378a027

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.