Synthesis and antiallergic activity of 11-(aminoalkylidene)-6,11-dihydrodibenz[b,e]oxepin derivatives

J Med Chem. 1992 May 29;35(11):2074-84. doi: 10.1021/jm00089a020.


A new series of 11-substituted 6,11-dihydrodibenz[b,e]oxepin-2-carboxylic acid derivatives was synthesized and demonstrated to be orally active antiallergic agents. These compounds are structurally related to 1 (KW-4994), which we had reported previously to be a new antiallergic agent. Most compounds synthesized exhibited potent inhibitory effects on 48-h homologous passive cutaneous anaphylaxis (PCA) in rats and on IgG1-mediated bronchoconstriction in guinea pigs. Additionally, compounds possessing a terminal carboxyl group at the 2-position of the dibenz[b,e]oxepin ring system exhibited inhibitory effects on specific [3H]pyrilamine binding to guinea pig cerebellum histamine H1 receptors, whereas these demonstrated negligible effects on specific [3H]QNB binding to rat striatum muscarinic acetylcholine M1 receptors. Structure-activity relationship studies revealed that the following key elements were required for enhanced antiallergic activities: (1) a 3-(dimethylamino)propylidene group as the side chain at the 11-position, (2) a terminal carboxyl moiety at the 2-position, and (3) a dibenzoxepin ring system. Among the compounds synthesized, (Z)-11-[3-(dimethylamino)propylidene]-6,11-dihydrodibenz [b,e]oxepin-2-acetic acid hydrochloride (16) was selected for further evaluation. It had an ED50 value of 0.049 mg/kg po in the PCA test in rats and an ID50 value of 0.030 mg/kg po in inhibiting anaphylactic bronchoconstriction in guinea pigs. Furthermore, it had a Ki value of 16 +/- 0.35 nM for the histamine H1 receptor, while it exhibited negligible CNS side effects up to a dose of 600 mg/kg po. Compound 16 is now under clinical evaluation as KW-4679.

Publication types

  • Comparative Study

MeSH terms

  • Animals
  • Benzoxepins / chemical synthesis*
  • Benzoxepins / pharmacology
  • Benzoxepins / therapeutic use
  • Bronchial Diseases / drug therapy
  • Bronchial Diseases / immunology
  • Cerebellum / metabolism
  • Constriction, Pathologic / drug therapy
  • Constriction, Pathologic / immunology
  • Dibenzoxepins / chemical synthesis*
  • Dibenzoxepins / pharmacology
  • Dibenzoxepins / therapeutic use
  • Guinea Pigs
  • Histamine H1 Antagonists / chemical synthesis*
  • Histamine H1 Antagonists / pharmacology
  • Histamine H1 Antagonists / therapeutic use
  • Immunoglobulin G / immunology
  • Male
  • Molecular Structure
  • Olopatadine Hydrochloride
  • Passive Cutaneous Anaphylaxis / drug effects
  • Pyrilamine / metabolism
  • Rats
  • Rats, Inbred Strains
  • Receptors, Histamine H1 / drug effects
  • Receptors, Histamine H1 / metabolism
  • Structure-Activity Relationship
  • X-Ray Diffraction


  • Benzoxepins
  • Dibenzoxepins
  • Histamine H1 Antagonists
  • Immunoglobulin G
  • Receptors, Histamine H1
  • Olopatadine Hydrochloride
  • Pyrilamine