Synthesis, anticonvulsant properties and pharmacokinetic profile of novel 10,11-dihydro-10-oxo-5H-dibenz/b,f/azepine-5-carboxamide derivatives

Eur J Med Chem. 2001 Mar;36(3):227-36. doi: 10.1016/s0223-5234(01)01220-x.

Abstract

A series of novel derivatives of oxcarbazepine (5), 10,11-dihydro-10-oxo-5H-dibenz/b,f/azepine-5-carboxamide was synthesised and evaluated for their anticonvulsant activity and sodium channel blocking properties. The oxime 8 was found to be the most active compound from this series, displaying greater potency than its geometric isomer 9 and exhibiting also the highest protective index value. Importantly, the metabolic profile of 8 differs from the already established dibenz/b,f/azepine-5-carboxamide drugs such as 1 and 5 which undergo rapid and complete conversion in vivo to several biologically active metabolites. In contrast 8 is metabolised to only a very minor extent leading to the conclusion that the observed anti-convulsant effect is solely attributable to 8. It is concluded that 8 may be as effective as 1 and 5 at controlling seizures and that the low toxicity and consequently high protective index should provide the compound with an improved side-effect profile.

Publication types

  • Comparative Study
  • Evaluation Study

MeSH terms

  • Amides / chemical synthesis*
  • Amides / chemistry*
  • Animals
  • Anticonvulsants / chemical synthesis*
  • Anticonvulsants / pharmacokinetics
  • Anticonvulsants / pharmacology*
  • Azepines / chemical synthesis*
  • Azepines / pharmacokinetics
  • Azepines / pharmacology*
  • Brain / drug effects
  • Brain / metabolism
  • Carbamazepine / chemistry
  • Carbamazepine / pharmacology
  • Cell Membrane / drug effects
  • Cell Membrane / metabolism
  • Female
  • Male
  • Mice
  • Mice, Inbred Strains
  • Rabbits
  • Rats
  • Rats, Wistar
  • Sodium Channel Blockers
  • Sodium Channels / metabolism
  • Species Specificity

Substances

  • Amides
  • Anticonvulsants
  • Azepines
  • Sodium Channel Blockers
  • Sodium Channels
  • Carbamazepine