ABSTRACT
The anticonvulsant carbamazepine 1 is associated with adverse drug reactions (ADRs), including hepatotoxicity; oxidative metabolism of 1 has been implicated in the pathogenesis of the ADRs. We report the synthesis and evaluation of 2-monohalo and 2,8-dihalo analogues of 1 that were intended to minimize reactive metabolite formation via arene oxidation and 10,11-epoxidation. Halo analogues were obtained either by rearrangement of halogenated N-arylindoles or from specifically halogenated iminodibenzyl derivatives. In rat hepatocytes, none of the analogues underwent oxidative dehalogenation or glutathione adduction. Some formation of the 10,11-epoxide still occurred, but aromatic hydroxylation was not seen with the exception of 2-fluoro, which allowed minor monohydroxylation. Complete inhibition of aromatic hydroxylation required at least monochlorination or difluorination of 1. In human liver microsomes, difluoro analogue 5b underwent 10,11-epoxidation but gave no arene oxidation.
Subject(s)
Anticonvulsants/pharmacology , Carbamazepine/analogs & derivatives , Halogens/chemistry , Hepatocytes/drug effects , Microsomes, Liver/drug effects , Animals , Anticonvulsants/chemical synthesis , Carbamazepine/pharmacology , Cells, Cultured , Chromatography, High Pressure Liquid , Chromatography, Liquid , Glutathione/metabolism , Hepatocytes/metabolism , Humans , Male , Microsomes, Liver/metabolism , Molecular Structure , Oxidation-Reduction , Rats , Rats, Wistar , Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization , Structure-Activity RelationshipABSTRACT
Efficient procedures for the synthesis of benzo-fluorinated dibenz[b,f]azepines (iminostilbenes) from fluorinated isatins or indoles using a number of ring-expansion reactions are described. A range of mono- and difluorinated analogues is accessible, and the syntheses can deliver gram quantities of the final products, which are precursors of fluoro analogues of the important anticonvulsant carbamazepine.
