RESUMO
The dibenz[b,f]azepine heterocyclic system and related molecules with a single 10,11-bond are important templates for well-prescribed drug molecules, notably carbamazepine (anticonvulsant), clomipramine and imipramine (antidepressants). We synthesised a range of halogenated carbamazepine analogues, in connection with metabolic and immunological studies, as probes for structure-metabolism and hypersensitive effects and have published on their metabolic behaviour. While a number of synthetic routes to such analogues are possible, we naturally sought short and efficient methods for our target compounds. In the following report we present an effective two-step synthesis of a range of dibenz[b,f]azepines from appropriate indoles via N-arylation, then acid-catalysed rearrangement, with a critical analysis of other approaches. We showed earlier that this route was effective for fluoro analogues and here present a broader review of its scope. The 5-(carboxamido) side chain of carbamazepine may be added in various ways, affording overall a convenient access to drug molecules.
Assuntos
Dibenzazepinas/síntese química , Indóis/química , Anticonvulsivantes/síntese química , Anticonvulsivantes/química , Carbamazepina/análogos & derivados , Carbamazepina/síntese química , Catálise , Dibenzazepinas/química , HalogenaçãoRESUMO
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.
Assuntos
Anticonvulsivantes/farmacologia , Carbamazepina/análogos & derivados , Halogênios/química , Hepatócitos/efeitos dos fármacos , Microssomos Hepáticos/efeitos dos fármacos , Animais , Anticonvulsivantes/síntese química , Carbamazepina/farmacologia , Células Cultivadas , Cromatografia Líquida de Alta Pressão , Cromatografia Líquida , Glutationa/metabolismo , Hepatócitos/metabolismo , Humanos , Masculino , Microssomos Hepáticos/metabolismo , Estrutura Molecular , Oxirredução , Ratos , Ratos Wistar , Espectrometria de Massas por Ionização e Dessorção a Laser Assistida por Matriz , Relação Estrutura-AtividadeRESUMO
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.
