Haloarene Derivatives of Carbamazepine with Reduced Bioactivation Liabilities: 2-Monohalo and 2,8-Dihalo Derivatives

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.

Metabolic and Pharmaceutical Aspects of Fluorinated Compounds

“…Fluorine substitution is an approach that has been used commonly in medicinal chemistry to interfere with metabolic activation of aromatic rings. Under normal circumstances, oxidative metabolism of an aromatic ring may lead to the production of an arene oxide that is susceptible to nucleophilic attack by a biological nucleophile such as GSH. ,,− The electron-withdrawing properties of fluorine can reduce the electron density of the aromatic ring and lower the rate of oxidation by P450, although the net effect of fluorination on the metabolic stability can be modest. , An example is provided by 437 , the 2,10-difluoro-substituted analogue of the anticonvulsant agent carbamazepine ( 436 ), which is widely used to treat epilepsy and trigeminal neuralgia The clinical hepatotoxicity of 436 is well-documented, with several hundred cases reported in the literature.…”

Enhancing Reactivity and Selectivity of Aryl Bromides: A Complementary Approach to Dibenzo[b,f]azepine Derivatives

“…Notably, this one‐pot transformation gives access to symmetrical compounds, such as 5 g , useful for enantioselective applications . Halogenated dibenzoazepines with reduced ADRs (Adverse Drug Reactions), can be readily prepared in a one‐pot fashion (products 5 c – h ) . Other electron‐withdrawing functional groups, such as CO 2 R (R=Me, Et, t Bu), can be effectively employed on starting aryl bromides 1 and 2 .…”

Synthesis of Pyrimidine‐Fused Benzazepines from 5‐Allyl‐4,6‐dichloropyrimidines

“…[4][5][6][7][8][9][10] Additionally, imipramine has also been used as a template for development of anticancer agents. [12][13][14][15][16][17][18][19][20][21][22][23][24][25] In contrast, DBAs' 1,3-diaza analogues -namely benzo [b]pyrimido [5,4-f]azepines (BPAs), also containing a privileged 6-7-6 ring system -are a less investigated family of compounds, due, probably, to the lack of applicable methods for their synthesis. [12][13][14][15][16][17][18][19][20][21][22][23][24][25] In contrast, DBAs' 1,3-diaza analogues -namely benzo [b]pyrimido [5,4-f]azepines (BPAs), also containing a privileged 6-7-6 ring system -are a less investigated family of compounds, due, probably, to the lack of applicable methods for their synthesis.…”