Arylacetamide Antiarrhythmic Compounds

The chemistry of antiarrhythmic drugs derived conceptually from sotalol was described at the outset of this chapter. An earlier, small series of dmgs that are used clinically as antiarrhythmic agents is based on alkylated derivatives 

Replacement of the pyridine ring by a more strongly basic ethylpiperidine moiety leads to the antiarrhythmic dmg disobutamide (55-5). The synthesis of this compound also involves successive carbanion alkylation reactions. Thus, reaction of the anion from ortho-chloroacetonitrile (55-1) with A-(2-chloroethyl) piperidine gives the intermediate (55-3) alkylation of the anion from this leads to (55-4). Hydrolysis with sulfuric acid completes the preparation of disobutamide (55-5) [56]. 

One of the more common pathways for the metabolic transformation of tertiary amines involves A -dealkylation to a secondary amine. The observation that those products often show the same biological activity as the parent dmg in many cases confounds the issue of the identity of the chemical species responsible for the drug s action. The fact that the dealkylation product of disobutamide shows antiarrhythmic activity in its own right prompted the synthesis of the acetyl derivative of that secondary amine this agent may be considered a latent form of the active metabohte. This compound is prepared by first repeating the penultimate step in the disobutamide synthesis using (Af-benzyl-Af-isopropyl)-2-chloroethylamine instead of the diisopropyl intermediate. The product from that reaction (56-1) is then hydrolyzed to the 

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