18] Synthesis and characterization of calmodulin antagonistic drugs

Abstract

This chapter focuses on the preparation and characterization of several calmodulin antagonist pairs. The synthetic route for 2-substituted-10-aminopropylphenothiazines follows the procedures of Smith and Godefroi and Wittle by the reaction of the appropriate phenothiazine with acrylonitrile, in which case the nitrile is reduced to form the product. The first step of each synthesis uses acrylonitrile and benzyltrimethylammonium hydroxide, both of which are carcinogenic and/or highly reactive. N -(6-Aminohexyl)-[3H]-5-chloro-l-naphthalenesulfonamide (W-7) was synthesized from 5-amino-l-naphthalenesulfonic acid via a Sandmeyer reaction to the 5-chloro-l-naphthalenesulfonic acid, formation of the sulfonyl chloride, and reaction with 1,6-diaminohexane. The starting material is an α-naphthylamine and is potentially carcinogenic. N-(4-Aminobutyl)-2-naphthalenesulfonamide hydrochloride (W-12) and N-(4-aminobutyl)-5-chloro-2-naphthalenesulfonamide hydrochloride (W-13) were synthesized by reaction of the appropriate suifonyl chloride with 1,4-diaminobutane. 2-Naphthalenesulfonyl chloride was obtained commercially, and 5-chloro-2-naphthalenesulfonyl chloride was synthesized by a Sandmeyer reaction of 5-amino-2-naphthalenesulfonic acid followed by the formation of the acid chloride.