Synthetic studies towards the development of a novel class of acitretin-type retinoids

Abstract

3,4,5-Trimethoxyaniline, indole-3-carboxylic acid and the dicarboxylic acids fumaric, maleic, succinic and phthalic have been combined to produce novel analogs of the aromatic retinoid acitretin. These analogs are characterized by a highly electron-rich benzene ring in the lipophilic part and two amide bonds, replacing the C7-C8 and C11-C12 double bonds, with simultaneous restriction of the C9-C10 double bond, in the spacer compared to acitretin. In addition, the terminal trans C13-C14 double bond has been either retained or isomerized or reduced or incorporated within an indole nucleus with simultaneous replacement of the carboxy group by the indole imine function. The related syntheses involved coupling of the N-Boc protected indole-3-carboxylic acid with 3,4,5-trimethoxyaniline, acid-mediated removal of the Boc group, coupling of the thus obtained anilide with the anhydrides or suitable monoesters of the above mentioned dicarboxylic acids in liquid or on solid phase and finally deprotection.