Design And Synthesis Of Some Selective RAR Agonists And Methodology Study

Selective RAR-β,γagonists are effective compounds for treating acne. Due to the side effects of the marketed drugs, it is definitely necessary to search for new compounds in order to improve their receptor affinity and selectivity, the therapeutic index and so on. Leading from Adapalene and other active compounds and according to the traditional principle of isosterism, here in this thesis, four different types of compounds with potential RAR—β，γagonists were designed by introducing hetero atoms into the core rings or replacing hydrogen with fluorine of the leads. Seven novel compounds were synthesized via four routes and the synthetic methods were preliminarily studied in the paper.Ethyl 6-bromo-2-naphthoate or methyl 6-bromoquinoline-2-carboxylate were coupled via Suzuki reaction with 3-(1-adamantyl)-5-fluoro-4-methoxyphenylboronic acid that could be obtained from 2-fluorophenol in 5-step sequence consisting of bromination and Friedel-Crafts reaction and so on. Then the coupling products were easily hydrolyzed to give the target compounds LJA-1 and LJA-2.In order to synthesize target compounds LJA-3～LJA-7, a series of alkyl or alkoxyl benzaldehydes were first synthesized from 4-bromophenol in different routes, and ethyl 4-amino-3-(aminomethyl)benzoate was synthesized via a 4-step sequence from ethyl 4-aminobenzoate. Both of the prepared intermediates were cyclized, then conducted into oxidation and hydrolysis to give the corresponding targets.The bioactivity assay of the targets is now under investigation using Rabbit ear acne model, and some compounds show promising result.