Synthesis of Tricyclic Compounds as Steroid 5α-Reductase Inhibitors

Abstract

A series of 4-phenoxybutyric acid derivatives attached to a tricyclic skelton were prepared and evaluated as 5α-reductase inhibitors. Structure activity relationships for these compounds in terms of rat epididymls (type 2)5α-reductase inhibitory activities reveal that 1) the substitution pattern at the 11-position of dibenz[b, e]oxepin influenced potency, 2) higher lipophilicity of the tricylic skeleton improved potency, whereas the existence of a basic nitrogen atom in this skeleton was detrimental to potency, and 3) isobutyl substitution at the 8 position of the azepine skelton was tolerated. Among the tricyclic compounds studied, 4-[3-[5-benzyl-8-(2-methyl)propyl-10, 11-dihydrodibenz[b, f]azepine-2-carboxamido]phenoxy]butyric adid (26) was the most potent inhibitor of rat type 2 5α-reductase at 0.1μM.