Synthesis of tricyclic compounds as steroid 5 alpha-reductase inhibitors

A series of 4-phenoxybutyric acid derivatives attached to a tricyclic skele ton were prepared and evaluated as 5 alpha-reductase inhibitors. Structure activity relationships for these compounds in terms of rat epididymis (type 2) 5 alpha-reductase inhibitory activities reveal that 1) the substitution pattern at the Ii-position of dibenz[b,e]oxepin influenced potency, 2) hig her lipophilicity of the tricyclic skeleton improved potency, whereas the e xistence of a basic nitrogen atom in this skeleton was detrimental to poten cy, and 3) isobutyl substitution at the 8 positon of the azepine skeleton w as tolerated. Among the tricyclic compounds studied, 4-[3-[5-benzyl-8-(2-me thyl)propyl-10,11-dihydrodibenz[b,f]azepine-2-carboxamido]phenoxy]butyric a cid (26) was the most potent inhibitor of rat type 2 5 alpha-reductase at 0 .1 mu M acid (26) was the most potent inhibitor of rat type 2 5 alpha-reduc tase at 0.1 mu M.