Synthesis of steroidal [4,6-b,c]-benzothiazepines, a new class of aromatase inhibitor

Abstract

Several steroidal [4,6-b,c]benzothiazepines have been prepared via base-catalyzed Michael addition of 2-aminothiophenol to 3β,17β-diacetoxyandrost-4-en-6-one. The product of this reaction has the 4β,5α stereochemistry, but cyclizes to a benzothiazepine with the steroidal 4β,5β configuration, confirmed by X-ray crystallographic analysis. 2-Aminothiophenol reacts with 3β,17β-diacetoxyandrost-4-en-6-one under acidic conditions to give a steroidal 6-spiro-benzothiazole. An androst-4-ene-3,17-dione-based [4,6]benzothiazepine has been shown to be a moderate competitive inhibitor of the human placental aromatase enzyme with IC50 = 42.3 µM. Keywords: steroid, aromatase, benzothiazepine.