Nonsteroidal antiandrogens. Synthesis and structure-activity relationships of 3-substituted derivatives of 2-hydroxypropionanilides.

A series of 3-(substituted thio)-2-hydroxypropionanilides and some corresponding sulfones and sulfoxides of general structure 7, in which R' is methyl or trifluoromethyl, were prepared and tested for antiandrogen activity. Members of the trifluoromethyl series (7, R' = CF3) generally exhibited partial androgen agonist activity whereas the members of the methyl series (7, R' = CH3) were pure antagonists. Lead optimization in the methyl series has led to the discovery of novel, potent antiandrogens, which are peripherally selective. One of these, (RS)-4'-cyano-3-[(4-fluorophenyl)sulfonyl]-2-hydroxy-2-methyl-3'- (trifluoromethyl)propionanilide, 40 (ICI 176334), is being developed currently for the treatment of androgen-responsive benign and malignant disease.