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.

Pure antiandrogens, like flutamide, antagonize androgen action both peripherally and centrally at the hypothalamic-pituitary axis, which leads to an increase in LH and testosterone secretion. A new non-steroidal antiandrogen ICI 176,334 [2RS)-4'-cyano-3-(4-fluorophenylsulphonyl)-2-hydroxy-2-methyl-3'- trifluoromethyl)propion-anilide) has now been discovered which causes regression of the accessory sex organs but does not increase serum concentrations of LH and androgens. ICI 176,334 binds to rat prostate androgen receptors with an affinity around fourfold that of hydroxyflutamide. When administered s.c. concurrently with testosterone propionate (200 micrograms/kg) for 7 days to immature castrated rats, ICI 176,334 (10 mg/kg) significantly (P less than 0.001) inhibited growth of the seminal vesicles and ventral prostate gland. Oral administration of ICI 176,334 at doses of 1, 5 and 25 mg/kg for 14 days to adult rats caused a dose-related reduction in accessory sex organ weights but had no effect on the testes. None of these doses caused a significant increase in serum LH and testosterone. Flutamide was around fourfold less potent and significantly increased serum LH and testosterone at the higher doses. ICI 176,334 was well tolerated. ICI 176,334 should, therefore, prove useful for the treatment of androgen-responsive benign and malignant diseases.

The synthesis and potent fasciolicidal activity of novel salicylanilides, with benzoyl substituents in the salicyl ring, is described. Several compounds surpassed the activity of commercially used flukicides against Fasciola hepatica infections in rats. Compounds 10, 11, and 15 were poorly active against the parasite in sheep and inactive in infected calves. It is concluded that the benzoyl substituents potentiate antiparasitic action by virtue of their electron-withdrawing properties rather than by advantageous protein binding at parasite receptor sites. Poor activity in sheep is ascribed to in vivo reduction of the carbonyl in the benzoyl group of the anilides.

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