Isolation, synthesis, and biological activity of five metabolites of danazol

Abstract

Metabolites of danazol (17.alpha.-pregna-2,4-dien-20-yno[2,3-d]isoxazol-17-ol), an orally effective pituitary gonadotropin inhibitory agent devoid of estrogenic and progestational activities, were isolated from urine of a female subject who had taken danazol orally at a dose of 800 mg/day for 7 days. The metabolites isolated were 17-hydroxy-17.alpha.-pregn-4-en-20-yn-3-one, 17-hydroxy-2.alpha.-(hydroxymethyl)-17.alpha.-pregn-4-en-20-yn-3-one, 17-hydroxy-2-(hydroxymethyl)-17.alpha.-pregna-1,4-dien-20-yn-3-one, 6.beta.,17-dihydroxy-2.alpha.-(hydroxymethyl)-17.alpha.-pregn-4-en-20-yn-3-one, and 6.beta.,17-dihydroxy-2-(hydroxymethyl)-17.alpha.-pregna-1,4-dien-20-yn-3-one. None of these metabolites exhibited pituitary inhibiting activity comparable to danazol. [Studies were carried out with monkeys (Macaca mulatta) and humans.].