Patent Evaluation: 2β,19-Methyleneamino Bridged Steroids as Aromatase Inhibitors

Summary

Novelty: The compounds 2β-19(methyleneamino)androst-4-ene-3,17-dione and its 17β-ol are disclosed. They are said to be aromatase inhibitors and are potentially useful for the treatment of hyperoestrogenaemia. They may also be useful as antifertility agents, and could be used to treat breast cancer and other oestrogen-induced or oestrogen-stimulated tumours or hyperplastic tissue disorders.

Biology: The activity of the 3,17-dione in the inhibition of aromatase was demonstrated using the method of Johnston et al. (Endocrinology (1984) 115:776) and Burkhart et al. (Steroids (1985) 45:357). The inhibitor is pre-incubated with enzyme prior to assaying for activity in the presence of high substrate levels. The compound showed K_i = 259 nM, Λ₅₀ = 2.66 min, k^cat/K_i = 16 760.

Chemistry: Detailed synthesis of two end products and three intermediates is described. These are prepared by cyclization of 19(N-protected ((2-methoxyethoxy)methylamino)steroid using titanium tetrachloride followed by selective reduction of the 17-ketone 2β,19-(methylene amino) androst-4-ene, to give the 3,17-dione and its 17β-ol.