The synthetic approach to STS 557 - structure activity relationships in 17 alpha-CH2X-substituted 19-nortestosterone...

The synthesis of 17 alpha-CH2X-substituted 19-nortestosterone derivatives (X = halogen, CN, N3, OH, NH2 etc.) is described. Starting with 1,4-dihydroestradiol 3-methyl ether the 17 alpha-CH2X-17 beta-hydroxy-moiety was introduced via a 17 beta-spiroepoxide which could be cleaved with various nucleophilic agents giving the desired derivatives. In the McPhail assay with immature rabbits some of these substances showed good progestagenic activity on oral administration. The influence of structural modifications on the activity is discussed. The best effect is observed if an additional double bond is introduced in position 9(10). While the 19-nortestosterone derivative with X = CN has only an activity of about 20% of that of norethisterone acetate, the introduction of a second double bond leads to a compound (STS 557) which has an oral potency more than ten times as high as levonorgestrel.