Synthesis and biological activity of a new progestogen, 16-methylene-17alpha-hydroxy-18-methyl-19-norpregn-4-ene-3, 20-dione acetate.

The progestational activity of second- and third-generation progestins in oral contraceptives were markedly increased by addition of an 18-methyl group. A new progestin, the 18-methyl analog of Nestorone, 16-methylene-17alpha-hydroxy-18-methyl-19-norpregn-4-ene-3,2 0-dione acetate (10), was synthesized. The relative binding affinity and biologic activity of 10 was compared with Nestorone, levonorgestrel, and progesterone using a binding assay for rat progesterone receptors, the Clauberg assay in the rabbit, and by assessing pregnancy maintenance in the rat. These studies, as summarized in Table 4, show that 10 is three to ten times more potent than Nestorone. The addition of the 18-methyl group to Nestorone markedly increased its potency as noted above, but is unlikely to change its rate of delivery from sustained release systems. 10 should be ideally suited for administration by implants or small skin patches.

Steroids 49. Investigations on the dehydration of 17 alpha-ethynyl-17 beta-hydroxysteroids.

The acidic dehydration of 17 alpha-ethynyl-17 beta-hydroxysteroids (1-3) was investigated. On reaction with thionyl chloride, phosphorus oxychloride, and formic acid, the desired dehydration was accompanied by chlorination, Wagner-Meerwein rearrangement, and D-homoaromatic rearrangement. The structure of the product from the transformation of 17 beta-hydroxypregn-20-yne derivative (3) on reaction with formic acid was misjudged. It was regarded as a pregn-16-en-20-yne (10) instead of the actually rearranged D-homoaromatic compound (11). As a consequence, physical data corresponding to this latter structure have been cited in the literature as those of pregn-16-en-20-yne derivative (10). This confusion prompted us to prepare compounds of both types (4, 9, 10, and 11), the characterization of which is here described.