Csaba Molnar

Synthesis and biological activity of a new progestogen, 16-methylene-17α-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.

Hydrolytic behavior of 5α-hydroxy-11β- and 5β-hydroxy-11α-substituted 19-norsteroids

Abstract Teutsch G. and Belanger A. treated 5α,10α epoxides with Grignard-reagents catalyzed by copper(I) ions. The reaction with steroidal epoxides proceeded with complete regio- and stereospecificity, leading exclusively to the 11β-substituted compounds. According to our synthetic strategy, the 5,10 epoxide isomers were not separated; instead, the pure 11β, and in some cases, 11α-substituted molecules were isolated after the conjugate addition of the Grignard-reagents, followed by deketalization and dehydration. Surprisingly, appearance of a third compound was generally observed beside the expected deprotected products, and this compound turned out to have a 3-keto-5(10),9(11) structural unit. Starting from pure 3-ethylenedioxy-5α,10α-epoxy-estr-9(11)-ene-17-one and 3-ethylenedioxy-5β,10β-epoxy-estr-9(11)-ene-17-one, four model compounds were synthesized (11α- and 11β-{4-[1,1-(ethylenedioxy)-ethyl]phenyl}-estra-, as well as 11α- and 11β-cyclohexyl-estra-derivatives) to study the process of deprotection and dehydration. 3-keto-5(10),9(11)-derivatives were found to form after deketalization and dehydration only from 11α-substituted derivatives, while 11β-derivatives resulted in only the expected 3-keto-5,9-diene structure. After observing this remarkable difference between the behavior of 11α-, 11β-substituted isomers we decided to take a closer look at the processes of deketalization and dehydration. In order to carry out the hydrolysis under mild conditions, pyridinium paratoluenesulfonate, a weakly acidic salt, was applied. All the intermediate products observed by TLC were isolated. The outcome of the deprotection and elimination reactions can be rationalized by two factors: conjugation of olefins (with the 3-oxo-group or the 11-phenyl group) and orientation of groups to be eliminated.