ABSTRACT
The effect of a substituent in the 12-position of progestagens was studied. To this end, various approaches toward the preparation of 12 beta-alkyl- and 12-alkylidenenorpregnanes were investigated. Eventually, the desired compounds 17 beta-hydroxy-12 beta-methyl-18a-homo-19-nor-17 alpha-pregn-4-en-20-yn-3-one (37) and 17 beta-hydroxy-12-methylene-18a-homo-19-nor-17 alpha-pregn-4-en-20-yn- 3-one (38) were obtained in racemic form by total synthesis; they were shown to lack progestagenic activity.
Subject(s)
Desogestrel/chemistry , Pregnanes/chemical synthesis , Magnetic Resonance Spectroscopy , Methylation , Molecular Structure , Pregnanes/chemistry , Structure-Activity RelationshipABSTRACT
13-Ethyl-18-norpregn-4-ene-3, 20-dione (7) and 13-acetyl-18-norpregn-4-ene-3, 20-dione (4) were synthesized and tested in the s.c. Clauberg assay. The potencies of these compounds (1X and 1/3 X progesterone, respectively) are compared with those reported for 13-vinyl- and 13-cyanomethyl-18-norpregn-4-ene-3, 20-dione. A comparable activity (1/3 X progesterone) was found for 13-acetyl-18-norpregn-4-en-3-one (10) which lacks the 20-carbonyl group.
Subject(s)
Norpregnenes/chemical synthesis , Animals , Biological Assay , Chemical Phenomena , Chemistry , Female , Indicators and Reagents , Norpregnenes/pharmacology , Optical Rotation , Progesterone/pharmacology , Structure-Activity RelationshipABSTRACT
Using the strategy based on the Hansch method which analyses effects of substituents on biological activity in terms of their hydrophobic, electronic and steric effects we selectively synthesised a series of 11beta-substituted-17alpha-ethynyl-4-estren-17beta-ols that combine ease of synthesis with good discrimination between these factors aiming at finding the compounds with optimum biological activity in that series. The compounds were tested quantitatively in the Clauberg test (rabbit) and the ovulation inhibition test (rat). The differences in biological activity could reasonably be correlated with two steric effects introduced by the 11beta-substituent. These were a change in the overall shape of the 11beta-substituent and the angular methyl group, and direct steric hindrance of the steroid-receptor protein binding. Some exceptions were found possibly due to metabolic conversion of these compounds to the corresponding 11beta-substituted-17alpha-ethynyl-1,3,5(10)-estra-triene-3,17beta-diols.