11-OXA AND 17α-HYDROXYMETHYL ANALOGUES OF STEROID HORMONES AND THEIR DERIVATIVES

In view of the markedly reduced activity in the Clauberg test of 11-oxaprogesterone and of its significantly enhanced anovulatory activity in rabbits, ovulation stimulated with copper acetate, the synthesis and biological evaluation of other 11-oxa hormone analogues was undertaken. The syntheses of 11-oxa-17-acetoxyprogesterone, 11-oxa-17α-ethynyltestosterone, 11-oxa-estradiol, 11-oxa-17α-ethynylestradiol, and of 11-oxatestosterone are reported and some of their biological activites are discussed. In general, the replacement of the 11-methylene group by oxygen results in a diminution of the progestational, androgenic-anabolic, and estrogenic activities, this effect being the least pronounced in the case of the progestational activity of 11-oxa-ethisterone and particularly strong in the case of the uterotropic activity of 11-oxa-estradiol. On the other hand, the observation that the introduction of bulky 17α-substituents into progesterone and related products results in general in an increased progestational activity and that acylation of the progestationally inactive 17-hydroxyprogesterone leads to orally active progestogens and antifertility agents, prompted us to synthesize, by two pathways, 17α-acetoxymethylprogesterone and 17α-hydroxymethylprogesterone. It is shown that one of these pathways can be advantageously applied also to the synthesis of 17α-acyloxymethyl and 17α-hydroxymethyl glucocorticoids. Interestingly, 17α-acetoxymethylprogesterone proved inactive in the Clauberg test even at high dose levels. The primary objective of the investigations which we should like to present in the framework of this Symposium was, and is indeed, a contribution to the domain of structure-activity relationships of hormonal steroids. However, this lecture will be concerned to the greatest extent with results pertaining to the structural component of this tandem field—to the synthesis of new analogues of steroid hormones—and we shall touch its activity component only in a fragmentary and preliminary way; this, quite simply, because we are not yet in the possession of the full biological data. Still, we hope that the chemical aspects discussed will not be completely devoid of interest and we also hope that even some of the fragmentary biological results will not be meaningless to the intricate and problematic field of structure-activity relationships. We should like to divide our presentation into two parts: one dealing with 11-oxa analogues of steroidal sex hormones, the other with 17α-hydroxymethyl analogues of hormones of the progesterone-corticoid group, with the emphasis on derivatives of progesterone.