Steroidal Heterocycles. VII.¹ Androstano[2,3-d]isoxazoles and Related Compounds

Abstract

The preparation of steroidal heterocycles containing an isoxazole ring fused to the 2,3-positions of the steroid nucleus is described. These were prepared by the reaction of hydroxylamine with either a 2-hydroxymethylene-3-ketosteroid or a 2-acyl-3-ketosteroid. The factors which influence the ratio of androstano [2,3-d] isoxazole to androstano [3,2-c] isoxazole afforded by this reaction are discussed. Several of these novel steroidal heterocycles possess interesting, and often unpredictable, endocrinological activity. The cleavage of steroidal [2,3-d]isoxazoles by means of base leads to the corresponding 2-cyano-3-ketosteroids.In a previous publication2 we outlined attempts to alter the nucleophilic environment near position 3 of the steroid nucleus3 by the attachment of a pyrazóle ring at the 2,3-positions. This approach was based upon the rationalization that the cellular receptor sites would vary sufficiently to make the question of fit one of paramount importance.The success of our initial efforts in synthesizing steroidal [3,2-c [pyrazoles with very high anabolic/ androgenic ratios2 has led us to investigate the very closely related steroidal isoxazoles fused at the 2,3positions.4'5The reaction of hydroxylamine with a 2-hydroxymethylene-3-ketosteroid can conceivably afford both of the two isomeric derivatives,6 the steroidal [2,3-d]isoxazole (I) and the steroidal [3,2-c [isoxazole (II).I can be distinguished readily from II by its facile basecatalyzed conversion to the corresponding 2a-cyano-3ketosteroid. Under the same conditions II is recovered unchanged.7

Mitogen Induced Production of Polyclonal IgG is Decreased in Women With Severe Endometriosis

“…Although not directly tested in this study, our data support the hypothesis that danazol is a modulator of the immune system.i" An isoxazol derivative of l Zo-ethinyl testosterone, danazol has been used to treat women with endometriosis for nearly 25 years. 25 The clinical success of danazol is usually attributed to its inhibitory effects on hypothalamopituitary function, including the suppression of GnRH and/or gonadotropin secretion as well as inhibition of gonadal and adrenal steroidogenesis. [26][27][28][29] However, an alternative mechanism by which danazol may exert its beneficial effects in patients with endometriosis is via modulation of the immune response.…”

In vivo and in vitro metabolism of the designer anabolic steroid furazadrol in thoroughbred racehorses

“…Mixtures of F and IF were first identified in Orastan-A (Gaspari Nutrition) predominately as the tetrahydropyranyl ether [16] and more recently in Furazadrol (Axis Labs) [17], with incorrect labelling of the contents in both cases. Both F and IF have been reported to exert anabolic activity in the older steroid literature that was dependent on the mode of administration [18] [19] and more recently in both yeast and human HuH7 androgen bioassays [17], with the former isomer reported to display greater activity [18] [19]. Related isoxazole containing steroids, including the structurally similar danazol, are banned in competition by the World Anti-Doping Agency (WADA) and the International Federation of Horseracing Authorities (IFHA) [20] [21].…”

A review of designer anabolic steroids in equine sports

“…In both cases, these supplements had incorrect labelling of the content information . Furazadrol has been reported to exert anabolic activity in the older literature, and in more recent yeast and human HuH7 androgen bioassays …”