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
The steroidal sulfonylpyrazole 1 bound to the rat ventral prostate androgen receptor in vitro; it inhibited testosterone propionate induced increases in ventral prostate weight in vivo in the castrated, immature male rat with an ED50 of 15 mg/kg po. Compound 1 lacked androgenic activity in vivo in contrast to the parent steroidal pyrazole 5, which was both androgenic and antiandrogenic. The 2'- and 5'-methylsulfonyl isomers 6 and 6a did not bind to the androgen receptor. Introduction of an alkylsulfonyl at the N-1'-position has served, therefore, to isolate the intrinsic antiandrogenic properties of the steroidal heterocycle free of apparent hormone agonist properties. Structure-activity relationship studies revealed that a methylsulfonyl group at N-1' together with a C-17 alpha-substituent were the optimal combination for in vitro androgen receptor binding, in vivo antiandrogenic potency, and a lack of androgenic activity.
Dieckmann cyclization of the triester III (R = CH¡)-obtained by reduction and esterification of the Stobbe condensation product II of the keto ester I (R = CHg)-afforded the keto diester V, which alternatively could be prepared by a combined Stobbe-Dieckmann condensation to give IX (R = H), followed by reduction of the olefinic bond. Methylation (preferably in situ) of the keto diester V gave a mixture of epimers VI and VII. The former, which was isolated readily by crystallization, on submission to the Reformatsky reaction was converted into a mixture of lactone X and hydroxy ester XI, readily convertible into the isomeric lactone XII. Both lactones were cleaved with base to the same unsaturated diester acid XIII which, on cyclization, was converted into the ketone XVII.Catalytic reduction effected hydrogenolysis of the carbonyl group and stereoselective hydrogenation of the olefinic bond to yield the known diester XIX. Partial saponification of XIX, followed by Arndt-Eistert homologation and ketonic ring closure of the dibasic acid afforded dZ-estrone methyl ether. Hydrogenation of the unsaturated diester acid XIII proceeded stereoselectively to yield mainly the substance XIV (14-iso configuration). Cyclization to give XX, followed by hydrogenolysis, yielded the diester XXI (R = CH3). Completion of ring D as described above gave 14-isoestrone by the steps: XXI (R = CH«) -* XXI (R = H) -XXII -XXIII (R = CH3) -XXIII (R = H). This substance proved to be identical with Anner and Miescher's estrone-a. In attempts to improve the stereoselectivity of the estrone synthesis, the hydrogenation of the methylated unsaturated halfester XXIV and of the dienol lactone XXVI was studied which, however, led to the 14-iso series. Some preliminary experiments on the hydroxylation of XXVI were carried out. One isomeric form of the glycol XXVIII was isolated but failed to undergo dehydration to XXIX in preliminary experiments.
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