TRIALKYLSILYL TRIFLUORMETHANESULFONATE MEDIATED .ALPHA.-METHYLENIC CARBON FUNCTIONALIZATION OF 4-AZA-5.ALPHA.-ANDROSTAN-3-ONE STEROIDS

摘要

A novel single-pot trialkylsilyltrifluoromethanesulfonate (R3Si-OTf) mediated processproduces derivatives of 4-aza 3-keto steroids at the.alpha.-methylenic carbon through electrophilicsubstitution. These derivatives are useful in thepreparation, through elimination of the substituenton the .alpha.-methylene carbon, of .DELTA.-1 olefin 4-aza3-keto steroids which are potent inhibitors of 5-.alpha.reductase.5.alpha.-dihydrotestosterone, which is the principalmediator of androgenic activity in some organs.Inhibitors of testosterone-5.alpha.-reductasehave been shown to prevent or lessen symptoms ofhyperandrogenic stimulation. Nayfe et al.,[Steroids, 14, 269 (1969)] demonstrated in vitro thatmethyl 4-androsten-3-one-17.beta.-carboxylate was atestosterone-5.alpha.-reductase inhibitor. Voigt andHsia, [Endocrinology, 92, 1216 (1973), Canadian Pat.No. 970,692], demonstrated that the above ester andthe parent free acid,4-androsten-3-one-17.beta.-carboxylic acid are both activeinhibitors of testosterone-5.alpha.-reductase in vitro.Topical application of either testosteroneor 5.alpha.-dihydrotesterone caused enlargement of thefemale hamster flank organ, an androgen dependentsebaceous structure. However, concomitantadministration of 4-androsten-3-one-17.beta.-carboxylicacid, or its methyl ester, inhibited the responseelicited by testosterone but did not inhibit theresponse elicited by 5.alpha.-dihydrotestosterone. Theseresults indicated that the compounds areantiandrogenic by virtue of their ability to inhibittestosterone-5.alpha.-reductase.A number of 4-azasteroid compounds areknown. See, for example, U.S. Pat. Nos. 2,227,876;3,239,417; 3,264,301; and 3,285,918; French Pat. No.1,465,544; Doorenbos and Solomons, J. Pharm. Sci. 62,4, pp. 638-640 (1973); Doorenbos and Brown, J. Pharm.Sci., 60 8, pp. 1234-1235 (1971); and Doorenbos andKim, J. Pharm. Sci. 63, 4, pp. 620-622 (1974).In addition, U.S. Patents 4,377,584 and4,220,775 of Rasmusson et al., described a group of4-aza-17.beta.-substituted-5.alpha.-androstan-3-ones which aresaid to be useful in the treatment of hyperandrogenicconditions. Furthermore, in U.S. Patent 4,760,071,Rasmusson et al., disclosed novel17.beta.N-(monosubstituted)carbamoyl-4-aza-5.alpha.-androst-1-ene-3-ones, which are highly potent testosterone-5.alpha.-reductase inhibitors.The processes known in the art for preparingthe aformentioned compounds generally include a stepwherein a double bond is introduced into the lactamring of the azasteroid. Thus, selenic anhydrideoxidation [Back, T.G., J. Org. Chem., 46, 1442(1981)], sulfoxide elimination [U.S. Patent No.4,377,584; 4,220,775], and silylation mediated DDQ(2,3-dichloro-5,6-dicyano-1,4-benzoquinone) oxidationhave all been used heretofore for the introduction ofthe .DELTA.-1 olefin functionality.The instant invention discloses a methodwhereby a powerful silylating reagent mediatesregiospecific electrophilic substitution on thelactam ring to produce a versatile array ofazasteroid derivatives substituted at the.alpha.-methylenic carbon. These derivatives are useful,through elimination of the added substituents, formaking the .DELTA.1-olefin azasteroid derivative havingpotent 5-.alpha. reductase inhibitory activity.