+
[a]D 36.2' (found: C, 76.70; H, 9.55: 0, 10.00), 17j3-hydroxy-17a-methylandpost-Qeno [2,3d ]isom eole, IV, m.p. 175,0-179.2', [a$ 107.5O, sir: A, 285 my (11,eoO) (found: C, 76.90; H, 8.77; We have previously reported' the effect on endocrinological activity produced by the fusion of 8 0, 9.80), and 178-hydroxy-17a-methylandrostapyrazole ring to the 2,3-positions of several hor- 4,fMieno[2,3d]isoxaeole,V, m.p. 193,4-199.0', monally active steroids, Noteworthy changes in [CUI, -187.8', A- 245, 253, 319 mp (3000, 2500, the type of endocrinological activity, or in the sep 19,800 respectively) (found: C, 77.19; H, 8.29; aration of several activities, are also observed when 0, 10.05). From 2-hydroxymethylene-17a-rnethylan isoxazole ring is similarly fused to hormonally 19-norandrost-4en-l78-ol-~n~there WM obactive steroids. The resultant, steroidal [2,3d]- tained the corresponding 17&hydr~y-17a-methy~m.p. 19-norandroat-4-eno[2,3d]isoxmole, VI, 160.2-161.0', [ a ]~ 43.3', A- 287 w.4 (10,400) Steroidal[2,3-d]isoxazolee
+
-
(found:C,76.78;H,8.65;N,4.51). Compounds I, 1x1, and I V proved to be very
I
isomzoles, (e,g., I) constitute a new2 class of modified steroids. The reaction of 2-hydroxymethyleneandrostan17p-ol-3-one3 with hydroxylamine hydrochloride in ethanolic solution gave 178-hydroxyandrostano[2,3d]isoxazole, I, m.p. 179.&182.0', [a], 61.6', A, 228 mp (4900) (found: C, 75.93; H, 9.38; 0, 9.90'). Treatment of I with cyclohexylpropionic anhydride in pyridine solution gave 178(3-cyclohexylpropionoxy)androstano[2,3-d ] isoxazole, 11, m.p. 140.4-141.8', [a], 40.6' (Found: C,76.54;H,9.63;N,3.12). Similarly, the reaction of hydroxylamine hydrochloride with the intermediate 2-hydroxymethylene-3-ket osteroids gave 17p-hydroxy-17a-met hylandrostano[2,3d]isoxazole, 111, m.p. 171.4-173.2',
+
+
active when tested for myotrophic7 and anabolio activities, and in addition they have low androgenic activity, Compound V, however, is a considerably less active myotrophic agent (and less androgenic) than either I11 or IV, In contrast to the corresponding ste~oidal [3,2-~]pyrasoles,~ neither IV nor V show any estrogenicity. Compqund I1 is a very potent anabolic agent, with a long duration of action and minimal androgenicity, Peak response to this ester o c c w from three to four weeks after a single subcutaneous injection. Compound VI is progestational (equal in activity to progesterone intramuscularly, and at least as active as Ethisterone when given orally), highly active both anabolically and myotrophically, and in addition has a low degree of androgenic and estrogenic activities. The latter response, however, is atypical since considerable mucification and leucocytic infiltration accompany cornifying effects on the vaginal epithelium.
' q
(1) R. 0. Clinton, A. J. Manson, F. W. StOnner, A. L. Beyler, G. 0. Potta, and A. Arnold, J. Am. C h a . Soc., 81, 1513 (1959). (2) F. Wmtemitz, C. Menou, and E. Amal, BuU. mc. chim. France, 505 (1960), have recently prepared 2acyanocholestan-3-one Yia the intermediate choleatano[2,%d]koxamle; the latter compound was not isolated. (3) J. Edwards and H. J. Ringold, J. Am. Chem.Sa., 81, 5262 (1959). The compound described as Zhydroxymethylenedrostan-17~-01-3ne by F. L. Wekenborn and H. E. Applegate, J. Am. Chem. Soc., 81, 1960 (1959) is actually the corresponding enol ether, Zmethoxymethyleneandostan-17@1-3ne (data to be published from these laboratories). (4) Melting points are ~0rrect.d; rotations were taken
in chloroform solution and ultraviolet spectra in 95% ethanol. (5) H. J. Ringold, E. Batrea, 0. Balpern, and E. Necoechea, J . Am. Chem.Soc., 81,427 (1959).
STERLINQ-WINTEBOP RESEAWEINRENWLAEB,N. Y.
R. 0. CLINTON A. J. MhNSON F. W.STONNEB R. G. CHBISTUNSEN A. L. BEYLEB G. 0.P m AARONAENOLD
Received July 20, 1960
(6) J. Edwards and H. J. Ringold, ref. 3.
(7) Anabolic activity waa determined by nitrogen retention, myotrophic activity by the growth mporuje of the levator ani muscle, androgenicity by the gain in weight of the ventral prostate, and estrogenicity by vaginal cornification, all in rata. Progestational activity waa evaluated by the Clauberg teat in rabbits. Compounds I and I1 were sdministered by subcutaneous injection and compounds 111, IV, and V were given orally.
