May, 1963
Notes Esters of Some Steroidal 3P-Hydroxy-4,6-dienes and their Biological Activity
TABLE I” BIOLOGICAL ACTIVITIES
JOHK S.BARAN Diiiszon o/ Chemical Research, G . D. Searle & Co., Chicago 80,Illanozs Recezued December 24, 1962
It has been established that in biologically and clinically active steroids the introduction of a double bond a t C 6 1 or the transformation of a (&ketone to a 3P-acetoxyl derivative2 does not significantly alter biological activity. Because of such evidence and a continuous effort in these laboratories to obtain structure and activity relationships among steroids, an investigation was undertaken into the synthesis and biological activity of esters of some steroidal 3P-hydroxy-4 6-dienes. Chemistry.-The steroidal 3p-hydroxy 4-6-dienes were prepared by the reduction of the corresponding C3-ketones with lithium tri-tert-butoxy aluminum hydride in tetrahydrofuran a t 25.3 Treatment of the 3Phydroxy derivatives with acetic or propionic anhydride in pyridine yielded the respective acyl derivatives in good yields. 6-Dehydro-17-ethynyltestosteronewas prepared by the dehydrogenation of 17-ethynyltestosterone with chloraniL4 Biology .-Table I summarizes the biological activities of the compounds described herein. These data demonstrate again that biological activity is not significantly altered when a biologically active 3-ketosteroid is transformed to its 3P-hydroxy or 3P-acetoxy derivative. Experimental General Procedure for the Reduction of the Steroidal 3Keto-4,6-dienes with Lithium Tri-tert-butoxyaluminum Hydride.-To a solution of 1 g. of the steroidal 3-keto-4,6-diene in about 50 ml. of dry tetrahydrofuran was added 2 g. of lithium tri-teit-butoxyaluminum hydride. The solution was stirred a t room temperature for 1 hr., coo!ed to about 5 ” , and then diluted carefully with 100 ml. of 205& aqueous acetic acid. The mixture was then extracted with 200 inl. of chloroform. The chloroform solution was washed successively with 100 ml. of 1% aqueous acetic acid, two 100-ml. portions of water and saturated sodium bicarbonate and then dried over sodium sulfate and distiled to dryness zn vucuo. If the residue was not crystalline, trituration of the residue with ether or ether and Skellysolve B yielded a crystalline product. The yields of crude crystalline product ranged from 4 0 4 5 % .
(1) (a) H. J. Ringold, E. Bates, A. Bowers, and J. Edwards. J . ,4m. Chem. Soc., 81, 3485 (1959); (b) P. Soilman, R . L. Elton, and R . hl. Dodson, ibid., 81, 4135 (1959); (e) L. H. Knox, J. Zderic, J. P. Ruelas, C. Djerassi, and H. J. Ringold, ibid.,82, 1232 (19GO); (d) J. 8 . Cella, J . Org. Chem., 24, 1109 (1959). ( 2 ) ( a ) S. Bernstein, i b i d . , 22, 172 (1957); (b) F. B. Colton and P. D. Iilimstra. Excerpla .Medica Intern. Congress S w i r s , I n f e m . Congress 071 Hormonal Steroids, Milan, 1962, paper no. 48. (3) It is assumed t h a t the reduction of a 3-keto-1,G-diene proceeds in a n analogous manner t o the reduction of the 3-keto-4-ene system t o give the BB-hydroxy derivative, preponderantly or exclusively. See 0. H. Wheeler and J . Matteos, Chem. Ind. (London), 395 (1957), and footnote 2 (b). ( 4 ) E. .J. Agnello and G. D. Laubach, J . A m . Chem. SOC.,79, 1257 (1957).
11
RI
Compound
Ia Ib
H H
IC
A C
Id Ie
COCzHS Ac
If
H
I11 7cProgestational R2
Ra
H Ac H
CH3 CHI CHa
H
CHs
AC Ac
CH,
activity in Clausberg assayb Oral Subcutaneous
0 5
5 5
H Ig AC .4c H 6-Dehydr0-17-ethynyl-19-nortestos-
terone 17-.4cetatec 6-Dehydro-li-ethynyltestosterone 6-Deh ydro-17-ethynyltestosterone li-hcetate
IIa H Ac H IIb d C Ac H IIC H H CHa IId Ac H CH3 IIe COCZHj H CH, 6-Dehydro-17-methyltestosterone
0 10 -
100 100
“0
100 5
5 %
sc
Androgenic activity
.\Iyotroplcd actiiity
2 1
