Notes (2) A. J . Lin, R. S. Pardini, L. A. Cosby, B. J. Lillis, C. W. Shansky, and A. C. Sartorelli, J. Med. Chem., 16, 1268 (1973). (3) A. J. Lin, R. S. Pardini, B. J . Lillis, and A. C. Sartorelli, J. Med. Chem., submitted for publication. H. S. Schwartz, J . E. Sodirgren, and F. S. Philips, Science, 142, 1181 (1963). V.N. Iyer and W. Szybalski, Science, 145,55 (1964). A.J. Lin and A. C. Sartorelli, J . Org. Chem., 38,813 (1973). (a)D. E. Kvalines, J . Amer. Chem. SOC.,56, 670 (1934); (b) R. T. Arnold and H . E. Zaugg, ibid., 63, 1317 (1941); (c) M. E. Peover, J. Chem. Soc., 4540 (1962). D. W. Cameron, P. M. Scott, and L. Todd, J. Chem. Soc., 42 (1964). G . R. Allen, Jr., J. F. Poletto, and M. J. Weiss, J. Org. Chem., 30,2897 (1965). T. R. Witty and W . A. Remers, J. Med. Chem., 16, 1280 (1973). K. C. Agrawal, B. A . Booth, and A. C. Sartorelli, J. Med. Chem., 11, 700 (1968).
Journal ofMedicinul Chemistry, 2974, Vol. 27, No. 5 561
n
l, R = H 2, R = M e
4, Z=Se; R = O H
5, Z=Se; R = O A c
6, Z = T e ; R = O H 7, Z=S-S; R = O A c
Heterocyclic Steroids. 5.l Sulfur, Selenium, and Tellurium Be-Androstane Derivatives and Their 'la-Methylated Congenerst Gala1 Zanati, Gunhild Gaare,I and Manfred E . Wolff*x§
Department of Pharmaceutical Chemistry, School of Pharmacy, University of California, Sun Francisco, California 94143. Received Novem ber 8, 1973
3
8, Z = & ; R , = O H ; R , = H 9, Z = Te; R, =OH; R? = H 10, Z=S-S R , = O H ; R ? = H 11, Z = S ; R , = O H ; R 2 = C H , 12, Z = S; R1, RJ = 0
seven-membered carbocyclic ring containing a A double bond. Compound 13 has only about one-fifth the androgenic activity of testosterone, but the levator ani response is nearly as high as that of testosterone. In this respect, it is quite similar to the corresponding 2-oxa ana10g.~All of these data are in harmony with our postulate3 of the importance of an A ring, equivalent in size to a six-membered or larger carbocyclic ring, flattened in the vicinity of C-2and C-3, for androgenic-myotrophic activity.
As part of a continuing program in the preparation of ring A modified androgens, the preparation of some additional sulfur, selenium, and tellurium derivatives was unR, dertaken. H f ' c t R 2 &OH The 70-methyl steroids 8-10 were obtained by treatment of 7~-methyl-1,4-dibromo-1,4-seco-2,3-bisnor-5aandrostan-17P-01 acetate (2)2 with NazSe, NazTe, and I Na2S2, respectively, in refluxing ethanol. This sequence H A was taken from our previous preparation3 of 4-7, and the 13 14, R,R, = 0 details of the preparation of these compounds are given in 15, R, = OH; R2= Et the Experimental Section. The l7e-alkyl thiasteroid 11 was prepared by Oppenauer oxidation of 7~-methyl-2Experimental Section** thia-A-nor-5a-androstan-17/3-ol2 to give ketone 12 which on treatment with MeMgBr gave 11. A similar sequence 2-Selena-A-nor-501-androstan-17P-01 (4). To a solution of 0.4 g of l7 in 100 ml of refluxing EtOH there was added a tenfold exgave the 19-nor derivatives 14 and 15. cess of NazSe. Heating was continued for 24 hr when tlc indicated A thiasteroid containing a six-membered A ring (13) complete conversion of the dibromide to the product. The solution was produced by esterification of 17/3-hydroxy-1,2-seco-A- was poured into 600 ml of HzO, acidified to pH 3, and extracted nor-5cr-androstane-l,3-dioic acid4 followed by formation of with Et20 three times. The Et20 extract was washed with the C-17 tetrahydropyranyl ether. Reduction of the last NaHC03 and HzO, dried (NaZSOd), and evaporated to give 0.25 compound with LiAlH4 gave 3, which was converted to g of 4 as a white solid. Several recrystallizations from EtzO-hexane gave the analytical sample: mp 157-159"; M+ 328; m / e 328 the dimesylate and then to 13 using NaZS. ( M f ) , 248.2142 (M+ - Se); nmr 0.75, 0.83 ppm (C-18 and C-19). The data from the biological testing are given in Table Anal. (C17H2sOSe-HZO)C, H. I.,* As described in our previous ~ o r k , the ~ , activity ~ of 2-Selena-A-nor-5n-androstan-17~-01 Acetate (5). A solution the heterocyclic androstane derivatives rises in the order S of 0.1 g of 4 in 4 ml of pyridine and 2 ml of AczO was kept overSe < Te < S-S, and the introduction of the 70-methyl night a t 25", poured into 100 ml of ice-HzO, acidified with HCl, group enhances the activity of A-nor thiasteroids. By conand extracted with EtzO. The Et20 was washed several times with HzO, dried (NaSOd, and evaporated to give an oil, which trast, the present results show that the introduction of the was crystallized from hexane to give the analytical sample: mp 7a-methyl group into the Se, Te, and S-S derivatives does 92-94". Anal. Calcd for C19H3002Se.HzO: C, 58.91; H, 8.26. not raise activity. Found: C, 58.82; H, 7.77. The activity of the six-membered thiasteroid 13 is most 2-Telluria-A-nor-& -androstan-17@-01 (6). A refluxing solution interesting. This compound would be isosteric with a of 0.3 g of 1 in 100 ml of refluxing EtOH containing tenfold excess
-
of NazTe was allowed to react and worked up as described for 4. ?This research was supported in part by a Public Health Service Grant (AM 05016) from the National Institute of Arthritis and Metabolic Diseases, U. S. Public Health Services. tTaken in part from the Ph.D. Thesis of G. Gaare, University of California, San Francisco, Calif., 1972. $This paper is dedicated to my postdoctoral professor, Alfred Burger (1955-1957). :Pharmacological tests were performed a t the Endocrine Laboratories, Madison, Wis., using essentially the method of Hershberger, et ~ 1 . ~
**Melting points were determined with a Thomas-Hoover apparatus equipped with a corrected thermometer. Microanalyses were performed by the Microanalytical Department, University of California, Berkeley, Calif. Mass spectra were obtained hy MI. William Garland or Dr. Robert Weinkam on a MS-902 high-resolution instrument. Where analyses are indicated only by symbols of the elements or functions, analytical results obtained for those elements or functions were within +0.4% of the theoretical values.
562 Journal oiMedicinal Chemistry 1974, Vol. 17,
3
.YOtf'.\
Table I. Androgenic-Myotrophic Assay Compd (total dose, mg) C a s t r a t e control Testosterone 1 0 . 3 ) Testosterone ( 0 . 6 ) Testosterone 13.0) 8 (3.0)
Ventral prostate
15.6 C 0 . 4 1 25.6 * 2.47 52.5 = 3.48, p < 0.001 90.3 I 6 . 1 9 , p < 0.001 8 8 . 1 i 3.55, p
9 (3.0)
10 ( 3 . 0 ) 11 ( 3 . 0 )
13 ( 3 . 0 )
< 0.001
7 2 . 8 & 1.58, p < 0.001 9 1 . 6 i 4.75, p < 0.001 1 2 3 . 5 =k 5 . 7 0 , p < 0.001 54.2 & 1.57, p < 0.001
W t , mga Seminal vesicle
+
11 8 0.30 15.1 = 0.76 21.8 i 2.35, p < 0.01 7 7 . 9 3Z 1 . 7 5 , p < 0,001 7 0 . 0 3Z 2 . 2 4 , p
