Joiirnal o.f dipdieinn1 Chemistry, 1870, Vol. 1.7, -Yo. -7 531
THIASTEROII)~. IT1 and the separated solid was collected by filtration, washed repeatedly (H,Oj, and dried. On crystallizing from boilirig H?O, 3.2 g of an orange-colored product, mp 174-175' was obtained. ,4na(. (C15H1605) C, H. 3,6-Dihydroxy-4,5-dimethylxanthone.-Following the procedure of Grover, et a1.,22 2.5 g of 2,2',4,4'-tetrahydroxy-3,3'dimethylbenzophenone in 25 ml of H20, was heated in an autoclave a t 200-220" for 2.5 hr. After cooling the 3,6-dihydroxp4,5-dimethylxai1thone was collected and dried. I t did not, melt, below 310'. ilnal. (CIjH1401j C, H . 3-Propionoxyxanthone.-,4 mixture of 4 g of 3-hydroxyxant h ~ i i e and , ~ 10 ml of PrsO was refluxed for I hr and then poiired into ice-H?O. The separated solid was collected by filtration, washed (H20), and dried. On crystallizing from ligroin, 3.1 g of white solid, mp 151-152', was obtained. dnal. ( c ~ s H & ) C, H . 3-Hydroxy-4-propionyIxanthone.-To a melt consisting of 1 g of NaCl and 3 g of AlCl,, 1 g of 3-propionoxyxanthone was added and t,he temperature was kept a t 160-170" for 4.5 min. The mixtiire was hydrolyzed with dil €IC1 and ice-H20, and the separated solid was collected and washed with H20. This was dissolved in dil NaOH and reprecipitated with dil HCI. The 3eparated solid, on crystallizing from EtOH, gave 0.8 g of white prodiict, mp 170-li2". .lnal. (C16H,,01) C, H.
2,3-Dimethyl-lH,7H-pyrano[ 2,3-c]xanthene-1 ,7-dione (III).A mixture of 0.6 g of 3-hydroxp-4-propi(~11ylxaiithoiie, 0.7 g of anhyd NaOAc, and 3 g of AcZO was refliixed for X hr. By poiiriiig the reaction mixture into H2O a solid was isolated, which on crystallizing from EtOH, gave 0.5 g of white product, mp 266-267'. dnal. (CISHI~O,) C, H . 3-Hydroxyxanthonyl-(4)-styrilKetone.-To a solution of 0.5 g of 3-hydroxy-4acety1xanthone2j aiid 0.2 ml of BzH in 30 ml of 95Vc EtOH, .i ml of ;iOC;; aqueous KOH was added with stirring, arid the mixture was left to stand 12 hr. After dilution with H?O and acidification, the separated solid wa.; collerted, dried, and crystallized from ligroin yielding 0.5 g of light yellow prodiirt, mp 172-175'. dnal. (C2,HlrOd) C, H. 3-Phenyl-lH,7H-pyrano-12,3-elxanthene-l,7-dione (IV).-A mixture of 0.2 g of the preceding prodiict, 0.3 g of PeL),, arid 7 ml of AmOH was heated at 14j" for 7 hr. hftei, cooling, the reaction mixture was filtered aiid the collected solid ( a mixture of Se and product,) was extracted with EtOH t o give 0.15 g of white solid, mp 272-273". Anal. (C?ZHI?OI)C, H.
Acknowledgment.-The
authors are indebted to AIL-.
G. Cilia for his technical assistance.
~
(24)
F.Ullrnann and IT.Denzler, Chrm. Bw,,39, 4335 (ln06).
( 2 5 ) I'.S. ;\gasimundin and S. Rajagopal, .I. Org. Chrm., S O , 2081 f1965).
Thia Steroids. 111. Derivatives of Z-Thia-A-nor-5a-androstan-li'~-ol As Probes of Steroid-Receptor Interactions' 114 U r R E D E.
\%'OLFF,
SHARAD
GALALZ A N A T I , G. S H A N \ I U G A S U K D . 4 R U l I , GL-PTE,r l S D GUSHILDA A D A H L
Drpartmrnf of Pharmaceutacal Chemzstry, School of Pharmacy, Cnivrrszti, of Californza, San Franrisco, Califoinia ~ 4 1 2 2 RecczvPd January 26, 1970 The preparation of analogs of 2-thin-A-nor-501-androst an-170-01 having three typical modifications used in anabolic-androgenic compounds, o m , the introduction of a 7013Ie group, the 19-nor modification, and the introduction of a 1701-alkyl group, is described. I n addition, the SO and SO, derivatives of the parent compound were prepared. Biological evaluation shows that the SO arid SO, derivatives are inactive, and that the pharmacological effects of the other modifications on thiasteroids parallels their effects in the testosterone serie,. From this it is concluded that the three modifications affect drug-receptor interactions, and not drug distribution or drug metabolism. T h e effects of these groups map be direct, by interaction with the receptor, or indirert, by altering the conformation of the steroid itself through conformational transmission.
In a previous paper2 of this series, the synthesis of 2-thia-A-nor-5a-~ndrostan-l7(3-ol as a n isostere of 17phydroxy-3a-androst-2-ene was described. The androgenic-anabolic activity of this compound wajs taken as tvidence that steric effects, and not electronic factors, are important in connection with structural requirements at C-3 and 'or C-3 in androgens. As described in the Diwussion, the discovery of thi. new, biologically active ring system provides a powerful general tool in the examination of the relationship between chemical qtructure and biological activity in androgenicanabolic steroids. For this reason, thr preparation of thiasteroids having three typical enhancing groups used in anabolic-androgrnic compounds, viz., the 7 a - l I e group, the 19-nor modification, and the 17a-alkyl group, was undertaken. I n addition, the sulfoxide and sulfone derivatives of 2-thia-A-nor-5a-androstan-17p-ol acetate were synthesized. (1) This investigation was supported in part I,? a Puhlic Health Service Research Grant (.\hI-05016) from t h e National Insritiite of .\rthritis and .\Ietaholic Diseases, U. S. Pul)lic Health Service. (21 RI. E. Ir-olff and G. Zanati, J . -\fed. Chem.. 12, 629 (1969).
7a-11ethyltestosterone3 was prepared in 40YG yield by an improved procedure and the reduction of the double bond in this compound was studied. Hydrogenation in the presence of Pt02 gave a product which had a negative C D curve and a negative Cotton effect in tlit ORD. I t mas assigned the $3 configuration 2 o n this b a s k 4 The formation of 2 under these conditionis consistent5 with interference by the axial 7a-Ale group to adsorption of the a face of the steroid on the catalyst surface. By contrast, reduction of 7a-methyltestosterone with Li in liquid S H 3 cleanly gave the 5a-dihydro compound 3, as shown by the positive C D and Cotton effect curves of the corresponding acetate 4. The formation of 3 under conditions giving the thermodynamically favored isomer is in accord with the repulsive interaction in 2 of the 7a-JIe group and the l a - H , which is absent in 3. (3) .J. A . Campbell and *J. C. Bahcock, J . Amer.. Chem. Sac., 81, 4069 (1969). (4) IT. Moffitt. R. R . Woodward. A . lloscowitz, IT. Klyne, and C. lljerassi, i b i d , , 8 3 , 4013 (1969). ( 5 ) R. P. Linstead, W. E. Doerine, R. 11. n a r i s , P. Lerine, and R. R. IT-lietstone, ibid., 64, 1985 (1942).
i
I , .
= OH; R,= H 12,R1=CH,;R2=H:R = O H ; R , = H 13, Ri CH,,;RL= H;R,s= OXC; R, = H 14. R , = CHI: R2= H: R ; R, = O 15. R, = CH ,; RL= H: R , = OH; R, = Me 16; R, =CH,; R2= H; R,=OH; R, = Et 17. R, = CHj; RL = CHj: R,>= OH; R,= H 18. Ri = CH ); R? = CH,,;R,,= OAc; R, = H 19. R i = CH 1: R?= CH ,; R,, = OCOCH,CH $;R,= H
hle
0.k
H
Me
OAC
H 20
21
Osidation of 4 with CrOl-HOAc gave diacid 7. Di:icid:, 5,6 6,' and 7 were converted into dibromide- 8, 9, :itid 10, respectivel?, and tlic.tice to the thia steroid. 11. 14, 17, 18, and 19 by t h e route3 uied previously? (hee Schrmt~I). 1 7 ~ y - ~ ~ lderivativel~\-l 15 and 16 vert. obtained from 14 t i ith A\IelIgBror Et Li.
Discussion Since the discovery of activit?-euhancing groups i n strroids. efforts have been made t o quantitate til(, ( 6 ) . I . I:. I3ielrnan and 31. iiajir. Bull. d o c . C h i m . Pi.., 441 (1962). 1); 1'. 31. 1)rolaifzky. 11. 13, l i a p a n . anti .T. J a c q r l P n . hid, ,548(1961)
.Jonmn/ of .Il(tlicina/ Chtmistrrl, 1.970, I’d.12, -Yo. .7 533
Compd (total dose, m r )
Castrate control Teitorterone pr(ipioiiate (0.3) P Testosterone (0.3) P 12 ( 3 , O ) h P 13 ( 3 , 0 ) h P 17 i S . O ) P 1s ( 3 . 0 )
--15ody Initial
Ventral prostate
l j . 8 f 1.51
12.6 i 1.21
2 5 . 2 f 3.54
40.7 f 5 . 4 7 ,01
1.5.3 i 0 . 8 8 0 .1
