ANABOLIC STEROIDAL OXADIAZOLES
May 1966
327 SCHEME I
3.O
I
2 .o
1.0
0 I
I
‘
0’ \ H -fi&
3.0 I
Figure l.-Nmr
,
2.0
1.0
\/
fJ
spectra of compounds 4 (top) and 5 (bottom).
and co-workersZcdescribe similar activity in certain steroidal isoxazoles such as 17a-methyl-5a-androstano[2,3 - 4 [ 1’,2’,3 ’]isoxazol- 17p-01(1b) ,
17p-01 N-oxide (5) by treatment with sodium hypochlorite.4b Likewise, 2,3-dioximino-5a-cholestane (6) was prepared from 5a-cholestane-2,3-dione (2b). Analogously ?H ?H 6 was converted to 5a-cholestano [ 2 , 3 - c ][1’,2‘,5’]oxadiazole (7) by treatment with ammonium hydroxide and sodium hydroxide, or to 5,-cholestano[2,3-c][1’,2’,5’]oxadiazo1e N-oxide (8) by treatment with sodium hypochlorite. Nuclear magnetic resonance spectral analysis of the la lb six compounds confirmed their structures.j As expected, the oxadiazole X-oxides were found to be apWe wish to report the synthesis of isosteric steroidal proximately 1: 1 mixtures of the isomeric 2’- and 5’-Xoxadiazoles (4 and 7) and their N-oxide analogs (5 oxides. Figure 1 illustrates the nmr spectra of 1 i a and 8). Subsequent to the completion of our synthesis methyl-5a- androstano [2,3-c][1’,2’,5’]oxadiazol- 170- 01 program, compounds of the type 4 were reported to (4) and 17a-methyl-5a-androstano [2,3-c] 11’,2’,5’]oxapossess excellent oral anabolic activity with a favorable diazol-170-01 N-oxide (5). Significantly, the C-19 myotropic/androgenic ratio. methyl of the N-oxide appeared as a doublet of apScheme I illustrates the synthesis route employed. proximately equal intensities, the downfield peak at 2,3-Dioximino-17a-methyl-5 a-andros t an-170-01 (3) was 50.5 cps representing the 2‘-K-oxide interaction with prepared from 17a-methyl-5a-androstan-ol-l7p-2,3-di- the C-19 methyl group. The shifts observed for the one by treatment with hydroxylamine. ConiC-1 and C-4 methylene protons likewise confirmed the pound 3 was converted to 17a-methyl-5a-androstanoisomeric N-oxide mixtures. A similar spectrum was [2,3-c][1’,2’,5’]oxadiazol-l70-ol(4)by treatment with obtained for compound 8 but it did not shorn the C-19 ammonium hydroxide and sodium hydroxide,4b or methyl splitting as the region around 50 cps \vas more to 17a-niet~hyl-5a-androstano[2,3-c][ 1’,2’,5’]oxadiazolcomplicated than for compound 5. Compounds 2-6 and 8 were tested for androgenic (3) G. Ohta. T. Takegoshi, T. Onodera, A. Kasahara, Y. Oshima, RI. dhimisu, a n d K. Ueno, South African P a t e n t 641,540 (April 1, 1964). and anabolic activity according to Hershberger, (4) (a) B. Cemerino, B. Patelli, a n d R. Sciaky, U. S. P a t e n t 3,068,229 (Dec 11, 1962); (b) J. H. Boyer in “Heterocyclic Compounds,” Vol. 7, R. C . Elderfield, Ed., John Wiley and Sons, Ino., Kew York, iX,Y.,1961,
p 462.
( 5 ) W e wish t o thank Dr. Leonard R. .\xeirod for obtaining these spectra and M r . William H. Storey, Jr., for their interpretanon.
40
P
1
0.73
1.50 2.25 Total dose my.
17a-MethyI-Sa:-androstano[2,3-cjjl',2',5'joxadiazol-l7$-ol NOxide (5).--2,3-l~ioximino-licu-methyl-5a-:~ti~~ro~t:~ri-l7~-11l f 3. 6.0 g, 0.016 mole) was dissolved in 400 ml of 3 : 1 ethanol -1 I?( ) of NaOH. After c.ooliiig to O', 1.0 1111 ot itiori saturated with ("1: WIS u t l t l t ~ l \\,ill1 tit, bright yelluw mlor OF thc. NsOtl- o s i i i i t l mlurion wah proniptlj- discharged after the :iddiiioii of Ili.-20 1111 of the suO('1 solution. Thr mixturr w t s :dlon.f!cl t o G l i r jot, I Iir after thc additioti was conipletrd. Aftrr tiilutioii wil,li 1 1. of w t e r , the solution was cooled aiid the precipitiitc w t - [ , ( I ] Iwtrd. Chromatography on iieutr:tl alumina. follorwd 1)). r r ) ~ - l : ~ l lization from aretonr yielded 5.0 g of c.olorless g r a i ~ r i l r ~ :i i i p 175-178'; An,;ix ,..IS,6.16, 6.83 h. The r i m S ~ ~ ~ ~ I I I oI fI i l l ( ' product iiidicntrci 3 mixture of the isomeric, 2'- :ind >'-X-osidw (Figure I ) . :In(iL. (!dcd for C20~l:+oSzOa: C'. O ! ) . J X : 11, \.!KJ: N, Y.li(i, Found: c', 69.48; 13, 9.00; K, 8.16. 5a-Cholestane-2,3-dione (2b).- --Twom c t h ~ ~ ca ~e rs r cti~p111yc~l
Figure ,.-.liiat~olic~-:riidri~~eiiic uctivif y of cumpoiitid 4.
et ~ l . t)y , ~ wbcutaiieouy diiiiiii~tratioiito castrated
21-day-old male rat.. The rehults obtained indicated thnt all the coiiipounds poqse compared to teitostcrone, the anabolic-inyotropit. activity wa.; iubstaiitially enhanced while the androgenic activity n :LS appreciably lowered. Studies designed to detcriniric the oral activity of these oxadiazoles are ill 1)rogresyaiid will lie reported at a later date.
Experimental Section7 17a-Methyl-5a-androstan-l7~-ol-2,3-dione (2a) was prepared in 605; yield by the method of Camerino, et al., using 1ior-mechyl-jru-androstaI~-l7@-ol-:3-orie,potassium t-butoxide, aiid oxygen in f-butyl alcohol; mp 202-203" (lit.4 183-1234'); A,,,, 2.78, 2.90, 5.75, 6.00, 6.10 p ; A ~ ~ ~ 269 , O "mp; FeCI3 teat, positive. 2,3-Dioximino-17~-methyl-5a-androstan-l7@-01 (3).-To it d u t i o n of 6.0 g (0.019 mole) of 17a-methyl-5a-androstan17p-ol-2,,B-dione in 200 ml of ethanol was added a twofold mole e s w s of XH20H.IIC1 and KOH. The solution was refluxed 30 min after which time 25 ml of water was added and reflux continued an additional 30 min. The turbid mixture was diluted with 1 I . of water :md rooled, and the precipitate was collected. l~ecrystallizationof the Thite solid from ethanol and water gave 6.1 g (0.0164 mole) of 3 which melted above 256" dec (lit.3 2:i4-235'); ::A: 3.0, 3.19, 6.05-6.20 p. .lnal. Calcd for C20H32N20b: C, 68.93; 11, 9.50; N, 8.00. Fontid: C, 68.95; 13, 9.42; N, 8.08. 17~-Methyl-5~-androstano [2,3-c][ 1 ',2',5']oxadiazol-17p-ol (4). ~,3-l~ioximino-17a-methyl-:ia-androstan-l7~-ol (3, 9.0 g , 0.0'24 mole) was heated in an autoclave with 500 ml of concentrated NHaOH and 20 g of S a O H for 12 hr at 160". The product was collected by filtration and/or extraction with ether. Purifimtiori by crystallizat.ion from benzene -petroleum &her ( b p 40-60") gave 5.0 g (0.015 mole) of 4: mp 152-154°;3 A,,,,, 2.79, 3.42, 6.91, 7.15, T.24, 7.37 p . ;L?~al. Calcd for C?013,1iV~O,: C, i2.47; H, 9.43; N,6.45. 1;ound: C, 72.46; H, 9.32; N, 8.46.
cipitate vas c,r)llecicxi. The solid was recrystallized from rt ti:itiol and water t i , yield :;.I g (0.0066 mole): nip abovc L'Z>" t l i s c . : : ; : 1 "W, X l S
