268 Journal of Medicinal Chemistp, 2975, Vol. 18, N o . 3
and dried (MgS04). The Et20 solution was saturated with anhydrous HCI and evaporated to dryness in uacuo to yield 1.2 g (76%) of crude a-(fl-methadol hydrochloride (10). The nmr spectrum of crude 10 was identical with an nmr spectrum of an authentic sample of The crude product 10 was recrystallized with MeOHEtOAc to yield 1 g (64%) of 10: mp 199-200' (lit." mp 200-203').
Acknowledgments. T h e authors thank Dr. S. Smits and Dr. R. Nickander for biological testing, Ms. R. Billings who initially identified the primary amine metabolite, Mr. D. Cline and Mr. G. Maciak for microanalysis, and Dr. G. Wallace and staff for spectral data. T h e authors are especially indebted to Dr. N. Kornblum for stimulating discussions concerning formation and identification of the nitroalkane. References and Notes (1) R.E.McMahon, H. W. Culp, and F. S.Marshall, J . Pharmucol. Enp. Ther., 149,436 (1965). ( 2 ) R.E.Billings, R. N. Booher, S. Smits, A. Pohland, and R. E. McMahon,J. Med. Chem., 16,305 (1973).
A. Blake.. Llie . Sci ,. 14.. 1437 (1974); ( 4 ) A. Pohland. H. R. Sullivan. and H. hl. Lee. Abstracts. l X t h National Meeting of the American ('hemical Society, Sept 1959, p I , 5 i l For discussion on s~ereoclietnistryof niethaduls and a
i.3) 11. E. Billings, H E ~lcblahoti,and L)
methadols. see G. destevens, Ed.. "Analgetics," Academic Press, New York and London. 1965, pp 236 -238. M. G. Reinecke and R. G . Daubert, d . Org Chr.m.. 38, ,;?SI (197:3). Another report appeared after this wvtrrk was completed: ,I. .A. hlontzka, .J. I). Matiskella. a n d R. A . I'artyka. Tl'f~lralzedronL e t t . , l:?Zi 1974). S. 5 . Rawalay and H. Shechter, J O y ~ ' h < n .32, , ,il29 ;1967). A , .I V ~ i g e : "Practical . Organic, Chemis~ry.";id id, U'iley. Nwv 1 ork, K.Y.. 1956, p 1076. N.Koriiblum and u'.cJ. ,Jones, Org. S i n . , 4 3 , G (19ti;j). S. Smits, Res. Conimun. Chem. Pathol. Phnrniucoi.. 8. 575 (1974).
H. Nickander. K. N.Booher. and H. Miles. Life .+I.. 14, 2011 i 197-1i b:, I.. May and E. klosettig. .I.O r g . ( ' i i ~ m, 13, 459 (1948).
Synthesis of 15-Keto-GP,7~-rnethyleneprogesterone. Effect of the GP,7&Methylene Group on Mineralocorticoid Activity? Leland J. Chinn* and Bipin N. Desai Lkpartment of Chemical Research, Searie Laboratories, Di~'iszonof G I). Searle & Co., Chicago, Illinois 6'0680 Receiued October 15. 1974
15-Ketoprogesterone is as active as spironolactone in blocking the mineralocorticoid effect of deoxycorticosterone acetate. This activity is reduced when a methylene group is attached to the 68,7LI position. The title compound was prspared from 15a-acetoxy-6-dehydroprogesterone.Methylenation of the A6 double bond with dimethyloxosulfoniuni methylide proceeds stereoselectively from the'B side of the molecule. Information gained from metabolic and pharmacokinetic studies' and knowledge of the characteristics of various substituents2 have proved useful in the design of new drugs. By altering the biotransformation of a substance through structural changes, compounds with differing profiles of activity can be obtained. In seeking to develop more potent blockers of aldosterone, we have applied the knowledge acquired from the studies on the spirolactones to the development of antagonists which are structurally more closely related to progesterone. T h e latter substance had been shown by Landau, e t al., to block the activity of aldosterone when administered a t a high dose.3 Subsequently, Tweit and Kagawa showed that the antialdosterone effect of progesterone can be notably enhanced by introduction of an oxygen function a t C 15, either in the form of a keto or a @-hydroxygroup, and by insertion of a A1 or A6 double bond (la,b).4 This report is concerned with the attachment of a methylene group to the 6,7 position of 15-oxygenated progesterone derivatives and the effect which this group has on a n timineralocorticoid activity. Earlier we had found t h a t the spirolactone with a @-methylenegroup a t the 6,7 position (2) has a n activity somewhat greater than t h a t of spironolactone (3a).5Recently, it was reported t h a t a n inactive metabolite of spironolactone contains a hydroxyl group a t the 6p position (3b1.6 Attachment of a p substituent to C-6 would, of course, prevent hydroxylation from occurring at this site. Hence, the 6@,7fl-methylenegroup could be expected t o produce a desirable effect by this means. Alterna'Presented i n part at the 167th Xational Meeting ot the American ChemiSociety, L(is Angeles, Calif.. 1974.
till
tively, this effect could he produced by a-complex formation with the receptor site as a consequence of the unique electronic characteristic of the cyclopropane ring. Such a process had previously been proposed by Wolff, et ai.. t,o account for the androgenic effects of certain 2,3-methyleneandrostanes.; I t was our hope that the present study would provide some insight as to whether either of these processes is involved in blocking the effect of the mineralocorticoids. Methylenation a t the 6,'i position of a steroid is generally achieved by the addition of dimethyloxosulfonium methylide to a 3-keto-ldsc-dienone system. Previous investigators had shown that the methylenation of 6-dehydrotestosterone acetate by this procedure furnishes a pair of stereoisomers, 4 and 5 , of which the one possessing the ~nethylenr group in the p configuration (4) predominates. the ratio of' the @/aisomers being about 1.5:l..8,9 T h e starting material for our study was 15a-acetoxy-Gdehydroprogesterone (6). Addition of dimethyloxosulfonium methylide results not only in methylenation of the 6,7 double bond but also in oxirane formation a t C-20. Oxirane formation can readily be discerned from the upfield shift of the C-21 methyl group and the accompanying downfield shift of the C-18 methyl group in the nmr spectrum. T o prevent formation of the oxirane, the 20-carbonyl group of 6 was reduced with lithium tri-tert- butoxyaluminum hydride. Although the reduction was conducted a t 0". some reduction of the 3-keto group occurred. T h e allylic hydroxyl group at C-3 was selectively converted back to the keto group by means of dichlorodicyanobenzoquinone (DDQ). Treatment of the product ( 7 ) with dimethyloxosulfon-
16-Keto-GP,7P-methyleneprogesterone
Journal of Medicinal Chemistry, 1975, Vol. 18, No. 3 269
4;. /
,.'
4 R = OH; R = H b. R, R' = 0
2
0
II
R =H b, R = SCH,; R' = OH
3a, R = SCCH,;
of 11 having the @ configuration. Molecular rotation differences are also in accord with this conclusion. In the 6-dehydrotestosterone series, the introduction of a 6&7/3-methylene group results in a substantial negative shift (AMD -703) in t h e molecular rotation while a positive shift (AMD +287) is observed when the methylene group is attached t o t h e 6 a , 7 a position.a T h e difference in molecular rotation between 11 and the corresponding 6-dehydro compound 15 is -765. Of particular interest is the stereoselectivity observed in the addition of dimethyloxosulfonium methylide t o the 15u-acetoxy-3-keto-A4r6steroid. Although the yield in the methylenation process is only of the order of 35%, we believe our results do accurately reflect the effect which the 15a-acetoxy group has on the process; uit.,it causes methylenation to proceed preferentially from the 6 side of the molecule. An effort was made t o isolate the 6a,7a-methylene isomer b u t to no avail. Gas-liquid chromatography of the
I
0
8
0
.
I..
5
4
--OAc
r3;T"
--OAc
0 6
9
1. Li(@t-Bu)JlH
2. DEQ
L n
*
dPH
0
--OAc
7 ium methylide affords a mixture in which one product (8) is in preponderance according t o gas-liquid chromatography. Passage of t h e crude methylenated mixture through a column of alumina removes t h e highly polar by-products. Oxidation of t h e chromatographed mixture with Jones reagent a t room temperature furnishes a product (9) in which the 20-carbonyl group is regenerated. Hydrolysis of the acetoxy group occurs readily with sodium carbonate in aqueous methanol. Oxidation of the resultant l5a-hydroxy compound 10 with Jones reagent at Oo affords the 3,15,20trione 11. T h e double bond a t the 1,2 position can be introduced into 15a-acetoxy-6,7-methyleneprogesterone(9) with the aid of DDQ. Successive hydrolysis a n d oxidation as before yields t h e cross-conjugated dienone (14) with a keto group a t C-15 a n d a methylene group at C-6 and -7. T h e methylene group in this series of compounds was assigned t h e p configuration on t h e basis of spectral a n d molecular rotation d a t a (Tables I a n d 11).In t h e 6-dehydrotestosterore series, t h e 6&7@-methylenederivative 4 absorbs uv light maximally at 263 nm, a n d its C-4 proton signal appears a t 361 Hz in t h e n m r spectrum. T h e corresponding values for t h e Ga,Ta-methylene isomer 5 are 259 n m and 357 H Z .T~h e uv absorption maximum of 11 is 263 nm, a n d the chemical shift of t h e C-4 proton appears a t 360.5 Hz. These results are consistent with t h e 6,7-methylene group
270 Journal of Medicinal Chemisto, 1975, Vol 18. iVo 7
T a b l e I. Spectral Characteristics
T a b l e 11. Molecular Rotation Difference,
(MeOH), nm
4-H, iimr, Hz (CDCl,)
263" 264h
361" 360'
259' 262'
35VC 356b
263
360.5
Xm,
---
Structure 0 \I
