RING-D-BRIDGED STEROIDS.T'
Soveniber 19G7
1049
$fpJCF
-
CF
F C=CCF
RO
ACO
\
IIa, R = CH,CO b. R = H
I
/
I11
RO
IVa, R = CH,CO b, R = H
v
The low Clauberg activity of 14a,17a-ethenopregn4-ene-3,20-dione compared to that of 17a-ethylprogesteronezl was at first surprising in that the activity of these compounds supports the viewzz that interaction of a gestagen with a Clauberg receptor does not involve the a side of the gestagen, at least in the vicinity of t,he D ring. Moreover, both compounds should be resistant to metabolic degradation of the side chain, and they should have comparable polarities. However, insertion of a two-carbon bridge between the 14a and 17a positions of progesterone requires a small deformation of the D ring which results in the 17-acetyl group being deflected toward the CY side. Considerat'ion of possible reasons why such a deformation might result in a lowering of Clauberg activitj7 led us to the following hypothesis: if a plane, parallel to the average plane of a gestagen, is imagined to pass through the critical A ring and C-17 substituent^,^^ then, for maximum Clauberg activity, the protrusion of the molecule above the plane,
in the vicinity of the A/B junction, should be minimal. Activity seems to decrease as the bulk in this region increases and to disappear entirely as the height of the protrusion exceeds that of the lop-methyl group of progesterone. On the other hand, in the vicinity of the C/D junction, optimum activity requires that a group protrude above the plane at least as far as the 13pmethyl group of progesterone and preferably as far as a 13p-ethyl group. This rule is concerned only with the fit of the gestagen to the Clauberg receptor site and not with the shape of the molecule in its most stable conformation. Therefore, in applying this rule, the molecule must be viewed in that conformation which places the critical A- and D-ring substituents closest to the positions which they would occupy in progesterone or in ethisterone. We believe that this hypothesis not only correlates the activities of all normal progesterone and ethisterone analogs, but that it also accommodates skeletal isomers, such as the retroprogesterone~.~~ I n addition, it accounts for the fact that 14-iso-17-isoprogesterone is inactivez5while the corresponding 19-nor compound is highly active,26since in these compounds both the 10 and 14 positions are unusually far above the hypothetical plane. The presence of a 100-methyl group in such a situation presumably leads to prohibitive steric interaction with the receptor. The shape of the p face of our l 4 a ,17a-ethenopregn-4-ene-3,20-dione is strikingly similar to that of 14-iso-17-isoprogesterone, thus suggesting that the lorn activity of our ring-D-bridged compounds is due, at least in part, to greater than normal unfavorable interaction of the lop-methyl group with the receptor. A corollary of the above hypothesis is that the 13p substituent is not a specific binding point for the Clau-
(19) Biological testing was performed a t t h e Endocrine Laboratory, hladison, N-is. (20) Graphical estimate a t 2 . 0 + response level. (21) (a) R . Deghenghi, C. Revesz, a n d R . G a u d r y , J . M e d . Chem.. 6, 301 (1963); (b) M. J. W e k a , R . E. Schaub, J. F. Poletto, G. R. Allen, Jr., a n d C. J. Coscia. Chem. Ind. (London), 118 (1963). (22) H. J. Ringold in "hlechanism of Action of Steroid Hormones," C. A. Villee a n d L. L. Engel, E d . , Pergamon Press, Oxford, 1961, p 200.
(23) T h e critical C-17 substituent is usually t h e oxygen either of a n acetyl group or of a tertiary alcohol. T h e -4-ring substltuent is generally a double bond a t t h e 4 position. Both of t h e critical groups muat be available for pface binding. (24) H. F. L. Scholer, Acta Endocrtnol., 96, 188 (1960) (25) P. A. Plattner, H. Heusser, a n d A Segre, Helu. Chtm. Acta. 91, 249 (1948). (26) G. I T . Barber a n d M. Ehrenstein, Ann., 609, 89 (1957).
of 14a,l7a-ethenopregn-4-ene-3,20-dione,1 111, and V to immature estrogen-primed rabbits under the conditions of the modified Clauberg assay.l9 Histological preparations of uterine tissue were examined and graded from 0 to 4+ for degree of progestational proliferation.'Q The more extensive testing, reported here, indicates that 14a,17a-ethenopregn-4-ene-3,20-dioneis only about 54%zo as effective as progesterone in the Clauberg assay, rather than several times as effective, as found in the preliminary assay.' Introduction of the 1,5,16-di(trifluorometh?.1) groups results in a loss in activity, but the effect is not as great as that produced by a lh-carbomethoxy group.5
Discussion
III
herg receptor.2i This view is supportecl hotti hy the tionnl change might reiult either ill the c'rcx;itioli 01' (iofact 11i:~t hi~~~iolopat~ic~~i of t l i c l:$-nmctli>.l group of' 3>4,4aq4b.3>6, 7.9. 10,10n-dodecah~dropher1aiithreri~~ has appreciable Clauberg The lack of :IIL int:ict, 1.1 ring increases the ent,ropy of thp "C-17" suhstituerit arid may thus compensate for tlie lack o f :L "lXp-substituerit" in this compound. -1wcotid possible csplanation of the role of tlie 13p substituent is that i t :tcts as a wedge in the sense that it, protrudes into thcl receptor site it] such a way :is t o force :ic~c)tifornm:Ltioti:il rhatige in the receptor niolocule. j Stirli x confornin( 2 i ) It
1 8 not a s p t ~ c i t i cbindini. point in tile aen-e t i d e r tf'aals forces. (281 ( a ) K. A , I~:dgren. H . Sniitii, 11. I.. I ' r t e i s ~ n a i i i l I ) . I , , ( ~ a r i r . 1 , S t e ~ o i i i s ,2 , 319 ( 1 9 6 3 ) ; It)) ethyl acetate.
1031
~~,6-~IaRrr,HrDROn.APHTI-rALEn-oNEs AS , ~ S T I F E R T I L I T Y- 4 G E S T S
(
,t allixat ioii from acetone-hexane
gave
I11 in a yield of Y88 mg (62(,;) as fine white needles: mp 184.5vNujot 1710, 166.5, arid 1620 (m-l. The vinyl proton. :rlq)e:tretl ill the
iiinr :it 6 3.77 ( a ) : t i i d 7.01. A n a ( . Calcd for C1:If&602: C, 63.56: H, 5.31; F, 24.15. Foiund: C, 63.31 : IT, 3.X3: F, 23.92. 14a,17a-Ethano-15p,16p-di( trifluoromethyl)pregn-5-en-3p-ol20-one Acetate (IVa).-A wlutioit of 2.46 g of I I a in 200 ml of niethatiol plus 5 ml of water was hydrogenated over 256 mg of 10'( Pd-C at 3.66 kgjcni2 aiid room temperature for 12 hr. i\fter the catalyst had beeti filtered off, the solveiit was removed iinder redirced pressiire. The re>idiie was crystallized from hexane t o aftord I\.a, i l l a yield of 2.14 g (84%), as graniilar particles: mp 143-146': Y N u j o i 1730, 1707, and 1642 cm-'. The C-6 vitiyl proton appeared in the iinir at 6 5.42 (m). Anal. Calcd for C?;H:d&: C, 62.30; H, 6.58; F, 21.92. Foiuid: C, 62.54; 11, 6.39: F, 22.02. 14a,17a-Ethano-15p,lGp-di( trifluoromethyl)pregn-5-en-3p01-20-one (IVb).-A solution of 2.01 g of IVa, 2.05 g of KOH, and 5 ml of water in 55 ml of methanol was stirred a t room
M a m m a l i a n Antifertility Agents. D.4STEL
teniper:ti tire f o i , 24 hi.. Afier si aiidaid work-iip ( h e r i ~ i t l cIii,otliict ti from :ic.cioiir-hrsaiie t o a f f o d I\.t>,i l l ii J.ield ), a s t i t i > . white twis: irip l!~4-195°: ~ y l l l n l:$,j43, 1701, and 1643 cn1-I. The vinyl pvotnii a p p e a i ~ di n t hr nmr spectriim at 6 5.40. .-lnul. Calcti fur C2;H3&601: C, 62.76; H, 6.69. Foiind: C,
63.00; H , 6.37.
14~~,17a-Ethano-l5p,16@-di( trifluoromethy1)pre dione (V).-A solutioii of 1 .24 g of IVb, 12.0 ml of and 150 ml of tolueire m-as azeotroped as described for 111, 1.24 g of alumilium iropinpoxide was added, and refluxing iwiinied foi, 2 hr. iifter standard mwrk-up the residue was partitioiled between ether and HC1. The residue from the ether solution was chromatographed over 40 g of 1Ierck acid-washed alumina. Fractions eluted by passage of 400 ml of benzene followed by 400 nil of benzene contaiiiing 3ET)XICER, D. EDWARD EIIJIERT,GORDOX IT.DUNCAX, A N D STASLEIc. I,i-hrrEH Ircarnrrh Lnhoratmire, The T-pjohn Companrj, Kalnninzoo, .lltc.higan
$!"I2
Rereinred Jiine 6, 1967
A4series of derivatives of 5,8diphenyltetra- and -hexahydronaphthalenes was prepared, incorporating such features as carbonyls in the 2 position and an angular methyl group a t 4a. Several of the compounds are active as antifertility and uterotropic agents.
I t is well known that estrogenic responses are elicited by many organic molecules devoid of the steroid n u c l e ~ s ;suitable ~ modification of such structures has led to the development of an impressive array of structures which, at least in laboratory animals, will act as estrogen a~itagonists.~Except for a few reports of nonsteroidal a~idrogens,~ no similar success has met attempts to prepare nonsteroidal counterparts of the other gonadal hormones. I n the steroid wries, reduction of the aromatic A ring of ethynylestradiol to the corresponding %oxo derivative leads from a potent estrogen to a compound which exhibits many of the properties of a progestin. The observation that certain derivatives of 1,2-diphenyldihydronaphthalenes are potent estrogens5 prompted US to prepare the counterparts of those compounds in which the moiety corresponding t o the steroid A ring was reduced to a ketone. Our initial approach consisted in the straightforward reduction of the conjugated double bond by lithium in liquid ammonia (see Scheme I ) . Compounds 1 and 2 were treated with a controlled amount of the metal in ammonia to afford the tetralins 3 and 4; the observed 3-cps splitting constant for the proton at position 1 (1) Previous paper in this aeries: D. Lednicer, S. C. Lyster, a n d G . W. Duncan, J . .Wed. Chem., 10, i s (1967). (2) J. A. Hogg a n d J. Korman. "1Iedicinal Chemistry," 1701. 11, J o h n IViley a n d Sons, Inc., N e w I-ork, N . Y . , 1956, p 34. (3) F o r a recent review see D . Lednicer, Ann. R e p t . M e d , Chem., 2, 199
SCHEME I LITHIUM-AVMONI i R E D C C T I OOF N~ 1,Z-nI i R Y L - 3 , 4 - D I H Y D R 0 - 6 - ~ I E T H o X Y ~\PHTHt L E N E S
& &( C d H , orId-"H,-Pd , ,
CH,O
CH30
\
I,R=H 2, R'OH
'
3, R = H 4, R=OH
I
Li-"3,
R
7, R - H 8, R-OH
CdH,
R'OH
R
5, R-H 6, R-OH
leads to the conclusion that each of these has the czs ConfigurationP Support for this stereochemical assignment comes from the observation that catalytic reduction of 2 leads to a sample of the reduced product ident'ical in all respects with that obtained from t8he lithium-ammonia reduction. This departure from the
(1966). (4) See, for example, R. I. D o r f m a n a n d D. Stevens, Endocrinology, 67,
394 (1960). (5) D. Lednicer, S. C. Lyster. B. D. hspergren, a n d G. W. Duncan, J . ,Wed. C h e m . . 9 , li2 (1966).
(6) W. L. Bencze, R. IV. J. Carney, L. I. Barsky, A . A . Renzi, L. Dorfman, and G. deStevens, Ezperientin, 21, 261 (1965): these authors repurt a J value of 5 c p for ~ a n analogous system.
