The hdamantyl Group in Medicinal Agents. Anabolic Steroid 178-Maniaiitoates
11.
‘ h e synthesis of several steroidai liP-adamanloate esters is described. ”lie ad:iiiurti!oic ester of 19-iiurlcw tosterotie produce& a profound arid unique effect on anabolic potency as compared Kith other esters. The long diiratiori of high rnyotropic activity with diminished androgeriic.it,y-ma!- be an indication that, the ester is act’irrg in toto as opposed to prior hydrolysis to the parent compound. The action of this anabolic ester over a period of several weeks after a single injection is confirmed by t h e radioactive :tniirioisobut,yricacid (AIB) C14 uptake data.
ULR.\TION
OF
TABLEI ~IYOTROrIc-AKDROGEsICRESPONSE TO ESTERSO F TESTOSTEROKE (T) AND ~ W ~ ~ E T H Y L D I H Y D R O T E S T O S T E R O (Xe-DHT) ~E
Dose, Compd.
T adamantoate ( I ) 4-C1-T adamantoate (11) T adamantoate-3-Me (111) Me-DHT propionate Me-DHT adamantoate
-5
( 7 ) days-LA b
mg.=
svb
6.4 10.0 8.0 10.0
31.3 1.7 (12.8) 30.3
SV
8 8 6.7 (1.6) 21.2
__-15 (18) days--s7\ LA
(14) days--
-10
L.1
33.7 1.4 (38.4) 35 3
18 3 9 3 (-3 0) 38.6
----23
(-0.1)
(22,s)
LI (-0.2) -11.1 (-0.8) 44.1
(29.0) -0.5 (34.3) 27.4
0 ,8
32 0 (-0.6)
( 2 8 ) days---
SV
(21.1)
13.0 18 4 3 4 1:;. 7 0.5 (3.5) (7.2) 5.4 0.9 (IT) hIe-DHT adamantoate8.0 (0.7) (14.4) 3-lIe ( V ) (2.8) (5.4) (-2.1) (-13.0) fl Single sitbcutaneons injection in 0.2 nil. of eit,her 0.55; c . a r t ~ o ~ ~ r i i e t l i ~ l ~ ~fe i rl l,esanie u l o ~ e oil. lllilligrani increase of seminal vesicles and levator ani over control; aver:tge of 5 aniinals/group. TABLEI1 ljUR.\'I'IOX
O F R I Y O ' l . R O l l I c - A N u I t O ~ E h . l ~ 11ESPUh.
Dose, Cor11pd.
mg.O
-5 (7) daysSVb LA*
-11
sv
XT adaniantoate (\;I) 8.1 12.0 18.1 S T adaniaritoate-3-AIe (VII) 8.4 2.5 14.6 NT adamantoate-3,5-Mez (VIII) 8.7 3.8 7.3 8. 0 ( - 0 . 8 ) ( - 8,Y) 4-C1-NT adamantoate (IX) Single sitbcntaneous injection h i approxiinately 0.2 nil. of over control; average of 5 aiiirnals/gronp.
RUNE
-18
(14) day5-
( 2 1 ) days-
Lh
sv
9.3
23.9
6.3
17.7
4.9 (I). 6)
3.4
-23
(ST)
(28) days-
r
'48&ysL.1
sv
SV
L.l
5 . 5 30 4
9.4
73.8
9.6
73.1
5.4 l5,l
3.5
1, 3
1.6
12.5
LA
1.5
6.1
1.3 -!3,*5 2.6 -1.4 ( 4 6 ) (-0.3) -1.8 lX3 hIi1ligrani iiicrcase of seminal vesicles arid levator ani
( -1,6)
seaanie oil.
TABLE 111 DURATIOX OF RIYOTROPIC-AKDROGEXIC RESPONSE TO L O T G - ~ ~ C TESTERS IKG Dose, Compd.
mg.a
-1 weekSVb LAb
-2
sv
weeksLA
-3
sv
weeksLA
-4
SV
weeksLA
-6
sv
weeksLA
-8
sv
weeksLA
19-Nortestosterone 8.0 5 . 5 26.4 6 . 8 36.9 11.2 58.1 18.8 75.4 8 . 8 103.6 9 . 4 97.3 adamantoate (VI) 19-Xortestosterone 7 . 5 100.8 39.9 137.9 6 5 . 1 8 2 . 6 69.8 3.6 3.7 phenylpropionate (X) 19-Nortestosterone n-decanoate (XI) 8.0 5 5 . 7 45.4 48.2 6 4 . 3 57.5 '38.8 67.1 98.5 104.2 134.9 72.6 83.7 4-OH-19-nortestosterone c y clopentylpropionate (XI11 7.7 35.9 40.2 34.1 39.8 80.5 57.0 37.8 47.4 5 Single subcutaneous injection i n approximately 0.2 nil. of sesame oil. * Milligrani iiicrease of seminal vesicles aiid levator alii over control; average of 5 animalslgroup.
mature castrate male rats. The data are reported in Tables 1-111 and Figure 1. As seen in Table I, testosterone adamantoale (I) shows a good myotropic response as measured by levator ani muscle weight increases in 10-14 days while the 3-methyladamantoate ester (111) does not. Furthermore, the activity of I diminished rapidly by the 28th day. The anabolic activity of the 2a-methyldihydrotestosterone esters (IV and V), however, is greatly reduced. I n the 19-nortestosterone series included in Table 11, 19-nortestosterone adamantoate (VI) produced a highly significant levator ani resporiqe at all time periods studied, while a t each time the seminal vesicle response was only minimal. The myotropic response persists beyond the 48-day test period. The 3-methyl- and 3,s-dimethyladamantoate esters (VI1 and VIII), however, are much lower in potency. The effect of the unsubstituted adamantane esters is superior to that of the 3-mono or 3,S-dimethyl analogs both in regard to duration arid intensity of effect. Similar results were evidenced in the K'adamarityl-K'-aryl-sulfonylureas6 in which the unsubstituted adamantarie moiety also produced the most
active ageiit. From these data, it al)ljears that the iiiost aljproljriat e steroid for esterification with adamailtoic acid is 19-nortestoiterone. 111 order to coinpare 19-nortestosterone 17p-sdamantoate (VI)13b with
&
oco@
w VI
0
several other long-acting esters, an anabolic st udy was followed for a period of 8 weeks after a single subcutaneous injection of the compounds described iri Table 111. For 19-nortestosterone adamantoate, the ratios of the levator ani to seminal vesicle responses a t each time period were significantly higher than those of the other esters. The phenylpropionate ester (X) appears to peak in myotropic artivity at 4 weeks, the decanoate ester (XI) in 6 weeks, arid the cyclopentylpropionate (XII) in 3 weeks. Furthermore,
-
,
.i,ll
I
I.,? 1
I.
E I
0
;:i..j
-
5 ,{.I) "..i2.11-
I . i-
~
L A CONTROL-----
19-NORTESTOSTERONE l?.-ADAMANTOATE 8 MG DOSE19-NORTESTOSTERONE l?d-DECANOATE 8 N G DOSE .............
1 1
---% Coxnpd.
I I1 I11
Steroid
17pEster
AI p . , " C .
Testosterone 4-Chlorotestosterone Testosterone
17p-Adamantoate 178-Bdamantoate 3-Me t hyl-1 78adamantoate 178-Adamantoate 178-Adamantoate
217-220 304-306 168-170
1-11
4-Bromotestosterone AI-Androsten-( 5a)178-01-3-one 2a-Methyl-5a-androstan-178-01-3-one 201-Methy1-5a-androstan- 178-01-3-one 19-Xortestosterone 19-Kortestosterone
iI11
IO-Sortestosterone
IX
4-Chloro-19-nortestosterone
IV T'
TI
---%
calcd.---
found---
H
C
H
C30H4203 C30H41C103 C31H4403
79 95 74 27 80 13
9 39 8 51 9 55
79 73 74 31 79 55
9 44 8 59 9 96
222-224 216-219
C30H41Br03 C30H4203
68 04 79 95
7 80 9 39
68 85 79 50
8 04 9 40
178-ildamantoate
223-226
C31H4603
79 78
9.94
79.84
9 85
3-3Iethyl-178adamantoate 178-Adamantoate 3-3Iethyl-l'ipadamantoate 3,5-Dimethyl-lipadamantoate 178-Adamantoate
209-211
C32&03
79 95
10.07
80.13
10.35
203-206 159-161
C?gH4003 C3oH4203
79 i 7 79 95
9 23 39
79 65 79 83
9 30 9 40
tion was allowed t,o reflux for 18 hr. After cooling, 100 ml. of chloroform and 50 ml. of water were added. The layers were separated, and the organic layer was extracted sliccessively with water, lyGaqueous HC1, and water, and then dried (Na2G04). Evaporation of the organic solvent yielded a residue which upon trituration with ether gave crystalline material (1.8 g.), m.p. 246247'. Recrystallization from ether several times afforded +66.55'. ~ the analytical sample, m.p. 265-267' dec., [ a ] 2 5 Hydrolysis. A.-To 200 mg. of 19-nortestosterone 178cyclohexylcarboxylate dissolved in 20 ml. of methanol was added a solution of 0.2 g. of KOH in 0.5 ml. of water. After being allowed to reflux for 2 hr., the solution was cooled and then neutralized with glacial acetic acid. Water (20 ml.) was added, and the solution was extracted with three 100-ml. portions of ether. The combined ether solution was washed successively with dilute Pja2C03 solntion and water, and was then dried (NatSOa). Evaporation of the solvent afforded 162 mg. of a viscous residne which slowly crystallized. Thin layer chromatography (silica gel; chloroform-ether, 1: 1) indicated the presence of 19-nortestosterone and the absence of lip-ester.
Formula
(3
C
B.-When 200 mg. of 19-nortestosterone 178-adamantoate ( V I ) was h a t e d in the identical manner as above, there was recovered, upon addition of the Nrater, crystalline ester (190 mg.), n1.p. 203-205'. 19-Sortestosterone 17p-adamantoate (200 mg.) in 20 ml. of methanol was t,reated with 2 g. of XOH in 1 ml. of water, and t'he sohition r a s refluxed for 2 hr. Cooling, neutralization, and the addition of 20 ml. of water precipitated 105 mg. of ester, m.p. 193-107". The filtrate was evaporated to a smaller volume to remove methanol, and the solution was then extracted with ether. The organic sollition was washed with salt solution, dried (Na2S0,), and evaporated to a viscous residue (100 mg.). Thin layer chromatography showed that this residue consisted of 19-nortestosterone and some unhydrolyzed ester.
Acknowledgment.-The authors wish to express t'heir gratitude t,o Mr. E. Krumkalns for stimulating discussions as well as for supplies of the adamantoic acid chlorides.
Synthesis of w(pAminopheny1)- and a-(p-Chloropheny1)-0-arylpropionitriles by Catalytic Reduction of Stilbenenitriles GORDOSN. WALKER T h e Chemical liesearch Division, CIBA Pharmaceutical Company, Division of C I U J Corporation, Suwnit, S e u : Jersey
Received October 16, 1966 Hydrogenation of a-(p-nitropheny1)-8-arylacrylonitriles in the presence of palladiun-charcoal in ethyl acetate solution gives a-(p-aminopheny1)-8-arylpropionitriles. The bearing of some of the results in this work upon earlier reductive cyclization of o-nitrophenylacetonitriles is discussed. Two compounds, 01-( p-aminopheny1)-p(3-pyridy1)propionitrile and the similarly prepared a-(p-chlorophenyl)-fi-( 3-pyridyl)propionitrile, affect adrenal cortical steroid secretion.
The 1,l-diaryl- and I ,2-diarylethylenes and -ethanes, notably st'ilbestrol and its relatives, have been of interest in endocrinology for some tin1e.l Recently the field m a s given some new impetus by studies of adrenocortically active, similar basic ketones, the amphenones,*-' amphenone-related pyridyl ketones (1) J . A . Hogg and .I. Korman in "Medicinal Chemistry." Vol. 2, F. F. Blirke and C . RI. Huter, I M . , .John \Viley and Sons, Inc., New York, N . T., 1956, Chapter 2. (2) M. J . Allen and -4. H. Corwin, J . Am. Chem. Soc., 7 2 , 114, 117 11950). (3) W. L. Bencze and M. J. Allen, J . Org. Chem., 2 2 , 352 (1957). (4) W. L. Bencze. L. I. Barsky, M. J . .411en, and E . Schlittler, Helu. C h i n . Acta, 41, 882 (1958).
(e.g., metyrapone and relatives) ,*-lo arid aniinoindenes.6 There also have been recent further studies of the wellknown, weakly estrogenic stilbenenitriles'l in the di( 5 ) J. B. Wright and E. S. Gutsell, J . .4m. Chem. SOC.,81, 5193 (1959); J. B. Wright, U.S.Patent 2,881,216 (1959). (6) W.L. Bencze and M. J. Allen, J . M e d . Pharm. Chem., 1, 395 (1959). (7) J. J. Chart and H. Sheppard, ibid., 1, 407 (1959). (8) W.L. Bencze and 11. J . Allen, J . Am. Chem. Soc., 81, 4015 (1959). (9) Vi. I,. Bencze, C. A . Burckhardt, and \Ir. F. Yost, .I. Org. Chem., 2 7 , 2865 (1962). (10) J. J. Chart, H. Sheppard, 31. J. Allen, K.L.Bencze, and R. Gaunt, Ezperientia, 14, 151 (1958). (11) J. B . Niederl and A. Ziering, J . Am. Chem. Soc., 64, 885 (1942); see also S.Wanzonek, z6id., 68, 1157 (1946).
