Journal of Medicinal Chemistry 0 Copyright 1974 by the American Chemical Society
April 1974
Volume 17, Number 4
Diarylcyclobutane Analogs of Diethylstilbestrol John E. Lawson,* Ronnie D. Dennis, Robert F. Majewski, Department of Chemical Research
and Duane G . Gallo Department of Pharmacology, Mead Johnson Research Center, Euansuille, Indiana 47721. Received July 23, 1973 Several 1,3- (and 1,2-) diarylcyclobutanes related to diethylstilbestrol have been prepared. Two compounds, 1,3bis(p-hydroxypheny1)cyclobutane and its monomethyl ether, showed weak estrogenic and antifertility effects in rats.
Chemistry. The 1,3-diarylcyclobutanes (1) were preNonsteroidal estrogens can be used for a variety of purpared according to Scheme I. Conversion of styrene itself poses. In particular, diethylstilbestrol (DES) is effective to ketone 6 had been reported by Silversmith, et U L . , ~ and in treating cancers of the prostate' and breast2 and in that particular procedure worked for us just as described. controlling various disorders of women.3 Recently, DES The use of p-methoxystyrene to prepare ketone 7, howwas used successfully as a postcoital contraceptive agent ever, required several modifications to cope with the acid in sensitivity of the intermediates. The ethylene unit connecting the phenolic rings of DES can be modified in many ways with retention of estrogenic Scheme I activity.5-7 It occurred to us that a cyclobutane ring might effectively replace that ethylene unit. A study of Dreiding C12C=CF,, models indicated that the aromatic rings and phenolic hydroxyl groups of either tram-1,3-bis(p-hydroxyphenyl)cyclobutane (tram-la) or tram-1,2-bis(p-hydroxyphenyl)cyI R = H, OCH, Cl2 clobutane (trans-2a) can be nearly superimposable upon 3, R = OCH, those of DES. To learn if these cyclobutanes would in fact LKOH. EtOH
Et
I
C1
Et DES
5, R
= OCH,
M e O H , H,/Et,N.
la. R
0 -R
= R' = OH
4, R = OCH, Pd/C
+C
/ \
H 3 O a o C H 3
OCH, 6, R = H 7, R = OCH,
0
1
2a, R = R' = OH
R ' C ~ H , M ~(io) B~
behave at least qualitatively like DES, we prepared both of them and several of their derivatives and tested them for estrogenic and postcoital antifertility effects. All examples of 1 actually were obtained as mixtures of cis and trans isomers, while all preparations of 2 were formed as single isomeric entities. Two dialkylaminoethyl ether derivatives of l were prepared because some similar derivatives of DES analogs were found to be antiestrogenic.s All of the diarylcyclobutanes prepared are listed in Table I.
HCIO,. EtOH
9a, R = R' = OCH3
b, R=OCH,; R'=CYIW'
1
383
384 Journal o f Medicinal Chemistry, 1974, Vol. 17, No. 4
NO.
la lb IC Id le If 1g lh li 9a 9b 2a 2b 2c
___
Isomer ratioa
R
-
60:40 60~40 60:40 50:50 70: 30 60:40 Trans Cis Trans
R" = o k r
If
HO HO HO CH30 CHI0 OCHyCHpNEt2 OCHyCHyNEt2 CHjCO, KOsS CHaO OTHP HO CHI0 CHiO
'
L
D B D C B C C
67 67 68
A B-C D
34
55 4
26 82 7'
B B-E B-E B
c
A A
36 62
D
71
A
70 75
G
~-
l 2
HePrep Yield,', crystn method 7% solventc
.-
HO CHZO H H CHyO H CHyO CHiCO? KOyS CHSO CHaO HO CHaO CHiO
50:50
E''
R'
-
I
1.
9.
=
Lawson, Dennis, Majewski, Gallo
F D
M p or bp (rnm),'j "C
Formula
148-163.5 96-110 69.5--79.5 108-114 . 0 , 01 mm) 63-83 115-127 147.5-150.5 76-87.5 264.5-274.5 71-75 72-75 126.5-127 40 5-41.5 170-175 1 0 , 1mm) _._.
"In the numerical ratios, no cis or trans assignment is implied; 2a-c are pure isomers of the configurations indicated. bYields are of analytical material. cA, benzene; B, EtOH; C, H 2 0 ; D, heptane; E. I z-Pr)-O; F , cyclohexane; G, MeOH. dCorrected. 'Analyses are within limits of i.0 4% for the elements noted. Scheme I1 \
0
12. 9 = OH 13. X = ('I
11
II
I
II
I
U
L
ZC
2n
Conversion of ketones 6 or 7 to alcohols 9 was done by treating them with Grignard reagents 10 in which R' was variously OCH3, OTHP, or OCH2CH2NEtz. Two of the alcohols (9a,b) were purified: T o obtain l , the OH group of 9 was removed by catalytic hydrogenolysis in the presence of HC104. The THP-protecting group of 9b also was removed during this step, and methyl ethers were cleaved subsequently by pyrolysis with pyridine hydrochloride. Each example of 1 was obtained only as a mixture of the cis and trans isomers. None of the desired pure trans form was isolated in any instance. For several examples of 1 we were able to estimate the ratio of geometrical isomers from the relative nmr intensities o f t h e different aromatic peaks, but we were not able to make any cis or trans assignments within these ratios. From the bisphenol l a , a diacetate lh and a dipotassium sulfonate l i were prepared with the hope that these derivatives might be biologically active upon oral administration. trans-1,2-Bis(p-hydroxyphenyl)cyclobutane (2a) was produced by a route (Scheme 11) similar to that used by Dodson and Zielskell to prepare the unsubstituted phenyl analogs. As in Scheme I, however, methoxy groups on the
aromatic rings compelled us to change some experimental conditions. At first we prepared diketone 1 1 by the reported12 Friedel-Crafts acylation of anisole with succinoyl chloride, but the yields were poor (
