9 alpha, 11 beta and 11 beta-substituted estranes are disclosed which exhibit elevated estrogenic and postcoital contraceptive activities. A process for their manufacture and their use in pharmaceuticals is also disclosed.

BACKGROUND OF THE INVENTION 
1. Field of the Invention 
This invention concerns 9.alpha.,11.beta.- and 11.beta.-substituted 
estranes and their manufacture and their uses as active estrogenic and 
postcoital contraceptive agents. 
2. General Background and Prior Art 
It has long been recognized that estrogenic hormones are important 
pharmacologial materials which find a wide range of beneficial 
applications in human and veterinary therapy. Such applications include, 
for example, supplementing the estrogen levels in persons in need of the 
same; incorporation into birth control devices and compositions; and the 
like. Of the available natural and synthetic estrogens, estradiol has been 
among the most studied and is among the most active. Estradiol 
preparations are marketed commercially such as the product sold under the 
tradename Estrace. Estradiol is not orally active and must be administered 
parenterally. 
It has also been long recognized that estrogens which are orally active are 
very attractive because of the obvious advantages of nontraumatic oral 
administration. In the late 1930's, Inhoffen et al described ethynyl 
estradiol (19-Nor-17A-pregna-1,3,5(10)triene-20-yne-3,17-diol. 
##STR1## 
Naturwiss, 26, 96 (1938). This material is noted in such other early 
references as Inhoffen, et al. Ber. 71, 1024 (1938); German Pat. No. 
702,063; British Pat. No. 516,444; and U.S. Pat. Nos. 2,243,887; 
2,251,939; 2,265,976; and 2,267,257. As early as 1951, (Petit et al. Bull. 
Soc. Chim. France, 1951, 121) it was recognized that the material produced 
estrogenic effects in mammals when administered orally. This had led to 
its wide adoption as an oral estrogen and its marketing in a range of 
products and dosage forms under such proprietary names as, for example, 
Diogyn-E, Dyloform, Etinestryl, Ethidol, Estinyl, Etivex, Feminone, 
Inestra, Kolpolyn, Linoral, Lynoral, Novestrol, Oradiol, Orestralyn, 
Primogyn, and Progynon. 
Ethynyl estradiol is also widely employed together with progestins such as 
norethindrone and noresthindrone acetate in oral contraceptives to give 
products substantially superior in effectiveness to materials without 
ethynyl estradiol. Examples of these ethynyl estradiol-containing 
contraceptive products include materials marketed under the proprietary 
names of Brevicon, Demulen, Loestrin, Modicon, Norinyl, Ortho-Novum, 
Ovcon, Oural, and Tri-Norinyl. 
While the advantages of estradiol and ethynyl estradiol are substantial, as 
evidenced by their wide commercial adoption, these products are not 
without their drawbacks. These problems are extremely serious when viewed 
in terms of the large number of women who take preparations such as those 
listed above on a long and regular basis. These problems include enhancing 
the risk of endometrial carcinoma; induction of malignant carcinoma 
especially in the cervix, breast, vagina and liver; promotion of 
gallbladder disease, thromboembolic and thrombotic diseases, myocardial 
infarction, hepatic adenoma, elevated blood pressure, and hypercalcemia; 
and a worsening of glucose tolerance. These problems tend to manifest 
themselves at the dosage levels needed to achieve the desired primary 
estrogenic and contraceptive effects. Many of these side effects are 
considered to be dose-related. If more potent oral estrogens were 
available, they could be used in lower doses and the side effects could, 
at least in part, be reduced or eliminated. 
The present invention provides a family of such more active estrogens. The 
following publications and United States Patent are believed to be of 
interest to these new materials and their preparation: P. J. Sykes and F. 
J. Rutherford, Tet. Lett. 37, 3393, (1971); K. Tsuda, S. Nozoe and Y. 
Okada, Chem. Parm. Bull. 11, (8), 1022, (1963); B. Magerlein and J. Hogg, 
J. Am. Chem. Soc. 80 2220 (1958); J. Baran, J. Med. Chem. 10, 1188, 
(1967); and U.S. Pat. No. 3,755,574, issued Aug. 28, 1973. In comparison 
to the disclosures of these references, the present invention provides 
materials not shown by them and provides easier access to the general 
class of 11.beta. and 9.alpha.,11.beta.-substituted estranes not 
previously available. 
It is important to recognize that, notwithstanding the large volume of 
effort that has been devoted to research into the preparation and 
production and the testing of synthetic and naturally occurring steroids 
such as the estrogens, this is still very much an empirical field. Simple 
or seemingly insignificant shifts in one or two atoms or groups in a 
steroid can render a new compound active or inactive or change 
dramatically the entire character of its activity. 
STATEMENT OF THE INVENTION 
We have now discovered that certain 11.beta. and 
9.alpha.,11.beta.-substituted derivatives of estradiol, and in some 
instances in particular of ethynyl estradiol, offer estrogenic activity 
and postcoital contraceptive activity which is in many cases many times 
greater than that obtained with nonderivatized material. Thus, the present 
invention in one aspect provides these derivatized analogues of estradiol 
and ethynyl estradiol as new chemical compounds having the chemical 
formula 
##STR2## 
In this formula, R.sub.1 is hydrogen, a lower alkyl or cycloalkyl or a 
lower acyl; R.sub.2 is a nitrate, a halo, a lower alkyl or a hydroxyl; 
R.sub.3 is hydrogen, hydroxyl or a lower alkoxy; R.sub.4 is either a 
carbonyl oxygen or is a pair of groups, the alpha position one of which is 
hydrogen or a lower alkynyl and the beta one of which is hydroxyl, a lower 
alkyl or a N alkanoic acid ester; and R.sub.5 is hydrogen or a lower 
alkyl. When R.sub.2 is nitrate, R.sub.3 is hydroxyl, and R.sub.4 is 
carbonyl, R.sub.5 must be a lower alkyl. When R.sub.2 is a halo R.sub.3 
must be hydrogen. When R.sub.2 is hydroxyl R.sub.5 must be a lower alkyl. 
In other aspects this invention provides new estrogenic and postcoital 
contraceptive pharmaceutical preparations containing effective dosing 
amounts of these compounds and unit dosage forms thereof. In this aspect, 
the invention molecules provide the use of an additional material wherein 
R.sub.1 is lower acyl, R.sub.2 is nitrate, R.sub. 3 is hydroxyl, R.sub.4 
is a carboxyl carbon and R.sub.5 is hydrogen. This material is shown by 
Sikes above but its use in such pharmaceutical products is believed new. 
In yet another aspect the present invention provides methods of treatment 
to obtain estrogenic and postcoital contraceptive effects in a mammal by 
administering to said mammal an effective dose of the compounds (or more 
commonly the pharmaceutical preparations) of the invention. In a yet 
further aspect, this invention provides a process for introducing 
substituents into the 11.beta. and the 9.alpha. positions in an estrane, 
which process has the steps of first treating an R1, R4 and R5-substituted 
estrane with about four equivalents of ceric ammonium nitrate and R.sub.2 
- and R.sub.3 -inserting nucleophiles. This can insert nitrate, halo or 
alkoxy R.sub.2 groups and hydroxy or alkoxy R.sub.3 groups into the 
structure. 
The same insertions can be accomplished starting with the .DELTA.9,11 
equivalent starting steroid and using 2 equivalents of ceric ammonium 
nitrate in place of 4 equivalents of ceric ammonium nitrate. The R.sub.3 
group can be removed by treatment with a silane followed by BF.sub.3 in 
ether. An R.sub.2 nitro group can be converted to hydroxyl by reduction 
using a zinc catalyst. This reduction can also be carried out prior to 
removal of the R.sub.3 group in which case the final product has OH's as 
R.sub.2 and as R.sub.3. 
DETAILED DESCRIPTION OF THE INVENTION 
In this specification and in the claims which follow it reference will be 
made to a number of terms which shall be defined to have the following 
meanings: 
"lower alkyl" means a branched or unbranched saturated hydrocarbon group of 
one to four carbon atoms such as, methyl, ethyl, i-propyl and n-butyl and 
the like. For use herein, methyl and ethyl are preferred "lower alkyls" 
with methyl in general being the more preferred. 
"cycloalkyl" means a cyclic saturated hydrocarbon group of four to seven 
carbon atoms such as cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl. 
"lower acyl" means an R--CO-- group wherein R is a lower alkyl of one to 
three carbon atoms such that the acyl contains a total of from two to four 
carbon atoms. Of the lower acyls, CH.sub.3 --CO-- (acetyl) is preferred. 
"lower alkoxy" means an R--O-- group wherein R is a lower alkyl as defined 
above. Of the lower alkoxies, those having one or two carbon atoms are 
preferred with one carbon alkoxies (methoxy) being more preferred. 
"halo" and "halogen" mean a fluoro, chloro, bromo, or iodo substituent in 
an organic molecule. Of the halos, chloro and bromo are generally 
preferred with chloro generally being the more preferred. 
"lower alkynyl" means a linear or branched hydrocarbon chain containing 
from two to four carbon atoms, between two of which is a carbon-carbon 
acetylenic triple bond. Ethynyl and prop-2-ynyl are representative lower 
alkynyls with ethynyl being the preferred species. 
"alkanoic acid ester" means a group of the formula R--COO--, wherein R is a 
one to seven carbon atom alkyl. Such esters include, for example, acetate, 
propionate, butyrate, enanthate and the like. The acetic acid ester, 
CH.sub.3 --COO-- is generally preferred. 
"carbonyl oxygen" means an oxygen atom attached to a carbon atom through a 
C.dbd.O bond. 
In describing the location of groups and substituents on the estradiol and 
ethynyl estradiol rings, the following numbering system will be employed. 
##STR3## 
In these structures, the use of solid and dashed lines to denote 
particular conformation of groups follows the IU steroid-naming 
convention. 
In the compounds of the invention which are set forth in the structural 
formula given in the Statement of the Invention, R.sub.1 may be hydrogen, 
lower alkyl cycloalkyl or lower acyl. Although not known with certainty, 
it is believed that the latter two groups undergo cleavage in use of the 
body so that all of these R.sub.1 groups are essentially equivalent from 
an activity point of view. R.sub.1 groups that are preferred because of 
their simplicity are H--, CH.sub.3 -- and CH.sub.3 --CO--. 
R.sub.2 can be nitro, halo, lower alkoxy or hydroxyl. Among the halos, Cl, 
Br, and F are preferred with Br and Cl being more preferred. Among the 
lower alkoxies, methoxy is preferred. 
R.sub.3 can be hydrogen, hydroxyl or a lower alkoxy. (As above, methoxy is 
the preferred alkoxy.) 
R.sub.4 represents two bonds. These can be present as a single carbonyl 
oxygen or they can go to two groups which are arrayed in an alpha and beta 
configuration. The alpha group may be hydrogen or a lower alkynyl, 
especially ethynyl. The beta group may be hydroxyl, a lower alkyl or an 
alkanoic acid ester. A consideration regarding the choice of R.sub.4 is 
that the alkynyl alpha substituent may enhance the oral activity of the 
product significantly. Importantly, however, with some of the compounds of 
this invention unexpected significant oral activities (in some cases 7 to 
15 times that of ethynyl estradiol) are noted with materials having a 
carbonyl oxygen R.sub.4 and with molecules having a beta hydroxyl R.sub.4. 
R.sub.5 is a lower alkyl or a hydrogen. 
The selection of each of R.sub.1, R.sub.2, R.sub.3, R.sub.4, and R.sub.5 is 
not made entirely independently of one another. For example, when R.sub.2 
is nitro, and R.sub.3 is OH and R.sub.4 is a carbonyl oxygen, R.sub.5 
should be a lower alkyl. Similarly, when R.sub.2 is a halo, R.sub.3 should 
be hydrogen and when R.sub.2 is hydroxyl, R.sub.5 should be a lower alkyl 
to fall within the scope of this invention. 
As a general class, the compounds having a nitrate R.sub.2 are preferred. 
Special preference is given to the compounds set forth in Table 1. In this 
table the compounds are identified by listing their R.sub.1 through 
R.sub.5 substituents. 
TABLE 1 
______________________________________ 
Compound 
Identifica- 
tion No.* 
R.sub.1 R.sub.2 R.sub.3 R.sub.4 
R.sub.5 
______________________________________ 
1 Ac** --ONO.sub.2 
OH .dbd.O 
CH.sub.3 
3 Ac --ONO.sub.2 
OH .alpha.C.tbd.C 
H 
.beta.OAc 
4 Ac --ONO.sub.2 
OH .alpha.H 
H 
.beta. ethyl 
5 Ac --ONO.sub.2 
OH .alpha.H 
CH.sub.3 
.beta. ethyl 
6 Ac --ONO.sub.2 
H .dbd.O 
CH.sub.3 
8 H --ONO.sub.2 
H .alpha.H 
CH.sub.3 
.beta. OH 
7 Ac --ONO.sub.2 
H .dbd.O 
H 
10 Ac --ONO.sub.2 
OCH.sub.3 
.dbd.O 
H 
17 CH.sub.3 Cl H .alpha.C.tbd.C 
H 
.beta. OH 
18 CH.sub.3 Cl H .alpha. H 
H 
.beta. ethyl 
11 Ac Cl H .dbd.O 
H 
12 H OH OH .alpha.C.tbd.C 
CH.sub.3 
13 Ac OH OH .dbd. O 
CH.sub.3 
14 Ac OH H .dbd.O 
CH.sub.3 
9 Ac OCH.sub.3 
OCH.sub.3 
.dbd.O 
H 
15 Ac OCH.sub.3 
H .dbd.O 
H 
16 CH.sub.3 OCH.sub.3 
OH .dbd.O 
H 
19 H OCH.sub.3 
H .alpha. H 
H 
.beta. ethyl 
______________________________________ 
*This is also the number of the Example in wich the compound is 
demonstrated. 
**CH.sub.3 --CO 
The R.sub.2 and R.sub.3 substituted compounds of this invention can be 
prepared using one or more of the following reactions: 
##STR4## 
In this reaction, R.sub.1, R.sub.4 and R.sub.5 can be as defined above. A 
nitrate R.sub.2 group can be inserted by the use of ceric ammonium 
nitrate. Halo R.sub.2 's can be inserted by the use of ceric ammonium 
nitrate together with a halo-containing nucleophile such as lithium 
chloride or lithium bromide or the like. An alkoxy R.sub.2 can be inserted 
by the use of ceric ammonium nitrite together with the alkanol 
corresponding to the alkoxy. The R.sub.3 group will be OH if no alkanol is 
present and can be alkoxy if alkanol is present. 
This reaction is generally carried out using excess ceric ammonium nitrate, 
i.e., a 1.5 to 10 molar excess. When forming compounds having a nitrate 
R.sub.2 group the starting steroid and the ceric ammonium nitrate are 
mixed, generally in a polar solvent, especially 80-100% acetic acid and 
stirred at low to moderate temperatures such as 5.degree. to 40.degree. C. 
for from about 1 hour to about 24 hours. When adding halo R.sub.2 's an 
excess (2 to 20 molar) of halo nucleophile is used. It is added together 
with the ceric ammonium nitrate. When adding alkoxy R.sub.2 's, the polar 
solvent such as acetic acid solvent may at least in part be replaced by 
the alkanol. 
In all cases excess water is to be avoided and an inert gas cap over the 
reaction vessel is preferred. 
Alternatively, one can use the 9,11.DELTA. steroids as starting material in 
the reaction 
##STR5## 
In this reaction, less ceric ammonium nitrate (2 moles rather than 4) is 
consumed. The same reaction conditions as above can be used. 
The compounds of this invention wherein R.sub.3 is hydrogen (i.e., the 
11-substituted materials) can be formed from the above-described 
9,11-substituted materials by treatment with silane followed by reduction 
with boron trifluoride etherate. The silane employed may be a trialkyl 
silane such as trimethyl silane or triethyl silane. Generally a molar 
excess of silane and boron trifluoride etherate are employed. This 
reaction is generally carried out in dry solvent, such as dry methylene 
chloride, dry ethylene chloride or the like under an inert atmosphere 
initially at low temperatures such as -15.degree. to 10.degree. and 
thereafter at moderate temperatures such as 10.degree. to 50.degree. C. 
R.sub.2 --ONO.sub.2 groups can be converted to --OH's using zinc in the 
reaction 
##STR6## 
This reaction is generally carried out using an excess of powdered zinc in 
a polar solvent such as glacial acetic acid. This reaction is preferably 
conducted under an inert atmosphere and can be completed at temperatures 
of from 10.degree. to 50.degree. C. in from 0.1 to about 2 hours. 
A carbonyl R.sub.4 substituent can be converted to an alpha hydrogen and a 
beta hydroxyl by reduction with excess sodium borohydride. This reaction 
can be carried out in a dry oxyhydrocarbon solvent such as anhydrous lower 
alkanols or the like. Suitable reaction conditions are from 5 minutes to 
30 minutes at temperatures of from 10.degree. to 50.degree. C., preferably 
20.degree. to 50.degree. C. 
Other changes to R.sub.4 groups can be carried out. For example, a 
Grignard-type reaction can be carried out to react the R.sub.4 carbonyl 
with an alkyl, alkenyl, or alkynyl magnesium bromide thereby converting 
the R.sub.4 to the corresponding alpha alkyl, alkenyl or alkynyl, beta 
hydroxy R.sub.4. This reaction can be carried out by gradually adding the 
carbonyl oxygen-containing steroid to a stirred solution of the magnesium 
bromide reagent at low temperature such as -10.degree. to 20.degree. C. 
for a time of from a few hours (for example 5) to several days. Water 
should be excluded from this reaction. THF or another aprotic solvent can 
be used as the reaction medium for this reaction. 
After any of these reactions the products or intermediates can be collected 
and worked up by methods known in the art, including, without limitation, 
extraction, chromatography such as high pressure liquid chromatography, 
thin layer chromatography, paper chromatography, and liquid 
chromatography, precipitation, cyrstallization and the like. 
The invention will be further described by the following examples. These 
are provided only to illustrate embodiments of the invention and are not 
to be construed as limitations on the invention's scope.

EXAMPLE 1 
3,9.alpha.,11.beta.-Trihydroxy-7.alpha.-methyl-estra-1,3,5(10)-trien-17-one 
3-acetate 11-nitrate ester (1) 
To a stirred solution of 20 g (64.3 mM) of 7.alpha.-methylestrone acetate 
in 400 ml of 90% acetic acid under a nitrogen atmosphere, 140 g (266 mM) 
of ceric ammonium nitrate was added. The reaction mixture was stirred for 
6 hr at room temperature and then added to 2 l of water. The precipitated 
products were extracted into 750 ml of ether, and the aqueous phase was 
extracted with an additional 750 ml of ether. The ether extracts were 
combined and washed--three times with 750 ml portions of water, once with 
750 ml of a 5% sodium bicarbonate solution, and once with 750 ml of water. 
The ether solution was dried over sodium sulfate, and then the ether was 
removed at reduced pressure to afford 24.8 g of residue. Crystallization 
from ether gave 10.5 g of 1. An analytical sample was prepared by 
recrystallization from ether; mp, 184.degree.-186.degree.. 
Anal. high-resolution mass spec. for C.sub.21 H.sub.25 O.sub.5 
(M--NO.sub.2): Calcd. 357.1702; Found: 357.1712 
EXAMPLE 2 
Treatment of .DELTA.9,11-7.alpha.-methylestrone acetate with two 
equivalents of ceric ammonium nitrate gave 1 identical to the material 
obtained above. 
EXAMPLE 3 
17.alpha.-Ethynyl-3,9.alpha.,11.beta.-17.beta.-tetrahydroxy-estra-1,3,5(10) 
-trien 3,17-Diacetate 11-Nitrate Ester (3) 
The procedure of Example 1 was repeated but employing ethynyl estradiol 
acetate (1.0 g) as the starting material. This gave 300 mg of 3 on 
crystallization from ether. An analytical sample was prepared by 
recrystallization from ether; mp 173.degree.-175.degree.. 
Anal. high resolution mass spec. for C.sub.24 H.sub.27 NO.sub.8 : Calcd. 
357.2066. Found: 357.2103 
EXAMPLE 4 
3,9.alpha.,11.beta.-Trihydroxy-19-norpregna-1,3,5(10)-trien 3-Acetate 
11-Nitrate Ester (4) 
The procedure of Example 1 was repeated but employing 1 g of 3-hydroxy-19 
norpregna-1,3,5(10)-trien 3-acetate. This gave, on crystallization from 
ether-petroleum-ether, 350 mg of 4. An analytical sample was prepared by 
recrystallization from ether; mp 177.degree.-179.degree.. 
EXAMPLE 5 
3,9.alpha.,11.beta.-Trihydroxy-7.alpha.-methyl-19-norpregna-1,3,5(10)-trien 
3-Acetate 11-Nitrate Ester (5) 
The procedure of Example 1 was repeated but employing 
7.alpha.-methyl-19-norpregna-1,3,5(10)-trien. This gave, on separation by 
preparative tlc, 59 mg of 5. An analytical sample was prepared by 
recrystallization from ether; mp 140.degree.-143.degree.. 
Anal. high resolution mass spec. for C.sub.23 H.sub.31 O.sub.4 
(M-NO.sub.2): Calcd. for 371.222; Found: 371.2231. 
EXAMPLE 6 
3,11.beta.-Dihydroxy-7.alpha.-methyl-estra-1,3,5(10)-trien-17-one 3-acetate 
11-nitrate ester (6) 
To a stirred solution of 10.5 g (25.5 mM) of 1 in 400 ml of dry methylene 
chloride under a nitrogen atmosphere at salt-ice bath temperature, 10 g 
(76.5 mM) of triethyl silane followed by 26.8 ml of boron trifluoride 
etherate were added. The reaction mixture was stirred for 1 hr and then 
warmed to room temperature. The methylene chloride solution was washed 
three times with 150-ml portions of a 10% potassium carbonate solution and 
once with 150 ml of water; then it was dried over sodium sulfate. The 
methylene chloride was removed at reduced pressure, and crystallization 
from ether gave 5.75 g of 6. An analytical sample was prepared by 
recrystallization from ether; mp, 195.degree.-196.degree.. 
Anal. Calcd. for C.sub.21 H.sub.25 NO.sub.6 C, 65.10; H, 6.50; N, 3.62. 
Found: C, 65.11; H, 6.58; N, 3.57. 
EXAMPLE 7 
3,11.beta.-Dihydroxy-estra-1,3,5(10)-trien-17-one 3-Acetate 11-Nitrate 
Ester (7) 
Treatment of 5 g of estrone acetate with ceric ammonium nitrate by the 
procedure described in Example 1 gave, on crystallization from ether, 2.1 
g of the intermediate ester 
3,9.alpha.,11.beta.-Trihydroxy-estra-1,3,5(10)trien-17-one 3-Acetate 
11-Nitrate Ester. 
By the procedures used in Example 3, 310 mg of the ester just prepared 
gave, on crystallization from ether, 150 mg of pure 8, mp 
190.degree.-192.degree.. 
Anal. Calcd. for C.sub.20 H.sub.23 NO.sub.6 : C, 64.33; H, 6.21; N, 3.75. 
Found: C, 64.09; H, 5.95; N, 3.62. 
EXAMPLE 8 
3,11.beta.,17.beta.-Trihydroxy-7.alpha.-methyl-estra-1,3,5(10)-trien 11 
Nitrate ester (8) 
To a stirred solution of 100 mg of 6 from Example 6 in 12 ml of methanol 48 
mg of sodium borohydride was added. The reaction mixture was stirred for 
15 min then added to 75 ml of water. The product was extracted into 75 ml 
of ether and the etheral solution was washed with water then dried over 
sodium sulfate. The ether was removed at reduced pressure to give 100 mg 
of residue. An analytical sample was prepared by crystallization from 
methylene chloride: mp 179.degree.-182.degree.. 
Anal. GC mass spec for C.sub.19 H.sub.25 NO.sub.5 : Calcd. for 347; Found 
347. 
EXAMPLES 9 AND 10 
3,9.alpha.,11.beta.-Trihydroxy-estra-1,3,5(10)-trien-17-one 3-Acetate 
9.alpha.-Methy ether 11-Nitrate ester (9) and 
3,9.alpha.,11.beta.-trihydroxy-estra 1,3,5(10)trien-17-one 3-Acetate 
9,11-Dimethyl ether (10) 
To a stirred solution of 310 mg of .DELTA.9,11-estrone acetate in 10 ml of 
methanol under a nitrogen atmosphere 1.1 g of ceric ammonium nitrate was 
added. The reaction mixture was stirred for 45 min at room temperature 
then added to 100 ml of water. The reaction products were extracted into 
100 ml of ether, then the etheral solution was washed twice with water 
then dried over sodium sulfate. The solvent was removed at reduced 
pressure to give 370 mg of residue. Separation by preparative thin layer 
chromatography gave 160 mg of 9 and 160 mg of 10. 
Anal. 9 GC mass spec. for C.sub.22 H.sub.28 O.sub.5 : Calcd. for 362; 
Found: 362. 
Anal. 10 GC mass spec. for C.sub.21 H.sub.25 NO.sub.6 : Calcd. 403; Found: 
403. 
EXAMPLE 11 
11.beta.-Chloro-3-hydroxy-estra-1,3,5(10)-trien-17-one 3-Acetate (11) 
To a stirred solution of 1.0 g (3.3 mM) of .DELTA.9,11-estrone acetate and 
1.25 g (30 mM) of lithium chloride in 30 ml of 90% acetic acid under 
nitrogen was added 3.8 g (6.8 mM) of ceric ammonium nitrate. The reaction 
mixture was stirred for 3 hr and then added to 250 ml of ice water. The 
product was extracted into 100 ml of ether. The ether solution was washed 
three times with water, twice with 5% NaHCO.sub.3, and once with water and 
then dried over sodium sulfate. The solvent was removed at reduced 
pressure to afford 1.2 g of residue. Crystallization from ether gave 530 
mg of the intermediate 
11.beta.-Chloro-3,9.alpha.-dihydroxy-estra-1,3,5(10)-trien-17-one 
3-Acetate. An analytical sample was prepared by recrystallization from 
ether. 
Anal. GC mass spec. for C.sub.20 H.sub.23 ClO.sub.4 : Calcd. for 362; 
Found: 362. 
By the procedure used in Example 6, reaction of 362 mg of the intermediate 
gave, on crystallization from ether 190 mg of 11: mp 
187.degree.-190.degree.. 
Anal. GC mass spec. for C.sub.20 H.sub.23 ClO.sub.3 : Calcd. for 346; 
Found: 346. 
EXAMPLE 12 
17.alpha.-Ethylnyl-7.alpha.-methyl-estra-1,3,5(10)-trien-3,9.alpha.,11.beta 
.-tetraol (12) 
To a stirred solution of 10 mM of ethynyl magnesium bromide in 25 ml of THF 
at 0.degree. under nitrogen was added 360 mg of 
3,9.alpha.,11.beta.-trihydroxy-7-.alpha.-methyl-estra-1,3,5(10)-trien-17-o 
ne 3-acetate in 8 ml of THF dropwise over 10 min. The reaction mixture was 
warmed to room temperature and then stirred for 18 hr. A solution of 1 ml 
of saturated NH.sub.4 Cl was added and stirring was continued for 15 min. 
Then 100 ml of ether was added. The ether solution was washed three times 
with water and then dried over sodium sulfate. Removal of the solvent at 
reduced pressure gave 400 mg of residue. Fractionation by preparative tlc 
(benzene-50% ether SiGF) gave 100 mg of 12. 
Anal. high resolution mass spec. for C.sub.21 H.sub.24 O.sub.3 : Calcd. for 
324.1725. Found: 324.1754. 
EXAMPLE 13 
3,9.alpha.,11.beta.-Trihydroxy-7.alpha.-methyl-estra-1,3,5(10)-trien-17-one 
3-Acetate (13) 
To a stirred solution of 2.3 g of the nitrate ester of Example 1 in 100 ml 
of glacial acetic acid under nitrogen was added 9.2 g of powdered zinc. 
The reaction mixture was stirred for 1 hr. Then the zinc suspension was 
added to 800 ml of ice water and the acetic acid was neutralized with 2N 
sodium hydroxide. The product was extracted into 400 ml of ether, and the 
ether solution was washed three times with water and then dried over 
sodium sulfate. The solvent was removed at reduced pressure to afford 1.4 
g of residue. Crystallization from ether gave 361 mg of 13. An analytical 
sample was prepared by recrystallization from ether; mp 
188.degree.-190.degree.. 
Anal. high resolution mass spec. for C.sub.21 H.sub.26 O.sub.5 : Calcd. for 
358.1780. Found: 358,1776. 
EXAMPLE 14 
3,11.beta.-Dihydroxy-7.alpha.-methyl-estra-1,3,5(10)-trien-17-one 3-acetate 
(14) 
To a stirred solution of 5.2 g of the nitrate ester of Example 6 in 150 ml 
of glacial acetic acid under a nitrogen atmosphere, 7.5 g of zinc dust was 
added. The reaction mixture was stirred for 1 hr at room temperature and 
then filtered through celite, and the filter cake was washed with 100 ml 
of glacial acetic acid. Most of the acetic acid was removed at reduced 
pressure; then 300 ml of water was added, and precipitated product was 
extracted into 500 ml of ether. The ether solution was washed twice with 
150 ml of water, once with 150 ml of a 5% sodium bicarbonate solution, and 
with 150 ml of water; then it was dried over sodium sulfate. The ether was 
removed at reduced pressure to afford 4.5 g of crude 14. Crystallization 
from ether gave 2.3 g of pure 14. Preparative tlc (SiGF-benzene-25% ether) 
gave an additional 1.4 g of pure 14. An analytical sample was prepared by 
recrystallization from methylene chloride-ether; mp, 
130.degree.132.degree.. 
Anal. Calcd. for C.sub.21 H.sub.26 O.sub.4 : C, 73.66; H, 7.65. Found: C, 
73.84; H, 7.66. 
EXAMPLE 15 
3,11.beta.-Dihydroxy-estra-1,3,5(10)-trien-17-one 3-Acetate 11-Methy ether 
(15) 
The process of Example 6 is repeated substituting as feed stock, 150 mg of 
the nitrate ester produced in Example 9. This gave, on crystallization 
from ether, 100 mg of 15: mp 180.degree.-182.degree.. 
Anal. GC mass spec. for C.sub.22 H.sub.26 O.sub.4 : Calcd. for 342; Found: 
342. 
EXAMPLE .noteq. 
3,9.alpha.,11.beta.-Trihydroxy-estra-1,3,5(10)-trien-17-one 3,11-Dimethyl 
ether (16) 
To a slurry of 284 mg of estrone methyl ether in 20 ml of methanol under a 
nitrogen atmosphere a solution of 3.3 g of ceric ammonium nitrate in 30 ml 
of methanol was added dropwise over 3 hr. The reaction mixture was added 
to 150 ml of water and the products were extracted into 100 ml of ether. 
The ether solution was washed with water then dried over sodium sulfate. 
The ether was removed at reduced pressure to give 300 mg of residue. 
Separation by preparative thin layer chromatography gave 130 mg of 16. An 
analytical sample was prepared by crystallization from ether: mp 
191.degree.-194.degree.. 
Anal. GC mass spec. for C.sub.20 H.sub.26 O.sub.4 : Calcd. for 330; Found: 
330. 
EXAMPLE 17 
11.beta.-Chloroethynylestradiol 3-Methyl Ether (17) 
Precursor Preparation 
2-Chloro-1,1,2-trifluorotriethylamine 
1-chloro-1,2,2-trifluoroethylene was bubbled into 50.0 g of triethylamine 
for 8 hr at -5.degree. to -10.degree.. The reaction was the distilled 
under reduced pressure to yield 61 g of product, bp 35.degree./6 mm 
(lit.sup.10 bp 32.degree.-33.degree./6 mm). The 
2-chloro-1,1,2-trifluorotriethylamine was stored in vials under nitrogen, 
wrapped in aluminum foil and placed in a desicator. 
11.beta.-Chloroestrone 3-Methyl Ether 
To a solution of 3.0 g of 11.alpha.-hydyroxyestrone 3-methyl ether in 120 
ml of dry THF at 0.degree.-5.degree. (ice-water bath) was added 0.7 g of 
dry lithium chloride (dried in a desiccator at 80.degree. under vacuum at 
1.0 mm for 18 hr) and 2.25 ml of the above-prepared haloamine. The 
reaction was stirred at this temperature for 18 hr. Tlc indicated that the 
reaction had not gone to completion; therefore, an additional 0.2 ml of 
the haloamine reagent and 0.07 g of lithium chloride were added. After 
being stirred for an additional hr at 0.degree.-5.degree., the reaction 
was poured into ether and water. The ether phase was separated and washed 
with water. The ether solution was dried over sodium sulfate and 
evaporated at reduced pressure to yield 2.70 g of crude 21. The crude 
product was purified by hplc to yield 0.750 g of 21, which was 
recrystallized from methanol to yield 0.550 g; mp 129.5-130.0. 
Anal. high resolution mass spec calcd for C.sub.19 H.sub.23 O.sub.2 Cl: 
calcd 318.1389; found 318.1410. 
GRIGNARD REAGENT 
Dry acetylene was prepared by passing the gas through two traps (one cooled 
with dry-ice/acetone); and then through a column of KOH pellets, Drierite, 
and KOH pellets. The dry acetylene was bubbled into 25.0 ml of dry THF at 
0.degree.-5.degree. for 1.5 hr. To the acetylene solution was added 
dropwise 0.766 ml of 3.0 ethyl magnesium bromide. The reaction was stirred 
for an additional 0.20 hr at 0.degree.-5.degree.. 
THE DESIRED PRODUCT (17) 
To the Grignard reagent reaction solution was then added 0.18 g of the 
11.beta.-chloroestrone-3-methyl ether in 8.0 ml of dry THF. The reaction 
was allowed to warm to room temperature and stirring was continued for 18 
hr. To quench the reaction, 5 ml of saturated NH.sub.4 Cl was slowly 
added. The THF was evaporated at reduced pressure and the residue was 
dissolved in ether. The ether solution was washed with saturated NH.sub.4 
Cl, dried over Na.sub.2 SO.sub.4 and evaporated at reduced pressure to 
yield 0.172 g of crude product. The crude product was chromatographed on 
20 g of silica gel and eluted with benzene-7% ether to afford 0.063 g of 
pure 17; mp 173.degree.-174.degree.. 
Anal. high resolution mass spec calcd for C.sub.21 H.sub.25 O.sub.2 Cl: 
calcd 344.1543; found 344.1555. 
EXAMPLE 18 
Compound 18 was prepared using the general techniques taught herein. 
EXAMPLE 19 
Compound 19 was prepared using the general techniques taught herein. 
EXAMPLE 20 
3,9 alpha,11 beta-Trihydoxy-estra-1,3,5(10)trien-17-one 3-Acetate 
11-Nitrate Ester (20) 
The process of Example 1 is repeated but using 5 g of strone acetate as 
starting material. This gave, on crystallization from ether, 2.1 g of 20. 
An analytical sample was prepared by recrystallization from ether. The 
sample (m.p. 183.degree.-184.degree.) had spectral properties consistent 
with the structure of 20. 
BIOLOGICAL ACTIVITY 
The compounds of this invention exhibit significant estrogenic activity and 
postcoital contraceptive activity. This is demonstrated in the following 
tests. 
ORAL ESTROGENIC ACTIVITY 
The estrogenic acitivity was determined using immature female rats 
ovariectomized at 21 days of age. Treatment was by oral administration for 
4 days, beginning on the day of ovariectomy. Animals were autopsied on the 
day following the last administration of test compound. Vaginal smears 
were obtained from animals that had open vaginas at the time of autopsy. 
The endpoints for comparison with a standard estrogen will be the increase 
in uterin weight and cornification of vaginal smears. (The test compounds 
were diluted with a 0.5% Carboxymethyl cellulose suspension.) 
ORAL POSTCOITAL ACTIVITY 
Oral postcoital activity was determined using adult cycling female rats, 
obtained from the Holtzman Rat Company, were selected in the proestrous 
phase of the cyle. Treatment began on the day of proestrus. Each female 
was caged overnight with two adult males. The find of sperm in the vaginal 
smear the following morning was used as evidence of insemination. 
Treatment was continued for a total of 8 days. The rats were sacrificed on 
the day following the last treatment, and the number of implantation sites 
and the number of corpora lutea were counted. The test material was 
administered parenterally (sc or im or orally by intubation). 
SUBCUTANEOUS ESTROGENIC ACTIVITY 
Immature, 18-day-old rats are assigned randomly to groups of 5 to 10. 
Treatment by S.C. injection is started on the day the animals arrive and 
continues once daily for 4 days. On day 5, vaginal smears are obtained, 
and uteri--carefully dissected between precise areas between the cervix 
and the oviduct--are stripped of fat and connective tissue and then 
weighed on a torsion balance. Fluid in uteri is expressed before weighing. 
Body weights of rats are recorded on the first day and at autopsy. 
Comparison of the semilog dose-response curves of 3 to 4 dose levels of an 
active test compound with those of compounds of known activity (e.g., 
estrone administered s.c. or ethinyl estradiol given orally) helps 
determine whether the estrogen is strong, weak, or impeded and may give 
some indication of potential antiestrogenic activity. 
Contraceptive activity test 
The activities so determined are listed in Table 2. 
TABLE 2 
______________________________________ 
Estrogenic 
Activity 
Estrogenic Contraceptive 
relative to 
Activity Activity Estradiol 
Compound 
(Oral) (Oral) (Subcutaneous) 
______________________________________ 
Standard 
100 100 1000 
(Ethynyl 
Estradiol) 
1. 34 
2. 
3. 531 5000 
4. 228 4000 
5. 780 
6. 696 4000 7472 
7. 400 
8. 1400 
9. 8 
10. 5 
11. 7-12 
12. 445 400 
13. 1 
14. 26-69 
15. 60 
17. 300 &gt;100 
18. 22 200 
19. 37 &gt;2000 
20. 40 
______________________________________ 
As can be seen from these results, several of the compounds provide 
estrogenic activities that are as much as 7, 14 and even 26 times as great 
as ethynyl estradiol, itself one of the most potent estrogens. Similarly, 
compounds of this invention can exhibit postcoital infertility activity 40 
and 50 times as high as ethynyl estradiol. This points to significantly 
lowered use levels which could in turn reduce side effects. 
The compounds of this invention can be administered to humans or other 
mammals by any of the accepted modes of administration for steroidal 
agents. These methods include oral, parenteral, suppositories, topical and 
the like. The compounds can be administered alone or as part of a 
combination product--such as with a progestin or the like. 
Depending on the intended mode of administration, the compositions used may 
be in the form of solid, semi-solid or liquid dosage forms, such as, for 
example, injectables, tablets, suppositories, pills, capsules, powders, 
liquids, suspensions, or the like, preferably in unit dosage forms 
suitable for single administration of precise dosages. The compositions 
will include a conventional pharmaceutical carrier or excipient and an 
active compound of the invention and, in addition, may include other 
medicinal agents, pharmaceutical agents, carriers, adjuvants, etc. For 
oral administration, a pharmaceutically acceptable non-toxic composition 
is formed by the incorporation of any of the normally employed excipients, 
such as, for example pharmaceutical grades of mannitol, lactose, starch, 
magnesium stearate, sodium saccharin, talcum, cellulose, sucrose, 
magnesium, carbonate, and the like. Such compositions take the form of 
solutions, suspensions, tablets, pills, capsules, powders, sustained 
release formulations and the like. 
The compounds of the invention as defined above may be formulated as 
suppositories using, for example, polyalkylene glycols, for example, 
propylene glycol, as the carrier. 
Liquid pharmaceutically administerable compositions particularly for 
parenteral administration (generally characterized by 
injection--subcutaneously, intramuscularly or intravenously) can be 
prepared by dissolving, dispersing, etc. a compound of the invention and 
optional pharmaceutical adjuvants in a carrier, such as, for example, 
water, saline, aqueous dextrose, glycerol, ethanol, and the like, to 
thereby form a solution or suspension. If desired, the pharmaceutical 
composition to be administered may also contain minor amounts of nontoxic 
auxiliary substances such as wetting or emulsifying agents, pH buffering 
agents and the like, for example, sodium acetate, sorbitan monolaurate, 
triethanolamine sodium acetate, triethanolamine oleate, etc. Actual 
methods of preparing such dosage forms are known, or will be apparent, to 
those skilled in this art; for example, see Remington's Pharmaceutical 
Sciences, Mack Publishing Company, Easton, Pa., 15th Edition, 1975. The 
composition or formulation to be administered will, in any event, contain 
a quantity of the active compound(s) adequate to achieve the desired 
estrogenic or contraceptive effect in the subject being treated. 
The amount of active compound administered will, of course, be dependent on 
the activity of the compound, the effect desired and the view of the 
attending physician. As guidelines, conventional oral estradiol pills and 
tablets may contain from 0.5 to about 2 mg of active material, while a 
dose of injectable estradiol may be from about 1 to about 10 mg of the 
active material. Oral ethynyl estradiol tablets usually contain in the 
range of from 0.01 to 1 mg of the active material. Oral contraceptives 
employing ethynyl estradiol generally contain from about 0.02 to about 0.1 
mg of ethynyl estradiol. In view of the activities demonstrated with 
compounds of this invention one could obtain desired responses with from 
as little as 0.0002 mg of active material to as much as 5 or 10 mg. The 
following nonlimiting representative product formulations further 
illustrate the use of the present materials in pharmaceutical composition. 
FORMULATION A 
Estrogenic Tablet 
______________________________________ 
Ingredients Quantity, g 
______________________________________ 
Compound of Example 8 
0.005 
Cornstarch 40 
Lactose 58 
Magnesium stearate 
2 
______________________________________ 
The above materials are blended in a lab scale .nu.-blender and hand 
pressed into 100 mg tablets each of which administers a unit dose of 0.005 
mg of the estrogenic compound of example 8. 
FORMULATION B 
Estrogenic Capsule 
______________________________________ 
Ingredients Quantity, g 
______________________________________ 
Compound of Example 5 
0.05 
Lactose (spray dried) 
198 
Magnesium stearate 
2 
______________________________________ 
The above materials are mixed to give a free flowing powder. Hard shell 
gelatin capsules are filled with 200 mg of the above mixture to achieve a 
unit dosage form for 0.05 mg estrogen therapy. 
FORMULATION C 
Estrogenic Vaginal Cream 
A vaginal cream is formulated by admixing 0.15 mg/g of final product of 
Example 12 in a cream base made up of glycerin, mineral oil, glycerol 
monostearate, polyethylene glycol ether complex of fatty acids, cetyl 
alcohol, lanolin. When one cc of this product is administered an 
estrogenic response is achieved. 
FORMULATION D 
Androgen-Estrogen Tablets 
______________________________________ 
Ingredients Quantity, g 
______________________________________ 
Methyl testosterone 
1.25 
Compound 6 of Example 6 
0.10 
Cornstarch 75 
Lactose 168.75 
Magnesium stearate 5.0 
______________________________________ 
The above materials are intimately mixed and formed into 1000 250 mg 
tablets each of which delivers 1.25 mg of androgen and 0.10 mg of 
estrogen. 
FORMULATION E 
Oral Contraceptive Tablet 
______________________________________ 
Ingredient Quantity, g 
______________________________________ 
Compound 6 of Example 6 
0.001 
Norgestrol progestogen 
5.0 
Lactose 95 
Cornstarch 145 
Magnesium stearate 5 
______________________________________ 
The above ingredients are mixed and formed into 250 mg tablets which when 
administered to a female exhibit contraceptive activity. 
FORMULATION F 
Oral Contraceptive 
______________________________________ 
Ingredient Quantity, g 
______________________________________ 
Compound 3 of Example 3 
0.01 g 
Lactose 100 
Cornstarch 145 
Magnesium stearate 5 
______________________________________ 
The above ingredients are mixed and formed into 250 mg tablets which when 
administered to a female human exhibit postcoital contraceptive activity. 
FORMULATION G 
Topical Formulation 
______________________________________ 
Ingredients Quantity, g 
______________________________________ 
Active compound 12 of Example 12 
0.002 
Span 60 2 
Tween 60 2 
Mineral Oil 5 
Petrolatum 10 
Methyl paraben 0.15 
Propyl paraben 0.05 
BHA (butylated hydroxy anisole) 
0.01 
Water q.s. 100 
______________________________________ 
All of the above ingredients, except water, are combined and heated to 
60.degree. C. with stirring. A sufficient quantity of water at 60.degree. 
C. is then added with vigorous stirring to emulsify the ingredients, and 
water then added q.s. 100 g.