The use of naturally occurring estrogenic compositions of substantial purity and low toxicity such as PREMARIN (conjugated equine estrogens) has become a preferred medical treatment for alleviating the symptoms of menopausal syndrome, osteoporosis/osteopenia in estrogen deficient women and in other hormone related disorders.  The estrogenic components of the naturally occurring estrogenic compositions have been generally identified as sulfate esters of estrone, equilin, equilenin, 17xcex2-estradiol, dihydroequilenin and 17xcex2-dihydroequilenin (U.S. Pat.  No.  2,834,712).  The estrogenic compositions are usually buffered or stabilized with alkali metal salts of organic or inorganic acids at a substantially neutral pH of about 6.5 to 7.5.  Urea has also been used as a stabilizer (U.S. Pat.  No.  3,608,077).  The incorporation of antioxidants to stabilize synthetic conjugated estrogens and the failure of pH control with tris(hydroxymethyl)aminomethane (TRIS) to prevent hydrolysis is discussed in U.S. Pat.  No.  4,154,820. 
One of the compounds described herein, estra-5(10),7-dien-3xcex2-ol-17-one 3-sulfate ester sodium salt is a minor component of PREMARIN (conjugated equine estrogens).  The preparation of estra-5(10),7-dien-3xcex2-ol-17-one and estra-5(10),7-dien-3xcex1-ol-17-one have been disclosed by K. Junghans in Chem Ber.  112: 26 (1979); however, no utility is provided for this compound.  U.S. Pat.  No.  2,930,805 discloses the preparation of 3,17xcex2-dihydroxy-5(10),7-estradienes, and their use as antiestrogens.  U.S. Pat.  No.  3,340,278 discloses the preparation of 5(10),7-estradien-3,17-dione, 3,17xcex2-dihydroxy-5(10),7-estradiene, and 17xcex2-hydroxy -5(10),7-estradien-3-one, which are useful as intermediates in the preparation of equilin. 
In accordance with this invention, there are provided estra-5(10),7-dien-3xcex2-ol-17-one or a pharmaceutically acceptable salt of its 3-sulfate ester, estra-5(10),7-dien-3xcex2-ol-17-one 3-glucuronide or a pharmaceutically acceptable salt thereof, estra-5(10),7-dien-3xcex1-ol-17-one or a pharmaceutically acceptable salt of its 3-sulfate ester, and estra-5(10),7-dien-3xcex1-ol-17-one 3-glucuronide or a pharmaceutically acceptable salt thereof.  This invention also provides a compound which is a 3-alkali metal salt of estra-5(10),7-dien-3xcex2-ol-17-one or estra-5(10),7-dien-3xcex1-ol-17-one.  These are all collectively referred to as the compounds of this invention.  The structures of estra-5(10),7-dien-3xcex2-ol-17-one and estra-5(10),7-dien-3xcex1-ol-17-one are shown below as compounds 5B and 5A, respectively.  
Pharmaceutically acceptable salts of estra-5(10),7-dien-3xcex2-ol-17-one 3-sulfate ester, estra-5(10),7-dien-3xcex2-ol-17-one 3-glucuronide, estra-5(10),7-dien-3xcex1-ol-17-one 3-sulfate ester, or estra-5(10),7-dien-3xcex1-ol-17-one 3-glucuronide include, but are not limited to, the alkali metal salts, alkaline earth metal salts, ammonium salts, alkylammonium salts containing 1-6 carbon atoms or dialkylammonium salts containing 1-6 carbon atoms in each alkyl group, and trialkylammonium salts containing 1-6 carbon atoms in each alkyl group.  The alkali metal of the 3-alkali metal salts of estra-5(10),7-dien-3xcex2-ol-17-one or estra-5(10),7-dien-3xcex1-ol-17-one are lithium, sodium, or potassium. 
As estra-5(10),7-dien-3xcex2-ol-17-one 3-sulfate ester sodium salt is a minor component of PREMARIN (conjugated equine estrogens), this invention also provides estra-5(10),7-dien-3xcex2-ol-17-one 3-sulfate sodium salt in greater than one percent purity. 
This invention also provides a compound consisting essentially of estra-5(10),7-dien-3xcex2-ol-17-one or a pharmaceutically acceptable salt of its 3-sulfate ester or estra-5(10),7-dien-3xcex2-ol-17-one 3-glucuronide or a pharmaceutically acceptable salt thereof; and a compound consisting essentially of estra-5(10),7-dien-3xcex1-ol-17-one or a pharmaceutically acceptable salt of its 3-sulfate ester or estra-5(10),7-dien-3xcex1-ol-17-one 3-glucuronide or a pharmaceutically acceptable salt thereof. 
As used in accordance with this invention, treating covers treatment of an existing condition, ameliorating the condition, or providing palliation of the condition and inhibiting includes inhibiting or preventing the progress or development of the condition. 
The compounds of this invention can be prepared from readily available starting materials.  For example, the preparation of estra-5(10),7-dien-3xcex2-ol-17-one (5B), estra-5(10),7-dien-3xcex1-ol-17-one (5A), estra-5(10),7-dien-3xcex1-ol-17-one 3-sulfate ester sodium salt (7), and estra-5(10),7-dien-3xcex2-ol-17-one 3-sulfate ester triethylammonium salt (15) are shown in Schemes I and II starting from equilin methyl ether (U.S. Pat.  No.  3,644,439, which is hereby incorporated by reference) and 17xcex2-hydroxyestra-5(10),7-dien-3-one (8) (U.S. Pat.  No.  2,930,805, which is hereby incorporated by reference).  Estra-5(10),7-dien-3xcex2-ol-17-one 3-glucuronide sodium salt (16) and estra-5(10),7-dien-3xcex1-ol-17-one 3-glucuronide sodium salt (17) can be prepared according to Scheme III. 
As shown in Scheme I, the 17-ethylenedioxy derivative of equilin methylether 1 is converted to the triene 2 utilizing a Birch reduction with lithium in liquid ammonia.  Mild oxalic acid treatment allows the selective hydrolysis of the enol ether to provide the ketone 3.  Sequential reduction of the 3-ketone (lithium aluminum hydride); and deprotection of the 17-ketone (p-tolunesulfonic acid) affords the products 5A and 5B of the invention as a mixture in which the 3xcex1-isomer 5A predominates (4:1 ratio).  Separation can be realized directly by preparative high pressure liquid chromatography.  Alternatively, inversion of configuration at C-3 to a mixture in which the 3xcex2-isomer predominates can be achieved by a Mitsunobu reaction.  The highly crystalline 3-(3,5-dinitro)benzoates, products of the Mitsunobu inversion, are readily separable by column chromatography.  After hydrolysis, 5B was converted to its 3,xcex2-sulfate 7 with triethylamine:sufur trioxide reagent.  
Scheme II outlines the conversion of 17xcex2-hydroxyestra-5(10),7-dien-3-one (8) to a mixture of 5A and 5B (6.6:1 ratio) by a reduction-oxidation sequence requiring a differential protection-deprotection sequence for the C-3 and C-17 functionalities.  Reduction at C-3 utilized lithium tri-tertbutoxyaluminum hydride, a Swern-type oxidation provided the C-17 ketone.  Separation of 5A and 5B was achieved by HPLC.  The conversion of 5A to the 3xcex1-sulfate 15 with pyridine:sufur trioxide reagent is exemplified.  The alkali metal salts of 5A and 5B can be prepared by treatment of the respective alcohol with an alkali metal hydride, such as sodium hydride, in a non-aqueous solvent such as THF or DMF.  The alkali metal salts of 5A and 5B are useful as intermediates in the preparation of the sulfate esters (via amine:sulfur trioxide treatment) of 5A and 5B, and are also useful as estrogenic compounds.  
Scheme III shows the preparation of estra-5(10),7-dien-3xcex2-ol-17-one 3-glucuronide sodium salt (16) and estra-5(10),7-dien-3xcex1-ol-17-one 3-glucuronide sodium salt (17) from estra-5(10),7-dien-3xcex2-ol-17-one (5B) and estra-5(10),7-dien-3xcex1-ol-17-one (5A), respectively.  The sodium glucuronides (16) and (17) can be treated with mild acid to provide the respective 3-glucuronides.  
The compounds of this invention are estrogenic, as shown in the in vitro and in vivo standard pharmacological test procedures described below in which compounds estra-5(10),7-dien-3xcex2-ol-17-one (5B) and estra-5(10),7-dien-3xcex1-ol-17-one (5A) were evaluated as representative compounds of this invention. 
Estrogen Receptor Binding
An initial evaluation examined the competitive binding properties of 5B and 5A to the human estrogen receptor (hER-xcex1) prepared as a soluble cell extract (cytosol).  In this standard pharmacological test procedure, 5B and 5A demonstrated no specific binding activity.  However, when estrogen receptor binding was analyzed using a whole cell test procedure, specific binding was clearly demonstrated.  This test procedure indicated an IC50 of 1.5xc3x9710xe2x88x927 M or an estimated Ki of 150 nM for 5B. Similarly, 5A demonstrated an IC50 of 2xc3x9710xe2x88x927 M. This would be compared with a Ki for estrone, equilin and equilenen of 51, 67 and 375 nM, respectively. 
In Vitro Co-Transfection Test Procedure
In this standard pharmacological test procedure, hER-xcex1over-expressed in Chinese hamster ovary (CHO) cells infected with adeno-2x-ERE-tk-luciferase, an estrogen responsive reporter gene construct, cells were exposed to varying concentrations (10-xe2x88x9212xe2x88x9210xe2x88x925M) of 5B or 5A for 24 hours.  Cells were also exposed to 17xcex2-estradiol at 10xe2x88x929 M. Following the 24-hour treatment, cells were lysed and cell extracts assayed for luciferase activity.  The results provided that 5B had an EC50 of approximately 29 nM and 5A of 43 nM. Using a similar test procedure, previous data indicate a 5.6 nM EC50 for estrone. 
In Vivo Uterotropic Activity
Immature rats were treated with varying doses of 5B or 5A for three days (S.C.) as well as additional groups (n=6) of rats treated with 0.5 xcexcg ethinyl estradiol and vehicle as positive and negative controls, respectively.  The results of this standard pharmacological test procedure are presented in the table below. 
The results obtained demonstrate significant uterine stimulation compared with vehicle at almost all doses.  At doses above 10 xcexcg/rat, the difference from vehicle was significant at a p-value less than 0.001 for both 5B and 5A. The estimated EC50 from this test procedure would be approximately 30 xcexcg/rat or 0.6 mg/kg for 5B and somewhat lower for 5A. The EC50 for estrone has been estimated to be 0.2 mg/kg in similar test procedures.  Thus, the data from this in vivo standard pharmacological test procedure data demonstrate that 5B and 5A have significant estrogenic activity. 
Based on the results of these standard pharmacological test procedures using representative compounds of this invention, estra-5(10),7-dien-3xcex2-ol-17-one or a pharmaceutically acceptable salt of its 3-sulfate ester, estra-5(10),7-dien-3xcex2-ol-17-one 3-glucuronide or a pharmaceutically acceptable salt thereof, estra-5(10),7-dien-3xcex1-ol-17-one or a pharmaceutically acceptable salt of its 3-sulfate ester, estra-5(10),7-dien-3xcex1-ol-17-one 3-glucuronide or a pharmaceutically acceptable salt thereof, estra-5(10),7-dien-3xcex2-ol-17-one 3-alkali metal salt, and estra-5(10),7-dien-3xcex1-ol-17-one 3-alkali metal salt are useful in replacement therapy in estrogen deficiency.  The compounds of this invention are therefore useful in providing estrogen replacement therapy following ovariectomy or menopause, and in relieving symptoms related to estrogen deficiency, including vasomotor symptoms, such as hot flushes, and other menopausal related conditions, such as vaginal atrophy, vaginitis, and atrophic changes of the lower urinary tract which may cause increased urinary frequency, incontinence, and dysuria.  The compounds of this invention are useful in preventing bone loss and in the inhibition or treatment of osteoporosis.  The compounds of this invention are cardioprotective and they are useful in the treatment of atherosclerosis.  These cardiovascular protective properties are of great importance when treating postmenopausal patients with estrogens to prevent osteoporosis and in the male when estrogen therapy is indicated.  The compounds of this invention are also antioxidants, and are therefore useful in treating or inhibiting free radical induced disease states.  Specific situations in which antioxidant therapy is indicated to be warranted are with cancers, central nervous system disorders, Alzheimer""s disease, bone disease, aging, inflammatory disorders, peripheral vascular disease, rheumatoid arthritis, autoimmune diseases, respiratory distress, emphysema, prevention of reperfusion injury, viral hepatitis, chronic active hepatitis, tuberculosis, psoriasis, systemic lupus erythematosus, adult respiratory distress syndrome, central nervous system trauma and stroke.  Additionally, the compounds of this invention are useful in the suppression of lactation, and in the prophylaxis and treatment of mumps orchitis. 
The compounds of this invention can be used alone as a sole therapeutic agent or can be used in combination with other agents, such as other estrogens, progestins, or and androgens. 
The compounds of this invention can be formulated neat or with a pharmaceutical carrier for administration, the proportion of which is determined by the solubility and chemical nature of the compound, chosen route of administration and standard pharmacological practice.  The pharmaceutical carrier may be solid or liquid. 
A solid carrier can include one or more substances which may also act as flavoring agents, lubricants, solubilizers, suspending agents, fillers, glidants, compression aids, binders or tablet-disintegrating agents; it can also be an encapsulating material.  In powders, the carrier is a finely divided solid which is in admixture with the finely divided active ingredient.  In tablets, the active ingredient is mixed with a carrier having the necessary compression properties in suitable proportions and compacted in the shape and size desired.  The powders and tablets preferably contain up to 99% of the active ingredient Suitable solid carriers include, for example, calcium phosphate, magnesium stearate, talc, sugars, lactose, dextrin, starch, gelatin, cellulose, methyl cellulose, sodium carboxymethyl cellulose, polyvinylpyrrolidine, low melting waxes and ion exchange resins. 
Liquid carriers are used in preparing solutions, suspensions, emulsions, syrups, elixirs and pressurized compositions.  The active ingredient can be dissolved or suspended in a pharmaceutically acceptable liquid carrier such as water, an organic solvent, a mixture of both or pharmaceutically acceptable oils or fats.  The liquid carrier can contain other suitable pharmaceutical additives such as solubilizers, emulsifiers, buffers, preservatives, sweeteners, flavoring agents, suspending agents, thickening agents, colors, viscosity regulators, stabilizers or osmo-regulators.  Suitable examples of liquid carriers for oral and parenteral administration include water (partially containing additives as above, e.g. cellulose derivatives, preferably sodium carboxymethyl cellulose solution), alcohols (including monohydric alcohols and polyhydric alcohols, e.g. glycols) and their derivatives, lethicins, and oils (e.g. fractionated coconut oil and arachis oil).  For parenteral administration, the carrier can also be an oily ester such as ethyl oleate and isopropyl myristate.  Sterile liquid carriers are useful in sterile liquid form compositions for parenteral administration.  The liquid carrier for pressurized compositions can be halogenated hydrocarbon or other pharmaceutically acceptable propellant. 
Liquid pharmaceutical compositions which are sterile solutions or suspensions can be utilized by, for example, intramuscular, intraperitoneal or subcutaneous injection.  Sterile solutions can also be administered intravenously.  The compounds of this invention can also be administered orally either in liquid or solid composition form. 
The compounds of this invention may be administered rectally or vaginally in the form of a conventional suppository.  For administration by intranasal or intrabronchial inhalation or insufflation, the compounds of this invention may be formulated into an aqueous or partially aqueous solution, which can then be utilized in the form of an aerosol.  The compounds of this invention may also be administered transdermally through the use of a transdermal patch containing the active compound and a carrier that is inert to the active compound, is non toxic to the skin, and allows delivery of the agent for systemic absorption into the blood stream via the skin.  The carrier may take any number of forms such as creams and ointments, pastes, gels, and occlusive devices.  The creams and ointments may be viscous liquid or semisolid emulsions of either the oil-in-water or water-in-oil type.  Pastes comprised of absorptive powders dispersed in petroleum or hydrophilic petroleum containing the active ingredient may also be suitable.  A variety of occlusive devices may be used to release the active ingredient into the blood stream such as a semipermeable membrane covering a reservoir containing the active ingredient with or without a carrier, or a matrix containing the active ingredient.  Other occlusive devices are known in the literature. 
The dosage requirements vary with the particular compositions employed, the route of administration, the severity of the symptoms presented and the particular subject being treated.  Based on the results obtained in the standard pharmacological test procedures, projected daily dosages of active compound would be 0.02 xcexcg/kg-750 xcexcg/kg.  Treatment will generally be initiated with small dosages less than the optimum dose of the compound.  Thereafter the dosage is increased until the optimum effect under the circumstances is reached; precise dosages for oral, parenteral, nasal, or intrabronchial administration will be determined by the administering physician based on experience with the individual subject treated.  Preferably, the pharmaceutical composition is in unit dosage form, e.g. as tablets or capsules.  In such form, the composition is sub-divided in unit dose containing appropriate quantities of the active ingredient; the unit dosage forms can be packaged compositions, for example, packeted powders, vials, ampoules, prefilled syringes or sachets containing liquids.  The unit dosage form can be, for example, a capsule or tablet itself, or it can be the appropriate number of any such compositions in package form. 
The following provides the preparation of representative compounds of this invention.  In particular the preparation of the compounds shown in Schemes I and II are described.  The compound numbering used in these schemes is also used in the following examples.