MXPA00003695A - Estra-1,3,5(10)-triene-7alpha-thioethers - Google Patents

Abstract

The invention provides estrogens and antiestrogens of formula (I) having structure (I) wherein R is (II), (III), (IV), or (V);R1 and R2 are each, independently, alkyl of 1-6 carbon atoms, or are alkyl groups which are taken together to form a 5-7 membered satured heterocycle;X is hydroxy, alkoxy of 1-6 carbon atoms, or -OC(O)R3;W is (VI), hydroxy, alkyl of 1-6 carbon atoms, halogen, -CF3, alkoxy of 1-6 carbon atoms, -CHO, cyano, alkylcarbonyl of 2-7 carbon atoms, alkoxycarbonyl of 2-7 carbon atoms, amino, alkylamino of 1-6 carbon atoms, dialkylamino of 1-6 carbon atoms per alkyl group, trifluoromethoxy, hydroxyalkyl of 1-6 carbon atoms, alkoxyalkyl of 2-12 carbon atoms, -CN, -SO3H, or -CO2H;R3 is alkyl of 1-6 carbon atoms;Z is (VII), (VIII), (IX), or (X);Y is (XI), (XII), or (XIII);R4 is hydrogen, alkyl of 1-6 carbon atoms, alkoyl of 2-7 carbon atoms, or benzoyl;Q is hydrogen, -OR5, or -NR6R7;R5 is hydrogen or alkyl of 1-6 carbon atoms;R6 and R7 are each, independently, alkyl of 1-6 carbon atoms, or are alkyl groups which are taken together to form a 5-7 membered saturated heterocycle;n=4-12;and p=2-6;or a pharmaceutically acceptable salt thereof.

Description

ESTRA-l, 3,5 (10) -TRIEN-7alfa-TIOETERES BACKGROUND OF THE INVENTION This invention provides estra-1, 3, 5 (10) -trien-7a-thioethers which are useful as estrogenic and antiestrogenic agents.

The last decade has witnessed the introduction of a new class of antiestrogenics devoid of any estrogenic activity. The prototype compounds are substituted steroids 7a reported by ICI in the 1980's. (Alkeling and Bowler, J. Steroids Biochem 30: 141-147 (1988), US Patent 4,659,516). Since then, there have been additional reports of steroidal compounds that purported to have a purely estrogenic activity (see WO 93/10741 and some references contained therein). The potential advantage of these compounds is that they lack the residual agonistic properties of some agonist mixtures such as tamoxifen (sold as a Novadexen® brand tamoxifen citrate by Zeneca Pharmaceuticals, Wilmington, Delaware). The residual agonistic activity of tamoxifen may be significant in some tissues such as the uterus and bone. While the activity in the bone can be appreciated, the activity REF .: 119105 estrogen in the uterus may be associated with the increased risk of uterine cancer observed in users for long periods of tamoxifen. The pure antiestrogens reported by ICI did not show tropic or proliferative activity in the uterus and should not presumably increase the risk of uterine cancer associated with estrogen. Additionally, the trend for women who are being treated chronically with tamoxifen to develop tamoxifen-resistant tumors has been well documented. It is expected that the application of antiestrogens that are devoid of any agonistic activity should be able to enable the impact on tumors resistant to tamoxifen by supplying a more complete estrogen removed from estrogen-dependent type tumors. (Walkeling, et al., J. Mol.endocr., 2; 225-234 (1989)).

The substituents at position 7 of the estratrienes must have the stereochemistry a to show a good affinity for the estrogen receptors as well as good antiestrogenic efficacy (Walkeling, et al., Vide supra). The pre-date technique (related to antistrogens) on the estratriene substituents in position 7 has been limited to the side chains connected to the structure of the steroid by carbon-carbon bonds. A 7-thiopropionate linker has been described in the literature for the purpose of conjugation of bovine serum albumins. The compounds were synthesized by the radical addition of β-mercaptopropionate to 1, 3, 5 (109,6-estratetraenes (Cook, et al Life Sci, (1974), 14 (6), 1075-1087). , 3, 5 (10) stratrienes in which a large number of claims related to functionality in position 7 including thioalkenyl and thioalkynyl ethers have been described with a chain length of up to 6 carbons (Damato, et al, US 5504074).

Description of the invention This invention provides compounds of formula I that have the structure Where R1 and R2 are each independently, alkyl of 1-6 carbon atoms, or are alkyl groups that are taken together to form a 5-7 membered saturated heterocycle; X is hydroxyl, alkoxy of 1-6 carbon atoms, or -OC (0) R3; W is 20, hydroxyl, alkyl of 1-6 atoms carbon, halogen, -CF3, alkoxide of 1-6 carbon atoms, cyano, alkylcarbonyl of 2-7 carbon atoms, alkoxycarbonyl of 2-7 carbon atoms, amino, alkylamino of 1-6 carbon atoms, dialkylamino of 1 -6 carbon atoms per alkyl group, trifluoromethoxide, hydroxyalkyl of 1-6 carbon atoms, acolxyalkyl of 2-12 carbon atoms, -CN, -S03H, or -C02H; R is alkyl of 1-6 carbon atoms; R 4 is hydrogen, alkyl of 1-6 carbon atoms, or benzoyl; Q is hydrogen. -OR5, or -NR6R7; R5 is hydrogen or alkyl of 1-6 carbon atoms; R6 and R7 are each, independently, alkyl of 1-6 carbon atoms, or are alkyl groups that are taken together to form a 5-7 membered saturated heterocycle; N = 4-12; and P = 2-6; Or a pharmaceutically acceptable salt thereof which is useful as an estrogenic or antiestrogenic agent.

The alkyl, and the alkyl chain of the alkoxy including both the straight chain as well as the branched portions. The alkoxy of 2-7 carbon atoms is defined as an alkyl carbonyl moiety in which the alkyl chain is formed of 1-6 carbon atoms: for example, an acetyl group. Where R 4 is benzoyl the phenyl group may be optionally mono-, di- or tri- substituted with substituents selected from the group consisting of alkyl of 1-6 carbon atoms, alkoxy of 1-6 carbon atoms, amino, alkylamino of 1-6 carbon atoms, dialkylamino of 2-12 carbon atoms, hydroxyl, halogen, cyano, -C02H, nitro, alkylcarbonyl of 2-7 carbon atoms, alkoxycarbonyl of 2-7 carbon atoms and thiol. Halogen means bromide, chloride, fluoride, and iodide.

Pharmaceutically acceptable salts include derivatives of organic and inorganic acids such as, but not limited to: acetic, propionic, lactic, citric, tartaric, succinic, fumaric, maleic, malonic, mandelic, malic, phthalic, hydrochloric, hydrobromic, phosphoric, nitric , sulfuric, methanesulfonic, naphthalenesulfonic, benzenesulfonic, toluenesulfonic, camphorsulfonic and similar known acceptable acids. Carboxylate salts, preferably alkali metals eg sodium, lithium, or potassium can also be prepared as salts of carboxylic acids when the compounds of this invention contain a carboxylate moiety.

Preferred compounds are those in which those in which; lf 'and those in which: And R4 is hydrogen or 2-7 carbon atoms. The compounds of this invention wherein R is antiestrogenic, and the compounds of this invention in which R is They are estrogenic.

The compounds of this invention can be synthesized from the diacetate of 7a-bromo-3, 17β-dihydroxy-estra-1, 3, 5 (10) -trien-6-one I [CAS registration No. 97829-67-9 ] by the route shown in scheme 1. The reaction of I with the appropriate thiol and sodium hydride in DMF results in the substitution of the bromide that occurs with the retention of stereochemistry at position 7 to obtain II. The acetyl group in position 3 often breaks off (at least partially) during this step. If the acetyl group is only partially removed during this step, one may wish to complete the removal by stirring the compound in methanol with potassium carbonate. Ketone II can subsequently be reduced to a 6a-hydroxy-7a-thioether II, and this reduction occurs diastereoselectively (Wintersteiner, et al, J. Org. Chem., 29, 1325 (1964); Smith et al, J. Org. Chem., 37 4000 (1972)). Deoxygenation is subsequently completed with trufluoroacetic acid and triethylamine to give IV. The 17ß acetate can be hydrolyzed, if desired, to obtain V.

Scheme 1 The synthesis of the cinnamamides shown in scheme 2 is based on the same intermediate I as was used for the compounds of the type in scheme 1. The displacement of the 7a-bromo substituents occurs with retention of the configuration providing the 7a- (4 '-bromophenyl) thioether desired. This reaction results in the cleavage of labile 3-acétate. The reduction of the carbonyl group gives the 6a-hydroxy derivative VII as a mesylate and displaced with a suitable protected hydroxide or alkoxy. Alternatively, VII may be subject to the Mitsunobu reaction (triphenylphosphine, diethylazodicarboxylate, and acetic acid) followed by hydrolysis of the 6β-acétate intermediate.

The 6a-hydroxy compound is subsequently deoxygenated with triethylsilane and trifluoroacetic acid to give the compound VIII. The bromide is displaced by the alkyl acrylamide (or acrylate esters) using a Heck coupling reaction to give the compounds of type IX. If desired, the 17β-acetate and the acrylate ester can be hydrolyzed using NaOH / MeOH to give a 3, 17β-dihydroxy estratriene X.

Scheme 2 The dialkylethoxyethoxide derivatives can be synthesized according to Scheme 3. The bromoketone XI [CAS Registry No: 6218-36-6] is reduced with 4-hydroxythiophenol to give XII. The ketone is reduced to give XIII and subsequently deoxygenated with TFA / Et3SiH to give XIV. The free phenol is alkylated with the appropriate dialkylaminoethyl chloride to give the XV type compounds. The protective groups at position 17 can be removed if desired to give compounds of type XVI. The methyl ester in the C-3 position can be removed, if desired, through the use of reagents such as BBr3, AlCl3 / EtSH, Pyr, HCL, etc. Scheme 3 Scheme 4 NaH.THF The representative compounds of this invention were evaluated in a standard pharmacological test procedure of alkaline phosphatase using Ishikawa uterine cells to measure their estrogenic and antiestrogenic activity. The representative compounds were also tested for their ability to bind to the human estrogen receptor. Several representative compounds were also evaluated in a standard in vivo pharmacological test procedure to determine their effects on the uterus of rats. The compounds examined will be referred to by means of their example numbers that are given in Table 1. Table 1 The following briefly describes the procedures used and the results obtained in the evaluation of the compounds of this invention.

Test procedure for the binding of estrogen receptors in vitro.

Preparation of the receptors Cells of several Chinese hamsters (CHO) overexpressing the estrogen receptor were cultured in plates of 150 mm2 in DMEM + 10% vegetable charcoal coated with dextran, fetal bovine serum. Plates were washed twice with PBS and once with 10 nM tris-HCl, pH 7.4, EDM InM. The cells were harvested by scraping the surface and then the cell suspension was placed on ice. The cells were disrupted with a manual tissue grinder using two 10 second bursts. The crude preparation was centrifuged at 12,000g for 20 minutes followed by a 60 minute rotation at 100,000G to produce a cytosol free ribosome. The cytosol was then frozen and stored at 180 ° C. The protein concentration of the cytosol was estimated using a BCA assay with standard reference protein.

Conditions of the Link Testing Procedures. The competition tests were carried out on a plate of 96 tanks (polyethylene) to which they joined < 2.0% of the total entered [3H) -17ß-estradiol + competitor (or buffer) in a volume of 50 ul, was added in the preliminary competition when lOOx and 500x of the competition were evaluated, only 0.8 nM of [3H] was used -17ß-estradiol. The plate was incubated at room temperature for 2.5 h. At the end of this incubation period, 150 uL of dextran-coated charcoal (5% activated charcoal coated with 0.05% dextran 69K) was added to each tank and the dish was immediately centrifuged at 99g for 5 minutes at 4 ° C. . 200 uL of the supernatant solution was then removed for the scintillation count. Samples were counted at 2% or 10 minutes whichever occurred first. Because the polystyrene absorbs a small amount of [3H] 17β-estradiol deposits containing radioactivity and cytosol, but not processed with charcoal were included to quantify the amounts of available isotope. Also, deposits containing radioactivity but not cytosol that were processed with charcoal to estimate the MPR of [3H] 17β-estradiol not removed. 96-well plates were used because they have proven to retain the least amount of estradiol.

Analysis of results The counts per minute (CPM) of radioactivity were converted automatically to disintegrations per minute (DPM) using the Beckman LS 7500 scintillator using a set of standard suppressors to generate an H # for each example. To calculate the% of extradiol bound in the presence of 100 to 500 competitors folded the following formula was applied: (Sample DPM - DPM not removed by vegetative carbon) / (DPM estradiol - DPM not removed by charcoal) x 100 % =% of estradiol bound.

For the generation of the IC50 curves, the% of unions were plotted against the compound. IC50's are generated by compounds that show > 30% competition at competitor concentrations of 500x. The values are reported as IC50 values. For comparison, 17β-estradiol has an IC50 representation of 18"8-10 ~ 9. For a description of these methods, see Hulme, EC ed 1992. Receptor-Ligand Interactions: A Practical Approach, IRL Press, New York (see especially chapter 8).

Procedure of the Alkaline Phosphatase Test for Ichikawa Cells. Maintenance and treatment of cells Ishikawa cells were maintained in DMEM / F12 (50%: 50%) containing phenol red + 10% fetal bovine serum and the medium was supplemented with 2 mM Glutamax, 10% cornered / bound and 1 mM pyruvate of sodium. Five days prior to the start of each evaluation (cell treatment) the medium was changed to DMEM / F12 free of phenol red + 10% of whey discovered with charcoal coated with dextran. The day before the treatment, the cells were harvested using 0.5% trypsin / EDTA and placed in the dishes at a density of 5 × 10 04 cells / tank in tissue culture dishes 96. The test compounds were dosed at 10"6, 10" 7 and 10"8 in addition to 10" 6 M (of the compound) + 1O "9 M of 17β-estradiol, to evaluate the ability of the compounds to function as antiestrogens The cells were treated by 48 H prior to the test each of The 96-well dishes contained a control of 17β-estradiol The sample population for each dose was n = 8. Alkaline phosphatase test procedure At the end of 48 h the medium was aspirated and the cells were washed 3 times with phosphate buffered saline (PBS); 50 μL of buffer lysis (0.1 M tris HCl, pH 9.8 0.2 Triton X-100) were added to each tank. The avocados were placed at -80 ° C for a minimum of 15 minutes. Plates were thawed at 37 ° C followed by the addition of 150 μL of Tris-HCl, pH 9.8, containing 4 nM para-nitrophenyl phosphate p (NPP) to each well (final concentration, 3mM pNPP).

The absorbance and slope calculations were made using the KineticCalc application program (Bio-Tek Instruments, Inc., Winooski, VT). The results are expressed as the average +/- S.D. of the speed of the enzymatic reaction (slope) averaged over the linear portion of the reaction kinetic curve (the optical density readings every 5 minutes for 30 minutes of absorbance reading). The results for the compounds are summarized as percent response related to 1 mM 17β-estradiol.

The representative compounds of this invention were evaluated for estrogenic activity by the alkaline phosphatase method and the corresponding ED5o values (9.5% Cl) were calculated. Four compounds were used as reference standards: 17ß-estradiol 0.03 nM 17a-estradiol 1.42 nM estradiol 0.13 nM estrone 0.36 nM a description of these methods is described by Hilinka, C. F, Hata, H., Kuramoto, H. and Gurpide, E. (1086) Effects of steroids, hormones and antiesteroids on alkaline phosphatase activity in human endometrial cancer cells (Ishikawa line Cancer research 46: 2771-2774, and by Littlefield, BA, Gurpide, E., Markiewicz, L., Mckinley, B. and Hochberg, RB (1990) A simple and sensitive microtiter plate estrogen biossay based on stimulation alkaline phosphatase in Ishikawa cells; Estrogen action of D5 adrenal steroids Endocrinology, 6: 2757-2762.

Erotropic test procedure / autiutererotrofico in rats The estrogen and antiestrogenicas properties of the compounds were determined in a uterotropic trial of 4 days in immature rats (as previously described by L.J.Black and R.L.Goode, Life Sciences, .26 1453 (1980)). The immature Sprague-Dawley rats (females, 18 days old) were tested in groups of six. The animals were treated with a daily injection with 10 ug of compound, 100 ug of compound, (100 ug of compound + 1 uG of 17β-estradiol for compounds that were strongly antiestrogenic in the alkaline phosphatase assay) to check antiestrogenicity, and 1 ug of 17β-estradiol, with 50% DMSO / 50% saline as the vehicle of the injection. On day 4 the animals were sacrificed by C02 and their uteri were removed and discovered of excess lipids, any fluid was removed and the weight of the moisture was determined. A small section of a tube was subjected to histology and the rest was used to isolate the total RNA to evaluate the complementary components of gene 3 expression.

Results The following tables and description describe the results obtained in the standard pharmacological procedures. Table 2. Assay of the Fos atasa Alkaline in Ishikawa Cells Example Concentrations Table 2. Cont. Assay of Alkaline Phosphatase in Ishikawa Cells Example Concentrations Compounds that show low percentages in the agonist mode, as well as low percentages in the antagonist mode (# 17 and # 18, especially) behave as pure estrogen antagonists in this uterine cell line. Compounds that show intermediate values in the antagonist mode (# 9- # ll) behave as mixed agonists, thus have estrogen characteristics with partial efficacy and as antiestrogens with partial efficacy. Compounds that show total efficacy (100%) for at least the highest doses (# 5 and # 6) and do not antagonize a co-administered dose of estradiol are considered fully effective agonists in this uterine cell line. The compounds were tested for their ability to displace estradiol in preparations of human ER-receptors. The IC5o were derived from the competition curves and this is the number reported in Table 3. The 17ß-estradiol has an IC50 range of 10 ~ 8-10 ~ 9 M.

Table 3 ER receivers of IC50 for Examples # 1- # 18 As could be anticipated, compounds that had an acetate in the 17ß position compete less effectively for human estrogen receptors (compounds # 1, # 5, # 9, and # 14.) Some of these compounds could, however, have activity. in Ishikawa cells, probably indicating the ability of these cells to partially metabolize these compounds by enzymatic hydrolysis of the 17β-acetates.

Representative compounds of this invention were evaluated in the uterotropic / anti-uterotropic tests in the rats to determine their effects in vivo in the rat uteri. Examples # 3 and # 18 were tested in both the agonist mode as well as the antagonist mode (cmpd + 17β-estradiol). The results are given in Table 4 for the selected examples.

Table 4. Effect on rat uteri As can be seen from Table 4, some of the compounds functioned as full agonists giving stimulatory effects similar to 17β-estradiol, while other compounds did not show uterine effects when dosed alone or with a co-administered dose of 17β-estradiol.

Based on the results obtained in the procedures of standard pharmacological tests, the compounds of this invention in which R is are estrogenic, and the compounds of this invention in which R is cos The compounds of this invention that are estrogenic are useful in the treatment or prevention in a disease state in a mammal that is caused or associated with an estrogen deficiency (in certain tissues such as bone or cardiovascular) or an excess of estrogen. (in the uterus or mammary glands). Pure estrogen agonists can completely antagonize the tropic effects of estrogen agonists in uterine tissue and are useful in the treatment of diseases or disorders resulting from the proliferation or abnormal development, actions or growth of tissues such as endometrial or similar to endometrial Based on the results. obtained in standard pharmacological test procedures, the compounds of this invention are useful in the treatment of diseases or conditions resulting from the effects of estrogens and excess or deficiency of estrogens including osteoporosis, prostatic hypertrophy, skin atrophy and vaginal atrophy, acne , cardiovascular disease, contraception, Alzheimer's disease, cognitive decline and other CNS disorders. Additionally, the estrogenic compounds of this invention can be used for contraception in pro-menopausal women, as well as hormone replacement therapy in pro-menopausal women or in other estrogen deficiency states where estrogen supplementation should be beneficial. The estrogenic compounds of this invention are also useful in the treatment for and inhibition of bone loss, which can result from an inbalance in the formation of an individual from new bone tissue and the resorption of old tissue, leading to a net loss of bone. Such bone depletion results in a range of individuals particularly in post-menopausal women, women who have undergone bilateral oophorectomy, those who receive or have received extensive corticosteroid therapies, those who experience gonadal dysgenesis and those who suffer from Cushimg syndrome. In special needs for bone that include dental and oral bone, replacement can also be directed using these compounds in individuals with bone fractures, defective bone structures, and those who received bone-related surgeries and / or implantation of bone. prosthesis. In addition to those problems described above, these compounds can be used in the treatment of osteoarthritis, hypocalcemia, hypercalcemia, Paget's disease, osteomalacia, osteohalisterisis, multiple myeloma and other forms of cancer that have deleterious effects on the bone tissues.

Based on the results obtained in standard pharmacological test procedures, the compounds of this invention that are estrogen antagonists are useful in antiestrogen delivery therapies, particularly in the treatment of male pattern baldness, dysfunctional uterine bleeding, endometrial polyps, benign breast disease, uterine leiomyomas, adenomyosis, in the treatment of neoplasms such as ovarian cancer, breast cancer, endometrial cancer, melanoma, prostate cancer, colon cancer and CNS cancer, in the treatment of endometriosis, polycystic ovarian syndrome , and infertility and its prevention.

The effective administration of these compounds can be provided in a dose from about 0.1 mg / day to about 1000 mg / day. Preferably, the administration can be from about 10 mg / day to about 600 mg / day. Preferably from about 50 mg / day to about 600 mg / day, in a single dose or in two or more divided doses. Such doses may be administered in a manner useful for directing the activity of the active compounds from here to the bloodstream of the receptors, including orally, via implants, perenterally (including intravenous, intraperitoneal and subcutaneous injections), rectally, vaginally and transdermally. For the purposes of this disclosure, transdermal administrations are understood to include all administrations through the body surface or the inner linings of the body passages including the epithelial and mucosal tissues. Such administrations can be carried out using the present compounds, or pharmaceutically acceptable salts thereof, in lotions, creams, foams, patches, suspensions, solutions, and suppositories (rectal and vaginal).

Oral formulations containing the active compounds of this invention comprise any of the oral forms conventionally used, including tablets, capsules, mouth shapes, TROCHES, pills and oral fluids, suspensions or solutions. The capsules may contain mixtures of the active compound (s) with inert fillers and / or diluents such as pharmaceutically acceptable starches (eg, corn, potato or tapioca starches), sugar artificial sweetening agents, celluloses in powder, such as crystalline and microcrystalline celluloses, flours, gelatins, gums, etc. the formulations used in tablets can be made by conventional compression, wet granulation or dry granulation methods and using pharmaceutically acceptable diluents, binding agents, lubricants, disintegrants, suspending agents or stabilizers, including, but not limited to, magnesium stearate, acid stearic, talcum, sodium lauryl sulfate, microcrystalline cellulose, calcium carboxymethyl cellulose, polypyrrylline, gelatin, alginic acid, acacia gum, xanthan gum, sodium citrate, complex silicates, calcium carbonate, glycine, dextrin, sucrose, sorbitol , dicalcium phosphate, calcium sulfate, lactose, kaolin, mannitol, sodium chloride, talc, dried starches and powdered sugar. The oral formulations here can be used with standard delays or time-release formulations to alter the absorption of the active compound (s). Suppository formulations can be made from traditional materials, including cocoa butter, with or without the addition of waxes to alter the melting point of the suppository, and glycerin. Water-soluble suppository bases, such as polyethylene, glycols of various molecular weights, may also be used.

It is understood that the doses, regimen and mode of administration of these compounds could vary according to the disease and the individual being treated and will be subject to the judgment of the physician involved. It is preferred that the administration of one or more of the compounds here begin at a low dose and increase until the desired effects are achieved.

The following procedures describe the preparation of representative examples of this invention. The compound term is used when describing compounds of the text (compounds associated with numbering in Roman numerals). The term example, refers to specific examples listed in table 1.

All reactions were carried out under a nitrogen atmosphere. Chromatography was developed using 230-400 mesh silica gel. Layer chromatography was developed with Silica Gel in 60 F254 plates. The spectra - '? NRM were obtained in a Brunker AM-400 instrument in DMSO-d6 or CDC13 and the chemical changes are reported in ppm.

General Procedure 1: Substitution of diacetate of 6-oxo-7-bromo estradiol with nucleophiles thiol to form compounds of type II of scheme 1: A solution of an alkanethiol or benzenethiol (2-2.5 equivalents) in DMF was cooled to 0 ° C and treated with 2-2.5 equivalents of NaH (60% dispersion in mineral oil). The reaction mixture was stirred a few minutes, then bromoketone I (Scheme 1) (1 equivalent) was dissolved in DMF and added. The reaction mixture was allowed to come slowly to rt, stirred overnight, poured into HClaq 0.1 N and extracted with ethyl ether. The ether layer was washed with NaHC03 aq brine and then dried over sodium sulfate. The filtrate was concentrated and the residue was chromatographed on silica gel to produce the product, usually in a higher yield -large 50%. The bromo-substituted displacement proceeded with retention of the stereochemistry (diasteroselectivity> 95%) as determined by 1H NRM spectroscopy. The signal for proton-7 showed a very small coupling constant (< 3.5 Hz) with proton-8β, therefore. The 7th equatorial hydrogen (ß). The 3-O-acetyl group can be hydrolyzed or partially hydrolyzed during the course of the reaction. If the incomplete unfolding occurs as evaluated by TLC analysis (EtAc / hexanes), the crude mixture (material after the reaction but before chromatography or crystallization) can be dissolved in methanol and treated with an equivalent of K2C03. This can convert the material to a completely deacetylated material. Alternatively, if desired the compound can be reacetylated at this point by placing the crude reaction mixture in pyridine and treating with an excess of acetic anhydride and stirring until the complete reaction occurs. The reaction can be heated to accelerate the process. Re-acetylation is not necessary, however, to proceed with the synthesis so that the phenolic group does not interfere with any of the subsequent steps.

General Procedure 2: Reduction of the 6-oxo-7-thioter estratienos The 6-oxo-7-thio-estrogen II (Scheme 1) from the previous step was dissolved in EtOH and an excess of NaBH 4 was added. The reaction was followed by TLC until complete (typically a few hours). The reaction was developed by the addition of a saturated solution of aqueous ammonium chloride and more of the ethanol was evaporated on a rotary evaporator. The aqueous portion was extracted with ethyl acetate, washed with water, brine, dried over sodium sulfate and concentrated. Typically, this reaction is very clean and the compound can be taken to the next step without further purification. If desired, however, the reaction mixture can be chromatographed on silica gel using ethyl acetate / hexanes as solvents for elution.

General Procedure 3: Deoxygenation of the 6-hydroxy functionality and hydrolysis of the 17-acetate to form the structure compounds type IV and V of scheme 1.25 grams of 6-hydroxy-7-thioether estratriene III (Scheme 1) of the steps immediately previous were dissolved in 12 mL of acetonitrile, to which 14 mL of Et3SiH and 34 mL of CF3COOH were added. The reaction was heated to about 50 ° C from several hours to one night. After the TLC indicated that the reaction was complete, the reaction mixture was diluted with ether and washed several times with a saturated aqueous solution of sodium bicarbonate. The ether was washed with water, brine and dried over sodium sulfate. After concentration, the residue can be chromatographed on silica gel (typically with ethyl acetate / hexanes mixtures). If desired, the acetate at position -17 can be easily saponified by dissolving the acetate in methanol and adding an aqueous solution of NaOH. The reaction was monitored by TLC for the disappearance of the initial materials. If several equivalents of NaOH were used, the reaction was completed in one hour. The reaction was subsequently neutralized with aqueous HCl solution and the methanol was removed. The product was extracted with ethyl acetate or ether and washed with aqueous NaHCO 3 solution, brine water and dried over sodium sulfate. If necessary, the material can be chromatographed on silica gel.

General Procedure: Coupling reaction in excess for the synthesis of acrylates or acrylamides of Scheme 2 Y_il The compounds analogous to VIII (Scheme 2) or # 8 of Table 1 were used as starting materials for the synthesis of compounds # 9, # 10 and # 11 (Table 1). The starting materials were placed in triethylamine and purged with nitrogen. The resulting solution was treated with 1 mol% Pd (OAc) 2 and 4 mol% tri-ortolylphosphine and 1.25 to 1.50 equivalents of the appropriate acrylate or acrylamide. The reaction was typically run in closed pressure tubes in an oxygen-free environment. The reaction was heated to 100-120 ° C from a few hours to a few days depending on the specific substrate and the acrylate or acetylamide used. The reaction can be accelerated by the use of a larger amount of catalyst (up to 5 mol% of Pd (Oac) 2). When the reaction was complete by TLC analysis, the solution was concentrated and partitioned between 2N aq HCl and ethyl ether. The ether layer was washed with aq NaHCO 3, brine, and dried over sodium sulfate. It was concentrated and chromatography provided the desired compounds in yields generally > fifty%. If an acrylic acid such as compound # 11 (Table 1) is desired, then the hydrolysis of methyl acrylate # 9 (Table 1) can be easily completed in good yield by saponification with bases in MeOH / THF 2.5 NaOH 2.5 N aq. (8: 15: 2 v / v / v) at room temperature for one night. The acetate in C-17 (if present) also unfolds during this reaction. The reaction was developed by the addition of a 2N aq HCl solution to acidify and evaporation of MeOH and THF. The product was extracted with ether and washed with water, brine and dried over sodium sulfate. The residue can be chromatographed on silica gel (MeOH / CH2Cl2) to obtain the pure product in good yield.

General Procedure 5: Synthesis of compounds containing the basic base chain of Scheme 3: Compounds # 14 and # 15 (Table 1) can be readily synthesized from precursor compounds analogous to 3-methyl ether-17β-acetate estratriene XIV (Scheme 3). The starting material was dissolved in DMF and treated with 3 equivalents of K2C03 and 1.5 equivalents of the chloroethylamide hydrochloride salt and the reaction was developed by partition between water and ether, and the ether layer was washed with brine, and after dry on sodium sulfate. The ether was concentrated and the residue was chromatographed on silica gel using ethyl acetate. If the compound without an acetate at position -17 is desired (as compound # 15 (Table 1) then the saponification with base can be easily completed by dissolving the substrate in a 2.5N MeOH / THF / NaOH solution (1: 1: 1) and stirring at room temperature until the reaction is complete by TLC. The reaction mixtures were buffered between ether and water and the ether layer was washed with brine and dried over sodium sulfate. The ether was then concentrated and the residue was chromatographed on silica gel (CH2Cl2 / MeOH) to obtain compounds # 14 or # 15 (Table 1).

General Procedure 6: Synthesis of bifenyl analogues from Esquea: Compounds # 12 and # 13 (Table 1) can be prepared using a compound analogous to # 8 (Table 1) or compound VIII (Scheme 4) as a precursor. The precursor was dissolved in a dixane / water solution (3: 1) and treated with 1.5 equivalents of 4-formylbenzeneboronic acid and 1.5 equivalents of K3P04. The reaction mixture was purged with nitrogen and 5 mol% of Pd (PPh3) 4 were added and the reaction was heated to reflux for several hours to overnight. The solution was concentrated and the reaction mixture was partitioned between ether and water and the aqueous layer was acidified with IN HCl. The ether layer was washed with water and brine, and dried over sodium sulfate and concentrated. Chromatography on silica gel (EtOAc / hexanes) gave the desired pure compound. To make acrylate, 1.5 equivalents of (CH30) 2P (O) CH2C02CH3 was dissolved in THF and treated with 1.5 equivalents of NaH (60% dispersion in mineral oil) at 0 ° C. The initial material was dissolved in THF, added by syringe to the reaction at 0 ° C. After several minutes, the reaction was completed by TLC analysis. The development was completed by aqueous ammonium chloride solution and the THF was removed under reduced pressure. The resulting solution was extracted with ether and washed with water, brine, and dried over magnesium sulfate, concentrated and chromatographed on silica gel.

(EtOAc: hexane) gave the desired product in good yield. If acrylic acid was desired, then the ester can be hydrolysed with KOHaq lN / MeOH / THF (3: 2: 6) at room temperature (typically it takes at least 24 hours). The development was complete by acidifying the reaction with 2N HCl and the organics were removed under reduced pressure. The ether was added, and the ether layer was washed with water, brine and dried over MgSO4. The reaction mixture was concentrated and chromatographed using MeOH / CH2Cl2 / 0.5% CH3COOH to give the desired acrylic acid. Alternatively, the washings with NaHCO 3aq, provide the sodium salt (example # 13 used as the sodium salt of the carboxylic acid).

General Procedure 7: Preparation of analogues to undecamide similar to examples # 16, # 17 and # 18: These compounds were made according to the same general procedure as that given for phenylthio compounds (the first of three procedures listed in this section) . The only difference was the side chain used. The thioalkylamide side chains were synthesized according to standard procedures (Labrie, et al, J. Med. Chem 1994, 37, 1115-1125) and used in the same manner as the thiophenols in the first general procedure.

EXAMPLE 1 (7 a, 17 b) 17-Acetoxy-3-hydroxy-7- (4-hydroxyphenyl) thio-estra-1, 3, 5 (10) -trien-6-one: Prepared by General Procedure 2 M.p. 150-155 ° C; XH NMR (DMSO) 9.74 (s, 1H), 9.65 (s, 1H), 7.31 (d, 1H, J = 8.6 Hz), 7.28 (d, 1H, J = 2.9 Hz), 7.18 (d, 2H, J = 8.8 Hz), 7.00 (dd, 1 H, J = 8.6 Hz, 2.9 Hz), 6.72 (d, 2H, J = 8.6 Hz), 4.68 (t, 1H, J = 8.6 Hz), 3.48 (d, 1H , J = 3.1 Hz), 2.72 - 2.62 (m, 1H), 2.42 - 2.33 (m, 1H), 2.29 (dt, 1H, J = 11.0 Hz, 3.1 Hz), 2.20-2.14 (m, 1H), 2.01 (s, 3H), 1.96-1.89 (m, 1H), 1.79 - 1.68 (m, 2H), 1.58-1.30 (m, 4H), 0.79 (s, 3H); IR (KBr) 3300 br, 2890, 1735, 1660 cm "1; MS (EI) m / z 452 (M +).

EXAMPLE 2 (la, 17β) 3, 17-Dihydroxy-7- (4-hydroxyphenyl) thio-estra-1, 3, 5 (10) -trien-6-one: Prepared by General Procedure 2 M.p. 120-124 ° C; ? E NMR (DMSO) 9.73 (s, 1H), 9.64 (s, 1H), 7.31 (d, 1H, J = 8.6 Hz), 7.27 (d, 1H, J = 2.9 Hz), 7.15 (d, 2H, J = 8.6 Hz), 6.99 (dd, 1H, J = 8.3 Hz, 2.9 Hz), 6.72 (d, 2H, J = 8.8 Hz), 4.59 (d, 1H, J = 4.8 Hz), 3.63 - 3.58 (m , 1 H), 3.46 (d, 1H, J = 3.1 Hz), 2.64 (dt, 1H, J = 10.3 Hz, 3.3 Hz), 2.44 - 2.35 (m, 1H), 2.21 (dt, 1H, J = 10.5 Hz, 2.9 Hz), 2.00-1.86 (m, 1H), 1.82-1.62 (, 3H), 1.46-1.20 (m, 4H), 0.67 (s, 3H); IR (KBr) 3450 br, 2950, 1660 cm -1, MS (EI) m / z 410 (M +).

EXAMPLE 3 (6a, la, 17β) 7- (4-Hydroxyphenyl) thio-estra-1, 3, 5 (10) -trien-3, 6, 17 triol: Prepared by General Procedure 2 M.p. 220-225 ° C; * "H NMR (DMSO) 9.50 (s, 1H), 9.09 (s, 1H), 7.37 (d, 2H, J = 8.6 Hz), 7.02 (d, 1H, J = 8.6 Hz), 6.97 (d, 1H , J = 2.2 Hz), 6.68 (d, 2H, J = 8.8 Hz), 6.55 (dd, 1H, J = 8.3 Hz, 2.6 Hz), 5.18 (d, 1H, J = 7.9 Hz), 4.82 (dd, 1H, J = 6.2 Hz, 4.8 Hz), 4.49 (d, 1H, J = 4.8, Hz), 3.56 - 3.49 (m, 1H), 3.24 (dd, 1H, J = 4.4 Hz, 1.54 Hz), 2.56 - 2.50 (m, 1H), 2.28 - 2.20 (m, 1H), 1.85 - 1.70 (m, 3H), 1.63 (q, 1H, J = 9.4 Hz), 1.34 - 1.10 (, 5H), 0.65 (s, 3H) ); IR (KBr) 3400 br, 2900 cm-1; MS (E1) m / z 412 (M +). EXAMPLE 4 (la, 17β) 7- (4-Hydroxyphenyl) thio-estra-1, 3, 5 ( 10) -trien-3, 17-diol: Prepared by the General Procedure 3 Mp 140-145 ° C; XH NMR (DMS) 9.62 (s, 1H), 9.04 (s, 1H), 7.19 (d, 2H, J = 8.6 Hz), 7.08 (d, 1H, J = 8.6 Hz), 6.73 (d, 2H, J = 8.6 Hz), 6.54 (dd, 1H, J = 8.3 Hz, 2.4 Hz), 6.38 (d, 1H, J = 2.4 Hz), 4.52 (d, 1H, J = 4.8 Hz), 3.58 - 3.52 (m, 1H), 3.31 - 3.28 (m, 1H), 3.02 (dd, 1H, J = 16.7 Hz, 3.7 Hz) , 2.72 (d, 1H, J = 16.7 Hz), 2.40-2.25 (m. 2H), 1.94 - 1.84 (m, 1H), 1.82 - 1.71 (m, 2H), 1.62 - 1.45 (m, 2H), 1.41 - 1.10 (m, 4H), 0.66 (s, 3H), IR (KBr) 3390, 2900, 1600 cm "1; MS (EI) m / z 396 (M +).

EXAMPLE 5 (la, 17β) 17-Acetoxy-7- (4-bromophenyl) thio-3-hydroxy-estra-1, 3, 5 (10) -trien-6-one: prepared by General Procedure 2 M.p. 190-192 ° C; XH NMR (CDC13) 7.50 (d, 1H, J = 3.1 Hz), 7.42 (d, 2H, J = 8.8 Hz), 7.33-7.31 (1H + d, 2H, J = 8.8 Hz), 7.07 (dd, 1H , J = 8.6 Hz, 3.1 Hz), 5.07 (s, 1H), 4.79 (dd, 1H, J = 9.0 Hz, 8.1 Hz), 3.75 (d, 1H, J = 3.1 Hz), 2.88 -2.80 (m, 1H), 2.45 - 2.39 (m, 1H), 2.33 (dt, 1H, J = 10.8 Hz, 3.3 Hz), 2.36 - 2.26 (m, 1H), 2.08 (s, 3H), 2.05 - 1.90 (, 2H), 1.85-1.75 (m, 1H), 1.65-1.38 (m, 4H), 0.86 (s, 3H); IR (KBr) 3250 br, 2900, 1720, 1650 cm "1; Ms (EI) m / z 516, 514 (M +, Bromide isotopes).

EXAMPLE 6 (la, 17β) 7- (4-Bromophenyl) thio-3, 17-dihydroxy-estra-l, 3,5 (10) -trien-6-one: Prepared by General Procedure 2 M.P. 190-194 ° C; 1 H NMR (DMSO) 9.67 (s, 1H), 7.52 (d, 2H, J = 8.6 Hz), 7.36 (d, 2H, J = 8.6 Hz), 7.33 (d, 1H, J = 8.4 Hz), 7.25 (d, 1H, J = 2.9 Hz), 7.01 (dd, 1H, J = 8.6 Hz, 2.9 Hz), 4.60 (d, 1H, J = 4.8 Hz), 3.78 (d, 1H, J = 3.3 Hz), 3.61 - 3.56 (m, 1H), 2.62 (dt, 1H, J = 11.0 * Hz, 4.2 Hz ), 2.44 - 2.38 (, 1H), 2.31 (dt, 1H, J = 11.0 Hz, 3.5 Hz), 1.96 - 1.82 (m, 2H), 1.76 - 1.68 (m, 1H), 1.64 - 1.56 (m, 1H), 1.42- 1.20 (m, 4H), 0.68 (s, 3H); IR (KBr) 3410 br, 2900, 1660 cm-1; MS (EI) m / z 474, 472 (M +, isotopes of bromide).

EXAMPLE 7 (6a, la, 17ß) 7- (4-Bromophenyl) thio-estra-1, 3, 5 (10) -trien-3, 6,17-triol: Prepared by General Procedure 2 M.p. 140-145 ° C; XH NMR (DMSO) 9.11 (s, 1H), 7.45 (s, 4H), 7.04 (d, 1H, J = 8.6 Hz), 6.96 (d, 1H, J = 2.6 Hz), 6.56 (dd, 1H, J = 8.6 Hz, 2.6 Hz), 5.43 (d, 1H, J = 7.5 Hz), 4.94 -4.91 (m, 1H), 3.55 - 3.48 (m, 2H), 2.50 - 2.48 (m, 1H), 2.28 - 2.24 (m, 1H), 1.95-1.90 (m, 1H), 1.82-1.71 (m, 2H), 1.62-1.53 (m, 1H), 1.32-1.10 (m, 5H), 0.67 (s, 3H); IR (KBr) 3400 br, 2910 c "1; MS (EI) m / z 476, 474 (M +, isotopes of bromide).

EXAMPLE 8 (la, 17ß) 7- (4-Bromophenyl) thio-estra-1, 3, 5 (10) -trien-3, 17-diol: Prepared by General procedure 3 M.p. 165-166 ° C; XH NMR (DMSO) 9.05 (s, 1H), 7.50 (d, 2H, J = 8.6 Hz), 7.30 (d, 2H, J = 8.6 Hz), 7.09 (d, 1H, J = 8.8 Hz), 6.53 ( dd, 1H, J = 8.6 Hz, 2.6 Hz), 6.37 '(d, 1H, J = 2.6 Hz), 4.54 (d, 1H, J = 4.8 Hz), 3.66 - 3.62 (m, 1H), 3.56 3.50 ( m, 1H), 3.17 (dd, 1H, J = 17.3 Hz, 4.8 Hz), 2.76 (d, 1H, J = 17.1 Hz), 2.39-2.28 (m, 2H), 1.85 - 1.78 (m, 3H), 1.55 -1.40 (m, 2H), 1.40-1.25 (m, 3H), 1.10-1.07 (m, 1H), 0.68 (s, 3H); IR (KBr) 3390, 2910, 1610 cm "1, MS (EI) m / z 460, 458 (M +, isotopes of bromide).

EXAMPLE 9 (7a. 17ß) 7- [4- [2- (Methoxycarbonyl) -ethenyl] phenyl] thio-estra-1, 3, 5 (10), 6-trien-3, 17-diol-17-acetate Prepared by General Procedure 4 Mp 122-125 ° C; 1H NMR (CDC13) 7.65 (d, 1H, J = 16.0 Hz), 7.43 (d, 2H, J = 8.1 Hz), 7.35 (d, 2H, J = 8.3 Hz), 7.20 (d, 1H, J = 8.0 Hz), 6.68 (dd, 1H, J = 8.6 Hz, 2.6 Hz), 6.50 (d, 1H, J = 2.6 Hz), 6.41 (d, 1H, J = 16.0 Hz), 4.74 (dd, 1H, J = 9.2 Hz, 7.9 Hz), 4.62 (brs, 1H), 3.81 (s, 3H), 3.69 -3.66 (m, 1H), 3.25 (dd, 1H, J = 16.9Hz, 2.4 Hz), 2.99 (d, 1H) , J = 17.4 Hz), 2.65 - 2.56 (m, 1H), 2.41 - 2.35 (m, 1H), 2.28 - 2.18 (m, 1H), 2.06 (s, 3H), 1.96 - 1.85 (m, 2H), 1.78-1.69 (m, 2H), 1.61- 1.39 (m, 4H), 0.85 (s, 3H); IR (KBr) 3400, 2910, 1720, 1620 cm "1; MS (EI) m / z 506 (M +).

EXAMPLE 10 (la, 17ß) 7-. { 4- [(E) -2- (N, N-Dimethylcarbamoyl) -ethenyl] phen} thio-estra-1, 3,5 (10) -trien-3, 17-diol: Prepared by General Procedure 4 M.P. 152 - 155 ° C; XH NMR (DMSO) 9.05 (s, 1H), 7.64 (d, 2H, J = 8.3 Hz), 7.41 (d, 1 H, J = 15.4 Hz), 7.3 3 (d, 2H, J = 8.3 Hz), 7.16 (d, 1H, J = 15.6 Hz), 7.10 (d, 1H, J = 8.3 Hz), 6.54 (d, 1H, J = 8.3 Hz, 2.2 Hz), 6.37 (d, 1H, J = 2.4 Hz) , 4.53 (d, 1H, J = 4.8 Hz), 3.75 - 3.72 (, 1H), 3.56 - 3.51 (m, 1H), 3.24 - 3.19 (m, 1H), 3.14 (s, 3H), 2.91 (s, 3H), 2.79 (d, 1H, J = 16.7 Hz), 2.41-2.29 (, 2H), 1.86-1.78 (m, 2H), 1.55 - 1.42 (m, 2H), 1.40 - 1.27 (m, 4H) , 1.22 - 1.14 (m, 1H), 0.68 (s, 3H); IR (KBr) 3420, 2910, 1650 cm "1; MS (EI) m / z 478 (M +).

EXAMPLE 11 (la, 17ß) 7-. { 4- [2- (Carboxy) -ethenyl] phenyl} thio-estra-l, 3, 5 (10), 6-trien-3, 17-diol: Prepared by General Procedure 4 M.P. 215-220 ° C; XH NMR (DMSO) 13-10 (brs, 1H), 9.10 (br s, 1H), 7.59 (d, 2H, J = 8.6 Hz), 7.49 (d, 1H, J = 15.8 Hz.), 7.33 (d , 2H, J = 8.4 Hz), 7.09 (d, 1H, J = 8.6 Hz), 6.54 (dd, 1H, J = 8.6 Hz, 2.6 Hz), 6.48 (d, 1H, J = 16.0 Hz), 6.37 ( d, 1H, J = 2.4 Hz), 4.54 (br s, 1H), 3.76 (br s, 1H), 3.52 (t, 1H, J = 7.7 Hz), 3.28 - 3.20 (m, 2H), 2.79 (d , 1H, J = 18.2 Hz), 2.40 - 2.34 (, 2H), 1.88-1.78 (m, 3H), 1.55 - 1.50 (, 2H), 1.40 -1.24 (m, 2H), 1.22 - 1.16 (m, 1 H), 0.68 (s, 3 H); IR (KBr) 3300 br, 2900, 1685 cm "1; MS (EI) m / z 450 (M +).

EXAMPLE 12 (la, 17β) 7- (4- (4 '-Formylbiphenyl)] thio-estra-1, 3, 5 (10) -triene-3,17-diol: Prepared by the General Procedure 6 Mtp.140 - 145 ° C; XH NMR (DMSO) 10.04 (s, 1H), 9.05 (s, 1H), 7.98 (d, 2H, J = 8.3 Hz), 7.90 (d, 2H, J = 8.3 Hz), 7.73 (d , 2H, J = 8.3 Hz), 7.46 (d, 2H, J = 8.3 Hz), 7.11 (d, 1H, J = 8.6 Hz), 6.55 (dd, 1H, J = 8.3 Hz, 2.4 Hz), 6.38 ( d, 1H, J = 2.4 Hz), 4.54 (d, 1H, J = 4.6 Hz), 3.76 - 3.73 (m, 1H), 3.60 -3.53 (m, 1H), 3.23 (dd, 1H, J = 17.6 Hz , 4.2 Hz), 2.83 (d, 1H, J = 16.9 Hz), 2.41 - 2.32 (m, 2H), 1.90 - 1.80 (m, 3H), 1.58 -1.53 (m, 2H), 1.41- 1.26 (m, 3H), 1.22-1.18 (m, 1H), 0.69 (s, 3H), IR (KBr) 3400 br, 2900, 1700, 1670, 1600 cm "1; MS (EI) m / z 484 (M +). EXAMPLE 13 Sodium salt of (la, 17ß) 7- (4- (4 '- (2-Carboxy) - Ethenyl] biphenyl.} Thio-estra-1, 3,5 (10), 6-tetraen-3, 17-diol: Prepared by the General Procedure 6 Mp 219-221 ° C; XH NMR 9.05 (br 1 H), 7.68 (s, 4H), 7.65 (d, 2H, J = 8.6 Hz), 7.42 (d, 2H, J = 8.6 Hz), 7.44 (d, 1H, J = 16.3 Hz), 7.42 (d, 2H, J = 8.6 Hz), 7.10 (d, 1H, J = 8.6 Hz), 6.54 (dd, 1H, J = 8.8 Hz, 2.0 Hz), 6.52 (d, 1H, J = 15.8 Hz), 6.39 (d, 1H, J = 2.4 Hz), 4.54 (br s, 1H), 3.70 (br s, 1H), 3.58 - 3.54 (m, 1H), 3.26 - 3.22 (m, 1H), 2.81 (d, 1H, J = 17.4 Hz), 2.42 - 2.31 (m, 2H), 1.85 - 1.78 (m, 3H), 1.58-1.45 (m, 2H), 1.41-1.30 (m, 3H), 1.21-1.18 (m, 1H), 0.69 (s, 3H); IR (KBr) 3400, 2900, 1700, 1630 cm "1; MS FAB m / z 525 (M-H +).

EXAMPLE 14 (la, 17ß) 3-Methoxy-7-. { 4- [2- (piperidin-1-yl) -ethoxyphenyl) thio-estra-1, 3, 5 (10) -trien-17-ol-17-acetate: Prepared by General Procedure 5 M.P. 60-62 ° C; 1H NMR (CDC13) 7.35 (d, 2H, J = 8.8 Hz), 7.24 (d, 1H, J = 8 Hz), 6.84 (d, 2H, J = 8.8 Hz), 6.76 (dd, 1H, J = 8.8 Hz, 2.9 Hz), 6.58 (d, 1H, J = 2.6 Hz), 4.75 (dd, 1H, J = 9.0 HZ, 7.9 Hz), 4.09 (t, 2H, J = 6.2 Hz), 3.78 (s, 3H), 3.41 - 3.37 (m, 1H), 3.12 (dd, 1H, J = 16.9 Hz, 4.6 Hz), 2.96 (d, 1H, J = 16.9 Hz), 2.77 (t, 2H, J = 6.2 Hz), 2.69 - 2.60 (m, 1H), 2.55 - 2.46 (m, 3H), 2.41 -2.36 (m, 1H), 2.31 - 2.20 (m, 1H), 2.06 (s, 3H), 1.90 - 1.75 (m, 4H), 1.67 - 1.52 (m, 5H), 1.50 - 1.38 (m, 4H) ), 1.25 (s, 2H), 0.83 (s, 3H); IR (KBr) 3450, 2920, 1735 cm "1; MS FAB m / z 564 (M + H +).

EXAMPLE 15 (la, 17β) 3-Methoxy-7-14- [2- (Piperidin-1-yl)] ethoxyphenyl} thio-estra-1, 3, 5 (10) -trien-17-ol: Prepared by General Procedure 5 M.p. 116-118 ° C; NMR (DMSO) 7.29 (d, 2H, J = 8.8 Hz), 6. 91 (d, 1H, J = 8.8 Hz), 6.91 (d, 2H, J = 8.8 Hz), 6.71 (dd, 1H, J = 9.0 Hz, 2.9 Hz), 6.56 (d, 1H, J = 2.9Hz) , 4.54 (d, 1H, J = 4.8 Hz), 4.04 (t, 2H, J = 5.5 Hz), 3.68 (s, 3H), 3.58-3.53 (m, 1H), 3.42 - 3.37 (m, 1H), 3.16 - 3.07 (m, 1H), 2.83 (d, 1H, J = 17.0 Hz), 2.65- 2.61 (m, 2H), 2.47 - 2.30 (m, 4H), 1.94 - 1.86 (m, 3H), 1.61 - 1.44 (m, 7H), 1.41-1.24 (m, 6H), 1.22-1.16 (m, 2H), 0.67 (s, 3H); IR (KBr) 3400, 2910, 1620, 1600 cm "1; MS (EI) m / z 521 (M +). EXAMPLE 16 (la, 17ß) 7- [10- (N-Butyl-N-methyl-carbamoyl) -decyl] thio-3, 17-dihydroxy-estra-1, 3,5 (10) -triene-6-one: Prepared by the General Procedure 2 Mp N / A (foam); 1H NMR (CDC13) (spectrum in amide rotameter) 7.95, 7.91 (2s, 1H), 7.63 (t, 1H, J = 3.1 Hz), m 7.26, 7.24 (2 s, 1 H), 7.07, 7.05 (2 d, 1H, J = 2.9 Hz , J = 2.6 Hz), 3.82 - 3.77 (m, 1H), 3.41 - 3.37 (m, 2H), 3.30 - 3.26 (m, 1H), 3.00, 2.95 (2s, 3H), 2.78, 2.76 (2t, 1H, J = 11.2 Hz), 2.65 - 2.50 (m, 2H), 2.43 - 2.14 (, 5H), 1.97, 1.93 (2t, 1H, J = 3.3 Hz), 1.80 - 1.42 (m, 10H), 1.40 - 1.16 (, 17H), 0.96, 0.92 (2t, 3H, J = 7.2 Hz), 0.79 (s, 3H); IR (KBr) 3400 br, 2910, 1680, 1620 cm "1 MS (CI) m / z 572 (M + H +). (M + H +) EXAMPLE 17 (6a, la, 17β) 7- [10- (N-Butyl-N-methyl-carbamoyl) -decyl] thio-estra-l, 3.5 (10) -triene-3, 6,17-triol : Prepared by General Procedure 2 M.p. N / A (foam); 1H NMR (CDCI3) (amide rotameter in the spectrum) 7.26-7.21 (m, 1H), 7.09 (d, 1H, J = 8.8 Hz), 6.77, 6.71 (2s, 1H), 6.72 (dd, 1H, J = 8.6 Hz, 2.6 Hz), 4.83 (dd, 1H, J = 12.3 Hz, 4.8 Hz), 3.81 (m, 1H), 3.37, 3.27 (2t, 1H, J = 4.6 Hz, 7.2 Hz), 3.17, 3.15 (2d, 1H, J = 2.0 Hz, 1.8 Hz), 2.98, 2.93 (2 brs, 3H), 2.65 (t, 3H, J = 6.8 Hz), 2.59 (dt, 1H, J = 10.8 Hz, 3.7 Hz ), 2.48 - 2.36 (m, 3H), 2.21 - 2.12 (m, 1H), 1.94 - 1.83 (m, 2H), 1.78 - 1.38 (m, 14H), 1.38 - 1.24 (m, 14H), 0.99- 0.86 (m, 3H), 0.81 (s, 3H); IR (KBr) 3400 br, 2920, 1620 cm "1; MS (EI) m / z 573 (M +).

EXAMPLE 18 (la, 17β) 7- [10- (N-Butyl-N-methyl-carbamoyl) -decyl] thio-estra 1, 3, 5 (10) -trien-3, 17-diol: Prepared by the Procedure General 7 MP 71-75 ° C; XH NMR (CDC13) 7.14 (d, 1H, J = 7.9 Hz), 6.68 (dd, 1H, J = 8.3 Hz, 2.6 Hz), 6.62 (d, 1H, J = 2.4 Hz), 3.78 (t, 1H, J = 8.3 Hz), 3.42 - 3.33 (m, 1H), 3.32 - 3.18 (m, 1H), 3.12 - 3.07 (m, 1H), 3.04 - 2.90 (m, 4H), 2.56 - 2.47 (m, 3H), 2.38-2.29 (m, 3H), 2.21-2.10 (m, 1H), 1.94 -1.85 (m, 1H), 1.75 (dt, 1H, J = 11.2 Hz, 2.4 Hz), 1.71 - 1.45 (m, 10H), 1.40-1.12 (m, 19H), 1.01-0.88 (m, 3H), 0.78 (s, 3H); IR (KBr) 3350, 2910, 1620 cm "1; MS (CI) m / z 558 (M + H +).

Claims (38)

CLAIMS.

1. A compound of formula I having the structure Characterized because R1 and R2 are each independently, alkyl of 1-6 carbon atoms, or are alkyl groups that are taken together to form a 5-7 membered saturated heterocycle; X is hydroxyl, alkoxy of 1-6 carbon atoms, or -OC (0) R3; or W is "-1 ^^ - ^ 'hydroxyl, alkyl of 1-6 carbon atoms, halogen, -CF3, alkoxide of 1-6 carbon atoms, cyano, alkylcarbonyl of 2-7 carbon atoms, amino, alkylamino from 1-6 carbon atoms, dialkylamino of 1-6 carbon atoms per alkyl group, trifluoromethoxide, hydroxyalkyl of 1-6 carbon atoms, acolxyalkyl of 2-12 carbon atoms, -CN, -S03H, or -C02H; R3 is alkyl of 1-6 carbon atoms; R 4 is hydrogen, alkyl of 1-6 carbon atoms, or benzoyl; Q is hydrogen. -OR5, or -NR6R7; R5 is hydrogen or alkyl of 1-6 carbon atoms; R6 and R7 are each, independently, alkyl of 1-6 carbon atoms, or are alkyl groups that are taken together to form a 5-7 membered saturated heterocycle; n = 4-12; and P = 2-6; Or a pharmaceutically acceptable salt thereof.

2. The compound according to claim 1, characterized in that Or a pharmaceutically acceptable salt thereof.

3. The compound according to claim 1, characterized in that or a pharmaceutically acceptable salt thereof,

4. The compound according to claim 3, characterized in that R 4 is hydrogen or 2-7 carbon atoms or a pharmaceutically acceptable salt thereof.

5. The compound of claim 1, characterized in that R is or a pharmaceutically acceptable salt of these.

6. The compound according to claim 1, characterized in that R is or a pharmaceutically acceptable salt of East,

7. The compound according to claim 1, characterized in that it is (7a, 17β) 17-acetoxy-3-hydroxy-7- (4-hydroxyphenyl) thio-estra-1, 3, 5 (10) -trien-6-one a pharmaceutically acceptable salt thereof.

8. The compound according to claim 1, characterized in that it is (la, 17β) 3, 17-dihydroxy-7- (4-hydroxyphenyl) thio-estra-1,3,5 (10) -trien-6-one or a pharmaceutically acceptable salt thereof.

The compound according to claim 1, characterized in that it is (6a, la, 17β) 7- (4-hydroxyphenyl) thio-estra-1, 3, 5 (10) -trien-3, 6, 17-triol or a pharmaceutically acceptable salt thereof.

. The compound according to claim 1, characterized in that it is (la, 17β) 7- (4-hydroxyphenyl) thio-estra-1, 3, 5 (10) -trien-3, 17-diol or a pharmaceutically acceptable salt of East.

. The compound according to claim 1, characterized in that it is (the, 17β) 17-acetoxy-7- (4-bromophenyl) thio-3-hydroxy-estra-l, 3, 5 (10) -trien-6-one or a pharmaceutically acceptable salt thereof.

The compound according to claim 1, characterized in that it is (la, 17β) 7- (4-bromophenyl) thio-3, 17-dihydroxy-estra-l, 3, 5 (10) -trien-6-one or a pharmaceutically acceptable salt thereof.

. The compound according to claim 1, characterized in that it is (6a, la, 17β) 7- (4-bromophenyl) thio-estra-1,3,5 (10) -trien-3, 6, 17-trio or a pharmaceutically acceptable salt thereof.

. The compound according to claim 1, characterized in that it is (la, 17β) 7- (4-bromophenyl) thio-estra-1, 3, 5 (10) -trien-3, 17-diol or a pharmaceutically acceptable salt of East.

. The compound according to claim 1, characterized in that it is (la, 17β) 7-. { 4 [2 (methoxycarbonyl) -ethenyl] phenyl) thio-estra-1, 3, 5 (10) -trien-3,17-diol-17-acetate or a pharmaceutically acceptable salt thereof.

. The compound according to claim 1, characterized in that it is (la, 17β) 7-. { 4 [(E) -2 (N, N-dimethylcarbamiol-ethenyl] phenyl) thio-estra-1, 3, 5 (10) -trien-3, 17-diol-17-acetate or a pharmaceutically acceptable salt thereof.

. The compound according to claim 1, characterized in that it is (7a, 17ß) 7- (4 [2 (carboxy) -ethenyl] phenyl) thio-estra-1, 3, 5 (10), 6-trien-3, 17-diol or a pharmaceutically acceptable salt thereof.

. The compound according to claim 1, characterized in that it is (la, 17β) 7-. { 4- (4'-formylbiphenyl)] thio-estra-1, 3, 5 (10) -trien-3, 17-diol or a pharmaceutically acceptable salt thereof.

. The compound according to claim 1, characterized in that it is (la, 17β) 7-. { 4- (4 '- (2-carboxy) -ethenyl] biphenyl) thio-estra-1, 3, 5 (10) -trien-3, 17 or a pharmaceutically acceptable salt thereof.

The compound according to claim 1, characterized in that it is the sodium salt of (7a, 17ß) 7-. { 4 [4 '- (2-carboxy) -ethenyl] phenyl) thio-estra-1, 3, 5 (10), 6-tetraen-3,17-diol or a pharmaceutically acceptable salt thereof.

The compound according to claim 1, characterized in that it is (la, 17β) 3-methoxy-7. { 4 [2 (piperidin-1-yl) -ethoxyphenyl) thio-estra-1, 3, 5 (10) -trien-3, 17-ol-17-acetate or a pharmaceutically acceptable salt thereof.

. The compound according to claim 1, characterized in that it is (la, 17β) 3-methoxy-7-. { 4 [2- (piperidin-1-yl)] ethoxyphenyl) thio-estra-1, 3,5 (10) -trien-17-ol or a pharmaceutically acceptable salt thereof.

. The compound according to claim 1, characterized in that it is (la, 17β) 7- [10- (N-butyl-N-methyl-carbonyl) -decyl) thio-3, 17-dihydroxy-estral, 3, 5 ( 10) -trien-6-one or a pharmaceutically acceptable salt thereof.

The compound according to claim 1, characterized in that it is (6a, 7a, 17β) 7- [10- (N-butyl-N-methyl-carbamoyl) -decyl] thi-estra-1, 3, 5 (10) -trien-3-6-17-triol or a pharmaceutically acceptable salt thereof.

The compound according to claim 1, characterized in that it is (la, 17β) 7- [10- (N-butyl-N-methyl-carbonyl) -decyl] thio-estra-1, 3, 5 (10) trien- 3, 17-diol or a pharmaceutically acceptable salt thereof.

26. A compound of formula I having the structure Characterized because: R1 and R2 are each independently, alkyl of 1-6 carbon atoms, or are alkyl groups that are taken together to form a 5-7 membered saturated heterocycle; X is hydroxyl, alkoxy of 1-6 carbon atoms, or -0C (0) R3; W is «, H, hydroxyl, alkyl of 1-6 atoms carbon, halogen, -CF3, alkoxide of 1-6 carbon atoms, cyano, alkylcarbonyl of 2-7 carbon atoms, amino, alkylamino of 1-6 carbon atoms, dialkylamino of 1-6 carbon atoms per alkyl group, trifluoromethoxide, hydroxyalkyl of 1-6 carbon atoms, acolxyalkyl of 2-12 carbon atoms, -CN, -S03H, or -C02H; R3 is alkyl of 1-6 carbon atoms; R 4 is hydrogen, alkyl of 1-6 carbon atoms, or benzoyl; Q is hydrogen. -OR5, or -NR6R7; R5 is hydrogen or alkyl of 1-6 carbon atoms; R6 and R7 are each, independently, alkyl of 1-6 carbon atoms, or are alkyl groups that are taken together to form a 5-7 membered saturated heterocycle; n .. = 4-12; and P = 2-6; Or a pharmaceutically acceptable salt thereof; for use in the treatment of mammals.

27. A compound of formula I having the structure characterized because R1 and R2 are each independently, alkyl of 1-6 carbon atoms, or are alkyl groups that are taken together to form a 5-7 membered saturated heterocycle; X is hydroxyl, alkoxy of 1-6 carbon atoms, or -OC (0) R3; W is JI, hydroxyl, alkyl of 1-6 atoms carbon, halogen, -CF3, alkoxide of 1-6 carbon atoms, cyano, alkylcarbonyl of 2-7 carbon atoms, amino, alkylamino of 1-6 carbon atoms, dialkylamino of 1-6 carbon atoms per alkyl group, trifluoromethoxide, hydroxyalkyl of 1-6 carbon atoms, acolxyalkyl of 2-12 carbon atoms, -CN, -S03H, or -C02H; R3 is alkyl of 1-6 carbon atoms; R 4 is hydrogen, alkyl of 1-6 carbon atoms, or benzoyl; Q is hydrogen. -OR5, or -NR6R7; R5 is hydrogen or alkyl of 1-6 carbon atoms; R6 and R7 are each, independently, alkyl of 1-6 carbon atoms, or are alkyl groups that are taken together to form a 5-7 membered saturated heterocycle; n = 4-12; and p = 2-6; or a pharmaceutically acceptable salt thereof; for use in the supply of estrogen replacement in estrogen deficiency treatment therapies; treatment or inhibition of osteoporosis: treatment or inhibition of arteriosclerosis; inhibition of free radicals involved in the morbid development of cancer, central nervous system disorders, dementias, Alzheimer's disease, bone diseases, angina, inflammatory disorders, peripheral vascular disease, rheumatoid arthritis, autoimmune diseases, respiratory afflictions, emphysema, prevention of reperfusion damage, viral hepatitis, chronic active hepatitis, tuberculosis, psoriasis, systemic lupus erythematosus, respiratory distress syndrome in adults, attacks and traumas of the central nervous system, damage during reperfusion procedures; in a mammal in need of these.

28. A compound of formula I having the structure Characterized because: R1 and R2 are each independently, alkyl of 1-6 carbon atoms, or are alkyl groups that are taken together to form a 5-7 membered saturated heterocycle; X is hydroxyl, alkoxy of 1-6 carbon atoms, O -OC (0) R3; R3 is alkyl of 1-6 carbon atoms; R 4 is hydrogen, alkyl of 1-6 carbon atoms, or benzoyl; Q is hydrogen. -OR5, or -NR6R7; R5 is hydrogen or alkyl of 1-6 carbon atoms; R6 and R7 are each, independently, alkyl of 1-6 carbon atoms, or are alkyl groups that are taken together to form a 5-7 membered saturated heterocycle; n = 4-12; and P = 2-6; Or a pharmaceutically acceptable salt thereof; for use in the provision of antiestrogen therapy in a mammal in need thereof.

29. A method of supplying estrogen replacements or treatment in estrogen deficiency in a mammal in need thereof, which includes the administration of an estrogenic amount of a compound of formula I having the structure characterized because R1 and R2 are each independently, alkyl of 1-6 carbon atoms, or are alkyl groups that are taken together to form a 5-7 membered saturated heterocycle; X is hydroxyl, alkoxy of 1-6 carbon atoms, or -OC (0) R3; W is _ j? , hydroxyl, alkyl of 1-6 atoms of carbon, halogen, -CF3, alkoxide of 1-6 carbon atoms, cyano, alkylcarbonyl of 2-7 carbon atoms, amino, alkylamino of 1-6 carbon atoms, dialkylamino of 1-6 carbon atoms per alkyl group, trifluoromethoxide, hydroxyalkyl of 1-6 carbon atoms, acolxyalkyl of 2-12 carbon atoms, -CN, -S03H, or -C02H; R3 is alkyl of 1-6 carbon atoms; zz ßess v * W x- * -HG? ° - "* or v A-YES or R 4 is hydrogen, alkyl of 1-6 carbon atoms, or benzoyl; Q is hydrogen. -OR5, or -NR6R7; R5 is hydrogen or alkyl of 1-6 carbon atoms; R6 and R7 are each, independently, alkyl of 1-6 carbon atoms, or are alkyl groups that are taken together to form a 5-7 membered saturated heterocycle; n '= 4-12; and p = 2-6; or a pharmaceutically acceptable salt thereof.

30. A method of treating or inhibiting osteoporosis in a mammal in need of this characterized in that it comprises administering an amount of an effective anti-osteoporosis of a compound of formula I having the structure characterized because R1 and R2 are each independently, alkyl of 1-6 carbon atoms, or are alkyl groups that are taken together to form a 5-7 membered saturated heterocycle; X is hydroxyl, alkoxy of 1-6 carbon atoms, or -OC (0) R3; W is _ ji, hydroxyl, alkyl of 1-6 atoms of carbon, halogen, -CF3, alkoxide of 1-6 carbon atoms, cyano, alkylcarbonyl of 2-7 carbon atoms, amino, alkylamino of 1-6 carbon atoms, dialkylamino of 1-6 carbon atoms per alkyl group, trifluoromethoxide, hydroxyalkyl of 1-6 carbon atoms, acolxyalkyl of 2-12 carbon atoms, -CN, -S03H, or -C02H; R3 is alkyl of 1-6 carbon atoms; R 4 is hydrogen, alkyl of 1-6 carbon atoms, or benzoyl; Q is hydrogen. -OR5, or -NR6R7; R5 is hydrogen or alkyl of 1-6 carbon atoms; R6 and R7 are each, independently, alkyl of 1-6 carbon atoms, or are alkyl groups that are taken together to form a 5-7 membered saturated heterocycle; n = 4-12; and P = 2-6; or a pharmaceutically acceptable salt thereof.

31. A method of treatment or inhibition of atherosclerosis in a mammal in need of these characterized in that it comprises an effective anto-cholecylosis quantity of a compound of formula I having the structure characterized because R1 and R2 are each independently, alkyl of 1-6 carbon atoms, or are alkyl groups that are taken together to form a 5-7 membered saturated heterocycle; X is hydroxyl, alkoxy of 1-6 carbon atoms, or -OC (0) R3; W is _ • / i, hydroxyl, alkyl of 1-6 carbon atoms, halogen, -CF3, alkoxide of 1-6 carbon atoms, cyano, alkylcarbonyl of 2-7 carbon atoms, amino, alkylamino of 1-6 carbon atoms, dialkylamino of 1-6 carbon atoms per alkyl group, trifluoromethoxide, hydroxyalkyl of 1-6 carbon atoms, acolxyalkyl of 2-12 carbon atoms, -CN, -S03H, or -C02H; R3 is alkyl of 1-6 carbon atoms; R 4 is hydrogen, alkyl of 1-6 carbon atoms, or benzoyl; Q is hydrogen. -OR5, or -NR6R7; R5 is hydrogen or alkyl of 1-6 carbon atoms; R6 and R7 are each, independently, alkyl of 1-6 carbon atoms, or are alkyl groups that are taken together to form a 5-7 membered saturated heterocycle; n = 4-12; and p = 2-6; or a pharmaceutically acceptable salt thereof.

. A method of inhibiting endogenous free radicals involved in the development of cancers, central nervous system disorders, dementias, Alzheimer's disease, bone diseases, angina, inflammatory disorders, peripheral vascular disease, rheumatoid arthritis, autoimmune diseases, repiratory afflictions , emphysema, prevention of reperfusion damage, viral hepatitis, tuberculosis, psoriasis, systemic lupus erythematosus, respiratory distress syndrome in adults, attacks and traumas of the central nervous system or damage during reperfusion procedures in a mammal in need of these characterized because includes administration in an effective amount of a compound of formula I having the structure characterized because R1 and R2 are each independently, alkyl of 1-6 carbon atoms, or are alkyl groups that are taken together to form a 5-7 membered saturated heterocycle; X is hydroxyl, alkoxy of 1-6 carbon atoms, or -0C (0) R3; W is K? hydroxyl, alkyl of 1-6 atoms carbon, halogen, -CF3, alkoxide of 1-6 carbon atoms, cyano, alkylcarbonyl of 2-7 carbon atoms, amino, alkylamino of 1-6 carbon atoms, dialkylamino of 1-6 carbon atoms per alkyl group, trifluoromethoxide, hydroxyalkyl of 1-6 carbon atoms, acolxyalkyl of 2-12 carbon atoms, -CN, -S03H, or -C02H; R3 is alkyl of 1-6 carbon atoms; H H O H ^ OH Wl ^ H z is? X • ** • ¿- -? R 4 is hydrogen, alkyl of 1-6 carbon atoms, or benzoyl; Q is hydrogen. -OR5, or -NR6R7; R5 is hydrogen or alkyl of 1-6 carbon atoms; R6 and R7 are each, independently, alkyl of 1-6 carbon atoms, or are alkyl groups that are taken together to form a 5-7 membered saturated heterocycle; N = 4-12; and P = 2-6; or a pharmaceutically acceptable salt thereof.

33. A method of providing an anti-estrogen therapy in a mammal in need thereof characterized in that it comprises administering to said mammals an antiestrogen amount of a compound of formula 1 having the structure Characterized because: R1 and R2 are each independently, alkyl of 1-6 carbon atoms, or are alkyl groups that are taken together to form a 5-7 membered saturated heterocycle; X is hydroxyl, alkoxy of 1-6 carbon atoms, or -OC (0) R3; R3 is alkyl of 1-6 carbon atoms; R 4 is hydrogen, alkyl of 1-6 carbon atoms, or benzoyl; Q is hydrogen. -OR5, or -NR6R7; R5 is hydrogen or alkyl of 1-6 carbon atoms; R6 and R7 are each, independently, alkyl of 1-6 carbon atoms, or are alkyl groups that are taken together to form a 5-7 membered saturated heterocycle; N = 4-12; and P = 2-6; or a pharmaceutically acceptable salt thereof.

34. A pharmaceutical composition characterized in that it includes a compound of formula I having the structure where : R1 and R2 are each independently, alkyl of 1-6 carbon atoms, or are alkyl groups that are taken together to form a 5-7 membered saturated heterocycle; X is hydroxyl, alkoxy of 1-6 carbon atoms, or -OC (0) R3 R3 is alkyl of 1-6 carbon atoms; R 4 is hydrogen, alkyl of 1-6 carbon atoms, or benzoyl; Q is hydrogen. -OR5, or -NR6R7; R5 is hydrogen or alkyl of 1-6 carbon atoms; R6 and R7 are each, independently, alkyl of 1-6 carbon atoms, or are alkyl groups that are taken together to form a 5-7 membered saturated heterocy N = 4-12; and P = 2-6; or a pharmaceutically acceptable salt thereof.

35. A process for the preparation of a compound of formula I as defined in claim 1, characterized in that it includes the reaction of a compound of the formula: wherein Ac is acetyl, with an appropriate thiol of formula RSH in which R is as defined in claim 1, to give compounds of formula I having the structure: which if desired, can be reduced to give the compounds of formula I having the structure: OH which if desired, can be deoxygenated to give the compounds of formula I having the structure: which if desired, can be dehydrolyzed to give compounds of formula I having the structure: which if desired, can be converted to a pharmaceutically acceptable salt thereof.

36. A process for the preparation of compounds of formula I as defined in claim 1 characterized in that X is hydroxyl, R is and Y is which include a reaction with a compound of the formula: wherein Ac is acetyl, with a suitable brominated thiol of formula RSH, in which R is as defined above, to give a compound of formula I having the structure: which, if desired, can be reduced to give a compound of formula I having the structure: which if desired, can be deoxygenated to give a compound of formula I having the structure: and if desired, the bromide can be replaced by a dialkyl acrylamide or acrylic ester of the formula: wherein Q is -OR3, or -NR6R7 and R3, R6 and R7 are as defined in claim 1, to give the compound of formula I having the structure: which if desired, can be hydrolyzed to give the compounds of formula I having the structure: wherein Q is -OH, or -NR6R7, and which, if desired, can be converted to a pharmaceutically acceptable salt thereof.

37. A process for the preparation of compounds of formula I defined in claim characterized in that it comprises a reaction of a compound of formula: wherein Ac is acetyl, with 4-hydroxythiophenol to give a compound of formula I having the structure: which, if desired, can be reduced to give the compound of formula I having the structure. which if desired, can be deoxygenated to give the compound of formula I having the structure: which, if desired, can be alkylated with the appropriate dialkylaminoethyl chloride to give a compound of formula I having the structure wherein R1 and R2 are as defined in claim 1, and, if desired, the protecting group can be removed to give a compound of formula I having the structure: which, if desired, can be converted to a pharmaceutically acceptable salt thereof.

38. A process for the preparation of compounds of formula I as defined in claim 1, characterized in that it comprises the reaction of a compound of formula .1 having the structure: wherein Ac is acetyl, with a compound of the formula: to give a compound of formula I having the structure: and if it is desired to convert it to an acrylate by reaction with an appropriate phosphonate to give the compounds of formula I with the structure: which, if desired, can be hydrolyzed to a compound of formula I having the structure: which, if desired, can be converted to an amide by coupling with an amine to give a compound of formula I having the structure: wherein R1 and R2 are as defined in claim 1, and which, if desired, can be converted to a pharmaceutically acceptable salt thereof. ESTRA-1 f 3, 5 (10) -TRIEN-7alfa-TIOETERES SUMMARY The invention provides estrogens and antiestrogens of formula (I) having the structure (I) where R is (II), (III) ,. (IV) or (V); R1 and R2 are each independently, alkyl of 1-6 carbon atoms. 0 are alkyl groups that come together to form a 5-7 membered saturated heterocycle; X is hydroxyl, alkoxy of 1-6 carbon atoms, or -0C (0) R3; W is (VI), hydroxyl, alkyl of 1-6 carbon atoms, halogen, -CF3, alkoxy of 1-6 carbon atoms, -CHO, 10 cyano, alkylcarbonyl of 2-7 carbon atoms, alkoxycarbonyl of 2-7 carbon atoms, amino, alkylamino of 2-12 carbon atoms, dialkylamino of 1-6 carbon atoms per alkyl group, trifluororaethoxy, hydroxyalkyl of 1- 6 carbon atoms, alkoxyalkyl of 2-12 atoms Carbon, -CN, -S03H, or -C02H; R3 is alkyl of 1-6 carbon atoms; Z is (VII), (VIII), (IX) or (X); And it is (XI), (XII), or (XIII); R 4 is hydrogen, alkyl of 1-6 carbon atoms, alkyl of 2-7 carbon atoms, or benzoyl; Q is hydrogen. -OR5, or -NR6R7,; R5 is hydrogen or alkyl of 1-6 atoms 20 carbon; R6 and R7 are each, independently, alkyl of 1-6 carbon atoms, or are alkyl groups that are taken together to form a 5-7 membered saturated heterocycle; n = 4-12; and p = 2-6; or a pharmaceutically acceptable salt thereof.