MXPA06011716A - Crystalline polymorph of a bazedoxifene acetate - Google Patents

Abstract

The present invention is directed to a crystalline polymorph of bazedoxifene acetate, compositions containing the same, preparations thereof, and uses thereof.

Description

CRYSTALLINE POLYMORPHOST OF A BAZEDOX1FENO ACETATE FIELD OF THE INVENTION The present invention relates to a crystalline polymorph, designated form A, of the selective estrogen receptor modulator 1- [4- (2-azepan-1-yl-ethoxy) -benzyl] -2- (4-hydrox! feniI) -3-methyl-1 H-indol-5-olacetic acid (bazedoxifene acetate).

BACKGROUND OF THE INVENTION Bazedoxifene acetate (1 - [4- (2-azepan-1-yl-ethoxy) -benzyl] -2- (4-hydroxy-phenyl) -3-methyl-1-H-indole-5-olacetic acid) , which has the chemical formula shown below: It belongs to the class of drugs typically referred to as selective estrogen receptor modulators (SERMs). Consistent with its classification, bazedoxifene demonstrates affinity for receptors of estrogen (ER) but shows selective tissue estrogenic effects. For example, bazedoxifene acetate demonstrates little or no stimulation of uterine response in preclinical models of uterine stimulation. In contrast, bazedoxifene acetate demonstrates an effect similar to the estrogen agonist in the prevention of bone loss and cholesterol reduction in an ovariectomized rat model of osteopenia. In a MCF-7 cell line (human breast cancer cell line), bazedoxifene acetate behaves as an estrogen antagonist. These data demonstrate that bazedoxifene acetate is estrogenic on bone and cardiovascular and antiestrogenic lipid parameters on uterine and breast tissue and therefore has the potential to treat a number of different diseases or disease-like conditions wherein the recipient of Estrogen is involved. The patents of E.U.A. Nos. 5,998,402 and 6,479,535 report the preparation of bazedoxifene acetate and characterize the salt as having a melting point of 174-178 ° C. The synthetic preparation of bazedoxifene acetate has also appeared in the general literature. See, for example, Miller et al, J Med. Chem., 2001, 44, 1654-1657, which reports salt as a crystalline solid having a melting point of 170.5-172.5 ° C. An additional description of the biological activity of the drug has also appeared in the general literature (eg Miller, et al., Drugs of the Future, 2002, 27 (2), 117-121). It is well known that the crystalline polymorph form of a Particular drug is often an important determinant of the ease of preparation, stability, solubility, storage stability, ease of formulation and in vivo pharmacology of the drug. Polymorphic forms occur where the same material composition crystallizes in a different lattice arrangement resulting in different thermodynamic properties and specific stabilities for the particular polymorphic form. In cases where two or more polymorphic substances can be produced, it is desirable to have a method for making both polymorphs in pure form. When deciding which polymorph is preferable, one should compare the numerous properties of the polymorphs and the preferred polymorph chosen based on the many physical property variables. It is quite possible that a polymorph form may be preferable in some circumstances where certain aspects such as ease of preparation, stability, etc., are considered critical. In other situations, a different polymorph may be preferred for greater solubility and / or higher pharmacokinetics. Because improved drug formulations are consistently sought, which show, for example, better bioavailability or better stability, there is a current need for new or purer forms of existing drug molecules. The polymorph of bazedoxifene acetate described here helps meet these and other needs.

BRIEF DESCRIPTION OF THE DRAWINGS Figure 1 illustrates a powder X-ray diffraction pattern of the A form polymorph of bazedoxifene acetate, wherein the diffraction angle (2T) varies from 5o to 40 ° with a step of 0.02 °. Figure 2 illustrates an IR spectrum of the form A polymorph of bazedoxifene acetate in KBr tablet. Figure 3 illustrates a differential scanning calorimetry (DSC) trace of the form A polymorph of bazedoxifene acetate. Figure 4 illustrates a DSC trace of the polymorph of form B of bazedoxifene acetate as a comparison.

BRIEF DESCRIPTION OF THE INVENTION The present invention provides a crystalline polymorph (form A) of bazedoxifene acetate characterized in accordance with the powder X-ray diffraction data, IR data and DSC data provided herein. The present invention further provides compositions containing the form A of bazedoxifene acetate. The present invention further provides a method for preparing the polymorphic form A of bazedoxifene acetate comprising: a) reacting hexamethyleneiminobenzyloxyindole with a hydrogenation reagent in a solvent and optionally in the presence of a hydrogenation catalyst for a time and under suitable conditions to form a reaction mixture comprising bazedoxifene free base; b) treating the reaction mixture with acetic acid for a time and under suitable conditions to form the polymorphic form A of bazedoxifene acetate. The present invention further provides a method for treating a mammal having a disease or syndrome associated with estrogen deficiency or excess estrogen comprising administering to said mammal a therapeutically effective amount of the form A polymorph of bazedoxifene acetate. The present invention further provides a method for treating a mammal having a disease or disorder associated with proliferation or abnormal development of endometrial tissues comprising administering to said mammal a therapeutically effective or polymorph amount of A polymorph of bazedoxifene acetate. The present invention further provides a method for reducing cholesterol in a mammal comprising administering to said mammal a therapeutically effective amount of form A polymorph of bazedoxifene acetate. The present invention further provides a method for inhibiting bone loss or breast cancer in a mammal comprising administering to the mammal a therapeutically effective amount of form A polymorph of bazedoxifene acetate. The present invention further provides a method for treating a postmenopausal woman for one or more vasomotor disturbances, such as hot flushing, which comprises administering to the postmenopausal woman a therapeutically effective amount of form A polymorph of bazedoxifene acetate. The present invention also provides form A of crystalline polymorph of bazedoxifene acetate prepared by any of the methods described herein. The present invention further provides the crystalline polymorph of the invention for use in therapy. The present invention also provides the use of the crystalline polymorph of the invention for the preparation of a medicament.

DETAILED DESCRIPTION OF THE INVENTION The present invention provides an anhydrous, unsolvated crystalline polymorph of bazedoxifene acetate, referred to herein as Form A, which can be identified by one or more solid state analytical methods. For example, Form A can be identified by its powder X-ray diffraction pattern, which is provided in Figure 1. Powder X-ray diffraction data consistent with Form A is provided in Table 1 following.

TABLE 1 In some embodiments, the crystalline polymorph A form of bazedoxifene acetate is characterized by a powder X-ray diffraction pattern having characteristic peaks, in terms of 20, at about 12.7 ° and about 18.5 °. In further embodiments, the powder X-ray diffraction pattern further includes characteristic peaks, in terms of 2T, at approximately 16.0 °, approximately 20.7 ° and approximately 22.3 °. In further embodiments, the X-ray powder diffraction pattern of Form A includes 5 or more characteristic peaks, in terms of 2T, selected from about 9.8 °, about 12.7 °, about 15.2 °, about 16.0 °, about 17.1 ° , approximately 17.4 °, approximately 18.5 °. approximately 18.8 °, about 19.6 °, about 20.4 °, about 20.7 °, about 22.3 °, about 23.5 °, about 24.9 °, about 25.6 °, about 26.1 °, about 27.4 °, about 28.0 °, about 28.7 °, about 29.6 °, about 29.9 ° and approximately 30.7 °. In further embodiments, Form A is characterized by a powder X-ray diffraction pattern substantially as shown in Figure 1. The relative intensities of the peaks may vary, depending on the technique of sample preparation, the procedure of assembly of the sample and particular instrument used. Moreover, the variation of instruments and other factors can affect the values of 2-theta. Therefore, XRPD peak assignments can vary by plus or minus approximately 0.2 °. Form A can also be identified by its characteristic infrared (IR) absorption spectrum as provided in Figure 2. In some embodiments, Form A is characterized by an infrared spectrum in KBr that has one or more characteristic peaks selected from approximately 1511, approximately 1467 and approximately 1242 cm "1.

Form A can also be identified by its characteristic differential calorimetry (DSC) scan trace as shown in Figure 3. In some embodiments, Form A is characterized by a trace of DSC showing a maximum at approximately 176 ° C. For DSC, it is known that the temperatures observed will depend on the rate of change of temperature as well as the technique of sample preparation and the particular instrument used. Therefore, the values reported here in relationship with DSC thermograms may vary by more or less about 4 ° C. The polymorphic form A of baxedoxifene acetate is easily distinguishable from other crystalline polymorphs, such as the less soluble form B. The sample data for several physical properties are compared for the polymorphs of Form A and Form B, below in Table 2.

TABLE 2 Measurement Form A Form B Melting point 176 ° C 181 ° C Melting heat 94.6 J / G 108.4 J / G Solubility-water 0.49 mg / ml 0.23 mg / ml Solubility-organic 24.5 mg / ml 12.4 mg / ml (EtOH / EtOAc / Tol) Dissolution rate 0.125 mg / cm2-min 0.09 mg / cm2-min intrinsic DSC Fusion endotherm Individual individual fusion endotherm 176.1 ° C 181.1 ° C TGA Similar Similar X-ray powder 12.7 °, 16.0 °, 18.5 ° , 13.3 °, 20.8 °, 21.6 °, 20.7 °, 22.3 ° (2T) 25.0 ° (2T) Raman / IR 1511, 1467 cr? M 1513, 1449, 1406 cm -1 As can be seen in table 2, the two crystalline polymorphs have physical and spectroscopic characteristics that can not be separated. Form A appears to have higher solubility in aqueous and organic solvent systems than Form B, which is advantageous in particular formulations or dosages wherein the solubility of the particular composition is of concern. For example, the higher solubility may contribute to better biological absorption and drug distribution, as well as facilitate formulation in liquid vehicles. Form A can be prepared, for example, by deprotection of hexamethylenebenzyloxyindole (see, e.g., in U.S. Patent No. ,998,402) by hydrogenolysis in a solvent containing an alcohol (e.g., ethanol) in the presence of a hydrogenation catalyst (e.g., 10% palladium on carbon, 10% Pd / C). The hydrogenolysis can be carried out for any length of time and is typically carried out until the reaction is substantially complete as can be monitored by HPLC or any other suitable technique. The catalyst can be subsequently removed by filtration and an antioxidant (e.g., ascorbic acid) added to inhibit possible oxidative degradation of the hydrogenated product. Suitable exemplary weight ratios of the solvent to hexamethylenebenzyloxyindole include, for example, from about 10: 1 to about 2: 1, about 8: 1 to about 4: 1, or about 6: 1 to about 7: 1. Acetic acid can be added to the hydrogenated product (base free of bazedoxifene), which forms the acetate salt. Suitable amounts of acetic acid are typically sufficient to convert all the free base present in the reaction mixture to the salt form. Accordingly, one or more equivalents of acetic acid can be added (in relation to the amount of hexamethylenebenzyloxyindole starting material). In some embodiments, about 1 to about 2 equivalents of acetic acid are added. The entire desired amount of acetic acid can be added in one or multiple portions. The crystalline product is typically precipitated from the solution with the addition of acetic acid and can be recrystallized from a solvent containing alcohol in accordance with routine methods. Suitable alcohols used in the methods of preparation and recrystallization may include, for example, methanol, ethanol, ethanol, isopropanol, mixtures thereof and the like. In some embodiments, the alcohol is ethanol which may optionally be denatured with approximately 1-10% v / v toluene, approximately 1-10% v / v hexanes, approximately 1-10% v / v ethyl acetate, and the like. In further embodiments, the reaction solvent and / or the recrystallization solvent is ethanol containing 5% (by volume) ethyl acetate. In additional embodiments, the solvent is ethanol. The steps involved in the preparation of Form A can be carried out at any suitable temperature, such as at or below about 25, about 20 or about 15 ° C. For example, the hydrogenation can be carried out at room temperature such as 25 ° C. The addition of acetic acid can be carried out at about 20 ° C or less. The reaction mixture containing bazedoxifene acetate can be maintained for any length of time (e.g., at least about 1 hr, at least about 2 hr, at least about 6 hr, or at least about 12 hours). hr) at a temperature of about -20 to about 20 ° C. In some embodiments, the reaction mixture is maintained for at least 2 hours at 20 ° C. In some embodiments, the reaction mixture is maintained for at least about 2 hours at 0 ° C. The proportion of Form B, in a composition containing a mixture of Form A and Form B, can be increased in accordance with the following methods. For example, Form B may comprise less than about 10%, less than about 20%, less than about 30%, or less than about 40% by weight of total bazedoxifene acetate in the starting composition. The proportion of Form B can be increased by combining the solvent containing an alcohol with the starting composition and maintaining the resulting mixture at or above a temperature of about 25 ° C (e.g., from about 25 to about 60, from about 25 to about 40, or from about 25 to about 30 ° C) for a suitable length of time to increase the proportion of Form B in the composition. The solvent can be supplied in an amount sufficient to dissolve substantially all or less than all of the starting material of bazedoxifene acetate to form homogeneous or heterogeneous mixtures, respectively. The solvent can be provided in a weight ratio of total solvent to amount of bazedoxifene starting material of, for example, about 5: 1, about 3: 1, about 2: 1, or about 1: 1. In some embodiments, the mixture of bazedoxifene acetate and solvent is heated to reflux temperature, such as for several hours (e.g., about 1 to about 3 hours) then cooled slowly in a stepwise manner. For example, the mixture can be cooled to about 45 to about 55 ° C (e.g., about 50 ° C) during the course of a first period and then cooled to about 10 to about 30 ° C (e.g. , approximately 20 ° C) during the course of a second period. The first, second, and any additional periods may vary over many hours such as from about 1 to about 5 hours or from about 1 to about 3 hours. In some modalities, the first period is approximately 1 hour and the second period is approximately 3 hours. The mixture can be further maintained at the cooled temperature (e.g., about 10 to about 30 ° C) for an additional period sufficient for the precipitation of the product. He additional period may be, for example, from 2 hours to approximately 24 hours, from approximately 8 to approximately 18 hours, or approximately 13 hours. In some embodiments, Form A can be prepared by crystallizing bazedoxifene acetate from a solution comprising an alcohol wherein the solution is maintained at a temperature below about 20 ° C, below about 10 ° C, or below about 5 ° C. The alcohol may comprise methanol, ethanol, n-propanol, isopropanol, mixtures thereof and the like. In some embodiments, alcohol includes ethanol. Procedures for preparing Form A may also include seeding solutions containing bazedoxifene acetate with seed crystals of Form A, and procedures for preparing Form B may also include seeding solutions containing bazedoxifene acetate with crystals. of form B. An exemplary preparation of form A is provided in example 1. An example preparation of form B is provided in example 2. The methods for preparation of form A that are provided herein they can result in substantially pure Form A (v., compositions containing less than about 10%, less than about 5% or less than about 3% of Form B) as well as mixtures enriched in Form A (e.g., greater than about 50% form A in relation to form B). Accordingly, the present invention further provides compositions containing the form A. In some embodiments, at least about 50%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, at least about 97%, at least about 98.0%, at least about 98.1%, at least about 98.2%, at least about 98.3%, at least about 98.4%, at least about 98.5%, at least about 98.6%, at least about 98.7%, at least about 98.8%, at least about 98.9%, at least about 99.0%, at least about 99.1%, at least about 99.2 %, at least about 99.3%, at least about 99.4%, at least about 99.5%, at least about 99.6%, at least about 99.7%, at least about 99.8%, or at least about 99.9 wt.% of total bazedoxifene acetate in a composition is present as form A, In further embodiments, the compositions of the present invention essentially consist of bazedoxifene acetate wherein at least about 95%, at least about 97%, at least about 98.0%, at least about 98.1%, at least about 98.2%, at least about 98.3%, at least about 98. 4%, at least about 98.5%, at least about 98.6%, at least about 98.7%, at least about 98: 8%, at least about 98.9%, at least about 99.0%, at least about 99.1%, at least about 99.2%, at least about 99.3%, at least about 99.4%, at least about 99.5%, at least about 99.6%, at least about 99.7%, at least about 99.8%, or at least about 99.9% by weight of the bazedoxifene acetate is present in the compositions as the form 1A. In some embodiments, the remaining bazedoxifene acetate is present as Form B or as an amorphous material. Respective amounts of polymorphic forms of bazedoxifene acetate in a composition can be determined by any suitable spectroscopic method, such as powder X-ray diffraction or DSC. The present invention further provides composition comprising the polymorph of the invention (Form A) and Form B. In some embodiments, the composition comprises from about 70 to about 90% by weight of Form A and from about 10 to about 30. % by weight of Form B, from about 75 to about 85% by weight of Form A and from about 15 to about 25% by Weight of Form B, from 78 to about 92% by Weight of Form A and from about 18 to about 22% in weight of Form B, or about 80% by weight of Form A and about 20% by Weight of Form B. The present invention further provides composition comprising bazedoxifene acetate wherein from about 70% to about 90% by weight of the total bazedoxifene acetate in the composition is present as the polymorph of the invention (form A) and from about 10 to about 30% by weight of total bazedoxifene acetate in the composition is present as the form B, or in wherein from about 75% to about 85% by weight of total bazedoxifene acetate in the composition is present as the polymorph of the invention (form A) and from about 15 to about 25% by weight of total bazedoxifene acetate in the composition is present as Form B, or wherein from about 78% to about 82% by weight of total bazedoxifene acetate in the composition is present as the polymorph of the invention. (Form A) and from about 18 to about 22% by weight of total bazedoxifene acetate in the composition is present as Form B, or wherein about 80% by weight of total bazedoxifene acetate in the composition is present as the polymorph of the invention (Form A) and about 20% by weight of total bazedoxifene acetate in the composition is present as Form B The compositions containing the forms A and B can be prepared by any suitable method which includes the mixture of the A forms and B substantially pure made, for example, in accordance with any of the procedures provided herein.

Methods As described in the patent of E.U.A. No. 5,998,402, bazedoxifene and salts thereof are selective estrogen agonists with affinity for the estrogen receptor. Unlike other types of estrogen agonists, bazedoxifene and salts thereof are antiestrogenic in the uterus and can antagonize the trophic effects of estrogen agonists in uterine tissues. Accordingly, bazedoxifene acetate polymorphs and compositions containing the same can find many uses related to the treatment of disease states or syndromes associated with an estrogen deficiency or an excess of estrogen. The polymorph can also be used in treatment methods for diseases or disorders that result from proliferation or abnormal development, actions or growth of endometrial tissue or similar to endometria! The present polymorphic form of bazedoxifene acetate has the ability to behave as an estrogen agonist by reducing cholesterol and inhibiting bone loss. Therefore, the polymorph is useful for treating many conditions resulting from estrogen effects and excess or deficiency of estrogen including osteoporosis, prosthetic hypertrophy, male pattern baldness, vaginal and skin atrophy, acne, dysfunctional uterine bleeding, endometrial polyps, breast disease benign, uterine leiomyomas, adenomyosis, ovarian cancer, infertility, breast cancer, endometriosis, endometrial cancer, polycystic ovary syndrome, cardiovascular disease, contraception, Alzheimer's disease, cognitive decline and other CNS disorders, as well as certain cancers including melanoma, prostate cancer, colon cancer, CNS cancers, among others. In addition, these polymorphs can be used for contraception in pre-menopausal women, as well as hormone replacement therapy in postmenopausal women (such as to treat vasomotor disturbances such as hot flushing) or in other estrogen deficiency states where it would be beneficial estrogen supplementation. It can also be used in disease states where amenorrhea is advantageous, such as leukemia, endometrial ablation, chronic kidney or liver disease or diseases or coagulation disorders. The polymorph of the invention can also be used in methods of inhibiting bone loss. Bone loss often results from an imbalance in the formation of an individual from new bone tissues and the reabsorption of older tissues, leading to a net loss of bone. Said bone depletion occurs in a range of individuals, particularly in postmenopausal women, women who have undergone bilateral oophorectomy, those who receive or who have received prolonged corticosteroid therapies, those who experience gonadal dysginosis, and those who suffer from Cushing's syndrome. In special needs of bone, including teeth and oral bone, replacement can also be addressed using these polymorphs in individuals with bone fractures, defective bone structures, and those receiving related bone surgeries and / or prosthetic implantation. In addition to the problems described above, the polymorph can be used in treatments of osteoarthritis, hypocalcemia, hypercalcemia, Paget's disease, osteomalacia, osteohalisteresis, multiple myeloma and other forms of cancer that have deleterious effects on bone tissues. It is understood that the methods of treatment of the diseases and syndromes listed herein involve administration to an individual in need of such treatment of a therapeutically effective amount of the polymorph of the invention, or composition containing the same. As used herein, by the term "treatment", in reference to a disease, it is understood that it refers to preventing, inhibit and / or alleviate the disease. As used herein, the term "individual" or "patient," used interchangeably, refers to any animal, including mammals, preferably mice, rats, other rodents, rabbits, dogs, cats, swans, cattle, sheep, horses or primates, and very preferably humans. As used herein, the phrase "therapeutically effective amount" refers to the amount of active compound or pharmaceutical agent that induces the biological or medicinal response in response to a tissue, system, animal, individual or human that is being sought by a researcher , vet, physician or other clinician, which includes one or more of the following: (1) prevent the disease; for example, preventing a disease, condition or disorder in an individual who may be predisposed to the disease, condition or disorder but still does not experience or display the pathology or symptomatology of the disease; (2) inhibit the disease; for example, inhibiting a disease, condition or disorder in an individual who is experiencing or displaying the pathology or symptomatology of the disease, condition or disorder (ie, stopping or slowing down the later development of the pathology and / or symptomatology); and (3) alleviate the disease; for example, alleviating a disease, condition or disorder in an individual who is experiencing or displaying the pathology or symptomatology of the disease, condition or disorder (ie, reversing the pathology and / or symptomatology). Dosage and formulation The invention also includes pharmaceutical compositions that use one or more of the present polymorphs together with one or more pharmaceutically acceptable carriers, excipients, etc. Form A formulations of bazedoxifene acetate include therapeutically effective amounts that can be given in daily doses ranging from 0.1 mg to 1000 mg to a person in need thereof. The example dose ranges vary from 10 mg / day to approximately 600 mg / day or from 10 mg / day to approximately 60 mg / day. The dosage can be either in a single dose or two or more divided doses per day. Said doses may be administered in any manner that facilitates the entry of the compound into the bloodstream including oral, implant, parenteral (including intravenous, intraperitoneal and subcutaneous), vaginal, rectal and transdermal administration. In some embodiments, the formulations are administered transdermally, which includes all administrations through the body surface and internal linings of body passages including epithelial and mucosal tissues. Said administration may be in the form of a lotion, cream, colloid, foam, patch, suspension or solution. Oral formulations containing the present polymorph can comprise any conventionally used oral forms, including tablets, capsules, buccal forms, troches, lozenges and oral liquids, suspensions or solutions. The capsules may contain mixtures of the crystalline form A in the desired percentage together with any other polymorph (s) of bazedoxifene acetate or amorphous bazedoxifene acetate. Capsules or tablets of the desired crystalline form of the percentage of the desired composition can also be combined with mixtures of other active compounds or fillers and / or inert diluents such as pharmaceutically acceptable starches (e.g., corn starch, potato or tapioca), sugars, artificial sweetening agents, powdered celluloses, such as crystalline and microcrystalline celluloses, flours, gelatins, gums, etc.

Tablet formulations can be made by conventional compression, wet granulation or dry granulation methods and use pharmaceutically acceptable diluents (fillers), binding agents, lubricants, disintegrants, suspending agents or stabilizers, including, but not limited to, stearate magnesium, stearic acid, talcum, sodium lauryl sulfate, microcrystalline cellulose, calcium carboxymethylcellulose, polyvinylpyrrolidone, 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 used herein may use delayed or time-released standard or spansul formulations. Suppository formulations can be made from traditional materials, including cocoa butter, with or without the addition of waxes to alter the melting point of suppositories, and glycerin. Water-soluble suppository bases can also be used, such as polyethylene glycols of various molecular weights. Exemplary excipient systems suitable for preparing formulations of the present polymorph include one or more fillers, disintegrants and lubricants. The filler component can be any filler component known in the art including, but not limited to, lactose, microcrystalline cellulose, sucrose, mannitol, calcium phosphate, carbonate calcium, cellulose powder, maltodextrin, sorbitol, starch or xylitol. Disintegrants suitable for use in the present formulations can be selected from those known in the art, including pregelatinized starch and sodium starch glycolate. Other useful disintegrants include croscarmellose sodium, crospovidone, starch, alginic acid, sodium alginate, clays (e.g., Veegum or xanthan gum), cellulose floc, ion exchange resins or effervescent systems, such as those using acids. food (such as citric acid, tartaric acid, malic acid, fumaric acid, lactic acid, adipic acid, ascorbic acid, aspartic acid, erythorbic acid, glutamic acid and succinic acid) and an alkaline carbonate component (such as sodium bicarbonate, calcium carbonate, magnesium carbonate, potassium carbonate, ammonium carbonate, etc.). The disintegrants useful herein may comprise from about 4% to about 40% of the composition by weight, preferably from about 15% to about 35%, most preferably from about 20% to about 35%. The pharmaceutical formulations may also contain an antioxidant or a mixture of antioxidants, such as ascorbic acid. Other antioxidants that may be used include sodium ascorbate and ascorbyl palmitate, preferably together with an amount of ascorbic acid. An exemplary range for the antioxidant (s) is from about 0.5% to about 15% by weight, most preferably from about 0.5% to about 5% by weight.

An exemplary oral formulation contains the present polymorph and the following excipient systems: a) a filler and disintegrant together comprising from about 5% to about 82% by weight (w) of the total formulation, preferably between about 30% and about 80% of the formulation, wherein from about 4% to about 40% by weight of the total formulation comprises one or more pharmaceutically acceptable disintegrants; and b) a lubricant comprising from about 0.2% to about 10% of the composition (by weight), such as that selected from the group of magnesium stearate or other metal stearates (eg, calcium stearate or zinc stearate), fatty acid esters (e.g., sodium stearyl fumarate), fatty acids (e.g., stearic acid), fatty alcohols, glyceryl behenate, mineral oil, paraffins, hydrogenated vegetable oils, leucine, polyethylene glycols, metal lauryl sulfates and sodium chloride. A further excipient system may comprise: a) a filler and disintegrant together comprising from about 5.4% to about 89%, by weight or preferably from about 32.5% to about 87% by weight; and b) lubricant comprising from about 0.22% to about 10.9% by weight. The excipient systems can also use optionally pharmaceutically acceptable humectants, slippers and antioxidants. Said systems may comprise: a) a filler and disintegrant together comprising from about 5% to about 82% by weight (w) of the total formulation, preferably between about 30% and about 80% of the formulation, wherein about 4 % to about 40% by weight of the total formulation comprises one or more pharmaceutically acceptable disintegrants; b) optionally, a wetting agent comprising from about 0.2 to about 5% of the composition (by weight), such as that selected from the group of sodium lauryl sulfate, polyoxyethylene sorbitan fatty acid esters, polyoxyethylene alkyl ethers, acid esters sorbitan fatty acid, polyethylene glycols, polyoxyethylene castor oil derivatives, sodium docusate, quaternary ammonium compounds, fatty acid sugar esters and fatty acid glycerides; c) a lubricant comprising from about 0.2% to about 10% of the composition (by weight), such as that selected from the group of magnesium stearate or other metal stearates (e.g., calcium stearate or zinc stearate) esters of fatty acid (eg, sodium stearyl fumarate), fatty acids (eg, stearic acid), fatty alcohols, glyceryl behenate, mineral oil, paraffins, hydrogenated vegetable oils, leucine, polyethylene glycols, metal lauryl sulfates and sodium chloride; Y d) optionally, a slide comprising from about 0.1% to about 10% (by weight) of the final composition, the slider selected from those known in the art, including the group of silicon dioxide, talc, metal stearates, silicate calcium or metal lauryl sulfates. Additional excipient systems, in accordance with the present invention, may include, by weight: a) a filler and disintegrant together comprising between about 54% and about 80% of the formulation, with the disintegrating agent (s) in the same comprising from about 4% to about 40% by weight of the overall formulation; b) a wetting agent comprising between about 0.55% and about 2.5% of the formulation; c) a lubricant comprising between about 0.2% and about 5.5% of the formulation; and d) a slide comprising between about 0.1% and about 5.0% of the formulation. The above excipient systems also optionally contain an antioxidant component, e.g., ascorbic acid, at a concentration of from about 0.5% to about 5.0% by weight. Among the additional excipient systems of this invention are those comprising: a) a filler and disintegrant together comprising between about 50% and about 87% of the formulation, wherein the disintegrant (s) therein comprises from about 25% to about 35% of the formulation, by weight; b) a wetting agent comprising between about 0.55% and about 2.7% of the formulation; c) a lubricant comprising between about 0.2% and about 5.5% of the formulation; d) a slide comprising between about 0.1% and about 5.5% of the formulation; and e) an antioxidarite component, such as ascorbic acid, in an amount of from about 0.5% to about 5.5% by weight. The percentages listed above for the filler, disintegrant, lubricant and other components are based on the final pharmaceutical composition. The remaining percentage of the final composition is composed of the active pharmacological agent (s) and optionally a pharmaceutically acceptable surface coating, such as a coating or capsule, as described herein. In some embodiments of this invention, the active pharmacological agent (s) comprises from about 0.5% to about 20%, by weight, of the final composition, most preferably from about 1% to about 5%, and the coating or capsule comprises up to about 8%, by weight, of the final composition. The formulations described herein can be used in an uncoated or unencapsulated solid form. In some modalities, the Pharmacological compositions are optionally coated with a film coating, for example, comprising from about 0.3% to about 8% by weight of the overall composition. Film coatings useful with the present formulations are known in the art and generally consist of a polymer (usually a cellulose type of polymer), a colorant and a plasticizer. Additional ingredients such as wetting agents, sugars, flavors, oils and lubricants can be included in film coating formulations to impart certain characteristics to the film coating. The compositions and formulations herein can also be combined and processed as a solid, then placed in a capsule form, such as a gelatin capsule. Pharmaceutical compositions of bazedoxifene acetate can be formulated with steroidal estrogens, such as conjugated estrogens, USP. The amount of bazedoxifene acetate used in the formulation can be adjusted in accordance with the particular polymorph form or ratio of polymorph forms used, the amount and type of steroid estrogen in the formulation as well as the particular therapeutic indication being considered. In general, the bazedoxifene acetate of defined polymorphic composition ratio can be used in an amount sufficient to antagonize the effect of the particular estrogen at the desired level. The dose range of conjugated estrogens can be from about 0.3 mg to about 2.5 mg, about 0.3 mg at about 1.25 mg or about 0.3 mg to about 0.625 mg. An exemplary range for amount of bazedoxifene acetate in a combination formulation is from about 10 mg to about 40 mg. For the steroidal estrogen mestranol, a daily dose may be from about 1 μg to about 150 μg, and for ethinylestradiol a daily dose of about 1 μg to 300 μg may be used. In some embodiments, the daily dose is between about 2 μg and about 150 μg. In order that the invention described herein be understood more efficiently, examples are given below. It is to be understood that these examples are for illustrative purposes only and should not be considered as limiting the invention in any way.

EXAMPLES EXAMPLE 1 Preparation of form A polymorph of bazedoxifene acetate A 7.56-liter hydrogenation vessel with agitator was charged with hexamethyleneimino benzyloxyindole (250 g, 0.3841 mol, see US Patent No. 5,998,402 for one preparation), ethanol (denatured with 5% by volume ethyl acetate) (1578 g, 2000 ml), and 10% palladium on charcoal (25 g). The reagents were hydrogenated at 25 ° C and 3.5 kg / cm2 for 20 hours. The progress of the reaction was monitored by HPLC (Column: CSC-S ODS 2, 25 cm, mobile phase: 20% of 0.02 M NH4H2P04 (2 ml of TEA / L, pH = 3) and 80% of MeCN, Flow: 2 ml / min; Detector: 220 nm). The reaction was considered complete when less than 1% of the hexamethyleneimino benzyloxyindole (18.2 min retention time) or derivative was detected mono-debenzylated thereof (5.1 min retention time). The mixture was filtered through a cartridge that was subsequently rinsed with ethanol (denatured with 5% by volume ethyl acetate) (2 x 198 g, 2 x 250 ml). The filtrate was transferred to a 5-liter multi-neck flask with agitator loaded with L-ascorbic acid (2.04 g, 0.0116 mol) under nitrogen. Acetic acid (34.6 g, 0.5762 mol) was added at 20 ° C while stirring. The resulting reaction mixture was stirred for 2 hours (the pH was about 5 and the crystallization started within about 10 minutes of addition of acetic acid). The reaction mixture was then cooled to 0 ° C and maintained at this temperature for 2 hours. The resulting solid was collected by filtration in a Buchner funnel and washed with ethanol (denatured with 5% by volume ethyl acetate) (2 x 150 g, 2 x 190 ml) at 0 ° C. The solid product was further purified by charging a 3-liter multi-necked flask (with stirrer, thermometer and condenser under nitrogen) with the filtered solid, ethanol (denatured with 5% by volume ethyl acetate) (1105 g, 1400 ml) , and L-ascorbic acid (1.73 g, 0.01 mol). The resulting mixture was heated to 75 ° C and cooled to 20 ° C over the course of 2 hours. The resulting suspension was further cooled to 0 ° C and kept at this temperature for 2 hours. The resulting solid product was collected by filtration with a Buchner funnel and washed with ethanol (denatured with 5% by volume ethyl acetate) (2 x 79 g, 2 x 100 ml) at 0 ° C. the product was dried under vacuum at 60 ° C, 5 mm Hg for 24 hours giving 151.3 g of form A of bazedoxifene acetate (74.2% yield).

EXAMPLE 2 Preparation of form B of bazedoxifene acetate from Form A To a stirred solution of 594 g of ethanol (denatured with % acetone and 3% cyclohexane) and 184 g ethyl acetate, 400 g pure form A acetate of bazedoxifene were added under nitrogen (e.g., see Example 1). The heterogeneous mixture was maintained at 30 ° C and stirred overnight under nitrogen. The conclusion of the crystal transformation was determined by DSC analysis. The mixture was cooled to 0 ° C and stirred for 2 hr under nitrogen. The product was filtered, washed with a mixture of denatured ethanol and ethyl acetate as above and dried overnight at 60 ° C under vacuum to give 391 g (97.7% yield) of Form B polymorph of bazedoxifene acetate. A substantially identical result was obtained using absolute ethanol or ethanol denatured with 5% toluene.

EXAMPLE 3 Diffraction of X-ray powder (XRPD) XRPD analysis (see, eg, FIG. 1) was carried out on a powder X-ray diffractometer (Scintag X2) using Cu K a radiation. The instrument was equipped with tube powder, and the amperage was set at 45 kV and 40 mA. The divergence and dispersion slots were fixed at 1 ° and the receiving slit was set at 0.2 mm. A continuous theta-two theta scrutiny was used at 37 min (0.4 sec / 0.02 ° step) from 3 to 40 ° 2T.

EXAMPLE 4 Infrared spectroscopy (IR) IR spectra were acquired (see, e.g., figure 2) as follows. Samples were prepared as disks of potassium bromide (KBr) (or tablets). A small amount of each sample (approximately 3 mg) was ground in a hard surface mortar to a glossy appearance. Half a gram (0.5 g) of KBr was added to the sample and the mixture was ground continuously until well mixed. The mixture was then transferred to a die and pressed into a disk using a hydraulic press. The IR spectrum of Figure 2 was obtained using a DIGILAB EXCALIBUR Series FTS-4000 FT-IR spectrometer operated at a resolution of 4 cm "1 and 16 scrutinies between 400 - 4000 cm" 1.

EXAMPLE 5 Differential Scanning Calorimetry (DSC) Measurements of DSC were made (see, eg, Figures 3 and 4) in both sealed tray and vented tray at a scanning speed of 10 ° C / min from 25 ° C to 200 ° C under purging of nitrogen using a Pyris I DSC from Perkin-Elmer. Various modifications of the invention, in addition to those described herein, will be apparent to those skilled in the art from the foregoing description. It is also intended that said modifications fall within the scope of the appended claims. Each reference cited in the present application is incorporated herein by reference in its entirety.

Claims (86)

NOVELTY OF THE INVENTION CLAIMS

1. A crystalline polymorph (form A) of bazedoxifene acetate having a powder X-ray diffraction pattern comprising characteristic peaks, in terms of 20, at about 12.7 ° and about 18.5 °.

2. The polymorph according to claim 1, further characterized in that the powder X-ray diffraction pattern further comprises characteristic peaks, in terms of 20, at approximately 16.0 °, approximately 20.7 ° and approximately 22.3 °.

3. The polymorph according to claim 1, further characterized in that the powder X-ray diffraction pattern comprises at least 5 characteristic peaks, in terms of 20, selected from about 9.8 °, about 12.7 °, about 15.2 °. about 16.0 °, about 17.1 °, about 17.4 °, about 18.5 °, about 18.8 °, about 19.6 °, about 20.4 °, about 20.7 °, about 22.3 °, about 23.5 °, about 24.9 °, about 25.6 °, about 26.1 °, approximately 27.4 °, approximately 28.0 °, approximately 28.7 °, approximately 29.6 °, approximately 29.9 ° and approximately 30.7 °.

4. - The polymorph according to claim 1, further characterized in that it has a powder X-ray diffraction pattern substantially as shown in figure 1.

5. The polymorph according to claim 1, further characterized by having a spectrum infrared in KBr comprising one or more selected characteristic peaks of about 1511, about 1467, and about 1242 cm "1.

The polymorph in accordance with claim 1, further characterized by having an infrared spectrum in KBr substantially as is shown in figure 2.

7. The polymorph according to claim 1, further characterized in that it has a trace of differential scanning calorimetry showing a maximum at about 176 ° C.

8. The polymorph in accordance with the claim 1, further characterized in that it has a trace of differential scanning calorimetry substantially as shown in figure 3.

9.- A composition comprising the polymorph of any of claims 1 to 8.

10. The composition according to claim 9, further characterized in that at least about 50% by weight of total bazedoxifene acetate in the composition is present as the polymorphous.

11. The composition according to claim 9, further characterized in that at least about 70% by weight of total bazedoxifene acetate in the composition is present as the polymorph.

12. The composition according to claim 9, further characterized in that at least about 80% by weight of total bazedoxifene acetate in the composition is present as the polymorph.

13. The composition according to claim 9, further characterized in that at least about 90% by weight of total bazedoxifene acetate in the composition is present as the polymorph.

14. The composition according to claim 9, further characterized in that at least about 95% by weight of total bazedoxifene acetate in the composition is present as the polymorph.

15. The composition according to claim 9, further characterized in that at least about 97% by weight of total bazedoxifene acetate in the composition is present as the polymorph.

16. The composition according to claim 9, further characterized in that at least about 98.0% by weight of total bazedoxifene acetate in the composition is present as the polymorph.

17. The composition according to claim 9, further characterized in that at least about 98.1% by weight of total bazedoxifene acetate in the composition is present as the polymorph.

18. The composition according to claim 9, further characterized in that at least about 98.2% by weight of total bazedoxifene acetate in the composition is present as the polymorph.

19. The composition according to claim 9, further characterized in that at least about 98.3% by weight of total bazedoxifene acetate in the composition is present as the polymorph.

20. The composition according to claim 9, further characterized in that at least about 98.4% by weight of total bazedoxifene acetate in the composition is present as the polymorph.

21. The composition according to claim 9, further characterized in that at least about 98.5% by weight of total bazedoxifene acetate in the composition is present as the polymorph.

22. The composition according to claim 9, further characterized in that at least about 98.6% by weight of total bazedoxifene acetate in the composition is present as the polymorph.

23. The composition according to claim 9, further characterized in that at least about 98.7% by weight of total bazedoxifene acetate in the composition is present as the polymorph.

24. The composition according to claim 9, further characterized in that at least about 98.8% by weight of total bazedoxifene acetate in the composition is present as the polymorph.

25. The composition according to claim 9, further characterized in that at least about 98.9% by weight of total bazedoxifene acetate in the composition is present as the polymorph.

26. The composition according to claim 9, further characterized in that at least about 99.0% by weight of total bazedoxifene acetate in the composition is present as the polymorph.

27. The composition according to claim 9, further characterized in that at least about 99.1% by weight of total bazedoxifene acetate in the composition is present as the polymorph.

28. The composition according to claim 9, further characterized in that at least about 99.2% by weight of total bazedoxifene acetate in the composition is present as the polymorph.

29. The composition according to claim 9, further characterized in that at least about 99.3% by weight of total bazedoxifene acetate in the composition is present as the polymorph.

30. The composition according to claim 9, further characterized in that at least about 99.4% by weight of total bazedoxifene acetate in the composition is present as the polymorph.

31. The composition according to claim 9, further characterized in that at least about 99.5% by weight of total bazedoxifene acetate in the composition is present as the polymorph.

32. The composition according to claim 9, further characterized in that at least about 99.6% by weight of total bazedoxifene acetate in the composition is present as the polymorph.

33. The composition according to claim 9, further characterized in that at least about 99.7% by weight of total bazedoxifene acetate in the composition is present as the polymorphous.

34. The composition according to claim 9, further characterized in that at least about 99.8% by weight of total bazedoxifene acetate in the composition is present as the polymorph.

35.- The composition according to claim 9, further characterized in that at least about 99.9% by weight of total bazedoxifene acetate in the composition is present as the polymorph.

36.- A composition comprising the polymorph of any of claims 1 to 9 (form A) and form B.

37.- The composition according to claim 36, further characterized in that it comprises from about 70 to about 90% by weight of Form A and from about 10 to about 30% by weight of Form B.

38.- The composition according to claim 36, further characterized in that it comprises from about 75 to about 85% by weight of Form A and about 15 to about 25% by weight of Form B.

39. The composition according to claim 36, further characterized in that it comprises from about 78 to about 92% by weight of Form A and from about 18 to about 22%. in weight of form B.

40. - The composition according to claim 36, further characterized in that it comprises about 80% by weight of Form A and about 20% by Weight of Form B.

41.- A composition comprising bazedoxifene acetate wherein from about 70% to about 90% by weight of total bazedoxifene acetate in said composition is present as the polymorph of claim 1 (form A) and from about 10 to about 30% by weight of acetate of total bazedoxifene in said composition is present as form B.

42. A composition comprising bazedoxifene acetate wherein from about 75% to about 85% by weight of total bazedoxifene acetate in said composition is present as the polymorph of the claim 1 (form A) and from about 15 to about 25% by weight of total bazedoxifene acetate in said composition is present as form B.

43.- A composition comprising bazedoxifene acetate wherein from about 78% to about 82 % by weight of total bazedoxifene acetate in said composition is present as the polymorph of claim 1 (form A) and of about 18 to about 22% by weight of total bazedoxifene acetate in said composition is present as form B.

44. A composition comprising bazedoxifene acetate wherein about 80% by weight of total bazedoxifene acetate in said composition is present as the polymorph of claim 1 (form A) and about 20% by weight of total bazedoxifene acetate in said composition is present as the form B.

45. A composition comprising the polymorph of any of the claims 1 to 8 and a pharmaceutically acceptable vehicle.

46.- A composition consisting essentially of bazedoxifene acetate wherein at least 95% by weight of said bazedoxifene acetate is present in the composition as the polymorph of any of claims 1 to 8.

47.- A composition consisting of essentially of bazedoxifene acetate wherein at least 97% by weight of said bazedoxifene acetate is present in the composition as the polymorph of any of claims 1 to 8.

48. A composition consisting essentially of bazedoxifene acetate wherein at least 98.0% by weight of said bazedoxifene acetate is present in the composition as the polymorph of any of claims 1 to 8.

49. A composition consisting essentially of bazedoxifene acetate wherein at least 98.1% by weight of said bazedoxifene acetate is present in the composition as the polymorph of any of claims 1 to 8.

50.- A composition that essentially of bazedoxifene acetate wherein at least 98.2% by weight of said acetate bazedoxifene is present in the composition as the polymorph of any of claims 1 to 8.

51. A composition consisting essentially of bazedoxifene acetate wherein at least 98.3% by weight of said bazedoxifene acetate is present in the composition as the polymorph of any one of claims 1 to 8.

52. A composition consisting essentially of bazedoxifene acetate wherein at least 98.4% by weight of said bazedoxifene acetate is present in the composition as the polymorph of any of the claims. 1 to 8.

53. A composition consisting essentially of bazedoxifene acetate wherein at least 98.5% by weight of said bazedoxifene acetate is present in the composition as the polymorph of any of claims 1 to 8.

54.- A composition consisting essentially of bazedoxifene acetate wherein at least 98.6% by weight of said bazedoxifene acetate is present in the composition as the polymorph of any of claims 1 to 8.

55.- A composition consisting essentially of bazedoxifene acetate wherein at least 98.7% by weight of said bazedoxifene acetate is present in the composition as the polymorph of any of claims 1 to 8.

56.- A composition consisting essentially of acetate of bazedoxifene wherein at least 98.8% by weight of said bazedoxifene acetate is present in the composition as the polymorph of any of claims 1 to 8.

57.- A composition consisting essentially of bazedoxifene acetate wherein at least 98.9 % by weight of said bazedoxifene acetate is present in the composition as the polymorph of any of claims 1 to 8.

58. A composition consisting essentially of bazedoxifene acetate wherein at least 99.0% by weight of said acetate bazedoxifene is present in the composition as the polymorph of any of claims 1 to 8.

59. A composition consisting essentially of bazedoxifene acetate wherein at least 99.1% by weight of said bazedoxifene acetate is present in the composition as the polymorph of any of claims 1 to 8.

60.- A composition consisting essentially of bazedoxifene acetate wherein at least 99.2% by weight of said bazedoxifene acetate is present in the composition as the polymorph of any of claims 1 to 8.

61.- A composition consisting of essentially of bazedoxifene acetate wherein at least 99.3% by weight of said bazedoxifene acetate is present in the composition as the polymorph of any of claims 1 to 8.

62. A composition consisting essentially of bazedoxifene acetate wherein at least 99.4% by weight of said bazedoxifene acetate is present in the composition as the polymorph of any of claims 1 to 8.

63. A composition consisting essentially of bazedoxifene acetate wherein at least 99.5% by weight of said bazedoxifene acetate is present in the composition as the polymorph of any of claims 1 to 8. 64.- A composition consisting essentially of bazedoxifene acetate wherein minus 99.6% by weight of said bazedoxifene acetate is present in the composition as the polymorph of any of claims 1 to 8. 65.- A composition consisting essentially of bazedoxifene acetate wherein at least 99.7% by weight of said Bazedoxifene acetate is present in the composition as the polymorph of any of claims 1 to 8. 66.- A composition that essentially of bazedoxifene acetate wherein at least 99.8 wt% of said bazedoxifene acetate is present in the composition as the polymorph of any of claims 1 to 8. 67. A composition consisting essentially of bazedoxifene acetate in wherein at least 99.9% by weight of said bazedoxifene acetate is present in the composition as the polymorph of any of claims 1 to 8. 68. A composition comprising the polymorph of any of claims 1 to 8 and one or more steroidal estrogens. 69.- The composition according to claim 68, further characterized in that the steroidal estrogen component comprises conjugated estrogens. A method for preparing the polymorphic form A of bazedoxifene acetate comprising: a) reacting hexamethyleneiminobenzyloxyindole with a hydrogenation reagent in a solvent and optionally in the presence of a hydrogenation catalyst for a time and under suitable conditions to form a reaction mixture comprising bazedoxifene free base; b) treating the reaction mixture with acetic acid for a time and under suitable conditions to form the polymorphic form A of bazedoxifene acetate. 71.- The method according to claim 70, further characterized in that the solvent comprises an alcohol. 72. The method according to claim 71, further characterized in that said alcohol comprises ethanol. 73.- The method according to claim 70 or claim 71, further characterized in that the solvent comprises ethyl acetate. 74.- The method according to any of claims 70 to 73, further characterized in that the reagent of Hydrogenation is H2. The method according to any of claims 70 to 74, further characterized in that the hydrogenation catalyst is Pd / C. The method according to any of claims 70 to 75, further characterized in that the treatment of step b) is carried out in the presence of an antioxidant. 77. The method according to claim 76, further characterized in that the antioxidant is ascorbic acid. 78. The method according to any of claims 70 to 77, further characterized in that the treatment of step b) is carried out at a temperature of about 25 ° C or less. The method according to any of claims 70 to 78, further characterized in that it comprises maintaining the reaction mixture of step b) at a temperature of about -20 to about 20 ° C for at least about 2 hours. The method according to any of claims 70 to 78, further characterized in that it comprises maintaining the reaction mixture of step b) at a temperature of about 20 ° C for at least about 2 hours. 81. The method according to any of claims 70 to 78, further characterized in that it comprises maintaining the reaction mixture of step b) at a temperature of about 0 ° C for at least 2 hours. 82. A method for preparing the polymorphic form A of bazedoxifene acetate comprising crystallizing bazedoxifene acetate from a solution comprising an alcohol wherein the solution is maintained at a temperature below about 20 ° C. 83. The method according to claim 82, further characterized in that the solution is maintained at a temperature below about 10 ° C. 84. The method according to claim 82 or 83, further characterized in that the alcohol is ethanol. 85.- The use of a polymorph as defined in any of claims 1 to 8 in the preparation of a medicament for the treatment of a mammal having a disease or syndrome associated with deficiency or excess of estrogen; or for the treatment of a mammal having a disease or disorder associated with the proliferation or abnormal development of endometrial tissues; or decrease of cholesterol in a mammal; or inhibition of bone loss in a mammal; or treatment of breast cancer in a mammal; or treatment of a menopausal woman for one or more vasomotor disturbances. 86.- The use claimed in claim 85, wherein the vasomotor disturbance is a shame.