WO2008030771A1 - Cyclic alkylidene compounds as selective estrogen receptor modulators - Google Patents

Abstract

The present invention relates to novel compounds with a variety of therapeutic uses, more particularly novel substituted cyclic alkylidene compounds that are particularly useful for selective estrogen receptor modulation.

Description

CYCLIC ALKYLIDENE COMPOUNDS AS SELECTIVE ESTROGEN RECEPTOR

MODULATORS

FIELD OF THE INVENTION The present invention relates to novel compounds with a variety of therapeutic uses, more particularly novel substituted cycloalkylidene compounds that are particularly useful for selective estrogen receptor modulation.

BACKGROUND OF THE INVENTION Estrogens are well-known endocrine regulators in the cellular processes involved in the development and maintenance of the reproductive system. Estrogens have also been shown to have important effects in many non-reproductive tissues such as bone, liver, the cardiovascular system, and the central nervous system. The most widely accepted hypothesis of how estrogens exert their effects is by binding to an intracellular steroid hormone receptor. After the receptor and bound ligand are transferred to the nucleus of the cell, the complex binds to recognition sites in DNA, which allows for the modulation of certain genes. Additionally, it is now becoming apparent that estrogens may mediate their effects via membrane-initiated signaling cascade, though much of this work is still experimental. Kousteni et al., Journal of Clinical Investigation, (2003), 111, 1651-1664, herein incorporated by reference with regard to such teaching.

Certain substances have demonstrated the ability to exhibit their biological activity in a "tissue-selective" manner. In other words, tissue selectivity allows functionality as estrogen agonists in certain tissues, while acting as estrogen antagonists in other tissues. The term "selective estrogen receptor modulators" (SERMs) has been given to these molecules. Examples of SERMs include tamoxifen, raloxifene, lasofoxifene, clomiphene, and nafoxidine. The molecular basis for this tissue-selective activity is not completely understood. Without being limited to any particular theory, the ability of the ligand to place the estrogen receptor into different conformational states and allowing for differential capabilities in recruiting coactivator and corepressor proteins, as well as other important proteins involved in transcriptional regulation, is believed to play a role. See, McDonnell, D. P., The Molecular Pharmacology of SERMs, Trends Endocrinol. Metab. 1999, 301-311 , herein incorporated by reference with regard to such description.

Historically estrogens were believed to manifest their biological activity through a single estrogen receptor, now termed estrogen receptor alpha (ERa). More recently, however, there was the discovery of second subtype of estrogen receptor, termed estrogen receptor beta (ERβ). See, Kuiper et al., WO 97/09348 and Kuiper et al., Cloning of a Novel Estrogen Receptor Expressed in Rat Prostate and Ovary, Proc. Natl. Acad. Sci. U.S.A., 1996, pp. 5925-5930, herein incorporated by reference with regard to such subtype. ERβ is expressed in humans. See, Mosselman et al., ERβ: Identification and Characterization of a Novel Human

Estrogen Receptor, FEBR S Lett., 1996, pp. 49-53, herein incorporated by reference with regard to such expression. The discovery of this second subtype of estrogen receptor significantly increased the biological complexity of estrogen signaling and may be responsible for some of the tissue-selective actions of the currently available SERMs.

As noted above, estrogens have important effects in many non-reproductive tissues. Thus, estrogen modulation is believed useful in the treatment or prophylaxis of diseases and conditions associated with such tissues, including bone, liver, and the central nervous system. For example, osteoporosis is characterized by the net loss of bone mass per unit volume. Such bone loss results in a failure of the skeleton to provide adequate structural support for the body, thereby creating an increased risk of fracture. One of the most common types of osteoporosis is postmenopausal osteoporosis, which is associated with accelerated bone loss subsequent to cessation of menses and declining levels of endogenous estrogen in women. There is an inverse relationship between densitometric measures of bone mass and fracture risk, for peri- and postmenopausal women in the process of rapid bone loss due to declining levels of estrogen. See, Slemenda, et al., Predictors of Bone Mass in Perimenopausal Women, A Prospective Study of Clinical Data Using Photon Abr sorptiometry, Ann. Intern. Med., 1990, pp. 96-101 and Marshall, et al., Meta-Analysis of How Well Measures of Bone Mineral Density Predict Occurrence of Osteoporotic Fractures, Br Med. J., 1996, pp. 1254-1259, each of which is herein incorporated by reference with regard to such relationship. Elderly women currently have a lifetime risk of fractures of about 75%. In addition there is an approximate 40% risk of hip fracture for Caucasian women over age 50 in the United States. The economic burden from osteoporotic fractures is considerable because of the necessity of hospitalization. In addition, although osteoporosis is generally not thought of as life- threatening, the mortality within 4 months of hip fracture is currently approximately 20 to 30%. Current therapies for postmenopausal osteoporosis include hormone replacement therapy or treatment with other antiresorptive agents such as bisphosphonates or calcitonin. Similarly, SERMS have been shown to be effective in the treatment of postmenopausal osteoporosis (see, Lindsay, R.: Sex steroids in the pathogenesis and prevention of osteoporosis. In: Osteoporosis 1988. Etiology, Diagnosis and Management. Riggs BL (ed)l, Raven Press, New York, USA (1988):333-358; Barzel US: Estrogens in the prevention and treatment of postmenopausal osteoporosis: a review. Am J. Med (1988) 85:847-850; and Ettinger, B., Black, D. M., et al., Reduction of Vertebral Fracture Risk in

Postmenopausal Women with Osteoporosis Treated with Raloxifene, JAMA, 1999, 282, 637-645, each of which is incorporated by reference with regard to such teaching).

As another example, the effects of estrogens on breast tissue, particularly breast cancer, have been well documented. For example, a previously identified

SERM, tamoxifen, decreases the risk of recurrent breast cancer, contralateral breast cancer, and mortality as well as increases the disease-free survival rate of patients with breast cancer at multiple stages of the disease. See, Cosman, F., Lindsay, R. Selective Estrogen Receptor Modulators: Clinical Spectrum, Endocrine Rev., 1999, pp. 418-434, herein incorporated by reference with regard to such teaching. The profile of tamoxifen, however, is not ideal due to potential interactive properties on reproductive tissues, such as uterine tissues. There is room for an improved therapy for the treatment of such cancers, namely a SERM with no agonist properties on any reproductive tissues. Cardiovascular disease is the leading cause of death among postmenopausal women. Until recently, the preponderance of data suggested that estrogen replacement therapy in postmenopausal women reduced the risk of cardiovascular disease, although some studies reported no beneficial effect on overall mortality. See, Barrett-Connor, E. et al., The Potential of SERMs for Reducing the Risk of Coronary Heart Disease, Trends Endocrinol. Metab., 1999, pp. 320-325, herein incorporated by reference. The mechanism(s) by which estrogens were believed to exert their beneficial effects on the cardiovascular system are not entirely clear. Potentially estrogen's effects on serum cholesterol and lipoproteins, antioxidant properties, vascular smooth muscle proliferation, and inhibition of arterial cholesterol accumulation were believed to play a role. Id. See also, Cosman, F., Lindsay, R. Selective Estrogen Receptor Modulators: Clinical Spectrum, Endocrine Rev., 1999, pp. 418-434, herein incorporated by reference. In light of the recent reports of the HERS Il and WHI studies, however, continuous combined Hormone Therapy, namely, CEE + MPA [Conjugated Equine Estrogen + Medroxy Progesterone Acetate], confers no cardiovascular benefit in menopausal women. See, Hulley S., Grady, D., Bush, T., et al., Randomized trial of estrogen plus progestin for secondary prevention of coronary heart disease in postmenopausal women. Heart and Estrogen/progestin Replacement Study (HERS) Research Group. J. Am. Med. Assoc. (1998) 280:605-613 and Wassertheil-Smoller S., Hendrix, S. L., Limacher, M., et al., for the WHI Investigators. Effect of estrogen plus progestin on stroke in postmenopausal women: the Women's Health Initiative: a randomized trial. JAMA (2003) 289, 2673-2684, each herein incorporated by reference with regard to such teaching). To what extent these findings may be extrapolated to SERMs is an issue that remains to be determined.

Other therapeutic alternatives include estrogen replacement therapy and/or hormone replacement therapy, which may be useful in the treatment of vasomotor symptoms, genitourinary atrophy, depression, and diabetes. Over 75% of women experience vasomotor symptoms during the climacteric years. Clinical signs, such as vasomotor symptoms and genitourinary atrophy, abate upon treatment with estrogen replacement therapy. Sagraves, R., J. Clin. Pharmacol. (1995), 35(9 Suppl):2S-10S, herein incorporated by reference with regard to such teaching. Preliminary data suggest that estradiol may alleviate depression during perimenopause and that the combination of estrogens and selective serotonin reuptake inhibitors may alleviate depression during the postmenopausal period. Soares, C. N., Poitras, J. R., and Prouty, J., Drugs Aging, (2003), 20(2;, 85-100, herein incorporated by reference with regard to such teaching. Furthermore, hormone replacement therapy may improve glycemic control among women with diabetes. PaNn, S. L. et al., Diabetes Research and Clinical Practice, (2001 ), 54, 67- 77; Ferrara, A. et al., Diabetes Care, (2001 ), 24(7), 1 144-1150), each incorporated herein by reference with regard to such teaching. There is a need, however, for improved therapies that present better side effect profiles.

The present inventors discovered a novel group of cycloalkylidene compounds, which bind to and modulate estrogen receptor alpha and estrogen receptor beta. As SERMS, these compounds are believed to be useful for the treatment and/or prophylaxis of menopausal or postmenopausal disorders, including vasomotor symptoms, urogenital or vulvar vaginal atrophy, atrophic vaginitis, female sexual dysfunction, breast cancer, depressive symptoms, diabetes, bone demineralization, and the treatment and/or prevention of osteoporosis.

SUMMARY OF THE INVENTION The present invention includes novel compounds. The present invention includes compounds of formula (I):

including salts, solvates, and pharmacologically functional derivatives thereof wherein

X is -(CH₂)n- where n is 0, 1 , 2, or 3;

R¹ is -O-(Ci-6)-R⁴ where Ci_6 is a branched or unbranched alkyl chain having the specified number of carbon atoms; each of R² and R³ are selected from H and Ci_-6; and R⁴ is selected from NH₂, N(Ci_-6)H, and N(Ci_-6)(Ci_-6).

In one embodiment, n is 1 and each of R² and each of R³ is Ci_-6.

In one embodiment, each of R² and each of R³ is selected from H and CH₃.

In one embodiment, each of R² and R³ is H.

In one embodiment, n is 2 or 3 and each of R² and R³ is H

In one embodimemt, R¹ is -0-(CHz)₂-N(CH₃)(CH₃).

In one embodiment, R¹ is -O-(CH₂)₂-N(CH₃)(CH₃), and n is 1.

In one embodimemt, R¹ is -O-(CH₂)₂-N(CH₃)(CH₃), n is 2 or 3, and each of R² and R³ is H.

Particularly preferred compounds of the present invention include: 4-[cycloheptylidene(4-{[2-(dimethylamino)ethyl]oxy}phenyl) methyl]phenol; 4-[(4-{[2-(dimethylamino)ethyl]oxy}phenyl)(3,3,5,5- tetramethylcyclohexylidene)methyl]phenol; and

4-[Cyclooctylidene(4-{[2-(dimethylamino)ethyl]oxy}phenyl)methyl]phenol, including salts, solvates, and pharmacologically functional derivatives thereof.

Another aspect of the present invention includes compounds of formula (I) substantially as hereinbefore defined with reference to any one of the Examples.

Another aspect of the present invention includes pharmaceutical compositions comprising the compounds of formula (I) and a pharmaceutically acceptable carrier.

Another aspect of the present invention includes the compounds of formula (I) for use as an active therapeutic substance. Another aspect of the present invention includes the compounds of formula (I) for use in the treatment or prophylaxis of conditions or disorders affected by selective estrogen receptor modulation. Preferably the treatment or prophylaxis relates to the following conditions hereinafter collectively referred to as "List A": osteoporosis, bone demineralization, reduced bone mass, density, or growth, osteoarthritis, acceleration of bone fracture repair and healing, acceleration of healing in joint replacement, periodontal disease, acceleration of tooth repair or growth, Paget's disease, osteochondrodysplasias, muscle wasting, the maintenance and enhancement of muscle strength and function, frailty or age-related functional decline ("ARFD"), sarcopenia, chronic fatigue syndrome, chronic myaligia, acute fatigue syndrome, acceleration of wound healing, maintenance of sensory function, chronic liver disease, AIDS, weightlessness, burn and trauma recovery, thrombocytopenia, short bowel syndrome, irritable bowel syndrome, inflammatory bowel disease, Crohn's disease and ulcerative colitis, obesity, eating disorders including anorexia associated with cachexia or aging, hypercortisolism and Cushing's syndrome, cardiovascular disease or cardiac dysfunction, congestive heart failure, high blood pressure, breast cancer, malignant tumore cells containing the androgen receptor including breast, brain, skin, ovary, bladder, lymphatic, liver, kidney, uterine, pancreas, endometrium, lung, colon, and prostate, prostatic hyperplasia, hirsutism, acne, seborrhea, androgenic alopecia, anemia, hyperpilosity, adenomas and neoplasis of the prostate, hyperinsulinemia, insulin resistance, diabetes, syndrome X, dyslipidemia, urinary incontinence, artherosclerosis, libido enhancement, sexual dysfunction, depression, depressive symptoms, nervousness, irritability, stress, reduced mental energy and low self-esteem, improvement of cognitive function, endometriosis, polycystic ovary syndrome, counteracting preeclampsia, premenstral syndrome, contraception, uterine fibroid disease, and/or aortic smooth muscle cell proliferation, vaginal dryness, pruritis, dyspareunia, dysuria, frequent urination, urinary tract infections, hypercholesterolemia, hyperlipidemia, peripheral vascular disease, restenosis, vasospasm, vascular wall damage due to immune responses, Alzheimer's disease, bone disease, aging, inflammation, inflammatory pain, rheumatoid arthritis, respiratory disease, emphysema, reperfusion injury, viral hepatitis, tuberculosis, psoriasis, systemic lupus erythematosus, amyotrophic lateral sclerosis, stroke, CNS trauma, dementia, neurodegeneration, breast pain and dysmenorrhea, menopausal or postmenopausal disorders, vasomotor symptoms, urogenital or vulvar vaginal atrophy, atrophic vaginitis, female sexual dysfunction, for enhancing libido, for the treatment of hypoactive sexual disorder, sexual arousal disorder, for increasing the frequency and intensity of orgasms, vaginismus, osteopenia, endometriosis, BPH (benign prostatic hypertrophy), dysmenorrhea, autoimmune diseases, Hashimoto's thyroiditis, SLE (systemic lupus erythematosus), myasthenia gravis, or reperfusion damage of ischemic myocardium. More preferably the treatment or prophylaxis relates to menopausal or postmenopausal disorders, including vasomotor symptoms, urogenital or vulvar vaginal atrophy, atrophic vaginitis, endometriosis, female sexual dysfunction, breast cancer, depressive symptoms, diabetes, bone demineralization, or osteoporosis.

Another aspect of the present invention includes the use of the compounds in the manufacture of a medicament for use in the treatment or prophylaxis of conditions or disorders associated with selective estrogen receptor modulation. Preferably the medicament is for use in the treatment or prophylaxis of those conditions selected from List A. More preferably the condition or disorder is menopausal or postmenopausal disorders, including vasomotor symptoms, urogenital or vulvar vaginal atrophy, atrophic vaginitis, endometriosis, female sexual dysfunction, breast cancer, depressive symptoms, diabetes, bone demineralization, or osteoporosis.

Another aspect of the present invention includes a method for the treatment or prophylaxis of conditions or disorders associated with selective estrogen receptor modulation comprising the administration of the compounds. Preferably the treatment or prophylaxis relates to conditions selected from List A. More preferably the condition or disorder is menopausal or postmenopausal disorders, including vasomotor symptoms, urogenital or vulvar vaginal atrophy, atrophic vaginitis, endometriosis, female sexual dysfunction, breast cancer, depressive symptoms, diabetes, bone demineralization, or osteoporosis.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT The present invention is described in terms known and appreciated by those skilled in the art. For ease of reference certain terms hereafter are defined. The fact that certain terms are defined, however, should not be considered as indicative that any term that is undefined is indefinite. Rather, all terms used herein are believed to describe the invention in terms such that one of ordinary skill can appreciate the scope of the present invention.

As used herein the term "alkyl" refers to a straight or branched chain hydrocarbon, preferably having from one to six carbon atoms. Examples of "alkyl" as used herein include, but are not limited to, methyl, ethyl, propyl, isopropyl, isobutyl, n- butyl, tert-butyl, isopentyl, n-pentyl, and the like. As used herein, the term "alkylene" refers to a straight or branched chain divalent hydrocarbon radical, preferably having from one to ten carbon atoms. Examples of "alkylene" as used herein include, but are not limited to, methylene, ethylene, n-propylene, n-butylene, and the like. As used herein the term "halogen" refers to fluorine, chlorine, bromine, or iodine.

As used herein the term "haloalkyl" refers to an alkyl group, as defined herein, which is substituted with at least one halogen. Examples of branched or straight chained "haloalkyl" groups useful in the present invention include, but are not limited to, methyl, ethyl, propyl, isopropyl, n-butyl, and t-butyl substituted independently with one or more halogens, for example, fluoro, chloro, bromo, and iodo. The term "haloalkyl" should be interpreted to include such substituents as perfluoroalkyl groups and the like.

As used herein the term "alkoxy" refers to the group -OR, where R is alkyl as defined above.

As used herein the term "acyl" refers to the group -C(O)R, where R is alkyl, aryl, heteroaryl, or heterocyclyl, as each is defined herein.

As used herein the term "hydroxy" refers to the group -OH.

As used herein the term "carboxy" refers to the group -C(O)OH. As used herein the term "nitro" refers to the group -NO₂.

As used herein the term "amino" refers to the group -NH₂, or when referred to as substituted amino defines such groups substituted with alkyl.

As used herein, the term "cycloalkyl" refers to a non-aromatic cyclic hydrocarbon ring, preferably having from three to ten carbon atoms. Exemplary "cycloalkyl" groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl.

As used herein, the term "aryl" refers to a benzene ring or to a benzene ring system fused to one or more additional benzene rings to form, for example, anthracene, phenanthrene, or naphthalene ring systems. Examples of "aryl" groups include, but are not limited to, phenyl, 2-naphthyl, 1-naphthyl, biphenyl, and the like.

As used herein, the term "heteroaryl" refers to a monocyclic five to seven membered aromatic ring, or to a fused bicyclic aromatic ring system comprising two of such monocyclic five to seven membered aromatic rings. These heteroaryl rings contain one or more nitrogen, sulfur, and/or oxygen atoms, where N-oxides, sulfur oxides, and dioxides are permissible heteroatom substitutions. Examples of "heteroaryl" groups used herein include, but should not be limited to, furan, thiophene, pyrrole, imidazole, pyrazole, triazole, tetrazole, thiazole, oxazole, isoxazole, oxadiazole, thiadiazole, isothiazole, pyridine, pyridazine, pyrazine, pyrimidine, quinoline, isoquinoline, benzofuran, benzothiophene, indole, indazole, and the like. As used herein, the term "heterocycle" or "heterocyclyl" refers to a mono- or poly-cyclic ring system containing optionally one or more degrees of unsaturation and also containing one or more heteroatoms. Preferred heteroatoms include N, O, and/or S, including N-oxides, sulfur oxides, and dioxides. Preferably the ring is three to ten-membered and is either saturated or has one or more degrees of unsaturation. Such rings may be optionally fused to one or more of another "heterocyclic" ring(s), heteroaryl ring(s), aryl ring(s), or cycloalkyl ring(s). Examples of "heterocyclic" groups include, but are not limited to, tetrahydrofuran, pyran, 1 ,4-dioxane, 1 ,3- dioxane, piperidine, pyrrolidine, morpholine, tetrahydrothiopyran, and tetrahydrothiophene. As used herein throughout the present specification, the phrase "optionally substituted" or variations thereof denote an optional substitution, including multiple degrees of substitution, with one or more substituent group. The phrase should not be interpreted so as to be imprecise or duplicative of substitution patterns herein described or depicted specifically. Rather, those of ordinary skill in the art will appreciate that the phrase is included to provide for obvious modifications, which are encompassed within the scope of the appended claims.

Exemplary optional substituent groups include acyl; alkyl; alkenyl; alkynyl; alkylsulfonyl; alkoxy; cyano; halogen; haloalkyl; hydroxy; nitro; cycloalkyl, which may be further substituted with acyl, alkoxy, alkyl, alkenyl, alkynyl, alkylsulfonyl, cyano, halogen, haloalkyl, hydroxy, or nitro; heterocyclyl, which may be further substituted with acyl, alkoxy, alkyl, alkenyl, alkynyl, alkylsulfonyl, cyano, halogen, haloalkyl, hydroxy, or nitro; aryl, which may be further substituted with acyl, alkoxy, alkyl, alkenyl, alkynyl, alkylsulfonyl, cyano, halogen, haloalkyl, hydroxy, or nitro; heteroaryl, which may be further substituted with acyl, alkoxy, alkyl, alkenyl, alkynyl, alkylsulfonyl, cyano, halogen, haloalkyl, hydroxy, or nitro.

The compounds of formulas (I) may crystallize in more than one form, a characteristic known as polymorphism, and such polymorphic forms ("polymorphs") are within the scope of formula (I). Polymorphism generally can occur as a response to changes in temperature, pressure, or both. Polymorphism can also result from variations in the crystallization process. Polymorphs can be distinguished by various physical characteristics known in the art such as x-ray diffraction patterns, solubility, and melting point.

Certain of the compounds described herein contain one or more chiral centers, or may otherwise be capable of existing as multiple stereoisomers. The scope of the present invention includes mixtures of stereoisomers as well as purified enantiomers or enantiomerically/diastereomerically enriched mixtures. Also included within the scope of the invention are the individual isomers of the compounds represented by formula (I), as well as any wholly or partially equilibrated mixtures thereof. The present invention also includes the individual isomers of the compounds represented by the formulas above as mixtures with isomers thereof in which one or more chiral centers are inverted.

Typically, the salts of the present invention are pharmaceutically acceptable salts. Salts encompassed within the term "pharmaceutically acceptable salts" refer to non-toxic salts of the compounds of this invention. Salts of the compounds of the present invention may comprise acid addition salts. Representative salts include acetate, benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, bromide, calcium edetate, camsylate, carbonate, chloride, clavulanate, citrate, dihydrochloride, edetate, edisylate, estolate, esylate, fumarate, gluceptate, gluconate, glutamate, glycollylarsanilate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isethionate, lactate, lactobionate, laurate, malate, maleate, mandelate, mesylate, methylbromide, methylnitrate, methylsulfate, monopotassium maleate, mucate, napsylate, nitrate, N- methylglucamine, oxalate, pamoate (embonate), palmitate, pantothenate, phosphate/diphosphate, polygalacturonate, potassium, salicylate, sodium, stearate, subacetate, succinate, sulfate, tannate, tartrate, teoclate, tosylate, triethiodide, trimethylammonium, and valerate salts. Other salts, which are not pharmaceutically acceptable, may be useful in the preparation of compounds of this invention and these should be considered to form a further aspect of the invention.

As used herein, the term "solvate" refers to a complex of variable stoichiometry formed by a solute (in this invention, a compound of Formula I, or a salt or physiologically functional derivative thereof) and a solvent. Such solvents, for the purpose of the invention, should not interfere with the biological activity of the solute. Non-limiting examples of suitable solvents include, but are not limited to water, methanol, ethanol, and acetic acid. Preferably the solvent used is a pharmaceutically acceptable solvent. Non-limiting examples of suitable pharmaceutically acceptable solvents include water, ethanol, and acetic acid. Most preferably the solvent used is water.

As used herein, the term "physiologically functional derivative" refers to any pharmaceutically acceptable derivative of a compound of the present invention that, upon administration to a mammal, is capable of providing (directly or indirectly) a compound of the present invention or an active metabolite thereof. Such derivatives, may more specifically be considered to include salts, solvates, esters, amides, or salts or solvates of such esters or amides, and will be clear to those skilled in the art, without undue experimentation. Reference may be made to the teaching of Burger's Medicinal Chemistry And Drug Discovery, 5^th Edition, VoI 1 : Principles and Practice, which is incorporated herein by reference to the extent that it teaches physiologically functional derivatives.

As used herein, the term "effective amount" means that amount of a drug or pharmaceutical agent that will elicit the biological or medical response of a tissue, system, animal or human that is being sought, for instance, by a researcher or clinician. The term "therapeutically effective amount" means any amount which, as compared to a corresponding subject who has not received such amount, results in improved treatment, healing, prevention, or amelioration of a disease, disorder, or side effect, or a decrease in the rate of advancement of a disease or disorder. The term also includes within its scope amounts effective to enhance normal physiological function.

For use in therapy, therapeutically effective amounts of a compound of formula (I), as well as salts, solvates, and physiological functional derivatives thereof, may be administered as the raw chemical. Additionally, the active ingredient may be presented as a pharmaceutical composition. Accordingly, the invention further provides pharmaceutical compositions that include effective amounts of compounds of the formula (I) and salts, solvates, and physiological functional derivatives thereof, and one or more pharmaceutically acceptable carriers, diluents, or excipients. The compounds of formula (I) and salts, solvates, and physiologically functional derivatives thereof, are as described above. The carrier(s), diluent(s) or excipient(s) must be acceptable, in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient of the pharmaceutical composition. In accordance with another aspect of the invention there is also provided a process for the preparation of a pharmaceutical formulation including admixing a compound of the formula (I) or salts, solvates, and physiological functional derivatives thereof, with one or more pharmaceutically acceptable carriers, diluents or excipients.

A therapeutically effective amount of a compound of the present invention will depend upon a number of factors. For example, the age and weight of the animal, the precise condition requiring treatment and its severity, the nature of the formulation, and the route of administration are all factors to be considered. The therapeutically effective amount ultimately should be at the discretion of the attendant physician or veterinarian. For example, an effective amount of a compound of formula (I) for the treatment of humans suffering from osteoporosis, generally, should be in the range of 0.1 to 100 mg/kg body weight of recipient (mammal) per day. More usually the effective amount should be in the range of 1 to 10 mg/kg body weight per day. Thus, for a 70 kg adult mammal the actual amount per day would usually be from 70 to 700 mg. This amount may be given in a single dose per day or in a number (such as two, three, four, five, or more) of sub-doses per day such that the total daily dose is the same. An effective amount of a salt, solvate, or physiologically functional derivative thereof, may be determined as a proportion of the effective amount of the compound of formula (I) per se. Similar dosages should be appropriate for treatment of the other conditions referred to herein that are mediated by estrogen. Pharmaceutical formulations may be presented in unit dose forms containing a predetermined amount of active ingredient per unit dose. Such a unit may contain, as a non-limiting example, 0.5mg to 1 g of a compound of the formula (I), depending on the condition being treated, the route of administration, and the age, weight, and condition of the patient. Preferred unit dosage formulations are those containing a daily dose or sub-dose, as herein above recited, or an appropriate fraction thereof, of an active ingredient. Such pharmaceutical formulations may be prepared by any of the methods well known in the pharmacy art.

Pharmaceutical formulations may be adapted for administration by any appropriate route, for example by an oral (including buccal or sublingual), rectal, nasal, topical (including buccal, sublingual or transdermal), vaginal, or parenteral (including subcutaneous, intramuscular, intravenous or intradermal) route. Such formulations may be prepared by any method known in the art of pharmacy, for example by bringing into association the active ingredient with the carrier(s) or excipient(s). Pharmaceutical formulations adapted for oral administration may be presented as discrete units such as capsules or tablets; powders or granules; solutions or suspensions, each with aqueous or non-aqueous liquids; edible foams or whips; or oil-in-water liquid emulsions or water-in-oil liquid emulsions. For instance, for oral administration in the form of a tablet or capsule, the active drug component can be combined with an oral, non-toxic pharmaceutically acceptable inert carrier such as ethanol, glycerol, water, and the like. Generally, powders are prepared by comminuting the compound to a suitable fine size and mixing with an appropriate pharmaceutical carrier such as an edible carbohydrate, as, for example, starch or mannitol. Flavorings, preservatives, dispersing agents, and coloring agents can also be present. Capsules are made by preparing a powder, liquid, or suspension mixture and encapsulating with gelatin or some other appropriate shell material. Glidants and lubricants such as colloidal silica, talc, magnesium stearate, calcium stearate or solid polyethylene glycol can be added to the mixture before the encapsulation. A disintegrating or solubilizing agent such as agar-agar, calcium carbonate or sodium carbonate can also be added to improve the availability of the medicament when the capsule is ingested. Moreover, when desired or necessary, suitable binders, lubricants, disintegrating agents, and coloring agents can also be incorporated into the mixture. Examples of suitable binders include starch, gelatin, natural sugars such as glucose or beta-lactose, corn sweeteners, natural and synthetic gums such as acacia, tragacanth or sodium alginate, carboxymethylcellulose, polyethylene glycol, waxes, and the like. Lubricants useful in these dosage forms include, for example, sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride, and the like. Disintegrators include, without limitation, starch, methyl cellulose, agar, bentonite, xanthan gum, and the like. Tablets are formulated, for example, by preparing a powder mixture, granulating or slugging, adding a lubricant and disintegrant, and pressing into tablets. A powder mixture may be prepared by mixing the compound, suitably comminuted, with a diluent or base as described above. Optional ingredients include binders, such as carboxymethylcellulose, aliginates, gelatins, or polyvinyl pyrrolidone, solution retardants, such as paraffin, resorption accelerators such as a quaternary salt and/or abr sorption agents such as bentonite, kaolin, or dicalcium phosphate. The powder mixture can be wet-granulated with a binder such as syrup, starch paste, acadia mucilage or solutions of cellulosic or polymeric materials, and forcing through a screen. As an alternative to granulating, the powder mixture can be run through the tablet machine and the result is imperfectly formed slugs broken into granules. The granules can be lubricated to prevent sticking to the tablet forming dies by means of the addition of stearic acid, a stearate salt, talc or mineral oil. The lubricated mixture is then compressed into tablets. The compounds of the present invention can also be combined with a free flowing inert carrier and compressed into tablets directly without going through the granulating or slugging steps. A clear or opaque protective coating consisting of a sealing coat of shellac, a coating of sugar or polymeric material, and a polish coating of wax can be provided. Dyestuffs can be added to these coatings to distinguish different unit dosages.

Oral fluids such as solutions, syrups, and elixirs can be prepared in dosage unit form so that a given quantity contains a predetermined amount of the compound. Syrups can be prepared, for example, by dissolving the compound in a suitably flavored aqueous solution, while elixirs are prepared through the use of a non-toxic alcoholic vehicle. Suspensions can be formulated generally by dispersing the compound in a non-toxic vehicle. Solubilizers and emulsifiers such as ethoxylated isostearyl alcohols and polyoxy ethylene sorbitol ethers, preservatives; flavor additives such as peppermint oil, or natural sweeteners, saccharin, or other artificial sweeteners; and the like can also be added.

Where appropriate, dosage unit formulations for oral administration can be microencapsulated. The formulation can also be prepared to prolong or sustain the release as for example by coating or embedding particulate material in polymers, wax or the like.

The compounds of formula (I) and salts, solvates, and physiological functional derivatives thereof, can also be administered in the form of liposome delivery systems, such as small unilamellar vesicles, large unilamellar vesicles, and multilamellar vesicles. Liposomes can be formed from a variety of phospholipids, such as cholesterol, stearylamine, or phosphatidylcholines.

The compounds of formula (I) and salts, solvates, and physiologically functional derivatives thereof may also be delivered by the use of monoclonal antibodies as individual carriers to which the compound molecules are coupled. The compounds may also be coupled with soluble polymers as targetable drug carriers. Such polymers can include polyvinylpyrrolidone (PVP), pyran copolymer, polyhydroxypropylmethacrylamide-phenol, polyhydroxyethylaspartamidephenol, or polyethyleneoxidepolylysine substituted with palmitoyl residues. Furthermore, the compounds may be coupled to a class of biodegradable polymers useful in achieving controlled release of a drug; for example, polylactic acid, polyepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates, and cross-linked or amphipathic block copolymers of hydrogels. Pharmaceutical formulations adapted for transdermal administration may be presented as discrete patches intended to remain in intimate contact with the epidermis of the recipient for a prolonged period of time. For example, the active ingredient may be delivered from the patch by iontophoresis as generally described in Pharmaceutical Research, 3(6), 318 (1986), incorporated herein by reference as related to such delivery systems.

Pharmaceutical formulations adapted for topical administration may be formulated as ointments, creams, suspensions, lotions, powders, solutions, pastes, gels, sprays, aerosols, or oils. For treatments of the eye or other external tissues, for example mouth and skin, the formulations may be applied as a topical ointment or cream. When formulated in an ointment, the active ingredient may be employed with either a paraffinic or a water-miscible ointment base. Alternatively, the active ingredient may be formulated in a cream with an oil-in-water cream base or a water-in-oil base. Pharmaceutical formulations adapted for topical administrations to the eye include eye drops wherein the active ingredient is dissolved or suspended in a suitable carrier, especially an aqueous solvent. Pharmaceutical formulations adapted for topical administration in the mouth include lozenges, pastilles, and mouthwashes.

Pharmaceutical formulations adapted for nasal administration, where the carrier is a solid, include a coarse powder having a particle size for example in the range 20 to 500 microns. The powder is administered in the manner in which snuff is taken, i.e., by rapid inhalation through the nasal passage from a container of the powder held close up to the nose. Suitable formulations wherein the carrier is a liquid, for administration as a nasal spray or as nasal drops, include aqueous or oil solutions of the active ingredient.

Pharmaceutical formulations adapted for administration by inhalation include fine particle dusts or mists, which may be generated by means of various types of metered, dose pressurized aerosols, nebulizers, or insufflators.

Pharmaceutical formulations adapted for rectal administration may be presented as suppositories or as enemas.

Pharmaceutical formulations adapted for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams, or spray formulations.

Pharmaceutical formulations adapted for parenteral administration include aqueous and non-aqueous sterile injection solutions which may contain anti-oxidants, buffers, bacteriostats, and solutes that render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents. The formulations may be presented in unit-dose or multi-dose containers, for example sealed ampules and vials, and may be stored in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example water for injections, immediately prior to use. Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules, and tablets.

In addition to the ingredients particularly mentioned above, the formulations may include other agents conventional in the art having regard to the type of formulation in question. For example, formulations suitable for oral administration may include flavoring agents.

The compounds of the present invention and their salts, solvates, and physiologically functional derivatives thereof, may be employed alone or in combination with other therapeutic agents for the treatment of the conditions herein described. For example, in osteoporosis therapy, combination with other osteoporosis therapeutic agents is envisaged. Osteoporosis combination therapies according to the present invention thus comprise the administration of at least one compound of formula (I) or a salt, solvate, or physiologically functional derivative thereof, and the use of at least one other osteoporosis treatment method. Preferably, combination therapies according to the present invention comprise the administration of at least one compound of formula (I) or a salt, solvate, or physiologically functional derivative thereof, and at least one other osteoporosis treatment agent, for example, a bone building agent. The compound(s) of formula (I) and the other pharmaceutically active agent(s) may be administered together or separately and, when administered separately, administration may occur simultaneously or sequentially in any order. The amounts of the compound(s) of formula (I) and the other pharmaceutically active agent(s) and the relative timings of administration will be selected in order to achieve the desired combined therapeutic effect. The administration in combination of a compound of formula (I) salts, solvates, or physiologically functional derivatives thereof with other osteoporosis treatment agents may be in combination by administration concomitantly in: (1 ) a unitary pharmaceutical composition including each compound; or (2) separate pharmaceutical compositions each including one of the compounds. Alternatively, the combination may be administered separately in a sequential manner wherein one treatment agent is administered first and the other(s) subsequently or vice versa. Such sequential administration may be close in time or remote in time. The compounds of the present invention and their salts, solvates, and physiologically functional derivatives thereof, may be employed alone or in combination with other therapeutic agents for the treatment of the conditions herein described. For example, regarding the use of the compounds of the present invention in the prevention of reduced bone mass, density, or growth, combination may be had with other anabolic or osteoporosis therapeutic agents. As one example, osteoporosis combination therapies according to the present invention would thus comprise the administration of at least one compound of the present invention or a salt, solvate, or physiologically functional derivative thereof, and the use of at least one other osteoporosis therapy. As a further example, combination therapies according to the present invention inlcude the administration of at least one compound of the present invention or a salt, solvate, or physiologically functional derivative thereof, and at least one other osteoporosis treatment agent, for example, an anti-bone resorption agent. The compound(s) of the present invention and the other pharmaceutically active agent(s) may be administered together or separately and, when administered separately, administration may occur simultaneously or sequentially, in any order. The amounts of the compound(s) and the agent(s) and the relative timings of administration will be selected in order to achieve the desired combined therapeutic effect. The administration in combination of a compound of the present invention including salts, solvates, or physiologically functional derivatives thereof with other treatment agents may be in combination by administration concomitantly in: (1 ) a unitary pharmaceutical composition including both compounds; or (2) separate pharmaceutical compositions each including one of the compounds. Alternatively, the combination may be administered separately in a sequential manner wherein one treatment agent is administered first and the other second or vice versa. Such sequential administration may be close in time or remote in time.

As noted, one potential additional osteoporosis treatment agent is a bone building (anabolic) agent. Bone building agents can lead to increases in parameters such as bone mineral density that are greater than those than can be achieved with anti-resorptive agents. In some cases, such anabolic agents can increase trabecular connectivity leading to greater structural integrity of the bone.

Other potential therapeutic combinations include the compounds of the present invention combined with other compounds of the present invention, growth promoting agents, growth hormone secretagogues, growth hormone releasing factor and its analogs, growth hormone and its analogs, somatomedins, alpha-ardenergic agonists, serotonin 5-HT_D agonists, selective serotonin reuptake inhibitors, agents that inhibit somatostatin or its release, 5-α-reductase inhibitors, aromatase inhibitors, GnRH inhibitors, parathyroid hormone, bisphosphonates, estrogen, testosterone, SERMs, progesterone receptor agonists, and/or with other modulators of nuclear hormone receptors.

The compounds of the present invention may be used in the treatment of a variety of disorders and conditions and, as such, the compounds of the present invention may be used in combination with a variety of other suitable therapeutic agents useful in the treatment or prophylaxis of those disorders or conditions. Non- limiting examples include combinations of the present invention with anti-diabetic agents, anti-osteoporosis agents, anti-obesity agents, anti-inflammatory agents, antianxiety agents, anti-depressants, anti-hypertensive agents, anti-platelet agents, antithrombotic and thrombolytic agents, cardiac glycosides, cholesterol or lipid lowering agents, mineralocorticoid receptor antagonists, phosphodiesterase inhibitors, kinase inhibitors, thyroid mimetics, anabolic agents, viral therapies, cognitive disorder therapies, sleeping disorder therapies, sexual dysfunction therapies, contraceptives, cytotoxic agents, radiation therapy, anti-proliferative agents, and anti-tumor agents. Additionally, the compounds of the present invention may be combined with nutritional supplements such as amino acids, triglycerides, vitamins, minerals, creatine, piloic acid, carnitine, or coenzyme Q10.

An aspect of the present invention is the use of the compounds of the present invention for the treatment or prophylaxis of a variety of disorders including, but not limited to, conditions selected from List A.

In particular, the compounds of the present invention are believed useful, either alone or in combination with other agents, in the treatment of menopausal or postmenopausal disorders, vasomotor symptoms, urogenital or vulvar vaginal atrophy, atrophic vaginitis, female sexual dysfunction, breast cancer, depressive symptoms, diabetes, bone demineralization, and the treatment and/or prevention of osteoporosis. The compounds of this invention may be made by a variety of methods, including well-known standard synthetic methods. Illustrative general synthetic methods are set out below and then specific compounds of the invention are prepared in the working Examples.

In all of the examples described below, protecting groups for sensitive or reactive groups are employed where necessary in accordance with general principles of synthetic chemistry. Protecting groups are manipulated according to standard methods of organic synthesis (T. W. Green and P. G. M. Wuts (1991 ) Protecting Groups in Organic Synthesis, John Wiley & Sons, incorporated by reference with regard to protecting groups). These groups are removed at a convenient stage of the compound synthesis using methods that are readily apparent to those skilled in the art. The selection of processes as well as the reaction conditions and order of their execution shall be consistent with the preparation of compounds of formula (I).

Those skilled in the art will recognize if a stereocenter exists in compounds of formula (I). Accordingly, the present invention includes all possible stereoisomers and includes not only racemic compounds but the individual enantiomers as well. When a compound is desired as a single enantiomer, such may be obtained by stereospecific synthesis, by resolution of the final product or any convenient intermediate, or by chiral chromatographic methods as are known in the art. Resolution of the final product, an intermediate, or a starting material may be effected by any suitable method known in the art. See, for example, Stereochemistry of Organic Compounds by E. L. ENeI, S. H. Wilen, and L. N. Mander (Wiley-

Interscience, 1994), incorporated by reference with regard to stereochemistry.

EXPERIMENTAL SECTION Abbreviations:

As used herein the symbols and conventions used in these processes, schemes and examples are consistent with those used in the contemporary scientific literature, for example, the Journal of the American Chemical Society or the Journal of Biological Chemistry. Specifically, the following abbreviations may be used in the examples and throughout the specification: g (grams); mg (milligrams); L (liters); ml. (milliliters); μl_ (microliters); psi (pounds per square inch);

M (molar); mM (millimolar);

Hz (Hertz); MHz (megahertz); mol (moles); mmol (millimoles); RT (room temperature); h (hours); d (days); El (electron impact); min (minutes); TLC (thin layer chromatography); mp (melting point); RP (reverse phase);

Tr (retention time); TFA (trifluoroacetic acid); TEA (triethylamine); THF (tetrahydrofuran);

TFAA (trifluoroacetic anhydride); CD₃OD (deuterated methanol); CDCI₃ (deuterated chloroform); DMSO (dimethylsulfoxide);

SiO₂ (silica); atm (atmosphere);

EtOAc (EtOAc); CHCI₃ (chloroform);

HCI (hydrochloric acid); Ac (acetyl);

DMF (Λ/,Λ/-dimethylformamide); Me (methyl);

Cs₂CO₃ (cesium carbonate); EtOH (ethanol);

Et (ethyl); tBu (tert-butyl);

MeOH (methanol); CH₂CI₂ (dichloromethane);

MgSO₄ (magnesium sulfate); CH₃CN (acetonitrile);

K₂CO₃ (potassium carbonate); TiCI₄ (titanium tetrachloride);

EtOAc (EtOAc); CO₂ (carbon dioxide);

Pd(OAc)₂ (palladium acetate); Et₂O (diethyl ether);

P(o-tolyl)₃ (tri-o-tolylphosphine); Na₂SO₄ (sodium sulfate);

NaH (sodium hydride); DME (1 ,2-dimethoxyethane);

NaI (sodium iodide); NaOH (sodium hydroxide);

NH₄CI (ammonium chloride); NaHCO₃ (sodium bicarbonate);

AICI₃ (aluminum chloride); (C₂H₅O)₂P(O)H (diethyl phosphite);

NaN₃ (sodium azide); CBr₄ (carbon tetrabromide);

PPh (triphenylphosphine); CuI (copper (I) iodide);

Pd(Ph₃P)₄ (tetrakis(triphenylphosphine)palladium (O));

(/PrO)₃B (triisopropyl borate); nBuLi (butyllithium);

Na₂CO₃ (sodium carbonate); DMAP (4-(dimethylamino)pyridine); eq (equivalents);

HRMS (high resolution mass spectrometry);

LCMS (liquid chromatography mass spectrometry);

LRMS (low resolution mass spectrometry);

APCI (Atmospheric Pressure Chemical Ionization);

LiHMDS (lithium bis(trimethylsilyl)amide);

Pd(Ph₃P)₂CI₂ (dichlorobis(triphenylphosphine)palladium(ll));

EDC (Λ/-(3-dimethylaminopropyl)-Λ/'-ethyl-carbodimide; dpppe (1 ,5-bis(diphenylphosphanyl)pentane;

DMAc (Λ/,Λ/-dimethylacetamide);

HPLC (high performance liquid chromatography); tmeda (Λ/,Λ/,Λ/',Λ/',-tetramethylethylenediamine);

Pd₂(dba)₃ (dipalladiumtris(dibenzylidene acetone)). Unless otherwise noted, reagents and solvents were obtained from commercial suppliers and were used without further purification. Unless otherwise indicated, all reactions were conducted at room temperature and all temperatures are expressed in ⁰C (degrees Centigrade). Thin-layer chromatography (TLC) was performed on silica gel 60 F₂5₄ precoated plates. Detection was effected by exposure to UV light (254 nm). Flash and flush column chromatography was performed using Silica Gel 60. Reverse phase preparative and analytical HPLC were performed using C18 columns and acetonitrile:water gradients with 0.05% TFA as a modifier. Compound purity and characterization were determined by ¹H-NMR, liquid chromatography-mass spectrometry (LCMS), high resolution mass spectrometry (HRMS), combustion (elemental) analysis, HPLC, and melting point. Compounds of general formula I were typically found to have purities of > 90%.

¹H NMR spectra were recorded on Varian INOVA-300 and Varian INOVA-400 intruments. Chemical shifts are expressed in parts per million (ppm, δ units).

Coupling constants are in units of hertz (Hz). Splitting patterns describe apparent multiplicities and are designated as s (singlet), d (doublet), dd (doublet of doublet), t (triplet), q (quartet), m (multiplet), or br (broad).

Low resolution mass spectra were obtained on Micromass ZQ, Micromass ZMD, Micromass QuattroMicro, and Micromass GCT instruments from Micromass

Ltd., Altricham, UK, using either Atmospheric Pressure Chemical Ionization (APCI) or ESI Ionization (ESI).

High resolution mass spectral data (HRMS) were recorded with Micromass LCT and Micromass GCT instruments. Combustion analyses were performed by Atlantic Microlab, Inc. (Norcross,

Georgia).

Melting points were recorded in open capillary tubes and are uncorrected.

The bolded numerals reference the compounds as depicted in the following schemes. For the following scheme, depending on subsequent chemistry and functional group compatibility, one of the phenol groups of specific intermediates may need to be protected using synthetic methods appreciated by those skilled in the art. Scheme 1 General Route to Substituted Cycloalkylidene Diphenylethylenes e₂N(CH₂J to reflux

Pd/C

IV Vl VIII

The amine substituted symmetric alkylidene compounds III can be prepared as described in Scheme 1. McMurry coupling between substituted benzophenones I, Il or IV and ketone V provides the cycloalkylidene diphenylethylenes VII, III or Vl respectively. Amine substituted side chains can be introduced by standard alkylation procedures prior to or following McMurry coupling. Alternatively, one of the phenol groups of I can be protected (such as IV) using synthetic procedures appreciated by those skilled in the art. McMurry coupling of IV to yield Vl followed by alkylation and deprotection yields compound III. For McMurry reaction conditions, see Mukaiyama et al., Chem. Lett. (1973), 1041 ; Lenoir, Synthesis, (1977), 553; Lenoir and Burghard, J. Chem. Res. (S) (1980), 396; McMurry, Chem. Rev. (1989), 89, 1513-1524; McMurry, Ace. Chem. Res. (1983) 16, 405-51 1 ; and S. Gauthier et al., J. Org.

Chem., (1996), 61, 3890-3893, each herein incorporated by reference with regard to such teaching. Ketone V is either commercially available or may be prepared by synthetic methods appreciated by those skilled in the art. EXAMPLES

The following specific examples are included as illustrations and are not to be construed as limiting the scope of the present invention.

Example 1

4-[cycloheptylidene(4-{[2-(dimethylamino)ethyl]oxy}phenyl)methyl]phenol (2)

Step 1 : 4,4'-(Cycloheptylidenemethanediyl)diphenol (V) To a stirred suspension of zinc powder (15.0 g, 0.23 mol) in THF (300 ml.) was slowly added TiCI₄ (12.5 ml_, 0.115 mol) via a syringe at room temperature under a nitrogen atmosphere. The reaction mixture was heated at reflux for 1 h. A solution of bis(4-hydroxyphenyl)methanone (4.9 g, 0.023 mol) and cycloheptanone (7.74 g, 0.07 mol) in THF (100 ml.) was added to the reaction mixture. The reaction mixture was heated at reflux with stirring under a nitrogen atmosphere for an additional 2 h. The reaction mixture was allowed to cool to room temperature. The reaction mixture was poured into a 10% aqueous K₂CO3 (1 L). The reaction mixture was filtered through a pad of Celite and the pad was washed with EtOAc. The filtrate was transferred to a separatory funnel and the layers were separated. The aqueous phase was further extracted with EtOAc (4 x 250 ml_). The combined organic phase was washed with brine (2 x 100 ml_), dried (Na₂SO₄), filtered, and then concentrated under reduced pressure to give the crude product as a gold-yellow oil. The crude product was purified by flash chromatography on silica gel with hexanes:EtOAc (100:0 to 50:50) as an eluent to afford 6.75 g (99%) of the title compound 1 as a white solid. ¹H NMR (DMSO-d₆): δ 9.21 (s, 2 H), 6.84 (d, J = 6.3 Hz, 4 H), 6.63 (d, J = 6.3 Hz, 4 H), 2.19 (br s, 4 H), 1.48 (br s, 8 H). LCMS (ESI): m/z 294 (M + H) ⁺. Step 2: 4-[cycloheptylidene(4-{[2- (dimethylamino)ethyl]oxy}phenyl)methyl]phenol (2) To a round-bottom flask containing 4,4'-(cycloheptylidenemethanediyl)diphenol (0.35 g, 1.19 mmol) in DMF (4 mL) was added Cs₂CO₃ (1.94 g, 5.94 mmol). After several minutes of stirring at room temperature, 2-(dimethylamino)ethyl chloride hydrochloride (0.154 g, 1.07 mmol), and NaI (0.178 g, 1.19 mmol) were added to the flask and the reaction mixture was heated at 80 ⁰C overnight. The reaction mixture was allowed to cool to room temperature then it was quenched with saturated NH₄CI and extracted with EtOAc. The organic layer was washed with brine, dried over Na₂SO₄, filtered and the filtrate was concentrated to give the crude product as an oil. The crude oil was purified by flash chromatography over silica gel using

EtOAc:MeOH (0 to 25% MeOH) to afford partially purified product. The partially purified sample was dissolved in hot EtOH and allowed to cool to room temperature. Upon standing, precipitate formed and it was filtered and washed with cold EtOH and dried under house vacuum to give 0.048 g (11 %) of 2 as a white powder. ¹H NMR (400 MHz, DMSO-d₆): δ 1.50 (m, 8 H), 2.17 (m, 10 H), 2.56 (t, J = 11.7 Hz, 2 H), 3.97 (t, J = 11.5 Hz, 2 H), 6.64 (d, J = 8.4 Hz, 2 H), 6.81 (d, J = 8.7 Hz, 2 H), 6.87 (d, J = 8.4 Hz, 2 H), 6.97 (d, J = 8.7 Hz, 2 H), 9.24 (s, 1 H). HRMS (ESI): m/z 366 (M + H) ⁺.

Example 2 4-[(4-{[2-(dimethylamino)ethyl]oxy}phenyl)(3,3,5,5- tetramethylcyclohexylidene)methyl]phenol hydrochloride (4)

Step 1 : (4-{[2-(dimethylamino)ethyl]oxy}phenyl)(4-hydroxyphenyl)methanone (3)

To a round-bottom flask containing 4,4'-dihydroxybenzophenone (1 g, 4.67 mmol) in DMF (10 ml.) was added CS₂CO3 (6 g, 18.7 mmol). After several minutes of stirring at reflux, 2-(dimethylamino)ethyl chloride hydrochloride (0.61 g, 4.20 mmol) was added to the reaction mixture and heated at reflux overnight. The reaction mixture was allowed to cool to room temperature then quenched with saturated NH₄CI (45 ml.) and extracted with EtOAc. The organic layer was washed with brine, dried over Na₂SO₄, filtered and the filtrate was concentrated. The crude material was purified by flash chromatography on silica gel using EtOAc:MeOH (0 to 10% MeOH) to afford 0.52 g, (39%) of the title compound as a white powder. ¹H NMR (400 MHz, DMSO- ck): δ 2.20 (m, 6 H), 2.63 (t, J = 11.6 Hz, 2 H), 4.12 (t, J = 1 1.5 Hz, 2 H), 6.86 (d, J = 8.6 Hz, 2 H), 7.05 (d, J = 8.6 Hz, 2 H), 7.60 (d, J = 8.6 Hz, 2 H), 7.65 (d, J = 8.8 Hz, 2 H), 10.32 (s, 1 H). Step 2: 4-[(4-{[2-(dimethylamino)ethyl]oxy}phenyl)(3, 3,5,5- tetramethylcyclohexylidene)methyl]phenol hydrochloride (4)

To a round-bottom flask containing zinc dust (0.91 g, 13.9 mmol) in dry THF (16 ml.) was added TiCI₄ (0.74 ml_, 6.74 mmol) slowly and the reaction was heated at 75 ⁰C. After 2.5 h of heating, (4-{[2-(dimethylamino)ethyl]oxy}phenyl)(4-hydroxyphenyl) methanone (0.52 g, 1.82 mmol) and 3,3,5,5-tetramethylcyclohexanone (0.96 ml_, 5.47 mmol) in dry THF (16 ml.) were added to the reaction mixture and heated at above temperature for another 2.5 h. The reaction mixture was cooled to room temperature and diluted with water (10 ml.) followed by 10% K₂CO3 (10 ml_). The reaction mixture was filtered over a pad of celite and the celite pad was washed with EtOAc. The filtrate was extracted with EtOAc and the combined organics then washed with brine, dried (Na₂SO₄), filtered and concentrated. The crude material was dissolved in MeOH and purified using reverse phase HPLC with CH₃CN:H₂O (50 to 100% CH₃CN) to afford an amorphous solid. The solid was partitioned between saturated K₂CO₃ and EtOAc and the organic layer dried (Na₂SO₄), filtered and concentrated. This material was stirred in 1 M HCI and ether and the resulting precipitate washed with ether and dried in vacuo to afford 0.19 g (26%) of the title compound. ¹H NMR (400 MHz, DMSO-d₆): δ 0.87 (m, 12 H), 1.24 (s, 2 H), 1.89 (d, J = 6.9 Hz, 4 H), 2.82 (s, 6 H), 3.46 (t, J = 9.7 Hz, 2 H), 4.27 (t, J = 10.1 Hz, 2 H), 6.65 (d, J = 8.5 Hz, 2 H), 6.89 (m, 4 H), 7.05 (d, J = 8.6 Hz, 2 H), 9.25 (s, 1 H), 9.82 (br s, 1 H). HRMS (ESI): m/z 408 (M + H) ⁺.

Example 3 4-[Cyclooctylidene(4-{[2-(dimethylamino)ethyl]oxy}phenyl)methyl]phenol (8)

Step 1 : 4-Benzyloxy-4'-hydroxybenzophenone (5)

To a solution of 4,4'-dihydroxybenzophenone (2.0 g, 9.3 mmol) in dry DMF (20 ml) was added benzyl bromide (1.22 ml_, 10.2 mmol) and K₂CO₃ (1.4 g, 10.1 mmol). The reaction mixture was heated to 60 ⁰C for 48 h. After cooling to room temperature and filtering off solids, the filtrate was concentrated. The resulting residue was dissolved in EtOAc, and the solution was then washed with 1 N HCI followed by brine. The solution was dried over Na₂SO₄, concentrated under reduced pressure, and purified by flash column chromatography on silica gel (0 to 15% EtOAc in CH₂CI₂ elution) to afford 5 (1.6 g, 57%) as a white solid. ¹H NMR (400 MHz, CDCI₃): δ 5.17 (s, 2 H), 6.92 (d, J = 8.8 Hz, 2 H), 7.05 (d, J = 8.8 Hz, 2 H), 7.28 - 7.48 (m, 5 H), 7.75 - 7.82 (m, 4 H). LRMS (ESI): m/z 303 (M - H) ^" and 305 (M + H) ⁺. Step 2: 4-(Cyclooctylidene{4-[benzyloxy]phenyl}methyl)phenol (6) To a stirring suspension of Zn (0.88 g, 14 mmol) in THF under N₂ at 0 ⁰C was added TiCI₄ (0.64 ml_, 5.8 mmol) dropwise over approximately 3 min. The reaction mixture was then heated to 65 ⁰C. After 2 h, a mixture of 4-benzyloxy-4'- hydroxybenzophenone (5) (0.82 g, 2.7 mmol) and cyclooctanone (0.57 g, 4.5 mmol) in THF (5 ml.) was added, and heating was continued overnight. The reaction mixture was then added to 10% aqueous NaHCO₃ (50 ml_), and the resulting suspension was filtered. The residue was washed with EtOAc (3 x 25 ml_), and the filtrates were combined, concentrated, and purified by flash column chromatography on silica gel (50 to 100% CH₂CI₂:hexanes elution) to yield 6 (0.56 g, 52%) as a viscous yellow oil which solidified upon standing. ¹H NMR (400 MHz, CDCI₃): δ 1.49 - 1.72 (m, 10 H), 2.27 - 2.31 (m, 4 H), 5.04 (s, 2 H), 6.76 (d, J = 8.6 Hz, 2 H), 6.92 (d, J = 8.6 Hz, 2 H), 7.06 (d, J = 8.6 Hz, 2 H), 7.10 (d, J = 8.5 Hz, 2 H), 7.34 - 7.46 (m, 5 H). LRMS (APCI): m/z 395 (M - H) and 397 (M + H) ⁺. Step 3: (2-{[4-(Cyclooctylidene{4-

[benzyloxy]phenyl}methyl)phenyl]oxy}ethyl)dimethylamine (7) To a stirring suspension of 4-(cyclooctylidene{4-[benzyloxy]phenyl}methyl)phenol (6) (0.22 g, 0.55 mmol) and Cs₂CO₃ (0.65 g, 2.0 mmol) in DMF (8 mL) at 70 ⁰C was added (2-chloroethyl)dimethylamine hydrochloride 90.21 g, 1.5 mmol) in one portion. After stirring overnight, the reaction mixture was partitioned between H₂O and EtOAc (25 mL each) and extracted with EtOAc (2 x 25 mL). The combined organics were washed with H₂O (2 x 25 mL), dried over Na₂SO₄, and purified by flash column chromatography on silica gel (0 to 10% MeOH in CH₂CI₂ elution) to yield compound 7 as an off-white solid (0.19 g, 74%). ¹H NMR (400 MHz, CDCI₃): δ 1.48 - 1.71 (m, 10 H), 2.27 - 2.33 (m, 4 H), 2.35 (s, 6 H), 2.73 (t, J = 6.5 Hz, 2 H), 4.05 (t, J = 6.5 Hz, 2 H), 6.84 (d, J = 8.8 Hz, 2 H), 6.90 (d, J = 8.9 Hz, 2 H), 7.07 - 7.12 (m, 4 H), 7.33 - 7.46 (m, 5 H). LRMS (APCI): m/z 470 (M + H) ⁺. Step 4: 4-[Cyclooctylidene(4-{[2- (dimethylamino)ethyl]oxy}phenyl)methyl]phenol (8) To a stirring solution of (2-{[4-(cyclooctylidene{4-[benzyloxy]phenyl}methyl) phenyl]oxy}ethyl)dimethylamine (7) (0.19 g, 0.40 mmol) in EtOAc (20 ml.) was added 10% Pd/C (50 mg). The flask was flushed with H₂ and allowed to stir. After 2 h, the reaction mixture was filtered through celite, and the filtrate was purified by flash column chromatography on silica gel (0 to 10% MeOH in CH₂CI₂ elution) to yield compound 8 as a white solid (136 mg, 88%). ¹H NMR (400 MHz, MeOD-c/₄): δ 1.48 - 1.73 (m, 10 H), 2.27 - 2.32 (m, 4 H), 2.38 (s, 6 H), 2.81 (t, J = 6.5 Hz, 2 H), 4.10 (t, J = 6.5 Hz, 2 H), 6.70 (d, J = 8.8 Hz, 2 H), 6.88 (d, J = 8.9 Hz, 2 H), 6.98 (d, J = 8.8 Hz, 2 H), 7.08 (d, J = 8.8 Hz, 2 H). LRMS (ESI): m/z 378 (M - H) and 380 (M + H) ⁺.

BIOLOGICAL DATA

Competition Binding Assay:

Recombinant full length human ERa and ERβ protein was purchased from PanVera (PanVera-lnvitrogen Discovery Screening, Discovery Center, 501

Charmany Drive, Madison, Wisconsin 53719, USA). Polylysine coated Yttrium Silicate SPA beads (Amersham #RPNQ 0010) are resuspended in assay buffer [10 mM potassium phosphate buffer pH 7.0 containing 2 mM EDTA, 50 mM NaCI, 1 mM DTT, 2 mM CHAPS, 10% glycerol] to a concentration of 1 g/60ml. 30 ul (0.5 mg) of the SPA beads are then added to each well of a Packard OptiPlate (Packard

6005190, Packard Instruments, Meriden, CT). The ERa or ERβ protein is diluted to the appropriate concentration (empirically determined for each protein prep by generating a protein curve using 0.5 to 10 ug total protein and 1 nM [3H] Estradiol and selecting a protein concentration that does not deplete the radioligand) and added as 30 μl aliquots to each well. [2, 4, 6, 7, 16, 17-3H(N)]-Estradiol is added as a 30 μl aliquot to give a final assay concentration of 1 nM. To give a final volume of 100ul, either 10 μl of a test compound solution (typically in 10% DMSO as solvent), solvent containing no test compound (to determine total binding, T), or solvent containing 17-b-estradiol at 100 μM (to determine non-specific binding, NS) are finally added to the plate. The plates are shaken vigorously for two hours then counted on a Packard TopCount using the protocol for counting tritium yttrium silicate SPA beads. Data analysis was done by standard methods.

% Bound was Calcd for each concentration of each test compound using the equation %Bound =100^*((Test - NS)/(T-NS)). % Bound was plotted vs concentration and curve fitting was accomplished using non-linear regression.

At least two binding curves were generated for each compound.

The compounds of the Examples 1-3 exhibited plC₅₀ values ranging from 10 μM to 1 nM.

Test compounds were employed in free or salt form.

All research complied with the principles of laboratory animal care (NIH publication No. 85-23, revised 1985) and GlaxoSmithKline policy on animal use.

Although specific embodiments of the present invention are herein illustrated and desribed in detail, the invention is not limited thereto. The above detailed descriptions are provided as exemplary of the present invention and should not be construed as constituting any limitation of the invention. Modifications will be obvious to those skilled in the art, and all modifications that do not depart from the spirit of the invention are intended to be included with the scope of the appended claims.

Claims

What is claimed is

1. A compound of formula (I):

including salts, solvates, and pharmacologically functional derivatives thereof wherein X is -(CH₂J_n- where n is 0, 1 , 2, or 3;

R¹ is -O-(Ci.a)-R⁴ where Ci_-8 is a branched or unbranched alkyl chain having the specified number of carbon atoms; each of R² and R³ are selected from H and Ci-s; and R⁴ is selected from NH₂, N(C^)H, and N(Ci_-8)(Ci_-6).

2. The compound of claim 1 , wherein n is 1 and each of R² and each of R* is Ci._β.

3. The compound of claim 1 , wherein each of R² and each of R³ is selected from

4. The compound of claim 1 , wherein each of R² and R³ is H.

5. The compound of claim 4, wherein n is 2 or 3.

6. The compound of claim 1, wherein R¹ is -0-(CH₂)_J-N(CH₃)(CH₃).

7. The compound of claim 6, wherein π is 1.

8. The compound of claim 6, wherein n Is 2 or 3, and each of R* and R^s is H.

9. A compound selected from: 4-[cycloheptylidene(4-{[2-(dimethylamino)θthyl]oxy}phenyl) methyl]phenol; 4-[(4-{[2-(dimethylamino)ethyl]oxy}phenyl)(3,3,5,5- tetrametnylcycloheχylideπe)methyljphenol; and

4-[Cyclooctylidene(4-{[2-(dimethylamino)ethyl]oxy}phenyi)methyl]phenol, including salts, solvates, and pharmacologically functional derivatives thereof.

10. The compound of claims 1 to 9 substantially as hereinbefore defined with reference to any one of the Examples.

11. A pharmaceutical composition comprising a compound according to claims 1 to 9, and a pharmaceutically acceptable carrier.

12. A compound according to claims 1 to 9 for use as an active therapeutic substance.

13. A compound according to claims 1 to 9 for use in the treatment or prophylaxis of conditions or disorders affected by selective estrogen receptor modulation.

14. The compound of claim 13 wherein treatment or prophylaxis relates to osteoporosis, bone demineralization, reduced bone mass, density, or growth, osteoarthritis, acceleration of bone fracture repair and healing, acceleration of healing in joint replacement, periodontal disease, acceleration of tooth repair or growth, Paget's disease, osteochondrodysplasias, muscle wasting, the maintenance and enhancement of muscle strength and function, frailty or age-related functional decline ("ARFD"), sarcopenia, chronic fatigue syndrome, chronic myaligia, acute fatigue syndrome, acceleration of wound healing, maintenance of sensory function, chronic liver disease, AIDS, weightlessness, bum and trauma recovery, thrombocytopenia, short bowel syndrome, irritable bowel syndrome, inflammatory bowel disease, Crohn's disease and ulcerative colitis, obesity, eating disorders including anorexia associated with cachexia or aging, hypercortisolism and Cushing's syndrome, cardiovascular disease or cardiac dysfunction, congestive heart failure, high blood pressure, breast cancer, malignant tumore cells containing the androgen receptor including breast, brain, skin, ovary, bladder, lymphatic, liver, kidney, uterine, pancreas, endometrium, lung, colon, and prostate, prostatic hyperplasia, hirsutism, acne, seborrhea, androgenic alopecia, anemia, hyperpilosity, adenomas and neoplasis of the prostate, hyperinsulinemia, insulin resistance, diabetes, syndrome X, dyslipidemia, urinary incontinence, artherosclerosis, libido enhancement, sexual dysfunction, depression, depressive symptoms, nervousness, irritability, stress, reduced mental energy and low salf-esteem, improvement of cognitive function, endometriosis, polycystic ovary syndrome, counteracting preeclampsia, premenstral syndrome, contraception, uterine fibroid disease, and/or aortic smooth muscle cell proliferation, vaginal dryness, pruritis, dyspareunia, dysuria, frequent urination, urinary tract infections, hypercholesterolemia, hyperlipidemia, peripheral vascular disease, restenosis, vasospasm, vascular wall damage due to immune responses, Alzheimer's disease, bone disease, aging, inflammation, inflammatory pam, rheumatoid arthritis, respiratory disease, emphysema, reperfusion injury, viral hepatitis, tuberculosis, psoriasis, systemic lupus erythematosus, amyotrophic lateral sclerosis, stroke, CNS trauma, dementia, πeurodegeneration, breast pain and dysmenorrhea, menopausal or postmenopausal disorders, vasomotor symptoms, urogenital or vulvar vaginal atrophy, atrophic vaginitis, female sexual dysfunction, for enhancing libido, for the treatment of hypoactive sexual disorder, sexual arousal disorder, for increasing the frequency and intensity of orgasms, vaginismus, osteopenia, endometriosis, BPH (benign prostatic hypertrophy), dysmenorrhea, autoimmune diseases. Hashimoto's thyroiditis, SLE (systemic lupus erythematosus), myasthenia gravis, or reperfusion damage of ischemic myocardium

15. The compound of claim 14 wherein treatment or prophylaxis relates to menopausal or postmenopausal disorders, vasomotor symptoms, urogenital or vulvar vaginal atrophy, atrophic vaginitis, endometriosis, female sexual dysfunction, breast cancer, depressive symptoms, diabetes, bone demineralization, or osteoporosis.

16 Use of a compound according to claims 1 to 9 in the manufacture of a medicament for use in the treatment or prophylaxis of conditions or disorders associated with selective estrogen receptor modulation.

17. Use of a compound according to claim 16 in the manufacture of a medicament for use in the treatment or prophylaxis of osteoporosis, bone demineralization, reduced bone mass, density, or growth, osteoarthritis, acceleration of bone fracture repair and healing, acceleration of healing in joint replacement, periodontal disease, acceleration of tooth repair or growth, Paget's disease, osteochondrodysplasias, muscle wasting, the maintenance and enhancement of muscle strength and function, frailty or age- related functional decline ("ARFD"), sarcopenia, chronic fatigue syndrome, chronic myaligia. acute fatigue syndrome, acceleration of wound healing, maintenance of sensory function, chronic liver disease, AIDS, weightlessness, burn and trauma recovery, thrombocytopenia, short bowel syndrome, irritable bowel syndrome, inflammatory bowel disease, Crohn's disease and ulcerative colitis, obesity, eating disorders including anorexia associated with cachexia or aging, hypercortisolism and Cushlng's syndrome, cardiovascular disease or cardiac dysfunction, congestive heart failure, high blood pressure, breast cancer, malignant tumore cells containing the androgen receptor including breast, brain, skin, ovary, bladder, lymphatic, liver, kidney, uterine, pancreas, endometrium, lung, colon, and prostate, prostatic hyperplasia, hirsutism, acne, seborrhea, androgenic alopecia, anemia, hyperpilosity, adenomas and neoplasis of the prostate, hyperinsuliπemia, insulin resistance, diabetes, syndrome X₁ dyslipidemia, urinary incontinence, artherosclerosts, libido enhancement, sexual dysfunction, depression, depressive symptoms, nervousness, irritability, stress, reduced mental energy and low self-esteem, improvement of cognitive function, endometriosis, polycystic ovary syndrome, counteracting preeclampsia, premenstral syndrome, contraception, uterine fibroid disease, and/or aortic smooth muscle cell proliferation, vaginal dryness, pruritis, dyspareunia, dysuria, frequent urination, urinary tract infections, hypercholesterolemia, hyperlipidemia, peripheral vascular disease, restenosis, vasospasm, vascular wall damage due to immune responses, Alzheimer's disease, bone disease, aging, inflammation, inflammatory pain, rheumatoid arthritis, respiratory disease, emphysema, reperfusion injury, viral hepatitis, tuberculosis, psoriasis, systemic lupus erythematosus, amyotrophic lateral sclerosis, stroke, CNS trauma, dementia, neurodegeneration, breast pain and dysmenorrhea, menopausal or postmenopausal disorders, vasomotor symptoms, urogenital or vulvar vaginal atrophy, atrophic vaginitis, female sexual dysfunction, for enhancing libido, for the treatment of hypoactive sexual disorder, sexual arousal disorder, for increasing the frequency and intensity of orgasms, vaginismus, osteopenia, endometriosis, BPH (benign prostatic hypertrophy), dysmenorrhea, autoimmune diseases, Hashimoto's thyroiditis. SLE (systemic lupus erythematosus), myasthenia gravis, or reperfusion damage of ischemic myocardium.

18. Use of a compound as in claim 17 wherein the condition or disorder is menopausal or postmenopausal disorders, vasomotor symptoms, urogenital or vulvar vaginal atrophy, atrophic vaginitis, endometriosis, female sexual dysfunction, breast cancer, depressive symptoms, diabetes, bone demineralization, or osteoporosis.

19. A method for the treatment or prophylaxis of conditions or disorders associated with selective estrogen receptor modulation comprising the administration of a compound according to any one of claims 1 to 9.

20. A method for the treatment or prophylaxis of osteoporosis, bone demineralization, reduced bone mass, density, or growth, osteoarthritis, acceleration of bone fracture repair and healing, acceleration of healing in joint replacement, periodontal disease, acceleration of tooth repair or growth, Paget's disease, osteochoπdrodysplasias, muscle wasting, the maintenance and enhancement of muscle strength and function, frailty or age-related functional decline ("ARFD"), sarcopenia, chronic fatigue syndrome, chronic myaligia, acute fatigue syndrome, acceleration of wound healing, maintenance of sensory function, chronic liver disease, AIDS, weightlessness, burn and trauma recovery, thrombocytopenia, short bowel syndrome, irritable bowel syndrome, inflammatory bowel disease, Crohn's disease and ulcerative colitis, obesity, eating disorders including anorexia associated with cachexia or aging, hypercortisolism and Cushiπg's syndrome, cardiovascular disease or cardiac dysfunction, congestive heart failure, high blood pressure, breast cancer, malignant turn ore cells containing the androgen receptor including breast, brain, skin, ovary, bladder, lymphatic, liver, kidney, uterine, pancreas, endometrium, lung, colon, and prostate, prostatic hyperplasia, hirsutism, acne, seborrhea, androgenic alopecia, anemia, hyperpilosity, adenomas and neoplasis of the prostate, hyperinsulinemia, insulin resistance, diabetes, syndrome X, dyshpidemia, urinary incontinence, atherosclerosis, libido enhancement, sexual dysfunction, depression, depressive symptoms, nervousness, irritability, stress, reduced mental energy and low self- esteem, improvement of cognitive function, endometriosis, polycystic ovary syndrome, counteracting preeclampsia, premenstral syndrome, contraception, uterine fibroid disease, and/or aortic smooth muscle cell proliferation, vaginal dryness, pruritis, dyspareunia, dysuna, frequent uπnation, uπnary tract infections, hypercholesterolemia, hyperlipidemia, peripheral vascular disease, restenosis, vasospasm, vascular wail damage due to immune responses, Alzheimer's disease, bone disease, aging, inflammation, inflammatory pain, rheumatoid arthritis, respiratory disease, emphysema, reperfusion injury, viral hepatitis, tuberculosis, psoriasis, systemic lupus erythematosus, amyotrophic lateral sclerosis, stroke, CNS trauma, dementia, neυrodegeneration, breast pain and dysmenorrhea, menopausal or postmenopausal disorders, vasomotor symptoms, urogenital or vulvar vaginal atrophy, atrophic vaginitis, female sexual dysfunction, for enhancing libido, for the treatment of hypoactive sexual disorder, sexual arousal disorder, for increasing the frequency and intensity of orgasms, vaginismus, osteopenia, endometriosis, BPH (benign prostatic hypertrophy), dysmenorrhea, autoimmune diseases, Hashimoto's thyroiditis, SLE (systemic lupus erythematosus), myasthenia gravis, or reperfusion damage of ischemic myocardium comprising the administration of a compound according to any one of claims 1 to 9.

21 The method of claim 20, wherein the condition or disorder is menopausal or postmenopausal disorders, vasomotor symptoms, urogenital or vulvar vaginal atrophy, atrophic vaginitis, endometriosis, female sexual dysfunction, breast cancer, depressive symptoms, diabetes, bone demineralization, or osteoporosis.