MXPA00004423A - 2-aryl-3-aroylbenzo[b]thiophenes useful for the treatment of estrogen deprivation syndrome - Google Patents

Abstract

This invention provides methods which are useful for the inhibition of the various medical conditions associated with estrogen deprivation syndrome including osteoporosis and hyperlipidemia utilizing compounds of formula (I).

Description

2-ARIL-3-AR0ILBENZ0 [b] USEFUL TIOFENES FOR THE TREATMENT OF DEPRIVATION SYNDROME ESTROGEN FIELD OF THE INVENTION This invention relates to the fields of pharmaceutical and organic chemistry, and provides 2-ar i lbenz or [b] thioes which are useful for the inhibition of the different conditions of estrogen deficiency.

BACKGROUND OF THE INVENTION "Estrogen deprivation syndrome" is a term used to describe various pathological conditions that frequently affect women who have insufficient levels of the hormone estrogen. The most common cause of estrogen deprivation in women, is the natural cessation of menstruation, with age, ie menopause. Additionally, unnatural circumstances, which include surgical oophorectomy, chemotherapy that causes the cessation of production of hormones or pharmacological action, and the like, may induce estrogen deprivation. Although numerous pathologies are contemplated through the use of this term, two main effects of the estrogen deprivation syndrome are the source of the greatest long-term medical concern: osteoporosis and cardiovascular effects, especially hyperlipidemia. Osteoporosis describes a group of diseases that can arise from various etiologies, but all are characterized by the net loss of bone mass per unit volume. The consequence of this loss of bone mass is the failure of the skeleton to provide adequate structural support for the body, that is, fracture of the bones. One of the most common types of osteoporosis is one that is associated with menopause. Most women lose from approximately 20% to approximately 60% of the bone mass in the trabecular compartment of the bone, in a period of 3 to 6 years after the cessation of menstruation. This rapid loss is generally associated with an overall increase in bone resorption and the bone formation cycle, where the resorption cycle is most dominant. The obvious result is a net loss of bone mass. Osteoporosis is a common and serious disease among postmenopausal women. There is an estimated 25 million women in the United States alone, who suffer from this disease. The results of osteoporosis are personally harmful and also represent a great economic loss due to its chronicity and the need for extensive and long-term support or assistance (hospitalization and nurse care at home) of the aftermath of the disease. This is especially true in elderly patients. Additionally, although it is generally thought that osteoporosis is not a life-threatening condition, a mortality rate of 20% to 30% is attributed to hip fractures in elderly women. A large percentage of this mortality rate can be directly associated with postmenopausal osteoporosis. Throughout the entire first year, most women have a lower incidence of cardiovascular disease than men of the same age. However, after menopause, the rate of cardiovascular disease in women increases slowly until it equals the rate seen in men. This loss of protection has been related to the loss of estrogen and, in particular, to the loss of estrogen's ability to regulate the levels of serum lipids. The nature of the estrogen's ability to regulate serum lipids is not well understood, but evidence to date indicates that estrogen may override low-density-lipid (LBD) receptors in the liver. Eliminate excess cholesterol. Additionally, estrogen seems to have some effect on cholesterol biosynthesis, and other beneficial effects on cardiovascular health. Although estrogen replacement therapy is often prescribed for the syndrome of estrogen deprivation, suffers from poor acceptance by patients, since many women object to some of the side effects and the inconvenience of the pharmaceutical forms of the medication. For example, 17-β-is-t-radiol is often administered through a transdermal t-patch, due to its poor oral absorption. As a result, most women stop taking estrogen in the first year after starting estrogen replacement therapy. The compounds of formula I: I; wherein: R and R1 are independently hydrogen, hydroxy, alkoxy of 1 to 4 carbon atoms, cycloalkoxy of 3 to 6 carbon atoms, OCH2Ar, OCO (alkyl of 1 to 6 carbon atoms), OCOAr; Ar is phenyl or substituted phenyl; and R2 is hydrogen, chlorine, bromine, hydroxy, alkoxy of 1 to 6 carbon atoms, cycloalkoxy of 3 to 6 carbon atoms, OCH2Ar OCO (at least 1 to 6 carbon atoms), OCOAr; or a solvate thereof; they are known as chemical intermediates for oral pharmaceutical agents, for example raloxifene hydrochloride. The present invention concerns the discovery of utilities recently attributed to compounds of formula I, especially that they are useful agents for inhibiting the estrogen deprivation syndrome.

BRIEF DESCRIPTION OF THE INVENTION The present invention provides methods for inhibiting the estrogen deprivation syndrome, in mammals, which includes administering to a mammal having an effective amount of a compound of formula I: I; wherein: R and R1 are independently hydrogen, hydroxy, alkoxy, of 1 to 6 carbon atoms, OCH2Ar, OCO (alkyl of 1 to 6 carbon atoms), OCOAr; Ar is phenyl or substituted phenyl; and R2 is hydrogen, chlorine, bromine, hydroxy, alkoxy of 1 to 6 carbon atoms, OCH2Ar, OCO (alkyl of 1 to 6 carbon atoms), OCOAr; or a solvate thereof; Additionally, the present invention provides methods for inhibiting the estrogen deprivation syndrome, which includes administering to a mammal. in need thereof, an effective amount of a compound of formula I and a compound of formula II: II; where R; R1 are independently hydrogen, alkyl of 1 to 6 carbon atoms, CO (alkyl of 1 to 6 carbon atoms), or COAr; R5 is pyrrolidin-1-yl, piper i din-1-i lo, 0 hexa et i 1 enimin- 1 -i 1 o; wherein the nitrogen of the group R5 is optionally the N-oxide; or a pharmaceutical salt or solvate thereof. In addition, the present invention concerns pharmaceutical formulations comprising a compound of formula I, or compounds of formula 1 and II, and to excipients, diluents, or carriers, pharmaceuticals.

DETAILED DESCRIPTION OF THE INVENTION The general terms, used in the description of the compounds, methods, and formulations herein, have their usual meanings, for example, "alkyl of 1 to 4 carbon atoms" refers to methyl, ethyl, propyl, iso-propyl , cyclopropyl, n-butyl, s-butyl, t-butyl, and cyclobutyl. The term "alkyl of 1 to 6 carbon atoms" embraces those listed for the alkyl of 1 to 4 carbon atoms, in addition to monovalent, straight, branched, or cyclic aliphatic chains of 5 or 6 carbon atoms, which include pentyl, cyclopentyl, hexyl, 2-methylpenther, cyclohexyl, and the like. The term "C 1 -C 4 alkoxy" refers to methoxy, ethoxy, n-propoxy, iso-propoxy, cyclopropoxy, n-butoxy, s-butoxy, t-butoxy, and cyclobutoxy. The term "C 1-6 alkoxy" embraces those listed for the alkoxy of 1 to 4 carbon atoms, in addition to straight, branched, or cyclic aliphatic chains, of 5 or 6 carbon atoms, which are attached through of a monovalent oxygen atom and include, but are not limited to, pentoxy, cyclopentoxy, hexoxy, 2-methyl tipentoxy, cyclohexoxy, and the like. The term "halide" refers to chloride, bromide, or iodide. The term "substituted phenyl" refers to a phenyl group having 1 to 3 substituents selected from the group consisting of alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 4 carbon atoms, hydroxy, nitro, chloro, fluoro , or tri (chloro or fluoro) ethyl Although the free base form of the compounds of the formula II can be used in the methods of the present invention, it is preferred to prepare or use a pharmaceutical salt form. Typical salts include those salts prepared by the reaction of the compounds of formula II with an organic or mineral acid.These salts are known as acid addition salts., the term "pharmaceutical salt" refers to acid addition salts, of a compound of formula II, which are substantially non-toxic in the doses administered and are commonly known in the pharmaceutical literature. See, for example, Berge, S.M., Bighley, L.D., and Monkhouse, D.C., J. Pharm. Sci., 66,. 1, 1977. Pharmaceutical salts generally have enhanced solubility characteristics, compared to the compound from which they are derived, and thus, are more favorable for use in pharmaceutical formulations. Examples of pharmaceutical salts are the iodide, acetate, pheny Tato lace, trifluoroacetate, acrylate, ascorbate, benzoate, chlorobenzoate, dini t robenzoato, hydroxybenzoate, I toxibenz or to I ti lbenzoa to, o-acetoxybenzoate, 2-benzoate naphthalene , bromide, isobutyrate, f-enylbutyrate, g-hydroxybutyl irat or, b-hydroxybutyl, 1,4-butyne dioate, hexane-1,4-dioate, hexane-1,6-dioate, caproate, caprylate, chloride, cinnamate, citrate, decanoate, formate, fumarate, glycollate, heptanoate, hippurate, lactate, malate, maleate, hidroximaleat or, malonate, mandelate, mesylate, nicotinate, i soni co t ina to, nitrate, oxalate, phthalate, teraphthalate, phosphate, monohydrogenphosphate, dihydrogenphosphate, I TAFOS me sulphate, pyrophosphate, propiolate, propionate, f eni lpropionat or, salicylate, sebacate, succinate, suberate, sulfate, bisulfate, pyrosulfate, sulfite, bisulfite, sulfonate, fona bencensul to, p-bro or phenyl sulfonate, chlorobenzenesulfonate, propansul f ona to, e tan sul sulfonate, 2-hidroxie tansul fona to I tansul fona to, naphthalene-1-sulfonate, na fta in- 1 2 - sui fona to, pt to one oluensul f, xylenesulfonate, tartarate, and the like of a compound of formula II . The term "solvate" represents an aggregate comprising one or more molecules of the solute, such as a compound of formula I or II, with one or more molecules of the solvent. These solvent molecules would be those commonly used in the pharmaceutical literature, known to not be harmful to the patient, for example, water and ethanol. The term "thermodynamic basis" refers to a base that provides a reversible deprophonation of an acid substrate, or is used as a proton trap when a proton is a byproduct of a reaction, and is reactive enough to effect the desired reaction. without significantly affecting any of the unwanted reactions. Examples of thermodynamic bases include, but are not limited to, carbonates, bicarbonates, and hydroxides (eg, carbonate, bicarbonate, or lithium hydroxide, sodium or potassium), tri- (alkyl of 1 to 4 carbon atoms) amines, heterocycles containing aromatic nitrogen (for example pyridine). The term "estrogen deprivation syndrome" contemplates those pathologies and conditions produced by the loss of ovarian function (either natural, or surgically or chemically induced) and specifically the loss of hormones from the ovaries, especially estrogen. Since the loss of estrogen is the cause of the symptoms of the syndrome, each of these symptoms responds to the replacement of the hormone estrogen loss, by administering the compounds of the present invention. In this manner, the compounds and methods of the present invention would be useful and beneficial for the treatment or prevention of estrogen deficiency symptoms, including, but not limited to, the following: osteoporosis, hyperlipidemia, atherosclerosis, vasomotor abnormalities ( hot flares), autoimmune diseases, skin and hair abnormalities, cardiovascular disease and degeneration, dementia and Alzheimer's disease, depression, weight gain or loss, certain types and conditions of diabetes, healing and inappropriate tissue repair , vaginal atrophy, urinary incotinence, sequelae of abnormal regulation of genes controlled by estrogen, i n t ra l l a. It should be recognized that not all patients who are treated for the symptoms of estrogen deprivation syndrome, will necessarily have all the pathologies, upra, in this way, the specific use of the compounds and methods of the present invention, may vary depending of the idiosyncratic nature and severity of those symptoms. The terms "inhibit" or "inhibition" mean prohibit, treat, alleviate, improve, interrupt, restrict, slow or reverse the progression, or reduce the severity of a pathological symptom related to, or resulting from, the estrogen deprivation syndrome. . As such, these methods include both therapeutic (acute) and / or prophylactic (prevention), medical administration, as appropriate. As used herein, the term "effective amount" means an amount of a compound or compounds, of the present invention, that is capable of inhibiting the symptoms of different conditions and pathological symptoms, described herein. By "pharmaceutical formulation", "pharmaceutical carrier", "pharmaceutical diluent", and "pharmaceutical excipient" is meant, in a formulation containing a compound of formula I or in a formulation containing a combination of a compound of formula I and II, the carrier, diluent, excipients, and salt, are compatible with the other ingredients of the formulation, and not harmful to the container thereof. Although all of the compounds of the present invention are useful, certain of the compounds are particularly interesting and preferred. For example, compounds of formula I wherein R, R1, and R2 are independently hydroxy or methoxy, are preferred. More preferred are the compounds of formula I wherein R, R1 and R2 are each hydroxy. The most preferred compound, of formula I, wherein R2 is in the 4-position of the benzoyl ring and R, R1 and R2 are each hydroxy, ie 2- (4-hydroxyphenyl) -3- (4-hydroxybenzoyl) - 6-hydroxybenzo [b] thiophene. In addition, the hydrochloride salt of the compound of formula II wherein R3 and R4 are both hydrogen, and R5 is piperidin-1-yl, is particularly preferred. This compound of formula II is [2- (4-hydroxy-f-enyl) -6-hydroxy-benzo [b] thien-3-yl] [4- [2- (1-piperidinyl) ethoxy] phenyl] -methanone hydrochloride, is say raloxifene hydrochloride. Although all formulations and methods employing a combination of a compound of formula I and II are useful, possible combinations employing the preferred compounds, listed above, are particularly of interest and preferred. Most preferred is the combination of 2- (4-hydroxybenzo [b] thiophene and Raloxy phenohydrate.) Compounds of formula I can be prepared from the compound of formula III and IV as illustrated in the scheme 1 later, where R, R1, - and R2, are as described above.

Scheme I III IV V VI VII The compounds of formula III can be alkylated at S with a phenacyl halide of formula IV. These Alktions in S are carried out in a solvent, in the presence of a thermodynamic base, at temperatures between 0 ° C and 100 ° C, for a time of one to twenty hours. A preferred solvent and base are typically ethanol and potassium hydroxide, respectively. The reaction is preferably carried out at room temperature for a time of one to three hours. A preferred halide for the compound of formula IV is the bromide. The resulting compounds of formula V are cyclized to form the compounds of formula VI, by treatment with an acid in a suitable solvent, at a temperature of between 50 ° C and 200 ° C for a time of one to twenty-four hours. A preferred solvent and acid is polyphosphoric acid. The compounds of formula VI are then acylated with an acid halide of formula VII. These acylations occur under the standard Friedel-Craft conditions, which are well known in the art, See, for example, Olah, Friedel-Crafts and Related Reactions, Interscience Publ., New York, London, and Sydney, 1963. In general, these acylations are carried out in inert solvents, in the presence of a Lewis acid catalyst, at temperatures between 0 ° C and 100 ° C, for a time of one to twenty-four hours. 1,2-Dichloroethane is typically a preferred solvent. A preferred temperature and reaction time is usually from 0 ° C to 10 ° C, for a time of one to three hours. A preferred halide for the compound of formula VII is chloride, and a preferred Lewis acid catalyst is typically aluminum chloride. When any or all of the radicals, R, R1 and R2 are to be hydroxy, it is preferred that the above sequence be carried out with a compound of formula III, IV, and / or VII, wherein some or all of the radicals R, R1 and R2 are alkoxy of 1 to 6 carbon atoms, OCH2Ar, OCO (alkyl of 1 to 6 carbon atoms), or OCOAr. The compounds of formula I wherein some or all of the R, R1 and R2 are hydroxy, can be prepared after the acylation step, by removing the alkyl of the 6 carbon atoms, CH2Ar, CO (alkyl of 1 to 6 carbon atoms) ), or COAr portions (protecting groups) of the resulting compounds of formula I. Methods for removing these protecting groups can be found in the section of examples that follow, or in chapter 2 of "Protective Groups in Organic Synthesis, 2nd Edition , TH Greene, et al., John Wiley & Sons, New York, 1991. In addition, methods for the selective removal of protecting groups can also be found in the examples section and the Greene reference cited above. For further instructions regarding the preparation of the compounds of formula I, see U.S. Patent Nos. 4,133,814, 5,514,703, 5,514,704, and 5,532,382 the descriptions of each of them are incorporated herein by reference. Compounds of formula II which are not N-oxides, and their pharmaceutical salts, can also be prepared as described in the previously incorporated US patents, in addition to US Patent Nos. 4,418,068, 5393,763, and 5,629,425, and the PCT publication. # US97 / 04259, the descriptions of which are incorporated herein by reference. The compounds of formula II which are N-oxides, can be prepared by dissolving or suspending a compound of formula II which is not an N-oxide, in dilute aqueous solutions, of hydrogen peroxide, with an all-in-one cosolvent, such as methanol or ethanol. The reaction conditions for this reaction can vary from room temperature to 100 ° C, and for a duration of 24 to 72 hours. It will be noted that care must be taken in selecting the oxidizing agent and that many agents, commonly used, for example, chromic anhydride, potassium permanganate,, and the like, capable of oxidizing nitrogen, can not be used, since they would oxidize the sulfur of benzo [b] thiophene. In this way, a softer agent, such as hydrogen peroxide, is preferred. The optimal time to carry out the reactions described herein can be determined by inspecting the progress of the reaction, through conventional chromatographic techniques. In addition, it is preferred to carry out the reactions of the invention, under an inert atmosphere, such as for example, argon, or particularly, nitrogen. The selection of the solvent is generally not critical as long as the solvent used is inert for the ongoing reaction, and the reagents are sufficiently solubilized, to effect the desired reaction. The intermediate compound and the final products can be purified, if desired by common techniques such as recrystallization or chromatography on solid supports such as silica gel or alumina. The compounds of formula III, IV, and VII are either commercially available, or can be prepared by methods well known in the art. The discussion of the synthesis does not intend to be limiting of the scope of the present invention, and should not be considered in that way. The application of the above chemistry allows the synthesis of the compounds of formula I, which include, but are not imitated to: 2- (4-methoxyphenyl) -3- (4-methoxybenzoyl) -6-methoxybenzo [b] thiophene; 2- (4-hydroxyphenyl) -3- (4-methoxybenzoyl) -6-hydroxybenzo [b] thiophene; 2- (4-methoxyphenyl) -3- (4-methoxybenzoyl) -6-idroxybenzo [b] thiophene; 2- (4-hydroxyphenyl) -3- (4-methoxybenzoyl) -6-methoxybenzo [b] thiophene; 2- (-methoxy phenyl) -3- (4-hydroxybenzoyl) 6-methoxybenzo [b] thiophene; 2- (4-hydroxyphenyl) -3- (4-hydroxybenzoyl) -6-methoxybenzo [b] thiophene; 2- (4-methoxyphenyl) -3- (4-hydroxybenzoyl) 6-hydroxybenzo [b] thiophene; 2- (4-hydroxyphenyl) -3- (4-hydroxybenzoyl) -6-hydroxybenzo [b] thiophene; 2- (4-acetoxyphenyl) -3- (4-methoxybenzoyl) -6-acetoxybenzo [b] thiophene; 2- (4-acetoxyphenyl) -3- (4-acetoxybenzoyl) -6-acetoxybenzo [b] thiophene; 2- (4-methoxyphenyl) -3- (4-benzoyloxybenzoyl) -6-methoxybenzo [b] thiophene; 2- (4-acetoxyphenyl) -3- (4-methoxybenzoyl) -6-methoxybenzo [b] thiophene; 2- (4-cyclopentoxyphenyl) -3- (4-hydroxybenzoyl) -6-cyclopentoxybenzo [b] thiophene; and imi lares.

Formulations and methods employing both a compound of formula I or formula II include, but are not limited to, the following combinations of the two compounds: 2- (4-methoxy-phenyl) -3- (4-methoxybenzoyl) -6-metoxibenzo [b] thiophenoxy and [2- (4-hydroxyphenyl) -6-hydroxybenzo [b] thienyl hydrochloride] 3-yl] [4- [2 - (1-piperidinyl) ethoxy] phenyl] methanone 2- (4-Hydroxy-phenyl) -3- (4-methoxybenzoyl) -6-me toxibenzo [b] thiophene hydrochloride and [2- (4-hydroxyphenyl) -6-hydroxybenzo [b] thien-3-yl] [4- [2- (1-piperidinyl) ethoxy] phenyl Jmetanone 2 - (4-methoxy f eni 1) -3 - (-me toxibenzoyl) -6-hydroxybenzo [b] thiophene hydrochloride and [2- (4-hydroxy-phenyl-1) -6-hydroxybenzo [b] ti en- 3 - i lo] [4- [2- (1-piperidinyl) ethoxy] phenyl Jmetanone 2- (4-methoxy-phenyl) -3- (4-hydroxy-benzoyl) -6-methoxy-benzo [b] thiophene hydrochloride and [2- (4-hydroxy-phenyl) -6-hydroxy-benzo [b] thien-3-yl] [4- [2- (1-piperidinyl) ethoxy] phenyl] methanone 2- (4-methoxy phenyl) -3- (4-hydroxybenzoyl) -6-hydroxybenzo [b] thiophene hydrochloride and [2- (4-hydroxyphenyl) -6-hydroxybenzo [b] thien-3-yl]] 4- [2- (1-piperidinyl) ethoxy] phenyl] methanone 2- (4-Hydroxy-phenyl) -3- (methoxy-benzoyl-1) -6-hydroxy-benzo [b] t -ophene hydrochloride and [2- (4'-hydroxyphenyl) -6-hydroxy-benzo [b] thien-3-yl] [4] - [2 - (1-piperidinyl) ethoxy] phenyl] methanone 2- (4-Hydroxy-phenyl) -3- (4-hydroxy-benzo-1-yl) -6-metoxibenzo [b] thiophene hydrochloride and [2- (4-hydroxy-phenyl) -6-hydroxy-benzo [b] thien-3 -yl] [4- [2- (1-piperidinyl) ethoxy] phenyl] methanone 2 - (4-Hydroxy-phenyl-1) -3- (4-hydroxy-ibenzo-1) -6-hydroxy-benzo [b] thio-phenohydrochloride and [2- (4-hydroxy-phenyl-1) -6-hydroxybenzo [b ] t ien-3-yl] [4- [2- (1-piperidinyl) ethoxy] phenyl] methanone 2- (4-Hydroxy phenyl) -3- (4-hydroxybenzoyl-) -6-hydroxybenzo [b] thiophene N-oxide and [2- (4-hydroxy phenyl) -6-hydroxybenzo [b] thien-3- ilo] [4- [2- (1-piperidinyl) ethoxy] phenyl] methanone 2- (4-acetoxy f eni 1) - 3 - (4-hydroxybenzoyl) -6-acetoxybenzo [] thiophene hydrochloride and [2- (4-hydroxy f eni 1) - 6-hydroxybenzo [b] t- 3-i lo] [4- [2- (1-pyrrolidinyl) ethoxy] phenyl] ethanone; and s imilar.

The following preparations and examples further illustrate the synthesis of the compounds of the present invention. The examples are not intended, in any way, to be limiting of the scope of the invention, and should not be considered in that way. The terms and abbreviations used in the preparations and examples herein have their normal meanings, unless designated otherwise. For example "° C", "N", "mmol", "g" "mL", "M", "HPLC", "pf", "AE", "MS", and "1H NMR", refer to degrees Celsius, normal or normal, millimole or millimoles, grams or grams, milliliters or milliliters, molar or molarity, high resolution liquid chromatography, melting point, elemental analysis, mass spectrum, and proton nuclear magnetic resonance, respectively.

Preparations Preparation 1 2- (3-Methoxyphenylthio) -4 '-Methoxyacetophenone 3-methoxy thio phenol (50.0 grams, 0.356 mol) was dissolved in 700 milliliters of ethanol. To this mixture was added (20 grams, 0.36 mol) of potassium hydroxide pellets. A total of (82.5 grams, 0.36 mol) of 2-bromo-4'-methoxyacetophenone was added in small portions to maintain the reaction temperature at a value of about 25 ° C. The reaction was allowed to proceed at room temperature for three hours. The reaction was terminated by evaporation of the alcohol, which resulted in the production of a brown oil. The oil was divided between two liters of water and 1.5 liters of diethyl ether. The ether layer was separated and washed with water, dried with anhydrous magnesium sulfate, and evaporated to a solid. The solid was crystallized from a mixture of diethyl ether: petroleum ether (3: 1) to yield 78.5 grams of the title compound as a pink crystalline solid. p.f 53 ° C-54 ° C. AE calculated for Ci6H? 603S: C, 66.64; H, 5.59; 0.16.64; S, 11.12. Found: C, 66.55; H, 5.87; 0.1682; S, 10.86.

Preparation 2 2- (4-Methoxyphenyl) -6-methoxybenzo [b] thiophene 2 -. (3-Me-toxy-phenyl-11-o-) -4-methoxy-acetone phenone (50 grams, 0.173 mol) was added to 250 grams of polyphosphoric acid at 95 ° C. The mixture was stirred and the temperature was raised to 120 ° C and ice was added cautiously. As the temperature increased, to 130 ° C, after 30 minutes, more ice was added and the crystals of the product began to appear. Water was added to the reaction mixture and the product was collected by filtration. The final product was recrystallized from ethyl acetate to give 30 grams of the title compound. mp 193 ° C-194 ° C. AE calculated for C_.6H1.O2S: C, 71.08; H, 5.22; O, 11.84; S, 11.86. Found: C, 71.03; H, 5.30; O, 11.81; S, 11.60.

Examples Example 1 2- (4-Methoxyphenyl) -3- (4-Methoxybenzoyl) -6 'Methoxybenzo [b] thiophene 2- (4-Methoxyphenyl-6-Me toxibenzo [b] thiophene (10 g, 37 mmol) was dissolved in 700 milliliters of 1,2-di c 1 oroetane, and the mixture was cooled to 0 ° C. The reaction solution was slowly added a mixture of 4-methoxybenzoyl chloride (6.31 grams, 37 millimole) and aluminum chloride (5.07 grams, 38 millimole) The reaction was allowed to proceed at 0 ° C for 2 hours and The organic layer was separated and the aqueous layer was extracted with chloroform.The organic layers were combined, washed with saturated aqueous dicarbonate solution and water, dried over magnesium sulfate, and filtered. The volatiles were removed by evaporation, yielding a yellow oil, which was dissolved in 500 milliliters of methanol and 15 milliliters of 5 N sodium hydroxide and refluxed until the methanol had evaporated (30 minutes). dissolved in diethyl ether, washed with saline It was evaporated and this produced 14.6 grams of a yellow oil which was purified by chromatography. This produced 13.9 grams of the title compound as a yellow oil. AE calculated for C 24 H 20 O.S: C, 71.25; H, 4.98; O, 15.82; S, 7.93. Found: C, 71.25; H, 4.90; O, 15.78; S, 7.65. MS (EI): m / e = 404 (M +).

Example 2 2- (4-Hydroxyphenyl) -3- (4-methoxybenzoyl) -6- Hydrox ibenzo [b] thiophene 2- (4-Methoxyphenyl) -3- (4-methoxybenzoyl) -6-methoxybenzo [b] thiophene (53 grams, 131 mmol) was dissolved in chloroform and cooled to 10 ° C. To this stirred mixture was added sodium tribromide (75 grams, 296 millimole) and the reaction was allowed to proceed for 24 hours at room temperature. The reaction was finalized by pouring it into water. The organic layer was separated, filtered, and evaporated to dryness. The residue was dissolved in benzene, filtered, and evaporated to dryness. The crude product was further purified by chromatography on silica gel, eluting with diethyl ether and co-benzene (9: 1) and then chromatographed over alumina, eluting with diethyl ether, followed by a methanol-wash. ether (1: 9) of the solvents, to yield 5.8 grams of the title compound. p.f. 138 ° C-140 ° C. AE calculated for C22H_.6O.S: C, 70.20; H, 4.28; O, 17.00. Found: C, 70.46; H, 4.50; O, 16.87.

E j us 3 2- (4-Methoxyphenyl) -3- (4-Hydroxybenzoyl) - 6- Me toxibenzo [b] thiophene 2- (4-Methoxyphenyl) -3- (4-methoxybenzoyl) -6-methoxybenzo [b] thiophene (19.8 grams, 49 millimole) was dissolved in dimethylformamide and sodium hydride (10 grams of a dispersion in 50% oil) was added. %). The reaction was cooled and ethyl mercaptan (12.4 grams) was slowly added. The reaction was heated to a temperature of 65 ° C to 70 ° C until the reaction was complete. The volatiles were removed by evaporation, water was added to the reaction mixture, and the resulting reaction mixture was extracted with ethyl acetate. The ethyl acetate extracts were washed with water and evaporated to dryness. The residue was chromatographed on a column with silica gel, eluting with 1500 milliliters of benzene-ethyl acetate (99: 1), then with benzene-ethyl acetate (97: 3). The fractions containing the title compound were evaporated to dryness. and the residue was crystallized from benzene, to give 10.7 grams of the title compound. p.f. 114 ° C-116 ° C. AE calculated for C23H? 8O.S: C, 70.75; H, 4.64; O, 16.39. Found: C, 70.88; H, 4.50; O, 16.11.

E j empl o 4 2- (4-Hydroxy phenyl) -3- (4-Hydroxybenzoyl) -6-Hydroxybenzo [b] thiophene 2- (4-Methoxyphenyl) -3- (4-methoxybenzoyl) -6-methoxybenzo [b] thiophene became in the title compound through the procedure of Example 2. The examples provided below demonstrate the utility of the present invention and are provided with the aim of providing an illustration and should not be considered as limiting in any way. The experimental model used in this demonstration is a model developed to simulate two of the main pathologies associated with human estrogen deprivation, that is, the hyperlipidemia and the isoporosis.

General procedure Female, 75-day-old Sprague Dawley rats (weighing 200 grams to 225 grams) were obtained from Charles River Laboratories (Portage, MI). The animals had their ovaries removed bilaterally (OVX) or were exposed to a Sham surgical procedure, at Charles River Laboratories, and then boarded after a week. Upon arrival, they were locked in hanging metal cages, in groups of 3 or 4 per cage and had access to food at d U bi t um v (calcium content of approximately 0.5%) and water, for a week,. The ambient temperature was maintained at 22.2 ° ± 1.7 ° C with a minimum relative humidity of 40%. The period of light in the room was 12 hours of light and 12 hours of darkness.

Tissue Collection with Regimens of Dosing After a week of acclimation period (two weeks after the OVX) the daily dosing with the test compound of 17-a-e t ini les t radiol is started. Doses are given orally, unless otherwise stated, as a suspension in 1% carboxymethylcellulose or dissolved in 20% cyclodextrin. The animals were dosed daily for 4 days. Following the dosing regimen, the animals were weighed and anesthetized with a ketamine: the xylazine mixture (2: 1, V: V) and a blood sample was collected by cardiac puncture. Then the animals were sacrificed by asphyxia with C02, the uterus was removed through a medium excision, and the wet uterine weight was determined.

Hyperlipidemia (Anal i sis del Cholesterol) The blood samples were allowed to coagulate at room temperature for 2 hours, and the serum was obtained followed by centrifugation for 10 minutes at 3000 rpm. Serum cholesterol is determined using a high-resolution cholesterol assay from Boehringer Mannheim Diagnostic. Briefly, cholesterol is oxidized to colé s t-4-en-3 -ona and hydrogen peroxide. The hydrogen peroxide is then reacted with phenol and 4-amino phenazone in the presence of peroxidase, to produce a p-quinone imine dye, which is spectrally red, and truncated at 500 nanometers. Then the cholesterol concentration is calculated against a standard curve. The entire trial is automated using an automated Biomek workstation. The representative compounds of the present invention produced cholesterol in the serum, compared to the control animals to which the ovaries had been removed.

Os teoporosi s Following the general procedure, infra, the rats were treated daily for 35 days (6 rats per treatment group) and sacrificed with asphyxiation with carbon dioxide, on day 36. The time period of 35 days is sufficient to allow the maximum reduction in bone density, measured as described herein. At the time of sacrifice, the uteri are removed, dissected by removing any foreign tissue, and the fluid content is expelled before the determination of wet weight, in order to confirm the estrogen deficiency associated with complete ovariectomy. The uterine weight is routinely reduced by approximately 75% in response to ovariectomy. The uteri are then placed in 10% neutral formalin with buffer, to allow subsequent histological analysis. The right femurs are cut and digital X-ray images are generated and analyzed through a program for image analysis (NIH image) in the distal metaphysis. The proximal aspect of the tibia of these animals is also explored through quantitative computed tomography. In accordance with the above procedures, representative compounds of the present invention and ethynyl estradiol (EE2) in 20% hydroxy-pipyl-β-cyclodextrin are orally administered to the test animals and have a positive result, ie, a reduction in the loss of mineral density in the bones. The specific dose of a compound of formula I will, of course, be determined by the particular circumstances that correspond to the case. Similarly, the administration route in a factor determined by the specific situations of each case. In this way, the exact dose and the route of administration are determined in the best way by the doctor who attends the case. A typical daily dose of a compound of formula I would contain a non-toxic dosage level of from about 0.001 milligrams to about 800 milligrams master / day. Preferred daily doses will generally be from about 0.001 milligrams to about 60 microns / day. That dosage can be provided as a single dose or can be divided into two or three separate doses per day, as needed. As mentioned, upra, the compounds of formula I can be used with a compound of formula II. Again, the exact amounts of two agents (formula of compounds I and II) may vary depending on the nature of the symptoms to be treated, as well as the patient's medical status. In general, such combinations would include from 0.001 milligrams to 60 milligrams of a compound of formula I, and from 1.0 to 120 milligrams of a compound of formula II. A preferred combination would be one comprising 0.001 to 1 milligram of a compound of formula I, and 59 to 59.999 milligrams of a compound of formula II. A more preferred combination would be one comprising 0.001 to 0.1 milligrams of a compound of formula I and 59.9 to 59.999 milligrams of a compound of formula II. An even more preferred combination would comprise 0.001 to 0.1 milligrams of a preferred compound of formula I (wherein R, R1 and R2 are independently hydroxy or methoxy) and 59.9 to 59.999 milligrams of raloxifene hydrochloride. Most preferred is the combination comprising 0.001 milligrams to 0.1 milligrams of the most preferred compound of formula I (wherein R, R1 and R2 are each hydroxy) and 59.9 to 59.999 milligrams of Raloxifene hydrochloride. The compounds of this invention can be administered through a variety of routes including oral, rectal, transdermal, buccal, aerosol, topical, ophthalmic, subcutaneous, intravenous, intramuscular, intranasal, and the like. These compounds are preferably formulated before administration, the selection of which will be decided by the attending physician. In this way, another aspect of the present invention is a pharmaceutical formulation comprising an effective amount of a compound of formula I or a formulation comprising an effective amount of a compound of formula I and II, or a pharmaceutical salt thereof, and a carrier , diluent, or excipient, pharmacist. The total active ingredients in those formulations comprise from 0.1% to 99.9% by weight of the formulation. The pharmaceutical formulations of the present invention can be prepared from methods known in the art, using well-known and readily available ingredients. For example, the compounds of formula I, or the compounds of formula I or II, can be formulated with common excipients, diluents, or carriers, and given the form of tablets, capsules, suspensions, powders, and the like. Examples of excipients, diluents, and carriers, which are suitable for those formulations, include the following: fillers and extension materials such as starch, sugars, mannitol, and silicic derivatives; binding agents such as carboxymethylcellulose and other cellulose derivatives, alginates, gelatin, and polyvinylpyrrolidone; wetting agents such as glycerol; disintegrating agents such as calcium carbonate and sodium bicarbonate; agents for retarding dissolution, such as paraffin; resorption accelerators such as quaternary ammonium compounds; surface active agents such as cetyl alcohol, glycerol monostearate; adsorptive carriers such as kaolin and bentonite; and lubricants such as talc, calcium and magnesium stearate, and solid polyethylic glycols. The compounds may also be formulated as elixirs or resolved for convenient oral administration, or as solutions suitable for parenteral administration, for example, by the intramuscular, subcutaneous and intravenous routes. In addition, the compounds are well suited for formulation as sustained release dosage forms and the like. The formulations may be constituted in such a way that they release the active ingredient only or preferably, in a particular physiological location, possibly afterwards. of a certain period of time. The coatings, layers, and protective matrices can be made, for example, from polymeric substances or waxes.

Formulation Examples The following formulation examples are illustrative only and are not intended to limit the scope of the present invention in any way.

Formulation 1: Gelatin capsules Hard gelatin capsules are prepared using the following: Ingredient Quantity (thousand i grams / capsule Compound of formula 0.001 - 200 I Starch, NF 0 - 650 Dust fluid of 0 - 650 starch Silicon fluid of 350 centistokes 0 - 15 The formulation can be changed according to the variations provided.

Formulation 2: Tablets A tablet formulation is prepared using the following ingredients: Ingredi ent e Quantity (milligrams / tablet) Compound of formula I 0.001 - 200 Cellulose, microcrystalline 200 - 650 Silicon dioxide, vapor recovery 10 - 650 Stearic acid 5 - 15 The components are mixed and compressed to form tablets.

Formulation 3: Tablets The tablets, each containing 2.5 to 1000 milligrams of active ingredient, are produced as follows: Ingredient Quantity (my 1 gram i / tablet Compound of formula I 0.001 - 200 Starch 45 Microcrystalline cellulose 35 Polyvinylpyrrolidone 4 (as a 10% solution in water) Carboxymethylcellulose 4.5 sodium Magnesium stearate 0.5 Talc The active ingredient, starch, and cellulose are passed through a No. 45 mesh American sieve, and mixed thoroughly. The polyvinylpyrrolidone solution is mixed with the resulting powders which are then passed through a No. 14 mesh American sieve. The granules thus produced are dried at a temperature of 50 ° C to 60 ° C and passed through a American sieve mesh No. 18. Sodium carboxymethylcellulose, starch, magnesium stearate, and talcum, previously passed through a No. 60 mesh American sieve, are then added to the granules which, after mixing, are compressed into a tablet forming machine to produce tablets.

Formulation 4: Suspensions Suspensions that each contain 0.1 to 1000 milligrams of the drug, per 5 milliliter dose, are produced as follows: Ingredient Amount (mi 1 gram i / 5 thousand i 1ers) Compound of formula I 0.001 - 200 Carbox ime t ilcelulosa 50 mg sodium Syrup 1.25 mg Solution of acid 0.10 mL benzoic S abor q. v Color q. v Purified water for 5 mL The drug is passed through a No. 45 mesh American screen and mixed with the sodium carboxymethyl cellulose and the syrup to form a smooth paste. The benzoic acid solution, flavor, and color, are diluted with some water and added, with stirring. Then enough water is added to produce the required volume.

Formulation 5: Combination Tablets Ingredient Amount. { milligrams / tablet a) Compound of formula I 0.001 - 1 Compound of formula II 59 - 59,999 Starch 45 Microcrystalline cellulose 35 Polyvinylpyrrolidone 4 (as a 10% solution in water) Carboxymethylcellulose 4.5 sodium Magnesium stearate 0.5 Talc The active ingredient, starch, and cellulose are passed through a No. 45 mesh American sieve, and mixed thoroughly. The polyvinylpyrrolidone solution is mixed with the resulting powders which are then passed through a No. 14 mesh American sieve. The granules thus produced are dried at a temperature of 50 ° C to 60 ° C and passed through a American sieve mesh No. 18. Sodium carboxymethylcellulose, starch, magnesium stearate, and talcum, previously passed through a No. 60 mesh American sieve, are then added to the granules which, after mixing, are compressed into a tablet forming machine to produce tablets.

Formulation 5: Combination Tablets Ingredient Quantity (milligrams / tablet) A preferred compound of 0.001 - 0.1 formula I Raloxifene hydrochloride 59-59,999 Starch 45 Microcrystalline cellulose 35 Polyvinylpyrrolidone 4 (as a 10% solution in water) Carboxymethylcellulose 4.5 sodium Magnesium stearate 0.5 Talc The active ingredient, starch, and cellulose are passed through a No. 45 mesh American sieve, and mixed thoroughly. The solution of polyvinylpyrrolidone is mixed with the resulting powders which are then passed through a. North American sieve mesh number 14. The granules thus produced are dried at a temperature of 50 ° C to 60 ° C and passed through a No. 18 mesh American sieve. Sodium carboxymethylcellulose, starch, magnesium stearate, and The talcum, previously passed through a North American sieve mesh number 60, is then added to the granules which, after mixing, are compressed in a tablet forming machine to produce tablets. It is noted that in relation to this date, the best method known to the applicant to carry out the aforementioned invention, is that which is clear from the present description of the invention. Having been described - the invention as above, property is claimed as contained in the following:

Claims (30)

1. A method for inhibiting the estrogen deprivation syndrome, in mammals, characterized in that it includes administering to a mammal suffering therefrom, an effective amount of a compound of the formula I: i; wherein R and R1 are independently hydrogen, hydroxy, alkoxy, of 1 to 6 carbon atoms, OCH2Ar, OCO (alkyl of 1 to 6 carbon atoms), OCOAr; Ar is phenyl or substituted phenyl; and R2 is hydrogen, chlorine, bromine, hydroxy, alkoxy of 1 to 6 carbon atoms, 0CH2Ar, 0C0 (alkyl of 1 to 6 carbon atoms), OCOAr; or a solvate thereof.

2. A method according to claim 1, characterized in that the mammal is a female human.

3. A method according to claim 2, characterized in that the pathology of the estrogen deprivation syndrome is osteoporosis.

4. A method according to claim 2, characterized in that the pathology of the estrogen deprivation syndrome is hyperlipidemia.

5. A method according to claim 2, characterized in that the compound of formula I is a compound wherein R, R1, and R2 are independently hydroxy or methoxy, or a solvate thereof.

6. A method according to claim 5, characterized in that the compound of formula I is a compound wherein R2 is in the para position and R, R1 and R2 are all hydroxy, or a solvate thereof.

7. A method according to claim 2, characterized in that the female human is per imenopáusico or po smenopáus i co.

8. A method according to claim 2, characterized in that the compound of formula I is a compound selected from the group consisting of: 2- (4-methoxyphenyl) -3- (4-methoxybenzoyl) -6-me toxibenzo [b] thiof eno 2- (4-Hydroxy phenyl) -3- (4-methoxybenzoyl) -6-hydroxybenzo [b] thiophene; 2- (4-methoxyphenyl) -3- (4-methoxybenzoyl) -6-hydroxybenzo [b] thiophene; 2- (4-hydroxyphenyl) -3- (4-methoxybenzoyl) -6-ethoxybenzo [b] thiophene; 2- (4-methoxyphenyl) -3- (4-hydroxybenzoyl) -6-methoxybenzo [b] thiophene; 2- (4-hydroxyphenyl) -3- (4-hydroxybenzoyl) -6-me toxibenzo [b] thioben; 2- (4-methoxyphenyl) -3- (4-hydroxybenzoyl) -6-hydroxybenzo [b] thiophene; 2- (4-hydroxyphenyl) -3- (4-hydroxybenzoyl) -6-hydroxybenzo [b] thiophene; 2- (4-acetoxyphenyl) -3- (4-methoxybenzoyl) -6-acetoxybenzo [b] thiophene; 2- (4-acetoxyphenyl) -3- (4-acetoxybenzoyl) -6-acetoxybenzo [b] thiophene; 2- (4-methoxy phenyl) -3- (4-benzoyloxybenzoyl) -6-methoxybenzo [b] thiophene; 2- (4-acetoxy phenyl) -3- (4-methoxybenzoyl) -6-methoxybenzo [b] thiofen; and 2- (4-cyclo? entoxyphenyl) -3- (4-hydroxybenzoyl) -6-cyclopentoxybenzo [b] thiophene; or a solvate of the same.

9. A pharmaceutical formulation characterized in that it comprises a compound of the formula I: I; wherein R and R1 are independently hydrogen, hydroxy, alkoxy, of 1 to 6 carbon atoms, OCH2Ar, OCO (alkyl of 1 to 6 carbon atoms), OCOAr; Ar is phenyl or substituted phenyl; and R2 is hydrogen, chlorine, bromine, hydroxy, alkoxy of 1 to 6 carbon atoms, OCH2Ar, OCO (alkyl of 1 to 6 carbon atoms), OCOAr; or a solvate thereof; and excipient carriers, or pharmaceutical diluents.

10. A formulation according to claim 9, characterized in that the compound of the formula I is a compound selected from the group consisting of: 2- (4-methoxyphenyl) -3- (4-methoxybenzoyl) -6-methoxybenzo [b] thiophene; 2- (4-hydroxyphenyl) -3- (4-methoxybenzoyl) -6-hydroxybenzo [b] thiophene; 2- (4-methoxyphenyl) -3- (4-methoxybenzoyl) -6-hydroxybenzo [b] thiophene; 2- (4-hydroxyphenyl) -3- (4-methoxybenzoyl) -6-methoxybenzo [b] thiofen; 2- (4-methoxyphenyl) -3- (4-hydroxybenzoyl) -6-me tox iben z or [b] thiophene; 2- (4-hydroxyphenyl) -3- (4-hydroxybenzoyl) -6-me to ibenzo [b] thiophene; 2- (4-methoxyphenyl) -3- (4-hydroxybenzoyl) -6-hydroxybenzo [b] thiophene; 2- (4-hydroxyphenyl) -3- (4-hydroxybenzoyl) -6-hydroxybenzo [b] thiophene; 2- (4-acetoxyphenyl) -3- (4-methoxybenzoyl) -6-acetoxybenzofb] thiophene; 2- (4-acetoxyphenyl) -3- (4-acetoxybenzoyl) -6-acetoxybenzo [b] thiophene; 2- (4-methoxyphenyl) -3- (4-benzoyloxybenzoyl) -6-methoxybenzo [b] thiophene; 2- (4-acetoxyphenyl) -3- (4-methoxybenzoyl) -6-metoxyl benzo [b] t i or f ene; and 2- (4-cyclopentoxy phenyl) -3- (4-hydroxybenzoyl) -6-cyclopentoxybenzo [b] thiophene; or a solvate thereof.

11. A method for inhibiting the estrogen deprivation syndrome, in mammals, characterized in that it comprises administering to a mammal in need thereof an effective amount of a compound of formula I: I; wherein R and R1 are independently hydrogen, hydroxy, alkoxy, of 1 to 6 carbon atoms, OCH2Ar, OCO (alkyl of 1 to 6 carbon atoms), OCOAr; Ar is phenyl or substituted phenyl; and R2 is hydrogen, chlorine, bromine, hydroxy, alkoxy of 1 to 6 carbon atoms, OCH2Ar, OCO (alkyl of 1 to 6 carbon atoms), OCOAr; or a solvate thereof; and a compound of formula II II; wherein R3 and R4 are independently hydrogen, alkyl of 1 to 6 carbon atoms, CO (alkyl of 1 to 6 carbon atoms), or COAr; R 5 is pyrolidin-1-yl, piper i din-1-ylo, or hexamethyleneimin-1-yl; wherein the nitrogen of the group R4 is optionally the N-oxide; or a pharmaceutical salt or solvate thereof.

12. A method according to claim 11, characterized in that the mammal is a female human.

13. A method according to claim 12, characterized in that the pathology of the estrogen deprivation syndrome is osteoporosis.

14. A method according to claim 12, characterized in that the pathology of the estrogen deprivation syndrome is hyperlipidemia.

15. A method according to claim 12, characterized in that the compound of formula I is a compound wherein R, R1 and R2 are independently hydroxy or methoxy, or a solvate thereof.

16. A method of compliance with the 8 claim 15, characterized in that the compound of formula I is a compound wherein R2 is in the para position and R, R1 and R2 are all hydroxy or a solvate thereof.

17. A method according to claim 16, characterized in that the compound of formula II is the hydrochloride salt, R3 and R4 are both hydrogen, and R5 is piperidin-1-yl.

18. A method according to claim 12, characterized in that the female human is menopausal.

19. A method according to claim 12, characterized in that the compound of formula I is a compound selected from the group consisting of: 2- (4-methoxyphenyl) -3- (4-methoxybenzoyl) -6-me toxibenz or [b] tiof eno; 2- (4-hydroxyphenyl) -3- (4-methoxybenzoyl) -6-hydroxybenzo [b] thiophene; 2- (4-methoxyphenyl) -3- (4-methoxybenzoyl) -6-hydroxybenzo [b] thiophene; 2- (4-hydroxy phenyl) -3- (4-methoxybenzoyl) -6-methoxybenzo [b] thiophene; 2- (4-methoxy phenyl) -3- (4-hydroxybenzoyl) -6-methoxybenzo [b] thiophene; 2- (4-hydroxyphenyl) -3- (4-hydroxybenzoyl) -6-methoxybenzo [b] thiophene; 2- (4-methoxyphenyl) -3- (4-hydroxybenzoyl) -6-hydroxylbenzo [b] thiophene; 2- (4-Hydroxy phenyl) -3- (4-hydroxybenzoyl) -6-hydroxybenzofb] thiophene; 2- (4-acetoxyphenyl) -3- (4-methoxybenzoyl) -6-acetoxybenzo [b] thiophene; 2- (4-acetoxyphenyl) -3- (4-acetoxybenzoyl) -6-acetoxybenzo [b] thiophene; 2- (4-methoxyphenyl) -3- (4-benzoyloxybenzoyl) -6-methoxybenzo [b] thiophene; 2- (4-acetoxyphenyl) -3- (4-methoxybenzoyl) -6-methoxybenzo [b] t i or pheno; and 2- (4-cyclopentoxy phenyl) -3- (4-hydroxybenzoyl) -6-cyclopentoxybenzo [b] thiophene; or a solvate of the same.

20. A method according to claim 11, characterized in that the compound of formula I is 2- (4-hydroxy phenyl) -3- (4-hydroxybenzoyl) -6-hydroxybenzo [b] thiophene, the compound of formula II it is raloxifene hydrochloride, and the pathology of the estrogen deprivation syndrome is osteoporosis.

21. A pharmaceutical formulation characterized in that it comprises a compound of formula I: i; wherein: R and R1 are independently hydrogen, hydroxy, alkoxy, of 1 to 6 carbon atoms, OCH2Ar, 0C0 (alkyl of 1 to 6 carbon atoms), OCOAr; Ar is phenyl or substituted phenyl; and R2 is hydrogen, chlorine, bromine, hydroxy, alkoxy of 1 to 6 carbon atoms, 0CH2Ar, OCO (alkyl of 1 to 6 carbon atoms), OCOAr; or a solvate thereof; and a compound of formula II II; wherein: R3 and R4 are independently hydrogen, alkyl of 1 to 6 carbon atoms, CO (alkyl of 1 to 6 carbon atoms), or COAr; R5 is pyro 1 idin- 1 -yl, piper idin- 1 -i lo, or hexame t i lenimin- 1 -i lo; wherein the nitrogen of the group R5 is optionally the N-oxide; or a pharmaceutical salt or solvate thereof; and excipient carriers, or pharmaceutical diluents.

22. A formulation according to claim 21, characterized in that it comprises from 0.001 to 60 milligrams of a compound of formula I wherein R, R1 and R2 are independently hydroxy or methoxy, or a solvate thereof, and from 1 to 120 milligrams of a compound of formula II consist of raloxifene hydrochloride.

23. A formulation according to claim 22, characterized in that the compound of formula I is 2- (4-hydroxy-phenyl) -3- (4-hydroxybenzoyl) -6-hydroxybenzo [b] thiophene, or a solvate thereof.

24. A formulation according to claim 23, characterized in that it comprises from 0.001 to 1 milligram of the compound of formula I, or a solvate thereof, and from 59 to 59,999 milligrams of raloxifene hydrochloride.

25. A formulation according to claim 24, characterized in that it comprises from 0.001 to 0.1 milligrams of the compound of formula I, or a solvate thereof, and from 59.1 to 59.999 milligrams of raloxy phenohydrochloride.

26. A formulation according to claim 21, characterized in that the compound of formula I is a compound selected from the group consisting of: 2- (4-methoxyphenyl) -3- (4-methoxybenzoyl) -6-methoxybenzo [b] thiophene; 2- (4-hydroxyphenyl) -3- (4-methoxybenzoyl) -6-hydroxybenzo [b] thiophene; 2- (4-methoxyphenyl) -3- (4-methoxybenzoyl) -6-hydroxybenzo [b] thiophene; 2- (4-hydroxyphenyl) -3- (4-methoxybenzoyl) -6-methoxybenzo [b] thiophene; 2- (4-methoxyphenyl) -3- (4-hydroxybenzoyl) -6-methoxybenzo [b] thiophene; 2- (4-hydroxyphenyl) -3- (4-hydroxybenzoyl) -6-methoxybenzo [b] thiophene; 2- (4-methoxyphenyl) -3- (4-hydro-? Ibenzoyl) -6-hydroxybenzo [b] thiophene; 2- (4-hydroxyphenyl) -3- (4-hydroxybenzoyl) -6-hydroxybenzo [b] thiophene; 2- (4-acetoxyphenyl) -3- (4-methoxybenzoyl) -6-acetoxybenzo [b] thiophene; 2- (4-acetoxyphenyl) -3- (4-acetoxybenzoyl) -6-acetoxybenzo [b] thiophene; 2- (4-methoxyphenyl) -3- (4-benzoyloxybenzoyl) -6-metoxyl benzo [b] thiophene; 2- (4-acetoxyphenyl) -3- (4-methoxybenzoyl) -6-methoxybenzo [b] thiophene; and 2- (4-cyclopentoxy phenyl) -3- (4-hydroxybenzoyl) -6-cyclopentoxybenzo [b] iiophen; or a solvate of the same.

27. A manufactured article, characterized in that it comprises a packaging material and a pharmaceutical formulation contained within the packaging material, wherein the packaging material comprises a label indicating that the pharmaceutical formulation can be administered to inhibit a pathology of the syndrome of estrogen deprivation , and wherein the pharmaceutical formulation comprises a compound of formula I (a): wherein: R6, R7, and R8 are independently hydroxy or methoxy; or a solvate thereof; and a compound of the formula: or a solvate of it

28. A manufactured article, according to claim 27, characterized in that it comprises from 0.001 to 1 milligram of a compound of formula I (a), or a solvate thereof, and from 59 to 59,999 milligrams of a compound of the formula: or a solvate of it

29. A manufactured article, according to claim 28, characterized in that the compound of formula I (a) is 2- (4-hydroxyphenyl) -3- (4-hydroxybenzoyl) -6-hydroxybenzo [b] thiophene, or a Solvate of it.

30. A manufactured article, according to claim 29, characterized in that the pathology is osoporos os. -A I - -AROILBENZO T OR TREATMENT OF THE DEPRIVATION SYNDROME OF ESTROGEN SUMMARY OF THE INVENTION This invention provides methods that are useful for the inhibition of various medical conditions associated with the estrogen deprivation syndrome, including osteoporosis and hyperlipidemia, using the compounds of formula (I).