MXPA00004482A

MXPA00004482A - 2-arylbenzo[b]thiophenes useful for the treatment of estrogen deprivation syndrome

Info

Publication number: MXPA00004482A
Application number: MXPA/A/2000/004482A
Authority: MX
Inventors: George Joseph Cullinan
Original assignee: Eli Lilly And Company
Priority date: 1997-11-14
Filing date: 2000-05-09
Publication date: 2001-05-07

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-ARILBENZO [b] USEFUL TIOFENES FOR THE TREATMENT OF THE STRONGEN SUPPRESSION SYNDROME FIELD OF THE INVENTION This invention relates to the pharmaceutical and organic chemistry fields and provides 2-arylbenzo [b] thiophenes which are useful for the inhibition of various conditions of estrogen deficiency.

BACKGROUND OF THE INVENTION "Estrogen suppression syndrome" is a term used to describe various pathological conditions that frequently affect a woman who has levels of estrogen hormone insufficiency. The most common cause of estrogen suppression in women is the natural suspension of menstruation with age, i.e., menopause. Additionally, unnatural circumstances including a surgical ovariectomy, chemotherapy cause the suspension of the hormone production or pathological action, and the similar ones, can induce the suppression of estrogen. Although many pathologies are. contemplated through the use of REF .: 119285 this term, two main effects of the syndrome of suppression of estrogen are source of the greatest prolonged medical terms that concern: osteoporosis and cardiovascular effects, especially hyperlipidemia.

Osteoporosis describes a group of diseases that appear from different etiologies, but all are characterized by the loss of the net weight of bone mass per unit volume. The consequence of this loss of bone mass is the lack of a skeleton to provide a support structure suitable for the body i.e., bone fracture. One of the most common types of osteoporosis is that associated with menopause. More women lose approximately 20% to approximately 60% of the bone mass in trabecular bone behavior within 3 to 6 years after the suspension of menstruation. This rapid loss is generally associated with an overall increase in bone resorption and periodic bone formation where the cycle reabsorber is more dominant. The most obvious result is a loss of weight of the bone mass. Osteoporosis is a common and serious disease among post-enopausal women.

There is an estimate of 25 million women in the United States, alone, who are affected with this disease. The results of osteoporosis are personally harmful and are also considered by a great economic loss due to this chronicity and the need to sustain an expensive and prolonged term (hospitalization and care of a nurse at home) for the sequel of the disease. These are especially true in older patients. Additionally, although osteoporosis is not generally not addressed as a life-threatening condition, a 20% to 30% mortality rate is attributed to hip fracture in older women. A large percentage of this mortality ratio is directly associated with post-menopausal osteoporosis.

During the whole pre-menopauisic period, more women have a lower incidence of cardiovascular disease than men of the same age, however, the proportion of cardiovascular disease in women increases slowly, as does the proportion seen in men. This loss of protection is related to the loss of estrogen and, in particular, to the loss of estrogen's ability to regulate serum lipid levels. Estrogen's natural ability to regulate lipid serums is not well understood, but an efficiency today indicates that estrogen can further regulate low-density (LDL) receptors in the liver to remove excess cholesterol. Additionally, estrogen appears to have some effects on cholesterol biosynthesis, and other beneficial effects on cardiovascular health.

Although estrogen replaces the therapy often prescribed by the estrogen suppression syndrome, these conditions in poorly compliant patients like many women object to some of the effects of size and inconvenience of the pharmaceutical forms of the medication.

For example, 17-ß-estradiol is often • a route administered in a transdermal piece, due to poor oral absorption. As a result, a majority of women end up taking estrogen within the first year of the start of nitrogen replacement with therapy.

Compounds of the formula I I? Where: R and R 'are independently hydrogen, hydroxy, C? -C6 alkoxy, OCH2Ar, OCO (C? -C6 alkyl), OCOAr, and Ar is phenyl or substitutable phenyl; Oral chemical intermediary pharmaceutical agents, e.g., are known. Raloxifene hydrochloride. The present invention deals with the discovery of new utilities attributed to the compounds of formula I, that is, that there are agents useful in the inhibition of the estrogen suppression syndrome.

BRIEF DESCRIPTION OF THE INVENTION The present invention provides methods for inhibiting estrogen suppression syndrome in mammals which include administration to a mammal in need thereof of an effective amount. of a compound of formula I: i; Where: R and R 'are independently hydrogen, hydroxy, C? -C6 alkoxy, OCH2Ar, OCO (C? -C6 alkyl), OCOAr; and Ar is phenyl or substituted phenyl; or a solvate thereof.

Additionally, the present invention provides methods for inhibiting the estrogen suppression syndrome which includes administration for a substance in need thereof in an effective amount of a compound of the formula I and a compound of the formula II: II; Where: R2 and R3 are independently hydrogen, C? -C6 alkyl, CO (C? -C6 alkyl), or COAr; R 4 is pyrolidin-1-yl, piperidin-1-yl, or hexamethylene-imin-1-yl; Where the nitrogen of the group R4 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 I and I, and pharmaceutical excipients, diluents, or carriers.

DETAILED DESCRIPTION OF THE INVENTION The general terms used herein in the description of the compounds, methods and formulations bear their usual meanings. For example, "Ci-Cß alkyl" refer to methyl, ethyl, propyl, iso-propyl, cyclopropyl, n-butyl, s-butyl, t-butyl, and cyclobutyl. The term "Ci-Ce alkyl" encompasses those listed by C1-C4 alkyl in addition to monovalent, straight, branched, or cyclic aliphatic chains of 5 or 6 carbon atoms including pentyl, cyclphenyl, hexyl, 2-methyl pentyl, cyclohexyl, and the similar ones. 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 "Ci-Cβ alkoxy" embraces the terms listed by the C 1 -C 4 alkoxy in addition to straight, branched, or cyclic aliphatic chains of 5 or 6 carbon atoms which are linked by a monovalent oxygen and include but are not limited by the, pentoxy, cyclopentoxy, hexoxy, 2-methylpentoxy, cyclohexoxy, and the like.

The terms "halide" refers to chloride, bromide, or iodide.

The term "substituted phenyl" refers to a phenyl group having one to three substituents selected from the group consisting of Ci-Cß alkyl, Ci- C4 alkoxy, hydroxy, nitro, chloro, fluoro, or tri (chloro or fluoro) methyl In addition to the free base form of the compounds of formula II used in the methods of the present invention, it is preferred to prepare and use a pharmaceutical salt form. Typical pharmaceutical salts include these salts prepared by the reaction of the compounds of formula II with a mineral or organic acid. Thus, the term "pharmaceutical salt" refers to salts of the acid addition of a compound of formula II which are substantially non-toxic in administered doses and are commonly known in the pharmaceutical literature. See e.g. Berge, S.M. Bighley, L.D., and Monkhouse, D.C., < J. Pharm. Sci., 66, 1, 1977. Pharmaceutical salts generally have characteristics of increased solubility by comparing the compound from which there are derivatives, and moreover they are often more suitable for use in pharmaceutical formulations.

Examples of pharmaceutical salts are the iodide, acetate, phenylacetate, trifluoroacetate, acrylate, ascorbate, benzoate, chlorobenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, methylbenzoate, o-acetoxybenzoate, ríaftalen-2-benzoate, bromide, isobutyrate, phenylbutyrate, g-hydroxybutyrate, b-hydroxybutyrate, butyne-1, 4-dioate, hexyne-1,4-dioate, hexyne-1, 6-dioate, caproate, caprylate, chloride, cinnamate, citrate, decanoate, formate, fumarate, glycollate, hepoato, hippurate, lactate, malate, maleate, hydroxyalate, malonate, mandelate, mesylate, nicotinate, isonicotinate, nitrate, oxalate, phthalate, terephthalate, phosphate, monohydrogen phosphate, dihydrogen phosphate, ethaphosphate, pyrophosphate, propiolate, propionate, phenylpropionate, salicylate, sebacate, succinate, suberate, sulfate, bisulfate, pyrosulfate, sulfite, bisulfite, sulfonate, benzensulfanato, p-bromophenylsulfonate, clorobenzensulfonato, propanesulfonate, ethanesulfonate, 2-hidroxiesulfonato, mesulfonato, naphthalene-1-sulfonate, naphth alen-2-sulfonate, p-toluenesulfonate, xylene sulfonate, tartarate, and the like of a compound of formula II.

The term "solvate" represents an aggregate that contains one or more molecules of the solute, such as nn composed of the formula I or II, with one or more molecules of the solvent. Such solvent molecules could be those commonly used in the pharmaceutical literature, which are known to be non-deleterious to the container, e.g., water and ethanol. • "" " The term "thermodynamic basis" refers to a base that provides reversible descronotation of an acid substrate, or is used as a proton trap when a proton is a bioproduct of a reaction, and is a reasonably effective reagent for the desired reaction without significant effects of an unwanted reaction. Examples of thermodynamic bases included, but not limited to, carbonates, bicarbonates, and hydroxides (eg lithium, sodium, or potassium carbonate, bicarbonate, or hydroxide), tri- (C1-C4) mines, or aromatic nitrogen heterocycles containing (eg pyridine).

The term "withdrawal syndrome estrogen" includes those diseases and conditions caused by the loss of ovarian function (either natural, surgical, or chemically, especially induced by the loss of the ovarian hormones, especially estrogen. Since then lost estrogen is responsible for the symptoms of the syndrome, each of these symptoms respond to the replacement of the estrogen hormone loss by the administration of the compounds of the present invention.In addition, the compounds and methods of the present invention could be useful and beneficial in treating or preventing symptoms of estrogen deficiency, which include but are not limited to the following: osteoporosis, hyperlipidemia, atherosclerosis, abnormalities vasomotor (hot flashes), auto-imune diseases, abnormalities skin and hair, cardiovascular disease and degeneration, dementia and disease Alzheimer's, depression, weight loss or gain, certain types and conditions of diabetes, inadequate healing and recovery gauze, vaginal atrophy, urinary incontinence, sequelae of abnormal regulation of the estrogen-controlling genes, intra alia. This could be recognized by not all patients treated for the estrogen suppression syndrome should necessarily have all the various pathologies listed, supra, in addition, the specific use of the compounds and methods of the current invention may vary depending on the natural idiosyncratic and the severity of these symptoms.

The terms "inhibitor" or "inhibition" are intended to prohibit, treat, alleviate, improve, weaken, coerce, slow or reverse progress, or reduce the severity of a related pathological symptom to or result from the estrogen suppression syndrome. As such, these methods include both medical therapy (acute) and / or prophylactic administration (prevention) as appropriate.

As used herein, the term "effective amount" refers to an amount of a compound or compounds of the present invention that is capable of inhibiting the symptoms of various conditions and pathological symptoms, described herein.

• By the "pharmaceutical formulation", "pharmaceutical carrier", "pharmaceutical diluent", and "pharmaceutical excipient" this refers to a formulation containing a compound of formula I or a formulation containing a combination of a compound of the formula I and II, the carrier, the diluent, the excipients, and the salt are compatible with the other ingredients of the formulation, and not harmful to the recipient thereof.

All the time of the compounds of the present invention are useful, certain compounds are particularly interesting and are preferred. For example, the compounds of formula I wherein R and R1 are independently hydroxy or methoxy are preferred. The compound of formula I where R and R1 are both hydroxy, i.e. 2- (4-hydroxyphenyl) -6-hydroxybenzo [b] thiophene, is more preferred. In addition, the hydrochloride salt of the compound of the formula -II where R2"and R3 are both hydrogen, and R4 is piperidin-1-yl is also particularly preferred.This compound of the formula II is hydrochloride of [2- (4- hydro-phenyl) -6-hydroxybenzo [b] thien-3-yl] [4- [2- (1-piperidinyl) ethoxy] phenyl] methanone ie Raloxifene hydrochloride.

All the time the formulations and methods employed a combination of a compound of formula I and II are useful, the possible combinations employing the preferred compounds listed above are particularly interesting and preferred. More preferred is the combination of 2- (4-hydroxyphenyl) -6-hydroxybenzo [b] thiophene and Raloxifene hydrochloride.

The compounds of formula I can be prepared from the compounds of formula III and IV as illustrated below in scheme 1 where R and R1 are as described supra.

Scheme I The compounds of formula III can be S-alkylated with a phenacyl halide of formula IV. Such S-alkylations are transported out in a solvent in the presence of a thermodynamic base at a temperature between 0 ° C and 100 ° C from one to twenty-four hours. A preferred solvent and base are typically ethanol and potassium hydrochloride respectively. The reaction is preferably carried out at room temperature for one to three hours. A preferred halide for the compound of formula IV is bromide.

The resulting compounds of formula V are cyclized to the compounds of formula I by treatment with an acid in a suitable solvent at a temperature of between 50 ° C and 200 ° C from one to twenty-four hours. A solvent and a preferred acid is polyphosphoric acid.

Where R and / or R1 is to make hydroxy, this is preferred in the above scheme to be carried out with a compound of formula III and / or IV where R and / or R1 is alkoxy C? -C6, 0CH2Ar, OCO (C? -C6 alkyl), or OCOAr. The compounds of the formula I wherein R and / or R1 are hydroxy can then be prepared after the cyclization step by removing the C alqu-C6 alkyl, CH2Ar, CO (C alqu-C6 alkyl), or portions of COAr (protective groups) of the compounds resulting from the formula I. Methods for removing these protecting groups can be found in the examples in the following section or in chapter 2 of "Protective Groups in Organic Synthesis, 2nd Edition, TH et al., John Wiley &Sons, New York, 1991".

The compounds of the formula I where R and R are not hydrogen and only one of R or R1 is hydroxy, can be prepared from the compounds of the formula I wherein R and R1 are independently and differently Ci-Cβ alkoxy, OCH2Ar, OCO ( Ci-Cß alkyl), or OCOAr by selectively removing one of the protecting groups. The protective groups that facilitate a removal and methods for the selective removal of a protective group on the others well known in the art. An example where selective removal is possible is where one protective group is benzyl and the other is C1-C4 alkyl. The benzyl group can be selectively removed by a catalytic hydrogenation. For more extensive instruction on the selective removal of these protective groups see the examples in the section that follow and the Greene reference cited above.

For a more extensive instruction on the preparation of the compounds of the formula I see U.S. Us. 4,133,814 and 4,418,068 and the publication, Jones, C.D., et al. , J. Med. Chem., 27, pp. 1057-1066 (1984), the teachings of each of which are here incorporated into the reference.

The compounds of formula II which are not N-oxides and their pharmaceutical salts, can also be prepared as taught in the U.S. applications. previously incorporated and also cone taught in the U.S. No.'s 5,393,763 and 5,629,425, and PCT publication # US97 / 04259, the teachings of each of which are incorporated herein.

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 a co-solvent such as methanol or ethanol. The reaction conditions for this reaction can vary from room temperature to 100 ° C and in a duration of 24 to 72 hours. This remarkable care must be taken into account in the selection of the oxidizing agent and that they are commonly used agents, eg, chromic anhydride, potassium permanganate, and the like, the capacity of the oxidation nitrogen may not be used, then they could also oxidize the sulfide of benzo [b] thiophene. In addition, a softening agent such as hydrogen peroxide is preferred.

The optimal time to perform the reactions described herein can be determined by monitoring the progress of the technical action via conventional chromatography. In addition, the reactions of the invention under an inert atmosphere are preferred by the reaction conduit of the invention under an inert atmosphere, such as, for example, argon, or particularly, nitrogen. The choice of the solvent is generally not critical while the solvent employed is an inert for the progress of the reaction and the reactants sufficiently soluble for the desired effect of the reaction. The intermediates and end products can be purified, if desired by common techniques such as recrystallization or chromatography on solid supports such as silica or alumina.

The compounds of formula III and IV are either commercially available or can be prepared by methods well known in the art.

The field of the present invention is not limited to the discussion of synthesis, and could not be constructed. The application of the above chemical capabilities of the synthesis of the compounds of formula I, which includes, but is not limited to: 2-phenylbenzo [bltiofen; 2- (4-hydroxyphenyl) benzo [b] thiophene; 2- (4-methoxyphenyl) benzo [b] thiophene; 2- (4-acetoxyphenyl) benzo [b] thiophene; 2- (4-benzoyloxyphenyl) benzo [b] thiophene; 2- (4-isopropoxyphenyl) benzo [b] thiophene; 2-phenyl-6-hydroxybenzo [b] thiophene; 2-phenyl-6-methoxybenzo [b] thiophene; 2-phenyl-6-isopropoxybenzo [b] thiophene; "~ 2-phenyl-6-acetoxybenzo [b] thiophene; 2-phenyl-6- (4-methylbenzoyl) oxybenzo [b] thiophene; 2- (4-hydroxyphenyl) -6-hydroxybenzo [b] thiophene; (4-methoxyphenyl) -6-methoxybenzo [b] thiophene; 2- (4-t-ethoxyphenyl) -6-hydroxybenzo [b] thiophene; 2- (4-hydroxyphenyl) -6-methoxybenzo [b] thiophene; - (4-isopropoxyphenyl) -6-methoxybenzo [b] thiophene, 2- (4-isopropoxyphenyl) -6-hydroxybenzo [b] thiophene, 2- (4-methoxyphenyl) -6-isopropoxybenzo [b] thiophene; 2- (4-hydroxyphenyl) -6-isopropoxybenzo [b] thiophene; 2- (4-acetoxyphenyl) -6-acetoxybenzo [b] thiophene; 2- (4-methoxyphenyl) -6-acetoxybenzo [b] thiophene; 2- (4-acetoxyphenyl) -6-methoxybenzo [b] thiophene; 2- (4-acetoxyphenyl) -6-hydroxybenzo [b] thiophene; 2- (4-hydroxyphenyl) -6-acetoxybenzo [b] thiophene; 2- (4-benzoyloxyphenyl) -6-hydroxybenzo [b] thiophene; 2- (4-benzoyloxyphenyl) -6-benzoyloxybenzo [b] thiophene; 2- (4-cyclopentoxyphenyl) -6-hydroxybenzo [b] thiophene; 2- (4-hydroxyphenyl) -6-cyclopentoxybenzo [b] thiophene; 2- (4-cyclopentoxyphenyl) -6-cyclopentoxybenzo [b] thiophene; 2- (4-butoyloxyphenyl) -6-hydroxybenzo [b] thiophene; 2- (4-cyclopentoxyphenyl) -6-acetoxybenzo [b] thiophene; the similar ones. • ~~ The formulations and methods employing both a compound included in formula I and II, but are not limited to, the following combinations of two compounds: 2- (4-methoxyphenyl) -6-methoxybenzo [b] thiophene and [2- (4-Hydroxyphenyl) -6-hydroxybenzo [b] thien-3-yl] [4- [2- (1-piperidinyl) ethoxyphenyl] -mene hydrochloride; 2- (-hydroxyphenyl) -6-methoxybenzo [b] thiophene and [2- (4-hydroxyphenyl) -6-hydroxybenzo [b] thien-3-yl] [4- [2- (1-piperidinyl) ethoxy] hydrochloride ] phenyl] meone; 2- (4-methoxyphenyl) -6-hydroxybenzo [b] thiophene and [2- (4-hydroxyphenyl) -6-hydroxybenzo [b] thien-3-yl] [4- [2 (1-piperidinyl) ethoxy] hydrochloride ] phenyl] meone; 2- (4-hydroxyphenyl) -6-hydroxybenzo [bltiophene and [2- (4-hydroxyphenyl) -6-hydroxybenzo [b] thien-3-yl] [4- [2 (1-piperidinyl) ethoxy] phenyl] hydrochloride ] meona; 2- (4-methoxyphenyl) -6-methoxybenzo [b] thiophene and N-oxide of [2- (4-hydroxyphenyl) -6-hydroxybenzo [b] thien-3-yl] [4- [2 (1-piperidinyl ) ethoxy] phenyl] meone; 2- (4-hydroxyphenyl) -6-hydroxybenzo [b] thiophene and [2- (4-hydroxyphenyl) -6-hydroxybenzo [b] thien-3-yl] [4- [2- (1- piperidinyl) ethoxy] phenyl] meone; 2- (4-methoxyphenyl) -6-methoxybenzo [bltiophene] and [2- (4-hydroxyphenyl) -6-hydroxybenzo [b] thien-3-yl] [4- [2- (1-pyrrolidinyl) ethoxy hydrochloride] ] phenyl] meone; 2- (4-hydroxyphenyl) -6-hydroxybenzo [b] thiophene and [2- (4-hydroxyphenyl) -6-hydroxybenzo [b] thien-3-yl] [4- [2 (1-pyrrolidinyl) ethoxy] hydrochloride ] phenyl] meone; 2- (4-methoxyphenyl) -6-hydroxybenzo [b] thiophene and [2- (4-methoxyphenyl) -6-hydroxybenzo [b] thien-3-yl] [4- [2 (1-piperidinyl) ethoxy] hydrochloride ] phenyl] meone; 2- (4-acetoxyphenyl) -6-acetoxybenzo [b] thiophene and [2- (4-hydroxyphenyl) -6-hydroxybenzo [b] thien-3-yl] [4- [2 (1-piperidinyl) ethoxy] hydrochloride ] phenyl] meone; 2- (4-cyclopentoxyphenyl) -6-rt? Ethoxybenzo [b] thiophene and [2- (4-hydroxyphenyl) -6-hydroxybenzo [b] thien-3-yl] [4- [2- (1- piperidinyl) ethoxy] phenyl] meone; 2- (4-methoxyphenyl) -6-hydroxybenzo [b] thiophene and [2- (4-hydroxyphenyl) -6-hydroxybenzo [b] thien-3-yl] [4- [2 (1-piperidinyl) N-oxide] ) ethoxy] phenyl] meone; 2- (4-hydroxyphenyl) -6-methoxybenzo [b] thiophene and [2- (4-hydroxyphenyl) -6-hydroxybenzo [b] thien-3-yl] [4- [2- (1- piperidinyl) ethoxy] phenyl] meone; and the similar ones. - ~ The following preparations and examples more broadly illustrate the syntheses of the compounds of the present invention. The examples are not intended to be limited to the scope of the invention in any respect, and could then not be analyzed. The terms and abbreviations used in the instant preparations and examples have their normal meanings unless otherwise designated. For example "° C", "N", "mmol", "g", "mi", "M", "HPLC", "mp", "EA", "MS", and wlH-NMR ", refers to the degrees Celcius, normal or normal, iliraol or millimoles, gram or grams, milliliter or milliliters, molar or molarity, liquid chromatography of high performance, melting point, elemental analysis, mass spectrum, and proton nuclear magnetic resonance respectively .

Prepared 2- (3-Methoxyphenylethithio) -4'-Methoxyacetophenone 3-Methoxythiophenol (50.0 g, 0.356 mol) was dissolved in 700 ml of ethanol. To this mixture were added (20 g, 0.36 mol) pellets of potassium hydroxide. A total of (82.5 g, 0.36 mol) of 2-bromo-β-methoxyacetophenone was added in small portions to maintain the reaction temperature at approximately 25 ° C. The reaction was allowed to proceed at room temperature for three hours. The reaction was terminated by the evaporation of the alcohol, which resulted in obtaining a brown oil. The oil was subdivided between 2 L of water and 1.5 L of diethyl ether. The ether layer was separated and washed with water, dried with anhydrous magnesium sulfate, and evaporated still solid. The solid was crystallized from a mixture of diethylether-petroleum ether (3: 1) to yield 78.5 g of the title compound as a pink crystalline solid, mp 53 ° C-54 ° C. EA calculated by C? 6H? 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-phenylthioacetophenone The thiophenol and the 2-bromoacetophenone were converted to the title compound by the procedure d preparation 1. mp 52 ° C-53 ° C. EA calculated by C 4 H 2 2: C, 73.65; H, 5.30; 0, 7.01; S, 14.04. Found: C, 73.46; H, 5.50; OR, 7. 25; S, 14.30.

Preparation 3 2-phenylthio-4'-methoxyacetophenone Thiophenol and 2-bromo-4'-methoxyacetophenone were converted to the title compound by the procedure of preparation 1. mp 83 ° C-85 ° C. EA calculated by C15H14O2S: C, 69.74; H, 5.46. Found: C, 69.52; H, 5.48.

Preparation 4 2- (3-Isopropoxyphenii) - '-Methoxyacetophenone 3-Isopropoxythiophenol and 2-bromo-4'-methoxyacetophenone were converted to the title compound by the procedure of preparation 1.

Examples Example 1 2- (4-Methoxyphenyl) -6-methoxybenzo [b] thiophene 2- (3-Methoxyphenylthio) -4-methoxyacetophenone (50 g, 0.173 mol) were added to 250 g of polyphosphoric acid at 95 ° C. The mixture was stirred and the temperature rose to 120 ° C and the ice was added cautiously. As the temperature rose to 130 ° C, after 30 minutes, additional ice was added and crystals of the product began to appear. The water was added to the reaction mixture and the product collected by filtration. The final product was recrystallized by ethyl acetate to give 30 g of the title compound. mp 193 ° C-194 ° C. EA calculated by C? 6H? 402S: 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.

Example 2 2- (4-Hydroxyphenyl) -6-hydroxybenzo [b] thiophene 2- (4-Hydroxyphenyl) -6-hydroxybenzo [b] thiophene (10 g, 35.5 mmol) was suspended in 50 mL of 48% bromihydric acid and 100 mL of glacial acetic acid. The reaction was heated to reflux under a nitrogen atmosphere for 120 hours. The reaction was allowed to cool and filter. The solid product was washed with water and dried to yield 6.46 g of the title compound. 1 H NMR: (CDCl 3 -d 6 DMSO): d 7.54 (d, 1 H), 7.48 (d, 2 H), 7.27 (s, 1 H), 7.24 (m, 1 H), 6.39 (d, 1 H), 6.85 (d, 2 H) ). MS (FD): m / e = 242 (M +).

Example 3 2- (4-Acetoxyphenyl) -6-Acetoxybenzo [b] t-Topoen The 2- (4-Acetoxyphenyl) -6-Acetoxybenzo [b] thiophene (2.42 g, 10 mmol) was dissolved in 100 mL of tetrahydrofuran and triethylamine (8 g, 100 mL) were added. The reaction mixture was stirred under a nitrogen atmosphere at room temperature, at the same time acetylchloride (2 g, 30 mmol) were added slowly. After sixteen hours, the reaction was terminated by the addition of water. The product began to crystallize at the interface, the water layer was discarded, and the product crystallized out of the tetrahydrofuran layer. The product was filtered out and dried to give 2.06 of the title compound. XH NMR: (d6-DMSO) d 7.86 (s, 1H) 7.85 (d, 1H), 7.83 (s, 1H), 7.81 (d, 1H), 8.70 (d, 2H), 7.25 (d, 2H), 7.18 (dd, 1H). EA calculated by C? 8H? 404S: C, 66.24; H, 4.32 Found: C, 66.14; H, 4.38. MS (FD): m / e = 326 (M +).

Example 4 2- (4-Benzoyloxyphenyl) -6-Benzoyloxybenzo [b] thiophene 2- (4-Hydroxyphenyl) -6-hydroxybenzo [b] thiophene and benzoyl chloride were converted to the title compound by the procedure of Example 3 to produce a white crystalline solid. mp 216 ° C-218 ° C.

Example 5 2-Phenylbenzo [b] thiophene The 2-phenylthioacetophenone (63.8 g) was added to 450 g of polyphosphoric acid at 100 ° C and then further heated at 190 ° C for 3 hours. The reaction was allowed to cool down to 100 ° C before spilling it into a mixture of ice and water. The aqueous solution was extracted with ether. The ether layer was dried with magnesium sulfate and evaporated to produce a tanned, amorphous solid. The residue was crystallized from acetone-eol to give 35.2 of the title compound. p 171 ° C-172 ° C.

Example 6 2- (4-Methoxyphenyl) benzo [b] thiophene The 2-phenylthio-4'-methoxyacetophenone was converted to the title compound by the procedure of example 2. mp 188 ° C-190 ° C. EA calculated by Ci5H? 2OS: C, 74.97; H, 5.03; or, 6.66 Found: C, 74.69; H, 5.19; O, 6.75.

Example 7 2- (-methoxyphenyl) -6-Isopropoxybenzo [b] thiophene 2- (3-Isopropoxyphenylthio) -4'-methoxyacetophenone was converted to the title compound by the procedure of Example 2.

Example 8 2- (4-Methoxyphenyl) -6-Hydroxybenzo [b] thiophene 2- (4-Methoxyphenyl) -6-isopropoxybenzo [b] thiophene (1.0 g, 3.35 mmol) was dissolved in 10 L of methylene chloride and heated to 30 ° C. Boron trichloride (3.685 L, 3.685 mmol 1M in methylene chloride) was added slowly to the stirring reaction solution. The reaction was allowed to proceed for one hour at room temperature. The reaction was quenched with the dropwise addition of the eol (0.536 g, 16.75 mmol). The reaction was stirred for two hours and a white precipitate formed. The solid was filtered off, washed three times with 10 mL portions of methylene chloride and dried to yield the title compound as a white solid. EA calculated by C15H12O2S: C, 70.29; H, 4.72; S, 12.51. Found: C, 67.69; H, 4.65; S, 12.02 MS (FD): m / e = 256 (M +).

The examples given below show the usefulness of the present invention these given for the purpose of illustrating and should not be limited in any way. The experimental model used in this demonstration is a mimic model developed of two of the major pathologies associated with the suppression of estrogen in humans, i.e., hyperlipidemia and osteoporosis.

General procedure Seventy-five days (weight variation from 200 g to 225 g) are obtained from Charles River Laboratories (Portage, MI). The animals are either bilaterally ovariectomized (OVX) or exposed to a Sham surgical procedure at Charles River Laboratories, and then shipped after a week. Upon arrival, they are placed in suspended metal containers in groups of 3 or 4 per container and have access ab libitum to food (calcium content of approximately 0.5%) and water for a week. The ambient temperature is maintained 22.2 ° C ± 1.7 ° C with a minimum relative humidity of 40% The photoperiod in the medium is 12 hours in the light and 12 hours in the dark.

Dosage of the collection tissue treatment After a week of the acclimation period (two weeks post-OVX) a daily dosing is started with the test compound or 17-a-ethinyl estradiol. The dose is given orally, unless otherwise stated, as a suspension in 1% carboxymethylcellulose or dissolved in 20% cyclodextrin. The animals are daily dosed for 4 days. Following the dosing treatment, the animals are weighed and anaesthetized with ketamine: a mixture of Xylazine (2: 1, V: V) and a blood sample is collected by a cardiac puncture. The animals are then sacrificed by asphyxiation with C02, the uterus is moved through a midline incision, and a wet uterine weight is determined.

Hyperlipidemia (Cholesterol Analysis) The blood samples were allowed to coagulate at room temperature for 2 hours, and the serum was obtained immediately after centrifugation for 10 minutes at 300 rpm. Cholesterol serum is determined using a High Diagnostic Boehringer Mannheim performing a cholesterol assay. In summary, Cholesterol is oxidized to cholest-4-in-3-one and to hydrogen peroxide. The hydrogen peroxide then reacts with phenol and 4-aminophenazone in the presence of a peroxidase to produce a p-quinone imine dye, which is read spectrophotometrically at 500 nM. The concentration of cholesterol is then. calculated compared to a standard curve. The complete test is automated using an automated Biomek workstation.

Representative compounds of the present invention are reduced to cholesterol serum compared to ovariectomized control animals.

Osteoporosis Following the general procedure, infra, the rats were treated daily for 35 days (6 rats per treatment group) and slaughtered by asphyxiation with carbon dioxide on the 36th day. The time period of 35 days is sufficient to allow a maximum reduction in bone density, precise as described aguí. At the time of sacrifice, the uterines were removed, dissected free of foreign tissue, and fluid contained are expelled after wet weight determination in order to confirm the estrogen deficiency associated with complete ovariectomy. The uterine weight is routinely reduced to approximately 75% in response to ovariectomy. The uterines are then placed in 10 neutral buffered formalin to allow for a subsequent histological analysis.

The right femurs are cut and digitized with x-rays generated and analyzed by an image analysis program (NIH image) in the distal metaphysics. The proximal aspect of the tibia of these animals are also explored by quantitative computed tomography.

In accordance with the above procedures, the representative compounds of the present invention ethinyl estradiol (EE2) in 20% hydroxypropyl β-cyclodextrin are orally administered in the test animals and demonstrated a positive result, ie, a reduction in the loss of the mineral density in the bone.

The specific dose of a compound of formula I to taste, of the course, was determined by the particular circumstances surrounding the case. Similarly, the route of administration is a factor determined by the specifications of each case. In addition, the dose and exact route of administration are best determined by medical attention. A typical daily dose of a compound of formula I should contain non-toxic dose levels from about 0.001 mg to about 800 mg / day. Preferred daily doses should generally be from about 0.001 mg to about 60 mg / day. Such a dose can be given as a single dose or can be divided into two or three separate doses per day as needed.

As mentioned, supra, the compounds of formula I can be used with a compound of formula II. Again, the exact amounts of the two agents (the compounds of formula 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 could include 0.001 mg to 60 mg of a compound of formula I and 1.0 to 120 mg of a compound of formula II. A preferred combination could be one containing from 0.001 to 1 mg of a compound of formula I and from S9 to 59,999 mg of a compound of formula II. A more preferred combination could be one containing 0.001 to 0.01 mg of a compound of formula I and 59.9 to 59.999 mg of a compound of formula II. An equally preferred combination may contain from 0.001 to 0.1 mg of a preferred compound of formula I (where R and R1 are independently hydroxy or methoxy) and from 59.9 to 59.999 mg of Raloxifene hydrochloride. Even more preferred is the combination containing 0.001 to 0.1 mg of the most preferred compound of formula I (where R and R1 are both hydroxy) and 59.9 to 59.999 mg of Raloxifene hydrochloride.

The compounds of this invention can be administered by a variety of routes including oral, rectal, transdermal, buccal, aerosal, topical, ophthalmic, subcutaneous, intravenous, intramuscular, intranasal, and the like. These preferred compounds are formulated mainly for administration, the selection of such should be decided by medical attention. In addition, another aspect of the present invention is a pharmaceutical formulation containing an effective amount of a compound of formula I or a pharmaceutical formulation containing an effective amount of a compound of formula I and II, or a pharmaceutical salt thereof, and a pharmaceutical carrier, diluent, or excipient. The total activity of the ingredients in such formulations that contain from 0.1% to 99.9% by weight of the formulation.

The pharmaceutical formulations of the present invention can be prepared by methods known in the art using good knowledge and readily suitable ingredients. For example, the compounds of formula I or the compounds of formula I and II can be formulated with common excipients, diluents, or carriers, and formed into tablets, capsules, suspensions, powders, and the like. Examples of excipients, diluents, and carriers that are suitable for such formulations include the following: fillers and spreads such as starch, sugars, mannitol, and silicic derivatives; fixing agents such as carboxymethyl cellulose and other cellulose derivatives, alginates, gelatins, and polyvinyl pyrrolidone; wetting agents such as glycerol; disintegrating agents such as calcium carbonate and sodium bicarbonate; retarding agents for dissolution such as paraffin, resorption accelerators such as quaternary ammonium compounds; active surface agents such as cetyl alcohol, glycerol monStearate; absorption conveyors such as kaolin and bentonite; and lubricants such as talc, calcium, and magnesium stearate and polyethylic glycols.

The compounds may also be formulated as elixirs or solutions for convenient oral administration or as appropriate solutions for parenteral administration, for example, intramuscular, subcutaneous or intravenous routes. Additionally, the compounds are good for the formulation of sustained release dosage forms and the like. The formulations can then be constituted by them releasing only the active ingredient or preferably in a physiological location particle, possibly over a period of time. The coating, cover, and protective matrices can be made, for example, of polymeric substances or polymeric waxes.

Examples of formulations The following examples of formulations are only illustrations 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: The above formulations can be changed in accordance with the provision of reasonable variables.

Formulation 2: Tablets A formulation of a tablet is prepared using the following ingredients: The components are mixed and compressed to form tablets.

Formulation 3: Tablets: Each of the tablets contains 2.5 - 1000 mg of active ingredient and are manufactured as follows: The active ingredient, starch, and cellulose are passed through a No. 45 mesh U.S. and they are completely mixed. The polyvinylpyrrolidone solution is mixed with the resultant powders which are then passed through a No. 14 U.S. The granules are produced and dried at 50 ° C-60 ° C and passed through a No. 18 U.S. Sodium carboxymethyl starch, magnesium stearate, and talcum, are previously passed through a US No. 60 sieve, are then added to the tablet, which is then mixed, and compressed into a tablet machine. produce tablets.

Formulation 4: Suspensions.

Each of the suspensions contains 0.1 - 1000 mg of the medication per 5 mL of doses are made of the following: The medicament is passed through a No. 45 U.S. and mixed with sodium carboxymethyl cellulose and the syrup to form a uniform paste. Benzoic acid, flavor, and color are diluted with some water and added, with agitation. Sufficient water is then added to produce the required volume.

Formulation 5: Combination of tablets The active ingredient, starch, and cellulose are passed through a No. 45 U.S. and completely mixed. The polyvinylpyrrolidone solution is mixed with the resultant powders which are then passed through a US No. 14 mesh screen.The granules are produced and dried at 50 ° C-60 ° C and passed through a wire mesh. US No. 18 sieve Sodium carboxymethyl starch, magnesium stearate, and talc, are previously passed through a No. 60 US sieve, are then added to the granules which, after mixing, are compressed in a tablet to produce tablets.

Formulation 5: Combination of tablets The active ingredient, starch, and cellulose are passed through a No. 45 U.S. and completely mixed. The solution of the polyvinylpyrrolidone is mixed with the resultant powders which are then passed through a No. 14 mesh screen of U.S. The granules are produced and dried at 50 ° C - 60 ° C and passed through a No. 18 U.S. Sodium carboxymethyl starch, magnesium stearate, and talc, are previously passed through a No. 60 US sieve, are then added to the granules which, after mixing, are compressed into a tablet machine to produce tablets.

It is noted that in relation to this date, the best method known by the request, to carry out the aforementioned invention, is that which is clear from the present description of the invention.

Having described the invention as an antecedent, the content of the following is claimed as property:

Claims

Claims:

1. A method for inhibiting the estrogen suppression syndrome in mammals, characterized in that it includes administration to a mammal in need thereof in an effective amount of a compound of the formula I: l Where: R and R1 are independently hydrogen, hydroxy, C? -C6 alkoxy, OCHiAr, OCO (C? -C6 alkyl), OCOAr; and Ar is phenyl or a substitute for phenyl; or a solvate thereof.

2. A method that 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 suppression syndrome is osteoporosis.

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

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

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

7. A method according to claim 2 characterized in that the female human is peri- or post-enopausic.

8. A method according to claim 2 characterized in that the compound of the formula I is a compound selected from the group comprised of: 2-phenylbenzo [b] thiophene; 2- (4-hydroxyphenyl) benzo [b] thiophene; 2- (4-methoxyphenyl) benzo [b] thiophene; 2- (4-acetoxyphenyl) benzo [b] thiophene; 2- (4-benzoyloxyphenyl) benzo [b] thiophene; 2- (4-isopropoxyphenyl) benzo [b] thiophene; 2-phenyl-6-hydroxybenzo [b] thiophene; 2-phenyl-6-methoxybenzo [b] thiophene; 2-phenyl-6-isopropoxybenzo [b] thiophene; 2-phenyl-6-acetoxybenzo [b] thiophene; 2-phenyl-6- (4-methylbenzoyl) oxybenzo [b] thiophene; 2- (4-hydroxyphenyl) -6-hydroxybenzo [b] thiophene; 2- (4-methoxyphenyl) -6-methoxybenzo [b] thiophene; 2- (4-methoxyphenyl) -6-hydroxybenzo [b] thiophene; 2- (4-hydroxyphenyl) -fl-methoxybenzo [b] thiophene; 2- (4-isopropoxyphenyl) -6-methoxybenzo [b] thiophene; 2- (4-isopropoxyphenyl) -6-hydroxybenzo [b] thiophene; 2- (4-methoxyphenyl) -6-isopropoxybenzo [b] thiophene; 2- (4-hydroxyphenyl) -6-isopropoxybenzo [b] thiophene; 2- (4-acetoxyphenyl) -6-acetoxybenzo [b] thiophene; 2- (4-methoxyphenyl) -6-acetoxybenzoate. [b] thiophene; 2- (4-acetoxyphenyl) -6-methoxybenzo [b] thiophene; 2- (4-acetoxyphenyl) -6-hydroxybenzo [b] thiophene; 2- (4-hydroxyphenyl) -6-acetoxybenzo [b] thiophene; 2- (4-benzoyloxyphenyl) -6-hydroxybenzo [b] thiophene; 2- (4-benzoyloxyphenyl) -6-benzoyloxybenzo [b] thiophene; 2- (4-cyclopentoxyphenyl) -6-hydroxybenzo [b] thiophene; 2- (4-hydroxyphenyl) -6-cyclopentoxybenzo [b] thiophene; 2- (4-cyclopentoxyphenyl) -6-cyclopentoxybenzo [b] thiophene; 2- (4-butoyloxyphenyl) -6-hydroxybenzo [b] thiophene; and 2- (4-cyclopentoxyphenyl) -6-acetoxybenzo [b] thiophene; or a solvate thereof.

9. A pharmaceutical formulation characterized in that it comprises a compound of formula I: I; where: R and R 1 are independently hydrogen, hydroxy, C 1 -C 6 alkoxy, 0CH 2 Ar, OCO (C 1 -C 6 alkyl), OCOAr; and Ar is phenyl or a substitute for phenyl; or a solvate thereof; a pharmaceutical carrier, excipients, or 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-phenylbenzo [b] thiophene; 2- (4-hydroxyphenyl) benzo [b] thiophene; 2- (4-methoxyphenyl) benzo [b] thiophene; 2- (4-acetoxyphenyl) benzo [b] thiophene; 2- (4-benzoyloxyphenyl) benzo [b] thiophene; 2- (4-isopropoxyphenyl) benzo [b] thiophene; 2-phenyl-6-hydroxybenzo [b] thiophene; 2-phenyl-6-methoxybenzo [b] thiophene; 2-phenyl-6-isopropoxybenzo [b] thiophene; 2-phenyl-6-acetoxybenzo [b] thiophene; 2-phenyl-6- (4-methylbenzoyl) oxybenzo [b] thiophene; 2- (4-hydroxyphenyl) -6-hydroxybenzo [b] thiophene; 2- (4-methoxyphenyl) -6- ethoxybenzo [b] thiophene; 2- (4-methoxyphenyl) -6-hydroxybenzo [b] thiophene; 2- (4-hydroxyphenyl) -6-methoxybenzo [b] thiophene; 2- (4-isopropoxyphenyl) -6-methoxybenzo [b] thiophene; 2- (4-isopropoxyphenyl) -6-hydroxybenzo [b] thiophene; 2- (4-methoxyphenyl) -6- isopropoxybenzo [b] thiophene; 2- (4-hydroxyphenyl) -6- isopropoxybenzo [b] thiophene; 2- (4-acetoxyphenyl) -6-acetoxybenzo [b] thiophene; 2- (4-methoxyphenyl) -6-acetoxybenzo [b] thiophene; 2- (4-acetoxyphenyl) -6-methoxybenzo [b] thiophene; 2- (4-acetoxyphenyl) -6-hydroxybenzo [b] thiophene; 2- (-hydroxyphenyl) -6- acetoxybenzo [b] thiophene; 2- (4-benzoyloxyphenyl) -6-hid oxybenzo [b] thiophene; 2- (4-benzoyloxyphenyl) -6-benzoyloxybenzo [b] thiophene; 2- (4-cyclopentoxyphenyl) -6-hydroxybenzo [b] thiophene; 2- (4-hydroxyphenyl) -6-cyclopentoxybenzo [b] thiophene; 2- (4-cyclopentoxyphenyl) -6-cyclopentoxybenzo [b] thiophene; 2- (4-butoyloxyphenyl) -6-hydroxybenzo [b] thiophene; and 2- (4-cyclopentoxyphenyl) -6-acetoxybenzo [b] thiophene; or a solvate thereof.

11. A method for inhibiting the estrogen suppression syndrome in mammals characterized in that it comprises administering to a mammal in need thereof an effective amount of a compound of the formula I: I; where R and R1 are independently hydrogen, hydroxy, C? -C6 alkoxy, 0CH2Ar, OCO (C? -C6 alkyl), OCOAr; and Ar is phenyl or a substitute for phenyl; or a solvate thereof; And a compound of formula II: II; Where: R2 and R3 are independently hydrogen, Ci-C6 alkyl, CO (C? -C6 alkyl), or COAr; R 4 is pyrrolidin-1-yl, piperidin-1-yl, or hexamethyleneimin-1-yl; Where the nitrogen of the group of R4 is optionally the N-oxide; or A pharmaceutical salt or a 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 said estrogen suppression syndrome is osteoporosis.

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

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

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

17. A method according to claim 16 characterized in that the compound of formula II is the hydrochloride salt, R2 and R3 are both hydrogen, and R4 is piperidin-1-yl.

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

19. A method according to claim 12, characterized in that the compound of the formula I is a compound selected from the group consisting of: 2-phenylbenzo [b] thiophene; 2- (4-hydroxyphenyl) benzo [b] thiophene; 2- (4-methoxyphenyl) benzo [b] thiophene; 2- (4-acetoxyphenyl) benzo [b] thiophene; 2- (4-benzoyloxyphenyl) benzo [b] thiophene; 2- (4-isopropoxyphenyl) benzo [b] thiophene; 2-phenyl-6-hydroxybenzo [b] thiophene; 2-phenyl-6-ethoxybenzo [b] thiophene; 2-phenyl-6-isopropoxybenzo [b] thiophene; 2-phenyl-6-acetoxybenzo [b] thiophene; 2-phenyl-6- (4-methylbenzoyl) oxybenzo [b] thiophene; 2- (4-hydroxyphenyl) -6-hydroxybenzo [b] thiophene; 2- (4-methoxyphenyl) -6-methoxybenzo [b] thiophene; 2- (4-methoxyphenyl) -6-hydroxybenzo [b] thiophene; 2- (4-hydroxyphenyl) -6-methoxybenzo [b] thiophene; 2- (4-isopropoxyphenyl) -6-methoxybenzo [b] thiophene; 2- (4-isopropoxyphenyl) -6-hydroxybenzo [b] thiophene; 2- (4-methoxyphenyl) -6- isopropoxybenzo [b] thiophene; 2- (4-hydroxyphenyl) -6- isopropoxybenzo [b] thiophene; 2- (4-acetoxyphenyl) -6-acetoxybenzo [b] thiophene; 2- (4-methoxyphenyl) -6-acetoxybenzo [b] thiophene; 2- (4-acetoxyphenyl) -6-methoxybenzo [b] thiophene; 2- (4-acetoxyphenyl) -6-hydroxybenzo [b] thiophene; 2- (4-hydroxyphenyl) -6-acetoxybenzo [b] thiophene; 2- (4-benzoyloxyphenyl) -6-hydroxybenzo [b] thiophene; 2- (4-benzoyloxyphenyl) -6-benzoyloxybenzo [b] thiophene; 2- (4-cyclopentoxyphenyl) -6-hydroxybenzo [b] thiophene; 2- (4-hydroxyphenyl) -6-cyclopentoxybenzo [b] thiophene; 2- (4-cyclopentoxyphenyl) -6-cyclopentoxybenzo [b] thiophene; 2- (4-butoyloxyphenyl) -6-hydroxybenzo [b] thiophene; Y 2- (4-cyclopentoxyphenyl) -6-acetoxybenzo [b] thiophene; or a solvate thereof.

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

21. A pharmaceutical formulation characterized in that it comprises a compound of formula I: I; wherein: R and R 1 are independently hydrogen, hydroxy, C 1 -C 6 alkoxy, OCH 2 Ar, OCO (C 1 -C 6 alkyl), OCOAr; and Ar is phenyl or a substitute for phenyl; or a solvate thereof. And a compound of formula II: II; where; R 2 and R 3 are independently hydrogen, C 1 -C 6 alkyl, CO (C 1 -C 6 alkyl), or COAr; R5 is pyrolidin-1-yl, piperidin-1-yl, or hexamethylene-imin-1-yl; wherein the nitrogen of the group of R4 is optionally the N-oxide; or a pharmaceutical salt or a solvate thereof; and pharmaceutical carriers; excipients, or diluents.

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

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

24. A formulation according to claim 23 characterized in that it comprises 0.001 a '- "i mg of the compound of formula I), or a solvate thereof, and 59 to 59,999 mg raloxifene hydrochloride.

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

26. A phonation according to claim characterized in that the compound of formula I is a compound selected from the group consisting of: 2-phenylbenzo [b] thiophene; 2- (4-hydroxyphenyl) benzo [b] thiophene; 1- (4-methoxyphenyl) benzo [b] thiophene; 2- (4-acetoxyphenyl) benzo [b] thiophene; 2- (4-benzoyloxyphenyl) benzo [b] thiophene; 2- (4-isopropoxyphenyl) benzo [b] thiophene; 2-phenyl-6-hydroxybenzo [b] thiophene; 2-phenyl-6-methoxybenzo [b] thiophene; 2-phenyl-6-isopropoxybenzo [b] thiophene; 2-phenyl-6-acetoxybenzo [b] thiophene; 2-phenyl-6- (4-methylbenzoyl) oxybenzo [b] thiophene; 2- (4-hydroxyphenyl) -6-hydroxybenzo [b] thiophene; 2- (4-methoxyphenyl) -6-methoxybenzo [b] thiophene; 2- (4-α-ethoxyphenyl) -6- ~ hydroxybenzo [b] thiophene; 2- (4-hydroxyphenyl) -6-ethoxybenzo [b] thiophene; 2- (4-isopropoxyphenyl) -6-ethoxybenzo [b] thiophene; 2- (4-isopropoxyphenyl) -6-hydroxybenzo [b] thiophene; 2- (4-methoxyphenyl) -6- isopropoxybenzo [b] thiophene; 2- (4-hydroxyphenyl) -6-isopropoxybenzo [b] thiophene; 2- (4-acetoxyphenyl) -6-acetoxybenzo [b] thiophene; 2- (4-methoxyphenyl) -6-acetoxybenzo [b] thiophene; 2- (4-acetoxyphenyl) -6-methoxybenzo [b] thiophene; 2- (4-acetoxyphenyl) -6-hydroxybenzo [b] thiophene; 2- (4-hydroxyphenyl) -6-acetoxybenzo [b] thiophene; 2- (4-benzoyloxyphenyl) -6-hydroxybenzo [b] thiophene; 2- (4-benzoyloxyphenyl) -6-benzoyloxybenzo [b] thiophene; 2- (4-cyclopentoxyphenyl) -6-hydroxybenzo [b] thiophene; 2- (4-hydroxyphenyl) -6-cyclopentoxybenzo [b] thiophene; 2- (4-cyclopentoxyphenyl) -6-cyclopentoxybenzo [b] thiophene; 2- (4-butoyloxyphenyl) -6-hydroxybenzo [b] thiophene; and 2- (4-cyclopentoxyphenyl) -6-acetoxybenzo [b] thiophene; a solvate of it.

27. An article of manufacture characterized in that it comprises a package and a pharmaceutical formulation contained within the packaging material, wherein the packaging material contains a label indicating that the pharmaceutical formulation can be administered to inhibit a pathology of the estrogen suppression syndrome, and wherein the pharmaceutical formulation contains a compound of the formula Ka): wherein: R5 and R6 are independently hydroxy or methoxy; or a solvate thereof; and a compound of the formula: or a solvate thereof.

28. An article of manufacture according to claim 27, characterized in that it contains from 0.001 to I mg of a compound of the formula I (a), or a solvate thereof, and from 59 to 59,999 mg of a compound of the formula: or a solvate thereof.

29. An article of manufacture. according to claim 28 characterized in that the compound of the formula I (a) is 2- (4-hydroxyphenyl) -6-hydroxybenzo [b] thiophene, or a solvate thereof.

30. An article of manufacture that according to claim 29 characterized in that said pathology is osteoporosis.