CZ20001682A3 - Pharmaceutical preparation for inhibition of estrogenic deprivation syndrome and kit for this purpose - Google Patents

Abstract

Use of a compound of formula (I) wherein the substituents have a specific meaning or solvate thereof, and optionally also compounds of formula (II) wherein the substituents have specific meanings, or a pharmaceutical salt or solvate thereof, for the manufacture of a pharmaceutical composition for inhibiting estrogen deprivation syndrome including osteoporosis and hyperlipidemia. Also disclosed are pharmaceutical compositions containing them and kits containing them.

Description

A pharmaceutical composition for inhibiting estrogen deprivation syndrome and a kit for this purpose

Technical field

The present invention relates to the use of the compounds of formula (I) as defined below, and optionally also a compound of formula (II), for the manufacture of a pharmaceutical composition for inhibiting estrogen deprivation syndrome, including osteoporosis and hyperlipidemia. The invention also relates to pharmaceutical compositions containing them as well as kits containing them.

BACKGROUND OF THE INVENTION

Estrogen Deprivation Syndrome is a term used to describe various pathological conditions that often affect women with insufficient estrogen hormone levels.

The most common cause of estrogen deprivation is natural age-related menses, i.e. menopause. Furthermore, some unnatural circumstances may cause estrogen deprivation, including surgical ovariectomy, hormone-inducing chemotherapy or its pharmacological effect, and the like. Although a number of pathological conditions may be conceived using this term, two main effects of estrogen deprivation syndrome are the main source of long-term medical interest: osteoporosis and cardiovascular effects, especially hyperlipidemia.

The term osteoporosis describes a group of diseases based on various etiologies, all of which are characterized by a net loss of bone mass per unit volume. This bone loss results in a skeletal failure providing adequate structural support to the body, i.e., a bone fracture. Osteoporosis associated with menopause is one of the most common types of osteoporosis. Within 3 to 6 years after menses arrest, most women in the trabecular compartment lose bone from about 20 to about 60% of the bone mass. This rapid loss is usually associated with a general increase in bone resorption and a bone formation cycle in which a resorption cycle predominates. The clear result is net bone loss. Osteoporosis is a common and serious disease in postmenopausal women.

In the United States alone, an estimated 25 million women are affected by the disease. The results of osteoporosis are individually harmful and also the budgetary impact is deleterious due to its chronicity and the need for extensive and long-term care (hospitalization and nursing home care). This is especially true in older patients. In addition, although osteoporosis is not generally considered to be a life-threatening condition, hip fractures in the old women are attributed a 20-30% mortality index. A large percentage of this mortality index can be directly associated with postmenopausal osteoporosis.

During the pre-menopausal period, most women have a lower incidence of cardiovascular disease than men of age. In contrast, after menopause, the number of cardiovascular diseases in women slowly increases to reach the number observed in men. This loss of protection has been associated with estrogen depletion and in particular with estrogen's ability to regulate serum lipid levels. The nature of estrogen's ability to regulate serum lipid levels is not well known, but recent evidence suggests that estrogen can increase the number of low density lipid (LDL) receptors in the liver and thus remove excess cholesterol. In addition, estrogen has been shown to have some effect on cholesterol biosynthesis and other beneficial effects on cardiovascular health.

Although estrogen deprivation syndrome is often prescribed by estrogen replacement therapy, it suffers from low patient compliance, as many women have reservations about some side effects and the inconvenience of the pharmaceutical form of medication. For example, 17β-Estradiol is often administered via transdermal patches, due to poor oral absorption. As a result, most women stop taking estrogen during the first year after starting estrogen replacement therapy.

Compounds of formula (I):

in which

R ¹ 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 substituted phenyl;

are known as chemical intermediates of oral pharmaceutical agents, for example raloxifene hydrochloride.

The present invention relates to the discovery of uses that are newly ascribed to the compounds of formula (I), in particular that they are useful agents for inhibiting the estrogen deprivation syndrome.

SUMMARY OF THE INVENTION

The present invention provides the use of a compound of formula (I)

in which

R a 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 substituted phenyl;

or solvates thereof for the manufacture of a pharmaceutical composition for inhibiting estrogen deprivation syndrome.

Another object of the present invention is the use of a compound of the above formula (I) wherein all substituents are as defined above, or solvates thereof, and a compound of the formula (II)

(II) in which

R ² and R ³ are independently hydrogen, C 1 -C 6 alkyl, -CO (C 1 -C 6 alkyl) in the alkyl moiety, or -COAr; and

R ⁴ is pyrrolidin-1-yl, piperidin-1-yl or hexamethylenimine-1-yl;

wherein the nitrogen atom in the R ⁴ group is optionally an N-oxide group;

or a pharmaceutical salt or solvate thereof, for the manufacture of a medicament for inhibiting estrogen deprivation syndrome.

The present invention also provides a pharmaceutical composition comprising a compound of formula (I) and optionally also a compound of formula (II), and pharmaceutical excipients, diluents and carriers. The invention also provides a kit comprising such a pharmaceutical composition.

DETAILED DESCRIPTION OF THE INVENTION

The general terms used herein to describe compounds, methods and compositions have their usual meanings. The term C 1 -C 4 alkyl (C _1-4 alkyl) means, for example, methyl, ethyl, propyl, isopropyl. , cyclopropyl, n-butyl, sec-butyl, tert-butyl and cyclobutyl. The term C 1-6 alkyl (C 1-6 alkyl) includes those listed for C 1-4 alkyl and additionally monovalent, straight, branched, or cyclic aliphatic C 5 or C 6 aliphatic chains including pentyl, cyclopentyl, hexyl, 2-methylpentyl, cyclohexyl and the like. The term alkoxy of 1 to 4 carbon atoms (0 _τ _ ₄ alkoxy group) is methoxy, ethoxy, n-propoxy, isopropoxy, cyclopropoxy, n-butoxy, sec-butoxy, tert-butoxy, and cyclobutoxy. The term C 1 -C 6 alkoxy (O _1-6 alkoxy) includes those listed for C 1 -C 4 alkoxy and, in addition, straight, branched or cyclic aliphatic C 5 or C 6 aliphatic chains attached to the monovalent and include, but are not limited to, pentyloxy, cyclopentyloxy, hexyloxy, 2-methylpentyloxy, cyclohexyloxy, and the like.

The term halide refers to a chloride, bromide or iodide group.

The term substituted phenyl refers to a phenyl group having 1 to 3 substituents selected from the group consisting of an alkyl group having 1 to 6 carbon atoms, an alkoxy group having 1 to 4 carbon atoms, a hydroxy group, a nitro group, a chlorine, fluorine or tri (chlorine or fluorine) methyl groups.

Although the free base form of the compounds of formula (II) may be used in the methods of the invention, it is

- Ί preferable to prepare and use a pharmaceutical salt form. Typical pharmaceutical salts include salts prepared by reacting compounds of formula (II) with mineral or organic acids. Such salts are known as acid addition salts. Thus, the term pharmaceutical salt refers to acid addition salts of compounds of formula (II), which are administered at doses substantially nontoxic and are generally known in the pharmaceutical literature, see for example S.M. Berge, L.D. Bighley and D.C. Monkhouse, J. Pharm. Sci. 66, 1 (1997). Pharmaceutical salts generally have increased solubility as compared to the compounds from which they are derived and are therefore often more suitable for use in pharmaceutical compositions.

Examples of pharmaceutical salts are iodide, acetate, phenylacetate, trifluoroacetate, acrylate, ascorbate, benzoate, chlorobenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, methylbenzoate, o-acetoxybenzoate, naphthalene-2-benzoate, bromide, isobutyrate, phenylbutyrate, g- hydroxybutyrate, butin-1,4-dioate, hexin-1,4-dioate, hexin-1,6-dioate, caproate, caprylate, chloride, cinnamate, citrate, formate, fumarate, glycolate, heptanoate, hippurate, lactate, malat, maleat, hydroxymaleat, malonate, mandelat, mesylate, nicotinate, isonicotinate, nitrate, oxalate, phthalate, terephthalate, phosphate, hydrogen phosphate, dihydrogen phosphate, metaphosphate, pyrophosphate, propiolate, propionate, phenylpropionate, sulfate, succinate, sebacate, sebacate, sebacate, sebacate, sebacate pyrosulfate, sulfite, hydrogensulfite, sulfonate, benzenesulfonate, p-bromophenylsulfonate, chlorobenzenesulfonate, propanesulfonate, ethanesulfonate, 2-hydroxyethanesulfonate, methanesulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate, p-toluenesulfonate at, tartrate and the like, compounds of formula (II).

The term solvate refers to a cluster comprising one or more molecules of a solute, such as a compound of formula (I) or (II), with one or more solvent molecules. These would be those solvent molecules commonly used in the pharmaceutical literature that are known not to be harmful to the recipient, such as water or ethanol.

The term thermodynamic base refers to a base providing reversible deprotonation of an acid substrate or which is used as a proton trap in reactions where the by-product is a proton and which is reactive enough to cause the desired reaction without significantly causing any undesirable reactions. Examples of thermodynamic bases include carbonates, hydrogen ^; carbonates, hydroxides (e.g., carbonate, bicarbonate or hydroxide of lithium, sodium or potassium), tri (C ₁ _ ₆ alkyl) amines, or aromatic nitrogen containing heterocycles (e.g., pyridine), which include, but are not limited to.

The term estrogen deprivation syndrome includes pathologies and conditions caused by loss of ovarian function (induced either naturally, surgically or chemically) and specifically loss of ovarian hormones, especially estrogen. Since estrogen loss is causally related to the symptoms of the syndrome, each of the symptoms responds to the replacement of the lost estrogenic hormone by administration of the compounds of the invention. Therefore, the compounds and methods of the invention would be useful and beneficial in the treatment or prevention of estrogen deficiency symptoms, including but not limited to: osteoarthritis porosis, hyperlipidemia, atherosclerosis, vasomotor abnormalities (hot flash), autoimmune disease , skin and hair abnormalities, cardiovascular disease and degenerative conditions, dementia and Alzheimer's disease, depression, weight gain or weight loss, some types of diabetes and diabetic conditions, poor healing and tissue restoration, vaginal atrophy, urinary incontinence and the consequences of abnormal estrogen-regulated gene control, to which, however, the list is not limited. It should be noted that not all of the above pathological conditions may necessarily occur in all patients treated for estrogen deprivation syndrome, therefore the specific use of the compounds and methods of this invention may vary depending on the individual nature and severity of these symptoms.

The term inhibits or inhibits means preventing, treating, ameliorating, ameliorating, arresting, suppressing, retarding or causing reversal of the progression, or reducing the severity of pathological symptoms related to or resulting from estrogen deprivation syndrome. As such, such methods include, as appropriate, medical (acute) and / or prophylactic (preventive) administration.

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

By pharmaceutical composition, pharmaceutical carrier, pharmaceutical solvent and pharmaceutical excipient it is meant that in a composition comprising a compound of formula (I) or in a composition comprising a combination of compounds of formulas (I) and (II), the carrier, solvent and excipient compatible with other ingredients not harmful to the recipient thereof.

While all of the compounds of the invention are suitable, some of the compounds are particularly interesting and preferred. Preferred are, for example, compounds of formula (I) in which the groups R and R ¹ are independently hydroxy or methoxy. Most preferred is a compound of formula (I) wherein R ¹ and R ¹ are each hydroxy, i.e. 2- (4-hydroxyphenyl) -6-hydroxybenzo [b] thiophene. Also particularly preferred is the hydrochloride salt of a compound of formula (II) wherein R ² and R ³ are each hydrogen and R ⁴ is piperidin-1-yl. The compound of formula (II) is [2- (4-hydroxyphenyl) -6-hydroxybenzo [b] thien-3-yl] [4- / 2- (1-piperidinyl) ethoxy / phenyl] methanone hydrochloride, i.e. raloxifene hydrochloride .

While all compounds and methods utilizing combinations of compounds of formulas (I) and (II) are suitable, some combinations utilizing the above preferred compounds are particularly interesting and preferred. Most preferred is a combination of 2- (4-hydroxyphenyl) -6-hydroxybenzo [b] thiophene and raloxifene hydrochloride.

Compounds of formula (I) may be prepared from compounds of formula (III) and (IV) as illustrated in Scheme 1 below, wherein R and R ¹ are as previously described.

Scheme 1 ♦ ··· • · · »·

9 4 5 4 9

44 99

94

9 9 4

9 4 4

4 9 9

9 4 9

III IV / V

Compounds of formula (III) may be alkylated on the sulfur atom with a phenacyl halide of formula (IV).

Such alkylation on a sulfur atom is carried out for between 1 and 24 h in a solvent in the presence of a thermodynamic base at temperatures between 0 and 100 ° C. Ethanol and potassium hydroxide are typically preferred solvents and bases. The reaction is carried out preferably at room temperature for 1 to 3 h. A preferred halide of the compound of formula (IV) is bromide.

The resulting compounds of formula (V) are cyclized to a compound of formula (I) by treatment with an acid for between 1 and 24 h, in a suitable solvent, at a temperature between 50 and 200 ° C. The preferred solvent and acid is polyphosphoric acid.

If the groups R and / or ^R1 is hydroxy, it is preferred that the above procedure is carried out with the compound

of formula (III) and / or (IV) wherein R and / or R ¹ are alkoxy of 1 to 6 carbon atoms, -OCH 2 Ar, -OCO (alkyl) of 1 to 6 carbon atoms in the alkyl moiety or a group of formula -OCOAr. Compounds of formula (I) in which the groups R and / or R ¹ are hydroxy may then be prepared after the cyclization step by removing the alkyl moiety of 1 to 6 carbon atoms, the moiety of the formula -CH 2 Ar, -CO (alkyl) moieties of 1 to 6 6 carbon atoms in the alkyl moiety or moiety of -COAr (protecting groups) from the resulting compound of formula (I). Methods for removing these protecting groups can be found in the Examples section that follows or in the second chapter of TH Green et al., Protective Groups in Organic Synthesis,

2nd ed., John Wiley & Sons, New York (1991).

Compounds of formula (I) in which RaR ¹ groups are not hydrogen and only one of R or R ¹ is hydroxy may be prepared by the selective removal of one of the protecting groups from compounds of formula (I) in which RaR ¹ groups are independently and differently C 1 -C 6 alkoxy, -OCH ₂ Ar, -OCO (C 1 -C 6 alkyl), -OCOAr. Protecting groups that facilitate selective removal and methods for selectively removing one protecting group without the other are well known in the art. One example in which selective removal is possible is when one protecting group is a benzyl group and the other is an alkyl group of 1 to 6 carbon atoms. The benzyl group can be selectively removed by catalytic hydrogenation. For further guidance on deprotection, see the Examples section and Green's reference cited above.

4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 ··· · 4 ·

For further guidance on the preparation of compounds of Formula (I), see U.S. Patents 4,133,814 and 4,418,068 and C.D. Jones et al., J. Med. Chem., 27, 1057-1056 (1984), each of which is incorporated herein by reference.

Compounds of formula (II) that are not N-oxides and their pharmaceutical salts can also be prepared as disclosed in previously assigned US patents as well as US Patent Nos. 5,393,763 and 5,629,425 and PCT / US97 / 04259, the contents of each of which is incorporated herein by reference.

Compounds of formula (II) that are N-oxides can be prepared by dissolving or suspending a compound of formula (II) that is not an N-oxide in a dilute aqueous hydrogen peroxide solution with a cosolvent such as methanol or ethanol. The reaction conditions for this reaction may range between room temperature and 100 ° C and last between 24 and 72 h. It should be noted that care must be taken in selecting the oxidizing agent and that a number of commonly used atom oxidizing agents nitrogen, for example chromium trioxide or potassium permanganate and the like, cannot be used because they would also oxidize the sulfur atom in benzo [b] thiophene. Therefore, a milder 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 reaction by conventional chromatographic techniques. It is further preferred to carry out the reactions according to the invention under an inert atmosphere, such as, for example, an argon or especially nitrogen atmosphere. In general, the choice of solvent is not critical if the solvent used is inert to the reaction and sufficiently dissolves the reactants to achieve the desired reaction. The intermediates and end products can, if desired, be purified by conventional techniques such as recrystallization or chromatography on solid supports such as silica gel or alumina.

Compounds of formulas (III) and (IV) are either commercially available or can be prepared by methods well known in the art.

The discussion of the synthesis is not intended to limit the scope of the invention and should not be so construed. The application of the above chemical methods allows the synthesis of compounds of formula (I), including:

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;

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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 3 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-cyclopentyloxyphenyl) -6-hydroxybenzo [b] thiophene;

2- (4-hydroxyphenyl) -6-cyclopentyloxybenzo [b] thiophene;

2- (4-cyclopentyloxyphenyl) -6-cyclopentyloxybenzo [b] thiophene;

2- (4-butoyloxyphenyl) -6-hydroxybenzo [b] thiophene;

2- (4-cyclopentyloxyphenyl) -6-acetoxybenzo [b] thiophene;

and the like, but the choice is not limited thereto.

Compositions and methods utilizing both a compound of Formula (I) and Formula (II) include the following combinations of the two:

2- (4-methoxyphenyl) -6-methoxybenzo [b] thiophene and [2- (4-hydroxyphenyl) -6-hydroxybenzo [b] thien-3-yl] [4- / 2- (1-piperidinyl) ethoxy hydrochloride [phenyl] methanone;

2- (4-hydroxyphenyl) -6-methoxybenzo [b] thiophene and [2- (4-hydroxyphenyl) -6-hydroxybenzo [b] thien-3-yl] [4- / 2- (1-piperidinyl) ethoxy hydrochloride [phenyl] methanone;

2- (4-methoxyphenyl) -6-hydroxybenzo [b] thiophene and [2- (4-hydroxyphenyl) -6-hydroxybenzo [b] thien-3-yl] [4- / 2- (1-piperidinyl) ethoxy] hydrochloride (phenyl) methanone;

2- (4-hydroxyphenyl) -6-hydroxybenzo [b] thiophene and [2- (4-hydroxyphenyl) -6-hydroxybenzo [b) thien-3-yl] [4- / 2- (1-piperidinyl) ethoxy] hydrochloride (phenyl) methanone;

····

2- (4-methoxyphenyl) -6-methoxybenzo [b] thiophene and [2- (4-hydroxyphenyl) -6-hydroxybenzo [b] thien-3-yl] [4- (2- (1-piperidinyl) ethoxy)] phenyl] methanone N-oxide;

2- (4-hydroxyphenyl) -6-hydroxybenzo [b] thiophene and [2- (4-hydroxyphenyl) -6-hydroxybenzo [b] thien-3-yl] [4- (2- (1-piperidinyl) ethoxy)] phenyl] methanone N-oxide;

2- (4-methoxyphenyl) -6-methoxybenzo [b] thiophene and [2- (4-hydroxyphenyl) -6-hydroxybenzo [b] thien-3-yl] [4- / 2- (1-pyrrolidinyl) ethoxy] hydrochloride [phenyl] methanone;

2- (4-hydroxyphenyl) -6-methoxybenzo [b] thiophene and [2- (4-hydroxyphenyl) -6-hydroxybenzo [b] thien-3-yl] [4- / 2- (1-pyrrolidinyl) ethoxy] hydrochloride [phenyl] methanone;

2- (4-methoxyphenyl) -6-hydroxybenzo [b] thiophene and [2- (4-methoxyphenyl) -6-hydroxybenzo [b] thien-3-yl] [4- / 2- (1-piperidinyl) ethoxy] hydrochloride [phenyl] methanone;

2- (4-acetoxyphenyl) -6-acetoxybenzo [b] thiophene and [2- (4-hydroxyphenyl) -6-hydroxybenzo [b] thien-3-yl] [4- / 2- (1-piperidinyl) ethoxy] hydrochloride [phenyl] methanone;

2- (4-cyclopentyloxyphenyl) -6-methoxybenzo [b] thiophene and [2- (4-hydroxyphenyl) -6-hydroxybenzo [b] thien-3-yl] [4- / 2- (1-piperidinyl) ethoxy] hydrochloride [phenyl] methanone;

2- (4-methoxyphenyl) -6-hydroxybenzo [b] thiophene and [2- (4-hydroxyphenyl) -6-hydroxybenzo [b] thien-3-yl] [4- / 2- (1-piperidinyl)] ethoxy / phenyl] methanone N-oxide;

2- (4-hydroxyphenyl) -6-methoxybenzo [b] thiophene and [2- (4-hydroxy-18-phenyl) -6-hydroxybenzo [b] thien-3-yl] [4- / 2- (1-piperidinyl) ethoxy / phenyl] methanone N-oxide;

and the like, but the choice is not limited thereto.

DETAILED DESCRIPTION OF THE INVENTION

The following Preparations and Examples further illustrate the synthesis of the compounds of this invention. The examples are not intended to limit the scope of the invention in any respect and should not be so construed. The terms and abbreviations used in these preparations and examples have their usual meanings unless otherwise indicated. For example, ° C, mmol, mmol, g, ml, Μ, HPLC, tt, elemental analysis, MS and ¹ H-NMR are degrees Celsius, normal or normality, millimol or millimoles, gram or grams, molar or molarity, high performance liquid chromatography , melting point, elemental analysis, mass spectrum and proton nuclear magnetic resonance.

Preparation 1

2- (3-Methoxyphenylthio) -4-methoxyacetophenone g (0.356 mol) of 3-methoxythiophenol was dissolved in 700 ml of ethanol. To this mixture was added 20 g (0.36 mol) of potassium hydroxide pellets. A total amount of 82.5 g (0.36 mol) of methoxyacetophenone was added in small portions while maintaining the reaction temperature at about 25 ° C. The reaction was allowed to proceed at room temperature for 3 h. Evaporation of the alcohol stopped the reaction to give a brown oil. The oil was partitioned between 2 L of water and 1.5 L of diethyl ether. The ether layer was separated and washed with water, dried over anhydrous magnesium sulfate and evaporated to a solid. The solid was crystallized from diethyl ether / petroleum ether (3: 1) to give a solid

78.5 g of the title compound as a pink crystalline solid.

m.p. Mp 53-54 ° C

Elemental analysis calculated for C ₁₆ H ₁₆ O ₃ S: C, 66.64; H, 5.59; 0, 16.64; S, 11.12. Found: C, 66.55, H, 5.87, 0, 16.82, S 10.86.

Preparation 2

2-Phenylthioacetophenone

Thhoifenol and 2-bromoacetophenone were converted to the title compound according to Preparation 1.

m.p. 52-53 ° C.

Elemental analysis calculated for C ₁₄ H ₁₂ OS: C, 73.65, H, 5.30, 0, 7.01, S 14.04. Found: C, 73.46, H, 5.50, 0, 7.25, S 14.30.

Preparation 3

2-Phenylthio-4-methoxyacetophenone

Thhoifenol and 2-bromo-4-methoxyacetophenone were converted to the title compound according to Preparation 1.

m.p. 83 to 85 ° C • · φ · · · · • · · · ft · ft · ft · ft · ft · ft ·

ΦΦΦΦ

Elemental analysis calculated for ^C 15 ^H 14 ° 2 ^{S: c} ' ⁶⁹ ' ⁷⁴ ' ^H , 5.46. Found: C, 69.52, H, 5.46.

Preparation 4

2- (3-Isopropoxyphenyl) -4-methoxyacetophenone

3-Isopropoxyphenol and 2-bromo-4-methoxyacetophenone were converted to the title compound according to Preparation 1.

Example 1

2- (4-Methoxyphenyl) -6-methoxybenzo [b] thiophene g (0.173 mol) of 2- (3-methoxyphenylthio) -4-methoxyacetophenone is added at 250C to 250 g of polyphosphoric acid. The mixture was stirred, the temperature was raised to 125 ° C and ice was carefully added. After 30 min, when the temperature rose to 130 ° C, more ice was added and product crystals 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 g of the title compound.

m.p. Mp 193-194 ° C.

Elemental analysis calculated for ^C 16 ^H 14 ° 2 ^{S: C} + 71.08, ^h and 5.22, 0, 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 g (35.5 mmol) of 2- (4-methoxyphenyl) -6-methoxybenzo [b] thiophene is suspended in 50 ml of a 48% aqueous hydrobromic acid solution and ml of glacial acetic acid. The reaction mixture was heated under reflux for 120 h under nitrogen, allowed to cool and filtered. The solid product was washed with water and dried to give 6.46 g of the title compound.

1 H-NMR (CDCl ₃ - d ⁶ DMSO): δ 7.54 (d, 1H), 7.48 (d, 2H), 7.27 (s, 1H), 7.24 (m, 1H), 6.92 (d, 1 H), 6.85 (d, 2 H).

MS (FD): m / e = 242 (M ^& lt ^{; +} & gt ^; ).

Example 3

2- (4-Acetoxyphenyl) -6-acetoxybenzo [b] thiophene

2.42 g (10 mmol) of 2- (4-hydroxyphenyl) -6-hydroxybenzo [b] thiophene are dissolved in 100 ml of tetrahydrofuran and 8 g (100 mmol) of triethylamine are added. The reaction mixture was stirred at room temperature under nitrogen and 2 g (30 mmol) of acetyl chloride was slowly added. After 16 h, the reaction is stopped by adding water. The product begins to crystallize at the interface. The aqueous layer was removed and the product crystallized from the tetrahydrofuran layer. The product was filtered and dried to give 2.06 g of the title compound.

¹ H-NMR (CDC1 ₃ - d ^e DMSO): δ 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).

• 4 · 4 ···

4 ·· * ·· * · ♦♦ ·

Elemental analysis calculated for ^C ₁₄ ^H ₁₄ O ₄ S: 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 according to the procedure of Example 3 to give a white crystalline solid.

m.p. Mp 216-218 ° C.

Example 5

2-Phenylbenzo [b] thiophene

63.8 g of 2-phenylthioacetophenone are added at 450C to 450 g of polyphosphoric acid and further heated at 190C for 3 hours. The reaction mixture was allowed to cool to less than 100 ° C and then poured into ice-water. The aqueous solution was extracted with ether. The ether layer was dried with magnesium sulfate and evaporated to give a brown amorphous solid. The residue was crystallized from acetone / ethanol to give 35.2 g of the title compound.

m.p. Mp 171-172 ° C.

• 0 ·

Example 6

2- (4-Methoxyphenyl) benzo [b] thiophene

2-Phenylthio-4-methoxyacetophenone was converted to the title compound as in Example 2.

m.p. Mp 188-190 ° C.

Elemental analysis calculated for ^C 15 H ₁₂ OS: C, 74.97, H, 5.03, 0.66. Found: C, 74.69 H, 5.19, 0, 6.75.

Example 7

2- (4-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

1.0 g (3.35 mol) of 2- (4-methoxyphenyl) -6-isopropoxybenzo [b] thiophene was dissolved in 10 ml of methylene chloride and heated to 30 ° C. 3.685 ml of a 1M (3.685 mol) boron trichloride solution was added to the reaction solution with stirring. The reaction was allowed to proceed at room temperature for 1 h. The reaction was quenched by the dropwise addition of 0.536 g (16.75 mmol) of methanol. The reaction was stirred for 2 h and a white precipitate formed. The solid was filtered, washed three times with 10 ml portions of methylene chloride and dried to give the title compound.

• · • ·

Elemental analysis calculated for ^C 15 H ₁₂ ° 2 ^{S: 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 ^& lt ^{; +} & gt ^; ).

The examples below demonstrating the utility of the present invention are provided by way of illustration and are not intended to limit the scope of the invention in any way. The experimental model used in this demonstration is a model developed to simulate two major pathological conditions associated with human estrogen deprivation syndrome, i.e. hyperlipidemia and asteoporosis.

General procedures

75-day-old Sprague Dawley female rats weighing 200-225 g are obtained from Charles River Laboratories (Portage, MI). The animals are either ovariectomized (OVX) bilaterally (OVX) or subjected to Sham surgery at Charles River Laboratories. and after one week they will be sent. After delivery, the animals are housed in hanging metal cages for one week, in groups of three or four per cage, with access to food and water ad libitum (dietary calcium content approximately 0.5%). The room temperature is maintained at 22.2 ° C ± 1.7 ° C with a minimum relative humidity of 40%. The lighting period is 12 h light and 12 h dark.

Dosing regimen and tissue harvesting

After a one-week acclimation period, dosing of the test compound or 17-α-ethinyl estradiol is started daily. Doses are given unless otherwise stated

4 4 · 4 · 4 · 4 · 4 ·

4 4

Orally, as a suspension in 1% carboxymethylcellulose or dissolved in 20% cyclodextrin. Animals are dosed daily for 4 days. At the end of the dosing regimen, the animals are weighed and anesthetized with ketamine / xylazine (2: 1, v / v) and blood samples taken by cardiac puncture. The animals are then sacrificed by asphyxiation in CO ₂ , the uterine section is removed by incision and fresh weight is determined.

Hyperlipidemia (cholesterol analysis)

Blood samples were allowed to clot for two hours at room temperature, followed by centrifugation for 10 minutes at 3000 rpm to give serum. Serum chlesterol is determined by a high-performance cholesterol assay from Boehringer Manheim Diagnostics. Briefly, cholesterol is oxidized to cholest-4-en-3-one and hydrogen peroxide. Hydrogen peroxide then reacts in the presence of peroxidase with phenol and 4-aminophenazone to form a β-quinone imine dye, which is determined spectrophotometrically at 500 nm. The cholesterol concentration is then calculated from the standard curve. The whole test is automated using the Biomek Automated Workstation.

Representatives of the compounds of this invention reduce serum cholesterol compared to ovariectomized control animals.

Osteoporosis

In accordance with the above general procedures, rats are treated daily for 35 days (six rats per treatment group) and sacrificed by carbon dioxide asphyxiation on day 36. The 35-day time period is sufficient to maximize the reduction in bone density measured as described herein. At the time of sacrifice, the uterus is removed, the external tissues are removed, and the liquid content is drained, then its fresh weight is determined to confirm the estrogen deficiency associated with ovariectomy. The uterine weight is usually reduced by about 75% in response to ovariectomy. The uterus is then placed in 10% neutral pH buffered formalin to allow subsequent histological analysis.

Right femurs are excised and digitized with generated X-rays, and distal metaphyses analyzed with an image analysis program (NIH image). The proximal portion of the tibia in these animals is scanned by quantitative tomography.

In accordance with the above procedures, representatives of the compounds of this invention and ethinyl estradiol (EE ₂ ) in 20% β-cyclodextrin are administered orally to the test animals and demonstrate a positive result, i.e. a reduction in bone mineral density loss.

The specific doses of the compound of formula (I) will, of course, be determined according to the particular circumstances of the case. Similarly, the route of administration is a factor determined by the specificities of each case. Therefore, the exact dose and route of administration are best determined by the attending physician. A typical daily dose of a compound of formula (I) would contain a non-toxic dose level of from about 0.001 mg to about 800 mg per day. Preferred daily doses will generally be from about 0.001 g to about 60 mg per day. Such doses may be given as a single dose or, if necessary, may be divided into two or three separate doses per day.

ft · · · ft * ft

As mentioned above, compounds of formula (I) may be used with compounds of formula (II). The exact amounts of the two compounds (compounds of formula (I) and (II)) may again vary depending on the nature of the symptoms being treated, as well as the patient's medical condition. In general, such combinations would comprise 0.001 to 60 mg of a compound of formula (I) and 1.0 to 120 mg of a compound of formula (II). A combination comprising 0.001 to 1 mg of a compound of formula (I) and 59 to 59.999 mg of a compound of formula (II) would be preferred. More preferred would be a combination comprising 0.001 to 0.1 mg of a compound of formula (I) and 59.9 to 59.999 mg of a compound of formula (II). An even more preferred combination would comprise 0.001 to 0.1 mg of a compound of formula (I) (wherein R and R ¹ are independently hydroxy or methoxy) and 59.9 to 59.999 mg of raloxifene hydrochloride. Most preferred is a combination comprising 0.001 to 0.1 mg of the most preferred compound of formula (I) (wherein R and R ¹ are each hydroxy) and 59.9 to 59.999 mg of raloxifene hydrochloride.

The compounds of this invention may be administered by a variety of routes including oral, rectal, transdermal, buccal, aerosol, topical, ophthalmic, subcutaneous, intravenous, intramuscular, intranasal, and the like. These compounds are preferably pre-adapted for administration, the selection of which will be made by the attending physician. Therefore, a further aspect of the invention is a pharmaceutical composition comprising an effective amount of a compound of formula (I) and a pharmaceutical composition comprising an effective amount of a compound of formula (I) and (II) or a pharmaceutical salt thereof and a pharmaceutical carrier, diluent or excipient.

φφφφ φ * * · • φ φ

Φ ♦ ΦΦ · φ · φ · φ · · φφ · ·

Overall, the active ingredients in such a composition comprise from 0.1% to 99.9% by weight of the composition.

The pharmaceutical compositions of this invention may be prepared by methods known in the art using well known and readily available ingredients. For example, compounds of formula (I) or compounds of formula (I) and (II) may be prepared with conventional excipients, diluents or carriers and formed into tablets, capsules, suspensions, powders and the like. Examples of excipients, solvents and carriers suitable for such compositions include the following: fillers and extenders such as starch, sugars, mannitol, and silicon derivatives; binders such as carboxymethylcellulose and other cellulose derivatives, alginates, gelatin and polyvinylpyrrolidone; wetting agents such as glycerol; disintegrants such as calcium carbonate or sodium bicarbonate; solubility retarding agents such as paraffin; resorption accelerators such as quaternary ammonium compounds; surfactants such as cetyl alcohol, glycerol monostearate; adsorbent carriers such as kaolin and bentonite; and lubricants such as talc, calcium or magnesium stearate, and solid polyethylene glycols.

The compounds may also be formulated as elixirs or solutions for convenient oral administration or as solutions suitable for parenteral administration, for example by the intramuscular, subcutaneous or intravenous route. Furthermore, the compounds are well suited for adaptation to sustained release forms and the like. The compositions may be formulated to release the active ingredient only or preferably at certain physiological locations, with the possibility of release over a period of time. The coatings, shells and protective materials can be made, for example, from polymeric materials or waxes.

····

Examples of resources

The following examples of compositions are illustrative only and are not intended to limit the scope of the invention in any way.

Means 1

Gelatin capsules

Hard gelatin capsules are prepared using the following procedure.

Component

Quantity (mg / capsule)

Compound of Formula (I)

Starch, NF

Starch, fine powder

Liquid silicone, 350. 10 ^-6 m ² .s

0.001 - 200

- 650

- 650

0-15

The above composition may be varied in accordance with the reasonable variations provided.

· · · · 9 9 9 9 9 9 9 9 9 9

ΦΦ

Means 2

Tablets

A tablet formulation is prepared using the ingredients listed below.

Component Quantity (mg / tablet) Compound of Formula (I) 0.001 - 200 Microcrystalline cellulose 200 - 650 Silica, foam 10 - 650 Stearic acid 5-15

The components are mixed and compressed into tablets.

Means 3

Tablets

Tablets, each containing 2.5 to 1000 mg of active ingredient, are prepared as follows.

• 9 9 · 9 ·· 9

99 99 99

Component Quantity (mg / tablet) Compound of Formula (I) 0.001 - 200 Starch 45 Microcrystalline cellulose 35 Polyvinylpyrrolidone (as a 10% solution in water) 4 Sodium carboxymethylcellulose 4,5 Magnesium stearate 0.5 Talc 1

The active ingredient, starch and cellulose are passed through a sieve with a particle size of 0.300 mm and mixed thoroughly. The polyvinylpyrrolidone solution is mixed with the resulting powders and then passed through a 1.168 mm sieve. The granules so produced are dried at 50 to 60 ° C and passed through a sieve with a particle size of 0.912 mm. Starch sodium glycolate, magnesium stearate and talc, previously passed through a sieve with a particle size of 0.246 mm, are then added to the granules which are mixed and then compressed on a tabletting machine to give tablets.

• 44 4

4 4 • 4 4 4 • 4 4

4 4 ·

4 · 44

Means 4

Suspension

Suspensions, each containing 0.1 to 1000 mg of drug in a 5-ml dose, are prepared as follows.

Component Amount (mg / 5 ml) Compound of Formula (I) 0.001 - 200 Carboxymethylcellulose sodium 50 Syrup 1,25 Benzoic acid solution 0,10 ml Flavor as required Dye as required Purified water etc. 5 ml

The drug is passed through a 0.300 mm sieve and mixed with carboxymethylcellulose sodium and syrup to form a fine paste. Dilute the benzoic acid solution, flavor and color with a small amount of water and add with stirring. A sufficient amount of water is then added to obtain the desired volume.

ΦΦΦ ΦΦΦ Φ · · · · · · · · φ · φ φ φ φ φ φ φ φ

Means 5

Combination tablets

Component Quantity (mg / tablet) Compound of formula (AND) 0.001 - 1 Compound of formula (II) 59 - 59.999 Starch 45 Microcrystalline cellulose 35 Polyvinylpyrrolidone (as a 10% solution in water) 4 Sodium carboxymethylcellulose 4,5 Magnesium stearate 0.5 Talc 1 H

The active ingredients, starch and cellulose are passed through a sieve with a particle size of 0.300 mm and mixed thoroughly. The polyvinylpyrrolidone solution is mixed with the resulting powders and then passed through a 1.168 mm sieve. The granules so produced are dried at 50 to 60 ° C and passed through a sieve with a particle size of 0.912 mm.

Starch sodium glycolate, magnesium stearate and talc, previously passed through a sieve with a particle size of 0.246 mm, are then added to the granules which are mixed and then compressed on a tabletting machine to give tablets.

Means 6

Combination Tablets to * ·· · «

Component Amount (mg / tablet) Preferred compound of formula (I) 0,001 - 1 Raloxifene Hydrochloride 59 - 59 , 999 Starch 45 Microcrystalline cellulose 35 Polyvinylpyrrolidone (as a 10% solution in water) 4 Natriucarboxymethylcellulose 4,5 Magnesium stearate 0.5 Talc 1

0 0 0

0 0 *

0 0 0 0 · 0

000 ·· «* ·» · 00 »0 0 0

0 · · 0

The active ingredients, starch and cellulose are passed through a sieve with a particle size of 0.300 mm and mixed thoroughly. The polyvinylpyrrolidone solution is mixed with the resulting powders and then passed through a 1.168 mm sieve. The granules so produced are dried at 50 to 60 ° C and passed through a sieve with a particle size of 0.912 mm. Starch sodium glycolate, magnesium stearate and talc, previously passed through a sieve with a particle size of 0.246 mm, are then added to the granules which are mixed and then compressed on a tabletting machine to give tablets.

Claims (30)

PATENT CLAIMS Use of a compound of general formula (I) (I) in which R ¹ 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 substituted phenyl; or a solvate thereof for the manufacture of a pharmaceutical composition for inhibiting estrogen deprivation syndrome. Use according to claim 1, a compound of formula (I) or a solvate thereof for the manufacture of a pharmaceutical composition for inhibiting estrogenic deprivation syndrome in a female human. Use according to claim 2, of a compound of formula (I) or a solvate thereof for the manufacture of a pharmaceutical composition for inhibiting estrogen deprivation syndrome, which is osteoporosis. Use according to claim 2, of a compound of formula y * 9 «99 * 9? · 9 * 99 • 99 999 9 · · * * 999,999 9 9 9 9 99 (999) 999 (9) or a solvate thereof for the manufacture of a medicament for inhibiting the estrogen deprivation syndrome, which is hyperlipidemia. Use according to claim 2, of a compound of formula (I) wherein R ¹ and R ¹ are independently hydroxy or methoxy, or a solvate thereof for the manufacture of a medicament for inhibiting estrogen deprivation syndrome. Use according to claim 5, of a compound of formula (I) in which the groups R ¹ and R ¹ are both hydroxy groups, or a solvate thereof for the manufacture of a pharmaceutical composition for inhibiting the estrogen deprivation syndrome. Use according to claim 2, of a compound of formula (I) or a solvate thereof, for the manufacture of a medicament for inhibiting estrogenic deprivation syndrome in a female human, present in the peri- or post-menopausal period. Use according to claim 2, a compound of formula (I) or a solvate thereof for the manufacture of a pharmaceutical composition for inhibiting estrogen deprivation syndrome, wherein the compound of formula (I) is 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-methoxybenzo [b] thiophene; 2- (4-methoxyphenyl) -6-hydroxybenzo [b] thiophene; 2- (4-hydroxyphenyl) -6-methoxybenzo [b] thiophene; 2- (4-isopropoxyphenyl) -6-methoxybenzo [f] 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; • · · 4 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; or solvates thereof. 9. A pharmaceutical composition comprising a compound of formula (I) wherein: - (4) - (4) R ¹ 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 substituted phenyl or a solvate thereof; and pharmaceutical carriers, excipients or diluents. A composition according to claim 9, wherein the compound of 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; φφφφ φ • φ φ φφφ 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; and 2- (4-cyclopentoxyphenyl) -6-acetoxybenzo [b] thiophene; or solvates thereof. Use of a compound of formula (I) in which R ¹ 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 substituted phenyl or solvates thereof; and compounds of formula (II) 04 40 9 4 (II) in which R ² and R ³ are independently hydrogen, C 1 -C 6 alkyl, -CO (C 1 -C 6 alkyl) in the alkyl moiety, or -COAr; and R ⁴ is pyrrolidin-1-yl, piperidin-1-yl or hexamethylenimine-1-yl; wherein the nitrogen atom in the R ⁴ group is optionally an N-oxide group; or a pharmaceutical salt or solvate thereof, for the manufacture of a medicament for inhibiting estrogen deprivation syndrome. Use according to claim 11, a compound of formula (I) or solvates thereof and a compound of formula (II) or a pharmaceutical salt or solvates thereof for the manufacture of a pharmaceutical composition for inhibiting estrogenic deprivation syndrome in a female human. Use according to claim 12, a compound of formula (I) or solvates thereof and a compound of formula (II) or a pharmaceutical salt or solvates thereof for the manufacture of a medicament for inhibiting estrogen deprivation syndrome, which is osteoporosis. Use according to claim 12, a compound of formula (I) or solvates thereof and a compound of formula (II) or a pharmaceutical salt or solvates thereof for the manufacture of a medicament for inhibiting estrogenic deprivation syndrome, which is hyperlipidemia. Use according to claim 12, a compound of formula (I) or solvates thereof and a compound of formula (II) or a pharmaceutical salt or solvates thereof for the manufacture of a medicament for inhibiting estrogen deprivation syndrome, wherein the compound of formula (I) is a compound which R @ ¹ and R @ ¹ groups are each hydroxy or methoxy. Use according to claim 15, a compound of formula (I) or solvates thereof and a compound of formula (II) or a pharmaceutical salt or solvates thereof for the manufacture of a medicament for inhibiting estrogen deprivation syndrome, wherein the compound of formula (I) is a compound which R ¹ and R ¹ groups are both hydroxy. Use according to claim 16, a compound of formula (I) or solvates thereof and a compound of formula (II) or a pharmaceutical salt or solvates thereof for the manufacture of a medicament for inhibiting estrogen deprivation syndrome, wherein the compound of formula (II) is a hydrochloride salt. R ² and R ³ are both hydroxy and R ⁴ is piperidin-1-yl. Use according to claim 12, a compound of formula (I) or solvates thereof and a compound of formula ΗΓ - X - (II) or a pharmaceutical salt or solvate thereof for the manufacture of a pharmaceutical composition for inhibiting estrogen deprivation syndrome in a female human being in menopause. Use according to claim 12, a compound of formula (I) or solvates thereof and a compound of formula (II) or a pharmaceutical salt or solvates thereof for the manufacture of a medicament for inhibiting estrogenic deprivation syndrome in a female human, wherein the compound of 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-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; • 49 4 2- (4-hydroxyphenyl) -6-cyclopentoxybenzo [b] thiophenes; 2- (4-cyclopentoxyphenyl) -6-cyclopentoxybenzo [b] thiophenes; 2- (4-butoyloxyphenyl) -6-hydroxybenzo [b] thiophenes; and 2- (4-cyclopentoxyphenyl) -6-acetoxybenzo [b] thiophene; or solvates thereof. Use according to claim 11, a compound of formula (I) or solvates thereof and a compound of formula (II) or a pharmaceutical salt or solvates thereof for the manufacture of a medicament for inhibiting estrogen deprivation syndrome, wherein said compound of formula (I) is 2- (4-hydroxyphenyl) -6-hydroxybenzo [b] thiophene, said compound of formula (II) being raloxifene hydrochloride and the pathological condition of said estrogen deprivation syndrome is osteoporosis. 21. A pharmaceutical composition comprising a compound of formula (I) wherein: R ¹ and R ¹ are independently hydrogen, hydroxy, (C 1 -C 6) alkoxy, -OCH ₂ Ar, -OCO (alkyl) of 1 to 6 carbon atoms in the alkyl moiety, a group of formula -OCOAr; and Ar is phenyl or substituted phenyl; or a solvate thereof; (II) in which R ² and R ³ are independently hydrogen, C 1 -C 6 alkyl, -CO (C 1 -C 6 alkyl) in the alkyl moiety, or -COAr; and R ⁴ is pyrrolidin-1-yl, piperidin-1-yl or hexamethylenimine-1-yl; wherein the nitrogen atom in the R ⁴ group is optionally an N-oxide group; or a pharmaceutical salt or solvate thereof; and pharmaceutical carriers, excipients or diluents. A composition according to claim 21 comprising 0.001 to 60 mg of a compound of formula (I) wherein R ¹ and R ¹ are independently hydroxy or methoxy, or a solvate thereof, and 1 to 120 mg of a compound of formula (II), which is • 000 - sr 0 0 000 000 ·· 0 0 9 00 0 0 0 0 0 0 0 0 0 99 * 9099 • 0 090 999 99 09 09 raloxifene hydrochloride. 23. A composition according to claim 22 wherein said compound of formula (I) is 2- (4-hydroxyphenyl) -6-hydroxybenzo [b] thiophene or a solvate thereof. 24. A composition according to claim 23 comprising 0.001 to 1 mg of a compound of formula (I) or solvates thereof and 59 to 59.999 mg of raloxifene hydrochloride. A composition according to claim 24 comprising 0.001 to 0.1 mg of a compound of formula (I) or solvates thereof and 59.1 to 59.999 mg of raloxifene hydrochloride. A composition according to claim 21, wherein the compound of 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; 4 ··· 4 4 44 4 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) -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; Sri 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; - (4-butoyloxyphenyl) -6-hydroxybenzo [b] thiophene; and 2- (4-cyclopentoxyphenyl) -6-acetoxybenzo [b] thiophene; or solvates thereof. A kit comprising packaging material and a pharmaceutical composition contained in the packaging material, wherein the packaging material comprises a label indicating the possibility of administering the pharmaceutical composition to inhibit the pathological state of the estrogen deprivation syndrome, wherein the pharmaceutical composition comprises a compound of formula (Ia) in which R ⁵ and R ⁶ are independently hydroxy or methoxy; or a solvate thereof; - -5Ό ·· ·· »> · · < 4 and a compound of formula HCl or a solvate thereof. A kit according to claim 27 comprising 0.001 to 1 mg of a compound of formula (Ia) or solvates thereof and 59 to 59.999 mg of a compound of formula • HCl or solvates thereof. Kit according to claim 28, characterized in that the compound of formula (Ia) is 2- (4-hydroxyphenyl) -6-hydroxybenzo [b] thiophene or a solvate thereof. 30. The kit of claim 28, wherein said pathological condition is osteoporosis.