UA73085C2 - Crystalline hydrate of 6-hydroxy-3-(4-[2-(piperidin-1-yl)ethoxy]-phenoxy)-2-(4-methoxyphenyl)benzo[b]thiophene hydrochloride and method for obtaining thereof, active ingredient and pharmaceutical composition - Google Patents

Abstract

The present invention is directed to a novel crystalline hydrate of 6-hydroxy-3-(4-[2-(piperidin-1-yl)ethoxy]-phenoxy)-2-(4-methoxyphenyl)benzo[b]thiophene hydrochloride and uses for same, including inhibition of disease states associated with estrogen deprivation including cardiovascular disease, hyperlipidemia, and osteoporosis; and inhibition of other pathological conditions such as endometriosis, uterine fibrosis, estrogen-dependent cancer (including breast and uterine cancer), prostate cancer, benign prostatic hyperplasia, CNS disorders including Alzheimer's disease, prevention of breast cancer, and up-regulating ChAT.

Description

Description of the invention

For the first time, the description of b-hydroxy-3-(4-(2-(piperidin-1-ylethoxy|phenoxy)-2-(4-methoxyphenyl)benzoi|BIthiophene 2 hydrochloride (arzoxyphene)) as a typical representative of compounds of this kind was given in | US patents

Mo5,510,357, and disclosed, in particular, in US patent Mo5,723,474 (474) and European patent application

Mo0729956)|. Arzoxifene is a non-steroidal mixed estrogen antagonist/agonist suitable, ipieg, for lowering serum cholesterol levels and for inhibiting hyperlipidemia, osteoporosis, estrogen-dependent cancers, including breast and uterine cancers, endometritis, disorders of the central nervous system, in including Alzheimer's disease, aortic smooth muscle cell proliferation and restenosis.

In particular, arzoxifene is suitable (and currently undergoing clinical trials) for the treatment of receptor-positive metastatic breast cancer; adjuvant treatment of receptor-positive patients after appropriate systemic or local treatment; reduction of recurrences of invasive and non-invasive breast cancer; and reducing the number of cases of invasive breast cancer and cancer of the 12th duct of the mammary glands of the ip of the upper extremity (OSIB). Arzoxifen is also suitable for use in combination with radiotherapy, aromatase inhibitors, analogues of luteinizing hormone-releasing factor and acetylcholinesterase inhibitors (ACEI).

The results of later analysis of free-flowing arzoxifene, which was isolated by the procedures described in (474), by powder X-ray diffraction (XRD), thermogravimetric analysis (THA), nuclear magnetic resonance (NMR), and Karl analysis Fisher (Kap Rizspeg) (Fisher analysis) (KE) showed that the mentioned material was hydrated, weakly crystalline, and its lattice included variable amounts of volatile organic matter (ethyl acetate).

Low-crystalline materials are generally less desirable than highly crystalline materials for the preparation of dosage forms. In addition to this, pharmaceutical drugs containing significant amounts of an organic solvent (for example, ethyl acetate) are undesirable in the composition c 29, due to the possible toxicity of the solvent to the recipient of the said pharmaceutical drug and changes in the amount of the active substance in the composition of the said pharmaceutical drug in depending on the amount of the mentioned solvent.

Although arzoxifene obtained by the procedures described in (474) can be used as a pharmaceutical drug, it would be highly desirable and preferable to find a more crystalline form of arzoxifen whose crystal lattice would not accommodate an organic solvent such as can be reproducibly and efficiently obtained on an industrial scale.

This invention relates to a new non-stoichiometric hydrated crystalline form of β-hydroxy-3-(4-(2-(piperidin-1-ylethoxy|phenoxy)-2-(4-methoxyphenyl)benzoic|bithiophene hydrochloride (B-PU, o the X-ray pattern of which includes the following peaks: 4.6 0.29, 7.8-4-0.22, 9.3--0.292, 14.0-0.29, 17.6--0.29, 20 ,8-4-0.29 and 24.3--0.22 at 26; in the case of obtaining at a temperature of 25-29 and a relative humidity (RH) of 35-1095 from a copper radiation source.

Moreover, this invention relates to a pharmaceutical drug that includes P-III; one or more pharmaceutical carriers, diluents or fillers; and optionally estrogen, optionally a progestin, optionally an aromatase inhibitor, optionally an analog |NKN, and optionally an acetylcholinesterase inhibitor (ACEI). c In addition to this, this invention is related to the methods of using P-II for the suppression of "c" pathological conditions, namely: uterine fibrosis, endometritis, proliferation of smooth muscle cells of the aorta, restenosis, breast cancer, uterine cancer, cancer of the prostate gland, benign prostatic hyperplasia, thinning of bone tissue, osteoporosis, diseases of the cardiovascular system, hyperlipidemia, disorders of the central nervous system and Alzheimer's disease, and to the use of P-III for the manufacture of medicine for the suppression of the above-mentioned conditions. o This invention additionally relates to methods of using P-P for activation of choline acetyltransferase o (SPAT) and to the use of P-III for the manufacture of a medicament for activation of choline acetyltransferase.

Fig. 1 - representative curves of self-writing, which were obtained during analysis by the 5th method of differential scanning calorimetry (05C) and thermogravimetric analysis (TA). "n Fig. 2 - representative curves of self-writing, which were obtained during the analysis of E-I by the OZS/TOA method.

Fig. 3 - representative self-writing curves, which were obtained during the E-P analysis by the OBS/TOA method.

Figure 4 shows moisture sorption isotherms for P-I and P-IP.

Figure 5 shows the desolvation of 5-HER as a function of drying time and temperature.

Characteristics of free-flowing arzoxifene, which was obtained according to the procedures described in (474) (F) (Example 411, crystallization from a mixture of ethanol and ethyl acetate, filtration and drying of the filter cake ip

GI mass to constant mass at room temperature) was determined using X-ray powder (XR).

It was established that free-flowing arzoxifene is weakly crystalline. The data of the nuclear magnetic resonance (NMR) analysis confirmed that 695 ethyl acetate was included in the composition of the mentioned loose material.

The aforementioned crystallization procedure, described in (474), was further modified in such a way that ethanol was added to a suspension of crude arzoxifene in ethyl acetate, which was heated in a reflux flask at the distillation temperature. The solid obtained after cooling and vacuum filtration using the modified procedure mentioned is 65 Highly crystalline mixed ethyl acetate/aqueous solvate of arzoxifene (hereafter referred to as 5-III), which was later determined to be the starting material for obtaining P-II (another non-stoichiometric hydrated crystalline form of arzoxifene).

B-- can be obtained by removing ethyl acetate from the crystal lattice of 5-III by drying under vacuum/baking 5-III at elevated temperatures. Duration and temperature required for baking

The C-P to B-I will vary from batch to batch, but are typically about 5 days and about 1002. High temperatures are necessary to effect the conversion of 5-HI to

BE--- using the mentioned procedure, since suspending 5-II in water at ambient temperature or storing the sample at a relative humidity of 9895 for 3 weeks does not ensure conversion to Р-II. In addition to this, drying 5-II in a convection dryer at high temperatures also does not 7/0 lead to desolvation of the mentioned material. This allows us to make an assumption that a vacuum is also necessary to remove ethyl acetate from the 5-III lattice. In a preferred embodiment, E-I is readily prepared and isolated at ambient temperature by crystallization of arzoxifene (or any other polymorphic modification/solvate thereof) from tetrahydrofuran.

According to this invention, a particularly preferred form of arzoxifene is P-IS. P-IIIs are easily obtained and released 7/5 at ambient temperature. Only moderate drying conditions are necessary to remove low levels of residual crystallization solvent from the E-IS preparation. The mentioned moderate drying conditions ensure the continuous production of a solid of high purity (eg, free from residual organic solvent) and crystallinity, and thus the use of B-PI eliminates toxicological problems associated with residual amounts of organic solvent and with organic solvent that is part of the crystal lattice. In addition to this, the production of P-II is simple and efficient, that is, suitable for mass production.

E-III is easily prepared and released at ambient temperature by crystallization of arzoxifene (or any other polymorphic modification/solvate thereof) from a mixture of isopropyl alcohol (IPA) and water. In a typical case, arzoxifene can be suspended in a mixture of isopropyl alcohol and water and heated to ensure dissolution of the starting material. After dissolution is complete, the resulting solution is kept with slow cooling to room temperature, followed by additional cooling (using an ice bath or a refrigerator) to a temperature in the range from 0 to 5 C. After keeping for a period of time that is sufficient for crystallization to occur, the obtained the crystals can be filtered off under vacuum and dried to constant mass and mass to give B-P in yields exceeding 80905.

Suitable starting material for the aforementioned crystallization includes (but is not limited to) 5-II, E-I, arzoxifene, which has been prepared by the procedures described in (474), or any mixture thereof . The starting form of arzoxifene does not matter, since the result of crystallization from isopropyl alcohol and water according to the procedures described is to obtain crystals of

E-IS. The ratio of water to isopropyl alcohol (by volume) is usually from about 1:1 to 9:1. In a more preferred embodiment, said ratio is from 2.5:1 to 5.6:1. In the most preferred embodiment, said ratio is from 3:11 to 5.6:1. After vacuum filtration of the crystals, the wet B-III filter cake can be washed with cold, deionized water before drying by mass. In addition, slightly elevated drying temperatures (approximately 50 C for 12-24 hours) are preferred. For the synthesis of B-P on an industrial scale, for the crystallization of P-III to the solution, the preferred option is to introduce a seed. a According to the preferred method, RB-IS is obtained, isolated and purified simultaneously with the chemical removal of "" b-isopropylhydroxyl protecting group from b-isopropoxy-3-(4-(2-(piperidin-1-yl)ethoxy|phenoxy)-2- (4-Methoxyphenyl)benzo|p|thiophene hydrochloride (precursor A). The progress of said deprotection reaction is monitored for complete removal of said isopropyl protecting group. After determining that said removal is substantially complete, further process according to the preferred an option would be to include crystallization under conditions that would ensure the yield

E-Sh, as discussed before and will be discussed further. Methods for preparing precursor A and (av) removing said isopropyl group can be found in (US Patent No. 5,723,474), which is incorporated herein by reference in its entirety.

According to another preferred method, P-I is obtained, isolated and purified simultaneously with the chemical reduction of sl Z-oxide and the chemical removal of the benzyl protecting group from b-hydroxyl in b-benzyloxy-3-(4-(2-(piperidin-1-yl) ethoxy|phenoxy)-2-(4-methoxyphenyl)benzo||hyophene-(5-oxide). (precursor

IN). Said reduction and deprotection reactions are monitored to determine complete reduction of the sulfoxide to sulfide and complete removal of said benzyl hydroxyl protecting group. After determining that said reduction/removal has been substantially completed, the further process will preferably include crystallization under conditions that provide P-III as discussed herein. Methods for preparing precursor B, removing said benzyl group, and reducing the 1-sulfoxide to the corresponding sulfide can also be found in (US Pat. No. 5,723,474), which is hereby incorporated herein by reference.

Regardless of the chemical methods used in the deprotection and reduction steps, the crystallization of arzoxifene from the isopropyl alcohol/water solutions disclosed herein consistently provides high purity PE-I crystals.

To determine the characteristics of 5-II, B-I and B-Sh, the OBS/TOA and HKO methods were used. TOA often 65 proves to be very suitable for differentiating various solid forms of a material, since the temperature(s) at which the material physically changes is usually characteristic of the polymorphic modification or solvate. OS is a method that is often used to select compounds for the formation of polymorphic modifications and solvation. And, finally, XKO is a method by which the long-range order of the structure of a crystalline material is determined.

X-ray patterns of arzoxifene, which was obtained by the procedures described in (474), had poor signal-to-noise ratios and a raised baseline, indicating a weakly crystalline material.

Consequently, P-I and E-P are compared with the aforementioned material (5-II), which was obtained by a modified procedure for the crystallization of arzoxifene discussed before (adding ethanol to a suspension of arzoxifen in ethyl acetate heated in a reflux flask at distillation temperature). 70 Representative curves of self-writing, which were obtained during the analysis of Z-Y, B-I and B-S by the method of differential scanning calorimetry (05C) and thermogravimetric analysis (TOA), are presented in Fig. 1, 2 and 3, respectively. A representative autograph curve, which was obtained during the analysis of 5-II by the O5C method, is a broad endotherm, the beginning of which occurs at a temperature of approximately 62 C, which corresponds to the removal of ethyl acetate and water from the lattice. The endotherm, which begins at a temperature of approximately 1522C, 75 represents the melt. The mass loss, which according to the TOA is about 2.595, occurs simultaneously with the first transition, while a further 0.595 mass loss occurs before melting begins. This allows us to make an assumption that some solvent molecules are held in the lattice a little more firmly.

A representative autograph curve obtained from E-I analysis by the O5C method is a broad endotherm beginning at about 752C, followed by a second endotherm starting at about 155C, corresponding to the melt. A representative autograph curve obtained during B-I analysis by the TA method shows a gradual 0.390 mass loss followed by a sharp 1.595 loss, which, taken together, represent lattice dehydration. The beginning of the first transition, according to the results of О5С, and the corresponding mass loss, according to the results of TOA, are slightly shifted due to the difference in the heating rate. The initial mass loss represents weakly bound hydrated waters, while the second mass loss corresponds to approximately 0.5 moles of water present in the lattice at very low levels (5) of relative humidity (below 595 - see moisture sorption data).

A representative autograph curve obtained during EP analysis by the OS method is a broad low-temperature endotherm (approximately 302C) that begins at a temperature of approximately 70°C, and with a final transition that occurs at a temperature of approximately 1462C, corresponding to the melt. M

The sharp 1.595 mass loss (about 0.5 mol) according to TOSA, which coincides with the first endotherm, corresponds to the loss of loosely bound water molecules, while the additional about 1.695 mass loss above 602C represents the loss of more closely related bound water molecules, for example, water molecules present at very low levels of relative humidity. The mass loss observed after 1702C corresponds to the B-P schedule. with

X-ray diffraction patterns P-Y and E-III are characterized by sharp peaks and a flat output line, which indicates 3o highly crystalline materials. The angular positions of the peaks at 29 and the corresponding IL data for representative samples in

E-Y, E-II and 5-II are listed in Table 1. Despite the fact that the numerous intense reflections have, as a rule, similar diffraction angles, each of the mentioned forms gives different Debyegrams, which provides the possibility of a clear separation of 5-1, R-I and R-IPI. "

It is well known in crystallography that for any given polymorphic modification, the relative intensities of the C 50 diffraction peaks may differ due to the preferred orientation resulting from factors such as crystal morphology. In the presence of the effects of the predominant orientation, the intensity of the peaks

From" change, however, the characteristic positions of the peaks of the mentioned polymorphic modification remain unchanged.

See, for example, |US Pharmacopoeia Mo 23, Book of Prescription Formulas Mo 18, pages 1843-1844, 1995). Thus, based on the intensity, as well as the position of the peaks, P-III can be identified by the presence of peaks at 4.6-0.29, 7.8--0.22, 9.3--0.22, 14, 0--0.29, 17.6--0.22, 20.8--0.29 and 24.3--0.22 at 26; in the case of obtaining an X-ray at a temperature of 25-22C and a relative humidity of 35-4-1095 from a copper radiation source. (95) o sa 2 sl 53 6 tv za tyav 00 o yu vv vv vl vl 23 Bob) 59 v vv 15.52) 10.5 20.85) 8.8 18.09) 43.9 vav zd ty zvrola | with. 2025 ve 2620 ZA ov 132 o goth) in we? 2e Bo? in the hall at 000000ovet ve and zt tv | 010 tov vv. for zd00000 tya zao| 1361 vehicles for 000000 sales 4. yav ve zvya| 55 vok vl from the outside vv ztae| 2810000 dk tv zvlo la 000000 vav av zviz| 39 0000 pressed in cm 5 garden! for 111 o'clock 11 call 111111

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Additional determination of R-I and R-III characteristics 35 A study was conducted to determine the hygroscopicity of R-I and R-III. Moisture sorption isotherms for -

E-I and E-IPSH are presented in Fig. 4. After initial exposure of the samples to 590 RH, an immediate 1.595 and 1.795 increase in moisture content was recorded for B- and B-III, respectively, corresponding to approximately 0.5 mol of water. Both forms showed continuous sorption of moisture within the entire range of humidity, which is probably due to the inclusion of water molecules in the lattices. 40 The difference in moisture absorption of the two forms probably reflects the amount of water that can be included in the Cs of the two mentioned lattices (ie, the amount of available space in the said lattice in which c" water molecules can be accommodated). The absence of hysteresis in the B-I and E-PSh sorption-desorption isotherms indicates that the mentioned crystalline forms quickly equilibrate at any given level of humidity.

The aforementioned moisture sorption profiles for RB-I and P-III demonstrate that these forms are essentially non-stoichiometric 45 hydrates. At the relative humidity of the surrounding medium (approximately 5095 relative humidity), E-I accommodates approximately 1.795 of water, which corresponds to 0.5 mol of water, while B-I sorbs approximately 3.095 of water, which d) corresponds to approximately 0.85 mol water The mentioned bulk forms of P-I and E-I quickly equilibrate with the atmosphere, due to which the water content, which is determined using analytical methods, is a reflection of the relative humidity at the time of data collection. There may be batch-to-batch differences observed in data obtained by OS methods

Ho) 20 as a result of different degrees of hydration of the mentioned samples as a result of storage under different environmental conditions. sl The radiographs of samples E-I and P-ISH were obtained, which were stored at different levels of relative humidity (О95, 2295, 5095 and 8095). As the relative humidity increases, there is a gradual shift of the initial (RH 0905) E-W peaks to about 13.82, 17.62, 18.02, 20.52, and 24.02 at 26, and a slight shift

Fewer intense peaks. The changes that were observed in the X-rays of B-ISHA indicate that the dimensions

GF) of the unit cells are changed, possibly to accommodate weakly bound water molecules as the relative humidity increases. The mentioned continuous shift of the peaks depending on the humidity level correlates well with the moisture sorption data, which show a gradual increase in mass in this range of relative humidity, which is an indication of the variable formation of hydrates. for A similar experiment was carried out with E-I to determine whether a change in relative humidity produced the same effect on its lattice (095, 2595, 5295, 7395 and 9595 relative humidity). As the RH increases, there is a very slight shift of the 095 RH peaks to about 7.72, 18.32, 18.59, 20.59, 20.82 at 29. The peaks at about 7.72, 20.82, and 24.12 also appear to broaden slightly and become less distinct at higher RH levels, suggesting that water is sorbed by the amorphous 65 components (or plasticizes the solid), particularly at 7395 and 9595 RH. The shift of peaks on the radiographs of RG-I is much smaller than the shift of peaks that was observed in case of underestimation of R-II at different levels of relative humidity. This suggests that the E-I lattice does not undergo the same expansion and/or compression as the B-PI lattice.

It was established that B-I and B-P maintain stability in the entire range of relative humidity, despite the ability of E-PI to absorb almost twice as much water. The two mentioned forms were found to have comparable crystal size, morphology, water solubility and dissolution rate.

A study with drying was carried out in order to control the desolvation of 5-III depending on the duration and temperature of drying (see Fig. 5). Radiographs were taken at various control time points 7/o during desolvation experiments. Many diffraction peaks in the study of desolvation

Z-Y appear at angles similar to B-I, which indicates that the 5-II and B-I lattices are very similar.

The disappearance of the diffraction peaks at about 6.89, 7.22 and 14.02 at 20 after minimal drying suggests that these reflections can be explained by crystallographic planes that accommodate the partial electron concentration of ethyl acetate molecules.

The result of prolonged baking of the mentioned solvated material under vacuum at high temperatures is the production of B-I. Form B-I, which was obtained in the mentioned way, shows a high level of crystallinity, according to powder radiography. Thus, the material that was obtained by crystallization from a solution of ethanol and ethyl acetate followed by drying under vacuum for only a few hours, as described in (474), showed a very low level of crystallinity, since the result of such a procedure is the production of partially desolvated forms 5-1.

E-I and BR-III have several advantages over the known form of arzoxifene, the description of which was given earlier.

Regarding arzoxifene, which was obtained by the procedures described in G474|, B-! and

E-Sh are more stable at ambient temperature and, thus, more suitable for pharmaceutical use, for example, for obtaining a dosed medicinal product. In addition to this, the level of crystallinity of E-I and E-PI is much higher than the level of crystallinity of the form that was revealed in

G4741. Crystalline materials are generally less hygroscopic and more stable (i.e., less prone to chemical degradation, they retain constant activity) than amorphous materials, making them more desirable for use in drug discovery. In addition, unlike the mentioned form of arzoxifene, which was obtained by the procedures described in (474), whose lattice accommodates both ethyl acetate and water, P-I and P-II accommodate only water.

Measurements by the YZS method were carried out with the help of a modular differential scanning calorimeter system 2920 of the TA Ipzigitep company in combination with a thermal analyzer Tpepta! Apaiusi 3100, which was equipped with a cooling system with a refrigeration unit. Samples (3-5 mg) were heated in corrugated aluminum trays from 102 to 2402 at a heating rate of 22C/min. and,

Thermogravimetric analyzes were carried out using a thermogravimetric analyzer 2050 of the TA company

Ipvigitepov in combination with the thermal analyzer Tpegta! Apaiuzi 3100. Samples (5-10 mg) were heated on open pallets from 2523 to 2502 with a heating rate of 52C/min.

X-ray patterns were obtained with the X-ray diffractometer 05000 of the Zietepv company, equipped with a SiCo source (X-1.540567) and a solid-state detector of the Kemech company, which operates at 50 kV 40 . , - s and 40mMmA. Each sample was scanned between 492 and 3592 at 26. The samples were allowed to equilibrate for a minimum of 30 minutes at the required temperature and/or relative humidity prior to data collection.

Measurements of hygroscopicity of B-I and B-S were carried out according to the MT method! (viscosity-temperature index) as follows. Each sample was dried under vacuum at a temperature of 602C until the loss of -I mass stopped completely. The relative humidity in the chamber with the samples at this time was brought to 090. Moisture sorption isotherms were obtained at a temperature of 259C using vacuum balances with a scale graduated in percent humidity under the following conditions: sample size 10-15 mg, adsorption/desorption range - 0 -9595 relative av! humidity, 59o staggered interval, 10-minute time interval between sampling.

The following examples further illustrate methods of obtaining said hydrate according to the present invention. for the Examples mentioned are not intended to limit the scope of the mentioned methods in any way and should not be considered as such.

Example 1

E-Sh from 6-isopropoxy-3-(4-(2-(piperidin-1-yl)ethoxy|phenoxy)-2-(4-methoxyphenyl)benzo|Bigiophene hydrochloride

To a solution of b-isopropoxy-3-(4-(2-(piperidin-1-yl)ethoxy|phenoxy)-2-(4-methoxyphenyl)benzoyl|bithiophene hydrochloride (10 g, 18 mmol) in methylene chloride (10 Oml) in the atmosphere of nitrogen at a temperature from -109C to -2026 o, BSyz(y) (4.23g, 34 mmol) was added at a rate that made it possible to maintain the temperature of the mentioned reaction mixture below -102C. After completion of the addition, the resulting reaction mixture was additionally stirred for 2 hours. Isopropyl alcohol (IPA, 12.35 mL, 167 mmol) was slowly added to the reaction mixture at 60 °C below -102 °C and stirred for 30 minutes. 100 mL of water was poured into a separate flask and cooled with an ice bath to a temperature of approximately 02 °C. the product solution was transferred to water using a cannula with vigorous stirring. The resulting white suspension was stirred at 02C for 1 hour. The resulting product was filtered and rinsed first with 25 ml of 4095 mixture of СНоSiO/water, then with 25 ml of x cold water The obtained product was suspended in bOml of isopropyl alcohol and bOml of water and heated to a temperature of 602C. The solution was obtained at temperature

4820. Water (120 ml) was added additionally. The resulting solution was kept with cooling to a temperature of 352C; the obtained suspension was additionally slowly cooled to a temperature of 0-59 and stirred for several hours. The obtained product was filtered and washed with cold deionized water (25 ml).

Wet filter sediment of RB-III was dried to a constant weight and mass at a temperature of 509 for 12-24 hours to obtain Р-ІІІ. The X-ray pattern obtained at a temperature of 25--22C and a relative humidity of 35--1090 from a copper radiation source includes the following peaks: 4.6--0.22, 7.8--0.29, 9.3--0, 29, 14.0--0.22, 17.6--0.22, 20.8--0.2 and 24.3-4-0.22 at 26.

Example 2

E-Sh with 6-benzyloxy-3-(4-(2-(piperidin-1-yl)ethoxy|phenoxy)-2-(4-methoxyphenyl)benzo|bithiophene-(5-oxide)

Deionized water (5.25 ml), 1 M NOI (7.74 ml, 7.75 mmol), 1095 Ra/cС (type

AZ2110, 1.97 g, 1.29 mmol Ra),

I(b-benzyloxy-3-(4-(2-(piperidin-1-yl)ethoxy|phenoxy)-2-(4-methoxyphenyl)benzo|bithiophene-(5-oxide) (3g, 5.16 mmol) and isopropyl alcohol (32 mL) at ambient temperature.The flask was placed on a 75 Parr vibrator, successively evacuated and purged twice with nitrogen, then evacuated again and filled with hydrogen gas under an overpressure of 30 psig (2.109 kg/cm 7 ). The vibrator was started and the resulting reaction mixture was heated to a temperature of 602C. After approximately 4 hours, the completion of the reaction was determined by means of high-performance liquid chromatography. The resulting reaction mixture was filtered through a layer of diatomaceous earth and the mentioned layer was washed with 0.1M HC (2x10ml). The mentioned solvent was removed by i.p. at a temperature of approximately 502 C. The resulting residue was dissolved in 5095 isopropyl alcohol/deionized water (0 mL) mixture and gently heated on a steam bath until a solution was obtained.

Deionized water (22 ml) was added to the obtained solution and the solution was allowed to cool to ambient temperature. The product suspension was subjected to additional cooling to a temperature of 02C. The obtained product was filtered, washed with cold deionized water (2 x 15 ml) and dried in hot air at a temperature of 502C to a constant mass to obtain R-PI. (at)

Example C

E-Sh with (b-isopropoxy-3-(4-(2-(piperidin-1-yl)ethoxy)phenoxy1|-2-(4-methoxyphenyl)|Senzoi|bithiophene-(5-oxide)

Methylene chloride (1o5l) and an egg

1b-Isopropoxy-3-I4-(2-(piperidin-1-yl)ethoxy)phenoxy|-2-(4-methoxyphenyl)|benzo|BIgiophene-(5Z-oxide) (10.5 kg) is mixed and cooled to temperature from -159С to -202С. Boron trichloride (4.6 kg) is added, maintaining the -С9 reaction temperature in the range from -109С7 to -202С. Stirring is continued until the percentage content of the starting material, according to high-performance liquid chromatography, does not become less than 1905.

High performance liquid chromatography system (column 7° ZV-RNepui, internal diameter o 4.bmmx25cm, 302C, 70:30 methanol:0.01M sulfuric acid; flow 1.5ml/min; ZOOnm detector). Add isopropanol h- (10.2 vkg) while maintaining the reaction temperature in the range from -109С to -202С. The resulting reaction mixture is stirred for 30-45 minutes. The resulting crude reaction product is isolated by adding the mentioned reaction mixture to an additional 105 liters of water, which has previously been cooled to a temperature of 2-72C, while maintaining the reaction temperature in the range from 22C to 72C. After completion of the mentioned addition, the resulting reaction mixture is rinsed with methylene chloride (20 l), which was previously cooled to a temperature of 72°C to 29°C. The resulting crystalline suspension is stirred for 2-3 hours and filtered, after which it is washed with methylene chloride (26 bkg), which has been pre-cooled to a temperature in the range of 72°C to 22°C, and water (53C) which has been pre-cooled to a temperature in the range of 72°C to 220. The resulting crude wet residue is mixed with water (42L) and isopropanol (40L) and heated to a temperature of 85-709C for dissolution. The resulting hot solution is filtered. After the filtration is completed, it is rinsed first with a mixture of isopropanol (20 l) and water (21 l), which was heated to a temperature of 65-70 °C, (95) and then with water (12 °C), which was previously heated to a temperature ranging from 652C to 7020. The obtained the solution o is cooled to a temperature from 402 to 4592, the seed is introduced and stirred at the mentioned temperature of 5 o For 2-3 hours to ensure the growth of crystals. The mentioned suspension is cooled to a temperature of 0-50°C, stirred for 3-4 hours and filtered. The resulting filter sediment is washed with water (122.6 l), which was previously cooled to a temperature of 2-7 °C. The resulting product is dried under vacuum at a maximum temperature of 5092C until the change in the mass of the sediment is less than 0.05 kg within 2-4 - hour period. Output: 8,468 kg (87,390). Content of the active substance according to the data of high-efficiency liquid

Chromatography: 98,590.

Water content according to Fisher analysis: 3.095. Total content of related substances according to data on high-performance liquid chromatography: 1.790. Example 4

E-Sh with (b-benzyloxy-3-(4-(2-(piperidin-1-yl)ethoxy)phenoxy1|-2-(4-methoxyphenyl)|Cbenzo|bithiophene-(5-oxide) 60 Tetrahydrofuran (261 ml ), water (45 ml), concentrated sulfuric acid (6.14 g) and

I(b-benzyloxy-3-I4-(2-(piperidin-1-yl)ethoxy)phenoxy|-2-(4-methoxyphenyl)|benzo|BIgiophene-(5-oxide) (content of the active substance according to the data of high-efficiency liquid chromatography 9995, total content of congeners according to high-performance liquid chromatography 0.3595) were mixed and stirred until a homogeneous mixture was obtained. 1095 Pa/cC (5.6 g suspended in 22 ml of water) was added and rinsed with 65 ml of water. From the flask, containing the resulting suspension, was evacuated and filled with hydrogen at a pressure of bOlbs/in? (4.219 kg/cm7). The reaction temperature was adjusted to 302. After 2 hours,

1095 Ra/C (5.6g) with water (ZOml). Hydrogenation under bOpsi pressure? (4.219 kg/cm7) and at a temperature of 302C was additionally continued for 22 hours. Additionally, 4.40g of 1095 Ra/C was added to ZOml of water and hydrogenation under a pressure of bOlbs/inch (4.219kg/cm7) and at a temperature of 3093 was further continued for 2.5 hours.

The mentioned catalyst was filtered and the pH of the obtained filtrate was brought to the level of 7.24 with the help of 5095 sodium hydroxide. A solution of sodium chloride (8.66 mg) in water (18 ml) was added and the resulting biphasic solution was stirred for 30 minutes. The obtained phases were separated and the obtained aqueous phase was subjected to reverse extraction with BbOml of tetrahydrofuran. The obtained organic phases were mixed and concentrated by distillation under atmospheric pressure to a volume of 5 Oml. Methanol (180 ml for 1 hour) was added to the obtained concentrate at a temperature of 242C 70. The resulting crystalline suspension was stirred for 30 minutes at a temperature of 242C, cooled to 09 and stirred for 1 hour. The obtained solids were filtered and washed successively with 30 ml of water and 30 ml of methanol, after which they were dried under vacuum overnight at a temperature of 5020. Yield 15.52 g (67.8965).

Isopropanol (ZZml), water (bbml) and 10g of the solid substance that was obtained before were mixed. 1.8M NCI (21ml) is added to the resulting stirred mixture at a temperature of 2590°C. The mentioned solids are quickly dissolved, followed by re-precipitation with the help of hydrogen chloride salt. After stirring for 30 minutes, the resulting suspension is heated to a temperature of 702C to ensure the dissolution of all solids. The resulting solution was cooled to a temperature of 6092C and 3 ml

WATER The resulting solution was cooled to a temperature of 2523 for 3 hours, during the mentioned time period, hydrogen chloride salt precipitated. The obtained suspension was stirred for about 3 hours at a temperature of 259C, filtered, washed with water (30 ml) and dried under vacuum overnight at a temperature of 5090 to obtain 8.9 g (82.7905) of B-IP. The content of the active substance according to the data of high-performance liquid chromatography: 96,595. Water content according to Fisher analysis: 2.4495. The content of related substances according to the data of high-performance liquid chromatography: 1.0995.

As used in this specification, the term "effective amount" is referred to? means the amount of B-IS, which is capable of suppressing the conditions or their harmful consequences, the description of which is given. In the case of administration of P-III together with estrogen, progestin, aromatase inhibitor, HNKN analogue or ACRE inhibitor, the mentioned term "effective amount" also means the amount of such agent capable of carrying out its intended effect. oh

The mentioned terms "suppressing/inhibiting" and "suppressing/inhibiting" include their commonly accepted meaning, i.e. preventing, preventing, restraining, ameliorating, ameliorating, slowing down, terminating or reversing the development or severity of the pathological condition or its consequences described .

The mentioned terms "prevent", "prevention", "prophylaxis", "prophylactic" and "prevents" are used and.

In this description, they are used interchangeably and are related to reducing the probability that the recipient of P-III will be exposed to the danger of the occurrence or development of any of the mentioned pathological conditions or their consequences, the description of which is given.

The terms "deprived of estrogen" and "deprivation of estrogen" refer to a condition, natural or clinically induced, in which a woman is unable to produce sufficient endogenous estrogen hormones to support estrogen-dependent functions, such as menstruation, homeostasis of bone mass, , the functioning of neurons, the state of the cardiovascular system, etc. Such situations of estrogen deprivation occur as a result of (but are not limited to) menopause and surgical or chemical ovariectomy, including its functional equivalent, for example, treatment with an aromatase inhibitor, agonists or antagonists of SpKN, ISI182780, etc. Disease states associated with estrogen deprivation include, but are not limited to, bone thinning, osteoporosis, cardiovascular disease, and hyperlipidemia.

As used herein, the term "estrogen" referred to includes steroidal compounds having estrogenic activity, for example, 17β-estradiol, estrone, conjugated estrogen (Rhetagip?), equine estrogen av) 17β-ethinyl estradiol, etc. . The preferred estrogen-based compound is Rgetahip? and norethylnodrel. co 50 As used herein, the term "progestin" referred to includes compounds having progestogenic activity, for example, progesterone, norethylnodrel, nongestrel, megestrol acetate, norethindrone, and the like. sl Norethindrone is the preferred progestin-based agent.

As used herein, the term "aromatase inhibitor" referred to includes compounds capable of inhibiting aromatase, for example, commercially available inhibitors such as aminoglutemid (SUTAMOKEMF), anastrazole (AKIMIOEXPHO), letrozole (RHEMAKAF), formestane (I EMATCOMF), exemestane (AKOMAZIM) etc. o As used in this description, the term "analog | NCN" referred to refers to an analog of luteinizing hormone-releasing factor that inhibits the production of estrogen in women who are approaching the menopause, including, for example, goserlin (20ОЙ AОЕХФ) , leuprolide (I ORKOMO)), etc. 60 As used herein, the term "ASIPE inhibitor" referred to includes compounds that inhibit acetylcholinesterase, for example, physostigmine salicylate, tacrine hydrochloride, donepezil hydrochloride, and the like.

The mentioned term "activation of SNAT" means increase of enzymatic activity of SNAT, i.e. acceleration of conversion of choline to acetylcholine. Said acceleration may include an increase in the efficiency and/or speed of the reaction between SNAT and choline and/or an increase in the amount of SPAT present at the site of action. Said 65 The increase in the amount of the enzyme present may be due to gene regulation or another synthetic step in the formation of the enzyme and/or to a decrease in the deactivation and metabolism of said enzyme.

Selected testing procedures

General procedure for rat preparation: Seventy-five female Zrgadoe JuOuleu rats, one day old (unless otherwise specified) (weighing 200g to 225g) were obtained from Spagpez Kimeg I Arogaigiez (Rogiade, Michigan). The specialists of the SNagez Kimeg Iarogayogiez company subjected the mentioned animals to bilateral ovariectomy (0UH) or simulated a surgical procedure and after a week sent them to their destination. Upon arrival, the animals were placed in metal hanging cages in groups of 3 or 4 per cage and provided with feed (with a calcium content of approximately 0.595) and water ad Prisht for one week. The temperature in the room was maintained at the level of 22.22-1.72 with 4095 minimum relative humidity. Photoperiod in the mentioned 7/0 room: 12 hours of light, 12 hours of darkness.

Drug Administration Mode, Tissue Collection: After a one-week acclimatization period (ie, two weeks after ovariectomy), daily administration of P-IS was started. 17 o-ethynylestradiol or B-P was administered orally, in the absence of other indications, in the form of a suspension in 1965 carboxymethyl cellulose or dissolved in 2095 cyclodextrin. The animals were administered the mentioned substances daily for 4 days. 75 After completion of the administration, the animals were weighed, anesthetized with a mixture of ketamine:xylazine (2:11, by volume) and a blood sample was collected by cardiac puncture. After that, the animals were killed (by asphyxiation with CO2), the uterus was removed through a midline incision, and the raw weight of the uterus was determined. 17o-ethynylestradiol was obtained from Zidt Spetis! So., St. Louis, Missouri.

Diseases of the cardiovascular system/hyperlipidemia

The aforementioned blood samples, which were obtained before, were kept until coagulation at room temperature for 2 hours; serum was obtained by centrifugation for 10 minutes at Zb0OOrotations/min.

Serum cholesterol content was determined using the company's high-performance cholesterol test

Voepgipdeg Mapppeiyt Oiadpowiisv. In short, cholesterol is oxidized to cholest-4-en-3-one and hydrogen peroxide.

After that, the obtained hydrogen peroxide reacts with phenol and 4-aminophenazone in the presence of peroxidase with He to obtain p-quinoneimine dye, the content of which is read spectrophotometrically at 50 Ohm. After that, the cholesterol concentration is calculated according to (5) standard curve. The execution of the mentioned test is automated and it is performed at the automated workplace of Viotek Aciotagiea Uuogkziaiop.

Test for eosinophil peroxidase (ERO) of the uterus

The uteri, which were obtained before that, are stored at a temperature of 42C until enzyme analyses. IF)

After that, the uteri are homogenized in 50 volumes of 5X00MM TRIS buffer (pH 8.0), which includes 0.00590

Triton X-100 (Top X-100). After adding 0.01956 hydrogen peroxide and 10 mM O-phenylenediamine (final concentrations) to the TRIS buffer, the increase in optical density is monitored for 1 minute at 45 Ohm. (av)

The presence of eosinophils in the uterus is evidence of the estrogenic activity of the compound. The maximum speed with 15-second intervals is determined on the initial, straight section of the reaction curve.

The procedure for testing the inhibition of bone tissue thinning (osteoporosis) -

After completion of the general training procedure previously described, rats are treated daily for thirty-five days (6 rats per experimental group) and killed (by carbon dioxide asphyxiation) on the thirty-sixth day. The mentioned thirty-five-day period is sufficient to "provide the maximum thinning of the bone tissue, which was measured according to the description given before." At the time of slaughter, the uterus was removed, separated from extraneous tissues, and the liquid content was removed before determining the raw weight in order to confirm the estrogen deficiency, which was associated with a complete ovariectomy. Uterine mass typically decreased by approximately 7595 in response to oophorectomy. After that, the uteri were placed in 1095 neutral buffered formalin for further histological analysis.

The right femurs were exposed, digital X-rays were taken, images of the distal metaphysis were analyzed using an image analysis program (MIN etade). Images of the proximal areas of the tibia of these animals were also scanned using quantitative computer tomography.

According to the procedures previously described, B-P or ethinyl estradiol (EE 2 ) in 2095 ("in hydroxypropyl D-cyclodextrin) was administered orally to experimental animals. P-III is also suitable for co-administration in combination with estrogen or progestin .

MCE-7 proliferation assay Cell viability of the breast adenocarcinoma line MCE-7 (American Type Culture Collection (ATSC) NTV 22) was maintained using minimal support medium (MEM, without phenol red, Bidta Company, St. Louis, MO), which was supplemented with 1096 fetal bovine serum (EV5, by volume), I-glutamine (2 mM), sodium pyruvate (1 mM), HEPES buffer

GF! T(H-(2-hydroxyethyl|piperazine-M'-(2-ethanesulfonic acid| 10 mM), substitute amino acids and bovine insulin (1 μg/ml) (sustaining nutrient medium). Ten days before the analysis of MSE cells -7 were transferred to maintenance medium supplemented with 1095 experimental medium with fetal bovine serum desorbed with dextran-coated charcoal 60 (OSS-EB5) instead of 1095 fetal bovine serum (EB5) to deplete internal stores of steroids. 7 were removed from the protective flasks with the medium for cell dissociation (Hanks' balanced salt solution (HB55) without Ca"/Md" and phenol red, which was supplemented with 10 mM HEPES buffer and 2 mM ethylenediaminetetraacetic acid). The cells were washed twice with the medium for analysis and their the density was adjusted to 800OO cells/ml. Approximately 1OOml (8000 cells) was added to the wells of a multiwell plate for microculture (Soviag 3596) and incubated at temperature of 37 C in a humid chamber with 596 atmospheres of CO" for 48 hours to ensure cell adhesion and their equilibration after transfer. Serial dilutions of drugs or dimethyl sulfoxide as a diluent control were prepared in the medium for analysis; 5HOml was transferred to triplicate microcultures, after

What was added BOml of medium for analysis to the final volume of 200ml. After additional incubation for 48 hours at a temperature of 372C in a humid chamber with 5906 atmospheres of CO", the microcultures were subjected to pulse labeling with thymidine with radioactive tritium (Imicrocuries/well) for 4 hours. Cultivation was terminated by freezing the cultures at -70 °C for 24 hours, followed by thawing and harvesting of microcultures using a semi-automatic cell harvester of the ZKaigop company. The radioactivity content in the samples was determined using the liquid scintillation beta counter of the company

UmaiIas VeiagRiase.

Inhibition of mammary gland tumors induced by dimethylbenz(Ianthracene (OMVA)

In female Zrgadie-Oam/eu rats purchased from the Nagpap Ipdyzigiev Company, Indianapolis,

Indiana, induced estrogen-dependent mammary tumors. At the age of approximately 55 days, the mentioned rats 75 were once fed 20 mg of 7,12-dimethylbenzIlia)anthracene (OMVA). Approximately 6 weeks after administration

OMVA mammary glands were palpated at weekly intervals to detect tumors. In the case of the appearance of one or more tumors, the largest and smallest diameters of each tumor were measured using a metric caliper, the results of the measurements were recorded, and this animal was selected for the experiment. An attempt was made to evenly distribute tumors of various sizes among the experimental and control groups in such a way that medium-sized tumors were equally distributed among the experimental groups. Control and experimental groups for each experiment included from 5 animals to 9 animals.

E-SP was administered by intraperitoneal injections in 2905 gum arabic or orally. Compounds for oral administration were dissolved or suspended in 0.2 ml of corn oil. Each input, including Ga

Control injections in Arabic gum and corn oil were carried out once daily to each experimental animal. After initial measurement of tumors and selection of experimental animals, o tumors were measured weekly according to the aforementioned method. Administration and measurements of animals continued from 3 weeks to 5 weeks. During this time, the final plane of the tumors was determined. Changes in mean tumor plane were determined for each compound and control administration. yu

Uterine fibrosis testing procedures

Test1: 3-20 women with uterine fibrosis were administered PE-P. The amount of the injected compound ranged from 0.1mg/day to 100mg/day; the introduction period was equal to S months. The mentioned women were observed during the entire period of administration and up to 3 months after the cessation of administration in order to determine the effect on uterine fibrosis.

Test 2: The same procedure was followed as in Test 1, except that the administration period was 6 months. h-

Test 3: The same procedure was followed as in Test 1, except that the lead-in period was 1 year.

Test 4: To induce leiomyoma in sexually mature female guinea pigs, prolonged estrogen stimulation was used. Animals were injected with estradiol 3-5 times a week for 2-4 months or until tumors appeared. Treatment consisted of daily administration of RB-II or vehicle for 3-16 weeks, after which animals were sacrificed, uteri were removed and analyzed for tumor regression. Test 5: Human leiomyoma tissue was implanted into the abdominal cavity and/or uterine myometrium of sexually mature castrated "naked" female mice. Exogenous estrogen was administered to induce growth of the explanted tissue. In some cases, harvested tumor cells were cultured i.p. before implantation.

Treatment consisted of daily gavage administration of P-III or vehicle for 3-16 weeks, after which the implants were removed and measured for growth or regression. During slaughter, the uterus was removed in order to determine the status of the mentioned organ.

Mn Test 6: Tissue from human uterine fibroid tumors was collected and maintained as primary av) untransformed cultures. Surgical specimens were pushed through a sterile mesh or sieve, or, alternatively, separated from surrounding tissues to obtain a single-cell suspension. The cells were maintained in a nutrient medium containing 1095 serum and antibiotics. The growth rate was determined in the presence and absence of estrogen. The cells were analyzed for the ability to produce the complement component SZ and for the response to growth factors and somatotropin. We determined the proliferative reaction of myoblast cultures after treatment with progestins, SpKkN, B-PSh and carrier. Weekly

Levels of human steroid receptors were assessed to determine whether important characteristics of myoblasts are conserved. Tissues from 5-25 patients were used. o Test 7: The ability of E-IPS to inhibit estrogen-stimulated proliferation of cells of the EI line! T, which was obtained with leiomyo, was determined essentially according to the description given in the work of |(Fuchs-Young (Hisp8-ZhMotspa) and others, "Ippyriop oi Evigodep-ZiytytsiaiFvai Sgom(i oi Shegipe Ieiotuotaz ru Zeiiesime Evigodep Keseriog Moashiaigv" , 60 My. Sag., 17 (3):151-159 (1996)), which is incorporated herein by reference in its entirety.

Endometritis testing procedures

Test 1: Twelve to thirty adult female rats of the CO line were used as experimental animals. they were divided into three groups with equal numbers. The estrous cycle of all animals was monitored. On the day of proestrus, each female was subjected to surgery. In females of each group, the left horn of the uterus was removed and cut into small rectangles that were loosely sutured at various locations near the mesenteric blood flow. In addition, Group 2 females were ovariectomized. One day after surgery, animals in Group 1 and Group 2 were injected intraperitoneally with water.

Injections were made for 14 days, while Group C animals were injected intraperitoneally with 1.0mg of E-IP per kilogram of body weight for the same period. After 14 days of treatment, each female was sacrificed, removed and prepared for histological examination of endometrial explants, adrenal glands, residual uteri and ovaries, when available. The mass of the ovaries and adrenal glands was determined.

Test 2: Twelve to thirty adult female rats of the CO line were used as experimental animals. they were divided into two groups with equal numbers. The estrous cycle of all animals was monitored. On the day of proestrus, each female was subjected to surgery. In the females of each group, the left horn of the uterus was removed and cut into small rectangles, which were loosely sutured in various places near the mesenteric blood flow. Approximately 50 days after surgery, Group 1 animals were injected intraperitoneally with water. Injections were made for 21 days, while animals

Group 2 was intraperitoneally injected with 1.0 mg of B-P per kilogram of live weight during the same period of time.

After 21 days of treatment, each female was sacrificed, removed, and the mass of endometrial and /5 adrenal explants was determined. Explant sizes were measured as an indication of growth. The estrous cycle was monitored.

Test 3: Autografts of endometrial tissue were used to induce endometritis in rats and/or rabbits. Sexually mature female animals were bilaterally ovariectomized and exogenous estrogen was administered to ensure a specific and constant level of the hormone. Autologous endometrial tissue was implanted into the peritoneum of 5-150 animals; estrogen was administered to induce growth of explanted 2o tissue. Treatment consisted of daily administration of a compound of the present invention by gastric tube for 3-16 weeks; said implants were removed and measured to determine growth or regression. At the time of slaughter, the intact uterine horn was removed in order to determine the status of the endometrium.

Test 4: Human endometrial lesion tissue was implanted into the peritoneum of sexually mature castrated "naked" female mice. Exogenous estrogen was administered to induce the growth of explanted tissue. In some cases, the collected tumor cells were cultured immediately before implantation. Treatment consisted of daily administration of B-II by gastric tube for 3-16 weeks, after which the implants were removed and (8) measured for growth or regression. During the beating, the uterus was removed to determine the status of the intact endometrium.

Test 5: Tissue from human endometrial lesions was harvested and maintained as primary untransformed cultures. Surgical specimens were pushed through a sterile mesh or sieve, or, alternatively, separated from surrounding tissues to obtain a single-cell suspension. co

Cells were maintained in nutrient medium containing 1095 serum and antibiotics. at

Growth rate was determined in the presence and absence of estrogen. The cells were analyzed for the ability to produce the complement component SZ and for the response to growth factors and somatotropin. The proliferative reaction of myoblast cultures after treatment with progestins, SpKkN, B-PSh and carrier was determined. Human steroid receptor levels were assessed weekly to determine whether important characteristics of the myeloid cells were maintained. Tissues from 5-25 patients were used.

Disorders of the central nervous system, including Alzheimer's disease

Estrogens, for example, 17p-estradiol, regulate gene transcription by binding to estrogen receptors (EC), which are located in the cytoplasm of certain cell populations. Liganal activation of estrogen receptors is a prerequisite for the nuclear transfer of the mentioned complex, where binding to the palindromic sequence (13th base pair) of DNA (estrogen response element or EKE) begins the assembly of the transcriptional apparatus, the "" completion of which is the activation of the corresponding target genes . A variety of genes have been identified that are regulated by estrogen. These include cytoskeletal proteins, neurotransmitter biosynthetic and metabolic enzymes and receptors, as well as other hormones and neuropeptides. Estrogen-responsive elements have been identified in many estrogen-responsive genes, including vitellogenin, c-oz, prolactin, and luteinizing hormone. o EKE-like sequences, which play an important role in the central nervous system, have been (av) identified in p7579" and IgKA, both of which serve as signaling molecules for neurotrophins: nerve tissue growth factor 50 (NERV), nerve tissue growth factor , which was derived from the brain (VOMOR) and neurotrophin-3. sl VOME, like MORE, has been shown to stimulate the survival of cholinergic neurons in culture. It is postulated that when interactions between neurotrophins and estrogens are important for development and survival of the basal neurons of the forebrain (which degenerate in the case of Alzheimer's disease), then clinical conditions, according to

WHICH there is a deficiency of estrogen (such as after menopause) can contribute to the loss of the mentioned neurons.

The following experiment was carried out on ovariectomized rats (which were prepared according to the description of

IF) was given before) to determine the similarities and/or differences between P-III and estrogen with regard to the effect on gene co-expression in different regions of the brain. Six-week-old rats were daily subcutaneously injected with estradiol benzoate (0.0 mg/kg), B-IS or vehicle (control). Five weeks later, the animals were killed, the brains were removed, and the hippocampi were dissected. The collected hippocampi were subjected to accelerated freezing in liquid nitrogen and stored at a temperature of -702C. Total RNA was obtained from collected tissue from the respective experimental and control groups and subjected to reverse transcription using a 3' oligonucleotide primer selected for specific mRNA (roiu-Azh) populations.

Polymerase chain reaction (PCR) was carried out in a mixture that included: arbitrary 5' oligonucleotides 65 (length 10 base pairs; total 150), reaction buffer, Tad polymerase and ZgRTSR (T-cell precursors).

After 40 cycles of amplification, the obtained reaction products were fractionated according to their size per TBE

(tetrabutylethylene)-urea gel, dried and exposed on X-ray film. Received configurations

mRNA was compared between experimental groups.

Use of R-PI in combination with estrogen

Menopausal and postmenopausal women are often treated with hormone replacement therapy (HRT) to counteract the negative effects of declining circulating endogenous estrogen levels, such as hot flushes. IUDs, however, are associated with an increased risk of certain types of cancer, including uterine and breast cancer. To reduce the level of risk, RB-IP can be used in combination with hormone replacement therapy. 70 Use of R-P in combination with an aromatase inhibitor

The ovaries of a postmenopausal woman are, by definition, non-functioning. Thus, the only source of estrogen is thought to be the conversion of adrenal androgens into estrogens by the enzyme aromatase, which is found in peripheral tissues (including adipose, muscle, and breast tumor tissue itself). Thus, drugs that inhibit aromatase (aromatase inhibitors) deplete the supply of 7/5 circulating estrogen in a postmenopausal woman. Estrogen deprivation through aromatase inhibition is an important treatment option for patients with metastatic breast cancer. During treatment with an aromatase inhibitor, the absence of circulating estrogen may cause an unexpected negative side effect, for example, on serum lipid levels. This negative effect can be suppressed by the use of R-PI.

Application of P-III in combination with analog I! NCN

Continuous exposure to an analogue of LUKE (luteinizing hormone-releasing factor) suppresses estrogen production in pre-menopausal women due to desensitization of the pituitary gland, which no longer stimulates the ovaries to produce estrogen. The clinical effect is "medical ovariectomy", which is reversible in case of stopping the use of analog I NCN. During treatment with an analogue of NEN, the absence of circulating estrogen can cause a negative, unpredictable side effect, for example, on the level of lipids in the serum. This negative effect can be suppressed by the use of R-PI. and)

Increased levels of acetylcholine

Alzheimer's patients are known to have significantly lower levels of cholinergic neurons in the hippocampus than non-Alzheimer's patients. The progressive loss of the aforementioned Cholinergic neurons seems to reflect the gradual deterioration of memory and cognitive function in these patients. It is believed that one of the reasons for the decrease in the activity of the mentioned neurons is the loss or deterioration of the functioning of the neurotransmitter, acetylcholine. at

The level of acetylcholine in a neuron is determined mainly by the balance point between its biosynthesis and biodegradation. The enzyme i) choline acetyltransferase (CAT) is mainly responsible for its synthesis, while its breakdown depends on acetylcholinesterase (ACE). uh-

In order to determine the effect of R-P on the level of SNAT, an experiment was carried out, the description of which is given below: After the completion of the general procedure for the preparation of rats, 40 rats were daily injected with R-IS by subcutaneous injection or with the help of a gastric tube at a dose of Zmg/kg/day in a carrier , which included 1095 cyclodextrin, estradiol benzoate at a dose of 0.00 mg/kg/day or 0.00 mg/kg/day or vehicle control. Animals were treated for 3 days or 10 days. Twelve animals were provided for each administration regimen. z c After appropriate time intervals, the animals were killed with brain dissection. Certain portions of the brain were homogenized and subjected to analysis. Homogenates of the hippocampus and frontal cortex of the brain were subjected to; processing and the activity of SNAT was determined by analyzing the biosynthesis of acetylcholine with the help of a radioactive label.

This procedure can be found in the work of Schepp (Zspoerr) and others, U. Metzsch! Tgapztizv., 78:183-193, 1989), which is hereby incorporated by reference in its entirety. -I As expected, in ovariectomized animals, SPAT levels were reduced by 25095 (p«0.001) compared to sham-operated controls. o According to another version of the present invention, B-IPSH is used in combination with an ACRE inhibitor. The consequence of the use of the ASPE inhibitor is an increase in the levels of acetylcholine as a result of blocking its breakdown. Through 5p inhibition of AspE. co Benign prostatic hyperplasia (BPH) sp For information regarding the relationship between the action of estrogen and the treatment of BPH and carcinoma of the prostate gland, see (publication of international application MoUUO 98/07274, publication date October 15, 1998.

In the experiments, the description of which is given below, the ability of P-III to bind estrogen receptors of several lines of human prostate cancer cells was evaluated.

F) Lysates of lines I MSaR, 00-45 and RO-3 of human prostate cancer cells were obtained in the nutrient medium of TES, which included ZKHONM TRIS-buffer NS (pH 74), 1.5 mM ethylenediaminetetraacetic acid (EOTA), 04M KSI, 1095 glycerol, 0.5 mM 2-ME (2-aminoethanol) and 10 mM sodium molybdate, as well as protease inhibitors pepstatin (1mg/ml), leupeptin (2mg/ml), aprotinin (5mg/ml) and phenylmethylsulfonyl fluoride (PMP , 0.1 mm) (TESR).

The obtained cell lysates were centrifuged, the sediment was resuspended in cold TESOR medium (Tml

TEOSR/100 mg sediment) and subjected to sonication for 30 minutes (7095 duty cycle, output 1.8) using an ultrasonic disintegrator of Vgapzop company, model 450. Lysates were precipitated by centrifugation at 10,000 rpm for 15 minutes at a temperature of 49C, after which the supernatants were removed and used immediately or stored at -7090.

Competitive binding analysis: The binding buffer is TES, in which 04M KSI was replaced

B5OMM Masi and to which 1mg/ml ovalbumin (TEO) was additionally added. E-P was diluted to 20 nm in TESO, followed by obtaining threefold serial dilutions. Analyzes are performed on polypeptide microplates with a flat bottom in triple wells for microcultures. Zoml of 17 p-estradiol, which was treated with radioactive tritium (0.5 nM, specific activity 60.1 Curie/mmol, company OyRopi-Mem/Epadiapa) is added to each well

Misieag, Boston, MA), ZbOml of cold competitive experimental compound (0.1nM-5mM) or TESO, followed by incubation for 5 minutes at 42C with shaking and 7Oml of cell line lysate

MS-7.

Tablets are incubated for 24 hours at a temperature of 42C, after which 7Oml of dextran-coated charcoal (OCS) is added to each well, followed by vigorous shaking for 8 minutes at a temperature of 42C. After that, the mentioned tablets are centrifuged at 1500 rpm for 10 minutes at a temperature of 42°C. The supernatant from each well is collected in a flexible polystyrene microplate for scintillation counting using a Uoyas Misoreia counter, model 1450. The radioactivity level is expressed as 715 decays per minute (cpm) after correction for counting efficiency (35-4090) and background.

Additional controls are the total number and the total number of OSS to determine the lower limit of the number without OSS. The results of the mentioned competitive binding analyzes are expressed as the average percentage binding (95 Voshpa) 4 root mean square deviation using the formula:

Average BRM experimental compound 7 ORM total amount ОСС percentage (ВЗЖМЗ-- 9 Ш - Е ж - - 2 - -- - -« - - ж ж - 4 - 5 -.- - е- - x 100 binding of РМ ez experimental compound 7. ЮР M total number of crСs

Prevention of breast cancer p

This invention is also related to the administration of P-III to a recipient who is at risk of developing breast cancer. The mentioned term "de pomo", which is used in this description, means the absence of transformation or metamorphosis of normal breast cells into cancerous or malignant cells in the first case. Such transformation may occur in stages in the same or daughter cells through an evolutionary process or may occur as a single key event. This process de pomo contrasts MO with metastases, the colonization or spread of already transformed or malignant cells from the site of the primary tumor to new locations.

A person who does not have a particular risk of developing breast cancer is one of those who can (2) develop breast cancer de pomo: such a person has no symptoms or suspicions of the potential of said disease that would exceed the normal level of risk, and such a person has never had a diagnosis of

Due to the presence of the mentioned disease. The biggest risk factor that contributes to the development of breast carcinoma is a life history of suffering from the mentioned disease, or a previous case of the mentioned disease, even in the case of its remission without the presence of symptoms. Another risk factor is a family history of the mentioned disease. "

Induction of mammary gland tumors in rats by administration of the carcinogen, M-nitroso-M-methylurea, is a commonly accepted animal model for the study of mammary gland cancer, which has been found suitable for c) c analyzing the effect of chemopreventive agents. "» In two separate studies, 55-day-old female Zrgadoe-Oauleu rats were administered intravenously (Study 1) or intraperitoneally (Study 2) at a dose of 50 mg of M-nitroso-M-methylurea per kilogram of body weight one week before feeding ai Irisht ration, the composition of which, in a mixture, included different amounts of B-Sh, (2)-2-ID-(1,2-diphenyl-1-butenyl)phenoxy|-M,M-dimethylethanamine base (tamoxifen base) or controls co In Study 1, the dietary doses of bOmg/kg diet and 20 mg/kg diet were translated to roughly comparable doses

Zmg/kg and mg/kg body weight of experimental animals. o In Study 2, dietary doses of 2Omg/kg, bmg/kg, 2mg/kg, and 0.bmg/kg of diet were roughly translated into 20 comparable doses of mg/kg, 0.Zmg/kg, 0.1mg/kg, and O0, 0 Zmg/kg body weight of experimental animals.

Rats were monitored for signs of toxicity, weighed once a week and palpated to determine tumor formation. After thirteen weeks (Study 1) or eighteen weeks (Study 2), said animals were sacrificed and tumors were necropsied and weighed.

Medicinal forms 29 The mentioned term "pharmaceutical", in the case of its use in this description as an adjective, essentially means

Ge) is harmless to the recipient mammal. The mentioned term "pharmaceutical drug" means that the carrier, diluent, excipients and active ingredient(s) must be compatible with the other ingredients of the dosage form and harmless to the recipient.

E-IS, according to the preferred option, is introduced into the composition of the dosage form before administration. The decision regarding the choice of 60 dosage form should be made by the physician taking into account the factors involved in determining the effective amount.

The total amount of active ingredients in such dosage forms ranges from 0.19U0 (wt.) to 99.995 (wt.) of the mentioned dosage form. According to the preferred version, the composition of the mentioned dosage form includes no more than two active ingredients. This means that it is preferable to introduce P-III in the composition of the dosage form together with the second active ingredient, which is chosen from among estrogen, progestin, aromatase inhibitor, analogue of NCN I, and ASPE inhibitor. The most preferred dosage forms include those whose only active ingredient is P-II.

The pharmaceutical compositions of this invention are prepared by procedures known in the art using well known and readily available ingredients. For example, B-I, alone or in combination with estrogen, progestin, aromatase inhibitor, analog I! NKN or ASNE inhibitor compound, are introduced into the composition of the medicinal product with traditional fillers, diluents or carriers, and give the said medicinal product the form of tablets, capsules, suspensions, solutions, solutions for injection, aerosols, powders and the like.

Pharmaceutical drugs according to this invention for parenteral administration include 70 sterile aqueous or non-aqueous solutions, dispersions, suspensions or emulsions, as well as sterile powders that are reconstituted immediately before use to sterile solutions or suspensions. Examples of suitable sterile aqueous or nonaqueous carriers, diluents, or solvents are water, physiological saline, ethanol, polyols (e.g., glycerin, propylene glycol, poly(ethylene glycol) and the like), and their respective mixtures, vegetable oils (e.g., olive oil ) and organic ethers for injection, /5 for example, ethyl oleate. Adequate fluidity is maintained, for example, by means of coating materials, for example, lecithin, by maintaining an appropriate particle size composition in the case of dispersions and suspensions, or by the use of surface-active substances.

The composition of parenteral compositions can also include adjuvants, for example, preservatives, moisturizing components, emulsifiers and dispersing substances. Prevention of the action of microorganisms is ensured by the inclusion of antibacterial and antifungal agents, for example, paraben, chlorobutanol, phenolsorbic acid and the like. it may also be desirable to include isotonic agents, for example, sugars, sodium chloride, etc. Prolonged absorption of drugs for injection can be provided by the inclusion of agents that slow absorption, for example, aluminum monostearate and gelatin.

In some cases, in order to prolong the effect of the medicinal product, it is desirable to slow down the absorption of the aforementioned medicinal product after subcutaneous or intramuscular injection. This can be achieved through the use of a liquid suspension or crystalline material with low solubility in i) water or by dissolving or suspending said medicinal product in an oil carrier. In the case of subcutaneous or intramuscular injection of a suspension, the composition of which includes a form of medicine with low solubility in water, the rate of absorption of the mentioned medicine depends on the rate of its dissolution.

Depot medicinal forms of B-II for injection are obtained by manufacturing microencapsulated co-matrices of the mentioned medicinal product with biodegradable polymers, for example, o poly(lactic acid), poly(glycolic acid), copolymers of lactic and glycolic acid, poly( orthoethers) and poly(anhydrides) of those materials described in the prior art. The rate of drug release can be controlled depending on the ratio of the drug to the polymer, as well as the characteristics of the particular polymer that was used.

Dosage forms for injection are sterilized, for example, by filtering through bacterial filters or pre-sterilizing the components of said mixture before their mixing or during manufacture, or immediately before administration (as, for example, in the case of a two-chamber syringe bag). "

Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, RB-III is mixed with at least one inert pharmaceutical. with a carrier such as sodium citrate or calcium diphosphate and/or (a) with fillers or aggregates such as starches, sugars including lactose and glucose, mannitol and silicic acid, (b) with binders such as carboxymethylcellulose and other cellulose derivatives, alginates, gelatin, poly(vinylpyrrolidine), sucrose and gum arabic, (c) wetting agents, -I, for example, glycerin, (4) substances that promote disintegration, for example, agar-agar, calcium carbonate, sodium bicarbonate, potato or tapioca starch, alginic acid, silicates and o sodium carbonate, (e) moisturizing components, for example, glycerin; (Her) substances that slow down dissolution, for example, paraffin, (9) substances that accelerate absorption, for example, quaternary ammonium compounds, (n) moisturizing substances, for example, cetyl alcohol and glycerol monostearate, (1) with absorbents, e.g., kaolin and bentonite, and (|) emollients, e.g., talc, calcium stearate, sp magnesium stearate, solid poly(ethylene glycols), sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets and pills, said dosage form may also include buffering substances.

Solid compositions of this type can also include fillable soft and hard gelatin capsules with the use of fillers, for example, lactose, as well as high molecular weight poly(ethylene glycols) and the like. (F, Solid dosage forms, such as tablets, dragees, capsules, pills, and granules, may also be prepared with coatings or shells, such as enteric coatings or other coatings well known in the pharmaceutical industry. Said coatings may include opalescent components or substances that release said active ingredient(s) in a specific part of the gastrointestinal tract, such as acid-soluble coatings for the release of said active ingredient(s) in the stomach, or base-soluble coatings for the release of said active ingredient(- iv) in the intestinal tract.

Said active ingredient(s) may also be microencapsulated to a coating that provides its prolonged release, and said microcapsules may form part of the shell of said dosage form.

Liquid dosage forms of P-III for oral administration include solutions, emulsions, suspensions, syrups and elixirs. In addition to the mentioned active ingredients, liquid dosage forms may include inert diluents traditionally used in the art, such as water or other pharmaceutical solvents, solubilizers or emulsifiers, such as ethanol, isopropanol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (in particular, cottonseed, peanut, corn, germ oil, olive, castor and sesame oils), glycerin, tetrahydrofurfuryl alcohol, poly(ethylene glycol), sorbitol and fatty acid esters, and their mixtures.

In addition to inert diluents, liquid oral dosage forms may also include adjuvants such as wetting agents, emulsifiers and suspending agents, sweetening agents, 7/0 corrigents and flavoring additives.

The composition of the liquid suspension, in addition to the mentioned active ingredient(s), may include suspending agents, for example, ethoxylated isostearyl alcohols, polyoxyethylene and sorbitol or sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite clay, agar-agar, tragacanth and their mixtures.

Compositions for rectal or intravaginal administration are prepared by mixing P-II with suitable non-irritating excipients, such as cocoa butter, polyethylene glycol, or any suppository resin which is solid at room temperature but which becomes liquid at room temperature. body and, as a result, melts in the cavity of the rectum or vagina with the release of the mentioned active component(s). The mentioned compounds are dissolved in molten resin, they are given the necessary shape and they are kept until solidification in the form of a ready-made suppository medicinal product.

E-Sh can also be administered in the form of liposomes. As is known in the art, liposomes are generally derived from phospholipids or other lipid substances. Liposomal dosage forms are mono- or multilamellar hydrated liquid crystals that are dispersed in an aqueous medium. Any non-toxic, pharmaceutical and metabolizable lipid capable of forming liposomes can be used. In addition to R-PII, stabilizers, fillers, preservatives and the like can be included in the composition of the mentioned compositions in the form of liposomes. Predominant lipids include phospholipids and i) phosphatidylcholines (lecithins), both natural and synthetic.

Methods of obtaining liposomes are known in the art; a description of the methods of preparation of liposomes is given, for example, in Grobot, edited by Prescott (Rhessoy), Journal of Biochemistry, Vol. З3З and further).

The following examples of dosage forms are purely illustrative and are not intended to limit the scope of the present invention. at

Pharmaceutical Form 1: Gelatin capsules

Hard gelatin capsules are made using the following ingredients: i) , sho and -

Ingredient Amount (mg/capsule)

E-PI 0.1-1000

Starch, national pharmacopoeia o-650

Liquid starch powder o-650 "

Silicone liquid, 350 centistokes 0-15 shsh s The above dosage form may vary according to the acceptable anticipated options. :z» The tablet dosage form is made using the following ingredients:

Pharmaceutical form 2: Tablets

Ingredient Amount (mg/tablet) and E-PI 2.5-1000

OO Microcrystalline cellulose 200-650

Silicon dioxide, trace amount 10-650 o Stearic acid 0-15 o 50

The above components are mixed and pressed to form tablets. sl Pharmaceutical form 3: Tablets, each of which contains approximately 1Omg or 5Omg of R-P, respectively, are manufactured as follows: и (mg/tablet) (mg/tablet) о ю во 65 I Microcrystalline cellulose (external 0100130

The above components are mixed and pressed to form tablets. According to an alternative version, the tablets, each of which contains 2.5-100mg of B-IS, are manufactured as follows: Pharmaceutical form 4:

Tablets, etc

Ingredient Quantity (mg/tablet)

E-Sh 25-1000

Starch 45

Microcrystalline cellulose 5

Polyvinylpyrrolidone (in the form of a 1095 solution in water) 4

Sodium carboxymethylated cellulose 4.5

Magnesium stearate 0.5

Talc 1 75 BE-ISHSH, starch and cellulose are passed through a sieve Mo45 (0.353 mm) and thoroughly mixed. The polyvinylpyrrolidone solution is mixed with the obtained powders, which are then passed through a Mo14 sieve (1.41 mm).

The granules obtained in this way are dried at a temperature of 50-60 and passed through a Mo18 sieve (1.00 mm).

Sodium carboxymethylated starch, magnesium stearate and talc, previously passed through a Mobo sieve (0.24 in 8 mm), are added to the granules, which, after mixing, are pressed on a tablet machine to obtain tablets.

Suspensions, a 5-ml dose of each of which contains 0.1-100O0mg of medication, are obtained as follows:

Pharmaceutical form 5: Suspensions

Ingredient Amount (mg/5 ml)

E-Sh 0.1-1000 mg

Sodium carboxymethylated cellulose BO mg o

Syrup 1.25 mg

Benzoic acid solution 0.10 ml

Proofreader as needed, dye as needed

Distilled water up to 5 ml g)

The mentioned medication is passed through a Mo45 sieve and mixed with sodium carboxymethylated cellulose and syrup to form a homogeneous paste. Benzoic acid solution, corrector and dye are diluted with some water and added with stirring. After that, water is added in the amount sufficient to obtain the required volume. -

An aerosol solution is obtained, which includes the following ingredients:

Dosage form 6: Aerosol «

Ingredient Amount (wt. 95) 50 E-Sh 0.25 Z s Ethanol 25.75 :z» Propellant 22 (chlorodifluoromethane) 70.00

E-III is mixed with ethanol and the resulting mixture is added to the portion

Pharmaceutical form 9: Combined capsule -I s Ingredient Quantity (mg/capsule)

E-Sh BO ("in") Premarin 1 o 20 Avicel pH 101 BO

Starch 1500 117.50 ml Silicone oil 2

Twin 80 OBO

Cab-O-Seal 0.25

Gee! Pharmaceutical form 10: Combined capsule II ko Ingredient Amount (mg/capsule)

E-Sh BO bo Noretilnodrel 5

Avicel pH 101 82.50

Starch 1500 90

Silicone oil 2

Twin 80 OR b5

Pharmaceutical Form 11: Combined tablet

Ingredient Amount (mg/capsule)

E-PI BO

Premarin 1

Corn Starch, US National Pharmacopoeia 50

Povidone, K29-32 b

Avicel pH 101 1.50

Avicel pH 102 136.5 70 Crospovidone. XI/10 2.50

Magnesium stearate 0.50

Cab-O-Seal 0.50

Dosage

The specific dose of P-III administered according to this invention is determined by the specific circumstances surrounding each situation. These circumstances include the route of administration, the recipient's past medical history, the condition or symptom before treatment, the severity of the condition/symptom before treatment, and the age and gender of the recipient.

In general, the effective minimum daily dose of B-P is approximately mg, b5mg, 1Omg, 15mg or 20mg. Typically, the effective maximum dose is approximately 80Omg, 10Omg, bOmg, 5Omg, or 4Omg. In the most typical case, the mentioned dose is from 15mg to bOmg. The exact dose can be determined by standard medical practice by "dose titration" for the recipient; that is, a low dose of the mentioned compound is first determined and it is gradually increased until the necessary therapeutic effect is observed.

Despite the need for titration of the dose to the recipient in order to use the combined treatment methods discussed earlier, typical doses of active ingredients other than E-II are as follows: ethinylestrogen (0.01-0.0 µg/day), mestranol ( . (o) (1.0-10.Omg/day), nonethindrone (0.5-2.Omg/day), aminoglutemid (250-125Omg/day, preferably 250mg four times a day), anastrazole (1- 5mg/day, preferably 1mg once a day), letrozole (2.5-1mg/day, preferably 2.5mg once a day), formestane (250-1250mg per week, preferably 25mg) twice a week), exemestane (25-100mg/day, preferably 25mg once a day), goserline (3-15mg/three times a month, preferably 3.6-7.2mg once every three months) and leuprolide (3-15 mg/month, with and the preferred option is 3.75-7.5 mg once every month). at

Route of entry

E-IIs can be administered by a variety of routes, including oral, rectal, transdermal, subcutaneous, intravenous, intramuscular, and intranasal. The method of administration of each estrogen-based or progestin-based agent is consistent with that known in the art. E-II, alone or in combination with estrogen, progestin or an ASRPE inhibitor, in general, can be administered in a traditional dosage form.

The pharmaceutical compositions of this invention can be administered to humans or other mammals (eg, dogs, cats, horses, pigs, etc.) orally, rectally, intravaginally, parenterally, topically, subcutaneously, sublingually, or intranasally. The mentioned term "parenteral administration" means in this description with c methods of administration, which include intravenous, intramuscular, intraperitoneal, intrasternal, subcutaneous or intra-articular injection or infusion. :z» Method/duration of introduction

For most methods of the present invention, P-III is administered continuously, from 1 to 3 times per day, or as often as is necessary to administer an effective amount of P-III to said recipient. Intermittent treatment -I may be particularly suitable in the treatment of endometritis or may be used during painful attacks of the disease. In the case of restenosis, treatment may be limited to short (1-6 months) intervals with further medical procedures, for example, plastic surgery on vessels. («c) at 50 sl

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Claims (1)

The formula of the invention 1. Crystalline b-hydroxy-3-(4-(2-(piperidin-1-ylethoxy|phenoxy)-2-(4-methoxyphenyl)benzoi|Bithiophene) hydrochloride hydrate (P-III), the X-ray pattern of which has the following peaks: 4.6 --0.22, 7.854-0.22, 9.3-0.22, 14.0--0.29, 17.6--0.29, 40 20,840.22 and 24.3- 40.22 at 20, when obtained at a temperature of 2542 C and a relative humidity of 35-10 95 with a copper radiation source. or fillers. C. The method of obtaining the compound according to claim 1, which includes the crystallization of 45 β-hydroxy-3-(4-(2-(piperidin-1-yl)ethoxy|phenoxy)-2-(4-methoxyphenyl)benzo|B|Ithiophene hydrochloride from a mixture of isopropanol and water d) 4. The method according to claim 3, which is characterized by the fact that the volume ratio of water and isopropanol is from 1:1 to 9:1. o 5. The method according to claim 4, which differs in that the volume ratio of water and isopropanol is from bo 020 002.571 to 5.671. 6. The method according to claim 5, which differs in that the volume ratio of water and isopropanol is from 3:1 ml to 5.6:1. 7. The active ingredient of a medicinal product for the suppression of a pathological condition selected from the group: uterine fibrosis, endometritis, proliferation of smooth muscle cells of the aorta, restenosis, breast cancer, uterine cancer, prostate cancer 22, benign prostatic hyperplasia, thinning of bone tissue , F! osteoporosis, cardiovascular disease, hyperlipidemia, disorders of the central nervous system and Alzheimer's disease, which is distinguished by being a compound according to claim 1. Official Bulletin "Industrial Property". Book 1 "Inventions, useful models, topographies of integrated 60 microcircuits", 2005, M 6, 15.06.2005. State Department of Intellectual Property of the Ministry of Education and Science of Ukraine. b5