EA007978B1 - Crystalline non-solvated 1-(4-(2-piperidinylethoxy)phenoxy)-2(4-methanesulfonylphenyl)-6-hydroxynaphthalene hydrochloride - Google Patents

Abstract

The present invention relates to crystalline non-solvated 1-(4-2-piperidinylethoxy)phenoxy)-2-(4-methanesulfonylphenyl)-6-hydroxynaphthalene hydrochloride, useful as a selective estrogen receptor modulator.

Description

This application claims priority on the basis of the provisional application and § 60 / 450,233, filed February 25, 2003, and the international (JSC) application PCT No. 03/03349, filed July 16, 2003.

BACKGROUND OF THE INVENTION

Uterine leiomyoma or multiple leiomyomas (uterine fibroids) are a clinical problem denoted by various names, including uterine fibrosis, uterine hypertrophy, multiple uterine leiomyoma, myometrial hypertrophy, hypertrophy and fibrous metritis. In fact, uterine fibroma is a condition in which abnormal accumulation of fibrous tissue in the uterine wall is observed. This condition is the cause of dysmenorrhea and infertility in women.

Endometriosis is a condition of severe dysmenorrhea, which is accompanied by severe pain, bleeding into the mass of the endometrium or abdominal cavity and often leads to infertility. The cause of the symptoms is the ectopic growth of the endometrium, which pathologically responds to normal hormonal control and is observed in non-normal tissue. Due to the norm of the endometrial growth site in the tissue, a local, inflammation-like reaction is initiated that causes macrophage infiltration and a cascade of events leading to the occurrence of a pain reaction. Existing data suggest that the cause of uterine fibroids and endometriosis is a pathological reaction of fibrous tissue and / or endometrial tissue to estrogen.

Over the past ten years, there have been many publications on selective modulators of estrogen receptor (8EKM), for example, patents EG 5484795, 5484798, 5510358, 5998401 and AO 96/09040. It has been established that many of these 8EKMs, in general, have beneficial activity of an estrogen agonist in the bones and the cardiovascular system, simultaneously with the therapeutic activity of an estrogen antagonist in the mammary gland. A small set of such particularly effective compounds with the action of estrogen antagonists in the uterus has been discovered. The compound with the properties of 8EKM are especially promising in the treatment of uterine fibroids and / or endometriosis.

However, the clinical use of such 8EKM compounds for the treatment of uterine fibroids and / or endometriosis, especially in women in the premenopausal period, is difficult due to the tendency of these compounds to a significant ovarian stimulation effect. Therefore, at present, there is a great need for new 8EKM compounds that behave as estrogen antagonists in the uterus, but do not significantly stimulate the ovaries.

SUMMARY OF THE INVENTION

This invention relates to crystalline unsolvated hydrochloride of 1- (4- (2piperidinyl ethoxy) phenoxy) -2- (4-methanesulfonylphenyl) -6-hydroxy naphthalene, a substance with the structural formula

which is hereinafter referred to as RC; having an X-ray diffraction spectrum that includes the following peaks:

15.2 ± 0.1; 17.6 ± 0.1; 18.6 + 0.1 and 24.1 ± 0.1 ° on a 2Θ scale; when the spectrum is obtained using a copper radiation source (CuCos, λ = 1.54056 A).

This invention also relates to pharmaceutical forms containing RH and pharmaceutical carriers. In one embodiment, the pharmaceutical forms of this invention can be adapted for use in the treatment of endometriosis and / or uterine leiomyoma.

The present invention also relates to methods for treating endometriosis and / or leiomyomas, which include administering to a patient in need of treatment an effective amount of Rh.

In addition, this invention relates to the use of RH in the treatment of endometriosis and / or uterine leiomyoma. This invention also relates to the use of RH for the manufacture of a medicament for the treatment of endometriosis and / or uterine leiomyoma.

Brief Description of the Drawing

The drawing shows the spectrum of x-ray diffraction for RS.

DETAILED DESCRIPTION OF THE INVENTION

It should be understood that we are talking about 1- (4- (2-piperidinylethoxy) phenoxy) -2- (4 methanesulfonylphenyl) -6-hydroxy-naphthalene hydrochloride in an unsolvated crystalline form.

X-ray powder diffractometry (CID) was used to characterize the R-III. HKE) is a technique that determines the long-range order in a crystalline material. X-ray powder diffractometry (CKE) spectra) were obtained using an 81etep8 Ό5000 X-ray powder diffractometer equipped with a CuCos source (λ = 1.54056 A) and an 8ΐ (Εϊ) solid-state detector Κενεχ operating at minimum parameters of 50 kV and 40 mA. Samples were scanned from 4 to 35 ° in a 2Θ scale, with a step of 0.02 ° in a 2Θ scale with a maximum scanning speed of 3.0 seconds / step, input and output slits of 1 mm and a detector slit of 0.1 mm. Synthetic mica

- 1 007978 fluorophlogopite (ΝΙ8Τ 675) was used as an internal standard for the correction of any errors associated with the replacement of the sample.

The ΧΚΌ spectrum for P-ΙII obtained in this work is characterized by sharp peaks and a flat base line, which indicates a high crystallinity of the substance. The angular positions of the peaks in the 2Θ scale and the corresponding 1/1 ₀ data for all peaks with an intensity equal to or greater than 10% of the maximum peak for R – W are shown in Table. 1. All data in the table. 1 presented with precision

± 0.1 ° on a 2Θ scale. Table 1 Ρ-ΙΙΙ

2Θ angle 1 / s (%) 2Θ angle 1 / s (%) 4.6 13,2 22.0 14,4 13.8 30.1 22.2 25, 3 15,2 53,2 22.7 13, 0 16, 9 37.9 23.8 33, 4 17.6 54.5 24.1 89.5 17.9 27.8 24, 8 20, 8 18.3 25.9 26.0 11.1 18.6 100, 0 26.3 13, 7 19,2 46.8 26, 9 10.9 19.5 23,4 27.4 21, 0 19.7 27.0 27.9 13,2 20.7 28.3 29.0 12.9 21.3 41, 9 29.3 20, 3 21, 6 40.8

It is well known in crystallography that for each given crystal shape, the relative intensities of the diffraction peaks can vary due to the preferred orientation formed under the influence of factors such as the morphology and appearance of the crystal. Where preferential orientation effects are present, peak intensities change, but the characteristic position of the polymorph peaks remains unchanged. See for example. NOT 141 Des! 81a1e§ P11agtasore1a (United States Pharmacopeia) # 23, Payopa1 Rotiyaga # 18, Radez 1843-1844, 1995. In addition, it is also well known in crystallography that for each given crystalline form, the angular position of the peaks may vary slightly. For example, the peak position may shift depending on the temperature at which the sample is analyzed, due to the replacement of the sample or the presence or absence of an internal standard. In this case, the variability of ± 0.1 ° on a scale of 2 ° includes such potential variations, without causing doubt in the identification of crystalline salts according to this invention.

¹³ C-cross-polarization / NMR with rotation of the sample at a magic angle (CP / MA8) (solid-state NMR [ΝΜΚ or 88 также]) was also used to characterize R-III. The mentioned spectrum was obtained using a Wapap Zsh1u NMO spectrometer at 400 MHz operating at a carbon frequency of 100.573 MHz. The parameters of the data acquisition mode were as follows:

width 90 ° proton g. pulse 4.0 μs, contact time 2.5 ms, pulse repetition time 15 s, MAZ frequency (NMR with sample rotation at a magic angle) 10 kHz, spectrum width 50 kHz, accumulation time 50 ms. Chemical shifts were assigned to the methyl group of hexamethylbenzene (δ = 17.3 ppm) when the sample was replaced. The chemical shift data for EPP III are as follows: 20.7; 23.8; 25.3; 38.4; 51.2; 52.4; 56.8; 59.8; 110.8; 113.3; 114.6; 118.0; 118.3; 122.3; 122.9; 125.4; 127.2; 130.0; 132.0; 137.9; 142.2; 143.1; 147.3; 151.3; 153.8 and 158.0 ppm

Preparation 1. 1- (2- {4- [2- (4-methanesulfonylphenyl) -6-methosynaphthalen-1yloxy] phenoxy} ethyl) piperidine hydrochloride

To a three-necked flask equipped with a reflux condenser and a nitrogen purge tube, 6-methoxytetralone (1.0 equivalent), 4-bromophenylmethyl sulfone (1.02-1.05 equivalent (equiv.)), Palladium acetate Pc1 (0Ac) were added. ₂ (0.025 equiv.), [(Oxydi-2,1-phenylene) bis (diphenylphosphine)] (ligand ϋΡΕρΙιοδ, 0.026 equiv.) And 10-12 volumes of toluene. Sodium tert-butoxide (2.5 equiv.) Was added in one portion and the mixture was allowed to exothermically warm to approximately 40 ° C. The mixture was heated to 75-80 ° C. After completion of the reaction, as judged by analysis using high performance liquid chromatography (HPLC), cooled to room temperature. 12 volumes of water were slowly added, keeping the temperature below 40 ° C. It was stirred for 2-3 hours. It was filtered through a polypropylene filter septum and washed with water (3x2 volumes). The filter cake was dried overnight at 50 ° C to obtain 2- (4-methanesulfonylphenyl) -6-methoxytetralone.

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Combined 2- (4-methanesulfonylphenyl) -6-methoxytetralone (1.0 equiv.), Kieselguhr (20 wt.%) And toluene (7.5 volumes).

PBrh (1.5 ~ 1.75 equiv.) Was added in one portion with stirring at room temperature. The contents were boiled under reflux (~ 110 ° C) overnight. After completion of the reaction, as judged by HPLC analysis (usually after 15 hours), the solution was cooled to 45 or 90 ° C and 20 volumes of tetrahydrofuran (THP) were slowly added. Stirred for 30 min at 45 or 90 ° C and filtered hot through a layer of kieselguhr. The layer was washed with 2x2 volumes of THP at 45 or 90 ° C. The filtrate was concentrated to approximately 7 volumes. 7.5 volumes of water were added so that the temperature of the mixture remained below 40 ° C. (ATTENTION: adding water at the initial moment is very exothermic with the release of a large amount of HBg). The suspension was cooled to room temperature and stirred for 2-3 hours. It was filtered through a polypropylene filter septum and washed with 2x2 volumes of water. The filter cake was dried overnight at 60 ° C in vacuo to give 1-bromo-2- (4-methanesulfonylphenyl) -3,4-dihydro-6-methoxynaphthalene.

Combined 1-bromo-2- (4-methanesulfonylphenyl) -3,4-dihydro-6-methoxynaphthalene and 2,3-dichloro5,6-dicyano-1,4-benzoquinone (LLC. 1.8 equiv.) In 10 volumes acetonitrile and 5 volumes of THP. In a nitrogen atmosphere, the reaction mixture was heated to 73-75 ° C. The progress of the reaction was monitored by gas chromatography (OC) analysis until the reaction was completed. The contents were cooled to ambient temperature and 10 volumes of 1Ν sodium hydroxide were added. Stirred for approximately 1 h and filtered. The filter cake was washed with 2 volumes of water, 3x5 volumes of a 50% acetonitrile / water mixture and, finally, 3 volumes of methanol. The filter cake was then dried in vacuo at 65 ° C to give 1-bromo-2- (4-methanesulfonylphenyl) -6-methoxynaphthalene.

1-Bromo-2- (4-methanesulfonylphenyl) -6-methoxynaphthalene, 4- (2-piperidinyl ethoxy) phenol (2.0 eq.), Cesium carbonate (2.0-2.1 eq.) And copper chloride ( 0.15 equiv.) In 12 volumes of diglyme. The atmosphere from the flask was evacuated for approximately 2 minutes, after which it was purged with nitrogen. Repeated pumping / purging with nitrogen 3 times. The contents were heated to 130 ° C until completion of the reaction, as judged by the results of HPLC. After completion of the reaction, the contents were cooled to approximately ambient temperature, 12 volumes of ammonium hydroxide were added and stirred for approximately 30 minutes. Filtered to separate solid particles and washed solid particles with 9 volumes of 30% HeH / NH ₄ OH, suspending them on the filter. Again, 2 × 9 solid particles were washed with volumes of 30% NH ₄ ΟH / ΜеΟН, suspending them on the filter. Washed with 4 volumes of methanol. The filter cake was dried in vacuo at 60 ° C to give the free base of the title compound. The free base was suspended in 9 volumes of toluene and the suspension was heated to 70-75 ° C. 1.1 equivalents of hydrogen chloride gas were dissolved in 2 volumes of ethanol. An ethanolic solution of HC1 was added to the hot toluene suspension. The solution was cooled to ambient temperature and stirred for 1-2 hours. It was filtered and washed with a small amount of toluene. The filter cake was dried in vacuo at 65 ° C to give the title compound.

Example 1

P-ΙΙΙ

Combined 1 - (2- (4- [2- (4-methanesulfonylphenyl) -6-methoxy-naphthalen-1 yloxy] phenoxy) ethyl) piperidine hydrochloride with 5 volumes of 1,2-dichloroethane (ISE) and the mixture was cooled to a temperature below 10 ° C. 5 equivalents of boron trichloride was added under the surface of the mixture. Stirred at ambient temperature until completion of the reaction, as judged by HPLC data. The reaction was stopped with 5.6 volumes of 3A-ethanol (ethanol denatured with approximately 5% methanol), keeping the temperature of the contents below 50 ° C. It was cooled to ambient temperature and stirred for 1-3 hours. The solid fraction was filtered off and the filter cake was washed with 3A ethanol. The filter cake was dried in vacuo at 65 ° C.

The resulting product was dissolved in 9.8 volumes of 3A-ethanol and 1.5 volumes of deionized water at a temperature approximately equal to the boiling point of the mixture. The solution was refluxed for approximately 30 minutes and then allowed to cool to ambient temperature. At ambient temperature, the resulting suspension was left with stirring, then it was filtered and the filter cake was washed with 3A-ethanol. The filter cake was dissolved in 19 volumes of acetonitrile and 1.4 volumes of deionized water at boiling point. Azeotropically (with constant boiling), water was removed by distillation until 12.1 volumes of distillate were removed. The resulting suspension was cooled to ambient temperature, filtered and the filter cake washed with acetonitrile to give the title compound.

Form (Pharmaceutical Composition)

The compound of this invention is preferably prepared in dosage form, i.e. in the form of individual units, for example tablets or capsules, before administration to the patient. The term “patient” includes female and female animals, such as synanthropic animals (dogs, cats, horses and the like). The preferred patient for treatment is a woman.

These pharmaceutical compositions are prepared by known methods using widely known and readily available ingredients. In the preparation of the forms of this invention, the asset

- 3 007978 ingredient (P-ΙΙΙ) is usually mixed with a carrier or diluted with a carrier or enclosed in a carrier, which may be in the form of a capsule, sachet, paper or other container. When the carrier serves as a diluent, it may be a solid, semi-liquid or liquid material that acts as a carrier, excipient or medium for the active ingredient. Thus, the compositions may take the form of tablets, pills, powders, troches, sachets, starch wafers, elixirs, suspensions, emulsions, solutions, syrups, aerosols (in solid or liquid medium), soft or hard gelatin capsules, suppositories, sterile injectable solutions and sterile packaged powders.

Examples of suitable carriers, excipients and diluents include lactose, dextrose, sucrose, sorbitol, mannitol, starches, gum arabic, calcium phosphate, alginates, tragant, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, aqueous syrup, methyl cellulose, methyl cellulose and propylhydroxybenzoates, talc, magnesium stearate and liquid paraffin. Forms may further include lubricating agents, wetting agents, for example, polysorbate 80 or lauryl sulfate, emulsifying or suspending agents, preservatives, sweeteners or flavoring agents. The compositions of this invention can be prepared in such a way as to provide quick, prolonged or delayed release of the active ingredient after its administration to the patient.

Form Examples

10 mg capsules or tablets

About 156 mg of filler (lactose, mannitol or dextrose), about 20 mg of disintegrant (microcrystalline cellulose or starch), about 4 mg of super-deintegrant (crospovidone or starch sodium glycolate), about 4 mg of a binder (hydroxypropylmethyl cellulose or hydroxy) were placed in the granulator about 10 mg RH and mixed until the powders were evenly distributed. While mixing the powder at a constant speed, an aqueous granulating solution was sprayed containing povidone, hydroxypropyl methyl cellulose or hydroxypropyl cellulose (enough to add about 2-4 wt.% By weight of the dry powder) and a moisturizing agent such as polysorbate 80 or lauryl sulfate (just add from 0, 5 to 3 wt.%). Wet granular material was sieved through a sieve to break up large agglomerates. The filtered granular powder was dried either by heating in a fluidized bed or in a convection oven. The dried granular powder was ground to an equal size by passing through a mill or other suitable apparatus, and then the material was transferred to a mixer. The granular powder was evenly ground with a lubricating agent (magnesium stearate or sodium stearyl fumarate, constituting about 1 wt.% Of the total weight of the form) and an additional disintegrant (about 2-4 wt.% Of additionally applied powders). Hard gelatin capsules were filled with the prepared powder or pressed into tablets (after which they were coated with a film, as described below). The total weight of the capsule or tablet thus prepared was about 200 mg.

45 mg capsules or tablets

About 162 mg of filler (lactose, mannitol or starch), about 10 mg of disintegrant (crospovidone or sodium starch glycolate) and about 45 mg of P-внос were added to the granulator and mixed until the powders were evenly distributed. During mixing at a constant speed, an aqueous granulating solution was sprayed containing povidone (about 35% by weight) and polysorbate 80 (about 10% by weight). Wet granular material was sieved through a sieve to break up large agglomerates. The filtered granular powder was dried either by heating in a fluidized bed or in a convection oven. The dried granular powder was ground to an equal size by passing through a mill or other suitable apparatus, and then the material was transferred to a mixer. The granular powder was evenly ground with a lubricating agent (magnesium stearate; about 1 wt.% Of the total mass of the mold) and an additional disintegrant (about 2 wt.% Of the additionally applied powders). Hard gelatin capsules were filled with the prepared powder or pressed into tablets (after which they were coated with a film, as described below). The total weight of the capsule or tablet thus prepared was about 230 mg.

Alternatively, to prepare tablets, a filler, a disintegrant were placed in a mixer and ground until the powders were evenly distributed. When the powders were evenly distributed, a lubricant was added and again milled. The milled material was transferred to a tablet press, which was then coated with a film of an appropriate agent.

Biological tests

Test for cell proliferation on cells [Mnct. This test measures cell proliferation (using an alkaline phosphatase index) when the compound of this invention is acting as an agonist per se and when acting as an antagonist when the ability of the compound of this invention to measure growth stimulation by estradiol is measured.

IKAG cells of a human endometrial tumor were contained in MEM (minimal nutrient medium with Earl salts and P-glutamine, O1Eo VKB, Oaiyeshshd, MI) with the addition of 10% fetal bovine serum (PB8) (bulk %%) (OIeo VNI). One day before the test, the growth medium of the culture for

- 4 007978 was exchanged for the test medium Ρ / Ρ-12 (3: 1) (Dulbecco's modified Eagle medium / E-12 nutrient mixture, the mixture was in the ratio 3: 1, without Phenol red, C | bco VKE) with the addition of 5 % fetal bovine serum purified with Dextran-coated charcoal (ESS-BBZ) (Nus1ope, Boden. IT), L-glutamine (2 mM), sodium pyruvate (1 mM) in N, NEREZ (N- [2-hydroxyethyl] piperazine-I ' - [2-ethanesulfonic acid] 2 mM) all firms C | bCO BKE). After overnight incubation, 1Sykata cells were washed with physiological saline with Dulbecco's phosphate buffer (IX) (S-PBH) without Ca ⁺² and Md ⁺² (01bco WKB) and trypsinized by incubation for 3 min in 0.25% trypsin with EDTA (without phenol red) (01b with VKB). Cells were resuspended in the test medium and their density was set at 250,000 cells / ml. Approximately 25,000 cells in 100 μl of medium were added to a 96-well flat-bottomed culture microplate (Sozat 3596) and incubated at 37 ° C in a humidified incubator for 24 hours in 5% CO ₂ . The next day, a series of dilutions of the compounds was prepared in the test medium (6-fold concentration relative to the final concentration during the tests). The tests were carried out in a double mode - as an agonist and as an antagonist.

When tested as an agonist, 25 μl / well of test medium was added to the plate, as well as 25 μl / well of the diluted compound of this invention (at a concentration 6 times the final). To test as an antagonist, 25 μl / well of 6 nM E ₂ (β-estradiol, Z1dta, Z1. Lox, MO) was added to the plate, followed by 25 μl / well of the diluted compound of this invention (at a concentration of 6 times the final ) After an additional 48-hour incubation at 37 ° C in a humidified incubator with 5% CO ₂ , the medium was aspirated from the cells, and 100 μl of fresh test medium was added to each microculture cell. Serial dilutions of the compounds were prepared and added as described above. After an additional incubation for 72 h at 37 ° C in a humidified incubator with 5% CO _{2, the} test was terminated by removing the medium and washing the cells twice with physiological saline with Dulbecco's (IX) phosphate buffer (Ό-PBZ) (01bCO VKE). The tablets were dried for 5 minutes and frozen to -70 ° C for at least 1 hour. Then the tablets were removed from the refrigerator and allowed to warm at room temperature. 100 μl of 1-S1er ™ 1 (P1egse Syet1ca1 Sotrapu, Kosk & gO, 1b) was added to each well. After 20 minutes of incubation, the plates were read in a spectrophotometer at a wavelength of 405 nm.

The data were processed by linear interpolation to obtain EC50 values (for acting as an agonist) or 1C ₅₀ (for acting as an antagonist). For an antagonist,% efficacy for each compound was calculated relative to the action of E2 (1 nM) per se. For action as an agonist,% efficiency for each compound was calculated relative to the response to tamoxifen.

E-ΙΙΙ was tested as an agonist and showed a less stimulating effect than tamoxifen. As an antagonist, E-ΙΙΙ inhibits more than 70% of the response to 1 nM estradiol.

10-day hormone test in rats (ovarian stimulation). An initial ovarian toxicity test was performed using a 10-day study of hormones in rats by measuring levels of estradiol and luteinizing hormone after administration of ΟΥΝ 3ΕΚΜ E-ΙΙΙ. This test was performed by forced oral administration of the compound for 10 days to sexually mature female rats (9-10 weeks old) of the E344 line. Blood from the body was collected after rapid decapitation to determine the levels of LH (luteinizing hormone) and estradiol approximately 2 hours after the 10th dose. The serum obtained by centrifugation was separated and stored frozen at a temperature below -60 ° C until testing. The levels of LH and estradiol were measured using the method of radioimmunoassay.

Primary rat anti-LH antibodies and reference preparations (rat LH: KR-3) were obtained from Dr. A. E. Rat1ote, Director of the Center for Pituitary Hormones and Antisera (Riyuatu Nogtopes apO ApOzet Seshet), Natot-LSEA Seset Szet, Toggap , CA. The upper limit for determining LH was 30 ng / ml, and the lower limit for determining 0.1 ng / ml for a 100 μl sample.

Clinical trial E ₂ . P1aZopp zg. 1, Z1ndd1a (UetseSh), Ia1u. The upper limit of determination was 1000 pg / ml, and the lower limit of determination was 5 pg / ml. E-ΙΙΙ was tested using the above tests and found that the drug does not significantly increase levels of estradiol and LH in the circulating blood.

Industrial applicability

As an estrogen antagonist in the breast and uterine tissue, E-ΙΙΙ is suitable for treating conditions in which, as shown, estrogen plays the role of cause. As an estrogen agonist in skeletal and cardiovascular systems, E-ΙΙΙ is suitable for treating conditions in which, as shown, estrogen plays a beneficial role.

The terms “treat” and “treatment” as used herein include generally accepted meanings, for example, pain relief, improvement, cure, prevention, cessation, inhibition, retardation, stopping or reverse development of a disease or severity of a pathological condition, or their consequences described here. The term "warning" means a decrease in the likelihood that a patient receiving a compound of this invention will undergo a disease or the development of any pathological conditions or their consequences described herein.

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Diseases, disorders or conditions in which the compound of this invention is useful in treatment include, but are not limited to, (1) cancer of the uterus and / or breast; (2) endometriosis; (3) uterine leiomyoma / multiple leiomyomas; and (4) osteoporosis. Treating uterine leiomyomas / multiple leiomyomas as described here can also reduce disease-related symptoms such as pain, rapid urination, and uterine bleeding.

Dose

The term “effective amount,” as used herein, means an amount of TS that is capable of treating the disease states or their deleterious effects described herein.

The specific dose administered is determined by the specific circumstances surrounding each individual situation. These circumstances include: route of administration, previous medical history of the patient, treatable pathological condition or symptom, severity of the condition / symptom, and the age and gender of the recipient. The patient's physician must determine the administered therapeutic dose in the light of circumstances relevant to this.

In general, an effective minimum daily dose of Rh reaches about 5 mg. Usually, the effective maximum daily dose does not exceed about 350 mg. The exact dose can be determined in accordance with the standard practice of "dose titration" on the recipient, adopted in medicine, so that initially a low dose of the compound is given, and then it gradually increases until the desired therapeutic effect is observed.

Route of administration

P-ΙΙΙ can be administered in various ways, which include the intramuscular, intranasal, intravaginal, intravenous, oral, rectal, subcutaneous, local and transdermal routes. The preferred route of administration is the oral route.

Combination therapy

P-ΙΙΙ can be used in combination with other drugs that are used in the treatment of diseases or conditions for the treatment of which these compounds are suitable. Such other medicine (s) can be administered in the usual way by itself and in the usual amount, i.e. simultaneously or sequentially with the salt of this invention. When P-ΙΙΙ is used simultaneously with one or more drugs, a single dosage form of such other substances with the compound is preferred. Accordingly, the pharmaceutical compositions of this invention include those containing one or more other active ingredients. One example of another active ingredient that can be combined with a compound of this invention, or administered alone or as part of the same pharmaceutical compositions, includes agents used in hormone replacement therapy (tubing).

Claims (3)

CLAIM 1. Crystalline unsolvated hydrochloride of 1- (4- (2-piperidinylethoxy) phenoxy) -2- (4 methanesulfonylphenyl) -6-hydroxy-naphthalene, having an X-ray diffraction spectrum that has the following peaks: 15.2 ± 0.1; 17.6 ± 0.1; 18.6 ± 0.1 and 24.1 ± 0.1 ° on a 2Θ scale; the spectrum was obtained using a copper radiation source (CuKa, λ = 1.54056 A). 2. The compound according to claim 1, in which said X-ray diffraction spectrum further has the following peaks: 16.9 ± 0.1; 19.2 ± 0.1; 21.3 ± 0.1 and 21.6 ± 0.1 ° on a 2Θ scale. 3. The use of a compound according to claim 1 or 2 in the treatment of endometriosis and / or uterine leiomyoma.