CN1753676A - 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-methane-sulfonylphenyl)-6-hydroxynaphthalene hydrochloride, useful as a selective estrogen receptor modulator.

Description

Crystalline non-solvated 1-(4-(2-piperidinylethoxy)phenoxy)-2-(4-methylsulfonylphenyl)-6-hydroxynaphthalene hydrochloride

This application claims priority to US Provisional Patent Application No. 60/450,233, filed February 25, 2003, and International (WO) Patent Application PCT/IB03/03349, filed July 16, 2003.

Background of the invention

Uterine leiomyoma (leiomyomata) (uterine fibroid disease) is a clinical problem that goes by several names, including uterine fibrosis, uterine hypertrophy, uterine fibroids, myometrial hypertrophy, uterine fibrosis, and fibrotic metritis . In essence, uterine fibrosis is a condition in which fibrous tissue is inappropriately deposited on the uterine wall. This condition is responsible for dysmenorrhea and infertility in women.

Endometriosis is a condition of severe menstrual cramps with severe pain and bleeding into the endometrial mass or peritoneal cavity, often resulting in infertility. The cause of the symptoms may be an ectopic endometrial growth that responds inappropriately to normal hormonal control and localizes in inappropriate tissue. Due to inappropriate localization of the growth in the uterus, the tissue exhibits a local inflammation-like response, causing macrophage infiltration and a cascade of events leading to a pain response. Evidence suggests that uterine fibrosis and endometriosis result from an inappropriate response of fibrous tissue and/or endometrial tissue to estrogen.

The past decade has seen a large number of publications disclosing selective estrogen receptor modulators (SERMs), such as US Patents US 5,484,795, 5,484,798, 5,510,358, 5,998,401 and WO96/09040. In general, most of these SERMs have been found to have beneficial estrogen agonist activity in the bone and cardiovascular system, accompanied by beneficial estrogen antagonist activity in the breast. A particularly useful subclass of these compounds has also been found to act as estrogen antagonists in utero. Compounds with such SERM properties hold particular promise in the treatment of uterine fibroid disease and/or endometriosis.

However, the clinical use of these SERM compounds in the treatment of uterine fibroid disease and/or endometriosis, especially in premenopausal women, has been hampered by the propensity for these SERM compounds to have pronounced ovarian stimulating effects. Thus, there is currently a great need for new SERM compounds that act as estrogen antagonists in utero without overtly stimulating the ovaries.

Brief description of the invention

The present invention relates to crystalline ansolvated 1-(4-(2-piperidinylethoxy)phenoxy)-2-(4-methylsulfonylphenyl)-6-hydroxynaphthalene hydrochloride, namely the following Formula compound:

Hereinafter referred to as F-III; when the X-ray diffraction pattern is obtained by a copper radiation source (CuKα, λ=1.54056 Å), it has the following peaks: 2θ of 15.2±0.1, 17.6±0.1, 18.6±0.1 and 24.1±0.1° .

The present invention also relates to pharmaceutical preparations containing F-III and pharmaceutically acceptable carriers. In another embodiment, the pharmaceutical formulation of the present invention may be suitable for the treatment of endometriosis and/or uterine leiomyoma.

The present invention also relates to a method of treating endometriosis and/or uterine leiomyoma comprising administering to a patient in need thereof an effective amount of F-III.

In addition, the present invention relates to the use of F-III in the treatment of endometriosis and/or uterine leiomyoma. The present invention also relates to the use of F-III in the preparation of medicines for treating endometriosis and/or uterine leiomyoma.

Brief description of the drawings

Figure 1 is the characteristic XRD pattern of F-III.

Detailed description of the invention

Since F-III is an unsolvated crystalline form, it should be understood that F-III is 1-(4-(2-piperidinylethoxy)phenoxy)-2-(4-methylsulfonylphenyl)-6-hydroxy Anhydrous form of naphthalene hydrochloride.

X-ray powder diffraction (XRD) was used to characterize F-III. XRD is a technique for detecting long range in crystalline substances. X-ray powder diffraction (XRD) patterns were obtained on a SIiemens D5000 X-ray powder diffractometer equipped with a CuKα source (λ=1.54056_) and a Kevex solid-state Si(Li) detector, operating at a minimum of 50kv and 40mA . The sample was scanned from 4 to 35° in 2Θ, with a 2Θ step size of 0.02°, a maximum scan rate of 3.0 seconds per step, a divergence and reception slit of 1 mm, and a detector slit of 0.1 mm. Synthetic fluorophlogopite (NIST675) was used as an internal standard to correct for any sample displacement errors.

The XRD pattern of F-III herein discloses characteristic sharp peaks and a flat baseline, indicating a highly crystalline material. The angular peak positions in 2θ and the corresponding I/I ₀ data for all peaks of F-III with intensities equal to or greater than 10% of the maximum peak are given in Table 1. All data in Table 1 are expressed with an accuracy of ±0.1° 2Θ.

Table 1

F-III Angle 2θ I/I ₀ (%) Angle 2θ I/I ₀ (%) 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 the field of crystallography that for any given crystal form, the relative intensities of diffraction peaks can vary due to crystal orientation due to various factors such as crystal morphology and crystal habit. When there is an effect of preferred orientation, the peak intensity changes, but the characteristic peak position of the polymorph does not change. See eg US Pharmacopoeia #23, US Formulary #18 (pp. 1843-1844, 1995). Furthermore, it is also well known in the field of crystallography that for any given crystal form, the peak position may vary slightly. For example, peak positions may shift due to changes in sample analysis temperature, sample displacement, or the presence or absence of internal standards. In the context of the present application, a ±0.1° variation in peak position in 2Θ would allow for these potential variations without preventing the crystalline salts of the invention from being accurately identified.

¹³ C cross-polarization/magic-angle spinning (CP/MAS) NMR (solid-state NMR or SSNMR) was also used to characterize F-III. The spectra were obtained using a Varian Unity Inova 400 MHz NMR spectrometer at a carbon frequency of 100.573 MHz. The collected parameters are as follows: 90° proton rf, pulse width 4.0μs, contact time 2.5ms, pulse repetition time 15s, MAS frequency 10kHz, spectrum width 50kHz, and acquisition time 50ms. Chemical shifts are referenced to the methyl group of hexamethylbenzene displaced by the sample (δ = 17.3 ppm). The chemical shift data for formula 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 158.0ppm.

Preparation Example 1

1-(2-{4-[2-(4-Methanesulfonyl-phenyl)-6-methoxy-naphthalen-1-yloxy]-phenoxy}-ethyl)-piperidinium salt

Acidic compounds

To a 3-neck flask equipped with a reflux condenser and a nitrogen purge vent, add 6-methoxytetralone (1.0 eq), 4-bromophenyl-methyl-sulfone (1.02-1.05 eq), acetic acid Palladium Pd(OAc) ₂ (0.025 eq), [(oxy-di-2,1-phenylene)bis(diphenylphosphine)] (DPEphos ligand, 0.026 eq) and toluene (10-12 vol). Sodium tert-butoxide (2.5 equiv) was added in one portion and the mixture exothermed to -40°C. Heat to 75°C to 80°C. After the reaction was complete (as judged by HPLC analysis), it was cooled to room temperature. 12 volumes of water were slowly added, maintaining the temperature <40°C. Stir for 2 to 3 hours. Filter through a pad of polypropylene and wash with water (3 x 2 volumes). The filter cake was dried overnight at 50°C to obtain 2-(4-methanesulfonylphenyl)-6-methoxytetralone.

Mix 2-(4-methylsulfonylphenyl)-6-methoxytetralone (1.0 equivalent), hyflo (20%/weight) and toluene (7.5 volume), add PBr ₃ (1.5～1.75 equivalent ), while stirring at room temperature. The components were heated to reflux (~110°C) overnight. After the reaction was complete (typically 15 hours, as judged by HPLC analysis), the solution was cooled to 45°C or 90°C, and 20 volumes of tetrahydrofuran (THF) was added slowly. Stir at 45°C or 90°C for 30 minutes and filter while hot through a pad of hyflo. Wash the pad with 2x2 volumes of THF at 45°C or 90°C. The filtrate was concentrated to about 7 volumes. 7.5 volumes of water were added to the remaining mixture, keeping the temperature below 40°C (Caution: Excessive exotherm after initial addition of water and significant HBr formation). Cool the slurry to room temperature and stir for 2 to 3 hours. Filter through a pad of polypropylene and wash with 2 x 2 volumes of water. The filter cake was vacuum dried at 60°C to obtain 1-bromo-2-(4-methylsulfonylphenyl)-3,4-dihydro-6-methoxynaphthalene.

1-Bromo-2-(4-methylsulfonylphenyl)-3,4-dihydro-6-methoxynaphthalene and 2,3-dichloro-5,6-dicyano-1,4- Benzoquinone (DDQ, 1.8 equiv) was mixed in 10 volumes of acetonitrile and 5 volumes of THF. Under a nitrogen atmosphere, the reaction contents were heated to 73-75°C. The progress of the reaction was monitored by GC analysis until the reaction was complete. Additional DDQ (0.2-0.3 equiv) may be required to complete the reaction. Cool the components to ambient temperature and add 10 volumes of 1N sodium hydroxide. Stir for about 1 hour and filter. The filter cake was rinsed with 2 volumes of water, 3 x 5 volumes of 50% acetonitrile/water, and finally 3 volumes of methanol. The filter cake was dried under vacuum at 65°C to obtain 1-bromo-2-(4-methylsulfonylphenyl)-6-methoxynaphthalene.

1-Bromo-2-(4-methylsulfonylphenyl)-6-methoxynaphthalene, 4-(2-piperidinylethoxy)phenol (2.0 equivalents), cesium carbonate (2.0-2.1 equivalents) and copper chloride (0.15 equivalents) were added to 12 volumes of diglyme. The flask was vented for ~2 minutes, then purged with nitrogen. The exhaust/nitrogen purge was repeated 3 times. The components were heated to 130°C until the reaction was complete as judged by HPLC analysis. After the reaction was complete, the components were cooled to near ambient temperature, 12 volumes of ammonium hydroxide were added and stirred for about 30 minutes. The solid was removed by filtration and washed with 9 volumes of 30% MeOH/ _NH4OH and slurried on the filter support. The solid was washed with 2 x 9 volumes of 30% _NH4OH /MeOH and slurried on a filter support. Wash with 4 volumes of methanol. The filter cake was dried under vacuum at 60°C to obtain the free base of the title compound. Slurry the free base in 9 volumes of toluene and heat the slurry to 70-75°C. Dissolve 1.1 equivalents of hydrogen chloride gas in 2 volumes of ethanol. The ethanolic HCl solution was added to the hot toluene slurry. The solution was cooled to ambient temperature and stirred for 1-2 hours. Filter and wash with a little toluene. The filter cake was dried under vacuum at 65°C to obtain the title compound.

Example 1

F-III

1-(2-{4-[2-(4-Methanesulfonyl-phenyl)-6-methoxy-naphthalen-1-yloxy]-phenoxy}-ethyl)-piperidine hydrochloride The compound was mixed with 5 volumes of 1,2-dichloroethane (DCE), and the mixture was cooled to <10°C. Add 5 equivalents of boron trichloride under the liquid surface. Stir at room temperature until the reaction is complete (as judged by HPLC analysis). The reaction contents were quenched into 5.6 volumes of 3A-ethanol (ethanol denatured with about 5% methanol), keeping the contents <50°C. Cool to ambient temperature and stir for 1-3 hours. The solid was filtered and the filter cake was washed with 3A-ethanol. The filter cake was dried under vacuum at 65°C. The isolated product was dissolved in 9.8 volumes of 3A-ethanol and 1.5 volumes of deionized water (approximately the reflux temperature of the mixture). The solution was refluxed for about 30 minutes, then the mixture was allowed to cool to ambient temperature. Once cooled to ambient temperature, the resulting slurry was allowed to stir at room temperature for 1-2 hours, then filtered and the filter cake washed with 3A-ethanol. The filter cake was dissolved in refluxing 19 volumes of acetonitrile and 1.4 volumes of deionized water. Water was removed by azeotropic distillation until 12.1 volumes of distillate were removed. The resulting slurry was cooled to ambient temperature, filtered and the filter cake washed with acetonitrile to afford the title compound.

Preparation (pharmaceutical composition)

The compounds of the invention are preferably formulated in dosage unit form, ie, as individual delivery vehicles such as tablets or capsules, prior to administration to the recipient patient. The term "patient" includes females and non-human female animals, such as paired animals (dogs, cats, horses, etc.). Preferred patients for treatment are females.

The pharmaceutical compositions of this invention are prepared by known methods using well known and readily available ingredients. In preparing the preparation of the present invention, the active ingredient (F-III) is usually mixed with a carrier, or diluted with a carrier, or embedded in a carrier, which may be in the form of capsules, sachets, paper preparations or other containers. When the carrier serves as a diluent, it can be a solid, semi-solid or liquid material which acts as a carrier, excipient or medium for the active ingredient. Thus, the composition may be a tablet, pill, powder, lozenge, sachet, cachet, elixir, suspension, emulsion, solution, syrup, aerosol (as a solid or in a liquid medium), Soft and hard gelatin capsules, suppositories, sterile injectable solutions or sterile packaged powders.

Some examples of suitable carriers, excipients and diluents include lactose, dextrose, sucrose, sorbitol, mannitol, starch, acacia, calcium phosphate, alginate, tragacanth, gelatin, calcium silicate, Microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water syrup, methylcellulose, methyl and propylparabens, talc, magnesium stearate and mineral oil. The formulations may additionally include lubricating agents, wetting agents such as polysorbate 80 or lauryl sulfate, emulsifying and suspending agents, preservatives, sweetening or flavoring agents. The compositions of the present invention can be formulated to provide immediate, sustained or delayed release of the active ingredient after administration to the recipient patient.

Formulation example

                                                             

Add about 156 mg of filler (lactose, sorbitol, or dextrose), about 20 mg of disintegrant (microcrystalline cellulose or starch), about 4 mg of super disintegrant (crospovidone or starch glycolate) Sodium), about 4 mg of binder (hydroxypropyl methylcellulose or hydroxypropyl cellulose), and about 10 mg of F-III were added to the granulator and mixed to distribute the powder evenly. Mix a mixture of povidone, hydroxypropylmethylcellulose, or hydroxypropylcellulose (enough to transfer about 2-4% by weight of dry powder) and a wetting agent such as polysorbate 80 or sodium lauryl sulfate (enough to An aqueous granulation solution consisting of 0.5 and 3% by weight) was sprayed onto the powder while mixing. The granulated material is wet sieved through a sieve to separate large agglomerates. The filtered granulated powder is dried by fluid bed processing or in a convection oven. The dry granulated powder is reduced to a uniform particle size by a co-mill or other suitable device, and the material is then transferred to a blender. The granulated powder is homogenized with a lubricant (magnesium stearate or sodium stearyl fumarate, about 1% by weight of the total formulation) and an additional disintegrant (about 2-4% by weight of the external powder) mix. The prepared powder is filled into hard gelatin capsules, or the powder is compressed into tablets (the tablets are then film-coated as described below). Capsules or tablets prepared in this way have a total weight of about 200 mg.

                                      45 mg capsule or tablet

Add about 162 mg of filler (lactose, sorbitol, or starch), about 10 mg of disintegrant (crospovidone or sodium starch glycolate), and about 45 mg of F-III into the granulator and mix to distribute the powder evenly. An aqueous granulation solution consisting of povidone (about 35% by weight) and polysorbate 80 (about 10% by weight) was sprayed onto the powder at a uniform rate while mixing. The granulated material is wet sieved through a sieve to separate large agglomerates. The filtered granulated powder is dried by fluid bed processing or in a convection oven. The dry granulated powder is passed through a co-mill or other suitable device, and the material is transferred to a blender. The granulated powder was uniformly mixed with a lubricant (magnesium stearate; about 1% by weight of the total formulation) and an additional disintegrant (about 2% by weight of the external powder). The prepared powder is filled into hard gelatin capsules, or the powder is compressed into tablets (the tablets are then film-coated as described below). The total weight of capsules or tablets prepared in this way is about 230 mg.

Alternatively, to prepare tablets, the filler, disintegrant and F-III are added to a blender and mixed into a uniformly distributed powder. Once the powder is evenly distributed, add the lubricant and mix again. The mixed material is transferred to a tablet press to prepare tablets which are subsequently coated with a suitable film former.

biological test

Ishikawa Cell Proliferation Assay: This assay measures cell proliferation (using an alkaline phosphatase reader) in both an agonist model and an The ability of compounds of the invention to block estradiol stimulation of growth was determined in .

In MEM (minimum essential medium with Earle's salts and L-glutamine, Gibco BRL, Gaithersburg, MD) supplemented with 10% fetal bovine serum (FBS) (V/V) (Gibco BRL) Maintenance of Ishikawa human endometrial tumor cells. The day before the test, the growth medium was switched to the test medium: DMEM/F-12 (3:1) (Dulbecco's Modified Eagle Medium: Nutrient Mixture F-12, 3:1 mixture without phenol red , Gibco BRL), supplemented with 5% dextran-coated charcoal-stripped fetal bovine serum (DCC-FBS) (Hyclone, Logen, UT), L-glutamine (2mM), MEM sodium pyruvate (1mM), HEPES ( N-[2-Hydroxyethyl]piperazine-N'-[2-ethanesulfonic acid] 2 mM), both from Gibco BRL. After overnight incubation, Ishikawa cells were washed with Dulbecco's phosphate-buffered saline (1X) (D-PBS) without Ca ⁺² and Mg ⁺² (Gibco BRL) and washed with 0.25% phenol red-free trypsin/ It was trypsinized with EDTA (Gibco BRL) for 3 minutes. Cells were resuspended in assay medium and adjusted to 250,000 cells/mL. Approximately 25,000 cells in 100 [mu]l medium were plated into flat-bottomed 96-well microplates (Costar 3596) and incubated for 24 hours at 37[deg.]C in a 5% _CO2 humidified incubator. The next day, serial dilutions of the compound in the test medium (6 times the final concentration in the test) were prepared. Experiments were performed in a dual model - agonist model and antagonist model.

For the agonist model, plates received 25 μl/well of assay medium followed by 25 μl/well of diluted compound of the invention (at 6-fold final concentration). For the antagonist model, plates received 25 μl/well of 6 nM E ₂ (β-estradiol, Sigma, St. Louis, MO), and then received 25 μl/well of diluted compounds of the invention (at 6 times the final concentration). ). After an additional 48 h incubation at 37 °C in a 5% _CO2 humidified incubator, the medium was aspirated from the wells and 100 μl of fresh assay medium was added to each microculture. Serial dilutions of compounds were prepared and added to the above cells. After an additional 72 hours of incubation at 37°C in a 5% _CO2 humidified incubator, the medium quench assay was removed and the plates were washed twice in Dulbecco's phosphate buffered saline (1X) (D-PBS) (Gibco BRL). The plates were dried for 5 minutes and frozen at -70°C for at least 1 hour. Plates were then removed from the freezer and thawed at room temperature. 100 [mu]l of 1-Step( ^TM) PNPP (Pierce Chemical Company, Rockford, IL) was added to each well. After 20 minutes of incubation, the plate was read on a spectrophotometer at 405 nm.

Data were fitted with linear interpolation to yield EC50 values (for agonist models) or IC50 values (for antagonist models). For the antagonist model, the % potency of each compound relative to E2 alone (1 nM) was calculated. For the agonist model, the % effect of each compound relative to the response to tamoxifen was calculated.

In the agonist model, F-III was tested, which was less stimulatory than tamoxifen. In the antagonist model, F-III suppressed the 1 nM estradiol response by at least 70%.

10-Day Rat Hormone (Ovarian Stimulation) Screen: An initial initial screen for ovarian toxicity was performed using a 10-day rat hormone study to measure estradiol and luteinizing hormone levels following administration of GYN SERM F-III. The screen is performed by administering compound to mature (9-10 week old) F344 female rats by oral gavage for 10 days. About 2 hours after the 10th dose, trunk blood was taken by rapid decapitation for evaluation of LH and estradiol levels. Serum obtained by centrifugation was removed and stored frozen below -60°C until analysis. Serum levels of LH and estradiol were measured by radioimmunoassay (RIA).

Rat LH primary antibody and reference preparation (rat LH: RP-3) were obtained from Dr.A.E. Parlow, Director, Pituitary Hormones and Antisera Center, Harbor-UCLA Medical Center, Torrance, CA. For 100 μl sample, the upper detection limit of LH assay is 30 ng/mL, and the lower detection limit is 0.1 ng/mL.

E2 clinical assay. DiaSorin s.r.l., Saluggia (Vercelli), Italy. The upper limit of detection is 1000pg/mL, and the lower limit of detection is 5pg/mL. Testing F-III in the assay described above did not significantly increase circulating levels of estradiol or LH.

Practicality

As an antagonist of estrogen in breast and uterine tissue, F-III can be used to treat diseases in which estrogen has been proven to play a key role. As an agonist of estrogen in the skeletal and cardiovascular systems, F-III is useful in the treatment of diseases in which estrogen has been shown to play a beneficial role.

The term "treating" as used herein includes their commonly accepted meanings of alleviating, ameliorating, controlling, preventing, inhibiting, arresting, slowing, terminating or reversing the development or severity of the pathological conditions described herein or their sequelae. The term "preventing" refers to reducing the likelihood that a recipient of a compound of the invention will suffer from or develop any of the pathological conditions described herein or its sequelae.

Diseases, disorders or conditions for which the compounds of the present invention are useful include, but are not limited to, (1) uterine cancer and/or breast cancer; (2) endometriosis; (3) uterine leiomyomas/fibroids; and ( 4) Osteoporosis. Treatment of uterine leiomyomas/fibroids as described herein may reduce associated symptoms such as pain, urinary frequency and uterine bleeding.

dose

The term "effective amount" as used herein refers to an amount of F-III capable of treating the diseases described herein or its deleterious effects.

The particular dosage administered will be specific to each condition. These particular circumstances include the route of administration, the recipient's past medical history, the pathological condition or symptom being treated, the severity of the condition/symptom being treated, and the age and sex of the recipient. The attending physician receiving the patient should determine the therapeutic dose to be administered according to the relevant circumstances.

Generally, the minimum effective daily dose of F-III exceeds about 5 mg. Generally, the maximum effective daily dose will not exceed about 350 mg. The exact dosage will be determined according to "dose escalation" of the recipient according to standard practice in the medical arts; that is, lower doses of the compound are administered initially and the dosage is gradually increased until the desired therapeutic effect is observed.

Route of administration

F-III can be administered by a variety of routes including intramuscular, intranasal, intravaginal, intravenous, oral, rectal, subcutaneous, topical and transdermal. The preferred route of administration is oral.

combination therapy

F-III can be used in combination with other drugs used in the treatment of diseases or conditions in which these compounds are useful. Said other drugs can be administered simultaneously or sequentially with the salts of the present invention by usual routes and doses. When F-III is used simultaneously with one or more other drugs, a pharmaceutical unit dosage form containing said other drugs in addition to the compound of the present invention is preferred. Accordingly, pharmaceutical compositions of the present invention include those that contain one or more other active ingredients. An example of another other active ingredient that may be administered alone or in the same pharmaceutical composition in combination with a compound of the invention includes drugs used in hormone replacement therapy (HRT).

Claims (5)

1. crystalline non-solvent 1-(4-(2-piperidyl ethyoxyl) phenoxy group)-2-(4-mesyl phenyl)-6-hydroxyl naphthalene salts acidulants; when by copper radioactive source (CuK α; λ=when 1.54056_) obtaining X-ray diffracting spectrum; have following peak: 2 θ are 15.2 ± 0.1; 17.6 ± 0.1,18.6 ± 0.1 and 24.1 ± 0.1 °.

2. the salt of claim 2, wherein said X-ray diffracting spectrum also comprises following peak: 2 θ are 16.9 ± 0.1,19.2 ± 0.1,21.3 ± 0.1 and 21.6 ± 0.1 °.

3. treat endometriotic method, this method comprises uses the claim 1 of effective dose or 2 chemical compound to its patient of needs.

4. the method for treatment leiomyoma of uterus, this method comprises uses the claim 1 of effective dose or 2 chemical compound to its patient of needs.

5. claim 1 or 2 chemical compound are used for the treatment of endometriosis and/or leiomyoma of uterus.