Salts and crystal forms of furanopyrimidine compounds and their pharmaceutical uses

Abstract

The salt and crystalline form of the compound of Chemical Formula 1 according to the present invention (i.e., (R)-4-((2-(1-(2-fluoro-6-(trifluoromethyl)benzyl)-2,4-dioxo-1'-((5-(trifluoromethyl)furan-2-yl)methyl)-1H-spiro[furano[3,4-d]pyrimidine-5,4'-piperidinyl]-3(2H,4H,7H)-yl)-1-phenylethyl)amino)butyric acid) are excellent in general physicochemical properties, such as hygroscopicity, related substances, chemical stability, etc., and therefore can be used for pharmaceutical purposes, such as preparing a pharmaceutical composition comprising it as an active ingredient.

Description

Technical Field

[0001] The present invention relates to a salt and a crystal form of a furanopyrimidine compound and its pharmaceutical use. More specifically, the present invention relates to a salt and a crystal form of (R)-4-((2-(1-(2-fluoro-6-(trifluoromethyl)benzyl)-2,4-dioxo-1'-((5-(trifluoromethyl)furan-2-yl)methyl)-1H-spiro[furano[3,4-d]pyrimidine-5,4'-piperidin]-3(2H,4H,7H)-yl)-1-phenylethyl)amino)butyric acid and its pharmaceutical use. Background Art

[0002] The compound of formula 1, which is named (R)-4-((2-(1-(2-fluoro-6-(trifluoromethyl)benzyl)-2,4-dioxo-1'-((5-(trifluoromethyl)furan-2-yl)methyl)-1H-spiro[furano[3,4-d]pyrimidine-5,4'-piperidin]-3(2H,4H,7H)-yl)-1-phenylethyl)amino)butyric acid, is disclosed in Korean Patent No. 1495260 and U.S. Patent No. 9,481,684. The compound is known to be used as a gonadotropin-releasing hormone (GnRH) receptor antagonist and is therefore useful for preventing or treating a variety of sex hormone-related symptoms.

[0003] [Formula 1]

[0004] Summary of the invention

[0005] Technical issues

[0006] In terms of physical properties, the compound of formula 1 (free base) disclosed in the prior art cannot be well used as an active pharmaceutical ingredient (API).

[0007] First, the compound of formula 1 is unsolidified, which causes great difficulty in controlling the residual solvent. In particular, when the compound of formula 1 in a dissolved state is concentrated as much as possible and dried in a vacuum, the compound of formula 1 in the form of a foam can be obtained; however, the compound of formula 1 in the form of a foam is easily wetted and becomes a viscous oily form.

[0008] Second, the compound of Formula 1 has poor stability. Specifically, the compound of Formula 1 decomposes over time to generate related substances because the aminobutyric acid portion in its structure easily forms a lactam ring.

[0009] The present inventors prepared various salts and crystal forms of the compound of formula 1 and tested their physical properties. As a result, the present inventors found that specific salts and crystal forms of the compound reduced decomposition and hygroscopicity and had good stability, which made such salts and crystal forms suitable for pharmaceutical uses, such as the preparation of pharmaceutical compositions; and thus the present invention was completed.

[0010] Therefore, an object of the present invention is to provide a salt and a crystalline form of a furanopyrimidine compound of formula 1, and its pharmaceutical use.

[0011] Solution to the problem

[0012] The present invention provides a salt of the compound of formula 1, wherein the salt is selected from benzenesulfonate, hydrochloride, oxalate, sodium salt and potassium salt.

[0013] [Formula 1]

[0014]

[0015] In addition, the present invention provides a crystalline form of a benzenesulfonate salt of the compound of formula 1.

[0016] In addition, the present invention provides a pharmaceutical composition comprising the salt or crystal form and a pharmaceutically acceptable additive, wherein the pharmaceutical composition is used for preventing or treating sex hormone-related diseases.

[0017] In addition, the present invention provides use of the salt or crystal form for inhibiting sex hormone-related diseases, and use of the salt or crystal form for preparing a medicament for inhibiting sex hormone-related diseases.

[0018] In addition, the present invention provides use of the salt or crystal form for preventing or treating sex hormone-related diseases, and use of the salt or crystal form for preparing a medicament for preventing or treating sex hormone-related diseases.

[0019] In addition, the present invention provides a method for preventing or treating a sex hormone-related disease, comprising the step of administering the salt or crystal form to a subject in need thereof.

[0020] Advantageous Effects of the Invention

[0021] The salts and crystal forms of the compound of formula 1 according to the present invention are excellent in various physicochemical properties, namely hygroscopicity, related substances, physicochemical stability, etc., and can therefore be used for pharmaceutical purposes, such as preparing pharmaceutical compositions containing them as active ingredients. BRIEF DESCRIPTION OF THE DRAWINGS

[0022] Figures 1 to 3 The powder X-ray diffraction (PXRD) spectrum, infrared (IR) spectrum and differential scanning calorimetry (DSC) curve of the crystalline form of the dibenzenesulfonate salt of the compound of Formula 1 according to Example 1 are respectively shown.

[0023] Figure 4 Powder X-ray diffraction (PXRD) spectra of the crystalline form of dibenzenesulfonate of the compound of Formula 1 according to Example 1 before and after storage at 50° C. are shown.

[0024] Best Mode for Carrying Out the Invention

[0025] Hereinafter, the present invention will be described in detail.

[0026] <Salt of the compound of formula 1>

[0027] The present invention provides a salt of the compound of formula 1, wherein the salt is selected from benzenesulfonate, hydrochloride, oxalate, sodium salt and potassium salt.

[0028] [Formula 1]

[0029]

[0030] The compound of Formula 1 can be prepared according to the methods disclosed in Korean Patent No. 1495260 and US Patent No. 9,481,684, the disclosures of which are incorporated herein by reference in their entirety.

[0031] The benzenesulfonate of the compound of formula 1 is obtained by reaction with benzenesulfonic acid and is also referred to as benzenesulfonate. Benzenesulfonate includes monobenzenesulfonate containing one benzenesulfonate group in the molecule, dibenzenesulfonate containing two benzenesulfonate groups in the molecule, etc. Among these, dibenzenesulfonate is conducive to crystallization and is more preferred in terms of physicochemical properties.

[0032] The hydrochloride of the compound of formula 1 includes a monohydrochloride containing one hydrochloride group in the molecule, a dihydrochloride containing two hydrochloride groups in the molecule, etc. Among these, the dihydrochloride is more preferred in terms of physicochemical properties.

[0033] The oxalate salt of the compound of formula 1 includes monooxalate salt containing one oxalate group in the molecule, dioxalate salt containing two oxalate groups in the molecule, etc. Among these, dioxalate salt is more preferred in terms of physicochemical properties.

[0034] The sodium or potassium salt of the compound of formula 1 may contain one sodium or potassium atom in the molecule.

[0035] Meanwhile, the compounds of formula 1 (free base) described in the above-mentioned documents are not solidified and therefore cannot be well used as active pharmaceutical ingredients (API). However, the salts of the compounds of formula 1 according to the present invention are obtained in the solid state and have good physicochemical properties, which makes such salts suitable for use as active pharmaceutical ingredients.

[0036] As a specific example, the salt of the compound of formula 1 can be a solid dibenzenesulfonate, dihydrochloride or dioxalate. As a more specific example, the salt of the compound of formula 1 can be a solid dibenzenesulfonate.

[0037] Furthermore, salts of the compound of Formula 1 can be used for preparing pharmaceutical compositions since such salts have reduced decomposition and hygroscopicity and have good stability.

[0038] For example, the hygroscopicity of the salt may be less than 10 wt%, less than 5 wt%, less than 3 wt%, or less than 1 wt% when placed at 25°C and 60% relative humidity for 1 week. More specifically, the hygroscopicity of the salt may be less than 0.5 wt% when placed at 25°C and 60% relative humidity for 1 week.

[0039] Furthermore, the solubility of the salt in water at 25° C. may be 10 mg / mL or more, 15 mg / mL or more, 20 mg / mL or more, or 25 mg / mL or more, and more specifically, 10 mg / mL to 40 mg / mL, 15 mg / mL to 35 mg / mL, or 20 mg / mL to 30 mg / mL.

[0040] For example, the salt may have a hygroscopicity of less than 0.5 wt % when left at 25°C and 60% relative humidity for 1 week, and a solubility of 15 mg / mL or more in water at 25°C.

[0041] In addition, when the salt is placed at 80°C for 20 hours, the increase of the related substances relative to the initial weight of the salt may be less than 3 wt% or less than 2 wt%. Specifically, when the salt is placed at 80°C for 20 hours, the increase of the related substances relative to the initial weight of the salt may be less than 1 wt%. More specifically, when the salt is placed at 80°C for 20 hours, the increase of the related substances relative to the initial weight of the salt may be less than 0.5 wt% or less than 0.1 wt%.

[0042] <Crystalline Form of Compound of Formula 1>

[0043] The salt of the compound of formula 1 may be prepared in crystalline form, amorphous form or as a mixture thereof, with the crystalline form being preferred.

[0044] Therefore, the present invention provides a crystalline form of a benzenesulfonate salt of the compound of formula 1.

[0045] Generally, salts must possess various physicochemical properties, such as reproducibility in preparing a specific crystalline form, high crystallinity, stability of the crystalline form, chemical stability, and non-hygroscopicity, in order to be used in the pharmaceutical field.

[0046] From this point of view, the crystalline form of the benzenesulfonate salt of the compound of Formula 1 is preferred because it has good stability and physicochemical properties that facilitate formulation. Specifically, the crystalline form may be a crystalline form of a dibenzenesulfonate salt containing two benzenesulfonate groups in the molecule.

[0047] For the benzenesulfonate salt of the compound of Formula 1, tests show that a specific crystal form (hereinafter referred to as "crystal form A") is more advantageous in terms of non-hygroscopicity and physicochemical stability. Such properties may have a positive impact on the dissolution, stability and physical properties of the active pharmaceutical ingredient and its drug product, so the crystal form may be more suitable as an active ingredient of a pharmaceutical composition.

[0048] On the other hand, the benzenesulfonate salt of the compound of Formula 1 may exist in at least one crystalline form; however, another crystalline form obtained therefrom (hereinafter referred to as "crystalline form B") may be in a relatively metastable crystalline state and undergo some crystalline transformations due to changes over time.

[0049] The crystalline form of the besylate salt (Form A) may have a powder X-ray diffraction (PXRD) spectrum including peaks at diffraction angles (2θ±0.2°) of 5.97°, 7.22°, 10.23°, 11.91°, 15.25°, 16.20°, 18.26°, 18.48°, 20.53°, and 23.94°.

[0050] In addition, in addition to the above-mentioned peaks, the powder X-ray diffraction (PXRD) spectrum of the crystalline form (crystalline form A) may also include peaks at diffraction angles (2θ±0.2°) of 6.70°, 12.68°, 13.41°, 19.62°, 19.79°, 22.14°, 22.96° and 24.34°.

[0051] In addition, in addition to the above-mentioned peaks, the powder X-ray diffraction (PXRD) spectrum of the crystalline form (crystalline form A) may also include peaks at diffraction angles (2θ+0.2°) of 9.88°, 15.66°, 17.23°, 17.48°, 18.85°, 19.27° and 29.28°.

[0052] Peak as exemplified above can be a peak with a relative intensity of about 10% or more, 20% or more, 30% or more or 50% or more. In this specification, the relative intensity of a peak is expressed as a percentage of a relative intensity ratio (I / I0), wherein "I0" refers to the maximum peak intensity on a PXRD spectrum, which is set to 100, and "I" refers to the corresponding peak intensity thereon.

[0053] When measured by differential scanning calorimetry (DSC) analysis under a temperature increase condition of 10° C. / min, the crystalline form (crystalline form A) may have an endothermic peak in the range of 200° C. to 300° C. Here, the maximum endothermic peak may exist in the range of about 225° C. to 245° C. or about 232° C. to 236° C. For example, when measured by DSC analysis, the crystalline form (crystalline form A) may have an endothermic peak that starts at 225° C. to 235° C. and reaches a maximum at about 230° C. to 240° C.

[0054] Furthermore, the crystal form (Crystal Form A) can be applied to the preparation of a pharmaceutical composition because such a crystal form has reduced decomposition and hygroscopicity and has good stability.

[0055] For example, when placed at 25° C. and 60% relative humidity for 1 week, the hygroscopicity of the crystalline form (Form A) may be less than 10 wt %, less than 5 wt %, less than 3 wt %, less than 1 wt % or less than 0.5 wt %.

[0056] In addition, the solubility of the crystalline form (crystalline form A) in water at 25° C. may be 10 mg / mL or more, 15 mg / mL or more, 20 mg / mL or more, or 25 mg / mL or more, and more specifically, 10 mg / mL to 40 mg / mL, 15 mg / mL to 35 mg / mL, or 20 mg / mL to 30 mg / mL.

[0057] In addition, when placed at 80°C for 20 hours, the increase in related substances relative to the initial weight of the crystalline form (crystalline form A) may be less than 3 weight %, less than 2 weight %, less than 1 weight %, less than 0.5 weight % or less than 0.1 weight %.

[0058] The crystalline form (crystalline form A) can be prepared by crystallization of the compound of formula 1 or its salt using at least one solvent. The solvent for crystallization can be selected from ethyl acetate, acetone, acetonitrile, and a mixed solvent thereof. Alternatively, the method for preparing the salt of the compound of formula 1 can be the same as the method for preparing its crystalline form.

[0059] <Drug Use>

[0060] As disclosed in U.S. Pat. No. 9,481,684 and the like, the compound of formula 1 has been demonstrated to be useful as a gonadotropin-releasing hormone (GnRH) receptor antagonist and is therefore useful for preventing or treating a variety of sex hormone-related symptoms.

[0061] From this viewpoint, the salt or crystal form of the compound of formula 1 can be used to prevent or treat sex hormone-related diseases.

[0062] As used herein, the term "prevention" refers to any action that inhibits or delays the occurrence, spread or recurrence of a disease by administering a salt or crystalline form of a compound of Formula 1, and the term "treatment" refers to any action that improves or beneficially changes a disease by administering a salt or crystalline form of a compound of Formula 1.

[0063] The present invention provides the use of a salt or a crystal form of a compound of formula 1 for preventing or treating a sex hormone-related disease. In addition, the present invention provides the use of a salt or a crystal form of a compound of formula 1 for preparing a medicament for preventing or treating a sex hormone-related disease.

[0064] In addition, the present invention provides a method for preventing or treating a sex hormone-related disease, comprising the step of administering a salt or a crystal form of the compound of formula 1 to a subject in need thereof.

[0065] As used herein, the term "subject in need thereof" refers to any animal suffering from or capable of developing a disease, particularly mammals, including humans (patients), monkeys, cows, horses, sheep, pigs, chickens, turkeys, quails, cats, dogs, mice, rats, rabbits and guinea pigs. In addition, a subject in need thereof may refer to a biological sample.

[0066] In addition, as used herein, the term "administering" means providing a predetermined substance to a subject in need thereof by any suitable method. For the administration route of the compound of the present invention, any conventional route can be used for administration as long as the route allows the compound to reach its target tissue.

[0067] In addition, the present invention provides a pharmaceutical composition comprising the salt or crystal form and a pharmaceutically acceptable additive.

[0068] The pharmaceutical composition comprising the salt or crystal form of the compound of Formula 1 can be used to prevent or treat sex hormone-related diseases.

[0069] For example, the sex hormone-related disease can be selected from: prostate cancer, breast cancer, ovarian cancer, uterine cancer, pituitary cancer, endometriosis, amenorrhea, menstrual disorders, uterine fibroids, uterine fibroids, polycystic ovary disease, lupus erythematosus, hirsutism, precocious puberty, short stature, acne, alopecia, gonadotropin adenoma, sleep apnea, irritable bowel syndrome, premenstrual syndrome, benign prostatic hyperplasia, infertility and Alzheimer's disease.

[0070] In particular, the pharmaceutical composition comprising the salt or crystalline form of the compound of Formula 1 is effective in preventing or treating endometriosis and uterine fibroids.

[0071] The dosage of the salt or crystal form of the compound of formula 1 or the pharmaceutical composition comprising it can vary according to the severity of the object to be treated, the disease or the condition, the rate of administration and the judgment of the prescribing doctor. Generally, based on the free alkali of the compound of formula 1 as the active ingredient, the compound can be administered once to twice a day or using an on / off schedule to mammals including humans by oral or parenteral routes in an amount of 0.01mg / kg (body weight) to 100mg / kg (body weight), preferably 0.2mg / kg (body weight) to 50mg / kg (body weight). In some cases, a smaller dosage than the above range may be more appropriate, and a larger dosage that does not cause harmful side effects may also be used. In the case of using a larger dose, the dosage can be divided into several smaller dosages in one day.

[0072] The pharmaceutical composition according to the present invention can be formulated according to conventional methods, and can be prepared into various oral dosage forms, such as tablets, pills, powders, capsules, syrups, emulsions and microemulsions, or parenteral dosage forms, such as for intramuscular, intravenous or subcutaneous administration.

[0073] The pharmaceutical composition may contain any conventional non-toxic pharmaceutically acceptable additives, such as carriers, diluents, adjuvants and excipients. In the case where the pharmaceutical composition according to the present invention is prepared in the form of an oral dosage form, some examples of the carrier used include cellulose, calcium silicate, corn starch, lactose, sucrose, dextrose, calcium phosphate, stearic acid, magnesium stearate, calcium stearate, gelatin, talc, surfactants, suspending agents and emulsifiers. In addition, in the case where the pharmaceutical composition according to the present invention is prepared in the form of an oral dosage form, some examples of the diluent used include lactose, mannitol, sugar, microcrystalline cellulose and cellulose derivatives and dried corn starch. In the case where the pharmaceutical composition according to the present invention is prepared in the form of an injection, some examples of the carrier used include water, saline, glucose aqueous solution, pseudo sugar aqueous solution, Alcohols, glycols, ethers (e.g., polyethylene glycol 400), oils, fatty acids, fatty acid esters, glycerides, surfactants, suspending agents, and emulsifiers.

[0074] Invention Mode

[0075] Hereinafter, the present invention will be described by specific examples. However, the following examples are only for illustrating examples of the present invention, and the scope of the present invention is not limited thereto.

[0076] Preparation Example 1: Preparation of the compound of formula 1

[0077] According to the method of U.S. Patent No. 9,481,684 cited herein or a method analogous thereto, the free base of the compound of Formula 1 (i.e., (R)-4-((2-(1-(2-fluoro-6-(trifluoromethyl)benzyl)-2,4-dioxo-1'-((5-(trifluoromethyl)furan-2-yl)methyl)-1H-spiro[furo[3,4-d]pyrimidine-5,4'-piperidin]-3(2H,4H,7H)-yl)-1-phenylethyl)amino)butanoic acid) is obtained as a white foam.

[0078] 1 H-NMR (600MHz, DMSO-d6) δ1.39 (d, 1H, J = 11.5Hz), 1.43-1.52 (m, 3H), 2.00 (td, 1H, J =13.2, 4.5Hz), 2.09-2.21(m, 4H), 2.21-2.31(m, 3H), 2.63-2.72(m, 2H), 3.60(s, 2H) , 3.78-3.87(m, 2H), 3.87-3.94(m, 1H), 4.88(s, 2H), 4.98(s, 2H), 6.53(d, 1H, J=3.4H z), 7.12-7.19 (m, 4H), 7.22 (t, 2H, J=7.3Hz)), 7.52-7.62 (m, 2H), 7.62-7.66 (m, 1H).

[0079] <Preparation of Salt of Compound of Formula 1>

[0080] Example 1. Preparation of dibenzenesulfonate of compound of formula 1

[0081] A solution (20 mL) of ethyl acetate / acetone (1 / 3, volume / volume) of the compound of formula 1 (free base, 2.0 g) was cooled to 5° C., and 2.2 equivalents of benzenesulfonic acid (2M solution in acetone, 2.9 mL) were then added thereto. Stirring was performed at 5° C. for 3 hours under a nitrogen atmosphere, and then at room temperature for 12 hours. The resulting solid was filtered and dried in a vacuum at room temperature for 12 hours to obtain 2.6 g of a white solid (91% yield).

[0082] 1H-NMR (600MHz, DMSO-d6) δ1.56 (d, 1H, J=14.6Hz), 1.67-1.80 (m, 3H), 2.13 (t, 1H, J=12.1Hz), 2. 23(td, 2H, J=7.2, 3.0Hz), 2.27-2.35(m, 1H), 2.59-2.68(m, 1H), 2.86-2.94(m, 1H), 3.09-3.20( m, 2H), 3.32-3.51 (m, 2H), 4.08-4.18 (m, 1H), 4.40-4.51 (m, 2H), 4.57 (s, 2H), 4.98 (s, 2H), 4.99 (s, 2H), 6.93 (s, 1H), 7.22 (s, 1H), 7.23 (s, 1H), 7.27-7.40 (m, 10H), 7.57-7.68 (m, 7H), 9.01 (br s, 1H), 9.08 (br s, 1H), 9.97 (br s, 1H), 12.22 (br s, 1H).

[0083] 13 C-NMR (600MHz, DMSO-d6) δ21.12, 30.33, 31.11, 31.23, 41.80, 43.82, 45.06, 48.13, 50.57, 59.21 , 69.05, 82.90, 109.39, 114.46, 115.73, 116.17, 117.94, 119.71, 120.76, 120.90, 121.48, 121.7 5, 121.84, 122.50, 122.60, 124.42, 125.52, 127.73, 128.19, 128.62, 128.69, 128.80, 129.43, 130.39, 130.47, 132.07, 141.26, 147.84, 147.92, 151.10, 153.85, 157.47, 160.23, 161.87, 173.47.

[0084] Example 2. Preparation of dihydrochloride salt of compound of formula 1

[0085] A 1,4-dioxane solution (50 mL) of the compound of formula 1 (free base, 1.4 g) was cooled to 5 ° C, and then 2.2 equivalents of hydrochloric acid (350 μL concentrated HCl aqueous solution) were added thereto. Stirring was carried out at room temperature for 1 hour. Sodium sulfate was added to the reaction solution. The resultant was dried and filtered, and then washed with 1,4-dioxane (10 mL). The filtrate was concentrated to 1 / 5 of the volume under reduced pressure. The resulting solid was filtered and dried in a vacuum at room temperature for 24 hours to obtain 1.5 g of a white solid (yield: 94%).

[0086] 1 H-NMR (400MHz, MeOD-d4) 1.85-2.03 (m, 4H), 2.40 (t, 2H, J=6.9Hz), 2.43-2.60 (m, 2H), 2.80-2.8 9(m, 1H), 2.95-3.04(m, 1H), 3.33-3.42(m, 2H), 3.45-3.55(m, 2H), 4.42(dd, 1H, J=13.7, 7.5Hz), 4.51 (dd, 1H, J=13.8, 6, 7Hz), 4.56 (s, 2H), 4.66 (t, 1H, J=7.1Hz), 5.02 (s, 2H) 5.13 (dd, 2H, J=32 .2, 16.2Hz), 6.96 (d, lH, J=3.3Hz), 7.15 (d, 1H, J=2.8Hz), 7.37-7.47 (m, 6H), 7.58-7.66 (m, 2H).

[0087] Example 3. Preparation of dioxalate of compound of formula 1

[0088] A solution of the compound of formula 1 (free base, 1.5 g) in ethyl acetate (10 mL) was cooled to 5 ° C, and then 2.2 equivalents of oxalic acid (0.55 M solution in ethyl acetate, 8 mL) were added thereto. Stirring was performed at room temperature for 4 hours under a nitrogen atmosphere. The reaction solution was concentrated to 1 / 2 volume and stirred at 5 ° C for 5 hours. The resulting solid was filtered and dried in a vacuum at room temperature for 12 hours to obtain 1.8 g of a white solid (yield: 93%).

[0089] 1 H-NMR (300MHz, MeOD-d4) δ1.78-1.98 (m, 4H), 2.33 (t, 2H, J=7.0Hz), 2.40-2.60 (m, 2H), 2.7 1-2.82 (m, 1H), 2.87-2.98 (m, 1H), 3.22-3.29 (m, 2H), 3.42-3.51 (m, 2H), 4.32 (dd, 1H, J=13. 3, 6.4Hz), 4.44-4.51 (m, 3H), 4.70 (dd, 1H, J=8.3, 6.0Hz), 4.96 (s, 2H), 5.13 (dd, 2H, J=42. 8, 16.2Hz), 6.88 (d, 1H, J = 3.4Hz), 7.07-7.11 (m, 1H), 7.37-7.44 (m, 6H), 7.52-7.64 (m, 2H).

[0090] Example 4. Preparation of the sodium salt of the compound of formula 1

[0091] 1.1 equivalents of sodium hydroxide (2mL methanol solution) are added to a solution (5mL) of Formula 1 compound (free alkali, 1.5g) in methanol. Stirring was carried out at room temperature for 2 hours. The reaction solution was concentrated. Then, distilled water (13mL) and n-butanol (12mL) were added. 30% by weight of NaOH aqueous solution (2mL) was added. The reaction solution was shaken to separate the layers. Then, the organic layer was recovered, and the water layer was extracted twice more with n-butanol (5mL). The organic layer was collected and sequentially washed with saturated sodium chloride aqueous solution (10mL) and distilled water (10mL). The organic layer was concentrated and dried in a vacuum to obtain a yellow foam. It was dissolved in methyl tert-butyl ether (MTBE, 20mL), and then filtered through a polytetrafluoroethylene (PTFE) membrane (0.45 μm). The filtrate was concentrated. The concentrate was dissolved in MTBE (2mL), and then stirred while slowly adding n-heptane (10mL). The resultant was stirred for another 1 hour, filtered, and dried in vacuo to obtain 1.2 g of a white solid (yield: 82%).

[0092] 1 H-NMR (300MHz, CDCl3) δ1.30-1.57 (m, 4H), 1.88-2.02 (m, 2H), 2.11-2.35 (m, 6H), 2.63-2.74 (m, 2H), 3.54 (s, 2H), 3.87-4. 09 (m, 3H), 4.57 (s, 2H), 4.96-5.11 (m, 2H), 6.25 (d, 1H, J=3.2Hz), 6.65-6.69 (m, 1H), 7.05-7.24 (m, 6H), 7.34-7.49 (m, 2H).

[0093] Example 5. Preparation of potassium salt of compound of formula 1

[0094] 1.1 equivalents of potassium hydroxide (2mL methanol solution) are added to a methanol solution (5mL) of formula 1 compound (free alkali, 1.5g). Stirring was carried out at room temperature for 17 hours. The reaction solution was concentrated. Then, distilled water (13mL) and n-butanol (12mL) were added. A 30% by weight KOH aqueous solution (2mL) was added. The reaction solution was shaken to separate the layers. Then, the organic layer was recovered, and the water layer was extracted once more with n-butanol (10mL). The organic layer was collected and sequentially washed with saturated potassium chloride aqueous solution (10mL) and distilled water (10mL). The organic layer was concentrated and dried in a vacuum to obtain a yellow foam. It was dissolved in methyl tert-butyl ether (MTBE, 20mL), and then filtered through a polytetrafluoroethylene (PTFE) membrane (0.45 μm). The filtrate was concentrated. The concentrate was dissolved in MTBE (2mL), and then stirred while slowly adding n-heptane (10mL). The resultant was stirred for another 1 hour, filtered, and dried in vacuo to obtain 1.3 g of a white solid (yield: 84%).

[0095] 1 H-NMR (300MHz, CDCl3) δ1.26-1.54(m, 4H), 1.85-1.97(m, 2H), 2.08-2.35(m, 6H), 2.64-2.74(m, 2H), 3.54(s, 2H), 3.89- 4.06 (m, 3H), 4.58 (s, 2H), 5.02 (s, 2H), 6.25 (d, 1H, J=3.1Hz), 6.66-6.70 (m, 1H), 7.05-7.24 (m, 6H), 7.36-7.49 (m, 2H).

[0096] Comparative Example 1. Preparation of diphosphate salt of compound of formula 1

[0097] A dichloromethane solution (2 mL) of the compound of formula 1 (free base, 1.5 g) was cooled to 5 ° C, and then 2.2 equivalents of phosphoric acid (1M solution in ethanol, 4.4 mL) were added thereto. Stirring was performed at room temperature for 12 hours under a nitrogen atmosphere. The reaction solution was concentrated under reduced pressure, dissolved in 5 mL of ethanol, and stirred at 5 ° C for 5 hours under a nitrogen atmosphere. The reaction solution was concentrated under reduced pressure, and then dried in a vacuum at room temperature for 12 hours to obtain 1.9 g of white foam (yield: 98%).

[0098] 1H-NMR (300 MHz, MeOD-d4) δ 1.73-1.92(m, 4H), 2.33(t, 2H, J=6.9Hz), 2.37-2.56(m, 2H), 2.69-2.89 (m, 2H), 3.06 (t, 2H, J=11.2Hz), 3.22-3.32 (m, 2H), 4.28 (s, 2H), 4.33-4. 43(m, 2H), 4.56(t, 1H, J=7.1Hz), 4.91(s, 2H), 4.99-5.12(m, 2H), 6.85(d , 1H, J=3.5Hz), 7.01-7.05(m, 1H), 7.30-7.41(m, 6H), 7.48-7.60(m, 2H).

[0099] Comparative Example 2. Preparation of disulfate salt of compound of formula 1

[0100] A dichloromethane solution (1 mL) of the compound of formula 1 (free base, 0.50 g) was cooled to 5° C., and then 2.2 equivalents of sulfuric acid (a solution obtained by dissolving 77 μL of sulfuric acid in 1 mL of dichloromethane) was added thereto. Stirring was performed at room temperature for 1 hour under a nitrogen atmosphere. The reaction solution was concentrated under reduced pressure and dried in a vacuum at room temperature for 12 hours to obtain 0.40 g of a white foam (yield: 64%).

[0101] 1 H-NMR (300MHz, MeOD-d4) δ1.65-1.90 (m, 4H), 2.34-2.54 (m, 4H), 2.76-2.92 (m, 4H), 3.16 (d, 2H, J=12.0Hz), 4.13 (s, 2H), 4.32-4.47 (m, 2H) ), 4.59 (t, 1H, J=7.2Hz), 4.93 (s, 2H), 5.02-5.15 (m, 2H), 6.80 (d, 1H, J=3.5Hz), 7.00-7.04 (m, 1H), 7.35-7.44 (m, 6H), 7.52-7.63 (m, 2H).

[0102] Comparative Example 3. Preparation of ditoluene sulfonate of the compound of formula 1

[0103] A dichloromethane solution (1 mL) of the compound of formula 1 (free base, 0.50 g) was cooled to 5° C., and then 2.2 equivalents of toluenesulfonic acid (a solution obtained by dissolving 276 mg of toluenesulfonic acid in 1 mL of ethanol / ethyl acetate (3 / 7, volume / volume)) was added thereto. Stirring was performed at room temperature for 12 hours under a nitrogen atmosphere. The reaction solution was concentrated under reduced pressure and then dried in a vacuum at room temperature for 12 hours to obtain 0.59 g of a white foam (yield: 81%).

[0104] 1 H-NMR (300MHz, MeOD-d4) δ1.76-1.86 (m, 2H), 1.90-1.98 (m, 2H), 2.22 (t, 2H, J=7.0Hz), 2.37 (s, 6H), 2.40-2.58(m, 2H), 2.68-2.78(m, 1H), 2.82-2.92(m, 1H), 3.33-3.41(m, 2H), 3.44-3.54(m, 2H), 4.33- 4.48 (m, 2H), 4.54 (s, 2H), 4.61-4.66 (m, 1H), 4.98 (s, 2H), 5.12 (dd, 2H, J=36.9, 16.2Hz), 6.93 (d, 1H, J=6.94Hz), 7.11-7.14(m, 1H), 7.24(d, 4H), 7.36-7.45(m, 6H), 7.54-7.64(m, 2H), 7.69-7.73(m, 4H).

[0105] <Evaluation of Physical Properties of Salts of Compounds of Formula 1>

[0106] Test Example 1. Hygroscopicity

[0107] Each salt (dibenzenesulfonate, dihydrochloride, dioxalate, sodium salt, potassium salt) prepared in the above examples was placed at 25°C and 60% or 90% relative humidity for 1 week, and its hygroscopicity was measured. Here, hygroscopicity is measured as the percentage of weight increase relative to the initial weight measured after the hygroscopicity test. The results are shown in Table 1 below.

[0108] [Table 1]

[0109] Hygroscopicity Dibenzenesulfonate Dihydrochloride Dioxalate Sodium salt Potassium salt 25℃, 60%RH 0.06 wt% 2.1 wt% 3.5 wt% 8.7 wt% 9.2 wt% 25℃, 90%RH 0.9 wt% 16 wt% 19 wt% 35 wt% 38 wt%

[0110] As shown in the above table, the salts in the Examples showed low hygroscopicity at 25° C. and 60% relative humidity, and in particular, the dibenzenesulfonate in Example 1 showed very low hygroscopicity even at 25° C. and 90% relative humidity. In contrast, the salts prepared in the Comparative Examples, i.e., the diphosphate, disulfate and dibenzenesulfonate, were obtained in the form of foams similar to the free base and were easily wetted and turned into a viscous oily form.

[0111] Test Example 2. Chemical Purity

[0112] Each salt (dibenzenesulfonate, dihydrochloride, sodium salt, potassium salt) prepared in the above embodiment is placed at 80°C for 20 hours, and then the change amount of the related substance is measured. In addition, each salt is placed at 80°C for 21 days, and then the remaining amount of the main compound (formula 1 compound) is measured. In order to measure the related substances and the main compound, samples are obtained before and after exposure to 80°C, dissolved in a diluted solution at a concentration of 1mg / mL, and then subjected to high performance liquid chromatography (HPLC). According to the obtained data, the increase of the related substances is calculated by measuring the peak area of ​​the related substances based on lactam relative to the peak area of ​​the main compound. In addition, for comparison, the same test was also carried out for the free base of the compound of formula 1. The results are shown in Tables 2 and 3 below.

[0113] Furthermore, in a similar manner, the dibenzenesulfonate prepared in the above example was stored for 3 months (at 40°C and 75% relative humidity), and the changes in the amounts of related substances and the main compound based on lactam were measured. The results are shown in Table 4 below.

[0114] [Table 2]

[0115] Increase in related substances Free base Dibenzenesulfonate Dihydrochloride Sodium salt Potassium salt After 20 hours at 80°C 79.0％ 0.0％ 0.9％ 0.6％ 0.4％

[0116] [Table 3]

[0117] Remaining amount of main compound Free base Dibenzenesulfonate Dihydrochloride Sodium salt Potassium salt After 21 days at 80°C 1.4％ 99.6％ 69.4％ 77.0％ 72.6％

[0118] [Table 4]

[0119]

[0120]

[0121] As shown in Tables 2 and 3, the free base showed an increase of about 79% of related substances, while the salts in Examples showed a small increase of related substances and thus had good stability. In particular, the dibenzenesulfonate in Example 1 did not produce any related substances and thus had very good stability. In addition, as shown in Table 4, it was confirmed that the salts in Examples were very stable even when left at 40° C. and 75% relative humidity for 3 months.

[0122] Test Example 3. Water Solubility

[0123] The dibenzenesulfonate salt, which showed the best results in the hygroscopicity and stability tests, was compared with the free base in terms of water solubility. Water solubility was obtained as follows. The free base and dibenzenesulfonate salt were each dissolved in distilled water at 25°C to make it supersaturated. Then, the solution was taken out and diluted 20 times with a diluent for dissolution. Then, the result was subjected to high performance liquid chromatography (HPLC). In the obtained data, the dissolved amount was calculated from the peak area of ​​the main compound. The results are shown in Table 5 below.

[0124] [Table 5]

[0125]

[0126] As shown in Table 5, the dibenzenesulfonate salt exhibits greatly improved water solubility compared to the low water solubility of the free base. This increase in water solubility improves its disintegration and dissolution rate in drug products, which makes this compound very ideal for use as an active pharmaceutical ingredient (API).

[0127] Test Example 4. Stability of Drug Products

[0128] Each salt (dibenzenesulfonate, dihydrochloride, sodium salt, potassium salt) prepared in the above examples is used, together with the excipient composition as shown in Table 6 below, to prepare a drug product in the form of an oral capsule. The drug product is placed at 50 ° C and 80% humidity for 3 weeks, and then the change in the amount of the related substance is measured. In order to measure the related substance, the contents are separated from the capsule and then all placed in a dilute solution so that the active ingredient reaches a concentration of 1 mg / mL. Shake for 5 minutes. Take the supernatant and filter. Take the filtrate and perform high performance liquid chromatography (HPLC). According to the obtained data, the peak area of ​​the main compound (active ingredient) and the percentage of the peak area of ​​the related substance based on lactam are measured. In addition, for comparison, the free base of Formula 1 compound is also tested in the same manner. The salt and free base used for this test all have a chemical purity of 98% or higher. The results are shown in Table 7 below.

[0129] [Table 6]

[0130] Element effect quantity Free base or salt Active ingredients 3mg Silicon dioxide Lubricants 0.6mg Lactose hydrate Fillers 121mg Crospovidone Disintegrants 15mg talc Glidants 1.2mg

[0131] [Table 7]

[0132] Stability of drug products Active ingredients Related substances Free base based drug products 14.6％ 80.6％ Dibenzenesulfonate-based pharmaceutical products 98.3％ 0.60％ Sodium salt-based pharmaceutical products 55.7％ 37.3％ Potassium salt-based pharmaceutical products 60.9％ 31.0％ Hydrochloride-based drug products 49.7％ 41.4％

[0133] As shown in Table 7, the salts in the examples maintained high chemical purity compared to the free base. In particular, the dibenzenesulfonate salt in Example 1 showed very good stability. In contrast, the free base-based drug product showed greatly reduced stability when stored at 50°C and 80% relative humidity for 3 weeks.

[0134] <Crystallization Analysis of Dibenzenesulfonate Salt of Formula 1 Compound>

[0135] Test Example 5. Powder X-ray Diffraction (PXRD)

[0136] The solid product (crystal form A) obtained in Example 1 was subjected to powder X-ray diffraction (PXRD). The results are shown in Figure 1 and Table 8 below.

[0137] -Instrument: Maker BrukerAXS, D8 FOCUS

[0138] -Conditions: 40 kV, 30 mA, 2θ / θ scanning range from 3° to 50°

[0139] [Table 8]

[0140]

[0141] Test Example 6. Infrared (IR) Spectrum

[0142] The solid product (crystal form A) obtained in Example 1 was subjected to infrared (IR) spectroscopy. The instrument and conditions used for infrared spectroscopy and the results thereof are shown in Tables 9 and Figure 2 middle.

[0143] [Table 9]

[0144]

[0145] Test Example 7. Differential Scanning Calorimetry (DSC)

[0146] The solid product (form A) obtained in Example 1 was subjected to differential scanning calorimetry (DSC). The results are shown in Figure 3 middle.

[0147] -Instrument: PERKIN ELMER DSC8000

[0148] -Analysis conditions: 3.8 mg sample, temperature rise 10°C per minute

[0149] like Figure 3 As shown in , the DSC curve shows an endothermic peak starting at 230.73°C and reaching a maximum value at about 235.18°C.

[0150] Test Example 8. Evaluation of Crystal Stability

[0151] The solid product (crystal form A) obtained in Example 1 was dried at 50° C. in vacuum and then subjected to powder X-ray diffraction as described above. Figure 4 Examples are given in the following sections.

[0152] like Figure 4 As illustrated in , it was found that the solid product (Form A) obtained in Example 1 retained the same crystal structure as it initially had even after drying at 50° C. in vacuum, and thus had good stability.

[0153] On the other hand, a solid product (crystal form B) was obtained in a similar manner to Example 1 using 1,4-dioxane as a solvent, and powder X-ray diffraction was performed as described above. As a result, it was determined that the solid product did not retain some of its original crystal structure after drying in a vacuum at 50° C., and therefore had relatively low stability compared to the solid product (crystal form A) obtained in Example 1.

Claims

1. A crystalline form of a dibenzenesulfonate salt of a compound of formula 1, wherein the crystalline form has a powder X-ray diffraction spectrum comprising peaks at diffraction angles of 5.97°, 7.22°, 10.23°, 11.91°, 15.25°, 16.20°, 18.26°, 18.48°, 20.53° and 23.94°: [Formula 1] 2. The crystalline form of claim 1, wherein when measured by differential scanning calorimetry (DSC) analysis under a temperature increase condition of 10°C / min, the crystalline form has a maximum endothermic peak in the range of 225°C to 245°C.

3. A pharmaceutical composition comprising: The crystalline form according to any one of claims 1 to 2; and Pharmaceutically acceptable additives.

4. Use of the crystalline form according to any one of claims 1 to 2 for preparing a medicament for preventing or treating a sex hormone-related disease, wherein the sex hormone-related disease is selected from the group consisting of prostate cancer, breast cancer, ovarian cancer, uterine cancer, pituitary cancer, endometriosis, amenorrhea, menstrual disorders, uterine fibroids, uterine fibroids, polycystic ovary disease, lupus erythematosus, hirsutism, precocious puberty, short stature, acne, alopecia, gonadotropin adenoma, sleep apnea, irritable bowel syndrome, premenstrual syndrome, benign prostatic hyperplasia, infertility and Alzheimer's disease.

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