SALT AND CRYSTAL OF TRIAZOLOPYRAZINE DERIVATIVE

Abstract

[Problem] Provided are a salt of (4-fluorophenyl)[(8R)-8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6-dihydro[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl]methanone, and a crystal of the salt.

[Element for Solution] Salts of (4-fluorophenyl)[(8R)-8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6-dihydro[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl]methanone with various acids have been studied. As a result, a pharmaceutically acceptable salt of the compound and a crystal of the salt have been found.

That is, the present invention relates to a salt of the compound and a crystal of the salt. Furthermore, the present invention relates to a pharmaceutical composition including a salt of the compound or a crystal of the salt, and one or more excipients.

Claims

1. A pharmaceutically acceptable salt of (4-fluorophenyl)[(8R)-8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6-dihydro[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl]methanone.

2. The salt according to claim 1, wherein the salt is a hydrochloride, a hydrobromide, a sulfate, a p-toluenesulfonate, a methanesulfonate, or a benzenesulfonate.

3. The salt according to claim 2, wherein the salt is the hydrochloride.

4. The salt according to claim 2, wherein the salt is the hydrobromide.

5. The salt according to claim 2, wherein the salt is the sulfate.

6. The salt according to claim 2, wherein the salt is the p-toluenesulfonate.

7. The salt according to claim 2, wherein the salt is the methanesulfonate.

8. The salt according to claim 2, wherein the salt is the benzenesulfonate.

9. A crystal of the salt according to claim 3.

10. The crystal according to claim 9, wherein in a powder X-ray diffraction using Cu as a radiation source, the crystal has peaks at 2θ(°) of 6.4, 10.2, 12.0, 12.9, 14.5, 16.1, 16.8, 17.9, 22.7 and 26.7.

11. A crystal of the salt according to claim 4.

12. The crystal according to claim 11, wherein in a powder X-ray diffraction using Cu as a radiation source, the crystal has peaks at 2θ(°) of 6.4, 9.2, 10.3, 12.0, 12.8, 14.5, 17.0, 18.4, 22.6 and 26.1.

13. A crystal of the salt according to claim 5.

14. The crystal according to claim 13, wherein in a powder X-ray diffraction using Cu as a radiation source, the crystal has peaks at 2θ(°) of 6.2, 10.9, 12.5, 14.0, 15.3, 16.3, 18.7, 19.5, 21.3 and 24.1.

15. The crystal according to claim 13, wherein in a powder X-ray diffraction using Cu as a radiation source, the crystal has peaks at 2θ(°) of 7.1, 10.0, 15.2, 16.7, 17.6, 18.5, 19.7, 23.5, 24.2, and 25.3.

16. A crystal of the salt according to claim 6.

17. The crystal according to claim 16, wherein in a powder X-ray diffraction using Cu as a radiation source, the crystal has peaks at 2θ(°) of 6.7, 8.1, 10.0, 12.5, 13.0, 13.4, 14.9, 15.3, 18.0, and 23.5.

18. A crystal of the salt according to claim 7.

19. The crystal according to claim 18, wherein in a powder X-ray diffraction using Cu as a radiation source, the crystal has peaks at 2θ(°) of 7.0, 9.9, 15.1, 16.6, 17.5, 18.4, 19.3, 19.6, 23.2, and 24.0.

20. A crystal of the salt according to claim 8.

21. The crystal according to claim 20, wherein in a powder X-ray diffraction using Cu as a radiation source, the crystal has peaks at 2θ(°) of 6.8, 8.2, 10.1, 11.6, 12.6, 14.9, 15.5, 18.1, 22.5, and 23.5.

22. The salt according to claim 1, wherein the salt is 1-hydroxy-2-naphthoate.

23. A crystal of the salt according to claim 22.

24. The crystal according to claim 23, wherein in a powder X-ray diffraction using Cu as a radiation source, the crystal has peaks at 2θ(°) of 3.8, 6.4, 7.7, 8.5, 11.3, 12.9, 16.0, 16.7, 17.1, and 18.7.

25. A pharmaceutical composition comprising the salt according to claim 1 and a pharmaceutically acceptable excipient.

26. The pharmaceutical composition according to claim 25, which is a pharmaceutical composition for treating a disease associated with an NK3 receptor.

27. A method for the manufacture of a pharmaceutical composition for treating a disease associated with an NK3 receptor comprising providing the salt of claim 1, and combining the salt with a pharmaceutically acceptable excipient.

28. (canceled)

29. The salt according to claim 1, for use in treating a disease associated with an NK3 receptor.

30. A method for treating a disease associated with an NK3 receptor, the method comprising administering an effective amount of the salt according to claim 1 to a subject.

Description

TEST EXAMPLE

[0029] Test methods, measurement conditions, and results of a solubility test of Compound A and various salts of Compound A are shown below.

Test Method 1: Test Method of Free Form, Hydrochloride, Hydrobromide, Sulfate, Methanesulfonate, and Benzenesulfonate

[0030] Into a 10 mL centrifuge tube, 0.5 to 1 mg of a sample was weighed and each dissolving solution (see below) was added thereto to be approximately 150 μg/mL. In order to uniformly disperse the sample in the dissolving solution, the sample was irradiated with ultrasonic waves in a water tank for a short time, and then vigorously shaken at room temperature for 10 minutes using a shaker SA-31 manufactured by Yamato Scientific Co., Ltd. The solution after shaken was filtered with a filter, and a concentrations of the compound in filtrate was quantified by HPLC. The following was used as the dissolving solution.

[0031] JP1 (Japanese Pharmacopoeia 1.sup.st Fluid for disintegration test): manufactured by Nacalai Tesque Inc.

[0032] JP2 (Japanese Pharmacopoeia 2.sup.nd Fluid for disintegration test): manufactured by Nacalai Tesque Inc.

[0033] JP2+TC: Add sodium taurocholate to Japanese Pharmacopoeia 2.sup.nd Fluid for disintegration test to obtain a concentration of 15 mM.

[0034] FaSSIF (artificial intestinal fluid (fasted state)): To 1 L of water, 3 mmol of sodium taurocholate, 0.75 mmol of lecithin, 3.9 g of potassium dihydrogen phosphate, and 7.7 g of potassium chloride are added, and a pH thereof is adjusted to approximately 6.5 using sodium hydroxide.

[0035] FeSSIF (artificial intestinal fluid (fed state)): To 1 L of water, 15 mmol of sodium taurocholate, 3.75 mmol of lecithin, 8.65 g of acetic acid, and 15.2 g of potassium chloride are added, and a pH is adjusted to approximately 5.0 using sodium hydroxide.

Test Method 2: Test Method for p-Toluenesulfonate and 1-Hydroxy-2-Naphthoate

[0036] Into a 10 mL centrifuge tube, 1 to 1.3 mg of a sample was weighed, and each dissolving solution (see below) was added thereto to be approximately 300 μg/mL. In order to uniformly disperse the sample in the dissolving solution, the sample was irradiated with ultrasonic waves in a water tank for a short time, and then vigorously shaken at room temperature for 10 minutes using a shaker SA-31 manufactured by Yamato Scientific Co., Ltd. The solution after shaken was filtered with a filter, and a concentration of the compound in filtrate was quantified by HPLC. The same dissolving solution as in Test Method 1 was used.

[0037] (Measurement condition 1 using HPLC: Measurement conditions of free form, hydrochloride, hydrobromide, sulfate, methanesulfonate, and benzenesulfonate)

[0038] Equipment: LC-1260 manufactured by Agilent Technologies

[0039] Mobile phase: A: 0.01 M aqueous solution of ammonium acetate, B: 0.01 M methanol solution of ammonium acetate

[0040] Flow rate: 0.3 mL/min

[0041] Column: Develosil Combi-RP-5 5 μm (2.0 mm×50 mm)

[0042] Column temperature: 40° C.

[0043] Gradient conditions: proportion of mobile phase B 10-50% (0-0.5 min), 50-100% (0.5-5 min), 100% (5-7 min), 10% (7.1-11.5 min)

[0044] Injection volume: 10 μL

[0045] Detection wavelength: 254 nm

[0046] (Measurement condition 2 using HPLC: Measurement conditions of p-toluenesulfonate and 1-hydroxy-2-naphthoate)

[0047] Equipment: LC-1260 manufactured by Agilent Technologies

[0048] Mobile phase: A: 0.1% aqueous perchloric acid, B: methanol

[0049] Flow rate: 0.3 mL/min

[0050] Column: YMC-Triart C18 S-3 μm (2.0 mm×50 mm)

[0051] Column temperature: 40° C.

[0052] Gradient conditions: proportion of mobile phase B 10-50% (0-0.5 min), 50-100% (0.5-5 min), 100% (5-7 min), 10% (7.1-11.5 min)

[0053] Injection volume: 10 μL

[0054] Detection wavelength: 254 nm

[0055] (Result)

[0056] Table 1 shows results of solubility of Compound A and various salts of Compound A in terms of their free forms. Ex indicates Example Number to be described later.

TABLE-US-00001 TABLE 1 Ex Solubility (μg/mL) JP1 JP2 JP2 + TC FaSSIF FeSSIF Compound A 66.6 65.4 82.9 36.5 31.9 1 Hydrochloride of Compound A >100 >100 >100 >100 >100 2 Hydrobromide of Compound A >100 >100 >100 >100 >100 3 Sulfate of Compound A >100 >100 >100 >100 >100 4 Sulfate of Compound A >100 >100 >100 >100 >100 5 p-Toluenesulfonate of Compound A >100 >100 >100 >100 >100 6 Methanesulfonate of Compound A >100 >100 >100 >100 >100 7 Benzenesulfonate of Compound A >100 >100 >100 >100 >100 8 1-Hydroxy-2-naphthoate of 58.9 >100 >100 >100 >100 Compound A

EXAMPLE

[0057] Hereinafter, the present invention will be described specifically with reference to Examples. However, the present invention is not limited by these Examples and does not limit the scope of the present invention.

[0058] In addition, in Examples, the following abbreviations may be used.

[0059] ESI+: m/z value in mass spectrometry (ionization method ESI, unless otherwise noted, [M+H].sup.+), NMR (DMSO-d6): δ (ppm) of a peak in .sup.1H-NMR in DMSO-d.sub.6), s: single line (spectrum), d: double line (spectrum), m: multiple line (spectrum), br: broad line (spectrum). In addition, br s indicates a wide single line, br d indicates a wide double line, and ddd indicates three double lines having different J values.

[0060] The measurement of powder X-ray diffraction was carried out using RINT-TTRII, under conditions of tube: Cu, tube current: 300 mA, tube voltage: 50 kV, sampling width: 0.020°, scanning speed: 4°/min, wavelength: 1.5418 Λ, and diffraction angle range to be measured (2θ): 2.5° to 40°. Handling of the apparatus including data processing followed the method and procedure instructed by each apparatus.

[0061] In addition, for convenience, a concentration mol/L is represented as M. For example, a 1 M aqueous sodium hydroxide solution refers to a 1 mol/L of aqueous sodium hydroxide solution.

Reference Example 1 Production of Compound A

[0062] It was produced according to a method described in WO 2014/154895.

Example 1

[0063] A mixture of (4-fluorophenyl)[(8R)-8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6-dihydro[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl]methanone (100 mg) and ethyl acetate (3 mL) was stirred at 60° C. to be dissolved, and hydrogen chloride (4 M ethyl acetate solution, 84 μL) was added thereto, and stirred at room temperature for 15 hours. A precipitated solid was collected by filtration and dried under reduced pressure to obtain crystals (109 mg) of (4-fluorophenyl)[(8R)-8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6-dihydro[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl]methanone hydrochloride.

[0064] NMR(DMSO-d6): 1.62 (3H, d, J=6.8 Hz), 2.70 (3H, s), 3.59-3.71 (1H, m), 4.09-4.37 (3H, m), 4.65-4.72 (1H, m), 5.23-5.90 (1H, m), 7.30-7.36 (2H, m), 7.58-7.62 (2H, m)

[0065] ESI+: 359

[0066] Elemental analysis (%) (values in parentheses indicate theoretical values): C: 48.75 (48.67), H: 4.10 (4.08), N: 21.22 (21.28), S: 8.20 (8.12), 8.64 (8.98), F: 4.80 (4.81)

[0067] The crystals obtained in Example 1 have peaks at 2θ(°) of 6.4, 10.2, 12.0, 12.9, 14.5, 16.1, 16.8, 17.9, 22.7, and 26.7 in the powder X-ray diffraction.

Example 2

[0068] A mixture of (4-fluorophenyl)[(8R)-8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6-dihydro[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl]methanone (200 mg) and 2-propanol (3 mL) was stirred at 75° C. to be dissolved, and hydrobromic acid (47%, 77 μL) was added thereto, and stirred at room temperature for 15 hours. A precipitated solid was collected by filtration and dried under reduced pressure to obtain crystals (214 mg) of (4-fluorophenyl)[(8R)-8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6-dihydro[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl]methanone hydrobromide.

[0069] NMR(DMSO-d6): 1.62 (3H, d, J=6.8 Hz), 2.70 (3H, s), 3.59-3.70 (1H, m), 3.89-4.17 (1H, m), 4.26-4.35 (1H, m), 4.65-4.72 (1H, m), 4.77-5.16 (1H, m), 5.57-5.95 (1H, m), 7.31-7.36 (2H, m), 7.58-7.62 (2H, m)

[0070] ESI+: 359

[0071] Elemental analysis (%) (values in parentheses indicate theoretical values): C: 43.93 (43.74), H: 3.74 (3.67), N: 19.23 (19.13), S: 7.31 (7.30), Br: 17.94 (18.19), F: 4.29 (4.32)

[0072] The crystals obtained in Example 2 have peaks at 2θ(°) of 6.4, 9.2, 10.3, 12.0, 12.8, 14.5, 17.0, 18.4, 22.6, and 26.1 in the powder X-ray diffraction.

Example 3

[0073] A concentrated sulfuric acid (8.2 μL) was added to a mixture of (4-fluorophenyl)[(8R)-8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6-dihydro[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl]methanone (100 mg) and 2-butanone (3 mL), and stirred at room temperature for 15 hours. A precipitated solid was collected by filtration and dried under reduced pressure to obtain crystals (62 mg) of (4-fluorophenyl)[(8R)-8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6-dihydro[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl]methanone sulfate.

[0074] NMR(DMSO-d6): 1.62 (3H, d, J=6.8 Hz), 2.70 (3H, s), 3.59-3.70 (1H, m), 3.91-4.20 (1H, m), 4.26-4.36 (1H, m), 4.65-4.72 (1H, m), 5.54-5.88 (1H, m), 7.22-7.50 (4H, m), 7.58-7.64 (2H, m)

[0075] ESI+: 359

[0076] Elemental analysis (%) (values in parentheses indicate theoretical values): C: 42.25 (42.10), H: 3.79 (3.75), N: 18.32 (18.41), S: 13.90 (14.05), F: 4.02 (4.16)

[0077] The crystals obtained in Example 3 have peaks at 2θ(°) of 6.2, 10.9, 12.5, 14.0, 15.3, 16.3, 18.7, 19.5, 21.3, and 24.1 in the powder X-ray diffraction.

Example 4

[0078] A concentrated sulfuric acid (33 μL) was added to a mixture of (4-fluorophenyl)[(8R)-8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6-dihydro[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl]methanone (200 mg) and 2-butanone (2 mL), and stirred at room temperature for 15 hours. A precipitated solid was collected by filtration and dried under reduced pressure to obtain crystals (212 mg) of (4-fluorophenyl)[(8R)-8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6-dihydro[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl]methanone sulfate.

[0079] NMR(DMSO-d6): 1.62 (3H, d, J=6.8 Hz), 2.70 (3H, s), 3.59-3.70 (1H, m), 3.84-4.16 (1H, m), 4.25-4.35 (1H, m), 4.65-4.77 (1H, m), 5.54-5.90 (1H, m), 7.18-7.42 (4H, m), 7.57-7.62 (2H, m)

[0080] ESI+: 359

[0081] Elemental analysis (%) (values in parentheses indicate theoretical values): C: 42.22 (42.10), H: 3.84 (3.75), N: 18.43 (18.41), S: 14.04 (14.05), F: 4.15 (4.16) The crystals obtained in Example 4 have peaks at 2θ(°) of 7.1, 10.0, 15.2, 16.7, 17.6, 18.5, 19.7, 23.5, 24.2, and 25.3 in the powder X-ray diffraction.

Example 5

[0082] p-Toluenesulfonic acid monohydrate (64 mg) was added to a mixture of (4-fluorophenyl)[(8R)-8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6-dihydro[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl]methanone (100 mg) and ethyl acetate (4 mL), and stirred at 60° C. for 5 minutes, and then stirred at room temperature for 15 hours. A precipitated solid was collected by filtration and dried under reduced pressure to obtain crystals (140 mg) of (4-fluorophenyl)[(8R)-8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6-dihydro[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl]methanone p-toluenesulfonate.

[0083] NMR(DMSO-d6): 1.62 (3H, d, J=6.8 Hz), 2.28 (3H, s), 2.69 (3H, s), 3.57-3.69 (1H, m), 3.88-4.17 (1H, m), 4.25-4.36 (1H, m), 4.64-4.72 (1H, m) 4.81-5.14 (1H, m), 5.55-5.88 (1H, m), 7.11 (2H, d, J=8.0 Hz), 7.30-7.36 (2H, m), 7.47 (2H, d, J=8.0 Hz), 7.57-7.62 (2H, m)

[0084] ESI+: 359

[0085] Elemental analysis (%) (values in parentheses indicate theoretical values): C: 51.83 (52.06), H: 4.21 (4.37), N: 15.65 (15.84), S: 12.16 (12.09), F: 3.55 (3.58)

[0086] The crystals obtained in Example 5 have peaks at 2θ(°) of 6.7, 8.1, 10.0, 12.5, 13.0, 13.4, 14.9, 15.3, 18.0, and 23.5 in the powder X-ray diffraction.

Example 6

[0087] Methanesulfonic acid (22 μL) was added to a mixture of (4-fluorophenyl)[(8R)-8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6-dihydro[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl]methanone (100 mg) and ethyl acetate (4 mL), and stirred at 60° C. for 5 minutes, and then stirred at room temperature for 15 hours. A precipitated solid was collected by filtration and dried under reduced pressure to obtain crystals (110 mg) of (4-fluorophenyl)[(8R)-8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6-dihydro[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl]methanone methanesulfonate.

[0088] NMR(DMSO-d6): 1.63 (3H, d, J=6.8 Hz), 2.38 (3H, s), 2.70 (3H, s), 3.60-3.71 (1H, m), 3.90-4.16 (1H, m), 4.26-4.36 (1H, m), 4.65-4.73 (1H, m), 5.23-5.92 (2H, m), 7.31-7.37 (2H, m), 7.58-7.63 (2H, m)

[0089] ESI+: 359

[0090] Elemental analysis (%) (values in parentheses indicate theoretical values): C: 44.86 (44.92), H: 4.10 (4.21), N: 18.51 (18.49), S: 14.42 (14.11), F: 4.17 (4.18)

[0091] The crystals obtained in Example 6 have peaks at 2θ(°) of 7.0, 9.9, 15.1, 16.6, 17.5, 18.4, 19.3, 19.6, 23.2, and 24.0 in the powder X-ray diffraction.

Example 7

[0092] Benzenesulfonic acid monohydrate (59 mg) was added to a mixture of (4-fluorophenyl)[(8R)-8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6-dihydro[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl]methanone (100 mg) and ethyl acetate (4 mL), and stirred at 60° C. for 5 minutes, and then stirred at room temperature for 15 hours. A precipitated solid was collected by filtration and dried under reduced pressure to obtain crystals (106 mg) of (4-fluorophenyl)[(8R)-8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6-dihydro[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl]methanone benzenesulfonate.

[0093] NMR(DMSO-d6): 1.62 (3H, d, J=6.8 Hz), 2.69 (3H, s), 3.59-3.69 (1H, m), 3.88-4.17 (1H, m), 4.26-4.34 (1H, m), 4.52-4.80 (2H, m), 5.57-5.88 (1H, m), 7.27-7.35 (5H, m), 7.57-7.62 (4H, m)

[0094] ESI+: 359

[0095] Elemental analysis (%) (values in parentheses indicate theoretical values): C: 50.85 (51.15), H: 4.07 (4.10), N: 16.22 (16.27), S: 12.58 (12.41), F: 3.67 (3.68)

[0096] The crystals obtained in Example 7 have peaks at 2θ(°) of 6.8, 8.2, 10.1, 11.6, 12.6, 14.9, 15.5, 18.1, 22.5, and 23.5 in the powder X-ray diffraction.

Example 8

[0097] Methanol (1.5 mL) was added to a mixture of (4-fluorophenyl)[(8R)-8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6-dihydro[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl]methanone (312 mg) and 1-hydroxy-2-naphthoic acid (173 mg), and the mixture was heated to 60° C. (bath temperature) to be dissolved, and then stirred at room temperature overnight. A precipitated solid was collected by filtration and dried under reduced pressure to obtain crystals (210 mg) of (4-fluorophenyl)[(8R)-8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6-dihydro[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl]methanone 1-hydroxy-2-naphthoate.

[0098] NMR (DMSO-d6): 1.62 (3H, d, J=6.9 Hz), 2.69 (3H, s), 3.57-3.73 (1H, m), 3.85-4.21 (1H, m), 4.24-4.40 (1H, m), 4.60-4.76 (1H, m), 5.54-5.95 (1H, m), 7.30-7.36 (2H, m), 7.40 (1H, d, J=8.6 Hz), 7.57-7.63 (3H, m), 7.68 (1H, ddd, J=8.2, 6.9, 1.5 Hz), 7.75 (1H, d, J=8.9 Hz), 7.91 (1H, br d, J=8.1 Hz), 8.27-8.31 (1H, m), 12.70 (1H, br s), 14.06 (1H, br s)

[0099] ESI+: 359

[0100] Elemental analysis (%) (values in parentheses indicate theoretical values): C: 59.44 (59.33), H: 4.32 (4.24), N: 15.28 (15.38), S: 5.95 (5.87), F: 3.46 (3.48) The crystals obtained in Example 8 have peaks at 2θ(°) of 3.8, 6.4, 7.7, 8.5, 11.3, 12.9, 16.0, 16.7, 17.1, and 18.7 in the powder X-ray diffraction.

INDUSTRIAL APPLICABILITY

[0101] The present invention can provide a novel salt of Compound A and a crystal of the salt. The salt of the Compound A and the crystal of the salt are expected to be useful as active ingredients of a pharmaceutical composition for preventing and/or treating NK3 receptor related diseases such as depression, anxiety, psychosis, schizophrenia, psychotic disorders, bipolar disorder, cognitive disorder, Parkinson's disease, Alzheimer's disease, attention deficit hyperactivity disorder (ADHD), pain, convulsions, obesity, inflammatory disease such as irritable bowel syndrome (IBS) and inflammatory bowel disorder, emesis, pre-eclampsia, chronic obstructive pulmonary disease, asthma, airway-related diseases such as airway hyperreactivity, bronchoconstriction, and cough, urinary incontinence, reproduction disorders, contraception and sex hormone-dependent diseases (examples of the sex hormone-dependent disease include, but are not limited to, benign prostatic hyperplasia (BPH), prostatic hyperplasia, metastatic prostatic carcinoma, testicular cancer, breast cancer, ovarian cancer, androgen-dependent acne, male pattern baldness, endometriosis, abnormal puberty, uterine fibrosis, uterine fibroid, uterine leiomyoma, hormone-dependent cancer, hyperandrogenism, hirsutism, virilization, polycystic ovary syndrome (PCOS), premenstrual dysphoric disorder (PMDD), HAIR-AN syndrome (hyperandrogenism, insulin resistance, and acanthosis nigricans), ovarian hyperthecosis (HAIR-AN with hyperplasia of luteinized theca cells, in ovarian stroma), other manifestations of high intraovarian androgen concentrations (such as follicular maturation arrest, atresia, anovulation, dysmenorrhea, dysfunctional uterine bleeding, and infertility), androgen producing tumors (virilizing ovarian or adrenal tumors), menorrhagia, and adenomyosis), and hot flash (including hot flashes associated with pre-menopausal, menopausal, and post-menopausal conditions, and hot flashes with hormonal therapy that lowers sex hormone levels, such as hot flashes caused by treatment of breast cancer, uterine cancer, or prostate cancer).