Succinate salts of the compound octahydrothienoquinoline and crystals of it.

Abstract

Invention details;

Description

Succinate salt of octahydrothienoquinoline compound and its crystal

[0001] The present invention relates to a succinate salt of 1-{[(4aR,6R,8aR)-2-amino-3-cyano-8-methyl-4,4a,5,6,7,8,8a,9-octahydrothieno[3,2-g]quinolin-6-yl]carbonyl}-3-[2-(dimethylamino)ethyl]-1-propylurea (hereinafter, sometimes abbreviated as "the succinate salt of the present invention"), which has a dopamine D2 receptor agonist activity and is useful as a prophylactic or therapeutic agent for Parkinson's disease, restless legs syndrome, hyperprolactinemia, and the like.

[0002] 1. A compound of the formula:

[0003] A compound represented by the formula (chemical name: 1-{[(4aR,6R,8aR)-2-amino-3-cyano-8-methyl-4,4a,5,6,7,8,8a,9-octahydrothieno[3,2-g]quinolin-6-yl]carbonyl}-3-[2-(dimethylamino)ethyl]-1-propylurea; hereinafter, sometimes abbreviated as "compound B"), or a hydrochloride thereof, is disclosed in Patent Documents 1 to 3. However, the succinate salt of compound (B) is only described as a general salt, and no report is made on the properties of the succinate salt of compound (B).

[0004] International Publication No. 2012 / 124649 Pamphlet Japanese Patent Application Laid-Open No. 2014-088362 Japanese Patent Application Laid-Open No. 2014-073013

[0005] As a result of extensive investigations by the present inventors, the hydrochloride salt of compound (B) described in Patent Documents 1 to 3 is unstable to heat and undergoes crystal form transition due to high hygroscopicity, as described in the stability tests in the following Test Examples 4 and 5. Therefore, the storage stability is poor and improvement of the physical properties is necessary for use as a drug substance. An object of the present invention is to provide a different form of compound (B) that has high storage stability and is suitable for use as a drug substance.

[0006] The present inventors have conducted extensive research in light of the above-mentioned problems and have found that the succinate salt of 1-{[(4aR,6R,8aR)-2-amino-3-cyano-8-methyl-4,4a,5,6,7,8,8a,9-octahydrothieno[3,2-g]quinolin-6-yl]carbonyl}-3-[2-(dimethylamino)ethyl]-1-propylurea has excellent storage stability and crystallinity, making it suitable for industrial production, and is therefore a suitable compound as a drug substance, thereby completing the present invention. That is, the present invention relates to the following [1] to

[17] , etc. [1] 1-{[(4aR,6R,8aR)-2-amino-3-cyano-8-methyl-4,4a,5,6,7,8,8a,9-octahydrothieno[3,2-g]quinolin-6-yl]carbonyl}-3-[2-(dimethylamino)ethyl]-1-propylurea succinate. [2] The salt according to [1] above, which is represented by the following formula (A-1) or (A-2): [3] The salt according to [1] above, represented by the following formula (A-1): [4] The salt according to [1] above, represented by the following formula (A-2): [5] The salt according to [3] above, which is crystalline. [6] The salt according to [4] above, which is crystalline. [7] The salt according to [5] above, which has peaks at diffraction angles (2θ (°)) of 11.2±0.3 and 11.8±0.3 in a powder X-ray diffraction pattern. [8] The salt according to [5] above, which is characterized by having an endothermic peak at around 150°C in a thermogravimetric differential thermal analysis chart. [9] １３The salt according to [5] above, having peaks at chemical shift values ​​(δ (ppm)) of 183.6±0.5, 180.5±0.5, 174.1±0.5, 170.0±0.5, 165.1±0.5, and 157.3±0.5 in a C solid-state NMR spectrum chart.

[10] The salt according to [5] above, characterized by two or three physical properties selected from the group consisting of the following (a1) to (a3): (a1) a powder X-ray diffraction pattern having peaks at diffraction angles (2θ (°)) of 11.2±0.3 and 11.8±0.3; (a2) a chemical shift value (δ (ppm)) having peaks at 183.6±0.5, 180.5±0.5, 174.1±0.5, 170.0±0.5, 165.1±0.5, and 157.3±0.5. １３ (a3) a thermogravimetric and differential thermal analysis chart having an endothermic peak onset temperature around 150° C.

[11] The salt according to the above item [6], which has peaks at diffraction angles (2θ (°)) of 8.3±0.3, 12.4±0.3, 15.6±0.3, and 23.2±0.3 in a powder X-ray diffraction pattern. １３ The salt according to the above [6], which has peaks at chemical shift values ​​(δ (ppm)) of 177.7, 176.4, 166.2, 160.4, 154.0, and 152.4 in a C solid state NMR spectrum chart.

[13] A pharmaceutical composition containing the salt according to any of the above [1] to

[12] .

[14] The pharmaceutical composition according to the above

[13] , which is for treating or preventing Parkinson's disease, restless legs syndrome, or hyperprolactinemia.

[15] Use of the salt according to any of the above [1] to

[12] for producing an agent for treating or preventing Parkinson's disease, restless legs syndrome, or hyperprolactinemia.

[16] A method for treating or preventing Parkinson's disease, restless legs syndrome, or hyperprolactinemia, comprising administering an effective amount of the compound according to any of the above [1] to

[12] .

[17] A pharmaceutical composition comprising the salt according to [1] above and at least one additional excipient, wherein the pharmaceutical composition has peaks at diffraction angles (2θ (°)) of 11.2±0.3 and 11.9±0.3 in a powder X-ray diffraction pattern.

[18] A pharmaceutical composition comprising the salt according to [1] above and at least one additional excipient. １３A pharmaceutical composition comprising the salt according to [1] above, which has peaks at chemical shift values ​​(δ (ppm)) of 183.5±0.5 and 180.4±0.5 in a C solid state NMR spectrum chart, and at least one additional excipient.

[0007] The succinate salt of the present invention has excellent storage stability because it does not absorb moisture during long-term storage and shows almost no decrease in purity. Furthermore, it has very good solubility, crystallinity, and excellent flowability, making it an easy compound to handle, for example, in formulations.

[0008]

[0033] Figure 1 is a powder X-ray diffraction pattern of type I crystal of salt (A-1). The vertical axis indicates X-ray diffraction intensity (Counts), and the horizontal axis indicates diffraction angle (2θ (°)). Figure 2 is a powder X-ray diffraction pattern of type II crystal of salt (A-1). The vertical axis indicates X-ray diffraction intensity (Counts), and the horizontal axis indicates diffraction angle (2θ (°)). Figure 3 is a powder X-ray diffraction pattern of type I crystal of salt (A-2). The vertical axis indicates X-ray diffraction intensity (Counts), and the horizontal axis indicates diffraction angle (2θ (°)). Figure 4 is a thermogravimetric differential thermal analysis chart (TG-DTA measurement diagram) of type I crystal of salt (A-1). The vertical axis (left) indicates weight (%) in the thermogravimetric (TG) curve, the vertical axis (right) indicates heat flux (μV) in the differential thermal analysis (DTA) curve, and the horizontal axis indicates temperature (°C). This is a DSC measurement diagram of the type I crystals of salt (A-1). The vertical axis (left) shows the weight (%) in the thermogravimetry (TG) curve, the vertical axis (right) shows the heat flux (μV) in the differential thermal analysis (DTA) curve, and the horizontal axis shows the temperature (°C). １３ 1 is a C solid-state NMR spectrum chart. The vertical axis indicates intensity, and the horizontal axis indicates chemical shift value (δ (ppm)). １３1 is a C solid-state NMR spectrum chart. The vertical axis represents intensity, and the horizontal axis represents chemical shift value (δ (ppm)). This is a powder X-ray diffraction pattern of the hydrochloride salt obtained in Comparative Example 1. The vertical axis represents X-ray diffraction intensity (Counts), and the horizontal axis represents diffraction angle (2θ (°)). This is a powder X-ray diffraction pattern of the sebacate crystal obtained in Comparative Example 2. The vertical axis represents X-ray diffraction intensity (Counts), and the horizontal axis represents diffraction angle (2θ (°)). This is a powder X-ray diffraction pattern of the adipate crystal obtained in Comparative Example 3. The vertical axis represents X-ray diffraction intensity (Counts), and the horizontal axis represents diffraction angle (2θ (°)). This is a moisture adsorption / desorption isotherm of type I crystal of salt (A-1). The solid line represents the adsorption isotherm, and the dashed line represents the desorption isotherm. The vertical axis represents mass change (%), and the horizontal axis represents relative humidity (% RH). 1 shows a moisture adsorption / desorption isotherm for the hydrochloride salt obtained in Comparative Example 1. The solid line indicates the adsorption isotherm, and the dashed line indicates the desorption isotherm. The vertical axis indicates the mass change (%), and the horizontal axis indicates relative humidity (% RH). 1 shows a moisture adsorption / desorption isotherm for the sebacate crystals obtained in Comparative Example 2. The solid line indicates the adsorption isotherm, and the dashed line indicates the desorption isotherm. The vertical axis indicates the mass change (%), and the horizontal axis indicates relative humidity (% RH). 1 shows a powder X-ray diffraction pattern for the pharmaceutical composition obtained in Example 4. The vertical axis indicates the X-ray diffraction intensity (Counts), and the horizontal axis indicates the diffraction angle (2θ (°) ... １３ 1 is a C solid-state NMR spectrum chart, where the vertical axis represents intensity and the horizontal axis represents chemical shift value (δ (ppm)).

[0009] Embodiments of the present invention will be described in more detail below. The succinate salt of the present invention can be produced, for example, by the following method. That is, for example, compound (B), which can be produced by the method described in Patent Document 1 or a method based thereon, is mixed with 0.5 to 2 equivalents of succinic acid in an appropriate solvent, dissolved under heating, and then concentrated or added as appropriate as necessary, followed by cooling to isolate the precipitated succinate salt. Furthermore, the succinate salt can also be purified by recrystallization using a similar solvent. The good solvent may be any solvent that does not interfere with salt formation, and examples of such solvents include alcohols such as methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, and 2-butanol, as well as tetrahydrofuran, dimethyl sulfoxide, N,N-dimethylformamide, and N,N-dimethylacetamide. Alternatively, two or more good solvents may be used in combination, such as alcohols such as methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, and 2-butanol; ethers such as tetrahydrofuran and 1,4-dioxane; and solvents such as acetone, acetonitrile, dimethyl sulfoxide, N,N-dimethylformamide, and N,N-dimethylacetamide, and water. Examples of poor solvents that can be appropriately added to the good solvent after salt formation include carboxylic acid esters such as methyl acetate, ethyl acetate, and isopropyl acetate; ketones such as acetone, methyl ethyl ketone, and methyl isobutyl ketone; ethers such as tetrahydrofuran and 1,4-dioxane; acetonitrile; and toluene. Two or more poor solvents may also be used in combination. The succinate salt of the present invention can be purified by recrystallizing the succinate salt produced according to the above-described method, if necessary, using an appropriate recrystallization solvent, such as an acetone-water mixed solvent, a methanol-water mixed solvent, an ethanol-water mixed solvent, or dimethyl sulfoxide.

[0010] The succinate salt of the present invention also includes a salt co-crystal with succinic acid, a co-crystal with succinic acid, a hydrate, or a solvate with a pharmaceutically acceptable solvent such as ethanol.

[0011] The succinate salt of the present invention has a dopamine D2 receptor agonist action and is useful as a drug for preventing or treating Parkinson's disease, restless legs syndrome, hyperprolactinemia, and the like.

[0012] The pharmaceutical compositions of the present invention contain the succinate salt of the present invention as an active ingredient. These pharmaceutical compositions can be prepared according to conventional pharmaceutical techniques by appropriately mixing pharmaceutical additives such as excipients, disintegrants, binders, and lubricants depending on the dosage form and dispensing them in a conventional manner. For example, powders can be prepared by adding appropriate excipients, lubricants, etc. to the active ingredient as needed and thoroughly mixing them to form powders. For example, tablets can be prepared by adding appropriate excipients, disintegrants, binders, lubricants, etc. to the active ingredient and compressing them in a conventional manner to form tablets. If necessary, they can be further coated to form film-coated tablets, sugar-coated tablets, enteric-coated tablets, etc. For example, capsules can be prepared by adding appropriate excipients, lubricants, etc. to the active ingredient and thoroughly mixing them, or by forming them into granules or fine granules in a conventional manner and then filling them into appropriate capsules to form capsules. Furthermore, such oral formulations can be prepared as immediate-release or sustained-release formulations depending on the preventive or therapeutic method.

[0013] When the pharmaceutical composition of the present invention is actually used for prevention or treatment, the dosage of the succinate salt of the present invention, which is its active ingredient, is appropriately determined depending on the patient's age, sex, weight, disease, degree of treatment, etc. For example, in the case of oral administration, it can be administered in a single dose or in divided doses in the range of approximately 0.1 to 300 mg per day for an adult. It is preferable to prepare the pharmaceutical composition so that the succinate salt of the present invention is administered in the range of 0.1 to 300 mg per day for an adult in the case of oral administration.

[0014] It is well known that the relative intensity (relative peak height) of each peak in a powder X-ray diffraction pattern can vary depending on sample conditions, measurement conditions, or measurement equipment. Therefore, the relative intensity should not be interpreted strictly because it may vary slightly depending on the direction of crystal growth, particle size, measurement conditions, etc. It is also well known that the 2θ value of each peak in powder X-ray diffraction varies slightly depending on sample conditions and measurement conditions. The present invention encompasses not only crystals in which the diffraction angles (2θ (°)) of the peaks in powder X-ray diffraction completely match, but also crystals in which the diffraction angles (2θ (°)) of all or some of the peaks match within a range of ±0.3°.

[0015] In a thermogravimetric differential thermal analysis chart, the "endothermic peak" in the DTA curve is indicated by the temperature at the apex of the peak (peak top) or the "extrapolated onset temperature." The "extrapolated onset temperature" refers to the point where the rising or falling portion of the DTA curve intersects with the extrapolated baseline, and is also called the "extrapolated onset temperature." The "extrapolated onset temperature" is the temperature at the start of the peak, and refers to the exothermic or endothermic onset temperature determined by extrapolation. The peak top and extrapolated onset temperature in a thermogravimetric differential thermal analysis chart may also vary somewhat depending on the measurement conditions. A typical temperature fluctuation is, for example, within a range of ±5°C. In other words, the crystals identified by the above peaks may coincide within a range of ±5°C. In the present invention, "near" as used in thermal analysis means a range of ±5°C.

[0016] １３ In a C solid-state NMR spectrum chart, the chemical shift value (δ (ppm)) can vary somewhat depending on the measurement conditions. Therefore, even if the chemical shift value differs slightly, the identity of the crystalline form should be recognized, and crystals within such an error range are also included in the present invention. The error in the chemical shift value can be, for example, ±0.5 ppm. In other words, crystals identified by chemical shift values ​​(δ (ppm)) include those that match within a range of ±0.5 ppm. Furthermore, peak intensities may change, or peaks may appear or disappear, depending on the rotational frequency or measurement equipment.

[0017] The present invention will be explained in more detail using the following examples and test examples, but the present invention is not limited to these examples.

[0018] Example 1 1-{[(4aR,6R,8aR)-2-amino-3-cyano-8-methyl-4,4a,5,6,7,8,8a,9-octahydrothieno[3,2-g]quinolin-6-yl]carbonyl}-3-[2-(dimethylamino)ethyl]-1-propylurea sesquisuccinate monohydrate (Form I crystals of salt (A-1)) 102.8 g of acetone was added to 1-{[(4aR,6R,8aR)-2-amino-3-cyano-8-methyl-4,4a,5,6,7,8,8a,9-octahydrothieno[3,2-g]quinolin-6-yl]carbonyl}-3-[2-(dimethylamino)ethyl]-1-propylurea (22.00 g), the mixture was suspended, and the suspension was heated and stirred at an external temperature of 52°C to dissolve the suspension. Activated carbon (2.2 g) was added to this solution and stirred for 10 minutes. This suspension was hot filtered and washed with 35.2 g of acetone. 220.0 g of acetone was then added, and the reaction solution was heated to an external temperature of 52°C and stirred. Next, 44.0 g of water was added to the reaction solution. Separately, 8.73 g of succinic acid was dissolved in a mixed solution of 156.1 g of acetone and 19.8 g of water. This succinic acid solution was added dropwise to the reaction solution over approximately 10 minutes. The dropping funnel was washed with a mixed solution of 17.4 g of acetone and 2.2 g of water and then added dropwise to the reaction solution. The reaction solution was stirred at an internal temperature of 50°C for 1 hour and cooled to 15°C over 30 minutes. The reaction solution was stirred at an external temperature of 10°C for 2 hours, and the crystals were collected by filtration. The crystals were washed twice with 52.8 g of acetone. The obtained wet crystals were dried under reduced pressure at 50°C for 37 hours and then returned to room temperature under reduced pressure over 3 hours. The crystals were stored under air for 24 hours to give the title compound as crystals (27.75 g). １H-NMR(DMSO-d6)(δ(ppm)):0.85(3H,t,J=7.4H z),1.32(1H,ddd,J=12.2Hz,12.2Hz,12.2Hz),1.42‐1.57(2H,m),1.57‐1.70(1H,m),1.89‐2.00(2H,m),2.20‐2.13(1H,m),2.13‐2.28(2H,m),2.21(3H,s),2.24(6H,s),2.35‐2.48(1H,m),2.40(6H,s),2.46(2H,t,J=6.4Hz),2.81‐2.96(2H,m),3.00‐3.12(1H,m),3.21‐3.33(2H,m),3.47‐3.66(2H,m),6.99(2H,s),8.50‐8.90(1H,br).

[0019] Single Crystal X-Ray Structural Analysis A single crystal of Form I of 1-{[(4aR,6R,8aR)-2-amino-3-cyano-8-methyl-4,4a,5,6,7,8,8a,9-octahydrothieno[3,2-g]quinolin-6-yl]carbonyl}-3-[2-(dimethylamino)ethyl]-1-propylurea sesquisuccinate monohydrate (salt (A-1)) was prepared and subjected to X-ray structural analysis. (Single Crystal Preparation and Measurement Preparation) 1-{[(4aR,6R,8aR)-2-amino-3-cyano-8-methyl-4,4a,5,6,7,8,8a,9-octahydrothieno[3,2-g]quinolin-6-yl]carbonyl}-3-[2-(dimethylamino)ethyl]-1-propylurea (30 g) was suspended in a mixed solution of 84 g of acetone and 110 g of water, to which 11.9 g of succinic acid was added, and the mixture was heated to an internal temperature of 51°C to dissolve. This solution was passed through a filter paper and added to 720 mL of acetone at 50°C with stirring. The container and filter paper were washed with 110 g of acetone. 6 mg of type I crystals of salt (A-1) were added to the mixture of the filtrate and washings to initiate crystallization. The mixture was stirred at an internal temperature of 50°C for 1 hour, and then stirred for 2 hours and 30 minutes with ice cooling. The resulting suspension was filtered, and the solid on the filter paper was washed twice with 72 g of acetone. The resulting wet crystals were dried under reduced pressure at 50°C for 18 hours to obtain crystals of the title compound (43.2 g). Powder X-ray diffraction of the resulting crystals was measured using the method of Test Example 1, and it was confirmed that the crystal form was identical to that of the crystals obtained in Example 1. A single crystal was collected from the powder, cut and shaped with a razor, mounted on a microloop using grease, and quickly frozen in the gas flow of a cryogenic device.

[0020] X-ray diffraction data was measured and obtained using an XtaLAB P200 MM007 (Rigaku Corporation) under the following measurement conditions: (Measurement conditions) X-ray source: CuKα Wavelength: 1.54187 Å Tube voltage / current: 40 kV, 30 mA Measurement temperature: -100°C Crystal size: 0.15 x 0.08 x 0.04 mm Oscillation angle: 1° Exposure time: 2 seconds / frame Total number of measured frames: 1637 Total measurement time: 55 minutes (Data analysis program) Data measurement, diffraction data processing: Crystal Clear Structural analysis / refinement method: Crystal Structure, SIR2011, SHELXL2013 (Measurement results) The measurement results obtained are shown in Table 1.

[0021] a, b, c = unit cell length α, β, γ = unit cell angle Z = number of molecules in the unit cell

[0022] Elemental analysis was performed using a CHN automatic analyzer Vario EL (Elemental). (Elemental analysis results (C, H, N)) Theoretical values: 52.40%, 7.07%, 13.10% Measured values: 52.25%, 7.07%, 12.98%

[0023] From the above measurement results, the type I crystal of salt (A-1) is a crystal having a monoclinic crystal system, a C2 space group, and a z value of 4, and containing two molecules of 1-{[(4aR,6R,8aR)-2-amino-3-cyano-8-methyl-4,4a,5,6,7,8,8a,9-octahydrothieno[3,2-g]quinolin-6-yl]carbonyl}-3-[2-(dimethylamino)ethyl]-1-propylurea, three molecules of succinic acid, and two molecules of water in the asymmetric unit.

[0024] Example 2 1-{[(4aR,6R,8aR)-2-amino-3-cyano-8-methyl-4,4a,5,6,7,8,8a,9-octahydrothieno[3,2-g]quinolin-6-yl]carbonyl}-3-[2-(dimethylamino)ethyl]-1-propylurea sesquisuccinate (Form II crystals of salt (A-1)) 121 mg of 1-{[(4aR,6R,8aR)-2-amino-3-cyano-8-methyl-4,4a,5,6,7,8,8a,9-octahydrothieno[3,2-g]quinolin-6-yl]carbonyl}-3-[2-(dimethylamino)ethyl]-1-propylurea sesquisuccinate was dissolved in 3 mL of a 1,4-dioxane / water (volume ratio 1:1) mixed solvent by heating to 60°C and filtering. The resulting filtrate was lyophilized. 2.5 mL of n-heptane was added to the resulting powder, and the suspension was heated to 60°C and stirred for 1 hour. After stirring at room temperature for 1 day, the solid was collected by filtration and dried under reduced pressure at 40°C to obtain crystals of the title compound (92 mg). １ H-NMR (MeOH-d4) (δ (ppm)): 0.96 (3H, t, J = 7.2Hz), 1.50 (1H, ddd, J = 12.0Hz , 12.4Hz, 12.4Hz), 1.57-1.70 (2H, m), 1.75-1.88 (1H, m), 2.03-2.26 (3H, m ), 2.31-2.46 (4H, m), 2.46-2.56 (7H, m), 2.58-2.66 (1H, m), 2.71 (6H, s), 2 98-3.10 (4H, m), 3.15-3.25 (1H, m), 3.52-3.59 (2H, m), 3.62-3.72 (2H, m).

[0025] Example 3 1-{[(4aR,6R,8aR)-2-amino-3-cyano-8-methyl-4,4a,5,6,7,8,8a,9-octahydrothieno[3,2-g]quinolin-6-yl]carbonyl}-3-[2-(dimethylamino)ethyl]-1-propylurea monosuccinate (Form I crystals of salt (A-2)) 1-{[(4aR,6R,8aR)-2-amino-3-cyano-8-methyl-4,4a,5,6,7,8,8a,9-octahydrothieno[3,2-g]quinolin-6-yl]carbonyl}-3-[2-(dimethylamino)ethyl]-1-propylurea (357 mg) was dissolved in 3.5 mL of acetone while heating at an internal temperature of 50 to 55°C, and then the solution was cooled to an internal temperature of 4°C by immersion in an ice bath to obtain a reaction solution. Separately, succinic acid (94 mg) was dissolved in 0.3 mL of an acetone / water (volume ratio 1:1) mixed solvent while heating at an internal temperature of 55°C. The succinic acid solution was added dropwise to the cooled reaction solution, and the mixture was concentrated to dryness under reduced pressure. To the residue was added 1.35 mL of an acetone / water (volume ratio 1:1) mixed solvent, and the mixture was dissolved while heating at an internal temperature of 55°C. The mixture was stirred at room temperature to precipitate crystals. After stirring for 10 minutes, an acetone / water (volume ratio 1:1) mixed solvent (0.45 mL) was further added to the suspension and stirred at room temperature for 10 minutes. Further, 7.2 mL of acetone was added in three portions over 2 hours, and the mixture was stirred at room temperature for 1 hour. The precipitated crystals were collected by filtration, washed with a small amount of acetone, and dried under reduced pressure at room temperature for 1 hour to obtain crystals of the title compound (393 mg). １ H-NMR (MeOH-d4) (δ (ppm)): 0.96 (3H, t, J = 7.6Hz), 1.50 (1H, ddd, J = 12. 4, 12.4, 12.4Hz), 1.59-1.69 (2H, m), 1.73-1.86 (1H, m), 2.03-2.21 (3H , m), 2.30-2.42 (4H, m), 2.43-2.55 (5H, m), 2.57-2.70 (7H, m), 2.92 (2H , t, J=6.8Hz), 2.97-3.07 (2H, m), 3.49-3.55 (2H, m), 3.63-3.82 (2H, m).

[0026] Example 4 Pharmaceutical composition containing type I crystals of salt (A-1) Type I crystals of salt (A-1) of Example 1 (8.7 mg) were added to a mixture (78.1 mg) of mannitol (49 parts), crystalline cellulose (50 parts), and sodium stearyl fumarate (1 part), and the mixture was thoroughly mixed at room temperature to obtain a pharmaceutical composition containing 10% of salt (A-1).

[0027] (Test Example 1) Measurement of Powder X-ray Diffraction The powder X-ray diffraction of the type I crystals of salt (A-1) and the type I crystals of salt (A-2) was measured using a powder X-ray diffractometer X'Pert Pro MPD (Panalytical Division, Spectris Inc.) under the following measurement conditions after lightly crushing the crystals in a mortar to crush coarse particles. (Measurement conditions) Radiation source: CuKα radiation (CuKα1 and CuKα2), 1.5418 Å Tube voltage: 45 kV Tube current: 40 mA Data analysis software: X'Pert HighScore (Panalytical Division, Spectris Inc.) Data analysis method (peak search): Minimum significance (1.00), minimum peak tip (0.01, 2θ (°)), maximum peak tip (1.00, 2θ (°)), peak base (2.00, 2θ (°)), method (smoothed peak top) (2θ (°))

[0028] Powder X-ray diffraction of the Form II crystal of salt (A-1) was measured using a powder X-ray diffractometer SmartLab (Rigaku Corporation) under the following measurement conditions after lightly crushing the crystal in a mortar to remove coarse particles. (Measurement conditions) Radiation source, wavelength: CuKα radiation (CuKα1 and CuKα2), 1.5418 Å Tube voltage: 40 kV Tube current: 50 mA Data analysis software: SmartLabStudio II (Rigaku Corporation) Data analysis method (peak definition): peak position (peak top position, diffraction angle when irradiated with CuKα1 and CuKα2), peak height (background not included)

[0029] The diffraction pattern of the type I crystal of salt (A-1) is shown in FIG. 1, and the diffraction angles (2θ(°)) of representative diffraction peaks and the relative intensities (%) of the diffraction peaks are shown in Table 2. The diffraction pattern of the type II crystal of salt (A-1) is shown in FIG. 2, and the diffraction angles (2θ(°)) of representative diffraction peaks and the relative intensities (%) of the diffraction peaks are shown in Table 3. The diffraction pattern of the type I crystal of salt (A-2) is shown in FIG. 3, and the diffraction angles (2θ(°)) of representative diffraction peaks and the relative intensities (%) of the diffraction peaks are shown in Table 4.

[0030]

[0031]

[0032]

[0033] Form I crystals of salt (A-1) can be identified using, for example, the following sets of peaks at diffraction angles (2θ (°)). One set of peaks is 11.2±0.3 and 11.8±0.3. Another set of peaks is 11.2±0.3, 11.8±0.3, and 16.2±0.3. Yet another set of peaks is 11.2±0.3, 11.8±0.3, and 23.6±0.3. Yet another set of peaks is 11.2±0.3, 11.8±0.3, 23.6±0.3, and 25.4±0.3. Yet another set of peaks are 11.2±0.3, 11.8±0.3, 16.2±0.3, 19.7±0.3, 22.3±0.3, 22.4±0.3, 23.0±0.3, 23.6±0.3 and 25.4±0.3.

[0034] The Form II crystal of Salt (A-1) can be identified using, for example, the following sets of peaks at diffraction angles (2θ (°)). One set of peaks is 5.8±0.3, 20.4±0.3, and 24.4±0.3. Another set of peaks is 5.8±0.3, 11.7±0.3, 11.9±0.3, 16.0±0.3, 20.4±0.3, and 24.4±0.3.

[0035] Form I crystals of salt (A-2) can be identified using, for example, the following sets of peaks at diffraction angles (2θ (°)). One set of peaks is 8.3±0.3, 12.4±0.3, 15.6±0.3, and 23.2±0.3. Another set of peaks is 8.3±0.3, 11.5±0.3, 12.4±0.3, 15.6±0.3, 22.1±0.3, 22.7±0.3, 23.2±0.3, 24.1±0.3, and 24.7±0.3.

[0036] (Test Example 2) Thermal Analysis Measurements Thermal analysis was performed using a differential thermobalance TG-DTA TG8120 (Rigaku Corporation) under the following conditions in a nitrogen gas atmosphere: (Measurement Conditions) Heating rate: 10°C / min Reference material: aluminum oxide Atmosphere: under nitrogen gas flow

[0037] The TG-DTA measurement diagram of the type I crystals of salt (A-1) is shown in Figure 4. Endothermic peak of type I crystals of salt (A-1): A broad endothermic peak from 80 to 130°C, around 150°C (peak top (extrapolated onset temperature around 142°C (melting))) Mass loss (around 23°C to 150°C): 2.7%

[0038] The DSC chart of the type I crystals of salt (A-1) is shown in Figure 5. Endothermic peak of type I crystals of salt (A-1): a broad endothermic peak from 80 to 130°C, around 153°C (peak top) (extrapolation onset temperature around 145°C)

[0039] (Test Example 3) １３ Measurement of C solid-state NMR spectrum of type I crystals of salt (A-1) and type I crystals of salt (A-2) １３ For the C solid state NMR spectrum, the sample was loaded into a rotor for solid state NMR spectroscopy with an inner diameter of 3.2 mm, and the measurement was performed under the following measurement conditions to obtain an NMR chart. (Measurement conditions) NMR apparatus: 600 MHz AVANCE III (Bruker) Probe: Cross-polarization magic angle spinning (CP / MAS) accessory Contact time: 3 milliseconds Recycle delay: 5 seconds 1H pulse: 3 microseconds Spin rate: 15 kHz Number of accumulations: 2048 Chemical shift correction: Glycine was used as a reference (δ = 176.46 ppm for the C=O resonance).

[0040] The solid-state NMR spectrum of the type I crystals of salt (A-1) obtained in Example 1 is shown in Figure 6, and the chemical shifts (ppm) are shown in Table 5. The solid-state NMR spectrum of the type I crystals of salt (A-2) obtained in Example 3 is shown in Figure 7, and the chemical shifts (ppm) are shown in Table 6.

[0041]

[0042]

[0043] The type I crystal of salt (A-1) can be identified, for example, by the following method. １３ A set of chemical shift values ​​(δ(ppm)) from the C solid-state NMR spectrum can be used. One set is 183.6±0.5, 180.5±0.5, 174.1±0.5, 170.0±0.5, 165.1±0.5, and 157.3±0.5. Another set is 183.6±0.5, 180.5±0.5, 174.1±0.5, 170.0±0.5, 165.1±0.5, 157.3±0.5, 129.7±0.5, 115.7±0.5, 81.7±0.5, 66.7±0.5, 58.9±0.5, 22.7±0.5, and 11.1±0.5. Another set is 183.6±0.5, 180.5±0.5, 174.1±0.5, 170.0±0.5, 165.1±0.5, 157.3±0.5, 129.7±0.5, 115.7±0.5, 58.9±0.5, 22.7±0.5, and 11.1±0.5. Yet another set is 183.6±0.5, 180.5±0.5, 174.1±0.5, 170.0±0.5, 165.1±0.5, 157.3±0.5, 129.7±0.5, 118.7±0.5, 115.7±0.5, 81.7±0.5, 66.7±0.5, 58.9±0.5, 57.0±0.5, 50.1±0.5, 44.7±0.5, 41.7±0.5, 41.1±0.5, 37.6±0.5, 36.9±0.5, 36.5±0.5, 35.0±0.5, 33.4±0.5, 32.1±0.5, 31.8±0.5, 29.8±0.5, 27.6±0.5, 22.7±0.5 and 11.1±0.5.

[0044] For identification of type I crystals of salt (A-2), for example, the following sets of chemical shift values ​​(δ (ppm)) can be used. One set is 177.7, 176.4, 166.2, 160.4, 154.0, and 152.4. Another set is 177.7, 177.2, 176.4, 175.9, 166.2, 160.4, 154.0, and 152.4. Another set is 177.7, 177.2, 176.4, 175.9, 168.8, 168.2, 167.3, 166.2, 160.4, 154.0, and 152.4. Another set is 177.7, 176.4, 166.2, 160.4, 154.0, 152.4, 125.2, 114.4, 110.9, 77.1, 62.2, 54.6 and 7.5. Yet another set is 177.7, 177.2, 176.4, 175.9, 168.8, 168.2, 167.3, 166.2, 160.4, 154.0, 152.4, 125.2, 114.4, 110.9, 77.1, 62.2, 54.6, 53.6, 44.3, 43.5, 41.0, 39.1, 37.0, 36.4, 33.8, 33.2, 32.6, 31.8, 29.3, 28.7, 27.5, 27.3, 25.3, 23.1, 17.9, 17.5, 16.9, 16.5, 10.2, 9.0, 7.5 and 6.6.

[0045] In the present invention, the type I crystal of the salt (A-1) is obtained by powder X-ray diffraction, １３ The peaks in the C solid-state NMR spectrum and the thermogravimetric differential thermal analysis chart can also be combined to identify the compound.

[0046] Examples of ways to identify the type I crystal of salt (A-1) include the following (c1) to (c4): (c1) A powder X-ray diffraction pattern having peaks at diffraction angles (2θ (°)) of 11.2±0.3 and 11.8±0.3; and chemical shift values ​​(δ (ppm)) of 183.6±0.5, 180.5±0.5, 174.1±0.5, 170.0±0.5, 165.1±0.5, and 157.3±0.5. １３(c2) A powder X-ray diffraction pattern having peaks at diffraction angles (2θ (°)) of 11.2±0.3 and 11.8±0.3; and a thermogravimetric differential thermal analysis chart having an extrapolated onset temperature of an endothermic peak around 150°C (hereinafter, the "extrapolated onset temperature" will be referred to as the "onset temperature"). (c3) A chemical shift value (δ (ppm)) having peaks at 183.6±0.5, 180.5±0.5, 174.1±0.5, 170.0±0.5, 165.1±0.5, and 157.3±0.5. １３ (c3) A C solid-state NMR spectrum chart; and a thermogravimetric differential thermal analysis chart having an endothermic peak onset temperature around 150° C. (c4) A powder X-ray diffraction pattern having peaks at diffraction angles (2θ (°)) of 11.2±0.3 and 11.8±0.3; and a chemical shift value (δ (ppm)) of 183.6±0.5, 180.5±0.5, 174.1±0.5, 170.0±0.5, 165.1±0.5, and 157.3±0.5. １３ C solid-state NMR spectrum chart; and a thermogravimetric differential thermal analysis chart having an endothermic peak onset temperature around 150°C.

[0047] (Comparative Example 1) Crystals of hydrochloride of compound (B) Powder X-ray diffraction of crystals of hydrochloride of compound (B) obtained by the method described in Example 4-1 of Patent Document 1 was measured in the same manner as in Test Example 1. The obtained diffraction pattern is shown in Figure 8.

[0048] Comparative Example 2: Crystals of Sebacate of Compound (B) Compound (B) (500 mg) and sebacic acid (226 mg) were added to ethanol (3 mL) and heated to 50°C to dissolve. The resulting solution was stirred at room temperature for 1 hour, and then diisopropyl ether (3 mL) was added, followed by further stirring at room temperature for 3 days. The precipitated solid was collected by filtration and washed with a mixture of ethanol and diisopropyl ether (1:1), then air-dried at room temperature for 3 hours, and further dried under reduced pressure at 60°C for 3 hours to obtain the title compound (0.4938 g). １H-NMR (MeOH-d4) (δ (ppm)): 0.95 (3H, t, J = 7.6Hz), 1.33 (6H, br), 1.52 (1H, q, J = 12.4Hz), 1 .55-1.70 (5H, m), 1.72-1.85 (1H, m), 2.04-2.10 (1H, m), 2.10-2.21 (2H, m), 2.24 (3H, t, J=7 .. 2Hz), 2.29-2.40 (4H, m), 2.45 (1H, t, J = 11.2Hz), 2.51 (6H, s), 2.57-2.65 (1H, m), 2.78 (2H , t, J=6.4Hz), 2.95-3.06 (2H, m), 3.13-3.23 (1H, m), 3.45-3.52 (2H, m), 3.63-3.81 (2H, m).

[0049] The powder X-ray diffraction of the resulting crystals of sebacate of compound (B) was measured in the same manner as in Test Example 1, and the resulting diffraction pattern is shown in FIG.

[0050] Comparative Example 3 Crystals of adipate salt of compound (B) Compound (B) (500 mg), adipic acid (164 mg), and 3 mL of ethanol were added and heated to 50°C to dissolve. The resulting solution was stirred at room temperature for 1 hour, and then 3 mL of diisopropyl ether was added and stirred at room temperature for an additional 1 hour. The mixture was heated at 50°C for 10 minutes and then stirred at room temperature for 1 hour. The precipitated solid was collected and washed with 1 mL of ethanol. The resulting solid was air-dried overnight under laboratory conditions and then dried under reduced pressure at 60°C for 3 hours to obtain the title compound (0.3854 g). １ H-NMR (MeOH-d4) (δ (ppm)): 0.95 (3H, t, J = 7.6Hz), 1.49 (1H, q, J = 12.4Hz ), 1.58-1.69 (4H, m), 1.71-1.85 (1H, m), 2.03-2.22 (3H, m), 2.23-2.40 ( 6H, m), 2.40-2.54 (7H, m), 2.56-2.66 (1H, m), 2.74 (2H, t, J=6.4Hz), 2.9 6-3.05 (2H, m), 3.10-3.23 (1H, m), 3.45-3.52 (2H, m), 3.62-3.81 (2H, m).

[0051] The powder X-ray diffraction of the resulting crystals of the adipate salt of compound (B) was measured in the same manner as in Test Example 1, and the resulting diffraction pattern is shown in FIG.

[0052] Test Example 4 Stability Test 1 Form I crystals of Salt (A-1), Form I crystals of Salt (A-2), crystals of Compound (B) hydrochloride, crystals of the sebacate salt and crystals of the adipate salt of Compound (B) were stored in the open at 60°C, and the physical and chemical stability of each crystalline form was examined. Powder X-ray diffraction of the samples at the start of the test and after two months was measured in the same manner as in Test Example 1 to confirm the physical stability of the crystalline form, and the amount of related substances was measured using the HPLC measurement conditions below to confirm the chemical stability. Changes in appearance were also observed at the same time. The results are shown in Table 7. No changes in the crystalline form of Form I crystals of Salt (A-1) and Form I crystals of Salt (A-2) were observed upon storage in the open at 60°C. Furthermore, Form I crystals of Salt (A-1) and Form I crystals of Salt (A-2) were chemically stable and showed almost no change in appearance. On the other hand, the crystalline form of Compound (B) hydrochloride and the sebacate salt of Compound (B) changed and were chemically unstable. Furthermore, the hydrochloride of compound (B), the sebacate of compound (B), and the adipate of compound (B) were colored. (HPLC conditions) Detector: UV-visible spectrophotometer / Wavelength: 225 nm Column: L-column 2 ODS, 3 μm, 4.6 × 150 mm (manufactured by Chemicals Evaluation and Research Institute, Japan) Column temperature: Constant temperature around 30°C Flow rate: 1.0 mL / min Mobile phase A: Water mixed with potassium dihydrogen phosphate and dipotassium hydrogen phosphate at 10 mmol / L each (pH 6.9) Mobile phase B: Acetonitrile Mobile phase ratio 0 to 25 minutes: Mobile phase A / Mobile phase B = 79 / 21 25 to 45 minutes: Mobile phase A / Mobile phase B = 79 / 21 to 25 / 75 (gradient) 45 to 50 minutes: Mobile phase A / Mobile phase B = 25 / 75 Injection volume: 5 μL Sample cooler: 4°C Dissolution solvent: a mixed solution prepared by adding 20 parts of acetonitrile to 80 parts of a 20 mmol / L aqueous solution of potassium dihydrogen phosphate adjusted to pH 3. Sample solution: a solution prepared by dissolving a specimen in a dissolution solvent to a concentration of approximately 1.0 mg / mL of compound (B). Peaks derived from the blank were excluded, and each peak area was measured by automatic integration, and the values ​​were calculated by the area percentage method.

[0053]

[0054] Test Example 5: Stability Test 2 Form I crystals of Salt (A-1), Form I crystals of Salt (A-2), crystals of the hydrochloride salt of Compound (B), crystals of the sebacate salt and crystals of the adipate salt of Compound (B) were stored in the open at 40°C and 75% relative humidity, and the physical and chemical stability of each crystalline form was examined. Powder X-ray diffraction of the samples at the start of the test and after two months was measured in the same manner as in Test Example 1 to confirm the physical stability of the crystalline form, and the amount of related substances was measured using the HPLC measurement conditions below to confirm the chemical stability. At the same time, changes in appearance were also observed. The results are shown in Table 8. No changes in the crystalline form of Form I crystals of Salt (A-1) and Form I crystals of Salt (A-2) were observed during storage at 40°C and 75% relative humidity in the open. Furthermore, Form I crystals of Salt (A-1) and Form I crystals of Salt (A-2) were chemically stable and showed no changes in appearance. On the other hand, the crystal forms of the hydrochloride of compound (B) and the sebacate of compound (B) changed. In addition, the sebacate of compound (B) was chemically unstable, and the adipate of compound (B) was chemically unstable and became discolored. (HPLC conditions) Detector: UV-visible spectrophotometer / Wavelength: 225 nm Column: L-column 2 ODS, 3 μm, 4.6 × 150 mm (manufactured by Chemicals Evaluation and Research Institute, Japan) Column temperature: Constant temperature around 30°C Flow rate: 1.0 mL / min Mobile phase A: Water mixed with potassium dihydrogen phosphate and dipotassium hydrogen phosphate at 10 mmol / L each (pH 6.9) Mobile phase B: Acetonitrile Mobile phase ratio 0 to 25 minutes: Mobile phase A / Mobile phase B = 79 / 21 25 to 45 minutes: Mobile phase A / Mobile phase B = 79 / 21 to 25 / 75 (gradient) 45 to 50 minutes: Mobile phase A / Mobile phase B = 25 / 75 Injection volume: 5 μL Sample cooler: 4°C Dissolution solvent: a mixed solution prepared by adding 20 parts of acetonitrile to 80 parts of a 10 mmol / L aqueous solution of potassium dihydrogen phosphate adjusted to pH 3. Sample solution: a solution prepared by dissolving a specimen in a dissolution solvent to a concentration of approximately 1.0 mg / mL of compound (B). Peaks derived from the blank were excluded, and each peak area was measured by the automatic integration method, and the values ​​were calculated by the area percentage method.

[0055]

[0056] Test Example 6: Moisture Adsorption / Desorption Test The moisture adsorption / desorption behavior of type I crystals of salt (A-1), crystals of the hydrochloride of compound (B), and crystals of the sebacate of compound (B) was measured using an IGA-Sorp (manufactured by HIDEN isochema) under the following conditions. The moisture adsorption / desorption isotherm of type I crystals of salt (A-1) is shown in Figure 11, the moisture adsorption / desorption isotherm of the hydrochloride of compound (B) is shown in Figure 12, and the moisture adsorption / desorption isotherm of the sebacate of compound (B) is shown in Figure 13. Samples and amounts used in the measurement: Form I crystals of salt (A-1): 14.7 mg; Hydrochloride crystals of compound (B): 10.4 mg; Sebacate crystals of compound (B): 13.2 mg. Pretreatment: Equilibration: Each sample was placed in a moisture adsorption / desorption measuring device, and the temperature and humidity were set to 25°C / 40% RH or 50% RH. The sample was equilibrated for 60 minutes or more to stabilize the mass. Measurement: For each of the mass-balanced samples, the sample mass was continuously measured while changing the relative humidity in 5% RH increments during adsorption and desorption. The measurement conditions for the moisture adsorption / desorption measuring device were as shown in Table 9, and the mass change within each common humidity range is shown in Table 10.

[0057]

[0058]

[0059] The mass % is based on a dry sample, and the change in mass before and after adsorption (or desorption) is expressed as a mass percentage. Under the above conditions, it was found that while type I crystals of salt (A-1) do not exhibit hygroscopicity, the hydrochloride of compound (B) is 25 to 41 times more hygroscopic, and the sebacate of compound (B) is 6 to 15 times more hygroscopic than type I crystals of salt (A-1). As described above, the succinate salt of the present invention is not hygroscopic and is therefore more preferable as a pharmaceutical active ingredient.

[0060] (Test Example 7) Powder X-ray Diffraction Diagram of Pharmaceutical Composition A sample of the pharmaceutical composition was loaded onto a measurement plate for X-ray diffraction measurement, and measurement was performed under the following measurement conditions to obtain a diffraction diagram. The powder X-ray diffraction diagram of the pharmaceutical composition obtained in Example 4 is shown in Figure 14, and the diffraction angles (2θ (°)) of representative diffraction peaks are shown in Table 11. (Measurement Conditions) Powder X-ray Diffraction Apparatus: SmartLab (Rigaku Corporation) Radiation Source: CuKα ray Tube Voltage: 40 kV Tube Current: 50 mA Data Analysis Software: SmartLabStudio II (Rigaku Corporation) Data Analysis Method (Peak Definition): Peak Position (Peak Top Position, Diffraction Angle when Irradiated with CuKα1 and CuKα2), Peak Height (Background Not Included)

[0061]

[0062] The type I crystals of Salt (A-1) in the pharmaceutical composition can be identified using, for example, the following sets of peaks at diffraction angles (2θ (°)). One set of peaks is 11.2±0.3 and 11.9±0.3. Another set of peaks is 11.2±0.3, 11.9±0.3, and 16.2±0.3.

[0063] (Test Example 8) Pharmaceutical composition １３ C Solid State NMR Spectrum A sample of the pharmaceutical composition was loaded into a rotor for solid state NMR spectroscopy with an inner diameter of 3.2 mm, and measurement was performed under the following measurement conditions to obtain a solid state NMR spectrum chart. The solid state NMR spectrum of the pharmaceutical composition obtained in Example 4 is shown in Figure 15, and the chemical shifts (ppm) derived from the type I crystals of Salt (A-1) are shown in Table 12. (Measurement Conditions) Nuclear Magnetic Resonance Apparatus: 600 MHz AVANCE III (Bruker) Probe: Cross-Polarization Magic Angle Spinning (CP / MAS) Accessory Contact Time: 3 milliseconds Recycle Delay: 5 seconds 1H Pulse: 3 microseconds Spin Rate: 15 kHz Number of Accumulations: 2048 Chemical Shift Correction: Glycine was used as a reference. (δ = 176.46 ppm for C = O resonance)

[0064]

[0065] The identification of the type I crystal of the salt (A-1) in the pharmaceutical composition can be carried out, for example, by the following method. １３A set of C solid-state NMR spectral chemical shifts (ppm) can be used. One set of peaks is 183.5±0.5 and 180.4±0.5. Another set of peaks is 183.5±0.5, 180.4±0.5, 174.0±0.5, 169.8±0.5, 164.9±0.5, and 157.0±0.5.

[0066] The succinate salt of the present invention has excellent storage stability and other physical properties, and is useful as a drug substance and is suitable for industrial production of pharmaceuticals.

Claims

1. A succinate salt of 1-{[(4aR,6R.8aR)-2-amino-3-cyano-8-methyl-4,4a,5,6,7,8,8a,9-octahydrothiono[3,2-g]quinolin-6-yl]carbonyl}-3-[2-(dimethylamino)ethyl]-1-propylurea.

2. A salt under claim 1, in which the salt is substituted by the following formula (A-1) or (A-2) [chemical 1] (chemical formula).

3. A salt under claim 1, in which the salt is substituted by the following formula (A-1) [chemical 2] (chemical formula).

4. A salt under claim 1, in which the salt is substituted by the following formula (A-2) [chemical 3] (chemical formula).

5. A salt under claim 3, which is crystalline.

6. A salt under claim 4.

7. A crystalline salt according to claim 5, which has a peak at a diffraction angle (2 theta (degrees)) of 11.2 plus or minus 0.3 and 11.8 plus or minus 0.3 in the powder X-ray diffraction diagram.

8. A salt according to claim 5, which has a peak of heat absorption at approximately 150 degrees Celsius in the thermogravimetric differential thermolanalysis chart.

9. A salt according to claim 5, which has a peak at a chemical movement value (delta (ppm)) of 183.

6. Positive or negative 0.5,180.5, positive or negative 0.5,174.1, positive or negative 0.5,170.0, positive or negative 0.5,165.1, positive or negative 0.5 and 157.3 positive or negative 0.5 in the 13C solid-state NMR spectrum chart (13Csolid-stateNMRspectrumchart).

10. Salt according to claim 5, which is characterized by 2 or 3 physical characteristics selected from the following groups of (a1) to (a3): (a1) Powder X-ray diffraction diagram with peaks at diffraction angles (2 theta (degrees)) at 11.2 positive or negative 0.3 and 118 positive or negative 0.

5. (a2) NMR spectrum chart of 13C solid state with peaks at chemical displacement angle (delta (ppm) at 183.6 positive or negative 0.5, 180.5 positive or negative 0.5, 174.1 positive or negative 0.5, 170.0 positive or negative 0.5, 165.1 positive or negative 0.5 and 157.3 positive or negative 0.5; and (a3) ​​thermogravimetric thermal transition analysis chart with the initial temperature of the absorption peak at approximately 150°C11. Salt according to claim 6, which has a peak at diffraction angle (2 theta (degrees) at 8.

11. A salt under claim 6, which has peak chemical displacement (delta) values ​​of 177.7, 176.4, 166.2, 160.4, 15.6, 23.2, and 23.2 in the powder X-ray diffraction diagram.

12. A salt under claim 6, which has peak chemical displacement (delta) values ​​of 177.7, 176.4, 166.2, 160.4, 154.0, and 152.4 in the NMR spectrum chart of the solid-state 13C.

13. A pharmaceutical compound containing any one of the salts under claims 1 through 12.

14. A pharmaceutical compound under claim 13, which is intended for the treatment or prevention of Parkinson's disease, paroxysmal positional malformations, and limb incontinence.

15. A pharmaceutical composition containing the salts as per claim 1, with a peak at a diffraction angle (2 theta (degrees)) of 11.2 plus or minus 0.3 and 11.9 plus or minus 0.3 in the powder X-ray diffraction diagram of the pharmaceutical composition and at least one additional original drug component.

16. A pharmaceutical composition containing the salts as per claim 1, with a peak at a chemical movement value (delta (ppm)) of 183.5 plus or minus 0.5 and 180.

4. A positive or negative 0.5 value in the NMR chart of the 13C solid-state spectrum of the pharmaceutical component and at least one original active ingredient added to the drug;