Succinates and crystals of octahydrothiophenequinoline compounds

Abstract

[Problem] The technical problem solved by this invention is to provide a compound with high storage stability and suitable for use as a pharmaceutical ingredient. [Solution] This invention relates to a succinate of 1-{[(4aR,6R,8aR)-2-amino-3-cyano-8-methyl-4,4a,5,6,7,8,8a,9-octahydrothieno[3,2-g]quinoline-6-yl]carbonyl}-3-[2-(dimethylamino)ethyl]-1-propylurea, which is suitable as a pharmaceutical ingredient, has excellent storage stability and crystallinity, and can be used to treat or prevent Parkinson's disease, restless legs syndrome, hyperprolactinemia, etc.

Description

Technical Field

[0001] This invention relates to the succinate of 1-{[(4aR,6R,8aR)-2-amino-3-cyano-8-methyl-4,4a,5,6,7,8,8a,9-octahydrothieno[3,2-g]quinoline-6-yl]carbonyl}-3-[2-(dimethylamino)ethyl]-1-propylurea (hereinafter sometimes referred to as "the succinate of this invention"), which has dopamine D2 receptor agonist activity and can be used as a medicament for the prevention or treatment of Parkinson's disease, restless legs syndrome, hyperprolactinemia, etc. Background Technology

[0002] Compounds represented by the following formulas are disclosed in Patent Documents 1 to 3:

[0003] [Chemical Formula 1]

[0004]

[0005] (Chemical name: 1-{[(4aR,6R,8aR)-2-amino-3-cyano-8-methyl-4,4a,5,6,7,8,8a,9-octahydrothieno[3,2-g]quinoline-6-yl]carbonyl}-3-[2-(dimethylamino)ethyl]-1-propylurea; hereinafter sometimes referred to as “compound (B)”) or its hydrochloride salt, which has dopamine D2 receptor agonist activity and can be used as a drug for the prevention or treatment of Parkinson's disease, restless legs syndrome, hyperprolactinemia, etc. However, compound (B) succinate is described only as a general salt and no properties of compound (B) succinate are reported.

[0006] List of referenced files

[0007] Patent documents

[0008] Patent Document 1: International Publication No. WO2012 / 124649.

[0009] Patent document 2: Japanese Patent Publication No. 2014-088362.

[0010] Patent document 3: Japanese Patent Publication No. 2014-073013. Summary of the Invention

[0011] The problem to be solved by the present invention

[0012] As a result of the inventors’ in-depth research, the hydrochloride salt of compound (B) described in Patent Documents 1 to 3 is thermally unstable and has poor storage stability due to the transformation of its crystal form caused by high hygroscopicity as described in the stability tests of Test Examples 4 and 5 below. Therefore, it is necessary to improve its physical properties for use as a pharmaceutical ingredient.

[0013] The objective of this invention is to provide a compound (B) in a different form that has high storage stability and is suitable for use as a pharmaceutical ingredient.

[0014] Problem-solving methods

[0015] As a result of in-depth research into the above-mentioned problems, the inventors discovered that the succinate of 1-{[(4aR,6R,8aR)-2-amino-3-cyano-8-methyl-4,4a,5,6,7,8,8a,9-octahydrothiopheno[3,2-g]quinoline-6-yl]carbonyl}-3-[2-(dimethylamino)ethyl]-1-propylurea has excellent storage stability and excellent crystallinity, making it suitable for industrial production. Therefore, it is a compound suitable as a pharmaceutical raw material, and the inventors thus completed this invention.

[0016] That is, the present invention relates to the following [1] to

[17] , etc.

[0017] [1] A succinate of 1-{[(4aR,6R,8aR)-2-amino-3-cyano-8-methyl-4,4a,5,6,7,8,8a,9-octahydrothiopheno[3,2-g]quinoline-6-yl]carbonyl}-3-[2-(dimethylamino)ethyl]-1-propylurea.

[0018] [2] According to the salt described in [1] above, the salt is represented by the following formula (A-1) or formula (A-2).

[0019] [Chemical Formula 2]

[0020]

[0021] [3] The salt according to [1] above is represented by the following formula (A-1).

[0022] [Chemical Formula 3]

[0023]

[0024] [4] The salt described in [1] above is represented by the following formula (A-2).

[0025] [Chemical Formula 4]

[0026]

[0027] [5] The salt described in [3] above is a crystal.

[0028] [6] The salt described in [4] above is a crystal.

[0029] [7] The salt described in [5] above has peaks at diffraction angles (2θ(°)) of 11.2±0.3 and 11.8±0.3 in the powder X-ray diffraction pattern.

[0030] [8] The salt according to [5] above is characterized by having an endothermic peak at about 150°C in the thermogravimetric-differential thermal analysis diagram.

[0031] [9] Based on the salt described in [5] above, it in 13 The solid-state NMR spectrum shows 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.

[0032]

[10] The salt according to [5] above is characterized by having two or three physical characteristics selected from the following (a1) to (a3):

[0033] (a1) Powder X-ray diffraction pattern with peaks at diffraction angles (2θ(°)) of 11.2±0.3 and 11.8±0.3;

[0034] (a2) Possessing 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. 13 C solid-state NMR spectrum; and

[0035] (a3) Thermogravimetric-differential thermal analysis plot showing the onset temperature of the endothermic peak at approximately 150 °C.

[0036]

[11] The salt described in [6] above has peaks in the powder X-ray diffraction pattern at diffraction angles (2θ(°)) of 8.3±0.3, 12.4±0.3, 15.6±0.3 and 23.2±0.3.

[0037]

[12] According to the salt described above [6], it in 13 The solid-state NMR spectrum shows peaks at chemical shift values ​​(δ(ppm)) of 177.7, 176.4, 166.2, 160.4, 154.0, and 152.4.

[0038]

[13] A pharmaceutical composition comprising the salt according to any one of [1] to

[12] above.

[0039]

[14] The pharmaceutical composition described above

[13] is used to treat or prevent Parkinson's disease, restless legs syndrome or hyperprolactinemia.

[0040]

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

[12] above for the manufacture of a medicament for the treatment or prevention of Parkinson's disease, restless legs syndrome or hyperprolactinemia.

[0041]

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

[12] above.

[0042]

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

[0043]

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

[0044] Effects of the present invention

[0045] The succinate of the present invention exhibits excellent storage stability because it does not absorb moisture and shows almost no decrease in purity during long-term storage. Furthermore, the succinate possesses excellent solubility, crystallinity, and flowability, thus making it a compound that is easy to handle, for example, during formulation. Attached Figure Description

[0046] [ Figure 1 ] Figure 1 This is a powder X-ray diffraction pattern of salt (A-1) form I crystal. The vertical axis shows the X-ray diffraction intensity (count), and the horizontal axis shows the diffraction angle (2θ (°)).

[0047] [ Figure 2 ] Figure 2 This is a powder X-ray diffraction pattern of salt (A-1) form II crystal. The vertical axis shows the X-ray diffraction intensity (count), and the horizontal axis shows the diffraction angle (2θ (°)).

[0048] [ Figure 3 ] Figure 3 This is a powder X-ray diffraction pattern of salt (A-2) form I crystal. The vertical axis shows the X-ray diffraction intensity (count), and the horizontal axis shows the diffraction angle (2θ (°)).

[0049] [ Figure 4 ] Figure 4This is a thermogravimetric-differential thermal analysis (TG-DTA) plot of salt (A-1) form I crystal. The vertical axis (left) shows the weight (%) in the thermogravimetric (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).

[0050] [ Figure 5 ] Figure 5 This is a DSC measurement plot of salt (A-1) form I crystal. The vertical axis (left) shows the weight (%) in the thermogravimetric (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).

[0051] [ Figure 6 ] Figure 6 It is a salt (A-1) form of crystal I. 13 Solid-state NMR spectrum. The vertical axis represents intensity, and the horizontal axis represents chemical shift values ​​(δ (ppm)).

[0052] [ Figure 7 ] Figure 7 It is a salt (A-2) form of crystal I. 13 Solid-state NMR spectrum. The vertical axis represents intensity, and the horizontal axis represents chemical shift values ​​(δ (ppm)).

[0053] [ Figure 8 ] Figure 8 This is a powder X-ray diffraction pattern of the hydrochloride obtained in Comparative Example 1. The vertical axis shows the X-ray diffraction intensity (count), and the horizontal axis shows the diffraction angle (2θ (°)).

[0054] [ Figure 9 ] Figure 9 This is a powder X-ray diffraction pattern of sebacic acid salt crystals obtained in Comparative Example 2. The vertical axis shows the X-ray diffraction intensity (count), and the horizontal axis shows the diffraction angle (2θ (°)).

[0055] [ Figure 10 ] Figure 10 This is a powder X-ray diffraction pattern of the adipate crystals obtained in Comparative Example 3. The vertical axis shows the X-ray diffraction intensity (count), and the horizontal axis shows the diffraction angle (2θ (°)).

[0056] [ Figure 11 ] Figure 11 These are the water adsorption and desorption isotherms for salt (A-1) form I crystals. Solid lines represent adsorption isotherms, and dashed lines represent desorption isotherms. The vertical axis shows the mass change (%), and the horizontal axis shows the relative humidity (%RH).

[0057] [ Figure 12 ] Figure 12These are the water adsorption and desorption isotherms of the hydrochloride obtained in Comparative Example 1. Solid lines represent adsorption isotherms, and dashed lines represent desorption isotherms. The vertical axis shows the mass change (%), and the horizontal axis shows the relative humidity (%RH).

[0058] [ Figure 13 ] Figure 13 These are the water adsorption and desorption isotherms of the sebacic acid salt crystals obtained in Comparative Example 2. Solid lines represent adsorption isotherms, and dashed lines represent desorption isotherms. The vertical axis shows the mass change (%), and the horizontal axis shows the relative humidity (%RH).

[0059] [ Figure 14 ] Figure 14 This is a powder X-ray diffraction pattern of the pharmaceutical composition obtained in Example 4. The vertical axis shows the X-ray diffraction intensity (count), and the horizontal axis shows the diffraction angle (2θ (°)).

[0060] [ Figure 15 ] Figure 15 It is the pharmaceutical composition obtained in Example 4. 13 Solid-state NMR spectrum. The vertical axis represents intensity, and the horizontal axis represents chemical shift values ​​(δ (ppm)). Detailed Implementation

[0061] The embodiments of the present invention will be described in more detail below.

[0062] The succinate of the present invention can be produced, for example, by the following method. Specifically, for example, it can be produced by mixing 0.5 to 2 equivalents of succinic acid with the compound (B) produced using the method described in Patent Document 1 or the method according to the method, dissolving it under heating, then concentrating or adding solvent as needed, and separating the succinate precipitated by cooling. Furthermore, the succinate can be purified by recrystallization using the same or similar solvent.

[0063] A good solvent can be any solvent as long as it does not interfere with salt formation. Examples include methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, 2-butanol, tetrahydrofuran, dimethyl sulfoxide, N,N-dimethylformamide, and N,N-dimethylacetamide. Two or more good solvents can also be used in combination, such as methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, 2-butanol, ethers such as tetrahydrofuran and 1,4-dioxane, solvents such as acetone, acetonitrile, dimethyl sulfoxide, N,N-dimethylformamide, N,N-dimethylacetamide, and water.

[0064] As a poor solvent that can be appropriately added to a good solvent after salt formation, 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 can be used. Furthermore, two or more poor solvents can be used in combination.

[0065] The succinate of the present invention can be purified: the succinate produced according to the above method, etc., can be recrystallized when necessary using a suitable recrystallization solvent such as an acetone-water mixture, a methanol-water mixture, an ethanol-water mixture, dimethyl sulfoxide, etc.

[0066] The succinates of the present invention also include eutectic salts with succinic acid, eutectic salts with succinic acid, and hydrates or solvates with pharmaceutically acceptable solvents such as ethanol.

[0067] The succinate of the present invention has dopamine D2 receptor agonist activity and can be used as a drug for the prevention or treatment of Parkinson's disease, restless legs syndrome, hyperprolactinemia, etc.

[0068] The pharmaceutical compositions of the present invention contain the succinate of the present invention as the active ingredient.

[0069] The production of these pharmaceutical compositions may vary depending on their formulation, and may optionally be carried out by mixing appropriate pharmaceutical additives such as excipients, disintegrants, binders, lubricants, etc., according to conventional pharmaceutical methods and formulating the mixture according to conventional methods.

[0070] For example, if desired, the active ingredient can be formulated into a powder by thoroughly mixing it with appropriate excipients, lubricants, etc. Tablets can be formulated by, for example, by preparing the active ingredient into tablets together with appropriate excipients, disintegrants, binders, lubricants, etc., according to conventional methods. Furthermore, if desired, the tablets can be appropriately coated to provide film-coated tablets, sugar-coated tablets, enteric-coated tablets, etc. Capsules can be formulated by thoroughly mixing the active ingredient with appropriate excipients, lubricants, etc., or by formulating it into granules or fine granules according to conventional methods, and then encapsulating it in appropriate capsules. In addition, in the case of such oral administration formulations, depending on the prevention or treatment method, the formulation can also be a rapid-release or sustained-release formulation.

[0071] When the pharmaceutical composition of the present invention is used for actual prevention or treatment, the dosage of the succinate of the present invention as the active ingredient is appropriately determined depending on the individual patient's age, sex, weight, severity of illness, and treatment. However, for example, in the case of oral administration, the dosage is approximately in the range of 0.1 to 300 mg per adult per day, and the dosage can be administered once or in several divided doses. Preferably, in the case of oral administration, the above-described pharmaceutical composition is produced in a manner that administers the succinate of the present invention in the range of 0.1 to 300 mg per adult per day.

[0072] It is common knowledge that the relative intensity (relative peak height) of each peak in a powder X-ray diffraction pattern may fluctuate depending on sample conditions, measurement conditions, or measuring equipment. Therefore, the relative intensity can vary slightly depending on crystal growth direction, particle size, measurement conditions, etc., and should not be interpreted rigorously.

[0073] It is common knowledge that the 2θ values ​​of each peak in powder X-ray diffraction vary slightly depending on the sample and measurement conditions. This invention covers not only crystals in which the diffraction angles (2θ(°)) of the peaks in powder X-ray diffraction are perfectly matched, but also crystals in which the diffraction angles (2θ(°)) of all or some peaks are matched within the range of ±0.3°.

[0074] In thermogravimetric-differential thermal analysis (DTA) plots, the "endothermic peak" in the DTA curve is represented by the peak temperature (peak top) or the "extrapolated starting temperature". The "extrapolated starting temperature" refers to the intersection of the starting point or offset point in the DTA curve with the extrapolated baseline, also known as the "extrapolated starting temperature".

[0075] "Extrapolated onset temperature" is the temperature at which the peak begins; it refers to the temperature at which exothermic or endothermic reactions begin, calculated through extrapolation. The peak and extrapolated onset temperatures in the thermogravimetric-differential thermal analysis (TGA) plot will also vary slightly depending on the measurement conditions. For example, generally, the temperature can fluctuate within ±5°C. That is, the crystals defined by the above peaks encompass crystals that conform within the ±5°C range.

[0076] In this invention, the term “about” used in thermal analysis refers to a range of ±5°C.

[0077] exist 13 In solid-state NMR spectra, since the chemical shift value (δ(ppm)) may vary slightly depending on the measurement conditions, the identity of the crystal form should be considered even when the chemical shift value varies slightly. This invention also includes crystals within such error ranges. For example, a chemical shift value error of ±0.5 ppm is conceivable. That is, crystals defined by the chemical shift value (δ(ppm)) encompass those conforming to the ±0.5 ppm range. Furthermore, peak intensities may vary due to differences in rotation frequency or measuring device, or peaks may appear or disappear.

[0078] Example

[0079] The invention is further illustrated in detail by the following embodiments and test examples. However, the invention is not limited thereto.

[0080] (Example 1)

[0081] 1-{[(4aR,6R,8aR)-2-amino-3-cyano-8-methyl-4,4a,5,6,7,8,8a,9-octahydrothiopheno[3,2-g]quinoline-6-yl]carbonyl}-3-[2-(dimethylamino)ethyl]-1-propylurea sesquisuccinate monohydrate (salt (A-1) form I crystal)

[0082] 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]quinoline-6-yl]carbonyl}-3-[2-(dimethylamino)ethyl]-1-propylurea (22.00 g), and the mixture was suspended. The mixture was then heated and stirred at an external temperature of 52 °C to dissolve it. Activated carbon (2.2 g) was added to the solution, and the mixture was stirred for 10 minutes. The suspension was hot-filtered and washed with 35.2 g of acetone. Additionally, 220.0 g of acetone was added to the mixture, and the reaction liquid was heated to an external temperature of 52 °C and stirred. Then, 44.0 g of water was added to the reaction liquid. 8.73 g of succinic acid was separately dissolved in a mixture of 156.1 g of acetone and 19.8 g of water. Succinic acid solution was added dropwise to the reaction liquid over approximately 10 minutes. The dropping funnel was washed with a mixture of 17.4 g acetone and 2.2 g water, and the washings were added dropwise to the reaction liquid. The reaction liquid was stirred at an internal temperature of 50 °C for 1 hour and cooled to 15 °C over 30 minutes. The reaction liquid was stirred at an external temperature of 10 °C for 2 hours, and crystals were collected by filtration. The crystals were washed twice with 52.8 g acetone. The obtained wet crystals were dried under reduced pressure at 50 °C for 37 hours and then brought back to room temperature under reduced pressure over 3 hours. These crystals were stored at atmosphere for 24 hours to give crystals of the title compound (27.75 g).

[0083] 1H-NMR(DMSO-d6)(δ(ppm)):0.85(3H,t,J=7.4Hz),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).

[0084] Single-crystal X-ray structural analysis

[0085] Single crystals of 1-{[(4aR,6R,8aR)-2-amino-3-cyano-8-methyl-4,4a,5,6,7,8,8a,9-octahydrothiopheno[3,2-g]quinoline-6-yl]carbonyl}-3-[2-(dimethylamino)ethyl]-1-propylurea sesquisuccinate monohydrate (salt (A-1)) were prepared and subjected to X-ray structural analysis.

[0086] (Single crystal preparation and measurement preparation)

[0087] 1-{[(4aR,6R,8aR)-2-amino-3-cyano-8-methyl-4,4a,5,6,7,8,8a,9-octahydrothiopheno[3,2-g]quinoline-6-yl]carbonyl}-3-[2-(dimethylamino)ethyl]-1-propylurea (30 g) was suspended in a mixture of 84 g acetone and 110 g water, and 11.9 g succinic acid was added. The mixture was heated to an internal temperature of 51 °C to dissolve it. The solution was added to 720 mL of acetone and passed through filter paper while stirring at 50 °C. The container and filter paper were washed with 110 g acetone. 6 mg of salt (A-1) form I crystals were added to the mixture of 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 under ice cooling. The resulting suspension was filtered, and the solids on the filter paper were washed twice with 72 g acetone. The obtained 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 obtained crystals was measured by the method of Example 1, confirming that the crystal form was the same as that of the crystals obtained in Example 1. Single crystals were collected from the powder, cut and shaped with a razor, fixed in microrings with grease, and rapidly frozen in a gas flow in a cryogenic apparatus.

[0088] X-ray diffraction data were measured and acquired using an XtaLAB P200 MM007 (Rigaku Corporation) under the following measurement conditions.

[0089] (Measurement conditions)

[0090] X-ray source: CuKα

[0091] wavelength:

[0092] Tube voltage and tube current: 40kV, 30mA

[0093] Temperature measured: -100℃

[0094] Crystal size: 0.15 × 0.08 × 0.04 mm

[0095] Vibration angle: 1°

[0096] Exposure time: 2 seconds / image

[0097] Total number of sheets measured: 1637

[0098] Total measurement time: 55 minutes

[0099] (Data Analysis Program)

[0100] Data measurement and diffraction data processing: Crystal Clear

[0101] Structural Analysis and Refinement Methods: Crystal Structure, SIR2011, SHELXL2013

[0102] (Measurement Results)

[0103] Table 1 shows the measurement results obtained.

[0104] [Table 1]

[0105]

[0106] a, b, c = unit lattice length

[0107] α, β, γ = angles per unit lattice length

[0108] Z = Number of molecules in a unit lattice.

[0109] Elemental analysis was performed using the CHN automated analyzer vario EL (Elemental). (Elemental analysis results (C, H, N))

[0110] Theoretical values: 52.40%, 7.07%, 13.10%

[0111] Measured values: 52.25%, 7.07%, 12.98%.

[0112] The above measurement results show that the salt (A-1) form I crystal is a monoclinic crystal with space group C2 and z value of 4. The asymmetric unit contains 2 molecules of 1-{[(4aR,6R,8aR)-2-amino-3-cyano-8-methyl-4,4a,5,6,7,8,8a,9-octahydrothiopheno[3,2-g]quinoline-6-yl]carbonyl}-3-[2-(dimethylamino)ethyl]-1-propylurea, 3 molecules of succinic acid and 2 molecules of water.

[0113] (Example 2)

[0114] 1-{[(4aR,6R,8aR)-2-amino-3-cyano-8-methyl-4,4a,5,6,7,8,8a,9-octahydrothieno[3,2-g]quinoline-6-yl]carbonyl}-3-[2-(dimethylamino)ethyl]-1-propylurea sesquisuccinate (salt (A-1) form II crystals)

[0115] 1-{[(4aR,6R,8aR)-2-amino-3-cyano-8-methyl-4,4a,5,6,7,8,8a,9-octahydrothieno[3,2-g]quinoline-6-yl]carbonyl}-3-[2-(dimethylamino)ethyl]-1-propylurea sesquisuccinate was added in a volume of 121 mg to 3 mL of a mixed solvent of 1,4-dioxane / water (volume ratio 1:1). The mixture was heated to 60 °C, dissolved, and filtered. The resulting filtrate was lyophilized. 2.5 mL of n-heptane was added to the resulting powder, and the mixture was heated to 60 °C and stirred for 1 hour in suspension. 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).

[0116] 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).

[0117] (Example 3)

[0118] 1-{[(4aR,6R,8aR)-2-amino-3-cyano-8-methyl-4,4a,5,6,7,8,8a,9-octahydrothiopheno[3,2-g]quinoline-6-yl]carbonyl}-3-[2-(dimethylamino)ethyl]-1-propylurea monosuccinate (salt (A-2) form I crystal)

[0119] 1-{[(4aR,6R,8aR)-2-amino-3-cyano-8-methyl-4,4a,5,6,7,8,8a,9-octahydrothieno[3,2-g]quinoline-6-yl]carbonyl}-3-[2-(dimethylamino)ethyl]-1-propylurea (357 mg) was dissolved in 3.5 mL of acetone under heating at an internal temperature of 50 to 55 °C, and the solution was then cooled to an internal temperature of 4 °C in an ice bath to prepare the reaction liquid. Succinic acid (94 mg) was dissolved separately in 0.3 mL of a 1:1 mixture of acetone and water under heating at an internal temperature of 55 °C. The succinic acid solution was added dropwise to the cooled reaction liquid, and the mixture was concentrated under reduced pressure to dryness. A 1.35 mL mixture of 1:1 acetone and water was added to the residue, and the mixture was dissolved under heating at an internal temperature of 55 °C. The mixture was stirred at room temperature to allow crystals to precipitate. After stirring for 10 minutes, a mixture of acetone and water (1:1 v / v) (0.45 mL) was added to the suspension, and the mixture was stirred at room temperature for 10 minutes. Then, 7.2 mL of acetone was added in three portions over 2 hours, and the mixtures were stirred at room temperature for 1 hour each time. 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).

[0120] 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).

[0121] (Example 4)

[0122] Pharmaceutical compositions containing salt (A-1) form I crystals

[0123] A mixture of mannitol (49 parts), crystalline cellulose (50 parts), and sodium stearate fumarate (1 part) (78.1 mg) was mixed with 8.7 mg of salt (A-1) form I crystals from Example 1 and thoroughly mixed at room temperature to obtain a pharmaceutical composition containing 10% salt (A-1).

[0124] (Experimental Example 1) Powder X-ray Diffraction Measurement

[0125] Powder X-ray diffraction of salt (A-1) form I crystal and salt (A-2) form I crystal was performed using a powder X-ray diffractometer X'Pert Pro MPD (Panalytical, Spectris Ltd.) under the following measurement conditions after the crystals were slightly pounded in a mortar to break down coarse particles.

[0126] (Measurement conditions)

[0127] Radiation source: CuKα rays (CuKα1 and CuKα2),

[0128] Tube voltage: 45kV

[0129] Tube current: 40mA

[0130] Data analysis software: X'Pert HighScore (Panalytical, Spectris Ltd.)

[0131] Data analysis methods (peak finding): minimum significance (1.00), minimum peak (0.01, 2θ(°)) and maximum peak (1.00, 2θ(°)), peak base (2.00, 2θ(°)), method (smoothing peak) (2θ(°))

[0132] Powder X-ray diffraction of salt (A-1) form II crystals was performed using a SmartLab powder X-ray diffractometer (Rigaku Corporation) under the following measurement conditions after the crystals were slightly pounded in a mortar to break down coarse particles.

[0133] (Measurement conditions)

[0134] Radiation source, wavelength: CuKα rays (CuKα1 and CuKα2),

[0135] Tube voltage: 40kV

[0136] Tube current: 50mA

[0137] Data analysis software: SmartLabStudio II (Rigaku Corporation)

[0138] Data analysis methods (peak definition): Peak position (peak apex position, diffraction angle when illuminated with CuKα1 and CuKα2), peak height (excluding background).

[0139] Figure 1 The diffraction pattern of salt (A-1) form I crystal is shown. Table 2 shows the diffraction angles (2θ (°)) of representative diffraction peaks and the relative intensities (%) of said diffraction peaks. Furthermore, Figure 2 The diffraction pattern of salt (A-1) form II crystal is shown. Table 3 shows the diffraction angles (2θ (°)) of representative diffraction peaks and the relative intensities (%) of said diffraction peaks. Furthermore, Figure 3 The diffraction pattern of salt (A-2) form I crystal is shown. Table 4 shows the diffraction angle (2θ (°)) of representative diffraction peaks and the relative intensity (%) of the diffraction peaks.

[0140] [Table 2]

[0141]

[0142]

[0143] [Table 3]

[0144] 5.8 98 11.7 88 11.9 98 16.0 100 19.7 46 20.4 75 24.4 57

[0145] [Table 4]

[0146] 8.3 26 11.5 34 12.4 100 15.6 28 22.1 34 22.7 28 23.2 69 24.1 25 24.7 42

[0147] To identify salt (A-1) form I crystals, for example, the following sets of peaks at diffraction angles (2θ (°)) can be used. 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. Another set of peaks is 11.2±0.3, 11.8±0.3, and 23.6±0.3. Another set of peaks is 11.2±0.3, 11.8±0.3, 23.6±0.3, and 25.4±0.3. Another set of peaks is 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.

[0148] To identify salt (A-1) form II crystals, for example, the following sets of peaks at diffraction angles (2θ (°)) can be used. 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.

[0149] To identify salt (A-2) form II crystals, for example, the following sets of peaks at diffraction angles (2θ (°)) can be used. 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.

[0150] (Experimental Example 2) Thermal Analysis Measurement

[0151] Thermal analysis was performed under a nitrogen atmosphere using a differential thermal balance TG-DTA TG8120 (Rigaku Corporation) under the following measurement conditions.

[0152] (Measurement conditions)

[0153] Heating rate: 10℃ / min

[0154] Reference material: Alumina

[0155] Atmosphere: Under nitrogen flow

[0156] Figure 4 The TG-DTA measurement diagram of salt (A-1) form I crystal is shown.

[0157] The endothermic peak of salt (A-1) form I crystal: a broad endothermic peak in the range of 80 to 130 °C, with an extrapolated onset temperature of approximately 142 °C (melting point) at about 150 °C.

[0158] Mass reduction: approximately 2.7% from 23°C to 150°C.

[0159] Figure 5 The DSC diagram of salt (A-1) form I crystal is shown.

[0160] The endothermic peak of salt (A-1) form I crystal: a broad endothermic peak in the range of 80 to 130 °C, about 153 °C (peak tip (extrapolated onset temperature is about 145 °C).

[0161] (Experimental Example 3) 13 Solid-state NMR spectroscopy measurement

[0162] Salt (A-1) form I crystal and salt (A-2) form I crystal 13 Solid-state NMR spectra were obtained by measuring a sample filled in a solid-state NMR spectra measurement rotor with an inner diameter of 3.2 mm under the following measurement conditions.

[0163] (Measurement conditions)

[0164] NMR instrument: 600MHz AVANCE III (Bruker)

[0165] Probe: Cross-polarized magic angle rotation (CP / MAS) attachment

[0166] Contact time: 3 milliseconds

[0167] Loop delay: 5 seconds

[0168] 1H pulse: 3 microseconds

[0169] Rotation speed: 15kHz

[0170] Points earned: 2048

[0171] Chemical shift correction: reference to glycine. (For C=O resonance, δ = 176.46 ppm)

[0172] Figure 6 The solid-state NMR spectrum of the salt (A-1) form I crystal obtained in Example 1 is shown, and Table 5 shows the chemical shifts (ppm). Furthermore, Figure 7 The solid-state NMR spectrum of the salt (A-2) form I crystal obtained in Example 3 is shown, and Table 6 shows the chemical shifts (ppm).

[0173] [Table 5]

[0174]

[0175] [Table 6]

[0176]

[0177] To identify salt (A-1) form I crystals, for example, the following groups can be used. 13Chemical shift values ​​(δ(ppm)) of C solid-state NMR spectra. One group 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 group 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 group consists of 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. Another group consists of 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, and 50. 0.1±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.

[0178] To identify salt (A-2) form I crystals, for example, the following groups of chemical shift values ​​(δ (ppm)) can be used. One group is 177.7, 176.4, 166.2, 160.4, 154.0, and 152.4. Another group is 177.7, 177.2, 176.4, 175.9, 166.2, 160.4, 154, and 152.4. Yet another group is 177.7, 177.2, 176.4, 175.9, 168.8, 168.2, 167.3, 166.2, 160.4, 154.0, and 152.4. The other group consists of 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. The other group consists of 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.

[0179] In this invention, the salt (A-1) form I crystal can also be synthesized by combining the above-mentioned powder X-ray diffraction peaks, 13 Identification was performed using solid-state NMR spectra and thermogravimetric-differential thermal analysis (TGA) plots.

[0180] For example, as one embodiment for identifying salt (A-1) form I crystals, the following embodiments (c1) to (c4) are described.

[0181] (c1) The peaks in the powder X-ray diffraction pattern are at diffraction angles (2θ(°)) of 11.2±0.3 and 11.8±0.3; 13 The peaks in the C solid-state NMR spectrum are located 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.

[0182] (c2) The peaks in the powder X-ray diffraction pattern are at diffraction angles (2θ (°)) of 11.2 ± 0.3 and 11.8 ± 0.3; the extrapolated starting temperature of the endothermic peak in the thermogravimetric-differential thermal analysis pattern is about 150 °C (hereinafter referred to as "extrapolated starting temperature").

[0183] (c3) 13The peaks in the C solid-state NMR spectrum are 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; and the endothermic peak in the thermogravimetric-differential thermal analysis plot has an onset temperature of approximately 150 °C.

[0184] (c4) The peaks in the powder X-ray diffraction pattern are at diffraction angles (2θ(°)) of 11.2±0.3 and 11.8±0.3; 13 The peaks in the C solid-state NMR spectrum are 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; and the endothermic peak in the thermogravimetric-differential thermal analysis plot has an onset temperature of approximately 150 °C.

[0185] (Comparative Example 1)

[0186] Compound (B) hydrochloride crystals

[0187] Powder X-ray diffraction of the compound (B) hydrochloride crystals obtained by the method described in Example 4-1 of Patent Document 1 was measured in the same manner as in Test Example 1. Figure 8 The obtained diffraction pattern is shown.

[0188] (Comparative Example 2)

[0189] Compound (B) sebacate crystals

[0190] Compound (B) (500 mg) and sebacic acid (226 mg) were added to ethanol (3 mL), heated to 50 °C, and dissolved. The resulting solution was stirred at room temperature for 1 hour, and then diisopropyl ether (3 mL) was added. The mixture was stirred at room temperature for another 3 days. The precipitated solid was collected by filtration, washed with a mixture of ethanol and diisopropyl ether (1:1), air-dried at room temperature for 3 hours, and then dried under reduced pressure at 60 °C for another 3 hours to give 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).

[0191] The powder X-ray diffraction of the obtained compound (B) sebacate crystals was measured in the same manner as in Experimental Example 1. Figure 9 The obtained diffraction pattern is shown.

[0192] (Comparative Example 3)

[0193] Compound (B) adipate crystals

[0194] Compound (B) (500 mg) and adipic acid (164 mg) were added to 3 mL of ethanol 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. The mixture was stirred at room temperature for another 1 hour. The mixture was heated to 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 obtained solid was air-dried overnight under a laboratory atmosphere, and then dried under reduced pressure at 60 °C for 3 hours to give the title compound (0.3854 g).

[0195] 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).

[0196] The powder X-ray diffraction of the obtained compound (B) adipate crystals was measured in the same manner as in Experimental Example 1. Figure 10 The obtained diffraction pattern is shown.

[0197] (Experimental Example 4) Stability Test 1

[0198] Salt (A-1) form I crystals, salt (A-2) form I crystals, compound (B) hydrochloric acid crystals, compound (B) sebacic acid crystals, and adipate crystals were stored at 60°C under open conditions, and the physical and chemical stability of each crystal form was examined. Powder X-ray diffraction of samples at the beginning of the test and after 2 months was measured in the same manner as in Example 1, and the physical stability and the amount of relevant substances in the crystal forms were measured using the following HPLC measurement conditions to observe chemical stability. Appearance changes were also observed. The results are shown in Table 7.

[0199] No change in crystal form was observed in salt (A-1) form I and salt (A-2) form I crystals during storage at 60°C. Furthermore, the chemical properties of salt (A-1) form I and salt (A-2) form I crystals remained stable, with almost no change in appearance. On the other hand, the crystal form of compound (B) hydrochloride and compound (B) sebacic acid salt changed, and their chemical properties became unstable. Additionally, compounds (B) hydrochloride, (B) sebacic acid salt, and (B) adipate salt exhibited discoloration.

[0200] (HPLC conditions)

[0201] Detector: UV-Vis spectrophotometer / Wavelength: 225nm

[0202] Column: L-column 2ODS, 3μm, 4.6×150mm (manufactured by the Japan Chemical Evaluation Institute)

[0203] Column temperature: approximately 30℃

[0204] Flow rate: 1.0 mL / min

[0205] Mobile phase A: A solution of potassium dihydrogen phosphate and dipotassium hydrogen phosphate mixed in water, each at a concentration of 10 mmol / L (pH 6.9).

[0206] Mobile phase B: Acetonitrile

[0207] Flow ratio

[0208] 0 to 25 minutes: Mobile phase A / Mobile phase B = 79 / 21

[0209] 25 to 45 minutes: Mobile phase A / Mobile phase B = 79 / 21 to 25 / 75 (gradient)

[0210] 45 to 50 minutes: Mobile phase A / Mobile phase B = 25 / 75

[0211] Injection volume: 5μL

[0212] Sample cooler: 4℃

[0213] Dissolving solvent: A mixed solution prepared by adding 20 parts of acetonitrile to 80 parts of a 20 mmol / L potassium dihydrogen phosphate aqueous solution adjusted to pH 3.

[0214] Sample solution: A liquid obtained by dissolving the sample in a solvent and adjusting the concentration of compound (B) to approximately 1.0 mg / mL.

[0215] Peaks derived from blank data are removed, and the peak area of ​​the corresponding peak is measured by automatic integration, and its value is determined by area normalization.

[0216] [Table 7]

[0217] Salt (A-1) form I crystal No increase constant White (slight staining observed) Salt (A-2) form I crystal +0.05％ constant White (slight staining observed) Compound (B) hydrochloride crystals +12.6％ Change From white to brown Compound (B) sebacate crystals +2.20％ Change From white to dark gray Compound (B) adipate crystals +0.54％ constant From light brown to brown

[0218] (Experimental Example 5) Stability Test 2

[0219] Salt (A-1) form I crystals, salt (A-2) form I crystals, compound (B) hydrochloride crystals, compound (B) sebacic acid salt crystals, and adipate crystals were stored under open conditions at 40°C and 75% relative humidity, and the physical and chemical stability of each crystal form was examined. Powder X-ray diffraction of samples at the start of testing and after 2 months was measured in the same manner as in Example 1, and the physical stability and the amount of relevant substances in the crystal forms were measured using the following HPLC measurement conditions to observe chemical stability. Appearance changes were also observed. The results are shown in Table 8.

[0220] No change in crystal form was observed in salt (A-1) form I and salt (A-2) form I crystals during storage under open conditions of 40°C and 75% relative humidity. Furthermore, the chemical properties of salt (A-1) form I and salt (A-2) form I crystals remained stable, and their appearance did not change. On the other hand, the crystal forms of compound (B) hydrochloride and compound (B) sebacic acid salt changed. Furthermore, compound (B) sebacic acid salt was chemically unstable. Compound (B) adipate was also chemically unstable and its appearance changed color.

[0221] (HPLC conditions)

[0222] Detector: UV-Vis spectrophotometer / Wavelength: 225nm

[0223] Column: L-column 2ODS, 3μm, 4.6×150mm (manufactured by the Japan Chemical Evaluation Institute)

[0224] Column temperature: approximately 30℃

[0225] Flow rate: 1.0 mL / min

[0226] Mobile phase A: A solution of potassium dihydrogen phosphate and dipotassium hydrogen phosphate mixed in water, each at a concentration of 10 mmol / L (pH 6.9).

[0227] Mobile phase B: Acetonitrile

[0228] Flow ratio

[0229] 0 to 25 minutes: Mobile phase A / Mobile phase B = 79 / 21

[0230] 25 to 45 minutes: Mobile phase A / Mobile phase B = 79 / 21 to 25 / 75 (gradient)

[0231] 45 to 50 minutes: Mobile phase A / Mobile phase B = 25 / 75

[0232] Injection volume: 5μL

[0233] Sample cooler: 4℃

[0234] Dissolving solvent: A mixed solution prepared by adding 20 parts of acetonitrile to 80 parts of a 10 mmol / L potassium dihydrogen phosphate aqueous solution adjusted to pH 3.

[0235] Sample solution: A liquid obtained by dissolving the sample in a solvent and adjusting the concentration of compound (B) to approximately 1.0 mg / mL.

[0236] Peaks derived from blank data are removed, and the peak area of ​​the corresponding peak is measured by automatic integration, and its value is determined by area normalization.

[0237] [Table 8]

[0238] Salt (A-1) form I crystal +0.01％ constant White remains unchanged Salt (A-2) form I crystal No increase constant White remains unchanged Compound (B) hydrochloride crystals +0.19％ Change White remains unchanged Compound (B) sebacate crystals +6.16％ Change From light brown to dark brown Compound (B) adipate crystals +0.94％ constant From light brown to reddish brown

[0239] (Experimental Example 6) Water Adsorption and Desorption Test

[0240] Under the following conditions, the water adsorption and desorption properties of salt (A-1) form I crystals, compound (B) hydrochloride crystals, and compound (B) sebacic acid crystals were measured using an IGA-Sorp (manufactured by HIDEN isochema). Figure 11 The isotherms for water adsorption and desorption of salt (A-1) form I crystals are shown. Figure 12 The water adsorption and desorption isotherms of compound (B) hydrochloride are shown. Figure 13The water adsorption and desorption isotherms of compound (B) sebacate are shown.

[0241] Samples and dosages used for measurement

[0242] Salt (A-1) form I crystals: 14.7 mg

[0243] Compound (B) hydrochloride crystals: 10.4 mg

[0244] Compound (B) sebacate crystals: 13.2 mg

[0245] Preprocessing: Balancing

[0246] Place each sample in the water adsorption and desorption measuring device. Set the temperature and humidity to 25℃ / 40% RH or 50% RH and allow it to equilibrate for 60 minutes or longer to stabilize the quality.

[0247] Measurement

[0248] In adsorption and desorption, the mass of each sample undergoing mass equilibrium was continuously measured at 5% RH changes in relative humidity. Table 9 shows the measurement conditions set for the water adsorption and desorption measurement equipment, and Table 10 shows the mass changes within the commonly used humidity range.

[0249] [Table 9]

[0250]

[0251] [Table 10]

[0252]

[0253] Mass % can be expressed as the percentage change in mass of the dry sample before and after adsorption (or desorption). Under the above conditions, it was found that salt (A-1) form I crystals did not exhibit hygroscopicity, while the hygroscopicity of compound (B) hydrochloride was 25 to 41 times that of salt (A-1) form I crystals, and the hygroscopicity of compound (B) sebacic acid salt was 6 to 15 times that of compound (B) sebacic acid salt.

[0254] As described above, the succinate of the present invention is more preferably used as a pharmaceutical ingredient because it is non-hygroscopic.

[0255] (Example 7) Powder X-ray diffraction pattern of the pharmaceutical composition

[0256] A sample of the pharmaceutical composition was filled onto a measuring plate for X-ray diffraction measurement, and the measurement was performed under the following conditions to obtain a diffraction pattern. Figure 14 The powder X-ray diffraction pattern of the pharmaceutical composition obtained in Example 4 is shown, and Table 11 shows the diffraction angles (2θ (°)) of the representative diffraction peaks.

[0257] (Measurement conditions)

[0258] Powder X-ray diffractometer: SmartLab (Rigaku Corporation)

[0259] Radiation source: CuKα rays

[0260] Tube voltage: 40kV

[0261] Tube current: 50mA

[0262] Data analysis software: SmartLabStudio II (Rigaku Corporation)

[0263] Data analysis methods (peak definition): Peak position (peak apex position, diffraction angle when illuminated with CuKα1 and CuKα2), peak height (excluding background).

[0264] [Table 11]

[0265] 11.2 11.9 16.2

[0266] To identify salt (A-1) form I crystals in a pharmaceutical composition, for example, the following sets of peaks at diffraction angles (2θ (°)) can be used. 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.

[0267] (Experimental Example 8) Pharmaceutical Composition 13 solid-state NMR spectrum

[0268] A sample of the pharmaceutical composition was filled onto a solid-state NMR spectrometer rotor with an inner diameter of 3.2 mm, and measurements were performed under the following conditions to obtain solid-state NMR spectra. Figure 15 Solid-state NMR spectra of the pharmaceutical composition obtained in Example 4 are shown. Table 12 shows the chemical shifts (ppm) obtained from salt (A-1) form I crystals.

[0269] (Measurement conditions)

[0270] Nuclear Magnetic Resonance Imaging Equipment: 600MHz AVANCE III (Bruker)

[0271] Probe: Cross-polarized magic angle rotation (CP / MAS) attachment

[0272] Contact time: 3 milliseconds

[0273] Loop delay: 5 seconds

[0274] 1H pulse: 3 microseconds

[0275] Rotation speed: 15kHz

[0276] Points earned: 2048

[0277] Chemical shift correction: reference to glycine. (For C=O resonance, δ = 176.46 ppm)

[0278] [Table 12]

[0279]

[0280]

[0281] To identify salt (A-1) form I crystals in a pharmaceutical composition, for example, the following methods can be used. 13 The peaks of chemical shifts (ppm) in the 183.5 ± 0.5 C solid-state NMR spectrum. 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.

[0282] Industrial applicability

[0283] The succinate of the present invention has excellent storage stability and other physical properties, and can be used as a raw material for pharmaceutical products, suitable for industrial production.

Claims

1. 1-{[(4aR,6R,8aR)-2-amino-3-cyano-8-methyl-4,4a,5,6,7,8,8a,9-octahydrothiopheno[3,2-g]quinoline-6-yl]carbonyl}-3-[2-(dimethylamino)ethyl]-1-propylurea succinate, Its appearance in powder X-ray diffraction patterns at diffraction angles (2...) θ (°)) Peaks at 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, The succinate therein is a sesquisuccinate monohydrate and is crystalline. 2.1-{[(4aR,6R,8aR)-2-amino-3-cyano-8-methyl-4,4a,5,6,7,8,8a,9-octahydrothiopheno[3,2-g]quinoline-6-yl]carbonyl}-3-[2-(dimethylamino)ethyl]-1-propylurea succinate, Its appearance in powder X-ray diffraction patterns at diffraction angles (2...) θ (°)) Peaks at 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, The succinate therein is a monosuccinate and is crystalline.

3. The succinate according to claim 1, which has an endothermic peak at 150℃±5℃ in the thermogravimetric-differential thermal analysis diagram. 4.1-{[(4aR,6R,8aR)-2-amino-3-cyano-8-methyl-4,4a,5,6,7,8,8a,9-octahydrothiopheno[3,2-g]quinoline-6-yl]carbonyl}-3-[2-(dimethylamino)ethyl]-1-propylurea succinate, Its in 13 The solid-state NMR spectrum shows 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. The succinate therein is a sesquisuccinate monohydrate and is crystalline. 5.1-{[(4aR,6R,8aR)-2-amino-3-cyano-8-methyl-4,4a,5,6,7,8,8a,9-octahydrothiopheno[3,2-g]quinoline-6-yl]carbonyl}-3-[2-(dimethylamino)ethyl]-1-propylurea succinate, Its features Choose two or three physical characteristics from (a1) to (a3) ​​below: (a1) has the ability to diffract at an angle (2) θ Powder X-ray diffraction patterns of peaks at 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; (a2) Possesses 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. 13 C solid-state NMR spectrum; and (a3) Thermogravimetric-differential thermal analysis plot showing the onset temperature of the endothermic peak at 150℃±5℃. The succinate therein is a sesquisuccinate monohydrate and is crystalline. 6.1-{[(4aR,6R,8aR)-2-amino-3-cyano-8-methyl-4,4a,5,6,7,8,8a,9-octahydrothiopheno[3,2-g]quinoline-6-yl]carbonyl}-3-[2-(dimethylamino)ethyl]-1-propylurea succinate, Its in 13 The solid-state NMR spectrum shows peaks at chemical shift values ​​(δ (ppm)) of 177.7±0.5, 176.4±0.5, 166.2±0.5, 160.4±0.5, 154.0±0.5, and 152.4±0.

5. The succinate therein is a monosuccinate and is crystalline.

7. A pharmaceutical composition comprising a succinate according to any one of claims 1 to 6.

8. Use of the pharmaceutical composition of claim 7 in the preparation of a medicament for the treatment or prevention of Parkinson's disease, restless legs syndrome, or hyperprolactinemia.

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