Crystals of aromatic ring derivatives, their preparation method and use

Abstract

Crystals of aromatic ring derivatives and their preparation and use are disclosed, in particular salt forms, crystals, pharmaceutical compositions and uses of the compound represented by formula (I). [Formula 1] JPEG2024544717000036.jpg2453

Description

[Technical Field]

[0001] This application claims priority to: CN202111555458.X, filing date: December 17, 2021.

[0002] The present invention relates to crystalline forms, salt forms, pharmaceutical compositions of compounds of formula (I) and their use as S1P1 agonists. [Background technology]

[0003] Sphingosine-1-phosphate (S1P) is an amphipathic biological signaling molecule belonging to the lysophospholipid (LP) family. S1P activates complex downstream signals by acting on five G protein-coupled receptor subtypes, the sphingosine-1-phosphate receptors (S1PR1-5), thereby regulating important physiological and biochemical functions. S1P binds to various S1P receptors to regulate various physiological functions, thereby playing an important role in maintaining body health and the development of diseases.

[0004] S1P1 receptor agonists disrupt lymphocyte trafficking, leading to lymphocyte sequestration in lymph nodes and other secondary lymphoid tissues. This reduces peripheral circulating lymphocytes, and the clinical value of lymphocyte sequestration is its exclusion from the sphere of inflammatory and / or autoimmune responses in surrounding tissues. This lymphocyte sequestration (e.g., in lymph nodes) is thought to result from the simultaneous action of agonist-driven functional antagonism of S1P1 receptors on T cells (thus reducing the ability of S1P to recruit T cells out of lymph nodes) and sustained agonism of S1P1 receptors on lymph node endothelium (thus improving the barrier function against lymphocyte migration). Therefore, S1P1 receptor agonists can be used as immunosuppressants to treat various autoimmune diseases because they reduce the body's autoimmune potential by interfering with lymphocyte trafficking.

[0005] Among these, the S1P1 agonist fingolimod (FTY720) has been approved by the FDA for the treatment of relapsing multiple sclerosis (MS), opening up a new therapeutic field in the treatment of immune disorders. Although FTY720 has clinical efficacy, it is a nonselective S1P receptor agonist, and its binding to S1P3 in vivo often causes a series of significant side effects, including bradycardia, significantly limiting its use in the treatment of immune disorders. Therefore, the discovery of second-generation, highly selective S1P1 agonists with greater efficacy, fewer side effects, and a broader range of applications for the treatment of immune disorders has become a hot topic in pharmaceutical research.

[0006] The application, application number PCT / CN2019 / 123485 (filed December 6, 2019), provides an S1P1 agonist having the following structure: [ka] Summary of the Invention

[0007] The present invention provides a calcium salt of the compound of formula (I). [ka]

[0008] In some embodiments of the present invention, the calcium salt is [ka] is.

[0009] The present invention further provides a G-type crystal of the calcium salt of the compound represented by formula (II), which has a powder X-ray diffraction pattern having characteristic diffraction peaks at the following 2θ angles: 8.98±0.2°, 10.12±0.2°, 13.56±0.2°, 14.66±0.2°, 15.22±0.2°, and 18.48±0.2°.

[0010] In some embodiments of the present invention, the powder X-ray diffraction pattern of the G-type crystals has characteristic diffraction peaks at the following 2θ angles: 8.98±0.2°, 10.12±0.2°, 13.56±0.2°, 14.66±0.2°, 15.22±0.2°, 16.34±0.2°, 16.92±0.2°, 18.48±0.2°, 22.67±0.2°, and 23.06±0.2°.

[0011] In some embodiments of the present invention, the powder X-ray diffraction pattern of the above-mentioned G-type crystals has essentially the powder X-ray diffraction pattern shown in FIG.

[0012] In some embodiments of the present invention, the analytical data of the powder X-ray diffraction pattern of the above-mentioned G-type crystals are as shown in Table 7.

[0013] [Table 1]

[0014] In some embodiments of the present invention, the G-type crystal further contains water and a solvent,

[0015] however, the solvent is selected from ethanol and isopropyl alcohol; The content of the solvent is 0.1% to 6.0%; The water content is 0.1 to 4.0%. In some embodiments of the present invention, the content of the solvent is 1.0% to 5.5%, and the content of water is 3.0% to 4.5%. In some embodiments of the present invention, the solvent is ethanol, the content of the ethanol is 1.0% to 5.5%, and the content of the water is 3.0% to 4.5%.

[0016] In some embodiments of the present invention, the content of the solvent is 1.64% to 4.77%, and the content of water is 3.09% to 4.37%.

[0017] In some embodiments of the present invention, the solvent is ethanol, the ethanol content is 1.64% to 4.77%, and the water content is 3.09% to 4.37%.

[0018] In some embodiments of the present invention, the solvent is ethanol, where the ethanol content is 4.77% and the water content is 3.09%.

[0019] In some embodiments of the present invention, the solvent is ethanol, where the ethanol content is 3.05% and the water content is 3.89%.

[0020] In some embodiments of the present invention, the solvent is ethanol, where the ethanol content is 1.97% and the water content is 4.37%.

[0021] In some embodiments of the present invention, the solvent is ethanol, where the ethanol content is 1.64% and the water content is 3.75%.

[0022] As used herein, a characteristic diffraction peak is a peak selected from an observed diffraction pattern. When distinguishing between multiple crystalline solids, a peak that is visible in one crystalline solid but not in other crystalline solids relative to its size is a preferred characteristic peak for identifying the crystalline solid. Even one or two such characteristic peaks can characterize the crystalline solid.

[0023] In particular, the presence of characteristic diffraction peaks in the G-type crystals can be distinguished from other crystalline forms (e.g., anhydrous forms) disclosed herein. Furthermore, by comparing measured X-ray diffraction patterns, if the characteristic peaks match, the powder X-ray diffraction patterns can be said to be substantially identical. The hydration state of the G-type crystals may change depending on the solvent and water content. Such G-type crystals with different solvent hydration contents share common characteristic peaks as shown in Figure 1 and Figures 18-21.

[0024] In some embodiments of the present invention, the common characteristic peaks are at least three peaks selected from the diffraction angles (2θ): 8.98±0.2°, 10.12±0.2°, 13.56±0.2°, 14.66±0.2°, 15.22±0.2°, and 18.48±0.2°.

[0025] In some embodiments of the present invention, the common characteristic peaks are at least three peaks selected from the following diffraction angles (2θ): 8.98±0.2°, 10.12±0.2°, 13.56±0.2°, 14.66±0.2°, 15.22±0.2°, 16.34±0.2°, 16.92±0.2°, 18.48±0.2°, 22.67±0.2°, and 23.06±0.2°.

[0026] In the present invention, the content (%) represents a mass ratio, and the unit is g / g.

[0027] In a further aspect of the present invention, the present invention further provides a method for preparing type G crystals. According to an embodiment of the present invention, the method comprises dissolving a compound represented by formula (I) in a sodium ethoxide solution, followed by stirring in the presence of calcium chloride, filtering, and drying under reduced pressure to obtain type G crystals. This method differs from the general method for forming calcium salt crystals in the prior art, in that the method of the present invention employs conditions in which calcium chloride is present instead of calcium hydroxide, and requires drying before obtaining type G crystals.

[0028] In some embodiments of the present invention, the method includes heating a compound represented by Formula (I) and absolute ethanol to 35 to 45°C, stirring for 5 to 30 minutes, adding a sodium ethoxide solution and stirring for 2 to 3 hours, adding a calcium chloride solution dropwise and stirring for 1 to 3 hours to react, cooling to 20 to 30°C, stirring for 4 to 6 hours, filtering, rinsing the cake with purified water, rinsing with ethanol, and drying the cake under reduced pressure at 25 to 35°C to obtain Type G crystals.

[0029] In some embodiments of the present invention, the mass ratio of sodium ethoxide to absolute ethanol in the sodium ethoxide solution is (0.01-0.05):(0.40-0.80).

[0030] In some embodiments of the present invention, the mass ratio of sodium ethoxide to absolute ethanol in the sodium ethoxide solution is 0.035:0.631.

[0031] In some embodiments of the present invention, the mass ratio of calcium chloride to pure water in the calcium chloride solution is (0.01 to 0.08):(0.20 to 1.00).

[0032] In some embodiments of the present invention, the mass ratio of calcium chloride to pure water in the calcium chloride solution is 0.040:0.847.

[0033] The present invention provides [ka] Further provided is a type A crystal of the compound of formula (I), which has a powder X-ray diffraction pattern with characteristic diffraction peaks at the following 2θ angles: 5.25±0.2°, 6.28±0.2°, 10.5±0.2°, 12.69±0.2°, 15.45±0.2°, and 16.02±0.2°.

[0034] In some embodiments of the present invention, the powder X-ray diffraction pattern of the above-mentioned Type A crystals has characteristic diffraction peaks at the following 2θ angles: 5.25±0.2°, 6.28±0.2°, 10.5±0.2°, 12.69±0.2°, 15.45±0.2°, 16.02±0.2°, 16.60±0.2°, 20.66±0.2°, 21.39±0.2°, and 22.28±0.2°.

[0035] In some embodiments of the present invention, the powder X-ray diffraction pattern of the above-mentioned Form A crystals has essentially the powder X-ray diffraction pattern shown in FIG.

[0036] In some embodiments of the present invention, the analytical data of the powder X-ray diffraction pattern of the above-mentioned Form A crystal is as shown in Table 1 below.

[0037] [Table 2]

[0038] The present invention further provides a B-type crystal of the compound represented by formula (I), which has a powder X-ray diffraction pattern having characteristic diffraction peaks at the following 2θ angles: 6.96±0.2°, 11.71±0.2°, 15.55±0.2°, 17.35±0.2°, 20.62±0.2°, and 21.16±0.2°.

[0039] In some embodiments of the present invention, the powder X-ray diffraction pattern of the above-mentioned type B crystals has characteristic diffraction peaks at the following 2θ angles: 6.96±0.2°, 10.80±0.2°, 11.71±0.2°, 13.39±0.2°, 15.55±0.2°, 17.35±0.2°, 18.45±0.2°, 20.62±0.2°, 21.16±0.2°, and 21.81±0.2°.

[0040] In some embodiments of the present invention, the powder X-ray diffraction pattern of the above-mentioned B-type crystals has essentially the powder X-ray diffraction pattern shown in FIG.

[0041] In some embodiments of the present invention, the analytical data of the powder X-ray diffraction pattern of the above-mentioned B-type crystals are as shown in Table 2.

[0042] [Table 3]

[0043] The present invention further provides a C-type crystal of the compound represented by formula (I), which has a powder X-ray diffraction pattern having characteristic diffraction peaks at the following 2θ angles: 12.69±0.2°, 14.38±0.2°, 16.23±0.2°, 17.40±0.2°, 18.61±0.2°, and 19.74±0.2°.

[0044] In some embodiments of the present invention, the powder X-ray diffraction pattern of the above-mentioned C-type crystals has characteristic diffraction peaks at the following 2θ angles: 12.69±0.2°, 14.38±0.2°, 16.23±0.2°, 17.40±0.2°, 18.61±0.2°, 19.74±0.2°, 20.46±0.2°, 20.94±0.2°, 21.75±0.2°, and 25.44±0.2°.

[0045] In some embodiments of the present invention, the powder X-ray diffraction pattern of the above-mentioned C-type crystals has essentially the powder X-ray diffraction pattern shown in FIG.

[0046] In some embodiments of the present invention, the analytical data of the powder X-ray diffraction pattern of the above-mentioned C-type crystals are as shown in Table 3.

[0047] [Table 4]

[0048] The present invention further provides a D-type crystal of the compound represented by formula (I), which has a powder X-ray diffraction pattern having characteristic diffraction peaks at the following 2θ angles: 9.33±0.2°, 13.94±0.2°, 18.82±0.2°, 22.76±0.2°, 24.24±0.2°, and 27.90±0.2°.

[0049] In some embodiments of the present invention, the powder X-ray diffraction pattern of the above-mentioned D-type crystals has an X-ray powder diffraction pattern essentially as shown in FIG.

[0050] In some embodiments of the present invention, the analytical data of the powder X-ray diffraction pattern of the above-mentioned D-type crystals are as shown in Table 4.

[0051] [Table 5]

[0052] The present invention further provides type E crystals of the compound represented by formula (I), which have a powder X-ray diffraction pattern having characteristic diffraction peaks at the following 2θ angles: 6.84±0.2°, 10.65±0.2°, 11.53±0.2°, 15.41±0.2°, 17.29±0.2°, and 20.65±0.2°.

[0053] In some embodiments of the present invention, the powder X-ray diffraction pattern of the E-form crystals has characteristic diffraction peaks at the following 2θ angles: 6.84±0.2°, 10.65±0.2°, 11.53±0.2°, 13.78±0.2°, 15.41±0.2°, 17.29±0.2°, 20.22±0.2°, 20.65±0.2°, 23.90±0.2°, and 25.26±0.2°.

[0054] In some embodiments of the present invention, the powder X-ray diffraction pattern of the above-mentioned Form E crystals has essentially the powder X-ray diffraction pattern shown in FIG.

[0055] In some embodiments of the present invention, the analytical data of the powder X-ray diffraction pattern of the above-mentioned E-form crystals are as shown in Table 5.

[0056] [Table 6]

[0057] The present invention further provides a diethylamine salt of the compound of formula (I).

[0058] The present invention further provides type F crystals of the diethylamine salt of the compound represented by formula (I), which have a powder X-ray diffraction pattern having characteristic diffraction peaks at the following 2θ angles: 10.36±0.2°, 10.96±0.2°, 12.01±0.2°, 13.05±0.2°, 16.66±0.2°, and 18.99±0.2°.

[0059] In some embodiments of the present invention, the powder X-ray diffraction pattern of the above-mentioned F-type crystals has characteristic diffraction peaks at the following 2θ angles: 10.36±0.2°, 10.96±0.2°, 12.01±0.2°, 13.05±0.2°, 16.66±0.2°, 18.99±0.2°, 20.42±0.2°, 20.98±0.2°, 22.11±0.2°, and 23.93±0.2°.

[0060] In some embodiments of the present invention, the powder X-ray diffraction pattern of the above-mentioned Form F crystals has essentially the powder X-ray diffraction pattern shown in FIG.

[0061] In some embodiments of the present invention, the analytical data of the powder X-ray diffraction pattern of the above-mentioned F-type crystals are as shown in Table 6.

[0062] [Table 7]

[0063] The present invention further provides an H-type crystal of the calcium salt of the compound represented by formula (I), which has a powder X-ray diffraction pattern having characteristic diffraction peaks at the following 2θ angles: 7.32±0.2°, 9.57±0.2°, 11.83±0.2°, 12.76±0.2°, 13.48±0.2°, and 14.83±0.2°.

[0064] In some embodiments of the present invention, the powder X-ray diffraction pattern of the H-type crystals has characteristic diffraction peaks at the following 2θ angles: 7.32±0.2°, 9.57±0.2°, 11.83±0.2°, 12.76±0.2°, 13.48±0.2°, 14.83±0.2°, 16.64±0.2°, 17.69±0.2°, 18.91±0.2°, and 21.33±0.2°.

[0065] In some embodiments of the present invention, the powder X-ray diffraction pattern of the above-mentioned H-form crystals has essentially the powder X-ray diffraction pattern shown in FIG.

[0066] In some embodiments of the present invention, the analytical data of the powder X-ray diffraction pattern of the above-mentioned H-form crystals are as shown in Table 8.

[0067] [Table 8]

[0068] The present invention further provides Type I crystals of the calcium salt of the compound represented by formula (I), which have a powder X-ray diffraction pattern having characteristic diffraction peaks at the following 2θ angles: 7.27±0.2°, 8.93±0.2°, 11.23±0.2°, 12.34±0.2°, 13.66±0.2°, and 16.06±0.2°.

[0069] In some embodiments of the present invention, the powder X-ray diffraction pattern of the above-mentioned Form I crystal has characteristic diffraction peaks at the following 2θ angles: 7.27±0.2°, 8.93±0.2°, 11.23±0.2°, 12.34±0.2°, 13.66±0.2°, 16.06±0.2°, 17.97±0.2°, 20.82±0.2°, 23.42±0.2°, and 24.38±0.2°.

[0070] In some embodiments of the present invention, the powder X-ray diffraction pattern of the above-mentioned Form I crystals has an X-ray powder diffraction pattern essentially as shown in FIG.

[0071] In some embodiments of the present invention, the analytical data of the powder X-ray diffraction pattern of the above-mentioned Form I crystal is as shown in Table 9.

[0072] [Table 9]

[0073] The present invention further provides a J-type crystal of the calcium salt of the compound represented by formula (I), which has a powder X-ray diffraction pattern having characteristic diffraction peaks at the following 2θ angles: 8.73±0.2°, 9.49±0.2°, 11.99±0.2°, 12.89±0.2°, 15.16±0.2°, and 19.58±0.2°.

[0074] In some embodiments of the present invention, the powder X-ray diffraction pattern of the above-mentioned J-type crystals has characteristic diffraction peaks at the following 2θ angles: 4.52±0.2°, 8.73±0.2°, 9.49±0.2°, 11.99±0.2°, 12.89±0.2°, 15.16±0.2°, 19.58±0.2°, 21.96±0.2°, 24.84±0.2°, and 26.66±0.2°.

[0075] In some embodiments of the present invention, the powder X-ray diffraction pattern of the above-mentioned J-type crystals has an X-ray powder diffraction pattern essentially as shown in FIG.

[0076] In some embodiments of the present invention, the analytical data of the powder X-ray diffraction pattern of the above-mentioned J-type crystals are as shown in Table 10.

[0077] [Table 10]

[0078] The present invention further provides a K-type crystal of the calcium salt of the compound represented by formula (I), which has a powder X-ray diffraction pattern having characteristic diffraction peaks at the following 2θ angles: 8.57±0.2°, 9.32±0.2°, 11.06±0.2°, 12.65±0.2°, 14.08±0.2°, and 14.71±0.2°.

[0079] In some embodiments of the present invention, the powder X-ray diffraction pattern of the above-mentioned K-type crystals has characteristic diffraction peaks at the following 2θ angles: 7.66±0.2°, 8.57±0.2°, 9.32±0.2°, 11.06±0.2°, 12.65±0.2°, 14.08±0.2°, 14.71±0.2°, 15.08±0.2°, 15.79±0.2°, and 19.29±0.2°.

[0080] In some embodiments of the present invention, the powder X-ray diffraction pattern of the above-mentioned K-type crystals has essentially the powder X-ray diffraction pattern shown in FIG.

[0081] In some embodiments of the present invention, the analytical data of the powder X-ray diffraction pattern of the above-mentioned K-type crystals are as shown in Table 11 below.

[0082] [Table 11]

[0083] The present invention further provides a form L crystal of the calcium salt of the compound represented by formula (I), which has a powder X-ray diffraction pattern having characteristic diffraction peaks at the following 2θ angles: 8.69±0.2°, 9.78±0.2°, 13.46±0.2°, 14.72±0.2°, 15.40±0.2°, and 15.98±0.2°.

[0084] In some embodiments of the present invention, the powder X-ray diffraction pattern of the above-mentioned Form L crystals has essentially the powder X-ray diffraction pattern shown in FIG.

[0085] In some embodiments of the present invention, the analytical data of the powder X-ray diffraction pattern of the above-mentioned Form L crystal is as shown in Table 12.

[0086] [Table 12]

[0087] The present invention further provides an M-type crystal of the calcium salt of the compound represented by formula (I), which has a powder X-ray diffraction pattern having characteristic diffraction peaks at the following 2θ angles: 8.09±0.2°, 10.87±0.2°, 13.62±0.2°, 14.55±0.2°, 15.77±0.2°, and 16.39±0.2°.

[0088] In some embodiments of the present invention, the powder X-ray diffraction pattern of the above-mentioned M-type crystals has an X-ray powder diffraction pattern essentially as shown in FIG.

[0089] In some embodiments of the present invention, the analytical data of the powder X-ray diffraction pattern of the above-mentioned M-type crystals are as shown in Table 13.

[0090] [Table 13]

[0091] The present invention further provides an N-type crystal of the calcium salt of the compound represented by formula (I), which has a powder X-ray diffraction pattern having characteristic diffraction peaks at the following 2θ angles: 7.79±0.2°, 12.44±0.2°, 14.94±0.2°, 16.11±0.2°, 17.50±0.2°, and 20.98±0.2°.

[0092] In some embodiments of the present invention, the powder X-ray diffraction pattern of the N-type crystals described above has essentially the powder X-ray diffraction pattern shown in FIG.

[0093] In some embodiments of the present invention, the analytical data of the powder X-ray diffraction pattern of the N-type crystals is as shown in Table 14.

[0094] [Table 14]

[0095] The present invention further provides an O-type crystal of the calcium salt of the compound represented by formula (I), which has a powder X-ray diffraction pattern having characteristic diffraction peaks at the following 2θ angles: 7.40±0.2°, 8.52±0.2°, 12.01±0.2°, 12.24±0.2°, 14.67±0.2°, and 16.86±0.2°.

[0096] In some embodiments of the present invention, the powder X-ray diffraction pattern of the O-type crystals has characteristic diffraction peaks at the following 2θ angles: 7.40±0.2°, 8.52±0.2°, 12.01±0.2°, 12.24±0.2°, 14.67±0.2°, 15.35±0.2°, 16.86±0.2°, 18.05±0.2°, 19.77±0.2°, and 22.02±0.2°.

[0097] In some embodiments of the present invention, the powder X-ray diffraction pattern of the above-mentioned O-type crystals has essentially the powder X-ray diffraction pattern shown in FIG.

[0098] In some embodiments of the present invention, the analytical data of the powder X-ray diffraction pattern of the above-mentioned O-type crystals are as shown in Table 15.

[0099] [Table 15]

[0100] The present invention further provides a P-type crystal of the calcium salt of the compound represented by formula (I), which is characterized in that its powder X-ray diffraction pattern has characteristic diffraction peaks at the following 2θ angles: 11.49±0.2°, 13.38±0.2°, 14.04±0.2°, 16.28±0.2°, 16.78±0.2°, 20.22±0.2°, and 20.86±0.2°.

[0101] In some embodiments of the present invention, the powder X-ray diffraction pattern of the P-type crystal has characteristic diffraction peaks at the following 2θ angles: 11.49±0.2°, 13.38±0.2°, 14.04±0.2°, 16.28±0.2°, 16.78±0.2°, 18.81±0.2°, 20.22±0.2°, 20.86±0.2°, 23.16±0.2°, 24.66±0.2°, and 25.87±0.2°.

[0102] In some embodiments of the present invention, the powder X-ray diffraction pattern of the P-type crystals described above has essentially the powder X-ray diffraction pattern shown in FIG.

[0103] In some embodiments of the present invention, the analytical data of the powder X-ray diffraction pattern of the P-type crystals is as shown in Table 16.

[0104] [Table 16]

[0105] The present invention further provides a strontium salt of the compound of formula (I).

[0106] In some embodiments of the present invention, the Q-type crystal of the strontium salt of the compound represented by formula (I) is characterized in that its powder X-ray diffraction pattern has characteristic diffraction peaks at the following 2θ angles: 5.01±0.2°, 8.96±0.2°, 10.08±0.2°, 13.54±0.2°, 14.84±0.2°, and 24.67±0.2°.

[0107] In some embodiments of the present invention, the powder X-ray diffraction pattern of the Q-type crystals has characteristic diffraction peaks at the following 2θ angles: 5.01±0.2°, 8.96±0.2°, 10.08±0.2°, 13.54±0.2°, 14.84±0.2°, 18.43±0.2°, 21.10±0.2°, 22.10±0.2°, 23.80±0.2°, and 24.67±0.2°.

[0108] In some embodiments of the present invention, the powder X-ray diffraction pattern of the above-mentioned Type Q crystals has essentially the powder X-ray diffraction pattern shown in FIG.

[0109] In some embodiments of the present invention, the analytical data of the powder X-ray diffraction pattern of the above-mentioned Q-type crystals are as shown in Table 17.

[0110] [Table 17]

[0111] The present invention further provides a pharmaceutical composition comprising the A-type crystals, B-type crystals, C-type crystals, D-type crystals, E-type crystals, diethylamine salt, F-type crystals, calcium salt, G-type crystals, H-type crystals, I-type crystals, J-type crystals, K-type crystals, L-type crystals, M-type crystals, N-type crystals, O-type crystals, P-type crystals, strontium salt, or Q-type crystals.

[0112] In some embodiments of the present invention, the pharmaceutical composition further comprises a pharmaceutically acceptable carrier, excipient, diluent, adjuvant, vehicle, or a combination thereof.

[0113] The present invention further provides use of the A-type crystals, B-type crystals, C-type crystals, D-type crystals, E-type crystals, diethylamine salts, F-type crystals, calcium salts, G-type crystals, H-type crystals, I-type crystals, J-type crystals, K-type crystals, L-type crystals, M-type crystals, N-type crystals, O-type crystals, P-type crystals, strontium salts, Q-type crystals or pharmaceutical compositions in the preparation of medicines for use in treating S1P1 receptor-related diseases.

[0114] In some embodiments of the present invention, the S1P1 receptor-associated disease is selected from ulcerative colitis, Crohn's disease, multiple sclerosis, systemic lupus erythematosus, lupus nephritis, rheumatoid arthritis, primary biliary cholangitis, atopic dermatitis, intracerebral hemorrhage, graft-versus-host disease, psoriasis, type I diabetes, acne, microbial infections or diseases, and viral infections and diseases.

[0115] Definitions and Explanations

[0116] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. All patents and published publications referenced herein are incorporated by reference in their entirety. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, the preferred methods, devices, and materials are described herein.

[0117] "Crystal" or "crystalline form" refers to a solid having a highly ordered chemical structure, including, but not limited to, single-component or multi-component crystals and / or crystalline polymorphs of a compound, solvates, hydrates, clathrates, eutectics, salts, solvates of salts, and hydrates of salts. Crystalline forms of a substance can be obtained by many methods known in the art. Such methods include, but are not limited to, melt crystallization, melt cooling, solvent crystallization, crystallization in confined spaces (e.g., in nanopores or capillaries), crystallization on surfaces or templates (e.g., on polymers), crystallization in the presence of additives such as co-crystallized antimolecules, desolvation, dehydration, rapid evaporation, rapid cooling, slow cooling, vapor diffusion, sublimation, reactive crystallization, antisolvent addition, milling, and solvent drop milling.

[0118] "Amorphous" or "amorphous form" refers to a substance formed when its particles (molecules, atoms, ions) are arranged in three-dimensional space without periodicity, resulting in a powder X-ray diffraction pattern lacking diffuse peaks. Amorphous is a special physical form of solid matter, whose locally ordered structural characteristics suggest that amorphous is inseparably related to crystalline matter. Amorphous forms of substances can be obtained by many methods known in the art, including, but not limited to, quenching, antisolvent aggregation, ball milling, spray drying, freeze drying, wet granulation, and solid dispersion techniques.

[0119] "Solvent" refers to a substance (usually a liquid) that can completely or partially dissolve another substance (usually a solid). Solvents that may be used in the practice of the present invention include, but are not limited to, water, acetic acid, acetone, acetonitrile, benzene, chloroform, carbon tetrachloride, dichloromethane, dimethyl sulfoxide, 1,4-dioxane, ethanol, ethyl acetate, butanol, tert-butanol, N,N-dimethylacetamide, N,N-dimethylformamide, formamide, formic acid, heptane, hexane, isopropyl alcohol, methanol, methyl ethyl ketone, 1-methyl-2-pyrrolidone, mesitylene, nitromethane, polyethylene glycol, propanol, 2-propanone, pyridine, tetrahydrofuran, toluene, xylene, mixtures thereof, and the like.

[0120] "Antisolvent" refers to a fluid that promotes precipitation of a product (or product precursor) from a solvent. Antisolvents may include cold gases, or fluids that promote precipitation by chemical reaction, or fluids that reduce the solubility of the product in the solvent, and may be the same liquid as the solvent but at a different temperature, or a different liquid than the solvent.

[0121] The term "solvate" refers to a solvent present on the surface, within the crystal lattice, or both. The solvent may be water, acetic acid, acetone, acetonitrile, benzene, chloroform, carbon tetrachloride, dichloromethane, dimethyl sulfoxide, 1,4-dioxane, ethanol, ethyl acetate, butanol, tert-butanol, N,N-dimethylacetamide, N,N-dimethylformamide, formamide, formic acid, heptane, hexane, isopropyl alcohol, methanol, methyl ethyl ketone, methylpyrrolidone, mesitylene, nitromethane, polyethylene glycol, propanol, 2-propanone, pyridine, tetrahydrofuran, toluene, xylene, or mixtures thereof. A specific example of a solvate is a hydrate, in which the solvent present on the surface, within the crystal lattice, or both on the surface and within the crystal lattice of a substance is water. The hydrate may or may not contain a solvent other than water on the surface, within the crystal lattice, or both on the surface and within the crystal lattice of the substance.

[0122] Crystalline or amorphous can be distinguished by various technical methods such as X-ray powder diffraction (XRPD), infrared absorption spectroscopy (IR), melting point, differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), nuclear magnetic resonance, Raman spectroscopy, X-ray single crystal diffraction, solution calorimetry, scanning electron microscopy (SEM), quantitative analysis, solubility and dissolution rate.

[0123] X-ray powder diffraction (XRPD) can detect information such as crystalline changes, crystallinity, and crystalline structure state, and is a common method for identifying crystals. Peak positions in an XRPD pattern primarily depend on the crystal structure and are relatively insensitive to experimental details, while relative peak heights depend on many factors related to sample preparation and instrument geometry. Thus, in some embodiments, the crystals of the present invention are characterized by XRPD patterns with specific peak positions substantially as shown in the XRPD patterns provided in the accompanying drawings. At the same time, the measurement of 2θ in an XRPD pattern may involve experimental error, and the measurement of 2θ in an XRPD pattern may vary slightly between different instruments and different samples, so the 2θ value cannot be considered absolute. Due to the condition of the instrument used in the testing of the present invention, there is a ±0.2° error tolerance for diffraction peaks.

[0124] Differential scanning calorimetry (DSC) is a technique that measures the energy difference between a sample and an inert reference material (usually α-Al2O3) as a function of temperature by continuously heating or cooling under program control. The height of the melting peak in a DSC curve depends on many factors related to sample preparation and instrument geometry, while the position of the peak is relatively insensitive to experimental details. Thus, in some embodiments, the crystals described herein are characterized by DSC patterns with characteristic peak positions substantially as shown in the DSC patterns provided in the drawings of the present invention. At the same time, experimental error may exist in DSC patterns, and the peak positions and values ​​of DSC patterns may vary slightly between different instruments and different samples, so the peak positions and values ​​of the DSC endothermic peaks cannot be considered absolute. Depending on the condition of the instrument used in the present testing, there is a ±3°C error margin for the melting peak.

[0125] Solids with the same chemical composition often form isomers or variants with different crystal structures under different thermodynamic conditions, a phenomenon known as polymorphism. When temperature and pressure conditions change, variants can transform into each other, a phenomenon known as crystal transformation. Crystal transformations can significantly alter the mechanical, electrical, magnetic, and other properties of the crystal. If the temperature of the crystal transformation is within a measurable range, this transformation process can be observed in a differential scanning calorimetry (DSC) pattern. The DSC pattern is characterized by the simultaneous presence of two or more endothermic peaks, which are characteristic of different crystals before and after the transformation. Crystals or amorphous forms of the compounds of the present invention may undergo crystal transformation under appropriate conditions.

[0126] Thermogravimetric analysis (TGA) is a programmable technique for measuring the mass change of a substance as a function of temperature. It is suitable for investigating the reduction of solvents in crystals and the sublimation and decomposition processes of samples, and can be used to infer the presence of crystallized water or crystallization solvents in crystals. The mass change displayed by a TGA curve depends on many factors, including sample preparation and instrumentation, and the mass change detected by TGA varies slightly depending on the instrument and sample. In some examples, the A-type crystals of the calcium salt described herein exhibit a weight loss of approximately 5.1% at a temperature of approximately 150°C. Depending on the condition of the instrument used in the present testing, there is a ±0.3% margin of error for the mass change.

[0127] In the context of the present invention, all 2θ values ​​in powder X-ray diffraction patterns are expressed in degrees (°).

[0128] The term "essentially as shown" refers to at least 50%, or at least 60%, or at least 70%, or at least 80%, or at least 90%, or at least 95%, or at least 99% of the peaks in an X-ray powder diffraction pattern or a DSC pattern or a TGA result being represented in the pattern.

[0129] When referring to data appearing in a pattern or graph, a "peak" refers to a feature recognizable by one of ordinary skill in the art that is not due to background noise.

[0130] In the context of the present invention, the terms "about" or "approximately," when used or not, mean within 10%, suitably within 5%, and particularly within 1% of a given value or range. Alternatively, to those skilled in the art, the terms "about" or "approximately" mean within an acceptable standard error of the mean. Whenever a numerical value with a value of N is disclosed, a numerical value within N+ / -1%, N+ / -2%, N+ / -3%, N+ / -5%, N+ / -7%, N+ / -8%, or N+ / -10% is expressly disclosed, where "+ / -" refers to plus or minus.

[0131] The term "comprises" is open-ended, i.e. includes the subject matter specified in the present invention, but does not exclude other aspects.

[0132] The salt forms or crystals or pharmaceutical compositions of the present invention can be used to prepare a medicament for treating an S1P1 receptor-associated disease, wherein the S1P1 receptor-associated disease is selected from ulcerative colitis, Crohn's disease, multiple sclerosis, systemic lupus erythematosus, lupus nephritis, rheumatoid arthritis, primary biliary cholangitis, atopic dermatitis, intracerebral hemorrhage, graft versus host disease, psoriasis, Type I diabetes, acne, microbial infections or diseases, and viral infections or diseases. [Brief explanation of the drawings]

[0133] [Figure 1] 1 is a powder X-ray diffraction (XRPD) pattern of the A-type crystal. [Figure 2] 1 is a powder X-ray diffraction (XRPD) pattern of the B-type crystals. [Figure 3] This is the powder X-ray diffraction (XRPD) pattern of the C-type crystal. [Figure 4] This is the powder X-ray diffraction (XRPD) pattern of the D-type crystal. [Figure 5] 1 is a powder X-ray diffraction (XRPD) pattern of E-form crystals. [Figure 6] This is the powder X-ray diffraction (XRPD) pattern of the F-type crystal. [Figure 7] 1 is a powder X-ray diffraction (XRPD) pattern of the G-type crystal. [Figure 8]This is the powder X-ray diffraction (XRPD) pattern of the H-type crystal. [Figure 9] 1 is a powder X-ray diffraction (XRPD) pattern of the type I crystal. [Figure 10] This is the powder X-ray diffraction (XRPD) pattern of the J-type crystal. [Figure 11] This is the powder X-ray diffraction (XRPD) pattern of the K-type crystal. [Figure 12] 1 is a powder X-ray diffraction (XRPD) pattern of the L-form crystal. [Figure 13] 1 is a powder X-ray diffraction (XRPD) pattern of M-type crystals. [Figure 14] This is the powder X-ray diffraction (XRPD) pattern of the N-type crystal. [Figure 15] This is the powder X-ray diffraction (XRPD) pattern of the O-type crystal. [Figure 16] This is a powder X-ray diffraction (XRPD) pattern of P-type crystals. [Figure 17] 1 is a powder X-ray diffraction (XRPD) pattern of the Q-type crystal. [Figure 18] 1 is a powder X-ray diffraction (XRPD) pattern of the G-type crystal. [Figure 19] 1 is a powder X-ray diffraction (XRPD) pattern of the G-type crystal. [Figure 20] 1 is a powder X-ray diffraction (XRPD) pattern of the G-type crystal. [Figure 21] 1 is a powder X-ray diffraction (XRPD) pattern of the G-type crystal. DETAILED DESCRIPTION OF THE INVENTION

[0134] The present invention will now be described in detail with reference to examples, which should not be construed as limiting the present invention in any way. The present invention has been described in detail herein, and specific embodiments thereof have been disclosed. It will be apparent to those skilled in the art that various changes and modifications can be made to the specific embodiments of the present invention without departing from the spirit and scope of the present invention.

[0135] The powder X-ray diffraction analysis method used in this invention is performed at room temperature using a Bruker D2 PHASER diffractometer (300W low-power X-ray emitter). During the test, a silicon wafer is used to place the sample powder, and an X-ray Cu (Kα) tube is used, with the Kα2 / Kα1 intensity ratio being 0.50 (1.54439 Å / 1.5406 Å). The instrument is set to 30 kV and 10 mA, with a step size of 0.02° (2θ), a scan time per step of 0.15 seconds, and a total of 1837 steps.

[0136] The differential scanning calorimetry (DSC) analysis method used in this invention involves collecting differential scanning calorimetry data using a TA Discovery DSC. Specifically, a few milligrams of sample is weighed into a Tzero aluminum tray and sealed with the corresponding Tzero aluminum tray lid. Under a nitrogen gas atmosphere, the sealed sample is heated from room temperature to 300°C at a heating rate of 10°C / min.

[0137] The thermogravimetric analysis (TGA) data used in this invention is collected using a TA Discovery TGA. Specifically, a few milligrams of sample is heated from room temperature to 350°C at a heating rate of 10°C / min under a nitrogen gas atmosphere.

[0138] The polarized light microscopy (PLM) analysis method used in this invention analyzes the morphology of samples at room temperature using an Olympus BX53M polarized light microscope.

[0139] The high performance liquid chromatography (HPLC) analysis method used in the present invention was to test the purity and stability of the samples using an Agilent 1260, and the conditions used were as shown in Table 18 below.

[0140] [Table 18]

[0141] The hygroscopicity analysis method used in the present invention uses SMS ADVENTURE DVS to evaluate the hygroscopicity of a sample under a nitrogen gas atmosphere at 25° C. Approximately 30 mg of sample is used for the test, and the test method is as follows:

[0142] Method 1 (for anhydrous crystals): 0%RH~95%RH, 10%RH increase in each step (90~95%RH: 5%RH increase), 95%RH~0%RH, 10% RH decrease in each step (5% RH decrease from 95~90%RH).

[0143] Method 2 (for water cosolvates): Ambient humidity up to 95%RH, 10%RH increase in each step (90~95%RH: 5%RH increase), 95%RH~0%RH, 10%RH decrease in each step (5%RH decrease from 95% to 90%RH), 0%RH~95%RH, 10% RH increase in each step (5% RH increase from 90~95%RH).

[0144] The analytical method for measuring water content in this invention involves collecting sample water content data using a Karl Fischer titrator (Karl Fischer, KF) from Switzerland, a Metrohm 870 / 803. Measurements were performed using the volumetric method, with Hydranal Composite-2 (Sigma-Aldrich, P / N: 34806) as the titrant and anhydrous methanol as the solvent, with a stirring time of 30 seconds. Specifically, a sample weighing ~50 mg (with an accuracy of 0.001 g) was used to measure the water content of the sample using the KF titrator. The measurements were performed twice in parallel and the average value was calculated.

[0145] The liquid nuclear magnetic resonance (1H NMR) of the present invention: Sample analysis is performed using a Bruker 400M nuclear magnetic resonance instrument, and DMSO-d6 is used as the solvent.

[0146] The solid-state nuclear magnetic resonance (ssNMR) of the present invention was performed using a Bruker 500 MHz wide-bore solid-state nuclear magnetic resonance spectrometer (400 MHz WB Solid-State Nuclear Magnetic Resonance Spectrometer) with a 4 mm double-resonance magic-angle coil rotation probe. The cross-polarization / magic-angle rotation (CP / MAS) method was used, and a sideband suppression technique (TOSS) was simultaneously implemented to avoid the effects of rotation sidebands. The 13C fingerprint pattern of the sample was collected. The cross-polarization matching conditions were optimized using adamantane, and the chemical shift was corrected using the adamantane high-field signal (29.5 ppm). The magic-angle velocity was 8 kHz, the 1H 90-degree pulse was 3.45 us, and the decoupling method was TPPM. The specific test conditions were as follows:

[0147] 2# Test: Pulse delay 8s, contact time 2ms, cumulative 1500 times. 3# Test: Pulse delay 2s, contact time 2ms, cumulative 1500 times. 4# Test: Pulse delay 2s, contact time 0.2ms, cumulative 3100 times.

[0148] The abbreviations or English-Japanese meanings of the solvents used in the present invention are as shown in Table 19 below:

[0149] [Table 19]

[0150] DETAILED DESCRIPTION OF THE INVENTION In the following, specific examples of the present invention will be described in order to enable those skilled in the art to better understand the present invention.

[0151] Example 1: Preparation of type A crystals The compound represented by formula (I) was stirred in anisole / n-heptane (4:3, v / v) at room temperature to precipitate a solid, which was filtered and dried in vacuo at 45°C for 36 hours to obtain type A crystals.

[0152] Example 2: Preparation of B-type crystals The compound represented by formula (I) (2.0 g) was dissolved in IPAC (10 mL), heated to 60°C, heptane (40 mL) was added dropwise, and the mixture was cooled to 40°C. A large amount of solid began to precipitate, and heptane (10 mL) was added, stirred for 2 hours, filtered, and dried in vacuo at 45°C for 36 hours to obtain type B crystals.

[0153] Example 3: Preparation of D-type crystals The compound represented by formula (I) was stirred in MeOH / HO (9:2, v / v) at room temperature to precipitate a solid, which was then filtered and dried in vacuo at 45°C for 36 hours to obtain type D crystals.

[0154] Example 4: Preparation of C-type crystals The D-type crystals were heated to 137°C to obtain C-type crystals.

[0155] Example 5: Preparation of E-type crystals The compound represented by formula (I) was stirred in CPME / heptane (2:3, v / v) at room temperature to precipitate a solid, which was filtered and dried in vacuo at 45°C for 36 hours to obtain E-type crystals.

[0156] Example 6: Preparation of F-type crystals (including salt formation step) The compound represented by formula (I) (0.4 g) was dissolved in EtOH (3.0 mL) at room temperature, stirred to dissolve, and then an ethanol solution of diethylamine (diethylamine: 69.4 mg, ethanol: 0.8 mL) was slowly added. The mixture was stirred at room temperature for 19 hours to precipitate a solid, which was then filtered and vacuum dried at 30°C for 3 hours to obtain F-type crystals.

[0157] Example 7: G-type crystals [ka]

[0158] Method 1: Compound (I) (0.2651 kg, 0.595 mol) and absolute ethanol (0.9488 kg) were added to a reactor, heated to 35-45°C, and stirred for 5-30 minutes. Sodium ethoxide solution (sodium ethoxide: 0.035 kg, 0.514 mol, absolute ethanol: 0.6310 kg) was added and stirred for 2-3 hours. Calcium chloride solution (calcium chloride: 0.040 kg, 0.357 mol, purified water: 0.847 kg) was added dropwise and stirred for 1-3 hours. The reaction was allowed to cool to 20-30°C, stirred for 4-6 hours, filtered, and the cake was rinsed with purified water and then ethanol. The cake was dried under reduced pressure at 25-35°C to obtain 0.2185 kg of G-type crystals of Compound (II) for a yield of 79.1%.

[0159] Method 2: 10.72 g of compound of Formula (I) was weighed into a single-neck flask, EtOH (105 mL) was added, and the mixture was stirred magnetically for 0.5 hours. CHOna (1.64 g) was added and stirred at room temperature for 1.5 hours. Anhydrous CaCl (1.5 g) was dissolved in EtOH / HO (2:1, v / v, 45 mL), and 1% calcium chloride solution (G-type crystals) was added dropwise. The mixture was stirred for 16 hours. The suspension was collected and the XRPD of the sample was performed, which showed that it was D-type crystals. The cake was filtered, and the cake was washed twice with HO and EtOH. The XRPD of the wet sample was performed, which showed that it was J-type crystals. The cake was dried under vacuum at 50 °C for 4 hours, and the XRPD of the wet sample was performed, which showed that it was G-type crystals.

[0160] Method 3: To the compound of formula (I) (21 mg), Ca(OH) (2 mg) was added, and 0.2 mL of EtOH / HO (9:1, v / v) was added. The mixture was stirred magnetically at room temperature for 3 days, filtered, and dried under vacuum at 50°C for 2 hours to obtain G-type crystals.

[0161] Method 4: To the compound of formula (I) (21 mg), Ca(OH) (2 mg) was added, and 0.2 mL of IPA / HO (9:1, v / v) was added. The mixture was stirred magnetically at room temperature for 4 days, filtered, and dried under vacuum at 50°C for 2 hours to obtain G-type crystals.

[0162] For the product filtered by Method 3, the water and solvent contents were measured using different drying times, temperatures, or vacuum levels, and their XRPD was detected, and the results are shown in Table 20 below.

[0163] [Table 20] [Table 21] [Table 22] [Table 23] [Table 24]

[0164] Stability of Form G crystals in different solvents:

[0165] Method 1: 0.5 mL of the corresponding solvent (corresponding solvent can be EtOH, HO, EtOH / HO=970 / 30, 927 / 73, 855 / 145, 704 / 296, v / v) was added to the G-type crystals (50 mg), and the mixture was stirred magnetically at room temperature for 4 days, filtered, and dried under vacuum at 50°C for 2 hours to obtain the G-type crystals.

[0166] Method 2: Form G crystals (15 mg) were added to a 4 mL vial and placed in a 20 mL vial containing 3 mL of a volatile solvent (which may be MeOH or EtOH). The 20 mL vial was tightly capped and left at room temperature for about a week, then filtered and dried in vacuum at 50°C for 2 hours to obtain Form G crystals.

[0167] Example 8: Preparation of H-type crystals MeOH (0.5 mL) was added to the G-type crystals (50 mg), and the mixture was stirred magnetically at room temperature for 4 days and filtered to obtain H-type crystals.

[0168] Example 9: Preparation of Form I Crystals The G-type crystals (50 mg) were placed in an HPLC vial, and MeOH (0.5 mL) was added thereto. The mixture was stirred magnetically at 50° C. for 7 days to obtain a suspension, which was then filtered to obtain the I-type crystals.

[0169] Example 10: Preparation of J-type crystals Method 1: 0.5 mL of solvent (the solvent can be 2-butanol or toluene) was added to the G-type crystals (50 mg), and the mixture was stirred magnetically at room temperature for 4 days, and then filtered to obtain the J-type crystals. Method 2: Type G crystals (50 mg) were placed in an HPLC vial, and IPA (0.5 mL) was added. The mixture was stirred magnetically at 50° C. for 7 days to obtain a suspension, which was then filtered to obtain type J crystals. Method 3: Type G crystals (50 mg) were placed in an HPLC vial, and 0.5 mL of EtOAc / n-heptane (1 / 2, v / v) was added. The mixture was stirred magnetically at 50° C. for 7 days to obtain a suspension, which was then filtered to obtain type J crystals. Method 4: ~21 mg of the compound of formula (I) in Example 1 (purity 93 area%) and ~2 mg of Ca(OH) were weighed into an HPLC vial, 0.2 mL of EtOH / HO (9:1, v / v) was added, and the mixture was magnetically stirred at room temperature for 3 days. After centrifugation, the wet sample was detected by XRPD to be a J-type crystal.

[0170] Example 11: Preparation of K-type crystals The G-type crystals (50 mg) were placed in an HPLC vial, and 2-MeTHF / n-heptane=1 / 2, v / v (0.5 mL) was added thereto. The mixture was stirred magnetically at 50° C. for 7 days to obtain a suspension, which was then filtered to obtain the K-type crystals.

[0171] Example 12: Preparation of L-type crystals Under nitrogen gas protection, the K-type crystals were heated to 80°C and cooled to room temperature to obtain L-type crystals.

[0172] Example 13: Preparation of M-type crystals The G-type crystals (15 mg) were placed in a 20 mL glass bottle, and DMF was added. The mixture was stirred at room temperature to dissolve the crystals. H2O was gradually added to the glass bottle until a solid appeared, and the mixture was filtered to obtain the M-type crystals.

[0173] Example 14: Preparation of N-type crystals G-type crystals (15 mg) were placed in a 4 mL glass bottle and DMF was added to dissolve the crystals until they were clear. If they were not clear, the suspension was filtered through a nylon membrane (pore size 0.22 μm), and the solution was poured into a 20 mL glass bottle containing 4 mL of HO. The 20 mL glass bottles were tightly capped and left at room temperature until a solid precipitated. The N-type crystals were then filtered.

[0174] Example 15: Preparation of O-type crystals The G-type crystal sample was dissolved in acetone and allowed to stand for about 10 minutes, after which a solid precipitated and was filtered to obtain O-type crystals.

[0175] Example 16: Preparation of P-type crystals The G-type crystals (15 mg) were placed in a 20 mL glass bottle, and acetone was added. The mixture was stirred at room temperature to dissolve the G-type crystals. MTBE was gradually added to the glass bottle until a solid appeared, and the mixture was filtered to obtain the P-type crystals.

[0176] Example 17: Preparation of Q-type crystals The compound represented by formula (I) (110 mg) was added to a 20 mL one-neck flask, EtOH (1 mL) was added, and the mixture was stirred magnetically until it became transparent. Sodium ethoxide (16 mg) was added, and the mixture was reacted at 40°C for 1 hour with magnetic stirring. 0.1 mL of an aqueous strontium chloride solution (300 mg / mL) was added dropwise, and the mixture was reacted at 28°C for 12 hours with stirring. The mixture was filtered and dried to obtain type Q crystals.

[0177] Example 18 The inventors found that among the A-Q type crystals disclosed above, some have poor preparation reproducibility and some cannot be purified. Therefore, they selected four types, namely, A-type crystals, B-type crystals, G-type crystals, and Q-type crystals, which have good preparation reproducibility and are easy to purify, and performed tests under the same conditions, namely, high temperature, high humidity, and light exposure, to examine their stability. The test protocol and results are shown in Table 25 below, and the changes in shape are shown in Table 26.

[0178] [Table 25] [Table 26]

[0179] From Tables 25 and 26 above, it can be seen that the G-type crystal has higher stability under high temperature, high humidity and light conditions than the other crystals.

[0180] Example 19 The purities of the A-type crystals, B-type crystals, G-type crystals, and Q-type crystals of the same mass and packaging examined under storage conditions of 25°C and 40°C are shown in Table 27.

[0181] [Table 27]

[0182] From Table 27 above, it can be seen that the G-type crystals have higher stability when stored at 25°C and 40°C for 90 days. The present application includes the following aspects. [Section 1] A calcium salt of the compound of formula (I). [ka] [Section 2] [ka] Item 2. The calcium salt according to Item 1, [Section 3] A G-type crystal of the compound represented by formula (II), characterized in that the powder X-ray diffraction pattern has characteristic diffraction peaks at the following 2θ angles: 8.98±0.2°, 10.12±0.2°, 13.56±0.2°, 14.66±0.2°, 15.22±0.2°, and 18.48±0.2°. [Section 4] Item 4. The G-type crystal according to Item 3, characterized in that the powder X-ray diffraction pattern of the G-type crystal has characteristic diffraction peaks at the following 2θ angles: 8.98±0.2°, 10.12±0.2°, 13.56±0.2°, 14.66±0.2°, 15.22±0.2°, 16.34±0.2°, 16.92±0.2°, 18.48±0.2°, 22.67±0.2°, and 23.06±0.2°. [Section 5] Item 3 or 4. The G-type crystal according to Item 3 or 4, characterized in that the powder X-ray diffraction pattern of the G-type crystal is essentially the powder X-ray diffraction pattern shown in FIG. 7. [ Item 6 ] further comprising water and a solvent; however, the solvent is selected from ethanol and isopropyl alcohol; The content of the solvent is 0.1% to 6.0%; Item 3 or 4. The G-type crystal according to Item 3 or 4, wherein the water content is 0.1% to 4.0%. [Section 7] A method for preparing G-type crystals, comprising dissolving the compound of formula (I) in a sodium ethoxide solution, followed by stirring in the presence of calcium chloride, filtering, and drying under reduced pressure to obtain G-type crystals. [Section 8] A pharmaceutical composition comprising the calcium salt according to claim 1 or 2, or the G-type crystal according to any one of items 3 to 6. [Section 9] Item 1 or 2 in the preparation of a medicament for use in an S1P1 receptor-related disease. Use of the calcium salt of the compound of the formula (I), or the G-type crystal according to any one of Items 3 to 6, or the pharmaceutical composition according to Item 8. [Section 10] Item 10. The use according to Item 9, wherein the S1P1 receptor-associated disease is selected from ulcerative colitis, Crohn's disease, multiple sclerosis, systemic lupus erythematosus, lupus nephritis, rheumatoid arthritis, primary biliary cholangitis, atopic dermatitis, intracerebral hemorrhage, graft-versus-host disease, psoriasis, type I diabetes, acne, microbial infections or diseases, and viral infections or diseases.

Claims

1. A G-type crystal of the compound represented by formula (II), characterized in that the powder X-ray diffraction pattern has characteristic diffraction peaks at the following 2θ angles: 8.98±0.2°, 10.12±0.2°, 13.56±0.2°, 14.66±0.2°, 15.22±0.2°, and 18.48±0.2°. 【Chemical 1】

2. The G-type crystal according to claim 1, characterized in that the powder X-ray diffraction pattern of the G-type crystal has characteristic diffraction peaks at the following 2θ angles: 8.98±0.2°, 10.12±0.2°, 13.56±0.2°, 14.66±0.2°, 15.22±0.2°, 16.34±0.2°, 16.92±0.2°, 18.48±0.2°, 22.67±0.2°, and 23.06±0.2°.

3. further comprising water and a solvent; however, the solvent is selected from ethanol and isopropyl alcohol; The content of the solvent is 0.1% to 6.0%; The G-type crystal according to claim 1, characterized in that the water content is 0.1% to 4.0%.

4. A method for preparing the G-type crystals according to any one of claims 1 to 3, comprising dissolving the compound represented by formula (I) in a sodium ethoxide solution, followed by stirring in the presence of calcium chloride, filtering, and drying under reduced pressure to obtain the G-type crystals. 【Chemistry 2】

5. A pharmaceutical composition comprising the G-type crystal according to any one of claims 1 to 3.

6. Use of the G-type crystal according to any one of claims 1 to 3 in the preparation of a medicine for use in treating an S1P1 receptor-related disease.

7. 7. The use according to claim 6, wherein the S1P1 receptor-associated disease is selected from ulcerative colitis, Crohn's disease, multiple sclerosis, systemic lupus erythematosus, lupus nephritis, rheumatoid arthritis, primary biliary cholangitis, atopic dermatitis, intracerebral hemorrhage, graft-versus-host disease, psoriasis, type I diabetes, acne, microbial infections or diseases, and viral infections and diseases.

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