WO2023109931A1 - 一种芳环衍生物的晶型及其制备方法和应用 - Google Patents

一种芳环衍生物的晶型及其制备方法和应用 Download PDF

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WO2023109931A1
WO2023109931A1 PCT/CN2022/139461 CN2022139461W WO2023109931A1 WO 2023109931 A1 WO2023109931 A1 WO 2023109931A1 CN 2022139461 W CN2022139461 W CN 2022139461W WO 2023109931 A1 WO2023109931 A1 WO 2023109931A1
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crystal form
ray powder
powder diffraction
present
diffraction pattern
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PCT/CN2022/139461
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English (en)
French (fr)
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张勇
叶龙兵
康樟平
程宏明
彭建彪
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上海济煜医药科技有限公司
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Priority to CN202280083100.8A priority Critical patent/CN118382615A/zh
Publication of WO2023109931A1 publication Critical patent/WO2023109931A1/zh

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/4025—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil not condensed and containing further heterocyclic rings, e.g. cromakalim
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/06—Antipsoriatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
    • C07D209/18—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals

Definitions

  • the present invention relates to the crystal form, salt form and pharmaceutical composition of the compound represented by formula (I), and its application as S1P1 agonist.
  • Sphingosine-1-phosphate is an amphoteric biological signal molecule belonging to lysophospholipid (LP). S1P can regulate important physiological and biochemical functions by acting on five G protein-coupled receptor subtypes, sphingosine-1-phosphate receptors (S1PR1-5), to activate complex downstream signals. The combination of S1P and different S1P receptors can regulate different physiological functions, and plays an important role in the maintenance of body health and the occurrence of diseases.
  • S1P1 receptor agonists interfere with lymphocyte trafficking, sequestering them in lymph nodes and other secondary lymphoid tissues. This results in a decrease in peripheral circulating lymphocytes, and the clinical value of lymphocyte sequestration is to exclude them from the field of inflammation and/or autoimmune responses in surrounding tissues.
  • This sequestration of lymphocytes (e.g. in lymph nodes) is thought to be the result of a simultaneous agonist-driven antagonism of the S1P1 receptor on T cells (thus reducing S1P mobilization of T cell efflux from the lymph node). ability) and sustained agonism of S1P1 receptors on lymph node endothelium (thereby improving barrier function against lymphocyte migration). Therefore, S1P1 receptor agonists reduce the body's autoimmunity by preventing the transportation of lymphocytes, and thus can be used as immunosuppressants for the treatment of various autoimmune diseases.
  • the S1P1 agonist Fingolimod has been approved by the FDA for the treatment of relapsing multiple sclerosis (Multiple Scleorosis, MS), which has opened up a new therapeutic field for the treatment of immune diseases.
  • FTY720 has clinical efficacy, it is a non-selective S1P receptor agonist, and the binding of FTY720 to S1P3 in vivo often leads to a series of important side effects, such as bradycardia, etc., which greatly limits its therapeutic immunity The range of application in the field of disease. Therefore, the discovery of the second-generation highly selective S1P1 agonist, making it a drug for the treatment of immune diseases with better curative effect, fewer side effects and wider application range, has become one of the hot spots of drug research.
  • An S1P1 agonist is provided in the application number PCT/CN2019/123485 (application date is December 6, 2019), the structure of which is as follows:
  • the present invention provides calcium salts of compounds represented by formula (I),
  • the above-mentioned calcium salt is
  • the present invention also provides crystal form G of the calcium salt of the compound represented by formula (II), whose X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2 ⁇ angles: 8.98 ⁇ 0.2°, 10.12 ⁇ 0.2°, 13.56 ⁇ 0.2°, 14.66 ⁇ 0.2°, 15.22 ⁇ 0.2°, 18.48 ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the above crystal form G has characteristic diffraction peaks at the following 2 ⁇ 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°, 23.06 ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the above crystal form G has an X-ray powder diffraction pattern substantially as shown in FIG. 7 .
  • the above-mentioned crystal form G is characterized in that it further comprises water and a solvent;
  • the solvent is selected from ethanol and Virahol;
  • the content of the solvent is 0.1%-6.0%;
  • the content of the water is 0.1-4.0%.
  • the content of the above-mentioned solvent is 1.0%-5.5%, and the content of the above-mentioned water is 3.0%-4.5%.
  • the above-mentioned solvent is ethanol
  • the content of the ethanol is 1.0%-5.5%
  • the content of the above-mentioned water is 3.0%-4.5%.
  • the content of the above-mentioned solvent is 1.64%-4.77%, and the content of the above-mentioned water is 3.09%-4.37%.
  • the above-mentioned solvent is ethanol
  • the content of the ethanol is 1.64%-4.77%
  • the content of the above-mentioned water is 3.09%-4.37%.
  • the above-mentioned solvent is ethanol, wherein the content of ethanol is 4.77%, and the content of water is 3.09%.
  • the above-mentioned solvent is ethanol, wherein the content of ethanol is 3.05%, and the content of water is 3.89%.
  • the above-mentioned solvent is ethanol, wherein the content of ethanol is 1.97%, and the content of water is 4.37%.
  • the above-mentioned solvent is ethanol, wherein the content of ethanol is 1.64%, and the content of water is 3.75%.
  • the characteristic diffraction peaks used in this specification are peaks selected from observed diffraction patterns. When distinguishing a plurality of crystalline solids, a peak that is visible in one crystalline solid but not in other crystalline solids is a preferred characteristic peak for identifying the crystalline solid, rather than the size of the peak. If there are such characteristic peaks, even one or two peaks can characterize the crystalline solid.
  • crystal form G can be distinguished from other crystal forms disclosed in this specification (such as anhydrate, etc.) by the presence of characteristic diffraction peaks.
  • characteristic diffraction peaks when the measured graphs are compared, if these characteristic peaks coincide, it can be said that the powder X-ray diffraction spectra are substantially coincident.
  • Form G can change the hydration state of the solvent due to the change of solvent and water content.
  • Such crystal forms G with different solvent hydration contents have common characteristic peaks as shown in Figure 1 and Figures 18-21.
  • the common characteristic peak is selected from diffraction angle (2 ⁇ ): 8.98 ⁇ 0.2°, 10.12 ⁇ 0.2°, 13.56 ⁇ 0.2°, 14.66 ⁇ 0.2°, 15.22 ⁇ 0.2°, 18.48 ⁇ 0.2° at least 3 peaks.
  • the common characteristic peak is selected from the diffraction angle (2 ⁇ ): 8.98 ⁇ 0.2°, 10.12 ⁇ 0.2°, 13.56 ⁇ 0.2°, 14.66 ⁇ 0.2°, 15.22 ⁇ 0.2°, 16.34 ⁇ 0.2°, At least 3 peaks at 16.92 ⁇ 0.2°, 18.48 ⁇ 0.2°, 22.67 ⁇ 0.2°, 23.06 ⁇ 0.2°.
  • the content (%) in the present invention represents the mass ratio, and the unit is g/g.
  • the present invention also proposes a method for preparing crystal form G.
  • the method includes: dissolving the compound represented by formula (I) in sodium ethoxide solution, then stirring in the presence of calcium chloride, filtering, and drying under reduced pressure to obtain Form G.
  • This method is different from the general method of forming calcium salt crystal form in the prior art.
  • the method of the present invention adopts the condition of the presence of calcium chloride instead of the condition of calcium hydroxide, and the crystal form G can only be obtained after drying.
  • the above method comprises: heating up the compound represented by formula (I) and absolute ethanol to 35-45° C., stirring for 5-30 minutes, adding sodium ethoxide solution, stirring for 2-3 hours, dropwise Add calcium chloride solution, stir and react for 1-3 hours, lower the temperature to 20-30°C, stir for 4-6 hours, filter, rinse the filter cake with purified water, rinse with ethanol, dry the filter cake under reduced pressure at 25-35°C to obtain crystal form G .
  • the mass ratio of sodium ethylate to absolute ethanol in the above-mentioned sodium ethylate solution is (0.01-0.05):(0.40-0.80).
  • the mass ratio of sodium ethoxide to absolute ethanol in the above sodium ethoxide solution is 0.035:0.631.
  • the mass ratio of calcium chloride to pure water in the calcium chloride solution is (0.01-0.08):(0.20-1.00).
  • the mass ratio of calcium chloride to pure water in the calcium chloride solution is 0.040:0.847.
  • the present invention also provides crystal form A of the compound represented by formula (I),
  • Its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2 ⁇ 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°.
  • the X-ray powder diffraction pattern of the above crystal form A has characteristic diffraction peaks at the following 2 ⁇ 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°, 22.28 ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the above crystal form A has an X-ray powder diffraction pattern substantially as shown in FIG. 1 .
  • the present invention also provides the crystal form B of the compound represented by formula (I), whose X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2 ⁇ angles: 6.96 ⁇ 0.2°, 11.71 ⁇ 0.2°, 15.55 ⁇ 0.2°, 17.35 ⁇ 0.2 °, 20.62 ⁇ 0.2°, 21.16 ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the above crystal form B has characteristic diffraction peaks at the following 2 ⁇ 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°, 21.81 ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the above-mentioned crystal form B has an X-ray powder diffraction pattern substantially as shown in FIG. 2 .
  • the present invention also provides the crystal form C of the compound represented by formula (I), whose X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2 ⁇ 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°.
  • the X-ray powder diffraction pattern of the above crystal form C has characteristic diffraction peaks at the following 2 ⁇ 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°, 25.44 ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the above crystal form C has an X-ray powder diffraction pattern substantially as shown in FIG. 3 .
  • the present invention also provides the crystal form D of the compound represented by formula (I), whose X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2 ⁇ angles: 9.33 ⁇ 0.2°, 13.94 ⁇ 0.2°, 18.82 ⁇ 0.2°, 22.76 ⁇ 0.2 °, 24.24 ⁇ 0.2°, 27.90 ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the above crystal form D has an X-ray powder diffraction pattern substantially as shown in FIG. 4 .
  • the present invention also provides crystal form E of the compound represented by formula (I), whose X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2 ⁇ angles: 6.84 ⁇ 0.2°, 10.65 ⁇ 0.2°, 11.53 ⁇ 0.2°, 15.41 ⁇ 0.2 °, 17.29 ⁇ 0.2°, 20.65 ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the above crystal form E has characteristic diffraction peaks at the following 2 ⁇ 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°, 25.26 ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the above-mentioned crystal form E has an X-ray powder diffraction pattern substantially as shown in FIG. 5 .
  • the present invention also provides the diethylamine salt of the compound represented by formula (I).
  • the present invention also provides crystal form F of the diethylamine salt of the compound represented by formula (I), whose X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2 ⁇ 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°.
  • the X-ray powder diffraction pattern of the above crystal form F has characteristic diffraction peaks at the following 2 ⁇ 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°, 23.93 ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the above crystal form F has an X-ray powder diffraction pattern substantially as shown in FIG. 6 .
  • the present invention also provides crystal form H of the calcium salt of the compound represented by formula (I), whose X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2 ⁇ 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°.
  • the X-ray powder diffraction pattern of the above crystal form H has characteristic diffraction peaks at the following 2 ⁇ 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°, 21.33 ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the above crystal form H has an X-ray powder diffraction pattern substantially as shown in FIG. 8 .
  • the present invention also provides crystal form I of the calcium salt of the compound represented by formula (I), whose X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2 ⁇ 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°.
  • the X-ray powder diffraction pattern of the above crystal form I has characteristic diffraction peaks at the following 2 ⁇ 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°, 24.38 ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the above-mentioned crystal form I has an X-ray powder diffraction pattern substantially as shown in FIG. 9 .
  • the present invention also provides crystal form J of the calcium salt of the compound represented by formula (I), whose X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2 ⁇ angles: 8.73 ⁇ 0.2°, 9.49 ⁇ 0.2°, 11.99 ⁇ 0.2°, 12.89 ⁇ 0.2°, 15.16 ⁇ 0.2°, 19.58 ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the above crystal form J has characteristic diffraction peaks at the following 2 ⁇ 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°, 26.66 ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the above crystal form J has an X-ray powder diffraction pattern substantially as shown in FIG. 10 .
  • the present invention also provides crystal form K of the calcium salt of the compound represented by formula (I), whose X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2 ⁇ angles: 8.57 ⁇ 0.2°, 9.32 ⁇ 0.2°, 11.06 ⁇ 0.2°, 12.65 ⁇ 0.2°, 14.08 ⁇ 0.2°, 14.71 ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the above crystal form K has characteristic diffraction peaks at the following 2 ⁇ 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°, 19.29 ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the above crystal form K has an X-ray powder diffraction pattern substantially as shown in FIG. 11 .
  • the X-ray powder diffraction pattern analysis data of the above-mentioned crystal form K is shown in Table 11 below.
  • the present invention also provides crystal form L of the calcium salt of the compound represented by formula (I), whose X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2 ⁇ angles: 8.69 ⁇ 0.2°, 9.78 ⁇ 0.2°, 13.46 ⁇ 0.2°, 14.72 ⁇ 0.2°, 15.40 ⁇ 0.2°, 15.98 ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the above crystal form L has an X-ray powder diffraction pattern substantially as shown in FIG. 12 .
  • the present invention also provides crystal form M of the calcium salt of the compound represented by formula (I), whose X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2 ⁇ angles: 8.09 ⁇ 0.2°, 10.87 ⁇ 0.2°, 13.62 ⁇ 0.2°, 14.55 ⁇ 0.2°, 15.77 ⁇ 0.2°, 16.39 ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the above crystal form M has an X-ray powder diffraction pattern substantially as shown in FIG. 13 .
  • the present invention also provides crystal form N of the calcium salt of the compound represented by formula (I), whose X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2 ⁇ angles: 7.79 ⁇ 0.2°, 12.44 ⁇ 0.2°, 14.94 ⁇ 0.2°, 16.11 ⁇ 0.2°, 17.50 ⁇ 0.2°, 20.98 ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the above crystal form N has an X-ray powder diffraction pattern substantially as shown in FIG. 14 .
  • the present invention also provides crystal form O of the calcium salt of the compound represented by formula (I), whose X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2 ⁇ angles: 7.40 ⁇ 0.2°, 8.52 ⁇ 0.2°, 12.01 ⁇ 0.2°, 12.24 ⁇ 0.2°, 14.67 ⁇ 0.2°, 16.86 ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the above crystal form O has characteristic diffraction peaks at the following 2 ⁇ 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°, 22.02 ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the above-mentioned crystal form O has an X-ray powder diffraction pattern substantially as shown in FIG. 15 .
  • the present invention also provides crystal form P of the calcium salt of the compound represented by formula (I), characterized in that its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2 ⁇ 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°, 20.86 ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the above crystal form P has characteristic diffraction peaks at the following 2 ⁇ 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°, 25.87 ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the above crystal form P has an X-ray powder diffraction pattern substantially as shown in FIG. 16 .
  • the present invention also provides the strontium salt of the compound represented by formula (I).
  • the crystal form Q of the strontium salt of the compound represented by the above formula (I) is characterized in that its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2 ⁇ angles: 5.01 ⁇ 0.2°, 8.96 ⁇ 0.2 °, 10.08 ⁇ 0.2°, 13.54 ⁇ 0.2°, 14.84 ⁇ 0.2°, 24.67 ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the above crystal form Q has characteristic diffraction peaks at the following 2 ⁇ 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°, 24.67 ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the above crystal form Q has an X-ray powder diffraction pattern substantially as shown in FIG. 17 .
  • the present invention also proposes a pharmaceutical composition, which comprises the aforementioned crystal form A, crystal form B, crystal form C, crystal form D, crystal form E, diethylamine salt, crystal form F, Calcium salt, Form G, Form H, Form I, Form J, Form K, Form L, Form M, Form N, Form O, Form P, strontium salt, or Form Q.
  • the above pharmaceutical composition further comprises a pharmaceutically acceptable carrier, excipient, diluent, adjuvant, vehicle or a combination thereof.
  • the present invention also proposes the aforementioned crystal form A, crystal form B, crystal form C, crystal form D, crystal form E, diethylamine salt, crystal form F, calcium salt, crystal form G, crystal form H, crystal form Form I, crystalline form J, crystalline form K, crystalline form L, crystalline form M, crystalline form N, crystalline form O, crystalline form P, strontium salt, crystalline form Q or pharmaceutical composition are used as S1P1 receptor-related diseases in preparation use in medicines.
  • the above-mentioned S1P1 receptor-related diseases are selected from ulcerative colitis, Crohn's disease, multiple sclerosis, systemic lupus erythematosus, lupus nephritis, rheumatoid arthritis, primary biliary Cholangitis, allergic dermatitis, cerebral hemorrhage, graft-versus-host disease, psoriasis, type I diabetes, acne, microbial infection or microbial disease and viral infection and viral disease.
  • Crystal form or “crystalline form” refers to a solid with a highly regular chemical structure, including, but not limited to, single-component or multi-component crystals, and/or polymorphs, solvates, hydrates, Clathrate, co-crystal, salt, solvate of salt, hydrate of salt. Crystalline forms of substances can be obtained by a number of 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-crystal anti-molecules, desolvation, dehydration, rapid evaporation, rapid cooling, slow cooling, vapor diffusion, sublimation, reactive crystallization, anti-solvent addition, milling and solvent drop milling, etc.
  • additives such as co-crystal anti-molecules, desolvation, dehydration, rapid evaporation, rapid cooling, slow cooling, vapor diffusion, sublimation, reactive crystallization, anti-solvent addition, milling and solvent drop milling, etc.
  • Amorphous or “amorphous form” refers to a substance formed when the particles (molecules, atoms, ions) of a substance are arranged in a three-dimensional space without periodicity, and is characterized by a diffuse X-ray powder diffraction pattern without sharp peaks.
  • Amorphous is a special physical form of solid substances, and its locally ordered structural features suggest that it is inextricably linked with crystalline substances.
  • Amorphous forms of substances can be obtained by a number of methods known in the art. Such methods include, but are not limited to, quenching, anti-solvent flocculation, ball milling, spray drying, freeze drying, wet granulation and solid dispersion techniques, among others.
  • Solvent means a substance (typically a liquid) that is capable of completely or partially dissolving another substance (typically a solid).
  • Solvents used in the practice of the present invention include, but are not limited to, water, acetic acid, acetone, acetonitrile, benzene, chloroform, carbon tetrachloride, methylene chloride, dimethyl sulfoxide, 1,4-dioxane, ethanol , ethyl acetate, butanol, tert-butanol, N,N-dimethylacetamide, N,N-dimethylformamide, formamide, formic acid, heptane, hexane, isopropanol, methanol, Methyl ethyl ketone, l-methyl-2-pyrrolidone, mesitylene, nitromethane, polyethylene glycol, propanol, 2-propanone, pyridine, tetrahydrofuran
  • Anti-solvent refers to a fluid that facilitates the precipitation of a product (or product precursor) from a solvent.
  • An anti-solvent can include a cold gas, or a fluid that promotes precipitation through a chemical reaction, or a fluid that reduces the solubility of a product in a solvent; it can be the same liquid as the solvent but at a different temperature, or it can be a different liquid than the solvent.
  • Solidvate means that the crystal has a solvent on the surface, or in the crystal lattice, or both on the surface and in the crystal lattice, wherein the solvent can be water, acetic acid, acetone, acetonitrile, benzene, chloroform, tetrachloro Carbon dioxide, methylene chloride, dimethyl sulfoxide, 1,4-dioxane, ethanol, ethyl acetate, butanol, tert-butanol, N,N-dimethylacetamide, N,N- Dimethylformamide, formamide, formic acid, heptane, hexane, isopropanol, methanol, methyl ethyl ketone, methylpyrrolidone, mesitylene, nitromethane, polyethylene glycol, propanol, 2-propanone, pyridine, tetrahydrofuran, toluene, xylene and their mixture
  • a specific example of a solvate is a hydrate, wherein the solvent on the surface, or in the crystal lattice, or on the surface and in the crystal lattice is water. Hydrates may or may not have other solvents than water on the surface of the substance, or in the crystal lattice, or both.
  • Crystal form or amorphous form can be identified by various technical means, such as X-ray powder diffraction (XRPD), infrared absorption spectroscopy (IR), melting point method, differential scanning calorimetry (DSC), thermogravimetric analysis (TGA ), NMR, Raman spectroscopy, X-ray single crystal diffraction, solution calorimetry, scanning electron microscopy (SEM), quantitative analysis, solubility and dissolution rate, etc.
  • XRPD X-ray powder diffraction
  • IR infrared absorption spectroscopy
  • DSC differential scanning calorimetry
  • TGA thermogravimetric analysis
  • NMR Raman spectroscopy
  • X-ray single crystal diffraction X-ray single crystal diffraction
  • solution calorimetry X-ray single crystal diffraction
  • SEM scanning electron microscopy
  • X-ray powder diffraction can detect information such as changes in crystal forms, crystallinity, crystal structure state, etc., and is a common method for identifying crystal forms.
  • the peak positions of an XRPD pattern mainly depend on the structure of the crystalline form and are relatively insensitive to experimental details, while their relative peak heights depend on many factors related to sample preparation and instrument geometry. Accordingly, in some embodiments, the crystalline forms of the present invention are characterized by XRPD patterns having certain peak positions substantially as shown in the XRPD patterns provided in the accompanying figures of the present invention.
  • the measurement of 2 ⁇ in the XRPD pattern may have experimental errors, and the measurement of 2 ⁇ in the XRPD pattern may be slightly different between different instruments and different samples, so the value of 2 ⁇ in the XRPD pattern cannot be regarded as absolute. According to the state of the instrument used in the test of the present invention, there is an error tolerance of ⁇ 0.2° for the diffraction peaks.
  • DSC Differential Scanning Calorimetry
  • an inert reference usually ⁇ -Al 2 O 3
  • the melting peak height of a DSC curve depends on many factors related to sample preparation and instrument geometry, while peak position is relatively insensitive to experimental details. Accordingly, in some embodiments, the crystalline forms described herein are characterized by a DSC pattern having characteristic peak positions substantially as shown in the DSC patterns provided in the accompanying figures of the present invention.
  • the DSC spectrum may have experimental errors, and the peak position and peak value of the DSC spectrum may be slightly different between different instruments and different samples, so the peak position or peak value of the DSC endothermic peak cannot be regarded as absolute. According to the conditions of the equipment used in the experiment of the present invention, there is an error tolerance of ⁇ 3°C for the melting peak.
  • Solids with the same chemical composition often form isomers with different crystal structures, or variants, under different thermodynamic conditions.
  • This phenomenon is called homogeneous polycrystal or homogeneous multiphase phenomenon.
  • the variants can transform into each other, this phenomenon is called crystal transformation. Due to the transformation of the crystal form, the mechanical, electrical, magnetic and other properties of the crystal will change dramatically.
  • the temperature of the crystal transformation is within the measurable range, this transformation process can be observed on the differential scanning calorimetry (DSC) diagram, and it is characterized in that the DSC diagram has an exothermic peak reflecting the transformation process, and At the same time, it has two or more endothermic peaks, which are the characteristic endothermic peaks of different crystal forms before and after transformation.
  • the crystal form or amorphous form of the compound of the present invention can undergo crystal transformation under appropriate conditions
  • Thermogravimetric analysis is a technique for determining the quality of a substance as a function of temperature under program control. It is suitable for checking the loss of solvent in the crystal or the process of sublimation and decomposition of the sample. It can be speculated that the crystal contains crystal water or crystal solvent. Case.
  • the mass change shown by the TGA curve depends on many factors such as sample preparation and instrumentation; the mass change detected by TGA varies slightly between different instruments and different samples.
  • the calcium salt crystal form A of the present invention loses about 5.1% of its weight at a temperature of about 150°C. Depending on the conditions of the apparatus used in the experiments of the present invention, there is a ⁇ 0.3% error margin for mass variation.
  • 2 ⁇ values in X-ray powder diffraction patterns are all in degrees (°).
  • substantially as shown means at least 50%, or at least 60%, or at least 70%, or at least 80%, or at least 90%, or at least 95% of the X-ray powder diffraction pattern or DSC pattern or TGA result %, or at least 99% of the peaks are shown in their plots.
  • Pheak when referring to a spectrum and/or data appearing in a graph refers to a feature that one skilled in the art would recognize and would not attribute to background noise.
  • the salt form or crystal form or pharmaceutical composition of the present invention can be used to prepare medicines for S1P1 receptor-related diseases.
  • S1P1 receptor-related diseases are selected from the group consisting of ulcerative colitis, Crohn's disease, multiple sclerosis, systemic lupus erythematosus, lupus nephritis nephritis), Rheumatoid arthritis, Primary Biliary Cholangitis, Atopic Dermatitis, Intracerebral hemorrhage, Graft versus host disease Disease), psoriasis (Psoriasis), type I diabetes (Type I diabetes), acne (Acne), microbial infection or microbial disease and viral infection or viral disease.
  • Figure 1 is an X-ray powder diffraction (XRPD) pattern of Form A.
  • Figure 2 is an X-ray powder diffraction (XRPD) pattern of Form B.
  • Figure 3 is an X-ray powder diffraction (XRPD) pattern of Form C.
  • Figure 4 is an X-ray powder diffraction (XRPD) pattern of Form D.
  • Figure 5 is an X-ray powder diffraction (XRPD) pattern of Form E.
  • Figure 6 is an X-ray powder diffraction (XRPD) pattern of Form F.
  • Figure 7 is an X-ray powder diffraction (XRPD) pattern of Form G.
  • Figure 8 is an X-ray powder diffraction (XRPD) pattern of Form H.
  • FIG. 9 is an X-ray powder diffraction (XRPD) pattern of Form I.
  • Figure 10 is an X-ray powder diffraction (XRPD) pattern of Form J.
  • Figure 11 is an X-ray powder diffraction (XRPD) pattern of Form K.
  • Figure 14 is an X-ray powder diffraction (XRPD) pattern of Form N.
  • Figure 15 is an X-ray powder diffraction (XRPD) pattern of Form O.
  • Figure 16 is an X-ray powder diffraction (XRPD) pattern of Form P.
  • Figure 17 is an X-ray powder diffraction (XRPD) pattern of Form Q.
  • Figure 18 is an X-ray powder diffraction (XRPD) pattern of Form G.
  • Figure 19 is an X-ray powder diffraction (XRPD) pattern of Form G.
  • Figure 20 is an X-ray powder diffraction (XRPD) pattern of Form G.
  • Figure 21 is an X-ray powder diffraction (XRPD) pattern of Form G.
  • the X-ray powder diffraction analysis method used in the present invention is as follows: at room temperature, a Bruker D2 PHASER diffractometer (300W low-power X-ray emitter) is selected to carry out the X-ray powder diffraction test. In the test, the sample powder is placed on a silicon wafer, an X-ray Cu(K ⁇ ) tube is used, and the intensity ratio of K ⁇ 2/K ⁇ 1 is 0.50 Set the instrument to 30kV and 10mA, the step size is 0.02° (2 ⁇ ), and the scanning time of each step is 0.15s, a total of 1837 steps.
  • the differential scanning calorimetry (DSC) analytical method used in the present invention is: adopt TA Discovery DSC to collect the data of differential scanning calorimetry.
  • the specific method is: weigh several milligrams of the sample into a Tzero aluminum pan, and seal it with a corresponding Tzero aluminum pan lid. In a nitrogen atmosphere, the sealed sample was raised from room temperature to 300°C at a rate of 10°C/min.
  • thermogravimetric (TGA) analysis method of the present invention is: adopt TA Discovery TGA to collect the data of thermogravimetric analysis.
  • the specific method is: in a nitrogen environment, several milligrams of samples are raised from room temperature to 350°C at a heating rate of 10°C/min.
  • the polarizing microscope (PLM) analysis method used in the present invention is: at room temperature, use the polarizing microscope of Olympus BX53M to analyze the sample morphology.
  • HPLC high performance liquid chromatography
  • the analysis method adopted for the hygroscopicity of the present invention is: use SMS ADVENTURE DVS to evaluate the hygroscopicity of the sample under a nitrogen environment of 25°C. About 30 mg of sample is used in the test, and the test method is as follows:
  • each stage increases by 10% RH (90 to 95% RH increases by 5% RH);
  • each stage drops 10% RH (95 to 90% RH drops 5% RH).
  • each stage drops 10% RH (95 to 90% RH drops 5% RH);
  • the analytical method of measuring moisture content of the present invention is: use the Cassette type moisture titrator (Karl Fischer, KF) of Switzerland Metrohm 870/803 to collect the moisture content data of sample.
  • the volumetric method to measure is HYDRANAL Composite-2 (Sigma-Aldrich, P/N: 34806)
  • the solvent is anhydrous methanol
  • the stirring time is 30s.
  • the specific operation is: weigh ⁇ 50mg sample (accurate to 0.001g), test the water content of the sample with the above-mentioned KF moisture titrator, measure twice in parallel, and take the average value.
  • Liquid NMR (1H NMR) of the present invention Bruker 400M NMR is used for sample analysis, and DMSO-d6 is used as a solvent.
  • the solid-state NMR (ssNMR) of the present invention a 500MHz wide-cavity solid-state NMR spectrometer from Bruker Company and a 4mm double-resonance magic-angle rotating probe are used to collect data.
  • the 13C fingerprints of the samples were collected using the cross-polarization/magic-angle spinning (CP/MAS) method, in order to avoid the effect of rotational sidebands, while embedding the sideband suppression technique (TOSS).
  • the cross-polarization matching conditions were optimized using adamantane, and the chemical shifts were corrected using the adamantane high-field signal (29.5ppm).
  • Magic angle speed 8kHz, 1H 90 degree pulse 3.45us, decoupling mode TPPM The specific test conditions are as follows:
  • Embodiment 1 the preparation of crystal form A
  • Embodiment 2 the preparation of crystal form B
  • Embodiment 3 the preparation of crystal form D
  • Embodiment 4 Preparation of Form C
  • Form D was heated to 137°C to obtain Form C.
  • Embodiment 5 the preparation of crystal form E
  • Embodiment 6 Preparation of crystal form F (including one step of salt formation)
  • Method 1 Add the compound represented by formula (I) (0.2651kg, 0.595mol) and absolute ethanol (0.9488kg) into the reactor, heat up to 35-45°C, and stir for 5-30 minutes.
  • Add sodium ethoxide solution sodium ethoxide: 0.035Kg, 0.514mol; absolute ethanol: 0.6310kg
  • stir for 2 to 3 hours add dropwise calcium chloride solution (calcium chloride: 0.040Kg, 0.357mol; purified water: 0.847Kg ), stirring and reacting for 1 to 3 hours, cooling to 20 to 30° C., stirring for 4 to 6 hours, filtering, rinsing the filter cake with purified water and ethanol.
  • the filter cake was dried under reduced pressure at 25-35° C. to obtain 0.2185 kg of the compound represented by formula (II) in crystal form G, yield: 79.1%.
  • Method 2 Weigh 10.72g of the compound represented by formula (I) into a single-necked bottle, add EtOH (105mL) and magnetically stir for ⁇ 0.5h, add C 2 H 5 Ona (1.64g), and stir at room temperature for 1.5h; anhydrous CaCl 2 (1.5g) was dissolved in EtOH/H 2 O (2:1, v/v, 45mL), and added 1% seed crystal (form G) calcium chloride solution; the calcium chloride solution was added dropwise, Stir for 16 hours; take the suspension, measure the XRPD of the sample, it shows that it is crystal form D, filter it, wash the filter cake twice with H 2 O and EtOH, test the XRPD of the wet sample, it shows that it is crystal form J, and dry it under reduced pressure at 50°C After 4 hours, XRPD was determined, showing Form G.
  • Method 3 Add Ca(OH) 2 (2 mg) to the compound represented by formula (I) (21 mg), add 0.2 mL EtOH/H 2 O (9:1, v/v), stir magnetically at room temperature for 3 days, filter, Vacuum drying at 50°C for 2 hours to obtain Form G.
  • Method 4 Add Ca(OH) 2 (2 mg) to the compound represented by formula (I) (21 mg), add 0.2 mL IPA/H 2 O (9:1, v/v), stir magnetically at room temperature for 4 days, filter, Vacuum drying at 50°C for 2 hours to obtain Form G.
  • Method 2 Add Form G (15mg) into a 4mL glass bottle, and put it into a 20mL glass bottle filled with 3mL of a volatile solvent (which can be MeOH or EtOH). Tightly cap the 20mL glass bottle, let it stand at room temperature for about a week, filter, and vacuum-dry at 50°C for 2 hours to obtain Form G.
  • a volatile solvent which can be MeOH or EtOH.
  • Form G (50 mg) was added with MeOH (0.5 mL), magnetically stirred at room temperature for 4 days, and filtered to obtain Form H.
  • Embodiment 9 Preparation of Form I
  • Form G (50 mg) was added to an HPLC vial, MeOH (0.5 mL) was added, and magnetic stirring was performed at 50° C. for 7 days to obtain a suspension, which was filtered to obtain Form I.
  • Method 1 Form G (50mg), add 0.5mL solvent (solvent can be 2-Butanol or Toluene), magnetically stir at room temperature for 4 days, filter to obtain Form J.
  • solvent can be 2-Butanol or Toluene
  • Method 2 Add crystalline form G (50 mg) and IPA (0.5 mL) to an HPLC vial, and perform magnetic stirring at 50° C. for 7 days to obtain a suspension, which is filtered to obtain crystalline form J.
  • Method 4 Weigh ⁇ 21mg of the compound represented by formula (I) in Example 1 (purity 93area%) and ⁇ 2mg Ca(OH) 2 into a HPLC vial; add 0.2mL EtOH/H2O (9:1, v/v) , magnetically stirred at room temperature; centrifuged after stirring for 3 days, and tested the XRPD of the wet sample, it was crystal form J.
  • the crystal form K was heated to 80°C and cooled to room temperature to obtain the crystal form L.
  • crystalline form G (15mg) into a 4mL glass bottle, and add DMF to dissolve it. If it cannot be dissolved, the suspension is subjected to membrane filtration treatment (nylon membrane, membrane pore size 0.22 ⁇ m), and the solutions are respectively put into 20 mL glass bottles filled with 4 mL H 2 O. Cap the 20mL glass bottle tightly and place it at room temperature until a solid precipitates out, then filter to obtain Form N.
  • membrane filtration treatment nylon membrane, membrane pore size 0.22 ⁇ m
  • the crystal form G sample was dissolved in Acetone, and after standing for about 10 minutes, a solid precipitated out, and was filtered to obtain crystal form O.
  • Form G (15mg) into a 20mL glass bottle, add Acetone and stir to dissolve at room temperature. Gradually add MTBE to the glass bottle until a solid appears, and filter to obtain Form P.
  • crystal form A crystal form A
  • crystal Form B crystal Form B
  • Form G Form G
  • Form Q crystal form A
  • Table 25 The test scheme and results are shown in Table 25, and the shape changes are shown in Table 26.
  • Form G has higher stability when stored at 25°C and 40°C for 90 days.

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Abstract

公开了一种芳环衍生物的晶型及其制备方法和应用，具体地，公开了式(I)所述化合物的盐型、晶型、药物组合物及其用途。

Description

一种芳环衍生物的晶型及其制备方法和应用
本申请主张如下优先权：
CN 202111555458.X，申请日2021年12月17日。
技术领域
本发明涉及式(Ⅰ)所示化合物的晶型、盐型、药物组合物，以及其作为S1P1激动剂的应用。
背景技术
鞘氨醇-1-磷酸(Sphingosine-1-phosphate，S1P)是属于溶血磷脂(lysophospholipid，LP)的一种两性生物信号分子。S1P可通过作用于5种G蛋白偶联受体亚型——鞘氨醇-1-磷酸受体(S1PR1-5)激活复杂的下游信号，从而调节重要的生理生化功能。S1P与不同的S1P受体结合可调节不同的生理功能，在维持机体健康以及疾病发生过程中起着重要的作用。
S1P1受体激动剂干扰淋巴细胞归巢(lymphocyte trafficking)，将它们隔离(sequestering)在淋巴结和其它二级淋巴组织中。这导致外周循环淋巴细胞减少，淋巴细胞隔离在临床上的价值是将它们从周围组织中的炎症和/或自身免疫反应视域中排除。这种对淋巴细胞的隔离(例如在淋巴结中)被认为是以下同时作用的结果：由激动剂驱动的对T细胞上S1P1受体的功能性拮抗作用(因此降低S1P动员T细胞从淋巴结中流出的能力)和对淋巴结内皮上S1P1受体的持续激动作用(从而提高对抗淋巴细胞迁移的屏障功能)。因此，S1P1受体激动剂通过阻止淋巴细胞的运输来降低人体自身免疫能力，因而可以作为免疫抑制剂用于治疗各种身免疫性疾病。
其中S1P1激动剂芬戈莫德(Fingolimod，FTY720)被FDA批准用于复发性多发性硬化症(Multiple Scleorosis，MS)的治疗，为免疫性疾病的治疗开辟了新的治疗领域。尽管FTY720具有临床功效，但它是一个非选择性的S1P受体激动剂，FTY720在体内与S1P3的结合往往会导致一系列重要的副作用，如心动过缓等，从而大大限制了其治疗免疫性疾病领域的应用范围。因此，发现第二代高选择性S1P1激动剂，使之成为疗效更好、副作用更小以及应用范围更广的免疫性疾病治疗药物成为了药物研究的热点之一。
申请号为PCT/CN2019/123485(申请日为2019年12月6日)的申请中提供了一种S1P1激动剂，结构如下所示：
Figure PCTCN2022139461-appb-000001
发明内容
本发明提供了式(Ⅰ)所示化合物的钙盐，
Figure PCTCN2022139461-appb-000002
本发明的一些方案中，上述钙盐，其为
Figure PCTCN2022139461-appb-000003
本发明还提供了式(ⅠI)所示化合物钙盐的晶型G，其X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：8.98±0.2°、10.12±0.2°、13.56±0.2°、14.66±0.2°、15.22±0.2°、18.48±0.2°。
本发明的一些方案中，上述晶型G的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：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°、23.06±0.2°。
本发明的一些方案中，上述晶型G的X射线粉末衍射图谱具有基本上如图7所示的X射线粉末衍射图谱。
本发明的一些方案中，上述晶型G的X射线粉末衍射图谱的解析数据如表7所示。
表7
Figure PCTCN2022139461-appb-000004
本发明的一些方案中，上述晶型G，其特征在于，其进一步包含水和溶剂；
其中，
所述溶剂选自乙醇和异丙醇；
所述溶剂的含量为0.1％-6.0％；
所述水的含量为0.1-4.0％。
本发明的一些方案中，上述溶剂的含量为1.0％～5.5％，上述水的含量为3.0％～4.5％。
本发明的一些方案中，上述溶剂为乙醇，所述乙醇的含量为1.0％～5.5％，上述水的含量为3.0％～4.5％。
本发明的一些方案中，上述溶剂的含量为1.64％～4.77％，上述水的含量为3.09％～4.37％。
本发明的一些方案中，上述溶剂为乙醇，所述乙醇的含量为1.64％～4.77％，上述水的含量为3.09％～4.37％。
本发明的一些方案中，上述溶剂为乙醇，其中乙醇的含量为4.77％，水的含量为3.09％。
本发明的一些方案中，上述溶剂为乙醇，其中乙醇的含量为3.05％，水的含量为3.89％。
本发明的一些方案中，上述溶剂为乙醇，其中乙醇的含量为1.97％，水的含量为4.37％。
本发明的一些方案中，上述溶剂为乙醇，其中乙醇的含量为1.64％，水的含量为3.75％。
本说明书中所使用的特征衍射峰为选自所观察的衍射图案中的峰。于区别复数种结晶固体时，相较于峰的大小，于该结晶固体可见而于其他结晶固体不可见的峰更成为对确定出该结晶固体而言优选的特征峰。若为此种特征峰，即便一或两个峰，也可对该结晶固体进行表征。
尤其晶型G可通过特征衍射峰的存在而与本说明书中揭示的其他结晶形态(例如无水物等)加以区别。另外，比较所测得的图表，若它们的特征峰一致，则粉末X射线衍射光谱可谓实质上一致。晶型G可因溶剂、水含量的变化，而溶剂水合状态发生变化。此种溶剂水合含量不同的晶型G如图1、图18-21所示的那样具有共同的特征峰。
本发明的一些方案中，共同的特征峰为选自衍射角度(2θ)：8.98±0.2°、10.12±0.2°、13.56±0.2°、14.66±0.2°、15.22±0.2°、18.48±0.2°中的至少3个峰。
本发明的一些方案中，共同的特征峰为选自衍射角度(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°、23.06±0.2°的至少3个峰。
需要说明的是，本发明中含量(％)代表质量比，单位为g/g。
在本发明的再一方面，本发明还提出了一种制备晶型G的方法。根据本发明的实施例，所述方法包括：将式(I)所示化合物溶解在乙醇钠溶液中，之后在氯化钙存在的情况下进行搅拌、过滤、减压干燥，获得晶型G。该方法不同于现有技术中一般成钙盐晶型的方法，本发明的方法采用氯化钙存在的条件，而不是氢氧化钙的条件，同时该晶型G需要在干燥后方可得到。
在本发明的一些方案中，上述方法包括：将式(I)所示化合物、无水乙醇，升温至35～45℃，搅拌5～30分钟，加入乙醇钠溶液，搅拌2～3小时，滴加氯化钙溶液，搅拌反应1～3小时，降温至20～30℃，搅拌4～6小时，过滤，滤饼纯化水漂洗，乙醇漂洗，滤饼25～35℃减压干燥得到晶型G。
在本发明的一些方案中，上述乙醇钠溶液中乙醇钠和无水乙醇的质量比为(0.01-0.05):(0.40-0.80)。
在本发明的一些方案中，上述乙醇钠溶液中乙醇钠和无水乙醇的质量比为0.035:0.631。
在本发明的一些方案中，上述氯化钙溶液中氯化钙与纯水的质量比为(0.01-0.08):(0.20-1.00)。
在本发明的一些方案中，上述氯化钙溶液中氯化钙与纯水的质量比为0.040:0.847。
本发明还提供了式(Ⅰ)所示化合物晶型A，
Figure PCTCN2022139461-appb-000005
其X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：5.25±0.2°、6.28±0.2°、10.5±0.2°、12.69±0.2°、15.45±0.2°、16.02±0.2°。
本发明的一些方案中，上述晶型A的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：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°、22.28±0.2°。
本发明的一些方案中，上述晶型A的X射线粉末衍射图谱具有基本上如图1所示的X射线粉末衍射图谱。
本发明的一些方案中，上述晶型A的X射线粉末衍射图谱解析数据如下表1所示。
表1
Figure PCTCN2022139461-appb-000006
本发明还提供了式(Ⅰ)所示化合物晶型B，其X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：6.96±0.2°、11.71±0.2°、15.55±0.2°、17.35±0.2°、20.62±0.2°、21.16±0.2°。
本发明的一些方案中，上述晶型B的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：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°、21.81±0.2°。
本发明的一些方案中，上述晶型B的X射线粉末衍射图谱具有基本上如图2所示的X射线粉末衍射图谱。
本发明的一些方案中，上述晶型B的X射线粉末衍射图谱解析数据如表2所示。
表2
Figure PCTCN2022139461-appb-000007
Figure PCTCN2022139461-appb-000008
本发明还提供了式(Ⅰ)所示化合物晶型C，其X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：12.69±0.2°、14.38±0.2°、16.23±0.2°、17.40±0.2°、18.61±0.2°、19.74±0.2°。
本发明的一些方案中，上述晶型C的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：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°、25.44±0.2°。
本发明的一些方案中，上述晶型C的X射线粉末衍射图谱具有基本上如图3所示的X射线粉末衍射图谱。
本发明的一些方案中，上述晶型C的X射线粉末衍射图谱解析数据如表3所示。
表3
Figure PCTCN2022139461-appb-000009
Figure PCTCN2022139461-appb-000010
本发明还提供了式(Ⅰ)所示化合物晶型D，其X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：9.33±0.2°、13.94±0.2°、18.82±0.2°、22.76±0.2°、24.24±0.2°、27.90±0.2°。
本发明的一些方案中，上述晶型D的X射线粉末衍射图谱具有基本上如图4所示的X射线粉末衍射图谱。
本发明的一些方案中，上述晶型D的X射线粉末衍射图谱的解析数据如表4所示。
表4
Figure PCTCN2022139461-appb-000011
本发明还提供了式(Ⅰ)所示化合物晶型E，其X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：6.84±0.2°、10.65±0.2°、11.53±0.2°、15.41±0.2°、17.29±0.2°、20.65±0.2°。
本发明的一些方案中，上述晶型E的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：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°、25.26±0.2°。
本发明的一些方案中，上述晶型E的X射线粉末衍射图谱具有基本上如图5所示的X射线粉末衍射图谱。
本发明的一些方案中，上述晶型E的X射线粉末衍射图谱解析数据如表5所示。
表5
Figure PCTCN2022139461-appb-000012
Figure PCTCN2022139461-appb-000013
本发明还提供了式(Ⅰ)所示化合物的二乙胺盐。
本发明还提供了式(Ⅰ)所示化合物二乙胺盐的晶型F，其X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：10.36±0.2°、10.96±0.2°、12.01±0.2°、13.05±0.2°、16.66±0.2°、18.99±0.2°。
本发明的一些方案中，上述晶型F的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：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°、23.93±0.2°。
本发明的一些方案中，上述晶型F的X射线粉末衍射图谱具有基本上如图6所示的X射线粉末衍射图谱。
本发明的一些方案中，上述晶型F的X射线粉末衍射图谱解析数据如表6所示。
表6
Figure PCTCN2022139461-appb-000014
Figure PCTCN2022139461-appb-000015
本发明还提供了式(Ⅰ)所示化合物钙盐的晶型H，其X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：7.32±0.2°、9.57±0.2°、11.83±0.2°、12.76±0.2°、13.48±0.2°、14.83±0.2°。
本发明的一些方案中，上述晶型H的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：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°、21.33±0.2°。
本发明的一些方案中，上述晶型H的X射线粉末衍射图谱具有基本上如图8所示的X射线粉末衍射图谱。
本发明的一些方案中，上述晶型H的X射线粉末衍射图谱解析数据如表8所示。
表8
Figure PCTCN2022139461-appb-000016
本发明还提供了式(Ⅰ)所示化合物钙盐的晶型I，其X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：7.27±0.2°、8.93±0.2°、11.23±0.2°、12.34±0.2°、13.66±0.2°、16.06±0.2°。
本发明的一些方案中，上述晶型I的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：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°、24.38±0.2°。
本发明的一些方案中，上述晶型I的X射线粉末衍射图谱具有基本上如图9所示的X射线粉末衍射图谱。
本发明的一些方案中，上述晶型I的X射线粉末衍射图谱解析数据如表9所示。
表9
Figure PCTCN2022139461-appb-000017
Figure PCTCN2022139461-appb-000018
本发明还提供了式(Ⅰ)所示化合物钙盐的晶型J，其X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：8.73±0.2°、9.49±0.2°、11.99±0.2°、12.89±0.2°、15.16±0.2°、19.58±0.2°。
本发明的一些方案中，上述晶型J的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：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°、26.66±0.2°。
本发明的一些方案中，上述晶型J的X射线粉末衍射图谱具有基本上如图10所示的X射线粉末衍射图谱。
本发明的一些方案中，上述晶型J的X射线粉末衍射图谱解析数据如表10所示。
表10
Figure PCTCN2022139461-appb-000019
本发明还提供了式(Ⅰ)所示化合物钙盐的晶型K，其X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：8.57±0.2°、9.32±0.2°、11.06±0.2°、12.65±0.2°、14.08±0.2°、14.71±0.2°。
本发明的一些方案中，上述晶型K的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：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°、19.29±0.2°。
本发明的一些方案中，上述晶型K的X射线粉末衍射图谱具有基本上如图11所示的X射线粉末衍射图谱。
本发明的一些方案中，上述晶型K的X射线粉末衍射图谱解析数据如下表11所示。
表11
Figure PCTCN2022139461-appb-000020
Figure PCTCN2022139461-appb-000021
本发明还提供了式(Ⅰ)所示化合物钙盐的晶型L，其X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：8.69±0.2°、9.78±0.2°、13.46±0.2°、14.72±0.2°、15.40±0.2°、15.98±0.2°。
本发明的一些方案中，上述晶型L的X射线粉末衍射图谱具有基本上如图12所示的X射线粉末衍射图谱。
本发明的一些方案中，上述晶型L的X射线粉末衍射图谱解析数据如表12所示。
表12
Figure PCTCN2022139461-appb-000022
本发明还提供了式(Ⅰ)所示化合物钙盐的晶型M，其X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：8.09±0.2°、10.87±0.2°、13.62±0.2°、14.55±0.2°、15.77±0.2°、16.39±0.2°。
本发明的一些方案中，上述晶型M的X射线粉末衍射图谱具有基本上如图13所示的X射线粉末衍射图谱。
本发明的一些方案中，上述晶型M的X射线粉末衍射图谱解析数据如表13所示。
表13
Figure PCTCN2022139461-appb-000023
Figure PCTCN2022139461-appb-000024
本发明还提供了式(Ⅰ)所示化合物钙盐的晶型N，其X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：7.79±0.2°、12.44±0.2°、14.94±0.2°、16.11±0.2°、17.50±0.2°、20.98±0.2°。
本发明的一些方案中，上述晶型N的X射线粉末衍射图谱具有基本上如图14所示的X射线粉末衍射图谱。
本发明的一些方案中，上述晶型N的X射线粉末衍射图谱解析数据如表14所示。
表14
Figure PCTCN2022139461-appb-000025
本发明还提供了式(Ⅰ)所示化合物钙盐的晶型O，其X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：7.40±0.2°、8.52±0.2°、12.01±0.2°、12.24±0.2°、14.67±0.2°、16.86±0.2°。
本发明的一些方案中，上述晶型O的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：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°、22.02±0.2°。
本发明的一些方案中，上述晶型O的X射线粉末衍射图谱具有基本上如图15所示的X射线粉末衍射图谱。
本发明的一些方案中，上述晶型O的X射线粉末衍射图谱解析数据如表15所示。
表15
Figure PCTCN2022139461-appb-000026
Figure PCTCN2022139461-appb-000027
本发明还提供了式(Ⅰ)所示化合物钙盐的晶型P，其特征在于，其X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：11.49±0.2°、13.38±0.2°、14.04±0.2°、16.28±0.2°、16.78±0.2°、20.22±0.2°、20.86±0.2°。
本发明的一些方案中，上述晶型P的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：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°、25.87±0.2°。
本发明的一些方案中，上述晶型P的X射线粉末衍射图谱具有基本上如图16所示的X射线粉末衍射图谱。
本发明的一些方案中，上述晶型P的X射线粉末衍射图谱解析数据如表16所示。
表16
Figure PCTCN2022139461-appb-000028
本发明还提供了式(Ⅰ)所示化合物的锶盐。
本发明的一些方案中，上述式(Ⅰ)所示化合物锶盐的晶型Q，其特征在于，其X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：5.01±0.2°、8.96±0.2°、10.08±0.2°、13.54±0.2°、14.84±0.2°、24.67±0.2°。
本发明的一些方案中，上述晶型Q的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：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°、24.67±0.2°。
本发明的一些方案中，上述晶型Q的X射线粉末衍射图谱具有基本上如图17所示的X射线粉末衍射图谱。
本发明的一些方案中，上述晶型Q的X射线粉末衍射图谱解析数据如表17所示。
表17
Figure PCTCN2022139461-appb-000029
Figure PCTCN2022139461-appb-000030
本发明还提出了一种药物组合物，所述药物组合物包含前面所述的晶型A、晶型B、晶型C、晶型D、晶型E、二乙胺盐、晶型F、钙盐、晶型G、晶型H、晶型I、晶型J、晶型K、晶型L、晶型M、晶型N、晶型O、晶型P、锶盐或晶型Q。
在本发明的一些方案中，上述药物组合物进一步包含药学上可接受的载体，赋形剂，稀释剂，辅剂，媒介物或它们的组合。
本发明还提出了前面所述的晶型A、晶型B、晶型C、晶型D、晶型E、二乙胺盐、晶型F、钙盐、晶型G、晶型H、晶型I、晶型J、晶型K、晶型L、晶型M、晶型N、晶型O、晶型P、锶盐、晶型Q或药物组合物在制备用作S1P1受体相关疾病的药物中的用途。
在本发明的一些方案中，上述S1P1受体相关疾病选自溃疡性结肠炎、克罗恩病、多发性硬化症、系统性红斑狼疮、狼疮性肾炎、类风湿性关节炎、原发性胆汁胆管炎、过敏性皮肤炎、脑出血、移植物抗宿主病、牛皮癣、I型糖尿病、痤疮、微生物感染或微生物疾病及病毒感染和病毒疾病。
定义和说明
除非另有说明，本发明使用的所有技术和科学术语与本发明所属领域的普通技术人员所通常理解的具有相同含义。本发明涉及的所有专利和公开出版物通过引用方式整体并入本发明。尽管在本发明的 实践或者测试中可以使用与本发明所述相似或者相同的任何方法和物质，但是本发明中描述的是优选的方法、设备和物质。
“晶型”或“结晶形式”是指具有高度规则化学结构的固体，包括，但不限于，单组分或者多组分晶体，和/或化合物的多晶型物、溶剂化物、水合物、包合物、共晶、盐、盐的溶剂化物、盐的水合物。物质的结晶形式可通过本领域已知的许多方法得到。这种方法包括，但不限于，熔体结晶、熔体冷却、溶剂结晶、在限定的空间中结晶，例如，在纳米孔或者毛细管中，在表面或者模板上结晶，例如，在聚合物上，在添加剂如共结晶反分子的存在下结晶、去溶剂、脱水、快速蒸发、快速冷却、缓慢冷却、蒸气扩散、升华、反应结晶、反溶剂添加、研磨和溶剂滴研磨等。
“无定形”或“无定形形式”是指物质的质点(分子、原子、离子)在三维空间排列无周期性时形成的物质，其特征是具有漫射的不具尖峰的X射线粉末衍射图。无定形是固体物质的一种特殊的物理形式，其局部有序的结构特征，提示其与晶型物质有着千丝万缕的联系。物质的无定形形式可通过本领域已知的许多方法得到。这种方法包括，但不限于，骤冷法、反溶剂絮凝法、球磨法、喷雾干燥法、冷冻干燥法、湿法制粒法和固体分散体技术等等。
“溶剂”是指一种物质(典型地是一种液体)，该物质能够完全地或部分地溶解另一种物质(典型地是一种固体)。用于本发明实施的溶剂包括但并不限于，水、乙酸、丙酮、乙腈、苯、氯仿、四氯化碳、二氯甲烷、二甲基亚砜、1,4-二氧六环、乙醇、乙酸乙酯、丁醇、叔丁醇、N,N-二甲基乙酰胺、N,N-二甲基甲酰胺、甲酰胺、蚁酸、庚烷、己烷、异丙醇、甲醇、甲基乙基酮、l-甲基-2-吡咯烷酮、均三甲苯、硝基甲烷、聚乙二醇、丙醇、2-丙酮、吡啶、四氢呋喃、甲苯、二甲苯、它们的混合物等等。
“反溶剂”是指促进产物(或产物前体)从溶剂中沉淀的流体。反溶剂可以包括冷气体、或通过化学反应促进沉淀的流体、或降低产物在溶剂中的溶解度的流体；其可以是与溶剂相同的液体但是处于不同温度，或者它可以是与溶剂不同的液体。
“溶剂化物”是指晶体在表面上、或在晶格中、或者在表面上和在晶格中具有溶剂，其中，所述溶剂可以是水、乙酸、丙酮、乙腈、苯、氯仿、四氯化碳、二氯曱烷、二甲基亚砜、1,4-二氧六环、乙醇、乙酸乙酯、丁醇、叔丁醇、N,N-二甲基乙酰胺、N,N-二甲基甲酰胺、甲酰胺、蚁酸、庚烷、己烷、异丙醇、甲醇、甲基乙基酮、甲基吡咯烷酮、均三甲苯、硝基甲烷、聚乙二醇、丙醇、2-丙酮、吡啶、四氢呋喃、甲苯、二甲苯以及它们的混合物等等。溶剂化物的一个具体例子是水合物，其中在表面上、或在晶格中、或者在表面上和在晶格中的溶剂是水。在物质的表面上、或在晶格中、或者在表面上和在晶格中，水合物可以具有或者不具有除了水以外的其它溶剂。
晶型或无定形可以通过多种技术手段进行鉴别，例如X射线粉末衍射(XRPD)、红外吸收光谱法(IR)、熔点法、差示扫描量热法(DSC)、热重分析法(TGA)、核磁共振法、拉曼光谱、X射线单晶衍射、溶解量热法、扫描电子显微镜(SEM)、定量分析、溶解度和溶解速度等等。
X射线粉末衍射(XRPD)可检测晶型的变化、结晶度、晶构状态等信息，是鉴别晶型的常用手段。XRPD图谱的峰位置主要取决于晶型的结构，对实验细节相对不敏感，而其相对峰高取决于与样品制备和仪器几何形状有关的许多因素。因此，在一些实施例中，本发明的晶型的特征在于具有某些峰位置的XRPD图，其基本上如本发明附图中提供的XRPD图所示。同时，XRPD图谱的2θ的量度可以有实验误差，不同仪器以及不同样品之间，XRPD图谱的2θ的量度可能会略有差别，因此所述2θ的数值不能视为绝对的。根据本发明试验所用仪器状况，衍射峰存在±0.2°的误差容限。
差示扫描量热(DSC)是在程序控制下，通过不断加热或降温，测量样品与惰性参比物(常用α-Al 2O 3)之间的能量差随温度变化的一种技术。DSC曲线的熔化峰高取决于与样品制备和仪器几何形状有关的 许多因素，而峰位置对实验细节相对不敏感。因此，在一些实施例中，本发明所述晶型的特征在于具有特征峰位置的DSC图，其基本上如本发明附图中提供的DSC图所示。同时，DSC图谱可以有实验误差，不同仪器以及不同样品之间，DSC图谱的峰位置和峰值可能会略有差别，因此所述DSC吸热峰的峰位置或峰值的数值不能视为绝对的。根据本发明试验所用仪器状况，熔化峰存在±3℃的误差容限。
化学组成相同的固体，在不同的热力学条件下，常会形成晶体结构不同的同质异构体，或称为变体，这种现象称为同质多晶或同质多相现象。当温度和压力条件变化时，变体之间会发生相互转变，此现象称为晶型转变。由于晶型转变，晶体的力学、电学、磁学等性能会发生巨大的变化。当晶型转变的温度在可测范围内时，在差示扫描量热(DSC)图上可观察到这一转变过程，其特征在于，DSC图具有反映这一转变过程的放热峰，且同时具有两个或多个吸热峰，分别为转变前后的不同晶型的特征吸热峰。本发明化合物的晶型或无定形在适当条件下可发生晶型转变
热重分析(TGA)是在程序控制下，测定物质的质量随温度变化的一种技术，适用于检查晶体中溶剂的丧失或样品升华、分解的过程，可推测晶体中含结晶水或结晶溶剂的情况。TGA曲线显示的质量变化取决于样品制备和仪器等许多因素；不同仪器以及不同样品之间，TGA检测的质量变化略有差别。在一些实施例中，本发明所述的钙盐晶型A在温度150℃左右失重5.1％左右。根据本发明试验所用的仪器状况，质量变化存在±0.3％的误差容限。
在本发明的上下文中，X射线粉末衍射图中的2θ值均以度(°)为单位。
术语“基本上如图所示”是指X射线粉末衍射图或DSC图或TGA结果中至少50％，或至少60％，或至少70％，或至少80％，或至少90％，或至少95％，或至少99％的峰显示在其图中。
当提及谱图或/和出现在图中的数据时，“峰”指本领域技术人员能够识别的不会归属于背景噪音的一个特征。
在本发明的上下文中，当使用或者无论是否使用“大约”或“约”等字眼时，表示在给定的值或范围的10％以内，适当地在5％以内，特别是在1％以内。或者，对于本领域普通技术人员而言，术语“大约”或“约”表示在平均值的可接受的标准误差范围内。每当公开一个具有N值的数字时，任何具有N+/-1％，N+/-2％，N+/-3％，N+/-5％，N+/-7％，N+/-8％或N+/-10％值以内的数字会被明确地公开，其中“+/-”是指加或减。
术语“包含”为开放式表达，即包括本发明所指明的内容，但并不排除其他方面的内容。
本发明的盐型或晶型或药物组合物可以用于制备用作S1P1受体相关疾病的药物。其中S1P1受体相关疾病选自溃疡性结肠炎(Ulcerative colitis)、克罗恩病(Crohn’s disease)、多发性硬化症(Multiple sclerosis)、系统性红斑狼疮(Systemic lupus erythematosus)、狼疮性肾炎(Lupus nephritis)、类风湿性关节炎(Rheumatoid arthritis)、原发性胆汁胆管炎(Primary Biliary Cholangitis)、过敏性皮肤炎(Atopic Dermatitis)、脑出血(Intracerebral hemorrhage)、移植物抗宿主病(Graft versus Host Disease)、牛皮癣(Psoriasis)、I型糖尿病(Type I diabetes)、痤疮(Acne)、微生物感染或微生物疾病及病毒感染或病毒疾病。
附图说明
图1为晶型A的X射线粉末衍射(XRPD)图。
图2为晶型B的X射线粉末衍射(XRPD)图。
图3为晶型C的X射线粉末衍射(XRPD)图。
图4为晶型D的X射线粉末衍射(XRPD)图。
图5为晶型E的X射线粉末衍射(XRPD)图。
图6为晶型F的X射线粉末衍射(XRPD)图。
图7为晶型G的X射线粉末衍射(XRPD)图。
图8为晶型H的X射线粉末衍射(XRPD)图。
图9为晶型I的X射线粉末衍射(XRPD)图。
图10为晶型J的X射线粉末衍射(XRPD)图。
图11为晶型K的X射线粉末衍射(XRPD)图。
图12为晶型L的X射线粉末衍射(XRPD)图。
图13为晶型M的X射线粉末衍射(XRPD)图。
图14为晶型N的X射线粉末衍射(XRPD)图。
图15为晶型O的X射线粉末衍射(XRPD)图。
图16为晶型P的X射线粉末衍射(XRPD)图。
图17为晶型Q的X射线粉末衍射(XRPD)图。
图18为晶型G的X射线粉末衍射(XRPD)图。
图19为晶型G的X射线粉末衍射(XRPD)图。
图20为晶型G的X射线粉末衍射(XRPD)图。
图21为晶型G的X射线粉末衍射(XRPD)图。
具体实施方式
下面通过实施例对本申请进行详细描述，但并不意味着存在对本申请而言任何不利的限制。本文已经详细地描述了本申请，其中也公开了其具体实施例方式，对本领域的技术人员而言，在不脱离本申请精神和范围的情况下针对本申请具体实施方式进行各种变化和改进将是显而易见的。
本发明所用X射线粉末衍射分析方法为：在室温条件下，选用Bruker D2 PHASER衍射仪(300W小功率X射线发射器)进行X射线粉末衍射测试。测试中用硅片放置样品粉末，使用X射线Cu(Kα)管，Kα2/Kα1的强度比为0.50
Figure PCTCN2022139461-appb-000031
设置仪器为30kV和10mA，步长0.02°(2θ)，每步扫描时间0.15s，共1837步。
本发明所用差示扫描量热(DSC)分析方法为：采用TA Discovery DSC收集差示扫描量热的数据。具体方法是：称若干毫克的样品到Tzero铝盘中，用相应的Tzero铝盘盖密封。在氮气的环境下，将密封好的样品以10℃/min的升温速率从室温上升到300℃。
本发明所用热失重(TGA)分析方法为：采用TA Discovery TGA收集热重分析的数据。具体方法是：在氮气的环境下，将若干毫克样品，以10℃/min的升温速率从室温上升到350℃。
本发明所用偏光显微镜(PLM)分析方法为：在室温下，使用Olympus BX53M的偏光显微镜分析样品形态。
本发明所用高效液相色谱(HPLC)分析方法为：使用Agilent 1260对样品进行纯度和稳定性测试，采用的条件如下表18所示。
表18：HPLC纯度方法
Figure PCTCN2022139461-appb-000032
Figure PCTCN2022139461-appb-000033
本发明吸湿性采用的分析方法为：在25℃氮气环境下使用SMS ADVENTURE DVS评估样品的吸湿性。试验时使用约30毫克的样品，测试方法如下：
方法一(针对无水晶型)：
0％RH至95％RH，每阶段上升10％RH(90至95％RH上升5％RH)；
95％RH至0％RH，每阶段下降10％RH(95至90％RH下降5％RH)。
方法二(针对水共溶剂合物)：
环境湿度至95％RH，每阶段上升10％RH(90至95％RH上升5％RH)；
95％RH至0％RH，每阶段下降10％RH(95至90％RH下降5％RH)；
0％RH至95％RH，每阶段上升10％RH(90至95％RH上升5％RH)。
本发明测定水分含量的分析方法为：使用瑞士万通Metrohm 870/803的卡式水分滴定仪(Karl Fischer,KF)收集样品的水分含量数据。使用容量法进行测量，滴定剂为HYDRANAL Composite-2(Sigma-Aldrich,P/N:34806)，溶剂为无水甲醇，搅拌时间为30s。具体操作为：称取～50mg样品(精确至0.001g)，用上述KF水分滴定仪测试样品水分含量，平行测定两次，取平均值。
本发明液态核磁(1H NMR)：采用Bruker 400M核磁进行样品分析，采用DMSO-d6作为溶剂。
本发明固态核磁(ssNMR)：采用Bruker公司500MHz宽腔固体核磁共振波谱仪，4mm双共振魔角旋转探头收集数据。使用交叉极化/魔角旋转(CP/MAS)方法，为了避免旋转边带影响，同时嵌入边带压制技术(TOSS)，收集样品的13C指纹谱。交叉极化的匹配条件使用金刚烷做优化，化学位移使用金刚烷高场信号(29.5ppm)校正。魔角转速8kHz，1H 90度脉冲3.45us，去耦方式TPPM。具体试验条件如下所示：
2#试验：脉冲延迟8s，接触时间2ms，累加1500次。
3#试验：脉冲延迟2s，接触时间2ms，累加1500次。
4#试验：脉冲延迟2s，接触时间0.2ms，累加3100次。
本发明采用的溶剂缩写或英文的中文含义如下表19所示：
表19溶剂中英文
英文 中文 英文 中文
MeOH 甲醇 EtOH 乙醇
IPA 异丙醇 2-Butanol 2-丁醇
Acetone 丙酮 MEK 丁酮
MIBK 4-甲基-2-戊酮 EtOAc 乙酸乙酯
IPAc 醋酸异丙酯 MTBE 甲基叔丁基醚
CPME 环戊基甲醚 THF 四氢呋喃
1,4-Dioxane 1,4-二氧六环 DMSO 二甲基亚砜
DMF 二甲基甲酰胺 DCM 二氯甲烷
CHCl 3 三氯甲烷 n-Heptane 正庚烷
2-MeTHF 2-甲基四氢呋喃 Toluene 甲苯
H 2O 水 ACN 乙腈
Butyl acetate 乙酸正丁酯 Methyl acetate 醋酸甲酯
Cumene 异丙苯 Anisole 苯甲醚
Hexane 己烷 -- --
为了使本领域技术人员更好地理解本发明，以下将介绍本发明的具体实施例。
实施例1：晶型A的制备
室温下，式(I)所示化合物在anisole/n-heptane(4:3，v/v)中搅拌析出固体，过滤，真空45℃干燥36h，得到晶型A。
实施例2：晶型B的制备
式(I)所示化合物(2.0g)溶于IPAC(10mL)，加热至60℃，滴加Heptane(40mL),降温至40℃，开始析出大量固体，补加Heptane(10mL)，搅拌2h，过滤，真空45℃干燥36h，得到晶型B。
实施例3：晶型D的制备
室温下，式(I)所示化合物在MeOH/H2O(9:2，v/v)中搅拌析出固体，过滤，真空45℃干燥36h，得到晶型D。
实施例4：晶型C的制备
晶型D加热至137℃，得到晶型C。
实施例5：晶型E的制备
室温下，式(I)所示化合物在CPME/Heptane(2:3，v/v)中搅拌析出固体，过滤，真空45℃干燥36h，得到晶型E。
实施例6：晶型F的制备(包括成盐的一步)
式(I)所示化合物(0.4g)室温溶于EtOH(3.0mL)，搅拌溶解，缓慢加入二乙胺的乙醇溶液(二乙胺：69.4mg；乙醇：0.8mL)，室温搅拌19h析出固体，过滤，真空30℃干燥3h，得到晶型F。
实施例7：晶型G
Figure PCTCN2022139461-appb-000034
方法一：反应釜中加入式(I)所示化合物(0.2651kg，0.595mol)，无水乙醇(0.9488kg)，升温至35～45℃，搅拌5～30分钟。加入乙醇钠溶液(乙醇钠：0.035Kg，0.514mol；无水乙醇：0.6310kg)，搅拌2～3小时，滴加氯化钙溶液(氯化钙：0.040Kg，0.357mol；纯化水：0.847Kg)，搅拌反应1～3小时，降温至20～30℃，搅拌4～6小时，过滤，滤饼纯化水漂洗，乙醇漂洗。滤饼25～35℃减压干燥得到0.2185kg晶型G的式(II)所示化合物，收率：79.1％。
方法二：称取10.72g式(I)所示化合物到单口瓶中，加入EtOH(105mL)磁力搅拌～0.5h将C 2H 5Ona(1.64g)加入，室温搅拌1.5h；将无水CaCl 2(1.5g)溶于的EtOH/H 2O(2:1,v/v，45mL)中，加入1％的晶种(晶型G)氯化钙溶液中；滴加氯化钙溶液，搅拌16h；取悬浮液，测定样品的XRPD，显示为晶型D，过滤，滤饼用H 2O和EtOH各洗涤2次，测试湿样XRPD，显示为晶型J，50℃下减压干燥4小时，测定XRPD，显示为晶型G。
方法三：式(I)所示化合物(21mg)中加入Ca(OH) 2(2mg)，加入0.2mL EtOH/H 2O(9:1,v/v)，室温磁力搅拌3天，过滤，50℃真空干燥2h，得到晶型G。
方法四：式(I)所示化合物(21mg)中加入Ca(OH) 2(2mg)，加入0.2mL IPA/H 2O(9:1,v/v)，室温磁力搅拌4天，过滤，50℃真空干燥2h，得到晶型G。
对于方法三中过滤所得产品，采用不同的烘干时间、温度或真空度，测试其中水和溶剂的含量，并检测其XRPD，结果如下表20所示。
表20
溶剂(乙醇)含量 水含量 解析表 图
4.77％ 3.09％ 表21 图18
3.05％ 3.89％ 表22 图19
1.97％ 4.37％ 表23 图20
1.64％ 3.75％ 表24 图21
解析表21
Figure PCTCN2022139461-appb-000035
Figure PCTCN2022139461-appb-000036
解析表22
Figure PCTCN2022139461-appb-000037
解析表23
Figure PCTCN2022139461-appb-000038
Figure PCTCN2022139461-appb-000039
解析表24
Figure PCTCN2022139461-appb-000040
晶型G在不同溶剂中的稳定性验证：
方法一：晶型G(50mg)，加入0.5mL相应溶剂(相应溶剂可为EtOH，H 2O，EtOH/H 2O＝970/30，927/73，855/145，704/296，v/v)室温磁力搅拌4天，过滤，50℃真空干燥2h，得到晶型G。
方法二：在4mL玻璃瓶中加入晶型G(15mg)，并将其放入装有3mL易挥发溶剂(可以是MeOH或EtOH)的20mL玻璃瓶中。将20mL玻璃瓶盖紧，在室温条件下静置约一周，过滤，50℃真空干燥2h，得到晶型G。
实施例8：晶型H的制备
晶型G(50mg)，加入MeOH(0.5mL)，室温磁力搅拌4天，过滤，得到晶型H。
实施例9：晶型I的制备
在HPLC小瓶中加入晶型G(50mg)，加入MeOH(0.5mL)，并在50℃条件下进行磁力搅拌7天，得到悬浊液，过滤，得到晶型I。
实施例10：晶型J的制备
方法一：晶型G(50mg)，加入0.5mL溶剂(溶剂可为2-Butanol或Toluene)室温磁力搅拌4天，过滤，得到晶型J。
方法二：在HPLC小瓶中加入晶型G(50mg)，加入IPA(0.5mL)，并在50℃条件下进行磁力搅拌7天，得到悬浊液，过滤，得到晶型J。
方法三：在HPLC小瓶中加入晶型G(50mg)，加入EtOAc/n-Heptane＝1/2,v/v(0.5mL)，并在50℃条件下进行磁力搅拌7天，得到悬浊液，过滤，得到晶型J。
方法四：称取～21mg实施例1中式(I)所示化合物(纯度93area％)和～2mg Ca(OH) 2到HPLC小瓶中；加入0.2mL EtOH/H2O(9:1,v/v)，室温磁力搅拌；搅拌3天后离心分离，测试湿样XRPD，为晶型J。
实施例11：晶型K的制备
在HPLC小瓶中加入晶型G(50mg)，加入2-MeTHF/n-Heptane＝1/2,v/v(0.5mL)，并在50℃条件下进行磁力搅拌7天，得到悬浊液，过滤，得到晶型K。
实施例12：晶型L的制备
氮气保护下，将晶型K加热到80℃冷却至室温，得到晶型L。
实施例13：晶型M的制备
在20mL玻璃瓶中加入晶型G(15mg)，加入DMF，室温搅拌溶解。向玻璃瓶中逐步加入H 2O直至出现固体，过滤，得到晶型M。
实施例14：晶型N的制备
在4mL玻璃瓶中加入晶型G(15mg)，加入DMF使其溶清。若不能溶清，则对悬浊液进行膜过滤处理(尼龙膜，膜孔径0.22μm)，将溶液分别放入装有4mLH 2O的20mL玻璃瓶中。将20mL玻璃瓶盖紧，放置在室温条件下，直至有固体析出，过滤，得到晶型N。
实施例15：晶型O的制备
将晶型G样品溶于Acetone中，静置约10min后析出固体，过滤，得到晶型O。
实施例16：晶型P的制备
在20mL玻璃瓶中加入晶型G(15mg)，加入Acetone室温搅拌溶解。向玻璃瓶中逐步加入MTBE直至出现固体，过滤，得到晶型P。
实施例17：晶型Q的制备
将式(I)所示化合物(110mg)加入到20mL单口瓶中，加入EtOH(1mL)，磁力搅拌至澄清，加入乙醇钠(16mg)，40℃下磁力搅拌反应1小时，滴加氯化锶水溶液(300mg/mL)0.1mL，28℃下搅拌反应12小时，过滤，干燥，得到晶型Q。
实施例18
发明人对上述公开的晶型A～Q中，部分晶型制备重现性差，部分不能提纯，因而发明人挑选了其中四个制备重现性好，容易提纯的晶型：晶型A、晶型B、晶型G、晶型Q在相同条件下，分别在高温、高湿、光照条件下进行试验，考察其稳定性，试验方案和结果如下25所示，形状变化如表26所示。
表25
Figure PCTCN2022139461-appb-000041
表26
Figure PCTCN2022139461-appb-000042
由上表25和26可知，晶型G在高温、高湿、光照条件下较其他晶型而言，其稳定性更高。
实施例19
对晶型A、晶型B、晶型G、晶型Q相同质量、相同包装在储存条件为25℃和40℃的条件下进行考察的纯度，见表27。
表27
Figure PCTCN2022139461-appb-000043
由上表27可知，晶型G在25℃和40℃的条件下储存90天的稳定性更高。

Claims (10)

  1. 式(Ⅰ)所示化合物的钙盐，
    Figure PCTCN2022139461-appb-100001
  2. 根据权利要求1所述的钙盐，其为
    Figure PCTCN2022139461-appb-100002
  3. 式(II)所示化合物晶型G，其特征在于，其X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：8.98±0.2°、10.12±0.2°、13.56±0.2°、14.66±0.2°、15.22±0.2°、18.48±0.2°。
  4. 根据权利要求3所述的晶型G，其特征在于，所述晶型G的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：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°、23.06±0.2°。
  5. 根据权利要求3或4所述的晶型G，其特征在于，所述晶型G的X射线粉末衍射图谱具有基本上如图7所示的X射线粉末衍射图谱。
  6. 根据权利要求3或4所述的晶型G，其特征在于，其进一步包含水和溶剂；
    其中，
    所述溶剂选自乙醇和异丙醇；
    所述溶剂的含量为0.1％～6.0％；
    所述水的含量为0.1％～4.0％。
  7. 一种制备晶型G的方法，其特征在于，包括：将式(I)所示化合物溶解在乙醇钠溶液中，之后在氯化钙存在的情况下进行搅拌、过滤、减压干燥，获得晶型G。
  8. 一种药物组合物，其特征在于，包含根据权利要求1或2所述的钙盐，或根据权利要求3-6任一项所述的晶型G。
  9. 权利要求1或2所述的钙盐，或权利要求3-6任一项所述的晶型G或权利要求8所述的药物组合物在制备用作S1P1受体相关疾病的药物中的用途。
  10. 根据权利要求9所述的用途，其中所述S1P1受体相关疾病选自溃疡性结肠炎、克罗恩病、多发性硬化症、系统性红斑狼疮、狼疮性肾炎、类风湿性关节炎、原发性胆汁胆管炎、过敏性皮肤炎、脑出血、移植物抗宿主病、牛皮癣、I型糖尿病、痤疮、微生物感染或微生物疾病及病毒感染和病毒疾病。
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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2007262009A (ja) * 2006-03-29 2007-10-11 Dai Ichi Seiyaku Co Ltd ヘテロアリール低級カルボン酸誘導体
CN102164891A (zh) * 2008-07-23 2011-08-24 艾尼纳制药公司 可用于治疗自身免疫性疾病和炎性疾病的经取代的1,2,3,4-四氢环戊并[b]吲哚-3-基乙酸衍生物
WO2020114475A1 (zh) * 2018-12-06 2020-06-11 上海济煜医药科技有限公司 作为免疫调节的芳环衍生物及其制备方法和应用

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2007262009A (ja) * 2006-03-29 2007-10-11 Dai Ichi Seiyaku Co Ltd ヘテロアリール低級カルボン酸誘導体
CN102164891A (zh) * 2008-07-23 2011-08-24 艾尼纳制药公司 可用于治疗自身免疫性疾病和炎性疾病的经取代的1,2,3,4-四氢环戊并[b]吲哚-3-基乙酸衍生物
WO2020114475A1 (zh) * 2018-12-06 2020-06-11 上海济煜医药科技有限公司 作为免疫调节的芳环衍生物及其制备方法和应用

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