WO2021098716A1 - 一种稠环化合物的晶型、其组合物、制备方法及其应用 - Google Patents

一种稠环化合物的晶型、其组合物、制备方法及其应用 Download PDF

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WO2021098716A1
WO2021098716A1 PCT/CN2020/129748 CN2020129748W WO2021098716A1 WO 2021098716 A1 WO2021098716 A1 WO 2021098716A1 CN 2020129748 W CN2020129748 W CN 2020129748W WO 2021098716 A1 WO2021098716 A1 WO 2021098716A1
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crystal form
ray diffraction
fused ring
ring compound
angles
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PCT/CN2020/129748
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French (fr)
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何俏军
陈斌辉
郑琳
翁勤洁
叶丁
蒋明勇
龚义
王晓玲
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杭州禹胜医药科技有限公司
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Priority to EP20890684.2A priority Critical patent/EP4063361A4/en
Priority to US17/756,277 priority patent/US20230029066A1/en
Publication of WO2021098716A1 publication Critical patent/WO2021098716A1/zh

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
    • 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
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/07—Optical isomers
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/13—Crystalline forms, e.g. polymorphs

Definitions

  • the invention belongs to the technical field of medicinal chemistry, and specifically relates to a crystal form of a fused ring compound, its composition, a preparation method and its application.
  • PI3K small molecule inhibitors As a new class of molecular targeted drugs, PI3K small molecule inhibitors have great potential and broad prospects. Therefore, there is a need for more PI3K inhibitors with novel structures, high biological activity, and good druggability for targeted therapy of tumors, as well as for anti-inflammatory or treatment of autoimmune diseases.
  • a new generation of PI3K small molecule inhibitors has a significant inhibitory effect on the proliferation activity of a variety of tumor cells.
  • the phenomenon of drug polymorphism is one of the important factors affecting the quality and clinical efficacy of drugs. Different crystal forms can lead to differences in stability, absorption and bioavailability, thereby affecting the clinical efficacy of drugs. Therefore, the polymorph of the fused ring compound and its preparation technology have very important significance for the application of the drug.
  • the purpose of the present invention is to provide a crystal form of a fused ring compound, its composition, a preparation method and its application.
  • the crystal form of the fused ring compound can be used for targeted therapy of tumors, as well as for anti-inflammatory or treatment of autoimmune diseases.
  • the present invention provides a polymorph of a fused ring compound:
  • the polymorphs include: crystal form I, using X-ray diffraction method, 2 ⁇ angles have characteristic diffraction peaks at about 11.3°, 17.2°, and 21.1°; crystal form II, using X-ray diffraction method, 2 ⁇ angles at about 25.1° There are characteristic diffraction peaks at °, 21.2°, and 14.1°; Form III, using X-ray diffraction method, 2 ⁇ angles have characteristic diffraction peaks at approximately 6.6°, 13.4°, and 8.0°; Form IV, using X-ray diffraction method , 2 ⁇ angles have characteristic diffraction peaks at about 11.8°, 13.3°, and 16.7°; crystal form V, using X-ray diffraction method, 2 ⁇ angles have characteristic diffraction peaks at about 6.5°, 13.3°, and 20.0°; among them, 2 ⁇ The error range of the angle is ⁇ 0.5°.
  • crystal form I uses X-ray diffraction, and the 2 ⁇ angles are about 11.3°, 17.2°, 21.1°, 22.7°, 18.5°, 13.8°, and there are characteristic diffraction peaks;
  • crystal form II uses X-ray diffraction method, 2 ⁇ angles have characteristic diffraction peaks at about 25.1°, 21.2°, 14.1°, 16.0°, 7.0°, 18.4°;
  • crystal form III using X-ray diffraction method, 2 ⁇ angles at about 6.6°, 13.4°, 8.0°, There are characteristic diffraction peaks at 20.0°, 21.1°, and 10.5°;
  • crystal form IV using X-ray diffraction method, has characteristic diffraction peaks at 2 ⁇ angles at approximately 11.8°, 13.3°, 16.7°, 17.8°, 21.8°, and 24.4°
  • Form V using X-ray diffraction method, 2 ⁇ angles have characteristic diffraction peaks at approximately 6.5°, 13.3°,
  • crystal form I using X-ray diffraction, the 2 ⁇ angles are 11.3°, 13.8°, 17.2°, 18.5°, 20.2°, 21.1°, 22.7°, 25.2°, 28.0°, 29.6°, 31.2°, 33.2
  • a characteristic diffraction peak at ° Form II, using X-ray diffraction, the 2 ⁇ angles are at 5.7°, 7.0°, 9.9°, 11.5°, 12.2°, 14.1°, 16.0°, 17.3°, 18.4°, 21.2°,
  • Form III using X-ray diffraction method, 2 ⁇ angles at 6.6°, 8.0°, 8.8°, 10.5°, 11.9°, 13.4°, 14.3°, 17.9°
  • crystal form IV using X-ray diffraction method, 2 ⁇
  • Another object of the present invention is to provide a polymorphic composition of a fused ring compound for targeted therapy of tumors, as well as for anti-inflammatory or treatment of autoimmune diseases.
  • a composition of crystal forms of a fused ring compound comprising one or a combination of two or more of the crystal form I, the crystal form II, the crystal form III, the crystal form IV, and the crystal form V; and the crystal form I And the crystal form IV accounts for more than 50% of the weight of the crystal composition.
  • Another object of the present invention is to provide a polymorphic composition of a fused ring compound for targeted therapy of tumors, as well as for anti-inflammatory or treatment of autoimmune diseases.
  • a composition of crystal forms of a fused ring compound comprising one or a combination of two or more of the crystal form I, the crystal form II, the crystal form III, the crystal form IV, and the crystal form V; and the crystal form I And the crystal form IV accounts for more than 80% of the weight of the crystal composition.
  • Another object of the present invention is to provide a fused-ring compound crystal form composition for targeted therapy of tumors, as well as for anti-inflammatory or treatment of autoimmune diseases.
  • a polymorphic composition of a fused ring compound wherein the crystal form I and the crystal form IV account for more than 90% of the weight of the crystal composition.
  • a composition of crystal forms of a fused ring compound comprising one or a combination of two or more of the crystal form I, the crystal form II, the crystal form III, the crystal form IV, and the crystal form V; and the crystal form I And the crystal form IV accounts for more than 90% of the weight of the crystal composition.
  • Another object of the present invention is to provide a pharmaceutical composition containing the above crystal form, which is used for targeted therapy of tumors, as well as for anti-inflammatory or treatment of autoimmune diseases.
  • Another object of the present invention is to provide a method for preparing crystal form I, adding a first organic solvent to the fused ring compound, heating to dissolve, and then adding a second organic solvent; stirring and crystallization; filtering and drying.
  • the first organic solvent is one or more of dichloromethane, chloroform, and tetrahydrofuran
  • the amount of the first organic solvent is 3-5 times the weight of the fused ring compound
  • the second The organic solvent is one or more of acetone, methyl ethyl ketone, ethanol, and ethyl acetate
  • the amount of the second organic solvent is 6-12 times the weight of the fused ring compound.
  • the stirring temperature for crystallization is 0-40°C
  • the crystallization time is 4-15 hours
  • the drying temperature is 60-150°C
  • the drying time is 4-15 hours.
  • Another object of the present invention is to provide a method for preparing crystal form IV, dissolving the fused-ring compound in an organic solvent and/or water, heating to dissolve; then stirring for crystallization; then filtering and drying.
  • the organic solvent and/or water is acetonitrile-water
  • the amount of acetonitrile is 30-90 times the weight of the fused ring compound
  • the amount of water is 0-20 times the weight of the fused ring compound.
  • the stirring temperature for crystallization is 0-40°C
  • the crystallization time is 0.5-30 hours
  • the drying temperature is 60-150°C
  • the drying time is 1-20 hours.
  • Another object of the present invention is to provide an application of the above crystal form in the preparation of drugs for inhibiting phosphatidylinositol 3-kinase.
  • the drug can be used for targeted therapy of tumors, as well as for anti-inflammatory or treatment of autoimmune diseases.
  • the tumor may be: brain cancer, head and neck cancer, esophageal cancer, lung cancer, liver cancer, stomach cancer, kidney cancer, pancreatic cancer, prostate cancer, colorectal cancer, ovarian cancer, breast cancer, thyroid cancer, skin cancer, leukemia , Myelodysplastic syndrome, sarcoma, osteosarcoma or rhabdomyomas.
  • the drug is an anti-inflammatory drug or a drug for treating autoimmune diseases.
  • the anti-inflammatory drug is a drug for treating chronic obstructive pulmonary disease or asthma
  • the autoimmune disease may be rheumatoid arthritis, psoriasis or systemic lupus erythematosus.
  • the crystal forms I, II, III, IV, and V of the present application all have obvious diffraction characteristic peaks of the crystal form, which can overcome the technical defects of amorphous and irregular crystal structure.
  • the stability of the crystal form I, crystal form II, and crystal form IV of the present invention under the conditions of high humidity test and high temperature test for 5 days is significantly better than the amorphous form of the reference (CN 201610235304.5).
  • the crystal form I and crystal form IV of the present invention have good solubility and stability in different solutions, are easily absorbed by the human body, and have excellent effects in treating diseases.
  • Fig. 1A is an X-ray diffraction pattern of the crystal form I in the present invention.
  • Fig. 1B is an X-ray diffraction peak data diagram of the crystal form I in the present invention.
  • Figure 1C is a DSC chart of the crystal form I in the present invention.
  • FIG. 2A is an X-ray diffraction pattern of the crystal form II obtained in Example 7.
  • FIG. 2A is an X-ray diffraction pattern of the crystal form II obtained in Example 7.
  • 2B is an X-ray diffraction peak data diagram of the crystal form II obtained in Example 7.
  • 3A is an X-ray diffraction pattern of crystal form III obtained in Example 9.
  • 3B is an X-ray diffraction peak data diagram of crystal form III obtained in Example 9.
  • Example 4A is an X-ray diffraction pattern of crystal form V obtained in Example 10.
  • 4B is an X-ray diffraction peak data diagram of the crystal form V obtained in Example 10.
  • Fig. 5A is an X-ray diffraction pattern of crystal form IV in the present invention.
  • Fig. 5B is an X-ray diffraction peak data chart of the crystal form IV in the present invention.
  • Fig. 5C is a DSC chart of the crystal form IV in the present invention.
  • FIG. 6 is an X-ray diffraction pattern of the crystal form I obtained in Example 6.
  • FIG. 7 is an X-ray diffraction pattern of the crystal form II obtained in Example 8.
  • FIG. 7 is an X-ray diffraction pattern of the crystal form II obtained in Example 8.
  • Fig. 8 is an X-ray diffraction pattern of the amorphous form obtained in Example 11.
  • Fig. 9 is an X-ray diffraction pattern of the amorphous form in Example 12 after a 5-day high-humidity test.
  • Fig. 10 is an X-ray diffraction pattern of the crystal form IV in Example 12 after a 5-day high-humidity test.
  • Fig. 11 is an X-ray diffraction pattern of the crystal form I in Example 12 after a 5-day high humidity test.
  • Fig. 12 is an X-ray diffraction pattern of the crystal form II in Example 12 after a 5-day high-humidity test.
  • Fig. 13 is an X-ray diffraction pattern of the amorphous form in Example 13 after a 5-day high temperature test.
  • Example 14 is an X-ray diffraction pattern of the crystal form IV in Example 13 after a high temperature test for 5 days.
  • Fig. 15 is an X-ray diffraction pattern of the crystal form I in Example 13 after a high temperature test for 5 days.
  • Fig. 16 is an X-ray diffraction pattern of the crystal form II in Example 13 after a high temperature test for 5 days.
  • Fig. 17 is an X-ray diffraction pattern of the crystal form IV in Example 14 after 30 days of accelerated test.
  • Fig. 18 is an X-ray diffraction pattern of the crystal form I in Example 14 after the accelerated test for 30 days.
  • Fig. 19 is an X-ray diffraction pattern of the crystal form II in Example 14 after 30 days of accelerated test.
  • a crystal form of a fused ring compound and its preparation method and application is:
  • Form I using X-ray diffraction method, 2 ⁇ angles have characteristic diffraction peaks at about 11.3°, 17.2°, and 21.1°;
  • Form II using X-ray diffraction method, 2 ⁇ angles at about 25.1°, 21.2°, 14.1° There are characteristic diffraction peaks at crystal form III, using X-ray diffraction method, 2 ⁇ angles have characteristic diffraction peaks at about 6.6°, 13.4°, and 8.0°;
  • crystal form IV using X-ray diffraction method, 2 ⁇ angle at about 11.8° There are characteristic diffraction peaks at, 13.3° and 16.7°;
  • crystal form V using X-ray diffraction method, 2 ⁇ angles have characteristic diffraction peaks at about 6.5°, 13.3°, and 20.0°; among them, the error range of 2 ⁇ angle is ⁇ 0.5 °.
  • the crystal form I uses X-ray diffraction method, and the 2 ⁇ angles have characteristic diffraction peaks at about 11.3°, 17.2°, 21.1°, 22.7°, 18.5°, and 13.8°;
  • the crystal form II uses X-ray diffraction method , 2 ⁇ angles still have characteristic diffraction peaks at about 25.1°, 21.2°, 14.1°, 16.0°, 7.0°, 18.4°;
  • crystal form III using X-ray diffraction method, 2 ⁇ angles are still about 6.6°, 13.4°, There are characteristic diffraction peaks at 8.0°, 20.0°, 21.1°, and 10.5°;
  • crystal form IV using X-ray diffraction, the 2 ⁇ angles are still at about 11.8°, 13.3°, 16.7°, 17.8°, 21.8°, 24.4°
  • crystal form V using X-ray diffraction method, 2 ⁇ angles are still about 6.5°, 13.3°, 20.0°,
  • the melting point of the crystal form I prepared by the above method is 207-209°C; in the X-ray diffraction diagram, the 2 ⁇ angles are 11.3°, 13.8°, 17.2°, 18.5°, 20.2°, 21.1°, 22.7°, 25.2°, 28.0 There are characteristic diffraction peaks at °, 29.6°, 31.2°, and 33.2° (see Figure 1A and Figure 1B).
  • Figure 1C is a thermal analysis chart of crystal form I. TGA shows that crystal form I starts to lose weight at about 145°C, and the DSC chart shows an absorption peak at about 209°C.
  • the crystal form IV prepared by the above method has a melting point of 185-188°C; in the X-ray diffraction diagram, the 2 ⁇ angles are at 6.6°, 8.2°, 9.7°, 11.8°, 13.3°, 15.0°, 16.7°, 17.8°, 20.2 There are characteristic diffraction peaks at °, 21.8°, 24.4°, 27.9°, 29.1°, and 30.4° (see Figure 5A and Figure 5B).
  • Fig. 5C is a thermal analysis chart of the crystal form IV. TGA shows that the crystal form IV begins to lose weight at about 250°C, and the DSC chart shows an absorption peak at about 188°C.
  • the crystal form IV prepared by the above method has a melting point of 185-187°C; in the X-ray diffraction diagram, the 2 ⁇ angles are at 6.6°, 8.2°, 9.7°, 11.8°, 13.2°, 15.0°, 16.7°, 17.8°, 20.2 There are characteristic diffraction peaks at °, 21.8°, 24.4°, 27.9°, 29.1°, and 30.4°.
  • the 2 ⁇ angles are at 10.4°, 11.3°, 13.9°, 17.3°, 18.0°, 18.6°, 20.3°, 20.8°, 21.3°, 22.8°, There are characteristic diffraction peaks at 25.3°, 28.0°, 29.7°, and 31.3° (see Figure 6).
  • characterization data of the crystal form II prepared by the above method are shown in Fig. 2A and Fig. 2B.
  • the 2 ⁇ angles are at 5.7°, 7.0°, 9.9°, 11.5°, 12.2°, 14.1°, 16.0°, 17.3°, 18.4°, 21.2°, 22.9°, 25.1°, 31.7° Characteristic diffraction peaks (see Figure 2A).
  • Fig. 3A and Fig. 3B The characterization data of the crystal form III prepared by the above method are shown in Fig. 3A and Fig. 3B.
  • Fig. 3A The characterization data of the crystal form III prepared by the above method are shown in Fig. 3A and Fig. 3B.
  • X-ray diffraction diagram there are characteristic diffraction peaks at 2 ⁇ angles at 6.6°, 8.0°, 8.8°, 10.5°, 11.9°, 13.4°, 14.3°, 17.9°, 20.0°, 21.1°, and 22.8° (see figure 3A).
  • characterization data of the crystal form V obtained by the above method are shown in Fig. 4A and Fig. 4B.
  • 2 ⁇ angles have characteristic diffraction peaks at 6.5°, 8.0°, 10.4°, 13.3°, 16.2°, 17.7°, 20.0°, 21.0°, 24.0°, 24.8°, 26.7°, 29.1° (See Figure 4A).
  • Step 1 Combine 6-bromo-4-chloro-quinoline-3-carbonitrile (1.605g, 6.0mmol) and (R)-3-methylmorpholine (1.821g, 18.0mmol, 3eq) in dioxane In the ring (30.0 mL), stir at 100°C. After the reaction, it was concentrated in vacuo, the concentrated solution was diluted with water (60 mL), and extracted with ethyl acetate (60 mL ⁇ 3).
  • Step 2 Add (R)-6-bromo-4-(3-methylmorpholine)quinoline-3-carbonitrile (1.0g, 3mmol), N-(2-methoxy-5-(4,4 ,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-yl)methanesulfonamide (1.18g, 3.6mmol, 1.2eq) and 2N potassium carbonate
  • the mixture of aqueous solution (4.5mL, 3.0eq) in dioxane (20mL) was degassed, and then [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (110mg, 0.15 mmol, 0.05eq).
  • the resulting reaction mixture was degassed and backfilled with nitrogen (three cycles), and then stirred in a nitrogen atmosphere at 100°C for 5 hours.
  • Example 11 Take 30 mg ⁇ 3 of each of the amorphous form obtained in Example 11, the crystal form IV obtained in Example 3, the crystal form I obtained in Example 6, and the crystal form II obtained in Example 8 into a vial, and put it in an open mouth at room temperature. In a desiccator with saturated potassium nitrate at the bottom, take samples after 5 days and send them to XRD for testing.
  • Fig. 9 The XRD after the amorphous high-humidity test for 5 days is shown in Fig. 9.
  • the 2 ⁇ angles are 7.2°, 10.3°, 11.3°, 16.9°, 17.3°, 21.2°.
  • the peak shape and peak intensity have a large range of changes, and there is an obvious phenomenon of crystal transformation in the amorphous form.
  • Fig. 10 The XRD of the crystal form IV after the high humidity test for 5 days is shown in Fig. 10, which is basically unchanged compared to the crystal form IV before the high humidity test (Fig. 5A).
  • Fig. 11 The XRD of the crystal form I after the high-humidity test for 5 days is shown in Fig. 11, which is basically unchanged compared to the crystal form I (Fig. 6) before the high-humidity test.
  • Fig. 12 The XRD of the crystal form II after the high-humidity test for 5 days is shown in Fig. 12, which is basically unchanged compared to the crystal form II before the high-humidity test (Fig. 7).
  • Fig. 14 The XRD of the crystal form IV after the high temperature test for 5 days is shown in Fig. 14, which is basically unchanged compared to the crystal form IV before the high temperature test (Fig. 5A).
  • Fig. 15 The XRD of the crystal form I after the high temperature test for 5 days is shown in Fig. 15, which is basically unchanged compared to the crystal form I (Fig. 6) before the high temperature test;
  • Fig. 16 The XRD of the crystal form II after the high temperature test for 5 days is shown in Fig. 16, which is basically unchanged compared to the crystal form II (Fig. 7) before the high temperature test.
  • Fig. 17 The XRD of the crystal form IV after 30 days of accelerated stability test is shown in Fig. 17, compared with the crystal form IV before the accelerated test (Fig. 5A), there is basically no change.
  • Fig. 18 The XRD of the crystal form I 30 days after the accelerated stability test is shown in Fig. 18, which is basically unchanged compared to the crystal form I (Fig. 6) before the accelerated test.
  • Fig. 19 The XRD of the crystal form II after 30 days of accelerated stability test is shown in Fig. 19, which is basically unchanged compared to the crystal form II (Fig. 7) before the accelerated test.
  • (R)-N-(5-(3-cyano-4-(3-methylmorpholinyl)quinolin-6-yl)-2 prepared by reference (CN201610235304.5) -Methoxypyridin-3-yl)methanesulfonamide is amorphous, and the amorphous form has obvious crystal transformation under the conditions of high humidity test and high temperature test for 5 days, and is not suitable for development as a drug crystal form.
  • the crystal forms I, II, III, IV, and V of the present application all have obvious diffraction characteristic peaks of the crystal form, which can overcome the technical defects of amorphous and irregular crystal structure.
  • the crystal form I, crystal form II, and crystal form IV in the present invention are stable under the conditions of high humidity test and high temperature test for 5 days, and the crystal form of crystal form I, crystal form II and crystal form IV is stable for 30 days in the accelerated test.
  • the stability of crystal form I, crystal form II, and crystal form IV is significantly better than the amorphous form of the reference (CN 201610235304.5).
  • the crystal form I and crystal form IV in the present invention can be used to prepare a variety of drugs, and according to the solubility of the crystal form I and the crystal form IV in different environments and the stability within 24 hours, it can be seen that there are many
  • the medicine prepared in the crystal form is easily absorbed by the human body and has an excellent effect on the treatment of diseases.

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Abstract

本发明公开了一种稠环化合物的晶型、其组合物、制备方法及其应用。所述晶型包括：晶型I、晶型II、晶型III、晶型IV和晶型V，使用X射线衍射法，分别在约11.3°、17.2°、21.1°处；在约25.1°、21.2°、14.1°处；在约6.6°、13.4°、8.0°处；在约11.8°、13.3°、16.7°处；在约6.5°、13.3°、20.0°处有特征衍射峰；稠环化合物加适宜的溶剂溶解，搅拌，过滤，干燥，得到晶型I或IV；晶型I或晶型IV在制备用于抑制磷脂酰肌醇3-激酶的抗癌药物中的应用。其用于肿瘤的靶向治疗，以及用于抗炎或治疗自身免疫性疾病。

Description

一种稠环化合物的晶型、其组合物、制备方法及其应用 技术领域
本发明属于药物化学的技术领域，具体涉及一种稠环化合物的晶型、其组合物、制备方法及其应用。
背景技术
恶性肿瘤是一类严重威胁人类健康的重大疾病，临床上应用的大部分小分子抗肿瘤药物或是影响DNA的结构和功能、或是干扰核酸的合成与修复、或是抑制某种管家蛋白(如微管蛋白)的合成与功能，因而具有普遍的细胞毒性，临床应用中存在毒副作用大、易产生耐药性等缺点。
PI3K小分子抑制剂作为新一类的分子靶向药物，潜力巨大，前景广阔。因此，需要更多结构新颖、生物活性高、成药性良好的PI3K抑制剂，用于肿瘤的靶向治疗，以及用于抗炎或治疗自身免疫性疾病。
新一代PI3K小分子抑制剂，对多种肿瘤细胞有明显的增殖活性抑制作用。但是，药物多晶型现象是影响药品质量与临床疗效的重要因素之一，不同晶型会导致稳定性、吸收和生物利用度的差异，从而影响药物临床疗效。因此该稠环化合物的多晶型及其制备技术对该药物应用具有非常重要的意义。
发明内容
本发明目的在于提供一种稠环化合物的晶型、其组合物、制备方法及其应用。该稠环化合物晶型的可用于肿瘤的靶向治疗，以及用于抗炎或治疗自身免疫性疾病。
本发明提供了一种稠环化合物的多晶型：
稠环化合物的结构式为：
Figure PCTCN2020129748-appb-000001
所述多晶型包括：晶型I，使用X射线衍射法，2θ角在约11.3°、17.2°、21.1°处有 特征衍射峰；晶型II，使用X射线衍射法，2θ角在约25.1°、21.2°、14.1°处有特征衍射峰；晶型III，使用X射线衍射法，2θ角在约6.6°、13.4°、8.0°处有特征衍射峰；晶型IV，使用X射线衍射法，2θ角在约11.8°、13.3°、16.7°处有特征衍射峰；晶型V，使用X射线衍射法，2θ角在约6.5°、13.3°、20.0°处有特征衍射峰；其中，2θ角的误差范围为±0.5°。
进一步的，晶型I，使用X射线衍射法，2θ角还约11.3°、17.2°、21.1°、22.7°、18.5°、13.8°处有特征衍射峰；晶型II，使用X射线衍射法，2θ角在约25.1°、21.2°、14.1°、16.0°、7.0°、18.4°处有特征衍射峰；晶型III，使用X射线衍射法，2θ角在约6.6°、13.4°、8.0°、20.0°、21.1°、10.5°处有特征衍射峰；晶型IV，使用X射线衍射法，2θ角在约11.8°、13.3°、16.7°、17.8°、21.8°、24.4°处有特征衍射峰；晶型V，使用X射线衍射法，2θ角在约6.5°、13.3°、20.0°、10.4°、24.0°、24.8°处有特征衍射峰；其中，2θ角的误差范围为±0.5°。
具体的，晶型I，使用X射线衍射法，2θ角在11.3°、13.8°、17.2°、18.5°、20.2°、21.1°、22.7°、25.2°、28.0°、29.6°、31.2°、33.2°处有特征衍射峰；晶型II，使用X射线衍射法，2θ角在5.7°、7.0°、9.9°、11.5°、12.2°、14.1°、16.0°、17.3°、18.4°、21.2°、22.9°、25.1°、31.7°处有特征衍射峰；晶型III，使用X射线衍射法，2θ角在6.6°、8.0°、8.8°、10.5°、11.9°、13.4°、14.3°、17.9°、20.0°、21.1°、22.8°处有特征衍射峰；晶型IV，使用X射线衍射法，2θ角在6.6°、8.2°、9.7°、11.8°、13.3°、15.0°、16.7°、17.8°、20.2°、21.8°、24.4°、27.9°、29.1°、30.4°处有特征衍射峰；晶型V，使用X射线衍射法，2θ角在6.5°、8.0°、10.4°、13.3°、16.2°、17.7°、20.0°、21.0°、24.0°、24.8°、26.7°、29.1°处有特征衍射峰。
本发明的另一目的在于提供一种稠环化合物多晶型的组合物，用于肿瘤的靶向治疗，以及用于抗炎或治疗自身免疫性疾病。
一种稠环化合物多晶型的组合物，所述晶型I和晶型IV占晶体组合物重量在50％以上。
一种稠环化合物晶型的组合物，包括所述晶型I、晶型II、晶型III、晶型IV和晶型V中的一种或两种以上的组合；且所述晶型I和晶型IV占晶体组合物重量在50％以上。
本发明的另一目的在于提供一种稠环化合物多晶型的组合物，用于肿瘤的靶向治疗，以及用于抗炎或治疗自身免疫性疾病。
一种稠环化合物多晶型的组合物，所述晶型I和晶型IV占晶体组合物重量在80％以上。
一种稠环化合物晶型的组合物，包括所述晶型I、晶型II、晶型III、晶型IV和晶型V中的一种或两种以上的组合；且所述晶型I和晶型IV占晶体组合物重量在80％以上。
本发明的另一目的在于提供一种稠环化合物晶型的组合物，用于肿瘤的靶向治疗，以 及用于抗炎或治疗自身免疫性疾病。
一种稠环化合物多晶型的组合物，所述晶型I和晶型IV占晶体组合物重量在90％以上。一种稠环化合物晶型的组合物，包括所述晶型I、晶型II、晶型III、晶型IV和晶型V中的一种或两种以上的组合；且所述晶型I和晶型IV占晶体组合物重量在90％以上。
本发明的另一目的在于提供一种含有上述晶型的药物组合物，用于肿瘤的靶向治疗，以及用于抗炎或治疗自身免疫性疾病。
一种含有所述的晶型I、晶型II、晶型III、晶型IV或者晶型V及药学上可接受的赋形剂作为成分。
本发明的另一目的在于提供一种晶型I的制备方法，向稠环化合物中加入第一有机溶剂，加热溶解，再加入第二有机溶剂；再搅拌析晶；再过滤，干燥。
进一步的，所述第一有机溶剂为二氯甲烷、三氯甲烷、四氢呋喃中的一种或者几种，所述第一有机溶剂的用量为稠环化合物重量的3-5倍，所述第二有机溶剂为丙酮、丁酮、乙醇、乙酸乙酯中的一种或者几种，所述第二有机溶剂的用量为稠环化合物重量的6-12倍。
进一步的，所述搅拌析晶的温度为0-40℃，所述析晶的时间为4-15小时，所述干燥的温度为60-150℃，所述干燥的时间为4-15小时。
本发明的另一目的在于提供一种晶型IV的制备方法，将所述稠环化合物溶于有机溶剂和/或水中，加热溶解；再搅拌析晶；再过滤，干燥。
进一步的，所述有机溶剂和/或水为乙腈-水，所述乙腈的用量为稠环化合物重量的30-90倍，所述水的用量是稠环化合物重量的0-20倍。
进一步的，所述搅拌析晶的温度为0-40℃，所述析晶的时间为0.5-30小时，所述干燥的温度为60-150℃，所述干燥的时间为1-20小时。
本发明的另一目的在于提供一种上述晶型在制备抑制磷脂酰肌醇3-激酶的药物中的应用。该药物可用于肿瘤的靶向治疗，以及用于抗炎或治疗自身免疫性疾病。
一种上述晶型在制备抑制磷脂酰肌醇3-激酶的药物中的应用，所述药物为抗肿瘤药物。
进一步的，所述肿瘤可以是：脑癌、头颈癌、食管癌、肺癌、肝癌、胃癌、肾癌、胰腺癌、前列腺癌、结直肠癌、卵巢癌、乳腺癌、甲状腺癌、皮肤癌、白血病、骨髓异常增生综合症、肉瘤、骨肉瘤或横纹肌瘤。
进一步的，所述药物为抗炎药物或治疗自身免疫性疾病的药物。
进一步的，所述抗炎药物是用于治疗慢性阻塞性肺病或哮喘的药物，所述自身免疫性疾病可以是风湿性关节炎、银屑病或系统性红斑狼疮。
本发明的有益效果为：
本申请的晶型I、II、III、IV、V均具有明显的晶型衍射特征峰，能够克服无定型没有 规则的晶体结构的技术缺陷。本发明的晶型I、晶型II、晶型IV在高湿试验、高温试验5天条件下稳定性显著优于参考文献(CN 201610235304.5)的无定型。本发明晶型I、晶型IV在不同溶液中的溶解度和稳定性良好，易于人体吸收，在治疗疾病上具备优异的效果。
附图说明
图1A为本发明中的晶型I的X射线衍射图。
图1B为本发明中的晶型I的X射线衍射峰数据图。
图1C为本发明中的晶型I的DSC图。
图2A为实施例7所得晶型II的X射线衍射图。
图2B为实施例7所得晶型II的X射线衍射峰数据图。
图3A为实施例9所得晶型III的X射线衍射图。
图3B为实施例9所得晶型III的X射线衍射峰数据图。
图4A为实施例10所得晶型V的X射线衍射图。
图4B为实施例10所得晶型V的X射线衍射峰数据图。
图5A为本发明中的晶型IV的X射线衍射图。
图5B为本发明中的晶型IV的X射线衍射峰数据图。
图5C为本发明中的晶型IV的DSC图。
图6为实施例6所得晶型I的X-射线衍射图。
图7为实施例8所得晶型II的X-射线衍射图。
图8为实施例11所得无定型的X-射线衍射图。
图9为实施例12中无定型高湿5天试验后的X-射线衍射图。
图10为实施例12中晶型IV高湿5天试验后的X-射线衍射图。
图11为实施例12中晶型I高湿5天试验后的X-射线衍射图。
图12为实施例12中晶型II高湿5天试验后的X-射线衍射图。
图13为实施例13中无定型高温5天试验后的X-射线衍射图。
图14为实施例13中晶型IV高温5天试验后的X-射线衍射图。
图15为实施例13中晶型I高温5天试验后的X-射线衍射图。
图16为实施例13中晶型II高温5天试验后的X-射线衍射图。
图17为实施例14中晶型IV加速试验30天后的X-射线衍射图。
图18为实施例14中晶型I加速试验30天试验后的X-射线衍射图。
图19为实施例14中晶型II加速试验30天试验后的X-射线衍射图。
具体实施方式
为了更清楚地说明本发明，下面结合优选实施例对本发明做进一步的说明。本领域技术人员应当理解，下面所具体描述的内容是说明性的而非限制性的，不应以此限制本发明的保护范围。
本发明所有数值指定(例如温度、时间、浓度及重量等，包括其中每一者的范围)通常可是适当以0.1或1.0的增量改变(+)或(-)的近似值。所有数值指定均可理解为前面有术语“约”。
一种稠环化合物的晶型及其制备方法和应用，稠环化合物的结构式为：
Figure PCTCN2020129748-appb-000002
晶型I，使用X射线衍射法，2θ角在约11.3°、17.2°、21.1°处有特征衍射峰；晶型II，使用X射线衍射法，2θ角在约25.1°、21.2°、14.1°处有特征衍射峰；晶型III，使用X射线衍射法，2θ角在约6.6°、13.4°、8.0°处有特征衍射峰；晶型IV，使用X射线衍射法，2θ角在约11.8°、13.3°、16.7°处有特征衍射峰；晶型V，使用X射线衍射法，2θ角在约6.5°、13.3°、20.0°处有特征衍射峰；其中，2θ角的误差范围为±0.5°。
进一步的，晶型I，使用X射线衍射法，2θ角在还约11.3°、17.2°、21.1°、22.7°、18.5°、13.8°处有特征衍射峰；晶型II，使用X射线衍射法，2θ角还在约25.1°、21.2°、14.1°、16.0°、7.0°、18.4°处有特征衍射峰；晶型III，使用X射线衍射法，2θ角还在约6.6°、13.4°、8.0°、20.0°、21.1°、10.5°处有特征衍射峰；晶型IV，使用X射线衍射法，2θ角还在约11.8°、13.3°、16.7°、17.8°、21.8°、24.4°处有特征衍射峰；晶型V，使用X射线衍射法，2θ角还在约6.5°、13.3°、20.0°、10.4°、24.0°、24.8°处有特征衍射峰；其中，2θ角的误差范围为±0.5°。
实施例1
晶型I的制备方法：
称取实施例11制备的稠环化合物10g、二氯甲烷30g加至反应瓶中，加热溶解，加 入90g乙醇，浓缩至剩余重量约为100g，20℃搅拌析晶4小时，过滤，100℃干燥得到晶型I。
由上述方法制得的晶型I熔点207-209℃；X-射线衍射图中，2θ角在11.3°、13.8°、17.2°、18.5°、20.2°、21.1°、22.7°、25.2°、28.0°、29.6°、31.2°、33.2°处有特征衍射峰(见图1A和图1B)。图1C为晶型I的热分析图，TGA显示晶型I在145℃左右开始失重，DSC图显示在209℃左右有吸收峰。
实施例2
晶型I在不同环境下的溶解性(μg/mL)如表1所示：
表1：
Figure PCTCN2020129748-appb-000003
实施例3
晶型IV的制备方法：
称取实施例11制备的稠环化合物10g、乙腈300g加至反应瓶中，加热溶解，25℃搅拌析晶4小时，过滤，80℃干燥10小时得到晶型IV。
由上述方法制得的晶型IV熔点185-188℃；X-射线衍射图中，2θ角在6.6°、8.2°、9.7°、11.8°、13.3°、15.0°、16.7°、17.8°、20.2°、21.8°、24.4°、27.9°、29.1°、30.4°处有特征衍射峰(见图5A和图5B)。图5C为晶型IV的热分析图，TGA显示晶型IV在250℃左右开始失重，DSC图显示在188℃左右有吸收峰。
实施例4
晶型IV的制备方法：
称取实施例11制备的稠环化合物10g、乙腈200g加至反应瓶中，加热溶解，然后加入50g水，5℃搅拌析晶20小时，过滤，120℃干燥2小时得到晶型IV。
由上述方法制得的晶型IV熔点185-187℃；X-射线衍射图中，2θ角在6.6°、8.2°、9.7°、11.8°、13.2°、15.0°、16.7°、17.8°、20.2°、21.8°、24.4°、27.9°、29.1°、30.4°处有特征衍射峰。
实施例5
晶型IV在不同环境下的溶解性(μg/mL)如表2所示：
表2：
Figure PCTCN2020129748-appb-000004
实施例6
晶型I的制备方法：
将1.0g实施例11制备的稠环化合物加入烧瓶，加入30mL溶剂(乙醇)，加热，油浴温度85℃，搅拌溶清后，静置于室温，冷却析晶，过滤并收集固体，常温真空干燥。
由上述方法制得的晶型I的X-射线衍射图中，2θ角在10.4°、11.3°、13.9°、17.3°、18.0°、18.6°、20.3°、20.8°、21.3°、22.8°、25.3°、28.0°、29.7°、31.3°处有特征衍射峰(见图6)。
实施例7
晶型II的制备方法：
称取4.0g实施例11制备的稠环化合物，加入12.0g二氯甲烷，加热溶解，加入36.0g无水甲醇，15℃搅拌16小时，过滤，少许甲醇洗涤滤饼，滤饼于60℃减压干燥，烘干得3.90g淡黄色固体。
由上述方法制得的晶型II的表征数据见图2A和图2B。X-射线衍射图中，2θ角在 5.7°、7.0°、9.9°、11.5°、12.2°、14.1°、16.0°、17.3°、18.4°、21.2°、22.9°、25.1°、31.7°处有特征衍射峰(见图2A)。
实施例8
晶型II的制备方法：
将1.0g实施例11制备的稠环化合物加入烧瓶，加入45mL溶剂(EA：MeOH＝1:1)，加热，油浴温度70℃，搅拌溶清后，静置于室温，冷却析晶，过滤并收集固体，常温真空干燥。
由上述方法制得的晶型II的X-射线衍射图中，2θ角在5.7°、7.0°、9.9°、11.5°、12.2°、14.2°、15.9°、17.2°、18.3°、21.2°、23.0°、25.1°、31.5°处有特征衍射峰(见图7)。
实施例9
晶型III的制备方法：
称取4.0g实施例11制备的稠环化合物，加入200mL乙酸乙酯，加热回流至固体溶解，降温析晶，15℃搅拌16小时，过滤，滤饼于60℃减压干燥，烘干得3.55g淡黄色固体。
由上述方法制得的晶型III的表征数据见图3A、图3B。X-射线衍射图中，2θ角在6.6°、8.0°、8.8°、10.5°、11.9°、13.4°、14.3°、17.9°、20.0°、21.1°、22.8°处有特征衍射峰(见图3A)。
实施例10
晶型V的制备方法
称取1.0g实施例11制备的稠环化合物，加入6.0g四氢呋喃，加热回流至固体溶解，降温析晶，15℃搅拌16小时，过滤，滤饼于60℃减压干燥，烘干得0.29g淡黄色固体。
由上述方法制得的晶型V的表征数据见图4A、图4B。X-射线衍射图中，2θ角在6.5°、8.0°、10.4°、13.3°、16.2°、17.7°、20.0°、21.0°、24.0°、24.8°、26.7°、29.1°处有特征衍射峰(见图4A)。
实施例11
参考文献(CN 201610235304.5)制备稠环化合物：(R)-N-(5-(3-氰基-4-(3-甲基吗啉基)喹啉-6-基)-2-甲氧基吡啶-3-基)甲磺酰胺。
Figure PCTCN2020129748-appb-000005
步骤1：将6-溴-4-氯-喹啉-3-甲腈(1.605g，6.0mmol)和(R)-3-甲基吗啉(1.821g，18.0mmol，3eq)于二氧六环(30.0mL)中、在100℃下搅拌。反应结束后真空浓缩，浓缩液用水(60mL)稀释，乙酸乙酯(60mL×3)萃取。合并有机层，依次用水(20mL)和食盐水(20mL)洗涤，无水硫酸钠干燥，过滤，浓缩，经快速柱色谱(硅胶，石油醚/乙酸乙酯＝3:1，v/v)纯化得到淡黄色固体(R)-6-溴-4-(3-甲基吗啉)喹啉-3-腈(1.566g，产率为78.5％)。
1H NMR(400MHz,CDCl 3)δ8.81(s,1H),8.30(d,J＝2.1Hz,1H),7.96(d,J＝8.9Hz,1H),7.86(dd,J＝8.9,2.2Hz,1H),4.13–4.05(m,2H),4.05–3.97(m,1H),3.91–3.83(m,1H),3.77(d,J＝9.8Hz,1H),3.66(dd,J＝11.9,5.9Hz,1H),3.33–3.26(m,1H),1.14(d,J＝6.4Hz,3H).
步骤2：将(R)-6-溴-4-(3-甲基吗啉)喹啉-3-腈(1.0g,3mmol)，N-(2-甲氧基-5-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)吡啶-3-基)甲磺酰胺(1.18g,3.6mmol，1.2eq)和2N碳酸钾水溶液(4.5mL,3.0eq)于二氧六环(20mL)中的混合物脱气，然后加入[1,1'-双(二苯基膦基)二茂铁]二氯化钯(110mg，0.15mmol，0.05eq)。将产生的反应混合物脱气并回充氮气(三个循环)，然后在100℃下氮气气氛中搅拌5小时。将反应混合物冷却至室温，用(30mL)水稀释，用乙酸乙酯(30mL×3)萃取。合并有机层并用食盐水(30mL)洗涤，无水硫酸钠干燥，过滤，浓缩，经快速柱色谱(硅胶，二氯甲烷/甲醇＝200:1，v/v)纯化得到白色固体(1.056g，产率为77.3％)。
1H NMR(400MHz,DMSO)δ9.47(s,1H),8.86(s,1H),8.45(d,J＝2.0Hz,1H),8.29(s,1H),8.19(dd,J＝8.8,1.3Hz,1H),8.10(d,J＝8.7Hz,1H),8.05(d,J＝2.0Hz,1H),4.14–4.04(m,2H),4.00(s,3H),3.99–3.93(m,1H),3.90–3.82(m,1H),3.80–3.70(m,1H),3.62(dd,J＝10.9,3.6Hz,1H),3.27(d,J＝13.6Hz,1H),3.14(s,3H),1.10(d,J＝6.2Hz,3H).
所得白色固体的XRD如图8所示，从图8可看出采用参考文献(CN 201610235304.5)制备方法得到的(R)-N-(5-(3-氰基-4-(3-甲基吗啉基)喹啉-6-基)-2-甲氧基吡啶-3-基)甲磺酰胺为无定型。
实施例12
考察晶型对稳定性的影响—高湿5天试验
将实施例11所得无定型、实施例3所得晶型IV、实施例6所得晶型I、实施例8所得晶型II各取30mg×3，分别装入西林瓶中，常温下敞口放入底部盛有饱和硝酸钾的干燥器中，于5日后取样，送XRD检测。
无定型高湿5天试验后XRD如图9所示，相较于高湿实验前(图8)在2θ角为7.2°、10.3°、11.3°、16.9°、17.3°、21.2°处有明显新增峰，峰形和峰强度变化幅度大，无定型有明显转晶现象。
晶型IV高湿5天试验后XRD如图10所示，相较于高湿实验前晶型IV(图5A)基本无变化。
晶型I高湿5天试验后XRD如图11所示，相较于高湿实验前晶型I(图6)基本无变化。
晶型II高湿5天试验后XRD如图12所示，相较于高湿实验前晶型II(图7)基本无变化。
实施例13
考察晶型对稳定性的影响—高温5天试验
将实施例11所得无定型、实施例3所得晶型IV、实施例6所得晶型I、实施例8所得晶型II各取30mg×3，分别装入西林瓶，敞口放入QG 2003ba培养干燥箱，调节温度至60℃，于5日后取样，送XRD检测。
无定型高温5天试验后XRD如图13所示，相较于高温实验前(图8)在2θ角为11.3°、17.2°、18.5°、20.2°、21.1°、22.7°、25.3°处有明显新增峰，峰形和峰强度变化幅度大，无定型有明显转晶现象。
晶型IV高温5天试验后XRD如图14所示，相较于高温实验前晶型IV(图5A)基本无变化。
晶型I高温5天试验后XRD如图15所示，相较于高温实验前晶型I(图6)基本无变化；
晶型II高温5天试验后XRD如图16所示，相较于高温实验前晶型II(图7)基本无变化。
实施例14
晶型I、II、IV加速稳定性考察
将实施例3所得晶型IV、实施例6所得晶型I、实施例8所得晶型II各取30mg×3， 分别装入封口袋中，放入BPN-80CH二氧化碳培养箱，设定温度40℃，于30日后取样，送XRD检测。
晶型IV加速稳定性试验30天后XRD如图17所示，相较于加速试验前晶型IV(图5A)基本无变化。
晶型I加速稳定性试验30天后XRD如图18所示，相较于加速试验前晶型I(图6)基本无变化。
晶型II加速稳定性试验30天后XRD如图19所示，相较于加速试验前晶型II(图7)基本无变化。
综上所述，参考文献(CN201610235304.5)制备得到的(R)-N-(5-(3-氰基-4-(3-甲基吗啉基)喹啉-6-基)-2-甲氧基吡啶-3-基)甲磺酰胺为无定型，该无定型在高湿试验、高温试验5天条件下有明显的转晶现象，不适合作为药物晶型进行开发。而本申请的晶型I、II、III、IV、V均具有明显的晶型衍射特征峰，能够克服无定型没有规则的晶体结构的技术缺陷。本发明中的晶型I、晶型II、晶型IV在高湿试验、高温试验5天条件下稳定，晶型I、晶型II、晶型IV加速试验30天晶型稳定，本发明的晶型I、晶型II、晶型IV稳定性显著优于参考文献(CN 201610235304.5)的无定型。本发明中的晶型I、晶型IV在可以用于制备多种药物，且根据晶型I和晶型IV的在不同环境下的溶解度及24小时内的稳定性可知，本发明中的多晶型制备的药物易于人体吸收，在治疗疾病上具备优异的效果。
显然，本发明的上述实施例仅仅是为清楚地说明本发明所作的举例，而并非是对本发明的实施方式的限定，对于所属领域的普通技术人员来说，在上述说明的基础上还可以做出其它不同形式的变化或变动，这里无法对所有的实施方式予以穷举，凡是属于本发明的技术方案所引伸出的显而易见的变化或变动仍处于本发明的保护范围之列。

Claims (17)

  1. 一种稠环化合物的晶型，所述稠环化合物的结构式为：
    Figure PCTCN2020129748-appb-100001
    其特征在于：所述晶型为：
    晶型I，使用X射线衍射法，2θ角在11.3°、17.2°、21.1°处有特征衍射峰；
    晶型II，使用X射线衍射法，2θ角在25.1°、21.2°、14.1°处有特征衍射峰；
    晶型III，使用X射线衍射法，2θ角在6.6°、13.4°、8.0°处有特征衍射峰；
    晶型IV，使用X射线衍射法，2θ角在11.8°、13.3°、16.7°处有特征衍射峰；或者
    晶型V，使用X射线衍射法，2θ角在6.5°、13.3°、20.0°处有特征衍射峰；
    其中，2θ角的误差范围为±0.5°。
  2. 根据权利要求1所述的晶型，其特征在于：
    所述晶型I，使用X射线衍射法，2θ角还在22.7°、18.5°、13.8°处有特征衍射峰；
    所述晶型II，使用X射线衍射法，2θ角还在16.0°、7.0°、18.4°处有特征衍射峰；
    所述晶型III，使用X射线衍射法，2θ角还在20.0°、21.1°、10.5°处有特征衍射峰；
    所述晶型IV，使用X射线衍射法，2θ角还在17.8°、21.8°、24.4°处有特征衍射峰；
    所述晶型V，使用X射线衍射法，2θ角还在10.4°、24.0°、24.8°处有特征衍射峰；
    其中，2θ角的误差范围为±0.5°。
  3. 一种组合物，其特征在于：所述组合物包括权利要求1或2中所述晶型I、晶型II、晶型III、晶型IV和晶型V中的一种或两种以上的组合；且所述晶型I或晶型IV占组合物重量在50％以上。
  4. 根据权利要求3所述的组合物，其特征在于：所述晶型I或晶型IV占组合物重量在80％以上。
  5. 根据权利要求3所述的组合物，其特征在于：所述晶型I或型IV占组合物重量在90％以上。
  6. 一种药物组合物，包含权利要求1或2所述晶型I、晶型II、晶型III、晶型IV或者晶型V，及药学上可接受的载体或赋形剂。
  7. 一种权利要求1或2中所述晶型I的制备方法，其特征在于：向所述稠环化合物中加入第一有机溶剂，加热溶解，再加入第二有机溶剂；再搅拌析晶；再过滤，干燥。
  8. 根据权利要求7所述的晶型I的制备方法，其特征在于：所述第一有机溶剂为二氯甲烷、三氯甲烷、四氢呋喃中的一种或者两种以上的组合，所述第一有机溶剂的用量为稠环化合物重量的3-5倍，所述第二有机溶剂为丙酮、丁酮、乙醇、乙酸乙酯中的一种或者两种以上的组合，所述第二有机溶剂的用量为稠环化合物重量的6-12倍。
  9. 根据权利要求7或8所述的晶型I的制备方法，其特征在于：所述搅拌析晶的温度为0-40℃，所述析晶的时间为4-15小时，所述干燥的温度为60-150℃，所述干燥的时间为4-15小时。
  10. 一种权利要求1或2所述晶型I的制备方法，其特征在于：将所述稠环化合物加入乙醇，加热溶解；再搅拌析晶；再过滤，干燥。
  11. 一种权利要求1或2中所述晶型IV的制备方法，其特征在于：将所述稠环化合物溶于有机溶剂和/或水中，加热溶解；再搅拌析晶；再过滤，干燥。
  12. 根据权利要求11所述的晶型IV的制备方法，其特征在于：将所述稠环化合物溶于乙腈-水中，所述乙腈的用量为稠环化合物重量的30-90倍，所述水的用量是稠环化合物重量的0-20倍。
  13. 根据权利要求11或12所述的晶型IV的制备方法，其特征在于：所述搅拌析晶的温度为0-40℃，所述析晶的时间为0.5-30小时，所述干燥的温度为60-150℃，所述干燥的时间为1-20小时。
  14. 一种权利要求1或2所述的晶型在制备抑制磷脂酰肌醇3-激酶的药物中的应用。
  15. 根据权利要求14所述的应用，其特征在于：所述药物为抗肿瘤药物；所述肿瘤为：脑癌、头颈癌、食管癌、肺癌、肝癌、胃癌、肾癌、胰腺癌、前列腺癌、结直肠癌、卵巢 癌、乳腺癌、甲状腺癌、皮肤癌、白血病、骨髓异常增生综合症、肉瘤、骨肉瘤或横纹肌瘤。
  16. 根据权利要求14所述的应用，其特征在于：所述药物为抗炎药物或治疗自身免疫性疾病的药物。
  17. 根据权利要求16所述的应用，其特征在于：所述抗炎药物是用于治疗慢性阻塞性肺病或哮喘的药物，所述自身免疫性疾病为风湿性关节炎、银屑病或系统性红斑狼疮。
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