WO2020011245A1 - Polymorphs of 1,2,4-triazine-3-amine derivative and preparation method therefor - Google Patents

Polymorphs of 1,2,4-triazine-3-amine derivative and preparation method therefor Download PDF

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WO2020011245A1
WO2020011245A1 PCT/CN2019/095724 CN2019095724W WO2020011245A1 WO 2020011245 A1 WO2020011245 A1 WO 2020011245A1 CN 2019095724 W CN2019095724 W CN 2019095724W WO 2020011245 A1 WO2020011245 A1 WO 2020011245A1
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compound
formula
peak
cancer
ray powder
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PCT/CN2019/095724
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French (fr)
Chinese (zh)
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徐超
邵启云
冯君
贺峰
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江苏恒瑞医药股份有限公司
上海恒瑞医药有限公司
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Priority to CN201980033424.9A priority Critical patent/CN112154144B/en
Publication of WO2020011245A1 publication Critical patent/WO2020011245A1/en

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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
    • A61K31/53—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with three nitrogens as the only ring hetero atoms, e.g. chlorazanil, melamine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • 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

Definitions

  • the invention belongs to the field of medicinal chemistry and relates to A, B, C, D, E, 6- (8-fluoroquinolin-6-yl) -5-phenyl-1,2,4-triazin-3-amine, F, G, H, J crystal forms and preparation methods.
  • Adenosine is a naturally occurring purine nucleoside and is an endogenous regulator of many physiological functions. It plays an important role in the regulation of the cardiovascular system, central nervous system, respiratory system, kidney, fat and platelets.
  • Adenosine by G protein-coupled receptor family are known to have at least four subtypes of adenosine receptors, classified as A 1, A 2a, A 2b and A 3. Among them, A 1 and A 3 receptors inhibit the activity of the enzyme adenylate cyclase, and A 2a and A 2b receptors stimulate the activity of the enzyme, thereby regulating the level of cyclic AMP in cells. Through these receptors, adenosine is widely regulated Physiological function.
  • a 2a receptor (A 2a R) is widely distributed in the body, mainly expressed in the striatum in the central nervous system, and also expressed in peripheral, heart, liver, lung, kidney and other tissues.
  • adenosine A 2a receptor antagonists have amazing effects on the treatment of neurodegenerative diseases, mainly Parkinson's disease, Huntington's disease or Alzheimer's disease (Trends in Neurosci. 2006, 29 (11), 647-654; Expert Opinion on Therapeutic Patents, 2007, 17, 979-991, etc.). It can also be used to treat other central nervous system (CNS) related diseases such as depression, hyperactivity syndrome, sleep disorders and anxiety (Clin. Neuropharmacol. 2010, 33, 55-60; J. Neurosci.
  • CNS central nervous system
  • adenosine A 2a receptor antagonists have therapeutic potential as neuroprotective agents (see Jenner PJ Neuro 1.2000; 24 7Supp 12: 1143-50).
  • a 2a receptors can play an important role in immune regulation during ischemic hypoxia, inflammation, trauma, transplantation and many other pathological processes, which may be related to A 2a receptors in T cells and B cells.
  • Monocyte macrophages, neutrophils and other immune cells have higher expression levels.
  • the activation of A 2a receptors can promote immune tolerance in the body, which is closely involved in the formation of tumor cells' immune escape or immunosuppression, creating favorable conditions for the development of tumors. Lokshin and colleagues (Cancer Res.
  • a 2a R activation on natural killer cells can inhibit cTA's killing of tumor cells by increasing cAMP and activating PKA.
  • Other studies have shown that the activation of A 2a receptors can promote the proliferation of melanoma A375 cells, fibroblasts NIH3T3 cells, and pheochromocytoma PC12 cells, which may be related to the activation of A 2a receptors on T cells. Inhibition of T cell activation and proliferation is associated with tumor cell adhesion and cytotoxic effects on tumor cells; mice with A 2a receptor gene knockout can strengthen the anti-tumor immune effect of CD8 + T cells and significantly inhibit the tumor proliferation.
  • a 2a receptor antagonists can be used in the treatment of tumors. Deepak Mittal et al. Found that A 2b receptor inhibitors combined with chemotherapeutic drugs or immune checkpoint inhibitors can significantly reduce tumor metastasis in mouse triple negative breast cancer models; knockout mice or human colon cancer cell lines A 2b receptors in colon cancer significantly reduce colon cancer metastasis and cell tumorigenicity; at the same time, studies have found that A 2b receptors are highly expressed in human triple-negative breast cancer cell lines, and the expression of A 2b receptors is closely related to tumor progression Related. These results indicate that inhibition of A 2b receptors can inhibit tumor metastasis, so A 2b receptors are expected to be an ideal target for treating tumors (Cancer Res. 2016 Aug 1; 76 (15): 4372-82). The study of A 2a receptor and A 2b receptor dual inhibitors has also become a direction worth exploring.
  • adenosine A 1 receptor is in tissue ischemia / hypoxia, in the central, circulatory, digestive system, and skeletal muscle, when cells are in a hypoxic and hypoxic stress environment, extracellular adenosine accumulates through activation The A 1 receptor on the cell membrane activates the corresponding protective mechanism, thereby increasing the cell's tolerance to hypoxia and hypoxia.
  • a 1 receptor Located on the immune cells in a hypoxic environment A 1 receptor can promote the cellular immune response.
  • the A 1 receptor can also reduce free fatty acids and triglycerides and participate in regulating blood sugar.
  • Adenosine A 3 receptor (as described by Gessi S et al., Pharmacol. Ther.
  • a 3 Continuous blockade of the receptor may increase the likelihood of complications caused by any pre-existing or developing ischemic heart disease, such as angina pectoris or heart failure.
  • the crystalline form as a medicinal active ingredient often affects the chemical stability of the drug. Differences in crystallization conditions and storage conditions may cause changes in the crystalline structure of the compound, sometimes accompanied by the generation of other forms.
  • amorphous pharmaceutical products do not have a regular crystalline structure and often have other defects, such as poor product stability, fine crystallization, difficult filtration, easy agglomeration, and poor fluidity.
  • Polymorphic forms of drugs have different requirements for product storage, production, and scale-up. Therefore, it is necessary to further study the crystal form of the compound of formula (1) and improve various aspects of the compound of formula (1).
  • the present invention provides A-form, B-form, C-form, D-form, E-form, F-form, G-form, H-form, J-form of a compound of formula (1), and a preparation method thereof.
  • the crystal form of the invention has good crystal form stability.
  • the present invention provides a crystal form A of the compound of formula (1), which is characterized in that the X-ray powder diffraction pattern of crystal form A has characteristic peaks at diffraction angles 2 ⁇ of 8.697, 13.216, 17.581, 18.245, 21.624, 23.458. .
  • the X-ray powder diffraction pattern of the form A has characteristic peaks at diffraction angles 2 ⁇ of 8.697, 13.216, 17.581, 18.245, 21.624, 23.458, 25.412, 26.496, 29.398, 31.981, 33.576.
  • the X-ray powder diffraction pattern of the crystal form A has a diffraction angle 2 ⁇ of 8.019, 8.697, 11.846, 13.216, 13.521, 15.602, 16.033, 16.658, 16.968, 17.581, 18.245, 19.660, 21.624, 23.458, There are characteristic peaks at 24.139, 25.412, 26.496, 29.398, 31.981, and 33.576.
  • the present invention provides a crystal form B of a compound of formula (1), which is characterized in that the X-ray powder diffraction pattern of crystal form B has a diffraction angle 2 ⁇ of 7.815, 12.972, 14.272, 15.835, 17.655, 19.448, 22.273. Characteristic peaks.
  • the X-ray powder diffraction pattern of the B-form has a characteristic peak at a diffraction angle 2 ⁇ of 7.815, 12.972, 14.272, 15.835, 17.655, 19.448, 22.273, 24.864, 27.601.
  • the X-ray powder diffraction pattern of the B-form has a diffraction angle 2 ⁇ of 6.212, 7.815, 8.657, 10.723, 11.654, 12.972, 14.272, 15.835, 17.655, 18.342, 19.448, 21.283, 22.273, 22.353, There are characteristic peaks at 23.915, 24.864, 26.562, 27.601, and 32.485.
  • the present invention provides a crystal form C of a compound of formula (1), which is characterized in that the X-ray powder diffraction pattern of the crystal form C has characteristic peaks at diffraction angles 2 ⁇ of 8.168, 16.543, 17.658, 19.774, 21.003, 23.319. .
  • the X-ray powder diffraction pattern of the crystal form C has characteristic peaks at diffraction angles 2 ⁇ of 8.168, 11.733, 12.178, 12.660, 13.923, 16.543, 17.658, 19.774, 21.003, 23.319, 24.995, 28.419.
  • the X-ray powder diffraction pattern of the C form has a diffraction angle 2 ⁇ of 8.168, 11.733, 12.178, 12.660, 13.923, 16.543, 17.658, 19.774, 21.003, 21.982, 23.319, 23.673, 24.995, 26.137, There are characteristic peaks at 27.799, 28.419, 30.947, and 31.817.
  • the invention provides a D crystal form of the compound of formula (1), which is characterized in that the X-ray powder diffraction pattern of the D crystal form has characteristic peaks at diffraction angles 2 ⁇ of 8.122, 12.200, 20.179, 24.973, and 27.303.
  • the X-ray powder diffraction pattern of the D crystal form has characteristic peaks at diffraction angles 2 ⁇ of 6.225, 6.234, 8.122, 12.200, 15.173, 20.179, 24.973, 27.303.
  • the present invention provides an E-form of a compound of formula (1), which is characterized in that the X-ray powder diffraction pattern of the E-form has a diffraction angle 2 ⁇ of 8.262, 12.398, 16.792, 20.417, 21.344, 22.819, 23.929, 25.347 There are characteristic peaks everywhere.
  • the X-ray powder diffraction pattern of the E form has characteristic peaks at diffraction angles 2 ⁇ of 8.262, 12.398, 13.080, 16.792, 20.417, 21.344, 22.819, 23.929, 25.347, 28.760, and 29.104.
  • the present invention provides a crystal form F of a compound of formula (1), which is characterized in that the X-ray powder diffraction pattern of crystal form F has characteristic peaks at diffraction angles 2 ⁇ of 8.081, 13.837, 16.514, 17.700, 19.758, and 20.953. .
  • the X-ray powder diffraction pattern of the F crystal form has characteristic peaks at diffraction angles 2 ⁇ of 8.081, 13.837, 16.514, 17.700, 19.758, 20.953, 23.039, 23.640, 24.777, and 28.277.
  • the X-ray powder diffraction pattern of the F crystal form has a diffraction angle 2 ⁇ of 5.717, 8.081, 9.022, 11.645, 12.581, 13.837, 16.514, 17.700, 19.758, 20.953, 21.859, 23.039, 23.640, 24.777, There are characteristic peaks at 26.164, 27.141, 28.277, 31.599, 33.303, 36.342, 43.863, 44.435, 46.344.
  • the present invention provides a G crystal form of a compound of formula (1), which is characterized in that the X-ray powder diffraction pattern of the G crystal form has a diffraction angle 2 ⁇ of 7.877, 8.328, 8.462, 12.457, 16.866, 21.399, 22.293. Characteristic peaks.
  • the X-ray powder diffraction pattern of the G crystal form has characteristic peaks at diffraction angles 2 ⁇ of 7.877, 8.328, 8.462, 12.457, 16.866, 21.399, 22.293, 22.502, 23.974, 24.868, 25.439, 27.617.
  • the X-ray powder diffraction pattern of the G crystal form has a diffraction angle 2 ⁇ of 7.877, 8.328, 8.462, 12.457, 13.115, 14.324, 16.201, 16.866, 18.034, 19.575, 20.453, 21.399, 22.293, 22.502, There are characteristic peaks at 23.974, 24.868, 25.439, 26.460, 27.617, 28.820, 29.199, 31.766.
  • the present invention provides an H crystal form of a compound of formula (1), characterized in that the X-ray powder diffraction pattern of the H crystal form has a diffraction angle 2 ⁇ of 8.277, 12.498, 16.800, 17.823, 20.204, 21.241, 23.774, 25.361 There are characteristic peaks everywhere.
  • the X-ray powder diffraction pattern of the H crystal form has characteristic peaks at diffraction angles 2 ⁇ of 8.277, 12.096, 12.498, 16.800, 17.823, 20.204, 21.241, 22.359, 23.774, 25.361, 28.719, 31.521, 32.534. .
  • the X-ray powder diffraction pattern of the H crystal form has a diffraction angle 2 ⁇ of 8.277, 12.096, 12.498, 14.237, 16.800, 17.823, 19.712, 20.204, 21.241, 22.359, 23.774, 25.361, 28.719, 31.521, There are characteristic peaks at 32.534 and 48.634.
  • the present invention provides a J-form of a compound of formula (1), characterized in that the X-ray powder diffraction pattern of the J-form has a characteristic peak at a diffraction angle 2 ⁇ of 8.004, 12.258, 19.183, 24.484, 26.059, 33.718. .
  • the X-ray powder diffraction pattern of the J form has characteristic peaks at diffraction angles 2 ⁇ of 8.004, 12.258, 13.839, 19.183, 21.759, 22.820, 24.484, 26.059, 28.875, and 33.718.
  • the X-ray powder diffraction pattern of the J form has a diffraction angle 2 ⁇ of 8.004, 8.942, 12.258, 13.839, 15.415, 17.197, 19.183, 20.314, 20.924, 21.759, 22.820, 24.484, 26.059, 27.140, There are characteristic peaks at 28.875 and 33.718.
  • the present invention also relates to a method for preparing A, B, C, D, E, F, G, H, and J compounds of the compound of formula (1). : Take a certain amount of the compound of formula (1), add an appropriate amount of solvent, crystallize, filter, and dry to obtain the compound of formula (1) in the form A, B, C, D, E, F Crystal Form, G Form, H Form, or J Form.
  • the crystalline solvent of the compound A, B, C, D, E, F, G, H, and J is selected from hydrocarbon solvents, One or more of ether solvents, alcohol solvents, ester solvents, ketone solvents, nitrile solvents, halogenated hydrocarbon solvents, nitrogen-containing solvents, water, and dimethyl sulfoxide.
  • the hydrocarbon solvents include, but are not limited to, cyclohexane, n-heptane, and para-xylene;
  • the ether solvents include, but are not limited to, tetrahydrofuran, diethyl ether, propylene glycol methyl ether, methyl tert-butyl ether, isopropyl ether, or 1 , 4-dioxane;
  • the alcohol solvents include, but are not limited to, methanol, ethanol, isopropanol, n-propanol, isoamyl alcohol, or trifluoroethanol;
  • the ester solvents include, but are not limited to, ethyl acetate, Isopropyl acetate or butyl acetate;
  • the ketone solvents include, but are not limited to, acetone, acetophenone, and 4-methyl-2-pentanone;
  • the nitrile solvents include, but are not limited to,
  • the crystallization method of the compound A, B, C, D, E, F, G, H, J is selected from room temperature crystallization. , Cooling crystallization, crystallization of volatile solvents or adding seeds to induce crystallization.
  • the invention also relates to a method for preparing a form A of a compound of formula (1), which comprises: taking a certain amount of a compound of formula (1), adding an appropriate amount of a solvent, crystallizing, filtering, and drying to obtain a form A of a compound of formula (1) .
  • the solvent is selected from one or more of dichloromethane, methanol, and acetonitrile.
  • the A-type crystallizing method is selected from room temperature crystallization, cooling crystallization, volatile solvent crystallization, or adding seed crystals to induce crystallization.
  • the invention also relates to a method for preparing a form A of a compound of formula (1), which comprises: taking a certain amount of a compound of formula (1), dissolving it in an appropriate amount of dichloromethane, beating it, and collecting a solid. The solid was added with an appropriate amount of dichloromethane / methanol to dissolve, and slurried to obtain Form A.
  • the invention also relates to a method for preparing a form A of a compound of formula (1), which comprises: taking a certain amount of a compound of formula (1), adding an appropriate amount of a mixed solvent of dichloromethane / methanol, stirring at room temperature without dissolving, and the filtrate naturally evaporating, A crystal form was obtained.
  • the invention also relates to a method for preparing a form A of a compound of formula (1), which comprises: taking a certain amount of a compound of formula (1), dissolving it in an appropriate amount of acetonitrile, heating and dissolving, program cooling, and stirring at room temperature to obtain a form A.
  • the invention also relates to a method for preparing the B-form of the compound of the formula (1), which comprises: taking a certain amount of the compound of the formula (1), adding an appropriate amount of solvent, crystallizing, filtering, and drying to obtain the B-form of the compound of the formula (1) .
  • the solvent is selected from one or more of methanol, dichloromethane, ethanol, isopropanol, acetone, acetonitrile, and water.
  • the B-type crystallization method is selected from room temperature crystallization, cooling crystallization, volatile solvent crystallization or adding seed crystals to induce crystallization.
  • the invention also relates to a method for preparing the B-form of the compound of the formula (1), which comprises: taking a certain amount of the compound of the formula (1), dissolving it in an appropriate amount of methanol, stirring at room temperature without dissolving it, and naturally evaporating the filtrate to obtain the B-form.
  • the invention also relates to a method for preparing the B-form of the compound of the formula (1), which comprises: taking a certain amount of the compound of the formula (1), dissolving it in an appropriate amount of a methanol / dichloromethane mixed solution, heating and dissolving, program cooling, and stirring at room temperature To obtain the B crystal form.
  • the invention also relates to a method for preparing the B crystal form of the compound of the formula (1), which comprises: taking a certain amount of the compound of the formula (1), dissolving it in an appropriate amount of a mixed solution of ethanol / dichloromethane, heating and dissolving, program cooling, and stirring at room temperature To obtain the B crystal form.
  • the invention also relates to a method for preparing the B-form of the compound of the formula (1), which comprises: taking a certain amount of the compound of the formula (1), dissolving it in an appropriate amount of isopropanol / dichloromethane mixed solution, heating and dissolving, and cooling the program, Stir at room temperature to obtain Form B.
  • the invention also relates to a method for preparing the B-form of the compound of the formula (1), which comprises: taking a certain amount of the compound of the formula (1), dissolving it in an appropriate amount of acetone, heating and dissolving, cooling the program, and stirring at room temperature to obtain the B-form.
  • the present invention also relates to a method for preparing Form B of a compound of formula (1), which comprises: taking a certain amount of Form A and Form B of a compound of Formula (1), dissolving in an appropriate amount of isopropyl alcohol or isopropyl ether, and beating, Form B is obtained.
  • the invention also relates to a method for preparing the B-form of the compound of the formula (1), which comprises: taking a certain amount of the B-form and the B-form of the compound of the formula (1) (different batches), dissolving in an appropriate amount of n-hexane, beating, Form B is obtained.
  • the invention also relates to a method for preparing the crystal form C of the compound of formula (1), which comprises: taking a certain amount of the compound of formula (1), adding an appropriate amount of solvent, crystallizing, filtering, and drying to obtain the crystal form C of the compound of formula (1) .
  • the solvent is tetrahydrofuran.
  • the C-type crystallizing method is selected from room temperature crystallization, cooling crystallization, volatile solvent crystallization or adding seed crystals to induce crystallization.
  • the invention also relates to a method for preparing the crystal form C of the compound of the formula (1), which comprises: taking a certain amount of the compound of the formula (1), dissolving it in an appropriate amount of tetrahydrofuran, heating and dissolving, and stirring at room temperature to obtain the crystal form C.
  • the invention also relates to a method for preparing the D crystal form of the compound of the formula (1), which comprises: taking a certain amount of the compound of the formula (1), adding an appropriate amount of solvent, crystallizing, filtering, and drying to obtain the D crystal form of the compound of the formula (1) .
  • the solvent is dichloroethane.
  • the D-type crystallization method is selected from room temperature crystallization, cooling crystallization, volatile solvent crystallization, or seeding to induce crystallization.
  • the invention also relates to a method for preparing the D crystal form of the compound of the formula (1), which comprises: taking a certain amount of the compound of the formula (1), dissolving it in an appropriate amount of dichloroethane, heating and dissolving, and stirring at room temperature to obtain the D crystal. type.
  • the invention also relates to a method for preparing the E-form of the compound of the formula (1), which comprises: taking a certain amount of the compound of the formula (1), adding an appropriate amount of solvent, crystallizing, filtering, and drying to obtain the E-form of the compound of the formula (1) .
  • the solvent is selected from one or more of methanol, ethyl acetate, and dichloromethane.
  • the E-type crystallizing method is selected from room temperature crystallization, cooling crystallization, volatile solvent crystallization or adding seed crystals to induce crystallization.
  • the invention also relates to a method for preparing the E-form of the compound of the formula (1), which comprises: taking a certain amount of the compound of the formula (1), dissolving it in an appropriate amount of methanol, heating and dissolving the solution, and stirring at room temperature to obtain the E-form.
  • the present invention also relates to a method for preparing the E crystal form of the compound of formula (1), which comprises: taking a certain amount of the compound of formula (1), dissolving it in an appropriate amount of a mixed solvent of ethyl acetate / dichloromethane, heating and dissolving, and reducing the temperature to room temperature. Stir to obtain the E crystal form.
  • the invention also relates to a method for preparing the F crystal form of the compound of the formula (1), which comprises: taking a certain amount of the compound of the formula (1), adding an appropriate amount of solvent, crystallizing, filtering, and drying to obtain the F crystal form of the compound of the formula (1) .
  • the solvent is 1,4-dioxane.
  • the F-type crystallization method is selected from room temperature crystallization, cooling crystallization, volatile solvent crystallization or adding seed crystals to induce crystallization.
  • the invention also relates to a method for preparing the F crystal form of the compound of formula (1), which comprises: taking a certain amount of the compound of formula (1), dissolving it in an appropriate amount of 1,4-dioxane, stirring undissolved at room temperature, and the filtrate naturally Evaporate to obtain F crystal form.
  • the invention also relates to a method for preparing the G crystal form of the compound of the formula (1), which comprises: taking a certain amount of the crystal form E of the compound of the formula (1) and grinding to obtain the G crystal form.
  • the invention also relates to a method for preparing the H crystal form of the compound of the formula (1), which comprises: taking a certain amount of the crystal form A and the B form of the compound of the formula (1), dissolving in an appropriate amount of acetone, and beating to obtain the H crystal form.
  • the invention also relates to a method for preparing the H crystal form of the compound of the formula (1), which comprises: taking a certain amount of the B crystal form and the H crystal form of the compound of the formula (1), dissolving in a proper amount of acetone, and beating to obtain the H crystal form.
  • the invention also relates to a method for preparing the J-form of the compound of formula (1), which comprises: taking a certain amount of the A-form and B-form of the compound of the formula (1), dissolving it in an appropriate amount of ethyl acetate, and beating to obtain the J-form.
  • the invention also relates to a method for preparing the J crystal form of the compound of the formula (1), which comprises: taking a certain amount of the B crystal form and the J crystal form of the compound of the formula (1), dissolving in a proper amount of ethyl acetate, and beating to obtain the J crystal form.
  • the invention also relates to Form A, Form B, Form C, Form D, Form E, Form F, Form G, Form H, or Form J, and optionally a compound of formula (1).
  • the pharmaceutical composition can be made into any pharmaceutically acceptable dosage form.
  • the drug comprising Form A, Form B, Form C, Form D, Form E, Form F, Form G, Form H, or Form J of the compound of formula (1) according to the present invention.
  • Preparations can be formulated as tablets, capsules, pills, granules, solutions, suspensions, syrups, injections (including injections, sterile powders for injection and concentrated solutions for injection), suppositories, inhalants or sprays .
  • the pharmaceutical composition of the present invention can also be administered to patients or subjects in need of such treatment in any suitable manner, such as oral, parenteral, rectal, pulmonary or topical administration.
  • the pharmaceutical composition can be made into an oral preparation, such as an oral solid preparation, such as tablets, capsules, pills, granules, etc .; or an oral liquid preparation, such as an oral solution, orally mixed Suspensions, syrups, etc.
  • the pharmaceutical preparation may further contain a suitable filler, a binder, a disintegrant, a lubricant, and the like.
  • the pharmaceutical preparation When used for parenteral administration, the pharmaceutical preparation can be made into injections, including injections, sterile powders for injections, and concentrated solutions for injections.
  • the pharmaceutical composition When prepared as an injection, the pharmaceutical composition can be produced by a conventional method in the existing pharmaceutical field.
  • an additional agent may not be added to the pharmaceutical preparation, or a suitable additional agent may be added according to the properties of the drug.
  • the pharmaceutical preparations When used for rectal administration, the pharmaceutical preparations can be made into suppositories and the like.
  • the pharmaceutical preparation When used for pulmonary administration, the pharmaceutical preparation can be made into an inhalant or a spray.
  • Form A, Form B, Form C, Form D, Form E, Form F, Form G, Form H, or Form J of the compound of formula (1) of the present invention Is present in a pharmaceutical composition or medicament in a therapeutically and / or prophylactically effective amount.
  • Form A, Form B, Form C, Form D, Form E, Form F, Form G, Form H, or J of the compound of formula (1) of the present invention The crystalline form is present in a pharmaceutical composition or drug in the form of a unit dose.
  • the present invention further relates to a method for preparing a pharmaceutical composition, which comprises forming a form A, a form B, a form C, a form D, a form E, a form F, a compound selected from the compound of formula (1) of the present invention,
  • a method for preparing a pharmaceutical composition which comprises forming a form A, a form B, a form C, a form D, a form E, a form F, a compound selected from the compound of formula (1) of the present invention,
  • One or more of the G, H, or J forms are mixed with at least one pharmaceutically acceptable carrier, diluent, or excipient.
  • the invention further relates to the A-form, B-form, C-form, D-form, E-form, F-form, G-form, H-form or J-form of the compound of formula (1).
  • the invention further relates to the A-form, B-form, C-form, D-form, E-form, F-form, G-form, H-form or J-form of the compound of formula (1) in the preparation and treatment.
  • the tumor described in the present invention is selected from melanoma, brain tumor (glioma with malignant astroglial and oligodendroglioma component, etc.), esophageal cancer, gastric cancer, liver cancer, pancreatic cancer, Colorectal cancer (colon cancer, rectal cancer, etc.), lung cancer (non-small cell lung cancer, small cell lung cancer, primary or metastatic squamous cell carcinoma, etc.), kidney cancer, breast cancer, ovarian cancer, prostate cancer, skin cancer, nerves Blastoma, sarcoma, osteochondroma, osteoma, osteosarcoma, seminoma, testicular tumor, uterine cancer (cervix cancer, endometrial cancer, etc.), head and neck tumor (maxillary bone cancer, laryngeal cancer, pharyngeal cancer , Tongue cancer, intraoral cancer, etc.), multiple myeloma, malignant lymphoma (reticulosarcoma, lymphosar
  • the neurodegenerative disorders described in the present invention are selected from Parkinson's disease, Huntington's disease, Alzheimer's disease, amyotrophic lateral sclerosis, ataxia capillaries, bovine spongiform encephalopathy, Creutzfeldt-Jakob Second's disease, cerebellar atrophy, multiple sclerosis, primary lateral sclerosis, spinal muscular atrophy.
  • ether solvent in the present invention refers to a chain compound or a cyclic compound containing an ether bond -O- and having 1 to 10 carbon atoms, and specific examples include, but are not limited to, tetrahydrofuran, ether, and propylene glycol methyl ether , Methyl tert-butyl ether, isopropyl ether, or 1,4-dioxane.
  • the "alcoholic solvent” in the present invention refers to a group derived by replacing one or more hydrogen atoms on the "C 1-6 alkyl” with one or more "hydroxy", and the "hydroxy" and “C “1-6 alkyl” is as defined above, and specific examples include, but are not limited to, methanol, ethanol, isopropanol, n-propanol, isoamyl alcohol, or trifluoroethanol.
  • ester solvent in the present invention refers to a combination of a lower organic acid having 1 to 4 carbon atoms and a lower alcohol having 1 to 6 carbon atoms. Specific examples include, but are not limited to, acetic acid Ethyl, isopropyl or butyl acetate.
  • keton solvent in the present invention refers to a compound in which a carbonyl group (-C (O)-) is connected to two hydrocarbon groups.
  • ketones can be divided into fatty ketones, alicyclic ketones, aromatic ketones, Specific examples of saturated ketones and unsaturated ketones include, but are not limited to, acetone, acetophenone, and 4-methyl-2-pentanone.
  • nitrile solvent in the present invention refers to a group derived by replacing one or more hydrogen atoms on the “C 1-6 alkyl group” with one or more “cyano groups”, and the “cyano group” and "C 1-6 alkyl” is as defined above, and specific examples include, but are not limited to, acetonitrile or propionitrile.
  • halogenated hydrocarbon solvent in the present invention refers to a group derived by replacing one or more hydrogen atoms on the “C 1-6 alkyl” with one or more “halogen atoms”, and the “halogen atom” "And” C 1-6 alkyl "are as defined above, and specific examples include, but are not limited to, methyl chloride, methylene chloride, chloroform, or carbon tetrachloride.
  • the "X-ray powder diffraction pattern or XRPD" in the present invention is obtained by Cu-K ⁇ ray diffraction.
  • the “differential scanning calorimetry or DSC” in the present invention refers to measuring the temperature difference and heat flow difference between a sample and a reference object during the temperature rising or constant temperature of the sample to characterize all physical changes and chemistry related to the thermal effect. Change to get the phase transition information of the sample.
  • the “2 ⁇ or 2 ⁇ angle” in the present invention refers to a diffraction angle, ⁇ is a Bragg angle, and a unit is ° or degree.
  • the error range of the 2 ⁇ may be ⁇ 0.3, ⁇ 0.2, or ⁇ 0.1.
  • Form A and Form B of 6- (8-fluoroquinolin-6-yl) -5-phenyl-1,2,4-triazine-3-amine (compound of formula (1)) provided by the present invention Form C, Form D, Form E, Form F, Form G, Form H, and Form J are more advantageous in terms of solubility, stability, and hygroscopicity, and are more suitable for drug development and biological utilization
  • the requirements of degree and efficacy can meet the medicinal requirements of production, transportation and storage.
  • the production process is stable, repeatable and controllable, and can be adapted to industrial production.
  • FIG. 1 is an XRPD pattern of a compound of formula (1) in the form of Form A;
  • FIG. 2 is a DSC chart of a compound of formula (1) in the form of Form A;
  • FIG. 3 is a comparison chart of XRPD before and after DSC heating of a compound of formula (1) in the form of Form A;
  • FIG. 6 is a comparison chart of XRPD before and after DVS of the compound of formula (1) in the form of Form A;
  • FIG. 7 is an XRPD pattern of the compound of formula (1) in the B-form form
  • FIG. 8 is a DSC chart of a compound of formula (1) in the B-form
  • FIG. 9 is a comparison chart of XRPD before and after DSC heating of a compound of formula (1) in the B-form form;
  • FIG. 10 is a TGA diagram of a compound of formula (1) in the B-form
  • FIG. 11 is a PSD diagram of a compound of formula (1) in the B-form form
  • FIG. 12 is a DVS diagram of a compound of formula (1) in the form of Form B;
  • FIG. 13 is a comparison chart of XRPD before and after DVS of the compound of formula (1) in the B crystal form
  • FIG. 14 is an XRPD pattern of the compound of formula (1) in the form of the C crystal form
  • FIG. 15 is a DSC chart of the compound of formula (1) in the form of the C crystal form
  • FIG. 16 is a TGA diagram of a compound of formula (1) in the form of C crystal form
  • FIG. 17 is an XRPD pattern of the compound of formula (1) in the D crystal form
  • FIG. 18 is a DSC chart of the compound of formula (1) in the D crystal form
  • FIG. 19 is a TGA diagram of a compound of formula (1) in the form of D crystal
  • FIG. 20 is an XRPD pattern of the compound of formula (1) in the form of E-form
  • FIG. 21 is a DSC chart of a compound of formula (1) in the form of an E-form
  • FIG. 22 is a TGA diagram of a compound of formula (1) in an E-form
  • FIG. 23 is an XRPD pattern of the compound of formula (1) in the F-form
  • FIG. 24 is an XRPD pattern of a compound of formula (1) in the form of a G crystal
  • FIG. 25 is an XRPD pattern of a compound of formula (1) in the form of H crystal
  • FIG. 26 is a DSC chart of a compound of formula (1) in the form of H crystal
  • FIG. 27 is a TGA diagram of a compound of formula (1) in the H crystal form
  • FIG. 28 is an XRPD pattern of a compound of formula (1) in the form of a J-form
  • FIG. 29 is a DSC chart of a compound of formula (1) in the J-form
  • FIG. 30 is a TGA diagram of a compound of formula (1) in the J-form.
  • the structure of the compound is determined by nuclear magnetic resonance (NMR) or / and mass spectrometry (MS).
  • NMR shift ( ⁇ ) is given in units of 10 -6 (ppm).
  • the NMR measurement was performed using Bruker AVANCE-400 nuclear magnetic analyzer.
  • the measurement solvents were deuterated dimethyl sulfoxide (DMSO-d 6 ), deuterated chloroform (CDCl 3 ), and deuterated methanol (CD 3 OD).
  • the internal standard was 4 Methylsilane (TMS).
  • MS was measured using a FINNIGAN LCQAd (ESI) mass spectrometer (manufacturer: Thermo, model: Finnigan LCQ advantage MAX).
  • XRPD is X-ray powder diffraction detection: The measurement is performed using a BRUKER D8 X-ray diffractometer.
  • the specific collection information Cu anode (40kV, 40mA), Cu-K ⁇ 1 ray K ⁇ 2 rays K ⁇ rays Scanning mode: ⁇ / 2 ⁇ , scanning range (2q range): 3 to 64 °.
  • DSC is differential scanning calorimetry: The measurement uses a METTLER TOLEDO DSC 3+ differential scanning calorimeter with a heating rate of 10 ° C / min, and the specific temperature range refers to the corresponding map (mostly 25-300 or 25-350 ° C), nitrogen purging The speed is 50 mL / min.
  • TGA thermogravimetric analysis: METTLER TOLEDO TGA 2 thermogravimetric analyzer is used for detection. The heating rate is 10 ° C / min, the specific temperature range refers to the corresponding map (mostly 25-300 ° C), and the nitrogen purge rate is 20mL / min.
  • DVS dynamic moisture adsorption: The detection uses SMS DVS Advantage. At 25 ° C, the humidity change is 50% -95% -0% -95% -50%, and the step is 10% (the last step is 5%) (the specific range of humidity) (Based on the corresponding map, most of the methods are listed here.) The judgment criterion is dm / dt not more than 0.02%.
  • HPLC was prepared using Waters 2767-SQ preparative chromatography.
  • PSD particle size distribution
  • instrument Malvern MS3000
  • test mode wet method
  • dispersion medium liquid paraffin
  • rotation speed 900 rmp / min
  • shading degree 9.11%.
  • the CombiFlash rapid preparation instrument uses Combiflash Rf 200 (TELEDYNE ISCO).
  • the monitoring of the reaction progress in the examples uses thin layer chromatography (TLC), a developing agent used in the reaction, a column chromatography eluent system for purifying compounds, and a thin layer chromatography developing system including: A: Dichloromethane / methanol system, B: n-hexane / ethyl acetate system, the volume ratio of the solvent is adjusted according to the polarity of the compound, and it can also be adjusted by adding a small amount of basic or acidic reagents such as triethylamine and acetic acid.
  • TLC thin layer chromatography
  • A Dichloromethane / methanol system
  • B n-hexane / ethyl acetate system
  • the volume ratio of the solvent is adjusted according to the polarity of the compound, and it can also be adjusted by adding a small amount of basic or acidic reagents such as triethylamine and acetic acid.
  • SGF is a simulated gastric juice.
  • the preparation method is: take 2.0g of sodium chloride, add 7.0mL of hydrochloric acid and water to dissolve it to 1000mL, and get it.
  • FaSSIF solution is the intestinal fluid in the small intestine under simulated pre-prandial hunger.
  • Preparation method Solution (A): Add 4.441g NaH2PO4 ⁇ 2H 2 O, 0.348g NaOH particles and 6.186g NaCl in 900mL ultrapure water, mix well, 1M NaOH was added to adjust the pH of the solution to 6.5 ⁇ 0.05, and the volume was adjusted to 1000 mL with water.
  • FeSSIF solution is the intestinal fluid in the small intestine that simulates the postprandial satiety of humans.
  • Preparation method Solution (A): Weigh accurately 20.2g NaOH particles, 43.25g glacial acetic acid and 59.37g sodium chloride. Make up to 5L and adjust the pH to 5.0 with 1M NaOH or 1M HCl. Refrigerate at 4 ° C until use;
  • 6-bromo-8-fluoroquinoline 1a (226 mg, 1.00 mmol), bis (pinacol) diboron (305 mg, 1.20 mmol), and [1,1'-bis (diphenyl) were added in this order.
  • Phosphino) ferrocene] palladium dichloride (146 mg, 0.20 mmol) and potassium acetate (294 mg, 3.00 mmol) were dissolved in 10 mL of ethylene glycol dimethyl ether solution, heated to 80 ° C., and stirred for 12 hours. The reaction was stopped, cooled to room temperature, filtered, and the filtrate was distilled under reduced pressure. The residue was purified with a CombiFlash rapid preparation device with eluent system B to obtain the title product 1b (220 mg), yield: 80.1%.
  • the compounds of formula (1) inhibitory activity against the adenosine A 2a receptor, adenosine A 1 receptor (adenosine A 1 receptor, A 1 R) cAMP signaling pathway, and adenosine A 3 receptor cAMP signaling pathway.
  • CHO-K1 / A 2a R cells were cultured in DMEM / F12 medium containing 10% fetal bovine serum and 800 ⁇ g / mL bleomycin.
  • buffer cells were digested with balanced salt buffer containing 20mM HEPES and 0.1% bovine serum albumin and resuspend the cells counted, and adjusted to a cell density of 10 6 / mL.
  • test compounds were incubated for 30 minutes at room temperature. Add 2.5 ⁇ L of 4 ⁇ concentration ethylcarbazole in a balanced salt buffer containing 20 mM HEPES, 0.1% bovine serum albumin, 54 ⁇ M rolipram and 2.7 U / mL adenosine deaminase in each well, and incubate at room temperature. 30 minutes. The final compound concentration was: 10,000, 2000, 400, 80, 16, 3.2, 0.64, 0.128, 0.0256, 0.00512, 0.001024 nM, and the final ethylcarbazole concentration was 20 nM. Intracellular cAMP concentration was measured using the cAMP Dynamic 2 kit.
  • the HTRF signal value was read using a PHERAstar multifunctional microplate reader. Calculated using Graphpad Prism software compound to inhibit the activity of IC 50 values.
  • CHO-K1 / A 1 R was cultured in DMEM / F12 medium containing 10% fetal bovine serum and 1 mg / mL G418. During the experiment, the cells were digested with cell isolation buffer, and then the cells were resuspended and counted with a balanced salt buffer containing 20 mM HEPES and 0.1% bovine serum albumin, and the cell density was adjusted to 5 ⁇ 10 5 cells / mL.
  • Amyl adenosine incubated for 30 minutes at room temperature.
  • the final compound concentrations were: 100,000, 10000, 1000, 100, 10, 1, 0.1, and 0 nM, the final concentration of forskolin was 10 ⁇ M, and the final concentration of CPA was 10 nM.
  • Intracellular cAMP concentration was measured using the cAMP Dynamic 2 kit. Dilute cAMP-d2 and anti-cAMP-Eu-cryptic compound with cAMP lysis buffer at a ratio of 1: 4. Add 12.5 ⁇ L of diluted cAMP-d2 to each well, then add 12.5 ⁇ L of diluted anti-cAMP-Eu-cryptic compound, and incubate for 1 hour at room temperature in the dark. The HTRF signal value was read using a PHERAstar multifunctional microplate reader. Calculated using Graphpad Prism software compound to inhibit the activity of IC 50 values.
  • CHO-K1 / A 3 R was cultured in DMEM / F12 medium containing 10% fetal bovine serum and 10 ⁇ g / mL puromycin. During the experiment, the cells were digested with cell separation buffer, and the cells were resuspended and counted with a balanced salt buffer containing 20 mM HEPES and 0.1% bovine serum albumin, and the cell density was adjusted to 5 ⁇ 10 5 / mL.
  • cAMP Dynamic 2 kit Dilute cAMP-d2 and anti-cAMP-Eu-cryptic compound with cAMP lysis buffer at a ratio of 1: 4. Add 12.5 ⁇ L of diluted cAMP-d2 to each well, and then add 12.5 ⁇ L of diluted anti-cAMP-Eu-cryptic compound, and incubate for 1 hour at room temperature in the dark.
  • the HTRF signal value was read using a PHERAstar multifunctional microplate reader. Calculated using Graphpad Prism software compound to inhibit the activity of IC 50 values.
  • Test animals 9 C57 mice, female, purchased from Shanghai Jiesijie Experimental Animal Co., Ltd., animal production license number: SCXK (Shanghai) 2013-0006.
  • Drug preparation Weigh out a certain amount of drug, add 5% volume of DMSO, 5% volume of tween80 and 90% physiological saline to configure 0.1mg / mL colorless and clear liquid.
  • mice were administered orally after fasting overnight.
  • the administration dose was 2.0 mg / kg, and the administration volume was 0.2 mL / 10 g.
  • mice were administered by gavage. 0.1 mL of blood was collected before and after 0.5, 1.0, 2.0, 4.0, 6.0, 8.0, 11.0, and 24.0 hours after administration. The blood was collected in a heparinized test tube and centrifuged at 3500 rpm for 10 minutes. The plasma was separated in minutes and stored at -20 ° C.
  • the crude product was dissolved in 20 mL of dichloromethane, beaten, and the reaction solution was filtered, and the filter cake was collected.
  • the filter cake was collected and dried under vacuum to obtain the product (2 g).
  • the product was defined as Form A, and the XRPD spectrum is shown in Figure 1.
  • the DSC spectrum is shown in Figure 2.
  • the peak values of the endothermic peaks are 230.97 ° C, 238.04 ° C, and there are small exothermic peaks at about 170 ° C.
  • the sample was heated to 150 ° C and 190 ° C in DSC, and the detection crystal forms were taken out, respectively. After the peak, the crystal form changed to the B crystal form, as shown in FIG. 3.
  • the TGA map is shown in Figure 4.
  • DVS characterization A crystal sample is stable in moisture absorption at 25 °C; according to the relative mass change curve, between 10% RH and 80% RH, with the increase of humidity, the mass increase is about 0.3805%, less than 2% But not less than 0.2%. According to the 2015 Pharmacopoeia Guidelines for Drug Hygroscopicity Test, the sample is slightly hygroscopic. Under normal storage conditions (ie, 25 ° C, 60% humidity), water absorption is about 0.2935%; under accelerated test conditions (ie, humidity 70%), water absorption is about 0.3508%; under extreme conditions (ie, humidity 90%), water absorption is about 0.5340%.
  • Peak 12 19.660 4.51193 0.5 Peak 13 21.624 4.10641 17.0 Peak 14 23.458 3.78928 4.9 Peak 15 24.139 3.68389 0.8 Peak 16 25.412 3.50219 8.2 Peak 17 26.496 3.36132 10.5 Peak 18 29.398 3.03575 11.1 Peak 19 31.981 2.79625 0.6 Peak 20 33.576 2.66696 1.4
  • the reaction solution was filtered, and the filter cake was collected and dried under vacuum to obtain the product (26 mg).
  • the product was found to be in Form A by X-ray powder diffraction.
  • the compound of formula (1) (1.2 g) was dissolved in 30 mL of acetonitrile, stirred at room temperature and heated to 70 ° C, dissolved and stirred for 30 minutes, the program was cooled, and then stirred at room temperature for 17 hours. The reaction solution was filtered and the filter cake was collected. And dried in vacuo to give the product (876 mg).
  • the compound (30 g) of formula (1) was prepared by high-performance liquid phase (Waters 2767-SQ, elution system (ammonium acetate, water, acetonitrile)), and the reaction solution was filtered. The filter cake was collected and dried under vacuum to obtain the product (15 g). .
  • the product was defined as Form B, and the XRPD spectrum is shown in FIG. 7.
  • the DSC spectrum is shown in Figure 8.
  • the endothermic peaks are 231.03 ° C and 237.78 ° C.
  • the sample was heated to 150 ° C and 190 ° C in DSC, and the detection crystal forms were taken out, but none were transformed, as shown in Figure 9.
  • the TGA map is shown in Figure 10.
  • the PSD map is shown in Figure 11.
  • Sample B crystal starts to absorb moisture quickly at P / P0 at 25 °C; according to the relative mass change curve, between 10% RH and 80% RH, with the increase of humidity, the mass increases by about 0.4010 %, Less than 2% but not less than 0.2%.
  • this sample is slightly hygroscopic. Under normal storage conditions (ie, 25 ° C, 60% humidity), water absorption is about 0.2150%; under accelerated test conditions (ie, humidity 70%), water absorption is about 0.283%; under extreme conditions (ie, humidity 90%), water absorption is about 0.760%.
  • the desorption process of the sample and the adsorption process basically coincide (see Figure 12); the X-ray powder diffraction comparison chart before and after DVS shows that the crystal form has not changed before and after DVS detection (see figure 13).
  • Peak 1 6.212 14.21684 8.70 Peak 2 7.815 11.30386 100.00 Peak 3 8.657 10.20554 9.80 Peak 4 10.723 8.24404 2.60 Peak 5 11.654 7.58756 2.90 Peak 6 12.972 6.81916 9.30 Peak 7 14.272 6.20102 17.10 Peak 8 15.835 5.59213 10.20 Peak 9 17.655 5.01967 8.60 Peak 10 18.342 4.83299 8.20 Peak 11 19.448 4.56058 9.00 Peak 12 21.283 4.17128 3.40 Peak 13 22.273 3.98814 50.10 Peak 14 22.353 3.97414 43.40 Peak 15 23.915 3.71784 7.90 Peak 16 24.864 3.57805 63.20 Peak 17 26.562 3.35306 5.80 Peak 18 27.601 3.22925 28.90 Peak 19 32.485 2.75397 3.10
  • the compound of formula (1) (50 mg) was dissolved in 2 mL of methanol, and the solution was stirred at room temperature to remove the solution. The filtrate was filtered, and the filtrate was naturally evaporated for 60 hours to precipitate a solid. The reaction solution was filtered, and the filter cake was collected and dried under vacuum to obtain the product (23 mg). The product was in the B-form by X-ray powder diffraction detection.
  • the compound of formula (1) (50 mg) was dissolved in 2 mL of acetone, stirred at room temperature for undissolved, heated to 70 ° C., dissolved and stirred for 30 minutes, the program was cooled, and the room temperature was stirred for 17 hours to precipitate a solid.
  • the reaction solution was filtered, and the filter cake was collected and dried under vacuum to obtain the product (26 mg).
  • the product was in the B-form by X-ray powder diffraction detection.
  • the compound of formula (1) (200 mg) was dissolved in 25 mL of tetrahydrofuran, heated to 60 ° C., dissolved and stirred for 30 minutes, slowly lowered to room temperature, and continued stirring for 17 hours. The reaction solution was filtered, and the filter cake was collected and dried under vacuum to obtain the product (123 mg).
  • the product was defined as the crystal form C, and the XRPD spectrum is shown in FIG. 14.
  • the DSC spectrum is shown in Fig. 15, and the endothermic peaks are 145.52 ° C, 231.45 ° C, and 238.60 ° C.
  • the TGA pattern is shown in Figure 16, with a weight loss of 9.0743% between 40 ° C and 150 ° C.
  • the 1 H-NMR data of the obtained product are shown below.
  • the nuclear magnetic data showed that the molar ratio of the main component to tetrahydrofuran in the salt was 1: 0.36, and the weight content of tetrahydrofuran was 7.6%.
  • Peak 1 8.168 10.81645 90.7 Peak 2 11.733 7.53656 6.5 Peak 3 12.178 7.26187 7.9 Peak 4 12.660 6.98640 5.4 Peak 5 13.923 6.35558 7.1 Peak 6 16.543 5.35430 20.2 Peak 7 17.658 5.01878 26.4 Peak 8 19.774 4.48612 18.8 Peak 9 21.003 4.22625 40.4 Peak 10 21.982 4.04027 7.2 Peak 11 23.319 3.81165 30.5 Peak 12 23.673 3.75541 3.5 Peak 13 24.995 3.55961 100.0 Peak 14 26.137 3.40662 2.0 Peak 15 27.799 3.20666 3.1 Peak 16 28.419 3.13808 15.2 Peak 17 30.947 2.88726 5.5 Peak 18 31.817 2.81025 2.5
  • the compound of formula (1) (200 mg) was dissolved in 30 mL of dichloroethane, heated to 60 ° C., dissolved and stirred for 30 minutes, slowly lowered to room temperature, and continued stirring for 17 hours. The reaction solution was filtered, and the filter cake was collected and dried under vacuum to obtain the product (117 mg).
  • the product was defined as the D crystal form, and the XRPD is shown in FIG. 17.
  • the DSC spectrum is shown in Fig. 18, which shows that the peak value of the endothermic peak is 238.18 ° C.
  • the TGA chart is shown in Figure 19, with a weight loss of 11.7726% between 40 ° C and 180 ° C.
  • the compound of formula (1) (1.2 g) was dissolved in 30 mL of methanol, and the solution was stirred at room temperature, heated to 70 ° C, and 10 ml of dichloromethane was added to the solution, and the mixture was stirred for 30 minutes. The temperature was lowered and the solution was stirred at room temperature for 17 hours. The reaction solution was filtered, and the filter cake was collected and dried under vacuum to obtain the product (838 mg).
  • the product was defined as the E form, and the XRPD spectrum is shown in FIG. 20.
  • the DSC spectrum is shown in Figure 21, which shows that the endothermic peaks are 232.02 ° C, 239.26 ° C.
  • the TGA pattern is shown in Figure 22, with a weight loss of 1.8556% between 40 ° C and 140 ° C.
  • Peak 1 8.262 10.69369 100.0 Peak 2 12.398 7.13362 1.6 Peak 3 13.080 6.76330 1.1 Peak 4 16.792 5.27561 12.4 Peak 5 20.417 4.34630 0.8 Peak 6 21.344 4.15963 2.5 Peak 7 22.819 3.89394 0.6 Peak 8 23.929 3.71577 2.6
  • Peak 9 25.347 3.51104 24.4 Peak 10 28.760 3.10160 1.1 Peak 11 29.104 3.06578 0.6
  • the compound (50 mg) of the formula (1) was dissolved in 2 mL of 1,4-dioxane, and the solution was stirred at room temperature to be undissolved, filtered through a filter, and naturally evaporated for 60 hours to precipitate a solid. The reaction solution was filtered, and the filter cake was collected and dried under vacuum to obtain the product (23 mg).
  • Peak 1 5.717 15.44599 1.7 Peak 2 8.081 10.93253 64.1 Peak 3 9.022 9.79375 5.4 Peak 4 11.645 7.59299 6.2 Peak 5 12.581 7.03009 4.4 Peak 6 13.837 6.39461 14.7 Peak 7 16.514 5.36381 11.2 Peak 8 17.700 5.00690 27.8 Peak 9 19.758 4.48987 13.6 Peak 10 20.953 4.23639 11.3 Peak 11 21.859 4.06272 4.4 Peak 12 23.039 3.85727 17.0 Peak 13 23.640 3.76061 30.2 Peak 14 24.777 3.59043 100.0 Peak 15 26.164 3.40318 4.4
  • Form E (5 mg) was ground for 30 minutes to obtain the product. After X-ray powder diffraction detection, the product was defined as the G crystal form.
  • Peak 1 7.877 11.21512 27.0 Peak 2 8.328 10.60847 100.0 Peak 3 8.462 10.44103 61.3 Peak 4 12.457 7.09981 13.9 Peak 5 13.115 6.74512 9.1 Peak 6 14.324 6.17838 4.8 Peak 7 16.201 5.46669 5.3 Peak 8 16.866 5.25270 18.4 Peak 9 18.034 4.91494 7.3 Peak 10 19.575 4.53138 5.8 Peak 11 20.453 4.33874 9.3 Peak 12 21.399 4.14896 23.6 Peak 13 22.293 3.98454 27.4 Peak 14 22.502 3.94800 20.9 Peak 15 23.974 3.70887 26.9 Peak 16 24.868 3.57758 31.2 Peak 17 25.439 3.49848 44.6
  • Peak 18 26.460 3.36586 3.5 Peak 19 27.617 3.22734 24.2 Peak 20 28.820 3.09528 7.9 Peak 21 29.199 3.05597 7.3 Peak 22 31.766 2.81465 3.2
  • Example 16 mixed crystal slurry
  • Form A 150 mg
  • Form B 150 mg
  • the reaction solution was filtered, and the filter cake was collected and dried under vacuum to obtain the product (266 mg).
  • the product was defined as the H crystal form, and the XRPD spectrum is shown in FIG. 25.
  • the DSC spectrum is shown in Fig. 26, and the endothermic peaks are 110 ° C, 230 ° C, and 240 ° C.
  • the TGA map is shown in Figure 27.
  • Form B (20 mg) and Form H (20 mg) were dissolved in 2 mL of acetone and mixed for 24 hours.
  • the reaction solution was filtered, and the filter cake was collected and dried under vacuum to obtain the product (33 mg).
  • the product was in the H crystal form by X-ray powder diffraction.
  • Form A 150 mg
  • Form B 150 mg
  • the reaction solution was filtered, and the filter cake was collected and dried under vacuum to obtain the product (269 mg).
  • the product was defined as the J form, and the XRPD spectrum is shown in FIG. 28.
  • the DSC spectrum is shown in Fig. 29, and the endothermic peaks are 108.43 ° C, 227.41 ° C, and 238.51 ° C.
  • the TGA chart is shown in Figure 30, with a weight loss of 11.422% between 40 ° C and 150 ° C.
  • Peak 12 24.484 3.63273 31.2 Peak 13 26.059 3.41666 43.2 Peak 14 27.140 3.28295 1.9 Peak 15 28.875 3.08954 4.6 Peak 16 33.718 2.65605 5.0
  • Form B (20 mg) and Form J (20 mg) were dissolved in 2 mL of ethyl acetate and mixed for 24 hours.
  • the reaction solution was filtered, and the filter cake was collected and dried under vacuum to obtain the product (33 mg).
  • the product was in the J-form by X-ray powder diffraction detection.
  • Form A (20 mg) and Form B (20 mg) were dissolved in 3 mL of isopropanol and mixed for 24 hours. Take 1 mL of the reaction solution for filtration, collect the filter cake, and dry it in vacuo to obtain the product (8 mg). The remaining reaction solution is continued to be slurried for 24 hours. The filter cake is collected and dried in vacuo to obtain the product (23 mg). A total of 31 mg of product is obtained.
  • X-ray powder diffraction detection the products obtained in both parts were in the B crystal form.
  • Form A (20 mg) and Form B (20 mg) were dissolved in 3 mL of isopropyl ether and mixed for 24 hours.
  • the reaction solution was filtered, and the filter cake was collected and dried under vacuum to obtain the product (35 mg).
  • the product was in the B-form by X-ray powder diffraction detection.
  • Form B (10 g) and Form B (10 g) of two different batches were dissolved in 30 mL of n-hexane and mixed for 1 hour.
  • the reaction solution was filtered, and the filter cake was collected and dried under vacuum to obtain the product (14.5 g).
  • the product was in the B-form by X-ray powder diffraction detection.
  • the crystal form sample of the compound B of the formula (1) obtained by the present invention is further evaluated for its solubility in FaSSIF, SGF, water, and Fessif solutions. After the solubility test, the supersaturated sample is recovered to detect the crystal form.
  • Form A and Form B of the compound of formula (1) are placed flat and open, and the samples are examined under the conditions of light (4500 Lux), high temperature (40 ° C, 60 ° C), and high humidity (RH 75%, RH 90%). Stability, the sampling inspection period is 30 days.
  • the A and B samples Under high temperature and high humidity conditions, the A and B samples have good chemical stability. After being left for 30 days under light, samples of Form A and Form B were slightly degraded. After the samples were left for 30 days, the re-testing of the crystalline forms did not change, and the physical stability was good. The above results show that the light has a slight effect on the A and B forms. It is recommended that the A and B forms be stored in a cool place under sealed conditions. Both forms have good physical and chemical stability.

Abstract

Provided are polymorphs of a 1,2,4-triazine-3-amine derivative and a preparation method therefor. Specifically, provided are polymorphs A, B, C, D, E, F, G, H, and J of a compound represented by formula (1) and a preparation method therefor. The polymorphs of the compound represented by formula (1) have good polymorph stability, and can be better used in clinical practice. (I)

Description

一种1,2,4-三嗪-3-胺类衍生物的晶型及制备方法Crystal form of 1,2,4-triazine-3-amine derivatives and preparation method thereof
本申请要求申请日为2018年7月13日的中国专利申请CN201810767419.8的优先权。本申请引用上述中国专利申请的全文。This application claims the priority of Chinese patent application CN201810767419.8 with a filing date of July 13, 2018. This application cites the full text of the aforementioned Chinese patent application.
技术领域Technical field
本发明属于药物化学领域，涉及6-(8-氟喹啉-6-基)-5-苯基-1,2,4-三嗪-3-胺的A、B、C、D、E、F、G、H、J晶型及制备方法。The invention belongs to the field of medicinal chemistry and relates to A, B, C, D, E, 6- (8-fluoroquinolin-6-yl) -5-phenyl-1,2,4-triazin-3-amine, F, G, H, J crystal forms and preparation methods.
背景技术Background technique
腺苷是天然存在的嘌呤核苷，是许多生理功能的内源性调节剂。在心血管***、中枢神经、呼吸***、肾脏、脂肪和血小板的功能调节中发挥重要作用。Adenosine is a naturally occurring purine nucleoside and is an endogenous regulator of many physiological functions. It plays an important role in the regulation of the cardiovascular system, central nervous system, respiratory system, kidney, fat and platelets.
腺苷的作用由G蛋白偶联受体家族介导，目前已知至少有四种亚型的腺苷受体，分类为A 1、A 2a、A 2b和A 3。其中A 1和A 3受体抑制酶腺苷酸环化酶的活性，而A 2a和A 2b受体刺激该酶的活性，由此调节细胞中环AMP水平，通过这些受体，腺苷调节广泛的生理功能。 Adenosine by G protein-coupled receptor family, are known to have at least four subtypes of adenosine receptors, classified as A 1, A 2a, A 2b and A 3. Among them, A 1 and A 3 receptors inhibit the activity of the enzyme adenylate cyclase, and A 2a and A 2b receptors stimulate the activity of the enzyme, thereby regulating the level of cyclic AMP in cells. Through these receptors, adenosine is widely regulated Physiological function.
A 2a受体(A 2aR)在机体分布较为广泛，在中枢神经***主要表达于纹状体，在外周、心、肝、肺、肾等组织也均有表达。数个临床前研究表明，腺苷A 2a受体拮抗剂对于治疗神经变性疾病，主要是帕金森病、亨廷顿病或阿尔茨海默病具有惊人疗效(Trends in Neurosci.2006,29(11),647-654；Expert Opinion on Therapeutic Patents,2007,17,979-991等)。而且也可以用于治疗其他中枢神经***(CNS)相关的疾病例如抑郁、多动综合征、睡眠障碍和焦虑症(Clin.Neuropharmacol.2010,33,55-60；J.Neurosci.2010,30(48),16284-16292；Parkinsonisn Relat.Disord.2010,16(6),423-426；及其中的参考献:Mov.Disorders,2010,25(2),S305)。此外腺苷A 2a受体拮抗剂还具有作为神经保护剂的治疗潜力(参见Jenner P.J Neuro l.2000；24 7Supp12:1143-50)。 A 2a receptor (A 2a R) is widely distributed in the body, mainly expressed in the striatum in the central nervous system, and also expressed in peripheral, heart, liver, lung, kidney and other tissues. Several preclinical studies have shown that adenosine A 2a receptor antagonists have amazing effects on the treatment of neurodegenerative diseases, mainly Parkinson's disease, Huntington's disease or Alzheimer's disease (Trends in Neurosci. 2006, 29 (11), 647-654; Expert Opinion on Therapeutic Patents, 2007, 17, 979-991, etc.). It can also be used to treat other central nervous system (CNS) related diseases such as depression, hyperactivity syndrome, sleep disorders and anxiety (Clin. Neuropharmacol. 2010, 33, 55-60; J. Neurosci. 2010, 30 ( 48), 16284-16292; Parkinsonisn Relat. Disord. 2010, 16 (6), 423-426; and references therein: Mov. Disorders, 2010, 25 (2), S305). In addition, adenosine A 2a receptor antagonists have therapeutic potential as neuroprotective agents (see Jenner PJ Neuro 1.2000; 24 7Supp 12: 1143-50).
近来研究表明，在缺血低氧、炎症、创伤、移植等诸多病理过程中，腺苷A 2a受体的激活可以发挥重要的免疫调节作用，这可能与A 2a受体在T细胞、B细胞、单核巨噬细胞、中性粒细胞等多种免疫细胞上表达水平较高有关。此外，A 2a受体的活化可以促使机体产生免疫耐受，密切参与了肿瘤细胞“免疫逃逸”或“免疫抑制”的形成，为肿瘤的发生发展创造了有利条件。Lokshin及其同事(Cancer Res.2006 Aug 1；66(15):7758-65)证实自然杀伤细胞上的A 2aR活化可以通过升高cAMP，激活PKA抑制自然杀伤细胞对肿瘤细胞的杀伤。还有研究表明，激活A 2a受体的活化可以促进黑色素瘤A375细胞、成纤维瘤NIH3T3 细胞及嗜铬细胞瘤PC12细胞等肿瘤细胞的增殖，其可能与T细胞上A 2a受体的活化可以抑制T细胞活化、增殖、与肿瘤细胞的黏附及对肿瘤细胞产生细胞毒性作用相关；而A 2a受体基因敲除的小鼠则可以加强CD8 +T细胞抗肿瘤的免疫作用,显著抑制肿瘤的增殖。因此，A 2a受体拮抗剂可用于肿瘤的治疗。Deepak Mittal等人研究发现，A 2b受体抑制剂与化疗药物或免疫检查点抑制剂联用可以显著降低小鼠三阴性乳腺癌模型中的肿瘤转移；敲除小鼠体内或人结肠癌细胞系中的A 2b受体显著降低结肠癌的转移和细胞的成瘤性；同时，研究发现A 2b受体在人三阴性乳腺癌细胞系中高表达，且A 2b受体的表达程度与肿瘤进展密切相关。这些结果均表明，抑制A 2b受体可抑制肿瘤的转移，因此A 2b受体有望成为***的一个理想靶点(Cancer Res.2016 Aug 1；76(15):4372-82)。研究A 2a受体和A 2b受体双抑制剂也成为一个值得探索的方向。 Recent studies have shown that activation of adenosine A 2a receptors can play an important role in immune regulation during ischemic hypoxia, inflammation, trauma, transplantation and many other pathological processes, which may be related to A 2a receptors in T cells and B cells. , Monocyte macrophages, neutrophils and other immune cells have higher expression levels. In addition, the activation of A 2a receptors can promote immune tolerance in the body, which is closely involved in the formation of tumor cells' immune escape or immunosuppression, creating favorable conditions for the development of tumors. Lokshin and colleagues (Cancer Res. 2006 Aug 1; 66 (15): 7758-65) confirmed that A 2a R activation on natural killer cells can inhibit cTA's killing of tumor cells by increasing cAMP and activating PKA. Other studies have shown that the activation of A 2a receptors can promote the proliferation of melanoma A375 cells, fibroblasts NIH3T3 cells, and pheochromocytoma PC12 cells, which may be related to the activation of A 2a receptors on T cells. Inhibition of T cell activation and proliferation is associated with tumor cell adhesion and cytotoxic effects on tumor cells; mice with A 2a receptor gene knockout can strengthen the anti-tumor immune effect of CD8 + T cells and significantly inhibit the tumor proliferation. Therefore, A 2a receptor antagonists can be used in the treatment of tumors. Deepak Mittal et al. Found that A 2b receptor inhibitors combined with chemotherapeutic drugs or immune checkpoint inhibitors can significantly reduce tumor metastasis in mouse triple negative breast cancer models; knockout mice or human colon cancer cell lines A 2b receptors in colon cancer significantly reduce colon cancer metastasis and cell tumorigenicity; at the same time, studies have found that A 2b receptors are highly expressed in human triple-negative breast cancer cell lines, and the expression of A 2b receptors is closely related to tumor progression Related. These results indicate that inhibition of A 2b receptors can inhibit tumor metastasis, so A 2b receptors are expected to be an ideal target for treating tumors (Cancer Res. 2016 Aug 1; 76 (15): 4372-82). The study of A 2a receptor and A 2b receptor dual inhibitors has also become a direction worth exploring.
尽管对多种腺苷受体亚型具有显著生物学活性的化合物可具有治疗作用，但它们可导致不想要的副作用。例如腺苷A 1受体在组织缺血/缺氧时，在中枢、循环、消化***和骨骼肌中，细胞在处于缺氧和低氧的应激环境时，胞外聚集的腺苷通过激活胞膜上的A 1受体启动相应的保护机制，从而增加细胞对缺氧低氧的耐受。位于免疫细胞上的A 1受体在低氧环境中能促进细胞免疫应答。另外，A 1受体还能降低游离脂肪酸和甘油三酯，参与调节血糖。因此，A 1受体的持续阻断可能会引起机体组织中各种不良反应的发生(Chinese Pharmacological Bulletin,2008,24(5),573-576)。如有文献报道，在动物模型上，阻断A 1受体将会产生焦虑、觉醒等不良反应(Basic&Clinical Pharmacology&Toxicology,2011,109(3),203-7)。腺苷A 3受体(如Gessi S等人，Pharmacol.Ther.117(1),2008,123-140所述)在心肌缺血期间释放的腺苷在心脏中发挥强力的保护作用，A 3受体的持续阻断可能增加由任何预先存在的或正在发展的缺血性心脏病引起的并发症的可能性，所述缺血性心脏病诸如心绞痛或心衰。 Although compounds that have significant biological activity on a variety of adenosine receptor subtypes can have therapeutic effects, they can cause unwanted side effects. For example, when adenosine A 1 receptor is in tissue ischemia / hypoxia, in the central, circulatory, digestive system, and skeletal muscle, when cells are in a hypoxic and hypoxic stress environment, extracellular adenosine accumulates through activation The A 1 receptor on the cell membrane activates the corresponding protective mechanism, thereby increasing the cell's tolerance to hypoxia and hypoxia. Located on the immune cells in a hypoxic environment A 1 receptor can promote the cellular immune response. In addition, the A 1 receptor can also reduce free fatty acids and triglycerides and participate in regulating blood sugar. Therefore, continuous blockade of the A 1 receptor may cause various adverse reactions in the body tissues (Chinese Pharmacological Bulletin, 2008, 24 (5), 573-576). If it is reported in the literature, blocking A 1 receptors will cause adverse reactions such as anxiety and awakening in animal models (Basic & Clinical Pharmacology & Toxicology, 2011, 109 (3), 203-7). Adenosine A 3 receptor (as described by Gessi S et al., Pharmacol. Ther. 117 (1), 2008, 123-140) adenosine released during myocardial ischemia plays a strong protective role in the heart, A 3 Continuous blockade of the receptor may increase the likelihood of complications caused by any pre-existing or developing ischemic heart disease, such as angina pectoris or heart failure.
目前，已有许多化合物被开发为A 2a受体的拮抗剂用于治疗很多疾病，如WO2007116106、WO2009080197、WO2011159302、WO2011095625、WO2014101373、WO2015031221中所述。 Currently, many compounds have been developed as antagonists of the A 2a receptor for the treatment of many diseases, as described in WO2007116106, WO2009080197, WO2011159302, WO2011095625, WO2014101373, WO2015031221.
申请号为PCT/CN2018/072308(申请日2018年1月12日)的申请中描述了一种腺苷A 2a受体拮抗剂，结构如下所示： An application with the application number PCT / CN2018 / 072308 (application date: January 12, 2018) describes an adenosine A 2a receptor antagonist with the following structure:
Figure PCTCN2019095724-appb-000001
Figure PCTCN2019095724-appb-000001
作为药用活性成分的晶型往往影响到该药物的化学稳定性，结晶条件及储存条件的不同有可能导致化合物的晶型结构的变化，有时还会伴随着产生其他形态的晶型。一般来说，无定形的药物产品没有规则的晶型结构，往往具有其它缺陷，比如产物稳定性较差，析晶较细，过滤较难，易结块，流动性差等。药物的多晶型对产品储存、生产及放大有不同的要求。因此，深入研究式(1)化合物的晶型，改善式(1)化合物的各方面性质是很有必要的。The crystalline form as a medicinal active ingredient often affects the chemical stability of the drug. Differences in crystallization conditions and storage conditions may cause changes in the crystalline structure of the compound, sometimes accompanied by the generation of other forms. In general, amorphous pharmaceutical products do not have a regular crystalline structure and often have other defects, such as poor product stability, fine crystallization, difficult filtration, easy agglomeration, and poor fluidity. Polymorphic forms of drugs have different requirements for product storage, production, and scale-up. Therefore, it is necessary to further study the crystal form of the compound of formula (1) and improve various aspects of the compound of formula (1).
发明内容Summary of the invention
本发明提供式(1)化合物的A晶型、B晶型、C晶型、D晶型、E晶型、F晶型、G晶型、H晶型、J晶型及其制备方法，本发明的晶型具备良好的晶型稳定性。The present invention provides A-form, B-form, C-form, D-form, E-form, F-form, G-form, H-form, J-form of a compound of formula (1), and a preparation method thereof. The crystal form of the invention has good crystal form stability.
本发明提供一种式(1)化合物的A晶型，其特征在于，A晶型的X-射线粉末衍射图谱，在衍射角2θ为8.697、13.216、17.581、18.245、21.624、23.458处有特征峰。The present invention provides a crystal form A of the compound of formula (1), which is characterized in that the X-ray powder diffraction pattern of crystal form A has characteristic peaks at diffraction angles 2θ of 8.697, 13.216, 17.581, 18.245, 21.624, 23.458. .
进一步地，所述A晶型的X-射线粉末衍射图谱，在衍射角2θ为8.697、13.216、17.581、18.245、21.624、23.458、25.412、26.496、29.398、31.981、33.576处有特征峰。Further, the X-ray powder diffraction pattern of the form A has characteristic peaks at diffraction angles 2θ of 8.697, 13.216, 17.581, 18.245, 21.624, 23.458, 25.412, 26.496, 29.398, 31.981, 33.576.
更进一步地，所述A晶型的X-射线粉末衍射图谱，在衍射角2θ为8.019、8.697、11.846、13.216、13.521、15.602、16.033、16.658、16.968、17.581、18.245、19.660、21.624、23.458、24.139、25.412、26.496、29.398、31.981、33.576处有特征峰。Furthermore, the X-ray powder diffraction pattern of the crystal form A has a diffraction angle 2θ of 8.019, 8.697, 11.846, 13.216, 13.521, 15.602, 16.033, 16.658, 16.968, 17.581, 18.245, 19.660, 21.624, 23.458, There are characteristic peaks at 24.139, 25.412, 26.496, 29.398, 31.981, and 33.576.
本发明提供一种式(1)化合物的B晶型，其特征在于，B晶型的X-射线粉末衍射图谱，在衍射角2θ为7.815、12.972、14.272、15.835、17.655、19.448、22.273处有特征峰。The present invention provides a crystal form B of a compound of formula (1), which is characterized in that the X-ray powder diffraction pattern of crystal form B has a diffraction angle 2θ of 7.815, 12.972, 14.272, 15.835, 17.655, 19.448, 22.273. Characteristic peaks.
进一步地，所述B晶型的X-射线粉末衍射图谱，在衍射角2θ为7.815、12.972、14.272、15.835、17.655、19.448、22.273、24.864、27.601处有特征峰。Further, the X-ray powder diffraction pattern of the B-form has a characteristic peak at a diffraction angle 2θ of 7.815, 12.972, 14.272, 15.835, 17.655, 19.448, 22.273, 24.864, 27.601.
更进一步地，所述B晶型的X-射线粉末衍射图谱，在衍射角2θ为6.212、7.815、8.657、10.723、11.654、12.972、14.272、15.835、17.655、18.342、19.448、21.283、22.273、22.353、23.915、24.864、26.562、27.601、32.485处有特征峰。Furthermore, the X-ray powder diffraction pattern of the B-form has a diffraction angle 2θ of 6.212, 7.815, 8.657, 10.723, 11.654, 12.972, 14.272, 15.835, 17.655, 18.342, 19.448, 21.283, 22.273, 22.353, There are characteristic peaks at 23.915, 24.864, 26.562, 27.601, and 32.485.
本发明提供一种式(1)化合物的C晶型，其特征在于，C晶型的X-射线粉末衍射图谱，在衍射角2θ为8.168、16.543、17.658、19.774、21.003、23.319处有特征峰。The present invention provides a crystal form C of a compound of formula (1), which is characterized in that the X-ray powder diffraction pattern of the crystal form C has characteristic peaks at diffraction angles 2θ of 8.168, 16.543, 17.658, 19.774, 21.003, 23.319. .
进一步地，所述C晶型的X-射线粉末衍射图谱，在衍射角2θ为8.168、11.733、12.178、12.660、13.923、16.543、17.658、19.774、21.003、23.319、24.995、28.419处有特征峰。Further, the X-ray powder diffraction pattern of the crystal form C has characteristic peaks at diffraction angles 2θ of 8.168, 11.733, 12.178, 12.660, 13.923, 16.543, 17.658, 19.774, 21.003, 23.319, 24.995, 28.419.
更进一步地，所述C晶型的X-射线粉末衍射图谱，在衍射角2θ为8.168、11.733、12.178、12.660、13.923、16.543、17.658、19.774、21.003、21.982、23.319、23.673、24.995、 26.137、27.799、28.419、30.947、31.817处有特征峰。Furthermore, the X-ray powder diffraction pattern of the C form has a diffraction angle 2θ of 8.168, 11.733, 12.178, 12.660, 13.923, 16.543, 17.658, 19.774, 21.003, 21.982, 23.319, 23.673, 24.995, 26.137, There are characteristic peaks at 27.799, 28.419, 30.947, and 31.817.
本发明提供一种式(1)化合物的D晶型，其特征在于，D晶型的X-射线粉末衍射图谱，在衍射角2θ为8.122、12.200、20.179、24.973、27.303处有特征峰。The invention provides a D crystal form of the compound of formula (1), which is characterized in that the X-ray powder diffraction pattern of the D crystal form has characteristic peaks at diffraction angles 2θ of 8.122, 12.200, 20.179, 24.973, and 27.303.
进一步地，所述D晶型的X-射线粉末衍射图谱，在衍射角2θ为6.225、6.234、8.122、12.200、15.173、20.179、24.973、27.303处有特征峰。Further, the X-ray powder diffraction pattern of the D crystal form has characteristic peaks at diffraction angles 2θ of 6.225, 6.234, 8.122, 12.200, 15.173, 20.179, 24.973, 27.303.
本发明提供一种式(1)化合物的E晶型，其特征在于，E晶型的X-射线粉末衍射图谱，在衍射角2θ为8.262、12.398、16.792、20.417、21.344、22.819、23.929、25.347处有特征峰。The present invention provides an E-form of a compound of formula (1), which is characterized in that the X-ray powder diffraction pattern of the E-form has a diffraction angle 2θ of 8.262, 12.398, 16.792, 20.417, 21.344, 22.819, 23.929, 25.347 There are characteristic peaks everywhere.
进一步地，所述E晶型的X-射线粉末衍射图谱，在衍射角2θ为8.262、12.398、13.080、16.792、20.417、21.344、22.819、23.929、25.347、28.760、29.104处有特征峰。Further, the X-ray powder diffraction pattern of the E form has characteristic peaks at diffraction angles 2θ of 8.262, 12.398, 13.080, 16.792, 20.417, 21.344, 22.819, 23.929, 25.347, 28.760, and 29.104.
本发明提供一种式(1)化合物的F晶型，其特征在于，F晶型的X-射线粉末衍射图谱，在衍射角2θ为8.081、13.837、16.514、17.700、19.758、20.953处有特征峰。The present invention provides a crystal form F of a compound of formula (1), which is characterized in that the X-ray powder diffraction pattern of crystal form F has characteristic peaks at diffraction angles 2θ of 8.081, 13.837, 16.514, 17.700, 19.758, and 20.953. .
进一步地，所述F晶型的X-射线粉末衍射图谱，在衍射角2θ为8.081、13.837、16.514、17.700、19.758、20.953、23.039、23.640、24.777、28.277处有特征峰。Further, the X-ray powder diffraction pattern of the F crystal form has characteristic peaks at diffraction angles 2θ of 8.081, 13.837, 16.514, 17.700, 19.758, 20.953, 23.039, 23.640, 24.777, and 28.277.
更进一步地，所述F晶型的X-射线粉末衍射图谱，在衍射角2θ为5.717、8.081、9.022、11.645、12.581、13.837、16.514、17.700、19.758、20.953、21.859、23.039、23.640、24.777、26.164、27.141、28.277、31.599、33.303、36.342、43.863、44.435、46.344处有特征峰。Furthermore, the X-ray powder diffraction pattern of the F crystal form has a diffraction angle 2θ of 5.717, 8.081, 9.022, 11.645, 12.581, 13.837, 16.514, 17.700, 19.758, 20.953, 21.859, 23.039, 23.640, 24.777, There are characteristic peaks at 26.164, 27.141, 28.277, 31.599, 33.303, 36.342, 43.863, 44.435, 46.344.
本发明提供一种式(1)化合物的G晶型，其特征在于，G晶型的X-射线粉末衍射图谱，在衍射角2θ为7.877、8.328、8.462、12.457、16.866、21.399、22.293处有特征峰。The present invention provides a G crystal form of a compound of formula (1), which is characterized in that the X-ray powder diffraction pattern of the G crystal form has a diffraction angle 2θ of 7.877, 8.328, 8.462, 12.457, 16.866, 21.399, 22.293. Characteristic peaks.
进一步地，所述G晶型的X-射线粉末衍射图谱，在衍射角2θ为7.877、8.328、8.462、12.457、16.866、21.399、22.293、22.502、23.974、24.868、25.439、27.617处有特征峰。Further, the X-ray powder diffraction pattern of the G crystal form has characteristic peaks at diffraction angles 2θ of 7.877, 8.328, 8.462, 12.457, 16.866, 21.399, 22.293, 22.502, 23.974, 24.868, 25.439, 27.617.
更进一步地，所述G晶型的X-射线粉末衍射图谱，在衍射角2θ为7.877、8.328、8.462、12.457、13.115、14.324、16.201、16.866、18.034、19.575、20.453、21.399、22.293、22.502、23.974、24.868、25.439、26.460、27.617、28.820、29.199、31.766处有特征峰。Furthermore, the X-ray powder diffraction pattern of the G crystal form has a diffraction angle 2θ of 7.877, 8.328, 8.462, 12.457, 13.115, 14.324, 16.201, 16.866, 18.034, 19.575, 20.453, 21.399, 22.293, 22.502, There are characteristic peaks at 23.974, 24.868, 25.439, 26.460, 27.617, 28.820, 29.199, 31.766.
本发明提供一种式(1)化合物的H晶型，其特征在于，H晶型的X-射线粉末衍射图谱，在衍射角2θ为8.277、12.498、16.800、17.823、20.204、21.241、23.774、25.361处有特征峰。The present invention provides an H crystal form of a compound of formula (1), characterized in that the X-ray powder diffraction pattern of the H crystal form has a diffraction angle 2θ of 8.277, 12.498, 16.800, 17.823, 20.204, 21.241, 23.774, 25.361 There are characteristic peaks everywhere.
进一步地，所述H晶型的X-射线粉末衍射图谱，在衍射角2θ为8.277、12.096、12.498、16.800、17.823、20.204、21.241、22.359、23.774、25.361、28.719、31.521、32.534处有特征峰。Further, the X-ray powder diffraction pattern of the H crystal form has characteristic peaks at diffraction angles 2θ of 8.277, 12.096, 12.498, 16.800, 17.823, 20.204, 21.241, 22.359, 23.774, 25.361, 28.719, 31.521, 32.534. .
更进一步地，所述H晶型的X-射线粉末衍射图谱，在衍射角2θ为8.277、12.096、 12.498、14.237、16.800、17.823、19.712、20.204、21.241、22.359、23.774、25.361、28.719、31.521、32.534、48.634处有特征峰。Furthermore, the X-ray powder diffraction pattern of the H crystal form has a diffraction angle 2θ of 8.277, 12.096, 12.498, 14.237, 16.800, 17.823, 19.712, 20.204, 21.241, 22.359, 23.774, 25.361, 28.719, 31.521, There are characteristic peaks at 32.534 and 48.634.
本发明提供一种式(1)化合物的J晶型，其特征在于，J晶型的X-射线粉末衍射图谱，在衍射角2θ为8.004、12.258、19.183、24.484、26.059、33.718处有特征峰。The present invention provides a J-form of a compound of formula (1), characterized in that the X-ray powder diffraction pattern of the J-form has a characteristic peak at a diffraction angle 2θ of 8.004, 12.258, 19.183, 24.484, 26.059, 33.718. .
进一步地，所述J晶型的X-射线粉末衍射图谱，在衍射角2θ为8.004、12.258、13.839、19.183、21.759、22.820、24.484、26.059、28.875、33.718处有特征峰。Further, the X-ray powder diffraction pattern of the J form has characteristic peaks at diffraction angles 2θ of 8.004, 12.258, 13.839, 19.183, 21.759, 22.820, 24.484, 26.059, 28.875, and 33.718.
更进一步地，所述J晶型的X-射线粉末衍射图谱，在衍射角2θ为8.004、8.942、12.258、13.839、15.415、17.197、19.183、20.314、20.924、21.759、22.820、24.484、26.059、27.140、28.875、33.718处有特征峰。Further, the X-ray powder diffraction pattern of the J form has a diffraction angle 2θ of 8.004, 8.942, 12.258, 13.839, 15.415, 17.197, 19.183, 20.314, 20.924, 21.759, 22.820, 24.484, 26.059, 27.140, There are characteristic peaks at 28.875 and 33.718.
本发明还涉及式(1)化合物的A晶型、B晶型、C晶型、D晶型、E晶型、F晶型、G晶型、H晶型、J晶型的制备方法，包括：取一定量的式(1)化合物，加入适量溶剂，析晶、过滤、干燥，得到式(1)化合物的A晶型、B晶型、C晶型、D晶型、E晶型、F晶型、G晶型、H晶型或J晶型。The present invention also relates to a method for preparing A, B, C, D, E, F, G, H, and J compounds of the compound of formula (1). : Take a certain amount of the compound of formula (1), add an appropriate amount of solvent, crystallize, filter, and dry to obtain the compound of formula (1) in the form A, B, C, D, E, F Crystal Form, G Form, H Form, or J Form.
式(1)化合物的A晶型、B晶型、C晶型、D晶型、E晶型、F晶型、G晶型、H晶型、J晶型的结晶溶剂选自烃类溶剂、醚类溶剂、醇类溶剂、酯类溶剂、酮类溶剂、腈类溶剂、卤代烃类溶剂、含氮溶剂、水、二甲基亚砜的一种或者多种。所述烃类溶剂包括但不限于环己烷、正庚烷、对二甲苯；所述醚类溶剂包括但不限于四氢呋喃、***、丙二醇甲醚、甲基叔丁基醚、异丙醚或1,4-二氧六环；所述醇类溶包括但不限于甲醇、乙醇、异丙醇、正丙醇、异戊醇或三氟乙醇；所述酯类溶剂包括但不限于乙酸乙酯、乙酸异丙酯或乙酸丁酯；所述酮类溶剂包括但不限于丙酮、苯乙酮、4-甲基-2-戊酮；所述腈类溶剂包括但不限于乙腈、丙腈；所述卤代烃类溶剂包括但不限于氯甲烷、二氯甲烷、1,2-二氯乙烷、氯仿或四氯化碳；所述含氮溶剂包括但不限于硝基甲烷、N,N-二甲基甲酰胺、N,N-二甲基乙酰胺。The crystalline solvent of the compound A, B, C, D, E, F, G, H, and J is selected from hydrocarbon solvents, One or more of ether solvents, alcohol solvents, ester solvents, ketone solvents, nitrile solvents, halogenated hydrocarbon solvents, nitrogen-containing solvents, water, and dimethyl sulfoxide. The hydrocarbon solvents include, but are not limited to, cyclohexane, n-heptane, and para-xylene; the ether solvents include, but are not limited to, tetrahydrofuran, diethyl ether, propylene glycol methyl ether, methyl tert-butyl ether, isopropyl ether, or 1 , 4-dioxane; the alcohol solvents include, but are not limited to, methanol, ethanol, isopropanol, n-propanol, isoamyl alcohol, or trifluoroethanol; the ester solvents include, but are not limited to, ethyl acetate, Isopropyl acetate or butyl acetate; the ketone solvents include, but are not limited to, acetone, acetophenone, and 4-methyl-2-pentanone; the nitrile solvents include, but are not limited to, acetonitrile and propionitrile; Halogenated hydrocarbon solvents include, but are not limited to, methyl chloride, methylene chloride, 1,2-dichloroethane, chloroform, or carbon tetrachloride; the nitrogen-containing solvents include, but are not limited to, nitromethane, N, N-dichloromethane, Methylformamide, N, N-dimethylacetamide.
式(1)化合物的A晶型、B晶型、C晶型、D晶型、E晶型、F晶型、G晶型、H晶型、J晶型的析晶方法选自室温析晶、冷却析晶、挥发溶剂析晶或加入晶种诱导析晶。The crystallization method of the compound A, B, C, D, E, F, G, H, J is selected from room temperature crystallization. , Cooling crystallization, crystallization of volatile solvents or adding seeds to induce crystallization.
本发明还涉及式(1)化合物的A晶型的制备方法，包括：取一定量的式(1)化合物，加入适量溶剂，析晶、过滤、干燥，得到式(1)化合物的A晶型。所述溶剂选自二氯甲烷、甲醇、乙腈的一种或多种。所述A晶型析晶方法选自室温析晶、冷却析晶、挥发溶剂析晶或加入晶种诱导析晶。The invention also relates to a method for preparing a form A of a compound of formula (1), which comprises: taking a certain amount of a compound of formula (1), adding an appropriate amount of a solvent, crystallizing, filtering, and drying to obtain a form A of a compound of formula (1) . The solvent is selected from one or more of dichloromethane, methanol, and acetonitrile. The A-type crystallizing method is selected from room temperature crystallization, cooling crystallization, volatile solvent crystallization, or adding seed crystals to induce crystallization.
本发明还涉及式(1)化合物的A晶型的制备方法，包括：取一定量的式(1)化合物，溶解于适量二氯甲烷中，打浆，收集固体。将固体加入适量二氯甲烷/甲醇溶解，打 浆，得到A晶型。本发明还涉及式(1)化合物的A晶型的制备方法，包括：取一定量的式(1)化合物，加入适量二氯甲烷/甲醇的混合溶剂，室温搅拌未溶清，滤液自然挥发，得到A晶型。本发明还涉及式(1)化合物的A晶型的制备方法，包括：取一定量的式(1)化合物，溶于适量乙腈，加热溶清，程序降温，室温搅拌，得到A晶型。The invention also relates to a method for preparing a form A of a compound of formula (1), which comprises: taking a certain amount of a compound of formula (1), dissolving it in an appropriate amount of dichloromethane, beating it, and collecting a solid. The solid was added with an appropriate amount of dichloromethane / methanol to dissolve, and slurried to obtain Form A. The invention also relates to a method for preparing a form A of a compound of formula (1), which comprises: taking a certain amount of a compound of formula (1), adding an appropriate amount of a mixed solvent of dichloromethane / methanol, stirring at room temperature without dissolving, and the filtrate naturally evaporating, A crystal form was obtained. The invention also relates to a method for preparing a form A of a compound of formula (1), which comprises: taking a certain amount of a compound of formula (1), dissolving it in an appropriate amount of acetonitrile, heating and dissolving, program cooling, and stirring at room temperature to obtain a form A.
本发明还涉及式(1)化合物的B晶型的制备方法，包括：取一定量的式(1)化合物，加入适量溶剂，析晶、过滤、干燥，得到式(1)化合物的B晶型。所述溶剂选自甲醇、二氯甲烷、乙醇、异丙醇、丙酮、乙腈、水的一种或多种。所述B晶型析晶方法选自室温析晶、冷却析晶、挥发溶剂析晶或加入晶种诱导析晶。The invention also relates to a method for preparing the B-form of the compound of the formula (1), which comprises: taking a certain amount of the compound of the formula (1), adding an appropriate amount of solvent, crystallizing, filtering, and drying to obtain the B-form of the compound of the formula (1) . The solvent is selected from one or more of methanol, dichloromethane, ethanol, isopropanol, acetone, acetonitrile, and water. The B-type crystallization method is selected from room temperature crystallization, cooling crystallization, volatile solvent crystallization or adding seed crystals to induce crystallization.
本发明还涉及式(1)化合物的B晶型的制备方法，包括：取一定量的式(1)化合物，溶解于适量甲醇中，室温搅拌未溶清，滤液自然挥发，得到B晶型。本发明还涉及式(1)化合物的B晶型的制备方法，包括：取一定量的式(1)化合物，溶解于适量甲醇/二氯甲烷混合溶液中，加热溶清，程序降温，室温搅拌，得到B晶型。本发明还涉及式(1)化合物的B晶型的制备方法，包括：取一定量的式(1)化合物，溶解于适量乙醇/二氯甲烷混合溶液中，加热溶清，程序降温，室温搅拌，得到B晶型。本发明还涉及式(1)化合物的B晶型的制备方法，包括：取一定量的式(1)化合物，溶解于适量异丙醇/二氯甲烷混合溶液中，加热溶清，程序降温，室温搅拌，得到B晶型。本发明还涉及式(1)化合物的B晶型的制备方法，包括：取一定量的式(1)化合物，溶解于适量丙酮中，加热溶清，程序降温，室温搅拌，得到B晶型。本发明还涉及式(1)化合物的B晶型的制备方法，包括：取一定量的式(1)化合物A晶型和B晶型，溶于适量异丙醇或异丙醚中，打浆，得到B晶型。本发明还涉及式(1)化合物的B晶型的制备方法，包括：取一定量的式(1)化合物B晶型和B晶型(不同批次)，溶于适量正己烷中，打浆，得到B晶型。The invention also relates to a method for preparing the B-form of the compound of the formula (1), which comprises: taking a certain amount of the compound of the formula (1), dissolving it in an appropriate amount of methanol, stirring at room temperature without dissolving it, and naturally evaporating the filtrate to obtain the B-form. The invention also relates to a method for preparing the B-form of the compound of the formula (1), which comprises: taking a certain amount of the compound of the formula (1), dissolving it in an appropriate amount of a methanol / dichloromethane mixed solution, heating and dissolving, program cooling, and stirring at room temperature To obtain the B crystal form. The invention also relates to a method for preparing the B crystal form of the compound of the formula (1), which comprises: taking a certain amount of the compound of the formula (1), dissolving it in an appropriate amount of a mixed solution of ethanol / dichloromethane, heating and dissolving, program cooling, and stirring at room temperature To obtain the B crystal form. The invention also relates to a method for preparing the B-form of the compound of the formula (1), which comprises: taking a certain amount of the compound of the formula (1), dissolving it in an appropriate amount of isopropanol / dichloromethane mixed solution, heating and dissolving, and cooling the program, Stir at room temperature to obtain Form B. The invention also relates to a method for preparing the B-form of the compound of the formula (1), which comprises: taking a certain amount of the compound of the formula (1), dissolving it in an appropriate amount of acetone, heating and dissolving, cooling the program, and stirring at room temperature to obtain the B-form. The present invention also relates to a method for preparing Form B of a compound of formula (1), which comprises: taking a certain amount of Form A and Form B of a compound of Formula (1), dissolving in an appropriate amount of isopropyl alcohol or isopropyl ether, and beating, Form B is obtained. The invention also relates to a method for preparing the B-form of the compound of the formula (1), which comprises: taking a certain amount of the B-form and the B-form of the compound of the formula (1) (different batches), dissolving in an appropriate amount of n-hexane, beating, Form B is obtained.
本发明还涉及式(1)化合物的C晶型的制备方法，包括：取一定量的式(1)化合物，加入适量溶剂，析晶、过滤、干燥，得到式(1)化合物的C晶型。所述溶剂为四氢呋喃。所述C晶型析晶方法选自室温析晶、冷却析晶、挥发溶剂析晶或加入晶种诱导析晶。The invention also relates to a method for preparing the crystal form C of the compound of formula (1), which comprises: taking a certain amount of the compound of formula (1), adding an appropriate amount of solvent, crystallizing, filtering, and drying to obtain the crystal form C of the compound of formula (1) . The solvent is tetrahydrofuran. The C-type crystallizing method is selected from room temperature crystallization, cooling crystallization, volatile solvent crystallization or adding seed crystals to induce crystallization.
本发明还涉及式(1)化合物的C晶型的制备方法，包括：取一定量的式(1)化合物，溶解于适量四氢呋喃中，加热溶清，降至室温搅拌，得到C晶型。The invention also relates to a method for preparing the crystal form C of the compound of the formula (1), which comprises: taking a certain amount of the compound of the formula (1), dissolving it in an appropriate amount of tetrahydrofuran, heating and dissolving, and stirring at room temperature to obtain the crystal form C.
本发明还涉及式(1)化合物的D晶型的制备方法，包括：取一定量的式(1)化合物，加入适量溶剂，析晶、过滤、干燥，得到式(1)化合物的D晶型。所述溶剂为二氯乙烷。所述D晶型析晶方法选自室温析晶、冷却析晶、挥发溶剂析晶或加入晶种诱导析 晶。The invention also relates to a method for preparing the D crystal form of the compound of the formula (1), which comprises: taking a certain amount of the compound of the formula (1), adding an appropriate amount of solvent, crystallizing, filtering, and drying to obtain the D crystal form of the compound of the formula (1) . The solvent is dichloroethane. The D-type crystallization method is selected from room temperature crystallization, cooling crystallization, volatile solvent crystallization, or seeding to induce crystallization.
本发明还涉及式(1)化合物的D晶型的制备方法，包括：取一定量的式(1)化合物，溶解于适量二氯乙烷中，加热溶清，降至室温搅拌，得到D晶型。The invention also relates to a method for preparing the D crystal form of the compound of the formula (1), which comprises: taking a certain amount of the compound of the formula (1), dissolving it in an appropriate amount of dichloroethane, heating and dissolving, and stirring at room temperature to obtain the D crystal. type.
本发明还涉及式(1)化合物的E晶型的制备方法，包括：取一定量的式(1)化合物，加入适量溶剂，析晶、过滤、干燥，得到式(1)化合物的E晶型。所述溶剂选自甲醇、乙酸乙酯、二氯甲烷的一种或几种。所述E晶型析晶方法选自室温析晶、冷却析晶、挥发溶剂析晶或加入晶种诱导析晶。The invention also relates to a method for preparing the E-form of the compound of the formula (1), which comprises: taking a certain amount of the compound of the formula (1), adding an appropriate amount of solvent, crystallizing, filtering, and drying to obtain the E-form of the compound of the formula (1) . The solvent is selected from one or more of methanol, ethyl acetate, and dichloromethane. The E-type crystallizing method is selected from room temperature crystallization, cooling crystallization, volatile solvent crystallization or adding seed crystals to induce crystallization.
本发明还涉及式(1)化合物的E晶型的制备方法，包括：取一定量的式(1)化合物，溶解于适量甲醇中，加热溶清，降至室温搅拌，得到E晶型。本发明还涉及式(1)化合物的E晶型的制备方法，包括：取一定量的式(1)化合物，溶解于适量乙酸乙酯/二氯甲烷混合溶剂中，加热溶清，降至室温搅拌，得到E晶型。The invention also relates to a method for preparing the E-form of the compound of the formula (1), which comprises: taking a certain amount of the compound of the formula (1), dissolving it in an appropriate amount of methanol, heating and dissolving the solution, and stirring at room temperature to obtain the E-form. The present invention also relates to a method for preparing the E crystal form of the compound of formula (1), which comprises: taking a certain amount of the compound of formula (1), dissolving it in an appropriate amount of a mixed solvent of ethyl acetate / dichloromethane, heating and dissolving, and reducing the temperature to room temperature. Stir to obtain the E crystal form.
本发明还涉及式(1)化合物的F晶型的制备方法，包括：取一定量的式(1)化合物，加入适量溶剂，析晶、过滤、干燥，得到式(1)化合物的F晶型。所述溶剂为1,4-二氧六环。所述F晶型析晶方法选自室温析晶、冷却析晶、挥发溶剂析晶或加入晶种诱导析晶。The invention also relates to a method for preparing the F crystal form of the compound of the formula (1), which comprises: taking a certain amount of the compound of the formula (1), adding an appropriate amount of solvent, crystallizing, filtering, and drying to obtain the F crystal form of the compound of the formula (1) . The solvent is 1,4-dioxane. The F-type crystallization method is selected from room temperature crystallization, cooling crystallization, volatile solvent crystallization or adding seed crystals to induce crystallization.
本发明还涉及式(1)化合物的F晶型的制备方法，包括：取一定量的式(1)化合物，溶解于适量1,4-二氧六环中，室温搅拌未溶清，滤液自然挥发，得到F晶型。The invention also relates to a method for preparing the F crystal form of the compound of formula (1), which comprises: taking a certain amount of the compound of formula (1), dissolving it in an appropriate amount of 1,4-dioxane, stirring undissolved at room temperature, and the filtrate naturally Evaporate to obtain F crystal form.
本发明还涉及式(1)化合物的G晶型的制备方法，包括：取一定量的式(1)化合物E晶型，研磨，得到G晶型。The invention also relates to a method for preparing the G crystal form of the compound of the formula (1), which comprises: taking a certain amount of the crystal form E of the compound of the formula (1) and grinding to obtain the G crystal form.
本发明还涉及式(1)化合物的H晶型的制备方法，包括：取一定量的式(1)化合物A晶型和B晶型，溶于适量丙酮，打浆，得到H晶型。本发明还涉及式(1)化合物的H晶型的制备方法，包括：取一定量的式(1)化合物B晶型和H晶型，溶于适量丙酮，打浆，得到H晶型。The invention also relates to a method for preparing the H crystal form of the compound of the formula (1), which comprises: taking a certain amount of the crystal form A and the B form of the compound of the formula (1), dissolving in an appropriate amount of acetone, and beating to obtain the H crystal form. The invention also relates to a method for preparing the H crystal form of the compound of the formula (1), which comprises: taking a certain amount of the B crystal form and the H crystal form of the compound of the formula (1), dissolving in a proper amount of acetone, and beating to obtain the H crystal form.
本发明还涉及式(1)化合物的J晶型的制备方法，包括：取一定量的式(1)化合物A晶型和B晶型，溶于适量乙酸乙酯，打浆，得到J晶型。本发明还涉及式(1)化合物的J晶型的制备方法，包括：取一定量的式(1)化合物B晶型和J晶型，溶于适量乙酸乙酯，打浆，得到J晶型。The invention also relates to a method for preparing the J-form of the compound of formula (1), which comprises: taking a certain amount of the A-form and B-form of the compound of the formula (1), dissolving it in an appropriate amount of ethyl acetate, and beating to obtain the J-form. The invention also relates to a method for preparing the J crystal form of the compound of the formula (1), which comprises: taking a certain amount of the B crystal form and the J crystal form of the compound of the formula (1), dissolving in a proper amount of ethyl acetate, and beating to obtain the J crystal form.
本发明还涉及包括式(1)化合物的A晶型、B晶型、C晶型、D晶型、E晶型、F晶型、G晶型、H晶型或J晶型和任选的一种或多种药用载体和/或稀释剂的药物组合物。所述药物组合物可以制成药学上可接受的任一剂型。例如，本发明所述包含式(1)化合物的A晶型、B晶型、C晶型、D晶型、E晶型、F晶型、G晶型、H晶型或J晶型的药 物制剂可以配制为片剂、胶囊剂、丸剂、颗粒剂、溶液剂、混悬剂、糖浆剂、注射剂(包括注射液、注射用无菌粉末与注射用浓溶液)、栓剂、吸入剂或喷雾剂。The invention also relates to Form A, Form B, Form C, Form D, Form E, Form F, Form G, Form H, or Form J, and optionally a compound of formula (1). A pharmaceutical composition of one or more pharmaceutically acceptable carriers and / or diluents. The pharmaceutical composition can be made into any pharmaceutically acceptable dosage form. For example, the drug comprising Form A, Form B, Form C, Form D, Form E, Form F, Form G, Form H, or Form J of the compound of formula (1) according to the present invention. Preparations can be formulated as tablets, capsules, pills, granules, solutions, suspensions, syrups, injections (including injections, sterile powders for injection and concentrated solutions for injection), suppositories, inhalants or sprays .
此外，本发明所述药物组合物还可以以任何合适的给药方式，例如口服、肠胃外、直肠、经肺或局部给药等方式施用于需要这种治疗的患者或受试者。当用于口服给药时，所述药物组合物可制成口服制剂，例如口服固体制剂，如片剂、胶囊剂、丸剂、颗粒剂等；或，口服液体制剂，如口服溶液剂、口服混悬剂、糖浆剂等。当制成口服制剂时，所述药物制剂还可包含适宜的填充剂、粘合剂、崩解剂、润滑剂等。当用于肠胃外给药时，所述药物制剂可制成注射剂，包括注射液、注射用无菌粉末与注射用浓溶液。当制成注射剂时，所述药物组合物可采用现有制药领域中的常规方法来进行生产。当配制注射剂时，所述药物制剂中可以不加入附加剂，也可根据药物的性质加入适宜的附加剂。当用于直肠给药时，所述药物制剂可制成栓剂等。用于经肺给药时，所述药物制剂可制成吸入剂或喷雾剂等。在某些实施方案中，本发明式(1)化合物的A晶型、B晶型、C晶型、D晶型、E晶型、F晶型、G晶型、H晶型或J晶型以治疗和/或预防有效量存在于药物组合物或药物中。在某些实施方案中，本发明所述式(1)化合物的A晶型、B晶型、C晶型、D晶型、E晶型、F晶型、G晶型、H晶型或J晶型以单位剂量的形式存在于药物组合物或药物中。In addition, the pharmaceutical composition of the present invention can also be administered to patients or subjects in need of such treatment in any suitable manner, such as oral, parenteral, rectal, pulmonary or topical administration. When used for oral administration, the pharmaceutical composition can be made into an oral preparation, such as an oral solid preparation, such as tablets, capsules, pills, granules, etc .; or an oral liquid preparation, such as an oral solution, orally mixed Suspensions, syrups, etc. When formulated into an oral preparation, the pharmaceutical preparation may further contain a suitable filler, a binder, a disintegrant, a lubricant, and the like. When used for parenteral administration, the pharmaceutical preparation can be made into injections, including injections, sterile powders for injections, and concentrated solutions for injections. When prepared as an injection, the pharmaceutical composition can be produced by a conventional method in the existing pharmaceutical field. When an injection is formulated, an additional agent may not be added to the pharmaceutical preparation, or a suitable additional agent may be added according to the properties of the drug. When used for rectal administration, the pharmaceutical preparations can be made into suppositories and the like. When used for pulmonary administration, the pharmaceutical preparation can be made into an inhalant or a spray. In certain embodiments, Form A, Form B, Form C, Form D, Form E, Form F, Form G, Form H, or Form J of the compound of formula (1) of the present invention Is present in a pharmaceutical composition or medicament in a therapeutically and / or prophylactically effective amount. In certain embodiments, Form A, Form B, Form C, Form D, Form E, Form F, Form G, Form H, or J of the compound of formula (1) of the present invention The crystalline form is present in a pharmaceutical composition or drug in the form of a unit dose.
本发明进一步涉及一种制备药物组合物的方法，包括使选自本发明的式(1)化合物的A晶型、B晶型、C晶型、D晶型、E晶型、F晶型、G晶型、H晶型或J晶型中的一种或多种晶型与至少一种药学上可接受的载体、稀释剂或赋形剂混合。The present invention further relates to a method for preparing a pharmaceutical composition, which comprises forming a form A, a form B, a form C, a form D, a form E, a form F, a compound selected from the compound of formula (1) of the present invention, One or more of the G, H, or J forms are mixed with at least one pharmaceutically acceptable carrier, diluent, or excipient.
本发明进一步涉及所述式(1)化合物的A晶型、B晶型、C晶型、D晶型、E晶型、F晶型、G晶型、H晶型或J晶型在制备用于治疗通过对A 2a受体抑制而改善的病况或病症的药物中的用途。本发明进一步涉及所述式(1)化合物的A晶型、B晶型、C晶型、D晶型、E晶型、F晶型、G晶型、H晶型或J晶型在制备治疗选自肿瘤、抑郁症、认知功能病症、神经退行性病症、注意力相关病症、锥体外症候群、异常运动障碍、肝硬化、肝纤维化、脂肪肝、皮肤纤维化、睡眠障碍、中风、脑损伤、神经炎症和成瘾行为的疾病的药物中的应用。本发明中所述的肿瘤选自黑色素瘤、脑瘤(具有恶性的星形神经胶质和少突神经胶质细胞瘤成分的神经胶质瘤等)、食管癌、胃癌、肝癌、胰腺癌、结肠直肠癌(结肠癌、直肠癌等)、肺癌(非小细胞肺癌、小细胞肺癌、原发或转移性鳞状癌等)、肾癌、乳腺癌、卵巢癌、***癌、皮肤癌、神经母细胞瘤、肉瘤、骨软骨瘤、骨瘤、骨肉瘤、***瘤、睾丸肿瘤、子宫癌(子***、子宫内膜癌等)、头颈肿瘤(上颌骨癌、喉癌、咽癌、舌癌、口内癌等)、多发性骨髓瘤、恶性淋巴瘤(网状细胞肉瘤、淋巴肉瘤、 霍奇金淋巴瘤等)、真性红细胞增多症、白血病、甲状腺肿瘤、输尿管肿瘤、膀胱癌、胆囊癌、胆管癌、绒毛膜上皮癌和儿科肿瘤(尤因家族性肉瘤、维尔姆斯肉瘤、横纹肌肉瘤、血管肉瘤、胚胎睾丸癌、成神经细胞瘤、视网膜母细胞瘤、肝胚细胞瘤、肾母细胞瘤等)；优选为肺癌。本发明中所述的神经退行性病症选自帕金森氏病、亨廷顿氏病、阿尔茨海默氏病、肌萎缩性侧索硬化、共济失调毛细血管扩张症、牛海绵状脑病、克雅二氏病、小脑萎缩症、多发性硬化症、原发性侧索硬化、脊髓性肌萎缩症。 The invention further relates to the A-form, B-form, C-form, D-form, E-form, F-form, G-form, H-form or J-form of the compound of formula (1). Use in a medicament for treating a condition or disorder ameliorated by inhibition of the A 2a receptor. The invention further relates to the A-form, B-form, C-form, D-form, E-form, F-form, G-form, H-form or J-form of the compound of formula (1) in the preparation and treatment. Selected from tumors, depression, cognitive disorders, neurodegenerative disorders, attention-related disorders, extrapyramid syndrome, abnormal movement disorders, cirrhosis, liver fibrosis, fatty liver, skin fibrosis, sleep disorders, stroke, brain Use of medicines for diseases of injury, neuroinflammation and addictive behavior. The tumor described in the present invention is selected from melanoma, brain tumor (glioma with malignant astroglial and oligodendroglioma component, etc.), esophageal cancer, gastric cancer, liver cancer, pancreatic cancer, Colorectal cancer (colon cancer, rectal cancer, etc.), lung cancer (non-small cell lung cancer, small cell lung cancer, primary or metastatic squamous cell carcinoma, etc.), kidney cancer, breast cancer, ovarian cancer, prostate cancer, skin cancer, nerves Blastoma, sarcoma, osteochondroma, osteoma, osteosarcoma, seminoma, testicular tumor, uterine cancer (cervix cancer, endometrial cancer, etc.), head and neck tumor (maxillary bone cancer, laryngeal cancer, pharyngeal cancer , Tongue cancer, intraoral cancer, etc.), multiple myeloma, malignant lymphoma (reticulosarcoma, lymphosarcoma, Hodgkin lymphoma, etc.), polycythemia vera, leukemia, thyroid tumor, ureteral tumor, bladder cancer, Gallbladder cancer, bile duct cancer, chorionic epithelial cancer, and pediatric tumors (Ewing's familial sarcoma, Wilms sarcoma, rhabdomyosarcoma, angiosarcoma, embryonic testicular cancer, neuroblastoma, retinoblastoma, hepatoblastoma, kidney Tumor cells, etc.); preferably is lung cancer. The neurodegenerative disorders described in the present invention are selected from Parkinson's disease, Huntington's disease, Alzheimer's disease, amyotrophic lateral sclerosis, ataxia capillaries, bovine spongiform encephalopathy, Creutzfeldt-Jakob Second's disease, cerebellar atrophy, multiple sclerosis, primary lateral sclerosis, spinal muscular atrophy.
发明详述Detailed description of the invention
在本申请的说明书和权利要求书中，除非另有说明，否则本文中使用的科学和技术名词具有本领域技术人员所通常理解的含义。然而，为了更好地理解本发明，下面提供了部分相关术语的定义和解释。另外，当本申请所提供的术语的定义和解释与本领域技术人员所通常理解的含义不一致时，以本申请所提供的术语的定义和解释为准。In the description and claims of this application, unless otherwise stated, scientific and technical terms used herein have the meanings commonly understood by those skilled in the art. However, in order to better understand the present invention, the definitions and explanations of some related terms are provided below. In addition, when the definitions and explanations of the terms provided in this application are not consistent with the meanings commonly understood by those skilled in the art, the definitions and explanations of the terms provided in this application shall prevail.
本发明所述的“醚类溶剂”是指含有醚键-O-且碳原子数为1至10个的链状化合物或环状化合物，具体实例包括但不限于：四氢呋喃、***、丙二醇甲醚、甲基叔丁基醚、异丙醚或1,4-二氧六环。The "ether solvent" in the present invention refers to a chain compound or a cyclic compound containing an ether bond -O- and having 1 to 10 carbon atoms, and specific examples include, but are not limited to, tetrahydrofuran, ether, and propylene glycol methyl ether , Methyl tert-butyl ether, isopropyl ether, or 1,4-dioxane.
本发明所述的“醇类溶剂”是指一个或多个“羟基”取代“C 1-6烷基”上的一个或多个氢原子所衍生的基团，所述“羟基”和“C 1-6烷基”如前文所定义，具体实例包括但不限于：甲醇、乙醇、异丙醇、正丙醇、异戊醇或三氟乙醇。 The "alcoholic solvent" in the present invention refers to a group derived by replacing one or more hydrogen atoms on the "C 1-6 alkyl" with one or more "hydroxy", and the "hydroxy" and "C "1-6 alkyl" is as defined above, and specific examples include, but are not limited to, methanol, ethanol, isopropanol, n-propanol, isoamyl alcohol, or trifluoroethanol.
本发明所述的“酯类溶剂”是指含碳原子数为1至4个的低级有机酸与含碳原子数为1至6个的低级醇的结合物，具体实例包括但不限于：乙酸乙酯、乙酸异丙酯或乙酸丁酯。The “ester solvent” in the present invention refers to a combination of a lower organic acid having 1 to 4 carbon atoms and a lower alcohol having 1 to 6 carbon atoms. Specific examples include, but are not limited to, acetic acid Ethyl, isopropyl or butyl acetate.
本发明所述的“酮类溶剂”是指羰基(-C(O)-)与两个烃基相连的化合物，根据分子中烃基的不同，酮可分为脂肪酮、脂环酮、芳香酮、饱和酮和不饱和酮，具体实例包括但不限于：丙酮、苯乙酮、4-甲基-2-戊酮。The "ketone solvent" in the present invention refers to a compound in which a carbonyl group (-C (O)-) is connected to two hydrocarbon groups. According to the different hydrocarbon groups in the molecule, ketones can be divided into fatty ketones, alicyclic ketones, aromatic ketones, Specific examples of saturated ketones and unsaturated ketones include, but are not limited to, acetone, acetophenone, and 4-methyl-2-pentanone.
本发明所述的“腈类溶剂”是指一个或多个“氰基”取代“C 1-6烷基”上的一个或多个氢原子所衍生的基团，所述“氰基”和“C 1-6烷基”如前文所定义，具体实例包括但不限于：乙腈或丙腈。 The “nitrile solvent” in the present invention refers to a group derived by replacing one or more hydrogen atoms on the “C 1-6 alkyl group” with one or more “cyano groups”, and the “cyano group” and "C 1-6 alkyl" is as defined above, and specific examples include, but are not limited to, acetonitrile or propionitrile.
本发明所述的“卤代烃类溶剂”是指一个或多个“卤素原子”取代“C 1-6烷基”上的一个或多个氢原子所衍生的基团，所述“卤素原子”和“C 1-6烷基”如前文所定义，具体实例包括但不限于：氯甲烷、二氯甲烷、氯仿或四氯化碳。 The “halogenated hydrocarbon solvent” in the present invention refers to a group derived by replacing one or more hydrogen atoms on the “C 1-6 alkyl” with one or more “halogen atoms”, and the “halogen atom” "And" C 1-6 alkyl "are as defined above, and specific examples include, but are not limited to, methyl chloride, methylene chloride, chloroform, or carbon tetrachloride.
本发明所述的“X-射线粉末衍射图谱或XRPD”是经Cu-Kα射线衍射得到。The "X-ray powder diffraction pattern or XRPD" in the present invention is obtained by Cu-Kα ray diffraction.
本发明所述的“差示扫描量热分析或DSC”是指在样品升温或恒温过程中，测量样品与参考物之间的温度差、热流差，以表征所有与热效应有关的物理变化和化学变化，得 到样品的相变信息。The “differential scanning calorimetry or DSC” in the present invention refers to measuring the temperature difference and heat flow difference between a sample and a reference object during the temperature rising or constant temperature of the sample to characterize all physical changes and chemistry related to the thermal effect. Change to get the phase transition information of the sample.
本发明所述的“2θ或2θ角度”是指衍射角，θ为布拉格角，单位为°或度，所述2θ的误差范围可以是±0.3、±0.2或±0.1。The “2θ or 2θ angle” in the present invention refers to a diffraction angle, θ is a Bragg angle, and a unit is ° or degree. The error range of the 2θ may be ± 0.3, ± 0.2, or ± 0.1.
发明的有益效果The beneficial effects of the invention
本发明提供的6-(8-氟喹啉-6-基)-5-苯基-1,2,4-三嗪-3-胺(式(1)化合物)的A晶型、B晶型、C晶型、D晶型、E晶型、F晶型、G晶型、H晶型和J晶型的溶解度、稳定性、吸湿性方面更有优势，更适合于药物开发，满足生物利用度和药效要求，能够满足生产运输储存的药用要求，生产工艺稳定、可重复可控，能够适应于工业化生产。Form A and Form B of 6- (8-fluoroquinolin-6-yl) -5-phenyl-1,2,4-triazine-3-amine (compound of formula (1)) provided by the present invention , Form C, Form D, Form E, Form F, Form G, Form H, and Form J are more advantageous in terms of solubility, stability, and hygroscopicity, and are more suitable for drug development and biological utilization The requirements of degree and efficacy can meet the medicinal requirements of production, transportation and storage. The production process is stable, repeatable and controllable, and can be adapted to industrial production.
附图说明BRIEF DESCRIPTION OF THE DRAWINGS
图1为以A晶型形式存在的式(1)化合物的XRPD图；FIG. 1 is an XRPD pattern of a compound of formula (1) in the form of Form A;
图2为以A晶型形式存在的式(1)化合物的DSC图；FIG. 2 is a DSC chart of a compound of formula (1) in the form of Form A;
图3为以A晶型形式存在的式(1)化合物DSC升温前后XRPD对比图；FIG. 3 is a comparison chart of XRPD before and after DSC heating of a compound of formula (1) in the form of Form A;
图4为以A晶型形式存在的式(1)化合物的TGA图；4 is a TGA diagram of a compound of formula (1) in the form of A form;
图5为以A晶型形式存在的式(1)化合物的DVS图；5 is a DVS diagram of a compound of formula (1) in the form of Form A;
图6为以A晶型形式存在的式(1)化合物DVS前后XRPD对比图；FIG. 6 is a comparison chart of XRPD before and after DVS of the compound of formula (1) in the form of Form A;
图7为以B晶型形式存在的式(1)化合物的XRPD图；FIG. 7 is an XRPD pattern of the compound of formula (1) in the B-form form; FIG.
图8为以B晶型形式存在的式(1)化合物的DSC图；FIG. 8 is a DSC chart of a compound of formula (1) in the B-form;
图9为以B晶型形式存在的式(1)化合物DSC升温前后XRPD对比图；FIG. 9 is a comparison chart of XRPD before and after DSC heating of a compound of formula (1) in the B-form form;
图10为以B晶型形式存在的式(1)化合物的TGA图；FIG. 10 is a TGA diagram of a compound of formula (1) in the B-form;
图11为以B晶型形式存在的式(1)化合物的PSD图；FIG. 11 is a PSD diagram of a compound of formula (1) in the B-form form; FIG.
图12为以B晶型形式存在的式(1)化合物的DVS图；FIG. 12 is a DVS diagram of a compound of formula (1) in the form of Form B;
图13为以B晶型形式存在的式(1)化合物DVS前后XRPD对比图；FIG. 13 is a comparison chart of XRPD before and after DVS of the compound of formula (1) in the B crystal form; FIG.
图14为以C晶型形式存在的式(1)化合物的XRPD图；FIG. 14 is an XRPD pattern of the compound of formula (1) in the form of the C crystal form; FIG.
图15为以C晶型形式存在的式(1)化合物的DSC图；FIG. 15 is a DSC chart of the compound of formula (1) in the form of the C crystal form; FIG.
图16为以C晶型形式存在的式(1)化合物的TGA图；FIG. 16 is a TGA diagram of a compound of formula (1) in the form of C crystal form; FIG.
图17为以D晶型形式存在的式(1)化合物的XRPD图；FIG. 17 is an XRPD pattern of the compound of formula (1) in the D crystal form; FIG.
图18为以D晶型形式存在的式(1)化合物的DSC图；FIG. 18 is a DSC chart of the compound of formula (1) in the D crystal form; FIG.
图19为以D晶型形式存在的式(1)化合物的TGA图；FIG. 19 is a TGA diagram of a compound of formula (1) in the form of D crystal;
图20为以E晶型形式存在的式(1)化合物的XRPD图；FIG. 20 is an XRPD pattern of the compound of formula (1) in the form of E-form; FIG.
图21为以E晶型形式存在的式(1)化合物的DSC图；FIG. 21 is a DSC chart of a compound of formula (1) in the form of an E-form; FIG.
图22为以E晶型形式存在的式(1)化合物的TGA图；FIG. 22 is a TGA diagram of a compound of formula (1) in an E-form;
图23为以F晶型形式存在的式(1)化合物的XRPD图；FIG. 23 is an XRPD pattern of the compound of formula (1) in the F-form;
图24为以G晶型形式存在的式(1)化合物的XRPD图；FIG. 24 is an XRPD pattern of a compound of formula (1) in the form of a G crystal;
图25为以H晶型形式存在的式(1)化合物的XRPD图；FIG. 25 is an XRPD pattern of a compound of formula (1) in the form of H crystal;
图26为以H晶型形式存在的式(1)化合物的DSC图；FIG. 26 is a DSC chart of a compound of formula (1) in the form of H crystal;
图27为以H晶型形式存在的式(1)化合物的TGA图；FIG. 27 is a TGA diagram of a compound of formula (1) in the H crystal form; FIG.
图28为以J晶型形式存在的式(1)化合物的XRPD图；FIG. 28 is an XRPD pattern of a compound of formula (1) in the form of a J-form; FIG.
图29为以J晶型形式存在的式(1)化合物的DSC图；FIG. 29 is a DSC chart of a compound of formula (1) in the J-form;
图30为以J晶型形式存在的式(1)化合物的TGA图。FIG. 30 is a TGA diagram of a compound of formula (1) in the J-form.
具体实施方式detailed description
以下将结合实施例更详细地解释本发明，本发明的实施例仅用于说明本发明的技术方案，并非限定本发明的实质和范围。The present invention will be explained in more detail with reference to the following embodiments. The embodiments of the present invention are only used to explain the technical solution of the present invention, and do not limit the essence and scope of the present invention.
实验所用仪器的测试条件：Test conditions of the instrument used in the experiment:
化合物的结构是通过核磁共振(NMR)或/和质谱(MS)来确定的。NMR位移(δ)以10 -6(ppm)的单位给出。NMR的测定是用Bruker AVANCE-400核磁仪，测定溶剂为氘代二甲基亚砜(DMSO-d 6)、氘代氯仿(CDCl 3)、氘代甲醇(CD 3OD)，内标为四甲基硅烷(TMS)。 The structure of the compound is determined by nuclear magnetic resonance (NMR) or / and mass spectrometry (MS). The NMR shift (δ) is given in units of 10 -6 (ppm). The NMR measurement was performed using Bruker AVANCE-400 nuclear magnetic analyzer. The measurement solvents were deuterated dimethyl sulfoxide (DMSO-d 6 ), deuterated chloroform (CDCl 3 ), and deuterated methanol (CD 3 OD). The internal standard was 4 Methylsilane (TMS).
MS的测定用FINNIGAN LCQAd(ESI)质谱仪(生产商：Thermo，型号：Finnigan LCQ advantage MAX)。MS was measured using a FINNIGAN LCQAd (ESI) mass spectrometer (manufacturer: Thermo, model: Finnigan LCQ advantage MAX).
HPLC的测定使用安捷伦1200DAD高压液相色谱仪(Sunfire C18 150×4.6mm色谱柱)和Waters 2695-2996高压液相色谱仪(Gimini C18 150×4.6mm色谱柱)。For HPLC measurement, an Agilent 1200 DAD high-pressure liquid chromatography (Sunfire C18 150 × 4.6 mm column) and a Waters 2695-2996 high-pressure liquid chromatography (Gimini C18 150 × 4.6 mm column) were used.
XRPD为X射线粉末衍射检测：测定使用BRUKER D8型X射线衍射仪进行，具体采集信息：Cu阳极(40kV，40mA)，Cu-Kα1射线
Figure PCTCN2019095724-appb-000002
Kα2射线
Figure PCTCN2019095724-appb-000003
Kβ射线
Figure PCTCN2019095724-appb-000004
扫描方式：θ/2θ，扫描范围(2q范围)：3～64°。 XRPD is X-ray powder diffraction detection: The measurement is performed using a BRUKER D8 X-ray diffractometer. The specific collection information: Cu anode (40kV, 40mA), Cu-Kα1 ray
Figure PCTCN2019095724-appb-000002
Kα2 rays
Figure PCTCN2019095724-appb-000003
Kβ rays
Figure PCTCN2019095724-appb-000004
Scanning mode: θ / 2θ, scanning range (2q range): 3 to 64 °.
DSC为差示扫描量热：测定采用METTLER TOLEDO DSC 3+示差扫描量热仪，升温速率10℃/min，温度具体范围参照相应图谱(多为25-300或25-350℃)，氮气吹扫速度50mL/min。DSC is differential scanning calorimetry: The measurement uses a METTLER TOLEDO DSC 3+ differential scanning calorimeter with a heating rate of 10 ° C / min, and the specific temperature range refers to the corresponding map (mostly 25-300 or 25-350 ° C), nitrogen purging The speed is 50 mL / min.
TGA为热重分析：检测采用METTLER TOLEDO TGA 2型热重分析仪，升温速率10℃/min，温度具体范围参照相应图谱(多为25-300℃)，氮气吹扫速度20mL/min。TGA is thermogravimetric analysis: METTLER TOLEDO TGA 2 thermogravimetric analyzer is used for detection. The heating rate is 10 ° C / min, the specific temperature range refers to the corresponding map (mostly 25-300 ° C), and the nitrogen purge rate is 20mL / min.
DVS为动态水分吸附：检测采用SMS DVS Advantage，在25℃，湿度变化为50％-95％-0％-95％-50％，步进为10％(最后一步为5％)(湿度具体范围以相应图谱为准，此处所列为大多使用方法)，判断标准为dm/dt不大于0.02％。DVS is dynamic moisture adsorption: The detection uses SMS DVS Advantage. At 25 ° C, the humidity change is 50% -95% -0% -95% -50%, and the step is 10% (the last step is 5%) (the specific range of humidity) (Based on the corresponding map, most of the methods are listed here.) The judgment criterion is dm / dt not more than 0.02%.
高效液相制备使用Waters 2767-SQ制备型色谱仪。HPLC was prepared using Waters 2767-SQ preparative chromatography.
PSD为粒径分布，仪器：Malvern MS3000，参数：测试模式：湿法，分散介质：液体石蜡，转速：900rmp/min，遮光度：9.11％。PSD is particle size distribution, instrument: Malvern MS3000, parameters: test mode: wet method, dispersion medium: liquid paraffin, rotation speed: 900 rmp / min, shading degree: 9.11%.
CombiFlash快速制备仪使用Combiflash Rf 200(TELEDYNE ISCO)。The CombiFlash rapid preparation instrument uses Combiflash Rf 200 (TELEDYNE ISCO).
实施例中的反应进程的监测采用薄层色谱法(TLC)，反应所使用的展开剂，纯化化合物采用的柱层析的洗脱剂的体系和薄层色谱法的展开剂体系包括：A：二氯甲烷/甲醇体系，B：正己烷/乙酸乙酯体系，溶剂的体积比根据化合物的极性不同而进行调节，也可以加入少量的三乙胺和醋酸等碱性或酸性试剂进行调节。The monitoring of the reaction progress in the examples uses thin layer chromatography (TLC), a developing agent used in the reaction, a column chromatography eluent system for purifying compounds, and a thin layer chromatography developing system including: A: Dichloromethane / methanol system, B: n-hexane / ethyl acetate system, the volume ratio of the solvent is adjusted according to the polarity of the compound, and it can also be adjusted by adding a small amount of basic or acidic reagents such as triethylamine and acetic acid.
SGF为模拟胃液，配制方法：取2.0g氯化钠，加7.0mL盐酸和水使溶解至1000mL，即得。SGF is a simulated gastric juice. The preparation method is: take 2.0g of sodium chloride, add 7.0mL of hydrochloric acid and water to dissolve it to 1000mL, and get it.
FaSSIF溶液为模拟人类餐前饥饿状态下小肠内的肠液，配制方法：溶液(A)：在900mL超纯水中加入4.441g NaH2PO4·2H 2O、0.348g NaOH颗粒和6.186g NaCl，混合均匀，并加入1M NaOH调节溶液pH至6.5±0.05，用水定容至1000mL。4℃冷藏备用；FaSSIF溶液(B)：20mL溶液(A)中溶解0.161g牛胆磺酸钠(NaTC，分子量537.68)和59mg卵磷脂(分子量788.13)，强力搅拌过夜，形成澄清的胶束溶液，加入溶液(A)至体积为100mL，4℃冷藏备用(不超过2周)。 FaSSIF solution is the intestinal fluid in the small intestine under simulated pre-prandial hunger. Preparation method: Solution (A): Add 4.441g NaH2PO4 · 2H 2 O, 0.348g NaOH particles and 6.186g NaCl in 900mL ultrapure water, mix well, 1M NaOH was added to adjust the pH of the solution to 6.5 ± 0.05, and the volume was adjusted to 1000 mL with water. Refrigerate at 4 ° C until use; FaSSIF solution (B): Dissolve 0.161g of sodium taurocholate (NaTC, molecular weight 537.68) and 59mg of lecithin (molecular weight 788.13) in 20mL solution (A), stir vigorously overnight to form a clear micelle solution Add solution (A) to a volume of 100 mL and refrigerate at 4 ° C until use (no more than 2 weeks).
FeSSIF溶液为模拟人类餐后饱食状态下小肠内的肠液，配制方法：溶液(A)：准确称量20.2g NaOH颗粒，43.25g冰醋酸与59.37g氯化钠，用适量超纯水溶解并定容至5L，用1M NaOH或1M HCl调节pH至5.0。4℃冷藏备用；FeSSIF溶液(B)：25mL溶液(A)中溶解0.80652g牛胆磺酸钠(NaTC，分子量537.68)和295.5mg卵磷脂(分子量788.13)，强力搅拌过夜，形成澄清的胶束溶液，加入溶液(A)至体积为100mL，4℃冷藏备用(不超过2周)。FeSSIF solution is the intestinal fluid in the small intestine that simulates the postprandial satiety of humans. Preparation method: Solution (A): Weigh accurately 20.2g NaOH particles, 43.25g glacial acetic acid and 59.37g sodium chloride. Make up to 5L and adjust the pH to 5.0 with 1M NaOH or 1M HCl. Refrigerate at 4 ° C until use; FeSSIF solution (B): Dissolve 0.80652g sodium taurocholate (NaTC, molecular weight 537.68) and 295.5mg in 25mL solution (A). Lecithin (molecular weight 788.13), stir vigorously overnight to form a clear micellar solution, add solution (A) to a volume of 100 mL, and refrigerate at 4 ° C until use (no more than 2 weeks).
式(1)化合物制备例Preparation Example of Compound of Formula (1)
6-(8-氟喹啉-6-基)-5-苯基-1,2,4-三嗪-3-胺1(式(1)化合物)6- (8-fluoroquinolin-6-yl) -5-phenyl-1,2,4-triazine-3-amine 1 (compound of formula (1))
Figure PCTCN2019095724-appb-000005
Figure PCTCN2019095724-appb-000005
Figure PCTCN2019095724-appb-000006
Figure PCTCN2019095724-appb-000006
第一步first step
8-氟-6-(4,4,5,5-四甲基-1,3,2-二氧杂戊硼烷-2-基)喹啉1b8-fluoro-6- (4,4,5,5-tetramethyl-1,3,2-dioxolane-2-yl) quinoline 1b
在氩气氛下依次加入6-溴-8-氟喹啉1a(226mg，1.00mmol)、双(频哪醇合)二硼(305mg，1.20mmol)、[1,1'-双(二苯基膦基)二茂铁]二氯化钯(146mg，0.20mmol)和乙酸钾(294mg，3.00mmol)溶解于10mL乙二醇二甲醚溶液中，加热至80℃，搅拌12小时。停止反应，冷却至室温，过滤，滤液减压蒸馏，残余物用CombiFlash快速制备仪以洗脱剂体系B纯化，得到标题产物1b(220mg)，产率：80.1％。Under an argon atmosphere, 6-bromo-8-fluoroquinoline 1a (226 mg, 1.00 mmol), bis (pinacol) diboron (305 mg, 1.20 mmol), and [1,1'-bis (diphenyl) were added in this order. Phosphino) ferrocene] palladium dichloride (146 mg, 0.20 mmol) and potassium acetate (294 mg, 3.00 mmol) were dissolved in 10 mL of ethylene glycol dimethyl ether solution, heated to 80 ° C., and stirred for 12 hours. The reaction was stopped, cooled to room temperature, filtered, and the filtrate was distilled under reduced pressure. The residue was purified with a CombiFlash rapid preparation device with eluent system B to obtain the title product 1b (220 mg), yield: 80.1%.
MS m/z(ESI):274.1[M+1]。MS m / z (ESI): 274.1 [M + 1].
第二步Second step
6-(8-氟喹啉-6-基)-5-苯基-1,2,4-三嗪-3-胺16- (8-fluoroquinolin-6-yl) -5-phenyl-1,2,4-triazine-3-amine 1
在氩气氛下依次加入1b(109mg，0.40mmol)、1c(100mg，0.40mmol，采用公知的方法“Journal of Medicinal Chemistry,2012,55(5),1898-1903”制备而得)、[1,1'-双(二苯基膦基)二茂铁]二氯化钯(58mg，0.08mmol)和碳酸钾(156mg，1.20mmol)溶解于12mL 1,4-二氧六环和水(V:V＝5:1)的混合溶液中，加热至80℃，搅拌2小时。停止反应，冷却至室温，过滤，滤液减压浓缩，残余物用CombiFlash快速制备仪以洗脱剂体系A纯化，得到标题产物1(20mg)，产率：15.9％。Under an argon atmosphere, 1b (109 mg, 0.40 mmol) and 1c (100 mg, 0.40 mmol, which were prepared by a well-known method "Journal of Medicine Chemistry, 2012, 55 (5), 1898-1903") were sequentially added, [1, 1'-bis (diphenylphosphino) ferrocene] palladium dichloride (58 mg, 0.08 mmol) and potassium carbonate (156 mg, 1.20 mmol) were dissolved in 12 mL of 1,4-dioxane and water (V: V = 5: 1) The mixed solution was heated to 80 ° C. and stirred for 2 hours. The reaction was stopped, cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified with a CombiFlash flash prep with eluent system A to give the title product 1 (20 mg), yield: 15.9%.
MS m/z(ESI):318.4[M+1]。MS m / z (ESI): 318.4 [M + 1].
1H NMR(400MHz,DMSO-d 6)δ8.95(m,1H),8.38-8.40(d,1H),7.91(s,1H),7.58-7.62(m,3H),7.41-7.46(m,4H),7.35-7.37(m,2H)。 1 H NMR (400MHz, DMSO-d 6 ) δ 8.95 (m, 1H), 8.38-8.40 (d, 1H), 7.91 (s, 1H), 7.58-7.62 (m, 3H), 7.41-7.46 (m , 4H), 7.35-7.37 (m, 2H).
式(1)化合物生物活性测试例Test Example for Biological Activity of Compound of Formula (1)
式(1)化合物对腺苷A 2a受体、腺苷A 1受体(adenosine A 1 receptor，A 1R)cAMP信号通路和腺苷A 3受体cAMP信号通路抑制活性。 The compounds of formula (1) inhibitory activity against the adenosine A 2a receptor, adenosine A 1 receptor (adenosine A 1 receptor, A 1 R) cAMP signaling pathway, and adenosine A 3 receptor cAMP signaling pathway.
腺苷A 2a受体 Adenosine A 2a receptor
CHO-K1/A 2aR细胞用含有10％胎牛血清和800μg/mL博来霉素的DMEM/F12培养基进行培养。实验时使用细胞分离缓冲液消化细胞，用含有20mM HEPES和0.1％牛血清白蛋白的平衡盐缓冲液重悬细胞并计数，将细胞密度调整为10 6个/mL。在384孔板中每孔加入5μL细胞悬液，2.5μL用含有20mM HEPES，0.1％牛血清白蛋白，54μM咯 利普兰和2.7U/mL腺苷脱氨酶的平衡盐缓冲液配制的4×浓度的受试化合物，室温孵育30分钟。每孔再加入2.5μL用含有20mM HEPES，0.1％牛血清白蛋白，54μM咯利普兰和2.7U/mL腺苷脱氨酶的平衡盐缓冲液配制的4×浓度的乙基咔唑，室温孵育30分钟。化合物终浓度是：10000，2000，400，80，16，3.2，0.64，0.128，0.0256，0.00512，0.001024nM，乙基咔唑终浓度是20nM。细胞内cAMP浓度使用cAMP动态2试剂盒检测。用cAMP裂解缓冲液按1:4的比例分别稀释cAMP-d2和抗cAMP-Eu-穴状化合物(Anti-cAMP-Eu-Cryptate)。每孔加入5μL稀释后的cAMP-d2，再加入5μL稀释后的抗cAMP-Eu-穴状化合物，室温避光孵育1小时。采用PHERAstar多功能酶标仪读取HTRF信号值。用Graphpad Prism软件计算化合物抑制活性的IC 50值。 CHO-K1 / A 2a R cells were cultured in DMEM / F12 medium containing 10% fetal bovine serum and 800 μg / mL bleomycin. When cell separation experiments using buffer cells were digested with balanced salt buffer containing 20mM HEPES and 0.1% bovine serum albumin and resuspend the cells counted, and adjusted to a cell density of 10 6 / mL. Add 5 μL of cell suspension to each well in a 384-well plate, 2.5 μL of 4 × prepared with a balanced salt buffer containing 20 mM HEPES, 0.1% bovine serum albumin, 54 μM Rolipram, and 2.7 U / mL adenosine deaminase. Concentrations of the test compounds were incubated for 30 minutes at room temperature. Add 2.5 μL of 4 × concentration ethylcarbazole in a balanced salt buffer containing 20 mM HEPES, 0.1% bovine serum albumin, 54 μM rolipram and 2.7 U / mL adenosine deaminase in each well, and incubate at room temperature. 30 minutes. The final compound concentration was: 10,000, 2000, 400, 80, 16, 3.2, 0.64, 0.128, 0.0256, 0.00512, 0.001024 nM, and the final ethylcarbazole concentration was 20 nM. Intracellular cAMP concentration was measured using the cAMP Dynamic 2 kit. Dilute cAMP-d2 and Anti-cAMP-Eu-Cryptate with cAMP lysis buffer at a ratio of 1: 4. Add 5 μL of diluted cAMP-d2 to each well, and then add 5 μL of diluted anti-cAMP-Eu-cryptic compound, and incubate for 1 hour at room temperature in the dark. The HTRF signal value was read using a PHERAstar multifunctional microplate reader. Calculated using Graphpad Prism software compound to inhibit the activity of IC 50 values.
腺苷A 1受体 Adenosine A 1 receptor
CHO-K1/A 1R用含有10％胎牛血清和1mg/mL G418的DMEM/F12培养基进行培养。实验时使用细胞分离缓冲液消化细胞，然后用含有20mM HEPES和0.1％牛血清白蛋白的平衡盐缓冲液重悬细胞并计数，将细胞密度调整为5×10 5个/mL。在384孔板中每孔加入12.5μL细胞悬液，6.25μL用含有20mM HEPES，0.1％牛血清白蛋白，54μM咯利普兰和2.7U/mL腺苷脱氨酶的平衡盐缓冲液配制的4×浓度的受试化合物，室温孵育30分钟。每孔再加入6.25μL用含有20mM HEPES，0.1％牛血清白蛋白，54μM咯利普兰和2.7U/mL腺苷脱氨酶的平衡盐缓冲液配制的4×浓度的毛喉素和N6-环戊基腺苷，室温孵育30分钟。化合物终浓度是：100000，10000，1000，100，10，1，0.1和0nM，毛喉素的终浓度是10μM，CPA的终浓度是10nM。细胞内cAMP浓度使用cAMP动态2试剂盒检测。用cAMP裂解缓冲液按照1:4的比例分别稀释cAMP-d2和抗cAMP-Eu-穴状化合物。每孔加入12.5μL稀释后的cAMP-d2，再加入12.5μL稀释后的抗cAMP-Eu-穴状化合物，室温避光孵育1小时。采用PHERAstar多功能酶标仪读取HTRF信号值。用Graphpad Prism软件计算化合物抑制活性的IC 50值。 CHO-K1 / A 1 R was cultured in DMEM / F12 medium containing 10% fetal bovine serum and 1 mg / mL G418. During the experiment, the cells were digested with cell isolation buffer, and then the cells were resuspended and counted with a balanced salt buffer containing 20 mM HEPES and 0.1% bovine serum albumin, and the cell density was adjusted to 5 × 10 5 cells / mL. Add 12.5 μL of cell suspension to each well in a 384-well plate, 6.25 μL of 4 prepared with a balanced salt buffer containing 20 mM HEPES, 0.1% bovine serum albumin, 54 μM Rolipram and 2.7 U / mL adenosine deaminase × concentration of the test compound and incubated at room temperature for 30 minutes. Add another 6.25 μL of 4 × concentration of forskolin and N6-cycline in a balanced salt buffer containing 20 mM HEPES, 0.1% bovine serum albumin, 54 μM rolipram, and 2.7 U / mL adenosine deaminase. Amyl adenosine, incubated for 30 minutes at room temperature. The final compound concentrations were: 100,000, 10000, 1000, 100, 10, 1, 0.1, and 0 nM, the final concentration of forskolin was 10 μM, and the final concentration of CPA was 10 nM. Intracellular cAMP concentration was measured using the cAMP Dynamic 2 kit. Dilute cAMP-d2 and anti-cAMP-Eu-cryptic compound with cAMP lysis buffer at a ratio of 1: 4. Add 12.5 μL of diluted cAMP-d2 to each well, then add 12.5 μL of diluted anti-cAMP-Eu-cryptic compound, and incubate for 1 hour at room temperature in the dark. The HTRF signal value was read using a PHERAstar multifunctional microplate reader. Calculated using Graphpad Prism software compound to inhibit the activity of IC 50 values.
腺苷A 3受体 Adenosine A 3 receptor
CHO-K1/A 3R用含有10％胎牛血清和10μg/mL嘌呤霉素的DMEM/F12培养基进行培养。实验时使用细胞分离缓冲液消化细胞，用含有20mM HEPES和0.1％牛血清白蛋白的平衡盐缓冲液重悬细胞并计数，将细胞密度调整为5×10 5/mL。在384孔板中每孔加入12.5μL细胞悬液，6.25μL用含有20mM HEPES，0.1％牛血清白蛋白，54μM咯利普兰和2.7U/mL腺苷脱氨酶的平衡盐缓冲液配制的4×浓度的受试化合物，室温孵育30分钟。每孔再加入6.25μL用含有20mM HEPES，0.1％牛血清白蛋白，54μM咯利普兰和2.7U/mL腺苷脱氨酶的平衡盐缓冲液配制的4×浓度的毛喉素和2Cl-IB-MECA，室温孵 育30分钟。化合物终浓度是：100000，10000，1000，100，10，1，0.1和0nM，毛喉素的终浓度是10μM，2Cl-IB-MECA的终浓度是5nM。细胞内cAMP浓度使用cAMP动态2试剂盒检测。用cAMP裂解缓冲液按照1:4的比例分别稀释cAMP-d2和抗cAMP-Eu-穴状化合物。每孔加入12.5μL稀释后的cAMP-d2，再加入12.5μL稀释后的抗cAMP-Eu-穴状化合物，室温避光孵育1小时。采用PHERAstar多功能酶标仪读取HTRF信号值。用Graphpad Prism软件计算化合物抑制活性的IC 50值。 CHO-K1 / A 3 R was cultured in DMEM / F12 medium containing 10% fetal bovine serum and 10 μg / mL puromycin. During the experiment, the cells were digested with cell separation buffer, and the cells were resuspended and counted with a balanced salt buffer containing 20 mM HEPES and 0.1% bovine serum albumin, and the cell density was adjusted to 5 × 10 5 / mL. Add 12.5 μL of cell suspension to each well in a 384-well plate, 6.25 μL of 4 prepared with a balanced salt buffer containing 20 mM HEPES, 0.1% bovine serum albumin, 54 μM Rolipram, and 2.7 U / mL adenosine deaminase. × concentration of the test compound and incubated at room temperature for 30 minutes. Add 6.25 μL of 4 × concentration of forskolin and 2Cl-IB in a balanced salt buffer containing 20 mM HEPES, 0.1% bovine serum albumin, 54 μM rolipram, and 2.7 U / mL adenosine deaminase. -MECA, incubate at room temperature for 30 minutes. The final compound concentrations were: 100,000, 10,000, 1000, 100, 10, 1, 0.1, and 0 nM, the final concentration of forskolin was 10 μM, and the final concentration of 2Cl-IB-MECA was 5 nM. Intracellular cAMP concentration was measured using the cAMP Dynamic 2 kit. Dilute cAMP-d2 and anti-cAMP-Eu-cryptic compound with cAMP lysis buffer at a ratio of 1: 4. Add 12.5 μL of diluted cAMP-d2 to each well, and then add 12.5 μL of diluted anti-cAMP-Eu-cryptic compound, and incubate for 1 hour at room temperature in the dark. The HTRF signal value was read using a PHERAstar multifunctional microplate reader. Calculated using Graphpad Prism software compound to inhibit the activity of IC 50 values.
Figure PCTCN2019095724-appb-000007
Figure PCTCN2019095724-appb-000007
式(1)化合物小鼠药代动力学实验Pharmacokinetic experiments of compounds of formula (1) in mice
试验动物：C57小鼠9只，雌性，购自上海杰思捷实验动物有限公司，动物生产许可证号：SCXK(沪)2013-0006。Test animals: 9 C57 mice, female, purchased from Shanghai Jiesijie Experimental Animal Co., Ltd., animal production license number: SCXK (Shanghai) 2013-0006.
药物配制：称取一定量药物，加5％体积的DMSO、5％体积的tween80和90％生理盐水配置成0.1mg/mL无色澄清透明液体。Drug preparation: Weigh out a certain amount of drug, add 5% volume of DMSO, 5% volume of tween80 and 90% physiological saline to configure 0.1mg / mL colorless and clear liquid.
给药：C57小鼠禁食过夜后灌胃给药，给药剂量均为2.0mg/kg，给药体积均为0.2mL/10g。Administration: C57 mice were administered orally after fasting overnight. The administration dose was 2.0 mg / kg, and the administration volume was 0.2 mL / 10 g.
操作：小鼠灌胃给药，于给药前及给药后0.5，1.0，2.0，4.0，6.0，8.0，11.0，24.0小时采血0.1mL，置于肝素化试管中，3500转/分钟离心10分钟分离血浆，于-20℃保存。Operation: Mice were administered by gavage. 0.1 mL of blood was collected before and after 0.5, 1.0, 2.0, 4.0, 6.0, 8.0, 11.0, and 24.0 hours after administration. The blood was collected in a heparinized test tube and centrifuged at 3500 rpm for 10 minutes. The plasma was separated in minutes and stored at -20 ° C.
测定不同浓度的药物灌胃给药后小鼠血浆中的待测化合物含量：取给药后各时刻的小鼠血浆25μL，加入内标溶液喜树碱50μL(100ng/mL)，乙腈200μL，涡旋混合5分钟，离心10分钟(4000转/分钟)，血浆样品取上清液5μL进行LC/MS/MS分析。Determine the content of test compound in mouse plasma after oral administration of drugs with different concentrations: Take 25 μL of mouse plasma at each time after administration, add 50 μL of internal standard solution camptothecin (100 ng / mL), 200 μL of acetonitrile, vortex Centrifuge for 5 minutes, centrifuge for 10 minutes (4000 rpm), and take 5 μL of the supernatant from the plasma sample for LC / MS / MS analysis.
Figure PCTCN2019095724-appb-000008
Figure PCTCN2019095724-appb-000008
实施例1 A晶型的制备Example 1 Preparation of Form A
将化合物1c(3.5g,13.94mmol)，1b(3.807g,13.94mmol)，[1,1'-双(二苯基膦基)二茂铁]二氯化钯(2.04g,2.79mmol)和碳酸钾(5.771g,41.82mmol)溶解于12mL 1,4-二氧六环和水(V:V＝5:1)的混合溶液中，氩气置换三次，加热至80℃，搅拌2小时。冷却，硅藻土过滤，滤液减压浓缩，残余物用CombiFlash快速制备仪以洗脱剂体系A纯化，得到粗品。粗品溶解于20mL二氯甲烷中，打浆，反应液过滤，收集滤饼。将滤饼溶解于二氯甲烷和甲醇(V:V＝30:1)的混合溶液中，再次打浆，反应液过滤，收集滤饼，真空干燥，得到产物(2g)。Compound 1c (3.5g, 13.94mmol), 1b (3.807g, 13.94mmol), [1,1'-bis (diphenylphosphino) ferrocene] palladium dichloride (2.04g, 2.79mmol) and Potassium carbonate (5.771 g, 41.82 mmol) was dissolved in 12 mL of a mixed solution of 1,4-dioxane and water (V: V = 5: 1), replaced with argon three times, heated to 80 ° C., and stirred for 2 hours. It was cooled, filtered through celite, and the filtrate was concentrated under reduced pressure. The residue was purified with a CombiFlash rapid preparation device using eluent system A to obtain a crude product. The crude product was dissolved in 20 mL of dichloromethane, beaten, and the reaction solution was filtered, and the filter cake was collected. The filter cake was dissolved in a mixed solution of dichloromethane and methanol (V: V = 30: 1), slurried again, and the reaction solution was filtered. The filter cake was collected and dried under vacuum to obtain the product (2 g).
经X-射线粉末衍射检测，将该产物定义为A晶型，XRPD谱图如图1。DSC图谱如图2，吸热峰峰值为230.97℃，238.04℃，在170℃左右有小的放热峰，将样品在DSC中升温至150℃、190℃，分别取出检测晶型，发现放热峰后晶型转变为B晶型，如图3。TGA图谱如图4所示。After X-ray powder diffraction detection, the product was defined as Form A, and the XRPD spectrum is shown in Figure 1. The DSC spectrum is shown in Figure 2. The peak values of the endothermic peaks are 230.97 ° C, 238.04 ° C, and there are small exothermic peaks at about 170 ° C. The sample was heated to 150 ° C and 190 ° C in DSC, and the detection crystal forms were taken out, respectively. After the peak, the crystal form changed to the B crystal form, as shown in FIG. 3. The TGA map is shown in Figure 4.
DVS表征：A晶型样品在25℃的条件下，样品稳定吸湿；根据相对质量变化曲线，在10％RH-80％RH之间，随着湿度增加，质量增加约为0.3805％，小于2％但不小于0.2％，根据《中华人民共和国药典》2015年版药物引湿性试验指导原则，该样品略有引湿性。在正常储存条件(即25℃、湿度60％)，吸水约为0.2935％；在加速试验条件(即湿度70％)，吸水约为0.3508％；在极端条件(即湿度90％)，吸水约为0.5340％。在0％-95％的湿度变化过程中，该样品的解吸附过程与吸附过程基本重合(见图5)；DVS前后X-射线粉末衍射对比图显示DVS检测前后晶型未发生转变(见图6)。DVS characterization: A crystal sample is stable in moisture absorption at 25 ℃; according to the relative mass change curve, between 10% RH and 80% RH, with the increase of humidity, the mass increase is about 0.3805%, less than 2% But not less than 0.2%. According to the 2015 Pharmacopoeia Guidelines for Drug Hygroscopicity Test, the sample is slightly hygroscopic. Under normal storage conditions (ie, 25 ° C, 60% humidity), water absorption is about 0.2935%; under accelerated test conditions (ie, humidity 70%), water absorption is about 0.3508%; under extreme conditions (ie, humidity 90%), water absorption is about 0.5340%. During the humidity change from 0% to 95%, the desorption process of the sample coincides with the adsorption process (see Figure 5); the X-ray powder diffraction comparison chart before and after DVS shows that the crystal form has not changed before and after DVS detection (see Figure 5). 6).
表1、A晶型的特征峰Table 1.Characteristic peaks of Form A
序号Serial number 2-Theta2-Theta d(A)d (A) I％I%
峰1Peak 1 8.0198.019 11.0164511.01645 2.62.6
峰2Peak 2 8.6978.697 10.1593810.15938 100.0100.0
峰3Peak 3 11.84611.846 7.464927.46492 0.70.7
峰4Peak 4 13.21613.216 6.693606.69360 6.36.3
峰5 Peak 5 13.52113.521 6.543686.54368 1.01.0
峰6 Peak 6 15.60215.602 5.675025.67502 0.40.4
峰7 Peak 7 16.03316.033 5.523535.52353 0.90.9
峰8 Peak 8 16.65816.658 5.317795.31779 0.90.9
峰9 Peak 9 16.96816.968 5.221165.22116 1.21.2
峰10 Peak 10 17.58117.581 5.040465.04046 7.07.0
峰11 Peak 11 18.24518.245 4.858424.85842 1.21.2
峰12 Peak 12 19.66019.660 4.511934.51193 0.50.5
峰13 Peak 13 21.62421.624 4.106414.10641 17.017.0
峰14 Peak 14 23.45823.458 3.789283.78928 4.94.9
峰15 Peak 15 24.13924.139 3.683893.68389 0.80.8
峰16 Peak 16 25.41225.412 3.502193.50219 8.28.2
峰17 Peak 17 26.49626.496 3.361323.36132 10.510.5
峰18 Peak 18 29.39829.398 3.035753.03575 11.111.1
峰19 Peak 19 31.98131.981 2.796252.79625 0.60.6
峰20 Peak 20 33.57633.576 2.666962.66696 1.41.4
实施例2 A晶型的制备Example 2 Preparation of Form A
将式(1)化合物(50mg)溶于2mL甲醇和二氯甲烷(V:V＝1:10)混合溶剂中，室温搅拌未溶清，滤膜过滤，滤液自然挥发60小时，析出固体。反应液过滤，收集滤饼，真空干燥，得到产物(26mg)。经X-射线粉末衍射检测，该产物为A晶型。The compound of formula (1) (50 mg) was dissolved in 2 mL of methanol and dichloromethane (V: V = 1: 10) in a mixed solvent, stirred at room temperature and undissolved, filtered through a filter, and the filtrate was naturally evaporated for 60 hours to precipitate a solid. The reaction solution was filtered, and the filter cake was collected and dried under vacuum to obtain the product (26 mg). The product was found to be in Form A by X-ray powder diffraction.
实施例3 A晶型的制备Example 3 Preparation of Form A
将式(1)化合物(1.2g)溶于30mL乙腈中，室温搅拌未溶清，加热至70℃，溶清后搅拌30分钟，程序降温，再室温搅拌17小时，反应液过滤，收集滤饼，真空干燥，得到产物(876mg)。The compound of formula (1) (1.2 g) was dissolved in 30 mL of acetonitrile, stirred at room temperature and heated to 70 ° C, dissolved and stirred for 30 minutes, the program was cooled, and then stirred at room temperature for 17 hours. The reaction solution was filtered and the filter cake was collected. And dried in vacuo to give the product (876 mg).
经X-射线粉末衍射检测，该产物为A晶型。After X-ray powder diffraction detection, the product was in Form A.
实施例4 B晶型的制备Example 4 Preparation of Form B
将式(1)化合物(30g)用高效液相制备(Waters 2767-SQ，洗脱体系(醋酸铵，水，乙腈))纯化，反应液过滤，收集滤饼，真空干燥，得到产物(15g)。The compound (30 g) of formula (1) was prepared by high-performance liquid phase (Waters 2767-SQ, elution system (ammonium acetate, water, acetonitrile)), and the reaction solution was filtered. The filter cake was collected and dried under vacuum to obtain the product (15 g). .
经X-射线粉末衍射检测，将该产物定义为B晶型，XRPD谱图如图7。DSC图谱如图8，吸热峰峰值231.03℃，237.78℃，将样品在DSC中升温至150℃、190℃，分别取出检测晶型，均未转变，如图9。TGA图谱如图10。PSD图谱如图11所示。After X-ray powder diffraction detection, the product was defined as Form B, and the XRPD spectrum is shown in FIG. 7. The DSC spectrum is shown in Figure 8. The endothermic peaks are 231.03 ° C and 237.78 ° C. The sample was heated to 150 ° C and 190 ° C in DSC, and the detection crystal forms were taken out, but none were transformed, as shown in Figure 9. The TGA map is shown in Figure 10. The PSD map is shown in Figure 11.
DVS表征：B晶型样品在25℃的条件下，在P/P0 70开始迅速吸湿；根据相对质量变化曲线，在10％RH-80％RH之间，随着湿度增加，质量增加约为0.4010％，小于2％但不小于0.2％，根据《中华人民共和国药典》2015年版药物引湿性试验指导原则，该样品略有引湿性。在正常储存条件(即25℃、湿度60％)，吸水约为0.2150％；在加速试验 条件(即湿度70％)，吸水约为0.283％；在极端条件(即湿度90％)，吸水约为0.760％。在0％-95％的湿度变化过程中，该样品的解吸附过程与吸附过程基本重合(见图12)；DVS前后X-射线粉末衍射对比图显示DVS检测前后晶型未发生转变(见图13)。DVS Characterization: Sample B crystal starts to absorb moisture quickly at P / P0 at 25 ℃; according to the relative mass change curve, between 10% RH and 80% RH, with the increase of humidity, the mass increases by about 0.4010 %, Less than 2% but not less than 0.2%. According to the 2015 Pharmacopoeia Guidelines for Drug Hygroscopicity Test, this sample is slightly hygroscopic. Under normal storage conditions (ie, 25 ° C, 60% humidity), water absorption is about 0.2150%; under accelerated test conditions (ie, humidity 70%), water absorption is about 0.283%; under extreme conditions (ie, humidity 90%), water absorption is about 0.760%. During the humidity change from 0% to 95%, the desorption process of the sample and the adsorption process basically coincide (see Figure 12); the X-ray powder diffraction comparison chart before and after DVS shows that the crystal form has not changed before and after DVS detection (see figure 13).
表2、B晶型的特征峰Table 2. Characteristic peaks of Form B
序号Serial number 2-Theta2-Theta d(A)d (A) I％I%
峰1Peak 1 6.2126.212 14.2168414.21684 8.708.70
峰2Peak 2 7.8157.815 11.3038611.30386 100.00100.00
峰3Peak 3 8.6578.657 10.2055410.20554 9.809.80
峰4Peak 4 10.72310.723 8.244048.24404 2.602.60
峰5Peak 5 11.65411.654 7.587567.58756 2.902.90
峰6Peak 6 12.97212.972 6.819166.81916 9.309.30
峰7Peak 7 14.27214.272 6.201026.20102 17.1017.10
峰8Peak 8 15.83515.835 5.592135.59213 10.2010.20
峰9Peak 9 17.65517.655 5.019675.01967 8.608.60
峰10 Peak 10 18.34218.342 4.832994.83299 8.208.20
峰11 Peak 11 19.44819.448 4.560584.56058 9.009.00
峰12 Peak 12 21.28321.283 4.171284.17128 3.403.40
峰13 Peak 13 22.27322.273 3.988143.98814 50.1050.10
峰14 Peak 14 22.35322.353 3.974143.97414 43.4043.40
峰15 Peak 15 23.91523.915 3.717843.71784 7.907.90
峰16 Peak 16 24.86424.864 3.578053.57805 63.2063.20
峰17 Peak 17 26.56226.562 3.353063.35306 5.805.80
峰18 Peak 18 27.60127.601 3.229253.22925 28.9028.90
峰19 Peak 19 32.48532.485 2.753972.75397 3.103.10
实施例5 B晶型的制备Example 5 Preparation of Form B
将式(1)化合物(50mg)溶于2mL甲醇中，室温搅拌未溶清，滤膜过滤，滤液自然挥发60小时，析出固体。反应液过滤，收集滤饼，真空干燥，得到产物(23mg)。经X-射线粉末衍射检测，该产物为B晶型。The compound of formula (1) (50 mg) was dissolved in 2 mL of methanol, and the solution was stirred at room temperature to remove the solution. The filtrate was filtered, and the filtrate was naturally evaporated for 60 hours to precipitate a solid. The reaction solution was filtered, and the filter cake was collected and dried under vacuum to obtain the product (23 mg). The product was in the B-form by X-ray powder diffraction detection.
实施例6 B晶型的制备Example 6 Preparation of Form B
将式(1)化合物(50mg)溶于2mL甲醇和二氯甲烷(V:V＝1:1)的混合溶液中，室温搅拌 未溶清，加热至70℃，溶清后搅拌30分钟，程序降温，室温搅拌17小时，析出固体。反应液过滤，收集滤饼，真空干燥，得到产物(23mg)。经X-射线粉末衍射检测，该产物为B晶型。Dissolve the compound (1) (50 mg) in a mixed solution of 2 mL of methanol and dichloromethane (V: V = 1: 1), stir the undissolved solution at room temperature, heat to 70 ° C, and stir for 30 minutes after dissolution. Procedure The temperature was lowered, and the mixture was stirred at room temperature for 17 hours to precipitate a solid. The reaction solution was filtered, and the filter cake was collected and dried under vacuum to obtain the product (23 mg). The product was in the B-form by X-ray powder diffraction detection.
实施例7 B晶型的制备Example 7 Preparation of Form B
将式(1)化合物(50mg)溶于2mL乙醇和二氯甲烷(V:V＝1:3)的混合溶液中，室温搅拌未溶清，加热至70℃，溶清后搅拌30分钟，程序降温，室温搅拌17小时，析出固体。反应液过滤，收集滤饼，真空干燥，得到产物(27mg)。经X-射线粉末衍射检测，该产物为B晶型。Dissolve the compound (1) (50 mg) in a mixed solution of 2 mL of ethanol and dichloromethane (V: V = 1: 3), stir the undissolved solution at room temperature, heat to 70 ° C, and stir for 30 minutes after dissolution. Procedure The temperature was lowered, and the mixture was stirred at room temperature for 17 hours to precipitate a solid. The reaction solution was filtered, and the filter cake was collected and dried under vacuum to obtain the product (27 mg). The product was in the B-form by X-ray powder diffraction detection.
实施例8 B晶型的制备Example 8 Preparation of Form B
将式(1)化合物(50mg)溶于2mL异丙醇和二氯甲烷(V:V＝1:5)的混合溶液中，室温搅拌未溶清，加热至70℃，溶清后搅拌30分钟，程序降温，室温搅拌17小时，析出固体。反应液过滤，收集滤饼，真空干燥，得到产物(26mg)。经X-射线粉末衍射检测，该产物为B晶型。Dissolve the compound (1) (50 mg) in a mixed solution of 2 mL of isopropanol and dichloromethane (V: V = 1: 5), stir the undissolved solution at room temperature, heat to 70 ° C, and stir for 30 minutes after dissolution. The program was cooled and stirred at room temperature for 17 hours, and a solid precipitated. The reaction solution was filtered, and the filter cake was collected and dried under vacuum to obtain the product (26 mg). The product was in the B-form by X-ray powder diffraction detection.
实施例9 B晶型的制备Example 9 Preparation of Form B
将式(1)化合物(50mg)溶于2mL丙酮中，室温搅拌未溶清，加热至70℃，溶清后搅拌30分钟，程序降温，室温搅拌17小时，析出固体。反应液过滤，收集滤饼，真空干燥，得到产物(26mg)。经X-射线粉末衍射检测，该产物为B晶型。The compound of formula (1) (50 mg) was dissolved in 2 mL of acetone, stirred at room temperature for undissolved, heated to 70 ° C., dissolved and stirred for 30 minutes, the program was cooled, and the room temperature was stirred for 17 hours to precipitate a solid. The reaction solution was filtered, and the filter cake was collected and dried under vacuum to obtain the product (26 mg). The product was in the B-form by X-ray powder diffraction detection.
实施例10 C晶型的制备Example 10 Preparation of Form C
将式(1)化合物(200mg)溶于25mL四氢呋喃中，加热至60℃，溶清后搅拌30分钟，缓慢降至室温，继续搅拌17小时。反应液过滤，收集滤饼，真空干燥，得到产物(123mg)。The compound of formula (1) (200 mg) was dissolved in 25 mL of tetrahydrofuran, heated to 60 ° C., dissolved and stirred for 30 minutes, slowly lowered to room temperature, and continued stirring for 17 hours. The reaction solution was filtered, and the filter cake was collected and dried under vacuum to obtain the product (123 mg).
经X-射线粉末衍射检测，将该产物定义为C晶型，XRPD谱图如图14。DSC图谱如图15，显示吸热峰峰值为145.52℃，231.45℃，238.60℃。TGA图谱如图16，在40℃-150℃之间失重9.0743％。After X-ray powder diffraction detection, the product was defined as the crystal form C, and the XRPD spectrum is shown in FIG. 14. The DSC spectrum is shown in Fig. 15, and the endothermic peaks are 145.52 ° C, 231.45 ° C, and 238.60 ° C. The TGA pattern is shown in Figure 16, with a weight loss of 9.0743% between 40 ° C and 150 ° C.
所得产物的 1H-NMR数据如下所示，核磁数据表明该盐中主成分与四氢呋喃的摩尔比为1:0.36，四氢呋喃重量含量为7.6％。 1H NMR(400MHz,DMSO-d 6)δppm 8.95(d,1H),8.39(d,1H),7.91(s,1H),7.54-7.69(m,3H),7.40-7.48(m,4H),7.33-7.38(m,2H),3.59(t,1.43H),1.72-1.79(m,1.44H)。 The 1 H-NMR data of the obtained product are shown below. The nuclear magnetic data showed that the molar ratio of the main component to tetrahydrofuran in the salt was 1: 0.36, and the weight content of tetrahydrofuran was 7.6%. 1 H NMR (400MHz, DMSO-d 6 ) δ ppm 8.95 (d, 1H), 8.39 (d, 1H), 7.91 (s, 1H), 7.54-7.69 (m, 3H), 7.40-7.48 (m, 4H) , 7.33-7.38 (m, 2H), 3.59 (t, 1.43H), 1.72-1.79 (m, 1.44H).
表3、C晶型的特征峰Table 3.Characteristic peaks of Form C
序号Serial number 2-Theta2-Theta d(A)d (A) I％I%
峰1Peak 1 8.1688.168 10.8164510.81645 90.790.7
峰2Peak 2 11.73311.733 7.536567.53656 6.56.5
峰3 Peak 3 12.17812.178 7.261877.26187 7.97.9
峰4Peak 4 12.66012.660 6.986406.98640 5.45.4
峰5 Peak 5 13.92313.923 6.355586.35558 7.17.1
峰6 Peak 6 16.54316.543 5.354305.35430 20.220.2
峰7Peak 7 17.65817.658 5.018785.01878 26.426.4
峰8Peak 8 19.77419.774 4.486124.48612 18.818.8
峰9Peak 9 21.00321.003 4.226254.22625 40.440.4
峰10 Peak 10 21.98221.982 4.040274.04027 7.27.2
峰11 Peak 11 23.31923.319 3.811653.81165 30.530.5
峰12 Peak 12 23.67323.673 3.755413.75541 3.53.5
峰13 Peak 13 24.99524.995 3.559613.55961 100.0100.0
峰14 Peak 14 26.13726.137 3.406623.40662 2.02.0
峰15 Peak 15 27.79927.799 3.206663.20666 3.13.1
峰16 Peak 16 28.41928.419 3.138083.13808 15.215.2
峰17 Peak 17 30.94730.947 2.887262.88726 5.55.5
峰18 Peak 18 31.81731.817 2.810252.81025 2.52.5
实施例11 D晶型的制备Example 11 Preparation of D crystal form
将式(1)化合物(200mg)溶于30mL二氯乙烷中，加热至60℃，溶清后搅拌30分钟，缓慢降至室温，继续搅拌17小时。反应液过滤，收集滤饼，真空干燥，得到产物(117mg)。The compound of formula (1) (200 mg) was dissolved in 30 mL of dichloroethane, heated to 60 ° C., dissolved and stirred for 30 minutes, slowly lowered to room temperature, and continued stirring for 17 hours. The reaction solution was filtered, and the filter cake was collected and dried under vacuum to obtain the product (117 mg).
经X-射线粉末衍射检测，将该产物定义为D晶型，XRPD如图17。DSC图谱如图18，显示吸热峰峰值为238.18℃。TGA图谱如图19，在40℃-180℃之间失重11.7276％。After X-ray powder diffraction detection, the product was defined as the D crystal form, and the XRPD is shown in FIG. 17. The DSC spectrum is shown in Fig. 18, which shows that the peak value of the endothermic peak is 238.18 ° C. The TGA chart is shown in Figure 19, with a weight loss of 11.7726% between 40 ° C and 180 ° C.
所得产物的 1H-NMR数据如下所示，核磁数据表明该盐中主成分与二氯乙烷的摩尔比为1:0.32，二氯乙烷重量含量为9.1％。 1H NMR(400MHz,DMSO-d 6)δppm 8.95((dd,1H),8.39(d,1H),7.90-7.94(m,1H),7.52-7.69(m,3H),7.39-7.48(m,4H),7.31-7.38(m,2H),3.90(s,1.28H)。 The 1 H-NMR data of the obtained product are shown below. Nuclear magnetic data showed that the molar ratio of the main component to dichloroethane in the salt was 1: 0.32, and the weight content of dichloroethane was 9.1%. 1 H NMR (400MHz, DMSO-d 6 ) δ ppm 8.95 ((dd, 1H), 8.39 (d, 1H), 7.90-7.94 (m, 1H), 7.52-7.69 (m, 3H), 7.39-7.48 (m , 4H), 7.31-7.38 (m, 2H), 3.90 (s, 1.28H).
表4、D晶型的特征峰Table 4. Characteristic peaks of Form D
序号Serial number 2-Theta2-Theta d(A)d (A) I％I%
峰1Peak 1 6.2256.225 14.1876814.18768 3.93.9
峰2Peak 2 6.2346.234 14.1674914.16749 3.53.5
峰3Peak 3 8.1228.122 10.8770610.87706 57.557.5
峰4Peak 4 12.20012.200 7.248687.24868 47.447.4
峰5Peak 5 15.17315.173 5.834675.83467 6.76.7
峰6 Peak 6 20.17920.179 4.397084.39708 27.127.1
峰7Peak 7 24.97324.973 3.562813.56281 47.947.9
峰8Peak 8 27.30327.303 3.263723.26372 100.0100.0
实施例12 E晶型的制备Example 12 Preparation of E crystal form
将式(1)化合物(1.2g)溶于30mL甲醇中，室温搅拌未溶清，加热至70℃，再加入10ml二氯甲烷至溶清后搅拌30分钟，程序降温，室温搅拌17小时。反应液过滤，收集滤饼，真空干燥，得到产物(838mg)。The compound of formula (1) (1.2 g) was dissolved in 30 mL of methanol, and the solution was stirred at room temperature, heated to 70 ° C, and 10 ml of dichloromethane was added to the solution, and the mixture was stirred for 30 minutes. The temperature was lowered and the solution was stirred at room temperature for 17 hours. The reaction solution was filtered, and the filter cake was collected and dried under vacuum to obtain the product (838 mg).
经X-射线粉末衍射检测，将该产物定义为E晶型，XRPD谱图如图20。DSC图谱如图21，显示吸热峰峰值为232.02℃,239.26℃。TGA图谱如图22，在40℃-140℃之间失重1.8556％。After X-ray powder diffraction detection, the product was defined as the E form, and the XRPD spectrum is shown in FIG. 20. The DSC spectrum is shown in Figure 21, which shows that the endothermic peaks are 232.02 ° C, 239.26 ° C. The TGA pattern is shown in Figure 22, with a weight loss of 1.8556% between 40 ° C and 140 ° C.
所得产物的 1H-NMR数据如下所示，核磁数据表明该盐中主成分与二氯甲烷的摩尔比为1:0.25，二氯甲烷重量含量为6.3％。 1H NMR(400MHz,DMSO-d 6)δppm 8.95(d,1H),8.39(d,1H),7.92(d,1H),7.55-7.67(m,3H),7.40-7.48(m,4H),7.32-7.38(m,2H),5.76(s,0.50H)。 The 1 H-NMR data of the obtained product are shown below. Nuclear magnetic data showed that the molar ratio of the main component to dichloromethane in the salt was 1: 0.25, and the dichloromethane content was 6.3% by weight. 1 H NMR (400MHz, DMSO-d 6 ) δ ppm 8.95 (d, 1H), 8.39 (d, 1H), 7.92 (d, 1H), 7.55-7.67 (m, 3H), 7.40-7.48 (m, 4H) , 7.32-7.38 (m, 2H), 5.76 (s, 0.50H).
表5、E晶型的特征峰Table 5.Characteristic peaks of Form E
序号Serial number 2-Theta2-Theta d(A)d (A) I％I%
峰1Peak 1 8.2628.262 10.6936910.69369 100.0100.0
峰2Peak 2 12.39812.398 7.133627.13362 1.61.6
峰3 Peak 3 13.08013.080 6.763306.76330 1.11.1
峰4Peak 4 16.79216.792 5.275615.27561 12.412.4
峰5Peak 5 20.41720.417 4.346304.34630 0.80.8
峰6 Peak 6 21.34421.344 4.159634.15963 2.52.5
峰7 Peak 7 22.81922.819 3.893943.89394 0.60.6
峰8 Peak 8 23.92923.929 3.715773.71577 2.62.6
峰9Peak 9 25.34725.347 3.511043.51104 24.424.4
峰10 Peak 10 28.76028.760 3.101603.10160 1.11.1
峰11 Peak 11 29.10429.104 3.065783.06578 0.60.6
实施例13 E晶型的制备Example 13 Preparation of crystalline form E
将式(1)化合物(50mg)溶于2mL乙酸乙酯和二氯甲烷(V:V＝1:2)的混合溶液中，室温搅拌未溶清，加热至70℃，溶清后搅拌30分钟，程序降温，室温搅拌17小时。反应液过滤，收集滤饼，真空干燥，得到产物(16mg)。经X-射线粉末衍射检测，该产物为E晶型。The compound of formula (1) (50 mg) was dissolved in 2 mL of a mixed solution of ethyl acetate and dichloromethane (V: V = 1: 2), stirred at room temperature to dissolve, heated to 70 ° C, and stirred for 30 minutes after dissolution The program was cooled down and stirred at room temperature for 17 hours. The reaction solution was filtered, and the filter cake was collected and dried under vacuum to obtain the product (16 mg). The product was in the E-form by X-ray powder diffraction detection.
实施例14 F晶型的制备Example 14 Preparation of F crystal form
将式(1)化合物(50mg)溶于2mL 1,4-二氧六环中，室温搅拌未溶清，用滤膜过滤，自然挥发60小时，析出固体。反应液过滤，收集滤饼，真空干燥，得到产物(23mg)。The compound (50 mg) of the formula (1) was dissolved in 2 mL of 1,4-dioxane, and the solution was stirred at room temperature to be undissolved, filtered through a filter, and naturally evaporated for 60 hours to precipitate a solid. The reaction solution was filtered, and the filter cake was collected and dried under vacuum to obtain the product (23 mg).
经X-射线粉末衍射检测，该产物为F晶型，XRPD谱图如图23。After X-ray powder diffraction detection, the product was in the F crystal form, and the XRPD spectrum is shown in FIG. 23.
表6、F晶型的特征峰Table 6.Characteristic peaks of Form F
序号Serial number 2-Theta2-Theta d(A)d (A) I％I%
峰1Peak 1 5.7175.717 15.4459915.44599 1.71.7
峰2Peak 2 8.0818.081 10.9325310.93253 64.164.1
峰3Peak 3 9.0229.022 9.793759.79375 5.45.4
峰4Peak 4 11.64511.645 7.592997.59299 6.26.2
峰5 Peak 5 12.58112.581 7.030097.03009 4.44.4
峰6 Peak 6 13.83713.837 6.394616.39461 14.714.7
峰7Peak 7 16.51416.514 5.363815.36381 11.211.2
峰8Peak 8 17.70017.700 5.006905.00690 27.827.8
峰9Peak 9 19.75819.758 4.489874.48987 13.613.6
峰10 Peak 10 20.95320.953 4.236394.23639 11.311.3
峰11 Peak 11 21.85921.859 4.062724.06272 4.44.4
峰12 Peak 12 23.03923.039 3.857273.85727 17.017.0
峰13 Peak 13 23.64023.640 3.760613.76061 30.230.2
峰14 Peak 14 24.77724.777 3.590433.59043 100.0100.0
峰15 Peak 15 26.16426.164 3.403183.40318 4.44.4
峰16 Peak 16 27.14127.141 3.282913.28291 4.04.0
峰17 Peak 17 28.27728.277 3.153493.15349 11.511.5
峰18 Peak 18 31.59931.599 2.829142.82914 3.13.1
峰19 Peak 19 33.30333.303 2.688222.68822 6.66.6
峰20 Peak 20 36.34236.342 2.470062.47006 8.28.2
峰21 Peak 21 43.86343.863 2.062402.06240 2.92.9
峰22 Peak 22 44.43544.435 2.037162.03716 2.92.9
峰23 Peak 23 46.34446.344 1.957611.95761 8.18.1
实施例15 G晶型的制备Example 15 Preparation of G crystal form
将E晶型(5mg)研磨30分钟，得到产物。经X-射线粉末衍射检测，将该产物定义为G晶型，XRPD谱图如图24。Form E (5 mg) was ground for 30 minutes to obtain the product. After X-ray powder diffraction detection, the product was defined as the G crystal form.
表7、G晶型的特征峰Table 7.Characteristic peaks of Form G
序号Serial number 2-Theta2-Theta d(A)d (A) I％I%
峰1Peak 1 7.8777.877 11.2151211.21512 27.027.0
峰2Peak 2 8.3288.328 10.6084710.60847 100.0100.0
峰3Peak 3 8.4628.462 10.4410310.44103 61.361.3
峰4Peak 4 12.45712.457 7.099817.09981 13.913.9
峰5Peak 5 13.11513.115 6.745126.74512 9.19.1
峰6 Peak 6 14.32414.324 6.178386.17838 4.84.8
峰7 Peak 7 16.20116.201 5.466695.46669 5.35.3
峰8 Peak 8 16.86616.866 5.252705.25270 18.418.4
峰9Peak 9 18.03418.034 4.914944.91494 7.37.3
峰10 Peak 10 19.57519.575 4.531384.53138 5.85.8
峰11 Peak 11 20.45320.453 4.338744.33874 9.39.3
峰12 Peak 12 21.39921.399 4.148964.14896 23.623.6
峰13 Peak 13 22.29322.293 3.984543.98454 27.427.4
峰14 Peak 14 22.50222.502 3.948003.94800 20.920.9
峰15 Peak 15 23.97423.974 3.708873.70887 26.926.9
峰16 Peak 16 24.86824.868 3.577583.57758 31.231.2
峰17 Peak 17 25.43925.439 3.498483.49848 44.644.6
峰18 Peak 18 26.46026.460 3.365863.36586 3.53.5
峰19 Peak 19 27.61727.617 3.227343.22734 24.224.2
峰20 Peak 20 28.82028.820 3.095283.09528 7.97.9
峰21 Peak 21 29.19929.199 3.055973.05597 7.37.3
峰22 Peak 22 31.76631.766 2.814652.81465 3.23.2
实施例16混合晶浆实验Example 16 mixed crystal slurry
将A晶型(150mg)和B晶型(150mg)溶于10mL丙酮中，混合打浆24小时。反应液过滤，收集滤饼，真空干燥，得到产物(266mg)。Form A (150 mg) and Form B (150 mg) were dissolved in 10 mL of acetone and mixed for 24 hours. The reaction solution was filtered, and the filter cake was collected and dried under vacuum to obtain the product (266 mg).
经X-射线粉末衍射检测，将该产物定义为H晶型，XRPD谱图如图25。DSC图谱如图26，吸热峰峰值为110℃、230℃、240℃。TGA图谱如图27。After X-ray powder diffraction detection, the product was defined as the H crystal form, and the XRPD spectrum is shown in FIG. 25. The DSC spectrum is shown in Fig. 26, and the endothermic peaks are 110 ° C, 230 ° C, and 240 ° C. The TGA map is shown in Figure 27.
所得产物的 1H-NMR数据如下所示，核磁数据表明该盐中主成分与丙酮的摩尔比为1:0.18，丙酮重量含量为3.3％。 1H NMR(400MHz,DMSO-d 6)δppm 8.95(d,1H),8.39(d,1H),7.91(s,1H),7.55-7.68(m,3H),7.40-7.48(m,4H),7.32-7.38(m,2H),2.08(s,1.09H)。 The 1 H-NMR data of the obtained product are shown below. Nuclear magnetic data showed that the molar ratio of the main component to acetone in the salt was 1: 0.18, and the weight content of acetone was 3.3%. 1 H NMR (400MHz, DMSO-d 6 ) δ ppm 8.95 (d, 1H), 8.39 (d, 1H), 7.91 (s, 1H), 7.55-7.68 (m, 3H), 7.40-7.48 (m, 4H) , 7.32-7.38 (m, 2H), 2.08 (s, 1.09H).
表8、H晶型的特征峰Table 8.Characteristic peaks of Form H
序号Serial number 2-Theta2-Theta d(A)d (A) I％I%
峰1Peak 1 8.2778.277 10.6737510.67375 100.0100.0
峰2Peak 2 12.09612.096 7.311317.31131 2.62.6
峰3 Peak 3 12.49812.498 7.076587.07658 10.110.1
峰4Peak 4 14.23714.237 6.216176.21617 1.21.2
峰5 Peak 5 16.80016.800 5.273045.27304 24.724.7
峰6Peak 6 17.82317.823 4.972734.97273 11.711.7
峰7Peak 7 19.71219.712 4.500124.50012 2.02.0
峰8 Peak 8 20.20420.204 4.391604.39160 10.010.0
峰9Peak 9 21.24121.241 4.179554.17955 28.828.8
峰10 Peak 10 22.35922.359 3.972963.97296 3.83.8
峰11 Peak 11 23.77423.774 3.739583.73958 21.021.0
峰12 Peak 12 25.36125.361 3.509073.50907 77.177.1
峰13 Peak 13 28.71928.719 3.106003.10600 11.811.8
峰14 Peak 14 31.52131.521 2.835962.83596 4.74.7
峰15 Peak 15 32.53432.534 2.749922.74992 3.13.1
峰16 Peak 16 48.63448.634 1.870631.87063 1.21.2
实施例17混合晶浆实验Example 17 mixed crystal slurry experiment
将B晶型(20mg)和H晶型(20mg)溶于2mL丙酮中，混合打浆24小时。反应液过滤，收集滤饼，真空干燥，得到产物(33mg)。经X-射线粉末衍射检测，该产物为H晶型。Form B (20 mg) and Form H (20 mg) were dissolved in 2 mL of acetone and mixed for 24 hours. The reaction solution was filtered, and the filter cake was collected and dried under vacuum to obtain the product (33 mg). The product was in the H crystal form by X-ray powder diffraction.
实施例18混合晶浆实验Example 18 mixed crystal slurry experiment
将A晶型(150mg)和B晶型(150mg)溶于10mL乙酸乙酯中，混合打浆24小时。反应液过滤，收集滤饼，真空干燥，得到产物(269mg)。Form A (150 mg) and Form B (150 mg) were dissolved in 10 mL of ethyl acetate and mixed for 24 hours. The reaction solution was filtered, and the filter cake was collected and dried under vacuum to obtain the product (269 mg).
经X-射线粉末衍射检测，将该产物定义为J晶型，XRPD谱图如图28。DSC图谱如图29，显示吸热峰峰值为108.43℃、227.41℃、238.51℃。TGA图谱如图30，在40℃-150℃之间失重11.1442％。After X-ray powder diffraction detection, the product was defined as the J form, and the XRPD spectrum is shown in FIG. 28. The DSC spectrum is shown in Fig. 29, and the endothermic peaks are 108.43 ° C, 227.41 ° C, and 238.51 ° C. The TGA chart is shown in Figure 30, with a weight loss of 11.422% between 40 ° C and 150 ° C.
所得产物的 1H-NMR数据如下所示，核磁数据表明该盐中主成分与乙酸乙酯的摩尔比为1:0.24，乙酸乙酯重量含量为6.2％。 1H NMR(400MHz,DMSO-d 6)δppm 8.95(d,1H),8.39(d,1H),7.91(s,1H),7.52-7.68(m,3H),7.39-7.47(m,4H),7.33-7.38(m,2H),4.02(d,0.53H),1.99(s,0.73H),1.17(t,0.73H)。 The 1 H-NMR data of the obtained product are shown below. Nuclear magnetic data showed that the molar ratio of the main component to ethyl acetate in the salt was 1: 0.24, and the ethyl acetate weight content was 6.2%. 1 H NMR (400MHz, DMSO-d 6 ) δ ppm 8.95 (d, 1H), 8.39 (d, 1H), 7.91 (s, 1H), 7.52-7.68 (m, 3H), 7.39-7.47 (m, 4H) , 7.33-7.38 (m, 2H), 4.02 (d, 0.53H), 1.99 (s, 0.73H), 1.17 (t, 0.73H).
表9、J晶型的特征峰Table 9.Characteristic peaks of Form J
序号Serial number 2-Theta2-Theta d(A)d (A) I％I%
峰1Peak 1 8.0048.004 11.0375811.03758 100.0100.0
峰2Peak 2 8.9428.942 9.881079.88107 5.75.7
峰3 Peak 3 12.25812.258 7.214967.21496 8.18.1
峰4Peak 4 13.83913.839 6.393946.39394 2.62.6
峰5 Peak 5 15.41515.415 5.743405.74340 3.23.2
峰6 Peak 6 17.19717.197 5.152285.15228 4.44.4
峰7 Peak 7 19.18319.183 4.623004.62300 13.713.7
峰8Peak 8 20.31420.314 4.368124.36812 5.35.3
峰9 Peak 9 20.92420.924 4.242074.24207 6.66.6
峰10 Peak 10 21.75921.759 4.081124.08112 6.36.3
峰11 Peak 11 22.82022.820 3.893783.89378 4.84.8
峰12 Peak 12 24.48424.484 3.632733.63273 31.231.2
峰13 Peak 13 26.05926.059 3.416663.41666 43.243.2
峰14 Peak 14 27.14027.140 3.282953.28295 1.91.9
峰15 Peak 15 28.87528.875 3.089543.08954 4.64.6
峰16 Peak 16 33.71833.718 2.656052.65605 5.05.0
实施例19混合晶浆实验Example 19 mixed crystal slurry experiment
将B晶型(20mg)和J晶型(20mg)溶于2mL乙酸乙酯中，混合打浆24小时。反应液过滤，收集滤饼，真空干燥，得到产物(33mg)。经X-射线粉末衍射检测，该产物为J晶型。Form B (20 mg) and Form J (20 mg) were dissolved in 2 mL of ethyl acetate and mixed for 24 hours. The reaction solution was filtered, and the filter cake was collected and dried under vacuum to obtain the product (33 mg). The product was in the J-form by X-ray powder diffraction detection.
实施例20混合晶浆实验Example 20 mixed crystal slurry experiment
将A晶型(20mg)和B晶型(20mg)溶于3mL异丙醇中，混合打浆24小时。取1mL反应液过滤，收集滤饼，真空干燥，得到产物(8mg)，剩余反应液继续打浆24小时，收集滤饼，真空干燥，得到产物(23mg)，共计得到产物31mg。经X-射线粉末衍射检测，两部分所得产物均为B晶型。Form A (20 mg) and Form B (20 mg) were dissolved in 3 mL of isopropanol and mixed for 24 hours. Take 1 mL of the reaction solution for filtration, collect the filter cake, and dry it in vacuo to obtain the product (8 mg). The remaining reaction solution is continued to be slurried for 24 hours. The filter cake is collected and dried in vacuo to obtain the product (23 mg). A total of 31 mg of product is obtained. By X-ray powder diffraction detection, the products obtained in both parts were in the B crystal form.
实施例21混合晶浆实验Example 21 mixed crystal slurry experiment
将A晶型(20mg)和B晶型(20mg)溶于3mL异丙醚中，混合打浆24小时。反应液过滤，收集滤饼，真空干燥，得到产物(35mg)。经X-射线粉末衍射检测，该产物为B晶型。Form A (20 mg) and Form B (20 mg) were dissolved in 3 mL of isopropyl ether and mixed for 24 hours. The reaction solution was filtered, and the filter cake was collected and dried under vacuum to obtain the product (35 mg). The product was in the B-form by X-ray powder diffraction detection.
实施例22混合晶浆实验Example 22 mixed crystal slurry experiment
将两个不同批次的B晶型(10g)和B晶型(10g)溶于30mL正己烷中，混合打浆1小时。反应液过滤，收集滤饼，真空干燥，得到产物(14.5g)。经X-射线粉末衍射检测，该产物为B晶型。Form B (10 g) and Form B (10 g) of two different batches were dissolved in 30 mL of n-hexane and mixed for 1 hour. The reaction solution was filtered, and the filter cake was collected and dried under vacuum to obtain the product (14.5 g). The product was in the B-form by X-ray powder diffraction detection.
实施例23本发明B晶型的溶解度测定Example 23 Determination of the solubility of Form B of the present invention
本发明得到的式(1)化合物B晶型样品进一步评价在FaSSIF、SGF、水、Fessif溶液中的溶解度，溶解度检测后回收过饱和样品检测晶型，均未转变。The crystal form sample of the compound B of the formula (1) obtained by the present invention is further evaluated for its solubility in FaSSIF, SGF, water, and Fessif solutions. After the solubility test, the supersaturated sample is recovered to detect the crystal form.
实验结果：Experimental results:
表10、式(1)所示化合物B晶型的溶解度测试实验结果Table 10: Experimental results of solubility test of the crystal form of compound B represented by formula (1)
Figure PCTCN2019095724-appb-000009
Figure PCTCN2019095724-appb-000009
实施例24本发明A晶型和B晶型影响因素实验Example 24 Experiments of influencing factors of Form A and Form B of the present invention
将式(1)化合物A晶型和B晶型敞口平摊放置，考察在光照(4500Lux)、高温(40℃、60℃)、高湿(RH 75％、RH 90％)条件下样品的稳定性，取样考察期为30天。Form A and Form B of the compound of formula (1) are placed flat and open, and the samples are examined under the conditions of light (4500 Lux), high temperature (40 ° C, 60 ° C), and high humidity (RH 75%, RH 90%). Stability, the sampling inspection period is 30 days.
实验结果：Experimental results:
表11、式(1)化合物A晶型和B晶型影响因素实验结果Table 11. Experimental results of factors affecting Form A and Form B of compound of formula (1)
Figure PCTCN2019095724-appb-000010
Figure PCTCN2019095724-appb-000010
Figure PCTCN2019095724-appb-000011
Figure PCTCN2019095724-appb-000011
实验结论：Experimental results:
在高温、高湿条件下，A晶型和B晶型样品化学稳定性好。在光照条件下放置30天，A晶型和B晶型样品略有降解；样品放置30天后复测晶型，均未转变，物理稳定性良好。上述结果表明：光照对A晶型和B晶型略有影响，建议A晶型和B晶型于阴凉处、密封条件下保存，两个晶型物理、化学稳定性良好。Under high temperature and high humidity conditions, the A and B samples have good chemical stability. After being left for 30 days under light, samples of Form A and Form B were slightly degraded. After the samples were left for 30 days, the re-testing of the crystalline forms did not change, and the physical stability was good. The above results show that the light has a slight effect on the A and B forms. It is recommended that the A and B forms be stored in a cool place under sealed conditions. Both forms have good physical and chemical stability.
虽然以上描述了本发明的具体实施方式，但是本领域的技术人员应当理解，这些仅是举例说明，在不背离本发明的原理和实质的前提下，可以对这些实施方式做出多种变更或修改。因此，本发明的保护范围由所附权利要求书限定。Although the specific embodiments of the present invention have been described above, those skilled in the art should understand that these are merely examples, and various changes or modifications can be made to these embodiments without departing from the principle and essence of the present invention. modify. Therefore, the protection scope of the present invention is defined by the appended claims.

Claims (21)

  1. 式(1)化合物6-(8-氟喹啉-6-基)-5-苯基-1,2,4-三嗪-3-胺的A晶型，其特征在于，其X-射线粉末衍射图谱中，在2θ为8.697、13.216、17.581、18.245、21.624、23.458处有特征峰，Form A of the compound of formula (1) 6- (8-fluoroquinolin-6-yl) -5-phenyl-1,2,4-triazin-3-amine, characterized in that its X-ray powder In the diffraction pattern, there are characteristic peaks at 2θ of 8.697, 13.216, 17.581, 18.245, 21.624, and 23.458.
    Figure PCTCN2019095724-appb-100001
    Figure PCTCN2019095724-appb-100001
  2. 如权利要求1所述的A晶型，其特征在于，其X-射线粉末衍射图谱中，在2θ为8.697、13.216、17.581、18.245、21.624、23.458、25.412、26.496、29.398、31.981、33.576处有特征峰。The crystal form A according to claim 1, wherein in the X-ray powder diffraction pattern, 2θ is 8.697, 13.216, 17.581, 18.245, 21.624, 23.458, 25.412, 26.496, 29.398, 31.981, 33.576 Characteristic peaks.
  3. 如权利要求1所述的A晶型，其特征在于，其X-射线粉末衍射图谱中，在2θ为8.019、8.697、11.846、13.216、13.521、15.602、16.033、16.658、16.968、17.581、18.245、19.660、21.624、23.458、24.139、25.412、26.496、29.398、31.981、33.576处有特征峰。The crystal form A according to claim 1, wherein in the X-ray powder diffraction pattern, 2θ is 8.019, 8.697, 11.846, 13.216, 13.521, 15.602, 16.033, 16.658, 16.968, 17.581, 18.245, 19.660 There are characteristic peaks at 21.624, 23.458, 24.139, 25.412, 26.496, 29.398, 31.981, and 33.576.
  4. 式(1)化合物6-(8-氟喹啉-6-基)-5-苯基-1,2,4-三嗪-3-胺的B晶型，其特征在于，其X-射线粉末衍射图谱中，在2θ为7.815、12.972、14.272、15.835、17.655、19.448、22.273处有特征峰,Form B of the compound of formula (1) 6- (8-fluoroquinolin-6-yl) -5-phenyl-1,2,4-triazin-3-amine, characterized by its X-ray powder In the diffraction pattern, there are characteristic peaks at 2θ of 7.815, 12.972, 14.272, 15.835, 17.655, 19.448, 22.273.
    Figure PCTCN2019095724-appb-100002
    Figure PCTCN2019095724-appb-100002
  5. 如权利要求4所述的B晶型，其特征在于，其X-射线粉末衍射图谱中，在2θ为7.815、12.972、14.272、15.835、17.655、19.448、22.273、24.864、27.601处有特征峰。The B-form according to claim 4, wherein the X-ray powder diffraction pattern has characteristic peaks at 2θ of 7.815, 12.972, 14.272, 15.835, 17.655, 19.448, 22.273, 24.864, 27.601.
  6. 如权利要求4所述的B晶型，其特征在于，其X-射线粉末衍射图谱中，在2θ为6.212、7.815、8.657、10.723、11.654、12.972、14.272、15.835、17.655、18.342、19.448、21.283、22.273、22.353、23.915、24.864、26.562、27.601、32.485处有特征峰。The crystal form B according to claim 4, wherein in the X-ray powder diffraction pattern, 2θ is 6.212, 7.815, 8.657, 10.723, 11.654, 12.972, 14.272, 15.835, 17.655, 18.342, 19.448, 21.283 There are characteristic peaks at 22.273, 22.353, 23.915, 24.864, 26.562, 27.601, and 32.485.
  7. 式(1)化合物6-(8-氟喹啉-6-基)-5-苯基-1,2,4-三嗪-3-胺的C晶型，其特征在于，其X-射线粉末衍射图谱中，在2θ为8.168、16.543、17.658、19.774、21.003、23.319处有特征峰，Form C of the compound of formula (1) 6- (8-fluoroquinolin-6-yl) -5-phenyl-1,2,4-triazin-3-amine, characterized by its X-ray powder In the diffraction pattern, there are characteristic peaks at 2θ of 8.168, 16.543, 17.658, 19.774, 21.003, and 23.319.
    Figure PCTCN2019095724-appb-100003
    Figure PCTCN2019095724-appb-100003
  8. 式(1)化合物6-(8-氟喹啉-6-基)-5-苯基-1,2,4-三嗪-3-胺的D晶型，其特征在于，其X-射线粉末衍射图谱中，在2θ为8.122、12.200、20.179、24.973、27.303处有特征峰，The D-form of a compound of formula (1) 6- (8-fluoroquinolin-6-yl) -5-phenyl-1,2,4-triazine-3-amine, characterized in that its X-ray powder In the diffraction pattern, there are characteristic peaks at 2θ of 8.122, 12.200, 20.179, 24.973, and 27.303.
    Figure PCTCN2019095724-appb-100004
    Figure PCTCN2019095724-appb-100004
  9. 式(1)化合物6-(8-氟喹啉-6-基)-5-苯基-1,2,4-三嗪-3-胺的E晶型，其特征在于，其X-射线粉末衍射图谱中，在2θ为8.262、12.398、16.792、20.417、21.344、22.819、23.929、25.347处有特征峰，The E-form of the compound of formula (1) 6- (8-fluoroquinolin-6-yl) -5-phenyl-1,2,4-triazin-3-amine is characterized by its X-ray powder In the diffraction pattern, there are characteristic peaks at 2θ of 8.262, 12.398, 16.792, 20.417, 21.344, 22.819, 23.929, 25.347.
    Figure PCTCN2019095724-appb-100005
    Figure PCTCN2019095724-appb-100005
  10. 式(1)化合物6-(8-氟喹啉-6-基)-5-苯基-1,2,4-三嗪-3-胺的F晶型，其特征在于，其X-射线粉末衍射图谱中，在2θ为8.081、13.837、16.514、17.700、19.758、20.953处有特征峰，Form F of the compound of formula (1) 6- (8-fluoroquinolin-6-yl) -5-phenyl-1,2,4-triazin-3-amine, characterized by its X-ray powder In the diffraction pattern, there are characteristic peaks at 2θ of 8.081, 13.837, 16.514, 17.700, 19.758, and 20.953.
    Figure PCTCN2019095724-appb-100006
    Figure PCTCN2019095724-appb-100006
  11. 式(1)化合物6-(8-氟喹啉-6-基)-5-苯基-1,2,4-三嗪-3-胺的G晶型，其特征在于，其X-射线粉末衍射图谱中，在2θ为7.877、8.328、8.462、12.457、16.866、21.399、22.293处有特征峰，Form G of the compound of formula (1) 6- (8-fluoroquinolin-6-yl) -5-phenyl-1,2,4-triazin-3-amine, characterized by its X-ray powder In the diffraction pattern, there are characteristic peaks at 2θ of 7.877, 8.328, 8.462, 12.457, 16.866, 21.399, 22.293.
    Figure PCTCN2019095724-appb-100007
    Figure PCTCN2019095724-appb-100007
  12. 式(1)化合物6-(8-氟喹啉-6-基)-5-苯基-1,2,4-三嗪-3-胺的H晶型，其特征在于，其X-射线粉末衍射图谱中，在2θ为8.277、12.498、16.800、17.823、20.204、21.241、23.774、25.361处有特征峰，H-form of the compound of formula (1) 6- (8-fluoroquinolin-6-yl) -5-phenyl-1,2,4-triazin-3-amine, characterized by its X-ray powder In the diffraction pattern, there are characteristic peaks at 2θ of 8.277, 12.498, 16.800, 17.823, 20.204, 21.241, 23.774, 25.361.
    Figure PCTCN2019095724-appb-100008
    Figure PCTCN2019095724-appb-100008
  13. 式(1)化合物6-(8-氟喹啉-6-基)-5-苯基-1,2,4-三嗪-3-胺的J晶型，其特征在于，其X-射线粉末衍射图谱中，在2θ为8.004、12.258、19.183、24.484、26.059、33.718处有特征峰，Form J of the compound of formula (1) 6- (8-fluoroquinolin-6-yl) -5-phenyl-1,2,4-triazin-3-amine, characterized by its X-ray powder In the diffraction pattern, there are characteristic peaks at 2θ of 8.004, 12.258, 19.183, 24.484, 26.059, 33.718.
    Figure PCTCN2019095724-appb-100009
    Figure PCTCN2019095724-appb-100009
  14. 如权利要求1-13任一项所述的式(1)化合物6-(8-氟喹啉-6-基)-5-苯基-1,2,4-三嗪-3-胺的A、B、C、D、E、F、G、H或J晶型的制备方法，包括：取一定量的式(1)化合物，加入适量溶剂，析晶、过滤、干燥，得到式(1)化合物的A晶型、B晶型、C晶型、D晶型、E晶型、F晶型、G晶型、H晶型或J晶型。A of compound 6- (8-fluoroquinolin-6-yl) -5-phenyl-1,2,4-triazin-3-amine according to any one of claims 1-13 , B, C, D, E, F, G, H or J crystal form preparation method, comprising: taking a certain amount of compound of formula (1), adding an appropriate amount of solvent, crystallizing, filtering and drying to obtain formula (1) A, B, C, D, E, F, G, H, or J forms of a compound.
  15. 如权利要求1-13任一项所述的晶型，其特征在于，其2θ值误差范围为±0.2。The crystal form according to any one of claims 1 to 13, wherein the error range of the 2θ value is ± 0.2.
  16. 一种药物组合物，其特征在于，其含有至少一种权利要求1-13、15任一项所述的晶型，还包含一种或多种药学上可接受的载体、稀释剂或赋形剂。A pharmaceutical composition, characterized in that it contains at least one crystalline form according to any one of claims 1-13, 15 and further comprises one or more pharmaceutically acceptable carriers, diluents or excipients Agent.
  17. 一种制备药物组合物的方法，其特征在于，使至少一种权利要求1-13、15任一项所述的晶型与至少一种药学上可接受的载体、稀释剂或赋形剂混合。A method for preparing a pharmaceutical composition, characterized in that at least one crystalline form according to any one of claims 1-13 and 15 is mixed with at least one pharmaceutically acceptable carrier, diluent or excipient .
  18. 权利要求1-13、15任一项所述的晶型在制备用于治疗通过对A 2a受体抑制而改善的病况或病症的药物中的用途。 Form according to any one of claims 1-13,15 in use for the treatment of a disorder or condition by A 2a receptor inhibition and improved medicament.
  19. 权利要求1-13、15任一项所述的晶型在制备治疗选自肿瘤、抑郁症、认知功能 病症、神经退行性病症、注意力相关病症、锥体外症候群、异常运动障碍、肝硬化、肝纤维化、脂肪肝、皮肤纤维化、睡眠障碍、中风、脑损伤、神经炎症和成瘾行为的疾病的药物中的应用。The crystalline form according to any one of claims 1-13, 15 is prepared for treatment selected from the group consisting of tumors, depression, cognitive disorders, neurodegenerative disorders, attention-related disorders, extrapyramid syndrome, abnormal movement disorders, and liver cirrhosis , Liver fibrosis, fatty liver, skin fibrosis, sleep disorders, stroke, brain injury, neuroinflammatory and addictive behavior diseases.
  20. 根据权利要求19所述的用途，其中肿瘤选自黑色素瘤、脑瘤、食管癌、胃癌、肝癌、胰腺癌、结肠直肠癌、肺癌、肾癌、乳腺癌、卵巢癌、***癌、皮肤癌、神经母细胞瘤、肉瘤、骨软骨瘤、骨瘤、骨肉瘤、***瘤、睾丸肿瘤、子宫癌、头颈肿瘤、多发性骨髓瘤、恶性淋巴瘤、真性红细胞增多症、白血病、甲状腺肿瘤、输尿管肿瘤、膀胱癌、胆囊癌、胆管癌、绒毛膜上皮癌、儿科肿瘤。The use according to claim 19, wherein the tumor is selected from the group consisting of melanoma, brain tumor, esophageal cancer, gastric cancer, liver cancer, pancreatic cancer, colorectal cancer, lung cancer, kidney cancer, breast cancer, ovarian cancer, prostate cancer, skin cancer, Neuroblastoma, sarcoma, osteochondroma, osteoma, osteosarcoma, seminoma, testicular tumor, uterine cancer, head and neck tumor, multiple myeloma, malignant lymphoma, polycythemia vera, leukemia, thyroid tumor, Ureteral tumor, bladder cancer, gallbladder cancer, bile duct cancer, chorionic epithelial cancer, pediatric tumor.
  21. 根据权利要求19所述的用途，其中神经退行性病症选自帕金森氏病、亨廷顿氏病、阿尔茨海默氏病、肌萎缩性侧索硬化、共济失调毛细血管扩张症、牛海绵状脑病、克雅二氏病、小脑萎缩症、多发性硬化症、原发性侧索硬化、脊髓性肌萎缩症。The use according to claim 19, wherein the neurodegenerative disorder is selected from the group consisting of Parkinson's disease, Huntington's disease, Alzheimer's disease, amyotrophic lateral sclerosis, ataxia telangiectasia, bovine spongiform Encephalopathy, Creutzfeldt-Jakob disease, cerebellar atrophy, multiple sclerosis, primary lateral sclerosis, spinal muscular atrophy.
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