WO2020011245A1 - Polymorphes de dérivé de 1,2,4-triazine-3-amine et leur procédé de préparation - Google Patents
Polymorphes de dérivé de 1,2,4-triazine-3-amine et leur procédé de préparation Download PDFInfo
- Publication number
- 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
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- compound
- formula
- peak
- cancer
- ray powder
- Prior art date
Links
- VRFCLZAHKHLWSF-UHFFFAOYSA-N Nc1nnc(-c(cc2F)cc3c2nccc3)c(-c2ccccc2)n1 Chemical compound Nc1nnc(-c(cc2F)cc3c2nccc3)c(-c2ccccc2)n1 VRFCLZAHKHLWSF-UHFFFAOYSA-N 0.000 description 2
- ASGIFKYKXSKOSJ-UHFFFAOYSA-N C=[Br]c1nnc(N)nc1-c1ccccc1 Chemical compound C=[Br]c1nnc(N)nc1-c1ccccc1 ASGIFKYKXSKOSJ-UHFFFAOYSA-N 0.000 description 1
- SWFSPGHWBKKMPD-UHFFFAOYSA-N CC1(C)OB(c2cc3cc(C)cnc3c(F)c2)OC1(C)C Chemical compound CC1(C)OB(c2cc3cc(C)cnc3c(F)c2)OC1(C)C SWFSPGHWBKKMPD-UHFFFAOYSA-N 0.000 description 1
- DDCOYWOYIUEOHQ-UHFFFAOYSA-N Fc1cc(Br)cc2cccnc12 Chemical compound Fc1cc(Br)cc2cccnc12 DDCOYWOYIUEOHQ-UHFFFAOYSA-N 0.000 description 1
Images
Classifications
-
- 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.
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Biomedical Technology (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- Engineering & Computer Science (AREA)
- Epidemiology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
L'invention concerne des polymorphes d'un dérivé de 1,2,4-triazine-3-amine et leur procédé de préparation . Spécifiquement, l'invention concerne des polymorphes A, B, C, D, E, F, G, H et J d'un composé représenté par la formule (1) et leur procédé de préparation. Les polymorphes du composé représenté par la formule (1) ont une bonne stabilité polymorphe, et peuvent être mieux utilisés dans la pratique clinique. (I)
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201980033424.9A CN112154144B (zh) | 2018-07-13 | 2019-07-12 | 一种1,2,4-三嗪-3-胺类衍生物的晶型及制备方法 |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201810767419 | 2018-07-13 | ||
CN201810767419.8 | 2018-07-13 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO2020011245A1 true WO2020011245A1 (fr) | 2020-01-16 |
Family
ID=69142090
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/CN2019/095724 WO2020011245A1 (fr) | 2018-07-13 | 2019-07-12 | Polymorphes de dérivé de 1,2,4-triazine-3-amine et leur procédé de préparation |
Country Status (3)
Country | Link |
---|---|
CN (1) | CN112154144B (fr) |
TW (1) | TWI728404B (fr) |
WO (1) | WO2020011245A1 (fr) |
Families Citing this family (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN114527042A (zh) * | 2021-12-24 | 2022-05-24 | 湖南醇健制药科技有限公司 | 一种黄体酮软胶囊内容物中黄体酮的粒度分布的检测方法 |
WO2024109937A1 (fr) * | 2022-11-25 | 2024-05-30 | 江苏恒瑞医药股份有限公司 | Sel pharmaceutiquement acceptable d'un composé de quinoléine amine, forme cristalline de celui-ci et son procédé de préparation |
Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2004092170A2 (fr) * | 2003-04-09 | 2004-10-28 | Biogen Idec Ma Inc. | Triazolotriazines et pyrazolotriazines et leurs procedes de fabrication et d'utilisation |
US20080064653A1 (en) * | 2006-06-19 | 2008-03-13 | University Of Virginia Patent Foundation | Use of adenosine a2a modulators to treat spinal cord injury |
CN102822150A (zh) * | 2010-02-05 | 2012-12-12 | 赫普泰雅治疗有限公司 | 1,2,4-三嗪-4-胺衍生物 |
CN102892761A (zh) * | 2010-03-31 | 2013-01-23 | 帕罗生物制药有限公司 | 4-氨基嘧啶衍生物和它们作为腺苷a2a 受体拮抗剂 |
CN108884061A (zh) * | 2017-01-13 | 2018-11-23 | 江苏恒瑞医药股份有限公司 | 1,2,4-三嗪-3-胺类衍生物、其制备方法及其在医药上的应用 |
-
2019
- 2019-07-12 CN CN201980033424.9A patent/CN112154144B/zh active Active
- 2019-07-12 TW TW108124692A patent/TWI728404B/zh not_active IP Right Cessation
- 2019-07-12 WO PCT/CN2019/095724 patent/WO2020011245A1/fr active Application Filing
Patent Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2004092170A2 (fr) * | 2003-04-09 | 2004-10-28 | Biogen Idec Ma Inc. | Triazolotriazines et pyrazolotriazines et leurs procedes de fabrication et d'utilisation |
US20080064653A1 (en) * | 2006-06-19 | 2008-03-13 | University Of Virginia Patent Foundation | Use of adenosine a2a modulators to treat spinal cord injury |
CN102822150A (zh) * | 2010-02-05 | 2012-12-12 | 赫普泰雅治疗有限公司 | 1,2,4-三嗪-4-胺衍生物 |
CN102892761A (zh) * | 2010-03-31 | 2013-01-23 | 帕罗生物制药有限公司 | 4-氨基嘧啶衍生物和它们作为腺苷a2a 受体拮抗剂 |
CN108884061A (zh) * | 2017-01-13 | 2018-11-23 | 江苏恒瑞医药股份有限公司 | 1,2,4-三嗪-3-胺类衍生物、其制备方法及其在医药上的应用 |
Also Published As
Publication number | Publication date |
---|---|
CN112154144B (zh) | 2022-05-27 |
TW202019898A (zh) | 2020-06-01 |
CN112154144A (zh) | 2020-12-29 |
TWI728404B (zh) | 2021-05-21 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
TWI664176B (zh) | 作為jak抑制劑之聯吡唑衍生物 | |
WO2017118277A1 (fr) | Forme cristalline d'un inhibiteur de la tyrosine kinase de bruton (btk) et son procédé de préparation | |
CN111253394A (zh) | 选择性cdk4/6抑制剂的固态形式 | |
TW201837033A (zh) | 一種阿片樣物質受體(mor)激動劑的鹽、其富馬酸鹽i晶型及製備方法 | |
WO2023061406A1 (fr) | Inhibiteur de parp contenant une structure tricyclique condensée, son procédé de préparation et son utilisation médicale | |
WO2020011245A1 (fr) | Polymorphes de dérivé de 1,2,4-triazine-3-amine et leur procédé de préparation | |
WO2016039398A1 (fr) | Dérivé hétérocyclique contenant de l'azote, agent neuroprotecteur, et composition pharmaceutique pour le traitement du cancer | |
WO2022063297A1 (fr) | Dérivé de quinazoline, son procédé de préparation et son utilisation | |
WO2022017494A1 (fr) | Forme cristalline d'un dérivé pyridazinique sous forme de base libre, son procédé de préparation et son utilisation | |
CN111278808B (zh) | 2-(5-(4-(2-吗啉代乙氧基)苯基)吡啶-2-基)-n-苄基乙酰胺的固体形式 | |
TWI772424B (zh) | 一種苯并呋喃類衍生物游離鹼的晶型及製備方法 | |
WO2018072742A1 (fr) | Forme cristalline de base libre de dérivé d'imidazo-isoindole et son procédé de préparation | |
WO2022206937A1 (fr) | Nouvelle forme cristalline de chlorhydrate de composé nicotinamide à substitution par pyrazole et son procédé de préparation | |
WO2019091046A1 (fr) | Procédé de préparation d'un dérivé de lénalidomide et application associée | |
US20220162185A1 (en) | Crystalline and amorphous forms of n-(5-((4-ethylpiperazin-1-yl)methyl)pyridine-2-yl)-5-fluoro-4-(3-isopropyl-2-methyl-2h-indazol-5-yl)pyrimidin-2-amine and its salts, and preparation methods and therapeutic uses thereof | |
WO2020052648A1 (fr) | Formes cristallines d'hétéroaryl[4,3-c]pyrimidine-5-amine, et leur procédé de préparation | |
WO2020140894A1 (fr) | Composé de benzothiophène substitué contenant du fluor, composition pharmaceutique et application de celui-ci | |
WO2018233591A1 (fr) | Sel de dérivé de benzopipéridine et forme cristalline de celui-ci, procédé de préparation du sel et de la forme cristalline de celui-ci | |
JP5983714B2 (ja) | 含フッ素アミノ酸プロドラッグの結晶形とその製造方法 | |
WO2023138647A1 (fr) | Forme cristalline d'un dérivé d'isoindoline contenant du soufre | |
JP7169695B2 (ja) | ピラジノ[2,1-c][1,2,4]トリアジン化合物の結晶(1) | |
CN110903291B (zh) | 一种杂芳基并[4,3-c]嘧啶-5-胺类衍生物的盐、盐的晶型及制备方法 | |
WO2023040863A1 (fr) | Polymorphe et application de dérivé de pyrimidine et sel pharmaceutiquement acceptable associé | |
WO2022166792A1 (fr) | Sel, solvate, polymorphe, procédé de préparation et utilisation d'un dérivé de benzazépine | |
WO2023236814A1 (fr) | Composé et son utilisation dans la préparation d'un inhibiteur de bcl-xl |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
121 | Ep: the epo has been informed by wipo that ep was designated in this application |
Ref document number: 19833911 Country of ref document: EP Kind code of ref document: A1 |
|
NENP | Non-entry into the national phase |
Ref country code: DE |
|
122 | Ep: pct application non-entry in european phase |
Ref document number: 19833911 Country of ref document: EP Kind code of ref document: A1 |