WO2024109936A1 - 一种喹啉胺类化合物晶型及其制备方法 - Google Patents

一种喹啉胺类化合物晶型及其制备方法 Download PDF

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WO2024109936A1
WO2024109936A1 PCT/CN2023/134047 CN2023134047W WO2024109936A1 WO 2024109936 A1 WO2024109936 A1 WO 2024109936A1 CN 2023134047 W CN2023134047 W CN 2023134047W WO 2024109936 A1 WO2024109936 A1 WO 2024109936A1
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crystal form
compound
ray powder
powder diffraction
product
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French (fr)
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赵祥虎
尤凌峰
冯君
贺峰
杨俊然
杜振兴
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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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Publication of WO2024109936A1 publication Critical patent/WO2024109936A1/zh

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4709—Non-condensed quinolines and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the present invention belongs to the pharmaceutical field and relates to a quinolineamine compound crystal form and a preparation method thereof.
  • miR-124 is widely expressed in tissues throughout the body, especially in brain tissues. Studies have shown that overexpression of miR-124 can promote the static transformation of activated macrophages-microglia, thereby inhibiting the autoimmune disease encephalomyelitis. In addition, miR-124 can promote the transformation of macrophages to M2 type, thereby exerting an anti-inflammatory effect. miR-124 also affects T cell differentiation, and the levels of IFN- ⁇ and TNF ⁇ in T cells treated with miR-124 are reduced. Overexpression of miR-124 exerts an anti-inflammatory effect by downregulating STAT3 protein, thereby reducing the expression of the inflammatory cytokine IL-17 and inhibiting the differentiation of Th17 cells. The above studies show that the development of a new type of small molecule drug can be used to effectively treat related inflammatory diseases by upregulating miR-124.
  • WO2022247920 discloses a class of quinoline amine compounds that can upregulate miR-124, the structure of which is shown below:
  • the crystal structure of the active pharmaceutical ingredient often affects the chemical and physical stability of the drug. Different crystallization and storage conditions may lead to changes in the crystal structure of the compound, and sometimes other forms of crystals may be produced.
  • amorphous drug products do not have a regular crystal structure and often have other defects, such as poor product stability, difficulty in filtration, easy agglomeration, poor fluidity, etc. Therefore, studying its crystal form is of great significance for the development of drugs suitable for industrial production and with good biological activity.
  • the present disclosure provides a crystalline form A of the compound 8-chloro-N-(2,2-difluorobenzo[d][1,3]dioxolan-5-yl)quinolin-2-amine, which has an X-ray powder diffraction pattern expressed as a diffraction angle of 2 ⁇ , with characteristic peaks at 7.237, 9.232, 13.702, 14.459 and 18.917.
  • the A crystal form has an X-ray powder diffraction pattern represented by a diffraction angle of 2 ⁇ , with characteristic peaks at 7.237, 9.232, 13.702, 14.459, 18.917, 24.428 and 29.321.
  • the A crystal form has an X-ray powder diffraction pattern represented by a diffraction angle of 2 ⁇ , with characteristic peaks at 7.237, 9.232, 13.702, 14.459, 18.033, 18.917, 24.428, 25.521 and 29.321.
  • the present disclosure also provides a method for preparing the aforementioned crystalline form of Compound A, wherein the method is selected from any one of the following methods:
  • the solvent (1) is selected from acetonitrile, methanol, ethanol, isopropanol, acetone, ethyl acetate, isopropyl acetate, tetrahydrofuran, methyl isopropyl ketone, dichloromethane, 10% water/methanol, 7% water/ethanol, 10% water/isopropanol or 10% water/acetone, and the solvent (2) is selected from water, cyclohexane or n-heptane;
  • solvent (3) is selected from tetrahydrofuran, ethyl acetate or dichloromethane;
  • solvent (4) is selected from water, cyclohexane, n-heptane, methanol, ethanol, isopropanol, dichloromethane, 1,4-dioxane, 10% water/methanol, 7% water/ethanol or 10% water/isopropanol.
  • the present disclosure provides a crystalline form B of the compound 8-chloro-N-(2,2-difluorobenzo[d][1,3]dioxolan-5-yl)quinolin-2-amine, which has an X-ray powder diffraction pattern represented by a diffraction angle of 2 ⁇ , with characteristic peaks at 8.205, 9.781, 12.87, 15.907 and 19.796.
  • the B crystalline form has an X-ray powder diffraction pattern represented by a diffraction angle of 2 ⁇ , with characteristic peaks at 8.205, 9.781, 12.870, 15.907, 19.448, 19.796, 20.264 and 23.185.
  • the B crystalline form has an X-ray powder diffraction pattern represented by a diffraction angle of 2 ⁇ , with characteristic peaks at 8.205, 9.781, 10.672, 12.87, 15.356, 15.907, 16.997, 19.448, 19.796, 20.264 and 23.185.
  • the X-ray powder diffraction pattern of the B crystal form represented by the diffraction angle 2 ⁇ is shown in Figure 2.
  • the present disclosure also provides a method for preparing the aforementioned crystalline form of compound B, the method comprising:
  • the solvent (5) is selected from dimethyl sulfoxide, and the solvent (6) is selected from water.
  • the present disclosure provides a C crystalline form of the compound 8-chloro-N-(2,2-difluorobenzo[d][1,3]dioxolan-5-yl)quinolin-2-amine, which has an X-ray powder diffraction pattern expressed as a diffraction angle of 2 ⁇ , with characteristic peaks at 9.296, 15.522, 18.784, 23.216 and 25.889.
  • the C crystalline form has an X-ray powder diffraction pattern represented by a diffraction angle of 2 ⁇ , with characteristic peaks at 7.753, 9.296, 15.522, 18.784, 21.398, 23.216 and 25.889.
  • the C crystal form has an X-ray powder diffraction pattern represented by a diffraction angle 2 ⁇ of 7.353, 7.753, There are characteristic peaks at 9.296, 14.475, 15.522, 16.248, 17.320, 18.784, 21.398, 23.216 and 25.889.
  • the X-ray powder diffraction pattern of the C crystal form represented by a diffraction angle of 2 ⁇ is shown in FIG3 .
  • the present disclosure also provides a method for preparing the aforementioned crystalline form of compound C, the method comprising:
  • the solvent (7) is selected from 1,4-dioxane, and the solvent (8) is selected from n-heptane.
  • the present disclosure provides a D-type crystalline compound of 8-chloro-N-(2,2-difluorobenzo[d][1,3]dioxolan-5-yl)quinolin-2-amine, which has an X-ray powder diffraction pattern expressed as a diffraction angle of 2 ⁇ , with characteristic peaks at 7.350, 12.084, 15.384, 18.643 and 29.312.
  • the D crystalline form has an X-ray powder diffraction pattern represented by a diffraction angle of 2 ⁇ , with characteristic peaks at 7.350, 12.084, 15.384, 16.260, 17.855, 18.643, 21.610 and 29.312.
  • the D crystalline form has an X-ray powder diffraction pattern represented by a diffraction angle of 2 ⁇ , with characteristic peaks at 7.350, 12.084, 15.384, 16.260, 17.855, 18.643, 21.610, 22.768, 24.347, 25.201, 26.038 and 29.312.
  • the X-ray powder diffraction pattern of the D crystal form represented by the diffraction angle 2 ⁇ is shown in Figure 4.
  • the present disclosure also provides a method for preparing the aforementioned crystalline form of compound D, the method comprising:
  • the solvent (9) is selected from tetrahydrofuran, and the solvent (10) is selected from water.
  • the present disclosure provides a crystalline form E of the compound 8-chloro-N-(2,2-difluorobenzo[d][1,3]dioxolan-5-yl)quinolin-2-amine, which has an X-ray powder diffraction pattern expressed as a diffraction angle of 2 ⁇ , with characteristic peaks at 13.489, 18.000, 23.559, 24.276 and 26.328.
  • the E crystalline form has an X-ray powder diffraction pattern represented by a diffraction angle of 2 ⁇ , with characteristic peaks at 13.489, 16.863, 18.000, 23.559, 24.276, 26.108, 26.328 and 27.094.
  • the E crystalline form has an X-ray powder diffraction pattern represented by a diffraction angle of 2 ⁇ , with characteristic peaks at 13.489, 14.587, 16.863, 18.000, 18.943, 23.279, 23.559, 24.276, 25.768, 26.108, 26.328 and 27.094.
  • the X-ray powder diffraction pattern of the E crystal form represented by a diffraction angle of 2 ⁇ is shown in FIG5 .
  • the present disclosure provides a crystalline form F of the compound 8-chloro-N-(2,2-difluorobenzo[d][1,3]dioxolan-5-yl)quinolin-2-amine, which has an X-ray powder diffraction pattern expressed as a diffraction angle of 2 ⁇ , with characteristic peaks at 9.299, 14.439, 15.621, 16.200 and 17.314.
  • the F crystalline form has an X-ray powder diffraction pattern represented by a diffraction angle of 2 ⁇ , with characteristic peaks at 7.734, 9.299, 14.439, 15.621, 16.200, 17.314, 21.395 and 25.814.
  • the F crystalline form has an X-ray powder diffraction pattern represented by a diffraction angle of 2 ⁇ , with characteristic peaks at 7.734, 9.299, 14.439, 15.621, 16.200, 17.314, 21.055, 21.395, 23.194, 25.814, 28.906, 34.485 and 43.544.
  • the X-ray powder diffraction pattern of the F crystalline form represented by a diffraction angle of 2 ⁇ is shown in FIG6 .
  • the X-ray powder diffraction pattern of the compound in the present disclosure is expressed in terms of a diffraction angle 2 ⁇ , wherein the error range of the 2 ⁇ angle is ⁇ 0.2.
  • the method for preparing the crystalline form described in the present disclosure further comprises any step of filtering, washing or drying.
  • the crystallization includes but is not limited to stirring crystallization (dissolution crystallization, slurry crystallization) and volatile crystallization.
  • the drying method includes but is not limited to forced air drying and vacuum drying.
  • the drying temperature is generally 25°C to 100°C, preferably 30°C to 70°C, such as 40°C, 50°C or 60°C.
  • the present disclosure also provides a pharmaceutical composition, which includes the aforementioned crystal form and a pharmaceutically acceptable excipient.
  • the present disclosure also provides a pharmaceutical composition prepared from the aforementioned crystal form and a pharmaceutically acceptable excipient.
  • the present disclosure also provides a method for preparing a pharmaceutical composition, comprising the step of mixing the aforementioned crystal form with a pharmaceutically acceptable excipient.
  • the present disclosure also provides use of the aforementioned crystal form or pharmaceutical composition in the preparation of a drug for regulating miRNA levels; preferably, the miRNA is miR-124.
  • the present disclosure also provides use of the aforementioned crystalline form or pharmaceutical composition in a drug for treating and/or preventing a disease or condition, wherein the disease or condition is selected from inflammation and cancer.
  • the inflammation is inflammatory bowel disease.
  • the cancer is melanoma or breast cancer.
  • the "2 ⁇ or 2 ⁇ angle" mentioned in the present disclosure refers to the diffraction angle, ⁇ is the Bragg angle, and the unit is ° or degree; the error range of each characteristic peak 2 ⁇ is ⁇ 0.20 (including the case where the number exceeding 1 decimal place is rounded off), specifically -0.20, -0.19, -0.18, -0.17, -0.16, -0.15, -0.14, -0.13, -0.12, -0.11, -0.10, -0.09, -0.08, -0.07, -0.06, -0.05, -0.04, -0.03, -0.02, -0.01, 0.00, 0.01, 0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09, 0.10, 0.11, 0.12, 0.13, 0.14, 0.15, 0.16, 0.17, 0.18, 0.19, 0.20.
  • the "differential scanning calorimetry or DSC” described in the present disclosure refers to measuring the temperature difference and heat flow difference between a sample and a reference object during the process of heating or maintaining a constant temperature of the sample to characterize all physical and chemical changes related to thermal effects and obtain phase change information of the sample.
  • the drying temperature in the present disclosure is generally 25° C.-100° C., preferably 30° C.-70° C., and the drying can be performed under normal pressure or reduced pressure.
  • compositions include, but are not limited to, any adjuvant, carrier, glidant, sweetener, diluent, preservative, dye/colorant, flavoring agent, surfactant, wetting agent, dispersant, suspending agent, stabilizer, isotonic agent or emulsifier approved by the U.S. Food and Drug Administration for use by humans or livestock animals.
  • the "beating” mentioned in the present disclosure refers to a method of purification that utilizes the property that a substance has poor solubility in a solvent, but impurities have good solubility in a solvent. Beating purification can remove color, change the crystal form, or remove a small amount of impurities.
  • the crystalline forms disclosed herein include but are not limited to solvates of the compound represented by formula (I), and the solvents include but are not limited to water.
  • Figure 1 is the XRPD spectrum of Form A of Compound 1.
  • Figure 2 is the XRPD spectrum of Form B of Compound 1.
  • Figure 3 is the XRPD spectrum of Form C of Compound 1.
  • FIG4 is an XRPD spectrum of Form D of Compound 1.
  • Figure 5 is the XRPD spectrum of Form E of Compound 1.
  • Figure 6 is the XRPD spectrum of Form F of Compound 1.
  • NMR nuclear magnetic resonance
  • MS mass spectrometry
  • ⁇ NMR shifts ( ⁇ ) are given in units of 10 -6 (ppm).
  • NMR measurements were performed using a Bruker AVANCE-400 NMR spectrometer, with deuterated dimethyl sulfoxide (DMSO-d 6 ), deuterated chloroform (CDCl 3 ), deuterated methanol (CD 3 OD) as the measuring solvent, and tetramethylsilane (TMS) as the internal standard.
  • DMSO-d 6 deuterated dimethyl sulfoxide
  • CDCl 3 deuterated chloroform
  • CD 3 OD deuterated methanol
  • TMS tetramethylsilane
  • MS was determined using Agilent 1200/1290 DAD-6110/6120 Quadrupole MS LC-MS (Manufacturer: Agilent, MS model: 6110/6120 Quadrupole MS), Waters ACQuity UPLC-QD/SQD (Manufacturer: Waters, MS model: Waters ACQuity Qda Detector/Waters SQ Detector), and THERMO Ultimate 3000-Q Exactive (Manufacturer: THERMO, MS model: THERMO Q 15 Exactive).
  • HPLC determinations were performed using an Agilent 1260DAD high pressure liquid chromatograph (Sunfire C18 150 ⁇ 4.6 mm column) and a Thermo U3000 high pressure liquid chromatograph (Gimini C18 150 ⁇ 4.6 mm column).
  • XRPD is X-ray powder diffraction detection: the measurement is carried out using a BRUKER D8 X-ray diffractometer, specific collection information: Cu anode (40kV, 40mA), ray: monochromatic Cu-Ka ray Scanning mode: ⁇ /2 ⁇ , scanning range: 3-48°.
  • DSC is differential scanning calorimetry: the measurement was performed using a METTLER TOLEDO DSC 3+ differential scanning calorimeter with a heating rate of 10°C/min, 25-300°C or 25-350°C, and a nitrogen purge rate of 50mL/min.
  • TGA thermogravimetric analysis: the test was performed using a METTLER TOLEDO TGA 2 thermogravimetric analyzer with a heating rate of 10°C/min.
  • the specific temperature range refers to the corresponding spectrum, and the nitrogen purge rate is 50mL/min.
  • DVS dynamic moisture adsorption: using Surface Measurement Systems instrument, humidity starts from 50%, the humidity range is 0%-95%, the step is 10%, the judgment standard is each gradient mass change dM/dT ⁇ 0.002%, TMAX 360min, two cycles.
  • the known starting materials disclosed herein can be synthesized by methods known in the art, or can be purchased from ABCR GmbH & Co. KG, Acros Organics, Aldrich Chemical Company, Accela ChemBio Inc, Darui Chemicals, etc.
  • the reaction progress in the embodiment is monitored by thin layer chromatography (TLC), the developing solvent used in the reaction, the eluent system of column chromatography used for purifying the compound and the developing solvent system of thin layer chromatography include: 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 a small amount of alkaline or acidic reagents such as triethylamine and acetic acid can also be added for adjustment.
  • TLC thin layer chromatography
  • Example 1 Synthesis of 8-chloro-N-(2,2-difluorobenzo[d][1,3]dioxolan-5-yl)quin-2-amine (see Application No. The preparation method of Example 1 in the application of WO2022247920)
  • 2,8-Dichloroquinoline 1a (100 mg, 0.51 mmol, Bidex Pharmaceuticals) and 5-amino-2,2-difluoro-1,3-benzo[1,3]dioxolane 1b (105 mg, 0.61 mmol, Shanghai Haohong) were dissolved in isopropanol (1 mL) and heated to 90 °C for 12 hours. The reaction solution was filtered and then subjected to high performance liquid chromatography (Waters 2767-SQ Detecor2, elution system: 0.1% formic acid aqueous solution and acetonitrile, acetonitrile gradient: 65%-85%, flow rate: 30 mL/min) to obtain the title compound 1 (150 mg, yield 89.0%).
  • Human interleukin 2 Human IL-2 (Peprotech, 200-02-100)
  • RNA extraction kit (microRNA extraction kit) (Qiagen, 217004)
  • Phosphate buffer PBS pH 7.4 (Shanghai Yuanpei Biotechnology Co., Ltd., B320)
  • RPMI1640 culture medium (Gibco, 11875119)
  • Magnetic bead separation rack (QuadroMACS Separator) (Miltenyi Biotec, 130-090-976)
  • the effect of the compound on the expression level of miR-124 was detected in T cells activated by CD3/CD28 antibodies. After the activated T cells were treated with the compound, the total RNA of the cells was extracted, and the cDNA obtained by reverse transcription was used as a template for quantification using SYBR green fluorescent quantitative PCR method using specific miR-124 primers.
  • T cells Purchased human peripheral blood mononuclear cells (PBMC), counted and filtered, washed once with separation buffer (PBS pH 7.4, containing 0.5% BSA and 2mM EDTA), discarded the supernatant, added 40 ⁇ L buffer and 10 ⁇ L T cell separation biotinylated mixed antibody (pan T Cell Biotin-Antibody Cocktail) per 1 ⁇ 10 7 cells, added each component to resuspend the precipitate and mixed, and incubated in a refrigerator at 4°C for 5 minutes.
  • separation buffer PBS pH 7.4, containing 0.5% BSA and 2mM EDTA
  • T cell separation biotinylated mixed antibody pan T Cell Biotin-Antibody Cocktail
  • Activation of T cells Add 25 ⁇ L of activated magnetic beads per 1 ⁇ 10 6 cells, take out the corresponding T cell activation CD3/CD28 magnetic beads and put them in a 1.5 mL filter tube. Oscillate on the oscillator for about 30 seconds before aspirating. Wash the activated magnetic beads 3 times with culture medium in a volume ratio greater than 1:1 in the filter tube. Remove all the washing solution in the last time and add complete culture medium equal to the starting volume to resuspend the activated magnetic beads. Add the washed activated magnetic beads to the cell resuspension and mix well. Take out the six-well plate, add cells at 3 mL per well, and culture in a cell culture incubator at 37°C and 5% CO 2 for 2 days.
  • Compound treatment The compound stock solution is 20mM, diluted to 200 ⁇ M with DMSO, and then diluted 4 times to 50 ⁇ M (50 ⁇ ) with complete medium, mix well for use. DMSO diluted 4 times (25% DMSO) is the negative control well.
  • DMSO diluted 4 times (25% DMSO) is the negative control well.
  • Activate T cells for two days blow the cells evenly, use a magnetic stand and install a 1.5mL filter tube, remove the activated magnetic beads, and collect the cell suspension. After counting the cells, filter at 300xg, 10min and discard the supernatant, resuspend the cells to 1.02 ⁇ 10 6 /mL, add 980 ⁇ L of cell suspension and 20 ⁇ L of 50 ⁇ compound to each 24-well plate, and the final concentration of the compound is 1 ⁇ M. Place the cells in a 37°C, 5% CO 2 cell culture incubator and continue to culture for 3 days.
  • RNA extraction Collect T cells by filtration, filter at 1500 rpm for 3 minutes, wash once with PBS, and discard the supernatant after filtration. Extract total RNA from cells using the extraction kit according to the instructions. Add 700 ⁇ L Trizol cell lysis buffer to the cell pellet, blow evenly with a pipette tip, and place at room temperature for 5 minutes. Add 140 ⁇ L chloroform, shake and mix, and place at room temperature for 3 minutes. Filter the chloroform-cell lysis buffer mixture at 12000xg for 15 minutes at 4°C. Transfer the upper solution to a new RNase-free filter tube, add 1.5 times the volume of anhydrous ethanol, and blow several times with a pipette tip.
  • Reverse transcription Place the extracted RNA template on ice, take out the small RNA reverse transcription kit, thaw some components (including 5 ⁇ miScript HiSpec Buffer, 10 ⁇ miScript nucleics Mix and RNase-free water) at room temperature, and thaw the miScript Reverse Transcriptase mix components on ice.
  • Each reaction (10 ⁇ L) contains: 5 ⁇ miScript HiSpec Buffer (2 ⁇ L), 10 ⁇ miScript nucleics Mix (1 ⁇ L), miScript Reverse Transcriptase mix (1 ⁇ L), RNase-free water (2 ⁇ L), RNA template (4 ⁇ L), and prepare the above reaction on ice. Place the sample in a PCR instrument and set the program as follows: 37°C, 60 minutes; 95°C, 5 minutes; store at 4°C. The sample that completes the reaction is the cDNA sample.
  • Fluorescence quantitative PCR Use SYBR green staining to detect the transcription level of miR-124, and detect the transcription level of housekeeping gene U6 as an internal reference. Thaw all reagents required for small RNA SYBR green PCR kit to room temperature, dilute each cDNA sample template 10 times with RNase-free water, and then dilute 5 times. Prepare the reaction mixture according to Table 1 below, add the reaction mixture to a 96-well PCR plate, seal the plate with a sealing film, and filter. Perform the PCR reaction on a fluorescence quantitative PCR instrument according to the steps in Table 2.
  • the product was defined as Form A by X-ray powder diffraction detection.
  • the X-ray powder diffraction data are shown in Table 4, and the X-ray powder diffraction spectrum is shown in FIG1 .
  • the DSC spectrum showed an endothermic peak of 177.14°C.
  • the TGA spectrum showed a weight loss of 0.22% from 30°C to 100°C.
  • DVS test shows that under normal storage conditions (i.e. room temperature, 60% RH), the sample has a moisture absorption weight gain of about 0.02%; under accelerated test conditions (i.e. 70% RH), the moisture absorption weight gain is about 0.02%; under extreme conditions (i.e. 90% RH), the moisture absorption weight gain is about 0.18%. After DVS test, the crystal form was retested and the crystal form did not change.
  • the product was defined as Form B by X-ray powder diffraction analysis.
  • the XRPD spectrum is shown in FIG2 , and the positions of its characteristic peaks are shown in Table 6.
  • the DSC spectrum showed endothermic peaks at 81.99 and 173.56 °C.
  • the TGA spectrum showed a weight loss of 18.35% from 30°C to 100°C.
  • the product was defined as Form C by X-ray powder diffraction analysis.
  • the XRPD spectrum is shown in FIG3 , and the positions of its characteristic peaks are shown in Table 7.
  • the DSC spectrum showed endothermic peaks at 141.90 and 176.81 °C.
  • the TGA spectrum showed a weight loss of 1.89% at 30°C-85°C and a weight loss of 5.94% at 85°C-160°C.
  • the product was defined as D-type by X-ray powder diffraction analysis.
  • the XRPD spectrum is shown in FIG4 , and the positions of its characteristic peaks are shown in Table 8.
  • the DSC spectrum showed an endothermic peak of 176.85°C.
  • the TGA spectrum showed a weight loss of 0.34% from 30°C to 100°C.
  • the product was defined as E crystal form by X-ray powder diffraction detection.
  • the X-ray powder diffraction data are shown in Table 9, and the X-ray powder diffraction spectrum is shown in FIG5 .
  • the DSC spectrum shows that the endothermic peaks are 88.25°C and 177.28°C.
  • the TGA spectrum showed that the compound lost 1.80% of its weight from 30°C to 115°C, and lost 5.29% of its weight from 115°C to 230°C.
  • the product was defined as Form F by X-ray powder diffraction analysis.
  • the XRPD spectrum is shown in FIG6 , and the positions of its characteristic peaks are shown in Table 10.
  • Test case 2 Influencing factors
  • the A crystal form was opened and spread out to examine the stability of the sample under light (4500 Lux), high temperature (40°C, 60°C), and high humidity (RH 75%, RH 92.5%) conditions.
  • the sampling period was 30 days.
  • Test Example 3 Long-term accelerated test
  • Form A The stability of Form A was investigated at 25°C/60% RH and 40°C/75% RH.

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Abstract

本公开涉及一种喹啉胺类化合物晶型及其制备方法。具体而言，本公开提供8-氯-N-（2,2-二氟苯并[d][1,3]二氧杂环戊烷-5-基）喹啉-2-胺的晶型及其制备方法，相应晶型具备良好的稳定性，可更好地用于临床治疗。

Description

一种喹啉胺类化合物晶型及其制备方法
本申请要求申请日为2022/11/25的中国专利申请2022114917970的优先权。本申请引用上述中国专利申请的全文。
技术领域
本公开属于制药领域，涉及一种喹啉胺类化合物晶型及其制备方法。
背景技术
miR-124在全身各组织有广泛表达，尤其在脑部组织中高表达。研究表明，过表达miR-124可促进激活的巨噬细胞-小胶质细胞向静态转变，从而抑制自身免疫疾病脑脊髓炎。另外，miR-124可促进巨噬细胞向M2型转化，从而发挥抗炎作用。miR-124也影响T细胞分化，miR-124处理的T细胞IFN-γ和TNFα水平都有所下降。过表达miR-124通过下调STAT3蛋白，进而减少炎症细胞因子IL-17的表达，抑制Th17细胞的分化发挥抗炎作用。以上研究表明，发展一种新型的小分子药物，通过上调miR-124，可以用于有效地治疗相关炎症疾病。
公开的相关专利申请包括WO2010143169A2、WO2015001518A1、WO2016009065A2、WO2017158201A1和WO2020127843A1等。
WO2022247920公开了一类可上调miR-124的喹啉胺类化合物，结构如下所示，
作为药用活性成分的晶型结构往往影响到该药物的化学和物理稳定性，结晶条件及储存条件的不同有可能导致化合物的晶体结构的变化，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体结构，往往具有其它缺陷，比如产物稳定性较差，过滤较难，易结块，流动性差等。因此，研究其晶型对开发适合工业生产且生物活性良好的药物具有重要意义。
发明内容
本公开一方面提供化合物8-氯-N-(2,2-二氟苯并[d][1,3]二氧杂环戊烷-5-基)喹啉-2-胺的A晶型，以衍射角2θ角度表示的X-射线粉末衍射图谱，在7.237、9.232、13.702、14.459和18.917处有特征峰。
在一些实施方案中，所述A晶型，以衍射角2θ角度表示的X-射线粉末衍射图谱，在7.237、9.232、13.702、14.459、18.917、24.428和29.321处有特征峰。
在一些实施方案中，所述A晶型，以衍射角2θ角度表示的X-射线粉末衍射图谱，在7.237、9.232、13.702、14.459、18.033、18.917、24.428、25.521和29.321处有特征峰。
在另一些实施方案中，所述A晶型，以衍射角2θ角度表示的X-射线粉末衍射图谱如图1所示。
本公开还提供了制备前述化合物A晶型的方法，所述方法选自如下任一方法：
方法一：
(a)将化合物8-氯-N-(2,2-二氟苯并[d][1,3]二氧杂环戊烷-5-基)喹啉-2-胺与溶剂(1)混合，搅拌溶解或加热溶解，
(b)加入溶剂(2)，析晶，
其中溶剂(1)选自乙腈、甲醇、乙醇、异丙醇、丙酮、乙酸乙酯、乙酸异丙酯、四氢呋喃、甲基异丙基酮、二氯甲烷、10％水/甲醇、7％水/乙醇、10％水/异丙醇或10％水/丙酮，溶剂(2)选自水、环己烷或正庚烷；
或，方法二：
(a)将化合物8-氯-N-(2,2-二氟苯并[d][1,3]二氧杂环戊烷-5-基)喹啉-2-胺与溶剂(3)混合，搅拌溶解或加热溶解，
(b)析晶，
其中溶剂(3)选自四氢呋喃、乙酸乙酯或二氯甲烷；
或，方法三：
(a)将化合物8-氯-N-(2,2-二氟苯并[d][1,3]二氧杂环戊烷-5-基)喹啉-2-胺与溶剂(4)混合，
(b)搅拌打浆，其中溶剂(4)选自水、环己烷、正庚烷、甲醇、乙醇、异丙醇、二氯甲烷、1,4-二氧六环、10％水/甲醇、7％水/乙醇或10％水/异丙醇。
本公开一方面提供化合物8-氯-N-(2,2-二氟苯并[d][1,3]二氧杂环戊烷-5-基)喹啉-2-胺的B晶型，以衍射角2θ角度表示的X-射线粉末衍射图谱，在8.205、9.781、12.87、15.907和19.796处有特征峰。
在一些实施方案中，所述B晶型，以衍射角2θ角度表示的X-射线粉末衍射图谱，在8.205、9.781、12.870、15.907、19.448、19.796、20.264和23.185处有特征峰。
在一些实施方案中，所述B晶型，以衍射角2θ角度表示的X-射线粉末衍射图谱，在8.205、9.781、10.672、12.87、15.356、15.907、16.997、19.448、19.796、20.264和23.185处有特征峰。
在另一些实施方案中，所述B晶型，以衍射角2θ角度表示的X-射线粉末衍射图谱如图2所示。
本公开还提供了制备前述化合物B晶型的方法，所述方法包括：
(a)将化合物8-氯-N-(2,2-二氟苯并[d][1,3]二氧杂环戊烷-5-基)喹啉-2-胺与溶剂(5)混合，搅拌溶解或加热溶解，
(b)加入溶剂(6)，析晶，
其中溶剂(5)选自二甲基亚砜，溶剂(6)选自水。
本公开一方面提供化合物8-氯-N-(2,2-二氟苯并[d][1,3]二氧杂环戊烷-5-基)喹啉-2-胺的C晶型，以衍射角2θ角度表示的X-射线粉末衍射图谱，在9.296、15.522、18.784、23.216和25.889处有特征峰。
在一些实施方案中，所述C晶型，以衍射角2θ角度表示的X-射线粉末衍射图谱，在7.753、9.296、15.522、18.784、21.398、23.216和25.889处有特征峰。
在一些实施方案中，所述C晶型，以衍射角2θ角度表示的X-射线粉末衍射图谱，在7.353、7.753、 9.296、14.475、15.522、16.248、17.320、18.784、21.398、23.216和25.889处有特征峰。
在另一些实施方案中，所述C晶型，以衍射角2θ角度表示的X-射线粉末衍射图谱如图3所示。
本公开还提供了制备前述化合物C晶型的方法，所述方法包括：
(a)将化合物8-氯-N-(2,2-二氟苯并[d][1,3]二氧杂环戊烷-5-基)喹啉-2-胺与溶剂(7)混合，搅拌溶解或加热溶解，
(b)加入溶剂(8)，析晶，
其中溶剂(7)选自1,4-二氧六环，溶剂(8)选自正庚烷。
本公开一方面提供化合物8-氯-N-(2,2-二氟苯并[d][1,3]二氧杂环戊烷-5-基)喹啉-2-胺的D晶型，以衍射角2θ角度表示的X-射线粉末衍射图谱，在7.350、12.084、15.384、18.643和29.312处有特征峰。
在一些实施方案中，所述D晶型，以衍射角2θ角度表示的X-射线粉末衍射图谱，在7.350、12.084、15.384、16.260、17.855、18.643、21.610和29.312处有特征峰。
在一些实施方案中，所述D晶型，以衍射角2θ角度表示的X-射线粉末衍射图谱，在7.350、12.084、15.384、16.260、17.855、18.643、21.610、22.768、24.347、25.201、26.038和29.312处有特征峰。
在另一些实施方案中，所述D晶型，以衍射角2θ角度表示的X-射线粉末衍射图谱如图4所示。
本公开还提供了制备前述化合物D晶型的方法，所述方法包括：
(a)将化合物8-氯-N-(2,2-二氟苯并[d][1,3]二氧杂环戊烷-5-基)喹啉-2-胺与溶剂(9)混合，搅拌溶解或加热溶解，
(b)加入溶剂(10)，析晶，
其中溶剂(9)选自四氢呋喃，溶剂(10)选自水。
本公开一方面提供化合物8-氯-N-(2,2-二氟苯并[d][1,3]二氧杂环戊烷-5-基)喹啉-2-胺的E晶型，以衍射角2θ角度表示的X-射线粉末衍射图谱，在13.489、18.000、23.559、24.276和26.328处有特征峰。
在一些实施方案中，所述E晶型，以衍射角2θ角度表示的X-射线粉末衍射图谱，在13.489、16.863、18.000、23.559、24.276、26.108、26.328和27.094处有特征峰。
在一些实施方案中，所述E晶型，以衍射角2θ角度表示的X-射线粉末衍射图谱，在13.489、14.587、16.863、18.000、18.943、23.279、23.559、24.276、25.768、26.108、26.328和27.094处有特征峰。
在另一些实施方案中，所述E晶型，以衍射角2θ角度表示的X-射线粉末衍射图谱如图5所示。
本公开一方面提供化合物8-氯-N-(2,2-二氟苯并[d][1,3]二氧杂环戊烷-5-基)喹啉-2-胺的F晶型，以衍射角2θ角度表示的X-射线粉末衍射图谱，在9.299、14.439、15.621、16.200和17.314处有特征峰。
在一些实施方案中，所述F晶型，以衍射角2θ角度表示的X-射线粉末衍射图谱，在7.734、9.299、14.439、15.621、16.200、17.314、21.395和25.814处有特征峰。
在一些实施方案中，所述F晶型，以衍射角2θ角度表示的X-射线粉末衍射图谱，在7.734、9.299、14.439、15.621、16.200、17.314、21.055、21.395、23.194、25.814、28.906、34.485和43.544处有特征峰。
在另一些实施方案中，所述F晶型，以衍射角2θ角度表示的X-射线粉末衍射图谱如图6所示。
进一步地，本公开所述化合物A晶型、B晶型、C晶型、D晶型、E晶型或F晶型，以衍射角2θ角度表示的X-射线粉末衍射图，其中2θ角度的误差范围为±0.2。
在某些实施方案中，本公开所述的晶型的制备方法还包括过滤、洗涤或干燥中任一步骤。
在一些实施方案中，所述析晶包括但不限于搅拌析晶(溶析析晶、打浆析晶)和挥发析晶。
在一些实施方案中，所述干燥方式包括但不限于鼓风干燥、真空干燥。干燥温度一般为25℃～100℃，优选30℃～70℃，如40℃、50℃或60℃。
另一方面，本公开还提供一种药物组合物，其包括前述晶型和药学上可接受的赋形剂。
本公开还提供一种药物组合物，由前述晶型和药学上可接受的赋形剂制备得到。
本公开还提供了一种药物组合物的制备方法，包括前述晶型与药学上可接受的赋形剂混合的步骤。
本公开还提供了前述晶型或药物组合物在制备用于调节miRNA水平的药物中的用途；优选地，所述miRNA为miR-124。
本公开还提供了前述晶型或药物组合物治疗和/或预防疾病或病况的药物中的用途，所述的疾病或病况选自炎症和癌症。
在一些实施方案中，所述炎症为炎性肠病。在一些实施方案中，所述癌症为黑色素瘤或乳腺癌。
本公开所述的“2θ或2θ角度”是指衍射角，θ为布拉格角，单位为°或度；每个特征峰2θ的误差范围为±0.20(包括超过1位小数的数字经过四舍五入后的情况)，具体为-0.20、-0.19、-0.18、-0.17、-0.16、-0.15、-0.14、-0.13、-0.12、-0.11、-0.10、-0.09、-0.08、-0.07、-0.06、-0.05、-0.04、-0.03、-0.02、-0.01、0.00、0.01、0.02、0.03、0.04、0.05、0.06、0.07、0.08、0.09、0.10、0.11、0.12、0.13、0.14、0.15、0.16、0.17、0.18、0.19、0.20。
本公开中所述的“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。
本公开中所述干燥温度一般为25℃-100℃，优选30℃-70℃，可以常压干燥，也可以减压干燥。
本公开中所述的“药学上可接受的赋形剂”包括但不限于任何已经被美国食品和药物管理局批准对于人类或家畜动物使用可接受的任何助剂、载体、助流剂、甜味剂、稀释剂、防腐剂、染料/着色剂、增香剂、表面活性剂、润湿剂、分散剂、助悬剂、稳定剂、等渗剂或乳化剂。
本公开所述的“打浆”是指利用物质在溶剂中溶解性差，但杂质在溶剂中溶解性好的特性进行纯化的方法，打浆提纯可以去色、改变晶型或去除少量杂质。
本公开所述的晶型包括但不限于式(I)所示化合物的溶剂合物，所述的溶剂包括但不限于水。
附图说明
图1为化合物1的A晶型XRPD谱图。
图2为化合物1的B晶型XRPD谱图。
图3为化合物1的C晶型XRPD谱图。
图4为化合物1的D晶型XRPD谱图。
图5为化合物1的E晶型XRPD谱图。
图6为化合物1的F晶型XRPD谱图。
具体实施方式
通过以下实施例和实验例进一步详细说明本公开。这些实施例和实验例仅用于说明性目的，并不用于限制本公开的范围。
实验所用仪器的测试条件：
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-d6)、氘代氯仿(CDCl3)、氘代甲醇(CD3OD)，内标为四甲基硅烷(TMS)。
MS的测定用Agilent 1200/1290 DAD-6110/6120 Quadrupole MS液质联用仪(生产商：Agilent，MS型号：6110/6120 Quadrupole MS)。waters ACQuity UPLC-QD/SQD(生产商：waters，MS型号：waters ACQuity Qda Detector/waters SQ Detector)THERMO Ultimate 3000-Q Exactive(生产商：THERMO，MS型号：THERMO Q 15 Exactive)。
HPLC的测定使用安捷伦1260DAD高压液相色谱仪(Sunfire C18 150×4.6mm色谱柱)和Thermo U3000高压液相色谱仪(Gimini C18 150×4.6mm色谱柱)。
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)，射线：单色Cu-Ka射线扫描方式：θ/2θ，扫描范围：3-48°。
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，25-300℃或25-350℃，氮气吹扫速度50mL/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，氮气吹扫速度50mL/min。
DVS为动态水分吸附：采用Surface Measurement Systems instrinsic，湿度从50％起，考察湿度范围为0％-95％，步进为10％，判断标准为每个梯度质量变化dM/dT≤0.002％，TMAX 360min，循环两圈。
本公开的已知的起始原料可以采用或按照本领域已知的方法来合成，或可购买自ABCR GmbH&Co.KG，Acros Organics，Aldrich Chemical Company，韶远化学科技(Accela ChemBio Inc)、达瑞化学品等公司
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。
实施例1. 8-氯-N-(2,2-二氟苯并[d][1,3]二氧杂环戊烷-5-基)喹-2-胺合成(参照申请号为 WO2022247920的申请中实施例1的制备方法)
将2,8-二氯喹啉1a(100mg，0.51mmol，毕得医药)，5-氨基-2,2-二氟-1,3-苯并[1,3]二氧杂环戊烷1b(105mg，0.61mmol，上海皓鸿)溶解在异丙醇(1mL)中，加热升温至90℃反应12小时。反应液过滤后经高效液相制备(Waters 2767-SQ Detecor2，洗脱体系：0.1％的甲酸水溶液和乙腈，乙腈的梯度：65％-85％，流速：30mL/min)得到标题化合物1(150mg，产率89.0％)。
MS m/z(ESI):335.0[M+1]。
1H NMR(500MHz,DMSO-d6)δ9.99(s,1H),8.88(d,1H),8.17(d,1H),7.81(dd,1H),7.77(dd,1H),7.50(dd,1H),7.39(d,1H),7.32(t,1H),7.14(d,1H)。
测试例1.对miR-124的上调作用
一、实验材料及仪器
1.人T细胞活化CD3/CD28磁珠(Dynabead Human T-Activator CD3/CD28for T Cell Expansion and Activation)(Gibco，11131D)
2.人总T细胞分离试剂盒(Pan T Cell Isolation Kit,human)(Miltenyi，130-096-535)
3.人白介素2(Human IL-2)(Peprotech，200-02-100)
4.小RNA抽提试剂盒(microRNA抽提试剂盒)(Qiagen，217004)
5.小RNA反转录试剂盒(miScript II RT Kit)(Qiagen，218161)
6.小RNA SYBR Green PCR试剂盒(miScript SYBR Green PCR Kit)(Qiagen，218073)
7.磷酸缓冲液PBS，pH7.4(上海源培生物科技股份有限公司，B320)
8.牛血清白蛋白，BSA(碧云天，ST023)
9.EDTA(0.5M),pH 8.0(Invitrogen，AM9260G)
10.LS分离柱(LS Columns)(Miltenyi,130-042-401)
11. 24孔细胞培养板(Corning，3524)
12. 96孔板(Corning，3788)
13.细胞培养箱(Thermo，Steri cycle i160)
14.实时荧光定量PCR仪(Applied biosystem，QuantStudio6Flex)
15.PCR仪(Applied biosystem，ProFlex)
16. 96孔透明PCR板，0.2mL(Applied biosystems，N8010560)
17.RPMI1640培养基(Gibco，11875119)
18.胎牛血清，FBS(Gibco，10099-141)
19.磁力架(Invitrogen，DynaMagTM-2)
20.六孔细胞培养板(Thermo，150239)
21.分光光度计(IMPLEN，NP80)
22.磁珠分离铁架(QuadroMACS Separator)(美天旎，130-090-976)
23.miR124-3P-F引物(金唯智公司定制)
24.hsa-U6检测引物(天根，CD201-0145)
二、实验步骤
化合物对miR-124表达水平的影响在CD3/CD28抗体激活后的T细胞中检测。激活的T细胞经过化合物处理后，提取细胞的总RNA，反转录所得的cDNA作为模板，使用特异性miR-124引物用SYBR green荧光定量PCR法来定量。
T细胞的分离：购买所得的人外周血单核细胞(PBMC)，计数过滤后用分离缓冲液(PBS pH 7.4,含有0.5％BSA和2mM EDTA))洗一遍，弃去上清，按每1×107个细胞加40μL缓冲液和10μL T细胞分离生物素化混合抗体(pan T Cell Biotin-Antibody Cocktail)的量，加入各成分重悬沉淀并混匀，4℃冰箱孵育5分钟。孵育完成后，按照每1×107个细胞加30μL缓冲液和20μL T细胞分离磁珠(Pan T Cell MicroBeads Cocktail)的量加入各成分，混匀后4℃冰箱孵育10分钟。用3毫升细胞分离缓冲液提前润洗分离柱子LS column，将上述细胞混悬液过柱，细胞悬液过柱后用1毫升细胞分离缓冲液重复洗柱子3遍，流出细胞液被收集在15毫升过滤管中即是富集的T细胞。对细胞进行计数，按1×106细胞/mL的密度加入含有10％FBS和40U/mL IL-2的RPMI1640培养基(完全培养基)，保存于冰上备用。
T细胞的活化：按每1×106个细胞加25μL活化磁珠的量，取出相应的T细胞活化CD3/CD28磁珠于1.5mL过滤管中，吸出前应在振荡器上振荡30s左右。在过滤管中以体积比大于1：1比例，使用培养基将活化磁珠洗3遍，最后一遍去除所有洗液，加入与起始体积等量的完全培养基重悬活化磁珠。将清洗好的活化磁珠加入细胞重悬液中，混合均匀。取出六孔板，以每孔3mL的量加入细胞，37℃，5％CO2细胞培养箱中培养2天。
化合物处理：化合物储存液为20mM，用DMSO稀释至200μM，再用完全培养基将化合物稀释4倍至50μM(50×)，混匀待用。DMSO稀释4倍(25％DMSO)为阴性对照孔。活化两天的T细胞，将细胞吹打均匀，使用磁力架并安装上1.5mL过滤管，去除活化磁珠，并收集细胞悬液。对细胞进行计数后，300xg，10min过滤弃上清，重悬细胞至1.02×106/mL，每个24孔板加入980μL细胞悬液和20μL 50×化合物，化合物最终浓度为1μM。将细胞置于37℃，5％CO2细胞培养箱中继续培养3天。
RNA抽提：将T细胞过滤收集，1500rpm过滤3分钟，PBS清洗1次，过滤后弃上清。使用小RNA抽 提试剂盒，根据说明书抽提细胞总RNA。细胞沉淀加入700μL Trizol细胞裂解液，枪头吹打均匀，于室温放置5分钟。加入140μL氯仿，振荡混匀，于室温静置3分钟。将氯仿-细胞裂解液混合物于4℃以12000xg过滤15分钟。将上层溶液转移至新的无RNA酶(RNase-free)的过滤管中，加入1.5倍体积的无水乙醇，枪头吹打数次。将溶液转移至RNA吸附柱中，8000xg过滤15s。将过滤柱用700μL RWT溶液洗一遍，8000xg过滤15s，加入500μL RPE溶液洗两遍，8000xg过滤2分钟。将吸附柱放入新的2mL过滤管中，12000xg过滤1min去除残余洗液。将吸附柱放入新的1.5mL过滤管中，加入30-50μL无RNA酶水(RNase-free water)，12000xg过滤2分钟，收集的溶液为RNA溶液，使用分光光度计测量RNA浓度。RNA溶液保存于-80度冰箱。
反转录：上述提取的RNA模板放置在冰上，取出小RNA反转录试剂盒，于室温解冻部分成分(包含5×miScript HiSpec Buffer，10×miScript nucleics Mix和无RNA酶水)，于冰上解冻miScript Reverse Transcriptase mix成分。每个反应(10μL)成分为：5×miScript HiSpec Buffer(2μL)，10×miScript nucleics Mix(1μL)，miScript Reverse Transcriptase mix(1μL)，无RNA酶水(2μL)，RNA模板(4μL)，在冰上配制上述反应。将样品放置于PCR仪中，设置程序如下：37℃，60分钟；95℃，5分钟；4℃保存。反应完成的样品为cDNA样品。
荧光定量PCR：使用SYBR green染色法检测miR-124的转录水平，同时检测管家基因U6的转录水平作为内参。解冻所有小RNA SYBR green PCR试剂盒所需试剂至常温，将每个cDNA样品模板用无RNA酶水稀释10倍，再稀释5倍。按照下表1配制反应混合物，并将反应混合物加入到96孔PCR板中，用封板膜封板，过滤。将PCR反应在荧光定量PCR仪上按照表2步骤进行。
表1荧光定量PCR反应成分表
表2荧光定量PCR步骤
表3荧光定量PCR检测引物表
数据分析：根据软件所算得的CT值，计算每个样品miR-124与内参U6表达水平的比值，即ΔCT(测试化合物)＝CTmiRNA-124(测试化合物)-CTU6(测试化合物)。相对表达量由以下公式计算，相对表达量(测试化合物)＝2(-[ΔCT(测试化合物)-ΔCT(DMSO)])。
化合物1 miR-124上调(倍数)3.9倍，具有良好的促进miR124上调的活性。
实施例2：A晶型的制备
取250mg化合物1，加入2.5mL乙腈中搅拌溶解，加入17.5mL水搅拌析晶，室温打浆4天，过滤，真空干燥得固体。
经X-射线粉末衍射检测，将该产物定义为A晶型，X-射线粉末衍射数据如表4所示，X-射线粉末衍射谱图如图1所示。
DSC谱图显示吸热峰峰值177.14℃。
TGA谱图显示30℃-100℃失重0.22％。
DVS检测显示在正常存储条件下(即室温、60％RH)，该样品吸湿增重约为0.02％；在加速实验条件(即70％RH)，吸湿增重约为0.02％；在极端条件下(即90％RH)，吸湿增重约为0.18％。且DVS检测后复测晶型，晶型未转变。
表4

实施例3：A晶型的制备
将化合物1(6mg，17.63μmol)溶于0.3mL四氢呋喃，溶清后慢挥发得固体，经45℃真空干燥3小时得到产物。
经X-射线粉末衍射检测，该产物为A晶型。
实施例4：A晶型的制备
将化合物1(11mg，32.87μmol)溶于0.4mL乙酸乙酯，溶清后慢挥发得固体，经45℃真空干燥3小时得到产物。
经X-射线粉末衍射检测，该产物为A晶型。
实施例5：A晶型的制备
将化合物1(14mg，41.83μmol)溶于0.5mL二氯甲烷，溶清后慢挥发得固体，经45℃真空干燥3小时得到产物。
经X-射线粉末衍射检测，该产物为A晶型。
实施例6：A晶型的制备
将化合物1(1.70g，5.08mmol)分散于35mL环己烷中，搅拌打浆48小时，过滤并收集滤饼，45℃真空干燥16小时得到产物。
经X-射线粉末衍射检测，该产物为A晶型。
实施例7：A晶型的制备
称取10mg化合物1，加入1ml纯化水室温打浆3天，过滤后固体真空干燥，得到产物。
经X-射线粉末衍射检测，该产物为A晶型。
实施例8：A晶型的制备
参照实施例7方法，称取10mg化合物1，加入溶剂中，打浆，过滤后固体真空干燥，得到产物。
经X-射线粉末衍射检测，产物为A晶型，数据见表5。
表5

实施例9：A晶型的制备
称取10mg化合物1，加入0.2ml甲醇室温搅拌溶清，加入0.2ml纯化水搅拌析晶，室温打浆1天，过滤后固体真空干燥，得到产物。
经X-射线粉末衍射检测，该产物为A晶型。
实施例10：A晶型的制备
称取10mg化合物1，加入0.2ml乙醇室温搅拌溶清，加入0.4ml正庚烷搅拌1天，挥发析晶得到产物。
经X-射线粉末衍射检测，该产物为A晶型。
实施例11：A晶型的制备
称取10mg化合物1，加入0.6ml异丙醇室温搅拌溶清，加入0.4ml正庚烷搅拌1天，挥发析晶得到产物。
经X-射线粉末衍射检测，该产物为A晶型。
实施例12：A晶型的制备
称取10mg化合物1，加入0.1ml丙酮室温搅拌溶清，加入0.4ml正庚烷搅拌1天，挥发析晶得到产物。
经X-射线粉末衍射检测，该产物为A晶型。
实施例13：A晶型的制备
称取10mg化合物1，加入0.1ml乙酸乙酯室温搅拌溶清，加入0.4ml正庚烷搅拌1天，挥发析晶得到产物。
经X-射线粉末衍射检测，该产物为A晶型。
实施例14：A晶型的制备
称取10mg化合物1，加入0.1ml乙酸异丙酯室温搅拌溶清，加入0.4ml正庚烷搅拌析晶，室温打浆1天，补加0.2ml正庚烷继续打浆3小时，过滤后固体真空干燥，得到产物。
经X-射线粉末衍射检测，该产物为A晶型。
实施例15：A晶型的制备
称取10mg化合物1，加入0.1ml四氢呋喃室温搅拌溶清，加入0.4ml正庚烷搅拌1天，挥发析晶得到产物。
经X-射线粉末衍射检测，该产物为A晶型。
实施例16：A晶型的制备
称取10mg化合物1，加入0.1ml甲基异丙基酮室温搅拌溶清，加入0.4ml正庚烷搅拌1天，挥发析晶得到产物。
经X-射线粉末衍射检测，该产物为A晶型。
实施例17：A晶型的制备
称取10mg化合物1，加入0.4ml二氯甲烷室温搅拌溶清，加入0.4ml正庚烷析晶，室温打浆1天，补加0.2ml正庚烷打浆3小时，过滤后固体真空干燥，得到产物。
经X-射线粉末衍射检测，该产物为A晶型。
实施例18：A晶型的制备
称取10mg化合物1，加入1ml 10％水/甲醇室温搅拌溶清，加入0.1ml水搅拌析晶，补加0.1ml水，继续打浆1天，过滤后固体真空干燥，得到产物。
经X-射线粉末衍射检测，该产物为A晶型。
实施例19：A晶型的制备
称取10mg化合物1，加入0.6ml 7％水/乙醇室温搅拌溶清，加入0.4ml正庚烷，挥发析晶得到产物。
经X-射线粉末衍射检测，该产物为A晶型。
实施例20：A晶型的制备
称取10mg化合物1，加入0.6ml 10％水/异丙醇室温搅拌溶清，加入0.4ml正庚烷，挥发析晶得到产物。
经X-射线粉末衍射检测，该产物为A晶型。
实施例21：A晶型的制备
称取10mg化合物1，加入0.1ml 10％水/丙酮室温搅拌溶清，加入0.4ml正庚烷，挥发析晶得到产物。
经X-射线粉末衍射检测，该产物为A晶型。
实施例22：A晶型的制备
称取10mg化合物1，加入0.2ml乙醇室温搅拌溶解，加入0.1ml纯化水搅拌析出，继续添加0.2ml纯化水后搅拌1天，过滤后固体真空干燥，得到产物。
经X-射线粉末衍射检测，该产物为A晶型。
实施例23：A晶型的制备
称取10mg化合物1，加入0.2ml乙醇室温搅拌溶解，加入0.4ml环己烷搅拌1天后，挥发析晶得到产物。
经X-射线粉末衍射检测，该产物为A晶型。
实施例24：A晶型的制备
称取10mg化合物1，加入0.1ml丙酮室温搅拌溶解，加入0.1ml纯化水搅拌析出，继续添加0.2ml纯化水后搅拌1天，过滤后固体真空干燥，得到产物。
经X-射线粉末衍射检测，该产物为A晶型。
实施例25：A晶型的制备
称取10mg化合物1，加入0.1ml丙酮室温搅拌溶解，加入0.4ml环己烷搅拌1天后，挥发析晶得到产物。
经X-射线粉末衍射检测，该产物为A晶型。
实施例26：A晶型的制备
称取10mg化合物1，加入0.1ml乙酸乙酯室温搅拌溶解，加入0.4ml环己烷搅拌1天后，挥发析晶得到产物。
经X-射线粉末衍射检测，该产物为A晶型。
实施例27：A晶型的制备
称取10mg化合物1，加入0.1ml乙酸乙酯室温搅拌溶解，加入0.4ml正庚烷搅拌1天后，挥发析晶得到产物。
经X-射线粉末衍射检测，该产物为A晶型。
实施例28：A晶型的制备
称取10mg化合物1，加入0.1ml甲基叔丁基醚室温搅拌溶解，加入0.1ml环己烷析出，继续添 加0.2ml环己烷后搅拌1天，过滤后固体真空干燥，得到产物。
经X-射线粉末衍射检测，该产物为A晶型。
实施例29：A晶型的制备
称取10mg化合物1，加入0.1ml四氢呋喃室温搅拌溶解，加入0.4ml环己烷搅拌1天后，挥发析晶得到产物。
经X-射线粉末衍射检测，该产物为A晶型。
实施例30：A晶型的制备
称取10mg化合物1，加入0.1ml甲基异丁基酮室温搅拌溶解，加入0.4ml环己烷搅拌1天后，挥发析晶得到产物。
经X-射线粉末衍射检测，该产物为A晶型。
实施例31：A晶型的制备
称取10mg化合物1，加入0.1ml10％水/丙酮室温搅拌溶解，加入0.1ml纯化水析出，继续添加0.2ml纯化水后搅拌1天，过滤后固体真空干燥，得到产物。
经X-射线粉末衍射检测，该产物为A晶型。
实施例32：A晶型的制备
称取10mg化合物1，加入0.1ml乙酸异丙酯室温搅拌溶解，加入0.4ml环己烷，挥发析晶得到产物。
经X-射线粉末衍射检测，该产物为A晶型。
实施例33：B晶型的制备
称取10mg化合物1，加入0.1ml二甲基亚砜溶清，加入0.2ml水析晶，继续打浆1天，过滤后真空干燥，得到固体。
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2，其特征峰位置如表6所示。
DSC谱图显示吸热峰峰值81.99、173.56℃。
TGA谱图显示30℃-100℃失重18.35％。
表6

实施例34：C晶型的制备
称取30mg化合物1，加入1.2ml 1,4-二氧六环中搅拌溶解，加入1.8ml正庚烷，搅拌析晶，过滤后真空干燥，得固体。
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3，其特征峰位置如表7所示。
DSC谱图显示吸热峰峰值141.90、176.81℃。
TGA谱图显示30℃-85℃失重1.89％，85℃-160℃失重5.94％。
表7

实施例35：D晶型的制备
称取30mg化合物1，加入0.3ml四氢呋喃室温搅拌溶解，加入1.2ml水搅拌析晶，搅拌析晶，过滤后真空干燥，得到产物固体。
经X-射线粉末衍射检测，将该产物定义为D晶型，XRPD谱图如图4，其特征峰位置如表8所示。
DSC谱图显示吸热峰峰值176.85℃。
TGA谱图显示30℃-100℃失重0.34％。
表8

实施例36：E晶型的制备
称取100mg化合物1分散于1mL乙腈中，搅拌打浆48小时，过滤后，收集固体，45℃真空干燥，得到产物固体。
经X-射线粉末衍射检测，将该产物定义为E晶型，X-射线粉末衍射数据如表9所示，X-射线粉末衍射谱图如图5所示。
DSC谱图显示：吸热峰峰值为88.25℃，177.28℃。
TGA谱图显示：从30℃到115℃，化合物失重1.80％；从115℃到230℃，化合物失重5.29％。
表9

实施例37：F晶型的制备
称取10mg化合物1，加入0.4ml 1,4-二氧六环溶清，加入0.4ml正庚烷搅拌1天析晶，补加0.2ml正庚烷打浆3小时，过滤后上清液挥发析晶得到产物固体。
经X-射线粉末衍射检测，将该产物定义为F晶型，XRPD谱图如图6，其特征峰位置如表10所示。
表10
测试例2：影响因素
将A晶型敞口平摊放置，分别考察在光照(4500Lux)、高温(40℃、60℃)、高湿(RH 75％、RH 92.5％)条件下样品的稳定性，取样考察期为30天。
表11晶型影响因素稳定性
结论：影响因素实验表明：在光照、高温40℃和60℃、高湿75％和92.5％条件下30天，游离态A晶型物理化学稳定性均良好。
测试例3：长期加速试验
将A晶型分别放置25℃/60％RH和40℃/75％RH条件考察稳定性。
表12晶型长期加速稳定性
结论：长期加速实验表明：在25℃/60％RH和40℃/75％RH条件下6个月，A晶型的物理化学稳定性均良好。

Claims (11)

  1. 化合物8-氯-N-(2,2-二氟苯并[d][1,3]二氧杂环戊烷-5-基)喹啉-2-胺的A晶型，其特征在于，以衍射角2θ角度表示的X-射线粉末衍射图谱，在7.237、9.232、13.702、14.459和18.917处有特征峰，优选在7.237、9.232、13.702、14.459、18.917、24.428和29.321处有特征峰，更优选在7.237、9.232、13.702、14.459、18.033、18.917、24.428、25.521和29.321处有特征峰，最优选以衍射角2θ角度表示的X-射线粉末衍射图谱如图1所示。
  2. 化合物8-氯-N-(2,2-二氟苯并[d][1,3]二氧杂环戊烷-5-基)喹啉-2-胺的B晶型，其特征在于，以衍射角2θ角度表示的X-射线粉末衍射图谱，在8.205、9.781、12.870、15.907和19.796处有特征峰，优选在8.205、9.781、12.870、15.907、19.448、19.796、20.264和23.185处有特征峰，更优选在8.205、9.781、10.672、12.870、15.356、15.907、16.997、19.448、19.796、20.264和23.185处有特征峰，最优选以衍射角2θ角度表示的X-射线粉末衍射图谱如图2所示。
  3. 化合物8-氯-N-(2,2-二氟苯并[d][1,3]二氧杂环戊烷-5-基)喹啉-2-胺的C晶型，其特征在于，以衍射角2θ角度表示的X-射线粉末衍射图谱，在9.296、15.522、18.784、23.216和25.889处有特征峰，优选在7.753、9.296、15.522、18.784、21.398、23.216和25.889处有特征峰，更优选在7.353、7.753、9.296、14.475、15.522、16.248、17.320、18.784、21.398、23.216和25.889处有特征峰，最优选以衍射角2θ角度表示的X-射线粉末衍射图谱如图3所示。
  4. 化合物8-氯-N-(2,2-二氟苯并[d][1,3]二氧杂环戊烷-5-基)喹啉-2-胺的D晶型，其特征在于，以衍射角2θ角度表示的X-射线粉末衍射图谱，在7.350、12.084、15.384、18.643和29.312处有特征峰，优选在7.350、12.084、15.384、16.260、17.855、18.643、21.610和29.312处有特征峰，更优选在7.350、12.084、15.384、16.260、17.855、18.643、21.610、22.768、24.347、25.201、26.038和29.312处有特征峰，最优选以衍射角2θ角度表示的X-射线粉末衍射图谱如图4所示。
  5. 化合物8-氯-N-(2,2-二氟苯并[d][1,3]二氧杂环戊烷-5-基)喹啉-2-胺的E晶型，其特征在于，以衍射角2θ角度表示的X-射线粉末衍射图谱，在13.489、18.000、23.559、24.276和26.328处有特征峰，优选在13.489、16.863、18.000、23.559、24.276、26.108、26.328和27.094处有特征峰，更优选在13.489、14.587、16.863、18.000、18.943、23.279、23.559、24.276、25.768、26.108、26.328和27.094处有特征峰，最优选以衍射角2θ角度表示的X-射线粉末衍射图谱如图5所示。
  6. 化合物8-氯-N-(2,2-二氟苯并[d][1,3]二氧杂环戊烷-5-基)喹啉-2-胺的F晶型，其特征在于，以衍射角2θ角度表示的X-射线粉末衍射图谱，在9.299、14.439、15.621、16.200和17.314处有特征峰，优选在7.734、9.299、14.439、15.621、16.200、17.314、21.395和25.814处有特征峰，更优选在7.734、9.299、14.439、15.621、16.200、17.314、21.055、21.395、23.194、25.814、28.906、34.485和43.544处有特征峰，最优选以衍射角2θ角度表示的X-射线粉末衍射图谱如图6所示。
  7. 根据权利要求1-6任一项所述的晶型，其特征在于所述2θ值误差范围为±0.2。
  8. 制备权利要求1-7任一项所述的晶型的制备方法，选自如下任一方法，
    方法一：
    (a)将化合物8-氯-N-(2,2-二氟苯并[d][1,3]二氧杂环戊烷-5-基)喹啉-2-胺与溶剂混合，搅拌溶解或加热溶解，
    (b)加入第二溶剂，析晶；
    或，方法二：
    (a)将化合物8-氯-N-(2,2-二氟苯并[d][1,3]二氧杂环戊烷-5-基)喹啉-2-胺与溶剂混合，搅拌溶解或加热溶解，
    (b)析晶；
    或，方法三：
    (a)将化合物8-氯-N-(2,2-二氟苯并[d][1,3]二氧杂环戊烷-5-基)喹啉-2-胺与溶剂混合，
    (b)搅拌打浆。
  9. 一种药物组合物，其包括如权利要求1-7任一项所述的晶型，和药学上可接受的赋形剂。
  10. 一种药物组合物，由如权利要求1-7任一项所述的晶型和药学上可接受的赋形剂制备得到。
  11. 权利要求1-7任一项所述的晶型，或权利要求9或10所述的药物组合物在制备用于治疗和/或预防疾病或病况的药物中的用途，所述的疾病或病况选自炎症和癌症，所述炎症优选炎性肠病，所述癌症优选黑色素瘤或乳腺癌。
PCT/CN2023/134047 2022-11-25 2023-11-24 一种喹啉胺类化合物晶型及其制备方法 WO2024109936A1 (zh)

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