WO2022037647A1 - 一种选择性Nav抑制剂的结晶形式及其制备方法 - Google Patents

一种选择性Nav抑制剂的结晶形式及其制备方法 Download PDF

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WO2022037647A1
WO2022037647A1 PCT/CN2021/113532 CN2021113532W WO2022037647A1 WO 2022037647 A1 WO2022037647 A1 WO 2022037647A1 CN 2021113532 W CN2021113532 W CN 2021113532W WO 2022037647 A1 WO2022037647 A1 WO 2022037647A1
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methoxy
crystal form
compound
characteristic peaks
pain
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English (en)
French (fr)
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徐谷军
邵成
杜振兴
王捷
尤凌峰
冯君
贺峰
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江苏恒瑞医药股份有限公司
上海恒瑞医药有限公司
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    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/50—Pyridazines; Hydrogenated pyridazines
    • 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
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • 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]
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D237/00—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings
    • C07D237/02—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings
    • C07D237/06—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
    • C07D237/10—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D237/22—Nitrogen and oxygen atoms

Definitions

  • the present disclosure belongs to the technical field of medicine, and relates to a crystalline form of a selective Na V 1.8 inhibitor and a preparation method thereof, in particular to the compound 4-((4-(5-chloro-2-(4-fluoro-2-(methyl) Oxy-d3)phenoxy)-4-(trifluoromethyl)benzamido)-6-oxopyridazin-1(6H)-yl)methoxy)-4-oxobutyric acid A, B, C, D, E crystal forms and preparation methods thereof.
  • Pain is one of the most common clinical symptoms and originates from nociceptors in the peripheral nervous system. This is a free nerve ending widely distributed in the skin, muscles, joints and visceral tissues of the body. It can convert thermal, mechanical or chemical stimuli felt into nerve impulses (action potentials) and transmit them through transmission. The incoming nerve fibers are transmitted to the cell body part of the dorsal root ganglia (DRG), and finally transmitted to the higher nerve centers, causing pain sensation. The generation and conduction of action potentials in neurons depend on voltage-gated sodium channels (Na V ) on the cell membrane.
  • Na V voltage-gated sodium channels
  • Non-selective Na V inhibitors such as lamotrigine, lacosamide, mexiletine have also been successfully used to treat chronic pain.
  • WO2020169042 provides a selective Na V 1.8 inhibitor whose chemical name is 4-((4-(5-chloro-2-(4-fluoro-2-(methoxy- d3 )phenoxy)- 4-(Trifluoromethyl)benzamido)-6-oxopyridazin-1(6H)-yl)methoxy)-4-oxobutyric acid (Formula I), which has been found to have With better pharmaceutical activity, it is expected to be developed into a new selective Na V 1.8 inhibitor, providing patients with new treatment options.
  • crystalline structure of the active ingredient of a drug often affects the physicochemical stability of the drug. Different crystallization conditions and storage conditions may lead to changes in the crystal structure of the compound, sometimes accompanied by the formation of other crystal forms. Generally speaking, amorphous pharmaceutical products have no regular crystal structure, and are often accompanied by defects such as poor product stability, finer crystallization, difficult filtration, easy agglomeration, and poor fluidity.
  • the compound 4-((4-(5-chloro-2-(4-fluoro-2-(methoxy-d 3 )phenoxy) base)-4-(trifluoromethyl)benzamido)-6-oxopyridazin-1(6H)-yl)methoxy)-4-oxobutyric acid free base crystalline form suitable for development Industrial production of drugs with good biological activity is of great significance.
  • the present disclosure provides the compound 4-((4-(5-chloro-2-(4-fluoro-2-(methoxy- d3 )phenoxy)-4-(trifluoromethyl)benzamido) )-6-oxopyridazin-1(6H)-yl)methoxy)-4-oxobutyric acid (Formula I) crystal form A, X-ray powder diffraction pattern represented by diffraction angle 2 ⁇ angle, There are characteristic peaks at 17.966, 19.759, 22.119, 23.676, 24.444, 25.003 and 29.122.
  • Form A of the compound of Formula I has characteristic peaks at 11.946, 17.966, 19.759, 22.119, 23.676, 24.444, 25.003, 29.122, 30.154, and 31.278.
  • Form A of the compound of Formula I has characteristic peaks at 5.919, 10.000, 11.946, 17.966, 19.759, 22.119, 23.676, 24.444, 25.003, 26.266, 29.122, 30.154, and 31.278.
  • the X-ray powder diffraction pattern of Form A of the compound of formula I expressed as a diffraction angle 2 ⁇ is shown in FIG. 1 .
  • the present disclosure also provides a method for preparing a crystal form of compound A of formula I, comprising:
  • the volume ( ⁇ l) of the solvent (I) described in the present disclosure may be 1-200 times the mass (mg) of the compound of formula I, and in non-limiting embodiments, it may be 1, 5, 10, 15, 20, 25, 30 , 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, 120, 125, 130, 135, 140, 145, 150, 155 , 160, 165, 170, 175, 180, 185, 190, 200.
  • the present disclosure provides an X-ray powder diffraction pattern of Form B of the compound of formula (I), expressed in diffraction angle 2 ⁇ , with characteristic peaks at 17.895, 18.438, 20.282, 21.661, 22.639, 22.912 and 30.946.
  • Form B of the compound of Formula I has characteristic peaks at 11.845, 15.281, 17.895, 18.438, 20.282, 21.661, 22.639, 22.912, 27.146, and 30.946.
  • Form B of the compound of Formula I has characteristic peaks at 10.781, 11.845, 12.865, 15.281, 17.895, 18.438, 20.282, 21.661, 22.639, 22.912, 25.964, 27.146, and 30.946.
  • the X-ray powder diffraction pattern of the crystalline form B of the compound of formula I expressed as a diffraction angle 2 ⁇ is shown in FIG. 2 .
  • the present disclosure also provides a method for preparing the crystal form of compound B of formula I, comprising:
  • solvent (II) 4-((4-(5-Chloro-2-(4-fluoro-2-(methoxy-d3)phenoxy)-4-(trifluoromethyl)benzamido)- 6-Oxopyridazin-1(6H)-yl)methoxy)-4-oxobutyric acid is mixed with solvent (II), stirred to dissolve or heated to dissolve, and the solvent (II) is selected from NN dimethyl formamide (DMF), NN dimethylacetamide (DMA), dimethyl sulfoxide (DMSO), N-methylpyrrolidone (NMP), acetone, 1,4-dioxane, tetrahydrofuran (THF) and at least one in water;
  • solvent (II) is selected from NN dimethyl formamide (DMF), NN dimethylacetamide (DMA), dimethyl sulfoxide (DMSO), N-methylpyrrolidone (NMP), acetone, 1,4-dioxane,
  • solvent (III) selected from tetrahydrofuran (THF), dimethyl sulfoxide at least one of (DMSO) and acetone;
  • solvent (IV) is selected from C 1-6 alkyl alcohol, isopropyl acetate, methyl tert-butyl ether, methyl isobutyl ketone, dichloromethane and at least one of water, the C 1-6 alkyl alcohol is preferably selected from ethanol or isopropanol.
  • the volume ( ⁇ l) of the solvent (II), (III), (IV) described in the present disclosure can be 1-200 times the mass (mg) of the compound of formula I, and in a non-limiting embodiment, it can be 1, 5, 10 , 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, 120, 125, 130, 135 , 140, 145, 150, 155, 160, 165, 170, 175, 180, 185, 190, 200.
  • the present disclosure provides an X-ray powder diffraction pattern of the compound of formula (I) in crystal form C, expressed in diffraction angle 2 ⁇ , with characteristic peaks at 4.836, 9.675, 14.266, 16.039, 22.856, 24.883 and 27.494.
  • Form C of the compound of Formula I has characteristic peaks at 4.836, 9.675, 10.965, 14.266, 16.039, 18.507, 22.856, 24.883, 26.173, and 27.494.
  • Form C of the compound of Formula I has characteristic peaks at 4.836, 9.675, 10.965, 14.266, 16.039, 17.900, 18.507, 19.581, 22.856, 24.883, 26.173, 27.494, and 29.485.
  • the X-ray powder diffraction pattern of the crystalline form C of the compound of formula I, expressed as a diffraction angle 2 ⁇ , is shown in FIG. 5 .
  • the present disclosure also provides a method for preparing the crystal form C of the compound of formula I, comprising:
  • the concentrated crystallization can be concentrated under reduced pressure.
  • the volume ( ⁇ l) of the solvent (V) described in the present disclosure may be 1-200 times the mass (mg) of the compound of formula I, and in non-limiting embodiments may be 1, 5, 10, 15, 20, 25, 30 , 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, 120, 125, 130, 135, 140, 145, 150, 155 , 160, 165, 170, 175, 180, 185, 190, 200.
  • the present disclosure provides an X-ray powder diffraction pattern of the compound of formula I, Form D, expressed in diffraction angle 2 ⁇ , with characteristic peaks at 11.819, 17.915, 18.337, 19.781, 21.577, 23.618, and 24.375.
  • Form D of the compound of formula I has characteristic peaks at 11.819, 15.201, 17.915, 18.337, 19.781, 20.050, 21.577, 22.832, 23.618, and 24.375.
  • Form D of the compound of Formula I has characteristic peaks at 10.704, 11.819, 15.201, 17.915, 18.337, 19.781, 20.050, 21.577, 22.832, 23.618, 24.375, 27.077, and 29.058.
  • the X-ray powder diffraction pattern of the crystalline form D of the compound of formula I expressed as a diffraction angle 2 ⁇ is shown in FIG. 6 .
  • the present disclosure also provides a method for preparing the crystal form D of the compound of formula I, comprising:
  • the present disclosure provides an X-ray powder diffraction pattern of Form E of the compound of formula I, expressed in diffraction angle 2 ⁇ , with characteristic peaks at 5.282, 10.624, 11.767, 20.355, 21.618, 22.599 and 25.184.
  • Form E of the compound of Formula I has characteristic peaks at 5.282, 10.624, 11.767, 15.963, 20.355, 21.618, 22.599, 22.958, 25.184, and 27.286.
  • Form E of the compound of Formula I has characteristic peaks at 5.282, 10.624, 11.767, 13.464, 15.963, 18.312, 20.355, 21.618, 22.599, 22.958, 25.184, 27.286, and 30.888.
  • the X-ray powder diffraction pattern of the crystalline form E of the compound of formula I in terms of diffraction angle 2 ⁇ is shown in FIG. 7 .
  • the present disclosure also provides a method for preparing the crystal form E of the compound of formula I, comprising:
  • the method for preparing a crystal form described in the present disclosure further comprises steps such as filtration, washing or drying.
  • crystallization in the present disclosure includes, but is not limited to, stirring crystallization or static crystallization or stirring cooling crystallization.
  • the present disclosure also provides a pharmaceutical composition prepared from any one of the aforementioned crystal forms.
  • the present disclosure also provides a pharmaceutical composition
  • a pharmaceutical composition comprising the aforementioned crystalline form of the compound of formula I or a crystalline form prepared by the aforementioned method, and optionally a pharmaceutically acceptable carrier, diluent or excipient.
  • the present disclosure also provides a preparation method of a pharmaceutical composition, comprising the step of mixing the aforementioned crystal form of the compound of formula I or the crystal form prepared by the aforementioned method with a pharmaceutically acceptable carrier, diluent or excipient.
  • the present disclosure also provides the crystalline form of the compound of formula I or the crystalline form of the compound of formula I prepared by the aforementioned method or the aforementioned composition or the composition prepared by the aforementioned preparation method.
  • the voltage-gated sodium channel is Na V 1.8.
  • the present disclosure also provides the crystalline form of the compound of formula I or the crystalline form of the compound of formula I prepared by the aforementioned method or the aforementioned composition or the composition prepared by the aforementioned preparation method in the preparation for the treatment and/or alleviation of pain and pain-related diseases , Multiple sclerosis, Sharma- Figure 3 syndrome, incontinence or use in medicine for arrhythmia, preferably, the pain is selected from chronic pain, acute pain, inflammatory pain, cancer pain, neuropathic pain , musculoskeletal pain, primary pain, bowel pain and idiopathic pain.
  • the “2 ⁇ or 2 ⁇ angle” in this disclosure refers to the diffraction angle, and ⁇ is the Bragg angle, in degrees or degrees; the error range of 2 ⁇ for each characteristic peak is ⁇ 0.20, and ⁇ 0.2 includes numbers with more than 1 decimal place after rounding. situation after.
  • DSC Different Scanning Calorimetry or DSC refers to the measurement of the temperature difference, heat flow difference between a sample and a reference during the heating or constant temperature of the sample to characterize all physical changes related to thermal effects and Chemical changes to obtain phase transition information of the sample.
  • the drying temperature mentioned in the present disclosure is generally 25°C to 100°C, preferably 40°C to 70°C, and can be dried under normal pressure or under reduced pressure.
  • “Pharmaceutical composition” means a mixture containing one or more of the compounds described herein, or a physiologically pharmaceutically acceptable salt or prodrug thereof, with other chemical components, and other components such as physiologically pharmaceutically acceptable carriers and excipients Form.
  • the purpose of the pharmaceutical composition is to facilitate the administration to the organism, facilitate the absorption of the active ingredient and then exert the biological activity.
  • the crystallization described in the present disclosure includes, but is not limited to, stirring, cooling, concentrating, volatilizing, and beating and crystallization.
  • CE crystal forms described in this disclosure include, but are not limited to, compound 4-((4-(5-chloro-2-(4-fluoro-2-(methoxy-d 3 )phenoxy)-4-(tris Solvate crystal form of fluoromethyl)benzamido)-6-oxopyridazin-1(6H)-yl)methoxy)-4-oxobutyric acid, the solvent includes but is not limited to Acetonitrile or tetrahydrofuran.
  • Solids as used in this disclosure include, but are not limited to, complexes formed by combining a compound of formula I with a solvent.
  • Figure 1 XRPD pattern of the crystalline form A of the compound of formula I.
  • Figure 2 XRPD pattern of the crystalline form B of the compound of formula I.
  • Figure 3 XRPD pattern of the crystalline form B of compound of formula I (Example 9).
  • Figure 5 XRPD pattern of the crystalline form C of the compound of formula I.
  • Figure 7 XRPD pattern of the crystalline form E of the compound of formula I.
  • the reagents used in this disclosure are commercially available.
  • DSC Differential Scanning Calorimeter
  • Heating rate 10.0°C/min
  • Heating rate 10.0°C/min
  • the eluent system for column chromatography and the developing solvent system for thin layer chromatography used for purifying the compound include: A: dichloromethane/methanol system, B: n-hexane/ethyl acetate system.
  • NMR nuclear magnetic resonance
  • MS mass spectrometry
  • MS used 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), THERMO Ultimate3000-Q Exactive (manufacturer: THERMO, MS model: THERMO Q Exactive).
  • Example 1 Compound of Formula I 4-((4-(5-Chloro-2-(4-fluoro-2-(methoxy- d3 )phenoxy)-4-(trifluoromethyl)benzyl Preparation of amido)-6-oxopyridazin-1(6H)-yl)methoxy)-4-oxobutyric acid
  • Step 4 4-Fluoro-2-(methoxy-d 3 )phenol 1f
  • the ice bath was cooled to 0°C, methanol (50 mL) was added, hydrogen peroxide (30 wt%, 10 mL) and 10% sodium hydroxide solution (40 mL) were added dropwise, and the mixture was stirred at room temperature for 1 hour. Saturated sodium thiosulfate solution (50 mL) was slowly added dropwise to the reaction solution, followed by extraction with ethyl acetate (200 mL ⁇ 3).
  • the fifth step 5-chloro-2-(4-fluoro-2-(methoxy-d 3 )phenoxy)-N-(6-oxo-1,6-dihydropyridazin-4-yl )-4-(trifluoromethyl)benzamide 1g
  • the sixth step 5-chloro-2-(4-fluoro-2-(methoxy-d3)phenoxy)-N-(1-(hydroxymethyl)-6-oxo-1,6-di Hydropyridazin-4-yl)-4-(trifluoromethyl)benzamide 1h
  • Step 7 4-((4-(5-Chloro-2-(4-fluoro-2-(methoxy-d3)phenoxy)-4-(trifluoromethyl)benzamido)- 6-Oxopyridazin-1(6H)-yl)methoxy)-4-oxobutyric acid I
  • Test Example 1 Determination of the Inhibitory Activity of Compounds of Formula I on Na V 1.8
  • Patch clamp amplifier patch clamp PC-505B (WARNER instruments)/MultiClamp 700A (Axon instruments).
  • Extracellular fluid was: NaCl, 137; KCl, 4; CaCl2 , 1.8; MgCl2 , 1; HEPES, 10; Glucose 10; pH 7.4 (NaOH titration).
  • Intracellular fluid (mM) was aspartate, 140; MgCl2 , 2; EGTA 11; HEPES, 10; pH 7.2 (CsOH titration). Both test compound and control compound solutions contained 1 ⁇ M TTX.
  • Test compounds were stored at 9 mM in dimethyl sulfoxide (DMSO). On the test day, it was redissolved in extracellular fluid to prepare the required concentration.
  • DMSO dimethyl sulfoxide
  • the data will be stored in a computer system for analysis. Data collection and analysis will use pCLAMP 10 (Molecular Devices, Union City, CA) and management will review the analysis results.
  • Current stabilization refers to the fact that the current varies with time within a limited range. The magnitude of the current after stabilization is used to calculate the effect of the compound's solubility here.
  • the inhibitory activity of the compound of the present disclosure on Na V 1.8 was determined by the above test, and the measured IC 50 value was 14.5 nM, which had a significant inhibitory effect on the Na V 1.8 channel activity.
  • Test Example 2 Room temperature solubility of the disclosed compound in PBS solution at pH 7.4
  • Reagents dimethyl sulfoxide (analytical grade), ethanol (analytical grade), acetonitrile (chromatographic grade), NaH 2 PO 4 ⁇ 2H 2 O (analytical grade), Na 2 HPO 4 ⁇ 12H 2 O (analytical grade), acetic acid Ammonium (analytical grade), sodium hydroxide, sodium chloride (analytical grade).
  • Solubility ( ⁇ M) peak area of sample / peak area of reference * reference concentration ( ⁇ M) * sample solution dilution
  • the solubility of the compound of the present disclosure in the PBS solution of pH 7.4 was measured to be 34.46 ⁇ M, indicating a relatively high solubility.
  • the compound of formula I (38.9 mg) was added to dimethyl ether (DME), heated and stirred to dissolve, filtered while hot, the mother liquor was stirred at room temperature, a solid was precipitated, filtered, the filter cake was collected, and dried in vacuo to obtain the target product 22 mg, Off-white solid, yield 56.6%.
  • DME dimethyl ether
  • the product is crystal form A
  • the XRPD spectrum is shown in Figure 1
  • the characteristic peak positions are shown in Table 1 below.
  • the DSC spectrum shows that the endothermic peaks are 174.74°C and 186.27°C.
  • the TGA spectrum showed that the weight loss was 1.89% at 25°C-145°C and 23.18% at 150°C-260°C.
  • the hygroscopic weight gain of the sample is about 0.401%; under 70% RH, the hygroscopic weight gain is about 0.513%; under extreme conditions (90% RH), the hygroscopic weight gain is about 0.962% .
  • the desorption process of this sample does not coincide with the adsorption process during the humidity change from 0% to 95% RH. After DVS detection, the crystal form was re-measured, and the crystal form did not change, indicating that the crystal form was stable.
  • the compound (1g) shown in formula I was added to 5mL of acetone and 0.1mL of dimethylformamide (DMF) mixed solvent, heated and stirred to dissolve, cooled for crystallization, filtered, the filter cake was collected, and vacuum-dried to obtain the target product 833mg , white solid, yield 83.3%.
  • DMF dimethylformamide
  • the XRPD spectrum of the B crystal sample is shown in Figure 2, and its characteristic peak positions are shown in Table 2 below.
  • the DSC spectrum shows that the endothermic peaks are 201.29°C and 217.66°C.
  • the TGA spectrum showed that the weight loss was 1.36% at 35°C-180°C and 22.22% at 185°C-260°C.
  • the hygroscopic weight gain of the sample is about 0.108%; under 70% RH, the hygroscopic weight gain is about 0.131%; under extreme conditions (90% RH), the hygroscopic weight gain is about 0.163% .
  • the desorption process of this sample is basically the same as the adsorption process during the humidity change from 0% to 95% RH. After DVS detection, the crystal form was re-measured, and the crystal form did not change, indicating that the crystal form was stable.
  • the compound represented by formula I (32.5 mg) was added to 0.5 mL of acetone, heated to dissolve, stirred for crystallization, filtered, the filter cake was collected, and dried in vacuo to obtain 23.4 mg of the target product as an off-white solid with a yield of 72%. It was detected as B crystal form by X-ray powder diffraction.
  • the compound shown in formula I (34.5mg) was added to 1mL of water, 1mL of DMF was added under heating conditions, stirred and dissolved, filtered while hot, the mother liquor was stirred at room temperature, filtered, the filter cake was collected, and vacuum-dried to obtain the target product 6.7mg, off-white Solid, the yield is 19.4%, and it is the B crystal form detected by X-ray powder diffraction.
  • the compound shown in formula I (35.7 mg) was added to 1 mL of aqueous ethanol solution, the volume ratio of ethanol to water was 1:1, heated and stirred, filtered, the filter cake was collected, and dried in vacuo to obtain the title product 31.2 mg, off-white solid, yield It was 87.4%, and it was detected as B crystal form by X-ray powder diffraction.
  • Embodiment 9 the preparation of formula I compound B crystal form In 50L reactor, add DMSO (5.10kg), acetone (9.0kg), turn on stirring, add compound shown in formula I (refer to 2.30kg), stir and dissolve clear back pressure Filter, wash with 9.0kg acetone, filter and transfer to D-class clean area.
  • Purified water (23.0 kg) was slowly added dropwise to the above filtrate, stirred for crystallization at room temperature, suction filtered, washed, and dried by blasting to obtain 2.07 kg of the title product with a yield of 90%.
  • the XRPD characteristic peak positions of the sample are shown in Table 3 below, and the spectrum is shown in Figure 3 .
  • the DSC spectrum shows that the peak of the endothermic peak is 203.21°C, and the spectrum is shown in Figure 4 .
  • the compound shown in formula I (37mg) was added to 0.5mL of acetonitrile, heated and stirred, added with 0.1mL of water, dissolved and filtered while hot, the mother liquor was stirred at room temperature, filtered, the filter cake was collected, and vacuum-dried to obtain the target product 29.3mg , off-white solid, yield 79.2%, X-ray powder diffraction detection, the XRPD spectrum of the C crystal sample is shown in Figure 5, and its characteristic peak positions are shown in Table 4 below.
  • the DSC spectrum shows that the endothermic peaks are 106.06°C, 117.19°C, 164.56°C, 184.61°C, 192.00°C and 240.79°C; TGA spectrum shows that the weight loss is 8.7% at 30°C-160°C and 22.33% at 160°C-260°C .
  • the compound represented by formula I (10 mg) was added to 500 ⁇ l of methanol and acetonitrile solution, the volume ratio of methanol and acetonitrile was 1:1, heated and stirred to dissolve, cooled and crystallized to obtain 8.6 mg of the title product, an off-white solid with a yield of 86%, It was detected as C crystal form by X-ray powder diffraction.
  • the compound represented by formula I (10 mg) was added to a 10% acetone aqueous solution and dissolved, added with dichloromethane, stirred for crystallization, filtered, and dried to obtain the target product, an off-white solid 3.2 mg, a yield of 32%, obtained by X-ray powder Diffraction detected as D crystal form.
  • the XRPD spectrum of the D crystal form sample is shown in FIG. 6 , and the characteristic peak positions thereof are shown in Table 5 below.
  • the compound shown in formula I (10mg) was added to 500m of tetrahydrofuran solution and dissolved, volatilized at room temperature, and centrifuged to dry to obtain the target product, off-white solid 8.9mg, yield 89%, detected as E crystal form by X-ray powder diffraction .
  • the XRPD spectrum of the E crystal form sample is shown in FIG. 7 , and the characteristic peak positions thereof are shown in Table 6 below.
  • the DSC spectrum shows that the endothermic peaks are 177.11°C, 195.88°C and 213.29°C; the TGA spectrum shows that the weight loss is 1.068% at 30°C-160°C and 22.919% at 160°C-260°C.
  • Example 14 Stability study of compound A crystal form of formula I under accelerated conditions
  • Example 15 Stability study of compound A crystal form of formula I under long-term accelerated conditions
  • Example 16 Stability study of compound B crystal form of formula I under accelerated conditions
  • Example 17 Stability study of compound B crystal form of formula I under long-term accelerated conditions

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Abstract

提供了一种选择性Na V抑制剂的结晶形式及其制备方法。具体而言，提供了化合物4-（（4-（5-氯-2-（4-氟-2-（甲氧基-d 3）苯氧基）-4-（三氟甲基）苯甲酰氨基）-6-氧代哒嗪-1（6H）-基）甲氧基）-4-氧代丁酸（式I）的A～E晶型及其制备方法；

Description

一种选择性Na V抑制剂的结晶形式及其制备方法
本申请要求申请日为2020年8月19日的中国专利申请CN202010835117.7的优先权。本申请引用上述中国专利申请的全文。
技术领域
本公开属于医药技术领域，涉及一种选择性Na V1.8抑制剂的结晶形式及其制备方法，具体涉及化合物4-((4-(5-氯-2-(4-氟-2-(甲氧基-d3)苯氧基)-4-(三氟甲基)苯甲酰氨基)-6-氧代哒嗪-1(6H)-基)甲氧基)-4-氧代丁酸的A、B、C、D、E晶型及其制备方法。
背景技术
疼痛是临床上最常见的症状之一，起源于周围神经系统的伤害感受器。这是一种游离的神经末梢，广泛分布于全身的皮肤、肌肉、关节和内脏组织中，它可以将感受到的热的、机械的或化学的刺激转化为神经冲动(动作电位)并经由传入神经纤维传递到其位于背根神经节(dorsal root ganglia，DRG)的胞体部分，最终传递到高级神经中枢，引起痛觉。而神经元中动作电位的产生和传导又依赖于细胞膜上的电压门控钠通道(voltage-gated sodium channels，Na V)。当细胞膜去极化时，钠离子通道激活，通道打开，引起钠离子内流，使细胞膜进一步去极化，导致动作电位的产生。因此，抑制异常的钠离子通道活动有助于疼痛的治疗、缓解。目前，局部麻醉药利多卡因就是通过抑制Na V来止痛。而非选择性的Na V抑制剂，例如拉莫三嗪，拉科酰胺，美西律也已经成功地用于治疗慢性疼痛。
然而，目前临床中使用的Na V抑制剂由于缺乏亚型选择性，治疗窗口较窄，应用范围受到限制。因此，有必要开发活性更高，选择性更好，药代动力学性质更佳，副作用更少的选择性Na V1.8抑制剂。WO2020169042提供了一种选择性Na V1.8抑制剂，其化学名为4-((4-(5-氯-2-(4-氟-2-(甲氧基-d 3)苯氧基)-4-(三氟甲基)苯甲酰氨基)-6-氧代哒嗪-1(6H)-基)甲氧基)-4-氧代丁酸(式I)，现已发现该化合物具有较好的药学活性，有望开发成为新的选择性Na V1.8抑制剂，为患者提供新的治疗选择。
Figure PCTCN2021113532-appb-000001
本领域人员应知，药物的活性成分的晶型结构往往影响到该药物的理化稳定性。结 晶条件及储存条件的不同有可能导致化合物的晶型结构的变化，有时还会伴随着产生其他形态的晶型。一般来说，无定型的药物产品没有规则的晶型结构，往往伴有产物稳定性较差，析晶较细，过滤较难，易结块，流动性差等缺陷。鉴于固体药物晶型及其稳定性在临床治疗中的重要性，深入研究化合物4-((4-(5-氯-2-(4-氟-2-(甲氧基-d 3)苯氧基)-4-(三氟甲基)苯甲酰氨基)-6-氧代哒嗪-1(6H)-基)甲氧基)-4-氧代丁酸自由碱晶型，对开发适合工业生产且生物活性良好的药物是具有重要意义。
发明内容
本公开提供了化合物4-((4-(5-氯-2-(4-氟-2-(甲氧基-d 3)苯氧基)-4-(三氟甲基)苯甲酰氨基)-6-氧代哒嗪-1(6H)-基)甲氧基)-4-氧代丁酸(式I)的A晶型，以衍射角2θ角度表示的X-射线粉末衍射图，在17.966、19.759、22.119、23.676、24.444、25.003和29.122处有特征峰。
Figure PCTCN2021113532-appb-000002
在一些实施方案中，所述式I化合物的A晶型在11.946、17.966、19.759、22.119、23.676、24.444、25.003、29.122、30.154和31.278处有特征峰。
在一些实施方案中，所述式I化合物的A晶型在5.919、10.000、11.946、17.966、19.759、22.119、23.676、24.444、25.003、26.266、29.122、30.154和31.278处有特征峰。
在一些实施方案中，所述式I化合物的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。
本公开还提供了一种制备式I化合物A晶型的方法，包括：
(a)将4-((4-(5-氯-2-(4-氟-2-(甲氧基-d3)苯氧基)-4-(三氟甲基)苯甲酰氨基)-6-氧代哒嗪-1(6H)-基)甲氧基)-4-氧代丁酸与溶剂(I)混合，加热或搅拌溶解，所述溶剂(I)选自二甲醚；
(b)析晶。
本公开所述溶剂(I)所用体积(μl)可以为式I化合物质量(mg)的1-200倍，在非限制性实施方案中可以为1、5、10、15、20、25、30、35、40、45、50、55、60、65、70、75、80、85、90、95、100、105、110、115、120、125、130、135、140、145、150、155、160、165、170、175、180、185、190、200。
本公开提供了式(I)化合物的B晶型，以衍射角2θ角度表示的X-射线粉末衍射图， 在17.895、18.438、20.282、21.661、22.639、22.912和30.946处有特征峰。
在一些实施方案中，所述式I化合物的B晶型在11.845、15.281、17.895、18.438、20.282、21.661、22.639、22.912、27.146和30.946处有特征峰。
在一些实施方案中，所述式I化合物的B晶型在10.781、11.845、12.865、15.281、17.895、18.438、20.282、21.661、22.639、22.912、25.964、27.146和30.946处有特征峰。
在一些实施方案中，所述式I化合物的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。本公开还提供了一种制备式I化合物B晶型的方法，包括：
方法一：
(a)将4-((4-(5-氯-2-(4-氟-2-(甲氧基-d3)苯氧基)-4-(三氟甲基)苯甲酰氨基)-6-氧代哒嗪-1(6H)-基)甲氧基)-4-氧代丁酸与溶剂(II)混合，搅拌溶解或加热溶解，所述溶剂(II)选自N-N二甲基甲酰胺(DMF)、N-N二甲基乙酰胺(DMA)、二甲基亚砜(DMSO)、N-甲基吡咯烷酮(NMP)、丙酮、1,4-二氧六环、四氢呋喃(THF)和水中的至少一种；
(b)析晶；
或者，方法二：
(a)将4-((4-(5-氯-2-(4-氟-2-(甲氧基-d3)苯氧基)-4-(三氟甲基)苯甲酰氨基)-6-氧代哒嗪-1(6H)-基)甲氧基)-4-氧代丁酸与溶剂(III)混合，所述溶剂(III)选自四氢呋喃(THF)、二甲基亚砜(DMSO)和丙酮中的至少一种；
(b)加入溶剂(IV)，析晶，所述溶剂(IV)选自C 1-6烷基醇、乙酸异丙酯、甲基叔丁基醚、甲基异丁基酮、二氯甲烷和水中的至少一种，所述C 1-6烷基醇优选自乙醇或异丙醇。
本公开所述溶剂(II)、(III)、(IV)所用体积(μl)可以为式I化合物质量(mg)的1-200倍，在非限制性实施方案中可以为1、5、10、15、20、25、30、35、40、45、50、55、60、65、70、75、80、85、90、95、100、105、110、115、120、125、130、135、140、145、150、155、160、165、170、175、180、185、190、200。
本公开提供了式(I)化合物的C晶型，以衍射角2θ角度表示的X-射线粉末衍射图，在4.836、9.675、14.266、16.039、22.856、24.883和27.494处有特征峰。
在一些实施方案中，所述式I化合物的C晶型在4.836、9.675、10.965、14.266、16.039、18.507、22.856、24.883、26.173和27.494处有特征峰。
在一些实施方案中，所述式I化合物的C晶型在4.836、9.675、10.965、14.266、16.039、17.900、18.507、19.581、22.856、24.883、26.173、27.494和29.485处有特征峰。
在一些实施方案中，所述式I化合物的C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。
本公开还提供了一种制备式I化合物的C晶型的方法，包括：
(a)将4-((4-(5-氯-2-(4-氟-2-(甲氧基-d 3)苯氧基)-4-(三氟甲基)苯甲酰氨基)-6-氧代哒嗪-1(6H)-基)甲氧基)-4-氧代丁酸与溶剂(V)混合，加热或搅拌溶解，所述溶剂(V)选自二甲基亚砜、水或C 1-6烷基醇中的至少一种与乙腈形成的混合溶剂，所述C 1-6烷基醇优 选甲醇；
(b)析晶。
在一些实施方案中，所述的浓缩析晶可以为减压浓缩。
本公开所述溶剂(V)所用体积(μl)可以为式I化合物质量(mg)的1-200倍，在非限制性实施方案中可以为1、5、10、15、20、25、30、35、40、45、50、55、60、65、70、75、80、85、90、95、100、105、110、115、120、125、130、135、140、145、150、155、160、165、170、175、180、185、190、200。
本公开提供了式I化合物的D晶型，以衍射角2θ角度表示的X-射线粉末衍射图，在11.819、17.915、18.337、19.781、21.577、23.618和24.375处有特征峰。
在一些实施方案中，所述式I化合物的D晶型在11.819、15.201、17.915、18.337、19.781、20.050、21.577、22.832、23.618和24.375处有特征峰。
在一些实施方案中，所述式I化合物的D晶型在10.704、11.819、15.201、17.915、18.337、19.781、20.050、21.577、22.832、23.618、24.375、27.077和29.058处有特征峰。
在一些实施方案中，所述式I化合物的D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。
本公开还提供了一种制备式I化合物D晶型的方法，包括：
(a)将4-((4-(5-氯-2-(4-氟-2-(甲氧基-d3)苯氧基)-4-(三氟甲基)苯甲酰氨基)-6-氧代哒嗪-1(6H)-基)甲氧基)-4-氧代丁酸与丙酮水溶液混合；
(b)加入反溶剂二氯甲烷溶液析晶。
本公开提供了式I化合物的E晶型，以衍射角2θ角度表示的X-射线粉末衍射图，在5.282、10.624、11.767、20.355、21.618、22.599和25.184处有特征峰。
在一些实施方案中，所述式I化合物的E晶型在5.282、10.624、11.767、15.963、20.355、21.618、22.599、22.958、25.184和27.286处有特征峰。
在一些实施方案中，所述式I化合物的E晶型在5.282、10.624、11.767、13.464、15.963、18.312、20.355、21.618、22.599、22.958、25.184、27.286和30.888处有特征峰。
在一些实施方案中，所述式I化合物的E晶型以衍射角2θ角度表示的X-射线粉末衍射图谱如图7所示。
本公开还提供了一种制备式I化合物的E晶型的方法，包括：
(a)将4-((4-(5-氯-2-(4-氟-2-(甲氧基-d3)苯氧基)-4-(三氟甲基)苯甲酰氨基)-6-氧代哒嗪-1(6H)-基)甲氧基)-4-氧代丁酸与四氢呋喃混合；
(b)析晶。
在一些实施方案中，本公开所述晶型制备方法还包括过滤、洗涤或干燥等步骤。另一方面，本公开“析晶”包括但不限于搅拌析晶或静止析晶或搅拌冷却析晶。
本公开还提供了一种由前述任意一种晶型制备得到药物组合物。
本公开还提供了一种药物组合物，含有前述式I化合物的晶型或由前述方法制备得到的晶型，和任选自药学上可接受的载体、稀释剂或赋形剂。
本公开还提供了一种药物组合物的制备方法，包括将前述式I化合物的晶型或前述方法制备得到的晶型与药学上可接受的载体、稀释剂或赋形剂混合的步骤。
本公开还提供了前述式I化合物的晶型或由前述方法制备的式I化合物晶型或前述组合物或前述制备方法制备得到的组合物在制备用于抑制受试者电压门控钠通道的药物中的用途，优选地，所述电压门控钠通道为Na V1.8。
本公开还提供了前述式I化合物的晶型或由前述方法制备的式I化合物晶型或前述组合物或前述制备方法制备得到的组合物在制备用于治疗和/或减轻疼痛和疼痛相关疾病、多发性硬化症、夏-马-图三氏综合症、失禁或心律失常的药物中的用途，优选地，所述疼痛选自慢性疼痛、急性疼痛、炎性疼痛、癌症疼痛、神经性疼痛、肌肉骨骼痛、原发性疼痛、肠痛和特发性疼痛。
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，±0.2包括超过1位小数的数字经过四舍五入后的情况。可以为-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40℃～70℃，可以常压干燥，也可以减压干燥。
“药物组合物”表示含有一种或多种本文所述化合物或其生理学上可药用的盐或前体药物与其他化学组分的混合物，以及其他组分例如生理学可药用的载体和赋形剂。药物组合物的目的是促进对生物体的给药，利于活性成分的吸收进而发挥生物活性。
本公开所述的析晶包括但不限于搅拌、降温、浓缩、挥发、打浆析晶。
本公开所述的C-E晶型包括但不限于化合物4-((4-(5-氯-2-(4-氟-2-(甲氧基-d 3)苯氧基)-4-(三氟甲基)苯甲酰氨基)-6-氧代哒嗪-1(6H)-基)甲氧基)-4-氧代丁酸的溶剂合物晶型，所述的溶剂包括但不限于乙腈或四氢呋喃。
本公开所述的“溶剂合物”包括但不限于式I化合物与溶剂结合形成的络合物。
附图说明
图1：式I化合物A晶型的XRPD图谱。
图2：式I化合物B晶型的XRPD图谱。
图3：式I化合物B晶型的XRPD图谱(实施例9)。
图4：式I化合物B晶型的DSC图谱(实施例9)。
图5：式I化合物C晶型的XRPD图谱。
图6：式I化合物D晶型的XRPD图谱。
图7：式I化合物E晶型的XRPD图谱。
具体实施方式
以下将结合实施例或实验例更详细地解释本公开，本公开中的实施例或实验例仅用于说明本公开中的技术方案，并非限定本公开中的实质和范围。
本公开中所用试剂可通过商业途径获得。
本公开中实验所用仪器的测试条件：
1、差示扫描量热仪(Differential Scanning Calorimeter,DSC)；
仪器型号：Mettler Toledo DSC 3+；
吹扫气：氮气；氮气吹扫速度：50mL/min；
升温速率：10.0℃/min；
温度范围：25-350℃；
2、X-射线粉末衍射谱(X-ray Powder Diffraction,XRPD)；
仪器型号：Bruker D8 Focus X-射线粉末衍射仪；
射线：单色Cu-Kα射线(λ＝1.5406)；
扫描方式：θ/2θ，扫描范围(2q范围)：3～50°；
电压：40kV，电流：40mA；
3、热重分析仪(Thermogravimetric Analysis，TGA)；
仪器型号：Mettler Toledo TGA2；
吹扫气：氮气；氮气吹扫速度：50mL/min；
升温速率：10.0℃/min；
温度范围：25-350℃；
4、有关物质及含量检测：高效液相色谱检测；仪器型号：Agilent 1200 DAD；色谱柱：Phenomenex kinetex EVOC18 4.6*250mm,5um；流动相A：KH 2PO 4，流动相B：乙腈；流速：1.0ml/min；柱温：40℃；检测波长：214nm。
5、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。
6、化合物的结构是通过核磁共振(NMR)或/和质谱(MS)来确定的。NMR位移(δ)以10 -6(ppm)的单位给出。NMR的测定是用Bruker AVANCE-400核磁仪，测定溶剂为氘代二甲基亚砜(DMSO-d 6)、氘代氯仿(CDCl 3)、氘代甲醇(CD 3OD)，内标为四甲基硅烷(TMS)。
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 Ultimate3000-Q Exactive(生产商：THERMO，MS型号：THERMO Q Exactive)。
实施例1：式I化合物4-((4-(5-氯-2-(4-氟-2-(甲氧基-d 3)苯氧基)-4-(三氟甲基)苯甲酰 氨基)-6-氧代哒嗪-1(6H)-基)甲氧基)-4-氧代丁酸的制备
Figure PCTCN2021113532-appb-000003
第一步：5-氯-2-氟-4-(三氟甲基)苯甲酰氯1b
将5-氯-2-氟-4-(三氟甲基)苯甲酸1a(5.00g,20.6mmol)加入15mL氯化亚砜，80℃反应2小时。反应液减压浓缩，得到粗品标题化合物1b(5.38g)，产物不经纯化，直接用于下一步反应。
第二步：5-氯-2-氟-N-(6-氧代-1,6-二氢哒嗪-4-基)-4-(三氟甲基)苯甲酰胺1c
将5-氨基哒嗪-3-酮(3.06g,24.8mmol,采用“WO2016004417中说明书第100页的实施例386”公开的方法制备而得)溶于40mL N-甲基吡咯烷酮中，冷却至0℃，缓慢分批加入氢化钠(2.06g,51.5mmol,60％纯度)，0℃搅拌30分钟。将化合物1b(5.38g,20.6mmol)溶于3mL N-甲基吡咯烷酮，缓慢滴加入上述反应液中，室温搅拌过夜。含有标题化合物1c的反应液不经纯化直接用于下一步。
第三步：1-溴-4-氟-2-(甲氧基-d 3)苯1e
将2-溴-5-氟苯酚1d(1g,5.2mmol,韶远化学科技(上海)有限公司)，氘代碘甲烷(911mg,6.3mmol,萨恩化学技术(上海)有限公司)，碳酸钾(1.45g,10.5mmol)，加入N,N-二甲 基甲酰胺(10mL)，搅拌反应6小时。反应液冷却至室温，加入乙酸乙酯(20mL)，用水洗涤(20mL×3)。合并有机相，有机相用无水硫酸钠干燥，过滤，滤液减压浓缩，用硅胶柱色谱法以展开剂体系A纯化，得到标题化合物1e(840mg)，产率：71％。
1H NMR(400MHz,CDCl 3):δ7.49-7.45(m,1H),6.66-6.57(m,2H)。
第四步：4-氟-2-(甲氧基-d 3)苯酚1f
将化合物1e(840mg,4mmol)和硼酸三异丙酯(987mg,5.25mmol,上海泰坦科技股份有限公司)加入到四氢呋喃/甲苯混合溶液中(150mL/30mL)。将反应瓶内空气置换为氩气，降温至-78℃，缓慢滴加正丁基锂(1.6M,3.8mL,6.1mmol)，20分钟滴加完毕。自然升至室温，搅拌过夜。冰浴降温至0℃，加入甲醇(50mL)，滴加双氧水(30wt％,10mL)和10％氢氧化钠溶液(40mL)，室温搅拌1小时。反应液中缓慢滴加饱和硫代硫酸钠溶液(50mL)，用乙酸乙酯萃取(200mL×3)。有机相用饱和碳酸氢钠溶液(150mL)洗涤，有机相用无水硫酸钠干燥，过滤，滤液减压浓缩，用硅胶柱色谱法以展开剂体系B纯化，得到标题化合物1f(570mg)，产率：97％。
MS m/z(ESI):144.0[M-1]
1H NMR(400MHz,DMSO-d 6):δ8.89(s,1H),6.85-6.82(m,1H),6.76-6.72(m,1H),6.59-6.54(m,1H)。
第五步：5-氯-2-(4-氟-2-(甲氧基-d 3)苯氧基)-N-(6-氧代-1,6-二氢哒嗪-4-基)-4-(三氟甲基)苯甲酰胺1g
将化合物1c(1g,2.98mmol)，化合物1f(433mg,2.98mmol)和碳酸铯(1.02g,3.13mmol,韶远化学科技(上海)有限公司)加入N-甲基吡咯烷酮(10mL)，80℃反应3小时。反应液冷却至室温，加入乙酸乙酯(20mL)，用水洗涤(10mL×3)。合并有机相，有机相用无水硫酸钠干燥，过滤，滤液减压浓缩，用硅胶柱色谱法以展开剂体系B纯化，得到标题化合物1g(280mg)，产率：20％。
MS m/z(ESI):461.0[M-1]
1H NMR(400MHz,DMSO-d 6):δ12.87(s,1H),11.03(s,1H),8.06(s,1H),7.93(d,1H),7.29-7.23(m,2H),7.16-7.13(m,1H),7.01(s,1H),6.88-6.83(m,1H)。
第六步：5-氯-2-(4-氟-2-(甲氧基-d3)苯氧基)-N-(1-(羟甲基)-6-氧代-1,6-二氢哒嗪-4-基)-4-(三氟甲基)苯甲酰胺1h
将化合物1g(6.1g,13.2mmol)加入到60mL甲醇，加入甲醛溶液(60mL,37wt％,国药集团化学试剂有限公司)，氩气保护加热回流16小时。反应液减压浓缩，抽滤得到滤饼，干燥得到标题化合物1h(5.6g)，产率：86％。
MS m/z(ESI):491.2[M+1]
第七步：4-((4-(5-氯-2-(4-氟-2-(甲氧基-d3)苯氧基)-4-(三氟甲基)苯甲酰氨基)-6-氧代哒嗪-1(6H)-基)甲氧基)-4-氧代丁酸I
将化合物1h(3.43g,7mmol)加入80mL二氯甲烷，再加入丁二酸酐(1.05g,10.5mmol,国药集团化学试剂有限公司)，4-二甲氨基吡啶(1.09g,8.8mmol)，N,N-二异丙基乙胺(1.81 g,14mmol)，30℃反应过夜。反应液减压浓缩，用高效液相色谱制备(Waters 2767-SQ De-tecor2，洗脱体系：乙酸铵，水，乙腈)纯化，得到标题化合物I(2.7g)，产率：65％。MS m/z(ESI):589.0[M-1],591.0[M+1] 1H NMR(400MHz,DMSO-d 6):δ12.21(s,1H),11.93(s,1H),8.07(s,1H),8.02(d,1H),7.34(d,1H),7.30-7.26(m,1H),7.16-7.13(m,1H),7.01(s,1H),6.88-6.83(m,1H),5.91(s,2H),2.67-2.46(m,4H)。
将上述化合物溶解于叔丁醇溶剂后，冷冻干燥得样品，XRPD测得最终产物为无定型。
测试例1：式I化合物对Na V1.8抑制活性的测定
1、实验材料及仪器
1)膜片钳放大器：patch clamp PC-505B(WARNER instruments)/MultiClamp 700A(Axon instrument)。
2)数模转换器：Digidata 1440A(Axon CNS)/Digidata 1550A(Axon instruments)。
3)微操控仪：MP-225(SUTTER instrument)。
4)倒置显微镜：TL4(Olympus)。
5)玻璃微电极拉制仪：PC-10(NARISHIGE)。
6)微电极玻璃毛细管：B12024F(武汉微探科学仪器有限公司)。
7)二甲基亚砜(DMSO)D2650(Sigma-Aldrich)。
8)TTX AF3014(Affix Scientific)。
2、实验步骤
2.1化合物配制
配制细胞内外液的化合物除用于酸碱滴定的NaOH和KOH外，均从Sigma(St.Louis,MO)公司购买。细胞外液(mM)为:NaCl,137；KCl,4；CaCl 2,1.8；MgCl 2,1；HEPES,10；葡萄糖10；pH 7.4(NaOH滴定)。细胞内液(mM)为天冬氨酸,140；MgCl 2,2；EGTA 11；HEPES,10；pH 7.2(CsOH滴定)。测试化合物和对照化合物溶液均含1μM TTX。
测试化合物的保存浓度为9mM，溶于二甲基亚砜(DMSO)。测试当天再溶于细胞外液，配制成要求浓度。
2.2手动膜片钳测试过程
1)化合物配制成指定浓度的溶液后，按浓度从从低到高顺序将药液依次加入各个管道，并对各个管道进行标记。
2)将细胞转移到灌流槽中，电极内施加正压，将电极尖端接触到细胞，抽气装置三通阀调成三通状态，然后对电极施加负压，使得电极与细胞形成高阻封接。继续施加负压，使得细胞膜破裂，形成电流通路。
3)待细胞破膜电流稳定后，依次进行不同的浓度的灌注。若电流稳定至少一分钟即可换下一个浓度进行灌流。每个浓度灌流时间不超过五分钟。
4)清洗灌流槽。按药液浓度从高到低进行冲洗，每个浓度药液冲洗20s。最后用细胞外液冲洗1min。
2.3测试电压方程(resting)及结果
将细胞钳制在–80mV，然后用持续10毫秒方波去极化到10mV，以得到Na V1.8电流。这一程序每5秒重复一次。检测方波引发的最大电流，待其稳定后，灌流测试化合物，当反应稳定后，计算阻断的强度。
3、数据分析
资料将存于计算机系统做分析。资料采集和分析将用pCLAMP 10(Molecular Devices,Union City，CA)，管理人员将审查分析结果。电流稳定指的是电流随时间变化在有限的范围内。电流稳定后的大小说用来计算化合物在此溶度的作用。
本公开化合物对Na V1.8的抑制活性通过以上的试验进行测定，测得的IC 50值为14.5nM，对Na V1.8通道活性具有明显的抑制效果。
测试例2：本公开化合物在pH 7.4的PBS溶液中的室温溶解度
1、实验材料
试剂：二甲亚砜(分析纯)、乙醇(分析纯)、乙腈(色谱纯)、NaH 2PO 4·2H 2O(分析纯)、Na 2HPO 4·12H 2O(分析纯)、乙酸铵(分析纯)、氢氧化钠、氯化钠(分析纯)。
仪器：液相色谱仪。
2、实验步骤
2.1 pH 7.4 PBS溶液的配制：称取0.57g NaH 2PO 4·2H 2O、5.55g Na 2HPO 4·12H 2O和6.48g NaCl，加入超纯水，用1M NaOH或1M HCl调节pH至7.4±0.05，加水定容至1L。放置4℃冰箱保存(保存期限为6个月)。
2.2化合物PBS 7.4溶液的配制：称取适量待测化合物用DMSO或DMSO：乙腈：乙醇＝1:1:1溶解，配制10mM待测化合物储备液。精密量取10μL待测化合物储备液与990μL pH7.4 PBS溶液于2mL样品瓶中，混匀，最终溶液DMSO浓度为1％(v/v)。该溶液平行配制两份，在平板床上室温振摇24小时，在5000rpm离心20min，上清液转移至液相色谱仪分析。
2.3参比溶液的配制：精密量取10μL待测样品储备液(浓度10mM，溶解在DMSO中)与990μL有机混合溶剂(通常为DMSO：乙腈：乙醇＝1:1:1)于2mL样品瓶中，混匀，得到澄清的100μM样品溶液。用0.45μm的有机相微孔滤膜过滤，续滤液进液相色谱仪分析。
3.数据处理
溶解度(μM)＝样品的峰面积/参比的峰面积*参比浓度(μM)*样品溶液稀释倍数
取两次测量值得平均值作为最终溶解度。测得本公开化合物在pH 7.4的PBS溶液中的溶解度为34.46μM，溶解度较高。
实施例2：式I化合物A晶型的制备
将式I化合物(38.9mg)加入到二甲醚(DME)中，加热搅拌溶清，趁热过滤，母液在室温下搅拌，析出固体，过滤，收集滤饼，真空干燥，得到目标产物22mg，类白色固体，收率56.6％。
经X-射线粉末衍射检测，该产物为A晶型，XRPD谱图如图1所示，其特征峰位置如下表1所示。DSC谱图显示，吸热峰峰值174.74℃，186.27℃。TGA谱图显示，25℃-145℃失重1.89％，150℃-260℃失重23.18％。
DVS检测显示在60％RH下，该样品吸湿增重约为0.401％；在70％RH下，吸湿增重约为0.513％；在极端条件下(90％RH)，吸湿增重约为0.962％。在0％-95％RH湿度变化过程中，该样品的解吸附过程与吸附过程不重合。DVS检测后复测晶型，晶型未转变，表明该晶型稳定。
表1
峰序号 2θ值[°或度] 相对强度％
1 5.919 9.6
2 10.000 6.2
3 10.777 3.2
4 11.946 13.9
5 12.453 3.3
6 14.278 3.4
7 16.945 7.1
8 17.966 20.5
9 18.636 3.8
10 19.759 50.3
11 22.119 20.5
12 23.676 92.0
13 24.444 100.0
14 25.003 20.2
15 26.266 9.6
16 27.122 5.3
17 28.779 7.0
18 29.122 35.7
19 30.154 13.0
20 31.278 13.1
21 34.346 2.4
22 36.045 5.8
23 39.576 3.7
实施例3：式I化合物B晶型的制备
将式I所示化合物(1g)加入到5mL丙酮和0.1mL二甲基甲酰胺(DMF)混合溶剂中，加热并搅拌溶解，降温析晶，过滤，收集滤饼，真空干燥，得到目标产物833mg，白色固体，收率83.3％。
经X-射线粉末衍射检测，该B晶型样品的XRPD谱图如图2所示，其特征峰位置如下表2所示。DSC谱图显示，吸热峰峰值为201.29℃，217.66℃。TGA谱图显示，35℃-180℃失重1.36％，185℃-260℃失重22.22％。
DVS检测显示在60％RH下，该样品吸湿增重约为0.108％；在70％RH下，吸湿增 重约为0.131％；在极端条件下(90％RH)，吸湿增重约为0.163％。在0％-95％RH湿度变化过程中，该样品的解吸附过程与吸附过程基本一致。DVS检测后复测晶型，晶型未转变，表明该晶型稳定。
表2
峰序号 2θ值[°或度] 相对强度％
1 10.781 13.6
2 11.845 34.7
3 12.865 12.4
4 15.281 27.4
5 17.895 47.0
6 18.438 100.0
7 20.282 36.5
8 21.661 51.4
9 22.639 77.9
10 22.912 35.2
11 23.859 8.1
12 25.964 17.2
13 27.146 28.5
14 28.211 2.4
15 28.668 3.9
16 29.170 6.9
17 29.897 7.5
18 30.946 39.6
19 34.743 7.6
实施例4：式I化合物B晶型的制备
式I所示化合物(32.5mg)加入到0.5mL丙酮中，加热溶清，搅拌析晶，过滤，收集滤饼，真空干燥，得到目标产物23.4mg，类白色固体，收率为72％。经X-射线粉末衍射检测为B晶型。
实施例5：式I化合物B晶型的制备
式I所示化合物(35.5mg)加入到0.5mL 1,4-二氧六环中，加热溶清，趁热过滤，搅拌析晶，过滤，收集滤饼，真空干燥，得到标题产物15.5mg，类白色固体，收率43.7％，经X-射线粉末衍射检测为B晶型。
实施例6：式I化合物B晶型的制备
式I所示化合物(34.5mg)加入到1mL水中，加热条件下加入1mL DMF，搅拌溶解，趁热过滤，母液在室温搅拌，过滤，收集滤饼，真空干燥，得到目标产物6.7mg，类白色固体，收率19.4％，经X-射线粉末衍射检测为B晶型。
实施例7：式I化合物B晶型的制备
式I所示化合物(35.7mg)加入到1mL乙醇水溶液中，乙醇与水体积比为1:1，加热搅拌，过滤，收集滤饼，真空干燥，得到标题产物31.2mg，类白色固体，收率为87.4％， 经X-射线粉末衍射检测为B晶型。
实施例8：式I化合物B晶型的制备
式I所示化合物(35.3mg)加入到0.5mL异丙醇水溶液中，异丙醇与水体积比为1:1，加热搅拌，过滤，收集滤饼，真空干燥，得到标题产物29.9mg，类白色固体，收率为84.7％，经X-射线粉末衍射检测为B晶型。
实施例9：式I化合物B晶型的制备向50L反应釜中加入DMSO(5.10kg)、丙酮(9.0kg)，开启搅拌，加入式I所示化合物(参照2.30kg)，搅拌溶清后压滤，用9.0kg丙酮洗涤后滤液压滤转移至D级洁净区。
将纯化水(23.0kg)缓慢滴加至上述滤液中，室温搅拌析晶，抽滤，洗涤，鼓风干燥得标题产物2.07kg，收率90％。
经X-射线粉末衍射检测，该样品的XRPD特征峰位置如下表3，谱图如图3所示。DSC谱图显示，吸热峰峰值为203.21℃，谱图如图4所示。
表3
峰序号 2θ值[°或度] 相对强度％
1 9.44 2.6
2 10.91 13.7
3 11.85 22.6
4 12.76 6.8
5 12.93 6.0
6 15.30 20.0
7 17.38 6.1
8 17.85 51.8
9 18.42 100.0
10 19.55 5.8
11 19.84 13.8
12 20.07 18.6
13 20.36 30.3
14 21.06 8.0
15 21.36 24.7
16 21.62 75.1
17 21.82 22.3
18 22.31 8.2
19 22.59 49.4
20 23.00 56.1
21 23.85 8.8
22 25.13 2.9
23 25.40 5.4
24 25.67 8.8
25 25.98 12.7
26 27.14 38.4
27 27.96 3.7
28 28.20 9.2
29 28.61 7.5
30 29.17 8.5
31 29.82 15.1
32 30.24 3.2
33 30.91 25.1
34 31.69 3.6
35 32.67 9.0
36 33.74 2.9
37 34.59 6.9
38 34.84 8.4
39 36.13 3.9
实施例10：式I化合物C晶型的制备
式I所示化合物(37mg)加入到0.5mL乙腈中，加热搅拌，加入0.1mL水，溶清，趁热过滤，母液在室温下搅拌，过滤，收集滤饼，真空干燥，得到目标产物29.3mg，类白色固体，收率79.2％，经X-射线粉末衍射检测，该C晶型样品的XRPD谱图如图5所示，其特征峰位置如下表4所示。DSC谱图显示，吸热峰峰值为106.06℃、117.19℃、164.56℃、184.61℃、192.00℃和240.79℃；TGA谱图显示，30℃-160℃失重8.7％，160℃-260℃失重22.33％。
表4
峰序号 2θ值[°或度] 相对强度％
1 4.836 44.9
2 9.675 81.5
3 10.965 37.3
4 11.746 19.1
5 14.266 46.2
6 15.560 15.6
7 16.039 71.1
8 17.900 19.8
9 18.507 32.6
10 19.581 20.5
11 21.335 16.2
12 21.633 17.3
13 22.076 18.8
14 22.856 38.8
15 23.820 14.1
16 24.883 100.0
17 26.173 28.4
18 27.494 43.8
19 28.187 9.8
20 29.033 15.5
21 29.485 25.9
22 30.704 14.6
23 32.651 7.2
24 33.464 7.4
[根据细则91更正 25.08.2021]　
实施例11：式I化合物C晶型的制备
式I所示化合物(10mg)加入到500μl甲醇乙腈溶液中，甲醇与乙腈体积比为1:1，加热搅拌溶解，降温析晶，得到标题产物8.6mg，类白色固体，收率为86％，经X-射线粉末衍射检测为C晶型。
[根据细则91更正 25.08.2021]　
实施例12：式I化合物D晶型的制备
将式I所示化合物(10mg)加入到10％的丙酮水溶液后溶解，加入二氯甲烷搅拌析晶，过滤，干燥得到目标产物，类白色固体3.2mg，收率32％，经X-射线粉末衍射检测为D晶型。该D晶型样品的XRPD谱图如图6所示，其特征峰位置如下表5所示。
表5
峰序号 2θ值[°或度] 相对强度％
1 5.923 20.0
2 10.704 29.4
3 11.819 71.1
4 12.654 15.0
5 15.201 41.4
6 17.915 60.1
7 18.337 100.0
8 19.781 64.3
9 20.050 47.5
10 21.577 83.1
11 22.832 43.2
12 23.618 93.9
13 24.375 92.3
14 24.968 16.5
15 25.333 9.9
16 25.836 11.7
17 27.077 38.4
18 28.120 6.4
19 28.485 6.2
20 29.058 37.3
21 29.936 11.9
22 30.932 30.3
23 32.642 7.5
24 34.606 5.7
[根据细则91更正 25.08.2021]　
实施例13：式I化合物E晶型的制备
将式I所示化合物(10mg)加入到500m合的四氢呋喃溶液后溶解，室温挥发，离心干燥得到目标产物，类白色固体8.9mg，收率89％，经X-射线粉末衍射检测为E晶型。该E晶型样品的XRPD谱图如图7所示，其特征峰位置如下表6所示。DSC谱图显示，吸热峰峰值为177.11℃、195.88℃和213.29℃；TGA谱图显示，30℃-160℃失重1.068％，160℃-260℃失重22.919％。
表6
峰序号 2θ值[°或度] 相对强度％
1 5.282 80.1
2 10.624 65.0
3 11.767 36.7
4 13.464 10.1
5 14.781 5.4
6 15.238 10.0
7 15.963 34.2
8 17.430 9.8
9 18.312 16.9
10 20.355 48.9
11 21.618 100.0
12 22.599 54.8
13 22.958 29.3
14 23.781 9.1
15 25.184 73.4
16 26.144 8.8
17 27.286 32.5
18 29.262 2.9
19 29.992 4.8
20 30.888 11.7
21 32.624 8.1
22 34.561 4.4
[根据细则91更正 25.08.2021]　
实施例14：式I化合物A晶型加速条件下稳定性研究
参照前述实施例制备得到式I化合物的A晶型(HPLC：99.3％)置于表7实验条件下进行加速条件下的稳定性考察，结果如下所示。
表7
Figure PCTCN2021113532-appb-000004
Figure PCTCN2021113532-appb-000005
实验结果显示式I化合物的A晶型在上述条件下的X-射线粉末衍射图谱和起始的X-射线粉末衍射相符，表示式I化合物的A晶型具有良好的物理稳定性，在60℃和92.5％RH条件下纯度绝对值变化量均较小，表示具有良好的化学稳定性。
[根据细则91更正 25.08.2021]　
实施例15：式I化合物A晶型长期加速条件下稳定性研究
参照前述实施例制备得到式I化合物的A晶型(HPLC：98.8％)置于表8实验条件下进行长期、加速稳定性考察，结果如下所示。
表8
Figure PCTCN2021113532-appb-000006
实验结果显示式I化合物的A晶型在上述条件下的X-射线粉末衍射图谱和起始的X-射线粉末衍射相符，表明式I化合物的A晶型具有良好的物理稳定性，在25℃，60％RH和40℃，75％RH条件下纯度绝对值变化量均较小，显示具有良好的化学稳定性。
[根据细则91更正 25.08.2021]　
实施例16：式I化合物B晶型加速条件下稳定性研究
参照前述实施例制备得到式I化合物的B晶型(HPLC：99.2％)置于表9实验条件下进行加速条件下的稳定性考察，结果如下所示。
表9
Figure PCTCN2021113532-appb-000007
Figure PCTCN2021113532-appb-000008
实验结果显示式I化合物的B晶型在上述条件下的X-射线粉末衍射图谱和起始的X-射线粉末衍射相符，表示式I化合物的B晶型具有良好的物理稳定性，在60℃和90％RH条件下纯度绝对值变化量均较小，表示具有良好的化学稳定性。
[根据细则91更正 25.08.2021]　
实施例17：式I化合物B晶型长期加速条件下稳定性研究
参照前述实施例制备得到式I化合物的B晶型(HPLC：99.2％)置于表10实验条件下进行长期、加速稳定性考察，结果如下所示。
表10
Figure PCTCN2021113532-appb-000009
实验结果显示式I化合物的B晶型在上述条件下的X-射线粉末衍射图谱和起始的X-射线粉末衍射相符，表明式I化合物的B晶型具有良好的物理稳定性，在25℃，60％RH和40℃，75％RH条件下纯度绝对值变化量均较小，显示具有良好的化学稳定性。
虽然以上描述了本发明的具体实施方式，但是本领域的技术人员应当理解，这些仅是举例说明，在不背离本发明的原理和实质的前提下，可以对这些实施方式做出多种变更或修改。因此，本发明的保护范围由所附权利要求书限定。

Claims (14)

  1. 化合物4-((4-(5-氯-2-(4-氟-2-(甲氧基-d 3)苯氧基)-4-(三氟甲基)苯甲酰氨基)-6-氧代哒嗪-1(6H)-基)甲氧基)-4-氧代丁酸的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，在17.966、19.759、22.119、23.676、24.444、25.003和29.122处有特征峰，优选在11.946、17.966、19.759、22.119、23.676、24.444、25.003、29.122、30.154和31.278处有特征峰，更优选在5.919、10.000、11.946、17.966、19.759、22.119、23.676、24.444、25.003、26.266、29.122、30.154和31.278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. 一种制备权利要求1所述A晶型的方法，包括：
    (a)将4-((4-(5-氯-2-(4-氟-2-(甲氧基-d 3)苯氧基)-4-(三氟甲基)苯甲酰氨基)-6-氧代哒嗪-1(6H)-基)甲氧基)-4-氧代丁酸与溶剂(I)混合，加热或搅拌溶解，所述溶剂(I)选自二甲醚；
    (b)析晶。
  3. 化合物4-((4-(5-氯-2-(4-氟-2-(甲氧基-d 3)苯氧基)-4-(三氟甲基)苯甲酰氨基)-6-氧代哒嗪-1(6H)-基)甲氧基)-4-氧代丁酸的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，在17.895、18.438、20.282、21.661、22.639、22.912和30.946处有特征峰或在11.845、15.281、17.895、18.438、20.282、21.661和22.639处有特征峰，优选在11.845、15.281、17.895、18.438、20.282、21.661、22.639、22.912、27.146和30.946处有特征峰，更优选在10.781、11.845、12.865、15.281、17.895、18.438、20.282、21.661、22.639、22.912、25.964、27.146和30.946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。
  4. 一种制备权利要求3所述B晶型的方法，包括：
    方法一：
    (a)将4-((4-(5-氯-2-(4-氟-2-(甲氧基-d3)苯氧基)-4-(三氟甲基)苯甲酰氨基)-6-氧代哒嗪-1(6H)-基)甲氧基)-4-氧代丁酸与溶剂(II)混合，搅拌溶解或加热溶解，所述溶剂(II)选自N-N二甲基甲酰胺、N-N二甲基乙酰胺、二甲基亚砜、N-甲基吡咯烷酮、丙酮、1,4-二氧六环、四氢呋喃和水中的至少一种；
    (b)析晶；
    或者，方法二：
    (a)将4-((4-(5-氯-2-(4-氟-2-(甲氧基-d3)苯氧基)-4-(三氟甲基)苯甲酰氨基)-6-氧代哒嗪-1(6H)-基)甲氧基)-4-氧代丁酸与溶剂(III)混合，所述溶剂(III)选自四氢呋喃、二甲 基亚砜和丙酮中的至少一种；
    (b)加入溶剂(IV)，析晶，所述溶剂(IV)选自C 1-6烷基醇、乙酸异丙酯、甲基叔丁基醚、甲基异丁基酮、二氯甲烷和水中的至少一种，所述C 1-6烷基醇优选自乙醇或异丙醇。
  5. 化合物4-((4-(5-氯-2-(4-氟-2-(甲氧基-d 3)苯氧基)-4-(三氟甲基)苯甲酰氨基)-6-氧代哒嗪-1(6H)-基)甲氧基)-4-氧代丁酸的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，在4.836、9.675、14.266、16.039、22.856、24.883和27.494处有特征峰，优选在4.836、9.675、10.965、14.266、16.039、18.507、22.856、24.883、26.173和27.494处有特征峰，更优选在4.836、9.675、10.965、14.266、16.039、17.900、18.507、19.581、22.856、24.883、26.173、27.494和29.485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。
  6. 一种制备权利要求5所述C晶型的方法，包括：
    (a)将4-((4-(5-氯-2-(4-氟-2-(甲氧基-d 3)苯氧基)-4-(三氟甲基)苯甲酰氨基)-6-氧代哒嗪-1(6H)-基)甲氧基)-4-氧代丁酸与溶剂(V)混合，加热或搅拌溶解，所述溶剂(V)选自二甲基亚砜、水或C 1-6烷基醇中的至少一种与乙腈形成的混合溶剂，所述C 1-6烷基醇优选甲醇；
    (b)析晶。
  7. 化合物4-((4-(5-氯-2-(4-氟-2-(甲氧基-d 3)苯氧基)-4-(三氟甲基)苯甲酰氨基)-6-氧代哒嗪-1(6H)-基)甲氧基)-4-氧代丁酸的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，在11.819、17.915、18.337、19.781、21.577、23.618和24.375处有特征峰，优选在11.819、15.201、17.915、18.337、19.781、20.050、21.577、22.832、23.618和24.375处有特征峰，更优选在10.704、11.819、15.201、17.915、18.337、19.781、20.050、21.577、22.832、23.618、24.375、27.077和29.058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。
  8. 化合物4-((4-(5-氯-2-(4-氟-2-(甲氧基-d 3)苯氧基)-4-(三氟甲基)苯甲酰氨基)-6-氧代哒嗪-1(6H)-基)甲氧基)-4-氧代丁酸的四氢呋喃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，在5.282、10.624、11.767、20.355、21.618、22.599和25.184处有特征峰，优选在5.282、10.624、11.767、15.963、20.355、21.618、22.599、22.958、25.184和27.286处有特征峰，更优选在5.282、10.624、11.767、13.464、15.963、18.312、20.355、21.618、22.599、22.958、25.184、27.286和30.888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。
  9. 根据权利要求1、3、5、7或8任意一项所述的晶型，其特征在于，所述2θ角误差范围为±0.20。
  10. 一种由权利要求1、3、5、7、8或9任意一项所述的晶型制备得到的药物组合物。
  11. 一种药物组合物，含有权利要求1、3、5、7、8或9任意一项所述的晶型或由权利要求2、4或6任意一项所述方法制备得到的晶型，和任选自药学上可接受的载体、稀释剂或赋形剂。
  12. 一种药物组合物的制备方法，包括将权利要求1、3、5、7、8或9任意一项所述的晶型或由权利要求2、4或6任意一项所述方法制备得到的晶型与药学上可接受的载体、稀释剂或赋形剂混合的步骤。
  13. 权利要求1、3、5、7、8或9任意一项所述的晶型、由权利要求2、4或6任意一项所述方法制备得到的晶型或权利要求10或11所述组合物或由权利要求12制备方法制备得到的组合物在制备用于抑制受试者电压门控钠通道的药物中的用途，优选地，所述电压门控钠通道为Na V1.8。
  14. 权利要求1、3、5、7、8或9任意一项所述的晶型、由权利要求2、4或6任意一项所述方法制备得到的晶型或权利要求10或11所述组合物或由权利要求12制备方法制备得到的组合物在制备用于治疗和/或减轻疼痛和疼痛相关疾病、多发性硬化症、夏-马-图三氏综合症、失禁或心律失常的药物中的用途，优选地，所述疼痛选自慢性疼痛、急性疼痛、炎性疼痛、癌症疼痛、神经性疼痛、肌肉骨骼痛、原发性疼痛、肠痛和特发性疼痛。
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WO2022256679A1 (en) 2021-06-04 2022-12-08 Vertex Pharmaceuticals Incorporated N-(hydroxyalkyl (hetero)aryl) tetrahydrofuran carboxamide analogs as modulators of sodium channels
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