WO2023098612A1 - Salt form and crystal form of dimethyl sulfoximine derivative - Google Patents

Salt form and crystal form of dimethyl sulfoximine derivative Download PDF

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WO2023098612A1
WO2023098612A1 PCT/CN2022/134641 CN2022134641W WO2023098612A1 WO 2023098612 A1 WO2023098612 A1 WO 2023098612A1 CN 2022134641 W CN2022134641 W CN 2022134641W WO 2023098612 A1 WO2023098612 A1 WO 2023098612A1
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crystal form
compound
formula
radiation
angles
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PCT/CN2022/134641
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Chinese (zh)
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廖勇刚
肖瑶
奚正英
刘超男
韦昌青
钱文远
陈曙辉
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南京明德新药研发有限公司
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Priority to CN202280080004.8A priority Critical patent/CN118355000A/en
Publication of WO2023098612A1 publication Critical patent/WO2023098612A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/426—1,3-Thiazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C13/00—Cyclic hydrocarbons containing rings other than, or in addition to, six-membered aromatic rings
    • C07C13/28—Polycyclic hydrocarbons or acyclic hydrocarbon derivatives thereof
    • C07C13/32—Polycyclic hydrocarbons or acyclic hydrocarbon derivatives thereof with condensed rings
    • C07C13/54—Polycyclic hydrocarbons or acyclic hydrocarbon derivatives thereof with condensed rings with three condensed rings
    • C07C13/547—Polycyclic hydrocarbons or acyclic hydrocarbon derivatives thereof with condensed rings with three condensed rings at least one ring not being six-membered, the other rings being at the most six-membered
    • C07C13/553—Polycyclic hydrocarbons or acyclic hydrocarbon derivatives thereof with condensed rings with three condensed rings at least one ring not being six-membered, the other rings being at the most six-membered with an indacene or hydrogenated indacene ring system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/04—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having no double bonds between ring members or between ring members and non-ring members

Definitions

  • the invention relates to a salt form, a crystal form and a preparation method of a dimethylsulfinimide derivative.
  • Inflammation is the basis for the occurrence and development of many diseases, and maintaining the balance of inflammatory responses is of great significance for the prevention and treatment of infection, autoimmune diseases and cancer.
  • the inflammasome plays an important role in the occurrence and development of inflammation-related diseases, and the nucleotide-binding oligomerization domain (NOD)-like receptor family contains pyrin domain protein 3 (NOD-like receptor family, pyrin domain-containing protein 3, NLRP3) inflammasome can be activated by a variety of pathogen-associated molecular patterns (pathogen-associated molecular patterns, PAMPs) and damage-associated molecular patterns (damage-associated molecular patterns, DAMPs), and then activate Caspase-1, which releases mature forms of the pro-inflammatory cytokines IL-1 ⁇ and IL-18, triggers an inflammatory response in the body, although this response can be used to defend against foreign pathogens , but aberrant or chronic activation of the NLRP3 inflammasome is known to cause downstream negative effects and
  • NLRP3 The activation of NLRP3 is closely related to the occurrence of many major human diseases. Mutations in NLRP3 itself can lead to a class of autoinflammatory diseases, including familial cold autoinflammatory syndrome (FCAS) and Moore-Weiss syndrome (MWS).
  • FCAS familial cold autoinflammatory syndrome
  • MFS Moore-Weiss syndrome
  • NLRP3 inflammasomes can be activated by various abnormal metabolites, including hyperglycemia, saturated fatty acids, cholesterol crystals, uric acid crystals, ⁇ -amyloid, etc. , neurodegenerative diseases, non-alcoholic fatty liver, inflammatory bowel disease and other diseases play an important role. Therefore, the NLRP3 inflammasome is an important potential target for various inflammation-related diseases.
  • NLRP3 antagonists have been reported in patents such as WO2018015445, WO2019025467, WO2020157069 and WO2021032591.
  • MCC950 a derivative of diarylsulfonylurea, can reduce the severity of mouse encephalomyelitis (experimental autoimmune encephalomyelitis, EAE) by inhibiting the activity of NLRP3 inflammasome.
  • Another small-molecule antagonist, CY-09 specifically blocks the assembly and activation of NLRP3 inflammasome, and is effective against cryopyrin-associated auto-inflammatory syndrome (CAPS) and type 2 diabetes in mice
  • CAS cryopyrin-associated auto-inflammatory syndrome
  • type 2 diabetes type 2 diabetes
  • Dapansutrile a very simple NLRP3 antagonist developed by Olatec, is currently in phase II clinical trials and is used for various inflammatory diseases such as gout and pain.
  • NLRP3 small molecule antagonists can provide potential therapeutic means for related inflammatory diseases, which has great significance and broad prospects.
  • the present invention provides a compound of formula (II),
  • m is selected from 0 to 1.5.
  • the above m is selected from 0 to 1.0.
  • the Cu K ⁇ radiation X-ray powder diffraction pattern of the A crystal form has characteristic diffraction peaks at the following 2 ⁇ angles: 15.26 ⁇ 0.20°, 15.98 ⁇ 0.20°, 17.54 ⁇ 0.20°, 19.12 ⁇ 0.20°.
  • the Cu K ⁇ radiation X-ray powder diffraction pattern of the A crystal form has characteristic diffraction peaks at the following 2 ⁇ angles: 15.26 ⁇ 0.20°, 15.98 ⁇ 0.20°, 17.54 ⁇ 0.20°, 19.12 ⁇ 0.20°.
  • the X-ray powder diffraction pattern of Cu K ⁇ radiation of the above-mentioned A crystal form has characteristic diffraction peaks at the following 2 ⁇ angles: 7.34 ⁇ 0.20°, 8.74 ⁇ 0.20°, 10.86 ⁇ 0.20°, 15.26 ⁇ 0.20° , 15.98 ⁇ 0.20°, 17.54 ⁇ 0.20°, 19.12 ⁇ 0.20°, 20.90 ⁇ 0.20°, 21.40 ⁇ 0.20°, 22.86 ⁇ 0.20°, 23.46 ⁇ 0.20°, 24.78 ⁇ 0.20°, 25.54 ⁇ 0.20°, 26.44 ⁇ 0.20° , 28.18 ⁇ 0.20°, 32.32 ⁇ 0.20°.
  • the X-ray powder diffraction pattern of Cu K ⁇ radiation of the above-mentioned A crystal form has characteristic diffraction peaks at the following 2 ⁇ angles: 15.26 ⁇ 0.20°, 15.98 ⁇ 0.20°, and 7.34 ⁇ 0.20°, and/or or 8.74 ⁇ 0.20°, and/or 10.86 ⁇ 0.20°, and/or 17.54 ⁇ 0.20°, and/or 19.12 ⁇ 0.20°, and/or 20.90 ⁇ 0.20°, and/or 21.40 ⁇ 0.20°, and/or 22.86 ⁇ 0.20°, and/or 23.46 ⁇ 0.20°, and/or 24.78 ⁇ 0.20°, and/or 25.54 ⁇ 0.20°, and/or 26.44 ⁇ 0.20°, and/or 28.18 ⁇ 0.20°, and/or 32.32 ⁇ 0.20 ° has a characteristic diffraction peak.
  • the X-ray powder diffraction pattern of Cu K ⁇ radiation of the above-mentioned A crystal form has characteristic diffraction peaks at the following 2 ⁇ angles: 3.24°, 7.34°, 8.74°, 10.86°, 12.86°, 15.26°, 15.98° °, 17.54°, 18.00°, 19.12°, 20.28°, 20.90°, 21.40°, 21.82°, 22.86°, 23.46°, 24.78°, 25.54°, 26.44°, 27.44°, 28.18°, 30.98°, 32.32°, 33.20°, 34.86°, 36.56°, 39.24°.
  • the X-ray powder diffraction pattern of the Cu K ⁇ radiation of the above-mentioned A crystal form has characteristic diffraction peaks at the following 2 ⁇ angles: 7.34°, 8.74°, 10.86°, 12.86°, 15.26°, 15.98°, 17.54° °, 18.00°, 19.12°, 20.28°, 20.90°, 21.40°, 21.82°, 22.86°, 23.46°, 24.78°, 25.54°, 26.44°, 27.44°, 28.18°, 30.98°, 32.32°, 33.20°, 34.86°, 36.56°, 39.24°.
  • the X-ray powder diffraction pattern of Cu K ⁇ radiation of the above-mentioned A crystal form has characteristic diffraction peaks at the following 2 ⁇ angles: 15.259 ⁇ 0.200°, 15.980 ⁇ 0.200°, 17.541 ⁇ 0.200°, 19.121 ⁇ 0.200° .
  • the differential scanning calorimetry (DSC) curve of the above-mentioned crystal form A shows an onset point of an endothermic peak at 163.06°C ⁇ 5°C.
  • the differential scanning calorimetry (DSC) curve of the above crystal form A shows a peak with an endothermic peak at 91.08°C ⁇ 3°C.
  • the TGA spectrum of the above crystal form A is shown in FIG. 3 .
  • the present invention also provides a preparation method for the above crystal form A, comprising the following steps:
  • compound Z is added to a mixed solvent of solvent X and solvent Y;
  • Compound Z is selected from the compound of formula (I), the crystal form of compound B of formula (I) and the crystal form of compound C of formula (I);
  • Solvent X is selected from dimethylsulfoxide, N,N-dimethylformamide, N-methylpyrrolidone, tetrahydrofuran, 2-methyltetrahydrofuran, ethyl acetate, acetone, acetonitrile, methanol, ethanol, isopropanol, n-butanol and water;
  • Solvent Y is absent, or solvent Y is selected from dichloromethane, water, toluene and n-heptane.
  • the present invention also provides a preparation method for the above crystal form A, comprising the following steps:
  • Compound Z is selected from the compound of formula (I), the crystal form of compound B of formula (I) and the crystal form of compound C of formula (I);
  • Solvent X is selected from dimethylsulfoxide, N,N-dimethylformamide, N-methylpyrrolidone, tetrahydrofuran, 2-methyltetrahydrofuran, ethyl acetate, acetone, acetonitrile, methanol, ethanol, isopropanol, n-butanol and water;
  • Solvent Y is absent, or solvent Y is selected from dichloromethane, water, toluene and n-heptane.
  • the present invention also provides a preparation method of the crystal form of compound A of the above formula (II),
  • the compound of formula (I) is added to a mixed solvent of solvent X and solvent Y;
  • Solvent X is selected from dimethylsulfoxide, N,N-dimethylformamide, acetone and acetonitrile;
  • Solvent Y is water.
  • the above-mentioned solvent X is acetone or acetonitrile
  • the volume ratio of solvent X and solvent Y is 1:2 to 3:1
  • the volume sum (mL) of solvent X and solvent Y is equal to that of the compound of formula (I)
  • the mass (g) ratio is 10:1 ⁇ 30:1; preferably, the volume ratio of solvent X and solvent Y is 2:1, the volume sum (mL) of solvent X and solvent Y and the mass of formula (I) compound ( g) The ratio is 15:1.
  • the above-mentioned solvent X is dimethyl sulfoxide or N,N-dimethylformamide, and the volume ratio of solvent X to solvent Y is 1:5 to 1:15; preferably, solvent X and The volume ratio of solvent Y is 1:9.
  • the present invention also provides the B crystal form of the compound of formula (I), the X-ray powder diffraction pattern of Cu K ⁇ radiation of the B crystal form has characteristic diffraction peaks at the following 2 ⁇ angles: 9.31 ⁇ 0.20°, 15.09 ⁇ 0.20°, 16.90 ⁇ 0.20°, 20.49 ⁇ 0.20°,
  • the X-ray powder diffraction pattern of the Cu K ⁇ radiation of the B crystal form has characteristic diffraction peaks at the following 2 ⁇ angles: 5.63 ⁇ 0.20°, 9.31 ⁇ 0.20°, 15.09 ⁇ 0.20°, 16.90 ⁇ 0.20° , 19.66 ⁇ 0.20°, 20.49 ⁇ 0.20°, 22.11 ⁇ 0.20°, 22.62 ⁇ 0.20°.
  • the X-ray powder diffraction pattern of the Cu K ⁇ radiation of the B crystal form has characteristic diffraction peaks at the following 2 ⁇ angles: 5.63 ⁇ 0.20°, 9.31 ⁇ 0.20°, 11.23 ⁇ 0.20°, 15.09 ⁇ 0.20° , 15.88 ⁇ 0.20°, 16.90 ⁇ 0.20°, 19.66 ⁇ 0.20°, 20.49 ⁇ 0.20°, 22.11 ⁇ 0.20°, 22.62 ⁇ 0.20°, 26.47 ⁇ 0.20°, 29.87 ⁇ 0.20°.
  • the X-ray powder diffraction pattern of the Cu K ⁇ radiation of the above B crystal form has characteristic diffraction peaks at the following 2 ⁇ angles: 5.63°, 9.31°, 11.23°, 15.09°, 15.88°, 16.90°, 19.66 °, 20.49°, 22.11°, 22.62°, 23.85°, 26.47°, 27.74°, 29.87°, 31.11°, 32.02°.
  • the XRPD spectrum of the above crystal form B is shown in FIG. 4 .
  • the differential scanning calorimetry (DSC) curve of the above crystal form B shows an onset point of an endothermic peak at 171.6°C ⁇ 5°C.
  • the differential scanning calorimetry (DSC) curve of the above crystal form B shows a peak with an endothermic peak at 174.0°C ⁇ 3°C.
  • thermogravimetric analysis (TGA) curve of the above crystal form B has a weight loss of 6.77% at 150.0°C ⁇ 3°C.
  • the TGA spectrum of the above crystal form B is shown in FIG. 6 .
  • the present invention also provides the C crystal form of the compound of formula (I), the X-ray powder diffraction pattern of the Cu K ⁇ radiation of the C crystal form has characteristic diffraction peaks at the following 2 ⁇ angles: 9.21 ⁇ 0.20°, 13.96 ⁇ 0.20°, 16.65 ⁇ 0.20°,
  • the X-ray powder diffraction pattern of the Cu K ⁇ radiation of the above C crystal form has characteristic diffraction peaks at the following 2 ⁇ angles: 9.21 ⁇ 0.20°, 13.96 ⁇ 0.20°, 16.65 ⁇ 0.20°, 17.41 ⁇ 0.20° , 18.45 ⁇ 0.20°, 22.94 ⁇ 0.20°, 24.36 ⁇ 0.20°.
  • the XRPD spectrum of the above crystal form C is shown in FIG. 7 .
  • the differential scanning calorimetry (DSC) curve of the above-mentioned crystal form C shows an onset point of an endothermic peak at 176.0°C ⁇ 5°C.
  • the differential scanning calorimetry (DSC) curve of the above crystal form C shows a peak with an endothermic peak at 178.3°C ⁇ 3°C.
  • the differential scanning calorimetry (DSC) curve of the above crystal form C shows the onset of endothermic peaks at 55.1°C ⁇ 5°C and 176.0°C ⁇ 5°C.
  • the DSC spectrum of the above crystal form C is shown in FIG. 8 .
  • thermogravimetric analysis (TGA) curve of the above crystal form C has a weight loss of 1.39% at 150.0°C ⁇ 3°C.
  • the TGA spectrum of the above crystal form C is shown in FIG. 9 .
  • the present invention also provides the application of the hydrate, sodium salt, potassium salt, A crystal form, B crystal form or C crystal form of the above compound in the preparation of drugs related to NLRP3 antagonists.
  • the present invention also provides a preparation method for the above-mentioned compound of formula (II), crystal form of compound A of formula (II), crystal form of compound B of formula (I), crystal form of compound C of formula (I) or crystal form of compound A of formula (II) Application in the preparation of medicines for treating diseases related to NLRP3 antagonists.
  • the present invention also provides sodium salt or potassium salt of the compound of formula (I).
  • the present invention also provides the use of the sodium salt or potassium salt of the compound of formula (I) in the preparation of medicines for treating diseases related to NLRP3 antagonists.
  • the compound of the present invention has good activity, good pharmacokinetic properties, and stable crystal form properties, and is used for treating various inflammation-related diseases with abnormal NLRP3 pathways, and has potential application value.
  • enantiomer or “optical isomer” refer to stereoisomers that are mirror images of each other.
  • ⁇ W% represents the moisture absorption weight gain of the test product at 25 ⁇ 1°C and 80 ⁇ 2%RH.
  • Fig. 7 is the XRPD spectrum of the crystal form C of the compound of formula (I).
  • Embodiment 3 Preparation of formula (II) compound A crystal form
  • Method 2 Suspend the compound of formula (I) (20mg) in acetone/water mixed solvent (1.2mL, 2:1, v/v), stir at 25-50°C for 24 hours, and centrifuge to obtain a solid, which is tested by XRPD as Formula (II) compound A crystal form.
  • Embodiment 4 Preparation of formula (I) compound B crystal form
  • Embodiment 6 Single crystal X-ray diffraction detection analysis of the compound of formula (I)
  • Embodiment 7 the solid stability test of formula (II) compound A crystal form
  • the hygroscopic weight gain of compound A crystal form of formula (II) at 80%RH/25°C is 2%> ⁇ W% ⁇ 0.2%, which is slightly hygroscopic.
  • Experimental example 1 IC 50 experiment of detecting NLRP3 antagonists using THP-1 cells
  • the human monocyte cell line THP1 was used to study the inhibitory activity (IC 50 ) of NLRP3 antagonists on the secretion of IL-1 ⁇ .
  • PMA crotyl alcohol-12-myristate-13-acetate
  • LPS lipopolysaccharide
  • Toll-like receptor TLR4 an antagonist of NLRP3 was added, followed by ATP to further mature and activate NLRP3 and activate downstream caspase-1.
  • Activated caspase-1 can enzymatically process pro-IL-1 ⁇ into mature IL-1 ⁇ that can be secreted.
  • NLRP3 antagonists can effectively inhibit the ATP-induced maturation and activation of NLRP3, as well as the activation of downstream caspase-1, thereby inhibiting the maturation and secretion of IL-1 ⁇ .
  • the cells were stimulated with LPS, the final concentration of LPS was 100ng/mL, 200 ⁇ L/well was added to a 96-well plate, and cultured at 37° C., 5% CO 2 for 3 hours.
  • test compounds into the wells are: 5 ⁇ M, 1 ⁇ M, 200 nM, 40 nM, 8 nM, 1.6 nM, 0.32 nM, 0.064 nM. Incubate for 1 h at 37°C in a 5% CO 2 incubator.
  • mice The purpose of the experiment: to test the pharmacokinetics of the compound in mice
  • mice the clear solution obtained after dissolving the test compound was administered to female C57BL/6J mice via tail vein injection and intragastric administration (vehicle: 10% DMSO/10% solutol/80% water) (overnight fasting, 6- 8 weeks old).
  • intravenous injection group (IV) at 0.0833, 0.25, 0.5, 1, 2, 4, 8 and 24 hours
  • intragastric administration group (PO) at 0.25, 0.5, 1, 2, 4, At 6, 8 and 24 hours, blood was collected from the mandibular vein and centrifuged to obtain plasma.
  • the blood drug concentration was determined by LC-MS/MS method, and relevant pharmacokinetic parameters were calculated by non-compartmental model linear logarithmic trapezoidal method using WinNonlin TM Version 6.3 pharmacokinetic software.
  • T 1/2 half-life
  • C max peak concentration
  • AUC 0-last the area under the plasma concentration-time curve from time 0 to the last time when the drug concentration can be detected
  • F% bioavailability
  • Vd apparent volume of distribution
  • Cl clearance rate
  • T max peak time.
  • Table 11 The test results are shown in Table 11:
  • the compound of the present invention has good oral bioavailability, high exposure and good pharmacokinetic properties.
  • the blood drug concentration was determined by LC-MS/MS method, and the relevant pharmacokinetic parameters were calculated by the non-compartmental model linear logarithmic trapezoidal method using WinNonlin TM Version 6.3 pharmacokinetic software.
  • T 1/2 half-life
  • C max peak concentration
  • AUC 0-last the area under the plasma concentration-time curve from time 0 to the last time when the drug concentration can be detected
  • F bioavailability
  • Vd apparent volume of distribution
  • Cl clearance rate
  • T max peak time.
  • Table 12 The test results are shown in Table 12:
  • the compound of the present invention has good oral bioavailability and higher oral exposure.
  • the blood drug concentration was determined by LC-MS/MS method, and the relevant pharmacokinetic parameters were calculated by the non-compartmental model linear logarithmic trapezoidal method using WinNonlin TM Version 6.3 pharmacokinetic software.
  • T 1/2 half-life
  • C max peak concentration
  • AUC 0-last area under the plasma concentration-time curve from time 0 to the last time when the drug concentration can be detected
  • F bioavailability
  • Vd apparent volume of distribution
  • Cl clearance rate
  • T max peak time.
  • Table 13 The test results are shown in Table 13:
  • the compound of the present invention has excellent oral bioavailability and higher oral exposure.

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Abstract

A salt form and a crystal form of a dimethyl sulfoximine derivative, and a preparation method therefor. Specifically disclosed are a hydrate, a salt form and crystal form of a compound of formula (I), and a method for preparing the compound of formula (I).

Description

二甲基亚磺酰亚胺衍生物的盐型及晶型Salt and Crystal Forms of Dimethylsulfinimide Derivatives
本发明主张如下优先权：The present invention claims the following priority:
CN202111467740.2，申请日2021年12月03日。CN202111467740.2, the application date is December 03, 2021.
技术领域technical field
本发明涉及一种二甲基亚磺酰亚胺衍生物的盐型、晶型及其制备方法。The invention relates to a salt form, a crystal form and a preparation method of a dimethylsulfinimide derivative.
背景技术Background technique
炎症是多种疾病发生、发展的基础，维持炎症应答平衡对防治感染、自身免疫疾病和癌症等有重要意义。炎症小体(inflammasome)在炎症相关疾病的发生发展中发挥重要作用，核苷酸结合寡聚化结构域(nucleotide-binding oligomerization domain,NOD)样受体家族含pyrin结构域蛋白3(NOD-like receptor family，pyrin domain-containing protein 3，NLRP3)炎症小体能够被多种病原相关分子模式(pathogen-associated molecular patterns,PAMPs)和损伤相关分子模式(damage-associated molecular patterns,DAMPs)激活，进而活化半胱氨酸天冬氨酸蛋白酶-1(caspase-1)，释放成熟形式的促炎因子白细胞介素IL-1β和IL-18，引起机体的炎症反应，虽然这种反应可用于抵御外来病原体，但已知NLRP3炎性体的异常或慢性激活会引起下游的负面影响以及许多疾病的发作和进展。Inflammation is the basis for the occurrence and development of many diseases, and maintaining the balance of inflammatory responses is of great significance for the prevention and treatment of infection, autoimmune diseases and cancer. The inflammasome plays an important role in the occurrence and development of inflammation-related diseases, and the nucleotide-binding oligomerization domain (NOD)-like receptor family contains pyrin domain protein 3 (NOD-like receptor family, pyrin domain-containing protein 3, NLRP3) inflammasome can be activated by a variety of pathogen-associated molecular patterns (pathogen-associated molecular patterns, PAMPs) and damage-associated molecular patterns (damage-associated molecular patterns, DAMPs), and then activate Caspase-1, which releases mature forms of the pro-inflammatory cytokines IL-1β and IL-18, triggers an inflammatory response in the body, although this response can be used to defend against foreign pathogens , but aberrant or chronic activation of the NLRP3 inflammasome is known to cause downstream negative effects and the onset and progression of many diseases.
NLRP3活化与多种人类重大疾病的发生有着密切的关系。NLRP3自身的突变会导致一类自身炎症性疾病，包括括家族性寒冷型自身炎症性综合征(FCAS)、穆-韦二氏综合征(MWS)。另外NLRP3炎症小体能够被各种异常代谢产物，包括高血糖、饱和脂肪酸、胆固醇结晶、尿酸结晶、β-淀粉样蛋白等激活，所以NLRP3炎症小体在2型糖尿病、动脉粥样硬化、痛风、神经退行性疾病、非酒精性脂肪肝、炎症性肠病等等疾病的发生中起重要作用。因此NLRP3炎症小体是多种炎症相关疾病重要的潜在靶点。The activation of NLRP3 is closely related to the occurrence of many major human diseases. Mutations in NLRP3 itself can lead to a class of autoinflammatory diseases, including familial cold autoinflammatory syndrome (FCAS) and Moore-Weiss syndrome (MWS). In addition, NLRP3 inflammasomes can be activated by various abnormal metabolites, including hyperglycemia, saturated fatty acids, cholesterol crystals, uric acid crystals, β-amyloid, etc. , neurodegenerative diseases, non-alcoholic fatty liver, inflammatory bowel disease and other diseases play an important role. Therefore, the NLRP3 inflammasome is an important potential target for various inflammation-related diseases.
有多种NLRP3拮抗剂在WO2018015445、WO2019025467、WO2020157069和WO2021032591等专利中被报道。二芳基磺酰脲的衍生物MCC950通过抑制NLRP3炎症小体活性，可以减轻小鼠脑脊髓炎(experimental autoimmune encephalomyelitis,EAE)的严重程度。另一种小分子拮抗剂CY-09，特异性地阻断NLRP3炎症小体的组装与活化，对于小鼠低温相关的自身炎症综合征(cryopyrin-associated auto-inflammatory syndrome,CAPS)和Ⅱ型糖尿病模型有显著的治疗效果。Olatec公司开发的结构非常简单的NLRP3拮抗剂Dapansutrile目前处于临床II期，用于痛风、疼痛等多种炎性疾病。A variety of NLRP3 antagonists have been reported in patents such as WO2018015445, WO2019025467, WO2020157069 and WO2021032591. MCC950, a derivative of diarylsulfonylurea, can reduce the severity of mouse encephalomyelitis (experimental autoimmune encephalomyelitis, EAE) by inhibiting the activity of NLRP3 inflammasome. Another small-molecule antagonist, CY-09, specifically blocks the assembly and activation of NLRP3 inflammasome, and is effective against cryopyrin-associated auto-inflammatory syndrome (CAPS) and type 2 diabetes in mice The model has a significant therapeutic effect. Dapansutrile, a very simple NLRP3 antagonist developed by Olatec, is currently in phase II clinical trials and is used for various inflammatory diseases such as gout and pain.
Figure PCTCN2022134641-appb-000001
Figure PCTCN2022134641-appb-000001
开发靶向的NLRP3小分子拮抗剂，能为与其相关的炎症性疾病提供潜在的治疗手段，有着重要意义和广阔的前景。目前，仍然存在开发新的NLRP3拮抗剂用于治疗炎症性疾病的需求。The development of targeted NLRP3 small molecule antagonists can provide potential therapeutic means for related inflammatory diseases, which has great significance and broad prospects. Currently, there remains a need to develop new NLRP3 antagonists for the treatment of inflammatory diseases.
发明内容Contents of the invention
本发明提供了式(II)化合物，The present invention provides a compound of formula (II),
Figure PCTCN2022134641-appb-000002
Figure PCTCN2022134641-appb-000002
其中，m选自0～1.5。Wherein, m is selected from 0 to 1.5.
本发明的一些方案中，上述m选自0，0.1，0.2，0.3，0.4，0.5，0.6，0.7，0.8，0.9，1.0，1.1，1.2，1.3，1.4和1.5。In some solutions of the present invention, the above m is selected from 0, 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4 and 1.5.
本发明的一些方案中，上述m选自0～1.0。In some solutions of the present invention, the above m is selected from 0 to 1.0.
本发明的一些方案中，上述m选自0.3，0.4，0.5，0.6，0.7和0.8。In some solutions of the present invention, the above m is selected from 0.3, 0.4, 0.5, 0.6, 0.7 and 0.8.
本发明的一些方案中，上述m选自0.5。In some solutions of the present invention, the above m is selected from 0.5.
本发明还提供了式(II)化合物的A晶型，The present invention also provides the A crystal form of the compound of formula (II),
Figure PCTCN2022134641-appb-000003
Figure PCTCN2022134641-appb-000003
所述A晶型的Cu Kα辐射的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：15.26±0.20°，15.98±0.20°，17.54±0.20°，19.12±0.20°。The Cu Kα radiation X-ray powder diffraction pattern of the A crystal form has characteristic diffraction peaks at the following 2θ angles: 15.26±0.20°, 15.98±0.20°, 17.54±0.20°, 19.12±0.20°.
本发明的一些方案中，上述式(II)化合物的A晶型，In some schemes of the present invention, the crystal form A of the compound of formula (II) above,
Figure PCTCN2022134641-appb-000004
Figure PCTCN2022134641-appb-000004
所述A晶型的Cu Kα辐射的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：15.26±0.20°，15.98±0.20°，17.54±0.20°，19.12±0.20°。The Cu Kα radiation X-ray powder diffraction pattern of the A crystal form has characteristic diffraction peaks at the following 2θ angles: 15.26±0.20°, 15.98±0.20°, 17.54±0.20°, 19.12±0.20°.
本发明的一些方案中，上述A晶型的Cu Kα辐射的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：8.74±0.20°，15.26±0.20°，15.98±0.20°，17.54±0.20°，19.12±0.20°，21.40±0.20°，22.86±0.20°，23.46±0.20°。In some solutions of the present invention, the X-ray powder diffraction pattern of Cu Kα radiation of the above-mentioned A crystal form has characteristic diffraction peaks at the following 2θ angles: 8.74±0.20°, 15.26±0.20°, 15.98±0.20°, 17.54±0.20° , 19.12±0.20°, 21.40±0.20°, 22.86±0.20°, 23.46±0.20°.
本发明的一些方案中，上述A晶型的Cu Kα辐射的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：8.74±0.20°，10.86±0.20°，15.26±0.20°，15.98±0.20°，17.54±0.20°，19.12±0.20°，21.40±0.20°，22.86±0.20°，23.46±0.20°，24.78±0.20°，26.44±0.20°，32.32±0.20°。In some solutions of the present invention, the X-ray powder diffraction pattern of Cu Kα radiation of the above-mentioned A crystal form has characteristic diffraction peaks at the following 2θ angles: 8.74±0.20°, 10.86±0.20°, 15.26±0.20°, 15.98±0.20° , 17.54±0.20°, 19.12±0.20°, 21.40±0.20°, 22.86±0.20°, 23.46±0.20°, 24.78±0.20°, 26.44±0.20°, 32.32±0.20°.
本发明的一些方案中，上述A晶型的Cu Kα辐射的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：7.34±0.20°，8.74±0.20°，10.86±0.20°，15.26±0.20°，15.98±0.20°，17.54±0.20°，19.12±0.20°，20.90±0.20°，21.40±0.20°，22.86±0.20°，23.46±0.20°，24.78±0.20°，25.54±0.20°，26.44±0.20°，28.18±0.20°，32.32±0.20°。In some solutions of the present invention, the X-ray powder diffraction pattern of Cu Kα radiation of the above-mentioned A crystal form has characteristic diffraction peaks at the following 2θ angles: 7.34±0.20°, 8.74±0.20°, 10.86±0.20°, 15.26±0.20° , 15.98±0.20°, 17.54±0.20°, 19.12±0.20°, 20.90±0.20°, 21.40±0.20°, 22.86±0.20°, 23.46±0.20°, 24.78±0.20°, 25.54±0.20°, 26.44±0.20° , 28.18±0.20°, 32.32±0.20°.
本发明的一些方案中，上述A晶型的Cu Kα辐射的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：15.26±0.20°，15.98±0.20°，还在7.34±0.20°，和/或8.74±0.20°，和/或10.86±0.20°，和/或17.54±0.20°，和/或19.12±0.20°，和/或20.90±0.20°，和/或21.40±0.20°，和/或22.86±0.20°，和/或23.46±0.20°，和/或24.78±0.20°，和/或25.54±0.20°，和/或26.44±0.20°，和/或28.18±0.20°，和/或32.32±0.20°处具有特征衍射峰。In some solutions of the present invention, the X-ray powder diffraction pattern of Cu Kα radiation of the above-mentioned A crystal form has characteristic diffraction peaks at the following 2θ angles: 15.26±0.20°, 15.98±0.20°, and 7.34±0.20°, and/or or 8.74±0.20°, and/or 10.86±0.20°, and/or 17.54±0.20°, and/or 19.12±0.20°, and/or 20.90±0.20°, and/or 21.40±0.20°, and/or 22.86 ±0.20°, and/or 23.46±0.20°, and/or 24.78±0.20°, and/or 25.54±0.20°, and/or 26.44±0.20°, and/or 28.18±0.20°, and/or 32.32±0.20 ° has a characteristic diffraction peak.
本发明的一些方案中，上述A晶型的Cu Kα辐射的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：3.24°，7.34°，8.74°，10.86°，12.86°，15.26°，15.98°，17.54°，18.00°，19.12°，20.28°，20.90°，21.40°，21.82°，22.86°，23.46°，24.78°，25.54°，26.44°，27.44°，28.18°，30.98°，32.32°，33.20°，34.86°，36.56°，39.24°。In some solutions of the present invention, the X-ray powder diffraction pattern of Cu Kα radiation of the above-mentioned A crystal form has characteristic diffraction peaks at the following 2θ angles: 3.24°, 7.34°, 8.74°, 10.86°, 12.86°, 15.26°, 15.98° °, 17.54°, 18.00°, 19.12°, 20.28°, 20.90°, 21.40°, 21.82°, 22.86°, 23.46°, 24.78°, 25.54°, 26.44°, 27.44°, 28.18°, 30.98°, 32.32°, 33.20°, 34.86°, 36.56°, 39.24°.
本发明的一些方案中，上述A晶型的Cu Kα辐射的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：7.34°，8.74°，10.86°，12.86°，15.26°，15.98°，17.54°，18.00°，19.12°，20.28°，20.90°，21.40°，21.82°，22.86°，23.46°，24.78°，25.54°，26.44°，27.44°，28.18°，30.98°，32.32°，33.20°，34.86°，36.56°，39.24°。In some solutions of the present invention, the X-ray powder diffraction pattern of the Cu Kα radiation of the above-mentioned A crystal form has characteristic diffraction peaks at the following 2θ angles: 7.34°, 8.74°, 10.86°, 12.86°, 15.26°, 15.98°, 17.54° °, 18.00°, 19.12°, 20.28°, 20.90°, 21.40°, 21.82°, 22.86°, 23.46°, 24.78°, 25.54°, 26.44°, 27.44°, 28.18°, 30.98°, 32.32°, 33.20°, 34.86°, 36.56°, 39.24°.
本发明的一些方案中，上述A晶型的Cu Kα辐射的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：7.34°，8.74°，10.86°，12.86°，15.26°，15.98°，17.54°，18.00°，19.12°，20.28°，20.90°，21.40°，21.82°，22.86°，23.46°，24.78°，25.54°，26.44°，27.44°，28.18°，30.98°，32.32°，33.20°。In some solutions of the present invention, the X-ray powder diffraction pattern of the Cu Kα radiation of the above-mentioned A crystal form has characteristic diffraction peaks at the following 2θ angles: 7.34°, 8.74°, 10.86°, 12.86°, 15.26°, 15.98°, 17.54° °, 18.00°, 19.12°, 20.28°, 20.90°, 21.40°, 21.82°, 22.86°, 23.46°, 24.78°, 25.54°, 26.44°, 27.44°, 28.18°, 30.98°, 32.32°, 33.20°.
本发明的一些方案中，上述A晶型的Cu Kα辐射的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：15.259±0.200°，15.980±0.200°，17.541±0.200°，19.121±0.200°。In some solutions of the present invention, the X-ray powder diffraction pattern of Cu Kα radiation of the above-mentioned A crystal form has characteristic diffraction peaks at the following 2θ angles: 15.259±0.200°, 15.980±0.200°, 17.541±0.200°, 19.121±0.200° .
本发明的一些方案中，上述A晶型的Cu Kα辐射的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：8.742±0.200°，15.259±0.200°，15.980±0.200°，17.541±0.200°，19.121±0.200°，21.400±0.200°，22.861±0.200°，23.461±0.200°。In some solutions of the present invention, the X-ray powder diffraction pattern of Cu Kα radiation of the above-mentioned A crystal form has characteristic diffraction peaks at the following 2θ angles: 8.742±0.200°, 15.259±0.200°, 15.980±0.200°, 17.541±0.200° , 19.121±0.200°, 21.400±0.200°, 22.861±0.200°, 23.461±0.200°.
本发明的一些方案中，上述A晶型的Cu Kα辐射的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：8.742±0.200°，10.860±0.200°，15.259±0.200°，15.980±0.200°，17.541±0.200°，19.121±0.200°，21.400±0.200°，22.861±0.200°，23.461±0.200°，24.782±0.200°，26.440±0.200°，32.318±0.200°。In some solutions of the present invention, the X-ray powder diffraction pattern of Cu Kα radiation of the above-mentioned A crystal form has characteristic diffraction peaks at the following 2θ angles: 8.742±0.200°, 10.860±0.200°, 15.259±0.200°, 15.980±0.200° , 17.541±0.200°, 19.121±0.200°, 21.400±0.200°, 22.861±0.200°, 23.461±0.200°, 24.782±0.200°, 26.440±0.200°, 32.318±0.200°.
本发明的一些方案中，上述A晶型的Cu Kα辐射的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：7.343°，8.742°，10.860°，12.862°，15.259°，15.980°，17.541°，17.999°，19.121°，20.282°，20.899°，21.400°，21.820°，22.861°，23.461°，24.782°，25.541°，26.440°，27.439°，28.181°，30.979°，32.318°，33.199°。In some solutions of the present invention, the X-ray powder diffraction pattern of the Cu Kα radiation of the above-mentioned A crystal form has characteristic diffraction peaks at the following 2θ angles: 7.343°, 8.742°, 10.860°, 12.862°, 15.259°, 15.980°, 17.541 °, 17.999°, 19.121°, 20.282°, 20.899°, 21.400°, 21.820°, 22.861°, 23.461°, 24.782°, 25.541°, 26.440°, 27.439°, 28.181°, 30.979°, 32.318° , 33.199°.
本发明的一些方案中，上述A晶型的XRPD图谱如图1所示。In some solutions of the present invention, the XRPD spectrum of the above crystal form A is shown in FIG. 1 .
本发明的一些方案中，上述A晶型的Cu Kα辐射的XRPD图谱中，衍射峰的峰位置及相对强度由下表所示：In some solutions of the present invention, in the XRPD spectrum of the Cu Kα radiation of the above-mentioned A crystal form, the peak position and relative intensity of the diffraction peak are shown in the following table:
表1式(II)化合物A晶型的XRPD衍射数据Table 1 XRPD diffraction data of formula (II) compound A crystal form
编号serial number 衍射角2θDiffraction angle 2θ 强度(计数)intensity (count) 相对强度％Relative Strength% 编号serial number 衍射角2θDiffraction angle 2θ 强度(计数)intensity (count) 相对强度％Relative Strength%
11 3.2383.238 161161 16.916.9 1515 22.86122.861 264264 27.627.6
22 7.3437.343 128128 13.413.4 1616 23.46123.461 294294 30.830.8
33 8.7428.742 221221 23.123.1 1717 24.78224.782 230230 24.124.1
44 10.86010.860 166166 17.417.4 1818 25.54125.541 139139 14.514.5
编号serial number 衍射角2θDiffraction angle 2θ 强度(计数)intensity (count) 相对强度％Relative Strength% 编号serial number 衍射角2θDiffraction angle 2θ 强度(计数)intensity (count) 相对强度％Relative Strength%
55 12.86212.862 4242 4.44.4 1919 26.44026.440 265265 27.727.7
66 15.25915.259 439439 46.046.0 2020 27.43927.439 9191 9.59.5
77 15.98015.980 954954 100.0100.0 21twenty one 28.18128.181 9999 10.410.4
88 17.54117.541 301301 31.531.5 22twenty two 30.97930.979 7070 7.47.4
99 17.99917.999 121121 12.612.6 23twenty three 32.31832.318 183183 19.219.2
1010 19.12119.121 424424 44.444.4 24twenty four 33.19933.199 6868 7.17.1
1111 20.28220.282 6969 7.27.2 2525 34.85934.859 4848 5.15.1
1212 20.89920.899 122122 12.712.7 2626 36.55936.559 4040 4.24.2
1313 21.40021.400 250250 26.226.2 2727 39.24139.241 5252 5.45.4
1414 21.82021.820 218218 22.822.8 -- -- -- --
本发明的一些方案中，上述A晶型的差示扫描量热(DSC)曲线显示在67.13℃±5℃和163.06℃±5℃处具有吸热峰的起始点。In some aspects of the present invention, the differential scanning calorimetry (DSC) curve of the above crystal form A shows the onset of endothermic peaks at 67.13°C±5°C and 163.06°C±5°C.
本发明的一些方案中，上述A晶型的差示扫描量热(DSC)曲线显示在67.13℃±5℃处具有吸热峰的起始点。In some solutions of the present invention, the differential scanning calorimetry (DSC) curve of the above-mentioned crystal form A shows an onset point of an endothermic peak at 67.13°C±5°C.
本发明的一些方案中，上述A晶型的差示扫描量热(DSC)曲线显示在163.06℃±5℃处具有吸热峰的起始点。In some solutions of the present invention, the differential scanning calorimetry (DSC) curve of the above-mentioned crystal form A shows an onset point of an endothermic peak at 163.06°C±5°C.
本发明的一些方案中，上述A晶型的差示扫描量热(DSC)曲线显示在91.08℃±3℃处具有吸热峰的峰值。In some solutions of the present invention, the differential scanning calorimetry (DSC) curve of the above crystal form A shows a peak with an endothermic peak at 91.08°C±3°C.
本发明的一些方案中，上述A晶型的差示扫描量热(DSC)曲线显示在167.39℃±3℃处具有吸热峰的峰值。In some solutions of the present invention, the differential scanning calorimetry (DSC) curve of the above crystal form A shows a peak with an endothermic peak at 167.39°C±3°C.
本发明的一些方案中，上述A晶型的差示扫描量热(DSC)曲线显示在172.61℃±3℃处具有放热峰的峰值。In some solutions of the present invention, the differential scanning calorimetry (DSC) curve of the above crystal form A shows a peak with an exothermic peak at 172.61°C±3°C.
本发明的一些方案中，上述A晶型的DSC图谱如图2所示。In some solutions of the present invention, the DSC spectrum of the above crystal form A is shown in FIG. 2 .
本发明的一些方案中，上述A晶型的热重分析(TGA)曲线在140.0℃±3℃时失重达1.72％。In some solutions of the present invention, the thermogravimetric analysis (TGA) curve of the above crystal form A has a weight loss of 1.72% at 140.0°C±3°C.
本发明的一些方案中，上述A晶型的TGA图谱如图3所示。In some solutions of the present invention, the TGA spectrum of the above crystal form A is shown in FIG. 3 .
本发明还提供了上述A晶型的制备方法，包括如下步骤：The present invention also provides a preparation method for the above crystal form A, comprising the following steps:
(a)将化合物Z加入溶剂X中，搅拌溶解，再滴加溶剂Y；(a) Add compound Z to solvent X, stir to dissolve, and then add solvent Y dropwise;
或者，将化合物Z加入溶剂X和溶剂Y的混合溶剂中；Alternatively, compound Z is added to a mixed solvent of solvent X and solvent Y;
(b)15～80℃搅拌1～24小时；(b) stirring at 15-80°C for 1-24 hours;
(c)15～30℃下收集固体；(c) collecting the solid at 15-30°C;
其中，in,
化合物Z选自式(I)化合物、式(I)化合物B晶型和式(I)化合物C晶型；Compound Z is selected from the compound of formula (I), the crystal form of compound B of formula (I) and the crystal form of compound C of formula (I);
溶剂X选自二甲基亚砜、N,N-二甲基甲酰胺、N-甲基吡咯烷酮、四氢呋喃、2-甲基四氢呋喃、乙酸乙酯、丙酮、乙腈、甲醇、乙醇、异丙醇、正丁醇和水；Solvent X is selected from dimethylsulfoxide, N,N-dimethylformamide, N-methylpyrrolidone, tetrahydrofuran, 2-methyltetrahydrofuran, ethyl acetate, acetone, acetonitrile, methanol, ethanol, isopropanol, n-butanol and water;
溶剂Y不存在，或者溶剂Y选自二氯甲烷、水、甲苯和正庚烷。Solvent Y is absent, or solvent Y is selected from dichloromethane, water, toluene and n-heptane.
本发明还提供了上述A晶型的制备方法，包括如下步骤：The present invention also provides a preparation method for the above crystal form A, comprising the following steps:
(a)将化合物Z加入溶剂X中，搅拌溶解，再滴加溶剂Y；(a) Add compound Z to solvent X, stir to dissolve, and then add solvent Y dropwise;
或者，将化合物Z加入溶剂X和溶剂Y的混合溶剂中；Alternatively, compound Z is added to a mixed solvent of solvent X and solvent Y;
(b)15～80℃搅拌1～24小时；(b) stirring at 15-80°C for 1-24 hours;
(c)15～30℃下收集固体，将固体加入水中，15～50℃搅拌1～24小时；(c) Collect the solid at 15-30°C, add the solid to water, and stir at 15-50°C for 1-24 hours;
(d)15～30℃下收集固体；(d) collecting the solid at 15-30°C;
其中，in,
化合物Z选自式(I)化合物、式(I)化合物B晶型和式(I)化合物C晶型；Compound Z is selected from the compound of formula (I), the crystal form of compound B of formula (I) and the crystal form of compound C of formula (I);
溶剂X选自二甲基亚砜、N,N-二甲基甲酰胺、N-甲基吡咯烷酮、四氢呋喃、2-甲基四氢呋喃、乙酸乙酯、丙酮、乙腈、甲醇、乙醇、异丙醇、正丁醇和水；Solvent X is selected from dimethylsulfoxide, N,N-dimethylformamide, N-methylpyrrolidone, tetrahydrofuran, 2-methyltetrahydrofuran, ethyl acetate, acetone, acetonitrile, methanol, ethanol, isopropanol, n-butanol and water;
溶剂Y不存在，或者溶剂Y选自二氯甲烷、水、甲苯和正庚烷。Solvent Y is absent, or solvent Y is selected from dichloromethane, water, toluene and n-heptane.
本发明还提供了上述式(II)化合物A晶型的制备方法，The present invention also provides a preparation method of the crystal form of compound A of the above formula (II),
Figure PCTCN2022134641-appb-000005
Figure PCTCN2022134641-appb-000005
包括如下步骤：Including the following steps:
(a)将式(I)化合物加入溶剂X中，搅拌溶解，再滴加溶剂Y；(a) adding the compound of formula (I) into solvent X, stirring and dissolving, and then adding solvent Y dropwise;
或者，将式(I)化合物加入溶剂X和溶剂Y的混合溶剂中；Alternatively, the compound of formula (I) is added to a mixed solvent of solvent X and solvent Y;
(b)15～80℃下搅拌1～24小时；(b) stirring at 15-80°C for 1-24 hours;
(c)15～30℃下收集固体；(c) collecting the solid at 15-30°C;
其中，in,
式(I)化合物的结构为
Figure PCTCN2022134641-appb-000006
The structure of formula (I) compound is
Figure PCTCN2022134641-appb-000006
溶剂X选自二甲基亚砜、N,N-二甲基甲酰胺、丙酮和乙腈；Solvent X is selected from dimethylsulfoxide, N,N-dimethylformamide, acetone and acetonitrile;
溶剂Y为水。Solvent Y is water.
本发明的一些方案中，上述溶剂X为丙酮或乙腈，溶剂X与溶剂Y的体积比为1:2～3:1，溶剂X与溶剂Y的体积总和(mL)与式(I)化合物的质量(g)比为10:1～30:1；优选的，溶剂X与溶剂Y的体积比为2:1，溶剂X与溶剂Y的体积总和(mL)与式(I)化合物的质量(g)比为15:1。In some schemes of the present invention, the above-mentioned solvent X is acetone or acetonitrile, the volume ratio of solvent X and solvent Y is 1:2 to 3:1, and the volume sum (mL) of solvent X and solvent Y is equal to that of the compound of formula (I) The mass (g) ratio is 10:1～30:1; preferably, the volume ratio of solvent X and solvent Y is 2:1, the volume sum (mL) of solvent X and solvent Y and the mass of formula (I) compound ( g) The ratio is 15:1.
本发明的一些方案中，上述溶剂X为二甲基亚砜或N,N-二甲基甲酰胺，溶剂X与溶剂Y的体积比为 1:5～1:15；优选的，溶剂X与溶剂Y的体积比为1:9。In some solutions of the present invention, the above-mentioned solvent X is dimethyl sulfoxide or N,N-dimethylformamide, and the volume ratio of solvent X to solvent Y is 1:5 to 1:15; preferably, solvent X and The volume ratio of solvent Y is 1:9.
本发明还提供了式(I)化合物的B晶型，所述B晶型的Cu Kα辐射的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：9.31±0.20°，15.09±0.20°，16.90±0.20°，20.49±0.20°，The present invention also provides the B crystal form of the compound of formula (I), the X-ray powder diffraction pattern of Cu Kα radiation of the B crystal form has characteristic diffraction peaks at the following 2θ angles: 9.31±0.20°, 15.09±0.20°, 16.90±0.20°, 20.49±0.20°,
Figure PCTCN2022134641-appb-000007
Figure PCTCN2022134641-appb-000007
本发明的一些方案中，上述B晶型的Cu Kα辐射的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：5.63±0.20°，9.31±0.20°，15.09±0.20°，16.90±0.20°，19.66±0.20°，20.49±0.20°，22.11±0.20°，22.62±0.20°。In some solutions of the present invention, the X-ray powder diffraction pattern of the Cu Kα radiation of the B crystal form has characteristic diffraction peaks at the following 2θ angles: 5.63±0.20°, 9.31±0.20°, 15.09±0.20°, 16.90±0.20° , 19.66±0.20°, 20.49±0.20°, 22.11±0.20°, 22.62±0.20°.
本发明的一些方案中，上述B晶型的Cu Kα辐射的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：5.63±0.20°，9.31±0.20°，11.23±0.20°，15.09±0.20°，15.88±0.20°，16.90±0.20°，19.66±0.20°，20.49±0.20°，22.11±0.20°，22.62±0.20°，26.47±0.20°，29.87±0.20°。In some solutions of the present invention, the X-ray powder diffraction pattern of the Cu Kα radiation of the B crystal form has characteristic diffraction peaks at the following 2θ angles: 5.63±0.20°, 9.31±0.20°, 11.23±0.20°, 15.09±0.20° , 15.88±0.20°, 16.90±0.20°, 19.66±0.20°, 20.49±0.20°, 22.11±0.20°, 22.62±0.20°, 26.47±0.20°, 29.87±0.20°.
本发明的一些方案中，上述B晶型的Cu Kα辐射的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：5.63°，9.31°，11.23°，15.09°，15.88°，16.90°，19.66°，20.49°，22.11°，22.62°，23.85°，26.47°，27.74°，29.87°，31.11°，32.02°。In some solutions of the present invention, the X-ray powder diffraction pattern of the Cu Kα radiation of the above B crystal form has characteristic diffraction peaks at the following 2θ angles: 5.63°, 9.31°, 11.23°, 15.09°, 15.88°, 16.90°, 19.66 °, 20.49°, 22.11°, 22.62°, 23.85°, 26.47°, 27.74°, 29.87°, 31.11°, 32.02°.
本发明的一些方案中，上述B晶型的XRPD图谱如图4所示。In some solutions of the present invention, the XRPD spectrum of the above crystal form B is shown in FIG. 4 .
本发明的一些方案中，上述B晶型的Cu Kα辐射的XRPD图谱中，衍射峰的峰位置及相对强度如下表所示：In some solutions of the present invention, in the XRPD spectrum of the Cu Kα radiation of the above-mentioned B crystal form, the peak position and relative intensity of the diffraction peak are shown in the following table:
表2 式(I)化合物B晶型的XRPD衍射数据Table 2 XRPD diffraction data of formula (I) compound B crystal form
编号serial number 衍射角2θDiffraction angle 2θ 峰高Peak height 相对强度％Relative Strength% 编号serial number 衍射角2θDiffraction angle 2θ 峰高Peak height 相对强度％ Relative Strength%
11 5.62685.6268 344.96344.96 42.8442.84 99 22.107422.1074 212.39212.39 26.3826.38
22 9.30639.3063 805.17805.17 100.00100.00 1010 22.618722.6187 193.47193.47 24.0324.03
33 11.232211.2322 105.27105.27 13.0713.07 1111 23.853223.8532 53.4153.41 6.636.63
44 15.090715.0907 494.57494.57 61.4261.42 1212 26.467326.4673 80.3880.38 9.989.98
55 15.879015.8790 167.56167.56 20.8120.81 1313 27.736727.7367 45.4745.47 5.655.65
66 16.895216.8952 360.03360.03 44.7144.71 1414 29.869529.8695 100.96100.96 12.5412.54
77 19.658419.6584 325.26325.26 40.4040.40 1515 31.110431.1104 68.8368.83 8.558.55
88 20.489920.4899 630.36630.36 78.2978.29 1616 32.020032.0200 58.1558.15 7.227.22
本发明的一些方案中，上述B晶型的差示扫描量热(DSC)曲线显示在171.6℃±5℃处具有吸热峰的起始点。In some solutions of the present invention, the differential scanning calorimetry (DSC) curve of the above crystal form B shows an onset point of an endothermic peak at 171.6°C±5°C.
本发明的一些方案中，上述B晶型的差示扫描量热(DSC)曲线显示在174.0℃±3℃处具有吸热峰的峰值。In some solutions of the present invention, the differential scanning calorimetry (DSC) curve of the above crystal form B shows a peak with an endothermic peak at 174.0°C±3°C.
本发明的一些方案中，上述B晶型的DSC图谱如图5所示。In some solutions of the present invention, the DSC spectrum of the above crystal form B is shown in FIG. 5 .
本发明的一些方案中，上述B晶型的热重分析(TGA)曲线在150.0℃±3℃时失重达6.77％。In some solutions of the present invention, the thermogravimetric analysis (TGA) curve of the above crystal form B has a weight loss of 6.77% at 150.0°C±3°C.
本发明的一些方案中，上述B晶型的TGA图谱如图6所示。In some solutions of the present invention, the TGA spectrum of the above crystal form B is shown in FIG. 6 .
本发明还提供了式(I)化合物的C晶型，所述C晶型的Cu Kα辐射的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：9.21±0.20°，13.96±0.20°，16.65±0.20°，The present invention also provides the C crystal form of the compound of formula (I), the X-ray powder diffraction pattern of the Cu Kα radiation of the C crystal form has characteristic diffraction peaks at the following 2θ angles: 9.21±0.20°, 13.96±0.20°, 16.65±0.20°,
Figure PCTCN2022134641-appb-000008
Figure PCTCN2022134641-appb-000008
本发明的一些方案中，上述C晶型的Cu Kα辐射的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：9.21±0.20°，13.96±0.20°，16.65±0.20°，17.41±0.20°，18.45±0.20°，22.94±0.20°，24.36±0.20°。In some solutions of the present invention, the X-ray powder diffraction pattern of the Cu Kα radiation of the above C crystal form has characteristic diffraction peaks at the following 2θ angles: 9.21±0.20°, 13.96±0.20°, 16.65±0.20°, 17.41±0.20° , 18.45±0.20°, 22.94±0.20°, 24.36±0.20°.
本发明的一些方案中，上述C晶型的Cu Kα辐射的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：9.21±0.20°，13.96±0.20°，16.12±0.20°，16.65±0.20°，17.41±0.20°，18.45±0.20°，21.13±0.20°，22.94±0.20°，24.36±0.20°，32.03±0.20°。In some solutions of the present invention, the X-ray powder diffraction pattern of the Cu Kα radiation of the above C crystal form has characteristic diffraction peaks at the following 2θ angles: 9.21±0.20°, 13.96±0.20°, 16.12±0.20°, 16.65±0.20° , 17.41±0.20°, 18.45±0.20°, 21.13±0.20°, 22.94±0.20°, 24.36±0.20°, 32.03±0.20°.
本发明的一些方案中，上述C晶型的Cu Kα辐射的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：9.21°，10.51°，13.96°，16.12°，16.65°，17.41°，18.45°，21.13°，22.94°，24.36°，28.86°，32.03°，33.55°。In some solutions of the present invention, the X-ray powder diffraction pattern of the Cu Kα radiation of the above C crystal form has characteristic diffraction peaks at the following 2θ angles: 9.21°, 10.51°, 13.96°, 16.12°, 16.65°, 17.41°, 18.45° °, 21.13°, 22.94°, 24.36°, 28.86°, 32.03°, 33.55°.
本发明的一些方案中，上述C晶型的XRPD图谱如图7所示。In some solutions of the present invention, the XRPD spectrum of the above crystal form C is shown in FIG. 7 .
本发明的一些方案中，上述C晶型的Cu Kα辐射的XRPD图谱中，衍射峰的峰位置及相对强度由下表所示：In some solutions of the present invention, in the XRPD spectrum of the Cu Kα radiation of the above-mentioned C crystal form, the peak position and relative intensity of the diffraction peak are shown in the following table:
表3 式(I)化合物C晶型的XRPD衍射数据Table 3 XRPD diffraction data of formula (I) compound C crystal form
编号serial number 衍射角2θDiffraction angle 2θ 峰高Peak height 相对强度％Relative Strength% 编号serial number 衍射角2θDiffraction angle 2θ 峰高Peak height 相对强度％ Relative Strength%
11 9.21379.2137 570.20570.20 24.8324.83 88 21.129821.1298 143.99143.99 6.276.27
22 10.514610.5146 55.2755.27 2.412.41 99 22.942322.9423 324.02324.02 14.1114.11
33 13.957513.9575 2296.322296.32 100.00100.00 1010 24.359624.3596 464.18464.18 20.2120.21
44 16.124116.1241 164.35164.35 7.167.16 1111 28.857128.8571 35.0335.03 1.531.53
55 16.650516.6505 834.87834.87 36.3636.36 1212 32.030032.0300 148.69148.69 6.486.48
66 17.413217.4132 564.52564.52 24.5824.58 1313 33.546233.5462 46.5146.51 2.032.03
77 18.449618.4496 202.83202.83 8.838.83 -- -- -- --
本发明的一些方案中，上述C晶型的差示扫描量热(DSC)曲线显示在176.0℃±5℃处具有吸热峰的起始点。In some solutions of the present invention, the differential scanning calorimetry (DSC) curve of the above-mentioned crystal form C shows an onset point of an endothermic peak at 176.0°C±5°C.
本发明的一些方案中，上述C晶型的差示扫描量热(DSC)曲线显示在178.3℃±3℃处具有吸热峰的峰值。In some solutions of the present invention, the differential scanning calorimetry (DSC) curve of the above crystal form C shows a peak with an endothermic peak at 178.3°C±3°C.
本发明的一些方案中，上述C晶型的差示扫描量热(DSC)曲线显示在55.1℃±5℃和176.0℃±5℃处具有吸热峰的起始点。In some aspects of the present invention, the differential scanning calorimetry (DSC) curve of the above crystal form C shows the onset of endothermic peaks at 55.1°C±5°C and 176.0°C±5°C.
本发明的一些方案中，上述C晶型的DSC图谱如图8所示。In some solutions of the present invention, the DSC spectrum of the above crystal form C is shown in FIG. 8 .
本发明的一些方案中，上述C晶型的热重分析(TGA)曲线在150.0℃±3℃时失重达1.39％。In some solutions of the present invention, the thermogravimetric analysis (TGA) curve of the above crystal form C has a weight loss of 1.39% at 150.0°C±3°C.
本发明的一些方案中，上述C晶型的TGA图谱如图9所示。本发明还提供了上述化合物的水合物、 钠盐、钾盐、A晶型、B晶型或C晶型在制备NLRP3拮抗剂相关药物上的应用。In some solutions of the present invention, the TGA spectrum of the above crystal form C is shown in FIG. 9 . The present invention also provides the application of the hydrate, sodium salt, potassium salt, A crystal form, B crystal form or C crystal form of the above compound in the preparation of drugs related to NLRP3 antagonists.
本发明还提供了上述式(II)化合物、式(II)化合物A晶型、式(I)化合物B晶型、式(I)化合物C晶型或式(II)化合物A晶型的制备方法在制备治疗NLRP3拮抗剂相关疾病的药物上的应用。The present invention also provides a preparation method for the above-mentioned compound of formula (II), crystal form of compound A of formula (II), crystal form of compound B of formula (I), crystal form of compound C of formula (I) or crystal form of compound A of formula (II) Application in the preparation of medicines for treating diseases related to NLRP3 antagonists.
本发明还提供了式(I)化合物钠盐或钾盐。The present invention also provides sodium salt or potassium salt of the compound of formula (I).
本发明还提供了上述式(I)化合物的钠盐或钾盐在制备治疗NLRP3拮抗剂相关疾病的药物上的应用。The present invention also provides the use of the sodium salt or potassium salt of the compound of formula (I) in the preparation of medicines for treating diseases related to NLRP3 antagonists.
技术效果technical effect
本发明化合物作为一类NLRP3拮抗剂，具有活性好，药代动力学性质良好，其晶型性质稳定，用于治疗多种与NLRP3通路异常的炎症相关疾病，具有潜在的应用价值。As a class of NLRP3 antagonists, the compound of the present invention has good activity, good pharmacokinetic properties, and stable crystal form properties, and is used for treating various inflammation-related diseases with abnormal NLRP3 pathways, and has potential application value.
定义和说明Definition and Description
除非另有说明，本文所用的下列术语和短语旨在含有下列含义。一个特定的短语或术语在没有特别定义的情况下不应该被认为是不确定的或不清楚的，而应该按照普通的含义去理解。当本文出现商品名时，旨在指代其对应的商品或其活性成分。Unless otherwise stated, the following terms and phrases used herein are intended to have the following meanings. A specific phrase or term should not be considered indeterminate or unclear if it is not specifically defined, but should be understood according to its ordinary meaning. When a trade name appears herein, it is intended to refer to its corresponding trade name or its active ingredient.
本发明的中间体化合物可以通过本领域技术人员所熟知的多种合成方法来制备，包括下面列举的具体实施方式、其与其他化学合成方法的结合所形成的实施方式以及本领域技术上人员所熟知的等同替换方式，优选的实施方式包括但不限于本发明的实施例。The intermediate compound of the present invention can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments listed below, the embodiments formed by its combination with other chemical synthesis methods, and the methods described by those skilled in the art. Known equivalents, preferred embodiments include, but are not limited to, the examples of the present invention.
术语“药学上可接受的盐”是指化合物的盐，由化合物与相对无毒的酸或碱制备；基本发明式(I)化合物的性质，优选为与相对无毒的酸制备。可以通过在纯的溶液或合适的惰性溶剂中用足够量的酸与这类化合物接触的方式获得酸加成盐。药学上可接受的酸加成盐的实例包括无机酸盐，所述无机酸包括例如盐酸、氢溴酸、碳酸，碳酸氢根，磷酸、磷酸一氢根、磷酸二氢根、硫酸、硫酸氢根、氢碘酸、亚磷酸等；以及有机酸盐，所述有机酸包括如乙酸、丙酸、异丁酸、马来酸、丙二酸、苯甲酸、琥珀酸、辛二酸、反丁烯二酸、乳酸、扁桃酸、邻苯二甲酸、苯磺酸、对甲苯磺酸、萘二磺酸、柠檬酸、酒石酸和甲磺酸等类似的酸。The term "pharmaceutically acceptable salt" refers to the salt of the compound, which is prepared from the compound with a relatively non-toxic acid or base; the nature of the compound of formula (I) of the basic invention is preferably prepared with a relatively non-toxic acid. Acid addition salts can be obtained by contacting such compounds with a sufficient amount of the acid, either neat or in a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include salts of inorganic acids including, for example, hydrochloric acid, hydrobromic acid, carbonic acid, bicarbonate, phosphoric acid, monohydrogenphosphate, dihydrogenphosphate, sulfuric acid, hydrogensulfate radical, hydriodic acid, phosphorous acid, etc.; Alkenedic acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, naphthalene disulfonic acid, citric acid, tartaric acid and methanesulfonic acid and similar acids.
本发明的化合物可以存在特定的几何或立体异构体形式。本发明设想所有的这类化合物，包括顺式和反式异构体、(-)-和(+)-对映体、(R)-和(S)-对映体、非对映异构体、(D)-异构体、(L)-异构体，及其外消旋混合物和其他混合物，例如对映异构体或非对映体富集的混合物，所有这些混合物都属于本发明的范围之内。烷基等取代基中可存在另外的不对称碳原子。所有这些异构体以及它们的混合物，均包括在本发明的范围之内。The compounds of the invention may exist in particular geometric or stereoisomeric forms. The present invention contemplates all such compounds, including cis and trans isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers isomers, (D)-isomers, (L)-isomers, and their racemic and other mixtures, such as enantiomerically or diastereomerically enriched mixtures, all of which are subject to the present within the scope of the invention. Additional asymmetric carbon atoms may be present in substituents such as alkyl groups. All such isomers, as well as mixtures thereof, are included within the scope of the present invention.
除非另有说明，术语“对映异构体”或者“旋光异构体”是指互为镜像关系的立体异构体。Unless otherwise stated, the terms "enantiomer" or "optical isomer" refer to stereoisomers that are mirror images of each other.
除非另有说明，术语“顺反异构体”或者“几何异构体”系由因双键或者成环碳原子单键不能自由旋转而引起。Unless otherwise stated, the terms "cis-trans isomers" or "geometric isomers" arise from the inability to rotate freely due to the double bond or the single bond of the carbon atoms forming the ring.
除非另有说明，术语“非对映异构体”是指分子具有两个或多个手性中心，并且分子间为非镜像的关系的立体异构体。Unless otherwise indicated, the term "diastereoisomer" refers to stereoisomers whose molecules have two or more chiral centers and which are not mirror images of the molecules.
除非另有说明，“(+)”表示右旋，“(-)”表示左旋，“(±)”表示外消旋。Unless otherwise specified, "(+)" means dextrorotation, "(-)" means levorotation, and "(±)" means racemization.
除非另有说明，用楔形实线键
Figure PCTCN2022134641-appb-000009
和楔形虚线键
Figure PCTCN2022134641-appb-000010
表示一个立体中心的绝对构型，用直形实线键
Figure PCTCN2022134641-appb-000011
和直形虚线键
Figure PCTCN2022134641-appb-000012
表示立体中心的相对构型。 Unless otherwise noted, keys with wedge-shaped solid lines
Figure PCTCN2022134641-appb-000009
and dotted wedge keys
Figure PCTCN2022134641-appb-000010
Indicates the absolute configuration of a stereocenter, with a straight solid-line bond
Figure PCTCN2022134641-appb-000011
and straight dashed keys
Figure PCTCN2022134641-appb-000012
Indicates the relative configuration of the stereocenter.
除非另有说明，X射线粉末衍射(XRPD)可检测晶型的变化、结晶度、晶构状态等信息，是鉴别晶型的常用手段。XRPD图谱的峰位置主要取决于晶型的结构，对实验细节相对不敏感，而其相对峰高取决于与样品制备和仪器几何形状有关的许多因素。因此，在一些实施方案中，本发明的晶型的特征在于具有某些峰位置的XRPD图，其基本上如本发明附图中提供的XRPD图所示。同时，XRPD图谱的2θ的量度可以有实验误差，不同仪器以及不同样品之间，XRPD图谱的2θ的量度可能会略有差别，因此所述2θ的数值不能视为绝对的。根据本试验所用仪器状况，衍射峰存在±0.20°的误差容限。Unless otherwise specified, X-ray powder diffraction (XRPD) can detect information such as changes in crystal forms, crystallinity, and crystal structure state, and is a common method for identifying crystal forms. The peak positions of an XRPD pattern mainly depend on the structure of the crystalline form and are relatively insensitive to experimental details, while their relative peak heights depend on many factors related to sample preparation and instrument geometry. Accordingly, in some embodiments, the crystalline forms of the present invention are characterized by XRPD patterns having certain peak positions substantially as shown in the XRPD patterns provided in the accompanying drawings of the present invention. At the same time, there may be experimental errors in the measurement of 2θ in the XRPD pattern, and there may be slight differences in the measurement of 2θ in the XRPD pattern between different instruments and different samples, so the value of 2θ in the XRPD pattern cannot be regarded as absolute. According to the condition of the instrument used in this test, there is an error tolerance of ±0.20° for the diffraction peaks.
本发明具体实施方式的化学反应是在合适的溶剂中完成的，所述的溶剂须适合于本发明的化学变化及其所需的试剂和物料。为了获得本发明的化合物，有时需要本领域技术人员在已有实施方式的基础上对合成步骤或者反应流程进行修改或选择。The chemical reactions of the specific embodiments of the present invention are completed in a suitable solvent, and the solvent must be suitable for the chemical changes of the present invention and the required reagents and materials. In order to obtain the compounds of the present invention, it is sometimes necessary for those skilled in the art to modify or select synthetic steps or reaction schemes on the basis of existing embodiments.
下面会通过实施例具体描述本发明，这些实施例并不意味着对本发明的任何限制。The present invention will be specifically described by examples below, and these examples do not imply any limitation to the present invention.
本发明的化合物可以通过本领域技术人员所熟知的常规方法来确认结构，如果本发明涉及化合物的绝对构型，则该绝对构型可以通过本领域常规技术手段予以确证。例如单晶X射线衍射法(SXRD)，把培养出的单晶用Bruker D8 venture衍射仪收集衍射强度数据，光源为CuKα辐射，扫描方式：
Figure PCTCN2022134641-appb-000013
扫描，收集相关数据后，进一步采用直接法(Shelxs97)解析晶体结构，便可以确证绝对构型。 The structure of the compounds of the present invention can be confirmed by conventional methods known to those skilled in the art. If the present invention involves the absolute configuration of the compound, the absolute configuration can be confirmed by conventional technical means in the art. For example, in single crystal X-ray diffraction (SXRD), the cultured single crystal is collected with a Bruker D8 venture diffractometer to collect diffraction intensity data, the light source is CuKα radiation, and the scanning method is:
Figure PCTCN2022134641-appb-000013
After scanning and collecting relevant data, the absolute configuration can be confirmed by further analyzing the crystal structure by direct method (Shelxs97).
本发明采用下述缩略词：ACN代表乙腈；DMSO代表二甲基亚砜；N 2：氮气；RH：相对湿度；mL：毫升；L：升；min：分钟；℃：摄氏度；μm：微米；mm：毫米；μL：微升；moL/L：摩尔每升；mg：毫克；s：秒；nm：纳米；MPa：兆帕；lux：勒克斯；μw/cm 2：微瓦每平方厘米；h：小时；Kg：千克；nM：纳摩尔，rpm：转速；XRPD代表X射线粉末衍射；DSC代表差示扫描量热分析；TGA代表热重分析；DVS：动态水分吸附分析； 1H NMR代表核磁共振氢谱；Solutol代表羟基硬脂酸酯。 The following abbreviations are used in the present invention: ACN stands for acetonitrile; DMSO stands for dimethylsulfoxide; N2 : nitrogen; RH: relative humidity; mL: milliliter; L: liter; min: minute; °C: degree Celsius; μm: micron ; mm: millimeter; μL: microliter; moL/L: mole per liter; mg: milligram; s: second; nm: nanometer; MPa: megapascal; lux: lux; μw/cm 2 : microwatt per square centimeter; h: hour; Kg: kilogram; nM: nanomole, rpm: rotational speed; XRPD stands for X-ray powder diffraction; DSC stands for differential scanning calorimetry; TGA stands for thermogravimetric analysis; DVS: Dynamic moisture adsorption analysis; 1 H NMR stands for Proton NMR; Solutol stands for hydroxystearate.
本发明化合物依据本领域常规命名原则或者使用
Figure PCTCN2022134641-appb-000014
软件命名，市售化合物采用供应商目录名称，本发明所使用的所有溶剂是市售可得的。 The compounds of the present invention are named according to the conventional naming principles in this field or used
Figure PCTCN2022134641-appb-000014
The software is named, the commercially available compounds adopt the supplier catalog name, and all the solvents used in the present invention are commercially available.
本发明仪器及分析方法Instrument and analysis method of the present invention
1.1X-射线粉末衍射(X-ray powder diffractometer,XRPD)方法1.1 X-ray powder diffraction (X-ray powder diffractometer, XRPD) method
测试方法：大约10mg样品用于XRPD检测。Test method: About 10 mg of sample is used for XRPD detection.
仪器型号一：DX-2700BH型X-射线衍射仪，详细的XRPD参数如下：Instrument model 1: DX-2700BH X-ray diffractometer, the detailed XRPD parameters are as follows:
射线源：Cu,k-α
Figure PCTCN2022134641-appb-000015
Ray source: Cu,k-α
Figure PCTCN2022134641-appb-000015
光管电压/光管电流：40kV/30mALight tube voltage/light tube current: 40kV/30mA
发散狭缝：1mmDivergence slit: 1mm
主光路轴向索拉狭缝：28mmMain optical path axial Sola slit: 28mm
次级光路轴向索拉狭缝：28mmSecondary Optical Path Axial Sola Slit: 28mm
探测器狭缝：0.3mmDetector slit: 0.3mm
防散射狭缝：1mmAnti-scatter slit: 1mm
扫描轴：θs-θdScan axis: θs-θd
步长：0.02degStep size: 0.02deg
每步停留时间：0.5秒Dwell time per step: 0.5 seconds
扫描角度范围：3-40degScanning angle range: 3-40deg
仪器型号二：PANalytical(X'Pert 3型)X-射线衍射仪，详细的XRPD参数如下： Instrument model 2: PANalytical (X'Pert 3 type) X-ray diffractometer, the detailed XRPD parameters are as follows:
X射线：Cu,kα，
Figure PCTCN2022134641-appb-000016
1.540598；
Figure PCTCN2022134641-appb-000017
1.544426；Kα2/Kα1＝0.50 X-ray: Cu, kα,
Figure PCTCN2022134641-appb-000016
1.540598;
Figure PCTCN2022134641-appb-000017
1.544426; Kα2/Kα1=0.50
光管电压/光管电流：45kV/40mALight tube voltage/light tube current: 45kV/40mA
发散狭缝：1/8度Divergence slit: 1/8 degree
扫描模式：连续Scan mode: continuous
扫描范围(2θ)：3-40°Scanning range (2θ): 3-40°
步长(2θ)：0.0263°Step size (2θ): 0.0263°
每步扫描时间：46.7秒Scan time per step: 46.7 seconds
1.2差式扫描量热法(Differential Scanning Calorimeter,DSC)和热重分析(Thermal Gravimetric Analyzer,TGA)1.2 Differential Scanning Calorimeter (DSC) and Thermal Gravimetric Analyzer (TGA)
仪器型号：差示扫描量热仪和热重分析仪，详细的参数如下表所示：Instrument model: differential scanning calorimeter and thermogravimetric analyzer, detailed parameters are shown in the table below:
表4 DSC和TGA仪器参数Table 4 DSC and TGA instrument parameters
Figure PCTCN2022134641-appb-000018
Figure PCTCN2022134641-appb-000018
1.3动态水分吸附分析(Dynamic Vapor Sorption,DVS)方法1.3 Dynamic Vapor Sorption (DVS) method
仪器型号：SMS DVS intrinsic动态水分吸附仪，详细的参数如下表所示：Instrument model: SMS DVS intrinsic dynamic moisture adsorption instrument, detailed parameters are shown in the table below:
表5 DVS仪器参数Table 5 DVS instrument parameters
Figure PCTCN2022134641-appb-000019
Figure PCTCN2022134641-appb-000019
引湿性评价分类如下表所示：The classification of hygroscopicity evaluation is shown in the table below:
表6 引湿性评价分类Table 6 Humidity evaluation classification
吸湿性分类Hygroscopicity Classification ΔW％ΔW%
潮解deliquescence 吸收足量水分形成液体Absorb enough water to form a liquid
极具吸湿性Very hygroscopic ΔW％≥15％ΔW%≥15%
有吸湿性Hygroscopic 15％>ΔW％≥2％15%>ΔW%≥2%
略有吸湿性slightly hygroscopic 2％>ΔW％≥0.2％2%>ΔW%≥0.2%
无或几乎无吸湿性No or almost no hygroscopicity ΔW％<0.2％ΔW%<0.2%
注：ΔW％表示受试品在25±1℃和80±2％RH下的吸湿增重。Note: ΔW% represents the moisture absorption weight gain of the test product at 25±1°C and 80±2%RH.
附图说明Description of drawings
图1为式(II)化合物A晶型的XRPD图谱。Fig. 1 is the XRPD spectrum of compound A crystal form of formula (II).
图2为式(II)化合物A晶型的DSC谱图。Fig. 2 is the DSC spectrum of the crystal form of compound A of formula (II).
图3为式(II)化合物A晶型的TGA谱图。Fig. 3 is the TGA spectrum of the crystal form of compound A of formula (II).
图4为式(I)化合物B晶型的XRPD谱图。Fig. 4 is the XRPD spectrum of the crystal form of compound B of formula (I).
图5为式(I)化合物B晶型的DSC谱图。Fig. 5 is the DSC spectrum of the crystal form of compound B of formula (I).
图6为式(I)化合物B晶型的TGA谱图。Fig. 6 is a TGA spectrum of the crystal form of compound B of formula (I).
图7为式(I)化合物C晶型的XRPD谱图。Fig. 7 is the XRPD spectrum of the crystal form C of the compound of formula (I).
图8为式(I)化合物C晶型的DSC谱图。Fig. 8 is a DSC spectrum of the crystal form C of the compound of formula (I).
图9为式(I)化合物C晶型的TGA谱图。Fig. 9 is a TGA spectrum of the crystal form C of the compound of formula (I).
图10为式(II)化合物A晶型的DVS谱图。Fig. 10 is a DVS spectrum of compound A crystal form of formula (II).
图11为式(I)化合物的立体结构椭球图。Fig. 11 is an ellipsoid diagram of the three-dimensional structure of the compound of formula (I).
具体实施方式Detailed ways
下面通过实施例对本发明进行详细描述，但并不意味着对本发明任何不利限制。本文已经详细地描述了本发明，其中也公开了其具体实施例方式，对本领域的技术人员而言，在不脱离本发明精神和范围的情况下针对本发明具体实施方式进行各种变化和改进将是显而易见的。The present invention will be described in detail through examples below, but it does not imply any unfavorable limitation to the present invention. The present invention has been described in detail herein, and its specific embodiments are also disclosed. For those skilled in the art, various changes and improvements can be made to the specific embodiments of the present invention without departing from the spirit and scope of the present invention. will be obvious.
实施例1：式(I)化合物的制备Embodiment 1: the preparation of formula (I) compound
Figure PCTCN2022134641-appb-000020
Figure PCTCN2022134641-appb-000020
Figure PCTCN2022134641-appb-000021
Figure PCTCN2022134641-appb-000021
步骤1：将碳酸钾(5.1g,37.0mmol)加入到苄硫醇(1.5g,12.3mmol)的二甲基甲酰胺(30mL)溶液中，25℃搅拌5分钟后加入化合物1-1(3.0g,12.4mmol)。反应升温至100℃继续搅拌5小时后降至25℃，加入水(60mL)淬灭，乙酸乙酯萃取(60mL*3)，合并后有机相用饱和食盐水(200mL)洗涤，无水硫酸钠干燥，过滤，减压浓缩得化合物1-2直接用于下一步反应。 1H NMR(400MHz,CDCl 3)δ＝7.51(s,1H),7.20-7.33(m,5H),4.35(s,2H)。MS ESI计算值C 10H 8BrNS 2[M+H；M+H+2] +286；288，实测值286；288。 Step 1: Add potassium carbonate (5.1g, 37.0mmol) to a solution of benzylthiol (1.5g, 12.3mmol) in dimethylformamide (30mL), stir at 25°C for 5 minutes and then add compound 1-1 (3.0 g, 12.4 mmol). The temperature of the reaction was raised to 100°C and continued to stir for 5 hours, then lowered to 25°C, quenched by adding water (60mL), extracted with ethyl acetate (60mL*3), the combined organic phase was washed with saturated brine (200mL), anhydrous sodium sulfate After drying, filtering and concentrating under reduced pressure, compound 1-2 was directly used in the next reaction. 1 H NMR (400 MHz, CDCl 3 ) δ=7.51 (s, 1H), 7.20-7.33 (m, 5H), 4.35 (s, 2H). MS ESI calcd for C10H8BrNS2 [M+H; M+H + 2] + 286; 288 , found 286; 288.
步骤2：在预先干燥的反应瓶中加入化合物1-2(1.0g,3.5mmol)，乙酸(10mL)，水(5mL)和二氯海因(2.8g,14.0mmol)，反应在40℃搅拌1.5小时。反应完成后向反应液加入水(20mL)淬灭，二氯甲烷(20mL*3)萃取，合并后的有机相用饱和食盐水(30mL)洗涤，有机相无水硫酸钠干燥，过滤，滤液减压浓缩。残余物中加入石油醚(1mL)和乙酸乙酯(1mL)，搅拌10分钟后过滤，滤液减压浓缩得化合物1-3立即用于下一步。Step 2: Add compound 1-2 (1.0g, 3.5mmol), acetic acid (10mL), water (5mL) and dichlorohydantoin (2.8g, 14.0mmol) into a pre-dried reaction flask, and stir the reaction at 40°C 1.5 hours. After the reaction was completed, water (20 mL) was added to the reaction solution to quench, dichloromethane (20 mL*3) was extracted, the combined organic phase was washed with saturated brine (30 mL), the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was reduced Concentrate under pressure. Petroleum ether (1 mL) and ethyl acetate (1 mL) were added to the residue, stirred for 10 minutes and then filtered. The filtrate was concentrated under reduced pressure to obtain compound 1-3 which was immediately used in the next step.
步骤3：将化合物1-3(800.0mg,3.1mmol)溶于1,2-二氯乙烷(10mL)中，加入二苄胺(2.4g,12.2mmol)。反应于80℃搅拌12小时后降至25℃，向反应液中加入水(40mL)淬灭，用乙酸乙酯(40mL*3)萃取，合并后有机相用饱和食盐水(100mL)洗涤，无水硫酸钠干燥，过滤，减压浓缩。残余物经柱层析分离(二氯甲烷：甲醇＝20:1)得化合物1-4。MS ESI计算值C 17H 15BrN 2O 2S 2[M+H；M+H+2] +423；425，实测值423；425。 Step 3: Compound 1-3 (800.0 mg, 3.1 mmol) was dissolved in 1,2-dichloroethane (10 mL), and dibenzylamine (2.4 g, 12.2 mmol) was added. The reaction was stirred at 80°C for 12 hours and then dropped to 25°C, quenched by adding water (40mL) to the reaction solution, extracted with ethyl acetate (40mL*3), and the combined organic phases were washed with saturated brine (100mL). Dry over sodium sulfate, filter, and concentrate under reduced pressure. The residue was separated by column chromatography (dichloromethane:methanol=20:1) to obtain compound 1-4. MS ESI calcd for C17H15BrN2O2S2 [M+H; M+H + 2] + 423; 425, found 423 ; 425 .
步骤4：在预先干燥的反应瓶中加入化合物1-4(390.0mg,992.1μmol)，1,4-二氧六环(10mL)，化合物1-5(138.6mg,1.5mmol)和碳酸铯(969.7mg,2.9mmol)，最后加入4,5-双二苯基膦-9,9-二甲基氧杂蒽(114.8mg,198.4μmol)和三(二亚苄基丙酮)二钯(90.8mg,99.2μmol)。反应在氮气保护下于110℃搅拌2小时降温至25℃，向反应液中加水(20mL)淬灭，用乙酸乙酯(20mL*3)萃取，合并后有机相用饱和食盐水(20mL*3)洗涤，无水硫酸钠干燥，过滤，减压浓缩。残余物经柱层析分离(二氯甲烷：甲醇＝10:1)得化合物1-6。MS ESI计算值C 19H 21N 3O 3S 3[M+H] +436，实测值436。 Step 4: Add compound 1-4 (390.0mg, 992.1μmol), 1,4-dioxane (10mL), compound 1-5 (138.6mg, 1.5mmol) and cesium carbonate ( 969.7mg, 2.9mmol), and finally added 4,5-bisdiphenylphosphine-9,9-dimethylxanthene (114.8mg, 198.4μmol) and tris(dibenzylideneacetone)dipalladium (90.8mg ,99.2μmol). The reaction was stirred at 110°C for 2 hours under the protection of nitrogen and cooled to 25°C, quenched by adding water (20mL) to the reaction solution, extracted with ethyl acetate (20mL*3), and combined the organic phases with saturated brine (20mL*3 ), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was separated by column chromatography (dichloromethane:methanol=10:1) to obtain compound 1-6. MS ESI calcd. for C19H21N3O3S3 [ M + H] + 436, found 436 .
步骤5：将化合物1-6(150mg,344.3μmol)溶于二氯甲烷(1mL)中，加入浓硫酸(1mL,浓度98％)。25℃反应0.5小时。反应完成后将反应液缓慢倒入冰水(5mL)中，用2mol/L的氢氧化钠溶液调节pH＝4～5，减压浓缩得残余物经柱层析分离(二氯甲烷：甲醇＝20:1)得化合物1-7。MS ESI计算值C 5H 9N 3O 3S 3[M+H] +256，实测值256。 Step 5: Compound 1-6 (150 mg, 344.3 μmol) was dissolved in dichloromethane (1 mL), and concentrated sulfuric acid (1 mL, concentration 98%) was added. React at 25°C for 0.5 hours. After the reaction was completed, the reaction solution was slowly poured into ice water (5 mL), adjusted to pH=4-5 with 2 mol/L sodium hydroxide solution, and concentrated under reduced pressure to obtain a residue that was separated by column chromatography (dichloromethane:methanol= 20:1) Compound 1-7 was obtained. MS ESI calcd . for C5H9N3O3S3 [M+H] +256 , found 256 .
步骤6：将化合物1-7(200.0mg,783.3μmol)溶于四氢呋喃(20mL)中，在0℃下加入氢化钠(78.3mg,1.9mmol,60％纯度)搅拌0.5小时，然后加入叔丁基二甲基氯硅烷(141.6mg,939.9μmol)，25℃搅拌1小时，反应完毕后用饱和氯化铵溶液(5mL)淬灭，乙酸乙酯(30mL*2)萃取，合并后有机相用无水硫酸钠干燥，浓 缩后残余物经柱层析分离(二氯甲烷：甲醇＝20:1)得化合物1-8。MS ESI计算值C 11H 23N 3O 3S 3Si[M+H] +370，实测值370。 Step 6: Dissolve compound 1-7 (200.0mg, 783.3μmol) in tetrahydrofuran (20mL), add sodium hydride (78.3mg, 1.9mmol, 60% purity) at 0°C and stir for 0.5 hours, then add tert-butyl Dimethylchlorosilane (141.6mg, 939.9μmol), stirred at 25°C for 1 hour, quenched with saturated ammonium chloride solution (5mL) after the reaction, extracted with ethyl acetate (30mL*2), combined the organic phase with Dry over sodium sulfate, concentrate and the residue is separated by column chromatography (dichloromethane:methanol=20:1) to obtain compound 1-8. MS ESI calcd . for C11H23N3O3S3Si [M+H] + 370, found 370 .
步骤7：将三乙胺(260.7mg,2.5mmol)于25℃下滴加到二氯三苯基膦(429.3mg,1.3mmol)的氯仿(10mL)溶液中，搅拌10分钟后降温至0℃加入化合物1-8(190.0mg,515.5μmol)的氯仿(3mL)溶液，反应于0℃下继续搅拌0.5小时。往该体系中通氨气15分钟后升温至25℃搅拌1小时。反应完毕后，将浓缩得化合物1-9，直接用于下一步反应。MS ESI计算值C 11H 24N 4O 2S 3Si[M+H] +369，实测值369。 Step 7: Add triethylamine (260.7mg, 2.5mmol) dropwise to a solution of dichlorotriphenylphosphine (429.3mg, 1.3mmol) in chloroform (10mL) at 25°C, stir for 10 minutes and cool down to 0°C A solution of compound 1-8 (190.0 mg, 515.5 μmol) in chloroform (3 mL) was added, and the reaction was stirred at 0° C. for 0.5 hours. Ammonia gas was passed through the system for 15 minutes, then the temperature was raised to 25°C and stirred for 1 hour. After the reaction was completed, the concentrated compound 1-9 was directly used in the next reaction. MS ESI calcd . for C11H24N4O2S3Si [ M+H]+ 369 , found 369 .
步骤8：将氢化钠(78.13mg,1.95mmol,60％纯度)加入到化合物1-9(180.0mg,488.32μmol)的四氢呋喃(20mL)溶液中，在25℃下搅拌0.5小时，再将化合物1-10(97.3mg,488.3μmol)加到体系中继续搅拌1小时。反应完毕后得化合物1-11的反应液直接用于下一步。MS ESI计算值C 24H 37N 5O 3S 3Si[M+H] +568，实测值568。 Step 8: Sodium hydride (78.13mg, 1.95mmol, 60% purity) was added to a solution of compound 1-9 (180.0mg, 488.32μmol) in tetrahydrofuran (20mL), stirred at 25°C for 0.5 hours, and compound 1 -10 (97.3mg, 488.3μmol) was added to the system and stirred for 1 hour. After the reaction was completed, the reaction solution of compound 1-11 was directly used in the next step. MS ESI calcd. for C24H37N5O3S3Si [ M+H]+ 568 , found 568 .
步骤9：于0℃下向上述化合物1-11的反应液中滴加浓盐酸(5.0mL，浓度37％)并搅拌10分钟，反应完毕后用乙酸乙酯(30mL)萃取，有机相用无水硫酸钠干燥。得的粗品经柱层析分离(二氯甲烷：甲醇＝10:1)得化合物1。MS ESI计算值C 18H 23N 5O 3S 3[M+H] +454，实测值454。 Step 9: Add concentrated hydrochloric acid (5.0 mL, concentration 37%) dropwise to the reaction solution of the above compound 1-11 at 0°C and stir for 10 minutes. water and sodium sulfate to dry. The obtained crude product was separated by column chromatography (dichloromethane:methanol=10:1) to obtain compound 1. MS ESI calcd. for C18H23N5O3S3 [ M+H]+ 454 , found 454 .
步骤10：化合物1(20mg)经制备超临界流体色谱法分离(色谱柱:DAICEL CHIRALCEL OD(250mm*50mm,10μm)；流动相:[A:二氧化碳，B:[0.1％氨水-甲醇]；梯度：B％:30％-30％)得到式(I)化合物(SFC分析方法：色谱柱:Chiralpak AS-3 150mm*4.6mm I.D.,3μm；流动相:[A:二氧化碳，B:乙醇(0.05％二乙胺)]；梯度：B％：5％～40％,5min；B％：40％,2.5min；B％：5％,2.5min，保留时间5.53min，ee＝100％)。 1H NMR(400MHz,DMSO-d 6)δppm 8.41(brs,1H),7.73(brs,2H),7.23(s,1H),6.87(s,1H),3.35(s,6H),2.78(brt,J＝7.3Hz,4H),2.67(brs,4H),1.86-1.97(m,4H).MS ESI计算值C 18H 23N 5O 3S 3[M+H] +454，实测值454。 Step 10: Compound 1 (20 mg) was separated by preparative supercritical fluid chromatography (column: DAICEL CHIRALCEL OD (250mm*50mm, 10 μm); mobile phase: [A: carbon dioxide, B: [0.1% ammonia water-methanol]; gradient : B%: 30%-30%) obtain formula (I) compound (SFC analysis method: chromatographic column: Chiralpak AS-3 150mm*4.6mm ID, 3 μ m; Mobile phase: [A: carbon dioxide, B: ethanol (0.05% Diethylamine)]; Gradient: B%: 5%-40%, 5min; B%: 40%, 2.5min; B%: 5%, 2.5min, retention time 5.53min, ee=100%). 1 H NMR (400MHz,DMSO-d 6 )δppm 8.41(brs,1H),7.73(brs,2H),7.23(s,1H),6.87(s,1H),3.35(s,6H),2.78(brt , J＝7.3Hz, 4H), 2.67(brs, 4H), 1.86-1.97(m, 4H) . MS ESI calculated value C 18 H 23 N 5 O 3 S 3 [M+H] + 454, measured value 454 .
实施例2：式(I)化合物钠盐的制备Embodiment 2: the preparation of formula (I) compound sodium salt
将式(I)化合物(80mg,176.37μmol)悬浮于水(2mL)中，再加入氢氧化钠水溶液(0.1M，1.76mL)，溶解，25℃搅拌1小时后，冷冻干燥得到式(I)化合物钠盐。Suspend the compound of formula (I) (80mg, 176.37μmol) in water (2mL), add aqueous sodium hydroxide solution (0.1M, 1.76mL), dissolve, stir at 25°C for 1 hour, freeze-dry to obtain formula (I) Compound sodium salt.
实施例3：式(II)化合物A晶型的制备Embodiment 3: Preparation of formula (II) compound A crystal form
方法一：向式(I)化合物(90g)悬浮于丙酮/水混合溶剂(1350mL,2:1,v/v)，25-30℃下搅拌24小时，过滤，将滤饼悬浮于水(1350mL)中，25-30℃下搅拌24小时，减压过滤，将滤饼于40℃、<-0.09MPa下真空干燥48小时，得到固体，经XRPD测试为式(II)化合物A晶型。XRPD谱图如图1所示，DSC谱图如图2所示，TGA谱图如图3所示。Method 1: Suspend the compound of formula (I) (90g) in acetone/water mixed solvent (1350mL, 2:1, v/v), stir at 25-30°C for 24 hours, filter, and suspend the filter cake in water (1350mL ), stirred at 25-30°C for 24 hours, filtered under reduced pressure, and vacuum-dried the filter cake at 40°C and <-0.09MPa for 48 hours to obtain a solid, which was the crystal form of compound A of formula (II) by XRPD test. The XRPD spectrum is shown in FIG. 1 , the DSC spectrum is shown in FIG. 2 , and the TGA spectrum is shown in FIG. 3 .
方法二：向式(I)化合物(20mg)悬浮于丙酮/水混合溶剂(1.2mL,2:1,v/v)，25-50℃下搅拌24小时，离心分离得到固体，经XRPD测试为式(II)化合物A晶型。Method 2: Suspend the compound of formula (I) (20mg) in acetone/water mixed solvent (1.2mL, 2:1, v/v), stir at 25-50°C for 24 hours, and centrifuge to obtain a solid, which is tested by XRPD as Formula (II) compound A crystal form.
方法三：向式(I)化合物(20mg)中加入二甲基亚砜，室温下溶解，然后缓慢滴加异丙醇直到固体出现，离心分离得到固体，经XRPD测试为式(II)化合物A晶型。Method 3: Add dimethyl sulfoxide to the compound of formula (I) (20 mg), dissolve at room temperature, then slowly add isopropanol dropwise until the solid appears, and centrifuge to obtain the solid, which is the compound A of formula (II) by XRPD crystal form.
方法四：向式(I)化合物(20mg)中加入N,N-二甲基甲酰胺，室温下溶解，然后缓慢滴加水直到固体出现，离心分离得到固体，经XRPD测试为式(II)化合物A晶型。Method 4: Add N,N-dimethylformamide to the compound of formula (I) (20 mg), dissolve at room temperature, then slowly add water dropwise until the solid appears, and centrifuge to obtain a solid, which is the compound of formula (II) by XRPD Form A.
实施例4：式(I)化合物B晶型的制备Embodiment 4: Preparation of formula (I) compound B crystal form
将式(II)化合物A晶型(20mg)加入甲醇(1.2mL)中，室温悬浮搅拌约5天后获得，将固体转至室 温敞口(室温：18-20℃，湿度：25-35％RH)干燥约1天后，得到固体，经XRPD测试为式(I)化合物B晶型。XRPD谱图如图4所示，DSC谱图如图5所示，TGA谱图如图6所示。Add the compound A crystal form (20mg) of formula (II) into methanol (1.2mL), suspend and stir at room temperature for about 5 days, and turn the solid to room temperature to expose (room temperature: 18-20°C, humidity: 25-35%RH ) after drying for about 1 day, a solid was obtained, which was the crystal form of compound B of formula (I) by XRPD test. The XRPD spectrum is shown in Figure 4, the DSC spectrum is shown in Figure 5, and the TGA spectrum is shown in Figure 6.
实施例5：式(I)化合物C晶型的制备Embodiment 5: Preparation of Formula (I) Compound C Crystal Form
将式(II)化合物A晶型(20mg)加入间二甲苯/乙酸乙酯(1.2mL，1:1,v/v)中，50℃悬浮搅拌约4天后获得，转至室温敞口(室温：21-23℃，室湿：43-46％RH)干燥约2天后，得到固体，经XRPD测试为式(I)化合物C晶型。XRPD谱图如图7所示，DSC谱图如图8所示，TGA谱图如图9所示。Add the compound A crystal form (20mg) of formula (II) into m-xylene/ethyl acetate (1.2mL, 1:1, v/v), obtain it after suspending and stirring at 50°C for about 4 days, and open it at room temperature (room temperature : 21-23° C., room humidity: 43-46% RH) After drying for about 2 days, a solid was obtained, which was the crystal form of compound C of formula (I) by XRPD test. The XRPD spectrum is shown in FIG. 7 , the DSC spectrum is shown in FIG. 8 , and the TGA spectrum is shown in FIG. 9 .
实施例6：式(I)化合物的单晶X射线衍射检测分析Embodiment 6: Single crystal X-ray diffraction detection analysis of the compound of formula (I)
Figure PCTCN2022134641-appb-000022
Figure PCTCN2022134641-appb-000022
取式(I)化合物(0.0154g)溶解于甲醇(2mL)中，加入DMSO(0.25mL)，将样品溶液置于4mL半密封样品瓶中，在室温下缓慢挥发。20天后得到无色针状晶体。收集晶体，用Bruker D8VENTURE衍射仪收集衍射强度数据。单晶数据显示，单晶为式(I)化合物，可以确定式(I)化合物的绝对构型。式(I)化合物的立体结构椭球图见附图11。式(I)化合物的晶体结构数据和参数见表7。Dissolve the compound of formula (I) (0.0154g) in methanol (2mL), add DMSO (0.25mL), place the sample solution in a 4mL semi-sealed sample bottle, and slowly evaporate at room temperature. After 20 days, colorless needle-like crystals were obtained. Crystals were collected and diffraction intensity data were collected with a Bruker D8VENTURE diffractometer. The single crystal data show that the single crystal is the compound of formula (I), and the absolute configuration of the compound of formula (I) can be determined. The three-dimensional structural ellipsoid diagram of the compound of formula (I) is shown in accompanying drawing 11. The crystal structure data and parameters of the compound of formula (I) are shown in Table 7.
表7 式(I)化合物的晶体数据Table 7 The crystal data of the compound of formula (I)
Figure PCTCN2022134641-appb-000023
Figure PCTCN2022134641-appb-000023
实施例7：式(II)化合物A晶型的固体稳定性试验Embodiment 7: the solid stability test of formula (II) compound A crystal form
依据《原料药与制剂稳定性试验指导原则》(中国药典2020版四部通则9001)，为评估式(II)化合物A晶型的固体稳定性，对A晶型进行了影响因素(高温、高湿及光照)、60℃/75％RH及40℃/75％RH条件的稳定性考察。将A晶型分别在高温(60℃，敞口)、高湿(25℃/92.5％RH，敞口)条件下各放置10天，按照ICH条件(可见光总照度达到1200000Lux·hrs、紫外光总照度达到200W·hrs/m 2)敞口放置在可见光及紫外光下(遮光对照组样品同时放置并用锡箔纸包裹)，在60℃/75％RH(敞口)条件下放置1、2个月，在40℃/75％RH(敞 口)条件下放置1、2个月。对所有稳定性样品进行了XRPD测试，以检测晶型的变化。 According to the "Guiding Principles for Stability Testing of Raw Materials and Preparations" (Chinese Pharmacopoeia 2020 Edition IV General Rule 9001), in order to evaluate the solid stability of the crystal form A of the compound of formula (II), the influencing factors (high temperature, high humidity, etc.) of the crystal form A were evaluated. and light), 60°C/75%RH and 40°C/75%RH conditions. Place the crystal form A under high temperature (60°C, open) and high humidity (25°C/92.5%RH, open) conditions for 10 days respectively, according to the ICH conditions (total illuminance of visible light reaches 1200000Lux·hrs, total ultraviolet light The illuminance reaches 200W·hrs/m 2 ) exposed to visible light and ultraviolet light (the samples of the shading control group are placed at the same time and wrapped in tin foil), and placed under the condition of 60°C/75%RH (open) for 1 or 2 months , Stored at 40°C/75%RH (open) for 1 or 2 months. XRPD testing was performed on all stability samples to detect changes in crystalline form.
准确称取该晶型约10mg置于干燥洁净的玻璃瓶中，摊成薄薄一层，敞口放置于影响因素试验条件下和加速条件下。光照(可见光1200000Lux·hrs，紫外200W·hrs/m 2)条件下放置的样品采用透明玻璃瓶，完全暴露，用于XRPD检测的样品单独放置。结果如表8所示。 Accurately weigh about 10 mg of the crystal form and place it in a dry and clean glass bottle, spread it into a thin layer, and place it open under the influence factor test conditions and accelerated conditions. The samples placed under the condition of light (visible light 1200000Lux·hrs, ultraviolet 200W·hrs/m 2 ) are in transparent glass bottles, fully exposed, and the samples for XRPD detection are placed separately. The results are shown in Table 8.
表8 式(II)化合物A晶型的固体稳定性试验结果Table 8 The solid stability test results of formula (II) compound A crystal form
Figure PCTCN2022134641-appb-000024
Figure PCTCN2022134641-appb-000024
结论：式(II)化合物A晶型在所有稳定性(高温，高湿，光照)条件下晶型均未发生明显变化，具有较好的稳定性。Conclusion: The crystal form of compound A of formula (II) does not change significantly under all stability conditions (high temperature, high humidity, light) and has good stability.
实施例8：式(II)化合物A晶型的吸湿性研究Embodiment 8: Research on the hygroscopicity of formula (II) compound A crystal form
实验材料：Experimental Materials:
SMS DVS intrinsic动态水分吸附仪SMS DVS intrinsic dynamic moisture adsorption instrument
实验方法：experimental method:
取式(II)化合物A晶型(约10mg)置于DVS样品盘内进行测试。Take the crystal form of compound A (about 10 mg) of formula (II) and place it in the DVS sample disk for testing.
实验结果：Experimental results:
式(II)化合物A晶型的DVS谱图如图10所示，在80％RH/25℃下的吸湿增重ΔW％为1.5％。The DVS spectrum of compound A crystal form of formula (II) is shown in Figure 10, and the moisture absorption weight gain ΔW% at 80%RH/25°C is 1.5%.
实验结论：Experimental results:
式(II)化合物A晶型在80％RH/25℃下的吸湿增重2％>ΔW％≥0.2％，略有吸湿性。The hygroscopic weight gain of compound A crystal form of formula (II) at 80%RH/25°C is 2%>ΔW%≥0.2%, which is slightly hygroscopic.
生物测试数据：Biological test data:
实验例1：利用THP-1细胞检测NLRP3拮抗剂的IC 50实验 Experimental example 1: IC 50 experiment of detecting NLRP3 antagonists using THP-1 cells
供实验用的本发明化合物其化学名称和结构式见各化合物的制备实施例。For the chemical names and structural formulas of the compounds of the present invention used in experiments, see the preparation examples of each compound.
1.实验原理：本实验利用人源的单核细胞系THP1，来研究NLRP3拮抗剂对细胞IL-1β分泌的抑制活性(IC 50)。利用PMA(巴豆醇-12-十四烷酸酯-13-乙酸酯)分化单核细胞系THP1变成成熟的巨噬细胞，然后利用Toll样受体TLR4的激动剂LPS(脂多糖)来对细胞进行刺激，激活炎症小体NLRP3的转录活性，以及IL-1β前体pro-IL-1β的表达。在此时，加入NLRP3的拮抗剂，然后再加入ATP来使得NLRP3进一步成熟和活化，并激活下游的caspase-1。活化的caspase-1可以对pro-IL-1β进行酶切加工成为可被分泌的成熟IL-1β。NLRP3拮抗剂可以有效抑制ATP诱导的NLRP3的成熟和活化，以及下游caspase-1的活化，从而抑制IL-1β的成熟和分泌。 1. Experimental principle: In this experiment, the human monocyte cell line THP1 was used to study the inhibitory activity (IC 50 ) of NLRP3 antagonists on the secretion of IL-1β. Using PMA (crotyl alcohol-12-myristate-13-acetate) to differentiate monocyte cell line THP1 into mature macrophages, and then using LPS (lipopolysaccharide), an agonist of Toll-like receptor TLR4, to Stimulation of the cells activates the transcriptional activity of the inflammasome NLRP3 and the expression of pro-IL-1β, the precursor of IL-1β. At this time, an antagonist of NLRP3 was added, followed by ATP to further mature and activate NLRP3 and activate downstream caspase-1. Activated caspase-1 can enzymatically process pro-IL-1β into mature IL-1β that can be secreted. NLRP3 antagonists can effectively inhibit the ATP-induced maturation and activation of NLRP3, as well as the activation of downstream caspase-1, thereby inhibiting the maturation and secretion of IL-1β.
2.实验材料：2. Experimental materials:
试剂和仪器信息见表9。See Table 9 for reagent and instrument information.
表9 试剂和仪器信息Table 9 Reagent and instrument information
名称name 供应商supplier 货号或编号Item number or serial number 储存条件Storage conditions
PMAPMA SigmaSigma 7934679346 -20℃-20°C
LPSLPS InvivoGenInvivoGen tlrl-eblpstlrl-eblps -20℃-20°C
ATPATP -- -- -20℃-20°C
1640培养基1640 Medium GibcoGibco 22400-08922400-089 4℃4°C
FBSFBS HyCloneHyClone SV30087.03SV30087.03 -80℃-80°C
青链霉素 Penicillin HyCloneHyClone SV30010SV30010 4℃4°C
β-巯基乙醇β-mercaptoethanol SigmaSigma M3148M3148 室温room temperature
NEAA非必需氨基酸NEAA non-essential amino acids GibcoGibco 1140-0501140-050 4℃4°C
人可溶性蛋白试剂盒Human Soluble Protein Kit BDBD 558265558265 室温room temperature
Human IL-1βFlex SetHuman IL-1βFlex Set BDBD 558279558279 室温room temperature
96孔平底板96-well flat bottom plate CorningCorning 35993599 室温room temperature
96孔U底板96-well U-bottom plate CorningCorning 37993799 室温room temperature
流式细胞仪Flow Cytometry BDBD LSRFortessaLSR Fortessa --
3.实验步骤：3. Experimental steps:
(1)将THP1细胞的密度调整到5*10 5细胞/mL，然后加入PMA，并且将终浓度调整为100ng/mL，200μL/孔接种至96孔平底板，37℃、5％CO 2刺激过夜(尽量<16小时)。 (1) Adjust the density of THP1 cells to 5*10 5 cells/mL, then add PMA, and adjust the final concentration to 100 ng/mL, inoculate 200 μL/well into a 96-well flat-bottom plate, stimulate at 37°C, 5% CO 2 Overnight (<16 hours if possible).
(2)第二天，将上清弃掉，然后小心用杜氏磷酸盐缓冲液清洗两次(200μL/次)。(2) The next day, the supernatant was discarded, and then carefully washed twice with Duchenne's phosphate buffered saline (200 μL/time).
(3)用LPS刺激细胞，LPS终浓度为：100ng/mL，200μL/孔加入96孔板，37℃、5％CO 2培养3h。 (3) The cells were stimulated with LPS, the final concentration of LPS was 100ng/mL, 200 μL/well was added to a 96-well plate, and cultured at 37° C., 5% CO 2 for 3 hours.
(4)将测试化合物加入孔内，筛选浓度分别为：5μM、1μM、200nM、40nM、8nM、1.6nM、0.32nM、0.064nM。在37℃、5％CO 2培养箱内孵育1h。 (4) Add test compounds into the wells, and the screening concentrations are: 5 μM, 1 μM, 200 nM, 40 nM, 8 nM, 1.6 nM, 0.32 nM, 0.064 nM. Incubate for 1 h at 37°C in a 5% CO 2 incubator.
(5)每孔加入ATP，终浓度为5mM，37℃、5％CO 2培养过夜(>18小时)。 (5) Add ATP to each well with a final concentration of 5 mM, and culture overnight (>18 hours) at 37° C. and 5% CO 2 .
(6)第三天，取出上清5μL，稀释10倍，并利用CBA检测上清中IL-1β的含量。(6) On the third day, 5 μL of the supernatant was taken out, diluted 10 times, and the content of IL-1β in the supernatant was detected by CBA.
4.实验结果：4. Experimental results:
化合物活性结果见表10。The activity results of the compounds are shown in Table 10.
表10 化合物NLRP3拮抗剂抑制活性结果Table 10 Compound NLRP3 antagonist inhibitory activity results
化合物compound THP-1细胞IL-1β抑制活性IC 50(nM) IC 50 (nM) of THP-1 cell IL-1β inhibitory activity
式(I)化合物Compound of formula (I) 9.89.8
实验结论：本发明化合物展示了良好的NLRP3抑制活性。Experimental conclusion: the compound of the present invention exhibits good NLRP3 inhibitory activity.
实验例2：化合物药代动力学评价Experimental Example 2: Pharmacokinetic Evaluation of Compounds
实验目的：测试化合物在小鼠体内药代动力学The purpose of the experiment: to test the pharmacokinetics of the compound in mice
实验材料：C57BL/6J小鼠(雄性，6-8周龄)Experimental material: C57BL/6J mice (male, 6-8 weeks old)
实验操作：将试验化合物溶解后得到的澄清溶液分别经尾静脉注射和灌胃(溶媒为10％DMSO/10％solutol/80％水)给予雌性C57BL/6J小鼠体内(过夜禁食，6-8周龄)。给予受试化合物或对照化合物后，静脉注射组(IV)在0.0833，0.25，0.5，1，2，4，8和24小时，灌胃组(PO)在0.25，0.5，1，2，4，6，8和24小时，分别从下颌静脉采血并离心后获得血浆。采用LC-MS/MS法测定血药浓度，使用WinNonlin TM Version 6.3药动学软件，以非房室模型线性对数梯形法计算相关药代动力学参数。各参数含义：T 1/2：半衰期；C max：达峰浓度；AUC 0-last：从0时间到最后能检测到药物浓度时的血浆浓度-时间曲线下面积；F％：生物利用度；Vd：表观分布容积；Cl：清除率；T max：达峰时间。测试结果如表11所示： Experimental operation: the clear solution obtained after dissolving the test compound was administered to female C57BL/6J mice via tail vein injection and intragastric administration (vehicle: 10% DMSO/10% solutol/80% water) (overnight fasting, 6- 8 weeks old). After giving test compound or control compound, intravenous injection group (IV) at 0.0833, 0.25, 0.5, 1, 2, 4, 8 and 24 hours, intragastric administration group (PO) at 0.25, 0.5, 1, 2, 4, At 6, 8 and 24 hours, blood was collected from the mandibular vein and centrifuged to obtain plasma. The blood drug concentration was determined by LC-MS/MS method, and relevant pharmacokinetic parameters were calculated by non-compartmental model linear logarithmic trapezoidal method using WinNonlin TM Version 6.3 pharmacokinetic software. The meaning of each parameter: T 1/2 : half-life; C max : peak concentration; AUC 0-last : the area under the plasma concentration-time curve from time 0 to the last time when the drug concentration can be detected; F%: bioavailability; Vd: apparent volume of distribution; Cl: clearance rate; T max : peak time. The test results are shown in Table 11:
表11 本发明化合物小鼠体内药代动力学测试结果Table 11 In vivo pharmacokinetic test results of compounds of the present invention in mice
Figure PCTCN2022134641-appb-000025
Figure PCTCN2022134641-appb-000025
“--”表示未测试。"--" means not tested.
结论：本发明的化合物具良好的口服生物利用度，较高的暴露量，药代动力学性质良好。Conclusion: The compound of the present invention has good oral bioavailability, high exposure and good pharmacokinetic properties.
实验例3：化合物药代动力学评价Experimental Example 3: Pharmacokinetic Evaluation of Compounds
实验目的：测试化合物在大鼠体内药代动力学The purpose of the experiment: to test the pharmacokinetics of the compound in rats
实验材料：SD大鼠(雄性，7-10周龄)Experimental material: SD rats (male, 7-10 weeks old)
实验操作：将试验化合物溶解后得到的澄清溶液分别经尾静脉注射(溶媒为5％Solutol/95％水)和灌胃(溶媒为5％Solutol/95％水pH＝9.48)给予雄性SD大鼠体内(自由进食)。给予受试化合物后，静脉注射组(IV) 在0.0833，0.25，0.5，1，2，4，8和24小时，灌胃组(PO)在0.25，0.5，1，2，4，6，8和24小时，分别从下颌静脉采血并离心后获得血浆。采用LC-MS/MS法测定血药浓度，使用WinNonlin TM Version 6.3药动学软件，以非房室模型线性对数梯形法计算相关药代动力学参数。各参数含义：T 1/2：半衰期；C max：达峰浓度；AUC 0-last：从0时间到最后能检测到药物浓度时的血浆浓度-时间曲线下面积；F：生物利用度，Vd：表观分布容积，Cl：清除率T max：达峰时间。测试结果如表12所示： Experimental operation: the clear solution obtained after dissolving the test compound was given to male SD rats via tail vein injection (vehicle 5% Solutol/95% water) and intragastric administration (vehicle 5% Solutol/95% water pH=9.48) In vivo (free feeding). After giving the test compound, the intravenous injection group (IV) was at 0.0833, 0.25, 0.5, 1, 2, 4, 8 and 24 hours, and the intragastric administration group (PO) was at 0.25, 0.5, 1, 2, 4, 6, 8 and 24 hours, blood was collected from the mandibular vein and centrifuged to obtain plasma. The blood drug concentration was determined by LC-MS/MS method, and the relevant pharmacokinetic parameters were calculated by the non-compartmental model linear logarithmic trapezoidal method using WinNonlin TM Version 6.3 pharmacokinetic software. The meaning of each parameter: T 1/2 : half-life; C max : peak concentration; AUC 0-last : the area under the plasma concentration-time curve from time 0 to the last time when the drug concentration can be detected; F: bioavailability, Vd : apparent volume of distribution, Cl: clearance rate T max : peak time. The test results are shown in Table 12:
表12 本发明化合物大鼠体内药代动力学测试结果Table 12 In vivo pharmacokinetic test results of compounds of the present invention in rats
Figure PCTCN2022134641-appb-000026
Figure PCTCN2022134641-appb-000026
结论：本发明的化合物具良好的口服生物利用度，较高的口服暴露量。Conclusion: the compound of the present invention has good oral bioavailability and higher oral exposure.
实验例4：化合物药代动力学评价Experimental Example 4: Pharmacokinetic Evaluation of Compounds
实验目的：测试化合物在比格犬体内药代动力学Purpose of the experiment: To test the pharmacokinetics of compounds in Beagle dogs
实验材料：比格犬(雄性，>6个月以上)Experimental material: Beagle (male, >6 months old)
实验操作：将试验化合物溶解后得到的澄清溶液分别经尾静脉注射(溶媒为in 5％Solutol/95％水，pH＝9.66)和灌胃(溶媒为5％Solutol/95％水，pH＝9.66)给予雄性性SD大鼠体内(自由进食)。给予受试化合物后，静脉注射组(IV)在0.0833，0.25，0.5，1，2，4，8和24小时，灌胃组(PO)在0.25，0.5，1，2，4，6，8和24小时，分别从下颌静脉采血并离心后获得血浆。采用LC-MS/MS法测定血药浓度，使用WinNonlin TM Version 6.3药动学软件，以非房室模型线性对数梯形法计算相关药代动力学参数。各参数含义：T 1/2：半衰期；C max：达峰浓度；AUC 0-last：从0时间到最后能检测到药物浓度时的血浆浓度-时间曲线下面积；F：生物利用度，Vd：表观分布容积，Cl：清除率T max：达峰时间。测试结果如表13所示： Experimental operation: the clear solution obtained after dissolving the test compound was injected through tail vein (vehicle is in 5% Solutol/95% water, pH=9.66) and intragastrically (vehicle is 5% Solutol/95% water, pH=9.66) ) were administered to male SD rats (free feeding). After giving the test compound, the intravenous injection group (IV) was treated at 0.0833, 0.25, 0.5, 1, 2, 4, 8 and 24 hours; and 24 hours, blood was collected from the mandibular vein and centrifuged to obtain plasma. The blood drug concentration was determined by LC-MS/MS method, and the relevant pharmacokinetic parameters were calculated by the non-compartmental model linear logarithmic trapezoidal method using WinNonlin TM Version 6.3 pharmacokinetic software. The meaning of each parameter: T 1/2 : half-life; C max : peak concentration; AUC 0-last : area under the plasma concentration-time curve from time 0 to the last time when the drug concentration can be detected; F: bioavailability, Vd : apparent volume of distribution, Cl: clearance rate T max : peak time. The test results are shown in Table 13:
表13 本发明化合物比格犬体内药代动力学测试结果Table 13 In vivo pharmacokinetic test results of compounds of the present invention in Beagle dogs
Figure PCTCN2022134641-appb-000027
Figure PCTCN2022134641-appb-000027
Figure PCTCN2022134641-appb-000028
Figure PCTCN2022134641-appb-000028
结论：本发明的化合物具有优异的口服生物利用度，较高的口服暴露量。Conclusion: The compound of the present invention has excellent oral bioavailability and higher oral exposure.

Claims (29)

  1. 式(II)化合物，A compound of formula (II),
    Figure PCTCN2022134641-appb-100001
    Figure PCTCN2022134641-appb-100001
    其中，m选自0～1.5。Wherein, m is selected from 0 to 1.5.
  2. 根据权利要求1所述的化合物，其中，m选自0，0.1，0.2，0.3，0.4，0.5，0.6，0.7，0.8，0.9，1.0，1.1，1.2，1.3，1.4和1.5；或者，m选自0.3，0.4，0.5，0.6，0.7和0.8；或者，m选自0.5。The compound according to claim 1, wherein m is selected from 0, 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4 and 1.5; or, m is selected from 0.3, 0.4, 0.5, 0.6, 0.7 and 0.8; alternatively, m is selected from 0.5.
  3. 根据权利要求1或2所述的式(II)化合物的A晶型，A crystal form of the compound of formula (II) according to claim 1 or 2,
    Figure PCTCN2022134641-appb-100002
    Figure PCTCN2022134641-appb-100002
    其特征在于，其Cu Kα辐射的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：15.26±0.20°，15.98±0.20°，17.54±0.20°，19.12±0.20°。It is characterized in that its Cu Kα radiation X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ angles: 15.26±0.20°, 15.98±0.20°, 17.54±0.20°, 19.12±0.20°.
  4. 根据权利要求3所述的A晶型，其Cu Kα辐射的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：8.74±0.20°，15.26±0.20°，15.98±0.20°，17.54±0.20°，19.12±0.20°，21.40±0.20°，22.86±0.20°，23.46±0.20°。According to claim 3, the X-ray powder diffraction pattern of its Cu Kα radiation has characteristic diffraction peaks at the following 2θ angles: 8.74±0.20°, 15.26±0.20°, 15.98±0.20°, 17.54±0.20° , 19.12±0.20°, 21.40±0.20°, 22.86±0.20°, 23.46±0.20°.
  5. 根据权利要求4所述的A晶型，其Cu Kα辐射的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：8.74±0.20°，10.86±0.20°，15.26±0.20°，15.98±0.20°，17.54±0.20°，19.12±0.20°，21.40±0.20°，22.86±0.20°，23.46±0.20°，24.78±0.20°，26.44±0.20°，32.32±0.20°。According to claim 4, the X-ray powder diffraction pattern of its Cu Kα radiation has characteristic diffraction peaks at the following 2θ angles: 8.74±0.20°, 10.86±0.20°, 15.26±0.20°, 15.98±0.20° , 17.54±0.20°, 19.12±0.20°, 21.40±0.20°, 22.86±0.20°, 23.46±0.20°, 24.78±0.20°, 26.44±0.20°, 32.32±0.20°.
  6. 根据权利要求5所述的A晶型，其Cu Kα辐射的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：7.34°，8.74°，10.86°，12.86°，15.26°，15.98°，17.54°，18.00°，19.12°，20.28°，20.90°，21.40°，21.82°，22.86°，23.46°，24.78°，25.54°，26.44°，27.44°，28.18°，30.98°，32.32°，33.20°。According to claim 5, the X-ray powder diffraction pattern of its Cu Kα radiation has characteristic diffraction peaks at the following 2θ angles: 7.34°, 8.74°, 10.86°, 12.86°, 15.26°, 15.98°, 17.54 °, 18.00°, 19.12°, 20.28°, 20.90°, 21.40°, 21.82°, 22.86°, 23.46°, 24.78°, 25.54°, 26.44°, 27.44°, 28.18°, 30.98°, 32.32°, 33.20°.
  7. 根据权利要求6所述的A晶型，其XRPD图谱如图1所示。According to the crystal form A according to claim 6, its XRPD pattern is as shown in Figure 1 .
  8. 根据权利要求3～7任意一项所述的A晶型，其差示扫描量热曲线在67.13℃±5℃和163.06℃±5℃处具有吸热峰的起始点。According to the crystal form A described in any one of claims 3-7, its differential scanning calorimetry curve has start points of endothermic peaks at 67.13°C±5°C and 163.06°C±5°C.
  9. 根据权利要求8所述的A晶型，其DSC图谱如图2所示。According to the crystal form A according to claim 8, its DSC spectrum is as shown in FIG. 2 .
  10. 根据权利要求3～7任意一项所述的A晶型，其热重分析曲线在140.0℃±3℃时失重达1.72％。According to any one of claims 3-7, the crystal form A has a weight loss of 1.72% at a thermogravimetric analysis curve at 140.0°C±3°C.
  11. 根据权利要求10所述的A晶型，其TGA图谱如图3所示。The crystal form A according to claim 10, whose TGA spectrum is as shown in FIG. 3 .
  12. 一种制备权利要求3～11任意一项所述的式(II)化合物A晶型的方法，A method for preparing the crystal form of compound A of formula (II) according to any one of claims 3 to 11,
    Figure PCTCN2022134641-appb-100003
    Figure PCTCN2022134641-appb-100003
    包括如下步骤：Including the following steps:
    (a)将式(I)化合物加入溶剂X中，搅拌溶解，再滴加溶剂Y；(a) adding the compound of formula (I) into solvent X, stirring and dissolving, and then adding solvent Y dropwise;
    或者，将式(I)化合物加入溶剂X和溶剂Y的混合溶剂中；Alternatively, the compound of formula (I) is added to a mixed solvent of solvent X and solvent Y;
    (b)15～80℃下搅拌1～24小时；(b) stirring at 15-80°C for 1-24 hours;
    (c)15～30℃下收集固体；(c) collecting the solid at 15-30°C;
    其中，in,
    式(I)化合物的结构为
    Figure PCTCN2022134641-appb-100004
    The structure of formula (I) compound is
    Figure PCTCN2022134641-appb-100004
    溶剂X选自二甲基亚砜、N,N-二甲基甲酰胺、丙酮和乙腈；Solvent X is selected from dimethylsulfoxide, N,N-dimethylformamide, acetone and acetonitrile;
    溶剂Y为水。Solvent Y is water.
  13. 式(I)化合物的B晶型，Form B of the compound of formula (I),
    Figure PCTCN2022134641-appb-100005
    Figure PCTCN2022134641-appb-100005
    其特征在于，其Cu Kα辐射的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：9.31±0.20°，15.09±0.20°，16.90±0.20°，20.49±0.20°。It is characterized in that its Cu Kα radiation X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ angles: 9.31±0.20°, 15.09±0.20°, 16.90±0.20°, 20.49±0.20°.
  14. 根据权利要求13所述的B晶型，其Cu Kα辐射的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：5.63±0.20°，9.31±0.20°，15.09±0.20°，16.90±0.20°，19.66±0.20°，20.49±0.20°，22.11±0.20°，22.62±0.20°。The B crystal form according to claim 13, its X-ray powder diffraction spectrum of Cu Kα radiation has characteristic diffraction peaks at the following 2θ angles: 5.63±0.20°, 9.31±0.20°, 15.09±0.20°, 16.90±0.20° , 19.66±0.20°, 20.49±0.20°, 22.11±0.20°, 22.62±0.20°.
  15. 根据权利要求14所述的B晶型，其Cu Kα辐射的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：5.63±0.20°，9.31±0.20°，11.23±0.20°，15.09±0.20°，15.88±0.20°，16.90±0.20°，19.66±0.20°，20.49±0.20°，22.11±0.20°，22.62±0.20°，26.47±0.20°，29.87±0.20°。According to the B crystal form according to claim 14, the X-ray powder diffraction pattern of its Cu Kα radiation has characteristic diffraction peaks at the following 2θ angles: 5.63±0.20°, 9.31±0.20°, 11.23±0.20°, 15.09±0.20° , 15.88±0.20°, 16.90±0.20°, 19.66±0.20°, 20.49±0.20°, 22.11±0.20°, 22.62±0.20°, 26.47±0.20°, 29.87±0.20°.
  16. 根据权利要求15所述的B晶型，其Cu Kα辐射的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：5.63°，9.31°，11.23°，15.09°，15.88°，16.90°，19.66°，20.49°，22.11°，22.62°，23.85°，26.47°，27.74°，29.87°，31.11°，32.02°。The B crystal form according to claim 15, the X-ray powder diffraction pattern of its Cu Kα radiation has characteristic diffraction peaks at the following 2θ angles: 5.63°, 9.31°, 11.23°, 15.09°, 15.88°, 16.90°, 19.66 °, 20.49°, 22.11°, 22.62°, 23.85°, 26.47°, 27.74°, 29.87°, 31.11°, 32.02°.
  17. 根据权利要求16所述的B晶型，其XRPD图谱如图4所示。The crystal form B according to claim 16, its XRPD pattern is as shown in Figure 4.
  18. 根据权利要求13～17任意一项所述的B晶型，其差示扫描量热曲线在171.6℃±5℃处具有吸热峰的起始点。According to the crystal form B according to any one of claims 13-17, its differential scanning calorimetry curve has an endothermic peak starting point at 171.6°C±5°C.
  19. 根据权利要求18所述的B晶型，其DSC图谱如图5所示。The B crystal form according to claim 18, its DSC spectrum is as shown in Figure 5.
  20. 式(I)化合物的C晶型，Form C of the compound of formula (I),
    Figure PCTCN2022134641-appb-100006
    Figure PCTCN2022134641-appb-100006
    其特征在于，其Cu Kα辐射的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：9.21±0.20°，13.96±0.20°，16.65±0.20°。It is characterized in that its Cu Kα radiation X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ angles: 9.21±0.20°, 13.96±0.20°, 16.65±0.20°.
  21. 根据权利要求20所述的C晶型，其Cu Kα辐射的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：9.21±0.20°，13.96±0.20°，16.65±0.20°，17.41±0.20°，18.45±0.20°，22.94±0.20°，24.36±0.20°。According to the crystal form C according to claim 20, the X-ray powder diffraction pattern of its Cu Kα radiation has characteristic diffraction peaks at the following 2θ angles: 9.21±0.20°, 13.96±0.20°, 16.65±0.20°, 17.41±0.20° , 18.45±0.20°, 22.94±0.20°, 24.36±0.20°.
  22. 根据权利要求21所述的C晶型，其Cu Kα辐射的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：9.21±0.20°，13.96±0.20°，16.12±0.20°，16.65±0.20°，17.41±0.20°，18.45±0.20°，21.13±0.20°，22.94±0.20°，24.36±0.20°，32.03±0.20°。According to the crystal form C according to claim 21, the X-ray powder diffraction pattern of its Cu Kα radiation has characteristic diffraction peaks at the following 2θ angles: 9.21±0.20°, 13.96±0.20°, 16.12±0.20°, 16.65±0.20° , 17.41±0.20°, 18.45±0.20°, 21.13±0.20°, 22.94±0.20°, 24.36±0.20°, 32.03±0.20°.
  23. 根据权利要求22所述的C晶型，其Cu Kα辐射的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：9.21°，10.51°，13.96°，16.12°，16.65°，17.41°，18.45°，21.13°，22.94°，24.36°，28.86°，32.03°，33.55°。According to the crystal form C according to claim 22, the X-ray powder diffraction pattern of its Cu Kα radiation has characteristic diffraction peaks at the following 2θ angles: 9.21°, 10.51°, 13.96°, 16.12°, 16.65°, 17.41°, 18.45° °, 21.13°, 22.94°, 24.36°, 28.86°, 32.03°, 33.55°.
  24. 根据权利要求23所述的C晶型，其XRPD图谱如图7所示。According to the crystal form C according to claim 23, its XRPD pattern is as shown in Figure 7.
  25. 根据权利要求20～24任意一项所述的C晶型，其差示扫描量热曲线在176.0℃±5℃处具有吸热峰的起始点。According to the crystal form C according to any one of claims 20-24, its differential scanning calorimetry curve has an endothermic peak starting point at 176.0°C±5°C.
  26. 根据权利要求25所述的C晶型，其DSC图谱如图8所示。According to the crystal form C according to claim 25, its DSC spectrum is as shown in Fig. 8 .
  27. 根据权利要求20～24任意一项所述的C晶型，其热重分析曲线在150.0℃±3℃时失重达1.39％。According to any one of claims 20-24, the crystal form C has a weight loss of 1.39% at a thermogravimetric analysis curve at 150.0°C±3°C.
  28. 根据权利要求27所述的C晶型，其TGA图谱如图9所示。According to the crystal form C according to claim 27, its TGA spectrum is as shown in Fig. 9 .
  29. 根据权利要求1或2所述的式(II)化合物、权利要求3～11任意一项所述的式(II)化合物A晶型、权利要求13～19任意一项所述的式(I)化合物B晶型、根据权利要求20～28任意一项所述的式(I)化合物C晶型或根据权利要求12的方法制备得到的式(II)化合物A晶型在制备治疗NLRP3拮抗剂相关疾病的药物上的应用。The compound of formula (II) according to claim 1 or 2, the crystal form of compound A of formula (II) according to any one of claims 3 to 11, the formula (I) according to any one of claims 13 to 19 The compound B crystal form, the formula (I) compound C crystal form according to any one of claims 20 to 28, or the formula (II) compound A crystal form prepared according to the method of claim 12 are related to the preparation and treatment of NLRP3 antagonists. Drug application for diseases.
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Citations (5)

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CN1245490A (en) * 1997-01-29 2000-02-23 辉瑞大药厂 Sulfonyl urea derivatives and their use in control of interleukin-1 activity
WO2017184623A1 (en) * 2016-04-18 2017-10-26 Ifm Therapeutics, Inc Compounds and compositions for treating conditions associated with nlrp activity
CN107428696A (en) * 2015-02-16 2017-12-01 昆士兰大学 Sulfonylureas and related compound and application thereof
CN111094243A (en) * 2017-07-24 2020-05-01 诺华炎症研究公司 Compounds and compositions for treating conditions associated with NLRP activity
WO2021249337A1 (en) * 2020-06-11 2021-12-16 南京明德新药研发有限公司 Dimethylsulfoximine derivative

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1245490A (en) * 1997-01-29 2000-02-23 辉瑞大药厂 Sulfonyl urea derivatives and their use in control of interleukin-1 activity
CN107428696A (en) * 2015-02-16 2017-12-01 昆士兰大学 Sulfonylureas and related compound and application thereof
WO2017184623A1 (en) * 2016-04-18 2017-10-26 Ifm Therapeutics, Inc Compounds and compositions for treating conditions associated with nlrp activity
CN111094243A (en) * 2017-07-24 2020-05-01 诺华炎症研究公司 Compounds and compositions for treating conditions associated with NLRP activity
WO2021249337A1 (en) * 2020-06-11 2021-12-16 南京明德新药研发有限公司 Dimethylsulfoximine derivative

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