WO2023193830A9 - Toll-like receptor 8-specific inhibitor hydrochloride, preparation method therefor and use thereof - Google Patents

Toll-like receptor 8-specific inhibitor hydrochloride, preparation method therefor and use thereof Download PDF

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WO2023193830A9
WO2023193830A9 PCT/CN2023/098478 CN2023098478W WO2023193830A9 WO 2023193830 A9 WO2023193830 A9 WO 2023193830A9 CN 2023098478 W CN2023098478 W CN 2023098478W WO 2023193830 A9 WO2023193830 A9 WO 2023193830A9
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compound
formula
crystal form
chart
crystal
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PCT/CN2023/098478
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French (fr)
Chinese (zh)
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WO2023193830A1 (en
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高萌
丁东
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北京拓领博泰生物科技有限公司
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Publication of WO2023193830A1 publication Critical patent/WO2023193830A1/en
Publication of WO2023193830A9 publication Critical patent/WO2023193830A9/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/20—Oxygen atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/13—Crystalline forms, e.g. polymorphs

Definitions

  • the present invention relates to the technical field of organic compounds, and specifically to Toll-like receptor 8 (TLR8) specific inhibitor hydrochloride and its preparation method, as well as pharmaceutical compositions containing the hydrochloride.
  • TLR8 Toll-like receptor 8
  • TLR Toll-like receptors
  • innate immunity non-specific immunity
  • TLRs are single, transmembrane, non-catalytic proteins that recognize molecules with conserved structures derived from microorganisms. When microorganisms break through the body's physical barriers, such as skin, mucous membranes, etc., TLRs can recognize them and activate the body to produce immune cell responses.
  • Toll-like receptors also play a certain role in some immune diseases. By inhibiting the activity of Toll-like receptors, they can treat related diseases.
  • WO2019/089648 discloses a series of compounds used as specific inhibitors of Toll-like receptor 8 (TLR8). In addition, the use of the compounds in inhibiting TLR8-dependent immune responses in individuals is also disclosed.
  • TLR8 Toll-like receptor 8
  • a first aspect of the present invention provides a compound of formula (I) and a preparation method thereof.
  • the structural formula of the compound of formula (I) is:
  • a second aspect of the present invention provides crystalline forms of the compound of formula (I), specifically including four crystal forms: Form A, Form B, Form C and Form D.
  • the crystalline form of the compound of formula (I) is an anhydrous crystalline form.
  • the third aspect of the present invention provides a pharmaceutical composition comprising a compound of formula (I) or a crystalline form thereof.
  • the pharmaceutical composition uses the compound of formula (I) or a crystalline form thereof as an active ingredient, and further comprises at least one pharmaceutically acceptable compound. Acceptable carrier or excipient.
  • a fourth aspect of the present invention provides a method for preparing a compound of formula (I), which includes the step of stirring a free compound of formula (I) with a concentrated hydrochloric acid/isopropyl alcohol mixed solution.
  • a fifth aspect of the invention provides the use of a compound of formula (I) or a crystalline form thereof for inhibiting TLR8-dependent immune responses in an individual.
  • the present invention has the following beneficial effects: the compound of formula (I) or its crystal form provided by the embodiment of the present invention has the advantages of high solubility, stable gastric juice simulated environment, thermodynamic stability, solid state stability, high temperature and high humidity stability, and low hygroscopicity, etc., and has the following advantages: It is beneficial to its development as a pharmaceutical preparation for Toll-like receptor inhibition.
  • Figure 1 is a diagram showing the mutual transformation relationship between polymorphic forms of the compound of formula (I);
  • Figure 2 is the XRPD pattern of the FormA crystal form of the compound of formula (I);
  • Figure 3 is a TGA diagram of the FormA crystal form of the compound of formula (I);
  • Figure 4 is a DSC chart of the FormA crystal form of the compound of formula (I);
  • Figure 5 is a 1 HMR chart of the FormA crystal form of the compound of formula (I);
  • Figure 6 is the XRPD pattern of the FormC crystal form of the compound of formula (I);
  • Figure 7 is the XRPD pattern of the FormD crystal form of the compound of formula (I);
  • Figure 8 is the XRPD pattern of the FormB crystal form of the compound of formula (I);
  • Figure 9 is a TGA diagram of the FormB crystal form of the compound of formula (I);
  • Figure 10 is a DSC chart of the FormB crystal form of the compound of formula (I);
  • Figure 11 is a 1 HMR chart of the FormB crystal form of the compound of formula (I);
  • Figure 12 is an XRPD overlay of the hydrochloride crystal form of the compound of formula (I);
  • Figure 13 is the XRPD pattern of the suspension competition of compounds of formula (I) FormA and FormB;
  • Figure 14 shows the XRPD pattern of the solid before and after the solubility test of free FormA
  • Figure 15 shows the XRPD pattern of the solid before and after the solubility test of FormA hydrochloride
  • Figure 16 is the XRPD comparison chart of the solid before and after the stability test of the crystalline form in hydrochloride FormA gastric simulation solution;
  • Figure 17 is the XRPD comparison chart of the solid before and after the one-week stability test of FormA hydrochloride
  • Figure 18 is the DVS diagram of FormA hydrochloride
  • Figure 19 shows the XRPD comparison chart of the solid before and after the DVS test of FormA hydrochloride.
  • the numerical ranges in the present invention are approximate and approximate, and therefore, unless otherwise specified, numerical values outside the range may be further included.
  • the disclosed numerical ranges include lower numbers, upper numbers, and all numbers therebetween. For example, when mentioning between 100 and 500, etc., it means enumerating all individual values, such as 123, 124, 125 etc., and sub-ranges such as 130-180, 180-260, 350-444, etc. are also included in the listed ranges.
  • crystal form In the present invention, “crystal form”, “crystal form”, “crystal form” and “crystalline state” have the same meaning.
  • the embodiment of the present invention provides a method for preparing a compound of formula (I), wherein the structural formula (I) is as follows:
  • the reaction is carried out with stirring.
  • Stirring can be done by conventional methods such as magnetic stirring, as long as it can promote the reaction.
  • the reaction is carried out at room temperature.
  • the reaction time can be several hours, such as 2 hours, 3 hours, 4 hours.
  • the product is in solid form.
  • the product is separated by vacuum filtration after the reaction.
  • the product is preferably dried, and the drying methods that can be adopted are drying methods known in the art, such as air drying, drying oven drying, etc.
  • the separated solid is dried in a blast drying oven at 50°C.
  • Form A and Form B is anhydrous crystalline form, also known as anhydrous crystal form.
  • Form C and Form D are metastable crystalline forms. Each crystal form can be transformed into each other, and the transformation relationship between each crystal form is shown in Figure 1.
  • the Form B crystal form of compound (I) can be obtained by rotary evaporation of the Form A crystal form in trifluoroethanol at 50°C.
  • the Form B crystal form of compound (I) was suspended in ethanol (room temperature and 50°C) and acetone (room temperature and 50°C) for 1 day to obtain the Form A crystal form of compound (I).
  • the Form A crystal form is evaporated at room temperature in a mixed solution of trifluoroethanol/water (volume ratio 2:1) to obtain the Form C crystal form of the compound of formula (I).
  • the Form C crystal form of the compound of formula (I) is left to dry for 2 days at room temperature, it will become the Form A crystal form.
  • the Form A crystal form can be obtained by adding trifluoroethanol/dichloromethane as an anti-antisolvent and then volatilizing at room temperature to obtain the Form D crystal form of the compound of formula (I). At the same time, the Form D crystal form of the compound of formula (I) will change into the Form A crystal form if left closed for 1 day at room temperature.
  • Form A crystal form of the compound of formula (I) set up polymorph screening tests under different conditions. Screening methods include: slow volatilization, slurry conversion (low temperature, room temperature and high temperature), anti-solvent addition, anti-anti-solvent addition, cooling crystallization, gas-liquid diffusion, gas-solid diffusion, water vapor stress, polymer induction, grinding, and circulation Heating and cooling, rotary evaporation, etc. According to the XRPD results of the obtained solid, a total of 4 crystal forms were found, including anhydrous hydrochloride FormA/B and metastable crystalline hydrochloride FormC/D.
  • the X-ray powder diffraction pattern of the non-crystalline hydrochloride FormA is 7.1 ⁇ 0.2°, 12.1 ⁇ 0.2°, 12.6 ⁇ 0.2°, 14.3 ⁇ 0.2°, 15.9 ⁇ 0.2°, 16.2 ⁇ 0.2°, 18.5 ⁇ 0.2°, 20.3 There are characteristic peaks at ⁇ 0.2°, 22.1 ⁇ 0.2°, 24.8 ⁇ 0.2°, 25.4 ⁇ 0.2°, and 26.8 ⁇ 0.2°.
  • the crystalline form includes 6 or more X-ray powder diffraction patterns selected from the following 2 ⁇ values (CuK ):
  • the crystalline form FormA includes 8 or more 2 ⁇ values selected from the following X-ray powder diffraction Figure (CuK ⁇ ):
  • the crystalline form FormA has one of the following (a) to (d):
  • the crystalline form FormB has one of the following (e) to (h):
  • FormA and FormB are both acrystalline forms
  • the suspension competition test found that the Form A crystalline form is the more thermodynamically stable acrystalline form at room temperature and 50°C.
  • the Form C crystal form has an X-ray powder diffraction pattern (XPRD pattern) that is basically consistent with Figure 6.
  • the Form D crystal form has an X-ray powder diffraction pattern (XPRD pattern) that is basically consistent with Figure 7.
  • the present invention also evaluates the properties of the hydrochloride salt Form A.
  • the evaluation includes equilibrium solubility, crystalline stability in gastric simulated fluid, solid-state physical and chemical stability, and hygroscopicity.
  • the results show that hydrochloride Form A, which has better physical and chemical stability and solid-state properties, is the dominant crystal form.
  • solvents such as trifluoroethanol and other solvent systems that can produce metastable crystal forms
  • Another embodiment of the present invention provides a pharmaceutical composition, the active ingredients of which include the aforementioned structural compound of formula (I) or its crystal form compound as an active ingredient. Other active ingredients that have been experimentally verified to have physiological activity can also be added. Include other pharmaceutically acceptable carriers or excipients.
  • the pharmaceutical composition of the present invention can be prepared into various dosage forms, including enteral administration dosage forms and parenteral administration dosage forms. For example, oral preparations, intravenous preparations and other common clinical dosage forms.
  • the present invention also provides the use of compound (I) as a specific inhibitor of Toll-like receptor 8 (TLR8), Included are uses of the compound to inhibit TLR8-dependent immune responses in an individual.
  • TLR8 Toll-like receptor 8
  • test in the present invention is carried out using the following methods and equipment.
  • the calorimetric (DSC) test parameters are as follows:
  • HPLC High performance liquid chromatography
  • free 2-methyl-4-(7-methoxyquinolinyl)phenol comes from Medicilon Laboratory, and can also be synthesized according to the method disclosed in WO2019/089648, the entire content of which is incorporated into this application.
  • the melting point of the product was measured using an MP70 melting point meter (manufactured by Mettler). Take an appropriate amount of dried sample and grind it into powder in a mortar for test sample. Take an appropriate amount of the test sample and place it in the melting point capillary tube. The height of the test sample is about 3mm and compacted. Set the initial temperature to 250°C, the heating rate to 1°C/min, and the end temperature to 265°C. The measurement result is: melting point 263.46°C.
  • Example 1 the product obtained in Example 1 was subjected to X-ray powder diffraction (XRPD), thermogravimetric analysis (TGA), differential scanning calorimetry (DSC), hydrogen nuclear magnetic spectrum ( 1 H NMR), ion chromatography/high performance liquid chromatography. Measurement results showed that the product obtained in Example 1 was an anhydrous compound, was in a crystalline state, and had high crystallinity, so it was named Form A crystal form. specific,
  • thermogravimetric analysis (TGA) experiment shows that when the temperature is raised to 170°C, the sample loses 0.1413% weight, that is, the Form A crystal form has no obvious weight loss when heated to 170°C. Its TGA chart is shown in Figure 3.
  • DSC Differential scanning calorimetry
  • Form A crystal form Since the Form A crystal form has no obvious weight loss when heated, and DSC has a single melting signal, it is inferred that the Form A crystal form is an amorphous form.
  • Ion chromatography/high performance liquid chromatography shows that the acid-base molar ratio of the Form A crystal form of the compound of formula (I) is 1.0:l.
  • Screening methods include: slow volatilization, slurry conversion (low temperature, room temperature and high temperature), anti-solvent addition, anti-anti-solvent addition, cooling crystallization, gas-liquid diffusion, gas-solid diffusion, water vapor stress, polymer induction, grinding, and circulation Heating and cooling and rotary evaporation.
  • the slow evaporation method is:
  • the low temperature 4-8°C slurry conversion method is:
  • the room temperature slurry conversion method is:
  • the high temperature slurry conversion method is:
  • the anti-solvent addition method is:
  • the anti-antisolvent addition method is:
  • the XRPD of Form D is shown in Figure 7. It is in a crystalline state with high crystallinity. If left at room temperature for 1 day with the lid closed, it will turn into hydrochloride Form A. It is speculated that it is a metastable crystal form.
  • the cooling crystallization method is:
  • the gas-liquid diffusion method is:
  • the gas-solid diffusion method is:
  • the polymer induction method is:
  • the grinding method is:
  • the cyclic heating and cooling method is:
  • the cycle temperature increase and decrease program is: keep the reaction temperature at 50°C for 120 minutes, then lower the temperature of the reaction solution to 5°C at a rate of 0.1°C per minute, and then maintain it at 5°C for 120 minutes. A total of 2 cycles are performed.
  • the rotary evaporation method is:
  • the crystal form Form B is in a crystalline state with weak crystallinity and is named hydrochloride Form B.
  • Form B was left closed at room temperature for 3 days, and the crystal form did not change.
  • TGA implementation shows that when the temperature is raised to 170°C, the sample weight loss is only 1.3807%.
  • DSC experiments show that Form B has a single endothermic peak with a melting point of 265.93°C (peak temperature Degree, 1 HNMR showed no obvious solvent residue. It is inferred that Form B is an acrylic form, and its HPLC experimental result is that the acid-base molar ratio is 1.1:1.
  • the present invention also set up suspension competition tests in different solvents at room temperature and 50°C.
  • the specific steps are as follows: First, prepare a saturated solution of hydrochloride Form A at the corresponding temperature and solvent, add equal masses of different crystalline samples to the filtered saturated solution to form a suspension, and store them at room temperature or 50°C. Suspend and stir. The results of the suspension competition are shown in Figure 13.
  • the hydrochloride FormA was obtained in both the ethanol system (room temperature and 50°C) and the acetone system (room temperature and 50°C) (suspension competition for 1 day). From this, it can be determined that the Form A crystal form of the hydrochloride of the compound of formula (I) is a crystalline form that is more thermodynamically stable at room temperature and 50°C.
  • hydrochloride salt Form A is an amorphous form that is more thermodynamically stable at room temperature and 50°C
  • this example evaluates the properties of this crystalline form.
  • the evaluation includes equilibrium solubility, crystalline stability in gastric simulated fluid, solid-state physical and chemical stability, and hygroscopicity.
  • the equilibrium solubility in water of free Form A and hydrochloride Form A was measured for 24 hours. test , mix 10 mg of solid and 1.0 ml of water in a 3 ml glass vial, add a stir bar, then fix the glass vial on a magnetic stirrer, and place the magnetic stirrer in a 37°C incubator. After 24 hours, the filtrate was separated to test the HPLC concentration, and the solid obtained was tested by XRPD.
  • Hydrochloride Form A samples were tested for crystalline stability in gastric simulated fluid.
  • an appropriate amount of solid and a certain amount of simulated gastric fluid (SGF) were mixed in a 3 ml glass vial, a stirrer was added, the glass vial was fixed on a magnetic stirrer, and the magnetic stirrer was placed in a 37°C incubator. . Samples were taken at time points 1 hour and 2 days after equilibrium, centrifuged, and the solids obtained were tested by XRPD.
  • SGF simulated gastric fluid
  • Hydrochloride Form A After placing the hydrochloride Form A sample at 25°C, 60% RH and 40°C, 75% RH for one week, HPLC purity and crystal form changes were tested. The results are shown in Table 25. Hydrochloride Form A has two After being placed under the same test conditions for a week, the HPLC purity showed no significant decrease, the chemical stability was good, and no change in crystal form was observed. The XRPD of the stability sample before and after placement is shown in Figure 17.

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Abstract

The present invention relates to the technical field of organic compounds, and in particular to a Toll-like receptor 8 (TLR8)-specific inhibitor hydrochloride and a preparation method therefor, and a pharmaceutical composition comprising the hydrochloride. The Toll-like receptor 8 (TLR8)-specific inhibitor hydrochloride has a structural formula of (I).

Description

Toll样受体8特异性抑制剂盐酸盐及其制备方法和用途Toll-like receptor 8 specific inhibitor hydrochloride and its preparation method and use 技术领域Technical field
本发明涉及有机化合物技术领域，具体而言，涉及Toll样受体8(TLR8)特异性抑制剂盐酸盐及其制备方法，以及包含该盐酸盐的药物组合物。The present invention relates to the technical field of organic compounds, and specifically to Toll-like receptor 8 (TLR8) specific inhibitor hydrochloride and its preparation method, as well as pharmaceutical compositions containing the hydrochloride.
背景技术Background technique
Toll样受体(Toll-like receptors,TLR)是参与非特异性免疫(天然免疫)的一类重要蛋白质分子，也是连接非特异性免疫和特异性免疫的桥梁。TLR是单个的跨膜非催化性蛋白质，可以识别来源于微生物的具有保守结构的分子。当微生物突破机体的物理屏障，如皮肤、粘膜等时，TLR可以识别它们并激活机体产生免疫细胞应答。Toll样受体在某些免疫疾病中也有一定作用，通过抑制Toll样受体活性，可以起到治疗相关疾病的功效。WO2019/089648公开了一系列用作Toll样受体8(TLR8)特异性抑制剂的化合物。此外，还公开了所述化合物在抑制个体中TLR8依赖性免疫反应的用途。Toll-like receptors (TLR) are an important class of protein molecules involved in non-specific immunity (innate immunity) and are also a bridge connecting non-specific immunity and specific immunity. TLRs are single, transmembrane, non-catalytic proteins that recognize molecules with conserved structures derived from microorganisms. When microorganisms break through the body's physical barriers, such as skin, mucous membranes, etc., TLRs can recognize them and activate the body to produce immune cell responses. Toll-like receptors also play a certain role in some immune diseases. By inhibiting the activity of Toll-like receptors, they can treat related diseases. WO2019/089648 discloses a series of compounds used as specific inhibitors of Toll-like receptor 8 (TLR8). In addition, the use of the compounds in inhibiting TLR8-dependent immune responses in individuals is also disclosed.
而特定药物的不同晶体型态会导致药物在溶解度、熔点、稳定性及生物利用率等出现差异。因此亟需找到一种均质、安定、可重复制造性及可加工性的Toll样受体8(TLR8)特异性抑制剂晶型以利后续发展。Different crystal forms of a specific drug will lead to differences in solubility, melting point, stability and bioavailability of the drug. Therefore, it is urgent to find a homogeneous, stable, reproducible and processable Toll-like receptor 8 (TLR8) specific inhibitor crystal form to facilitate subsequent development.
鉴于此，特提出本发明。In view of this, the present invention is proposed.
发明内容Contents of the invention
本发明的第一个方面，提供一种式(I)化合物及其制备方法。式(I)化合物的结构式为：
A first aspect of the present invention provides a compound of formula (I) and a preparation method thereof. The structural formula of the compound of formula (I) is:
本发明的第二个方面提供式(I)化合物的结晶形态，具体包括Form A、Form B、FormC和Form D四种晶型。优选式(I)化合物的结晶形态为无水结晶形式。A second aspect of the present invention provides crystalline forms of the compound of formula (I), specifically including four crystal forms: Form A, Form B, Form C and Form D. Preferably, the crystalline form of the compound of formula (I) is an anhydrous crystalline form.
本发明的第三个方面提供包含式(I)化合物或其结晶形态的药物组合物，药物组合物以式(I)化合物或其结晶形态化合物为活性成分，此外还包含至少一种药学上可接受的载体或者赋形剂。The third aspect of the present invention provides a pharmaceutical composition comprising a compound of formula (I) or a crystalline form thereof. The pharmaceutical composition uses the compound of formula (I) or a crystalline form thereof as an active ingredient, and further comprises at least one pharmaceutically acceptable compound. Acceptable carrier or excipient.
本发明的第四个方面提供式(I)化合物的制备方法，包括：将游离态的式(I)化合物与浓盐酸/异丙醇混合溶液搅拌的步骤。A fourth aspect of the present invention provides a method for preparing a compound of formula (I), which includes the step of stirring a free compound of formula (I) with a concentrated hydrochloric acid/isopropyl alcohol mixed solution.
本发明的第五个方面提供式(I)化合物或其结晶形态化合物在抑制个体中TLR8依赖性免疫反应中的用途。A fifth aspect of the invention provides the use of a compound of formula (I) or a crystalline form thereof for inhibiting TLR8-dependent immune responses in an individual.
本发明具有以下有益效果：本发明实施例提供的式(I)化合物或其结晶形态具有溶解度高、胃液模拟环境稳定、热力学稳定、固态稳定、高温高湿稳定、以及吸湿性小等优点，有利于其作为Toll样受体抑制的药物制剂开发。The present invention has the following beneficial effects: the compound of formula (I) or its crystal form provided by the embodiment of the present invention has the advantages of high solubility, stable gastric juice simulated environment, thermodynamic stability, solid state stability, high temperature and high humidity stability, and low hygroscopicity, etc., and has the following advantages: It is beneficial to its development as a pharmaceutical preparation for Toll-like receptor inhibition.
为让本发明的上述和其它目的、特征和优点能更明显易懂，下文特举出较佳实施例，并配合所附图式，作详细说明如下。In order to make the above and other objects, features and advantages of the present invention more clearly understood, preferred embodiments are cited below and described in detail with reference to the accompanying drawings.
附图说明Description of the drawings
为了更清楚地说明本发明实施例的技术方案，下面将对实施例中所需要使用的附图作简单地介绍，应当理解，以下附图仅示出了本发明的某些实施例，因此不应被看作是对范围的限定，对于本领域普通技术人员来讲，在不付出创造性劳动的前提下，还可以根据这些附图获得其他相关的附图。In order to explain the technical solutions of the embodiments of the present invention more clearly, the drawings required to be used in the embodiments will be briefly introduced below. It should be understood that the following drawings only show some embodiments of the present invention and therefore do not It should be regarded as a limitation of the scope. For those of ordinary skill in the art, other relevant drawings can be obtained based on these drawings without exerting creative efforts.
图1为式(I)化合物多晶型间相互转化关系图；Figure 1 is a diagram showing the mutual transformation relationship between polymorphic forms of the compound of formula (I);
图2为式(I)化合物FormA晶型的XRPD图； Figure 2 is the XRPD pattern of the FormA crystal form of the compound of formula (I);
图3为式(I)化合物FormA晶型的TGA图；Figure 3 is a TGA diagram of the FormA crystal form of the compound of formula (I);
图4为式(I)化合物FormA晶型的DSC图；Figure 4 is a DSC chart of the FormA crystal form of the compound of formula (I);
图5为式(I)化合物FormA晶型的1HMR图；Figure 5 is a 1 HMR chart of the FormA crystal form of the compound of formula (I);
图6为式(I)化合物FormC晶型的XRPD图；Figure 6 is the XRPD pattern of the FormC crystal form of the compound of formula (I);
图7为式(I)化合物FormD晶型的XRPD图；Figure 7 is the XRPD pattern of the FormD crystal form of the compound of formula (I);
图8为式(I)化合物FormB晶型的XRPD图；Figure 8 is the XRPD pattern of the FormB crystal form of the compound of formula (I);
图9为式(I)化合物FormB晶型的TGA图；Figure 9 is a TGA diagram of the FormB crystal form of the compound of formula (I);
图10为式(I)化合物FormB晶型的DSC图；Figure 10 is a DSC chart of the FormB crystal form of the compound of formula (I);
图11为式(I)化合物FormB晶型的1HMR图；Figure 11 is a 1 HMR chart of the FormB crystal form of the compound of formula (I);
图12为式(I)化合物盐酸盐晶型的XRPD叠图；Figure 12 is an XRPD overlay of the hydrochloride crystal form of the compound of formula (I);
图13为式(I)化合物FormA和FormB混悬竞争的XRPD图；Figure 13 is the XRPD pattern of the suspension competition of compounds of formula (I) FormA and FormB;
图14为游离态FormA溶解度测试前后固体的XRPD图；Figure 14 shows the XRPD pattern of the solid before and after the solubility test of free FormA;
图15为盐酸盐FormA溶解度测试前后固体的XRPD图；Figure 15 shows the XRPD pattern of the solid before and after the solubility test of FormA hydrochloride;
图16为盐酸盐FormA胃模拟液中晶型稳定性测试前后固体的XRPD对比图；Figure 16 is the XRPD comparison chart of the solid before and after the stability test of the crystalline form in hydrochloride FormA gastric simulation solution;
图17为盐酸盐FormA一周稳定性实验前后固体的XRPD对比图；Figure 17 is the XRPD comparison chart of the solid before and after the one-week stability test of FormA hydrochloride;
图18为盐酸盐FormA的DVS图；Figure 18 is the DVS diagram of FormA hydrochloride;
图19为盐酸盐FormA的DVS测试前后固体的XRPD对比图。Figure 19 shows the XRPD comparison chart of the solid before and after the DVS test of FormA hydrochloride.
具体实施方式Detailed ways
为使本发明实施例的目的、技术方案和优点更加清楚，下面将对本发明实施例中的技术方案进行清楚、完整地描述。实施例中未注明具体条件者，按照常规条件或制造商建议的条件进行。所用试剂或仪器未注明生产厂商者，均为可以通过市售购买获得的常规产品。In order to make the objectives, technical solutions, and advantages of the embodiments of the present invention clearer, the technical solutions in the embodiments of the present invention will be described clearly and completely below. If the specific conditions are not specified in the examples, the conditions should be carried out according to the conventional conditions or the conditions recommended by the manufacturer. If the manufacturer of the reagents or instruments used is not indicated, they are all conventional products that can be purchased commercially.
本发明中的数值范围为大约、约略的，因此除特别说明，皆可更进一步包括范围外的数值。所公开的数值范围包含下限、上限数值以及其间所有数值。例如，当提到100～500之间等，则代表以列举所有个别数值，如123、124、125 等，及其次范围如130～180、180～260、350～444等亦包含于列举的范围之中。The numerical ranges in the present invention are approximate and approximate, and therefore, unless otherwise specified, numerical values outside the range may be further included. The disclosed numerical ranges include lower numbers, upper numbers, and all numbers therebetween. For example, when mentioning between 100 and 500, etc., it means enumerating all individual values, such as 123, 124, 125 etc., and sub-ranges such as 130-180, 180-260, 350-444, etc. are also included in the listed ranges.
本发明中，“式(I)化合物”、“式(I)结构化合物”、“化合物(I)”具有相同含义，均指具有式(I)结构的化合物，化学名为：2-甲基-4-(7-甲氧基喹啉基)苯酚盐酸盐。In the present invention, "compound of formula (I)", "compound with structure of formula (I)" and "compound (I)" have the same meaning, and they all refer to compounds with the structure of formula (I). The chemical name is: 2-methyl -4-(7-Methoxyquinolinyl)phenol hydrochloride.
本发明中，“晶型”、“结晶形态”、“晶形”、“结晶态”具有相同含义。In the present invention, "crystal form", "crystal form", "crystal form" and "crystalline state" have the same meaning.
本发明实施例提供一种式(I)化合物的制备方法，其中结构式(I)如下所示：
The embodiment of the present invention provides a method for preparing a compound of formula (I), wherein the structural formula (I) is as follows:
将游离态式(I)化合物，即2-甲基-4-(7-甲氧基喹啉基)苯酚与浓盐酸反应，分离反应产物，即可得到式(I)化合物，即2-甲基-4-(7-甲氧基喹啉基)苯酚盐酸盐。The compound of formula (I), i.e., 2-methyl-4-(7-methoxyquinolyl)phenol, is reacted with concentrated hydrochloric acid to separate the reaction product to obtain the compound of formula (I), i.e., 2-methyl -4-(7-Methoxyquinolinyl)phenol hydrochloride.
优选地，浓盐酸与2-甲基-4-(7-甲氧基喹啉基)苯酚反应前，先与异丙醇混合，得到混合溶液；Preferably, before reacting concentrated hydrochloric acid with 2-methyl-4-(7-methoxyquinolyl)phenol, it is first mixed with isopropyl alcohol to obtain a mixed solution;
优选地，反应在搅拌下进行。搅拌可以选择磁力搅拌等常规方式，只要能够促进反应进行即可。Preferably, the reaction is carried out with stirring. Stirring can be done by conventional methods such as magnetic stirring, as long as it can promote the reaction.
优选地，反应在室温下进行。反应时间可为数小时，例如2小时，3小时，4小时。Preferably, the reaction is carried out at room temperature. The reaction time can be several hours, such as 2 hours, 3 hours, 4 hours.
产物为固体形式。优选反应后用真空抽滤方式分离产物。分离后优选将产物进行干燥，可以采取的干燥方法为本领域已知的干燥方法，如晾干、干燥箱干燥等。特别优选的是，将分离所得固体置于50℃的鼓风干燥箱中烘干。The product is in solid form. Preferably, the product is separated by vacuum filtration after the reaction. After separation, the product is preferably dried, and the drying methods that can be adopted are drying methods known in the art, such as air drying, drying oven drying, etc. Particularly preferably, the separated solid is dried in a blast drying oven at 50°C.
本发明的另一实施例提供式(I)化合物的结晶形态。其中，Form A和Form  B为无水结晶形态，也称为无水晶型。Form C和Form D为亚稳晶型。各晶型之间可以相互转化，各晶型之间的转化关系如图1所示。Another embodiment of the invention provides crystalline forms of compounds of formula (I). Among them, Form A and Form B is anhydrous crystalline form, also known as anhydrous crystal form. Form C and Form D are metastable crystalline forms. Each crystal form can be transformed into each other, and the transformation relationship between each crystal form is shown in Figure 1.
可以通过室温和50℃下在不同溶剂中的悬浮竞争实验研究无水晶型Form A和Form B之间的转化关系。结果表明，在乙醇体系(室温和50℃)、丙酮体系(室温和50℃)中，竞争悬浮1天，均得到式(I)化合物盐酸盐的Form A晶型。The transformation relationship between crystal-free Form A and Form B can be studied through suspension competition experiments in different solvents at room temperature and 50°C. The results show that in the ethanol system (room temperature and 50°C) and the acetone system (room temperature and 50°C), the Form A crystal form of the hydrochloride of the compound of formula (I) was obtained after competitive suspension for 1 day.
具体地，Form A晶型在三氟乙醇中，于50℃下旋转蒸发即可得到化合物(I)的Form B晶型。而式(I)化合物的Form B晶型在乙醇(室温和50℃)、丙酮(室温和50℃)下经悬浮竞争1天后得到化合物(I)的Form A晶型。Specifically, the Form B crystal form of compound (I) can be obtained by rotary evaporation of the Form A crystal form in trifluoroethanol at 50°C. The Form B crystal form of compound (I) was suspended in ethanol (room temperature and 50°C) and acetone (room temperature and 50°C) for 1 day to obtain the Form A crystal form of compound (I).
Form A晶型在三氟乙醇/水(体积比2:1)的混合溶液中，室温下挥发，即可得到式(I)化合物的Form C晶型。同时，式(I)化合物的Form C晶型室温下，敞口放置晾干2天，则变为Form A晶型。The Form A crystal form is evaporated at room temperature in a mixed solution of trifluoroethanol/water (volume ratio 2:1) to obtain the Form C crystal form of the compound of formula (I). At the same time, if the Form C crystal form of the compound of formula (I) is left to dry for 2 days at room temperature, it will become the Form A crystal form.
Form A晶型通过反反溶剂添加三氟乙醇/二氯甲烷后，在室温下挥发，即可得到式(I)化合物的Form D晶型。同时，式(I)化合物的Form D晶型室温下，闭口放置1天，则变为Form A晶型。The Form A crystal form can be obtained by adding trifluoroethanol/dichloromethane as an anti-antisolvent and then volatilizing at room temperature to obtain the Form D crystal form of the compound of formula (I). At the same time, the Form D crystal form of the compound of formula (I) will change into the Form A crystal form if left closed for 1 day at room temperature.
以式(I)化合物的Form A晶型为起始，设置不同条件下的多晶型筛选试验。筛选方法包括：缓慢挥发、浆料转化(低温、室温和高温)、反溶剂添加、反反溶剂添加、冷却结晶、气液扩散、气固扩散、水汽应激、高聚物诱导、研磨、循环升降温和旋转蒸发等。根据所得固体的XRPD结果，共发现4种晶型，包括无水晶型盐酸盐FormA/B、亚稳晶型盐酸盐FormC/D。Starting from the Form A crystal form of the compound of formula (I), set up polymorph screening tests under different conditions. Screening methods include: slow volatilization, slurry conversion (low temperature, room temperature and high temperature), anti-solvent addition, anti-anti-solvent addition, cooling crystallization, gas-liquid diffusion, gas-solid diffusion, water vapor stress, polymer induction, grinding, and circulation Heating and cooling, rotary evaporation, etc. According to the XRPD results of the obtained solid, a total of 4 crystal forms were found, including anhydrous hydrochloride FormA/B and metastable crystalline hydrochloride FormC/D.
无水晶型盐酸盐FormA的X射线粉末衍射图在7.1±0.2°、12.1±0.2°、12.6±0.2°、14.3±0.2°、15.9±0.2°、16.2±0.2°、18.5±0.2°、20.3±0.2°、22.1±0.2°、24.8±0.2°、25.4±0.2°、26.8±0.2°具有特征峰。The X-ray powder diffraction pattern of the non-crystalline hydrochloride FormA is 7.1±0.2°, 12.1±0.2°, 12.6±0.2°, 14.3±0.2°, 15.9±0.2°, 16.2±0.2°, 18.5±0.2°, 20.3 There are characteristic peaks at ±0.2°, 22.1±0.2°, 24.8±0.2°, 25.4±0.2°, and 26.8±0.2°.
优选所述晶型包括6个或更多个选自以下2θ值的X射线粉末衍射图(CuK)：Preferably, the crystalline form includes 6 or more X-ray powder diffraction patterns selected from the following 2θ values (CuK ):
优选所述晶型FormA包括8个或更多个选自以下2θ值的X射线粉末衍射 图(CuKα)：Preferably, the crystalline form FormA includes 8 or more 2θ values selected from the following X-ray powder diffraction Figure (CuKα ):
优选所述晶型FormA具有下述(a)至(d)之一：Preferably, the crystalline form FormA has one of the following (a) to (d):
(a)与图2基本一致的X射线粉末衍射图(XPRD图)；(a) X-ray powder diffraction pattern (XPRD pattern) that is basically consistent with Figure 2;
(b)与图3基本一致的热重量分析图(TGA图)；(b) Thermogravimetric analysis chart (TGA chart) basically consistent with Figure 3;
(c)与图4基本一致的差示扫描量热法图(DSC图)；(c) Differential scanning calorimetry chart (DSC chart) basically consistent with Figure 4;
(d)与图5基本一致的核磁氢谱图(1H NMR图)。(d) A hydrogen nuclear magnetic spectrum ( 1 H NMR chart) that is basically consistent with Figure 5.
所述晶型FormB具有下述(e)至(h)之一：The crystalline form FormB has one of the following (e) to (h):
(e)与图8基本一致的X射线粉末衍射图(XPRD图)；(e) X-ray powder diffraction pattern (XPRD pattern) that is basically consistent with Figure 8;
(f)与图9基本一致的热重量分析图(TGA图)；(f) Thermogravimetric analysis chart (TGA chart) basically consistent with Figure 9;
(g)与图10基本一致的差示扫描量热法图(DSC图)；(g) Differential scanning calorimetry chart (DSC chart) basically consistent with Figure 10;
(h)与图11基本一致的核磁氢谱图(1H NMR图)。(h) A hydrogen nuclear magnetic spectrum ( 1 H NMR chart) that is basically consistent with Figure 11.
虽然FormA和FormB均为无水晶型，但经混悬竞争试验发现，Form A晶型为室温和50℃下热力学更稳定的无水晶型。Although FormA and FormB are both acrystalline forms, the suspension competition test found that the Form A crystalline form is the more thermodynamically stable acrystalline form at room temperature and 50°C.
所述Form C晶型具有与图6基本一致的X射线粉末衍射图(XPRD图)。The Form C crystal form has an X-ray powder diffraction pattern (XPRD pattern) that is basically consistent with Figure 6.
所述Form D晶型具有与图7基本一致的X射线粉末衍射图(XPRD图)。The Form D crystal form has an X-ray powder diffraction pattern (XPRD pattern) that is basically consistent with Figure 7.
本发明还对盐酸盐Form A的性质进行了评估。评估内容包括平衡溶解度、胃模拟液中晶型稳定性、固态理化稳定性和引湿性等方面。结果表明，理化稳定性和固态性质较优的盐酸盐Form A是优势晶型。考虑到盐酸盐Form A在水中存在歧化的风险，在盐酸盐Fonn A的制备过程中，需要注意溶剂的选择(如三氟乙醇等能产生亚稳晶型的溶剂体系)，避免在特定溶剂中产生亚稳晶型。The present invention also evaluates the properties of the hydrochloride salt Form A. The evaluation includes equilibrium solubility, crystalline stability in gastric simulated fluid, solid-state physical and chemical stability, and hygroscopicity. The results show that hydrochloride Form A, which has better physical and chemical stability and solid-state properties, is the dominant crystal form. Considering the risk of disproportionation of hydrochloride Form A in water, during the preparation process of hydrochloride Fonn A, it is necessary to pay attention to the selection of solvents (such as trifluoroethanol and other solvent systems that can produce metastable crystal forms) to avoid specific Metastable crystalline forms are produced in solvents.
本发明的另一实施例提供一种药物组合物，其活性成分包括前述式(I)结构化合物或其结晶形态化合物作为活性成分，也可以添加经过实验验证具有生理活性的其他活性成分，还可以包括其他药学上可以接受的载体或赋形剂。本发明的药物组合物可以制成各种剂型，包括肠道给药剂型和非肠道给药剂型。如，口服制剂、静脉给药制剂及其他临床常见剂型。Another embodiment of the present invention provides a pharmaceutical composition, the active ingredients of which include the aforementioned structural compound of formula (I) or its crystal form compound as an active ingredient. Other active ingredients that have been experimentally verified to have physiological activity can also be added. Include other pharmaceutically acceptable carriers or excipients. The pharmaceutical composition of the present invention can be prepared into various dosage forms, including enteral administration dosage forms and parenteral administration dosage forms. For example, oral preparations, intravenous preparations and other common clinical dosage forms.
本发明还提供化合物(I)用作Toll样受体8(TLR8)特异性抑制剂的用途， 包括将该化合物用于抑制个体中TLR8依赖性免疫反应。The present invention also provides the use of compound (I) as a specific inhibitor of Toll-like receptor 8 (TLR8), Included are uses of the compound to inhibit TLR8-dependent immune responses in an individual.
如无特殊说明，本发明各测试采取以下方法和设备进行。Unless otherwise specified, each test in the present invention is carried out using the following methods and equipment.
X-射线粉末衍射实验及其测试参数如下：X-ray powder diffraction experiments and their test parameters are as follows:
表1：X-射线粉末衍射测试参数
Table 1: X-ray powder diffraction test parameters
量热(DSC)测试参数如下：The calorimetric (DSC) test parameters are as follows:
表2：热重量分析(TGA)和差示扫描量热(DSC)测试参数

Table 2: Thermogravimetric Analysis (TGA) and Differential Scanning Calorimetry (DSC) test parameters

核磁氢谱(1H NMR)实验及其测试参数如下：The hydrogen nuclear magnetic spectrum ( 1H NMR) experiment and its test parameters are as follows:
表3：核磁氢谱(1H NMR)测试参数
Table 3: Hydrogen Nuclear Magnetic Spectrum ( 1H NMR) test parameters
离子色谱及其测试参数如下：Ion chromatography and its test parameters are as follows:
表4：离子色谱测试参数
Table 4: Ion chromatography test parameters
高效液相色谱(HPLC)及其测试参数如下：High performance liquid chromatography (HPLC) and its test parameters are as follows:
表5：高效液相色谱(HPLC)测试参数
Table 5: High performance liquid chromatography (HPLC) test parameters
动态水分吸附(DVS)及其测试参数如下：Dynamic moisture adsorption (DVS) and its test parameters are as follows:
表6：DVS测试参数
Table 6: DVS test parameters
作进一步的详细描述。Describe in further detail.
实施例1：式(I)化合物的制备Example 1: Preparation of compounds of formula (I)
称取5000.83mg游离态2-甲基-4-(7-甲氧基喹啉基)苯酚于250mL圆底烧瓶中，另取2203μL浓盐酸加入到50mL异丙醇中混匀，将混匀后的溶液加入到装有游离态2-甲基-4-(7-甲氧基喹啉基)苯酚的圆底烧瓶中。然后加入搅拌子，在磁力搅拌器上进行室温悬浮搅拌。室温下搅拌3小时后，真空抽滤分离所得固体，置于50℃的鼓风干燥箱中烘干4小时，得到式(I)化合物，即2-甲基-4-(7-甲氧基喹啉基)苯酚盐酸盐。经称量，产物共计5352.99mg。Weigh 5000.83 mg of free 2-methyl-4-(7-methoxyquinolyl)phenol into a 250 mL round-bottomed flask, add another 2203 μL of concentrated hydrochloric acid to 50 mL of isopropanol, and mix well. The solution was added to a round bottom flask containing free 2-methyl-4-(7-methoxyquinolinyl)phenol. Then add a stir bar and perform suspension stirring at room temperature on a magnetic stirrer. After stirring at room temperature for 3 hours, the solid obtained was separated by vacuum filtration and dried in a blast drying oven at 50°C for 4 hours to obtain the compound of formula (I), namely 2-methyl-4-(7-methoxy). Quinolyl)phenol hydrochloride. After weighing, the product totaled 5352.99 mg.
其中，游离态2-甲基-4-(7-甲氧基喹啉基)苯酚来源于美迪西实验室，也可以按照WO2019/089648公开的方法合成，该文献的全部内容引入本申请。Among them, free 2-methyl-4-(7-methoxyquinolinyl)phenol comes from Medicilon Laboratory, and can also be synthesized according to the method disclosed in WO2019/089648, the entire content of which is incorporated into this application.
使用MP70熔点仪(Mettler生产)测量产物熔点。取适量干燥后的样品，置于研钵中研磨成粉末供试品。取供试品适量置于熔点用毛细管中，装入供试品高度约为3mm，压实。设定初始温度为250℃，升温速率为1℃/分钟，结束温度为265℃。测量结果为：熔点263.46℃。The melting point of the product was measured using an MP70 melting point meter (manufactured by Mettler). Take an appropriate amount of dried sample and grind it into powder in a mortar for test sample. Take an appropriate amount of the test sample and place it in the melting point capillary tube. The height of the test sample is about 3mm and compacted. Set the initial temperature to 250°C, the heating rate to 1°C/min, and the end temperature to 265°C. The measurement result is: melting point 263.46°C.
实施例2：式(I)化合物的晶型鉴别Example 2: Identification of crystal form of compound of formula (I)
测量实施例1获得的产物在室温条件下，在不同溶剂中的溶解度，结果如下： The solubility of the product obtained in Example 1 in different solvents at room temperature was measured. The results are as follows:
表7：产物溶解度
Table 7: Product solubility
另外，对实施例1获得的产物进行X射线粉末衍射(XRPD)、热重量分析(TGA)、差示扫描量热(DSC)、核磁氢谱(1H NMR)、离子色谱/高效液相色谱测定，结果显示：实施例1获得的产物为无水化合物，呈现结晶态，结晶度高，因此命名为Form A晶型。具体的， In addition, the product obtained in Example 1 was subjected to X-ray powder diffraction (XRPD), thermogravimetric analysis (TGA), differential scanning calorimetry (DSC), hydrogen nuclear magnetic spectrum ( 1 H NMR), ion chromatography/high performance liquid chromatography. Measurement results showed that the product obtained in Example 1 was an anhydrous compound, was in a crystalline state, and had high crystallinity, so it was named Form A crystal form. specific,
热重量分析(TGA)实验显示，在升温至170℃时，样品失重0.1413％，即Form A晶型加热至170℃时无明显失重，其TGA图如图3所示。The thermogravimetric analysis (TGA) experiment shows that when the temperature is raised to 170°C, the sample loses 0.1413% weight, that is, the Form A crystal form has no obvious weight loss when heated to 170°C. Its TGA chart is shown in Figure 3.
差示扫描量热(DSC)实验显示，Form A晶型具有单一吸收峰，熔点为263.46℃(峰值温度)，Form A晶型的DSC图如图4所示。Differential scanning calorimetry (DSC) experiments show that the Form A crystal form has a single absorption peak with a melting point of 263.46°C (peak temperature). The DSC chart of the Form A crystal form is shown in Figure 4.
由于Form A晶型加热无明显失重，且DSC有单一熔融信号，因此，推测Form A晶型为无水晶型。Since the Form A crystal form has no obvious weight loss when heated, and DSC has a single melting signal, it is inferred that the Form A crystal form is an amorphous form.
核磁氢谱(1H NMR)实验显示，残留0.117:1(溶剂:API,2.28wt％)的异丙醇，其核磁氢谱图如图5所示。The hydrogen nuclear magnetic spectrum ( 1 H NMR) experiment showed that 0.117:1 (solvent: API, 2.28wt%) isopropyl alcohol remained, and its hydrogen nuclear magnetic spectrum is shown in Figure 5.
离子色谱/高效液相色谱显示，式(I)化合物的Form A晶型酸碱摩尔比为1.0:l。Ion chromatography/high performance liquid chromatography shows that the acid-base molar ratio of the Form A crystal form of the compound of formula (I) is 1.0:l.
实施例3：多晶型筛选Example 3: Polymorph screening
以实施例获得的盐酸盐Form A晶型为起始，共设置了100种不同条件下的多晶型筛选试验。筛选方法包括：缓慢挥发、浆料转化(低温、室温和高温)、反溶剂添加、反反溶剂添加、冷却结晶、气液扩散、气固扩散、水汽应激、高聚物诱导、研磨、循环升降温和旋转蒸发。Starting from the hydrochloride Form A crystal form obtained in the example, a total of 100 polymorphic screening tests under different conditions were set up. Screening methods include: slow volatilization, slurry conversion (low temperature, room temperature and high temperature), anti-solvent addition, anti-anti-solvent addition, cooling crystallization, gas-liquid diffusion, gas-solid diffusion, water vapor stress, polymer induction, grinding, and circulation Heating and cooling and rotary evaporation.
缓慢挥发方法为：The slow evaporation method is:
称取约20mg的Form A晶型化合物至3mL小瓶中，分别加入一定体积的下表中的溶剂溶解，并使用0.45μm的PTFE滤头过滤至另一3mL小瓶，用封口膜封住小瓶，并在上面扎小孔，放置在室温下缓慢挥发。收集所得固体并进行XRPD测试。试验结果如下表8所示，得到盐酸盐Form A或盐酸盐Form C。Weigh approximately 20 mg of Form A crystalline compound into a 3 mL vial, add a certain volume of the solvent in the table below to dissolve, and use a 0.45 μm PTFE filter to filter into another 3 mL vial, seal the vial with a sealing film, and Poke a small hole in it and leave it at room temperature to slowly evaporate. The resulting solid was collected and subjected to XRPD testing. The test results are shown in Table 8 below, and hydrochloride Form A or hydrochloride Form C was obtained.
表8：缓慢挥发实验结果

Table 8: Slow evaporation experimental results

其中，Form A的X-RPD、DSC、TGA图与实施例2相同。Among them, the X-RPD, DSC, and TGA diagrams of Form A are the same as those in Example 2.
Form C的XRPD如图6所示。The XRPD of Form C is shown in Figure 6.
低温4-8℃浆料转化方法为：The low temperature 4-8℃ slurry conversion method is:
称取约20mg的Form A晶型化合物至3mL小瓶中，分别加入0.5mL表9中所列的溶剂，得到的悬浊液置于5℃下磁力搅拌约3天后，离心收集固体并进行XRPD测试。试验结果见表9，只得到盐酸盐Form A晶型。Weigh about 20 mg of Form A crystalline compound into a 3 mL vial, add 0.5 mL of the solvents listed in Table 9, and place the resulting suspension under magnetic stirring at 5°C for about 3 days. Centrifuge to collect the solid and conduct XRPD testing. . The test results are shown in Table 9. Only the hydrochloride Form A crystal form was obtained.
表9：低温浆料转化实验结果

Table 9: Low temperature slurry conversion experimental results

室温浆料转化方法为：The room temperature slurry conversion method is:
称取约20mg的Form A晶型化合物至3mL小瓶中，分别加入0.5mL表10所列的溶剂，得到的悬浊液置于室温下磁力搅拌约3天后,离心收集固体并进行XRPD测试。试验结果见表10，只得到盐酸盐Form A。Weigh approximately 20 mg of the Form A crystalline compound into a 3 mL vial, add 0.5 mL of the solvents listed in Table 10, and place the resulting suspension under magnetic stirring at room temperature for approximately 3 days. Centrifuge to collect the solid and conduct XRPD testing. The test results are shown in Table 10. Only hydrochloride Form A was obtained.
表10：室温浆料转化实验结果

Table 10: Room temperature slurry conversion experimental results

高温浆料转化方法为：The high temperature slurry conversion method is:
称取约20mg的Form A晶型化合物至3mL小瓶中，分别加入0.5mL表11中所列的溶剂，得到的悬浊液置于50℃下磁力搅拌约3天后，离心收集固体并进行XRPD测试。试验结果见表11，只得到盐酸盐FormA。Weigh about 20 mg of Form A crystalline compound into a 3 mL vial, add 0.5 mL of the solvents listed in Table 11, and place the resulting suspension under magnetic stirring at 50°C for about 3 days. Centrifuge to collect the solid and conduct XRPD testing. . The test results are shown in Table 11. Only hydrochloride FormA was obtained.
表11：高温浆料转化实验结果
Table 11: High temperature slurry conversion experimental results
反溶剂添加方法为：The anti-solvent addition method is:
称取约20mg的Form A晶型化合物加至5mL的小瓶内，用表12中的对应溶剂将固体完全溶解，并使用0.45μm的PTFE滤头过滤至另一20mL小瓶。向该澄清溶液中边搅拌边滴加表12中的反溶剂，直至有固体析出，或当溶剂总体积加至5mL后，转至室温下磁力搅拌，若无固体析出，仍然澄清的样品转至室温挥发或旋干。离心收集固体并进行XRPD测试。得到盐酸盐Form A或游离态Form B晶型，试验结果见表12。Weigh approximately 20 mg of the Form A crystalline compound into a 5 mL vial, completely dissolve the solid with the corresponding solvent in Table 12, and filter it into another 20 mL vial using a 0.45 μm PTFE filter. Add the antisolvent in Table 12 dropwise to the clear solution while stirring until solid precipitates, or when the total solvent volume reaches 5 mL, transfer to room temperature for magnetic stirring. If no solid precipitates, transfer the still clear sample to Evaporate at room temperature or spin dry. The solid was collected by centrifugation and subjected to XRPD testing. The hydrochloride Form A or the free Form B crystal form was obtained. The test results are shown in Table 12.
表12：反溶剂添加实验结果
Table 12: Antisolvent addition experimental results
反反溶剂添加方法为：The anti-antisolvent addition method is:
称取约20mg的Form A晶型化合物加至5mL的小瓶内，用表13中对应溶剂将固体完全溶解，并使用0.45μm的PTFE滤头过滤至另一5mL小瓶。将该澄清溶液滴加至表13中的反溶剂中，反溶剂体积为3mL，转至室温下磁力搅拌，若无固体析出，仍然澄清的样品转至室温挥发或者旋干。离心收集固体并进行XRPD测试。试验结果见表13,得到盐酸盐Form A或盐酸盐Form D。Weigh approximately 20 mg of the Form A crystalline compound into a 5 mL vial, completely dissolve the solid with the corresponding solvent in Table 13, and filter it into another 5 mL vial using a 0.45 μm PTFE filter. Add the clear solution dropwise to the antisolvent in Table 13. The volume of the antisolvent is 3 mL. Move to room temperature and stir magnetically. If no solid precipitates, move the still clear sample to room temperature to evaporate or spin to dryness. The solid was collected by centrifugation and subjected to XRPD testing. The test results are shown in Table 13, and hydrochloride Form A or hydrochloride Form D is obtained.
表13：反反溶剂添加实验结果

Table 13: Anti-antisolvent addition experimental results

Form D的XRPD如图7所示。其为结晶态，结晶度高，室温闭口放置1天，转为盐酸盐Form A，推测其为亚稳晶型。The XRPD of Form D is shown in Figure 7. It is in a crystalline state with high crystallinity. If left at room temperature for 1 day with the lid closed, it will turn into hydrochloride Form A. It is speculated that it is a metastable crystal form.
冷却结晶方法为：The cooling crystallization method is:
称取约20mg的Form A晶型化合物加至3mL的小瓶内，加入1.0mL表14中的对应溶剂，在50℃下搅拌约2小时后使用0.45μm的PTFE滤头过滤至另一3mL小瓶。将该澄清滤液放置在50℃下搅拌自然降温至5℃。若有固体析出，离心收集固体并进行XRPD测试。试验结果见表14，只得到盐酸盐FormA。Weigh about 20 mg of Form A crystalline compound into a 3 mL vial, add 1.0 mL of the corresponding solvent in Table 14, stir at 50°C for about 2 hours, and then use a 0.45 μm PTFE filter to filter into another 3 mL vial. The clear filtrate was placed at 50°C and stirred to naturally cool down to 5°C. If solid precipitates, centrifuge to collect the solid and perform XRPD testing. The test results are shown in Table 14. Only hydrochloride FormA was obtained.
表14：冷却结晶实验结果
Table 14: Cooling crystallization experimental results
气液扩散方法为：The gas-liquid diffusion method is:
称取约20mg Form A晶型化合物至3mL小瓶中，加入0.5-1.0mL溶剂溶解，并使用0.45μm的PTFE滤头过滤至另一3mL小瓶，另取20mL的小瓶，向其中加入约3mL的反溶剂，将装有清液的3mL小瓶敞口置于20mL小瓶后，密封20mL的小瓶并于室温下静置约1周。收集得到的固体并进行XRPD测试。试验结果如表15所示，只得到盐酸盐FormA。Weigh approximately 20 mg of Form A crystalline compound into a 3 mL vial, add 0.5-1.0 mL of solvent to dissolve, and use a 0.45 μm PTFE filter to filter into another 3 mL vial. Take another 20 mL vial and add approximately 3 mL of reaction solution to it. For solvents, place the open 3 mL vial containing the clear solution in the 20 mL vial, seal the 20 mL vial and let it stand at room temperature for about 1 week. The resulting solid was collected and subjected to XRPD testing. The test results are shown in Table 15. Only hydrochloride FormA was obtained.
表15：气液扩散实验结果
Table 15: Gas-liquid diffusion experiment results
气固扩散方法为：The gas-solid diffusion method is:
称取约20mg每份的Form A晶型化合物于3mL小瓶中，另在20mL小瓶中加入约3mL表16中对应溶剂，将3mL小瓶敞口置于20mL小瓶中后，将20mL小瓶密封。室温下静置约11天后收集固体并进行XRPD测试。试验结果如表16所示，只得到盐酸盐Form A。 Weigh approximately 20 mg of each portion of the Form A crystalline compound into a 3 mL vial, add approximately 3 mL of the corresponding solvent in Table 16 to the 20 mL vial, place the open end of the 3 mL vial into a 20 mL vial, and seal the 20 mL vial. After standing at room temperature for about 11 days, the solid was collected and subjected to XRPD testing. The test results are shown in Table 16. Only hydrochloride Form A was obtained.
表16：气固扩散实验结果
Table 16: Gas-solid diffusion experiment results
水汽应激方法为：Water vapor stress methods are:
称取约20mg每份的Form A晶型化合物于3mL小瓶中，将3mL小瓶敞口置于相应的恒湿器中后，将恒湿器密封。室温下静置约两周后收集固体并进行XRPD测试。试验结果如表17所示，只得到盐酸盐Form A。Weigh approximately 20 mg of each portion of the Form A crystalline compound into a 3 mL vial, place the 3 mL vial open in the corresponding humidistat, and seal the humidistat. After standing at room temperature for about two weeks, the solid was collected and subjected to XRPD testing. The test results are shown in Table 17. Only hydrochloride Form A was obtained.
表17：水汽应激实验结果
Table 17: Water vapor stress experiment results
高聚物诱导方法为：The polymer induction method is:
称取约20mg每份的Form A晶型化合物于3mL小瓶中，加入2.0-3.0mL溶剂溶解(使用0.45μm的PTFE滤头过滤)，加入1-2mg聚合物，用封口膜封住小瓶，在上面扎孔，放置在室温下缓慢挥发。试验结果如表18所示，只得到盐酸盐Form A。Weigh about 20 mg of each Form A crystalline compound into a 3 mL vial, add 2.0-3.0 mL of solvent to dissolve (filter using a 0.45 μm PTFE filter), add 1-2 mg of polymer, seal the vial with a sealing film, and place in the Prick a hole in the top and leave it at room temperature to evaporate slowly. The test results are shown in Table 18. Only hydrochloride Form A was obtained.
表18：高聚物诱导实验结果

Table 18: Results of polymer induction experiments

研磨方法为：The grinding method is:
称取约20mg每份的Form A晶型化合物于研钵中，研磨(或加其它溶剂研磨)15分钟后收集固体测试XRPD。试验结果如表19所示，只得到盐酸盐Form A。Weigh about 20 mg of each portion of the Form A crystalline compound in a mortar, grind (or grind with other solvents) for 15 minutes, and then collect the solid for XRPD testing. The test results are shown in Table 19. Only hydrochloride Form A was obtained.
表19：研磨实验结果
Table 19: Grinding test results
循环升降温方法为：The cyclic heating and cooling method is:
称取20mg的Form A晶型化合物加入到3.0mL小瓶，加入0.5mL表20中所列的溶剂溶解样品(涡旋、超声促进溶解)，记录溶解情况。加入搅拌子，在磁力搅拌器上进行循环升降温。试验结果如表20所示，只得到盐酸盐Form A。Weigh 20 mg of Form A crystalline compound into a 3.0 mL vial, add 0.5 mL of the solvent listed in Table 20 to dissolve the sample (vortex, ultrasound to promote dissolution), and record the dissolution. Add a stir bar and cycle the temperature up and down on a magnetic stirrer. The test results are shown in Table 20, and only hydrochloride Form A was obtained.
循环升降温程序为：保持反应温度在50℃下120分钟，然后以每分钟0.1℃的速率将反应液温度降至5℃，然后在5℃保持120分钟。共进行2个循环。The cycle temperature increase and decrease program is: keep the reaction temperature at 50°C for 120 minutes, then lower the temperature of the reaction solution to 5°C at a rate of 0.1°C per minute, and then maintain it at 5°C for 120 minutes. A total of 2 cycles are performed.
表20：循环升降温实验结果
Table 20: Results of cyclic heating and cooling experiments
旋转蒸发方法为：The rotary evaporation method is:
称取50mg的Form A晶型化合物加入到20.0mL小瓶，加入一定体积对应溶剂溶解样品(涡旋、超声促进溶解)，用注射器和0.45μm的PTFE滤膜过滤，滤液转移至20.0mL小瓶，进行旋转蒸发(50℃)。试验结果如表21所示，得到盐酸盐Form B。Weigh 50 mg of the Form A crystal compound into a 20.0 mL vial, add a certain volume of the corresponding solvent to dissolve the sample (vortex, ultrasound to promote dissolution), filter with a syringe and a 0.45 μm PTFE filter, transfer the filtrate to the 20.0 mL vial, and proceed Rotary evaporation (50°C). The test results are shown in Table 21, and hydrochloride Form B was obtained.
表21：旋转蒸发实验结果
Table 21: Rotary evaporation experimental results
晶型Form B呈结晶态，结晶度弱，命名为盐酸盐Form B。将Form B室温闭口放置3天，晶型未发生改变。TGA实现显示，升温至170℃，样品失重仅为1.3807％。DSC实验表明，Form B有单一吸热峰，熔点为265.93℃(峰值温 度，1HNMR未见明显溶剂残留。由此推测Form B为无水晶型，其HPLC实验结果酸碱摩尔比为1.1:1。The crystal form Form B is in a crystalline state with weak crystallinity and is named hydrochloride Form B. Form B was left closed at room temperature for 3 days, and the crystal form did not change. TGA implementation shows that when the temperature is raised to 170°C, the sample weight loss is only 1.3807%. DSC experiments show that Form B has a single endothermic peak with a melting point of 265.93°C (peak temperature Degree, 1 HNMR showed no obvious solvent residue. It is inferred that Form B is an acrylic form, and its HPLC experimental result is that the acid-base molar ratio is 1.1:1.
Form B的XRPD、TGA、DSC、1HNMR分别如图8-11所示。The XRPD, TGA, DSC, and 1 HNMR of Form B are shown in Figure 8-11 respectively.
通过以上多晶型筛选实验，共得到4种晶型，包括无水晶型盐酸盐FormA/B、亚稳晶型盐酸盐FormC/D。多晶型的表征数据汇总于表22中。Through the above polymorphic screening experiments, a total of 4 crystal forms were obtained, including anhydrous hydrochloride FormA/B and metastable crystalline hydrochloride FormC/D. Characterization data for the polymorphs are summarized in Table 22.
表22：盐酸盐不同晶型的表征结果
Table 22: Characterization results of different crystal forms of hydrochloride
各晶型的XRPD叠图如图12所示。The XRPD overlay of each crystal form is shown in Figure 12.
实施例3：晶型性质评估Example 3: Evaluation of Crystal Form Properties
为了确认无水晶型(盐酸盐Form A或B)在不同温度条件下的稳定性关系，本发明还设置了室温和50℃下不同溶剂中的混悬竞争试验。具体步骤如下：首先配置了盐酸盐Form A在相应温度和溶剂下的饱和溶液，将等质量的不同晶型样品分别加入到过滤后的饱和溶液中形成悬浊液，分别在室温或50℃下悬浮搅拌。混悬竞争结果如图13所示，在乙醇体系(室温和50℃)、丙酮体系(室温和50℃)均得到盐酸盐FormA(混悬竞争1天)。由此，可以确定式(I)化合物盐酸盐的Form A晶型为室温和50℃下热力学更稳定的无水晶型。In order to confirm the stability relationship of the crystalline form (hydrochloride Form A or B) under different temperature conditions, the present invention also set up suspension competition tests in different solvents at room temperature and 50°C. The specific steps are as follows: First, prepare a saturated solution of hydrochloride Form A at the corresponding temperature and solvent, add equal masses of different crystalline samples to the filtered saturated solution to form a suspension, and store them at room temperature or 50°C. Suspend and stir. The results of the suspension competition are shown in Figure 13. The hydrochloride FormA was obtained in both the ethanol system (room temperature and 50°C) and the acetone system (room temperature and 50°C) (suspension competition for 1 day). From this, it can be determined that the Form A crystal form of the hydrochloride of the compound of formula (I) is a crystalline form that is more thermodynamically stable at room temperature and 50°C.
鉴于盐酸盐Form A为室温和50℃下热力学更稳定的无水晶型，本实施例评估了该晶型的性质。评估内容包括平衡溶解度、胃模拟液中晶型稳定性、固态理化稳定性和引湿性。Given that the hydrochloride salt Form A is an amorphous form that is more thermodynamically stable at room temperature and 50°C, this example evaluates the properties of this crystalline form. The evaluation includes equilibrium solubility, crystalline stability in gastric simulated fluid, solid-state physical and chemical stability, and hygroscopicity.
平衡溶解度实验：Equilibrium solubility experiment:
分别测定游离态Form A及盐酸盐Form A 24小时的水中平衡溶解度。试验 中，分别将10毫克固体与1.0毫升水在3毫升玻璃小瓶中混合，加入搅拌子，再将玻璃小瓶固定在磁力搅拌器上，并将磁力搅拌器放置于37℃的恒温箱中。24小时后，分离滤液测试HPLC浓度,所得固体进行XRPD测试。The equilibrium solubility in water of free Form A and hydrochloride Form A was measured for 24 hours. test , mix 10 mg of solid and 1.0 ml of water in a 3 ml glass vial, add a stir bar, then fix the glass vial on a magnetic stirrer, and place the magnetic stirrer in a 37°C incubator. After 24 hours, the filtrate was separated to test the HPLC concentration, and the solid obtained was tested by XRPD.
结果如表23所示，盐酸盐Form A溶解度与游离态Form A相比显著提升。此外，游离态Form A在溶解度试验过程中部分转变为游离态Form B；而盐酸盐Form A仅有少量转化为游离态Form B。具体的XRPD对比图如图14和图15所示。The results are shown in Table 23. The solubility of Hydrochloride Form A is significantly improved compared with free Form A. In addition, free Form A was partially converted to free Form B during the solubility test; while hydrochloride Form A was only converted to free Form B in a small amount. The specific XRPD comparison diagrams are shown in Figures 14 and 15.
表23：平衡溶解度实验结果
Table 23: Equilibrium solubility experimental results
胃模拟液中晶型稳定性实验：Crystal form stability experiment in gastric simulated liquid:
对盐酸盐Form A样品测试胃模拟液中晶型稳定性。试验中，将适量固体与一定量胃模拟液(SGF)在3毫升玻璃小瓶中混合，加入搅拌子，再将玻璃小瓶固定在磁力搅拌器上，并将磁力搅拌器放置于37℃恒温箱中。分别在平衡1小时和2天后时间点取样，离心分离，所得固体进行XRPD测试。Hydrochloride Form A samples were tested for crystalline stability in gastric simulated fluid. In the test, an appropriate amount of solid and a certain amount of simulated gastric fluid (SGF) were mixed in a 3 ml glass vial, a stirrer was added, the glass vial was fixed on a magnetic stirrer, and the magnetic stirrer was placed in a 37°C incubator. . Samples were taken at time points 1 hour and 2 days after equilibrium, centrifuged, and the solids obtained were tested by XRPD.
结果如表24所示，盐酸盐Form A在胃模拟液中1小时和2天后，未发生晶型改变，未发现游离态Form B。具体的XRPD对比图如图16所示。The results are shown in Table 24. After 1 hour and 2 days in the gastric simulation solution, Form A hydrochloride did not change its crystal form, and no free Form B was found. The specific XRPD comparison chart is shown in Figure 16.
表24：胃模拟液中晶型稳定性实验结果
Table 24: Experimental results of crystal form stability in gastric simulated liquid
一周稳定性实验：One week stability experiment:
对盐酸盐Form A样品分别在25℃，60％RH和40℃，75％RH条件下放置一周后，测试HPLC纯度及晶型变化。结果如表25所示，盐酸盐Form A在两 种测试条件下放置一周后，HPLC纯度无明显下降，化学稳定性良好，未观察到晶型变化。稳定性样品放置前后的XRPD如图17所示。After placing the hydrochloride Form A sample at 25°C, 60% RH and 40°C, 75% RH for one week, HPLC purity and crystal form changes were tested. The results are shown in Table 25. Hydrochloride Form A has two After being placed under the same test conditions for a week, the HPLC purity showed no significant decrease, the chemical stability was good, and no change in crystal form was observed. The XRPD of the stability sample before and after placement is shown in Figure 17.
表25：一周稳定性实验结果
Table 25: One-week stability test results
引湿性实验：Hygroscopicity test:
评估25℃下，样品随湿度变化的稳定性风险，对盐酸盐Form A进行了DVS测试，收集测试后的固体样品进行XRPD测试。结果见表26。在80％RH条件下，盐酸盐吸水0.4％，表明样品略有引湿性。DVS及XRPD测试结果如图18和图19所示，DVS测试前后，盐酸盐Form A晶型未发生变化。To evaluate the stability risk of the sample with changes in humidity at 25°C, a DVS test was conducted on the hydrochloride Form A, and the solid samples after the test were collected for XRPD testing. The results are shown in Table 26. Under 80% RH conditions, hydrochloride absorbs 0.4% water, indicating that the sample is slightly hygroscopic. The DVS and XRPD test results are shown in Figures 18 and 19. The crystal form of hydrochloride Form A did not change before and after the DVS test.
表26：引湿性实验结果
Table 26: Hygroscopicity test results
以上所述仅为本发明的优选实施例而已，并不用于限制本发明，对于本领域的技术人员来说，本发明可以有各种更改和变化。凡在本发明的精神和原则之内，所作的任何修改、等同替换、改进等，均应包含在本发明的保护范围之内 The above descriptions are only preferred embodiments of the present invention and are not intended to limit the present invention. For those skilled in the art, the present invention may have various modifications and changes. Any modifications, equivalent substitutions, improvements, etc. made within the spirit and principles of the present invention shall be included in the protection scope of the present invention.

Claims (10)

  1. 一种式(I)化合物，其结构式为：
    A compound of formula (I) whose structural formula is:
  2. 根据权利要求1所述的式(I)化合物，其特征在于，所述化合物为结晶形态；The compound of formula (I) according to claim 1, wherein the compound is in crystalline form;
    优选地，化合物的晶型为Form A；或Preferably, the crystal form of the compound is Form A; or
    优选地，化合物的晶型为Form B；或Preferably, the crystal form of the compound is Form B; or
    优选地，化合物的晶型为Form C；或Preferably, the crystal form of the compound is Form C; or
    优选地，化合物的晶型为Form D。Preferably, the crystal form of the compound is Form D.
  3. 根据权利要求2所述的式(I)化合物，其特征在于，其结晶形态为基本上单纯的形式；优选地，结晶形态为无水物的形式。The compound of formula (I) according to claim 2, characterized in that its crystalline form is a substantially pure form; preferably, the crystalline form is an anhydrous form.
  4. 式(I)化合物的Form A晶型，其特征在于，式(I)化合物的结构式为：所述晶型包括6个或更多个选自以下的2θ值的X射线粉末衍射图(Cu-Kα)：7.1±0.2°、12.1±0.2°、12.6±0.2°、14.3±0.2°、15.9±0.2°、16.2±0.2°、18.5±0.2°、20.3±0.2°、22.1±0.2°、24.8±0.2°、25.4±0.2°、26.8±0.2°；The Form A crystal form of the compound of formula (I) is characterized in that the structural formula of the compound of formula (I) is: The crystalline form includes an X-ray powder diffraction pattern of 6 or more 2θ values selected from the following (Cu-Kα ): 7.1±0.2°, 12.1±0.2°, 12.6±0.2°, 14.3±0.2°, 15.9±0.2°, 16.2±0.2°, 18.5±0.2°, 20.3±0.2°, 22.1±0.2°, 24.8±0.2 °, 25.4±0.2°, 26.8±0.2°;
    优选地，所述晶型包括8个或更多个选自以下的2θ值的X射线粉末衍射图(Cu-Kα)：7.1±0.2°、12.1±0.2°、12.6±0.2°、14.3±0.2°、15.9 ±0.2°、16.2±0.2°、18.5±0.2°、20.3±0.2°、22.1±0.2°、24.8±0.2°、25.4±0.2°、26.8±0.2°；Preferably, the crystalline form includes 8 or more X-ray powder diffraction patterns with 2θ values selected from the following (Cu-Kα ): 7.1±0.2°, 12.1±0.2°, 12.6±0.2°, 14.3±0.2°, 15.9 ±0.2°, 16.2±0.2°, 18.5±0.2°, 20.3±0.2°, 22.1±0.2°, 24.8±0.2°, 25.4±0.2°, 26.8±0.2°;
    优选地，所述晶型的X射线粉末衍射图在7.1±0.2°、12.1±0.2°、12.6±0.2°、14.3±0.2°、15.9±0.2°、16.2±0.2°、18.5±0.2°、20.3±0.2°、22.1±0.2°、24.8±0.2°、25.4±0.2°、26.8±0.2°具有特征峰。Preferably, the X-ray powder diffraction pattern of the crystalline form is at 7.1±0.2°, 12.1±0.2°, 12.6±0.2°, 14.3±0.2°, 15.9±0.2°, 16.2±0.2°, 18.5±0.2°, 20.3 There are characteristic peaks at ±0.2°, 22.1±0.2°, 24.8±0.2°, 25.4±0.2°, and 26.8±0.2°.
  5. 根据权利要求4所述的式(I)化合物的Form A晶型，其特征在于，具有下述(a)至(d)之一：The Form A crystal form of the compound of formula (I) according to claim 4, characterized in that it has one of the following (a) to (d):
    (a)与图2基本一致的X射线粉末衍射图(XPRD图)；(a) X-ray powder diffraction pattern (XPRD pattern) that is basically consistent with Figure 2;
    (b)与图3基本一致的热重量分析图(TGA图)；(b) Thermogravimetric analysis chart (TGA chart) basically consistent with Figure 3;
    (c)与图4基本一致的差示扫描量热法图(DSC图)；(c) Differential scanning calorimetry chart (DSC chart) basically consistent with Figure 4;
    (d)与图5基本一致的核磁氢谱图(1H NMR图)。(d) A hydrogen nuclear magnetic spectrum ( 1 H NMR chart) that is basically consistent with Figure 5.
  6. 式(I)化合物的Form B晶型，其特征在于，式(I)化合物的结构式为：The Form B crystal form of the compound of formula (I) is characterized in that the structural formula of the compound of formula (I) is:
    具有下述(e)至(h)之一： Have one of the following (e) to (h):
    (e)与图8基本一致的X射线粉末衍射图(XPRD图)；(e) X-ray powder diffraction pattern (XPRD pattern) that is basically consistent with Figure 8;
    (f)与图9基本一致的热重量分析图(TGA图)；(f) Thermogravimetric analysis chart (TGA chart) basically consistent with Figure 9;
    (g)与图10基本一致的差示扫描量热法图(DSC图)；(g) Differential scanning calorimetry chart (DSC chart) basically consistent with Figure 10;
    (h)与图11基本一致的核磁氢谱图(1H NMR图)。(h) A hydrogen nuclear magnetic spectrum ( 1 H NMR chart) that is basically consistent with Figure 11.
  7. 式(I)化合物的Form C晶型，其特征在于，式(I)化合物的结构式为：所述Form C晶型具有与图6基本一致的X射 线粉末衍射图(XPRD图)。The Form C crystal form of the compound of formula (I) is characterized in that the structural formula of the compound of formula (I) is: The Form C crystal form has an X-ray pattern that is essentially consistent with Figure 6 Line powder diffraction pattern (XPRD pattern).
  8. 式(I)化合物的Form D晶型，其特征在于，式(I)化合物的结构式为：所述Form D晶型具有与图7基本一致的X射线粉末衍射图(XPRD图)。The Form D crystal form of the compound of formula (I) is characterized in that the structural formula of the compound of formula (I) is: The Form D crystal form has an X-ray powder diffraction pattern (XPRD pattern) that is substantially consistent with Figure 7.
  9. 一种药物组合物，其包含如权利要求1-8任一项所述化合物或晶型作为活性成分，及至少一种药学上可接受的载体或赋形剂。A pharmaceutical composition comprising the compound or crystal form according to any one of claims 1 to 8 as an active ingredient, and at least one pharmaceutically acceptable carrier or excipient.
  10. 权利要求1-9任一项化合物或晶型的制备方法，包括：将游离态的式(I)化合物与浓盐酸/异丙醇混合溶液搅拌的步骤。 The method for preparing the compound or crystal form of any one of claims 1 to 9, including the step of stirring the free compound of formula (I) with a concentrated hydrochloric acid/isopropyl alcohol mixed solution.
PCT/CN2023/098478 2022-04-07 2023-06-06 Toll-like receptor 8-specific inhibitor hydrochloride, preparation method therefor and use thereof WO2023193830A1 (en)

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