WO2023174399A1 - Crystal form of substituted oxopyridine derivative and preparation method therefor - Google Patents

Crystal form of substituted oxopyridine derivative and preparation method therefor Download PDF

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Publication number
WO2023174399A1
WO2023174399A1 PCT/CN2023/082138 CN2023082138W WO2023174399A1 WO 2023174399 A1 WO2023174399 A1 WO 2023174399A1 CN 2023082138 W CN2023082138 W CN 2023082138W WO 2023174399 A1 WO2023174399 A1 WO 2023174399A1
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crystal form
present
crystal
formula
compound
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PCT/CN2023/082138
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French (fr)
Chinese (zh)
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鲁霞
陈智雄
张晓宇
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苏州晶云药物科技股份有限公司
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4412—Non condensed pyridines; Hydrogenated derivatives thereof having oxo groups directly attached to the heterocyclic ring
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/10—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing aromatic rings

Definitions

  • the present invention relates to the field of chemical medicine, and in particular to the crystal form of substituted oxopyridine derivatives and their preparation method.
  • Factor XIa Factor XIa
  • FXIIa Factor XIa
  • thrombin also activates factor XI to factor XIa, whereby factor IX is converted into factor IXa, by which Of the factor IXa/factor VIIIa complex, factor
  • Patent WO2017005725A1 discloses the compound of formula (I) and its synthesis.
  • the disclosed synthesis method requires the use of Chiralpak AD-H SFC chromatographic column for separation. The method process is cumbersome and produces toxic and harmful waste liquid.
  • Patent WO2019175043A1 discloses three solvates of the compound of formula (I), namely isopropyl acetate solvate, tetrahydrofuran solvate and acetone solvate, which do not meet the safety requirements of pharmaceutical raw materials.
  • Patent WO2022189279A1 discloses two crystal forms of the compound of formula (I), namely modification I and II.
  • modification I needs to be prepared using modification A, an analogue of the compound of formula (I), as a seed crystal.
  • Modification II is obtained by vacuum drying the acetone solvate of the compound of formula (I) under high temperature conditions.
  • the preparation method is complicated. And it is difficult to control, so it is necessary to develop more crystal forms that meet the safety requirements of pharmaceutical raw materials and simple preparation methods.
  • the present invention provides crystalline form A of the compound of formula (I) and its preparation method.
  • a pharmaceutical composition comprising the crystal according to any one of 1 to 3 above and a pharmaceutically acceptable carrier.
  • a pharmaceutical composition having FXIa inhibitory activity which contains the crystal according to any one of 1 to 3 above as an active ingredient.
  • a drug for treating stroke and thromboembolism which contains the crystal according to any one of 1 to 3 above as an active ingredient.
  • the crystal form A of the compound of formula (I) provided by the present invention has better performance in solubility, melting point, stability, dissolution, hygroscopicity, adhesion, fluidity, biological effectiveness, processing performance, purification effect, It has advantages in at least one aspect of preparation production and safety, and provides a new and better choice for the preparation of pharmaceutical preparations containing compounds of formula (I), which is of great significance for drug development.
  • the X-ray powder diffraction of the crystalline form A has a 2 ⁇ value of 14.5° ⁇ 0.2°, 20.3° ⁇ 0.2°, 23.4° ⁇ 0.2° at one, two or three places. There are characteristic peaks.
  • the X-ray powder diffraction of the crystal form A has characteristic peaks at 2 ⁇ values of 14.5° ⁇ 0.2°, 20.3° ⁇ 0.2°, and 23.4° ⁇ 0.2°.
  • the X-ray powder diffraction of the crystal form A has a 2 ⁇ value of 13.6° ⁇ 0.2°, 19.3° ⁇ 0.2°, or 25.1° ⁇ 0.2° at one, two or three places. There are characteristic peaks.
  • the X-ray powder diffraction of the crystal form A has characteristic peaks at 2 ⁇ values of 13.6° ⁇ 0.2°, 19.3° ⁇ 0.2°, and 25.1° ⁇ 0.2°.
  • the X-ray powder diffraction of the crystal form A has a 2 ⁇ value of 6.6° ⁇ 0.2°, 12.4° ⁇ 0.2°, 13.6° ⁇ 0.2°, 14.5° ⁇ 0.2°, and 18.3° ⁇ Any 4, or 5, or 6, or 7, or 8, or 9 of 0.2°, 19.3° ⁇ 0.2°, 20.3° ⁇ 0.2°, 23.4° ⁇ 0.2°, 25.1° ⁇ 0.2° There are characteristic peaks everywhere.
  • the X-ray powder diffraction of the crystal form A has a 2 ⁇ value of 6.6° ⁇ 0.2°, 12.4° ⁇ 0.2°, 13.6° ⁇ 0.2°, 14.5° ⁇ 0.2°, and 18.3° ⁇ There are characteristic peaks at 0.2°, 19.3° ⁇ 0.2°, 20.3° ⁇ 0.2°, 23.4° ⁇ 0.2°, and 25.1° ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the crystal form A is shown in Figure 1.
  • the alcoholic solvent is ethanol or n-propanol.
  • the dissolution and volatilization temperature is 10-50°C, such as 20-30°C.
  • the alcoholic solvent is n-propanol; the antisolvent is pure water.
  • the dissolving, dropping, stirring and precipitation temperatures are 10°C to 50°C, such as 20°C to 30°C.
  • the compounds of formula (I) used as starting materials refer to their solid (crystalline or amorphous), semi-solid, waxy or oily form.
  • the compound of formula (I) used as starting material is in solid powder form.
  • the “stirring” is accomplished by conventional methods in the field, such as magnetic stirring or mechanical stirring.
  • the stirring speed is 50 to 1800 rpm.
  • the magnetic stirring is 200 to 1500 rpm, preferably 300 to 1000 rpm.
  • mechanical stirring is preferably 100 to 300 rpm.
  • the above-mentioned crystals of the present invention can be used to prepare pharmaceutical compositions, which contain the above-mentioned crystals of the present invention and pharmaceutically acceptable carriers.
  • the above-mentioned crystal of the present invention can be used to prepare a pharmaceutical composition with FXIa inhibitory activity, which contains the above-mentioned crystal of the present invention as an active ingredient.
  • the above-mentioned crystals of the present invention can be used to prepare preventive or therapeutic drugs for stroke and thromboembolism, which contain the above-mentioned crystals of the present invention as an active ingredient.
  • the present invention also provides a pharmaceutical composition, which contains the above-mentioned crystal of the present invention and a pharmaceutically acceptable carrier.
  • the present invention also provides a pharmaceutical composition with FXIa inhibitory activity, which contains the above-mentioned crystal of the present invention as an active ingredient.
  • the present invention provides a preventive or therapeutic drug for stroke and thromboembolism, which contains the crystal of the present invention as an active ingredient.
  • crystal or “polymorph” means that which is confirmed by the X-ray diffraction pattern characterization shown.
  • X-ray diffraction patterns often change with the conditions of the instrument. It is particularly important to point out that the relative intensity of X-ray diffraction patterns may also change with changes in experimental conditions, so the order of peak intensity cannot be used as the only or decisive factor. In fact, the relative intensity of the diffraction peaks in the X-ray diffraction pattern is related to the preferred orientation of the crystal.
  • the peak intensities shown in this article are illustrative and not used for absolute comparison.
  • the experimental error of the peak angle is usually 5% or less. The error of these angles should also be taken into account, and an error of ⁇ 0.2° is usually allowed.
  • the overall peak angle will shift. Usually A certain offset is allowed. Therefore, those skilled in the art can understand that the X-ray diffraction pattern of a crystalline form in the present invention does not have to be completely consistent with the X-ray diffraction pattern in the example referred to here.
  • the "X-ray diffraction pattern the same" mentioned herein does not mean that absolutely the same, the same peak position can differ by ⁇ 0.2° and the peak intensity allows certain variability.
  • Any crystalline form having the same or similar pattern as the characteristic peaks in these patterns falls within the scope of the present invention.
  • Those skilled in the art can compare the spectrum listed in the present invention with the spectrum of an unknown crystal form to confirm whether the two sets of patterns reflect the same or different crystal forms.
  • Form A of the present invention is pure and unitary, with substantially no admixture of any other crystalline forms.
  • substantially no when used to refer to a new crystal form means that the crystal form contains less than 20% (weight) of other crystal forms, especially less than 10% (weight) of other crystal forms, and even less Less than 5% (weight) of other crystalline forms refers to less than 1% (weight) of other crystalline forms.
  • the numerical values and numerical ranges mentioned in the present invention should not be narrowly understood as the numerical values or numerical ranges themselves. Those skilled in the art should understand that they can be determined according to different specific technical environments without departing from the spirit and scope of the present invention. There will be some fluctuation around the specific numerical value on the basis of principles. In the present invention, such a floating range that can be foreseen by those skilled in the art is often expressed by the term "about”.
  • room temperature in the present invention usually refers to 22°C to 28°C.
  • PSD particle size distribution
  • PLM Polarized Light Microscope
  • the X-ray powder diffraction patterns described in the present invention were collected on Empyrean type and X'Pert 3 type X-ray powder diffractometers of Panalytical Company.
  • the method parameters of X-ray powder diffraction according to the present invention are as follows:
  • differential scanning calorimetry analysis diagrams described in the present invention were collected on TA Company's Q200 and Discovery DSC 2500 differential scanning calorimeters.
  • the method parameters of differential scanning calorimetry analysis according to the present invention are as follows:
  • thermogravimetric analysis diagram described in the present invention was collected on the Discovery TGA 5500 and Q5000 thermogravimetric analyzers of TA Company.
  • the method parameters of thermogravimetric analysis according to the present invention are as follows:
  • the hydrogen nuclear magnetic resonance spectrum data ( 1 H NMR) described in the present invention is collected from a Bruker Avance II DMX 400M HZ nuclear magnetic resonance spectrometer. Weigh 1-5 mg of sample, dissolve it in 0.5 mL of deuterated dimethyl sulfoxide, and prepare a solution of 2-10 mg/mL for testing.
  • the dynamic moisture adsorption diagram of the present invention is collected on the Intrinsic type and Intrinsic Plus type dynamic moisture adsorption instruments of SMS Company.
  • the method parameters of the dynamic moisture adsorption test according to the present invention are as follows:
  • Relative humidity gradient 10% (0%RH-90%RH-0%RH), 5% (90%RH-95%RH and 95%RH-90%RH)
  • the particle size distribution results described in the present invention were collected on Microtrac's S3500 laser particle size analyzer.
  • Microtrac S3500 is equipped with SDC (Sample Delivery Controller) sampling system.
  • SDC Sample Delivery Controller
  • This test adopts the wet method, and the test dispersion medium is Isopar G (containing 0.2% lecithin).
  • the method parameters of the laser particle size analyzer are as follows: *: 60% of flow rate is 60% of 65mL/s
  • the polarized light microscope photos described in the present invention were collected at room temperature through a Zeiss microscope Axio Scope.A1.
  • the microscope is equipped with an Axiocam 305 color camera and 5 ⁇ , 10 ⁇ , 20 ⁇ and 50 ⁇ objective lenses.
  • the starting material of formula (I) used in the following examples can be prepared according to the existing technology, for example, according to the method described in patent WO2017005725A1, but the starting crystal form is not a limiting condition for preparing the crystal form of the present invention.
  • Example 1 Preparation of crystal form A (room temperature evaporation method)
  • the crystal form A of the present invention is prepared into a suspension using SGF (simulated artificial gastric juice), FaSSIF (artificial intestinal fluid in a fasting state), FeSSIF (artificial intestinal fluid in a satiated state) and pure water respectively. After equilibrating for 24 hours and 24 hours, filter and obtain a saturated solution. The content of the sample in the saturated solution was determined by high performance liquid chromatography (HPLC). The test results are shown in Table 4, and the solubility curves are shown in Figures 7 to 10. The test results show that the crystal form A of the present invention has good solubility in SGF, FaSSIF, FeSSIF and pure water, and meets the pharmaceutical needs.
  • SGF simulated artificial gastric juice
  • FaSSIF artificial intestinal fluid in a fasting state
  • FeSSIF artificial intestinal fluid in a satiated state
  • pure water pure water
  • Example 5 Compressibility of crystalline forms
  • Example 7 Comparative study on hygroscopicity
  • Hygroscopic weight gain by absorbing moisture is less than 15% but not less than 2%
  • weight gain due to moisture attraction is less than 2% but not less than 0.2%
  • weight gain due to moisture absorption is less than 0.2%
  • the test results show that the crystal form A of the present invention has a unimodal distribution with an average particle size of 13.14 microns and a uniform particle size distribution; the Form II has a bimodal distribution with an average particle size of 67.84 microns. It shows that the crystal form A of the present invention has a more uniform particle size distribution than the form II.

Abstract

The present invention relates to a crystal form of a substituted oxopyridine derivative and to a preparation method therefor. The invention provides a crystal form A of a compound shown in formula (I), as well as a preparation method therefor and a use thereof. The crystal form A of the formula (I) compound provided by the present invention has at least one of the advantages of: solubility, melting point, stability, degree of dissolution, hygroscopicity, adhesiveness, fluidity, bioavailability, processability, purification effect, preparation production, safety, etc.; a new better choice is provided for preparing a pharmaceutical preparation containing the formula (I) compound, with very important significance for drug development.

Description

取代的氧代吡啶类衍生物的晶型及其制备方法Crystal forms of substituted oxopyridine derivatives and preparation methods thereof 技术领域Technical field
本发明涉及化学医药领域，特别是涉及取代的氧代吡啶类衍生物的晶型及其制备方法。The present invention relates to the field of chemical medicine, and in particular to the crystal form of substituted oxopyridine derivatives and their preparation method.
背景技术Background technique
血液凝固是有机体的保护机制，其有助于迅速地和可靠地“封闭”血管壁中的缺陷。因子XIa(FXIa)是凝固背景下一种重要的酶，其可以通过凝血酶和因子XIIa(FXIIa)二者活化，并因此涉及凝固的两个必不可少的过程：它是从凝固启动到放大和蔓延的过渡的中心组件：在正反馈回路中，除了因子V和因子VIII之外，凝血酶还将因子XI活化为因子XIa，藉此因子IX被转化为因子IXa，通过以这种方式产生的因子IXa/因子VIIIa复合物，因子X被活化并因此依次高度刺激凝血酶形成，从而导致强有力的血栓生长并稳定血栓。Blood coagulation is a protective mechanism of the organism that helps to quickly and reliably "seal" defects in the walls of blood vessels. Factor XIa (FXIa) is an important enzyme in the context of coagulation, which can be activated by both thrombin and factor XIIa (FXIIa) and is therefore involved in two essential processes of coagulation: it is involved in coagulation initiation and amplification and the central component of the spreading transition: in a positive feedback loop, in addition to factor V and factor VIII, thrombin also activates factor XI to factor XIa, whereby factor IX is converted into factor IXa, by which Of the factor IXa/factor VIIIa complex, factor
4-({(2S)-2-[4-{5-氯-2-[4-(三氟甲基)-1H-1,2,3-三唑-1-基]苯基}-5-甲氧基-2-氧代吡啶-1(2H)-基]丁酰基}氨基)-2-氟苯甲酰胺是一种高选择性的FXIa抑制剂，临床上用于中风和血栓栓塞的治疗，其结构式如下所示：
4-({(2S)-2-[4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-5 -Methoxy-2-oxopyridin-1(2H)-yl]butyryl}amino)-2-fluorobenzamide is a highly selective FXIa inhibitor clinically used for stroke and thromboembolism Treatment, its structural formula is as follows:
专利WO2017005725A1公开了式(I)化合物及其合成，公开的合成方法需利用Chiralpak AD-H SFC色谱柱进行分离，方法过程繁琐且会产生有毒有害的废液。专利WO2019175043A1公开了式(I)化合物的三个溶剂合物，即乙酸异丙酯溶剂合物、四氢呋喃溶剂合物和丙酮溶剂合物，不满足药用原料药对安全性的要求。专利WO2022189279A1公开了式(I)化合物的两个晶型，即modification I和II。制备方法中，modification I需要以式(I)化合物的类似物晶型modification A作为晶种进行制备，modification II由式(I)化合物的丙酮溶剂合物在高温条件下真空干燥获得，制备方法繁杂且不易控制，因此有必要开发更多满足药用原料药安全性要求与简单制备方法的晶型。Patent WO2017005725A1 discloses the compound of formula (I) and its synthesis. The disclosed synthesis method requires the use of Chiralpak AD-H SFC chromatographic column for separation. The method process is cumbersome and produces toxic and harmful waste liquid. Patent WO2019175043A1 discloses three solvates of the compound of formula (I), namely isopropyl acetate solvate, tetrahydrofuran solvate and acetone solvate, which do not meet the safety requirements of pharmaceutical raw materials. Patent WO2022189279A1 discloses two crystal forms of the compound of formula (I), namely modification I and II. In the preparation method, modification I needs to be prepared using modification A, an analogue of the compound of formula (I), as a seed crystal. Modification II is obtained by vacuum drying the acetone solvate of the compound of formula (I) under high temperature conditions. The preparation method is complicated. And it is difficult to control, so it is necessary to develop more crystal forms that meet the safety requirements of pharmaceutical raw materials and simple preparation methods.
此外，同一药物的不同晶型在溶解度、熔点、密度、稳定性等方面有显著的差异，从而不同程度地影响药物的稳定性、均一性、生物利用度、疗效和安全性。因此，药物研发中进行全面系统的多晶型筛选，选择最适合开发的晶型，是不可忽视的重要研究内容之一。基于此，有必要对化合物(I)进行多晶型筛选，为药物的后续开发提供更多更好的选择。In addition, different crystal forms of the same drug have significant differences in solubility, melting point, density, stability, etc., thus affecting the stability, uniformity, bioavailability, efficacy and safety of the drug to varying degrees. Therefore, conducting comprehensive and systematic polymorph screening during drug research and development to select the most suitable crystal form for development is one of the important research contents that cannot be ignored. Based on this, it is necessary to screen polymorphs of compound (I) to provide more and better options for the subsequent development of drugs.
发明内容Contents of the invention
本发明提供了式(I)化合物的晶型A及其制备方法。 The present invention provides crystalline form A of the compound of formula (I) and its preparation method.
1.式(I)所示化合物4-({(2S)-2-[4-{5-氯-2-[4-(三氟甲基)-1H-1,2,3-三唑-1-基]苯基}-5-甲氧基-2-氧代吡啶-1(2H)-基]丁酰基}氨基)-2-氟苯甲酰胺的A型晶体、即晶型A，其特征在于，使用Cu-Kα辐射，所述晶型A的X射线粉末衍射在2θ值为6.6°±0.2°、12.4°±0.2°、18.3°±0.2°处有特征峰，
1. Compound 4-({(2S)-2-[4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazole- Type A crystal of 1-yl]phenyl}-5-methoxy-2-oxopyridin-1(2H)-yl]butyryl}amino)-2-fluorobenzamide, which The characteristic is that using Cu-Kα radiation, the X-ray powder diffraction of the crystal form A has characteristic peaks at 2θ values of 6.6°±0.2°, 12.4°±0.2°, and 18.3°±0.2°,
2.根据上述1所述的晶型A，其X射线粉末衍射在2θ值为14.5°±0.2°、20.3°±0.2°、23.4°±0.2°中的一处或两处或三处有特征峰。2. According to the crystalline form A described in the above 1, its X-ray powder diffraction is characterized by one, two or three 2θ values of 14.5°±0.2°, 20.3°±0.2°, and 23.4°±0.2°. peak.
3.根据上述1或2所述的所述晶型A，其X射线粉末衍射在2θ值为14.5°±0.2°、20.3°±0.2°、23.4°±0.2°有特征峰。3. According to the crystal form A described in 1 or 2 above, its X-ray powder diffraction has characteristic peaks at 2θ values of 14.5°±0.2°, 20.3°±0.2°, and 23.4°±0.2°.
4.上述1～3中任一项所述的晶型A的制备方法，其特征在于，4. The method for preparing crystal form A according to any one of 1 to 3 above, characterized in that:
(1)在10～50℃下，将式(I)化合物溶解于醇类溶剂中，将溶液挥发，直至固体析出，得到晶型A；或(1) Dissolve the compound of formula (I) in an alcohol solvent at 10 to 50°C, and evaporate the solution until the solid precipitates to obtain crystal form A; or
(2)在10～50℃下，将式(I)化合物溶解于醇类溶剂中，向其中加入纯水，直至固体析出，得到晶型A。(2) Dissolve the compound of formula (I) in an alcohol solvent at 10 to 50°C, and add pure water to it until the solid precipitates to obtain crystal form A.
5.药物组合物，其包含上述1～3中任一项所述的晶体和制药学可接受的载体。5. A pharmaceutical composition comprising the crystal according to any one of 1 to 3 above and a pharmaceutically acceptable carrier.
6.具有FXIa抑制活性的药物组合物，其含有上述1～3中任一项所述的晶体作为有效成分。6. A pharmaceutical composition having FXIa inhibitory activity, which contains the crystal according to any one of 1 to 3 above as an active ingredient.
7.中风和血栓栓塞的治疗药，其含有上述1～3中任一项所述的晶体作为有效成分。7. A drug for treating stroke and thromboembolism, which contains the crystal according to any one of 1 to 3 above as an active ingredient.
与现有技术相比，本发明提供的式(I)化合物晶型A，在溶解度、熔点、稳定性、溶出度、引湿性、黏附性、流动性、生物有效性以及加工性能、提纯作用、制剂生产、安全性等方面中的至少一方面上存在优势，为含式(I)化合物的药物制剂的制备提供了新的更好的选择，对于药物开发具有非常重要的意义。Compared with the existing technology, the crystal form A of the compound of formula (I) provided by the present invention has better performance in solubility, melting point, stability, dissolution, hygroscopicity, adhesion, fluidity, biological effectiveness, processing performance, purification effect, It has advantages in at least one aspect of preparation production and safety, and provides a new and better choice for the preparation of pharmaceutical preparations containing compounds of formula (I), which is of great significance for drug development.
附图说明Description of the drawings
图1实施例1晶型A的XRPD图Figure 1 XRPD pattern of crystal form A of Example 1
图2实施例2晶型A的XRPD图Figure 2 XRPD pattern of crystal form A of Example 2
图3实施例2晶型A的TGA图Figure 3 TGA diagram of crystal form A of Example 2
图4实施例2晶型A的DSC图Figure 4 DSC diagram of crystal form A of Example 2
图5实施例2晶型A的1H NMR图Figure 5 1 H NMR pattern of crystal form A of Example 2
图6实施例3晶型A的XRPD图 Figure 6 XRPD pattern of crystal form A of Example 3
图7晶型A室温下在SGF中的溶解度曲线Figure 7 Solubility curve of Form A in SGF at room temperature
图8晶型A室温下在FaSSIF中的溶解度曲线Figure 8 Solubility curve of Form A in FaSSIF at room temperature
图9晶型A室温下在FeSSIF中的溶解度曲线Figure 9 Solubility curve of Form A in FeSSIF at room temperature
图10晶型A室温下在水中的溶解度曲线Figure 10 Solubility curve of Form A in water at room temperature
图11晶型A压片前后的XRPD叠图Figure 11 XRPD overlay of crystal form A before and after tableting
图12晶型A在25℃/60％相对湿度下的XRPD叠图Figure 12 XRPD stack of Form A at 25°C/60% relative humidity
图13晶型A在40℃/75％相对湿度下的XRPD叠图Figure 13 XRPD overlay of Form A at 40°C/75% relative humidity
图14晶型A的动态水分吸附图Figure 14 Dynamic moisture adsorption diagram of Form A
图15晶型A在DVS测试前后的XRPD叠图Figure 15 XRPD overlay of Form A before and after DVS test
图16Form II的动态水分吸附图Figure 16 Dynamic moisture adsorption diagram of Form II
图17Form II在DVS测试前后的XRPD叠图Figure 17 XRPD overlay of Form II before and after DVS test
图18晶型A的PSD图Figure 18 PSD diagram of crystal form A
图19Form II的PSD图Figure 19 PSD diagram of Form II
具体实施方式Detailed ways
晶型AForm A
式(I)所示化合物4-({(2S)-2-[4-{5-氯-2-[4-(三氟甲基)-1H-1,2,3-三唑-1-基]苯基}-5-甲氧基-2-氧代吡啶-1(2H)-基]丁酰基}氨基)-2-氟苯甲酰胺的A型晶体、即晶型A，其特征在于，使用Cu-Kα辐射，所述晶型A的X射线粉末衍射在2θ值为6.6°±0.2°、12.4°±0.2°、18.3°±0.2°处有特征峰，
Compound 4-({(2S)-2-[4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazole-1-) represented by formula (I) Type A crystals of methyl]phenyl}-5-methoxy-2-oxopyridin-1(2H)-yl]butyryl}amino)-2-fluorobenzamide, which is characterized by: , using Cu-Kα radiation, the X-ray powder diffraction of the crystal form A has characteristic peaks at 2θ values of 6.6°±0.2°, 12.4°±0.2°, and 18.3°±0.2°,
在本发明的一个实施方式中，所述晶型A的X射线粉末衍射在2θ值为14.5°±0.2°、20.3°±0.2°、23.4°±0.2°中的一处或两处或三处有特征峰。In one embodiment of the present invention, the X-ray powder diffraction of the crystalline form A has a 2θ value of 14.5°±0.2°, 20.3°±0.2°, 23.4°±0.2° at one, two or three places. There are characteristic peaks.
在本发明的一个实施方式中，所述晶型A的X射线粉末衍射在2θ值为14.5°±0.2°、20.3°±0.2°、23.4°±0.2°处有特征峰。In one embodiment of the present invention, the X-ray powder diffraction of the crystal form A has characteristic peaks at 2θ values of 14.5°±0.2°, 20.3°±0.2°, and 23.4°±0.2°.
在本发明的一个实施方式中，所述晶型A的X射线粉末衍射在2θ值为13.6°±0.2°、19.3°±0.2°、25.1°±0.2°中的一处或两处或三处有特征峰。In one embodiment of the present invention, the X-ray powder diffraction of the crystal form A has a 2θ value of 13.6°±0.2°, 19.3°±0.2°, or 25.1°±0.2° at one, two or three places. There are characteristic peaks.
在本发明的一个实施方式中，所述晶型A的X射线粉末衍射在2θ值为13.6°±0.2°、19.3°±0.2°、25.1°±0.2°处有特征峰。 In one embodiment of the present invention, the X-ray powder diffraction of the crystal form A has characteristic peaks at 2θ values of 13.6°±0.2°, 19.3°±0.2°, and 25.1°±0.2°.
在本发明的一个实施方式中，所述晶型A的X射线粉末衍射在2θ值为6.6°±0.2°、12.4°±0.2°、13.6°±0.2°、14.5°±0.2°、18.3°±0.2°、19.3°±0.2°、20.3°±0.2°、23.4°±0.2°、25.1°±0.2°中的任意4处、或5处、或6处、或7处、或8处、或9处有特征峰。In one embodiment of the present invention, the X-ray powder diffraction of the crystal form A has a 2θ value of 6.6°±0.2°, 12.4°±0.2°, 13.6°±0.2°, 14.5°±0.2°, and 18.3°± Any 4, or 5, or 6, or 7, or 8, or 9 of 0.2°, 19.3°±0.2°, 20.3°±0.2°, 23.4°±0.2°, 25.1°±0.2° There are characteristic peaks everywhere.
在本发明的一个实施方式中，所述晶型A的X射线粉末衍射在2θ值为6.6°±0.2°、12.4°±0.2°、13.6°±0.2°、14.5°±0.2°、18.3°±0.2°、19.3°±0.2°、20.3°±0.2°、23.4°±0.2°、25.1°±0.2°处有特征峰。In one embodiment of the present invention, the X-ray powder diffraction of the crystal form A has a 2θ value of 6.6°±0.2°, 12.4°±0.2°, 13.6°±0.2°, 14.5°±0.2°, and 18.3°± There are characteristic peaks at 0.2°, 19.3°±0.2°, 20.3°±0.2°, 23.4°±0.2°, and 25.1°±0.2°.
在本发明的一个实施方式中，所述晶型A的X射线粉末衍射图如图1所示。In one embodiment of the present invention, the X-ray powder diffraction pattern of the crystal form A is shown in Figure 1.
所述的晶型A的制备方法，其特征在于，The preparation method of crystal form A is characterized by:
(1)将式(I)化合物溶解于醇类溶剂中，将溶液挥发，直至固体析出，得到晶型A。(1) Dissolve the compound of formula (I) in an alcoholic solvent, and evaporate the solution until the solid precipitates to obtain crystal form A.
在本发明的一个实施方式中，所述醇类溶剂为乙醇或正丙醇。In one embodiment of the present invention, the alcoholic solvent is ethanol or n-propanol.
在本发明的一个实施方式中，所述溶解和挥发温度为10～50℃，例如20～30℃。In one embodiment of the present invention, the dissolution and volatilization temperature is 10-50°C, such as 20-30°C.
(2)将式(I)化合物固体溶解于醇类溶剂中，搅拌状态下向其中逐滴加入反溶剂，直至固体析出，得到晶型A。(2) Dissolve the solid compound of formula (I) in an alcoholic solvent, and add the antisolvent dropwise thereto under stirring until the solid precipitates to obtain crystal form A.
在本发明的一个实施方式中，所述醇类溶剂为正丙醇；所述反溶剂为纯水。In one embodiment of the present invention, the alcoholic solvent is n-propanol; the antisolvent is pure water.
在本发明的一个实施方式中，所述溶解、滴加、搅拌和析出温度为10℃到50℃，例如20℃到30℃。In one embodiment of the present invention, the dissolving, dropping, stirring and precipitation temperatures are 10°C to 50°C, such as 20°C to 30°C.
根据本发明，作为原料的所述式(I)化合物指其固体(晶体或无定形)、半固体、蜡或油形式。优选地，作为原料的式(I)化合物为固体粉末形式。所述“搅拌”，采用本领域的常规方法完成，例如磁力搅拌或机械搅拌，搅拌速度为50～1800转/分钟，其中，磁力搅拌200～1500转/分钟，优选为300～1000转/分钟，机械搅拌优选为100～300转/分钟。According to the invention, the compounds of formula (I) used as starting materials refer to their solid (crystalline or amorphous), semi-solid, waxy or oily form. Preferably, the compound of formula (I) used as starting material is in solid powder form. The "stirring" is accomplished by conventional methods in the field, such as magnetic stirring or mechanical stirring. The stirring speed is 50 to 1800 rpm. Among them, the magnetic stirring is 200 to 1500 rpm, preferably 300 to 1000 rpm. , mechanical stirring is preferably 100 to 300 rpm.
上述本发明的晶体可以用于制备药物组合物，在制备药物组合物时含有上述本发明的晶体和制药学可接受的载体。上述本发明的晶体可以用于制备具有FXIa抑制活性的药物组合物，其包含上述本发明的晶体作为有效成分。上述本发明的晶体可以用于制备中风和血栓栓塞的预防药或治疗药，其包含上述本发明的晶体作为有效成分。The above-mentioned crystals of the present invention can be used to prepare pharmaceutical compositions, which contain the above-mentioned crystals of the present invention and pharmaceutically acceptable carriers. The above-mentioned crystal of the present invention can be used to prepare a pharmaceutical composition with FXIa inhibitory activity, which contains the above-mentioned crystal of the present invention as an active ingredient. The above-mentioned crystals of the present invention can be used to prepare preventive or therapeutic drugs for stroke and thromboembolism, which contain the above-mentioned crystals of the present invention as an active ingredient.
本发明还提供药物组合物，其包含上述本发明的晶体和制药学可接受的载体。The present invention also provides a pharmaceutical composition, which contains the above-mentioned crystal of the present invention and a pharmaceutically acceptable carrier.
本发明还提供具有FXIa抑制活性的药物组合物，其含有上述本发明的晶体作为有效成分。The present invention also provides a pharmaceutical composition with FXIa inhibitory activity, which contains the above-mentioned crystal of the present invention as an active ingredient.
本发明提供中风和血栓栓塞的预防药或治疗药，其含有上述本发明的晶体作为有效成分。The present invention provides a preventive or therapeutic drug for stroke and thromboembolism, which contains the crystal of the present invention as an active ingredient.
本发明中，“晶体”或“多晶型”指的是被所示的X射线衍射图表征所证实的。本领域技术人员能够理解，这里所讨论的理化性质可以被表征，其中的实验误差取决于仪器的条件、样品的准备和样品的纯度。特别是，本领域技术人员公知，X射线衍射图通常会随着仪器的条件而有所改变。特别需要指出的是，X射线衍射图的相对强度也可能随着实验条件的变化而变化，所以峰强度的顺序不能作为唯一或决定性因素。事实上，X射线衍射图中衍射峰的相对强度与晶体的择优取向有关，本文所示的峰强度为说明性而非用于绝对比较。另外，峰角度的实验误差通常在5％或更少，这些角度的误差也应该被考虑进去，通常允许有±0.2°的误差。另外，由于样品厚度等实验因素的影响，会造成峰角度的整体偏移，通常 允许一定的偏移。因而，本领域技术人员可以理解的是，本发明中一个晶型的X射线衍射图不必和这里所指的例子中的X射线衍射图完全一致，本文所述“X射线衍射图相同”并非指绝对相同，相同峰位置可相差±0.2°且峰强度允许一定可变性。任何具有和这些图谱中的特征峰相同或相似的图的晶型均属于本发明的范畴之内。本领域技术人员能够将本发明所列的图谱和一个未知晶型的图谱相比较，以证实这两组图谱反映的是相同还是不同的晶型。In the present invention, "crystal" or "polymorph" means that which is confirmed by the X-ray diffraction pattern characterization shown. Those skilled in the art will understand that the physicochemical properties discussed here can be characterized, with experimental error depending on instrument conditions, sample preparation, and sample purity. In particular, it is well known to those skilled in the art that X-ray diffraction patterns often change with the conditions of the instrument. It is particularly important to point out that the relative intensity of X-ray diffraction patterns may also change with changes in experimental conditions, so the order of peak intensity cannot be used as the only or decisive factor. In fact, the relative intensity of the diffraction peaks in the X-ray diffraction pattern is related to the preferred orientation of the crystal. The peak intensities shown in this article are illustrative and not used for absolute comparison. In addition, the experimental error of the peak angle is usually 5% or less. The error of these angles should also be taken into account, and an error of ±0.2° is usually allowed. In addition, due to the influence of experimental factors such as sample thickness, the overall peak angle will shift. Usually A certain offset is allowed. Therefore, those skilled in the art can understand that the X-ray diffraction pattern of a crystalline form in the present invention does not have to be completely consistent with the X-ray diffraction pattern in the example referred to here. The "X-ray diffraction pattern the same" mentioned herein does not mean that Absolutely the same, the same peak position can differ by ±0.2° and the peak intensity allows certain variability. Any crystalline form having the same or similar pattern as the characteristic peaks in these patterns falls within the scope of the present invention. Those skilled in the art can compare the spectrum listed in the present invention with the spectrum of an unknown crystal form to confirm whether the two sets of patterns reflect the same or different crystal forms.
在一些实施方案中，本发明的晶型A是纯的、单一的，基本没有混合任何其他晶型。本发明中，“基本没有”当用来指新晶型时指这个晶型含有少于20％(重量)的其他晶型，尤其指少于10％(重量)的其他晶型，更指少于5％(重量)的其他晶型，更指少于1％(重量)的其他晶型。需要说明的是，本发明中提及的数值及数值范围不应被狭隘地理解为数值或数值范围本身，本领域技术人员应当理解其可以根据具体技术环境的不同，在不背离本发明精神和原则的基础上围绕具体数值有所浮动，本发明中，这种本领域技术人员可预见的浮动范围多以术语“约”来表示。In some embodiments, Form A of the present invention is pure and unitary, with substantially no admixture of any other crystalline forms. In the present invention, "substantially no" when used to refer to a new crystal form means that the crystal form contains less than 20% (weight) of other crystal forms, especially less than 10% (weight) of other crystal forms, and even less Less than 5% (weight) of other crystalline forms refers to less than 1% (weight) of other crystalline forms. It should be noted that the numerical values and numerical ranges mentioned in the present invention should not be narrowly understood as the numerical values or numerical ranges themselves. Those skilled in the art should understand that they can be determined according to different specific technical environments without departing from the spirit and scope of the present invention. There will be some fluctuation around the specific numerical value on the basis of principles. In the present invention, such a floating range that can be foreseen by those skilled in the art is often expressed by the term "about".
本发明说明书中记载的数值范围的上限值和下限值可以任意地组合。The upper limit and lower limit of the numerical range described in the specification of the present invention can be combined arbitrarily.
实施例Example
以下将通过具体实施例进一步阐述本发明，但并不用于限制本发明的保护范围。本领域技术人员可在权利要求范围内对制备方法和使用仪器作出改进，这些改进也应视为本发明的保护范围。因此，本发明专利的保护范围应以所附权利要求为准。The present invention will be further described below through specific examples, but are not intended to limit the scope of the present invention. Those skilled in the art can make improvements to the preparation methods and instruments within the scope of the claims, and these improvements should also be regarded as the protection scope of the present invention. Therefore, the scope of protection of the patent of the present invention should be determined by the appended claims.
本发明中“室温”如果没有特别说明，通常是指22℃到28℃。Unless otherwise stated, "room temperature" in the present invention usually refers to 22°C to 28°C.
本发明中所用到的缩写的解释如下：The abbreviations used in the present invention are explained as follows:
XRPD：X射线粉末衍射XRPD: X-ray powder diffraction
DSC：差示扫描量热分析DSC: Differential Scanning Calorimetry
TGA：热重分析TGA: Thermogravimetric Analysis
1H NMR：核磁共振氢谱 1H NMR: Hydrogen Nuclear Magnetic Resonance Spectroscopy
DVS：动态水分吸附DVS: dynamic moisture adsorption
PSD：粒径分布PSD: particle size distribution
PLM：偏光显微镜PLM: Polarized Light Microscope
HPLC：高效液相色谱HPLC: high performance liquid chromatography
本发明所述的X射线粉末衍射图在Panalytical(帕纳科)公司的Empyrean型及X'Pert3型X射线粉末衍射仪上采集。本发明所述的X射线粉末衍射的方法参数如下：The X-ray powder diffraction patterns described in the present invention were collected on Empyrean type and X'Pert 3 type X-ray powder diffractometers of Panalytical Company. The method parameters of X-ray powder diffraction according to the present invention are as follows:
X射线光源：Cu,KαX-ray light source: Cu, Kα
1.54060；1.54443 1.54060; 1.54443
Kα2/Kα1强度比例：0.50Kα2/Kα1 intensity ratio: 0.50
电压：45千伏特(kV)Voltage: 45 kilovolts (kV)
电流：40毫安培(mA)Current: 40 milliamps (mA)
扫描范围：自3.0至40.0度(2θ角)Scanning range: from 3.0 to 40.0 degrees (2θ angle)
本发明所述的差示扫描量热分析图在TA公司的Q200型及Discovery DSC 2500型差示扫描量热仪上采集。本发明所述的差示扫描量热分析的方法参数如下： The differential scanning calorimetry analysis diagrams described in the present invention were collected on TA Company's Q200 and Discovery DSC 2500 differential scanning calorimeters. The method parameters of differential scanning calorimetry analysis according to the present invention are as follows:
扫描速率：10℃/分钟Scan rate: 10°C/min
保护气体：氮气Protective gas: nitrogen
本发明所述的热重分析图在TA公司的Discovery TGA 5500型及Q5000型热重分析仪上采集。本发明所述的热重分析的方法参数如下：The thermogravimetric analysis diagram described in the present invention was collected on the Discovery TGA 5500 and Q5000 thermogravimetric analyzers of TA Company. The method parameters of thermogravimetric analysis according to the present invention are as follows:
扫描速率：10℃/分钟Scan rate: 10°C/min
保护气体：氮气Protective gas: nitrogen
本发明所述的核磁共振氢谱数据(1H NMR)采自于Bruker Avance II DMX 400M HZ核磁共振波谱仪。称量1-5mg样品，用0.5mL氘代二甲亚砜溶解，配制成2-10mg/mL的溶液进行测试。The hydrogen nuclear magnetic resonance spectrum data ( 1 H NMR) described in the present invention is collected from a Bruker Avance II DMX 400M HZ nuclear magnetic resonance spectrometer. Weigh 1-5 mg of sample, dissolve it in 0.5 mL of deuterated dimethyl sulfoxide, and prepare a solution of 2-10 mg/mL for testing.
本发明所述的动态水分吸附图在SMS公司的Intrinsic型及Intrinsic Plus型动态水分吸附仪上采集。本发明所述的动态水分吸附测试的方法参数如下：The dynamic moisture adsorption diagram of the present invention is collected on the Intrinsic type and Intrinsic Plus type dynamic moisture adsorption instruments of SMS Company. The method parameters of the dynamic moisture adsorption test according to the present invention are as follows:
温度：25℃Temperature: 25℃
保护气体及流量：N2，200毫升/分钟Protective gas and flow rate: N 2 , 200 ml/min
dm/dt：0.002％/分钟dm/dt: 0.002%/minute
最小dm/dt平衡时间：10分钟Minimum dm/dt balancing time: 10 minutes
最大平衡时间：180分钟Maximum balancing time: 180 minutes
相对湿度范围：0％RH-95％RH-0％RHRelative humidity range: 0%RH-95%RH-0%RH
相对湿度梯度：10％(0％RH-90％RH-0％RH)、5％(90％RH-95％RH和95％RH-90％RH)Relative humidity gradient: 10% (0%RH-90%RH-0%RH), 5% (90%RH-95%RH and 95%RH-90%RH)
本发明中所述的粒径分布结果是在Microtrac公司的S3500型激光粒度分析仪上采集。Microtrac S3500配备SDC(Sample Delivery Controller)进样系统。本测试采用湿法，测试分散介质为Isopar G(含0.2％卵磷脂)。所述的激光粒度分析仪的方法参数如下：

*：流速60％为65mL/s的60％The particle size distribution results described in the present invention were collected on Microtrac's S3500 laser particle size analyzer. Microtrac S3500 is equipped with SDC (Sample Delivery Controller) sampling system. This test adopts the wet method, and the test dispersion medium is Isopar G (containing 0.2% lecithin). The method parameters of the laser particle size analyzer are as follows:

*: 60% of flow rate is 60% of 65mL/s
本发明中所述的偏光显微镜照片是通过蔡司显微镜Axio Scope.A1在室温条件下采集，显微镜配备Axiocam 305彩色相机以及5×、10×、20×和50×物镜。The polarized light microscope photos described in the present invention were collected at room temperature through a Zeiss microscope Axio Scope.A1. The microscope is equipped with an Axiocam 305 color camera and 5×, 10×, 20× and 50× objective lenses.
下述实施例中所使用的式(I)起始物可根据现有技术制备得到，例如根据专利WO2017005725A1中所记载的方法制备获得，但起始晶型并非制备本发明晶型的限定条件。The starting material of formula (I) used in the following examples can be prepared according to the existing technology, for example, according to the method described in patent WO2017005725A1, but the starting crystal form is not a limiting condition for preparing the crystal form of the present invention.
实施例1：晶型A的制备(室温挥发法)Example 1: Preparation of crystal form A (room temperature evaporation method)
室温条件下称取51.4毫克的式(I)化合物固体置于5毫升的玻璃小瓶中，加入2.0毫升的乙醇溶解固体。将样品置于室温条件下快速挥发，直至有固体析出，得到晶型A。其X射线粉末衍射数据如表1所示。该样品在约6.6°±0.2°、9.1°±0.2°、12.4°±0.2°、13.6°±0.2°、 14.5°±0.2°、15.1°±0.2°、18.3°±0.2°、19.3°±0.2°、20.3°±0.2°、23.4°±0.2°、25.1°±0.2°处有特征峰。其XRPD图如图1所示。Weigh 51.4 mg of the solid compound of formula (I) into a 5 ml glass vial at room temperature, and add 2.0 ml of ethanol to dissolve the solid. The sample is placed at room temperature to rapidly evaporate until solid precipitates to obtain crystal form A. Its X-ray powder diffraction data are shown in Table 1. The sample is at approximately 6.6°±0.2°, 9.1°±0.2°, 12.4°±0.2°, 13.6°±0.2°, There are characteristic peaks at 14.5°±0.2°, 15.1°±0.2°, 18.3°±0.2°, 19.3°±0.2°, 20.3°±0.2°, 23.4°±0.2°, and 25.1°±0.2°. Its XRPD pattern is shown in Figure 1.
表1
Table 1
实施例2：晶型A的制备(室温挥发法)Example 2: Preparation of crystal form A (room temperature evaporation method)
室温条件下称取521.3毫克的式(I)化合物固体置于20毫升的玻璃小瓶中，加入10.0毫升的正丙醇溶解固体。使用0.45微米孔径的聚四氟乙烯滤膜将样品溶液过滤至新的20毫升玻 璃小瓶中。将样品敞口置于室温条件下快速挥发，直至有固体析出，得到晶型A。其X射线粉末衍射数据如表2所示。其XRPD、TGA、DSC和1H NMR分别如图2～5所示。Weigh 521.3 mg of the solid compound of formula (I) into a 20 ml glass vial at room temperature, and add 10.0 ml of n-propanol to dissolve the solid. Use a 0.45 μm pore size polytetrafluoroethylene filter to filter the sample solution into a new 20 ml glass In a glass vial. Leave the sample exposed at room temperature to rapidly evaporate until solid precipitates to obtain crystal form A. Its X-ray powder diffraction data are shown in Table 2. Its XRPD, TGA, DSC and 1 H NMR are shown in Figures 2 to 5 respectively.
表2

Table 2

实施例3：晶型A的制备(反溶剂添加法)Example 3: Preparation of Crystal Form A (Antisolvent Addition Method)
室温条件下称取500.5毫克的式(I)化合物固体置于20毫升的玻璃小瓶中，加入8.0毫升的正丙醇形成澄清溶液。使用0.45微米孔径的聚四氟乙烯滤膜将样品溶液过滤至新的20毫升玻璃小瓶中。往上述清液中缓慢加入14毫升纯水，析出固体。抽滤分离固体，将所得固体置于室温真空干燥约3天，得到晶型A。其X射线粉末衍射数据如表3所示。其XRPD如图6所示。Weigh 500.5 mg of the solid compound of formula (I) into a 20 ml glass vial at room temperature, and add 8.0 ml of n-propanol to form a clear solution. Filter the sample solution into a new 20 ml glass vial using a 0.45 μm pore size Teflon filter. Slowly add 14 ml of pure water to the above clear liquid to precipitate solid. The solid was separated by suction filtration, and the obtained solid was vacuum dried at room temperature for about 3 days to obtain crystal form A. Its X-ray powder diffraction data are shown in Table 3. Its XRPD is shown in Figure 6.
表3

table 3

实施例4：晶型的溶解度Example 4: Solubility of crystalline forms
将本发明晶型A用SGF(模拟人工胃液)、FaSSIF(空腹状态下人工肠液)、FeSSIF(饱食状态下人工肠液)和纯水分别配制成悬浊液，在1小时、2小时、4小时和24小时平衡后过滤，得到饱和溶液。通过高效液相色谱法(HPLC)测定饱和溶液中样品的含量。试验结果如表4所示，溶解度曲线如图7～10所示。试验结果显示，本发明晶型A在SGF、FaSSIF、FeSSIF和纯水中具有较好的溶解度，满足药用需求。The crystal form A of the present invention is prepared into a suspension using SGF (simulated artificial gastric juice), FaSSIF (artificial intestinal fluid in a fasting state), FeSSIF (artificial intestinal fluid in a satiated state) and pure water respectively. After equilibrating for 24 hours and 24 hours, filter and obtain a saturated solution. The content of the sample in the saturated solution was determined by high performance liquid chromatography (HPLC). The test results are shown in Table 4, and the solubility curves are shown in Figures 7 to 10. The test results show that the crystal form A of the present invention has good solubility in SGF, FaSSIF, FeSSIF and pure water, and meets the pharmaceutical needs.
表4
Table 4
实施例5：晶型的可压性Example 5: Compressibility of crystalline forms
采用手动压片机进行压片，压片时，选择可以压制成圆柱体片剂的圆形平冲，加入93.9毫克本发明晶型A，采用10kN压力压制成圆形片剂，采用游标卡尺测量片剂的直径(D)和厚度(L)分别为6.10毫米和2.40毫米，采用片剂硬度测定仪测试其径向破碎力(硬度，H)为26.63牛。利用公式T＝2H/πDL计算出粉体的抗张强度为1.159兆帕。压片前后的XRPD叠图如图11所示。试验结果表明，本发明晶型A具有较大的抗张强度更大，具有较优的可压性。Use a manual tablet press to compress tablets. When compressing tablets, select a round flat punch that can be pressed into cylindrical tablets, add 93.9 mg of crystal form A of the present invention, use 10kN pressure to press into round tablets, and use a vernier caliper to measure the tablets. The diameter (D) and thickness (L) of the tablet are 6.10 mm and 2.40 mm respectively. The radial crushing force (hardness, H) measured using a tablet hardness tester is 26.63 N. The tensile strength of the powder is calculated to be 1.159 MPa using the formula T=2H/πDL. The XRPD overlays before and after tableting are shown in Figure 11. The test results show that the crystal form A of the present invention has greater tensile strength and better compressibility.
实施例6：稳定性对比研究Example 6: Comparative study on stability
称取本发明晶型A(起始纯度99.67％)约15mg，分别敞口放置于25℃/60％RH和40℃/75％RH条件的稳定箱中，在1周、4周和8周后取样测XRPD和HPLC纯度。试验结果如表5所示，晶型A的稳定性如图12～13所示。试验结果显示，本发明晶型A在25℃/60％RH和40℃/75％RH条件下具有较好的物理化学稳定性。Weigh about 15 mg of the crystal form A of the present invention (initial purity 99.67%), and place it in a stable box under 25°C/60%RH and 40°C/75%RH conditions respectively. After 1 week, 4 weeks and 8 weeks, Then take samples to measure XRPD and HPLC purity. The test results are shown in Table 5, and the stability of Form A is shown in Figures 12-13. The test results show that the crystal form A of the present invention has good physical and chemical stability under the conditions of 25°C/60%RH and 40°C/75%RH.
表5
table 5
实施例7：引湿性对比研究Example 7: Comparative study on hygroscopicity
称取本发明晶型A和WO2022189279A1的Form II各约10mg进行动态水分吸附(DVS)测试，然后取样测XRPD。试验结果如表6所示，晶型A的DVS如图14所示，晶型A测试DVS前后的XRPD如图15所示；Form II的DVS如图16所示，Form II测试DVS前后的XRPD如图17所示。试验结果显示，本发明晶型A与Form II相比具有更低的引湿性。Weigh about 10 mg each of the crystal form A of the present invention and the Form II of WO2022189279A1 for dynamic moisture adsorption (DVS) testing, and then take samples for XRPD measurement. The test results are shown in Table 6. The DVS of Form A is shown in Figure 14. The XRPD of Form A before and after DVS test is shown in Figure 15. The DVS of Form II is shown in Figure 16. The XRPD of Form II before and after DVS test. As shown in Figure 17. The test results show that the crystalline Form A of the present invention has lower hygroscopicity than Form II.
表6

Table 6

关于引湿性特征描述与引湿性增重的界定(中国药典2020年版四部药物引湿性试验指导原则)：Regarding the description of hygroscopic characteristics and the definition of hygroscopic weight gain (Guiding Principles for Hygroscopic Tests of Drugs in Four Parts of the Chinese Pharmacopoeia 2020 Edition):
潮解：吸收足量水分形成液体Deliquescence: Absorbing enough water to form a liquid
极具引湿性：引湿增重不小于15％Extremely hygroscopic: weight gain by attracting moisture is not less than 15%
有引湿性：引湿增重小于15％但不小于2％Hygroscopic: weight gain by absorbing moisture is less than 15% but not less than 2%
略有引湿性：引湿增重小于2％但不小于0.2％Slightly hygroscopic: weight gain due to moisture attraction is less than 2% but not less than 0.2%
无或几乎无引湿性：引湿增重小于0.2％No or almost no hygroscopicity: weight gain due to moisture absorption is less than 0.2%
实施例8：粒径分布对比研究Example 8: Comparative study of particle size distribution
称取本发明晶型A和WO2022189279A1的Form II各约10-30mg，然后加入约5mL Isopar G(含有0.2％卵磷脂)，将待测样品充分混合均匀后加入SDC进样系统中，使遮光度达到合适范围，开始实验，超声30秒后进行粒径分布的测试。试验结果如表7所示，晶型A的粒径分布图如图18所示，Form II的粒径分布图如图19所示。试验结果显示，本发明晶型A呈单峰分布，平均粒径为13.14微米，粒径分布均匀；Form II呈双峰分布，平均粒径为67.84微米。说明，本发明晶型A比Form II具有更加均匀的粒径分布。Weigh about 10-30 mg of Form II of crystal form A of the present invention and WO2022189279A1, then add about 5 mL of Isopar G (containing 0.2% lecithin), mix the sample to be tested evenly and then add it to the SDC sampling system to increase the opacity. When the appropriate range is reached, start the experiment and conduct the particle size distribution test after ultrasonic for 30 seconds. The test results are shown in Table 7, the particle size distribution diagram of Form A is shown in Figure 18, and the particle size distribution diagram of Form II is shown in Figure 19. The test results show that the crystal form A of the present invention has a unimodal distribution with an average particle size of 13.14 microns and a uniform particle size distribution; the Form II has a bimodal distribution with an average particle size of 67.84 microns. It shows that the crystal form A of the present invention has a more uniform particle size distribution than the form II.
表7
Table 7
实施例9：黏附性对比研究Example 9: Comparative study on adhesion
称取本发明晶型A和WO2022189279A1的Form II各约100mg，然后加入到6mm圆形平冲中，采用10kN的压力进行压片处理，压片后停留约半分钟，记录最后制成片剂的质量，并计算压制过程中的黏附量和黏附百分比，试验结果如表8所示。试验结果显示，本发明晶型A比Form II更不易粘冲。Weigh about 100 mg each of the crystal form A of the present invention and the Form II of WO2022189279A1, then add it to a 6mm round flat punch, and use a pressure of 10kN to perform tableting processing. After the tableting, stay for about half a minute, and record the final result of the tablet. quality, and calculate the adhesion amount and adhesion percentage during the pressing process. The test results are shown in Table 8. The test results show that the crystal form A of the present invention is less likely to stick than Form II.
表8
Table 8
上述实施例只为说明本发明的技术构思及特点，其目的在于让熟悉此项技术的人士能够了解本发明的内容并据以实施，并不能以此限制本发明的保护范围。凡根据本发明精神实质所作的等效变化或修饰，都应涵盖在本发明的保护范围之内。 The above embodiments are only for illustrating the technical concepts and characteristics of the present invention. Their purpose is to enable those familiar with this technology to understand the content of the present invention and implement it accordingly. They cannot limit the scope of protection of the present invention. All equivalent changes or modifications made based on the spirit and essence of the present invention should be included in the protection scope of the present invention.

Claims (7)

  1. 式(I)所示化合物4-({(2S)-2-[4-{5-氯-2-[4-(三氟甲基)-1H-1,2,3-三唑-1-基]苯基}-5-甲氧基-2-氧代吡啶-1(2H)-基]丁酰基}氨基)-2-氟苯甲酰胺的A型晶体、即晶型A，其特征在于，使用Cu-Kα辐射，所述晶型A的X射线粉末衍射在2θ值为6.6°±0.2°、12.4°±0.2°、18.3°±0.2°处有特征峰，
    Compound 4-({(2S)-2-[4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazole-1-) represented by formula (I) Type A crystals of methyl]phenyl}-5-methoxy-2-oxopyridin-1(2H)-yl]butyryl}amino)-2-fluorobenzamide, which is characterized by: , using Cu-Kα radiation, the X-ray powder diffraction of the crystal form A has characteristic peaks at 2θ values of 6.6°±0.2°, 12.4°±0.2°, and 18.3°±0.2°,
  2. 根据权利要求1所述的晶型A，其X射线粉末衍射在2θ值为14.5°±0.2°、20.3°±0.2°、23.4°±0.2°中的一处或两处或三处有特征峰。According to the crystalline form A according to claim 1, its X-ray powder diffraction has characteristic peaks at one, two or three of the 2θ values of 14.5°±0.2°, 20.3°±0.2°, and 23.4°±0.2°. .
  3. 根据权利要求1或2所述的所述晶型A，其X射线粉末衍射在2θ值为14.5°±0.2°、20.3°±0.2°、23.4°±0.2°有特征峰。According to the crystal form A according to claim 1 or 2, its X-ray powder diffraction has characteristic peaks at 2θ values of 14.5°±0.2°, 20.3°±0.2°, and 23.4°±0.2°.
  4. 权利要求1～3中任一项所述的晶型A的制备方法，其特征在于，The preparation method of crystal form A according to any one of claims 1 to 3, characterized in that:
    (1)在10～50℃下，将式(I)化合物溶解于醇类溶剂中，将溶液挥发，直至固体析出，得到晶型A；或(1) Dissolve the compound of formula (I) in an alcohol solvent at 10 to 50°C, and evaporate the solution until the solid precipitates to obtain crystal form A; or
    (2)在10～50℃下，将式(I)化合物溶解于醇类溶剂中，向其中加入纯水，直至固体析出，得到晶型A。(2) Dissolve the compound of formula (I) in an alcohol solvent at 10 to 50°C, and add pure water to it until the solid precipitates to obtain crystal form A.
  5. 药物组合物，其包含权利要求1～3中任一项所述的晶体和制药学可接受的载体。A pharmaceutical composition comprising the crystal according to any one of claims 1 to 3 and a pharmaceutically acceptable carrier.
  6. 具有FXIa抑制活性的药物组合物，其含有权利要求1～3中任一项所述的晶体作为有效成分。A pharmaceutical composition having FXIa inhibitory activity, which contains the crystal according to any one of claims 1 to 3 as an active ingredient.
  7. 中风和血栓栓塞的治疗药，其含有权利要求1～3中任一项所述的晶体作为有效成分。 A drug for treating stroke and thromboembolism, which contains the crystal according to any one of claims 1 to 3 as an active ingredient.
PCT/CN2023/082138 2022-03-18 2023-03-17 Crystal form of substituted oxopyridine derivative and preparation method therefor WO2023174399A1 (en)

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WO2022189279A1 (en) * 2021-03-09 2022-09-15 Bayer Aktiengesellschaft Crystalline forms of (4s)-24-chloro-4-ethyl-73-fluoro-35-methoxy-32,5-dioxo-14-(trifluoromethyl)-32h-6-aza-3(4,1)-pyridina-1(1)-[1,2,3]triazola-2(1,2),7(1)-5 dibenzenaheptaphane-74-carboxamide
WO2022189278A1 (en) * 2021-03-09 2022-09-15 Bayer Aktiengesellschaft Pharmaceutical dosage forms comprising (4s)-24-chloro-4-ethyl-73-fluoro-35-methoxy-32,5- dioxo-14-(trifluoromethyl)-32h-6-aza-3(4,1)-pyridina-1(1)-[1,2,3]triazola-2(1,2),7(1)- dibenzenaheptaphane-74-carboxamide

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CN108026072A (en) * 2015-07-09 2018-05-11 拜耳制药股份公司 Substituted oxo pyridine derivative
CN111770917A (en) * 2018-03-15 2020-10-13 拜耳股份公司 Two 4- { [ (2S) -2- {4- [ 5-chloro-2- (1H-1,2, 3-triazol-1-yl) phenyl ] -5-methoxy-2-oxopyridin-1 (2H) -yl } butyryl ] amino } -2-fluorobenzamide derivatives
CN113166099A (en) * 2018-12-17 2021-07-23 拜耳公司 Substituted oxopyridine derivatives for the treatment and/or prophylaxis of thrombotic or thromboembolic diseases and/or thrombotic or thromboembolic complications
WO2021242970A1 (en) * 2020-05-29 2021-12-02 Boulder Bioscience Llc Methods for improved endovascular thrombectomy using 3,3'-diindolylmethane
WO2022189280A1 (en) * 2021-03-09 2022-09-15 Bayer Aktiengesellschaft Solvates of (4s)-24-chloro-4-ethyl-73-fluoro-35-methoxy-32,5-dioxo-14-(trifluoro-methyl)-32 h-6- aza-3(4,1)-pyridina-1(1)-[1,2,3]triazola-2(1,2),7(1)-dibenzenaheptaphane-74-carboxamide
WO2022189279A1 (en) * 2021-03-09 2022-09-15 Bayer Aktiengesellschaft Crystalline forms of (4s)-24-chloro-4-ethyl-73-fluoro-35-methoxy-32,5-dioxo-14-(trifluoromethyl)-32h-6-aza-3(4,1)-pyridina-1(1)-[1,2,3]triazola-2(1,2),7(1)-5 dibenzenaheptaphane-74-carboxamide
WO2022189278A1 (en) * 2021-03-09 2022-09-15 Bayer Aktiengesellschaft Pharmaceutical dosage forms comprising (4s)-24-chloro-4-ethyl-73-fluoro-35-methoxy-32,5- dioxo-14-(trifluoromethyl)-32h-6-aza-3(4,1)-pyridina-1(1)-[1,2,3]triazola-2(1,2),7(1)- dibenzenaheptaphane-74-carboxamide

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