WO2023109939A1 - 吡啶类衍生物的晶型及其制备方法 - Google Patents

吡啶类衍生物的晶型及其制备方法 Download PDF

Info

Publication number
WO2023109939A1
WO2023109939A1 PCT/CN2022/139499 CN2022139499W WO2023109939A1 WO 2023109939 A1 WO2023109939 A1 WO 2023109939A1 CN 2022139499 W CN2022139499 W CN 2022139499W WO 2023109939 A1 WO2023109939 A1 WO 2023109939A1
Authority
WO
WIPO (PCT)
Prior art keywords
crystal form
present
crystal
formula
compound
Prior art date
Application number
PCT/CN2022/139499
Other languages
English (en)
French (fr)
Inventor
鲁霞
陈智雄
张晓宇
Original Assignee
苏州晶云药物科技股份有限公司
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by 苏州晶云药物科技股份有限公司 filed Critical 苏州晶云药物科技股份有限公司
Publication of WO2023109939A1 publication Critical patent/WO2023109939A1/zh

Links

Images

Classifications

    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen 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
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/81—Amides; Imides

Definitions

  • the invention relates to the field of chemistry and medicine, in particular to a crystal form of pyridine derivatives and a preparation method thereof.
  • CF transmembrane conductance regulator is a protein kinase A (PKA)-activated epithelial anion channel involved in salt and fluid transport in multiple organs.
  • PKA protein kinase A
  • Cystic fibrosis is a fatal genetic disease caused by mutations in the gene encoding CFTR, which typically reduce the number of CFTR channels on the cell surface or impair channel function. Studies have shown the potential to improve systemic inflammation, bacterial counts, and symptoms of airway disease by enhancing the CFTR ion channel on the cell surface.
  • Patent WO2011113894A1 discloses the compound of formula (I) and its synthesis.
  • the disclosed synthesis method needs to use supercritical fluid for chiral resolution or continuously use silica gel chromatography and isohexane/dichloromethane recrystallization for purification.
  • the present invention provides crystal form A of the compound of formula (I) and a preparation method thereof.
  • Compound 3-amino-6-methoxyl group-5-trifluoromethyl-pyridine-2-carboxylic acid ((S)-3,3,3-trifluoro-2-hydroxyl-2 -A type crystal of -methyl-propyl)-amide, i.e. crystal form A, is characterized in that, using Cu-K ⁇ radiation, the X-ray powder diffraction of the crystal form A has a 2 ⁇ value of 14.4° ⁇ 0.2°, 17.5 There are characteristic peaks at ° ⁇ 0.2°, 19.4° ⁇ 0.2°,
  • a pharmaceutical composition comprising the crystal according to any one of 1 to 3 above and a pharmaceutically acceptable carrier.
  • a pharmaceutical composition having CFTR-enhancing activity comprising the crystal according to any one of 1 to 3 above as an active ingredient.
  • a therapeutic agent for chronic obstructive pulmonary disease, cystic fibrosis and bronchiectasis comprising 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 solubility, melting point, stability, dissolution rate, hygroscopicity, adhesion, fluidity, bioavailability and processing performance, purification,
  • solubility melting point
  • stability dissolution rate
  • hygroscopicity adhesion
  • fluidity fluidity
  • bioavailability and processing performance purification
  • the X-ray powder diffraction of the crystal form A has one or two or three 2 ⁇ values of 15.9° ⁇ 0.2°, 20.7° ⁇ 0.2°, and 22.6° ⁇ 0.2° have characteristic peaks.
  • the X-ray powder diffraction of the crystal form A has characteristic peaks at 2 ⁇ values of 15.9° ⁇ 0.2°, 20.7° ⁇ 0.2°, and 22.6° ⁇ 0.2°.
  • the X-ray powder diffraction of the crystal form A has one or two or three 2 ⁇ values of 10.0° ⁇ 0.2°, 21.5° ⁇ 0.2°, and 25.2° ⁇ 0.2° have characteristic peaks.
  • the X-ray powder diffraction of the crystal form A has characteristic peaks at 2 ⁇ values of 10.0° ⁇ 0.2°, 21.5° ⁇ 0.2°, and 25.2° ⁇ 0.2°.
  • the X-ray powder diffraction of the crystal form A has a 2 ⁇ value of 10.0° ⁇ 0.2°, 14.4° ⁇ 0.2°, 15.9° ⁇ 0.2°, 17.5° ⁇ 0.2°, 19.4° ⁇ 0.2° Any 4, or 5, or 6, or 7, or 8, or 9 of 0.2°, 20.7° ⁇ 0.2°, 21.5° ⁇ 0.2°, 22.6° ⁇ 0.2°, 25.2° ⁇ 0.2° There are characteristic peaks.
  • the X-ray powder diffraction of the crystal form A has a 2 ⁇ value of 10.0° ⁇ 0.2°, 14.4° ⁇ 0.2°, 15.9° ⁇ 0.2°, 17.5° ⁇ 0.2°, 19.4° ⁇ 0.2° There are characteristic peaks at 0.2°, 20.7° ⁇ 0.2°, 21.5° ⁇ 0.2°, 22.6° ⁇ 0.2°, 25.2° ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the crystal form A is shown in FIG. 1 .
  • the halogenated alkane solvent is dichloromethane, and the alkane solvent is n-heptane.
  • the temperature of the dissolving, dropping and stirring is 10-50°C, for example, 20-30°C.
  • the suspension stirring time is 0.5-4 hours, such as 1 hour.
  • the ester solvent is isopropyl acetate
  • the ether solvent is methyl tert-butyl ether
  • the alkane solvent is n-heptane
  • the dissolution and volatilization temperature is 10-50°C, such as 20-30°C.
  • the mixed solvent is isopropanol/n-heptane, ethyl acetate/n-heptane, ethyl formate/cyclohexane.
  • the volume ratio of the isopropanol/n-heptane is 1:1 ⁇ 4, such as 1:2; the volume ratio of the ethyl acetate/n-heptane is 1:2 ⁇ 4. 6, such as 1:4; the volume ratio of ethyl formate/cyclohexane is 1:2-6, such as 1:4.
  • the dissolution and volatilization temperature is 10-50°C, for example, 20-30°C.
  • said compound of formula (I) as starting material refers to its solid (crystalline or amorphous), semi-solid, waxy or oily form.
  • the compound of formula (I) as starting material is in the form of a solid powder.
  • the "stirring” is accomplished by conventional methods in the art, such as magnetic stirring or mechanical stirring, with a stirring speed of 50-1800 rpm, wherein magnetic stirring is 200-1500 rpm, preferably 300-1000 rpm , The mechanical stirring is preferably 100 to 300 rpm.
  • the above-mentioned crystals of the present invention can be used to prepare a pharmaceutical composition, which contains the above-mentioned crystals of the present invention and a pharmaceutically acceptable carrier.
  • the above-mentioned crystals of the present invention can be used to prepare a pharmaceutical composition with CFTR-enhancing activity, which contains the above-mentioned crystals of the present invention as active ingredients.
  • the above-mentioned crystals of the present invention can be used to prepare preventive or therapeutic drugs for chronic obstructive pulmonary disease, cystic fibrosis and bronchiectasis, which contain the above-mentioned crystals of the present invention as active ingredients.
  • the present invention also provides a pharmaceutical composition comprising the above-mentioned crystal of the present invention and a pharmaceutically acceptable carrier.
  • the present invention also provides a pharmaceutical composition having CFTR enhancing 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 chronic obstructive pulmonary disease, cystic fibrosis, and bronchiectasis, which contains the above-mentioned crystal of the present invention as an active ingredient.
  • crystal or “polymorph” refers to what is characterized by the shown X-ray diffraction pattern.
  • X-ray diffraction patterns often vary with the conditions of the instrument.
  • the relative intensity of the X-ray diffraction pattern may also vary with the experimental conditions, so the order of peak intensities cannot be used as the only or decisive factor.
  • the relative intensity of the diffraction peaks in the X-ray diffraction pattern is related to the preferred orientation of the crystal, and the peak intensities shown here are illustrative rather than for absolute comparison.
  • the experimental error of the peak angle is usually 5% or less, and the error of these angles should also be taken into account, and the error of ⁇ 0.2° is usually allowed.
  • due to the influence of experimental factors such as sample thickness it will cause the overall deviation of the peak angle, and a certain deviation is usually allowed.
  • the X-ray diffraction pattern of a crystal form in the present invention does not have to be completely consistent with the X-ray diffraction pattern in the example referred to here, and the "same X-ray diffraction pattern" mentioned herein does not mean absolutely identical, identical peak positions may differ by ⁇ 0.2° and peak intensities allow for some variability. Any crystal 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 spectrum reflect the same or different crystal forms.
  • the crystalline Form A of the present invention is pure, single, substantially free of any other crystalline forms.
  • substantially free when used to refer to a new crystal form means that this crystal form contains less than 20% (weight) of other crystal forms, especially refers to less than 10% (weight) of other crystal forms, and even less More than 5% (weight) of other crystal forms, more refers to less than 1% (weight) of other crystal forms.
  • the numerical values and numerical ranges mentioned in the present invention should not be narrowly interpreted as numerical values or numerical ranges themselves, and those skilled in the art should understand that they can vary according to the specific technical environment without departing from the spirit and scope of the present invention. There are fluctuations around specific numerical values on the basis of principles, and in the present invention, such fluctuation ranges that are foreseeable by those skilled in the art are often expressed by the term "about”.
  • Root temperature in the present invention usually refers to 22°C to 28°C unless otherwise specified.
  • 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 (Panalytical) Company.
  • the method parameter of X-ray powder diffraction of the present invention is as follows:
  • the differential scanning calorimetry chart of the present invention is collected on the Q200 type and Discovery DSC 2500 type differential scanning calorimeter of TA company.
  • the method parameter of differential scanning calorimetry analysis of the present invention is as follows:
  • thermogravimetric analysis figure of the present invention is collected on the Discovery TGA 5500 type of TA company and Q5000 type thermogravimetric analyzer.
  • the method parameter of thermogravimetric analysis of the present invention is as follows:
  • the proton 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 1-5mg sample, dissolve it with 0.5mL deuterated dimethyl sulfoxide, and prepare a 2-10mg/mL solution for testing.
  • the dynamic moisture adsorption figure of the present invention is collected on the Intrinsic type and Intrinsic Plus type dynamic moisture adsorption instrument of SMS company.
  • the method parameters of the dynamic moisture adsorption test of 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 are collected on the S3500 laser particle size analyzer of Microtrac Company.
  • Microtrac S3500 is equipped with SDC (Sample Delivery Controller) sampling system.
  • SDC Sample Delivery Controller
  • This test adopts wet method, and the test dispersion medium is Isopar G (containing 0.2% lecithin).
  • the method parameter of described laser particle size analyzer is as follows:
  • the inherent dissolution rate data described in the present invention is collected on the Agilent 708DS type dissolution apparatus of Agilent Company.
  • the inherent dissolution test conditions described are as follows:
  • the polarizing microscope photos described in the present invention were collected at room temperature by Zeiss microscope Axio Scope.A1, and the microscope was equipped with 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 prior art, for example, according to the method described in patent WO2011113894A1, but the starting crystal form is not a limiting condition for preparing the crystal form of the present invention.
  • Embodiment 1 Preparation of crystal form A (anti-solvent addition-suspension stirring method)
  • the sample is at about 10.0° ⁇ 0.2°, about 14.4° ⁇ 0.2°, about 15.9° ⁇ 0.2°, about 17.5° ⁇ 0.2°, about 19.4° ⁇ 0.2°, about 20.2° ⁇ 0.2°, about 20.7° ⁇ 0.2 °, about 21.5° ⁇ 0.2°, about 22.6° ⁇ 0.2°, about 25.2° ⁇ 0.2°, and about 25.8° ⁇ 0.2° have characteristic peaks.
  • Its XRPD, TGA, DSC, and 1 H NMR are shown in Figures 1 to 4, respectively.
  • Embodiment 2 ⁇ 3 Preparation of crystal form A (gas-liquid diffusion method)
  • Embodiment 4 ⁇ 6 the preparation of crystal form A (room temperature volatilization method)
  • the crystal form A of the present invention was formulated into suspensions with SGF (simulated artificial gastric juice), FaSSIF (artificial intestinal juice in a fasting state), FeSSIF (artificial intestinal juice in a fed state) and pure water respectively, and the suspension was prepared in 1 hour, 2 hours, and 4 hours. After equilibrating for 24 hours and 24 hours, filter to obtain a saturated solution. The content of the samples in the saturated solution was determined by high performance liquid chromatography (HPLC). The test results are shown in Table 6, and the solubility curves are shown in Figures 5-8 respectively. The results show that the crystal form A of the present invention has good solubility in SGF, FaSSIF, FeSSIF and pure water.
  • Embodiment 9 Intrinsic dissolution rate of crystal form
  • the crystal form A of the present invention has a faster dissolution rate.
  • Embodiment 10 Stability comparative study
  • Embodiment 11 Contrastive research on moisture absorption
  • Moisture-absorbing the weight gain of moisture-absorbing is less than 15% but not less than 2%
  • Embodiment 12 crystal habit comparative study
  • Embodiment 13 comparative study of particle size distribution

Abstract

一种式（I）化合物的晶型A及其制备方法和用途，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存在优势，为含式（I）化合物的药物制剂的制备提供了新的选择，对于药物开发具有重要意义。

Description

吡啶类衍生物的晶型及其制备方法 技术领域
本发明涉及化学医药领域，特别是涉及吡啶类衍生物的晶型及其制备方法。
背景技术
CF跨膜电导调节物(CFTR)是参与多器官中盐和流体运输的蛋白激酶A(PKA)-活化的上皮阴离子通道。囊性纤维化(CF)是由编码CFTR基因发生突变导致的致命性遗传疾病，通常CF突变会减少细胞表面上的CFTR通道数量或损坏通道功能。研究显示，通过增强细胞表上的CFTR离子通道，具有改善全身性炎症、细菌定值和气道疾病症状的潜力。
3-氨基-6-甲氧基-5-三氟甲基-吡啶-2-甲酸((S)-3,3,3-三氟-2-羟基-2-甲基-丙基)-酰胺是一种高效的CFTR增强剂，临床上主要用于慢性阻塞性肺疾病、囊肿性纤维化和支气管扩张的治疗，其结构式如下所示：
Figure PCTCN2022139499-appb-000001
专利WO2011113894A1公开了式(I)化合物及其合成，公开的合成方法需利用超临界流体进行手性拆分或者连续使用硅胶色谱法和异己烷/二氯甲烷重结晶进行提纯。
上述制备方法过程繁琐且会产生有毒有害的废液，需开发更为简单、安全的制备方法。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***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。
发明内容
本发明提供了式(I)化合物的晶型A及其制备方法。
1.式(I)所示化合物3-氨基-6-甲氧基-5-三氟甲基-吡啶-2-甲酸((S)-3,3,3-三氟-2-羟基-2-甲基-丙基)-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14.4°±0.2°、17.5°±0.2°、19.4°±0.2°处有特征峰，
Figure PCTCN2022139499-appb-000002
2.根据上述1所述的晶型A，其X射线粉末衍射在2θ值为15.9°±0.2°、20.7°±0.2°、22.6°±0.2°中的一处或两处或三处有特征峰。
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15.9°±0.2°、20.7°±0.2°、22.6°±0.2°有特征峰。
4.上述1～3中任一项所述的晶型A的制备方法，其特征包括，
(1)在10～50℃下，将式(I)化合物溶解于卤代烷烃类溶剂中，向其中加入烷烃类溶剂，搅拌至有固体析出，然后继续悬浮搅拌0.5～4小时，得到晶型A；或
(2)在10～50℃下，将式(I)化合物溶解于酯类或醚类溶剂中，置于烷烃类溶剂气氛下进行气液扩散，直至析出固体，得到晶型A；或
(3)在10～50℃下，将式(I)化合物溶解于醇类、酯类或烷烃类溶剂的混合溶剂中，将溶液挥发直至固体析出，得到晶型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。
6.具有CFTR增强活性的药物组合物，其含有上述1～3中任一项所述的晶体作为有效成分。
7.慢性阻塞性肺疾病、囊肿性纤维化和支气管扩张的治疗药，其含有上述1～3中任一项所述的晶体作为有效成分。
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。
附图说明
图1晶型A的XRPD图
图2晶型A的TGA图
图3晶型A的DSC图
图4晶型A的 1H NMR图
图5晶型A在纯水中的溶解度曲线
图6晶型A在SGF中的溶解度曲线
图7晶型A在FaSSIF中的溶解度曲线
图8晶型A在FeSSIF中的溶解度曲线
图9晶型A在25℃/60％相对湿度下稳定测试的XRPD对比图
图10晶型A在40℃/75％相对湿度下稳定测试的XRPD对比图
图11晶型A的动态水分吸附图
图12晶型A测试DVS前后的XRPD对比图
图13晶型A的粒径分布图
具体实施方式
晶型A
式(I)所示化合物3-氨基-6-甲氧基-5-三氟甲基-吡啶-2-甲酸((S)-3,3,3-三氟-2-羟基-2-甲基-丙基)-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144°±02°、175°±02°、194°±0 .2°处有特征峰
Figure PCTCN2022139499-appb-000003
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15.9°±0.2°、20.7°±0.2°、22.6°±0.2°中的一处或两处或三处有特征峰。
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15.9°±0.2°、20.7°±0.2°、22.6°±0.2°处有特征峰。
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10.0°±0.2°、21.5°±0.2°、25.2°±0.2°中的一处或两处或三处有特征峰。
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10.0°±0.2°、21.5°±0.2°、25.2°±0.2°处有特征峰。
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10.0°±0.2°、14.4°±0.2°、15.9°±0.2°、17.5°±0.2°、19.4°±0.2°、20.7°±0.2°、21.5°±0.2°、22.6°±0.2°、25.2°±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。
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10.0°±0.2°、14.4°±0.2°、15.9°±0.2°、17.5°±0.2°、19.4°±0.2°、20.7°±0.2°、21.5°±0.2°、22.6°±0.2°、25.2°±0.2°处有特征峰。
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。
所述的晶型A的制备方法，其特征包括，
(1)将式(I)化合物溶解于正溶剂中，搅拌状态下向其中逐滴加入反溶剂，直至有固体析出；将前述固体继续悬浮搅拌，得到晶型A。所述正溶剂为卤代烷烃类溶剂，所述反溶剂为烷烃类溶剂。
在本发明的一个实施方式中，所述卤代烷烃类溶剂为二氯甲烷，烷烃类溶剂为正庚烷。
在本发明的一个实施方式中，所述溶解、滴加、搅拌的温度为10～50℃，例如20～30℃。
在本发明的一个实施方式中，所述悬浮搅拌的时间为0.5～4小时，例如1小时。
(2)将式(I)化合物溶解于正溶剂中，置于反溶剂氛围下进行气液扩散，直至有固体析出，得到晶型A。所述正溶剂为酯类或醚类溶剂，所述反溶剂为烷烃类溶剂。
在本发明的一个实施方式中，所述酯类溶剂为乙酸异丙酯，所述醚类溶剂为甲基叔丁基醚，所述烷烃类溶剂为正庚烷。
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℃。
(3)将式(I)化合物固体溶解于混合溶剂中，将溶剂挥发，直至固体析出，得到晶型A。
在本发明的一个实施方式中，所述混合溶剂为异丙醇/正庚烷、乙酸乙酯/正庚烷、甲酸乙酯/环己烷。
在本发明的一个实施方式中，所述异丙醇/正庚烷的体积比为1:1～4，例如1:2；所述乙酸乙酯/正庚烷的体积比为1:2～6，例如1:4；所述甲酸乙酯/环己烷的体积比为1:2～6，例如1:4。
在本发明的一个实施方式中，所述溶解、挥发的温度为10～50℃，例如20～30℃。
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。
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CFTR增强活性的药物组合物，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慢性阻塞性肺疾病、囊肿性纤维化和支气管扩张的预防药或治疗药，其包含上述本发明的晶体作为有效成分。
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。
本发明还提供具有CFTR增强活性的药物组合物，其含有上述本发明的晶体作为有效成分。
本发明提供慢性阻塞性肺疾病、囊肿性纤维化和支气管扩张的预防药或治疗药，其含有上述本发明的晶体作为有效成分。
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。
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。
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。
实施例
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。
本发明中“室温”如果没有特别说明，通常是指22℃到28℃。
本发明中所用到的缩写的解释如下：
XRPD：X射线粉末衍射
DSC：差示扫描量热分析
TGA：热重分析
1H NMR：核磁共振氢谱
DVS：动态水分吸附
PSD：粒径分布
PLM：偏光显微镜
HPLC：高效液相色谱
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'Pert 3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：
X射线光源：Cu,Kα
Figure PCTCN2022139499-appb-000004
1.54060；
Figure PCTCN2022139499-appb-000005
1.54443
Kα2/Kα1强度比例：0.50
电压：45千伏特(kV)
电流：40毫安培(mA)
扫描范围：自3.0至40.0度(2θ角)
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：
扫描速率：10℃/分钟
保护气体：氮气
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：
扫描速率：10℃/分钟
保护气体：氮气
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。
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：
温度：25℃
保护气体及流量：N 2，200毫升/分钟
dm/dt：0.002％/分钟
最小dm/dt平衡时间：10分钟
最大平衡时间：180分钟
相对湿度范围：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)
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***。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：
粒度分布：体积分布 采集时间：10秒
分散介质：Isopar G 粒度坐标：标准
采集次数：3次 分散介质折射率：1.42
透明度：透明 残差：启用
颗粒折射率：1.59 流速：60％*
颗粒形状：不规则 过滤：启用
超声功率：30瓦 超声时间：超声30s
*：流速60％为65mL/s的60％
本发明中所述的固有溶出速率数据是在Agilent公司的Agilent 708DS型溶出仪上采集。所述的固有溶出测试条件如下：
溶出仪 Agilent 708DS
方法 桨法
介质 pH 6.8磷酸盐缓冲液
介质体积 900mL
转速 100rpm
介质温度 37℃
取样点 1,2,3,4,5,10,15,20,25,30min
补充介质 No
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。
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WO2011113894A1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。
实施例1：晶型A的制备(反溶剂添加-悬浮搅拌法)
室温条件下称取约11克的式(I)化合物油状物置于500毫升的圆底烧瓶中，加入10毫升的二氯甲烷以溶解固体，缓慢加入250毫升正庚烷，固体析出。将样品继续置于室温条件下悬浮搅拌约1小时。抽滤收集固体，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10.0°±0.2°、约14.4°±0.2°、约15.9°±0.2°、约17.5°±0.2°、约19.4°±0.2°、约20.2°±0.2°、约20.7°±0.2°、约21.5°±0.2°、约22.6°±0.2°、约25.2°±0.2°、约25.8°±0.2°处有特征峰。其XRPD、TGA、DSC、 1H NMR分别如图1～4所示。
表1
衍射角2θ d值 强度％
10.00 8.85 4.07
14.44 6.13 90.18
15.05 5.89 7.45
15.87 5.58 26.71
17.53 5.06 61.42
18.76 4.73 37.24
18.96 4.68 30.28
19.42 4.57 100.00
20.23 4.39 12.99
20.75 4.28 98.64
21.51 4.13 13.95
22.62 3.93 29.23
24.18 3.68 11.49
24.67 3.61 8.88
25.19 3.54 16.40
25.85 3.45 24.08
26.70 3.34 9.97
27.65 3.23 12.09
29.02 3.08 7.68
29.58 3.02 16.38
30.36 2.94 4.68
31.70 2.82 7.19
33.77 2.65 12.60
35.22 2.55 2.01
实施例2～3：晶型A的制备(气液扩散法)
室温条件下称取适量的式(I)化合物固体置于3毫升的玻璃小瓶中，加入相应体积的正溶剂以溶解固体，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3毫升玻璃小瓶中，敞口置于预盛有4毫升相应反溶剂的20毫升玻璃瓶中。封口后置于室温条件下气液渗透约10天。固体析出，得到晶型A。
本实施例中所涉详细试验条件如表2所示。实施例3的X射线粉末衍射数据如表3所示。
表2
实施例 固体质量(毫克) 溶剂 溶剂体积(毫升) 反溶剂
2 20.1 乙酸异丙酯 0.2 正庚烷
3 20.5 甲基叔丁基醚 0.2 正庚烷
表3
衍射角2θ d值 强度％
9.89 8.95 27.06
12.35 7.16 1.51
13.09 6.76 1.73
14.28 6.20 37.78
15.71 5.64 20.90
17.43 5.09 51.32
18.63 4.76 3.40
18.83 4.71 3.45
19.42 4.57 75.19
20.01 4.44 48.69
20.57 4.32 14.38
21.37 4.16 7.15
22.50 3.95 2.27
23.50 3.79 0.83
24.03 3.70 1.22
24.48 3.64 5.33
24.63 3.61 5.36
25.13 3.54 100.00
25.73 3.46 5.11
26.53 3.36 6.33
27.63 3.23 5.06
28.87 3.09 2.38
29.44 3.03 1.53
30.30 2.95 7.55
31.53 2.84 1.00
32.79 2.73 1.24
33.61 2.67 3.22
35.47 2.53 0.84
37.56 2.39 0.99
衍射角2θ d值 强度％
38.03 2.37 0.85
39.42 2.29 0.58
实施例4～6：晶型A的制备(室温挥发法)
室温条件下称取适量的式(I)化合物固体置于HPLC小瓶中，加入0.5毫升相应的溶剂得到澄清溶液。将样品敞口置于室温条件下挥发约2天，固体析出，得到晶型A。本实施例中所涉详细试验条件如表4所示。实施例4的X射线粉末衍射数据如表5所示。
表4
实施例 固体质量(毫克) 溶剂(体积比)
4 20.2 异丙醇/正庚烷(1:2)
5 19.8 乙酸乙酯/正庚烷(1:4)
6 20.2 甲酸乙酯/环己烷(1:4)
表5
衍射角2θ d值 强度％
9.96 8.88 18.72
14.30 6.19 8.96
14.42 6.14 6.93
15.02 5.90 0.55
15.84 5.60 5.22
17.56 5.05 26.97
18.72 4.74 2.34
18.92 4.69 1.94
19.42 4.57 21.92
20.09 4.42 47.04
20.72 4.29 13.11
21.46 4.14 4.17
22.60 3.93 2.38
23.62 3.77 0.73
24.13 3.69 1.33
24.65 3.61 0.85
25.20 3.53 100.00
25.81 3.45 4.78
26.63 3.35 0.73
26.96 3.31 1.32
27.65 3.23 3.74
衍射角2θ d值 强度％
29.00 3.08 0.40
29.59 3.02 2.54
30.36 2.94 7.84
31.67 2.83 1.84
32.86 2.73 2.69
33.68 2.66 1.38
35.20 2.55 0.39
35.55 2.53 1.15
36.06 2.49 0.37
36.79 2.44 1.34
37.82 2.38 0.38
38.51 2.34 0.40
实施例7：晶型的溶解度
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6所示，溶解度曲线分别如图5～8所示。结果显示，本发明晶型A在SGF、FaSSIF、FeSSIF和纯水中均具有较好的溶解度。
表6
Figure PCTCN2022139499-appb-000006
Figure PCTCN2022139499-appb-000007
实施例8：晶型的可压性
称取100.4毫克本发明晶型A于可以压制成圆柱体片剂的圆形平冲中，采用手动压片机以10kN压力压制成圆形片剂。将片剂放置于干燥器中24小时，待完全弹性复原后采用片剂硬度测定仪测试其径向破碎力(硬度，H)为26.21牛。采用游标卡尺测量片剂的直径(D)为6.08毫米和厚度(L)为2.46毫米，利用公式T＝2H/πDL计算出粉体的抗张强度为1.12兆帕。在一定的压力下，抗张强度越大的，表示其可压性越好。结果显示，本发明晶型A具有较大的抗张强度，说明具有较优的可压性。
实施例9：晶型的固有溶出速率
称取本发明晶型A约100mg，倒入固有溶出模具，在5kN压力下持续1min，制成表面积0.5cm 2的薄片，取完整压片转移至溶出仪测试固有溶出速率，根据10～30min之间的测定点计算斜率，以mg/mL表示，根据斜率进一步计算固有溶出速率(Intrinsic dissolution rate,IDR)，以mg/min/cm 2表示。本发明晶型A具有较快的溶出速率。
实施例10：稳定性对比研究
称取本发明晶型A(起始纯度100.00％)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、2周、4周和8周后取样测XRPD和HPLC纯度。试验结果如表7所示，晶型A的稳定性如图9～10所示。结果显示，本发明晶型A在25℃/60％RH和40℃/75％RH条件下均具有较好的物理化学稳定性。
表7
Figure PCTCN2022139499-appb-000008
实施例11：引湿性对比研究
称取本发明晶型A约10mg进行动态水分吸附(DVS)测试，然后取样测XRPD。晶型A的DVS如图11所示，测试DVS前后的XRPD如图12所示。结果显示，本发明晶型A在80％相对湿度的增重为0.0939％，同时DVS测试前后未有明显晶型变化，说明本发明晶型A无或几乎无引湿性。
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)：
潮解：吸收足量水分形成液体
极具引湿性：引湿增重不小于15％
有引湿性：引湿增重小于15％但不小于2％
略有引湿性：引湿增重小于2％但不小于0.2％
无或几乎无引湿性：引湿增重小于0.2％
实施例12：晶习对比研究
称取本发明晶型A约10mg，置于载玻片上，滴加少许真空硅油分散样品，然后盖上盖玻片，置于偏光显微镜下观察。结果显示，本发明晶型A具有较优的晶习。
实施例13：粒径分布对比研究
称取本发明晶型A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***中，使遮光度达到合适范围，超声30秒后进行粒径分布的测试。试验结果如表8所示，晶型A的粒径分布如图13所示。结果显示，本发明晶型A呈单峰分布，平均粒径为7.64微米，说明晶型A具有较均匀的粒径分布。
表8
晶型 平均粒径(微米) D10(微米) D50(微米) D90(微米)
晶型A 7.64 6.14 7.67 9.12
实施例14：黏附性对比研究
称取本发明晶型A约100mg，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9所示。试验结果显示，本发明晶型A较不易粘冲。
表9
Figure PCTCN2022139499-appb-000009
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。

Claims (7)

  1. 式(I)所示化合物3-氨基-6-甲氧基-5-三氟甲基-吡啶-2-甲酸((S)-3,3,3-三氟-2-羟基-2-甲基-丙基)-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14.4°±0.2°、17.5°±0.2°、19.4°±0.2°处有特征峰，
    Figure PCTCN2022139499-appb-100001
  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15.9°±0.2°、20.7°±0.2°、22.6°±0.2°中的一处或两处或三处有特征峰。
  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15.9°±0.2°、20.7°±0.2°、22.6°±0.2°有特征峰。
  4. 权利要求1～3中任一项所述的晶型A的制备方法，其特征包括，
    (1)在10～50℃下，将式(I)化合物溶解于卤代烷烃类溶剂中，向其中加入烷烃类溶剂，搅拌至有固体析出，然后继续悬浮搅拌0.5～4小时，得到晶型A；或
    (2)在10～50℃下，将式(I)化合物溶解于酯类或醚类溶剂中，置于烷烃类溶剂气氛下进行气液扩散，直至析出固体，得到晶型A；或
    (3)在10～50℃下，将式(I)化合物溶解于醇类、酯类或烷烃类溶剂的混合溶剂中，将溶液挥发直至固体析出，得到晶型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。
  6. 具有CFTR增强活性的药物组合物，其含有权利要求1～3中任一项所述的晶体作为有效成分。
  7. 慢性阻塞性肺疾病、囊肿性纤维化和支气管扩张的治疗药，其含有权利要求1～3中任一项所述的晶体作为有效成分。
PCT/CN2022/139499 2021-12-17 2022-12-16 吡啶类衍生物的晶型及其制备方法 WO2023109939A1 (zh)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN202111556283 2021-12-17
CN202111556283.4 2021-12-17

Publications (1)

Publication Number Publication Date
WO2023109939A1 true WO2023109939A1 (zh) 2023-06-22

Family

ID=86774887

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2022/139499 WO2023109939A1 (zh) 2021-12-17 2022-12-16 吡啶类衍生物的晶型及其制备方法

Country Status (1)

Country Link
WO (1) WO2023109939A1 (zh)

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102892758A (zh) * 2010-03-19 2013-01-23 诺瓦提斯公司 用于治疗cf的吡啶和吡嗪衍生物
CN110072851A (zh) * 2016-12-19 2019-07-30 诺华股份有限公司 新的吡啶甲酸衍生物及其作为中间体的用途
WO2021009695A1 (en) * 2019-07-15 2021-01-21 Novartis Ag Formulations of (s)-3-amino-6-methoxy-n-(3,3,3-trifluoro-2-hydroxy-2-methylpropyl)-5-(trifluoromethyl)picolinamide

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102892758A (zh) * 2010-03-19 2013-01-23 诺瓦提斯公司 用于治疗cf的吡啶和吡嗪衍生物
CN110072851A (zh) * 2016-12-19 2019-07-30 诺华股份有限公司 新的吡啶甲酸衍生物及其作为中间体的用途
WO2021009695A1 (en) * 2019-07-15 2021-01-21 Novartis Ag Formulations of (s)-3-amino-6-methoxy-n-(3,3,3-trifluoro-2-hydroxy-2-methylpropyl)-5-(trifluoromethyl)picolinamide

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
GRAND DARREN LE, GOSLING MARTIN, BAETTIG URS, BAHRA PARMJIT, BALA KAMLESH, BROCKLEHURST CARA, BUDD EMMA, BUTLER REBECCA, CHEUNG AT: "Discovery of Icenticaftor (QBW251), a Cystic Fibrosis Transmembrane Conductance Regulator Potentiator with Clinical Efficacy in Cystic Fibrosis and Chronic Obstructive Pulmonary Disease", JOURNAL OF MEDICINAL CHEMISTRY, AMERICAN CHEMICAL SOCIETY, US, vol. 64, no. 11, 10 June 2021 (2021-06-10), US , pages 7241 - 7260, XP093071850, ISSN: 0022-2623, DOI: 10.1021/acs.jmedchem.1c00343 *

Similar Documents

Publication Publication Date Title
WO2017215617A1 (zh) 奥扎莫德的晶型、其盐酸盐的晶型及其制备方法
WO2018108101A1 (zh) {[5-(3-氯苯基)-3-羟基吡啶-2-羰基]氨基}乙酸的新晶型及其制备方法
WO2018050091A1 (zh) 奥扎莫德盐酸盐的晶型及其制备方法
WO2018033149A1 (zh) 奥扎莫德的晶型及其制备方法
WO2016124149A1 (zh) 一种治疗***癌的抗雄激素类药物的新晶型及其制备方法
WO2021129467A1 (zh) 一种bms-986165晶型及其制备方法和用途
WO2018036558A1 (zh) 一种雄激素受体拮抗剂药物的晶型及其制备方法和用途
WO2019242439A1 (zh) Arn-509的晶型及其制备方法和用途
WO2023040513A1 (zh) Amg510化合物的晶型及其制备方法和用途
WO2019042219A1 (zh) 奥扎莫德盐酸盐的晶型及其制备方法
WO2022170864A1 (zh) Belumosudil甲磺酸盐的晶型及其制备方法和用途
WO2023280132A1 (zh) 氧代二氢咪唑并吡啶类化合物的晶型及其制备方法
JP2020500912A (ja) ブロモドメインタンパク質阻害薬の結晶形及びその製造方法並びに用途
WO2021143498A1 (zh) 一种Deucravacitinib的晶型及其制备方法和用途
WO2021129589A1 (zh) Kd-025的新晶型及其制备方法
WO2017063572A1 (zh) 细胞凋亡诱导剂的新晶型及其制备方法
WO2021143430A1 (zh) 一种bms-986165盐酸盐晶型及其制备方法和用途
WO2021063367A1 (zh) 一种Resmetirom晶型及其制备方法和用途
WO2018133705A1 (zh) Gft-505的晶型及其制备方法和用途
WO2018233437A1 (zh) 巴瑞克替尼的晶型及其制备方法
WO2019205812A1 (zh) Acalabrutinib的新晶型及其制备方法和用途
WO2020057622A1 (zh) 卡博替尼苹果酸盐晶型及其制备方法和用途
WO2023109939A1 (zh) 吡啶类衍生物的晶型及其制备方法
WO2021249367A1 (zh) 二氮杂双环类化合物的对甲苯磺酸盐新晶型及其制备方法
WO2023025268A1 (zh) 哒嗪甲酰胺类化合物的晶型及其制备方法

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 22906684

Country of ref document: EP

Kind code of ref document: A1