WO2020198939A1 - 2,2-双(4-氟苯基)-2-苯乙酰胺的晶型a及其制备方法和应用 - Google Patents

2,2-双(4-氟苯基)-2-苯乙酰胺的晶型a及其制备方法和应用 Download PDF

Info

Publication number
WO2020198939A1
WO2020198939A1 PCT/CN2019/080419 CN2019080419W WO2020198939A1 WO 2020198939 A1 WO2020198939 A1 WO 2020198939A1 CN 2019080419 W CN2019080419 W CN 2019080419W WO 2020198939 A1 WO2020198939 A1 WO 2020198939A1
Authority
WO
WIPO (PCT)
Prior art keywords
crystal form
organic solvent
solvent
fluorophenyl
bis
Prior art date
Application number
PCT/CN2019/080419
Other languages
English (en)
French (fr)
Inventor
任国宾
弋东旭
季伟杰
黄嘉骏
Original Assignee
深圳仁泰医药科技有限公司
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 深圳仁泰医药科技有限公司 filed Critical 深圳仁泰医药科技有限公司
Priority to CN201980003580.0A priority Critical patent/CN112020353A/zh
Priority to PCT/CN2019/080419 priority patent/WO2020198939A1/zh
Publication of WO2020198939A1 publication Critical patent/WO2020198939A1/zh
Priority to US17/487,047 priority patent/US20220033347A1/en

Links

Images

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C233/00—Carboxylic acid amides
    • C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C233/02—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having nitrogen atoms of carboxamide groups bound to hydrogen atoms or to carbon atoms of unsubstituted hydrocarbon radicals
    • C07C233/11—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having nitrogen atoms of carboxamide groups bound to hydrogen atoms or to carbon atoms of unsubstituted hydrocarbon radicals with carbon atoms of carboxamide groups bound to carbon atoms of an unsaturated carbon skeleton containing six-membered aromatic rings
    • 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
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • 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 crystal form preparation, in particular to the crystal form A of 2,2-bis(4-fluorophenyl)-2-phenylacetamide and its preparation method and application.
  • the 2,2-bis(4-fluorophenyl)-2-phenylacetamide of the following formula (I), also known as senicapo, is a potassium circulation inhibitor developed by ICAGEN and is known It is a medicine capable of treating or preventing sickle cell disease, preventing red blood cell dehydration and inhibiting potassium circulation (Chinese authorized patent CN1344158B), and also a medicine capable of preventing or treating inflammatory processes or stroke (Chinese authorized patent CN101437403B). Recent studies have also found that senicapoc is expected to be used in the treatment of hereditary stem cell disease.
  • Chinese authorized patent document CN101437403B discloses the preparation method of the compound represented by formula (I), specifically, as shown in the following reaction formula, the preparation method of the compound represented by formula (I) is: phenyl magnesium bromide and two Bis (4-fluorophenyl) phenyl methanol is prepared by reaction of fluorophenyl ketone; (2) Bis (4-fluorophenyl) phenyl is prepared by reaction of bis (4-fluorophenyl) phenyl methanol with acetyl chloride Chloromethyl; (3) bis(4-fluorophenyl)phenylchloromethane is reacted with copper cyanide, and then the residue is separated and purified by HPLC to obtain the compound represented by formula (I).
  • the inventors prepared the compound represented by formula (I) according to the method disclosed in Chinese authorized patent document CN101437403B and analyzed the results, and found that the compound represented by formula (I) will crystallize when stored under high temperature, high humidity and light conditions. Type conversion, the physical state of the obtained product is unstable, so it cannot be used as a pharmaceutical raw material. It requires strict management during use and is not suitable for use as a pharmaceutical raw material.
  • the object of the present invention is to provide the crystal A of 2,2-bis(4-fluorophenyl)-2-phenylacetamide represented by the above formula (I) and its preparation method and application.
  • the crystal A has significantly improved
  • the stability of crystalline form A is significantly reduced to less than 0.03%.
  • the present invention provides 2,2-bis(4-fluorophenyl)-2-phenylacetamide crystal form A, using Cu-K ⁇ radiation, X-ray powder diffraction expressed in 2 ⁇ angles, at 10.4 ⁇ 0.2°, There are characteristic peaks at 11.8 ⁇ 0.2°, 18.8 ⁇ 0.2°, and 21.3 ⁇ 0.2°.
  • X-ray powder diffraction expressed in 2 ⁇ angles also has characteristic peaks at 7.2 ⁇ 0.2° and 20.8 ⁇ 0.2°.
  • the X-ray powder diffraction expressed in 2 ⁇ angles also has characteristic peaks at 15.2 ⁇ 0.2°, 23.0 ⁇ 0.2°, and 25.7 ⁇ 0.2°.
  • the X-ray powder diffraction expressed in 2 ⁇ angles is still 22.1 ⁇ 0.2°, 22.5 ⁇ 0.2°, 25.0 ⁇ 0.2°, 26.5 ⁇ 0.2°, 27.5 ⁇ 0.2°, 28.5 ⁇ 0.2°, 29.5 There are characteristic peaks at ⁇ 0.2°, 31.6 ⁇ 0.2°, and 32.6 ⁇ 0.2°.
  • the XRPD pattern data of the crystal form A is:
  • Peak number 2 ⁇ (°) I% 1 10.44 48.4 2 11.779 48.1 3 13.381 twenty four 4 14.299 32.1 5 15.22 38.1 6 18.76 100 7 19.24 47 8 19.78 57.3 9 20.28 52 10 20.84 69.3 11 21.339 80.1 12 22.96 40.4 13 24.08 32.7 14 25.699 48.5 .
  • the XRPD pattern data of the crystal form A is:
  • the crystal form A has an XRPD pattern basically as shown in FIG. 4.
  • the crystal form A has a characteristic endothermic peak in the temperature range of 177.0-191.0°C.
  • the crystal form A has a DSC curve substantially as shown in FIG. 5.
  • the TGA curve of the crystal form A is basically as shown in FIG. 6.
  • the present invention also provides a method for preparing any of the above-mentioned crystal form A, including the following steps:
  • the present invention also provides a method for preparing any of the above-mentioned crystal form A, including the following steps:
  • the good solvent is selected from a lower alcohol organic solvent, a lower ketone organic solvent, a lower ester organic solvent, a lower nitrile organic solvent or a lower ether organic solvent;
  • the lower alcohol organic solvent is selected from methanol, ethanol, isopropanol or n-butanol, the lower ketone organic solvent is acetone; the lower ester organic solvent is ethyl acetate, and the lower ether organic solvent is selected from ethyl acetate.
  • the solvent is selected from tetrahydrofuran or dioxane, and the lower nitrile organic solvent is selected from acetonitrile.
  • the dosage ratio of the 2,2-bis(4-fluorophenyl)-2-phenylacetamide to the good solvent is 10-40mg:0.1-5ml.
  • the poor solvent is selected from n-heptane, n-hexane, anhydrous ether, isopropyl ether or water.
  • the present invention provides a pharmaceutical composition comprising any one of the above-mentioned crystal form A and pharmaceutically acceptable excipients.
  • the present invention provides a medicinal effective amount of any one of the above-mentioned crystal form A, or any one of the above-mentioned preparation methods of the crystal form A, or the pharmaceutical composition for the preparation of prevention or treatment of inflammation Use in drugs for sexual processes or strokes.
  • the inflammatory process is a disease selected from the group consisting of multiple sclerosis, insulin-dependent diabetes, rheumatoid arthritis, peripheral neuritis and pulmonary hypertension.
  • the present invention provides a medicinal effective amount of any of the above-mentioned crystal form A, or any of the above-mentioned preparation methods of crystal form A, or the pharmaceutical composition for inhibiting cellular potassium channels, Reduce red blood cell dehydration, treat or prevent sickle cell disease and improve the use of phenyl-containing potassium channel inhibitors in resisting degradation in biological media.
  • the drug is administered orally, parenterally, intradermal, intrathecal, intramuscular, subcutaneous, transvaginal, buccal, sublingual, transrectal, topical, inhaled, intranasal or transdermal.
  • the present invention also provides a method for inhibiting cellular potassium channels, reducing red blood cell dehydration, treating or preventing sickle cell disease, improving phenyl-containing potassium channel inhibitors to resist degradation in biological media and preventing or treating inflammatory processes or strokes , which includes the step of administering a pharmaceutically effective dose of the pharmaceutical composition to the patient.
  • the crystal form A of the compound of formula (I) provided by the present invention has high purity and good solubility in water, buffer solutions or organic solvents, which is beneficial for preparing medicines.
  • the crystal form A of the compound of formula (I) provided by the present invention has good light stability, high temperature stability and high humidity stability, and the amount of water or other solvents in the crystal form is less than 0.03% (mass percentage) ,
  • the relative humidity rises from 0 to 90% RH the moisture-inducing weight gain of crystal form A is not more than 1%, the moisture-inducing process is slow, the preparation process is simple, the conditions are mild, the quality is stable, and it is easy for large-scale industrial production.
  • the crystal form A of the compound of formula (I) provided by the present invention has an improved powder mobile phase, and is suitable for preparing a preparation with a stable active ingredient content.
  • the crystalline form A of the compound of formula (I) provided by the present invention has better drug effect in animals, longer half-life and higher exposure.
  • Figure 1 is an X-ray diffraction diagram of crystal form I of Example 1 of the present invention.
  • Fig. 2 is a DSC of crystal form I of Example 1 of the present invention.
  • Fig. 3 is a TGA curve of crystal form I of Example 1 of the present invention.
  • Figure 4 is an X-ray diffraction pattern of crystal form A of Example 2 of the present invention (the peak positions are marked)
  • Figure 5 is a DSC of crystal form A of Example 2 of the present invention.
  • Fig. 6 is a TGA curve of crystal form A of Example 2 of the present invention.
  • Figure 7 is an XRPD pattern of crystal form A of Example 3 of the present invention.
  • Fig. 8 is an XRPD pattern of crystal form A of Example 4 of the present invention.
  • Figure 9 is an XRPD pattern of crystal form A of Example 5 of the present invention.
  • Figure 10 is the XRPD pattern of crystal form A of Example 6 of the present invention.
  • Figure 11 is the XRPD pattern of crystal form A of Example 7 of the present invention.
  • Example 12 is an ellipsoid diagram of the single crystal molecular structure of crystal form A of Example 8 of the present invention.
  • Example 13 is a comparison diagram of the data simulation of the single crystal of crystal form A in Example 8 of the present invention and the XRPD comparison of the experimentally cultivated single crystal;
  • Fig. 15 is a comparison diagram of XRPD of light stability of crystal form A of the present invention.
  • 16 is a comparison diagram of XRPD high temperature stability of crystal form A of the present invention.
  • Figure 17 is an XRPD comparison diagram of the high humidity stability 1 of crystal form A of the present invention.
  • the crude drug in the following examples of the present invention is 2,2-bis(4-fluorophenyl)-2-phenylacetamide provided by Shanghai Haoyuan Biomedical Technology Co., Ltd., with a chemical purity greater than 98.0%.
  • Method 25 degrees Celsius, 10% humidity per step, and the judgment standard is less than 0.02% for 10 minutes.
  • 2,2-Bis(4-fluorophenyl)-2-phenylacetamide was purchased from Shanghai Haoyuan Biomedical Technology Co., Ltd., with a chemical purity greater than 98%.
  • Example 1 83.05 98.0
  • Example 2 95.25 98.91
  • Example 3 97.14 98.88
  • Example 4 93.01 98.98
  • Example 5 92.44 98.67
  • Example 6 98.35 98.22
  • Example 7 88.22 99.13
  • the water adsorption experiment was performed on the crystal form A prepared in Example 2.
  • the experimental conditions were 25°C, the relative humidity was changed in steps of 10% humidity, gradually increasing from 0 to 90% RH, and the constant equilibrium time for each humidity was 10 minutes .
  • the crystal form A prepared in Example 2 was tested as follows.
  • High-humidity stability 1 Test the stability of the crystal form for 5 days and 10 days under the conditions of 25°C and 92.5%RH respectively, and compare it with the XRPD of form A at 0 days. The result is shown in Figure 17. As shown, the results show that the high humidity stability of the crystal form A is good.
  • High humidity stability 2 Test the stability of the crystal form at 40°C and 75%RH for 5 days and 10 days, and compare it with the XRPD of form A at 0 days. The results are shown in Figure 18. As shown, the results show that the high humidity stability of the crystal form A is good.
  • High-humidity stability 1 Using the same method as measuring the high-humidity stability of crystal form A, the test substance is placed at 25°C and a humidity of 92.5% RH to determine the stability of the crystal form for 5 days. The result of XRPD comparison of Form I at 0 days is shown in Fig. 21. The result shows that Form I is unstable under high humidity conditions and is easily converted to Form A.
  • High-humidity stability 2 Using the same method as measuring the high-humidity stability of crystal form A, the test substance is placed at 40°C and humidity 75%RH to determine the stability of the crystal form for 5 days. The result of XRPD comparison of Form I at 0 days is shown in Fig. 22. The result shows that Form I is unstable under high humidity conditions and is easily converted to Form A.
  • the crystalline form I of 2,2-bis(4-fluorophenyl)-2-phenylacetamide has poor light stability, high temperature stability, and high humidity stability, and it has 2 provided to this application.
  • FormA is crystal form A
  • Form I is crystal form I

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

本发明提供了2,2-双(4-氟苯基)-2-苯乙酰胺的晶型A，该晶型具有良好的光照稳定性、高温稳定性和高湿稳定性。

Description

2,2-双(4-氟苯基)-2-苯乙酰胺的晶型A及其制备方法和应用 技术领域
本发明涉及晶型制备技术领域，具体涉及2,2-双(4-氟苯基)-2-苯乙酰胺的晶型A及其制备方法和应用。
背景技术
下述式(I)的2,2-双(4-氟苯基)-2-苯乙酰胺，又名senicapo，是一种钾流通抑制剂，由安克进公司开发(ICAGEN)，已知其为具有治疗或预防镰刀型细胞病、预防红细胞脱水和抑制钾流通的药物(中国授权专利CN1344158B)，还为具有预防或治疗炎性过程或中风的药物(中国授权专利CN101437403B)。近期的研究还发现senicapoc有望用于遗传性干细胞增多症的治疗。
Figure PCTCN2019080419-appb-000001
中国授权专利文献CN101437403B公开了式(I)所示的化合物的制备方法，具体而言，如下述反应式所示，式(I)所示的化合物的制备方法为：苯基溴化镁与二氟苯基甲酮反应制得双(4-氟苯基)苯基甲醇；(2)双(4-氟苯基)苯基甲醇 与乙酰氯反应制得双(4-氟苯基)苯基氯甲烷；(3)双(4-氟苯基)苯基氯甲烷与氰化铜反应，然后经HPLC法对残留物进行分离纯化，得到式(I)所示的化合物。
本发明人根据中国授权专利文献CN101437403B所公开的方法制备式(I)所示的化合物并对结果进行分析，发现式(I)所示的化合物在高温、高湿和光照条件储存时会发生晶型的转变，所获得的生成物物理状态不稳定，从而无法用作医药原料，在使用过程中需要严格的管理，不适合用作医药原料。
发明内容
因此，本发明的目的在于提供上述式(I)所示的2,2-双(4-氟苯基)-2-苯乙酰胺的晶体A及其制备方法和用途，该晶体A具有明显提高的稳定性，且明显降低晶型A中残留的溶剂含量至0.03％以下。
本发明提供了2,2-双(4-氟苯基)-2-苯乙酰胺的晶型A，使用Cu-Kɑ辐射，以2θ角度表示的X-射线粉末衍射，在10.4±0.2°、11.8±0.2°、18.8±0.2°、21.3±0.2°处有特征峰。
使用Cu-Kɑ辐射，以2θ角度表示的X-射线粉末衍射，还在7.2±0.2°、20.8±0.2°处有特征峰。
使用Cu-Kɑ辐射，以2θ角度表示的X-射线粉末衍射，还在15.2±0.2°、23.0±0.2°、25.7±0.2°处有特征峰。
使用Cu-Kɑ辐射，以2θ角度表示的X-射线粉末衍射，还在13.4±0.2°、14.3±0.2°、16.4±0.2°、19.2±0.2°、19.8±0.2°、20.3±0.2°、24.1±0.2°处有特征峰。
使用Cu-Kɑ辐射，以2θ角度表示的X-射线粉末衍射，还在22.1±0.2°、22.5±0.2°、25.0±0.2°、26.5±0.2°、27.5±0.2°、28.5±0.2°、29.5±0.2°、31.6±0.2°、32.6±0.2°处有特征峰。
所述晶型A的XRPD图谱数据为：
峰编号 2θ(°) I％
1 10.44 48.4
2 11.779 48.1
3 13.381 24
4 14.299 32.1
5 15.22 38.1
6 18.76 100
7 19.24 47
8 19.78 57.3
9 20.28 52
10 20.84 69.3
11 21.339 80.1
12 22.96 40.4
13 24.08 32.7
14 25.699 48.5
。
所述晶型A的XRPD图谱数据为：
峰编号 2-Theta I％
1 7.163 6.4
2 10.44 48.4
3 11.779 48.1
4 13.381 24
5 14.299 32.1
6 15.22 38.1
7 16.401 7.4
8 18.76 100
9 19.24 47
10 19.78 57.3
11 20.28 52
12 20.84 69.3
13 21.339 80.1
14 22.96 40.4
15 24.08 32.7
16 24.962 12
17 25.699 48.5
18 26.5 11.1
19 27.54 8.4
20 28.46 25.9
21 29.517 15.8
22 31.58 36
23 32.599 18
。
所述晶型A具有基本上如图4所述的XRPD图谱。
利用差式扫描量热法，所述晶型A在177.0-191.0℃的温度区间具有特征吸热峰。
所述晶型A具有基本上如图5所示的DSC曲线。
所述晶型A的TGA曲线中，在100℃之前的失重为0.02584％。
所述晶型A的TGA曲线基本上如图6所示。
本发明还提供了一种制备上述任一所述的晶型A的方法，包括如下步骤：
将2,2-双(4-氟苯基)-2-苯乙酰胺中加入良溶剂溶解，溶剂挥发得固体或冷却析出得固体，干燥，得晶型A。
在温度为50-75℃下加入所述良溶剂溶解；在温度为-18～5℃下冷却析出得固体。
本发明还提供了一种制备上述任一所述的晶型A的方法，包括如下步骤：
将2,2-双(4-氟苯基)-2-苯乙酰胺中加入良溶剂溶解，然后加入不良溶剂，析出固体，干燥，得晶型A。
在温度为15-35℃下加入所述良溶剂溶解；在温度为15-35℃下加入所述不良溶剂析出固体。
所述良溶剂选自低级醇类有机溶剂、低级酮类有机溶剂、低级酯类有机溶剂、低级腈类有机溶剂或低级醚类有机溶剂；
优选地，所述低级醇类有机溶剂选自甲醇、乙醇、异丙醇或正丁醇，所述低级酮类有机溶剂选择丙酮；低级酯类有机溶剂选择乙酸乙酯，所述低级醚类有机溶剂选自四氢呋喃或二氧六环，所述低级腈类有机溶剂选择乙腈。
所述2,2-双(4-氟苯基)-2-苯乙酰胺与良溶剂的用量比为10-40mg：0.1-5ml。
所述不良溶剂选自正庚烷、正己烷、无水乙醚、异丙醚或水。
本发明提供了一种药物组合物，包括上述任一所述的晶型A和药学上可接受的赋形剂。
本发明提供了一种医药有效量的上述任一所述的晶型A，或上述任一所述的制备方法制得的晶型A，或所述的药物组合物用于制备预防或治疗炎性过程或中风的药物中的用途。
所述炎性过程是选自以下的疾病：多发性硬化，胰岛素依赖型糖尿病，类风湿性关节炎，周围神经炎和肺性高血压症。
本发明提供了一种医药有效量的上述任一所述的晶型A，或上述任一所述的制备方法制得的晶型A，或所述的药物组合物用于抑制细胞钾通道、减少红细胞脱水、治疗或预防镰刀形细胞病和提高含苯基的钾通道抑制剂在生物介质中抵抗降解中的用途。
所述药物经口、非经肠、真皮内、鞘内、肌内、皮下、经阴道、经颊、舌下、经直肠、局部、吸入、鼻内或经皮投与。
本发明还提供了一种抑制细胞钾通道、减少红细胞脱水、治疗或预防镰刀形细胞病、提高含苯基的钾通道抑制剂在生物介质中抵抗降解和预防或治疗炎性过程或中风的方法，其包括向患者施用药学有效剂量的所述药物组合物的步骤。
本发明技术方案，具有如下优点：
1、本发明提供的式(I)化合物的晶型A，纯度高，在水、缓冲溶液或有机溶剂中具有较好的溶解性，利于成药。
2、本发明提供的式(I)化合物的晶型A，具有良好的光照稳定性、高温稳定性、高湿稳定性，而且该晶型含水或其他溶剂的量低于0.03％(质量百分比)，在相对湿度从0升至90％RH时，晶型A的引湿增重不高于1％，引湿缓慢，制备工艺简单，条件温和，质量稳定易于大规模工业生产。
3、本发明提供的式(I)化合物的晶型A与晶型I相比，具有改进的粉体流动相，适合制备活性成分含量稳定的制剂。
4、本发明提供的式(I)化合物的晶型A与晶型I相比，在动物体内药效更好，半衰期更长，暴露量更高。
附图说明
为了更清楚地说明本发明具体实施方式或现有技术中的技术方案，下面将对具体实施方式或现有技术描述中所需要使用的附图作简单地介绍，显而易见地，下面描述中的附图是本发明的一些实施方式，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的附图。
图1是本发明实施例1晶型I的X射线衍射图；
图2是本发明实施例1晶型I的DSC；
图3是本发明实施例1晶型I的TGA曲线；
图4是本发明实施例2晶型A的X射线衍射图(标出出峰位置)
图5是本发明实施例2晶型A的DSC；
图6是本发明实施例2晶型A的TGA曲线；
图7是本发明实施例3晶型A的XRPD图谱；
图8是本发明实施例4晶型A的XRPD图谱；
图9是本发明实施例5晶型A的XRPD图谱；
图10是本发明实施例6晶型A的XRPD图谱；
图11是本发明实施例7晶型A的XRPD图谱；
图12是本发明实施例8晶型A的单晶分子结构椭球图；
图13是本发明实施例8晶型A的单晶的数据模拟与实验培养单晶的XRPD对比图；
图14是本发明实验例2中实施例2晶型A的DVS曲线；
图15是本发明晶型A的光照稳定性XRPD对比图；
图16是本发明晶型A的高温稳定性XRPD对比图；
图17是本发明晶型A的高湿稳定性1的XRPD对比图；
图18是本发明晶型A的高湿稳定性2的XRPD对比图；
图19是本发明实验例4中晶型I的光照稳定性XRPD对比图；
图20是本发明实验例4中晶型I的高温稳定性XRPD对比图；
图21是本发明实验例4中晶型I的高湿稳定性1的XRPD对比图；
图22是本发明实验例4中晶型I的高湿稳定性2的XRPD对比图。
具体实施方式
本发明下述实施例中原料药为上海皓元生物医药科技有限公司提供的2,2-双(4-氟苯基)-2-苯乙酰胺，化学纯度大于98.0％。
本申请采用的实验仪器及测试条件具体如下：
X射线粉末衍射仪XRPD
型号：日本理学(Rigaku)Uitima IV
方法：Cu靶Ka，电压40KV，电流40mA，测试角度3-45°，步长0.02，曝光时间0.2S，光管狭缝宽度2mm，Dtex探测器。
X射线单晶衍射仪SXRD
型号：德国布鲁克公司BRUKER D8 QUEST
方法：Cu靶电压40KV电流30mA
差式量热扫描仪DSC
型号：美国TA仪器公司TA2000
方法：升温速率10℃/min。
热重分析仪TGA
型号：美国TA仪器公司TA500
方法：升温速率10℃/min。
动态水分吸附仪DVS
型号：英国SMS公司DVS intrinsic
方法：25摄氏度，每步10％湿度，判断标准小于0.02％下10min。
光照培养箱
型号：泰仕电子工业股份有限公司TES-1330A
超声设备
型号：上海合金超声设备有限公司KQ-3200
可程式药品稳定恒温恒湿试验机
型号：上海普晗精密设备有限公司CMA-100C
实施例1原料药XRPD分析
2,2-双(4-氟苯基)-2-苯乙酰胺由上海皓元生物医药科技有限公司购买，化学纯度大于98％。
测得获得的原料药的XRPD图谱如图1所示，特征峰见下表所示，说明按照专利文献CN101437403B公开的方法制备的化合物为晶体，记为晶型I。
表1晶型I的特征峰
2-Theta d(A) I％
7.04 12.5464 15
12.28 7.2019 11.5
13.281 6.6612 25.2
14.1 6.2759 100
16.459 5.3814 16.8
17.879 4.9572 27.7
18.639 4.7566 10.8
19.582 4.5297 49.6
20.12 4.4096 16.3
21.259 4.1758 18.8
22.301 3.9831 10.8
25.541 3.4847 22.9
28.501 3.1292 17.7
进一步的检测原料药的DSC和TGA曲线如图2和3所示，其中，DSC曲线中，晶型I在184.0-191.0℃存在一特征吸热峰，TGA曲线中，晶型I在100℃之前的失重为0.2018％。
实施例2晶型A的制备
称取16.6mg原料药于样品瓶中，加入0.6ml无水乙醇室温溶解澄清，缓慢挥发得到橘黄色固体，室温真空干燥得到橘黄色粉末，即为晶型A，测得晶型A的XRPD图谱见图4所示，特征峰见下表。
表2晶型A的特征峰
Figure PCTCN2019080419-appb-000002
Figure PCTCN2019080419-appb-000003
进一步的检测橘黄色粉末的DSC和TGA曲线如图5和6所示，其中，DSC曲线中，晶型A在179.0-191.0℃存在一吸热峰，TGA曲线中，100℃之前的失重为0.02584％，晶型A存在熔融分解的情况，为非溶剂化物。
实施例3晶型A的制备
称取15.1mg原料药于样品瓶中，加入0.5ml乙酸乙酯室温溶解澄清，缓慢挥发得到粉红色固体，室温真空干燥得到粉红色粉末，测得XRPD图谱见图7所示，与实施例2中的图4基本一致。
实施例4晶型A的制备
称取15.2mg原料药于样品瓶中，加入0.2ml1,4-二氧六环室温溶解澄清，缓慢挥发得到白色固体，室温真空干燥得到白色粉末，测得XRPD图谱见图8所示，与实施例2中的图4基本一致。
实施例5晶型A的制备
称取38.0mg原料药至样品瓶中，加入0.3ml乙腈，升温至70℃溶解澄清，使用直径为0.45μm的滤头过滤得到滤液，放置于4℃环境冷却，析出白色固体，过滤得到固体，室温真空干燥得到白色固体，测得XRPD图谱见图9所示，与实施例2中的图4基本一致。
实施例6晶型A的制备
称取35.0mg原料药至样品瓶中，加入0.3ml丙酮，升温至70℃溶解澄清，使用直径为0.45μm的滤头过滤得到滤液，放置于4℃环境冷却，析出白色固体，过滤得到固体，室温真空干燥得到白色固体，测得XRPD图谱见图10所示，与实施例2中的图4基本一致。
实施例7晶型A的制备
称取14.2mg原料药至样品瓶中，加入0.5ml四氢呋喃室温溶解澄清，然后缓慢滴加2ml正庚烷，出现粉色浑浊，过滤得到固体，室温真空干燥后得到粉色固体，测得XRPD图谱见图11所示，与实施例2中的图4基本一致。
实施例8晶型A的单晶的制备
称取15.9mg原料药于样品瓶中，加入1.5ml无水乙醇室温溶解澄清，缓慢挥发得到晶型A单晶，采用X射线单晶衍射仪对得到的单晶进行检测，经晶体结构解析其单晶数据如下表所示，且单晶分子结构椭球图如图12所示，将利用单晶数据模拟得到的XRPD数据与实验培养得到的单晶测得的XRPD进行对比，如图13所示。
表3单晶数据
Figure PCTCN2019080419-appb-000004
Figure PCTCN2019080419-appb-000005
实验例1收率和纯度的结果比较
利用HPLC分析测定实施例1中的晶型I和实施例2～7制得的晶型A的纯度，结果如下表所示。
表4 HPLC实验结果
  收率/％ 纯度/％
实施例1 83.05 98.0
实施例2 95.25 98.91
实施例3 97.14 98.88
实施例4 93.01 98.98
实施例5 92.44 98.67
实施例6 98.35 98.22
实施例7 88.22 99.13
从上表可知，相比于实施例1中的晶型I，本发明实施例2～7制得的晶型A具有明显提高的纯度。
实验例2(吸湿性考察)
对实施例2制得的晶型A进行水吸附性实验，实验条件为25℃，相对湿度以10％的湿度变化步阶，从0逐渐增加到90％RH，每个湿度固定平衡时间为10min。
到湿度90％完成时，晶型A的引湿增重低于0.6％，且晶型A每步10分钟内重量变化小于0.02％，说明晶型A具有低吸湿性，有利于药物的运输和储存，见图14所示。
实验例3晶型A的稳定性
对实施例2制备的晶型A进行如下检测。
(1)光照稳定性：分别将受试物置于25℃，4500Lux光照条件下，测定5天和10天晶型稳定性，与0天的晶型A的XRPD对比，结果如图15所示，结果显示晶型A光照稳定性良好。
(2)高温稳定性：分别将受试物置于60℃下测定5天和10天晶型稳定性，与0天的晶型A的XRPD对比，结果如图16所示，结果显示晶型A的高温稳定性良好。
(3)高湿稳定性1：分别将受试物置于25℃，湿度92.5％RH条件下测定5天和10天晶型稳定性，与0天的晶型A的XRPD对比，结果如图17所示，结果显示晶型A的高湿稳定性良好。
(4)高湿稳定性2：分别将受试物置于40℃，湿度75％RH条件下测定5天和10天晶型稳定性，与0天的晶型A的XRPD对比，结果如图18所示，结果显示晶型A的高湿稳定性良好。
实验例4晶型I的稳定性
对实施例1中的晶型I进行如下检测。
(1)光照稳定性：采用与测定晶型A的光照稳定性相同的方法，将受试物置于25℃，4500Lux光照条件下测定放置5天的晶型稳定性，与0天的晶型I的XRPD对比，结果如图19所示，结果显示晶型I光照条件下不稳定，易转成晶型A。
(2)高温稳定性：采用与测定晶型A的高温稳定性相同的方法，将受试物置于60℃条件下测定放置5天的晶型稳定性，与0天的晶型I的XRPD对比， 结果如图20所示，结果显示晶型I高温条件下不稳定，易转成晶型A。
(3)高湿稳定性1：采用与测定晶型A的高湿稳定性1相同的方法，将受试物置于25℃，湿度92.5％RH条件下测定放置5天的晶型稳定性，与0天的晶型I的XRPD对比，结果如图21所示，结果显示晶型I高湿条件下不稳定，易转成晶型A。
(4)高湿稳定性2：采用与测定晶型A的高湿稳定性2相同的方法，将受试物置于40℃，湿度75％RH条件下测定放置5天的晶型稳定性，与0天的晶型I的XRPD对比，结果如图22所示，结果显示晶型I高湿条件下不稳定，易转成晶型A。
综上所述，2,2-双(4-氟苯基)-2-苯乙酰胺的晶型I光照稳定性、高温稳定性、高湿稳定性均不好，具有向本申请提供的2,2-双(4-氟苯基)-2-苯乙酰胺的晶型A转变的趋势，而本申请提供的2,2-双(4-氟苯基)-2-苯乙酰胺的晶型A具有良好的光照稳定性、高温稳定性、高湿稳定性。
需要说明的是，本发明中说明书附图中的FormA即为晶型A，Form I即为晶型I。
显然，上述实施例仅仅是为清楚地说明所作的举例，而并非对实施方式的限定。对于所属领域的普通技术人员来说，在上述说明的基础上还可以做出其它不同形式的变化或变动。这里无需也无法对所有的实施方式予以穷举。而由此所引伸出的显而易见的变化或变动仍处于本发明创造的保护范围之中。

Claims (25)

  1. 2,2-双(4-氟苯基)-2-苯乙酰胺的晶型A，其特征在于，使用Cu-Kɑ辐射，以2θ角度表示的X-射线粉末衍射，在10.4±0.2°、11.8±0.2°、18.8±0.2°、21.3±0.2°处有特征峰。
  2. 根据权利要求1所述的晶型A，其特征在于，使用Cu-Kɑ辐射，以2θ角度表示的X-射线粉末衍射，还在7.2±0.2°、20.8±0.2°处有特征峰。
  3. 根据权利要求1或2所述的晶型A，其特征在于，使用Cu-Kɑ辐射，以2θ角度表示的X-射线粉末衍射，还在15.2±0.2°、23.0±0.2°、25.7±0.2°处有特征峰。
  4. 根据权利要求1-3中任一所述的晶型A，其特征在于，使用Cu-Kɑ辐射，以2θ角度表示的X-射线粉末衍射，还在13.4±0.2°、14.3±0.2°、16.4±0.2°、19.2±0.2°、19.8±0.2°、20.3±0.2°、24.1±0.2°处有特征峰。
  5. 根据权利要求1-4中任一所述的晶型A，其特征在于，使用Cu-Kɑ辐射，以2θ角度表示的X-射线粉末衍射，还在22.1±0.2°、22.5±0.2°、25.0±0.2°、26.5±0.2°、27.5±0.2°、28.5±0.2°、29.5±0.2°、31.6±0.2°、32.6±0.2°处有特征峰。
  6. 根据权利要求1-5中任一所述的晶型A，其特征在于，所述晶型A的XRPD图谱数据为：
    Figure PCTCN2019080419-appb-100001
    Figure PCTCN2019080419-appb-100002
  7. 根据权利要求1-6中任一所述的晶型A，其特征在于，所述晶型A的XRPD图谱数据为：
    峰编号 2-Theta I％ 1 7.163 6.4 2 10.44 48.4 3 11.779 48.1 4 13.381 24 5 14.299 32.1 6 15.22 38.1 7 16.401 7.4 8 18.76 100 9 19.24 47 10 19.78 57.3 11 20.28 52 12 20.84 69.3 13 21.339 80.1 14 22.96 40.4 15 24.08 32.7 16 24.962 12 17 25.699 48.5 18 26.5 11.1 19 27.54 8.4 20 28.46 25.9 21 29.517 15.8 22 31.58 36 23 32.599 18
    。
  8. 根据权利要求1-7中任一所述的晶型A，其特征在于，所述晶型A具有基本上如图4所述的XRPD图谱。
  9. 根据权利要求1-8中任一所述的晶型A，其特征在于，利用差式扫描量热法，所述晶型A在177.0-191.0℃的温度区间具有特征吸热峰。
  10. 根据权利要求1-9中任一所述的晶型A，其特征在于，所述晶型A具有基本上如图5所示的DSC曲线。
  11. 根据权利要求1-10中任一所述的晶型A，其特征在于，所述晶型A的TGA曲线中，在100℃之前的失重为0.02584％。
  12. 根据权利要求1-11中任一所述的晶型A，其特征在于，所述晶型A的TGA曲线基本上如图6所示。
  13. 一种制备权利要求1-12中任一所述的晶型A的方法，其特征在于，包括如下步骤：
    将2,2-双(4-氟苯基)-2-苯乙酰胺中加入良溶剂溶解，溶剂挥发得固体或冷却析出得固体，干燥，得晶型A。
  14. 根据权利要求13所述的晶型A的制备方法，其特征在于，
    在温度为50-75℃下加入所述良溶剂溶解；在温度为-18～5℃下冷却析出得固体。
  15. 一种制备权利要求1-12中任一所述的晶型A的方法，其特征在于，包括如下步骤：
    将2,2-双(4-氟苯基)-2-苯乙酰胺中加入良溶剂溶解，然后加入不良溶剂，析出固体，干燥，得晶型A。
  16. 根据权利要求15所述的晶型A的制备方法，其特征在于，在温度为15-35℃下加入所述良溶剂溶解；在温度为15-35℃下加入所述不良溶剂析出固体。
  17. 根据权利要求13-16所述的晶型A的制备方法，其特征在于，
    所述良溶剂选自低级醇类有机溶剂、低级酮类有机溶剂、低级酯类有机溶剂、低级腈类有机溶剂或低级醚类有机溶剂；
    优选地，所述低级醇类有机溶剂选自甲醇、乙醇、异丙醇或正丁醇，所述低级酮类有机溶剂选择丙酮；低级酯类有机溶剂选择乙酸乙酯，所述低级醚类有机溶剂选自四氢呋喃或二氧六环，所述低级腈类有机溶剂选择乙腈。
  18. 根据权利要求13-17中任一所述的晶型A的制备方法，其特征在于，所述2,2-双(4-氟苯基)-2-苯乙酰胺与良溶剂的用量比为10-40mg：0.1-5ml。
  19. 根据权利要求15或16所述的晶型A的制备方法，其特征在于，所述不良溶剂选自正庚烷、正己烷、无水乙醚、异丙醚或水。
  20. 一种药物组合物，其特征在于，包括权利要求1-12中任一所述的晶型A和药学上可接受的赋形剂。
  21. 一种医药有效量的权利要求1-12中任一所述的晶型A，或权利要求13-19中任一所述的制备方法制得的晶型A，或权利要求20所述的药物组合物用于制备预防或治疗炎性过程或中风的药物中的用途。
  22. 根据权利要求21所述的用途，其特征在于，所述炎性过程是选自以下的疾病：多发性硬化，胰岛素依赖型糖尿病，类风湿性关节炎，周围神经炎和肺性高血压症。
  23. 一种医药有效量的权利要求1-12中任一所述的晶型A，或权利要求13-19中任一所述的制备方法制得的晶型A，或权利要求20所述的药物组合物用于抑制细胞钾通道、减少红细胞脱水、治疗或预防镰刀形细胞病和提高含苯基的钾通道抑制剂在生物介质中抵抗降解中的用途。
  24. 根据权利要求21-23中任一所述的用途，其特征在于，所述药物经口、非经肠、真皮内、鞘内、肌内、皮下、经阴道、经颊、舌下、经直肠、局部、 吸入、鼻内或经皮投与。
  25. 一种抑制细胞钾通道、减少红细胞脱水、治疗或预防镰刀形细胞病、提高含苯基的钾通道抑制剂在生物介质中抵抗降解和预防或治疗炎性过程或中风的方法，其包括向患者施用药学有效剂量的权利要求20所述药物组合物的步骤。
PCT/CN2019/080419 2019-03-29 2019-03-29 2,2-双(4-氟苯基)-2-苯乙酰胺的晶型a及其制备方法和应用 WO2020198939A1 (zh)

Priority Applications (3)

Application Number Priority Date Filing Date Title
CN201980003580.0A CN112020353A (zh) 2019-03-29 2019-03-29 2,2-双(4-氟苯基)-2-苯乙酰胺的晶型a及其制备方法和应用
PCT/CN2019/080419 WO2020198939A1 (zh) 2019-03-29 2019-03-29 2,2-双(4-氟苯基)-2-苯乙酰胺的晶型a及其制备方法和应用
US17/487,047 US20220033347A1 (en) 2019-03-29 2021-09-28 Crystalline form a of 2, 2-bis(4-fluorophenyl)-2-phenylacetamide and preparation method therefor and application thereof

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
PCT/CN2019/080419 WO2020198939A1 (zh) 2019-03-29 2019-03-29 2,2-双(4-氟苯基)-2-苯乙酰胺的晶型a及其制备方法和应用

Related Child Applications (1)

Application Number Title Priority Date Filing Date
US17/487,047 Continuation US20220033347A1 (en) 2019-03-29 2021-09-28 Crystalline form a of 2, 2-bis(4-fluorophenyl)-2-phenylacetamide and preparation method therefor and application thereof

Publications (1)

Publication Number Publication Date
WO2020198939A1 true WO2020198939A1 (zh) 2020-10-08

Family

ID=72664874

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2019/080419 WO2020198939A1 (zh) 2019-03-29 2019-03-29 2,2-双(4-氟苯基)-2-苯乙酰胺的晶型a及其制备方法和应用

Country Status (3)

Country Link
US (1) US20220033347A1 (zh)
CN (1) CN112020353A (zh)
WO (1) WO2020198939A1 (zh)

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6288122B1 (en) * 1999-02-23 2001-09-11 Icagen, Inc. Gardos channel antagonists
CN101437403A (zh) * 2005-12-20 2009-05-20 Icagen公司 使用三芳基甲烷化合物的治疗方法
WO2017070536A1 (en) * 2015-10-23 2017-04-27 Angion Biomedica Corp. Methods and agents for treating diseases

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20100056637A1 (en) * 2005-12-20 2010-03-04 Icagen, Inc. Treatment methods using triaryl methane compounds
WO2016134353A1 (en) * 2015-02-20 2016-08-25 Children's Medical Center Corporation Methods for treating malaria using potassium channel inhibitors

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6288122B1 (en) * 1999-02-23 2001-09-11 Icagen, Inc. Gardos channel antagonists
CN101437403A (zh) * 2005-12-20 2009-05-20 Icagen公司 使用三芳基甲烷化合物的治疗方法
WO2017070536A1 (en) * 2015-10-23 2017-04-27 Angion Biomedica Corp. Methods and agents for treating diseases

Also Published As

Publication number Publication date
CN112020353A (zh) 2020-12-01
US20220033347A1 (en) 2022-02-03

Similar Documents

Publication Publication Date Title
EP2873664B1 (en) Crystalline form i of tyrosine kinase inhibitor dimaleate and preparation methods thereof
AU2020382214B2 (en) Novel salt of terphenyl compound
JPWO2018117267A1 (ja) 置換ピペリジン化合物の塩
WO2021143954A2 (zh) 一种氟伐替尼或其甲磺酸盐的晶型及其制备方法
JP6785523B2 (ja) ナトリウム−グルコース共輸送体２阻害剤の結晶形
WO2020198939A1 (zh) 2,2-双(4-氟苯基)-2-苯乙酰胺的晶型a及其制备方法和应用
WO2022228352A1 (zh) 一种五环三萜类化合物结晶及其制备方法
EP2874628A2 (en) Salts and hydrates of antipsychotics
WO2020258660A1 (zh) 盐酸沃尼妙林水合物晶型及其制备方法与含有该晶型的药物组合物
WO2020198940A1 (zh) 2-(2,5-二氧代吡咯烷-1基)乙基甲基富马酸酯的晶型a及其制备方法和应用
WO2016050134A1 (zh) 一种钠-葡萄糖协同转运蛋白2抑制剂的l-脯氨酸复合物、其一水合物及晶体
CA3173878A1 (en) Organic acid addition salts of s-pindolol
RU2734549C2 (ru) Соляная форма ингибитора дипептидилпепдидазы iv и способ получения солевой формы
KR102544543B1 (ko) L,d-엘도스테인의 개별적 공결정화물
WO2023143455A1 (zh) 3-[(苯并[d][1,3]二氧戊环-4-基)氧基]丙胺盐酸盐及其光学异构体、晶体及制备方法
KR101640808B1 (ko) 4-[2-디메틸아미노-1-(1-하이드록시사이클로헥실)에틸]페닐 4-메틸벤조에이트 하이드로클로라이드의 다형체, 이의 제조 방법 및 이의 용도
WO2019011316A1 (zh) 一种btk激酶抑制剂的结晶形式及制备方法
WO2001068587A1 (fr) Nouveau derive de cristal de stilbene et son procede d'obtention
US12122804B2 (en) γ-aminobutyric acid modulator crystal form X, preparation method and application thereof
US20210147394A1 (en) Polymorph of hdac6-selective inhibitor and application thereof
WO2019001551A1 (zh) 一种咪唑并异吲哚类衍生物游离碱的晶型及其制备方法
CN118804748A (zh) 固态形式的fgfr抑制剂
NZ718201B2 (en) Hydrochloride salt form for ezh2 inhibition
NZ718201A (en) Hydrochloride salt form for ezh2 inhibition

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: 19922571

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

32PN Ep: public notification in the ep bulletin as address of the adressee cannot be established

Free format text: NOTING OF LOSS OF RIGHTS PURSUANT TO RULE 112(1) EPC (EPO FORM 1205A DATED 24/02/2022)

122 Ep: pct application non-entry in european phase

Ref document number: 19922571

Country of ref document: EP

Kind code of ref document: A1