WO2017152858A1 - Crystal form of ceritinib and preparation method thereof - Google Patents

Crystal form of ceritinib and preparation method thereof Download PDF

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WO2017152858A1
WO2017152858A1 PCT/CN2017/076179 CN2017076179W WO2017152858A1 WO 2017152858 A1 WO2017152858 A1 WO 2017152858A1 CN 2017076179 W CN2017076179 W CN 2017076179W WO 2017152858 A1 WO2017152858 A1 WO 2017152858A1
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crystal form
present
ray powder
powder diffraction
diffraction pattern
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PCT/CN2017/076179
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French (fr)
Chinese (zh)
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陈敏华
张炎锋
刁小娟
张晓宇
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苏州晶云药物科技有限公司
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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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • 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
    • C07D401/12—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 chain containing hetero atoms as chain links

Definitions

  • the invention relates to the field of chemical medicine, in particular to crystal form II of chromatinib and a preparation method thereof.
  • Ceritinib is a new anticancer drug developed by Novartis. The drug was approved by the US Food and Drug Administration (FDA) on April 29, 2014. Coloritinib is an anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitor that blocks the promotion of cancer cell protein for the treatment of crizotinib, but has a metastatic ALK positive non-small Patients with cell lung cancer (NSCLC).
  • ALK anaplastic lymphoma kinase
  • NSCLC metastatic ALK positive non-small Patients with cell lung cancer
  • rititinib is 5-chloro-N2-(2-isopropoxy-5-methyl-4-piperidin-4-yl-phenyl)-N4-[2-(propane-2-sulfonate) Acyl)-phenyl]-pyrimidine-2,4-diamine, the structural formula of which is as follows:
  • Drug polymorphism refers to the presence of two or more different crystalline forms of a drug. Polymorphism is widespread in medicine. Different crystal forms of the same drug have significant differences in solubility, melting point, density, stability, etc., which affect the stability, homogeneity, bioavailability, efficacy and safety of the drug to varying degrees.
  • WO2012082972A1 discloses two crystal forms A and Form B of chromatinib, but the patent does not relate to the hygroscopicity, stability and other physicochemical properties of the two crystal forms, and comprehensive system polycrystals are developed in drug development.
  • Type screening selecting the crystal form most suitable for development, is one of the important research contents that cannot be ignored. Based on this, it is necessary to further carry out the polymorphic screening of the compound of formula (1), and develop a crystal-free type with good stability, low wettability and suitable for industrial production, which provides more and better for the subsequent development of the drug. s Choice.
  • the invention provides a novel crystal form of the compound of the formula (1), and the crystal form provided by the invention has favorable properties such as good stability, low moisture absorption, process developability and easy handling, and the preparation method is simple and the cost is Low cost is of great value to the optimization and development of this drug in the future.
  • the X-ray powder diffraction pattern of Form II provided by the present invention has characteristic peaks at 2theta values of 5.03° ⁇ 0.20°, 10.05° ⁇ 0.20°, 14.40° ⁇ 0.20°, 18.11° ⁇ 0.20°, and 20.00° ⁇ 0.20°. .
  • the X-ray powder diffraction pattern of Form II provided by the present invention has characteristic peaks at 2theta values of 15.00 ° ⁇ 0.20 °, 21.85 ° ⁇ 0.20 °, 23.20 ° ⁇ 0.20 °, and 27.21 ° ⁇ 0.20 °.
  • the X-ray powder diffraction pattern of Form II provided by the present invention has a value of 2theta in 2theta There are characteristic peaks at 10.34° ⁇ 0.20° and 16.05° ⁇ 0.20°.
  • the X-ray powder diffraction pattern of Form II provided by the present invention comprises a value of 5.03° ⁇ 0.20°, 10.05° ⁇ 0.20°, 10.34° ⁇ 0.20°, 14.40° ⁇ 0.20°, 15.00° ⁇ 0.20° at 2theta. Characteristic peaks at 16.05° ⁇ 0.20°, 18.11° ⁇ 0.20°, 20.00° ⁇ 0.20°, 21.85° ⁇ 0.20°, 23.20° ⁇ 0.20°, and 27.21° ⁇ 0.20°.
  • the X-ray powder diffraction pattern of Form II provided by the present invention is substantially as shown in FIG.
  • thermogravimetric analysis when heated to 150 ° C, there is a mass loss gradient of about 1.0%, and the thermogravimetric analysis diagram is basically as shown in FIG. 3 .
  • Another object of the present invention is to provide a process for the preparation of Form II, which comprises adding a compound of the formula (I) and hydrochloric acid to one or more solvent systems selected from the group consisting of alcohols, ketones, nitriles
  • solvent systems selected from the group consisting of alcohols, ketones, nitriles
  • the cyclic ethers are stirred at room temperature and dried, and then redissolved in the solvent or a mixed solvent system thereof with water, followed by stirring with an aqueous solution of sodium hydroxide.
  • the solvent includes a single system of a saturated ketone, a lower alkyl alcohol, a hydrocarbyl nitrile and a cyclic ether solvent or a mixed system thereof.
  • the solvent is selected from the group consisting of acetone, acetonitrile or a mixture thereof.
  • the present invention also provides the crystalline form II of the compound of the formula (I) as a therapeutic anaplastic lymphoma Application in enzyme-mediated diseases of drugs.
  • the anaplastic lymphoma kinase-mediated diseases include anaplastic large cell lymphoma, non-Hodgkin's lymphoma, inflammatory myofibroblastic tumor, neuroblastoma, sarcoma, lung cancer, bronchial carcinoma, prostate Cancer, breast cancer, pancreatic cancer, gastrointestinal cancer, colon cancer, rectal cancer, colon cancer, colorectal adenoma, thyroid cancer, liver cancer, intrahepatic cholangiocarcinoma, hepatocellular carcinoma, adrenal cancer, glioma, glial Blastoma, endometrial cancer, melanoma, kidney cancer, renal pelvic cancer, small bowel cancer, bladder cancer, endometrial cancer, cervical cancer, vaginal cancer, ovarian cancer, multiple myeloma, esophageal cancer,
  • Another object of the invention is to provide a pharmaceutical composition or formulation comprising a therapeutically effective amount of Form II of a compound of formula (I) together with a pharmaceutically acceptable carrier, diluent or excipient.
  • a pharmaceutical composition or formulation is generally prepared by combining or contacting a therapeutically effective amount of Form II of a compound of Formula (I) with one or more pharmaceutical excipients, which are well known in the pharmaceutical arts. The way to prepare.
  • the present invention also provides the use of the crystalline form II of the compound of the formula (I) for the preparation of a pharmaceutical preparation for treating non-small cell lung cancer.
  • the crystal form provided by the present invention has good stability. It can well avoid drug storage and crystal transformation during development, thus avoiding changes in bioavailability and efficacy;
  • the crystal form provided by the invention has low wettability, meets the requirements of bioavailability and efficacy, does not require special drying conditions in the preparation process, simplifies the preparation process and post-treatment process of the drug, and is not easily affected by humidity, and the storage condition The requirements are not harsh, and it is convenient for long-term storage, which greatly reduces the cost of material storage and quality control;
  • the new crystal form provided by the invention can be directly obtained by desalting the hydrochloride salt, can be incorporated into the synthesis process, the preparation method is simple and reproducible, the process is controllable, the solvent is safe and the routine is easy to obtain, the cost is low, and the method is suitable for direct industrialization. produce.
  • phrases "effective therapeutic amount” or “therapeutically effective amount” as used herein refers to a biological response or drug response that is caused by a researcher, veterinarian, doctor or other clinician in a tissue, system, animal, individual or human. The amount of active compound or agent.
  • treating refers to one or more of the following: (1) preventing a disease; for example, a disease or condition that may be predisposed to a disease, disorder, or disorder, but has not yet suffered or manifested the disease. Preventing the disease, condition or disorder in the individual; (2) inhibiting the disease; for example, inhibiting the disease, condition or disorder in an individual who is suffering from or showing a disease or condition of the disease, condition or disorder; and (3) improving the disease A disease; for example, ameliorating the disease, condition or disorder (i.e., reversing the disease and/or condition) in an individual suffering from or showing a disease or condition of the disease, condition or disorder, e.g., reducing the severity of the disease.
  • a disease for example, a disease or condition that may be predisposed to a disease, disorder, or disorder, but has not yet suffered or manifested the disease.
  • Preventing the disease, condition or disorder in the individual (2) inhibiting the disease; for example, inhibiting the disease, condition or disorder in an individual who is suffering from or
  • polymorphic compound refers to different crystalline forms of the same compound and includes, but is not limited to, other solid molecular forms comprising hydrates and solvates of the same compound.
  • the phenomenon that a plurality of crystal forms are formed by the same drug molecule is called a drug polymorph, and a drug polymorph is a phenomenon commonly found in solid drugs.
  • X-ray powder diffraction pattern refers to an experimentally observed diffraction pattern or parameters derived therefrom.
  • the X-ray powder diffraction pattern was characterized by peak position and peak intensity.
  • the lower alkyl alcohol used in the present invention may be a C1-C3 alkyl alcohol.
  • the compound of the formula (I) and/or its salt as a raw material means a solid (crystalline or amorphous), semi-solid, wax or oil form.
  • the compound of the formula (I) and/or its salt as a raw material is in the form of a solid powder.
  • Figure 1 is an XRPD pattern of Form II of the present invention
  • Figure 2 is a DSC chart of Form II of the present invention.
  • Figure 3 is a TGA diagram of Form II of the present invention.
  • Figure 4 is a 1 H-NMR chart of Form II of the present invention.
  • Figure 5 is a DVS diagram of Form II of the present invention.
  • Figure 6 is an XRPD diagram of the DVS before and after the DVS hygroscopicity measurement of Form II of the present invention
  • Figure 7 is a comparison chart of XRPD of the Form II of the present invention placed at 25 ° C / 60% relative humidity for 30 days (the upper image shows the XRPD pattern before placement, and the lower image shows the XRPD pattern after placement);
  • Figure 8 is a comparison chart of XRPD of the Form II of the present invention placed at 40 ° C / 75% relative humidity for 30 days (the upper image shows the XRPD pattern before placement, and the lower figure shows the XRPD pattern after placement);
  • test methods described are generally carried out under conventional conditions or conditions recommended by the manufacturer; the raw materials of the colorizone are commercially available.
  • PSD particle size distribution
  • D10 indicates the particle size distribution (volume distribution) accounts for 10% of the particle size
  • D50 indicates the particle diameter corresponding to the particle size distribution (volume distribution), which is also called the median diameter.
  • D90 indicates the particle size distribution (volume distribution) accounts for 90% of the particle size
  • the X-ray powder diffraction pattern of the present invention was collected on a Panalytical Empyrean X-ray powder diffractometer.
  • the method parameters of the X-ray powder diffraction described in the present invention are as follows:
  • Scan range: from 3.0 to 40.0 degrees
  • the differential scanning calorimetry (DSC) map of the present invention was acquired on a TA Q2000.
  • the method parameters of the differential scanning calorimetry (DSC) described in the present invention are as follows:
  • thermogravimetric analysis (TGA) map of the present invention was taken on a TA Q5000.
  • the method parameters of the thermogravimetric analysis (TGA) described in the present invention are as follows:
  • the dynamic moisture adsorption (DVS) pattern of the present invention was collected on an Intrinsic dynamic moisture adsorber manufactured by SMS Corporation (Surface Measurement Systems Ltd.).
  • the method parameters of the dynamic moisture adsorber are as follows:
  • Relative humidity range 0%RH-95%RH
  • the X-ray powder diffraction data of Form II obtained in this example is shown in Table 1.
  • the XRPD pattern is shown in Fig. 1.
  • the DSC chart is shown in Fig. 2.
  • the TGA chart is shown in Fig. 3.
  • the 1 H-NMR chart is shown in Fig. 4.
  • the 1 H-NMR data is as follows: 1H-NMR (400 MHz, DMSO-d6) ⁇ 8.
  • the method for preparing the hydrochloride salt of the compound of the formula (1) is the same as in the first embodiment. 19.8 mg of the compound of the formula (1) hydrochloride was dissolved in 0.04 mL of acetonitrile and 0.4 mL of water, and 0.035 mL of a 1 mol/L sodium hydroxide aqueous solution was added thereto, and the mixture was stirred at 5 ° C for 24 hours, and the lower layer solid was centrifuged, and dried overnight at room temperature. The resulting solid was Form II.
  • the wetting weight gain is not less than 15%
  • Humidity Wet weight gain is less than 15% but not less than 2%
  • wetting gain is less than 2% but not less than 0.2%
  • wetting gain is less than 0.2%
  • the crystal form II prepared by the present invention was separately placed at 25 ° C / 60% relative humidity and 40 ° C / 75% relative humidity for 30 days and 90 days, respectively, and its XRPD was measured.
  • the experimental results are shown in Table 4.
  • the XRPD of the Form II of the present invention before and after being placed under the above two conditions for 30 days is shown in Figs. 7 and 8, respectively.
  • the crystalline form II of the compound of the formula (I) prepared in Example 1 and the amorphous form A of the patent WO2012082972A1 were respectively prepared into a saturated solution with high purity water, and the saturation was determined by high performance liquid chromatography after 1 hour, 4 hours and 24 hours. The amount of sample in the solution.
  • the experimental results are shown in Table 5.
  • the crystalline form II of the present invention has a higher solubility than the amorphous form A of the patent WO2012082972A1 after being placed in high-purity water for 1 hour, 4 hours and 24 hours.
  • the higher dissolution rate and solubility in water help to enhance the absorption and utilization of drugs in the organism and improve the efficacy.
  • Average particle size ( ⁇ m) Form II Crystal form A D10 5.47 3.68 D50 41.72 18.68 D90 197.1 102.5
  • the crystal form II of the present invention has a larger particle size and better fluidity than the crystal-free type A in the patent WO2012082972A1, and has excellent properties such as easy filtration in process production.

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Abstract

The present invention relates to crystal form II of 5-chlorine-N2-(2-isopropoxy-5-methyl-4-piperidine-4-yl-phenyl)-N4-[2-(propane-2-sulfonyl)-phenyl]-pyrimidine-2,4-diamine (ceritinib), and the present invention also relates to the method for preparing the crystal form, the pharmaceutical composition comprising the crystal form and the method for treating diseases with the crystal form and the pharmaceutical composition. The crystal form provided by the present invention has advantageous performances, such as a good stability, relatively low hygroscopicity, exploitability and strong treatability of process, and the preparation method is simple, is low cost, and has an important value for the optimization and development of the drug in the future.

Description

色瑞替尼的晶型及其制备方法Crystal form of color ribinib and preparation method thereof 技术领域Technical field
本发明涉及化学医药领域，特别是涉及色瑞替尼的晶型II及其制备方法。The invention relates to the field of chemical medicine, in particular to crystal form II of chromatinib and a preparation method thereof.
背景技术Background technique
色瑞替尼(Ceritinib)，是由诺华(Novartis)公司研发的抗癌新药。该药于2014年4月29日获美国食品药物管理局(FDA)批准。色瑞替尼是一种间变性淋巴瘤激酶(ALK)酪氨酸激酶抑制剂，可阻断促进癌细胞发生蛋白，用于既往使用过克唑替尼治疗，但有转移的ALK阳性非小细胞肺癌(NSCLC)患者。色瑞替尼化学名称为5-氯-N2-(2-异丙氧基-5-甲基-4-哌啶-4-基-苯基)-N4-[2-(丙烷-2-磺酰基)-苯基]-嘧啶-2,4-二胺，其结构式如下所示：Ceritinib is a new anticancer drug developed by Novartis. The drug was approved by the US Food and Drug Administration (FDA) on April 29, 2014. Coloritinib is an anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitor that blocks the promotion of cancer cell protein for the treatment of crizotinib, but has a metastatic ALK positive non-small Patients with cell lung cancer (NSCLC). The chemical name of rititinib is 5-chloro-N2-(2-isopropoxy-5-methyl-4-piperidin-4-yl-phenyl)-N4-[2-(propane-2-sulfonate) Acyl)-phenyl]-pyrimidine-2,4-diamine, the structural formula of which is as follows:
Figure PCTCN2017076179-appb-000001
Figure PCTCN2017076179-appb-000001
药物多晶型(drug polymorphism)是指药物存在有两种或两种以上的不同晶型物质状态。多晶型现象在药物中广泛存在。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。Drug polymorphism refers to the presence of two or more different crystalline forms of a drug. Polymorphism is widespread in medicine. Different crystal forms of the same drug have significant differences in solubility, melting point, density, stability, etc., which affect the stability, homogeneity, bioavailability, efficacy and safety of the drug to varying degrees.
如本领域技术人员所知，已知化学物质的新的固体多晶型形式的存在是不可预见的。多晶型化合物的存在或多晶型形式的数量均不可预见。另外，在什 么条件下发生结晶并得到特定的形式，以及所述多晶型形式的特性如何，也都是不可预测的。由于多晶型化合物的每种多晶型的特性(例如溶解度、稳定性)以及因此引起的应用与储存的适用性不同，因此研究药物物质的所有固态形式，包括所有的多晶型形式，对于提供具有改善的储存稳定性或可预测的溶解度特性的药物是必要的。As is known to those skilled in the art, the presence of new solid polymorphic forms of known chemical species is unpredictable. The presence of polymorphic compounds or the number of polymorphic forms are unpredictable. In addition, in the It is also unpredictable how crystallization occurs and the particular form is obtained, and the properties of the polymorphic form. Due to the nature of each polymorph of the polymorphic form (eg solubility, stability) and the resulting applicability to storage, the study of all solid forms of the drug substance, including all polymorphic forms, It is necessary to provide a drug with improved storage stability or predictable solubility characteristics.
目前，WO2012082972A1公开了色瑞替尼的两种晶型形式A、形式B，但专利中并未涉及两种晶型的吸湿性，稳定性等物化性质，而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，有必要进一步进行式(1)化合物色瑞替尼的多晶型筛选，开发出稳定性好、引湿性低、适合工业化生产的无水晶型，为药物的后续开发提供更多更好的选择。At present, WO2012082972A1 discloses two crystal forms A and Form B of chromatinib, but the patent does not relate to the hygroscopicity, stability and other physicochemical properties of the two crystal forms, and comprehensive system polycrystals are developed in drug development. Type screening, selecting the crystal form most suitable for development, is one of the important research contents that cannot be ignored. Based on this, it is necessary to further carry out the polymorphic screening of the compound of formula (1), and develop a crystal-free type with good stability, low wettability and suitable for industrial production, which provides more and better for the subsequent development of the drug. s Choice.
发明内容Summary of the invention
本发明提供一种式(1)化合物的新晶型，本发明提供的晶型具有良好的稳定性、较低的引湿性、工艺可开发和易处理性等有利性能，且制备方法简单，成本低廉，对未来该药物的优化和开发具有重要价值。The invention provides a novel crystal form of the compound of the formula (1), and the crystal form provided by the invention has favorable properties such as good stability, low moisture absorption, process developability and easy handling, and the preparation method is simple and the cost is Low cost is of great value to the optimization and development of this drug in the future.
具体地，本发明的一个目的是提供式(1)化合物的无水晶型，命名为晶型II。In particular, it is an object of the present invention to provide an anhydrous crystalline form of the compound of formula (1), designated as Form II.
本发明提供的晶型II的X射线粉末衍射图在2theta值为5.03°±0.20°、10.05°±0.20°、14.40°±0.20°、18.11°±0.20°和20.00°±0.20°处具有特征峰。The X-ray powder diffraction pattern of Form II provided by the present invention has characteristic peaks at 2theta values of 5.03°±0.20°, 10.05°±0.20°, 14.40°±0.20°, 18.11°±0.20°, and 20.00°±0.20°. .
进一步地，本发明提供的晶型II的X射线粉末衍射图在2theta值为15.00°±0.20°、21.85°±0.20°、23.20°±0.20°和27.21°±0.20°处具有特征峰。Further, the X-ray powder diffraction pattern of Form II provided by the present invention has characteristic peaks at 2theta values of 15.00 ° ± 0.20 °, 21.85 ° ± 0.20 °, 23.20 ° ± 0.20 °, and 27.21 ° ± 0.20 °.
更进一步地，本发明提供的晶型II的X射线粉末衍射图在2theta值为 10.34°±0.20°和16.05°±0.20°处具有特征峰。Further, the X-ray powder diffraction pattern of Form II provided by the present invention has a value of 2theta in 2theta There are characteristic peaks at 10.34°±0.20° and 16.05°±0.20°.
优选地，本发明提供的晶型II的X射线粉末衍射图包括在2theta值为5.03°±0.20°、10.05°±0.20°、10.34°±0.20°、14.40°±0.20°、15.00°±0.20°、16.05°±0.20°、18.11°±0.20°、20.00°±0.20°、21.85°±0.20°、23.20°±0.20°和27.21°±0.20°处具有特征峰。Preferably, the X-ray powder diffraction pattern of Form II provided by the present invention comprises a value of 5.03°±0.20°, 10.05°±0.20°, 10.34°±0.20°, 14.40°±0.20°, 15.00°±0.20° at 2theta. Characteristic peaks at 16.05°±0.20°, 18.11°±0.20°, 20.00°±0.20°, 21.85°±0.20°, 23.20°±0.20°, and 27.21°±0.20°.
更进一步地，本发明提供的晶型II的X射线粉末衍射图基本如图1所示。Further, the X-ray powder diffraction pattern of Form II provided by the present invention is substantially as shown in FIG.
当进行差示扫描量热分析时，加热至159℃附近开始出现吸热峰，其差示扫描量热分析图基本如图2所示。When performing differential scanning calorimetry, an endothermic peak begins to appear near 159 ° C, and the differential scanning calorimetry chart is substantially as shown in FIG. 2 .
当进行热重分析时，加热至150℃时，具有约1.0％的质量损失梯度，其热重分析图基本如图3所示。When the thermogravimetric analysis is performed, when heated to 150 ° C, there is a mass loss gradient of about 1.0%, and the thermogravimetric analysis diagram is basically as shown in FIG. 3 .
晶型II的核磁数据，1H-NMR(400MHz,DMSO-d6)δ8.41(s,1H),8.18(s,1H),7.81(d,J＝8.0Hz,1H),7.58(s,2H),7.29(s,1H),6.81(s,1H),4.54(dt,J1＝12.2Hz,J2＝6.1Hz,1H),3.02(d,J＝11.5Hz,2H),2.73–2.57(m,3H),2.11(s,3H),1.62–1.45(m,4H),1.22(d,J＝6.0Hz,6H),1.15(d,J＝6.8Hz,6H)，如图4所示。Nuclear magnetic data of Form II, 1 H-NMR (400 MHz, DMSO-d6) δ 8.41 (s, 1H), 8.18 (s, 1H), 7.81 (d, J = 8.0 Hz, 1H), 7.58 (s, 2H), 7.29 (s, 1H), 6.81 (s, 1H), 4.54 (dt, J1 = 12.2 Hz, J2 = 6.1 Hz, 1H), 3.02 (d, J = 11.5 Hz, 2H), 2.73 - 2.57 ( m, 3H), 2.11 (s, 3H), 1.62 - 1.45 (m, 4H), 1.22 (d, J = 6.0 Hz, 6H), 1.15 (d, J = 6.8 Hz, 6H), as shown in FIG. .
本发明的另一个目的是提供晶型II的制备方法，所述方法包括：将式(I)化合物和盐酸加入到一种或多种选自以下的溶剂体系中：醇类，酮类，腈类，环醚类，室温搅拌并干燥后，重新溶解于所述溶剂或它们与水的混合溶剂体系，后加入氢氧化钠水溶液搅拌即可得到。进一步地，所述溶剂包括饱和酮，低级烷基醇，烃基腈和环醚类溶剂的单一体系或它们的混合体系。更进一步地，所述溶剂选自丙酮、乙腈或它们的混合物。Another object of the present invention is to provide a process for the preparation of Form II, which comprises adding a compound of the formula (I) and hydrochloric acid to one or more solvent systems selected from the group consisting of alcohols, ketones, nitriles The cyclic ethers are stirred at room temperature and dried, and then redissolved in the solvent or a mixed solvent system thereof with water, followed by stirring with an aqueous solution of sodium hydroxide. Further, the solvent includes a single system of a saturated ketone, a lower alkyl alcohol, a hydrocarbyl nitrile and a cyclic ether solvent or a mixed system thereof. Further, the solvent is selected from the group consisting of acetone, acetonitrile or a mixture thereof.
本发明还提供所述的式(I)化合物的晶型II在作为治疗间变性淋巴瘤激 酶介导的疾病的药物中的应用。优选地，所述间变性淋巴瘤激酶介导的疾病包括间变性大细胞淋巴瘤、非霍奇金氏淋巴瘤、炎性肌纤维母细胞肿瘤、神经母细胞瘤、肉瘤、肺癌、支气管癌、***癌、乳癌、胰腺癌、胃肠癌、结肠癌、直肠癌、结肠癌、结直肠腺瘤、甲状腺癌、肝癌、肝内胆管癌、肝细胞癌、肾上腺癌、神经胶质瘤、神经胶质母细胞瘤、子宫内膜癌、黑色素瘤、肾癌、肾盂癌、小肠癌、膀胱癌、子宫体癌、子***、***癌、卵巢癌、多发性骨髓瘤、食道癌、白血病、急性骨髓性白血病、淋巴细胞性白血病、骨髓样白血病、脑癌、口腔及咽癌、喉癌、多发性骨髓瘤、食道癌和胃癌。The present invention also provides the crystalline form II of the compound of the formula (I) as a therapeutic anaplastic lymphoma Application in enzyme-mediated diseases of drugs. Preferably, the anaplastic lymphoma kinase-mediated diseases include anaplastic large cell lymphoma, non-Hodgkin's lymphoma, inflammatory myofibroblastic tumor, neuroblastoma, sarcoma, lung cancer, bronchial carcinoma, prostate Cancer, breast cancer, pancreatic cancer, gastrointestinal cancer, colon cancer, rectal cancer, colon cancer, colorectal adenoma, thyroid cancer, liver cancer, intrahepatic cholangiocarcinoma, hepatocellular carcinoma, adrenal cancer, glioma, glial Blastoma, endometrial cancer, melanoma, kidney cancer, renal pelvic cancer, small bowel cancer, bladder cancer, endometrial cancer, cervical cancer, vaginal cancer, ovarian cancer, multiple myeloma, esophageal cancer, leukemia, acute bone marrow Leukemia, lymphocytic leukemia, myeloid leukemia, brain cancer, oral and pharyngeal cancer, laryngeal cancer, multiple myeloma, esophageal cancer and gastric cancer.
本发明的另一个目的是提供一种药用组合物或制剂，其包含治疗有效量的式(I)化合物的晶型II以及药学上可接受的载体、稀释剂或赋形剂。一般是将治疗有效量的式(I)化合物的晶型II与一种或多种药用辅料混合或接触制成药用组合物或制剂，该药用组合物或制剂是以制药领域中熟知的方式进行制备的。Another object of the invention is to provide a pharmaceutical composition or formulation comprising a therapeutically effective amount of Form II of a compound of formula (I) together with a pharmaceutically acceptable carrier, diluent or excipient. A pharmaceutical composition or formulation is generally prepared by combining or contacting a therapeutically effective amount of Form II of a compound of Formula (I) with one or more pharmaceutical excipients, which are well known in the pharmaceutical arts. The way to prepare.
进一步地，本发明还提供所述的式(I)化合物的晶型II可用于制备治疗非小细胞肺癌药物制剂的用途。Further, the present invention also provides the use of the crystalline form II of the compound of the formula (I) for the preparation of a pharmaceutical preparation for treating non-small cell lung cancer.
本发明的有益效果为：The beneficial effects of the invention are:
本发明提供的晶型具有良好的稳定性。能很好地避免药物储存以及开发过程中发生转晶，从而避免生物利用度以及药效的改变；The crystal form provided by the present invention has good stability. It can well avoid drug storage and crystal transformation during development, thus avoiding changes in bioavailability and efficacy;
本发明提供的晶型引湿性较低，满足生物利用度和药效要求，在制备工艺中无需特殊的干燥条件，简化了药物的制备工艺和后处理工艺，且不易受湿度影响，对储存条件要求不苛刻，便于长期贮存，大大降低了物料储存以及质量控制方面的成本； The crystal form provided by the invention has low wettability, meets the requirements of bioavailability and efficacy, does not require special drying conditions in the preparation process, simplifies the preparation process and post-treatment process of the drug, and is not easily affected by humidity, and the storage condition The requirements are not harsh, and it is convenient for long-term storage, which greatly reduces the cost of material storage and quality control;
本发明提供的新晶型可通过盐酸盐脱盐直接得到，可以合并到合成过程中,制备方法简单且重复性好，过程可控，溶剂安全且常规易得，成本低廉，适合直接用于工业化生产。The new crystal form provided by the invention can be directly obtained by desalting the hydrochloride salt, can be incorporated into the synthesis process, the preparation method is simple and reproducible, the process is controllable, the solvent is safe and the routine is easy to obtain, the cost is low, and the method is suitable for direct industrialization. produce.
本文所使用的短语“有效治疗量”或“治疗有效量”是指引起由研究人员、兽医、医生或其他临床医师在组织、***、动物、个体或人中所要寻求的生物反应或药物反应的活性化合物或药剂的量。The phrase "effective therapeutic amount" or "therapeutically effective amount" as used herein refers to a biological response or drug response that is caused by a researcher, veterinarian, doctor or other clinician in a tissue, system, animal, individual or human. The amount of active compound or agent.
本文所使用的术语“治疗”是指下列中的一种或多种：(1)预防疾病；例如在可能倾向于罹患疾病、病症或障碍、但还没有遭受或显示该疾病的病变或症状的个体中预防该疾病、病症或障碍；(2)抑制该疾病；例如在正遭受或显示该疾病、病症或障碍的病变或症状的个体中抑制该疾病、病症或障碍；以及(3)改善该疾病；例如，在遭受或显示该疾病、病症或障碍的病变或症状的个体中改善该疾病、病症或障碍(即逆转病变和/或症状)，例如减低疾病的严重度。The term "treating" as used herein, refers to one or more of the following: (1) preventing a disease; for example, a disease or condition that may be predisposed to a disease, disorder, or disorder, but has not yet suffered or manifested the disease. Preventing the disease, condition or disorder in the individual; (2) inhibiting the disease; for example, inhibiting the disease, condition or disorder in an individual who is suffering from or showing a disease or condition of the disease, condition or disorder; and (3) improving the disease A disease; for example, ameliorating the disease, condition or disorder (i.e., reversing the disease and/or condition) in an individual suffering from or showing a disease or condition of the disease, condition or disorder, e.g., reducing the severity of the disease.
本文所使用的术语“多晶型化合物”是指相同化合物的不同晶型且包括但不限于包含相同化合物的水合物及溶剂合物的其它固态分子形式。同一种药物分子形成多种晶型的现象称为药物多晶型，药物多晶型是固体药物中普遍存在的现象。The term "polymorphic compound" as used herein refers to different crystalline forms of the same compound and includes, but is not limited to, other solid molecular forms comprising hydrates and solvates of the same compound. The phenomenon that a plurality of crystal forms are formed by the same drug molecule is called a drug polymorph, and a drug polymorph is a phenomenon commonly found in solid drugs.
本文所使用的术语“X射线粉末衍射图”是指实验观测到的衍射图或源自其的参数。通过峰位置及峰强度表征X射线粉末衍射图。The term "X-ray powder diffraction pattern" as used herein refers to an experimentally observed diffraction pattern or parameters derived therefrom. The X-ray powder diffraction pattern was characterized by peak position and peak intensity.
本发明所使用的低级烷基醇可以是C1～C3烷基醇。The lower alkyl alcohol used in the present invention may be a C1-C3 alkyl alcohol.
根据本发明，作为原料的所述式(I)化合物和/或其盐指其固体(晶型或无定形)、半固体、蜡或油形式。优选地，作为原料的所述式(I)化合物和/或其盐为固体粉末形式。 According to the invention, the compound of the formula (I) and/or its salt as a raw material means a solid (crystalline or amorphous), semi-solid, wax or oil form. Preferably, the compound of the formula (I) and/or its salt as a raw material is in the form of a solid powder.
附图说明DRAWINGS
图1为本发明的晶型II的XRPD图；Figure 1 is an XRPD pattern of Form II of the present invention;
图2为本发明的晶型II的DSC图；Figure 2 is a DSC chart of Form II of the present invention;
图3为本发明的晶型II的TGA图；Figure 3 is a TGA diagram of Form II of the present invention;
图4为本发明的晶型II的1H-NMR图；Figure 4 is a 1 H-NMR chart of Form II of the present invention;
图5为本发明的晶型II的DVS图；Figure 5 is a DVS diagram of Form II of the present invention;
图6为本发明的晶型II的DVS吸湿性测定前后的XRPD图；Figure 6 is an XRPD diagram of the DVS before and after the DVS hygroscopicity measurement of Form II of the present invention;
图7为本发明的晶型II放置在25℃/60％相对湿度条件下30天前后的XRPD对比图(上图为放置前的XRPD图，下图为放置后的XRPD图)；Figure 7 is a comparison chart of XRPD of the Form II of the present invention placed at 25 ° C / 60% relative humidity for 30 days (the upper image shows the XRPD pattern before placement, and the lower image shows the XRPD pattern after placement);
图8为本发明的晶型II放置在40℃/75％相对湿度条件下30天前后的XRPD对比图(上图为放置前的XRPD图，下图为放置后的XRPD图)；Figure 8 is a comparison chart of XRPD of the Form II of the present invention placed at 40 ° C / 75% relative humidity for 30 days (the upper image shows the XRPD pattern before placement, and the lower figure shows the XRPD pattern after placement);
具体实施方式detailed description
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 invention is further illustrated by the following examples, but is not intended to limit the scope of the invention. Improvements in the method of preparation and use of the apparatus may be made by those skilled in the art within the scope of the claims, and such modifications are also considered to be within the scope of the invention. Therefore, the scope of the invention should be determined by the appended claims.
下述实施例中，所述的试验方法通常按照常规条件或制造厂商建议的条件实施；所述的色瑞替尼的原料通过市售购买获得。In the following examples, the test methods described are generally carried out under conventional conditions or conditions recommended by the manufacturer; the raw materials of the colorizone are commercially available.
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
DVS：动态水分吸附DVS: Dynamic moisture adsorption
PSD：粒度分布PSD: particle size distribution
D10:表示粒径分布中(体积分布)占10％所对应的粒径D10: indicates the particle size distribution (volume distribution) accounts for 10% of the particle size
D50:表示粒径分布中(体积分布)占50％所对应的粒径，又称中位径D50: indicates the particle diameter corresponding to the particle size distribution (volume distribution), which is also called the median diameter.
D90:表示粒径分布中(体积分布)占90％所对应的粒径D90: indicates the particle size distribution (volume distribution) accounts for 90% of the particle size
本发明所述的X射线粉末衍射图在Panalytical Empyrean 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 pattern of the present invention was collected on a Panalytical Empyrean X-ray powder diffractometer. The method parameters of the X-ray powder diffraction described in the present invention are as follows:
X射线反射参数：Cu,KαX-ray reflection parameters: Cu, Kα
Kα1
Figure PCTCN2017076179-appb-000002
：1.540598；Kα2
Figure PCTCN2017076179-appb-000003
：1.544426Kα1
Figure PCTCN2017076179-appb-000002
:1.540598;Kα2
Figure PCTCN2017076179-appb-000003
:1.544426
Kα2/Kα1强度比例：0.50Kα2/Kα1 intensity ratio: 0.50
电压：45仟伏特(kV)Voltage: 45 volts (kV)
电流：40毫安培(mA)Current: 40 milliamps (mA)
发散狭缝：自动Divergence slit: automatic
扫描模式：连续Scan mode: continuous
扫描范围：自3.0至40.0度Scan range: from 3.0 to 40.0 degrees
取样步长：0.013度Sampling step size: 0.013 degrees
本发明所述的差示扫描量热分析(DSC)图在TA Q2000上采集。本发明所述的差示扫描量热分析(DSC)的方法参数如下：The differential scanning calorimetry (DSC) map of the present invention was acquired on a TA Q2000. The method parameters of the differential scanning calorimetry (DSC) described in the present invention are as follows:
扫描速率：10℃/minScan rate: 10 ° C / min
保护气体：氮气Protective gas: nitrogen
本发明所述的热重分析(TGA)图在TA Q5000上采集。本发明所述的热重分析(TGA)的方法参数如下： The thermogravimetric analysis (TGA) map of the present invention was taken on a TA Q5000. The method parameters of the thermogravimetric analysis (TGA) described in the present invention are as follows:
扫描速率：10℃/minScan rate: 10 ° C / min
保护气体：氮气Protective gas: nitrogen
本发明所述动态水分吸附(DVS)图在由SMS公司(Surface Measurement Systems Ltd.)生产的Intrinsic动态水分吸附仪上采集。所述的动态水分吸附仪的方法参数如下：The dynamic moisture adsorption (DVS) pattern of the present invention was collected on an Intrinsic dynamic moisture adsorber manufactured by SMS Corporation (Surface Measurement Systems Ltd.). The method parameters of the dynamic moisture adsorber are as follows:
温度：25℃Temperature: 25 ° C
载气，流速：N2,200毫升/分钟Carrier gas, flow rate: N 2 , 200 ml / min
单位时间质量变化：0.002％/分钟Unit time quality change: 0.002% / minute
相对湿度范围：0％RH-95％RHRelative humidity range: 0%RH-95%RH
实施例1Example 1
本发明的晶型II的制备方法：Preparation method of crystal form II of the invention:
将100.3mg式(1)化合物悬浮于4.0mL异丙醇中，加入0.02mL浓盐酸，室温搅拌24小时，离心取下层固体，室温下真空干燥得到式(1)化合物盐酸盐，将20.2mg式(1)化合物盐酸盐溶解于0.04mL丙酮和0.4mL水中，加入0.035mL的1mol/L氢氧化钠水溶液，置于5℃搅拌24小时，离心取下层固体，室温下干燥过夜，所得固体为晶型II。100.3 mg of the compound of the formula (1) was suspended in 4.0 mL of isopropanol, 0.02 mL of concentrated hydrochloric acid was added, and the mixture was stirred at room temperature for 24 hours, and the lower layer solid was centrifuged, and dried under vacuum at room temperature to obtain the hydrochloride of the compound of the formula (1), 20.2 mg. The hydrochloride of the compound of the formula (1) was dissolved in 0.04 mL of acetone and 0.4 mL of water, and 0.035 mL of a 1 mol/L sodium hydroxide aqueous solution was added thereto, and the mixture was stirred at 5 ° C for 24 hours, and the lower layer solid was centrifuged, and dried at room temperature overnight to obtain a solid. It is Form II.
本实施例得到的晶型II的X射线粉末衍射数据如表1所示。其XRPD图如图1，其DSC图如图2，其TGA图如图3，其1H-NMR图如图4，1H-NMR数据如下：1H-NMR(400MHz,DMSO-d6)δ8.41(s,1H),8.18(s,1H),7.81(d,J＝8.0Hz,1H),7.58(s,2H),7.29(s,1H),6.81(s,1H),4.54(dt,J1＝12.2Hz,J2＝6.1Hz,1H),3.02(d,J＝11.5Hz,2H),2.73–2.57(m,3H),2.11(s,3H),1.62–1.45(m,4H),1.22(d,J＝6.0Hz,6H),1.15(d,J＝6.8Hz,6H)。 The X-ray powder diffraction data of Form II obtained in this example is shown in Table 1. The XRPD pattern is shown in Fig. 1. The DSC chart is shown in Fig. 2. The TGA chart is shown in Fig. 3. The 1 H-NMR chart is shown in Fig. 4. The 1 H-NMR data is as follows: 1H-NMR (400 MHz, DMSO-d6) δ8. 41(s,1H), 8.18(s,1H), 7.81(d,J=8.0Hz,1H), 7.58(s,2H), 7.29(s,1H),6.81(s,1H),4.54(dt , J1 = 12.2 Hz, J2 = 6.1 Hz, 1H), 3.02 (d, J = 11.5 Hz, 2H), 2.73 - 2.57 (m, 3H), 2.11 (s, 3H), 1.62 - 1.45 (m, 4H) , 1.22 (d, J = 6.0 Hz, 6H), 1.15 (d, J = 6.8 Hz, 6H).
表1Table 1
2theta2theta d间隔d interval 强度％strength%
5.035.03 17.5617.56 100.00100.00
5.475.47 16.1616.16 5.115.11
8.958.95 9.889.88 4.714.71
9.589.58 9.249.24 9.069.06
10.0710.07 8.808.80 19.3219.32
10.3410.34 8.568.56 27.0327.03
12.2912.29 7.207.20 19.2619.26
12.7112.71 6.966.96 6.906.90
13.7013.70 6.466.46 7.337.33
14.0014.00 6.326.32 7.377.37
14.4014.40 6.156.15 29.2129.21
14.9614.96 5.925.92 36.3836.38
15.1215.12 5.865.86 28.2428.24
15.6615.66 5.665.66 11.4511.45
16.0516.05 5.525.52 32.5732.57
16.5716.57 5.355.35 28.2628.26
16.8616.86 5.265.26 13.2713.27
17.1117.11 5.185.18 19.7819.78
17.4417.44 5.095.09 6.656.65
18.0618.06 4.914.91 36.8636.86
18.8318.83 4.714.71 15.8515.85
19.2519.25 4.614.61 17.6517.65
20.0220.02 4.444.44 14.7114.71
20.6120.61 4.314.31 15.1915.19
20.8320.83 4.274.27 14.0114.01
21.3821.38 4.164.16 3.393.39
21.8621.86 4.074.07 22.7022.70
22.7622.76 3.913.91 5.295.29
23.2623.26 3.823.82 28.4928.49
24.1424.14 3.693.69 6.736.73
24.3824.38 3.653.65 8.178.17
24.6624.66 3.613.61 12.0912.09
24.9924.99 3.563.56 8.718.71
25.3925.39 3.513.51 11.3211.32
25.9225.92 3.443.44 17.7617.76
26.4826.48 3.373.37 7.957.95
27.1327.13 3.293.29 9.109.10
27.7927.79 3.213.21 8.568.56
28.0828.08 3.183.18 20.3520.35
28.8428.84 3.103.10 10.7310.73
29.5729.57 3.023.02 4.194.19
30.1530.15 2.962.96 2.832.83
31.2931.29 2.862.86 1.421.42
31.7031.70 2.822.82 5.305.30
32.8032.80 2.732.73 1.761.76
33.5633.56 2.672.67 1.061.06
34.1134.11 2.632.63 1.831.83
35.4435.44 2.532.53 2.272.27
36.4736.47 2.462.46 1.001.00
37.2837.28 2.412.41 2.172.17
37.6337.63 2.392.39 2.452.45
实施例2Example 2
本发明的晶型II的制备方法：Preparation method of crystal form II of the invention:
式(1)化合物盐酸盐制备方法同实施例1。将19.8mg式(1)化合物盐酸盐溶解于0.04mL乙腈和0.4mL水中，加入0.035mL的1mol/L氢氧化钠水溶液，置于5℃搅拌24小时，离心取下层固体，室温下干燥过夜，所得固体为晶型II。The method for preparing the hydrochloride salt of the compound of the formula (1) is the same as in the first embodiment. 19.8 mg of the compound of the formula (1) hydrochloride was dissolved in 0.04 mL of acetonitrile and 0.4 mL of water, and 0.035 mL of a 1 mol/L sodium hydroxide aqueous solution was added thereto, and the mixture was stirred at 5 ° C for 24 hours, and the lower layer solid was centrifuged, and dried overnight at room temperature. The resulting solid was Form II.
本实施例得到的晶型II的X射线粉末衍射数据如表2所示。The X-ray powder diffraction data of Form II obtained in this example is shown in Table 2.
表2Table 2
2theta2theta d间隔d interval 强度％strength%
4.114.11 21.4821.48 5.805.80
5.035.03 17.5617.56 27.4827.48
5.655.65 15.6515.65 10.5010.50
8.978.97 9.869.86 6.126.12
9.549.54 9.279.27 28.9328.93
10.0410.04 8.818.81 55.6855.68
10.2810.28 8.608.60 35.1035.10
12.3012.30 7.207.20 47.6847.68
12.6712.67 6.986.98 27.0627.06
13.6713.67 6.486.48 32.8832.88
14.3714.37 6.166.16 81.9081.90
15.0415.04 5.895.89 67.0867.08
15.5415.54 5.705.70 25.5625.56
16.0216.02 5.535.53 44.8644.86
16.5516.55 5.365.36 49.7949.79
16.8116.81 5.285.28 28.8228.82
17.0717.07 5.205.20 37.0137.01
18.0318.03 4.924.92 100.00100.00
18.8218.82 4.724.72 25.8025.80
19.1919.19 4.634.63 32.2932.29
19.9419.94 4.454.45 23.5823.58
20.5120.51 4.334.33 32.6532.65
21.8221.82 4.074.07 53.0153.01
23.1723.17 3.843.84 49.9849.98
24.3624.36 3.653.65 20.1320.13
25.9025.90 3.443.44 43.6343.63
27.1327.13 3.293.29 17.2017.20
28.0428.04 3.183.18 24.4224.42
28.7928.79 3.103.10 28.5228.52
29.5629.56 3.023.02 15.0915.09
31.1631.16 2.872.87 11.0111.01
31.5931.59 2.832.83 34.1634.16
33.5833.58 2.672.67 3.543.54
34.6134.61 2.592.59 6.506.50
35.4635.46 2.532.53 8.938.93
35.8535.85 2.502.50 8.278.27
38.6038.60 2.332.33 5.195.19
实施例3Example 3
本发明的晶型II的引湿性实验：The wettability test of Form II of the present invention:
在25℃条件下，取本发明晶型II约10mg采用动态水分吸附(DVS)仪测试其引湿性。实验结果如表3所示。引湿性实验的DVS图如图5所示，引湿性实验前后的XRPD结果如图6所示。About 10 mg of the crystalline form II of the present invention was taken at 25 ° C to test its wettability by a dynamic moisture adsorption (DVS) instrument. The experimental results are shown in Table 3. The DVS pattern of the wettability experiment is shown in Fig. 5, and the XRPD results before and after the wettability test are shown in Fig. 6.
表3 table 3
Figure PCTCN2017076179-appb-000004
Figure PCTCN2017076179-appb-000004
关于引湿性特征描述与引湿性增重的界定(中国药典2015年版通则9103药物引湿性试验指导原则，实验条件：25℃±1℃，80％相对湿度)：Defining the characteristics of wettability and the definition of wetting weight gain (Chinese Pharmacopoeia 2015 General Principles 9103 Guidelines for Drug Wetness Test, Experimental Conditions: 25 °C ± 1 °C, 80% Relative Humidity):
潮解：吸收足量水分形成液体Deliquescence: absorb enough water to form a liquid
极具引湿性：引湿增重不小于15％Very hygroscopic: the wetting weight gain is not less than 15%
有引湿性：引湿增重小于15％但不小于2％Humidity: Wet weight gain 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 wettability: wetting gain 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 wettability: wetting gain is less than 0.2%
结果表明，本发明的晶型II在25℃，80％湿度下平衡后增重3.15％，引湿性较低。The results showed that the crystal form II of the present invention had a weight gain of 3.15% after being equilibrated at 25 ° C and 80% humidity, and the wettability was low.
实施例4Example 4
本发明的晶型II的稳定性实验：Stability test of Form II of the present invention:
将本发明制备得到的晶型II分别在25℃/60％相对湿度和40℃/75％相对湿度的条件下分别放置30天和90天，测定其XRPD。实验结果见表4所示。本发明的晶型II在放置在上述两个条件下30天前后的XRPD分别如图7、图8所示。The crystal form II prepared by the present invention was separately placed at 25 ° C / 60% relative humidity and 40 ° C / 75% relative humidity for 30 days and 90 days, respectively, and its XRPD was measured. The experimental results are shown in Table 4. The XRPD of the Form II of the present invention before and after being placed under the above two conditions for 30 days is shown in Figs. 7 and 8, respectively.
表4Table 4
Figure PCTCN2017076179-appb-000005
Figure PCTCN2017076179-appb-000005
Figure PCTCN2017076179-appb-000006
Figure PCTCN2017076179-appb-000006
实施例5Example 5
本发明的晶型II的溶解度实验：Solubility test of Form II of the present invention:
将实施例1中制备得到的式(Ⅰ)化合物晶型II与专利WO2012082972A1无水晶型A样品分别用高纯水配制成饱和溶液，在1小时、4小时和24个小时后采用高效液相色谱测定饱和溶液中样品的含量。实验结果如表5所示。The crystalline form II of the compound of the formula (I) prepared in Example 1 and the amorphous form A of the patent WO2012082972A1 were respectively prepared into a saturated solution with high purity water, and the saturation was determined by high performance liquid chromatography after 1 hour, 4 hours and 24 hours. The amount of sample in the solution. The experimental results are shown in Table 5.
表5table 5
Figure PCTCN2017076179-appb-000007
Figure PCTCN2017076179-appb-000007
结果表明，在高纯水中放置1小时，4小时和24个小时后本发明的晶型II与专利WO2012082972A1无水晶型A相比，溶解度更高。在水中更高的溶出速率与溶解度，有助于提升药物在生物体内的吸收利用，提高药效。The results show that the crystalline form II of the present invention has a higher solubility than the amorphous form A of the patent WO2012082972A1 after being placed in high-purity water for 1 hour, 4 hours and 24 hours. The higher dissolution rate and solubility in water help to enhance the absorption and utilization of drugs in the organism and improve the efficacy.
实施例6Example 6
本发明的晶型II的PSD测试:PSD test of Form II of the present invention:
通过PSD测定本发明的晶型II和专利WO2012082972A1中的无水晶型A的粒径分布。结果如表6所示： The particle size distribution of the crystalline form A of the present invention and the amorphous form A of the patent WO2012082972A1 was measured by PSD. The results are shown in Table 6:
表6Table 6
平均粒径(μm)Average particle size (μm) 晶型IIForm II 晶型ACrystal form A
D10D10 5.475.47 3.683.68
D50D50 41.7241.72 18.6818.68
D90D90 197.1197.1 102.5102.5
本发明的晶型II与专利WO2012082972A1中的无水晶型A相比，本发明的晶型样品粒径更大，流动性好，在工艺生产中具备容易过滤等优良性质。The crystal form II of the present invention has a larger particle size and better fluidity than the crystal-free type A in the patent WO2012082972A1, and has excellent properties such as easy filtration in process production.
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 merely illustrative of the technical concept and the features of the present invention, and the purpose of the present invention is to enable those skilled in the art to understand the present invention and to implement the present invention, and the scope of the present invention is not limited thereto. Equivalent variations or modifications made in accordance with the spirit of the invention are intended to be included within the scope of the invention.

Claims (11)

  1. 一种式(I)化合物结晶形态的晶型II，a crystalline form II of a crystalline form of the compound of formula (I),
    Figure PCTCN2017076179-appb-100001
    Figure PCTCN2017076179-appb-100001
    其特征在于，其X射线粉末衍射图在2theta值为5.03°±0.20°、10.05°±0.20°、14.40°±0.20°、18.11°±0.20°和20.00°±0.20°处具有特征峰。It is characterized in that its X-ray powder diffraction pattern has characteristic peaks at 2theta values of 5.03°±0.20°, 10.05°±0.20°, 14.40°±0.20°, 18.11°±0.20°, and 20.00°±0.20°.
  2. 根据权利要求1所述的晶型II，其特征还在于，其X射线粉末衍射图在2theta值为15.00°±0.20°、21.85°±0.20°、23.20°±0.20°和27.21°±0.20°处具有特征峰。The crystal form II according to claim 1, further characterized in that the X-ray powder diffraction pattern has a 2theta value of 15.00 ° ± 0.20 °, 21.85 ° ± 0.20 °, 23.20 ° ± 0.20 °, and 27.21 ° ± 0.20 °. Has a characteristic peak.
  3. 根据权利要求1或2所述的晶型II，其特征还在于，其X射线粉末衍射图在2theta值为10.34°±0.20°和16.05°±0.20°处具有特征峰。The crystal form II according to claim 1 or 2, wherein the X-ray powder diffraction pattern has a characteristic peak at a 2theta value of 10.34 ° ± 0.20 ° and 16.05 ° ± 0.20 °.
  4. 根据权利要求1-3任一项所述的晶型II，其特征还在于，其X射线粉末衍射图在2theta值为5.03°±0.20°、10.05°±0.20°、10.34°±0.20°、14.40°±0.20°、15.00°±0.20°、16.05°±0.20°、18.11°±0.20°、20.00°±0.20°、21.85°±0.20°、23.20°±0.20°、27.21°±0.20°处具有特征峰。The crystal form II according to any one of claims 1 to 3, wherein the X-ray powder diffraction pattern has a value of 5.03 ° ± 0.20 °, 10.05 ° ± 0.20 °, 10.34 ° ± 0.20 °, 14.40. Characteristic peaks at °±0.20°, 15.00°±0.20°, 16.05°±0.20°, 18.11°±0.20°, 20.00°±0.20°, 21.85°±0.20°, 23.20°±0.20°, 27.21°±0.20° .
  5. 根据权利要求1-4任一项所述的晶型II，其特征在于，其X射线粉末衍射图基本上与图1一致。 Form II according to any one of claims 1 to 4, characterized in that its X-ray powder diffraction pattern is substantially identical to that of Figure 1.
  6. 根据权利要求1-5中任一项所述的晶型II，其特征在于：所述晶型II为无水晶型。The crystal form II according to any one of claims 1 to 5, wherein the crystal form II is an amorphous type.
  7. 一种权利要求1-6中任一项所述的晶型II的制备方法，其特征在于，将式(I)化合物和盐酸加入到一种或多种选自以下的溶剂体系中：醇类，酮类，腈类，环醚类，室温搅拌并干燥后，重新溶解于所述溶剂或它们与水的混合溶剂体系，后加入氢氧化钠水溶液搅拌即可得到。A process for the preparation of Form II according to any one of claims 1 to 6, wherein a compound of the formula (I) and hydrochloric acid are added to one or more solvent systems selected from the group consisting of alcohols The ketones, nitriles, and cyclic ethers are stirred at room temperature and dried, and then redissolved in the solvent or a mixed solvent system thereof with water, followed by stirring with an aqueous solution of sodium hydroxide.
  8. 根据权利要求7所述的制备方法，所述溶剂体系包括饱和酮，低级烷基醇，烃基腈和环醚类溶剂的单一体系或它们的混合体系。The process according to claim 7, wherein the solvent system comprises a single system of a saturated ketone, a lower alkyl alcohol, a hydrocarbyl nitrile and a cyclic ether solvent or a mixed system thereof.
  9. 根据权利要求8所述的制备方法，其中所述溶剂选自：丙酮、乙腈或它们的混合物。The production method according to claim 8, wherein the solvent is selected from the group consisting of acetone, acetonitrile or a mixture thereof.
  10. 一种药用组合物，所述药用组合物包含治疗有效量的权利要求1-6中的任一项所述的晶型II及药学上可接受的载体、稀释剂或赋形剂。A pharmaceutical composition comprising a therapeutically effective amount of Form II of any of claims 1-6 and a pharmaceutically acceptable carrier, diluent or excipient.
  11. 权利要求1-6中任一项的晶型II在生产用于制备治疗非小细胞肺癌药物制剂中的用途。 Use of Form II of any of claims 1-6 for the manufacture of a pharmaceutical formulation for the treatment of non-small cell lung cancer.
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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN112645929A (en) * 2019-10-11 2021-04-13 苏州泽璟生物制药股份有限公司 Polymorphs of isopropylsulfonylphenylpyrimidines or salts thereof

Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101616895A (en) * 2006-12-08 2009-12-30 Irm责任有限公司 Compound and composition as kinases inhibitor
CN103282359A (en) * 2010-12-17 2013-09-04 诺华股份有限公司 Crystalline forms of 5-chloro-N2-(2-isopropoxy-5-methyl-4-piperidin-4-yl-phenyl)-N4[2-(propane-2-sulfonyl)-phenyl]-pyrimidine-2,4-diamine
CN103992262A (en) * 2014-06-12 2014-08-20 苏州明锐医药科技有限公司 Preparation method of ceritinib and intermediate
CN104803908A (en) * 2015-03-26 2015-07-29 药源药物化学（上海）有限公司 Hydrate of 2-isopropoxy-5-methyl-4-(4-piperidyl) aniline dihydrochloride as well as preparation method and application of hydrate
CN105061397A (en) * 2015-08-07 2015-11-18 武汉英普瑞医药科技有限公司 C-type crystal form of ceritinib, preparation method therefor and application thereof
CN105294650A (en) * 2014-08-01 2016-02-03 江苏奥赛康药业股份有限公司 Ceritinib compound and pharmaceutical composition thereof
CN105601614A (en) * 2014-11-21 2016-05-25 奥浦顿（上海）医药科技有限公司 Ceritinib crystal form and preparation method thereof
WO2016098070A1 (en) * 2014-12-19 2016-06-23 Novartis Ag Crystalline form of 5-chloro-n2-(2-isopropoxy-5-methyl-4-piperidin-4-yl-phenyl)-n4-[2-(propane-2-sulfonyl)-phenyl]-pyrimidine-2, 4-diamine

Patent Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101616895A (en) * 2006-12-08 2009-12-30 Irm责任有限公司 Compound and composition as kinases inhibitor
CN103282359A (en) * 2010-12-17 2013-09-04 诺华股份有限公司 Crystalline forms of 5-chloro-N2-(2-isopropoxy-5-methyl-4-piperidin-4-yl-phenyl)-N4[2-(propane-2-sulfonyl)-phenyl]-pyrimidine-2,4-diamine
CN103992262A (en) * 2014-06-12 2014-08-20 苏州明锐医药科技有限公司 Preparation method of ceritinib and intermediate
CN105294650A (en) * 2014-08-01 2016-02-03 江苏奥赛康药业股份有限公司 Ceritinib compound and pharmaceutical composition thereof
CN105601614A (en) * 2014-11-21 2016-05-25 奥浦顿（上海）医药科技有限公司 Ceritinib crystal form and preparation method thereof
WO2016098070A1 (en) * 2014-12-19 2016-06-23 Novartis Ag Crystalline form of 5-chloro-n2-(2-isopropoxy-5-methyl-4-piperidin-4-yl-phenyl)-n4-[2-(propane-2-sulfonyl)-phenyl]-pyrimidine-2, 4-diamine
CN104803908A (en) * 2015-03-26 2015-07-29 药源药物化学（上海）有限公司 Hydrate of 2-isopropoxy-5-methyl-4-(4-piperidyl) aniline dihydrochloride as well as preparation method and application of hydrate
CN105061397A (en) * 2015-08-07 2015-11-18 武汉英普瑞医药科技有限公司 C-type crystal form of ceritinib, preparation method therefor and application thereof

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN112645929A (en) * 2019-10-11 2021-04-13 苏州泽璟生物制药股份有限公司 Polymorphs of isopropylsulfonylphenylpyrimidines or salts thereof

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