WO2016124149A1 - New crystalline form of antiandrogen drug which treats prostate cancer, and preparation method for new crystalline form - Google Patents

New crystalline form of antiandrogen drug which treats prostate cancer, and preparation method for new crystalline form Download PDF

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WO2016124149A1
WO2016124149A1 PCT/CN2016/073528 CN2016073528W WO2016124149A1 WO 2016124149 A1 WO2016124149 A1 WO 2016124149A1 CN 2016073528 W CN2016073528 W CN 2016073528W WO 2016124149 A1 WO2016124149 A1 WO 2016124149A1
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formula
compound
crystalline form
solvent
ray powder
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PCT/CN2016/073528
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French (fr)
Chinese (zh)
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陈敏华
张炎锋
李骄洋
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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • 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
    • C07D401/04—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 directly linked by a ring-member-to-ring-member bond
    • 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 invention relates to the field of chemical medicine, in particular to a novel crystal form of an antiandrogen drug (ARN-509) for treating prostate cancer and a preparation method thereof.
  • ARN-509 an antiandrogen drug
  • ARN-509 a compound of formula (I), is a second generation androgen receptor signaling inhibitor.
  • the drug was developed by Aragon Pharmaceuticals of the United States and later acquired by Johnson & Johnson (JNJ). The drug is used to treat castration-resistant prostate cancer and is currently in clinical development. If approved, it will be able to meet the needs of a wider range of prostate cancer patients.
  • 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. Therefore, the comprehensive systematic polymorph screening in drug development and the selection of the most suitable crystal form are one of the important research contents that cannot be ignored.
  • the present invention relates to two novel crystalline forms of the compound of formula (I), designated as Form I and Form II, respectively.
  • the crystal form of the invention has good stability, the solubility and the wettability are in compliance with the medicinal requirements, and the preparation method is simple and the cost is low, which is of great value for the optimization and development of the drug in the future.
  • the X-ray powder diffraction pattern of Form I provided by the present invention has a characteristic peak at a 2theta value of 16.7 ° ⁇ 0.2 °, 20.4 ° ⁇ 0.2 °, and 12.1 ° ⁇ 0.2 °.
  • the X-ray powder diffraction pattern of Form I provided by the present invention has a characteristic peak at 2theta values of 23.7° ⁇ 0.2°, 8.2° ⁇ 0.2°, and 16.0° ⁇ 0.2°.
  • the X-ray powder diffraction pattern of Form I provided by the present invention has a characteristic peak at a 2theta value of 17.8 ° ⁇ 0.2 °, 25.0 ° ⁇ 0.2 °, and 27.8 ° ⁇ 0.2 °.
  • the X-ray powder diffraction pattern of Form I provided by the present invention has a value of 8.2 ° ⁇ 0.2 °, 12.1 ° ⁇ 0.2 °, 16.0 ° ⁇ 0.2 °, 16.7 ° ⁇ 0.2 °, 17.8 °. There are characteristic peaks at ⁇ 0.2°, 20.4° ⁇ 0.2°, 23.7° ⁇ 0.2°, 25.0° ⁇ 0.2°, and 27.8° ⁇ 0.2°.
  • the X-ray powder diffraction pattern of Form I provided by the present invention is substantially as shown in FIG.
  • crystal form I provided by the present invention begins to exhibit an endothermic peak when heated to about 193 ° C, and the differential scanning calorimetry chart is substantially as shown in FIG. 2 .
  • the crystal form I provided by the present invention has a weight loss gradient of about 1.3% when heated to 160 ° C, and the thermogravimetric analysis chart is shown in FIG. 3 .
  • Another object of the present invention is to provide a process for the preparation of Form I comprising the addition of a compound of formula (I) to a crystallization solvent, by volatilization or suspension stirring.
  • the crystallization solvent is one or more kinds of alcohols, ketones, ethers, aliphatic hydrocarbons, esters, aromatic hydrocarbon solvents, preferably methanol, acetone, 1,4-dioxane
  • One or more kinds of cyclohexane, n-heptane, isopropyl acetate, ethyl acetate, toluene and xylene are mixed, and one or more kinds of cyclohexane, isopropyl acetate and toluene are more preferably mixed.
  • Another object of the invention is to provide a crystalline form II of a compound of formula (I).
  • the X-ray powder diffraction pattern of Form II provided by the present invention has characteristic peaks at 2theta values of 14.4 ° ⁇ 0.2 °, 16.6 ° ⁇ 0.2 °, and 17.9 ° ⁇ 0.2 °.
  • the X-ray powder diffraction pattern of Form II provided by the present invention has a characteristic peak at a 2theta value of 7.6 ° ⁇ 0.2 °, 8.9 ° ⁇ 0.2 °, and 15.5 ° ⁇ 0.2 °.
  • the X-ray powder diffraction pattern of Form II provided by the present invention has a characteristic peak at a 2theta value of 25.4° ⁇ 0.2°, 12.5° ⁇ 0.2°, and 13.3° ⁇ 0.2°.
  • the X-ray powder diffraction pattern of Form II provided by the present invention has a value of 7.6 ° ⁇ 0.2 °, 8.9 ° ⁇ 0.2 °, 12.5 ° ⁇ 0.2 °, 13.3 ° ⁇ 0.2 °, 14.4 °. Characteristic peaks at ⁇ 0.2°, 15.5° ⁇ 0.2°, 16.6° ⁇ 0.2°, 17.9° ⁇ 0.2°, 25.4° ⁇ 0.2°.
  • the X-ray powder diffraction pattern of Form II provided by the present invention is substantially as shown in FIG.
  • crystal form II provided by the present invention starts to have an endothermic peak when heated to about 170 ° C, and the differential scanning thereof
  • the calorimetric analysis chart is basically as shown in Figure 6.
  • the crystal form II provided by the present invention has a weight loss gradient of about 1.6% when heated to 170 ° C, and the thermogravimetric analysis chart is shown in FIG. 7 .
  • Another object of the present invention is to provide a process for the preparation of Form II comprising dissolving a compound of formula (I) in a positive solvent and adding an anti-solvent dropwise to precipitate a solid to obtain Form II.
  • the positive solvent is a mixture of one or more of an ester, an aromatic hydrocarbon, and a ketone solvent, preferably one or more of toluene, isopropyl acetate, and 4-methyl-2-pentanone. .
  • the anti-solvent is an aliphatic hydrocarbon solvent, preferably n-heptane.
  • Another object of the present invention is to provide a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I), Form I, Form II or a mixture of both in any proportion and a pharmaceutical excipient.
  • a pharmaceutical composition or formulation is generally prepared by mixing a therapeutically effective amount of Form I, Form II, or both in any proportion of a compound of Formula (I) with one or more pharmaceutical excipients. Or the formulations are prepared in a manner well known in the pharmaceutical art.
  • a further object of the present invention is to provide use of Form I, Form II or a pharmaceutical composition thereof of a compound of formula (I) for the manufacture of a medicament for the treatment of cancer, in particular a prostate cancer.
  • the present invention breaks through the prior art and provides a variety of new crystalline forms suitable for drug development of the compounds of formula (I).
  • the crystal forms I and II provided by the present invention have 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 high solubility and low moisture permeability, meets the requirements of bioavailability and efficacy, and is not easily affected by humidity, and is convenient for long-term storage.
  • Figure 1 is an XRPD pattern of Form I of the compound of formula (I) of the present invention.
  • Figure 2 is a DSC chart of the crystalline form I of the compound of the formula (I) of the present invention.
  • Figure 3 is a TGA diagram of Form I of the compound of formula (I) of the present invention.
  • Figure 4 is a DVS diagram of Form I of the compound of formula (I) of the present invention.
  • Figure 5 is an XRPD pattern of Form II of the compound of formula (I) of the present invention.
  • Figure 6 is a DSC chart of the crystalline form II of the compound of the formula (I) of the present invention.
  • Figure 7 is a TGA diagram of Form II of the compound of formula (I) of the present invention.
  • Figure 8 is a comparison chart of XRPD of the 90-day stability test of the crystalline form I of the compound of the formula (I) according to the invention under different test conditions (A: crystalline form I starting sample; B: crystalline form I at 25 ° C / 60% relative humidity) Placed under 90 days; C: Form I at 40 ° C / 75% Placed under humidity for 90 days);
  • Figure 9 is a comparison diagram of the DVS of the solid of the compound of the formula (I) of the formula (I) and the compound of the formula (I) obtained by the repeated patent method (test conditions: 80% relative humidity;
  • A represents the formula obtained by the method of repeating the patent CN101454002B ( I) a compound solid, B represents a crystalline form I) of the compound of formula (I) of the present invention;
  • Figure 10 is a PLM diagram of Form I of the compound of formula (I) of the present invention.
  • Figure 11 is a PLM diagram of the solid of the compound of formula (I) prepared by the process of repeating the patent CN101454002B.
  • the crystal XRPD data prepared by different preparation methods may not be identical for the same crystal form, but those skilled in the art can determine that they belong to the same crystal form according to the main characteristic peaks according to the description of the specification.
  • test method is usually carried out according to conventional conditions or conditions recommended by the manufacturer, wherein room temperature means 25 ° C ⁇ 2 ° C.
  • 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 solid of the compound of formula (I) used in the following examples (i.e., ARN 509) was prepared according to the method disclosed in Chinese Patent No. CN101454002B.
  • the X-ray powder diffraction data of Form I obtained in this example are shown in Table 1, and the X-ray powder diffraction, DSC and TGA patterns thereof are shown in Figures 1 to 3, respectively.
  • the X-ray powder diffraction data of Form II obtained in this example are shown in Table 7, and the X-ray powder diffraction, DSC and TGA patterns thereof are shown in Figures 5 to 7, respectively.
  • the crystal form I samples of the compound of the formula (I) obtained by the present invention were respectively placed under conditions of 25 ° C / 60% relative humidity and 40 ° C / 75% relative humidity for 90 days, and samples were taken for testing on the 90th day.
  • the test results show that the crystalline form I of the present invention has good stability, and its XRPD comparison chart is shown in Fig. 8, wherein A represents the starting form of the crystalline form I; and B represents the standing at 25 ° C / 60% relative humidity for 90 days; Indicates that it is left for 90 days at 40 ° C / 75% relative humidity.
  • Deliquescence absorbs a sufficient amount of water to form a liquid
  • the wetting weight gain is not less than 15%
  • the wetting 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 I of the compound of the formula (I) of the present invention is a relatively regular flaky crystal, has good fluidity, and has excellent properties such as easy filtration in process production, so that the crystal form I of the compound of the formula (I) is good, and its PLM diagram As shown in FIG. 10; the compound of the formula (I) obtained by the patent method has a solid agglomeration and a non-uniform particle, and has poor fluidity, and its PLM pattern is shown in FIG.

Abstract

Provided are a new crystalline form of an antiandrogen drug which treats prostate cancer, said drug being represented by formula I, and a preparation method for the new crystalline form. The crystalline form has good stability, and the solubility and hygroscopicity meet pharmaceutical requirements. The preparation method is simple and low-cost.

Description

一种治疗***癌的抗雄激素类药物的新晶型及其制备方法Novel crystal form of antiandrogen drugs for treating prostate cancer and preparation method thereof 技术领域Technical field
本发明涉及化学医药领域，特别是涉及一种治疗***癌的抗雄激素类药物(ARN-509)的新晶型及其制备方法。The invention relates to the field of chemical medicine, in particular to a novel crystal form of an antiandrogen drug (ARN-509) for treating prostate cancer and a preparation method thereof.
背景技术Background technique
ARN-509，式(I)所示化合物，是第二代雄激素受体信号抑制剂。该药由美国Aragon制药公司研发，后被强生(JNJ)收购。该药用于治疗去势抵抗性***癌，目前正处于临床开发，如果获批，将能够满足更广泛的***癌患者的需求。ARN-509, a compound of formula (I), is a second generation androgen receptor signaling inhibitor. The drug was developed by Aragon Pharmaceuticals of the United States and later acquired by Johnson & Johnson (JNJ). The drug is used to treat castration-resistant prostate cancer and is currently in clinical development. If approved, it will be able to meet the needs of a wider range of prostate cancer patients.
Figure PCTCN2016073528-appb-000001
Figure PCTCN2016073528-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。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。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. Therefore, the comprehensive systematic polymorph screening in drug development and the selection of the most suitable crystal form are one of the important research contents that cannot be ignored.
基于此，进行式(I)化合物的多晶型研究和筛选，开发出稳定性好、溶解度高、引湿性低、适合工业化生产的晶型，对后续药物开发具有重要意义。Based on this, the polymorph type research and screening of the compound of the formula (I) is carried out, and the development of a crystal form with good stability, high solubility, low wettability and suitable for industrial production is of great significance for the subsequent drug development.
发明内容Summary of the invention
本发明涉及式(I)化合物的两种新晶型，分别命名为晶型I和晶型II。本发明的晶型稳定性良好，溶解度、引湿性符合药用要求，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 present invention relates to two novel crystalline forms of the compound of formula (I), designated as Form I and Form II, respectively. The crystal form of the invention has good stability, the solubility and the wettability are in compliance with the medicinal requirements, and the preparation method is simple and the cost is low, which is of great value for the optimization and development of the drug in the future.
本发明的一个目的是提供式(I)化合物的晶型I。 It is an object of the present invention to provide Form I of the compound of formula (I).
本发明提供的晶型I的X射线粉末衍射图在2theta值为16.7°±0.2°、20.4°±0.2°、12.1°±0.2°处具有特征峰。The X-ray powder diffraction pattern of Form I provided by the present invention has a characteristic peak at a 2theta value of 16.7 ° ± 0.2 °, 20.4 ° ± 0.2 °, and 12.1 ° ± 0.2 °.
进一步地，本发明提供的晶型I的X射线粉末衍射图在2theta值为23.7°±0.2°、8.2°±0.2°、16.0°±0.2°处具有特征峰。Further, the X-ray powder diffraction pattern of Form I provided by the present invention has a characteristic peak at 2theta values of 23.7°±0.2°, 8.2°±0.2°, and 16.0°±0.2°.
更进一步地，本发明提供的晶型I的X射线粉末衍射图在2theta值为17.8°±0.2°、25.0°±0.2°、27.8°±0.2°处具有特征峰。Further, the X-ray powder diffraction pattern of Form I provided by the present invention has a characteristic peak at a 2theta value of 17.8 ° ± 0.2 °, 25.0 ° ± 0.2 °, and 27.8 ° ± 0.2 °.
在一个具体实施方案中，本发明提供的晶型I的X射线粉末衍射图在2theta值为8.2°±0.2°、12.1°±0.2°、16.0°±0.2°、16.7°±0.2°、17.8°±0.2°、20.4°±0.2°、23.7°±0.2°、25.0°±0.2°、27.8°±0.2°处具有特征峰。In a specific embodiment, the X-ray powder diffraction pattern of Form I provided by the present invention has a value of 8.2 ° ± 0.2 °, 12.1 ° ± 0.2 °, 16.0 ° ± 0.2 °, 16.7 ° ± 0.2 °, 17.8 °. There are characteristic peaks at ±0.2°, 20.4°±0.2°, 23.7°±0.2°, 25.0°±0.2°, and 27.8°±0.2°.
在另一个具体实施方案中，本发明提供的晶型I的X射线粉末衍射图基本如图1所示。In another embodiment, the X-ray powder diffraction pattern of Form I provided by the present invention is substantially as shown in FIG.
进一步地，本发明提供的晶型I在加热至193℃左右时开始出现吸热峰，其差示扫描量热分析图基本如图2所示。Further, the crystal form I provided by the present invention begins to exhibit an endothermic peak when heated to about 193 ° C, and the differential scanning calorimetry chart is substantially as shown in FIG. 2 .
更进一步地，本发明提供的晶型I在加热至160℃时具有约1.3％的重量损失梯度，其热重分析图如图3所示。Further, the crystal form I provided by the present invention has a weight loss gradient of about 1.3% when heated to 160 ° C, and the thermogravimetric analysis chart is shown in FIG. 3 .
本发明的另一个目的是提供晶型I的制备方法，包括将式(I)化合物加入析晶溶剂中，通过挥发或悬浮搅拌制得。Another object of the present invention is to provide a process for the preparation of Form I comprising the addition of a compound of formula (I) to a crystallization solvent, by volatilization or suspension stirring.
进一步地，所述析晶溶剂为醇类、酮类、醚类、脂肪烃类、酯类、芳香烃类溶剂的一种或多种混合，优选甲醇、丙酮、1,4-二氧六环、环己烷、正庚烷、乙酸异丙酯、乙酸乙酯、甲苯和二甲苯的一种或多种混合，更优选环己烷、乙酸异丙酯、甲苯的一种或多种混合。Further, the crystallization solvent is one or more kinds of alcohols, ketones, ethers, aliphatic hydrocarbons, esters, aromatic hydrocarbon solvents, preferably methanol, acetone, 1,4-dioxane One or more kinds of cyclohexane, n-heptane, isopropyl acetate, ethyl acetate, toluene and xylene are mixed, and one or more kinds of cyclohexane, isopropyl acetate and toluene are more preferably mixed.
本发明的另一个目的是提供式(I)化合物的晶型II。Another object of the invention is to provide a crystalline form II of a compound of formula (I).
本发明提供的晶型II的X射线粉末衍射图在2theta值为14.4°±0.2°、16.6°±0.2°、17.9°±0.2°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 14.4 ° ± 0.2 °, 16.6 ° ± 0.2 °, and 17.9 ° ± 0.2 °.
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7.6°±0.2°、8.9°±0.2°、15.5°±0.2°处具有特征峰。Further, the X-ray powder diffraction pattern of Form II provided by the present invention has a characteristic peak at a 2theta value of 7.6 ° ± 0.2 °, 8.9 ° ± 0.2 °, and 15.5 ° ± 0.2 °.
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25.4°±0.2°、12.5°±0.2°、13.3°±0.2°处具有特征峰。Further, the X-ray powder diffraction pattern of Form II provided by the present invention has a characteristic peak at a 2theta value of 25.4°±0.2°, 12.5°±0.2°, and 13.3°±0.2°.
在一个具体实施方案中，本发明提供的晶型II的X射线粉末衍射图在2theta值为7.6°±0.2°、8.9°±0.2°、12.5°±0.2°、13.3°±0.2°、14.4°±0.2°、15.5°±0.2°、16.6°±0.2°、17.9°±0.2°、25.4°±0.2°处具有特征峰。In a specific embodiment, the X-ray powder diffraction pattern of Form II provided by the present invention has a value of 7.6 ° ± 0.2 °, 8.9 ° ± 0.2 °, 12.5 ° ± 0.2 °, 13.3 ° ± 0.2 °, 14.4 °. Characteristic peaks at ±0.2°, 15.5°±0.2°, 16.6°±0.2°, 17.9°±0.2°, 25.4°±0.2°.
在另一个具体实施方案中，本发明提供的晶型II的X射线粉末衍射图基本如图5所示。In another embodiment, the X-ray powder diffraction pattern of Form II provided by the present invention is substantially as shown in FIG.
进一步地，本发明提供的晶型II在加热至170℃左右时开始出现吸热峰，其差示扫描 量热分析图基本如图6所示。Further, the crystal form II provided by the present invention starts to have an endothermic peak when heated to about 170 ° C, and the differential scanning thereof The calorimetric analysis chart is basically as shown in Figure 6.
更进一步地，本发明提供的晶型II在加热至170℃时具有约1.6％的重量损失梯度，其热重分析图如图7所示。Further, the crystal form II provided by the present invention has a weight loss gradient of about 1.6% when heated to 170 ° C, and the thermogravimetric analysis chart is shown in FIG. 7 .
本发明的另一个目的是提供晶型II的制备方法，包括将式(I)化合物溶解于正溶剂中，滴加反溶剂至固体析出得到晶型II。Another object of the present invention is to provide a process for the preparation of Form II comprising dissolving a compound of formula (I) in a positive solvent and adding an anti-solvent dropwise to precipitate a solid to obtain Form II.
进一步地，所述正溶剂为酯类、芳香烃类、酮类溶剂的一种或多种混合，优选甲苯、乙酸异丙酯、4-甲基-2-戊酮的一种或多种混合。Further, the positive solvent is a mixture of one or more of an ester, an aromatic hydrocarbon, and a ketone solvent, preferably one or more of toluene, isopropyl acetate, and 4-methyl-2-pentanone. .
进一步地，所述反溶剂为脂肪烃类溶剂，优选正庚烷。Further, the anti-solvent is an aliphatic hydrocarbon solvent, preferably n-heptane.
本发明的另一个目的是提供一种包含有效治疗量的式(I)化合物的晶型I、晶型II或两者任意比例混合和药用辅料的药用组合物。一般是将治疗有效量的式(I)化合物的晶型I、晶型II或两者任意比例混合与一种或多种药用辅料混合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 present invention is to provide a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I), Form I, Form II or a mixture of both in any proportion and a pharmaceutical excipient. A pharmaceutical composition or formulation is generally prepared by mixing a therapeutically effective amount of Form I, Form II, or both in any proportion of a compound of Formula (I) with one or more pharmaceutical excipients. Or the formulations are prepared in a manner well known in the pharmaceutical art.
本发明的又一个目的是提供式(I)化合物的晶型I、晶型II或其药用组合物用于制备治疗癌症药物，特别是***癌药物中的用途。A further object of the present invention is to provide use of Form I, Form II or a pharmaceutical composition thereof of a compound of formula (I) for the manufacture of a medicament for the treatment of cancer, in particular a prostate cancer.
本发明的有益效果为：The beneficial effects of the invention are:
本发明突破现有技术，提供了式(I)化合物的多种适合药物开发的新晶型。The present invention breaks through the prior art and provides a variety of new crystalline forms suitable for drug development of the compounds of formula (I).
本发明提供的晶型I和II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 forms I and II provided by the present invention have good stability. It can well avoid drug storage and crystal transformation during development, thus avoiding changes in bioavailability and efficacy.
本发明提供的晶型溶解度高、引湿性较低，满足生物利用度和药效要求，且不易受湿度影响，便于长期贮存。The crystal form provided by the invention has high solubility and low moisture permeability, meets the requirements of bioavailability and efficacy, and is not easily affected by humidity, and is convenient for long-term storage.
附图说明DRAWINGS
图1为本发明式(I)化合物晶型I的XRPD图；Figure 1 is an XRPD pattern of Form I of the compound of formula (I) of the present invention;
图2为本发明式(I)化合物晶型I的DSC图；Figure 2 is a DSC chart of the crystalline form I of the compound of the formula (I) of the present invention;
图3为本发明式(I)化合物晶型I的TGA图；Figure 3 is a TGA diagram of Form I of the compound of formula (I) of the present invention;
图4为本发明式(I)化合物晶型I的DVS图；Figure 4 is a DVS diagram of Form I of the compound of formula (I) of the present invention;
图5为本发明式(I)化合物晶型II的XRPD图；Figure 5 is an XRPD pattern of Form II of the compound of formula (I) of the present invention;
图6为本发明式(I)化合物晶型II的DSC图；Figure 6 is a DSC chart of the crystalline form II of the compound of the formula (I) of the present invention;
图7为本发明式(I)化合物晶型II的TGA图；Figure 7 is a TGA diagram of Form II of the compound of formula (I) of the present invention;
图8为本发明式(I)化合物晶型I在不同测试条件下的90天稳定性测试XRPD对比图(A：晶型I起始样品；B：晶型I在25℃/60％相对湿度下放置90天；C：晶型I在40℃/75％相 对湿度下放置90天)；Figure 8 is a comparison chart of XRPD of the 90-day stability test of the crystalline form I of the compound of the formula (I) according to the invention under different test conditions (A: crystalline form I starting sample; B: crystalline form I at 25 ° C / 60% relative humidity) Placed under 90 days; C: Form I at 40 ° C / 75% Placed under humidity for 90 days);
图9为本发明式(I)化合物晶型I与重复专利方法制得的式(I)化合物固体的DVS对比图(测试条件：80％相对湿度；A表示重复专利CN101454002B方法制得的式(I)化合物固体，B表示本发明式(I)化合物晶型I)；Figure 9 is a comparison diagram of the DVS of the solid of the compound of the formula (I) of the formula (I) and the compound of the formula (I) obtained by the repeated patent method (test conditions: 80% relative humidity; A represents the formula obtained by the method of repeating the patent CN101454002B ( I) a compound solid, B represents a crystalline form I) of the compound of formula (I) of the present invention;
图10为本发明式(I)化合物晶型I的PLM图；Figure 10 is a PLM diagram of Form I of the compound of formula (I) of the present invention;
图11为重复专利CN101454002B方法制得的式(I)化合物固体的PLM图。Figure 11 is a PLM diagram of the solid of the compound of formula (I) prepared by the process of repeating the patent CN101454002B.
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。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.
以下实施例中，针对同一晶型，不同制备方法制备得到的晶体XRPD数据可能不完全相同，但是本领域技术人员根据说明书的记载，依据其主要特征峰能够判定属于同一种晶型。In the following examples, the crystal XRPD data prepared by different preparation methods may not be identical for the same crystal form, but those skilled in the art can determine that they belong to the same crystal form according to the main characteristic peaks according to the description of the specification.
下述实施例中，试验方法通常按照常规条件或制造厂商建议的条件实施，其中室温是指25℃±2℃。In the following examples, the test method is usually carried out according to conventional conditions or conditions recommended by the manufacturer, wherein room temperature means 25 ° C ± 2 ° C.
本发明中所用到的缩写的解释如下：The abbreviations used in the present invention are explained as follows:
XRPD：X射线粉末衍射XRPD: X-ray powder diffraction
DSC：差示扫描量热分析DSC: Differential Scanning Calorimetry
TGA：热重分析TGA: Thermogravimetric analysis
DVS：动态水分吸附DVS: Dynamic moisture adsorption
PLM：偏光显微镜PLM: polarized light microscope
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,Kα辐射X-ray reflection parameters: Cu, Kα radiation
Figure PCTCN2016073528-appb-000002
1.540598；
Figure PCTCN2016073528-appb-000003
1.544426
Figure PCTCN2016073528-appb-000002
1.540598;
Figure PCTCN2016073528-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)
扫描范围：自3.0至40.0度Scan range: from 3.0 to 40.0 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
以下实施例中使用的式(I)化合物固体(即，ARN509)是根据中国专利CN101454002B中公开的方法制备的。The solid of the compound of formula (I) used in the following examples (i.e., ARN 509) was prepared according to the method disclosed in Chinese Patent No. CN101454002B.
实施例1Example 1
式(I)化合物晶型I的制备方法：Process for the preparation of crystalline form I of the compound of formula (I):
将24.5mg式(I)化合物加入0.8mL乙酸异丙酯/正庚烷(1:4,v/v)混合溶剂中，室温条件下悬浮搅拌24小时，离心分离固体并在室温下干燥2小时既得。24.5 mg of the compound of the formula (I) was added to 0.8 mL of a mixed solvent of isopropyl acetate/n-heptane (1:4, v/v), and the mixture was suspended and stirred at room temperature for 24 hours, and the solid was centrifuged and dried at room temperature for 2 hours. Decent.
本实施例得到的晶型I的X射线粉末衍射数据如表1所示，其X-射线粉末衍射、DSC以及TGA图谱分别如图1至3所示。The X-ray powder diffraction data of Form I obtained in this example are shown in Table 1, and the X-ray powder diffraction, DSC and TGA patterns thereof are shown in Figures 1 to 3, respectively.
表1Table 1
2theta2theta d间隔d interval 强度％strength%
4.954.95 17.8517.85 17.6417.64
8.278.27 10.6910.69 28.6128.61
9.999.99 8.858.85 3.903.90
12.0512.05 7.347.34 100.00100.00
12.6012.60 7.027.02 4.224.22
13.7013.70 6.466.46 9.049.04
15.2915.29 5.795.79 3.023.02
15.9915.99 5.545.54 89.6289.62
16.4516.45 5.395.39 44.0244.02
16.7316.73 5.305.30 83.1883.18
17.4817.48 5.075.07 11.4411.44
17.8117.81 4.984.98 37.9737.97
19.2519.25 4.614.61 4.044.04
19.5619.56 4.544.54 5.615.61
20.1820.18 4.404.40 72.4272.42
20.3820.38 4.364.36 97.0897.08
21.4821.48 4.144.14 10.4210.42
21.8921.89 4.064.06 19.0419.04
22.4522.45 3.963.96 13.0913.09
23.3623.36 3.813.81 8.738.73
23.7723.77 3.743.74 44.4144.41
24.0724.07 3.703.70 12.6312.63
25.0125.01 3.563.56 23.8323.83
25.5625.56 3.483.48 13.7613.76
26.0626.06 3.423.42 8.898.89
26.4126.41 3.373.37 6.426.42
27.3427.34 3.263.26 2.822.82
27.9327.93 3.193.19 18.5318.53
28.1828.18 3.173.17 9.009.00
28.8628.86 3.093.09 7.077.07
29.4629.46 3.033.03 7.987.98
30.3030.30 2.952.95 10.6610.66
30.7530.75 2.912.91 4.714.71
31.5931.59 2.832.83 4.204.20
32.0732.07 2.792.79 2.242.24
32.6932.69 2.742.74 4.374.37
33.3833.38 2.682.68 4.644.64
34.8634.86 2.572.57 1.571.57
35.5535.55 2.532.53 3.983.98
36.5636.56 2.462.46 1.841.84
37.2337.23 2.412.41 2.922.92
37.9037.90 2.372.37 1.201.20
38.5738.57 2.332.33 0.790.79
实施例2Example 2
式(I)化合物晶型I的制备方法： Process for the preparation of crystalline form I of the compound of formula (I):
将5.5mg式(I)化合物加入0.5mL甲苯中，将该悬浮液加热至85℃获得澄清溶液。将该澄清溶液在室温下挥发至有固体析出，离心分离固体并在室温下干燥2小时既得。5.5 mg of the compound of formula (I) was added to 0.5 mL of toluene and the suspension was heated to 85 ° C to obtain a clear solution. The clear solution was volatilized at room temperature until a solid precipitated, and the solid was centrifuged and dried at room temperature for 2 hours.
本实施例得到的晶型I的X射线粉末衍射数据如表2所示。经X-射线粉末衍射测定，确认为式(I)化合物晶型I。The X-ray powder diffraction data of Form I obtained in this example is shown in Table 2. It was confirmed by X-ray powder diffraction that it was a crystal form I of the compound of the formula (I).
表2Table 2
2theta2theta d间隔d interval 强度％strength%
5.055.05 17.5117.51 24.3324.33
8.228.22 10.7510.75 27.6827.68
10.1010.10 8.768.76 12.9712.97
12.0912.09 7.327.32 50.6150.61
13.6713.67 6.486.48 4.124.12
15.9915.99 5.545.54 35.3235.32
16.4516.45 5.395.39 37.8937.89
16.7316.73 5.305.30 48.7148.71
17.7917.79 4.994.99 21.6021.60
20.1320.13 4.414.41 89.4589.45
20.4020.40 4.354.35 100.00100.00
21.3821.38 4.164.16 12.3912.39
21.8821.88 4.064.06 16.0416.04
22.4222.42 3.973.97 4.894.89
23.3123.31 3.823.82 9.779.77
23.7023.70 3.753.75 27.8027.80
24.0624.06 3.703.70 12.1012.10
24.8924.89 3.583.58 9.029.02
25.4925.49 3.493.49 16.9816.98
25.9225.92 3.443.44 10.6110.61
26.3726.37 3.383.38 6.506.50
27.8327.83 3.213.21 10.2310.23
28.7328.73 3.113.11 8.718.71
29.3729.37 3.043.04 4.714.71
30.2130.21 2.962.96 12.3612.36
31.4831.48 2.842.84 6.406.40
32.5832.58 2.752.75 5.615.61
33.3333.33 2.692.69 3.083.08
37.8237.82 2.382.38 6.956.95
实施例3Example 3
式(I)化合物晶型I的制备方法：Process for the preparation of crystalline form I of the compound of formula (I):
将50mg式(I)化合物加入0.8mL甲醇中，置于50℃悬浮搅拌24小时，离心分离固体并在室温下干燥2小时既得。50 mg of the compound of the formula (I) was added to 0.8 mL of methanol, and the mixture was suspended and stirred at 50 ° C for 24 hours, and the solid was centrifuged and dried at room temperature for 2 hours.
本实施例得到的晶型I的X射线粉末衍射数据如表3所示。经X-射线粉末衍射测定，确认为式(I)化合物晶型I。The X-ray powder diffraction data of Form I obtained in this example is shown in Table 3. It was confirmed by X-ray powder diffraction that it was a crystal form I of the compound of the formula (I).
表3table 3
2theta2theta d间隔d interval 强度％strength%
8.258.25 10.7110.71 14.5114.51
12.0712.07 7.337.33 70.4070.40
16.0116.01 5.545.54 100.00100.00
16.4316.43 5.395.39 26.6526.65
16.7316.73 5.305.30 62.4262.42
17.8017.80 4.984.98 31.5931.59
20.1820.18 4.404.40 39.9539.95
20.4020.40 4.354.35 70.3070.30
21.8721.87 4.064.06 14.1614.16
22.4322.43 3.963.96 8.938.93
23.7423.74 3.753.75 30.3530.35
25.0225.02 3.563.56 31.7131.71
25.5325.53 3.493.49 7.187.18
27.9127.91 3.203.20 12.8612.86
28.7528.75 3.113.11 7.047.04
29.4329.43 3.043.04 7.637.63
30.2730.27 2.952.95 11.4211.42
31.5731.57 2.832.83 4.684.68
实施例4Example 4
式(I)化合物晶型I的制备方法：Process for the preparation of crystalline form I of the compound of formula (I):
将304.9mg式(I)化合物加入5.0mL乙酸乙酯/正庚烷(1:5，v/v)混合溶剂中，置于50℃悬浮搅拌24小时，离心分离固体并在室温下干燥2小时既得。304.9 mg of the compound of the formula (I) was added to 5.0 mL of a mixed solvent of ethyl acetate/n-heptane (1:5, v/v), and the mixture was suspended and stirred at 50 ° C for 24 hours, and the solid was centrifuged and dried at room temperature for 2 hours. Decent.
本实施例得到的晶型I的X射线粉末衍射数据如表4所示。经X-射线粉末衍射测定， 确认为式(I)化合物晶型I。The X-ray powder diffraction data of Form I obtained in this example is shown in Table 4. Determined by X-ray powder diffraction, It was confirmed to be the crystalline form I of the compound of the formula (I).
表4Table 4
2theta2theta d间隔d interval 强度％strength%
4.984.98 17.7317.73 18.0618.06
8.278.27 10.6910.69 24.7124.71
10.0110.01 8.848.84 6.276.27
12.0212.02 7.367.36 100.00100.00
13.6513.65 6.496.49 9.919.91
15.9415.94 5.565.56 63.9263.92
16.3816.38 5.415.41 47.1447.14
16.6516.65 5.335.33 74.4674.46
17.7117.71 5.015.01 29.7729.77
20.0720.07 4.424.42 65.1565.15
20.2820.28 4.384.38 77.1177.11
21.3521.35 4.164.16 11.9511.95
21.8021.80 4.084.08 20.4220.42
22.3922.39 3.973.97 10.6210.62
23.6323.63 3.763.76 40.9240.92
23.9323.93 3.723.72 14.3014.30
24.9024.90 3.583.58 17.6117.61
25.4625.46 3.503.50 16.5816.58
25.8625.86 3.453.45 8.348.34
26.3226.32 3.393.39 5.625.62
27.7827.78 3.213.21 18.7118.71
28.5628.56 3.133.13 7.627.62
28.9228.92 3.093.09 2.062.06
29.2629.26 3.053.05 7.487.48
30.1430.14 2.972.97 9.269.26
31.4131.41 2.852.85 3.683.68
32.4532.45 2.762.76 3.653.65
33.1533.15 2.702.70 4.054.05
33.4633.46 2.682.68 1.751.75
34.6534.65 2.592.59 1.651.65
35.3635.36 2.542.54 5.265.26
37.7137.71 2.392.39 2.352.35
实施例5Example 5
式(I)化合物晶型I的制备方法：Process for the preparation of crystalline form I of the compound of formula (I):
将5.2mg式(I)化合物加入到0.5mL环己烷中获得悬浮液。将该悬浮液加热至85℃并在该温度下放置2分钟，自然冷却至室温并在室温条件下搅拌24小时，离心分离固体并在室温下干燥2小时既得。5.2 mg of the compound of formula (I) was added to 0.5 mL of cyclohexane to obtain a suspension. The suspension was heated to 85 ° C and allowed to stand at this temperature for 2 minutes, naturally cooled to room temperature and stirred at room temperature for 24 hours, and the solid was centrifuged and dried at room temperature for 2 hours.
本实施例得到的晶型I的X射线粉末衍射数据如表5所示。经X-射线粉末衍射测定，确认为式(I)化合物晶型I。The X-ray powder diffraction data of Form I obtained in this example is shown in Table 5. It was confirmed by X-ray powder diffraction that it was a crystal form I of the compound of the formula (I).
表5table 5
2theta2theta d间隔d interval 强度％strength%
8.198.19 10.8010.80 23.6823.68
12.0812.08 7.337.33 86.7786.77
13.6413.64 6.496.49 15.5715.57
15.9615.96 5.555.55 100.00100.00
16.3716.37 5.425.42 37.0237.02
16.7016.70 5.315.31 83.5483.54
17.7517.75 5.005.00 39.8539.85
18.0118.01 4.924.92 31.4831.48
19.1519.15 4.644.64 14.4714.47
20.1420.14 4.414.41 60.7560.75
20.3220.32 4.374.37 70.2370.23
22.1322.13 4.024.02 25.0225.02
22.4222.42 3.973.97 11.8411.84
23.3023.30 3.823.82 24.4724.47
23.7023.70 3.753.75 26.7526.75
24.9124.91 3.583.58 11.1811.18
25.4925.49 3.493.49 36.0536.05
27.7327.73 3.223.22 15.4915.49
29.6829.68 3.013.01 22.2122.21
30.0630.06 2.972.97 13.4213.42
30.4430.44 2.942.94 11.3211.32
31.2931.29 2.862.86 14.5214.52
35.0435.04 2.562.56 17.8317.83
36.4836.48 2.462.46 12.3712.37
实施例6Example 6
式(I)化合物晶型I的制备方法：Process for the preparation of crystalline form I of the compound of formula (I):
将3.73mg式(I)化合物加入0.2mL 1,4-二氧六环/正庚烷(1:11，v/v)混合溶剂中，置于50℃悬浮搅拌24小时，离心分离固体并在室温下干燥2小时既得。3.73 mg of the compound of formula (I) was added to 0.2 mL of a mixed solvent of 1,4-dioxane/n-heptane (1:11, v/v), suspended and stirred at 50 ° C for 24 hours, and the solid was separated by centrifugation. Dry at room temperature for 2 hours.
本实施例得到的晶型I的X射线粉末衍射数据如表6所示。经X-射线粉末衍射测定，确认为式(I)化合物晶型I。The X-ray powder diffraction data of Form I obtained in this example is shown in Table 6. It was confirmed by X-ray powder diffraction that it was a crystal form I of the compound of the formula (I).
表6Table 6
2theta2theta d间隔d interval 强度％strength%
4.924.92 17.9517.95 17.3017.30
8.138.13 10.8710.87 17.2917.29
8.268.26 10.7110.71 26.0526.05
10.0010.00 8.858.85 5.085.08
12.0212.02 7.367.36 100.00100.00
12.5712.57 7.047.04 4.154.15
13.6613.66 6.486.48 9.149.14
14.1014.10 6.286.28 2.682.68
15.9415.94 5.565.56 88.6288.62
16.4016.40 5.415.41 41.6841.68
16.6916.69 5.315.31 86.0886.08
17.4217.42 5.095.09 12.1212.12
17.7617.76 4.994.99 37.4937.49
19.1919.19 4.624.62 3.373.37
19.5119.51 4.554.55 6.226.22
20.1120.11 4.424.42 73.4573.45
20.3020.30 4.384.38 90.9990.99
20.6020.60 4.314.31 10.0810.08
21.4521.45 4.144.14 9.459.45
21.8221.82 4.074.07 20.3620.36
22.3922.39 3.973.97 13.1413.14
23.2723.27 3.823.82 8.468.46
23.6323.63 3.763.76 35.6035.60
23.7323.73 3.753.75 40.4940.49
24.0024.00 3.713.71 12.9512.95
24.9824.98 3.563.56 25.2325.23
25.4425.44 3.503.50 13.7813.78
26.0126.01 3.433.43 9.239.23
26.3126.31 3.393.39 7.217.21
26.7226.72 3.343.34 1.441.44
27.2627.26 3.273.27 3.263.26
27.8227.82 3.213.21 22.4722.47
28.1128.11 3.173.17 9.879.87
28.6528.65 3.123.12 7.077.07
28.8528.85 3.093.09 7.327.32
29.3829.38 3.043.04 10.3810.38
30.0830.08 2.972.97 8.218.21
30.2330.23 2.962.96 11.5811.58
30.6930.69 2.912.91 5.235.23
31.5231.52 2.842.84 5.625.62
32.0232.02 2.802.80 3.023.02
32.5832.58 2.752.75 5.235.23
33.2733.27 2.692.69 6.756.75
34.7934.79 2.582.58 2.512.51
35.4935.49 2.532.53 6.226.22
36.4536.45 2.472.47 2.472.47
37.1637.16 2.422.42 5.385.38
37.7237.72 2.382.38 2.602.60
38.4438.44 2.342.34 2.612.61
39.2639.26 2.292.29 1.601.60
实施例7Example 7
式(I)化合物晶型II的制备方法：Process for the preparation of crystalline form II of the compound of formula (I):
将10.4mg式(I)化合物溶解于1.5mL甲苯中溶清，逐滴加入正庚烷至固体析出，离心分离固体并在室温下干燥2小时既得。10.4 mg of the compound of the formula (I) was dissolved in 1.5 mL of toluene, and n-heptane was added dropwise to solid precipitation, and the solid was centrifuged and dried at room temperature for 2 hours.
本实施例得到的晶型II的X射线粉末衍射数据如表7所示，其X-射线粉末衍射、DSC以及TGA图谱分别如图5至7所示。The X-ray powder diffraction data of Form II obtained in this example are shown in Table 7, and the X-ray powder diffraction, DSC and TGA patterns thereof are shown in Figures 5 to 7, respectively.
表7 Table 7
2theta2theta d间隔d interval 强度％strength%
7.617.61 11.6211.62 75.0475.04
8.888.88 9.969.96 58.9058.90
11.0811.08 7.987.98 31.5031.50
12.4812.48 7.097.09 45.7745.77
13.3013.30 6.666.66 18.9818.98
14.3614.36 6.176.17 100.00100.00
15.5015.50 5.725.72 84.0384.03
15.7615.76 5.625.62 34.3434.34
16.5916.59 5.345.34 68.4568.45
17.1717.17 5.175.17 35.6835.68
17.9217.92 4.954.95 78.4778.47
18.3918.39 4.824.82 14.9914.99
19.0719.07 4.654.65 35.2535.25
19.4919.49 4.554.55 53.1753.17
20.3820.38 4.364.36 34.5234.52
22.9022.90 3.883.88 30.7830.78
25.3825.38 3.513.51 62.4662.46
26.3726.37 3.383.38 39.8539.85
30.3130.31 2.952.95 15.7015.70
实施例8Example 8
式(I)化合物晶型II的制备方法：Process for the preparation of crystalline form II of the compound of formula (I):
将10.2mg式(I)化合物溶解于0.2mL 4-甲基-2-戊酮中溶清，逐滴加入正庚烷至有固体析出，离心分离固体并在室温下干燥2小时既得。10.2 mg of the compound of the formula (I) was dissolved in 0.2 mL of 4-methyl-2-pentanone, and n-heptane was added dropwise until a solid precipitated, and the solid was centrifuged and dried at room temperature for 2 hours.
本实施例得到的晶型II的X射线粉末衍射数据如表8所示。经X-射线粉末衍射测定，确认为式(I)化合物晶型II。The X-ray powder diffraction data of Form II obtained in this example is shown in Table 8. It was confirmed by X-ray powder diffraction that it was a crystal form II of the compound of the formula (I).
表8Table 8
2theta2theta d间隔d interval 强度％strength%
7.647.64 11.5711.57 100.00100.00
8.908.90 9.939.93 62.7562.75
10.9010.90 8.128.12 12.9912.99
12.5312.53 7.077.07 59.5159.51
13.3413.34 6.646.64 45.8045.80
14.3814.38 6.166.16 86.3486.34
14.8414.84 5.975.97 48.9748.97
15.4915.49 5.725.72 89.4989.49
15.8015.80 5.615.61 47.1147.11
16.6016.60 5.345.34 87.9887.98
17.9517.95 4.944.94 80.3980.39
18.5218.52 4.794.79 19.0719.07
19.4919.49 4.554.55 49.5349.53
20.4120.41 4.354.35 28.1028.10
23.0223.02 3.863.86 31.5331.53
25.4125.41 3.513.51 58.3758.37
26.4226.42 3.373.37 29.6629.66
26.9026.90 3.313.31 2.032.03
30.1530.15 2.962.96 3.183.18
实施例9Example 9
式(Ⅰ)化合物晶型I的稳定性测试:Stability test of the crystalline form I of the compound of formula (I):
将本发明制得的式(I)化合物晶型I样品分别放置于25℃/60％相对湿度和40℃/75％相对湿度的条件下90天，于第90天取样进行测试。测试结果表明本发明的晶型I具有良好的稳定性，其XRPD对比图如图8所示，其中A表示晶型I起始样品；B表示25℃/60％相对湿度下放置90天；C表示40℃/75％相对湿度下放置90天。The crystal form I samples of the compound of the formula (I) obtained by the present invention were respectively placed under conditions of 25 ° C / 60% relative humidity and 40 ° C / 75% relative humidity for 90 days, and samples were taken for testing on the 90th day. The test results show that the crystalline form I of the present invention has good stability, and its XRPD comparison chart is shown in Fig. 8, wherein A represents the starting form of the crystalline form I; and B represents the standing at 25 ° C / 60% relative humidity for 90 days; Indicates that it is left for 90 days at 40 ° C / 75% relative humidity.
实施例10Example 10
式(Ⅰ)化合物晶型I的引湿性测试:The wettability test of the crystalline form I of the compound of formula (I):
分别取10mg本发明的式(I)化合物晶型I和10mg由专利方法制得的式(I)化合物固体进行动态水分吸附(DVS)测试。测试结果表明，本发明的式(I)化合物晶型I在80％相对湿度下平衡后增重0.1676％，引湿性较低；而专利方法制得的式(I)化合物固体在80％相对湿度下平衡后增重3.148％，引湿性相对较高。测试结果如图9所示。10 mg of the compound of the formula (I) of the present invention, Form I, and 10 mg of the compound of the formula (I) obtained by the patent method were respectively subjected to a dynamic moisture adsorption (DVS) test. The test results show that the crystalline form I of the compound of the formula (I) of the present invention has a weight gain of 0.1676% after equilibrium at 80% relative humidity, and the wettability is low; and the solid of the compound of the formula (I) obtained by the patent method is at 80% relative humidity. After the lower balance, the weight gain is 3.148%, and the wettability is relatively high. The test results are shown in Figure 9.
关于引湿性特征描述与引湿性增重的界定(中国药典2010年版附录XIX J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 wettability weight gain (Chinese Pharmacopoeia 2010 edition Appendix XIX J drug wettability test guidelines, experimental conditions: 25 ° C ± 1 ° C, 80% relative humidity):
潮解：吸收足量水分形成液体；Deliquescence: absorbs a sufficient amount of 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％；It has hygroscopicity: the wetting 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 hygroscopic: 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%.
实施例11Example 11
式(Ⅰ)化合物晶型I的PLM测试:PLM test for Form I of the compound of formula (I):
在偏光显微镜(PLM)下观察本发明的式(Ⅰ)化合物晶型I和专利方法制得的式(I)化合物固体。观察结果如下： The crystalline form I of the compound of the formula (I) of the present invention and the solid of the compound of the formula (I) obtained by the patent method are observed under a polarizing microscope (PLM). The observation results are as follows:
本发明式(I)化合物晶型I为较为规则的片状晶体，流动性好，在工艺生产中具备容易过滤等优良性质，因此式(I)化合物晶型I的晶习良好，其PLM图如图10所示；而专利方法制得的式(I)化合物固体团聚严重且颗粒不均匀，流动性差，其PLM图如图11所示。 The crystal form I of the compound of the formula (I) of the present invention is a relatively regular flaky crystal, has good fluidity, and has excellent properties such as easy filtration in process production, so that the crystal form I of the compound of the formula (I) is good, and its PLM diagram As shown in FIG. 10; the compound of the formula (I) obtained by the patent method has a solid agglomeration and a non-uniform particle, and has poor fluidity, and its PLM pattern is shown in FIG.

Claims (17)

  1. 一种式(I)化合物的晶型I，a crystalline form I of a compound of formula (I),
    Figure PCTCN2016073528-appb-100001
    Figure PCTCN2016073528-appb-100001
    其特征在于，其X射线粉末衍射图在2theta值为16.7°±0.2°、20.4°±0.2°、12.1°±0.2°处具有特征峰。It is characterized in that its X-ray powder diffraction pattern has a characteristic peak at a 2theta value of 16.7 ° ± 0.2 °, 20.4 ° ± 0.2 °, and 12.1 ° ± 0.2 °.
  2. 根据权利要求1所述的晶型I，其特征在于，其X射线粉末衍射图在2theta值为23.7°±0.2°、8.2°±0.2°、16.0°±0.2°处具有特征峰。The crystal form I according to claim 1, wherein the X-ray powder diffraction pattern has a characteristic peak at a 2theta value of 23.7 ° ± 0.2 °, 8.2 ° ± 0.2 °, and 16.0 ° ± 0.2 °.
  3. 根据权利要求1所述的晶型I，其特征在于，其X射线粉末衍射图在2theta值为17.8°±0.2°、25.0°±0.2°、27.8°±0.2°处具有特征峰。The crystal form I according to claim 1, wherein the X-ray powder diffraction pattern has a characteristic peak at a 2theta value of 17.8 ° ± 0.2 °, 25.0 ° ± 0.2 °, and 27.8 ° ± 0.2 °.
  4. 根据权利要求1-3任一项所述的晶型I，其特征在于，其X射线粉末衍射图在2theta值为8.2°±0.2°、12.1°±0.2°、16.0°±0.2°、16.7°±0.2°、17.8°±0.2°、20.4°±0.2°、23.7°±0.2°、25.0°±0.2°、27.8°±0.2°处具有特征峰。The crystalline form I according to any one of claims 1 to 3, wherein the X-ray powder diffraction pattern has a value of 8.2 ° ± 0.2 °, 12.1 ° ± 0.2 °, 16.0 ° ± 0.2 °, 16.7 ° in the 2theta. Characteristic peaks are present at ±0.2°, 17.8°±0.2°, 20.4°±0.2°, 23.7°±0.2°, 25.0°±0.2°, and 27.8°±0.2°.
  5. 一种式(I)化合物晶型I的制备方法，其特征在于，将式(I)化合物加入析晶溶剂中，通过挥发或悬浮搅拌制得到晶型I。A process for the preparation of a crystalline form I of a compound of the formula (I), characterized in that a compound of the formula (I) is added to a crystallization solvent, and a crystalline form I is obtained by volatilization or suspension stirring.
  6. 根据权利要求5所述的制备方法，其特征在于，所述析晶溶剂为醇类、酮类、醚类、脂肪烃类、酯类、芳香烃类溶剂的一种或多种混合。The method according to claim 5, wherein the crystallization solvent is one or more of a mixture of an alcohol, a ketone, an ether, an aliphatic hydrocarbon, an ester, and an aromatic hydrocarbon solvent.
  7. 根据权利要求6所述的制备方法，其特征在于，所述析晶溶剂为甲醇、丙酮、1,4-二氧六环、环己烷、正庚烷、乙酸异丙酯、甲苯的一种或多种混合。The preparation method according to claim 6, wherein the crystallization solvent is a kind of methanol, acetone, 1,4-dioxane, cyclohexane, n-heptane, isopropyl acetate or toluene. Or a variety of blends.
  8. 根据权利要求7所述的制备方法，其特征在于，所述析晶溶剂为环己烷、乙酸异丙酯、甲苯的一种或多种混合。The preparation method according to claim 7, wherein the crystallization solvent is one or more kinds of cyclohexane, isopropyl acetate, and toluene.
  9. 一种式(I)化合物的晶型II，其特征在于，其X射线粉末衍射图在2theta值为14.4°±0.2°、16.6°±0.2°、17.9°±0.2°处具有特征峰。A crystalline form II of a compound of formula (I), characterized in that its X-ray powder diffraction pattern has characteristic peaks at 2theta values of 14.4° ± 0.2°, 16.6° ± 0.2°, 17.9 ° ± 0.2°.
  10. 根据权利要求9所述的晶型II，其特征在于，其X射线粉末衍射图在2theta值为7.6°±0.2°、8.9°±0.2°、15.5°±0.2°处具有特征峰。The crystal form II according to claim 9, wherein the X-ray powder diffraction pattern has a characteristic peak at a 2theta value of 7.6 ° ± 0.2 °, 8.9 ° ± 0.2 °, and 15.5 ° ± 0.2 °.
  11. 根据权利要求9所述的晶型II，其特征在于，其X射线粉末衍射图在2theta值为25.4°±0.2°、 12.5°±0.2°、13.3°±0.2°处具有特征峰。The crystal form II according to claim 9, wherein the X-ray powder diffraction pattern has a 2theta value of 25.4 ° ± 0.2 °, There are characteristic peaks at 12.5 ° ± 0.2 ° and 13.3 ° ± 0.2 °.
  12. 根据权利要求9-11任一项所述的晶型II，其特征在于，其X射线粉末衍射图在2theta值为7.6°±0.2°、8.9°±0.2°、12.5°±0.2°、13.3°±0.2°、14.4°±0.2°、15.5°±0.2°、16.6°±0.2°、17.9°±0.2°、25.4°±0.2°处具有特征峰。Form II according to any one of claims 9-11, characterized in that the X-ray powder diffraction pattern has a value of 7.6 ° ± 0.2 °, 8.9 ° ± 0.2 °, 12.5 ° ± 0.2 °, 13.3 ° at 2theta. Characteristic peaks are present at ±0.2°, 14.4°±0.2°, 15.5°±0.2°, 16.6°±0.2°, 17.9°±0.2°, 25.4°±0.2°.
  13. 一种式(I)化合物晶型II的制备方法，其特征在于，将式(I)化合物加入正溶剂中，滴加反溶剂至固体析出得到晶型II。A process for the preparation of a crystalline form II of a compound of the formula (I), characterized in that a compound of the formula (I) is added to a positive solvent, and an anti-solvent is added dropwise to precipitate a solid to obtain a crystal form II.
  14. 根据权利要求13所述的制备方法，其特征在于，所述正溶剂酯类、芳香烃类、酮类溶剂的一种或多种混合，所述反溶剂脂肪烃类溶剂。The method according to claim 13, wherein one or more of the positive solvent esters, the aromatic hydrocarbons, and the ketone solvent are mixed, and the anti-solvent aliphatic hydrocarbon solvent.
  15. 根据权利要求14所述的制备方法，其特征在于，所述正溶剂为甲苯、乙酸异丙酯、4-甲基-2-戊酮的一种或多种混合，所述反溶剂为正庚烷。The preparation method according to claim 14, wherein the positive solvent is one or more kinds of toluene, isopropyl acetate and 4-methyl-2-pentanone, and the anti-solvent is n-glycan. alkyl.
  16. 一种药用组合物，所述药用组合物包含有效治疗量的权利要求1至4任意一项所述的晶型I或权利要求9至12任意一项所述的晶型II或两者任意比例混合及药学上可接受的赋形剂。A pharmaceutical composition comprising a therapeutically effective amount of Form I according to any one of claims 1 to 4 or Form II of any one of Claims 9 to 12 or both Mix and pharmaceutically acceptable excipients in any ratio.
  17. 根据权利要求1至4任意一项所述的晶型I或权利要求9至12任意一项所述的晶型II或两者任意比例混合或根据权利要求16所述的药用组合物在制备治疗***癌药物中的用途。 The crystalline form I according to any one of claims 1 to 4 or the crystalline form II according to any one of claims 9 to 12 or a mixture of the two in any ratio or the pharmaceutical composition according to claim 16 is prepared. Use in the treatment of prostate cancer drugs.
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