WO2017121379A1 - 一种调节激酶化合物的对甲苯磺酸盐及其结晶 - Google Patents

一种调节激酶化合物的对甲苯磺酸盐及其结晶 Download PDF

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WO2017121379A1
WO2017121379A1 PCT/CN2017/071102 CN2017071102W WO2017121379A1 WO 2017121379 A1 WO2017121379 A1 WO 2017121379A1 CN 2017071102 W CN2017071102 W CN 2017071102W WO 2017121379 A1 WO2017121379 A1 WO 2017121379A1
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compound
formula
crystal
benefit
crystallization
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French (fr)
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李继军
朱岩
王虎庭
韩永信
黄体聪
李新路
赵锐
张喜全
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Centaurus Biopharma Co Ltd
Chia Tai Tianqing Pharmaceutical Group Co Ltd
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Centaurus Biopharma Co Ltd
Chia Tai Tianqing Pharmaceutical Group Co Ltd
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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
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A61K31/52—Purines, e.g. adenine
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D473/00—Heterocyclic compounds containing purine ring systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

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  • the present application belongs to the field of medicine, and relates to a p-toluenesulfonate and a crystal thereof for regulating a kinase compound, in particular, to N- ⁇ 3-[3-(9H- ⁇ -6-yl)pyridin-2-ylamino ]-4-Chloro-2-fluorophenyl ⁇ -3-fluoropropane-1-sulfonamide p-toluenesulfonate and its crystallization.
  • Example 9 of WO2013071865A1 discloses a kinase-regulating compound having the chemical name N- ⁇ 3-[3-(9H-indol-6-yl)pyridin-2-ylamino]-4-chloro-2 -Fluorophenyl ⁇ -3-fluoropropane-1-sulfonamide, the structure is as shown in Formula I:
  • Compound of Formula I as a free form is a kinase-modulating compound useful in the treatment of diseases and conditions associated with modulation of kinase activity.
  • the compounds of formula I have excellent anti-B-RAF enzyme activity in vitro and are useful in the treatment of diseases and conditions associated with modulation of B-RAF enzyme activity.
  • the application provides a compound of formula II,
  • the application provides crystallization of a compound of formula II,
  • the compound of formula II is crystallized using an X-ray powder diffraction pattern of Cu K ⁇ radiation, and the diffraction angle (2 ⁇ ⁇ 0.2°) has diffraction peaks at about 4.59°, 7.99°, 8.37°, 9.18°, 18.52°, and 20.78°. .
  • the present application provides a crystalline composition comprising a crystal of a compound of formula II as described herein, wherein the compound of formula II comprises more than 50% by weight of the crystalline composition, 80 More than %, more than 90%, more than 95% or more than 99%.
  • the present application provides a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula II as described herein or a crystalline form of said compound of formula II or a crystalline composition as described above, and one or A variety of pharmaceutically acceptable carriers.
  • the application provides a compound of formula II as described herein or a crystalline form of the compound of formula II or a crystalline composition as described above or a pharmaceutical composition as described above, in the manufacture of a medicament for the treatment of a protein kinase mediated disease or condition the use of.
  • the present application also provides a compound of Formula II described herein or a compound of Formula II described herein or a crystalline composition thereof or a pharmaceutical composition as described above for use in the treatment of a protein kinase mediated disease or condition.
  • the present application also provides a method of treating a protein kinase mediated disease or condition, the method comprising administering to a patient in need of treatment a therapeutically effective amount of a compound of formula II as described herein or a crystal of said compound of formula II or a combination of said crystals Or the above pharmaceutical composition.
  • the present application provides a process for the preparation of a crystallization of a compound of formula II comprising crystallizing a compound of formula II in a C 1-4 alcohol solvent to provide a crystallization of the compound of formula II.
  • the application provides N- ⁇ 3-[3-(9H-indol-6-yl)pyridin-2-ylamino]-4-chloro-2-fluorophenyl ⁇ -3 as shown in Formula II -Fluoropropane-1-sulfonamide p-toluenesulfonate (hereinafter referred to as a compound of formula II):
  • the compounds of formula II provided herein are superior to the compounds of formula I or other salts of the compounds of formula I in at least one aspect, such as bioavailability, hygroscopicity, stability, solubility, purity, ease of preparation, and the like.
  • the application provides crystallization of a compound of formula II,
  • crystals of the compound of formula II are substantially free of water of crystallization and/or other solvents.
  • Crystallization of the compound of formula II Using an X-ray powder diffraction pattern of Cu Ka radiation, the diffraction angle (2 ⁇ ⁇ 0.2°) is about 4.59°, 7.99°, 8.37°, 9.18°, 14.75°, 16.73°, 17.35°, 18.52. There are diffraction peaks at °, 20.78°, 21.60°, 21.92°, and 25.36°.
  • Crystallization of the compound of formula II Using an X-ray powder diffraction pattern of Cu Ka radiation, the diffraction angle (2 ⁇ ⁇ 0.2°) is about 4.59°, 7.99°, 8.37°, 9.18°, 10.86°, 14.75°, 16.73°, 17.35. There are diffraction peaks at °, 18.52, 18.98, 20.09, 20.78, 21.60, 21.92, 23.11, 24.30, 25.36, 26.08, 26.62, 27.41, 27.85 and 28.32.
  • the diffraction angle (2 ⁇ ⁇ 0.2°) is about 4.59°, 7.99°, 8.37°, 9.18°, 10.86°, 14.75°, 16.73°, 17.35.
  • a typical example of crystallizing a compound of formula II of the present application using an X-ray powder diffraction (XRD) pattern of Cu Ka radiation has the following characteristics:
  • a typical example of a crystal of a compound of formula II of the present application has an X-ray powder diffraction (XRD) pattern substantially as shown in FIG.
  • a typical example of a crystal of a compound of formula II of the present application has an XRD pattern substantially as shown in FIG.
  • a differential scanning calorimetry (DSC) measurement chart of a typical example of the crystallization of the compound of Formula II of the present application has an onset temperature of about 260.5 ° C, specifically, a difference substantially as shown in FIG.
  • a scanning calorimetry (DSC) measurement chart is shown.
  • a differential scanning calorimetry (DSC) measurement chart of a typical example of the crystallization of a compound of Formula II of the present application has an onset temperature of about 258.8 °C, specifically, a difference substantially as shown in FIG.
  • a scanning calorimetry (DSC) measurement chart is shown.
  • the crystallization of the compound of the formula II of the present application includes not only the diffraction angle of the peak in the X-ray powder diffraction completely coincides with the above diffraction angle or the crystal of ⁇ 0.2°, but also the diffraction angle having a uniform error of ⁇ 0.2°. crystallization.
  • the present application provides a crystalline composition comprising the crystal of the compound of the above formula II, wherein the crystal of the compound of the formula II accounts for 50% or more, 80% or more, 90% or more by weight of the crystal composition. More than 95% or more than 99%.
  • the present application provides a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula II or a compound of Formula II, or a crystalline composition thereof, and one or more pharmaceutically acceptable carriers .
  • the pharmaceutical compositions of the present application can be prepared by crystallizing a compound of formula II or a compound of formula II or a combination of the above crystalline compositions with a suitable pharmaceutically acceptable carrier.
  • the application provides the use of a compound of formula II or a compound of formula II above, or a crystalline composition as described above, or a pharmaceutical composition as described above, in the manufacture of a medicament for the treatment of a protein kinase mediated disease or condition, preferably in preparation thereof Use in a medicament for treating a B-raf kinase mediated disease or condition, such as a cancer, mediated by a protein kinase (including B-raf kinase).
  • the present application also provides a compound of formula II, or a crystalline composition of the above formula II, or a crystalline composition thereof, or a pharmaceutical composition as described above, for use in the treatment of a disease or condition mediated by a protein kinase, including a B-raf kinase.
  • a protein kinase including a B-raf kinase.
  • the disease or condition mediated by the protein kinase can be, for example, a cancer.
  • the present application also provides a method of treating a disease or condition mediated by a protein kinase, including B-raf kinase, comprising administering to a patient in need of treatment a therapeutically effective amount of a compound of Formula II described herein or a formula thereof.
  • the compound II crystallizes or the above crystalline composition or the above pharmaceutical composition.
  • the disease or condition mediated by the protein kinase can be, for example, a cancer.
  • the protein kinase (including B-raf kinase) mediated diseases or conditions described in the present application are selected from the group consisting of melanoma, colorectal cancer, colon cancer, gastric cancer, pelvic cancer, esophageal cancer, brain cancer, testicular cancer, bone cancer, lymph Cancer, lung cancer, breast cancer, pancreatic cancer, thyroid cancer, ovarian cancer, liver cancer, kidney cancer, glioma, sarcoma, medullary thyroid carcinoma, carcinoid, small cell lung cancer, leukemia, neurofibromatosis, myelodysplastic syndrome , tumor angiogenesis, neuropathic pain, inflammatory pain, acute and chronic pain, cancer-related pain, migraine, heart failure, ischemic stroke, cardiac hypertrophy, thrombosis, atherosclerosis, multiple infarct dementia, head Injury, spinal cord injury, Parkinson's disease, Alzheimer's disease, psoriasis, arthritis, osteoarthritis, fibrosis, r
  • the crystallization of the compound of formula II provided herein is at least one aspect superior to the compound of formula I or other salt of the compound of formula I in terms of bioavailability, hygroscopicity, stability, solubility, purity, ease of preparation, and the like.
  • the crystal of the compound of the formula II provided by the present application has excellent solubility parameters suitable for the preparation of the drug; has high stability, for example, has higher stability than other salts of the compound of the formula I (such as potassium salt); is not easily deliquescent, for example, the compound of the formula I, hydrochloric acid Salts and sulfates are easily deliquescent; their impurity content is easily controlled, for example, in the preparation, under the experimental conditions of conventional stability investigation.
  • the compound of formula II of the present application can be prepared by the following method: a compound of formula I and p-toluenesulfonic acid are salted in a solvent to provide a compound of formula II.
  • the crystallization of the compound of the formula II of the present application can be obtained by the following method: a compound of the formula I and p-toluenesulfonic acid are salted in a solvent to obtain a compound of the formula II; the compound of the formula II is crystallized in a C 1-4 alcohol solvent to give a compound of the formula II. crystallization.
  • a compound of formula I is added to p-toluenesulfonic acid in a solvent, stirred at room temperature or under heating to remove the solvent to give a compound of formula II; a compound of formula II in a C 1-4 alcoholic solvent at room temperature or under heating, for example, under reflux conditions
  • the solution is formed under the following conditions, and the compound of the formula II is crystallized by cooling to about 0 ° C to room temperature, and dried by filtration to obtain a crystal of the compound of the formula II. It is optional during the crystallization to mix the solution while slowly cooling, which may be shaking or stirring.
  • the solvent used for salt formation is one or more polar protic solvents including, but not limited to, acetonitrile, tetrahydrofuran, ethyl acetate, methyl acetate, methyl formate, acetone or methyl ethyl ketone. .
  • the solvent used to form the salt is tetrahydrofuran.
  • the molar ratio of the compound of the formula I to p-toluenesulfonic acid is from 1:1-5, preferably from 1:1 to 2.
  • the C 1-4 alcohol solvent is one or more selected from the group consisting of methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, sec-butanol or tert-butanol, preferably methanol or ethanol. Or one or more of isopropanol, most preferably one or both of methanol or ethanol.
  • Patient means a mammal, preferably a human.
  • “Pharmaceutically acceptable” is those compounds, materials, compositions and/or dosage forms that are within the scope of sound medical judgment and are suitable for use in contact with human and animal tissues without undue Toxic, irritating, allergic reactions or other problems or complications are commensurate with a reasonable benefit/risk ratio.
  • Treatment means administration of a compound or formulation described herein to prevent, ameliorate or eliminate a disease or one or more symptoms associated with the disease, and includes:
  • Incident light path divergence slit 1°, anti-scatter slit 2°;
  • test method for the DSC pattern of the crystal of the above formula II of the present application is as follows:
  • the diffraction spectrum obtained from the crystalline compound is often characteristic for a specific crystal form, wherein the relative intensity of the band (especially at a low angle) may be due to the crystal.
  • the dominant orientation effect due to the difference in conditions, particle size, and other measurement conditions varies. Therefore, the relative intensities of the diffraction peaks are not characteristic for the crystal form to be targeted.
  • the position of the peak can be shifted due to changes in temperature during sample analysis, sample movement, or calibration of the instrument, etc., and the measurement error of the 2 ⁇ value is sometimes about ⁇ 0.2°. Therefore, this error should be taken into account when determining each crystal structure.
  • the peak positions of the XRD spectrum have similarities as a whole, and the relative intensity error may be large.
  • DSC measures the transition temperature when a crystal absorbs or releases heat due to a change in its crystal structure or crystal melting.
  • the thermal transition temperature and melting point error is typically within about 5 ° C, usually within about 3 ° C, when we say a compound has a given DSC At the peak or melting point, this means the DSC peak or melting point ⁇ 5 °C.
  • DSC provides an auxiliary method for identifying different crystal forms. Different crystal morphology can be identified based on their different transition temperature characteristics. It should be noted that for the mixture, the DSC peak or melting point may vary over a larger range.
  • the melting temperature is related to the rate of temperature increase due to decomposition during the melting of the substance.
  • Figure 1 is an X-ray powder diffraction pattern of the crystal of the compound of formula II prepared in Example 3.
  • DSC differential scanning calorimetry
  • DSC differential scanning calorimetry
  • the compound of formula I is prepared according to the method disclosed in Example 9 of WO2013071865A1.
  • the compound of the formula II prepared in Example 3 was crystallized for a strong light irradiation test (4500 LX), a high temperature test (60 ° C) and a high humidity test (92.5%).
  • the investigation time was 10 days, and the purity was sampled on the 0th day and the 10th day respectively.
  • the test results are shown in Table 1.
  • Example 3 The crystallization of the compound of the formula II prepared in Example 3 was subjected to a wettability test. Test conditions: 25 ° C ⁇ 1 ° C, RH80% ⁇ 2% constant temperature and humidity box for more than 24h.
  • a dry stoppered glass weighing bottle (outer diameter 50 mm, height 15 mm) was taken and placed in a suitable 25 ° C ⁇ 1 ° C constant temperature dryer on the day before the test, and the weight (m 1 ) was accurately weighed.
  • the thickness of the test sample is generally about 1 mm, and the weight is accurately weighed (m 2 ).
  • the weighing bottle was opened and placed under the above constant temperature and humidity conditions for 24 hours with the cap, and the weighing cap was covered, and the weight (m 3 ) was accurately weighed.

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Abstract

本申请涉及一种调节激酶化合物的对甲苯磺酸盐及其结晶，具体而言，涉及N-{3-[3-(9H-嘌呤-6-基)吡啶-2-基氨基]-4-氯-2-氟苯基}-3-氟丙烷-1-磺酰胺对甲苯磺酸盐及其结晶。本申请提供的盐及其结晶在生物利用度、吸湿性、稳定性、溶解性、纯度、易制备等方面具有优势。

Description

一种调节激酶化合物的对甲苯磺酸盐及其结晶
相关申请的交叉引用
本申请要求于2016年1月15日向中国国家知识产权局提交的第201610028119.9号中国专利申请的优先权和权益，所述专利申请公开的内容通过引用整体并入本文中。
技术领域
本申请属于医药领域，涉及一种调节激酶化合物的对甲苯磺酸盐及其结晶，具体而言，涉及N-{3-[3-(9H-嘌呤-6-基)吡啶-2-基氨基]-4-氯-2-氟苯基}-3-氟丙烷-1-磺酰胺对甲苯磺酸盐及其结晶。
背景技术
WO2013071865A1中的实施例9公开了一种调节激酶的化合物，它的化学名称为N-{3-[3-(9H-嘌呤-6-基)吡啶-2-基氨基]-4-氯-2-氟苯基}-3-氟丙烷-1-磺酰胺，结构如式I所示：
Figure PCTCN2017071102-appb-000001
该专利文献公开的N-{3-[3-(9H-嘌呤-6-基)吡啶-2-基氨基]-4-氯-2-氟苯基}-3-氟丙烷-1-磺酰胺(式I化合物)作为游离体是一种调节激酶的化合物，可用于治疗与激酶活性调节相关的疾病和病症。特别地，式I化合物具有优异的体外抗B-RAF酶的活性，可用于治疗与B-RAF酶活性调节相关的疾病和病症。
然而，仍需要开发出与N-{3-[3-(9H-嘌呤-6-基)吡啶-2-基氨基]-4-氯-2-氟苯基}-3-氟丙烷-1-磺酰胺的游离体相比，在物性方面和动力学方面具有更优异的性质、作为药品的适用性高的调节激酶化合物。
发明概述
一方面，本申请提供了式II化合物，
Figure PCTCN2017071102-appb-000002
另一方面，本申请提供了式II化合物结晶，
Figure PCTCN2017071102-appb-000003
所述式II化合物结晶使用Cu Kα辐射的X-射线粉末衍射图谱中，衍射角度(2θ±0.2°)约为4.59°、7.99°、8.37°、9.18°、18.52°和20.78°处有衍射峰。
又一方面，本申请提供了一种结晶组合物，所述结晶组合物含有本申请所述的式II化合物结晶，其中所述式II化合物结晶占所述结晶组合物重量的50％以上、80％以上、90％以上、95％以上或99％以上。
再一方面，本申请提供了一种药物组合物，所述药物组合物包含治疗有效量的本申请所述的式II化合物或所述的式II化合物结晶或上述结晶组合物，以及一种或多种药学上可接受的载体。
另一方面，本申请提供了本申请所述的式II化合物或所述的式II化合物结晶或上述结晶组合物或上述药物组合物在制备用于治疗蛋白激酶介导的疾病或病症的药物中的用途。
本申请还提供了用于治疗蛋白激酶介导的疾病或病症的本申请所述的式II化合物或所述的式II化合物结晶或上述结晶组合物或上述药物组合物。
本申请还提供了治疗蛋白激酶介导的疾病或病症的方法，所述方法包括给予需要治疗的患者治疗有效量的本申请所述的式II化合物或所述的式II化合物结晶或上述结晶组合物或上述药物组合物。
再一方面，本申请提供了所述的式II化合物结晶的制备方法，包括将式II化合物在C1-4醇类溶剂中进行结晶得到式II化合物结晶。
发明详述
一方面，本申请提供了如式II所示的N-{3-[3-(9H-嘌呤-6-基)吡啶-2-基氨基]-4-氯-2-氟苯基}-3-氟丙烷-1-磺酰胺对甲苯磺酸盐(以下简称为式II化合物)：
Figure PCTCN2017071102-appb-000004
式II化合物中，N-{3-[3-(9H-嘌呤-6-基)吡啶-2-基氨基]-4-氯-2-氟苯基}-3-氟丙烷-1-磺酰胺与对甲苯磺酸的摩尔比约为1∶1。
本申请提供的式II化合物在生物利用度、吸湿性、稳定性、溶解性、纯度、易制备等至少一方面优于式I化合物或式I化合物的其它盐。
另一方面，本申请提供了一种式II化合物的结晶，
Figure PCTCN2017071102-appb-000005
其中，式II化合物的结晶基本上不含结晶水和/或其它溶剂。
式II化合物的结晶使用Cu Kα辐射的X-射线粉末衍射图谱中，衍射角度(2θ±0.2°)约为4.59°、7.99°、8.37°、9.18°、18.52°和20.78°处有衍射峰。
式II化合物的结晶使用Cu Kα辐射的X-射线粉末衍射图谱中，衍射角度(2θ±0.2°)约为4.59°、7.99°、8.37°、9.18°、18.52°、20.78°、21.60°和21.92°处有衍射峰。
式II化合物的结晶使用Cu Kα辐射的X-射线粉末衍射图谱中，衍射角度(2θ±0.2°)约为4.59°、7.99°、8.37°、9.18°、18.52°、20.78°、21.60°、21.92°和25.36°处有衍射峰。
式II化合物的结晶使用Cu Kα辐射的X-射线粉末衍射图谱中，衍射角度(2θ±0.2°)约为4.59°、7.99°、8.37°、9.18°、14.75°、16.73°、17.35°、18.52°、20.78°、21.60°、21.92°和25.36°处有衍射峰。
式II化合物的结晶使用Cu Kα辐射的X-射线粉末衍射图谱中，衍射角度(2θ±0.2°) 约为4.59°、7.99°、8.37°、9.18°、14.75°、16.73°、17.35°、18.52°、18.98°、20.09°、20.78°、21.60°、21.92°、23.11°、25.36°、26.08°、26.62°、27.41°、27.85°和28.32°处有衍射峰。
式II化合物的结晶使用Cu Kα辐射的X-射线粉末衍射图谱中，衍射角度(2θ±0.2°)约为4.59°、7.99°、8.37°、9.18°、10.86°、14.75°、16.73°、17.35°、18.52°、18.98°、20.09°、20.78°、21.60°、21.92°、23.11°、24.30°、25.36°、26.08°、26.62°、27.41°、27.85°和28.32°处有衍射峰。
式II化合物的结晶使用Cu Kα辐射的X-射线粉末衍射图谱中，衍射角度(2θ±0.2°)约为4.59°、7.99°、8.37°、9.18°、10.86°、14.75°、16.73°、17.35°、18.52°、18.98°、20.09°、20.78°、21.60°、21.92°、23.11°、24.30°、25.36°、26.08°、26.62°、27.41°、27.85°、28.32°、29.41°、30.19°、30.90°、31.97°、33.47°、34.06°、37.82°、39.38°、40.00°、42.33°和43.93°处有衍射峰。
非限制性地，本申请的式II化合物结晶的一个典型实例使用Cu Kα辐射的X-射线粉末衍射(XRD)图谱具有如下特征：
Figure PCTCN2017071102-appb-000006
Figure PCTCN2017071102-appb-000007
非限制性地，本申请的式II化合物结晶的一个典型实例具有基本上如图1所示的X-射线粉末衍射(XRD)图谱。
非限制性地，本申请的式II化合物结晶的一个典型实例具有基本上如图2所示的XRD图谱。
非限制性地，本申请的式II化合物结晶的一个典型实例的差示扫描量热(DSC)测量图具有约260.5℃的起始温度，具体而言，具有基本上如图3所示的差示扫描量热(DSC)测量图。
非限制性地，本申请的式II化合物结晶的一个典型实例的差示扫描量热(DSC)测量图具有约258.8℃的起始温度，具体而言，具有基本上如图4所示的差示扫描量热(DSC)测量图。
需要说明的是，本申请的式II化合物结晶不仅包括X-射线粉末衍射中峰的衍射角度与上述衍射角度完全一致或±0.2°的结晶，而且也包括衍射角度具有一致的±0.2°误差的结晶。
本申请的式II化合物结晶中，N-{3-[3-(9H-嘌呤-6-基)吡啶-2-基氨基]-4-氯-2-氟苯基}-3-氟丙烷-1-磺酰胺与对甲苯磺酸的摩尔比约为1∶1。
再一方面，本申请还提供一种结晶组合物，所述结晶组合物含有上述式II化合物结晶，其中上述式II化合物结晶占结晶组合物重量的50％以上、80％以上、90％以上、95％以上或99％以上。
又一方面，本申请提供了一种药物组合物，所述药物组合物包含治疗有效量的式II化合物或式II化合物结晶或上述结晶组合物，以及一种或多种药学上可接受的载体。本申请的药物组合物可通过将式II化合物或式II化合物结晶或上述结晶组合物与适宜的药学上可接受的载体组合而制备。
再一方面，本申请提供了式II化合物或上述式II化合物结晶或上述结晶组合物或上述药物组合物在制备用于治疗蛋白激酶介导的疾病或病症的药物中的用途，优选其在制备用于治疗B-raf激酶介导的疾病或病症的药物中的用途，所述蛋白激酶(包括B-raf激酶)介导的疾病或病症例如可以是癌症。
本申请还提供了用于治疗蛋白激酶(包括B-raf激酶)介导的疾病或病症的本申请所述的式II化合物或所述的式II化合物结晶或上述结晶组合物或上述药物组合物。所述蛋白激酶(包括B-raf激酶)介导的疾病或病症例如可以是癌症。
本申请还提供了治疗蛋白激酶(包括B-raf激酶)介导的疾病或病症的方法，所述方法包括给予需要治疗的患者治疗有效量的本申请所述的式II化合物或所述的式II化合物结晶或上述结晶组合物或上述药物组合物。所述蛋白激酶(包括B-raf激酶)介导的疾病或病症例如可以是癌症。
本申请中所述蛋白激酶(包括B-raf激酶)介导的疾病或病症选自黑色素瘤、结直肠癌、肠癌、胃癌、盆腔癌、食道癌、脑癌、睾丸癌、骨癌、淋巴癌、肺癌、乳腺癌、胰腺癌、甲状腺癌、卵巢癌、肝癌、肾癌、胶质瘤、肉瘤、甲状腺髓样癌、类癌、小细胞肺癌、白血病、神经纤维瘤、骨髓增生异常综合征、肿瘤血管生成、神经性疼痛、炎性疼痛、急慢性疼痛、癌症相关疼痛、偏头痛、心力衰竭、缺血性中风、心脏肥大、血栓形成、动脉粥样硬化、多发梗塞性痴呆、头部损伤、脊髓损伤、帕金森病、阿尔茨海默病、牛皮癣、关节炎、骨关节炎、纤维化病、类风湿性关节炎、炎性肠病、免疫缺陷疾病、器官移植排斥反应、移植物抗宿主病、糖尿病性肾病、多囊性肾病、肾硬化、肾小球肾炎、前列腺增生、糖尿病、肥胖、幽门螺旋杆菌感染、肝炎感染、流感病毒感染、发热、败血症、慢性阻塞性肺疾病、急性呼吸窘迫综合征、肌肉萎缩症、运动神经元疾病、神经肌肉接头疾病、内分泌异常疾病、周围神经疾病、腺体疾病、身体和肌肉代谢疾病。
本申请提供的式II化合物结晶在生物利用度、吸湿性、稳定性、溶解性、纯度、易制备等至少一方面优于式I化合物或式I化合物的其它盐。
本申请提供的式II化合物结晶具有优良的适用于成药的溶解度参数；具有高稳定性，例如比式I化合物的其它盐(比如钾盐)的稳定性高；不易潮解，例如式I化合物盐酸盐与硫酸盐易潮解；其杂质含量容易控制，例如在制备中，在常规稳定性考察的实验条件下。
本申请的式II化合物可通过以下方法制备得到：式I化合物和对甲苯磺酸于溶剂中成盐得到式II化合物。
本申请的式II化合物结晶可通过以下方法制备得到：式I化合物和对甲苯磺酸于溶剂中成盐得到式II化合物；式II化合物在C1-4醇类溶剂中进行结晶得到式II化合物结晶。
例如，式I化合物于溶剂中，加入对甲苯磺酸，在室温或加热条件下搅拌，除去溶剂得到式II化合物；式II化合物于C1-4醇类溶剂中，在室温或加热例如回流条件下形成溶液，冷却至0℃左右至室温使式II化合物结晶析出，过滤干燥得到式II化合物结晶。结晶过程中可 选的是缓慢冷却时混合溶液，所述混合可以是振摇或搅拌。
成盐所用的溶剂为一种或一种以上的极性质子类溶剂，所述极性质子类溶剂包括但不限于乙腈、四氢呋喃、乙酸乙酯、乙酸甲酯、甲酸甲酯、丙酮或丁酮。在本申请的一些具体实施方案中，成盐所用的溶剂为四氢呋喃。成盐反应中，式I化合物与对甲苯磺酸的摩尔比为1∶1-5，优选1∶1-2。
C1-4醇类溶剂选自甲醇、乙醇、正丙醇、异丙醇、正丁醇、异丁醇、仲丁醇或叔丁醇中的一种或一种以上，优选为甲醇、乙醇或异丙醇中的一种或一种以上，最优选甲醇或乙醇中的一种或两种。
除非另有说明，为本申请的目的，本说明书和权利要求书中所用的下列术语应具有下述含义。
“患者”是指哺乳动物，优选人。
“药学上可接受的”是针对那些化合物、材料、组合物和/或剂型而言，它们在可靠的医学判断的范围之内，适用于与人类和动物的组织接触使用，而没有过多的毒性、刺激性、过敏性反应或其它问题或并发症，与合理的利益/风险比相称。
“治疗”是指将本申请所述化合物或制剂进行给药以预防、改善或消除疾病或与所述疾病相关的一个或多个症状，且包括：
(i)预防疾病或疾病状态在哺乳动物中出现，特别是当这类哺乳动物易患有该疾病状态，但尚未被诊断为已患有该疾病状态时；
(ii)抑制疾病或疾病状态，即遏制其发展；
(iii)缓解疾病或疾病状态，即使该疾病或疾病状态消退。
本申请的式II化合物结晶的XRD图谱的测试方法如下：
1、仪器：荷兰PANalytical公司(原Philips分析仪器公司)，X’Pert PRO MPD X-射线衍射仪
2、测定条件：Cu Kα辐射，0.15418nm；管压：40kv；管流：40mA；Ni滤波片；超能阵列探头(X’Celerator)；
入射光路：发散狭缝1°、防散射狭缝2°；
反射光路：防散射狭缝6.6°；
扫描情况：0.033°/step；20s/step
本申请的上述式II化合物结晶的DSC图的测试方法如下：
1.仪器：Perkin Elmer Thermal Analysis。
2.测定条件：起始温度50℃，终止温度300℃，升温速率：10℃/min。
需要说明的是，在X-射线粉末衍射光谱中，由晶体化合物得到的衍射谱图对于特定的晶型往往是特征性的，其中谱带(尤其是在低角度)的相对强度可能会因为晶体条件、粒径和其它测定条件的差异而产生的优势取向效果而变化。因此，衍射峰的相对强度对所针对的晶型并非是特征性的，判断是否与已知的晶型相同时，更应该注意的是峰的相对位置而不是它们的相对强度。此外，对任何给定的晶型而言，峰的位置可能存在轻微误差，这在结晶学领域中也是公知的。例如，由于分析样品时温度的变化、样品移动、或仪器的标定等，峰的位置可以移动，2θ值的测定误差有时约为±0.2°。因此，在确定每种结晶结构时，应该将此误差考虑在内。在XRD图谱中通常用2θ角或晶面距d表示峰位置，两者之间具有简单的换算关系：d＝λ/2sinθ，其中d代表晶面距，λ代表入射X射线的波长，θ为衍射角。对于同种化合物的同种晶型，其XRD谱的峰位置在整体上具有相似性，相对强度误差可能较大。还应指出的是，在混合物的鉴定中，由于含量下降等因素会造成部分衍射线的缺失，此时，无需依赖高纯试样中观察到的全部谱带，甚至一条谱带也可能对给定的晶体是特征性的。
DSC测定当晶体由于其晶体结构发生变化或晶体熔融而吸收或释放热时的转变温度。对于同种化合物的同种晶型，在连续的分析中，热转变温度和熔点误差典型的在约5℃之内，通常在约3℃之内，当我们说一个化合物具有一给定的DSC峰或熔点时，这是指该DSC峰或熔点±5℃。DSC提供了一种辨别不同晶型的辅助方法。不同的晶体形态可根据其不同的转变温度特征而加以识别。需要指出的是对于混合物而言，其DSC峰或熔点可能会在更大的范围内变动。此外，由于在物质熔化的过程中伴有分解，因此熔化温度与升温速率相关。
附图简述
图1为实施例3制备得到的式II化合物结晶的X-射线粉末衍射图谱。
图2为实施例4制备得到的式II化合物结晶的X-射线粉末衍射图谱。
图3为实施例3制备得到的式II化合物结晶的差示扫描量热(DSC)测量图。
图4为实施例4制备得到的式II化合物结晶的差示扫描量热(DSC)测量图。
具体实施方式
实施例1N-{3-[3-(9H-嘌呤-6-基)吡啶-2-基氨基]-4-氯-2-氟苯基}-3-氟丙烷-1-磺酰胺(式I化合物)的制备
按照WO2013071865A1中实施例9公开的方法，制备得到式I化合物。
实施例2N-{3-[3-(9H-嘌呤-6-基)吡啶-2-基氨基]-4-氯-2-氟苯基}-3-氟丙烷-1-磺酰胺对甲苯磺酸盐(式II化合物)的制备
向实施例1制得的式I化合物(10.00g，0.021moL)的四氢呋喃(200mL)溶液中，滴加对甲苯磺酸(7.18g，0.042moL)的四氢呋喃溶液(50mL)。加完继续搅拌2小时，得到式II化合物(12.70g，94％)。
实施例3式II化合物结晶的制备
向装有实施例2制得的式II化合物(1.00g)的单口瓶中加入无水乙醇(200mL)，加热回流搅拌2小时。热过滤，滤液热溶后慢慢冷却至室温，继续搅拌过夜。过滤，用乙醇洗涤，40℃真空干燥得到式II化合物结晶(0.65g)。
实施例4式II化合物结晶的制备
向装有实施例2制得的式II化合物(1.00g)的单口瓶中加入甲醇(60mL)，加热回流搅拌2小时。热过滤，滤液热溶后慢慢冷却至室温，继续搅拌过夜。过滤，用甲醇洗涤，40℃真空干燥得到式II化合物结晶(0.52g)。
实施例5稳定性试验(方法参照中国药典2010版二部附录)
将实施例3制备得到的式II化合物结晶进行强光照射试验(4500LX)、高温试验(60℃)和高湿试验(92.5％)。考察时间为10天，分别于第0天、第10天取样检测纯度，试验结果如表1所示。
表1稳定性试验结果
时间 测定项目 HPLC归一化纯度/％
0天   99.92
10天 光照4500LX 99.91
10天 高温60℃ 99.91
10天 高湿92.5％ 99.91
实施例6引湿性试验
对实施例3制备得到的式II化合物结晶进行引湿性试验。试验条件：25℃±1℃，RH80％±2％的恒温恒湿箱中引湿24h以上。
实现步骤如下：
1.玻璃瓶准备
取干燥的具塞玻璃称量瓶(外径为50mm，高为15mm)，于试验前一天置于适宜的25℃±1℃恒温干燥器内，精密称定重量(m1)。
2.供试品
取供试品适量，平铺于上述称量瓶中，供试品厚度一般约为1mm，精密称定重量(m2)。
3.操作
将称量瓶敞口，并与瓶盖同置于上述恒温恒湿条件下24小时，盖好称量瓶盖，精密称定重量(m3)。
计算公式：
Figure PCTCN2017071102-appb-000008
4.结果如下：
表2引湿性试验结果
m1 m2 m3 增重％
50.5435 53.3926 53.3996 0.246

Claims (12)

  1. 式II化合物，
    Figure PCTCN2017071102-appb-100001
  2. 式II化合物结晶，
    Figure PCTCN2017071102-appb-100002
    所述式II化合物结晶使用Cu Kα辐射的X-射线粉末衍射图谱中，衍射角度(2θ±0.2°)约为4.59°、7.99°、8.37°、9.18°、18.52°和20.78°处有衍射峰。
  3. 如权利要求2所述的式II化合物结晶，其使用Cu Kα辐射的X-射线粉末衍射图谱中，衍射角度(2θ±0.2°)约为4.59°、7.99°、8.37°、9.18°、14.75°、16.73°、17.35°、18.52°、18.98°、20.09°、20.78°、21.60°、21.92°、23.11°、25.36°、26.08°、26.62°、27.41°、27.85°和28.32°处有衍射峰。
  4. 如权利要求2所述的式II化合物结晶，其使用Cu Kα辐射的X-射线粉末衍射图谱中，衍射角度(2θ±0.2°)约为4.59°、7.99°、8.37°、9.18°、10.86°、14.75°、16.73°、17.35°、18.52°、18.98°、20.09°、20.78°、21.60°、21.92°、23.11°、24.30°、25.36°、26.08°、26.62°、27.41°、27.85°、28.32°、29.41°、30.19°、30.90°、31.97°、33.47°、34.06°、37.82°、39.38°、40.00°、42.33°和43.93°处有衍射峰。
  5. 如权利要求2所述的式II化合物结晶，其具有基本上如图1所示的X-射线粉末衍射图谱。
  6. 如权利要求2所述的式II化合物的结晶，其差示扫描量热测量图具有约260.5℃的起始温度。
  7. 一种结晶组合物，所述结晶组合物含有权利要求2-6中任一项所述的式II化合物结晶， 其中所述式II化合物结晶占所述结晶组合物重量的50％以上、80％以上、90％以上、95％以上或99％以上。
  8. 一种药物组合物，所述药物组合物包含治疗有效量的权利要求1所述的式II化合物或权利要求2-6中任一项所述的式II化合物结晶或权利要求7所述的结晶组合物，以及一种或多种药学上可接受的载体。
  9. 权利要求1所述的式II化合物或权利要求2-6中任一项所述的式II化合物结晶或权利要求7所述的结晶组合物或权利要求8所述的药物组合物在制备用于治疗蛋白激酶介导的疾病或病症的药物中的用途。
  10. 用于治疗蛋白激酶介导的疾病或病症的权利要求1所述的式II化合物或权利要求2-6中任一项所述的式II化合物结晶或权利要求7所述的结晶组合物或权利要求8所述的药物组合物。
  11. 治疗蛋白激酶介导的疾病或病症的方法，所述方法包括给予需要治疗的患者治疗有效量的权利要求1所述的式II化合物或权利要求2-6中任一项所述的式II化合物结晶或权利要求7所述的结晶组合物或权利要求8所述的药物组合物。
  12. 权利要求2-6中任一项所述的式II化合物结晶的制备方法，包括将式II化合物在C1-4醇类溶剂中进行结晶得到式II化合物结晶。
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