WO2020186588A1 - 2'-氟-4'-取代核苷类似物i的晶型a及其制备方法和应用 - Google Patents

2'-氟-4'-取代核苷类似物i的晶型a及其制备方法和应用 Download PDF

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WO2020186588A1
WO2020186588A1 PCT/CN2019/083217 CN2019083217W WO2020186588A1 WO 2020186588 A1 WO2020186588 A1 WO 2020186588A1 CN 2019083217 W CN2019083217 W CN 2019083217W WO 2020186588 A1 WO2020186588 A1 WO 2020186588A1
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crystal form
compound
fluoro
substituted nucleoside
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常俊标
杜锦发
戈冬旭
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Henan Genuine Biotech Co Ltd
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Henan Genuine Biotech Co Ltd
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Priority to AU2019435643A priority Critical patent/AU2019435643B2/en
Priority to CA3133415A priority patent/CA3133415C/en
Priority to BR112021018204A priority patent/BR112021018204A2/pt
Priority to KR1020217032949A priority patent/KR102546496B1/ko
Priority to EP19920547.7A priority patent/EP3939984B1/en
Priority to JP2022502315A priority patent/JP2022525818A/ja
Publication of WO2020186588A1 publication Critical patent/WO2020186588A1/zh
Priority to US17/475,377 priority patent/US20220002333A1/en
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
    • C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
    • C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
    • C07H19/06—Pyrimidine radicals
    • C07H19/073—Pyrimidine radicals with 2-deoxyribosyl as the saccharide radical
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A61P31/18—Antivirals for RNA viruses for HIV
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/20—Antivirals for DNA viruses
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H1/00—Processes for the preparation of sugar derivatives
    • C07H1/06—Separation; Purification
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
    • C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
    • C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
    • C07H19/06—Pyrimidine radicals
    • 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

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  • the present invention relates to 2'-fluoro-4'-substituted nucleoside analogue I, in particular to its new crystal form, its preparation method and application, and belongs to the field of medicinal chemistry.
  • nucleoside analogs have significant antiviral activity, especially significant anti-AIDS virus (HIV), hepatitis B virus (HBV) and hepatitis C virus (HCV) activity, and are clinically used to treat viral infections.
  • HIV anti-AIDS virus
  • HBV hepatitis B virus
  • HCV hepatitis C virus
  • certain nucleosides also have anticancer activity.
  • these drugs have certain shortcomings. On the one hand, the efficacy is limited, and on the other hand, long-term use has serious side effects and drug resistance. Therefore, the design and synthesis of new nucleoside analogues is still an important research direction for the discovery of new antiviral drugs.
  • nucleoside analogues containing fluorine are an important category (Clark, J. PCT Patent Appl., WO 2005003174; Ismaili, HMAPCT Patent Appl., WO 0160315A22001).
  • the main purpose of the present invention is to provide a new crystal form A of the 2'-fluoro-4'-substituted nucleoside analogue I; another purpose of the present invention is to provide a method for preparing the new crystal form A of this type of compound.
  • Another object of the present invention is to provide the application of compound I crystal form A in the preparation of antiviral drugs, especially the application in the preparation of anti-AIDS drugs.
  • Another object of the present invention is to provide the application of compound I crystal form A in the preparation of anti-tumor drugs, especially in the preparation of drugs for lung cancer, gastric cancer, intestinal cancer or lymphoma, anti-Non-Hodgkin's lymphoma and anti-leukemia drugs Applications.
  • the 2'-fluoro-4'-substituted nucleoside analogue I of the present invention has the following structure:
  • the method of single element, binary element, cooling, dissolution (positive and negative), diffusion and other methods are used to screen the crystal form.
  • the analysis results show that the compound has two crystal forms, namely crystal form A and amorphous crystal form B.
  • the high-temperature, high-humidity and light stability evaluations of crystal form A and crystal form B were carried out.
  • the evaluation results showed that crystal form B can gradually transform into crystal form A within ten days under high humidity and high temperature conditions, and crystal form A is in the same condition. Stable under conditions.
  • These experimental conditions are as follows: high temperature conditions are 60 degrees Celsius for five days and ten days; high humidity conditions are 40 degrees Celsius and 75% humidity for five days and ten days; light conditions are 4500lux for five days and ten days.
  • Compound I was used to remove the solvent with a rotary evaporator in solvents such as methanol, ethanol, isopropanol, ethyl acetate, dichloromethane, etc. to obtain a solid, which was a sheet-shaped amorphous substance B.
  • solvents such as methanol, ethanol, isopropanol, ethyl acetate, dichloromethane, etc.
  • the flaky amorphous B solid has obvious static electricity and is easy to be adsorbed on the container wall.
  • 80-90% of the solid compound I with amorphous B traits is gradually transformed into stable crystal form A crystals.
  • the shape of the compound of crystal form A is a loose solid substance.
  • the design contains an average of 1 mg of compound I and 149 mg of excipients per tablet, with a total weight of 150 mg per tablet.
  • Compound I has a significant inhibitory effect on many types of cancer, and its anti-cancer activity and anti-lymphoma effect have also been verified in animal models.
  • the cancers for which Compound I has a significant inhibitory effect include B-cell non-Hodgkin's lymphoma, lung cancer and leukemia, etc., especially for non-Hodgkin's lymphoma.
  • the beneficial effect of the present invention is that the special structure of the 2'-fluoro-4'-substituted-nucleoside analogue I, such as the fluorine group and azide, makes up for the current D- and L-nucleoside analogues with greater toxic and side effects and higher activity
  • anti-HBV or anti-HCV or anti-HIV virus drugs and anti-tumor drugs especially lymphoma and non-Hodgkin lymphoma drugs, and has good application value. Because its crystal form A has good stability, no electrostatic generation, and is easy to mix with excipients uniformly, it is beneficial to the preparation of pharmaceutical preparations.
  • the compound I crystal form A is mixed with excipients to significantly improve the uniformity in the tablet, which is beneficial to the quality control of the drug, reduces the generation of drug resistance, and thereby ensures the efficacy of the drug. Therefore, the crystal form A of the compound I of the present invention can be used for preparing antiviral drugs, especially for preparing anti-AIDS drugs.
  • the crystalline form A of the compound I of the present invention can also be used to prepare anticancer drugs, especially for the preparation of anti-B-cell non-Hodgkin's lymphoma, lung cancer, leukemia and other cancer drugs.
  • Figure 1 shows the DSC and TGA spectra of the compound I crystal form A of the present invention.
  • Figure 2 is the CuK ⁇ -XRPD pattern of the compound I crystal form A of the present invention.
  • Figure 3 is a comparison of the stability of the compound I crystal form A at high temperature.
  • CuK ⁇ -XRPD pattern: 1 is the CuK ⁇ -XRPD pattern of compound I crystal form A
  • 2 is the compound I crystal of the present invention measured after five days at a high temperature of 60°C
  • 3 is the CuK ⁇ -XRPD pattern of crystal form A of compound I of the present invention measured after 10 days at a high temperature of 60°C.
  • Figure 4 is a comparison of XRPD patterns of the stability of compound I crystal form A of the present invention under high humidity conditions: 1 is the CuK ⁇ -XRPD pattern of compound I crystal form A, and 2 is measured after 10 days at a high temperature of 40°C and 75% humidity The CuK ⁇ -XRPD pattern of the compound I crystal form A of the present invention, 3 is the CuK ⁇ -XRPD pattern of the compound I crystal form A of the present invention measured after five days at a high temperature of 40°C and 75% humidity.
  • Fig. 5 is a comparison XRD pattern of the stability of compound I crystal form A of the present invention under light conditions: 1 is the CuK ⁇ -XRPD pattern of compound I crystal form A, and 2 is the CuK ⁇ of compound I crystal form A of the present invention measured ten days later at 4500lux -XRPD pattern, 3 is the CuK ⁇ -XRPD pattern of the compound I crystal form A of the present invention measured at 4500 lux five days later.
  • Fig. 6 is a comparison of CuK ⁇ -XRPD pattern of compound I crystal form B stability at high temperature: 1 is the CuK ⁇ -XRPD pattern of compound I crystal form B, 2 is the compound I crystal of the present invention measured after 10 days at a high temperature of 60°C The CuK ⁇ -XRPD pattern of Form B, 3 is the CuK ⁇ -XRPD pattern of Form B of Compound I of the present invention measured after five days at a high temperature of 60°C.
  • Fig. 7 is the CuK ⁇ -XRPD pattern of compound I crystal form B under high humidity stability comparison: 1 is the CuK ⁇ -XRPD pattern of compound I crystal form B, 2 is the high temperature 40°C, 75% humidity, measured after ten days The CuK ⁇ -XRPD pattern of the compound I crystal form B of the present invention, 3 is the CuK ⁇ -XRPD pattern of the compound I crystal form B of the present invention measured five days later at a high temperature of 40°C and 75% humidity.
  • Figure 8 is the CuK ⁇ -XRPD pattern of the stability of the compound I crystal form B under light conditions: 1 is the CuK ⁇ -XRPD pattern of the compound I crystal form B, and 2 is the compound I crystal form B of the present invention measured ten days later at 4500lux.
  • the CuK ⁇ -XRPD pattern of 3 is the CuK ⁇ -XRPD pattern of the compound I crystal form B of the present invention measured at 4500 lux five days later.
  • Figure 9 is a picture of the anti-T-cell lymphoma activity of compound I crystal form A in a PDX mouse model.
  • the 2'-fluoro-4'-substituted nucleoside analogue I of the present invention is dissolved in one of the following selected solvents, and the solution concentration is 7-20 mg/mL.
  • the solvent was evaporated with a rotary evaporator to obtain crystal form B.
  • the solvents used in this experiment are: methanol, ethanol, n-propanol, isopropanol, NN-dimethylformamide (DMF), ethyl acetate, isopropyl acetate, n-hexane, cyclohexane, water, ether , Isopropyl ether, methyl tert-butyl ether, 4-methyl-dipentanone, tetrahydrofuran, acetonitrile, dichloromethane, chloroform.
  • DMF dimethylformamide
  • crystal form A Use a soluble solvent to dissolve compound I at 60°C, and slowly drop the anti-solvent into the sample solution along the wall, and cool until solids precipitate out.
  • the crystal form of the obtained crystal is crystal form A.
  • the easily soluble solvent used here is: methanol, DMF or water.
  • the anti-solvent used here is: n-hexane, cyclohexane, isopropyl ether or ethyl acetate
  • the experimental results show that the stable crystal form of compound I is crystal form A, using Cu-K ⁇ radiation.
  • the X-ray powder diffraction (XRPD) of the crystal form at the diffraction angle 2 ⁇ is 8.56, 13.40, 15.76, 16.43, 18.38, 18.95, 19.49, 20.62, 20.86, 21.20, 25.99, 26.85, 27.89, 28.48, 29.78, 30.04, 30.84
  • the stable crystal form of compound I, Form A has characteristic peaks and their relative intensities (%) at the following characteristic peak diffraction angles 2 ⁇ :
  • the crystal form A is a stable crystal form of compound I.
  • the crystal form A has good stability in the stability evaluation.
  • crystal form B is general, and it can be transformed into crystal form A under proper conditions.
  • the crystal form B is transformed into crystal form A after ten days under high humidity and high temperature.
  • the uniformity in the tablet is obviously improved, which is beneficial to the quality control of the drug, reduces the generation of drug resistance, and thereby ensures the efficacy of the drug.
  • the anti-cancer (non-Hodgkin's lymphoma) activity of compound I crystal form A was determined according to the literature method (Asian Pacific Journal of Cancer Prevention 2014, 15, 6829).
  • Example 5 Anticancer effect of compound I crystal form A on B-cell non-Hodgkin's lymphoma, lung cancer, gastric cancer, intestinal cancer and leukemia
  • a human-derived tumor xenograft model (Patient-Derived tumor Xenograft, PDX) was used to determine the inhibitory effect of compound I crystal form A on T-cell lymphoma.
  • T-cell lymphoma tissue After retrieving the patient’s T-cell lymphoma tissue, pass the tissue into the SPF animal room through the delivery window; in the ultra-clean table, prepare PBS buffer with double antibodies, DMEM medium, petri dishes and ice packs, and pour the appropriate amount Put the PBS and DMEM in a petri dish on ice, remove the tissue, put it in PBS for preliminary washing, remove the necrotic and normal tissue, transfer the tissue in PBS to DMEM, and cut the remaining tissue into 20-30mm 3 small tissue Blocks were inoculated on the back of the axilla of the mouse with a puncture needle, each inoculated one site, and the tumors of the inoculated mice were regularly taken out, photographed, and the volume changes were compared (see Figure
  • a human tumor xenograft model was used to determine that compound I crystal form A can significantly inhibit the growth of T-cell lymphoma in the 2mg/kg ⁇ 4mg/kg and 8mg/kg dose groups, respectively.

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Abstract

2'-氟-4'-取代核苷类似物I的晶型A，属药物化学领域，其具有如下结构： (I) 化合物I晶型A的CuKα-XRPD图谱如图2，所述晶型A稳定性良好，容易与辅料混合均匀。晶型A的化合物I与辅料混合，使其在药片内的均匀度提高，有利于药品质量控制和保证药效。用于制备抗HBV或抗HCV或抗HIV病毒药物或抗肿瘤药物。

Description

2’-氟-4’-取代核苷类似物I的晶型A及其制备方法和应用 技术领域
本发明涉及2’-氟-4’-取代核苷类似物I，尤其涉及其新晶型及其制备方法和应用，属药物化学领域。
背景技术
某些核苷类似物具有显著的抗病毒活性，尤其具有显著的抗艾滋病病毒(HIV)、乙肝病毒(HBV)和丙肝病毒(HCV)的活性，在临床上用于治疗病毒感染疾病。除了抗病毒活性，某些核苷还具有抗癌活性。目前这些药物均存在一定的不足，一方面是药效有限，另一方面是长期服用有严重的毒副作用，并且会产生耐药性。因此，新型核苷类似物的设计和合成依然是发现新型抗病毒药物的一个重要研究方向。为了发现更有效的核苷类抗病毒药物，人们对核苷进行了各种各样的修饰，其中含有氟的核苷类似物即为其中重要的一类(Clark，J.PCT Patent Appl.，WO 2005003174；Ismaili，H.M.A.PCT Patent Appl.，WO 0160315A22001)。
发明人前期获得的授权专利CN2007101375480报道了系列“2’-氟-4’-取代核苷类似物”，具有较好的抗病毒活性。众所周知，同一种药物，晶型不同，其溶解度、生物利用度也可能会存在差异，另外其稳定性、流动性、可压缩性也可能会不同，这些理化性质对药物的应用产生一定的影响，从而影响药物的疗效。尤其是2’-氟-4’-取代核苷类似物I的抗HIV的活性非常高，临床上成人用药剂量仅1-3毫克，而发现和使用其性能稳定、容易与辅料混合均匀的晶型，才能有效地保证药片的质量，进而保证临床用药效果。因此，需要研究2’-氟-4’-取代核苷类似物I的晶型，有利于其在药物加工和药物组合物中使用。2’-氟-4’-取代核苷类似物I的晶型目前未见报道。
发明内容
本发明的主要目的在于提供2’-氟-4’-取代核苷类似物I的新晶型A；本发明的另一目的在于提供该类化合物新晶型A的制备方法。本发明的另一个目的是提供化合物I晶型A在制备抗病毒药物中的应用，尤其是在制备抗艾滋病药物中的应用。本发明的另一个目的是提供化合物I晶型A在制备抗肿瘤药物中的应用，尤 其是在制备抗肺癌、胃癌、肠癌或淋巴癌药物、抗非霍奇金淋巴癌和抗白血病药物中的应用。
为实现本发明目的，技术方案如下实现：
本发明2’-氟-4’-取代核苷类似物I，具有如下结构：
Figure PCTCN2019083217-appb-000001
采用一元、二元、降温、溶析(正反)、扩散等方法进行系统的晶型筛选，分析结果显示该化合物存在两种晶型，分别是晶型A和无定型晶型B。分别对晶型A和晶型B进行了高温、高湿和光照稳定性评价，评价结果显示晶型B在高湿度和高温条件下十天内可以逐渐转化为晶型A，晶型A则在同样条件下稳定。这些实验条件如下：高温条件为60摄氏度五天和十天；高湿条件为40摄氏度75％湿度五天和十天；光照条件为4500lux五天和十天。
化合物I在甲醇、乙醇、异丙醇、乙酸乙酯、二氯甲烷等溶剂中用旋转蒸发器除去溶剂得到固体，为片状的无定型B物质。片状无定型B固体具有明显的静电，容易吸附在容器壁上。在40℃/75％湿度保存10天后，80-90％的无定型B性状的固体化合物I逐步转化为稳定的晶型A结晶。晶型A的化合物的性状为松散的固体物质。由于化合物I用于治疗艾滋病的成人每天剂量仅1-3毫克，每片含药量极低，与辅料混合的均匀度对保证药物的抗HIV病毒的作用非常关键。片状的无定型B固体性状的化合物I不容易与辅料混合均匀(见表1)，影响药效的可控性。而化合物I的晶型A较无定型晶型B稳定，与辅料容易混合均匀，有利于药品质量控制和保证药效。
表1.无定型B和晶型A性状的化合物I在药片内的含量分布
Figure PCTCN2019083217-appb-000002
*设计每片平均含1毫克化合物I和149毫克辅料，每片总重量150毫克。
单晶研究结果显示，化合物I的晶型A为单斜晶系，空间群为P2 1。单晶结构如下：
Figure PCTCN2019083217-appb-000003
Table 1.化合物I的单晶A的表征数据.
Figure PCTCN2019083217-appb-000004
在进一步的研究中，本发明人发现化合物I对多类癌症有显著的抑制作用，其抗癌活性和抗淋巴癌的作用在动物模型上也得到了验证。实验证明化合物I对其有显著抑制作用的癌症包括B-细胞非霍奇金淋巴瘤、肺癌和白血病等，尤其对非霍奇金淋巴瘤有显著的抑制作用。
本发明有益效果在于，所述2’-氟-4’-取代-核苷类似物I含氟基团和叠氮等特殊结构弥补目前D-和L-核苷类似物毒副作用大、活性较小的不足，应用于制备抗HBV或抗HCV或抗HIV病毒药物和抗肿瘤药物，尤其是淋巴癌和非霍奇金淋巴癌药物，具有较好的应用价值。由于其晶型A稳定性良好，无静电产生，容易与辅料混合均匀，有利于药物制剂的制备。利用化合物I晶型A与辅料混合，使其在药片内的均匀度明显提高，有利于药品的质量控制、减少耐药性的产生，进而保证药效。因此，本发明化合物I的晶型A可以用于制备抗病毒药，尤其是用于制备抗艾滋病药物。本发明化合物I的晶型A还可以用于制备抗癌药，尤其是用于制备抗B-细胞非霍奇金淋巴癌、肺癌和白血病等癌症药物。
附图说明
图1为本发明化合物I晶型A的DSC和TGA图谱。
图2为本发明化合物I晶型A的CuKα-XRPD图谱。
图3为本发明化合物I晶型A在高温下稳定性对比CuKα-XRPD图谱：1为化合物I晶型A的CuKα-XRPD图谱，2为高温60℃下五天后测得的本发明化合物I晶型A的CuKα-XRPD图谱，3为高温60℃下十天后测得的本发明化合物I晶型A的CuKα-XRPD图谱。
图4为本发明化合物I晶型A在高湿条件下稳定性对比XRPD图谱：1为化合物I晶型A的CuKα-XRPD图谱，2为高温40℃下、75％湿度，十天后测得的本发明化合物I晶型A的CuKα-XRPD图谱，3为高温40℃下、75％湿度，五天后测得的本发明化合物I晶型A的CuKα-XRPD图谱。
图5为本发明化合物I晶型A在光照条件下稳定性对比XRD图谱：1为化合物I晶型A的CuKα-XRPD图谱，2为4500lux十天后测得的本发明化合物I晶型A的CuKα-XRPD图谱，3为4500lux五天后测得的本发明化合物I晶型A的CuKα-XRPD图谱。
图6为本发明化合物I晶型B在高温下稳定性对比CuKα-XRPD图谱：1为化合物I晶型B的CuKα-XRPD图谱，2为高温60℃下十天后测得的本发明化合物I晶型B的 CuKα-XRPD图谱，3为高温60℃下五天后测得的本发明化合物I晶型B的CuKα-XRPD图谱。
图7为本发明化合物I晶型B在高湿下稳定性对比CuKα-XRPD图谱：1为化合物I晶型B的CuKα-XRPD图谱，2为高温40℃下、75％湿度，十天后测得的本发明化合物I晶型B的CuKα-XRPD图谱，3为高温40℃下、75％湿度，五天后测得的本发明化合物I晶型B的CuKα-XRPD图谱。
图8为本发明化合物I晶型B在光照条件下稳定性对比CuKα-XRPD图谱：1为化合物I晶型B的CuKα-XRPD图谱，2为4500lux十天后测得的本发明化合物I晶型B的CuKα-XRPD图谱，3为4500lux五天后测得的本发明化合物I晶型B的CuKα-XRPD图谱。
图9为在PDX小鼠模型中化合物I晶型A的抗T-细胞淋巴癌的活性图片。
具体实施方式
为对本发明进行更好地说明，举实施例如下：
实施例1.制备晶型B
1.1悬浮实验
将本发明2’-氟-4’-取代核苷类似物I溶解于下列所选溶剂之一中，配置溶液浓度7-20mg/mL。用旋转蒸发器蒸去溶剂，得到晶型B。
本实验中所使用溶剂有：甲醇、乙醇、正丙醇、异丙醇、NN-二甲基甲酰胺(DMF)、乙酸乙酯、乙酸异丙酯、正己烷、环己烷、水、乙醚、异丙醚、甲基叔丁基醚、4-甲基-二戊酮、四氢呋喃、乙腈、二氯甲烷、氯仿。
1.2快速蒸发法实验
称取100毫克化合物I，加入过量的甲醇溶液升温溶解，放入50℃真空旋蒸仪中，去除溶剂后得到白色固体为晶型B。
实施例2.制备晶型A
2.1重结晶实验
称取一定量的本发明2’-氟-4’-取代核苷类似物I，用甲醇，或者乙醇，或者正丙醇，或者水加热至回流制备其饱和溶液，冷却结晶得到晶型A。
2.2液面扩散实验
采用易溶溶剂在60℃溶解化合物I，反溶剂缓慢沿壁滴入样品溶液中，冷却 待固体析出。所得结晶的晶型为晶型A。
这里所用的易溶溶剂为：甲醇、DMF或水。
这里所用的反溶剂为：正己烷、环己烷、异丙醚或乙酸乙酯
2.3二元溶剂实验
称取15毫克化合物I于样品瓶中，加入3mL二元混合溶剂，50℃放入200rpm摇床震荡48h，过滤，所得溶液缓慢挥发除去溶剂，所得结晶晶型为晶型A。
实验溶剂：甲醇(正丙醇、乙酸乙酯、正己烷、环己烷、异丙醚、MTBE、丙酮、乙腈、二氯甲烷或甲苯)，DMF(正丙醇、乙酸乙酯、正己烷、环己烷、异丙醚、MTBE、丙酮、乙腈、二氯甲烷或甲苯)，水(正丙醇、乙酸乙酯、正己烷、环己烷、异丙醚、MTBE、丙酮、乙腈、二氯甲烷或甲苯)；上述溶剂配置方法为：甲醇：正丙醇＝1:4(体积比)，DMF：正丙醇＝1:4(体积比)，水：正丙醇＝1:4(体积比)，其他溶剂以此类推。
实验结果表明，化合物I的稳定晶体形式为晶型A，使用Cu-Kα辐射，
Figure PCTCN2019083217-appb-000005
所述晶体形式的X射线粉末衍射(XRPD)在衍射角2θ为8.56、13.40、15.76、16.43、18.38、18.95、19.49、20.62、20.86、21.20、25.99、26.85、27.89、28.48、29.78、30.04、30.84、31.71、31.96、33.95、34.47处有特征峰，其中2θ值误差范围为±0.2(见图2)。
化合物I的稳定晶体形式晶型A在下列特征峰衍射角2θ处具有特征峰及其相对强度(％)：
Figure PCTCN2019083217-appb-000006
Figure PCTCN2019083217-appb-000007
结果：
1、根据DSC和XRD分析结果显示，晶型A为化合物I的稳定晶型。
2、晶型A在稳定性评价中稳定性良好。
3、晶型B稳定性一般，在适当条件下可以转化为晶型A。
4、晶型B在高湿条件下和高温十天后，转化为晶型A。
5、利用化合物I的晶型A与辅料混合，使其在药片内的均匀度明显提高，有利于药品的质量控制、减少耐药性的产生，进而保证药效。
实施例3.化合物I晶型A的抗病毒效果
化合物I晶型A的抗HIV的活性根据文献方法(Eur.J.Med.Chem.2011,46,4178)测定。
实施例4.化合物I晶型A的抑制效果
化合物I晶型A的抗癌(非霍奇金淋巴瘤)活性根据文献方法(Asian Pacific Journal of Cancer Prevention 2014,15,6829)测定。
实施例5.化合物I晶型A对B-细胞非霍奇金淋巴瘤、肺癌、胃癌、肠癌和白血病的抗癌作用
化合物I晶型A对B-细胞非霍奇金淋巴瘤、肺癌、胃癌、肠癌和白血病的抗 癌作用的测试根据文献方法进行(Wang,Q.et al Biochemical Pharmacology 2011,81,848；Asian Pacific Journal of Cancer Prevention 2014,15,6829)。
实施例6.化合物I晶型A在PDX模型抗T细胞淋巴癌的效果
采用人源肿瘤异种移植模型(Patient-Derived tumor Xenograft,PDX)测定化合物I晶型A抑制T细胞淋巴癌的效果。在取回病人T细胞淋巴癌组织后，将组织通过传递窗进入SPF动物房；在超净台内，准备好加了双抗的PBS缓冲液、DMEM培养基、培养皿和冰袋，倒入适量的PBS和DMEM于冰上的培养皿中，取出组织，放入PBS中初步清洗，剔除坏死和正常组织，将PBS中的组织转移至DMEM中，将剩余组织剪成20～30mm 3的组织小块，使用穿刺针接种于小鼠的腋下背部，每只接种一个部位，定期取出接种后的小鼠的肿瘤，拍照，比较其体积的变化(见图9)。
采用人源肿瘤异种移植模型测定化合物I晶型A分别在2mg/kg\4mg/kg和8mg/kg剂量组都能显著抑制T细胞淋巴癌生长。

Claims (8)

  1. 结构如下的2’-氟-4’-取代核苷类似物I的晶型A，其特征在于，其为单斜晶系，空间群为P2 1，单晶结构如下：
    Figure PCTCN2019083217-appb-100001
  2. 如权利要求1所述的2’-氟-4’-取代核苷类似物I的晶型A，其特征在于，其CuKα-XRPD图谱在2θ为8.56、13.40、15.76、16.43、18.38、18.95、19.49、20.62、20.86、21.20、25.99、26.85、27.89、28.48、29.78、30.04、30.84、31.71、31.96、33.95、34.47处有特征峰，其中2θ值误差范围为±0.2。
  3. 如权利要求1或2所述的2’-氟-4’-取代核苷类似物I的晶型A，其特征在于，其CuKα-XRPD图谱如附图2所示。
  4. 如权利要求1-3其中之一所述的2’-氟-4’-取代核苷类似物I的晶型A在药物制备中的应用，其特征在于，作为活性成分，将其用于制备抗病毒药物。
  5. 如权利要求4所述的2’-氟-4’-取代核苷类似物I的晶型A在药物制备中的应用，其特征在于，作为活性成分，将其用于制备治疗艾滋病药物。
  6. 如权利要求1-3其中之一所述的2’-氟-4’-取代核苷类似物I的晶型A在药物制备中的应用，其特征在于，作为活性成分，将其用于制备抗肿瘤药物。
  7. 如权利要求6所述的2’-氟-4’-取代核苷类似物I的晶型A在药物制备中的应用，其特征在于，作为活性成分，将其用于制备治疗肺癌、胃癌、肠癌、白血病或淋巴癌药物。
  8. 如权利要求7所述的2’-氟-4’-取代核苷类似物I的晶型A在药物制备中的应用，其特征在于，作为活性成分，将其用于制备治疗B-细胞非霍奇金淋巴癌药物。
PCT/CN2019/083217 2019-03-15 2019-04-18 2'-氟-4'-取代核苷类似物i的晶型a及其制备方法和应用 Ceased WO2020186588A1 (zh)

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