CN103058922B - 用于抗肿瘤药物的芳香脲的晶型及其制备方法 - Google Patents
用于抗肿瘤药物的芳香脲的晶型及其制备方法 Download PDFInfo
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- A—HUMAN NECESSITIES
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- A61P35/00—Antineoplastic agents
- A61P35/04—Antineoplastic agents specific for metastasis
Abstract
本发明涉及用于抗肿瘤药物的芳香脲的晶型及其制备方法。所述晶型为化合物N-（（4-氯-3-三氟甲基）苯基）-N’-（（2-氟-4-（2-氨基甲酰基)-4-吡啶基氧）苯基）脲的晶型A和晶型B。晶型A，其结晶在粉末X射线衍射下在(2θ)9.5°，12.4°，12.9°，14.3°，15.5°，16.4°，18.9°，20.0°，21.4°，22.4°，24.2°，25.3°，25.9°，27.5°，29.3°，30.0°，30.9°，31.4°，38.0°具有特征峰。晶型B，其结晶在粉末X射线衍射下在(2θ)10.0°，11.6°，12.6°，14.2°，16.4°，18.9°，20.3°，21.2°，21.6°，22.6°，23.6°，24.4°，26.6°，27.4°，28.6°，30.3°，31.6°，32.8°，38.4°具有特征峰。
Description
发明领域
本发明涉及N-（（4-氯-3-三氟甲基）苯基）-N’-（（2-氟-4-（2-氨基甲酰基)-4-吡啶基氧）苯基）脲的晶型A和晶型B及其制备方法。
背景技术
血管内皮生长因子(VEGF)是肿瘤血管生成过程中最重要的细胞生长因子，肿瘤血管对VEGF高度敏感，在很多肿瘤细胞中VEGF mRNA浓度显著地高于正常细胞，这些肿瘤包括肺癌(Mattern et al.Br.J Cancer 1996，73，93，1)，甲状腺癌(Viglietto et al.Oncogene 1995，11，1569)，乳腺癌(Brown et al.Human Pathol.1995，26，86)，胃腸癌(Brown et al.Cancer Res.1993，53，4727；Suzuki et al.Cancer Res.1996，56，3004)，肾癌和膀胱癌(Brown et al.Am.J Palhol.1993，143L 1255)，卵巢癌(Olson et al.Cancer Res.1994，54，1255)，宫颈癌(Guidi et al.J Nat’l Cancer30Inst.1995，87，12137)、以及血管肉瘤(Hashimoto et al.Lab.lnvest.1995，73，859)和多种颅内肿瘤(Plate et al.Nature 1992，359，845；Phillips et al.Int.J Oncol.1993，2，913；Berkman et al.J Clin.Invest.，1993，91；153)。所以继贝伐单抗、舒尼替尼、索拉非尼作为血管形成抑制剂成功地应用于临床以来，研发新型血管形成抑制剂(如VEGFR-2及PDGFR-β抑制剂等)作为广谱抗癌药物已成为十分热门的领域，并已取得了新的、前景看好的临床试验结果。
CN201210012485.7已经描述了一种用作VEGFR-2等激酶抑制剂的化合物N-（（4-氯-3-三氟甲基）苯基）-N’-（（2-氟-4-（2-氨基甲酰基)-4-吡啶基氧）苯基）脲，对应于式（I）化合物：
其中还涉及到N-（（4-氯-3-三氟甲基）苯基）-N’-（（2-氟-4-（2-氨基甲酰基)-4-吡啶基氧）苯 基）脲及其制备方法，以及用于制备治疗VEGFR-2等激酶所介导疾病的药物中的用途。
然而，CN201210012485.7仅仅公开了N-（（4-氯-3-三氟甲基）苯基）-N’-（（2-氟-4-（2-氨基甲酰基)-4-吡啶基氧）苯基）脲的无定形物，溶解性不佳，容易吸湿，稳定性较差，在临床上应用受到严重的限制。
发明详述
本发明涉及N-（（4-氯-3-三氟甲基）苯基）-N’-（（2-氟-4-（2-氨基甲酰基)-4-吡啶基氧）苯基）脲的两种热力学稳定的晶型A和晶型B。
作为本发明的晶型A，其结晶在粉末X射线衍射下在(2θ)9.5°，12.4°，12.9°，14.3°，15.5°，16.4°，18.9°，20.0°，21.4°，22.4°，24.2°，25.3°，25.9°，27.5°，29.3°，30.0°，30.9°，31.4°，38.0°具有特征峰。
作为本发明的晶型A，其结晶在粉末X射线衍射下在(2θ)10.0°，11.6°，12.6°，14.2°，16.4°，18.9°，20.3°，21.2°，21.6°，22.6°，23.6°，24.4°，26.6°，27.4°，28.6°，30.3°，31.6°，32.8，38.4°具有特征峰。
N-（（4-氯-3-三氟甲基）苯基）-N’-（（2-氟-4-（2-氨基甲酰基)-4-吡啶基氧）苯基）脲的无定形物按照CN201210012485.7中描述的方法制备。
作为本发明的晶型A的制备方法如下所示：
1、将N-（（4-氯-3-三氟甲基）苯基）-N’-（（2-氟-4-（2-氨基甲酰基)-4-吡啶基氧）苯基）脲的无定形物用DMF溶解，然后加入惰性溶剂，搅拌，析出晶体，经过滤，洗涤，减压干燥可得N-（（4-氯-3-三氟甲基）苯基）-N’-（（2-氟-4-（2-氨基甲酰基)-4-吡啶基氧）苯基）脲的DMF溶剂化物，每分子N-（（4-氯-3-三氟甲基）苯基）-N’-（（2-氟-4-（2-氨基甲酰基)-4-吡啶基氧）苯基）脲含有一分子的DMF。
2、用惰性溶剂将化合物N-（（4-氯-3-三氟甲基）苯基）-N’-（（2-氟-4-（2-氨基甲酰基)-4-吡啶基氧）苯基）脲的DMF溶剂化物悬浮后室温搅拌一天，或升温回流然后自然冷却至室温得白色晶型A。
3、将化合物N-（（4-氯-3-三氟甲基）苯基）-N’-（（2-氟-4-（2-氨基甲酰基)-4-吡啶基氧）苯基）脲的DMF溶剂化物加热至160°C，保持5分钟，然后缓慢降温至室温，得白色晶型A。
上述惰性溶剂为乙酸乙酯、乙腈、丙酮、水或四氢呋喃中的一种或其混合物。
作为本发明的晶型B的制备方法如下所示：
用乙醇水溶液将化合物N-（（4-氯-3-三氟甲基）苯基）-N’-（（2-氟-4-（2-氨基甲酰基)-4- 吡啶基氧）苯基）脲的DMF溶剂化物悬浮后，室温搅拌一天，得白色晶型B。
上述乙醇水溶液中乙醇和水的比例为5:95~95:5（v）。
本发明所涉及的化合物N-（（4-氯-3-三氟甲基）苯基）-N’-（（2-氟-4-（2-氨基甲酰基)-4-吡啶基氧）苯基）脲的晶型A是一种热力学稳定形势，与无定形物和溶剂化物相比，引湿性更弱，溶解性能更好，长期稳定性以及高温高湿下的稳定性均优于无定形物和溶剂化物，晶型B在一定条件下可转化为晶型A。
本发明所涉及的化合物N-（（4-氯-3-三氟甲基）苯基）-N’-（（2-氟-4-（2-氨基甲酰基)-4-吡啶基氧）苯基）脲的晶型A熔点为235.64℃。在80％RH下吸湿增重为0.04％，在95％RH下吸湿增重为0.08％，基本不吸湿。
对本发明所涉及的化合物N-（（4-氯-3-三氟甲基）苯基）-N’-（（2-氟-4-（2-氨基甲酰基)-4-吡啶基氧）苯基）脲的晶型A进行了稳定性测试，将晶型A样品置于玻璃容器中，于40℃/75％RH条件下放置0天，5天，10天，测定样品含量和杂质。结果表明晶型A在40℃/75％RH条件下保存10天，化合物含量没有下降，杂质没有升高，稳定性较好。
本发明所涉及的化合物N-（（4-氯-3-三氟甲基）苯基）-N’-（（2-氟-4-（2-氨基甲酰基)-4-吡啶基氧）苯基）脲的晶型A可以用于制造抑制VEGFR-2等激酶介导疾病的药物的用途。
本发明所涉及的化合物N-（（4-氯-3-三氟甲基）苯基）-N’-（（2-氟-4-（2-氨基甲酰基)-4-吡啶基氧）苯基）脲的晶型A可以用于制造抑制VEGFR-2等激酶介导的癌性细胞生长和转移的药物的用途。
本发明所涉及的化合物N-（（4-氯-3-三氟甲基）苯基）-N’-（（2-氟-4-（2-氨基甲酰基)-4-吡啶基氧）苯基）脲的晶型A还可以在制备治疗癌症疾病药物上的用途。
附图说明
图1为本发明化合物N-（（4-氯-3-三氟甲基）苯基）-N’-（（2-氟-4-（2-氨基甲酰基)-4-吡啶基氧）苯基）脲DMF溶剂化物的X-射线衍射图；
图2为本发明化合物N-（（4-氯-3-三氟甲基）苯基）-N’-（（2-氟-4-（2-氨基甲酰基)-4-吡啶基氧）苯基）脲DMF溶剂化物的TGA图谱；
图3为本发明化合物N-（（4-氯-3-三氟甲基）苯基）-N’-（（2-氟-4-（2-氨基甲酰基)-4-吡啶基氧）苯基）脲晶型A的X-射线衍射图；
图4为本发明化合物N-（（4-氯-3-三氟甲基）苯基）-N’-（（2-氟-4-（2-氨基甲酰基)-4-吡啶基氧）苯基）脲晶型A的热分析图谱；
图5为本发明化合物N-（（4-氯-3-三氟甲基）苯基）-N’-（（2-氟-4-（2-氨基甲酰基)-4-吡啶基氧）苯基）脲晶型A的IR图谱。
图6为本发明化合物N-（（4-氯-3-三氟甲基）苯基）-N’-（（2-氟-4-（2-氨基甲酰基)-4-吡啶基氧）苯基）脲晶型B的X-射线衍射图。
图7为本发明化合物N-（（4-氯-3-三氟甲基）苯基）-N’-（（2-氟-4-（2-氨基甲酰基)-4-吡啶基氧）苯基）脲晶型B的TGA图谱。
图8为本发明化合物N-（（4-氯-3-三氟甲基）苯基）-N’-（（2-氟-4-（2-氨基甲酰基)-4-吡啶基氧）苯基）脲晶型B的DSC图谱。
一般方法：
本发明的化合物N-（（4-氯-3-三氟甲基）苯基）-N’-（（2-氟-4-（2-氨基甲酰基)-4-吡啶基氧）苯基）脲的晶型A是利用本领域普通技术人员已知的方法制备的。
本发明所述化合物的X射线衍射图谱采用日本岛津XRD-6000X射线衍射仪进行谱图采集，主要扫描参数如下：
X射线源：Cu,kα, 1.54056
X射线光管设定：40kV，30mA
发散狭缝：自动
扫描模式：连续
扫描范围(°2θ)：5°-50°
扫描速度°/min：5
本发明所述化合物的热重分析TGA谱图在PerkinElmer公司的热重分析仪上采集，主要扫描参数如下：
扫描范围(°C)：30°C-350°C
扫描速度(°C)/min：20
本发明所述化合物的DSC谱图在PerkinElmer公司的差式扫描量热分析仪上采集，主要扫描参数如下：
扫描范围(°C)：30°C-300°C
扫描速度(°C)/min：20
本发明所述化合物的IR谱图在PerkinElmer公司的RX-I红外光谱仪上采集。
具体实施方式
以下通过具体实施方式进一步解释或说明本发明内容，但实施例不应被理解为对本发明保护范围的限制。
实施例1
化合物N-（（4-氯-3-三氟甲基）苯基）-N’-（（2-氟-4-（2-氨基甲酰基)-4-吡啶基氧）苯基）脲的DMF溶剂化物制备
100mg N-（（4-氯-3-三氟甲基）苯基）-N’-（（2-氟-4-（2-氨基甲酰基)-4-吡啶基氧）苯基）脲于70°C下慢慢溶解在0.2mlDMF中，慢慢加入二氯甲烷5ml至溶清，加热10分钟，冷却至室温，搅拌2h,有白色晶体产生，过滤，用洗涤，减压干燥得N-（（4-氯-3-三氟甲基）苯基）-N’-（（2-氟-4-（2-氨基甲酰基)-4-吡啶基氧）苯基）脲DMF溶剂化物。具有的X-射线衍射谱图有如下特征峰：
实施例2
化合物N-（（4-氯-3-三氟甲基）苯基）-N’-（（2-氟-4-（2-氨基甲酰基)-4-吡啶基氧）苯基）脲的晶型A制备
用2ml乙腈和2ml水将100mg化合物N-（（4-氯-3-三氟甲基）苯基）-N’-（（2-氟-4-（2-氨基甲酰基)-4-吡啶基氧）苯基）脲的DMF溶剂化物悬浮后搅拌，升温至100度回流60min,继续升温至110度保持15分钟，然后自然冷却至室温，过滤，80度真空干燥5小时得白色晶体。具有的X-射线衍射谱图有如下特征峰：
实施例3
化合物N-（（4-氯-3-三氟甲基）苯基）-N’-（（2-氟-4-（2-氨基甲酰基)-4-吡啶基氧）苯基）脲的晶型A制备
将化合物N-（（4-氯-3-三氟甲基）苯基）-N’-（（2-氟-4-（2-氨基甲酰基)-4-吡啶基氧）苯基）脲的DMF溶剂化物100mg加热至160°C，然后缓慢降温至室温，得约90mg白色晶体。
实施例4
化合物N-（（4-氯-3-三氟甲基）苯基）-N’-（（2-氟-4-（2-氨基甲酰基)-4-吡啶基氧）苯基）脲的晶型A制备
用1ml丙酮100mg化合物N-（（4-氯-3-三氟甲基）苯基）-N’-（（2-氟-4-（2-氨基甲酰基)-4-吡啶基氧）苯基）脲的DMF溶剂化物悬浮后室温搅拌一天，过滤，80度真空干燥5小时得白色晶体。
实施例5
化合物N-（（4-氯-3-三氟甲基）苯基）-N’-（（2-氟-4-（2-氨基甲酰基)-4-吡啶基氧）苯基）脲的晶型B制备
用1mL乙醇水溶液（50%）将N-（（4-氯-3-三氟甲基）苯基）-N’-（（2-氟-4-（2-氨基甲酰基)-4-吡啶基氧）苯基）脲的DMF溶剂化物100mg悬浮后，室温搅拌一天，过滤，80度真空干燥5小时得白色晶体。具有的X-射线衍射谱图有如下特征峰：
Claims (6)
1.化合物N-((4-氯-3-三氟甲基)苯基)-N’-((2-氟-4-(2-氨基甲酰基)-4-吡啶基氧)苯基)脲的晶型A，其中所述晶型A具有如下所示的X-射线衍射图谱：
2.权利要求1的化合物N-((4-氯-3-三氟甲基)苯基)-N’-((2-氟-4-(2-氨基甲酰基)-4-吡啶基氧)苯基)脲晶型A的制备方法，所述方法包括：
1)将N-((4-氯-3-三氟甲基)苯基)-N’-((2-氟-4-(2-氨基甲酰基)-4-吡啶基氧)苯基)脲的无定形物用DMF溶解，然后加入惰性溶剂，搅拌，析出晶体，经过滤，洗涤，减压干燥可得N-((4-氯-3-三氟甲基)苯基)-N’-((2-氟-4-(2-氨基甲酰基)-4-吡啶基氧)苯基)脲的DMF溶剂化物；
2)用惰性溶剂将化合物N-((4-氯-3-三氟甲基)苯基)-N’-((2-氟-4-(2-氨基甲酰基)-4-吡啶基氧)苯基)脲的DMF溶剂化物悬浮后室温搅拌一天，或升温回流，然后自然冷却至室温得白色晶型A，或直接将DMF溶剂化物加热至160℃，冷却得到晶型A。
3.权利要求2的制备方法，其中惰性溶剂为乙酸乙酯、乙腈、丙酮、四氢呋喃或水中的一种或其混合物。
4.权利要求1所述的化合物晶型A用于制造抑制VEGFR-2等激酶介导疾病的药物的用途。
5.权利要求1所述的化合物晶型A用于制造抑制VEGFR-2等激酶介导的癌性细胞生长和转移的药物的用途。
6.权利要求1所述的化合物晶型A在制备治疗癌症疾病药物上的用途。
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| PCT/CN2013/082986 WO2014036953A1 (zh) | 2012-09-06 | 2013-09-05 | 用于抗肿瘤药物的芳香脲的晶型及其制备方法 |
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| CN104288147A (zh) * | 2013-07-17 | 2015-01-21 | 湖南有色凯铂生物药业有限公司 | 芳香脲类化合物在制备治疗实体瘤药物中的用途 |
| ITMI20131856A1 (it) * | 2013-11-08 | 2015-05-09 | Gnosis Spa | Processo per la preparazione di differenti forme cristalline del s-acetil glutatione e loro utilizzi in formulazioni farmaceutiche e nutraceutiche |
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| CN102643229A (zh) * | 2012-01-17 | 2012-08-22 | 湖南有色凯铂生物药业有限公司 | N-((4-氯-3-三氟甲基)苯基)-n’-((2-氟-4-(2-氨基甲酰基)-4-吡啶基氧)苯基)脲及其作为抗癌药物的应用 |
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| CN102643229A (zh) * | 2012-01-17 | 2012-08-22 | 湖南有色凯铂生物药业有限公司 | N-((4-氯-3-三氟甲基)苯基)-n’-((2-氟-4-(2-氨基甲酰基)-4-吡啶基氧)苯基)脲及其作为抗癌药物的应用 |
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