CN104755463A - 非晶态形式的喹啉衍生物及其生产方法 - Google Patents

非晶态形式的喹啉衍生物及其生产方法 Download PDF

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CN104755463A
CN104755463A CN201380054667.3A CN201380054667A CN104755463A CN 104755463 A CN104755463 A CN 104755463A CN 201380054667 A CN201380054667 A CN 201380054667A CN 104755463 A CN104755463 A CN 104755463A
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amorphous compound
cancer
cyclopropylaminocarbonyl
chloro
amino
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后藤田正晴
吉田贤史
澁口奈央
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Eisai R&D Management Co Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/48—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/04—Antineoplastic agents specific for metastasis
    • 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

Abstract

本发明提供了一种非晶态形式的4-(3-氯-4-(环丙基氨基羰基)氨基苯氧基)-7-甲氧基-6-喹啉甲酰胺。

Description

非晶态形式的喹啉衍生物及其生产方法
技术领域
本发明涉及一种非晶态形式的4-(3-氯-4-(环丙基氨基羰基)氨基苯氧基)-7-甲氧基-6-喹啉甲酰胺及其生产方法。
背景技术
已知化合物4-(3-氯-4-(环丙基氨基羰基)氨基苯氧基)-7-甲氧基-6-喹啉甲酰胺对血管发生展现优异的抑制效应，并且有效于肿瘤的预防和治疗(专利文献1)。该化合物已经作为游离态的多晶形晶体(专利文献2)，以及结晶或非晶态形式的甲磺酸盐或乙磺酸盐被报道(专利文献3和4)。
引用清单
专利文献
专利文献1：美国专利申请公开号2004/0053908
专利文献2：美国专利申请公开号2007/0117842
专利文献3：美国专利申请公开号2007/0078159
专利文献4：美国专利申请公开号2007/0004773
发明概述
技术问题
本发明目标是提供一种新颖的非晶态形式的4-(3-氯-4-(环丙基氨基羰基)氨基苯氧基)-7-甲氧基-6-喹啉甲酰胺及其生产方法。
问题的解决方案
本发明提供了以下[1]至[11]。
[1]非晶态4-(3-氯-4-(环丙基氨基羰基)氨基苯氧基)-7-甲氧基-6-喹啉甲酰胺。[2]根据[1]所述的非晶态化合物，在X-射线粉末衍射中展现一个不具有特征峰的晕圈图(halo pattern)。
[3]根据[1]或[2]所述的非晶态化合物，于13C固体核磁共振谱中，在158.1ppm、107.4ppm、56.3ppm以及6.8ppm的化学位移处具有峰。
[4]一种用于生产非晶态4-(3-氯-4-(环丙基氨基羰基)氨基苯氧基)-7-甲氧基-6-喹啉甲酰胺的方法，该方法包括一个将4-(3-氯-4-(环丙基氨基羰基)氨基苯氧基)-7-甲氧基-6-喹啉甲酰胺晶体溶解于一种溶剂中的步骤。
[5]根据[4]所述的方法，进一步包括一个冷冻干燥4-(3-氯-4-(环丙基氨基羰基)氨基苯氧基)-7-甲氧基-6-喹啉甲酰胺溶液的步骤。
[6]根据[4]或[5]所述的方法，其中该溶剂选自下组，该组由以下各项组成：水、醇、醚和乙腈、及其组合。
[7]根据[4]或[5]所述的方法，其中该溶剂选自下组，该组由以下各项组成：水、C1-6醇及其组合。
[8]一种药物组合物，包括根据[1]至[3]中任一项所述的非晶态化合物。
[9]一种抗肿瘤剂，包括根据[1]至[3]中任一项所述的非晶态化合物。
[10]根据[9]所述的抗肿瘤剂，其中该肿瘤是甲状腺癌、子宫癌、卵巢癌、肾细胞癌、肺癌、神经胶质瘤、黑色素瘤、肝癌、胃癌、结肠直肠癌、乳腺癌、***癌、脑肿瘤或血液肿瘤。
[11]一种肿瘤转移抑制剂，包括根据[1]至[3]中任一项所述的非晶态化合物。
[12]一种用于预防或***的方法，该方法包括向一位患者给予一个药理学上有效量的根据[1]至[3]中任一项所述的非晶态化合物。
[13]根据[12]所述的方法，其中该肿瘤是甲状腺癌、子宫癌、卵巢癌、肾细胞癌、肺癌、神经胶质瘤、黑色素瘤、肝癌、胃癌、结肠直肠癌、乳腺癌、***癌、脑肿瘤或血液肿瘤。
[14]一种用于抑制肿瘤转移的方法，该方法包括向一位患者给予一个药理学上有效量的根据[1]至[3]中任一项所述的非晶态化合物。
[15]根据[1]至[3]中任一项所述的非晶态化合物，用于在预防或***的方法中使用。
[16]根据[15]所述的非晶态化合物，其中该肿瘤是甲状腺癌、子宫癌、卵巢癌、肾细胞癌、肺癌、神经胶质瘤、黑色素瘤、肝癌、胃癌、结肠直肠癌、乳腺癌、***癌、脑肿瘤或血液肿瘤。
[17]根据[1]至[3]中任一项所述的非晶态化合物，用于在抑制肿瘤转移的方法中使用。
[18]根据[1]至[3]中任一项所述的非晶态化合物用于制造一种抗肿瘤剂的用途。
[19]根据[18]所述的非晶态化合物的用途，其中该肿瘤是甲状腺癌、子宫癌、卵巢癌、肾细胞癌、肺癌、神经胶质瘤、黑色素瘤、肝癌、胃癌、结肠直肠癌、乳腺癌、***癌、脑肿瘤或血液肿瘤。
[20]根据[1]至[3]中任一项所述的非晶态化合物用于制造一种肿瘤转移抑制剂的用途。
本发明的有益效果
本发明的非晶态4-(3-氯-4-(环丙基氨基羰基)氨基苯氧基)-7-甲氧基-6-喹啉甲酰胺具有优异的水溶解度。
附图简要说明
图1是一个图表，显示实例1中获得的非晶态4-(3-氯-4-(环丙基氨基羰基)氨基苯氧基)-7-甲氧基-6-喹啉甲酰胺的X-射线粉末衍射图。
图2是一个图表，显示实例1中获得的非晶态4-(3-氯-4-(环丙基氨基羰基)氨基苯氧基)-7-甲氧基-6-喹啉甲酰胺的13C固体NMR谱。
实施方式说明
本发明的非晶态4-(3-氯-4-(环丙基氨基羰基)氨基苯氧基)-7-甲氧基-6-喹啉甲酰胺(在下文还称作“非晶态化合物A”)可以通过下述通用生产方法、或通过实例1中所述的方法来生产。
[通用生产方法]
通过混合结晶化合物A与一种溶剂并且冷冻干燥该溶液，本发明的非晶态形式的4-(3-氯-4-(环丙基氨基羰基)氨基苯氧基)-7-甲氧基-6-喹啉甲酰胺(在下文还称作“化合物A”)可以被生产为非晶态化合物A。在冷冻干燥之前，还可以将该溶剂的一部分蒸馏掉。
该结晶化合物A可以通过，例如，专利文献1或2中所述的方法获得，并且它可以是任何所希望的晶形或其混合物。
所用的溶剂可以是一种醇，包括C1-6醇，例如甲醇、乙醇、1-丙醇、2-丙醇以及叔丁醇，一种醚，例如四氢呋喃、乙腈、和/或水，其中C1-6醇和水是优选的。这些溶剂可以单独使用，或以共混物形式使用其两种或多种。
溶剂的量不特别受限，但其相对于1g的化合物A，可以是100至500mL，优选150至300mL并且甚至更优选200至250mL。当溶解化合物A时，可以将其适当地加热。用于加热的温度将取决于溶剂的类型而变化，但不特别受限，只要它低于所用溶剂的沸点，并且它可以是在40℃与该溶剂的沸点之间，并且优选在60℃与该溶剂的沸点之间。
对于冷冻干燥所需的时间没有特别限制，并且它可以是6至168小时，优选12至120小时并且更优选24至96小时。
本发明的非晶态化合物在X-射线粉末衍射中展现一个不具有特征峰的晕圈图。换言之，本发明的非晶态化合物在X-射线粉末衍射中不具有清晰可辨的或明确的衍射峰。
本发明的非晶态化合物在13C固体NMR谱中，在158.1ppm、107.4ppm、56.3ppm以及6.8ppm的化学位移处具有峰。
当13C固体NMR谱是在一般测量条件下或在与本说明书中所述的基本上相同的条件下进行测量时，由于通常获得的在13C固体NMR谱中的化学位移(ppm)具有一定程度的误差，应理解本发明不仅涵盖其在13C固体NMR谱中的峰(化学位移)完全匹配的非晶态形式，而且还涵盖具有基本上相等化学位移的峰的非晶态形式，并且具体地，其应该被解释为包含在约±0.5ppm范围内的值。具体地，本发明不仅包括其在13C固体NMR谱中的峰(化学位移)完全匹配的非晶态形式，而且还包括其峰(化学位移)在约±0.5ppm误差内匹配的非晶态形式。
本发明的非晶态化合物具有用作抗肿瘤剂的潜能，该抗肿瘤剂是用于甲状腺癌、子宫癌、卵巢癌、肾细胞癌、肺癌、神经胶质瘤、黑色素瘤、肝癌、胃癌、结肠直肠癌、乳腺癌、***癌、脑肿瘤或血液肿瘤。
当本发明的非晶态化合物作为抗肿瘤剂给予时，可以根据以下各项适当地选择其剂量：症状的严重性，患者的年龄、性别、体重以及敏感性，给予途径，给予时间，给予的时间间隔以及药物配制品的类型。一般地，对于口服给予成人(60kg体重)而言，其应是每天1-600mg，优选5至400mg并且更优选5至200mg。其能以每天1至3个剂量进行给予。
当本发明的非晶态化合物用作一种药剂时，它本身可以用作该药物物质或可以用作一种由已知方法制备的药物物质的配制品，例如，在第15版日本药典(Japanese Pharmacopeia)的制备总则(General Rules for Preparations)中所述的方法。
当配制本发明的非晶态化合物时，它可以是颗粒、细颗粒、片剂、胶囊等。如果必要的话，可以向本发明的非晶态化合物添加药理学上可接受的载体，并且具体地，可以添加赋形剂、粘合剂、崩解剂、滑润剂、抗氧化剂、矫味剂、着色剂、芳香剂等。
赋形剂的实例包括乳糖、蔗糖、葡萄糖、果糖、淀粉、马铃薯淀粉、玉米淀粉、小麦淀粉、稻淀粉、结晶纤维素、微晶纤维素、粉状甘草、甘露醇、赤藓糖醇、麦芽糖醇、山梨糖醇、海藻糖、硅酐、硅酸钙、碳酸氢钠、磷酸钙、无水磷酸钙、硫酸钙等。
粘合剂的实例包括明胶、淀粉、***树胶、黄芪胶、羧甲基纤维素、羟丙基纤维素、羟丙基甲基纤维素、聚乙烯吡咯烷酮、甲基纤维素、部分预胶化淀粉、预胶化淀粉、聚乙烯醇、海藻酸钠、普鲁兰(pullulan)、甘油等。
崩解剂包括玉米淀粉、部分预胶化淀粉、羟丙基淀粉、羧甲纤维素、羧甲纤维素钠、羧甲纤维素钙、羧甲淀粉钠、交联羧甲基纤维素钠、低取代的羟丙基纤维素、交聚维酮等。
润滑剂的实例包括硬脂酸镁、硬脂酸、硬脂酸钙、硬脂酰富马酸钠、滑石、聚乙二醇(macrogol)等。
抗氧化剂的实例包括抗坏血酸钠、L-半胱氨酸、亚硫酸钠、生育酚、大豆卵磷脂等。
矫味剂的实例包括柠檬酸、抗坏血酸、酒石酸、苹果酸、阿斯巴甜、乙酰磺胺酸钾、奇异果甜蛋白、糖精钠、甘草酸二钾、谷氨酸钠、5'-肌苷酸钠、5'-鸟苷酸钠等。
着色剂的实例包括氧化钛、三氧化二铁、黄三氧化二铁、胭脂虫红、洋红、核黄素、食品黄编号5、食品蓝编号2等。
芳香剂的实例包括柠檬油、橘油、薄荷醇、薄荷油、冰片、香草香精等。
实例
现在将通过实例进一步详细地解释本发明，应理解本发明不限于这些实例。
实例1：非晶态4-(3-氯-4-(环丙基氨基羰基)氨基苯氧基)-7-甲氧基-6-喹啉甲酰胺的生产
量出300mg 4-(3-氯-4-(环丙基氨基羰基)氨基苯氧基)-7-甲氧基-6-喹啉甲酰胺的B-型晶体(专利文献2)之后，将其置于200mL-容积的烧杯中并且添加40mL叔丁醇(tBA)。将其在加热板上加热至沸腾，并且添加一个适合量的tBA直到化合物A溶解，并且然后添加10mL水。然后对其进行轻微加热以使得该溶液不发生沸腾，从而制备样品溶液。最终，调节溶剂体积为60mL。将200mL-容积的茄形烧瓶在浸于用干冰冷却的醇中同时进行旋转。将样品溶液滴加到该烧瓶中并冷冻。冷冻总量的样品溶液之后，将烧瓶口用擦拭布擦拭并且进行冷冻干燥。由此产生290mg的非晶态化合物A。
测试实例1：溶解度的评估
通过浆板法(Paddle)测量实例1中获得的非晶态化合物A的溶解浓度。将大约40mg的非晶态化合物A上样到用于洗脱测试的设备中，并且在5、10、20、30、45和60分钟时各自取样500μL溶液。通过HPLC测量该溶液中化合物A的浓度。作为比较对照，使用了4-(3-氯-4-(环丙基氨基羰基)氨基苯氧基)-7-甲氧基-6-喹啉甲酰胺的B-型晶体(参见专利文献2)。
[用于浆板法的条件]
溶剂：100mL的空腹人工肠液(pH 6.5的缓冲液，包含29mM NaH2PO4、100mM KCl、7.5mM卵磷脂、以及30mM牛磺胆酸钠)
温度：37℃。
浆板转速：50rpm
[HPLC条件]
柱：YMC-UltraHT C18(YMC公司(YMC Inc.)产品，内径：2.0mm，柱长：50mm，粒度2μm)
柱温：40℃(使用柱烘箱)
流速：0.42mL/min
流动相：使用溶液A和溶液B以表1中示出的线性梯度进行洗脱。
溶液A H2O:CH3CN:HClO4 *＝990:10:1(V/V/V)
溶液B CH3CN:H2O:HClO4 *＝900:100:1(V/V/V)
(*：70％水性溶液)
注射体积：10μL
检测：紫外吸收比色计(测量波长：252nm)。
自动取样器温度：10℃
[表1]
时间[分钟] 溶液B的浓度[％]
0 10
3.5 100
4 100
[结果]
化合物A在每个取样时间时的浓度示于表2中。在每个取样时间，化合物A的浓度在当非晶态化合物溶解时比在当B-型晶体溶解时高5.3至6.1倍。
[表2]
测试实例2X-射线粉末衍射
根据第15版日本药典(B-370-374)的通用测试方法(General Test Methods)中描述的程序进行非晶态化合物A的X-射线粉末衍射。
[测量条件]
装置：RINT-TTR-III(日本理学公司(Rigaku Corp.)的产品)
X-射线：CuKα射线
计数器：闪烁计数器
管电压：50kV
管电流：300mA
扫描速度：5°/min
扫描轴：2θ/θ
扫描区域：2θ＝5°-35°
发散狭缝：0.5mm
散射狭缝：开
接收狭缝：开
针对非晶态化合物A的X-射线粉末衍射图示于图1中。实例1中获得的非晶态化合物A展现一个不具有特征峰的晕圈图。
测试实例3：13C固体NMR谱的测量
测量了非晶态化合物A的13C固体NMR谱。
[测量条件]
装置：AVANCE400(由布鲁克公司(Bruker Corp.)制造)
测量温度：室温(22℃)
参比材料：甘氨酸(外参：176.03ppm)
测量核：13C(100.6248425MHz)
脉冲重复时间：3秒
脉冲模式：TOSS
针对非晶态化合物A的13C固体NMR谱的示于图2中，并且化学位移示于表3中。
[表3]
*：叔丁醇的峰。

Claims (11)

1.非晶态4-(3-氯-4-(环丙基氨基羰基)氨基苯氧基)-7-甲氧基-6-喹啉甲酰胺。
2.根据权利要求1所述的非晶态化合物，在X-射线粉末衍射中展现一个不具有特征峰的晕圈图。
3.根据权利要求1或2所述的非晶态化合物，于13C固体核磁共振谱中，在158.1ppm、107.4ppm、56.3ppm以及6.8ppm的化学位移处具有峰。
4.一种用于生产非晶态4-(3-氯-4-(环丙基氨基羰基)氨基苯氧基)-7-甲氧基-6-喹啉甲酰胺的方法，该方法包括一个将4-(3-氯-4-(环丙基氨基羰基)氨基苯氧基)-7-甲氧基-6-喹啉甲酰胺晶体溶解于一种溶剂中的步骤。
5.根据权利要求4所述的方法，进一步包括一个冷冻干燥4-(3-氯-4-(环丙基氨基羰基)氨基苯氧基)-7-甲氧基-6-喹啉甲酰胺溶液的步骤。
6.根据权利要求4或5所述的方法，其中该溶剂选自下组，该组由以下各项组成：水、醇、醚和乙腈、及其组合。
7.根据权利要求4或5所述的方法，其中该溶剂选自下组，该组由以下各项组成：水、C1-6醇及其组合。
8.一种药物组合物，包括根据权利要求1至3中任一项所述的非晶态化合物。
9.一种抗肿瘤剂，包括根据权利要求1至3中任一项所述的非晶态化合物。
10.根据权利要求9所述的抗肿瘤剂，其中该肿瘤是甲状腺癌、子宫癌、卵巢癌、肾细胞癌、肺癌、神经胶质瘤、黑色素瘤、肝癌、胃癌、结肠直肠癌、乳腺癌、***癌、脑肿瘤或血液肿瘤。
11.一种肿瘤转移抑制剂，包括根据权利要求1至3中任一项所述的非晶态化合物。
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