CN112142726B - 一种抗肿瘤药物盐酸盐水合物晶型 - Google Patents
一种抗肿瘤药物盐酸盐水合物晶型 Download PDFInfo
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Abstract
本发明提供一种抗肿瘤药物4‑(3‑(4‑(1H‑咪唑并[4,5‑b]吡啶‑5‑基)哌嗪‑1‑羰基)‑4‑氟苄基)呔嗪‑1‑(2H)‑酮盐酸盐二水合物晶型A，通过向游离碱中滴加盐酸并控制反应温度制备得到。本发明制备的晶型A可用于因PARP活性抑制而改善的疾病中的治疗，该晶型具有优异的长期稳定性和低的吸湿性。
Description
技术领域
本发明涉及药物合成领域，具体涉及一种抗肿瘤药物4-(3-(4-(1H-咪唑并[4,5-b]吡啶-5-基)哌嗪-1-羰基)-4-氟苄基)呔嗪-1-(2H)-酮盐酸盐水合物及其晶型、制备方法及应用。
背景技术
聚腺苷二磷酸-核糖基化活性为特征的PARPs(Poly(ADP-ribose)polymerases)，构成了18种细胞核酶核细胞质酶的超家族。这种聚腺苷二磷酸-核糖基化作用可以调节目的蛋白的催化活性和蛋白质间相互作用，并且对许多基本生物过程进行调控，包括DNA修复，细胞死亡，基因组稳定性也与之相关。
PARP-1活性约占总的细胞PARP活性的80％，它和与其最相近的PARP-2共同成为PARP家族中具备修复DNA损伤能力的成员。作为DNA损伤的感应器和信号蛋白，PARP-1可以快速检测并直接结合至DNA损伤位点，之后诱导聚集DNA修复所需的多种蛋白，进而使DNA损伤得以修复。当细胞中的PARP-1缺乏时，PARP-2可以替代PARP-1实现DNA损伤的修复。研究表明，与正常细胞相比，PARPs蛋白在实体瘤中的表达普遍增强。此外，对于DNA修复相关基因缺失(如BRCA-1或BRCA-2)的肿瘤(如乳腺肿瘤和卵巢癌)，表现出对PARP-1抑制剂的极端敏感，这表明PARP抑制剂作为单剂在治疗这种被成为三阴性乳腺癌方面的潜在用途。同时，由于DNA损伤修复机制是肿瘤细胞应对化疗药物和电离辐射治疗产生耐受作用的主要机制，因此PARP-1被认为是探索新的癌症治疗方法的一个有效靶点。
早期开发设计的PARP抑制剂是以作为PARP催化底物的NAD的烟酰胺作为模板，开发其类似物。这些抑制剂作为NAD的竞争性抑制剂，与NAD竞争PARP的催化位点，进而阻止聚(ADP-核糖)链的合成。没有聚(ADP-核糖基化)修饰下的PARP无法从DNA损伤位点解离下来，将导致其他参与修复的蛋白质进入损伤为点，进而不能执行修复过程。因此，在细胞毒性药物或辐射的作用下，PARP抑制剂的存在使DNA受损的肿瘤细胞最终死亡。
此外，作为PARP催化底物而被消耗的NAD，是细胞合成ATP过程中必不可少的因此。在高PARP活性水平下，细胞内的NAD水平会显著下降，进而影响胞内的ATP水平。由于胞内的ATP含量不足，细胞无法实现ATP依赖的程序化死亡过程，只能转向坏死这一特殊凋亡过程。在坏死的过程中，大量的炎症因子会被释放出来，从而对其他器官和组织产生毒性作用。因此，PARP抑制剂也可以用于治疗与这一机制有关的多种疾病，包括神经退行性疾病(如老年痴呆症，亨廷顿舞蹈症，帕金森病)，糖尿病，缺血或缺血再灌注过程中的并发疾病，如心肌梗死和急性肾衰竭，循环系统疾病，如感染性休克，及炎症性疾病，如慢性风湿病等。
在WO2018068715A1公开了4-(3-(4-(1H-咪唑并[4,5-b]吡啶-5-基)哌嗪-1-羰基)-4-氟苄基)呔嗪-1-(2H)-酮，具有如下式I结构的多种药用盐及其制备，
包括盐酸盐、氢溴酸盐、甲磺酸盐、对甲苯磺酸盐、苯磺酸盐、羟乙磺酸盐。更优选为盐酸盐、硫酸盐、磷酸盐、甲磺酸盐、对甲苯磺酸盐、苯磺酸盐、羟乙磺酸盐。最优选为盐酸盐、甲磺酸盐、对甲苯磺酸盐、苯磺酸盐、羟乙磺酸盐。然而现有技术并未报道任何关于式(I)化合物盐酸盐的水合物及其晶型。
发明内容
本发明提供一种4-(3-(4-(1H-咪唑并[4,5-b]吡啶-5-基)哌嗪-1-羰基)-4-氟苄基)呔嗪-1-(2H)-酮盐酸盐水合物；作为本发明的优选方案，4-(3-(4-(1H-咪唑并[4,5-b]吡啶-5-基)哌嗪-1-羰基)-4-氟苄基)呔嗪-1-(2H)-酮盐酸盐水合物为一水合物或二水合物。
本发明再一方面提供4-(3-(4-(1H-咪唑并[4,5-b]吡啶-5-基)哌嗪-1-羰基)-4-氟苄基)呔嗪-1-(2H)-酮盐酸盐水合物晶型A，其X射线粉末衍射在2θ为：8.4±0.2°、8.8±0.2°、12.5±0.2°、19.6±0.2°、24.6±0.2°处有特征峰；进一步的，其X射线粉末衍射在2θ为8.4±0.2°、8.8±0.2°、12.1±0.2°、12.5±0.2°、15.8±0.2°、17.4±0.2°、18.0±0.2°、19.1±0.2°、19.6±0.2°、22.0±0.2°、22.8±0.2°、24.6±0.2°和27.6±0.2°处有特征峰；其特征峰相对强度和d值数据如下：
进一步的，4-(3-(4-(1H-咪唑并[4,5-b]吡啶-5-基)哌嗪-1-羰基)-4-氟苄基)呔嗪-1-(2H)-酮盐酸盐晶型A具有如图2所示的X射线粉末衍射图。所述晶型A为4-(3-(4-(1H-咪唑并[4,5-b]吡啶-5-基)哌嗪-1-羰基)-4-氟苄基)呔嗪-1-(2H)-酮盐酸盐二水合物，具有图5所示的TGA图谱。
本发明另一方面提供一种4-(3-(4-(1H-咪唑并[4,5-b]吡啶-5-基)哌嗪-1-羰基)-4-氟苄基)呔嗪-1-(2H)-酮盐酸盐晶型B，其X射线粉末衍射在2θ为9.3±0.2°、11.7±0.2°、16.6±0.2°、16.9±0.2°、24.8±0.2°、25.2±0.2°处有特征峰；优选地，其X射线粉末衍射在2θ为8.3±0.2°、9.3±0.2°、11.0±0.2°、11.7±0.2°、16.6±0.2°、16.9±0.2°、18.9±0.2°、24.8±0.2°、25.2±0.2°、26.0±0.2°、27.2±0.2°处有特征峰；其特征峰相对强度和d值数据如下：
| 2θ | d(A) | I％ |
| 8.3 | 10.7 | 24.3 |
| 9.3 | 9.5 | 59.3 |
| 11.0 | 8.0 | 37.9 |
| 11.7 | 7.6 | 50.1 |
| 16.6 | 5.3 | 44.7 |
| 16.9 | 5.2 | 63.8 |
| 18.9 | 4.7 | 38.4 |
| 24.8 | 3.6 | 53.2 |
| 25.2 | 3.5 | 100 |
| 26.0 | 3.4 | 20.1 |
| 27.2 | 3.3 | 39.2 |
进一步的，4-(3-(4-(1H-咪唑并[4,5-b]吡啶-5-基)哌嗪-1-羰基)-4-氟苄基)呔嗪-1-(2H)-酮盐酸盐晶型B具有图3所示的X射线粉末衍射图。所述的4-(3-(4-(1H-咪唑并[4,5-b]吡啶-5-基)哌嗪-1-羰基)-4-氟苄基)呔嗪-1-(2H)-酮盐酸盐晶型B为一水合物，KF法测定含水量为3.3％，且含有一分子甲醇，气相色谱测定甲醇含量为2.8％。
本发明另一方面提供一种4-(3-(4-(1H-咪唑并[4,5-b]吡啶-5-基)哌嗪-1-羰基)-4-氟苄基)呔嗪-1-(2H)-酮盐酸盐晶型C，其具有如图4所示的X射线粉末衍射图，在2θ为7.1±0.2°、8.6±0.2°、12.6±0.2°、13.9±0.2°、18.7±0.2°、19.1±0.2°、21.5±0.2°、23.7±0.2°、24.7±0.2°、26.8±0.2°、28.6±0.2°处有特征峰；其特征峰相对强度和d值数据如下：
| 2θ | d(A) | I％ |
| 7.1 | 12.4 | 8.6 |
| 8.6 | 10.2 | 13.5 |
| 12.6 | 7.0 | 28 |
| 13.9 | 6.4 | 52.8 |
| 18.7 | 4.7 | 36.4 |
| 19.1 | 4.6 | 45.5 |
| 21.5 | 4.1 | 25.9 |
| 23.7 | 3.7 | 38.3 |
| 24.7 | 3.6 | 20.5 |
| 26.8 | 3.3 | 100 |
| 28.6 | 3.1 | 25.8 |
本发明再一方面提供一种4-(3-(4-(1H-咪唑并[4,5-b]吡啶-5-基)哌嗪-1-羰基)-4-氟苄基)呔嗪-1(2H)-酮盐酸盐晶型的制备方法，通过以下步骤制备：
(1)将4-(3-(4-(1H-咪唑并[4,5-b]吡啶-5-基)哌嗪-1-羰基)-4-氟苄基)呔嗪-1(2H)-酮悬浮于有机溶剂中；
(2)控制反应温度下，加入一定浓度的盐酸，并在该温度下反应制备。
其中步骤(1)的有机溶剂优选甲醇；步骤(2)的反应温度控制可获得不同晶型。做为本发明的优选方案，当反应温度不高于45℃，优选反应温度不高于40℃时，可制备晶型A；当反应温度不低于40℃，优选反应温度不低于45℃时，可制备晶型B。
进一步的，本发明提供4-(3-(4-(1H-咪唑并[4,5-b]吡啶-5-基)哌嗪-1-羰基)-4-氟苄基)呔嗪-1(2H)-酮盐酸盐晶型A的制备方法，通过以下步骤制备：
(1)将4-(3-(4-(1H-咪唑并[4,5-b]吡啶-5-基)哌嗪-1-羰基)-4-氟苄基)呔嗪-1(2H)-酮悬浮于甲醇；
(2)控制反应温度不高于40℃，加入一定浓度的盐酸，并在不高于40℃下反应制备。
进一步的，本发明提供4-(3-(4-(1H-咪唑并[4,5-b]吡啶-5-基)哌嗪-1-羰基)-4-氟苄基)呔嗪-1(2H)-酮盐酸盐晶型B的制备方法，通过以下步骤制备：
(1)将4-(3-(4-(1H-咪唑并[4,5-b]吡啶-5-基)哌嗪-1-羰基)-4-氟苄基)呔嗪-1(2H)-酮悬浮于甲醇，
(2)控制反应温度不低于40℃，加入一定浓度的盐酸，并在不低于40℃下反应制备。
本发明再一方面提供一种4-(3-(4-(1H-咪唑并[4,5-b]吡啶-5-基)哌嗪-1-羰基)-4-氟苄基)呔嗪-1(2H)-酮盐酸盐晶型C的制备方法，所述方法通过晶型A在高温下干燥制备。所述方法优选在温度高于50℃下干燥制备；所述方法优选在真空条件下干燥。
本发明再一方面提供一种含有4-(3-(4-(1H-咪唑并[4,5-b]吡啶-5-基)哌嗪-1-羰基)-4-氟苄基)呔嗪-1(2H)-酮盐酸盐的口服固体组合物，所述4-(3-(4-(1H-咪唑并[4,5-b]吡啶-5-基)哌嗪-1-羰基)-4-氟苄基)呔嗪-1(2H)-酮盐酸盐为晶型A，或晶型B，或晶型C；所述口服固体组合物任选为片剂、胶囊剂、颗粒剂形式；作为本发明的优选方案，所述口服固体组合物含有4-(3-(4-(1H-咪唑并[4,5-b]吡啶-5-基)哌嗪-1-羰基)-4-氟苄基)呔嗪-1(2H)-酮盐酸盐晶型A。
所述的口服固体组合物可任选含有添加剂，添加剂包括：赋形剂，崩解剂，粘合剂，润滑剂，表面活性剂，调味剂等。赋形剂如乳糖，蔗糖，甘露醇；崩解剂如玉米淀粉，羧甲基纤维素，低取代羟丙基纤维素等；粘合剂包括聚乙二醇，羟丙甲基纤维素；润滑剂包括硬脂酸镁，硬脂酸钙，滑石等；表面活性剂包括十二烷基苯磺酸钠，甘油脂肪酸酯等。
本发明再一方面提供一种含有4-(3-(4-(1H-咪唑并[4,5-b]吡啶-5-基)哌嗪-1-羰基)-4-氟苄基)呔嗪-1(2H)-酮盐酸盐晶型A在制备治疗因PARP活性抑制而改善的疾病药物中的应用，所述疾病为血管疾病、炎性疾病、多发性硬化症、神经退行性疾病或癌症。
附图说明
图1化合物式(I)盐酸盐无定型X射线粉末衍射图。
图2化合物式(I)盐酸盐晶型A的X射线粉末衍射图。
图3化合物式(I)盐酸盐晶型B的X射线粉末衍射图。
图4化合物式(I)盐酸盐晶型C的X射线粉末衍射图。
图5晶型A的TGA图。
具体实施方式
实施例1
在溶有式(I)(3g，6.21mmol)的乙醇(30ml)溶液中滴入盐酸(2.1ml，24.84mmol)，25℃搅拌反应5小时。过滤并干燥，即化合物式(I)盐酸盐(2.5g，HPLC纯度95.5％)，为具有图1所示X射线粉末衍射图的无定型。
实施例2
4-(3-(4-(1H-咪唑并[4,5-b]吡啶-5-基)哌嗪-1-羰基)-4-氟苄基)呔嗪-1(2H)-酮盐酸盐晶型A
将游离碱4-(3-(4-(1H-咪唑并[4,5-b]吡啶-5-基)哌嗪-1-羰基)-4-氟苄基)呔嗪-1(2H)-酮(5g，10.3mmol)悬浮于50ml甲醇中，控温30℃下加入盐酸(3.44ml，20.6mmol)，加完后于30℃反应20小时，过滤，40-50℃干燥10小时得固体5.4g，为4-(3-(4-(1H-咪唑并[4,5-b]吡啶-5-基)哌嗪-1-羰基)-4-氟苄基)呔嗪-1(2H)-酮单盐酸盐二水合物(收率93.9％，KF法测定含水量为7.4％，热重分析显示100℃前减重7.39％，并具有图5的TGA图谱)，为具有图2所示X射线粉末衍射图的晶型A。
实施例3
4-(3-(4-(1H-咪唑并[4,5-b]吡啶-5-基)哌嗪-1-羰基)-4-氟苄基)呔嗪-1(2H)-酮盐酸盐晶型B
将游离碱4-(3-(4-(1H-咪唑并[4,5-b]吡啶-5-基)哌嗪-1-羰基)-4-氟苄基)呔嗪-1(2H)-酮(5g，10.3mmol)悬浮于50ml甲醇中，控温45-50℃下加入盐酸(1.72ml，20.6mmol)，加完后于45-50℃反应20小时，降至室温后过滤，40-50℃干燥10小时得4-(3-(4-(1H-咪唑并[4,5-b]吡啶-5-基)哌嗪-1-羰基)-4-氟苄基)呔嗪-1(2H)-酮盐酸盐晶型B(5.1g，KF法测定含水量为3.3％，气相色谱测定甲醇含量为2.8％)，具有图3所示X射线粉末衍射图。
实施例4
4-(3-(4-(1H-咪唑并[4,5-b]吡啶-5-基)哌嗪-1-羰基)-4-氟苄基)呔嗪-1(2H)-酮盐酸盐晶型C
将4-(3-(4-(1H-咪唑并[4,5-b]吡啶-5-基)哌嗪-1-羰基)-4-氟苄基)呔嗪-1(2H)-酮盐酸盐晶型A(3g)置于真空干燥箱中，控温50-55℃，真空度≤0.08Mpa条件下干燥5小时，得固体2.85g，为晶型C，KF法测定含水量为3.5％。具有图4所示X射线粉末衍射图。
实施例5
依照《中国药典》2015版通则9103的方法测定晶型吸湿性(温度：25±1℃，湿度：80％±2％，时间：24h)，结果见下表
| 晶型A | 晶型B | 晶型C | 无定形 | |
| 增重百分率(％) | 1.35％ | 3.05％ | 4.82％ | 5.53％ |
实施例6
稳定性测定(36月放置条件：30℃/65％RH)
本发明所述的4-(3-(4-(1H-咪唑并[4,5-b]吡啶-5-基)哌嗪-1-羰基)-4-氟苄基)呔嗪-1(2H)-酮盐酸盐晶型A具有更小的吸湿性以及更优异的长期稳定性。
Claims (7)
1.一种4-(3-(4-(1H-咪唑并[4,5-b]吡啶-5-基)哌嗪-1-羰基)-4-氟苄基)呔嗪-1-(2H)-酮盐酸盐晶型A，其特征在于所述晶型X射线粉末衍射2θ在8.4±0.2o、8.8±0.2o、12.1±0.2o、12.5±0.2o、15.8±0.2o、17.4±0.2o、18.0±0.2o、19.1±0.2o、19.6±0.2o、22.0±0.2o、22.8±0.2o、24.6±0.2o和27.6±0.2o处有特征峰。
2.根据权利要求1所述的晶型A，其具有与图2基本相同的X射线粉末衍射图。
3.一种制备权利要求1-2中任一项所述的4-(3-(4-(1H-咪唑并[4,5-b]吡啶-5-基)哌嗪-1-羰基)-4-氟苄基)呔嗪-1-(2H)-酮盐酸盐晶型A的方法，包括以下步骤：
（1）将4-(3-(4-(1H-咪唑并［4,5-b］吡啶-5-基)哌嗪-1-羰基)-4-氟苄基)呔嗪-1(2H)-酮悬浮于甲醇中；
（2）控制反应温度不高于45℃，加入盐酸，并在该温度下反应制备。
4.根据权利要求3所述的制备方法，其中步骤（2）的反应温度不高于40℃。
5.一种药物组合物，其含有权利要求1-2中任一项中所述的4-(3-(4-(1H-咪唑并[4,5-b]吡啶-5-基)哌嗪-1-羰基)-4-氟苄基)呔嗪-1-(2H)-酮盐酸盐晶型A和添加剂。
6.根据权利要求5所述的药物组合物，其为片剂、胶囊剂或颗粒剂。
7.权利要求1-2中任一项所述4-(3-(4-(1H-咪唑并[4,5-b]吡啶-5-基)哌嗪-1-羰基)-4-氟苄基)呔嗪-1-(2H)-酮盐酸盐晶型A在制备治疗因PARP活性抑制而改善的疾病药物中的应用，所述疾病为血管疾病、炎性疾病、多发性硬化症、神经退行性疾病或癌症。
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| CN106146492A (zh) * | 2015-04-17 | 2016-11-23 | 上海汇伦生命科技有限公司 | 杂环并咪唑类化合物、其药物组合物及其制备方法和用途 |
| CN107955001A (zh) * | 2016-10-14 | 2018-04-24 | 上海汇伦生命科技有限公司 | 抗肿瘤杂环并咪唑类化合物的药用盐 |
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| CN106146492A (zh) * | 2015-04-17 | 2016-11-23 | 上海汇伦生命科技有限公司 | 杂环并咪唑类化合物、其药物组合物及其制备方法和用途 |
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