WO2020113500A1 - 芦卡帕利樟脑磺酸盐的新晶型和制备方法及其用途 - Google Patents

芦卡帕利樟脑磺酸盐的新晶型和制备方法及其用途 Download PDF

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WO2020113500A1
WO2020113500A1 PCT/CN2018/119486 CN2018119486W WO2020113500A1 WO 2020113500 A1 WO2020113500 A1 WO 2020113500A1 CN 2018119486 W CN2018119486 W CN 2018119486W WO 2020113500 A1 WO2020113500 A1 WO 2020113500A1
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camphorsulfonate
cancer
rucapali
crystalline form
solution
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PCT/CN2018/119486
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French (fr)
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孟晓明
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上海诚妙医药科技有限公司
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Priority to CN201880002900.6A priority Critical patent/CN111542527A/zh
Priority to PCT/CN2018/119486 priority patent/WO2020113500A1/zh
Priority to US16/854,935 priority patent/US11352362B2/en
Publication of WO2020113500A1 publication Critical patent/WO2020113500A1/zh

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    • 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
    • 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
    • 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
    • C07D487/06—Peri-condensed systems
    • 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 a new crystal of lucapali camphorsulfonate, its preparation method and use.
  • Ovarian cancer is cancer that originates in women's ovaries and produces abnormal cells that can invade and transfer to other parts. The initial symptoms of ovarian cancer are not obvious. As the disease progresses, many typical symptoms of cancer will appear, including flatulence, abdominal distension, and pelvic pain. Cancer can easily spread to the peritoneum, lymph nodes, lungs, liver and other parts. In 2012, a total of 239,000 women worldwide suffered from ovarian cancer, causing 152,000 deaths. It is the seventh-largest cancer among cancers and the eighth-leading cancer among women. Ovarian cancer is more prevalent in North America and Europe than it is in Africa and Asia.
  • PARP Poly ADP ribose polymerase
  • Rucaparib was originally developed by Pfizer. Clovis Oncology obtained its authorization from Pfizer in 2011 and applied for sale in the United States. It was approved by the US FDA on December 19, 2016. The product name is The drug is the second PARP inhibitor on the market and is approved as a monotherapy for the treatment of patients with advanced ovarian cancer who have received two or more chemotherapy BRCA mutations.
  • rucapali camphorsulfonate 8-fluoro-2-(4-methylaminomethylphenyl)-1,3,4,5-tetrahydro-6H-aza And [5,4,3-cd] indole-6-one (S)-camphorsulfonate, the molecular formula is C 19 H 18 FN 3 O ⁇ C 10 H 16 O 4 S, and its molecular weight is 555.66.
  • the chemical structural formula of Lucapari is shown below:
  • the main purpose of the present invention is to provide a new crystal form of rucapali camphorsulfonate, its preparation method and pharmaceutical use.
  • step (ii) Place the solution obtained in step (i) under an ultrasonic environment, and add an anti-solvent (solvent with low solubility for rucapali camphorsulfonate) to precipitate the compound from the solution.
  • an anti-solvent solvent with low solubility for rucapali camphorsulfonate
  • a pharmaceutical composition containing crystalline form D of rucapali camphorsulfonate as an active ingredient containing crystalline form D of rucapali camphorsulfonate as an active ingredient.
  • the diseases are selected from breast cancer, ovarian cancer, prostate cancer, pancreatic cancer and other hereditary cancers with the same "PARP gene”.
  • the WO2011098971 patent discloses the crystalline forms A, B, and C of rucapali camphorsulfonate.
  • solubility of crystalline forms A, B, and C in low pH conditions, such as pH 1.2 is very low, which affects the reed The dissolution time of Capari camphorsulfonate in gastric juice.
  • patients take a relatively high dose of Rukapali daily.
  • the recommended dose is 600 mg (calculated as Rukapali free base, 300 mg twice a day), and the maximum daily dose is 1200 mg (with Lu (Calcium free base calculation, 600mg twice a day), if calculated according to Rukapali camphorsulfonate will be 1030.9mg and 2061.8mg.
  • Lu Calcium free base calculation, 600mg twice a day
  • the crystalline form D of rucapali camphorsulfonate found in the present invention compared with the existing crystalline forms A, B or C, can unexpectedly increase the solubility of rucapali camphorsulfonate in simulated gastric juice, thereby It can make high-dose lucapari fully absorbed, and the same dose can produce better clinical effect.
  • Fig. 1 is an X-ray powder diffraction pattern of crystalline form D of rucapali camphorsulfonate.
  • the abscissa is the angle 2 ⁇ (°), and the ordinate is the intensity.
  • Fig. 2 is a DSC chart of the crystalline form D of rucapali camphorsulfonate.
  • the abscissa is temperature (°C), and the ordinate is heat flow (w/g).
  • Fig. 3 is a TGA diagram of the crystalline form D of rucapali camphorsulfonate, the abscissa is temperature (°C), and the ordinate is weight percentage (%).
  • Fig. 4 is the X-ray powder diffraction pattern of the stability factor (thermal stability) of the crystal form D influencing factors of the crystalline form D of rucapali camphorsulfonate.
  • Fig. 5 is the X-ray powder diffraction pattern of the stability factor (humidity stability) of the crystal form D influencing factors of the crystalline form D of rucapali camphorsulfonate.
  • the abscissa is the angle 2 ⁇ (°), and the ordinate is the intensity.
  • Fig. 6 is the X-ray powder diffraction pattern of the stability factor (light stability) of the crystal form D influencing factors of the crystalline form D of rucapali camphorsulfonate.
  • a Rigaku Ultrama IV powder diffractometer was used, which was irradiated with Cu-K ⁇ (40kV, 40mA), and was performed at room temperature using a D/tex Ultra detector. Scanning range from 3° to 45° in 2 ⁇ interval, scanning speed is 20°/min
  • Measurement differences related to the results of such X-ray powder diffraction analysis are generated by a variety of factors including: (a) error in sample preparation (eg sample height), (b) instrument error, (c) calibration difference, ( d) Operator errors (including errors that occur when determining the peak position), and (e) the nature of the substance (eg, preferred orientation errors). Calibration errors and sample height errors often cause displacement of all peaks in the same direction. When a flat holder is used, a small difference in sample height will cause a large displacement of the XRPD peak position. Systematic studies have shown that a 1 mm difference in sample height can cause a peak shift of 2 ⁇ up to 1°.
  • displacements can be identified from the X-ray diffraction pattern, and can be eliminated by compensating for the displacements (using system calibration factors for all peak position values) or recalibrating the instrument. As mentioned above, by applying system calibration factors to make peak positions consistent, measurement errors from different instruments can be corrected.
  • Rukaparix camphorsulfonate Salt form D Dissolve 50mg of Rukaparix camphorsulfonate in 1ml of diethyl oxalate, place the solution in a bottle in an ultrasonic water bath, add an anti-solvent acetonitrile under an ultrasonic working environment, and produce a precipitate to obtain Rukaparix camphorsulfonate Salt form D.
  • the X-ray powder diffraction pattern of the crystalline form D of rucapali camphorsulfonate prepared by the present invention is shown in FIG. 1, and the diffraction peaks of the XRPD pattern of crystalline form D are listed in the following table:
  • DSC Differential scanning calorimetry
  • TGA Thermogravimetric
  • the differential scanning calorimetry (DSC) diagram of Form D is shown in Fig. 2, and the melting point (with the initial thermometer) is about 276.6°C.
  • the crystalline form D thermogravimetric (TGA) diagram is shown in Figure 3.
  • the experimental results of influencing factors show that the crystalline form D is stable under the experimental conditions of high temperature, high humidity and light. It shows that crystal form D is a very stable crystal form, which is suitable for drug development.
  • the crystalline form D of rucapali camphorsulfonate can be quickly dissolved at low pH, and the solubility at 20 min is significantly higher than that of the existing crystalline forms A, B and C of lucapali camphorsulfonate.
  • the recommended dose is 600 mg (calculated as Rukapali free base, 300 mg twice daily), and the maximum daily dosage is 1200 mg (as Rukapali free base) Calculated, 600mg twice a day) If calculated according to Rukapali camphorsulfonate, it will be 1030.9mg and 2061.8mg.

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Abstract

本发明公开了芦卡帕利樟脑磺酸盐的新多晶型D及其制备方法和药用用途。与现有晶型相比，新晶型在溶解度、稳定性和制备工艺方面具有明显优势。

Description

芦卡帕利樟脑磺酸盐的新晶型和制备方法及其用途 技术领域
本发明涉及芦卡帕利樟脑磺酸盐的新型晶体及其制备方法和用途。
背景技术
卵巢癌是发源自女性卵巢的癌症，会产生会入侵以及转移到其他部位的异常细胞。卵巢癌初期症状不明显，随病情进展，才会出现许多癌症的典型症状，包括胀气、腹胀、骨盆痛等。癌症较容易扩散到腹膜、淋巴结、肺脏、肝脏等部位。2012年全世界共有23万9千名女性罹患卵巢癌，造成15万2千人死亡。是癌症中罹患人数第七多的癌症，也是造成女性死亡癌症中的第八位。卵巢癌在北美洲及欧洲较盛行，比在非洲及亚洲要常见。
聚腺苷二磷酸核糖聚合酶(PARP)抑制剂是重要的DNA修复酶，它能够识别DNA单链断点启动修复。该靶点药物能抑制PARP的活性，起到增强放疗和DNA损伤类化疗药物的效果，除此之外单独使用也能选择性杀伤DNA修复缺陷的肿瘤细胞。
芦卡帕利(Rucaparib)最初是由辉瑞公司研发，Clovis Oncology于2011年从辉瑞获得其授权并申请在美国上市销售，于2016年12月19日获得美国FDA批准上市，商品名为
Figure PCTCN2018119486-appb-000001
该药是第二 个上市的PARP抑制剂，批准作为单一疗法用于接受过两次及以上化疗的BRCA突变的晚期卵巢癌患者的治疗。
芦卡帕利樟脑磺酸盐化学名为8-氟-2-(4-甲氨基甲基苯基)-1,3,4,5-四氢-6H-氮杂
Figure PCTCN2018119486-appb-000002
并[5,4,3-cd]吲哚-6-酮(S)-樟脑磺酸盐，分子式为C 19H 18FN 3O·C 10H 16O 4S，其分子量为555.66。芦卡帕利的化学结构式如下所示：
Figure PCTCN2018119486-appb-000003
化学原料药要成制剂，必须具备良好的纯度、稳定性、理化性质以及可操作性。而这些性质都与药物的结晶形态相关，不同晶型具有不同的理化性质。药物保存的稳定性和提高药物疗效的目的，需要将药物制成晶体的状态。
药物晶型不同，溶解度和溶出速率不同，从而影响药物的生物利用度，所以可以导致临床药效的差异。
发明内容
本发明的主要目的在于提供芦卡帕利樟脑磺酸盐的新晶型及其制备方法和药用用途。
制备芦卡帕利樟脑磺酸盐晶型D的方法，其特征在于：
(i)将芦卡帕利樟脑磺酸盐溶解于有机溶液中。
(ii)将步骤(i)中得到的溶液置于超声环境下，加入反溶剂(对芦卡帕利樟脑磺酸盐溶解度低的溶剂)，使化合物从溶液中析出。
(iii)固液分离后得到芦卡帕利樟脑磺酸盐晶型D。
医药组合物，其含有芦卡帕利樟脑磺酸盐晶型D作为有效成分。
芦卡帕利樟脑磺酸盐晶型D及其医药组合物的用途：用于治疗癌症。
用于治疗癌症相关疾病，疾病选自：乳腺癌、卵巢癌、前列腺癌以及胰腺癌等拥有相同“PARP基因”的遗传性癌症。
WO2011098971专利中披露了芦卡帕利樟脑磺酸盐晶型A、B、C，但是经研究发现晶型A、B、C在低pH条件下，如pH 1.2，溶解度很低，从而影响了芦卡帕利樟脑磺酸盐在胃液中的溶出时间。而在实际应用中，患者每天要服用芦卡帕利的剂量比较高，推荐剂量为600mg(以芦卡帕利游离碱计算，300mg每日两次)，每日最大加量为1200mg(以芦卡帕利游离碱计算，600mg每日两次)，如果按芦卡帕利樟脑磺酸盐计算将是1030.9mg和2061.8mg。在如此高的剂量下，只有化合物能够迅速溶解才能保证化合物在吸收窗内将药物吸收。对于不能及时溶出的药物，则会无法被机体吸收而浪费并产生不必要的副作用。本发明中发现的芦卡帕利樟脑磺酸盐晶型D，相较于 现有晶型A、B或C，可以意外的提高芦卡帕利樟脑磺酸盐在模拟胃液中的溶解度，从而可以使高剂量芦卡帕利充分吸收，相同剂量而产生更好的临床效果。
附图说明
图1为芦卡帕利樟脑磺酸盐的晶型D的X射线粉末衍射图，横坐标为角度2θ(°)，纵坐标为强度。
图2为芦卡帕利樟脑磺酸盐的晶型D的DSC图，横坐标为温度(℃)，纵坐标为热流(w/g)。
图3为芦卡帕利樟脑磺酸盐的晶型D的TGA图，横坐标为温度(℃)，纵坐标为重量百分比(％)。
图4为芦卡帕利樟脑磺酸盐的晶型D影响因素稳定性样品(热稳定性)的X射线粉末衍射图，横坐标为角度2θ(°)，纵坐标为强度。
图5为芦卡帕利樟脑磺酸盐的晶型D影响因素稳定性样品(湿度稳定性)的X射线粉末衍射图，横坐标为角度2θ(°)，纵坐标为强度。
图6为芦卡帕利樟脑磺酸盐的晶型D影响因素稳定性样品(光照稳定性)的X射线粉末衍射图，横坐标为角度2θ(°)，纵坐标为强度。
具体实施方式
下面结合附图和实施例，对本发明的具体实施方式作进一步详细描述。以下实施例用于说明本发明，但并不用来限制本发明的范围。本专利中X射线粉末衍射，操作和分析步骤如下：
采用Rigaku Ultima IV粉末衍射仪，该仪器采用Cu-Kα照射(40kV，40mA)，于室温下使用D/tex Ultra检测器进行。扫描范围在2θ区间自3°至45°，扫描速度为20°/分钟
由包括以下的多种因素产生与这类X射线粉末衍射分析结果相关的测量差异：(a)样品制备物(例如样品高度)中的误差，(b)仪器误差，(c)校准差异，(d)操作人员误差(包括在测定峰位置时出现的误差)，和(e)物质的性质(例如优选的定向误差)。校准误差和样品高度误差经常导致所有峰在相同方向中的位移。当使用平的支架时，样品高度的小差异将导致XRPD峰位置的大位移。系统研究显示1mm的样品高度差异可以导致高至1°的2θ的峰位移。可以从X射线衍射图鉴定这些位移，并且可以通过针对所述位移进行补偿(将系统校准因子用于所有峰位置值)或再校准仪器消除所述位移。如上所述，通过应用系统校准因子使峰位置一致，可校正来自不同仪器的测量误差。
实施例1
将50mg芦卡帕利樟脑磺酸盐溶解于1ml草酸二乙酯中，将溶液连瓶置于超声水浴中，在超声工作环境下，加入反溶剂乙腈，产生沉淀，得到芦卡帕利樟脑磺酸盐晶型D。
本发明制备的芦卡帕利樟脑磺酸盐的晶型D，其X射线粉末衍射图如图1所示，晶型D的XRPD图的衍射峰列于下表：
Figure PCTCN2018119486-appb-000004
对实施例1中的晶型D做差示扫描量热(DSC)分析，操作和分析步骤如下，采用TAQ2000差示扫描量热仪，采用N 2气氛，升温速度为10℃/min。对实施例1中的晶型D做热重(TGA)分析。采用TAQ500热重分析仪，采用N 2气氛，升温速度为10℃/min。
晶型D差示扫描量热(DSC)图如图2所示，熔点(以初始温度计)约为276.6℃。晶型D热重(TGA)图如图3所示，
实施例2
将50mg芦卡帕利樟脑磺酸盐溶解于1ml乙醇中，将溶液连瓶置于超声水浴中，在超声工作环境下，加入反溶剂乙腈，产生沉淀，得到芦卡帕利樟脑磺酸盐晶型D。所得晶型D的XRPD与图1一致。
实施例3
将50mg芦卡帕利樟脑磺酸盐溶解于1ml草酸二乙酯/乙醇混合溶剂中(体积比6:4)，将溶液连瓶置于超声水浴中，在超声工作环境 下，加入反溶剂乙腈，产生沉淀，得到芦卡帕利樟脑磺酸盐晶型D。所得晶型D的XRPD与图1一致。
实施例4
将50mg芦卡帕利樟脑磺酸盐溶解于1ml草酸二乙酯中，将溶液连瓶置于超声水浴中，在超声工作环境下，加入反溶剂2-丁酮，产生沉淀，得芦卡帕利樟脑磺酸盐晶型D。所得晶型D的XRPD与图1一致。
实施例5
为了评估晶型D的晶型稳定性，对晶型D进行了稳定性影响因素实验，考察晶型D在高温、高湿和光照条件下的稳定性。影响因素稳定性实验条件如下：
Figure PCTCN2018119486-appb-000005
将晶型D置于上述影响因素稳定性条件中，按照时间点取样后用XRPD表征样品的晶型变化情况，结果总结如下：
Figure PCTCN2018119486-appb-000006
影响因素实验结果表明，晶型D在高温、高湿和光照实验条件下稳定。说明晶型D是十分稳定的晶型，适合于药物开发。
实施例6
芦卡帕利樟脑磺酸盐在模拟人工胃液中的溶解度测定。称取芦卡 帕利樟脑磺酸盐的晶型A、晶型B、晶型C和晶型D的粉末各约1mg于2-mL塑料管中，加入1mL的模拟人工胃液(取稀盐酸16.4ml，加水约800ml，与胃蛋白酶10g，摇匀后，加水稀释成1000ml即得)。将混悬液振摇20min后，用针式过滤器过滤，得到澄清溶液。用HPLC方法分析溶液中芦卡帕利的含量。
Figure PCTCN2018119486-appb-000007
从以上结果可知，芦卡帕利樟脑磺酸盐晶型D在低pH条件下可以快速溶解，在20min时的溶解度显著高于现有芦卡帕利樟脑磺酸盐晶型A、B和C。由于患者每天要服用芦卡帕利的剂量比较高，推荐剂量为600mg(以芦卡帕利游离碱计算，300mg每日两次)，每日最大加量为1200mg(以芦卡帕利游离碱计算，600mg每日两次)如果按芦卡帕利樟脑磺酸盐计算将是1030.9mg和2061.8mg。在如此高的剂量下，只有化合物能够大量迅速溶解才能保证化合物在吸收窗内将药物吸收。对于不能及时溶出的药物，则会无法被机体吸收而浪费并产生不必要的副作用。新的芦卡帕利樟脑磺酸盐晶型D在模拟胃液中的溶解度和溶出速度显著高于现有技术的晶型，从而可以使高剂量芦卡帕利充分吸收，相同剂量而产生更好的临床效果。

Claims (5)

  1. 芦卡帕利樟脑磺酸盐晶型D，其特征在于，其X射线粉末衍射图中至少在2θ值为12.0±0.2、25.5±0.2、6.0±0.2、18.1±0.2、22.3±0.2处具有特征峰，优选的，还可以在2θ值为19.3±0.2、16.5±0.2、23.9±0.2、30.5±0.2、20.4±0.2、31.3±0.2处具有特征峰。
  2. 制备权利要求1所述的芦卡帕利樟脑磺酸盐晶型D的方法，其特征在于：
    (i)将芦卡帕利樟脑磺酸盐溶解于有机溶液中，
    (ii)将步骤(i)中得到的溶液置于超声环境下，加入反溶剂(对芦卡帕利樟脑磺酸盐溶解度低的溶剂)，使化合物从溶液中析出，
    (iii)固液分离后得到芦卡帕利樟脑磺酸盐晶型D。
  3. 医药组合物，其含有权利要求1任一所述的晶体作为有效成分。
  4. 如权利要求1任一项所述的芦卡帕利樟脑磺酸盐及其医药组合物的用途：用于治疗癌症。
  5. 如权利要求4所述的用途，用于治疗癌症相关疾病。疾病选自：乳腺癌、卵巢癌、前列腺癌以及胰腺癌等拥有相同“PARP基因”的遗传性癌症。
PCT/CN2018/119486 2018-12-06 2018-12-06 芦卡帕利樟脑磺酸盐的新晶型和制备方法及其用途 WO2020113500A1 (zh)

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