WO2019011316A1 - 一种btk激酶抑制剂的结晶形式及制备方法 - Google Patents

一种btk激酶抑制剂的结晶形式及制备方法 Download PDF

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WO2019011316A1
WO2019011316A1 PCT/CN2018/095573 CN2018095573W WO2019011316A1 WO 2019011316 A1 WO2019011316 A1 WO 2019011316A1 CN 2018095573 W CN2018095573 W CN 2018095573W WO 2019011316 A1 WO2019011316 A1 WO 2019011316A1
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crystal
formula
angle
compound
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武乖利
邱振均
潘廉洁
卢韵
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江苏恒瑞医药股份有限公司
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/50—Pyridazines; Hydrogenated pyridazines
    • 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

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  • the present invention relates to a crystalline form of BTK kinase inhibitor and a process for the preparation thereof, in particular to (R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-(2, Form II crystal of 6-difluorophenoxy)phenyl)-1,6-dihydro-7H-pyrrolo[2,3-d]pyridazin-7-one and preparation method thereof.
  • the compounds of formula (I) prepared according to the methods of the invention are useful in the treatment of B cell malignancies and autoimmune diseases.
  • BTK Bruton tyrosine protein kinase
  • Tec family kinase members also include Tec, Itk, Txk and Bmx. Most of these kinases are mainly expressed in hematopoiesis. cell.
  • BTK is critical for B cell development, differentiation, maturation and signaling. The loss-of-function mutation of BTK causes X-linked agammaglobulin deficiency (XLA) in humans, causing X-related immunodeficiency in mice.
  • XLA X-linked agammaglobulin deficiency
  • BTK plays a key role in B cell proliferation and activation mediated by B cell receptors (BCR).
  • BCR B cell receptors
  • BCR activation BTK translocates to the plasma membrane and phosphorylation of the plasma membrane, followed by initiation of signaling events including activation of phospholipase C ⁇ 2 (PLC ⁇ 2), which ultimately leads to calcium mobilization and transcriptional regulation involving nuclear factor kappa B.
  • PLC ⁇ 2 phospholipase C ⁇ 2
  • CN106939002A discloses an amorphous form and a crystalline form I of the compound of the formula (I), but both the above amorphous form and the crystalline form I have problems of poor stability, and therefore it is necessary to improve various aspects of the above products. Need to find a better crystal form.
  • the crystallization uses Cu-Ka radiation to obtain an X-ray powder diffraction pattern expressed by a diffraction angle 2 ⁇ angle, and the diffraction angle 2 ⁇ angles are 4.64, 5.18, 5.62, 11.13, 11.43, 12.21, 12.87, 14.03, 19.60.
  • the X-ray powder diffraction pattern of the crystal is as shown in FIG. 3, and the diffraction angle 2 ⁇ angle is 4.64 (19.04), 5.18 (17.05), 5.62 (15.71), 8.11 (10.89), 8.99 (9.83), 10.34 (8.55), 11.13 (7.94), 11.43 (7.74), 12.21 (7.24), 12.87 (6.87), 14.03 (6.31), 14.47 (6.12), 14.86 (5.96), 15.63 (5.66), 16.07 (5.51), 16.49 (5.37), 17.78 (4.98), 18.40 (4.82), 19.60 (4.53), 20.47 (4.34), 21.31 (4.17), 24.16 (3.68), 25.13 (3.54), 26.87 (3.32) and 28.50 (3.13) There are characteristic peaks in which the error range of the 2 ⁇ angle of each characteristic peak is ⁇ 0.2.
  • the invention also provides the preparation of (R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-(2,6-difluorophenoxy)phenyl)-1 A method of crystallizing Form II of 6-dihydro-7H-pyrrolo[2,3-d]pyridazin-7-one.
  • the method comprises the following steps:
  • the method of recrystallization is not particularly limited and can be carried out by a usual recrystallization operation method.
  • the compound represented by the starting material (I) can be slowly cooled and crystallized by heating in an organic solvent, and after completion of crystallization, it can be dried by filtration to obtain a desired crystal.
  • the crystals to be filtered are usually subjected to vacuum drying under reduced pressure at a temperature of about 30 to 100 ° C, preferably 40 to 60 ° C, to obtain an effect of removing the recrystallization solvent.
  • the crystal form of the obtained compound of the formula (I) was examined by differential scanning calorimetry (DSC) and X-ray diffraction pattern measurement, and the solvent residue of the obtained crystal was examined.
  • the compound of the formula II type represented by the formula (I) prepared according to the method of the present invention does not contain or contains only a low content of residual solvent, and meets the requirements of the national pharmacopoeia for the residual solvent of the pharmaceutical product, so that the crystal of the present invention can be compared. It is used as a pharmaceutical active ingredient.
  • the type II crystal of the compound of the formula (I) prepared by the present invention has good stability under the conditions of illumination, high temperature and high humidity, and the crystal form stability is good under the conditions of grinding, pressure and heat. It can meet the medicinal requirements of production, transportation and storage.
  • the production process is stable and repeatable and controllable, and can be adapted to industrial production.
  • Figure 1 is an X-ray powder diffraction pattern of an amorphous sample of the compound of formula (I).
  • Figure 2 is a DSC chart of an amorphous sample of the compound of formula (I).
  • Figure 3 is an X-ray powder diffraction pattern of the compound II type crystal represented by the formula (I).
  • Figure 4 is a DSC chart of the compound type II crystal of the formula (I).
  • Fig. 5 is an X-ray powder diffraction pattern of the compound I type crystal represented by the formula (I).
  • Fig. 7 is a DVS diagram of the compound type I crystal of the formula (I).
  • Fig. 8 is a DVS diagram of the compound II type crystal represented by the formula (I).
  • Example 1 The sample of the type II crystalline product obtained in Example 1 and the sample of the type I crystalline product obtained in Example 3 were placed in an open position, and examined under illumination (4,500 Lux), heated (40 ° C, 60 ° C), and high humidity (RH 75%, Stability of the sample under RH90%) conditions.
  • the sample of the type II crystal product obtained in Example 1 and the sample of the type I crystal product obtained in Example 2 were subjected to a DVS test at 25 ° C and different humidity.
  • the results of the study showed that the crystal form of the I crystal form was large, and the RH was 0%. At 80%, the weight gain is 4.18%. Under normal storage conditions (ie 25 ° C, RH 60%), the water absorption is about 3.26%.
  • the II crystal form has the hygroscopicity. When the RH is 0% to 80%, the weight gain is 1.18%. The water absorption under normal storage conditions (ie, 25 ° C, RH 60%) was about 0.93%.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
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Abstract

本发明涉及一种BTK激酶抑制剂的结晶形式及制备方法。具体地，本发明涉及(R)-1-(1-丙烯酰哌啶-3-基)-4-氨基-3-(4-(2,6-二氟苯氧基)苯基)-1,6-二氢-7H-吡咯并[2,3-d]哒嗪-7-酮(式(I)化合物)的II型结晶及制备方法。本发明所得到式(I)化合物的II型结晶具备良好的化学稳定性和晶型稳定性，并且所用结晶溶剂低毒低残留，可更好地用于临床治疗。

Description

一种BTK激酶抑制剂的结晶形式及制备方法 技术领域
本发明涉及一种BTK激酶抑制剂的结晶形式及制备方法，具体地涉及(R)-1-(1-丙烯酰哌啶-3-基)-4-氨基-3-(4-(2,6-二氟苯氧基)苯基)-1,6-二氢-7H-吡咯并[2,3-d]哒嗪-7-酮的II型结晶及制备方法。根据本发明的方法制备获得的式(I)化合物可用于B细胞恶性肿瘤和自身免疫疾病的治疗。
背景技术
Bruton酪氨酸蛋白激酶(BTK)是一个非受体胞质酪氨酸激酶，属于Tec家族激酶，其中Tec家族激酶成员还包括Tec，Itk，Txk和Bmx，这些激酶大多数都主要表达于造血细胞。BTK对于B细胞发育，分化，成熟和信令是至关重要的。BTK的功能丧失性突变在人体中引起X连锁丙球蛋白缺乏血症(XLA)，在小鼠中引起与X相关的免疫缺陷。XLA患者在他们的骨髓中具有正常的前B细胞群，但这些细胞无法成熟并进入循环。因此，这些患者基本上也没有循环的B细胞，并且不能产生抗体。BTK在由B细胞受体(BCR)介导的B细胞增殖和活化中起着关键性的作用。对于BCR活化，BTK易位到质膜，质膜被磷酸化，随后启动信号事件包括激活磷脂酶Cγ2(PLCγ2)，最终导致钙动员和涉及核因子κB的转录调控。因为在BCR信号通路中不可缺少的作用，BTK的激酶活性对于各种B细胞恶性肿瘤的发育和修护是关键性的，包括慢性淋巴细胞白血病(CLL)和一些非霍奇金淋巴瘤的(关键非霍奇金淋巴瘤)的亚型，套细胞淋巴瘤(MCL)，和弥漫性大B细胞淋巴瘤(DLBCL)。此外，B细胞在类风湿关节炎，系统性红斑狼疮，多发性硬化症，以及其他免疫疾病的发病机理中的作用已被临床证实。因此，靶向小分子抑制剂BTK在B细胞恶性肿瘤和自身免疫疾病的治疗过程中有好处。
WO2016/007185涉及一种式(I)化合物，即(R)-1-(1-丙烯酰哌啶-3-基)-4-氨基-3-(4-(2,6-二氟苯氧基)苯基)-1,6-二氢-7H-吡咯并[2,3-d]哒嗪-7-酮，该化合物为新型BTK激酶抑制剂，在激酶选择性， 临床疗效或适应症及安全性等方面均有所改善。但该专利中未对该化合物的结晶形式进行任何研究。
Figure PCTCN2018095573-appb-000001
CN106939002A公开了一种式(I)化合物的无定形物和I晶型，但上述无定形物和I晶型均存在稳定性不佳的问题，因此，改善上述产物的各方面性质是很有必要的，需要找到其更好的晶型。
发明内容
本发明提供了(R)-1-(1-丙烯酰哌啶-3-基)-4-氨基-3-(4-(2,6-二氟苯氧基)苯基)-1,6-二氢-7H-吡咯并[2,3-d]哒嗪-7-酮(如式(I)所示)的II型结晶及制备方法，
Figure PCTCN2018095573-appb-000002
式(I)所示化合物在不同结晶条件下得到的一系列结晶产物，对所得结晶产物进行了X-衍射及DSC检测，发现式(I)所示化合物在常规的结晶条件下，可以得到一种稳定性良好的晶型，我们称其为II型结晶。本申请中的II型结晶的DSC图谱显示在165℃附近有熔融吸 热峰，使用Cu-Ka辐射，得到以2θ角度和晶面间距(d值)表示的X-射线粉末衍射图谱，其衍射角2θ角在4.64、5.18、5.62、11.43、12.21和20.47处有特征峰，其中，每个特征峰2θ角的误差范围为±0.2。
进一步地，所述结晶使用Cu-Ka辐射，得到以衍射角2θ角度表示的X-射线粉末衍射图谱，其衍射角2θ角在4.64、5.18、5.62、11.13、11.43、12.21、12.87、14.03、19.60、20.47和24.16处有特征峰，其中，每个特征峰2θ角的误差范围为±0.2。
进一步地，所述结晶的X-射线粉末衍射图谱如图3所示，其衍射角2θ角在4.64(19.04)，5.18(17.05)，5.62(15.71)，8.11(10.89)，8.99(9.83)，10.34(8.55)，11.13(7.94)，11.43(7.74)，12.21(7.24)，12.87(6.87)，14.03(6.31)，14.47(6.12)，14.86(5.96)，15.63(5.66)，16.07(5.51)，16.49(5.37)，17.78(4.98)，18.40(4.82)，19.60(4.53)，20.47(4.34)，21.31(4.17)，24.16(3.68)，25.13(3.54)，26.87(3.32)和28.50(3.13)处有特征峰，其中，每个特征峰2θ角的误差范围为±0.2。
本发明还提供了制备(R)-1-(1-丙烯酰哌啶-3-基)-4-氨基-3-(4-(2,6-二氟苯氧基)苯基)-1,6-二氢-7H-吡咯并[2,3-d]哒嗪-7-酮的II型结晶的方法。该方法包括如下步骤：
(1)将任意晶型或无定型的式(I)所示化合物溶解于适量的有机溶剂中，或将任意晶型或无定型的式(I)所示化合物在有机溶剂中转晶，冷却、析晶，所述有机溶剂为乙腈。
(2)过滤结晶并洗涤，干燥。
重结晶的方法没有特别限定，可以用通常的重结晶操作方法进行。例如，可以用原料式(I)所示化合物在有机溶剂加热溶解后慢慢冷却析晶，结晶完成后，经过滤干燥，即可得到所需要的结晶。需特别说明的是，所滤取的结晶体通常在减压下，在30～100℃左右，优选在40～60℃加热条件下进行真空干燥，就能达到去除重结晶溶剂的效果。
通过差示扫描热分析(DSC)、X-衍射图谱测定，对得到的式(I)所示化合物结晶体进行了晶型研究，同时对所得结晶的溶剂残留进行了检测。
按照本发明的方法制备的式(I)所示化合物II型结晶不含有或仅含有较低含量的残留溶剂，符合国家药典规定的有关医药产品残留溶剂的限量要求，因而本发明的结晶可以较好地作为医药活性成分使用。
经研究表明，本发明制备的式(I)所示化合物的II型结晶在光照、高温、高湿的条件下稳定性良好，且在研磨、压力和受热等条件下，晶型稳定性良好，能够满足生产运输储存的药用要求，生产工艺稳定可重复可控，能够适应于工业化生产。
附图说明
图1式(I)所示化合物无定型样品的X-射线粉末衍射图谱。
图2式(I)所示化合物无定型样品的DSC图谱。
图3式(I)所示化合物II型结晶的X-射线粉末衍射图谱。
图4式(I)所示化合物II型结晶的DSC图谱。
图5式(I)所示化合物I型结晶的X-射线粉末衍射图谱。
图6式(I)所示化合物I型结晶的DSC图谱。
图7式(I)所示化合物I型结晶的DVS图。
图8式(I)所示化合物II型结晶的DVS图。
具体实施方式
以下将结合实施例更详细地解释本发明，本发明的实施例仅用于说明本发明的技术方案，并非限定本发明的实质和范围。
实验所用的测试仪器
1、DSC谱
仪器型号：Mettler Toledo DSC 1 STAR e System
吹扫气：氮气
升温速率：10.0℃/min
温度范围：40-250℃
2、X-射线衍射谱
仪器型号：Bruker D8 Focus X-射线粉末衍射仪
射线：单色Cu-Kα射线(λ＝1.5406)
扫描方式：θ/2θ，扫描范围：2-40 o
电压：40kV，电流：40mA
实施例1
取5g式(I)所示化合物(按WO2016/007185中公开的方法制备)于100ml单口瓶中，加入50ml乙腈，加热至固体全部溶解，降温析晶，搅拌过夜。次日，抽滤，干燥得固体4.03g，收率为80.6％。该结晶样品的X-射线衍射见图3，其中在约4.64(19.04)，5.18(17.05)，5.62(15.71)，8.11(10.89)，8.99(9.83)，10.34(8.55)，11.13(7.94)，11.43(7.74)，12.21(7.24)，12.87(6.87)，14.03(6.31)，14.47(6.12)，14.86(5.96)，15.63(5.66)，16.07(5.51)，16.49(5.37)，17.78(4.98)，18.40(4.82)，19.60(4.53)，20.47(4.34)，21.31(4.17)，24.16(3.68)，25.13(3.54)，26.87(3.32)和28.50(3.13)处有特征峰。DSC谱图见图4，在165℃附近有熔融吸热峰，将此晶型定义为II晶型。
实施例3
取300mg式(I)所示化合物(按WO2016/007185中公开的方法制备)于25ml单口瓶中，加入2ml乙醇，加热溶解，降温析晶，搅拌过夜。次日，抽滤，干燥得固体241mg，收率为80.3％。该结晶样品的X-射线衍射见图5，其中在约4.29(20.56)，6.58(13.42)，7.58(11.66)，10.07(8.78)，10.72(8.24)，11.68(7.57)，12.49(7.08)，13.74(6.44)，14.12(6.26)，15.86(5.58)和19.98(4.44)处有特征峰。DSC谱图见图6，在141℃附近有熔融吸热峰，将此晶型定义为I晶型。
实施例4
取200mg式(I)所示化合物(按实施例2制备)，加入2ml乙腈，搅拌过夜。次日，抽滤，干燥得固体172mg，收率为86.0％。该结晶样品的X-射线衍射和DSC图谱经研究比对，确定产物为II晶型。
实施例5
将实施例1所得的II型结晶产物样品和实施例3所得的I型结晶产物样品敞口平摊放置，考察在光照(4500Lux)，加热(40℃，60℃)，高湿(RH75％，RH90％)条件下样品的稳定性。考察取样时间为5天和10天，HPLC检测纯度见表1。
表1、式(I)所示化合物I晶型和II晶型样品的稳定性比较
Figure PCTCN2018095573-appb-000003
稳定性考察结果表明式(I)所示化合物I型结晶和II型结晶样品分别在敞口的条件下放置，光照、高温条件下，II型结晶的稳定性好于I型结晶样品，高湿条件下两者相当。
实施例6
将按实施例1方法制得的式(I)所示化合物II型结晶进行研磨、加热及压片处理，研究结果表明晶型稳定，详细的实验数据参见下表2。
表2、式(I)所示化合物II晶型特殊稳定性研究
Figure PCTCN2018095573-appb-000004
实施例7
将实施例1所得的II型结晶产物样品和实施例2所得的I型结晶产物样品在25℃，不同湿度下进行DVS试验，研究结果表明，I晶型引湿性较大，RH为0％～80％时，增重4.18％，在正常储存条件下(即25℃，RH60％)下吸水约3.26％，II晶型有引湿性，RH为0％～80％时，增重1.18％，在正常储存条件下(即25℃，RH60％)下吸水约0.93％，详细的实验数据参见图7、8。

Claims (6)

  1. 式(I)所示化合物的II型结晶，其特征在于：使用Cu-Ka辐射，得到以衍射角2θ角度表示的X-射线粉末衍射图谱，其衍射角2θ角在4.64、5.18、5.62、11.43、12.21和20.47处有特征峰，其中，每个特征峰2θ角的误差范围为±0.2，
    Figure PCTCN2018095573-appb-100001
  2. 根据权利要求1所述的式(I)所示化合物的II型结晶，其特征在于：使用Cu-Ka辐射，得到以衍射角2θ角度表示的X-射线粉末衍射图谱，其衍射角2θ角在4.64、5.18、5.62、11.13、11.43、12.21、12.87、14.03、19.60、20.47和24.16处有特征峰，其中，每个特征峰2θ角的误差范围为±0.2。
  3. 根据权利要求1所述的式(I)所示化合物的II型结晶，其特征在于具有如图3所示的X-射线粉末衍射图谱，其衍射角2θ角在4.64，5.18，5.62，8.11，8.99，10.34，11.13，11.43，12.21，12.87，14.03，14.47，14.86，15.63，16.07，16.49，17.78，18.40，19.60，20.47，21.31，24.16，25.13，26.87和28.50处有特征峰，其中，每个特征峰2θ角的误差范围为±0.2。
  4. 一种制备如权利要求1至3任意一项所述的式(I)所示化合物的II型结晶的方法，所述方法包括下述步骤：
    1)将任意晶型或无定型的式(I)所示化合物溶解于适量的有机溶 剂中，冷却、析晶，或将任意晶型或无定型的式(I)所示化合物在有机溶剂中转晶，所述有机溶剂为乙腈；
    2)过滤结晶并洗涤，干燥。
  5. 一种药物组合物，其含有权利要求1至3任意一项所述的式(I)所示化合物的II型结晶以及药学上可接受的载体。
  6. 权利要求1至3任意一项所述的II型结晶或权利要求5所述的药物组合物在制备治疗B细胞恶性肿瘤和自身免疫疾病的药物中的用途。
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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10960592B2 (en) 2019-05-30 2021-03-30 Coretech System Co., Ltd. Computer-implemented simulation method for injection-molding process

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2016007185A1 (en) * 2014-07-07 2016-01-14 Eternity Bioscience Inc. Aminopyridazinone compounds as protein kinase inhibitors
CN106939002A (zh) * 2016-01-05 2017-07-11 江苏恒瑞医药股份有限公司 一种btk激酶抑制剂的结晶形式及其制备方法

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2016007185A1 (en) * 2014-07-07 2016-01-14 Eternity Bioscience Inc. Aminopyridazinone compounds as protein kinase inhibitors
CN106939002A (zh) * 2016-01-05 2017-07-11 江苏恒瑞医药股份有限公司 一种btk激酶抑制剂的结晶形式及其制备方法

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10960592B2 (en) 2019-05-30 2021-03-30 Coretech System Co., Ltd. Computer-implemented simulation method for injection-molding process

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