WO2016110243A1 - 一种酪氨酸激酶抑制剂的苹果酸盐的结晶形式及其制备方法 - Google Patents

一种酪氨酸激酶抑制剂的苹果酸盐的结晶形式及其制备方法 Download PDF

Info

Publication number
WO2016110243A1
WO2016110243A1 PCT/CN2016/070136 CN2016070136W WO2016110243A1 WO 2016110243 A1 WO2016110243 A1 WO 2016110243A1 CN 2016070136 W CN2016070136 W CN 2016070136W WO 2016110243 A1 WO2016110243 A1 WO 2016110243A1
Authority
WO
WIPO (PCT)
Prior art keywords
formula
crystal
compound
tyrosine kinase
crystalline form
Prior art date
Application number
PCT/CN2016/070136
Other languages
English (en)
French (fr)
Inventor
武乖利
吴兵
边林
Original Assignee
江苏恒瑞医药股份有限公司
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by 江苏恒瑞医药股份有限公司 filed Critical 江苏恒瑞医药股份有限公司
Priority to CN201680000679.1A priority Critical patent/CN106029664A/zh
Publication of WO2016110243A1 publication Critical patent/WO2016110243A1/zh

Links

Images

Classifications

    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

Definitions

  • the present invention relates to a crystalline form of a malate salt of a tyrosine kinase inhibitor, particularly 5-(2-diethylamino-ethyl)-2-(5-fluoro-2-oxo-1,2 Form I crystal of -dihydro-indole-3-ylidene-methyl)-1,5,6,7-tetrahydro-pyrrole[3,2-c]pyridin-4-one L-malate.
  • a crystalline form of a malate salt of a tyrosine kinase inhibitor particularly 5-(2-diethylamino-ethyl)-2-(5-fluoro-2-oxo-1,2 Form I crystal of -dihydro-indole-3-ylidene-methyl)-1,5,6,7-tetrahydro-pyrrole[3,2-c]pyridin-4-one L-malate.
  • EGFR epidermal growth factor receptor
  • TKIs clinical tyrosine kinase inhibitors
  • TKIs can also inhibit the angiogenic factors of tumor cells and inhibit the signaling of EGFR to tumor vascular endothelial cells, and the "cross-talk" between EGFR and vascular endothelial growth factor receptor (VEGFR) signaling pathways.
  • VEGFR vascular endothelial growth factor receptor
  • the crystal structure of the pharmaceutically active ingredient often affects the chemical stability of the drug, and the difference in crystallization conditions and storage conditions may lead to changes in the crystal structure of the compound, sometimes accompanied by other Form of crystal form.
  • amorphous drug products have no regular crystal structure and often have other defects, such as poor product stability, fine crystallization, difficult filtration, easy agglomeration, and poor fluidity. Therefore, it is necessary to improve the various aspects of the above products. We need to study in depth to find new crystal forms with high purity and good chemical stability.
  • the present invention provides 5-(2-diethylamino-ethyl)-2-(5-fluoro-2-oxo-1,2-dihydro-indol-3-ylidene-methyl)-1 , a new crystalline form of 5,6,7-tetrahydro-pyrrole [3,2-c]pyridin-4-one L-malate (as shown in formula (I)).
  • a series of crystalline products obtained by the compound of the formula (I) under different crystallization conditions the obtained crystalline product was subjected to X-ray diffraction and DSC detection, and it was found that the compound represented by the formula (I) can be subjected to the specific crystallization conditions of the present invention.
  • a new crystal form is obtained, which we call type I crystal.
  • the DSC pattern of the type I crystal in the present application shows a melting endothermic peak near 240.64 ° C, and the X-ray powder diffraction pattern is shown in Fig.
  • the invention also provides the preparation of 5-(2-diethylamino-ethyl)-2-(5-fluoro-2-oxo-1,2-dihydro-indol-3-ylidene-methyl)
  • a method of crystallizing Form I of -1,5,6,7-tetrahydro-pyrrole[3,2-c]pyridin-4-one L-malic acid comprises the following steps:
  • the organic solvent is an alcohol, preferably methanol, ethanol or isopropanol.
  • the method of recrystallization is not particularly limited and can be carried out by a usual recrystallization operation method.
  • the compound of the formula (I) can be heated and dissolved in a solvent, and then slowly cooled and crystallized. After the crystallization is completed, 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 type I crystal of the compound of 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 I crystal of the compound of the formula (I) prepared by the present invention has good stability under high temperature and high humidity conditions, and has good crystal form stability under conditions of grinding, pressure and heat, and can satisfy production.
  • the medicinal requirements for transport 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 the compound I form crystal of the formula (I).
  • Figure 2 is a DSC spectrum of the compound type I crystal of the formula (I).
  • the crystallization is about 7.34 (12.02), 10.09 (8.76), 11.06 (7.99), 12.25 (7.22), 13.03 (6.79), 14.69 (6.02), 15.11 (5.86), 15.42 (5.74), 16.00 (5.54), 17.17. (5.16), 17.72 (5.00), 19.86 (4.47), 20.35 (4.36), 21.96 (4.04), 22.77 (3.90), 23.37 (3.80), 25.33 (3.51), 25.96 (3.43), 26.52 (3.36), 28.77 (3.10), characteristic peaks at 30.17 (2.96) and 31.65 (2.83).
  • the DSC spectrum is shown in Figure 2 and is sharp.
  • the compound of the formula (I) was added (1.0 g, 1.84 mmol) to a 250 ml single-mouth bottle, 60 ml of acetonitrile, 60 ml of water was added, dissolved by heating, cooled to room temperature, allowed to stand for crystallization, suction filtered, and dried in vacuo to give a solid. 0.37 g, yield 37.0%.
  • the X-ray diffraction and DSC spectra were compared by study to confirm that the product was crystalline form I.
  • Example 2 The sample of the type I crystalline product obtained in Example 1 was separately placed in an open position, and the stability of the sample under heating (40 ° C, 60 ° C) and high humidity (RH 75%, RH 90%) was examined. The sampling time was 5 days and 10 days, and the purity of HPLC was shown in Table 2.
  • the crystal of the compound type I represented by the formula (I) obtained by the method of Example 1 was subjected to grinding, heating and tableting. The results of the study showed that the crystal form was stable, and the detailed experimental data is shown in Table 3 below.

Landscapes

  • 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)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

可用作酪氨酸激酶抑制剂的5-(2-二乙胺基-乙基)-2-(5-氟-2-氧代-1，2-二氢-吲哚-3-亚基-甲基)-3-甲基-1，5，6，7-四氢-吡咯[3，2-c]吡啶-4-酮L-苹果酸盐(式(I)化合物)的I型结晶及其制备方法。所述方法包括将任意晶型和无定形的式（I）化合物或其成盐原料在优选为醇类的有机溶剂和水的混合溶剂中析晶的步骤。

Description

一种酪氨酸激酶抑制剂的苹果酸盐的结晶形式及其制备方法 技术领域
本发明涉及一种酪氨酸激酶抑制剂的苹果酸盐的结晶形态，特别是5-(2-二乙胺基-乙基)-2-(5-氟-2-氧代-1，2-二氢-吲哚-3-亚基-甲基)-1，5，6，7-四氢-吡咯[3，2-c]吡啶-4-酮L-苹果酸盐的I型结晶。
背景技术
近年来，随着分子生物学技术的进展和从细胞受体与增殖调控的分子水平对肿瘤发病机制认识的进一步深入，针对细胞受体、关键基因和调控分子为靶点的治疗开始进入临床，人们称之为“分子靶向治疗”。这些领域包括具有靶向性的表皮生长因子受体(EGFR)阻滞剂、针对某些特定细胞标志物的单克隆抗体、针对某些癌基因和癌的细胞遗传学标志的药物、抗肿瘤血管生成的药物、抗肿瘤疫苗和基因治疗等。
首先进入临床的酪氨酸激酶抑制剂(TKIs)的抗肿瘤作用机制可能通过以下途径实现：抑制肿瘤细胞的损伤修复、使细胞分裂阻滞在G1期、诱导和维持细胞凋亡、抗新生血管形成等。EGFR过度表达常预示病人预后差、转移快、对化疗药物抗拒、激素耐药、生存期较短等。TKIs还可通过下调肿瘤细胞的血管生成因子以及抑制EGFR对肿瘤血管内皮细胞的信号传导，EGFR和血管内皮生长因子受体(VEGFR)两种信号传导通路的“交叉对话”，为临床同时抑制这两种传导通路提供了合理的依据。临床试验结果显示，多靶点抑制剂在治疗方面优于单靶点抑制剂，多靶点联合阻断信号传导是肿瘤治疗和药物开发新的发展方向。
到目前为止，美国FDA批准3种多靶点TKIs上市，如：索拉非尼(sorafenib)、凡德他尼(vandetanib)和Sunitinib(Sutent，SU-11248)，其中Sunitinib于2006年1月份批准上市，治疗GIST和晚期肾癌。由于目前临床上除了伊马替尼外，没有治疗晚期GIST的药物，治疗肾癌的药物也很少，所以Sunitinib的结果令人鼓舞。WO2007085188公开了一种与Sunitinib类似的化合物，如下式(I)所示，其可能更好地应 用于上述肿瘤的治疗。
Figure PCTCN2016070136-appb-000001
本领域技术人员知道，药用的活性成分的晶型结构往往影响到该药物的化学稳定性，结晶条件及储存条件的不同有可能导致化合物的晶型结构的变化，有时还会伴随着产生其他形态的晶型。一般来说，无定型的药物产品没有规则的晶型结构，往往具有其它缺陷，比如产物稳定性较差，析晶较细，过滤较难，易结块，流动性差等。因此，改善上述产物的各方面性质是很有必要的，我们需要深入研究找到晶型纯度较高并且具备良好化学稳定的新晶型。
发明内容
本发明提供了5-(2-二乙胺基-乙基)-2-(5-氟-2-氧代-1，2-二氢-吲哚-3-亚基-甲基)-1，5，6，7-四氢-吡咯[3，2-c]吡啶-4-酮L-苹果酸盐(如式(I)所示)的新的结晶形式。
Figure PCTCN2016070136-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)所示化合物在本发明特定的结晶条件下，可以得到一种新晶型，我们称其为I型结晶。本申请中的I型结晶的DSC图谱显示在240.64℃附近有熔融吸热峰，X-射线粉末衍射图谱如图1所示，使用Cu-Ka辐射，以2θ角度和晶面间距(d值)表示的X-射线粉末衍射图谱，其中在7.34(12.02)，10.09 (8.76)，11.06(7.99)，12.25(7.22)，13.03(6.79)，14.69(6.02)，15.11(5.86)，15.42(5.74)，16.00(5.54)，17.17(5.16)，17.72(5.00)，19.86(4.47)，20.35(4.36)，21.96(4.04)，22.77(3.90)，23.37(3.80)，25.33(3.51)，25.96(3.43)，26.52(3.36)，28.77(3.10)，30.17(2.96)和31.65(2.83)有特征峰。
本发明还提供了制备5-(2-二乙胺基-乙基)-2-(5-氟-2-氧代-1，2-二氢-吲哚-3-亚基-甲基)-1，5，6，7-四氢-吡咯[3，2-c]吡啶-4-酮L-苹果酸的I型结晶的方法。该方法包括如下步骤：
(1)将L-苹果酸和5-(2-二乙胺基-乙基)-2-(5-氟-2-氧代-1，2-二氢-吲哚-3-亚基-甲基)-1，5，6，7-四氢-吡咯[3，2-c]吡啶-4-酮，或者将任意晶型或无定型的式(I)所示化合物溶解于有机溶剂和水的混合溶剂中析晶，所述有机溶剂选自碳原子数小于等于3的醇类、酮类、腈类、醚类或四氢呋喃中的一种或几种；
(2)过滤结晶并洗涤，干燥。
在本发明优选的实施方案中，步骤(1)中，有机溶剂为醇类，优选甲醇、乙醇、异丙醇。
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)所示化合物在溶剂中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40～60℃的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I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I型结晶在高温、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I型结晶的X-射线粉末衍射图谱。
图2式(I)所示化合物I型结晶的DSC谱图。
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 1StareeSystem
吹扫气：氮气
升温速率：10.0℃/min
温度范围：40-300℃
2、X-射线衍射谱
仪器型号：Bruker D8Focus 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°
电压：40KV，电流：40mA
实施例1
取(1.0g，1.84mmol)式(I)所示化合物(按WO2007085188中公开方法制备)加入到250ml单口瓶中，加入50ml乙醇，50ml水，加热溶解，再冷却至室温，静置析晶，抽滤，真空干燥，得到固体0.64g，收率64.0％。该结晶样品的X-射线衍射谱图见图1，该X-射线衍射谱图的峰值列表如表1。该结晶在约7.34(12.02)，10.09(8.76)，11.06(7.99)，12.25(7.22)，13.03(6.79)，14.69(6.02)，15.11(5.86)，15.42(5.74)，16.00(5.54)，17.17(5.16)，17.72(5.00)，19.86(4.47)，20.35(4.36)，21.96(4.04)，22.77(3.90)，23.37(3.80)，25.33(3.51)，25.96(3.43)，26.52(3.36)，28.77(3.10)，30.17(2.96)和31.65(2.83)处有特征峰。DSC谱图见图2，有尖锐。
表1、X-射线衍射谱图的峰值列表
Figure PCTCN2016070136-appb-000003
实施例2
取(1.0g，1.84mmol)式(I)所示化合物加入到250ml单口瓶中，加入74ml乙醇，37ml水，加热溶解，再冷却至室温，静置析晶，抽滤，真空干燥，得到固体0.33g，收率33.0％。其X-衍射和DSC图谱经研究比对，确定产物为I晶型。
实施例3
取(1.0g，1.84mmol)式(I)所示化合物加入到250ml单口瓶中，加入50ml甲醇，50ml水，加热溶解，再冷却至室温，静置析晶，抽滤，真空干燥，得到固体0.42g，收率42.0％。其X-衍射和DSC图谱经研究比对，确定产物为I晶型。
实施例4
取(1.0g，1.84mmol)式(I)所示化合物加入到250ml单口瓶中，加入60ml异丙醇，60ml水，加热溶解，再冷却至室温，静置析晶，抽滤，真空干燥，得到固体0.31g，收率31.0％。其X-衍射和DSC图谱经研究比对，确定产物为I晶型。
实施例5
取(1.0g，1.84mmol)式(I)所示化合物加入到250ml单口瓶中，加入50ml丙酮，50ml水，加热溶解，再冷却至室温，静置析晶，抽滤，真空干燥，得到固体0.35g，收率35.0％。其X-衍射和DSC图谱经研究比对，确定产物为I晶型。
实施例6
取(1.0g，1.84mmol)式(I)所示化合物加入到250ml单口瓶中，加入60ml乙腈，60ml水，加热溶解，再冷却至室温，静置析晶，抽滤，真空干燥，得到固体0.37g，收率37.0％。其X-衍射和DSC图谱经研究比对，确定产物为I晶型。
实施例7
取(1.0g，1.84mmol)式(I)所示化合物加入到250ml单口瓶中，加入50ml四氢呋喃，50ml水，加热溶解，再冷却至室温，静置析晶，抽滤，真空干燥，得到固体0.34g，收率34.0％。其X-衍射和DSC图谱经研究比对，确定产物为I晶型。
实施例8
将实施例1所得的I型结晶产物样品分别敞口平摊放置，考察在加热(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2。
表2、式(I)所示化合物I型结晶样品的稳定性
Figure PCTCN2016070136-appb-000004
稳定性考察结果表明，式(I)所示化合物I型结晶样品在敞口放置的条件下，经高温和高湿条件下的稳定性比较发现，高湿、高温对产品的质量影响不大，说明其具有较好的稳定性。
实施例9
将按实施例1方法制得的式(I)所示化合物I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3。
表3.式(I)所示化合物I晶型特殊稳定性研究
Figure PCTCN2016070136-appb-000005

Claims (5)

  1. 如式(I)所示化合物的I型结晶，其特征在于：使用Cu-Ka辐射，得到以2θ角度和晶面间距表示的X-射线粉末衍射图谱，所述结晶具有如图1所示的X-射线粉末衍射图谱，其中在约7.34(12.02)，10.09(8.76)，11.06(7.99)，12.25(7.22)，13.03(6.79)，14.69(6.02)，15.11(5.86)，15.42(5.74)，16.00(5.54)，17.17(5.16)，17.72(5.00)，19.86(4.47)，20.35(4.36)，21.96(4.04)，22.77(3.90)，23.37(3.80)，25.33(3.51)，25.96(3.43)，26.52(3.36)，28.77(3.10)，30.17(2.96)和31.65(2.83)有特征峰，
    Figure PCTCN2016070136-appb-100001
  2. 一种制备如权利要求1所述的如式(I)所示化合物的I型结晶的方法，所述方法包括下述步骤：
    1)将L-苹果酸和5-(2-二乙胺基-乙基)-2-(5-氟-2-氧代-1，2-二氢-吲哚-3-亚基-甲基)-1，5，6，7-四氢-吡咯[3，2-c]吡啶-4-酮，或者将任意晶型或无定型的式(I)所示化合物在有机溶剂和水的混合溶剂中析晶，所述有机溶剂选自碳原子数小于等于3的醇类、酮类、腈类、醚类或四氢呋喃中的一种或几种；
    2)过滤结晶并洗涤，干燥。
  3. 根据权利要求2所述的方法，其特征在于在步骤1)中所述的有机溶剂优选为醇类，进一步优选甲醇、乙醇、异丙醇。
  4. 一种药物组合物，其含有如权利要求1所述的如式(I)所示化合物的I型结晶以及药学上可接受的载体。
  5. 根据权利要求1所述的如式(I)所示化合物的I型结晶或权利要求4所述的药物组合物在制备治疗与酪氨酸激酶有关的疾病的药物中的用途；所述疾病优选肿瘤，更优选为非小细胞肺癌、肝癌、胃肠道基质肿瘤或肾癌。
PCT/CN2016/070136 2015-01-07 2016-01-05 一种酪氨酸激酶抑制剂的苹果酸盐的结晶形式及其制备方法 WO2016110243A1 (zh)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN201680000679.1A CN106029664A (zh) 2015-01-07 2016-01-05 一种酪氨酸激酶抑制剂的苹果酸盐的结晶形式及其制备方法

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN201510007973.2 2015-01-07
CN201510007973 2015-01-07

Publications (1)

Publication Number Publication Date
WO2016110243A1 true WO2016110243A1 (zh) 2016-07-14

Family

ID=56355527

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2016/070136 WO2016110243A1 (zh) 2015-01-07 2016-01-05 一种酪氨酸激酶抑制剂的苹果酸盐的结晶形式及其制备方法

Country Status (2)

Country Link
CN (1) CN106029664A (zh)
WO (1) WO2016110243A1 (zh)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN107629048A (zh) * 2016-07-18 2018-01-26 江苏恒瑞医药股份有限公司 一种酪氨酸激酶抑制剂的苹果酸盐的结晶形式及其制备方法
WO2020177678A1 (zh) * 2019-03-04 2020-09-10 江苏恒瑞医药股份有限公司 多靶点酪氨酸激酶抑制剂与egfr抑制剂联合在制备治疗肿瘤的药物中的用途

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101007815A (zh) * 2006-01-27 2007-08-01 上海恒瑞医药有限公司 吡咯并六元杂环化合物及其在医药上的用途

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101007815A (zh) * 2006-01-27 2007-08-01 上海恒瑞医药有限公司 吡咯并六元杂环化合物及其在医药上的用途

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN107629048A (zh) * 2016-07-18 2018-01-26 江苏恒瑞医药股份有限公司 一种酪氨酸激酶抑制剂的苹果酸盐的结晶形式及其制备方法
CN107629048B (zh) * 2016-07-18 2020-10-20 江苏恒瑞医药股份有限公司 一种酪氨酸激酶抑制剂的苹果酸盐的结晶形式及其制备方法
WO2020177678A1 (zh) * 2019-03-04 2020-09-10 江苏恒瑞医药股份有限公司 多靶点酪氨酸激酶抑制剂与egfr抑制剂联合在制备治疗肿瘤的药物中的用途
CN113301895A (zh) * 2019-03-04 2021-08-24 江苏恒瑞医药股份有限公司 多靶点酪氨酸激酶抑制剂与egfr抑制剂联合在制备治疗肿瘤的药物中的用途
CN113301895B (zh) * 2019-03-04 2023-04-04 江苏恒瑞医药股份有限公司 多靶点酪氨酸激酶抑制剂与egfr抑制剂联合在制备治疗肿瘤的药物中的用途

Also Published As

Publication number Publication date
CN106029664A (zh) 2016-10-12

Similar Documents

Publication Publication Date Title
TWI576343B (zh) ５－氯－ｎ２－（２－異丙氧基－５－甲基－４－六氫吡啶－４－基－苯基）－ｎ４－［２－（丙烷－２－磺醯基）－苯基］－嘧啶－２，４－二胺之結晶型式
TWI597277B (zh) 一種酪胺酸激酶抑制劑的二馬來酸鹽的第ｉ型結晶及製備方法
WO2016124067A1 (zh) 一种周期素依赖性蛋白激酶抑制剂的羟乙基磺酸盐、其结晶形式及制备方法
KR102516745B1 (ko) Ｃ-Ｍｅｔ 억제제의 결정질 유리 염기 또는 이의 결정질 산 염, 및 이들의 제조방법 및 용도
TWI745289B (zh) 一種週期素依賴性蛋白激酶抑制劑的結晶形式及其製備方法
JP6937322B2 (ja) 置換ピペリジン化合物の塩
WO2017152707A1 (zh) 吡啶胺基嘧啶衍生物甲磺酸盐的结晶形式及其制备和应用
WO2011023146A1 (en) Imatinib mesylate polymorphs generated by crystallization in aqueous inorganic salt solutions
WO2018006870A1 (zh) Galunisertib的晶型及其制备方法和用途
WO2017063572A1 (zh) 细胞凋亡诱导剂的新晶型及其制备方法
US9453011B2 (en) Crystal form of dabrafenib mesylate and preparation method thereof
WO2016110243A1 (zh) 一种酪氨酸激酶抑制剂的苹果酸盐的结晶形式及其制备方法
WO2020244612A1 (zh) Cdk9抑制剂的多晶型物及其制法和用途
WO2018072742A1 (zh) 一种咪唑并异吲哚类衍生物的游离碱的结晶形式及其制备方法
WO2016131406A1 (zh) 一种口服丝裂原活化蛋白激酶抑制剂的晶型及其制备方法
WO2018214877A1 (zh) 一种地佐辛晶型及其制备方法
WO2019080865A1 (zh) 一种炔基吡啶类脯氨酰羟化酶抑制剂的晶型及其制备方法
WO2016004873A1 (zh) 烟酰胺类衍生物的甲磺酸盐a晶型及其制备方法和应用
WO2016050134A1 (zh) 一种钠-葡萄糖协同转运蛋白2抑制剂的l-脯氨酸复合物、其一水合物及晶体
US10544129B2 (en) Crystalline forms of AP26113, and preparation method thereof
CN107629048B (zh) 一种酪氨酸激酶抑制剂的苹果酸盐的结晶形式及其制备方法
WO2017076358A1 (zh) 咪唑基联苯基化合物盐的新晶型及其制备方法
WO2018157741A1 (zh) Sb-939的盐的晶型及其制备方法和用途
WO2019011316A1 (zh) 一种btk激酶抑制剂的结晶形式及制备方法
WO2017016512A1 (zh) 马赛替尼甲磺酸盐的新晶型及其制备方法

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 16734903

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 16734903

Country of ref document: EP

Kind code of ref document: A1