WO2019029477A1 - 一种酪氨酸激酶抑制剂的二马来酸盐的晶型及其制备方法 - Google Patents

一种酪氨酸激酶抑制剂的二马来酸盐的晶型及其制备方法 Download PDF

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WO2019029477A1
WO2019029477A1 PCT/CN2018/098950 CN2018098950W WO2019029477A1 WO 2019029477 A1 WO2019029477 A1 WO 2019029477A1 CN 2018098950 W CN2018098950 W CN 2018098950W WO 2019029477 A1 WO2019029477 A1 WO 2019029477A1
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solvent
crystal form
crystallization
angle
formula
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PCT/CN2018/098950
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French (fr)
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曹笑立
王立坤
杜振兴
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江苏恒瑞医药股份有限公司
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Priority to CN201880004384.0A priority Critical patent/CN109963846A/zh
Publication of WO2019029477A1 publication Critical patent/WO2019029477A1/zh

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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
    • A61K31/435—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
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4709—Non-condensed quinolines and containing further heterocyclic rings
    • 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
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings

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  • the present invention relates to a crystalline form of a dimaleate salt of a tyrosine kinase inhibitor and a process for the preparation thereof.
  • Tyrosine kinase inhibitors have been on the market since 2001 and have become a new class of anticancer drugs.
  • Epidermal growth factor receptor is a member of the receptor tyrosine kinase family. Epidermal growth factor receptor pathway plays a very important role in tumorigenesis and development, and has become the most important research in the field of cancer therapy. One of the development targets. Such drugs already on the market include erlotinib, gefitinib and lapatinib (Tykerb, GW572016).
  • WO2011029265A1 Publication Day 2011.03.17 discloses an epidermal growth factor receptor (EGFR) inhibitor having the chemical name (R, E)-N-(4-(3-chloro-4-(pyridin-2-yl) Methoxy)phenylamino)-3-cyano-7-ethoxyquinolin-6-yl)-3-(1-methylpyrrolidin-2-yl)acrylamide, the drug molecule has obvious
  • EGFR epidermal growth factor receptor
  • WO2014008794A1 discloses a crystalline form I of a dimaleate salt of the compound of the formula (II), the structure of which is as shown in the formula (I):
  • the crystal structure of the pharmaceutically active ingredient often affects the chemical and physical stability of the drug, and the difference in crystallization conditions and storage conditions may cause changes in the crystal structure of the compound, sometimes accompanied by the formation of other forms of crystal form.
  • amorphous pharmaceutical products have no regular crystal structure and often have other defects, such as poor product stability, difficulty in filtration, easy agglomeration, and poor fluidity. Therefore, on the basis of the I crystal form, we have found the IV crystal form.
  • the technical problem to be solved by the present invention is to provide a (R,E)-N-(4-(3-chloro-4-(pyridin-2-ylmethoxy)phenylamino)-3-cyano-7 Form IV of ethoxylated quinolin-6-yl)-3-(1-methylpyrrolidin-2-yl)acrylamide dimaleate (as shown in formula (I)) and preparation thereof Method, the crystal form has good stability.
  • the present invention provides an IV crystal form of a compound of the formula (I), characterized in that an X-ray powder diffraction pattern represented by a diffraction angle 2 ⁇ angle is obtained using Cu-K ⁇ radiation, which is at 6.2, 6.4, 9.0, 10.3, 11.4, 18.1, 19.1, 20.8, 22.0, 23.6, and 25.1 have characteristic peaks, and the error range may be ⁇ 0.3, ⁇ 0.2, or ⁇ 0.1.
  • the IV crystal form has characteristic peaks at 6.2, 6.4, 9.0, 10.3, 11.4, 12.5, 18.1, 19.1, 20.8, 22.0, 23.6, 24.3, 25.1, 25.7, 26.9, 27.7, and the error range may be ⁇ 0.3. ⁇ 0.2 or ⁇ 0.1.
  • the IV crystal forms are 6.21, 6.45, 9.02, 9.84, 10.26, 11.41, 12.50, 16.16, 16.66, 18.10, 19.14, 20.76, 22.03, 22.60, 23.58, 24.27, 25.14, 25.71, 26.92, 27.69, 29.41 and There are characteristic peaks at 31.56, and the error range can be ⁇ 0.3, ⁇ 0.2 or ⁇ 0.1.
  • the invention also provides a method of preparing an IV crystal form, characterized in that the method is selected from the group consisting of:
  • the good solvent is selected from an alcohol solvent, the alcohol solvent It is selected from the group consisting of methanol, ethanol or isopropanol, the anti-solvent is selected from the group consisting of ether solvents, and the ether solvent is selected from 1,4-dioxane;
  • the crystallization method is selected from room temperature crystallization, cooling analysis Crystallization, crystallization of volatile solvent or addition of seed crystals to induce crystallization;
  • the compound of the formula (I) is added to a solvent, beaten, filtered, and dried to obtain a target crystal form IV;
  • the solvent is selected from a mixed solvent of an alcohol and an ether, and the alcohol solvent is preferably methanol. Ethanol or isopropanol, and the ether solvent is preferably 1,4-dioxane.
  • the invention further relates to a pharmaceutical composition of Form IV which consists of Form IV and a pharmaceutically acceptable carrier, diluent or excipient.
  • the invention further relates to the use of a pharmaceutical composition of Form IV, Form IV, in the manufacture of a medicament for the treatment and/or prophylaxis of a disease or condition associated with a protein kinase selected from the group consisting of an EGFR receptor tyrosine kinase or A HER-2 receptor tyrosine kinase, the disease or condition being selected from the group consisting of cancer, preferably lung cancer, breast cancer, epidermal squamous cell carcinoma or gastric cancer.
  • a protein kinase selected from the group consisting of an EGFR receptor tyrosine kinase or A HER-2 receptor tyrosine kinase
  • cancer preferably lung cancer, breast cancer, epidermal squamous cell carcinoma or gastric cancer.
  • the IV crystal form of the obtained compound of the formula (I) was subjected to structure measurement and crystal form study by X-ray powder diffraction pattern (XRPD) and differential scanning calorimetry (DSC).
  • XRPD X-ray powder diffraction pattern
  • DSC differential scanning calorimetry
  • the method of crystal recrystallization is not particularly limited and can be carried out by a usual recrystallization operation method.
  • the compound of the formula (I) can be dissolved in an organic solvent and then added to an anti-solvent to crystallize. After the crystallization is completed, it can be dried by filtration to obtain a desired crystal.
  • the method for crystallization of the present invention comprises room temperature crystallization, cooling crystallization, crystallization of a volatile solvent, seed crystal induced crystallization, etc., and the cooling temperature is selected from the group consisting of 40 ° C or lower, preferably -10 ° C to 40 ° C. It can also be stirred during the crystallization process.
  • the starting material used in the method for preparing a crystal form of the present invention may be any compound of the formula (I), and the specific forms include, but are not limited to, amorphous, arbitrary crystal forms and the like.
  • halogen or halogen atom as used in the present invention means a fluorine atom, a chlorine atom, a bromine atom, an iodine atom or the like.
  • C 1-6 alkyl group of the present invention means a linear or branched alkyl group having 1 to 6 carbon atoms, and specific examples include, but are not limited to, methyl, ethyl, n-propyl, isopropyl.
  • n-butyl isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, 2-methylbutyl, neopentyl, 1-ethylpropyl, n-hexyl, isohexyl, 3 -methylpentyl, 2-methylpentyl, 1-methylpentyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl, 2-ethylbutyl, 1,2-dimethylpropyl, and the like.
  • the "alcohol solvent” as used in the present invention means a group derived from one or more "hydroxyl groups” substituted with one or more hydrogen atoms on a "C 1-6 alkyl group", said “C 1-6 alkane”
  • the bases are as defined above, and specific examples include, but are not limited to, methanol, ethanol, isopropanol, n-propanol, n-butanol, isoamyl alcohol or trifluoroethanol.
  • ether solvent means a chain compound or a cyclic compound having an ether bond -O- and having 1 to 10 carbon atoms, and specific examples include, but are not limited to, tetrahydrofuran, diethyl ether, and propylene glycol methyl ether. , methyl tert-butyl ether or 1,4-dioxane.
  • the "anti-solvent" as used in the present invention means that the solubility to a molecule (or a solute) is low, poor or insoluble; by using a good solvent in combination with an anti-solvent, the solubility of the crystal to be crystallized in the solvent is lowered; The solvent combines with the good solvent to reduce the solubility of the molecule (or solute), thereby precipitating the molecule (or solute) to form a solid phase, then filtering out the solid from the liquid phase, and then separating the two solvents to obtain the target crystal. Things.
  • the “differential scanning calorimetry or DSC” described in the present invention refers to measuring the temperature difference and the heat flow difference between the sample and the reference during the temperature rise or constant temperature of the sample to characterize all physical changes and chemistry related to the thermal effect. Change to get the phase change information of the sample.
  • the "2 ⁇ or 2 ⁇ angle" as used in the present invention means a diffraction angle, ⁇ is a Bragg angle, and the unit is ° or degree, and the error range of 2 ⁇ is ⁇ 0.1 to ⁇ 0.5, preferably ⁇ 0.1 to ⁇ 0.3, more preferably ⁇ 0.2.
  • the "plane spacing or interplanar spacing (d value)" means that the spatial lattice selects three unit vectors a, b, c which are not parallel to each other and adjacent two lattice points, and they point the points.
  • the parallelepiped unit which is divided into juxtapositions, is called the interplanar spacing.
  • the spatial lattice is divided according to the determined parallelepiped unit lines, and a set of linear grids is obtained, which is called a space lattice or a lattice.
  • the lattice and the lattice reflect the periodicity of the crystal structure by geometric points and lines, respectively, and the interplanar spacing (ie, the distance between two adjacent parallel crystal planes) is different; Or ang.
  • the invention further relates to a pharmaceutical composition
  • a pharmaceutical composition comprising an IV crystalline form of a compound of formula (I), and optionally one or more pharmaceutically acceptable carriers and/or diluents.
  • the pharmaceutical composition can be formulated into any of the pharmaceutically acceptable dosage forms.
  • the IV crystal form or pharmaceutical preparation of the compound of the formula (I) of the present invention can be formulated into tablets, capsules, pills, granules, solutions, suspensions, syrups, injections (including injections, Sterile powder for injection and concentrated solution for injection), suppository, inhalation or spray.
  • the pharmaceutical compositions of the present invention may also be administered to a patient or subject in need of such treatment by any suitable mode of administration, such as oral, parenteral, rectal, pulmonary or topical administration.
  • the pharmaceutical composition can be formulated into an oral preparation, such as an oral solid preparation such as a tablet, a capsule, a pill, a granule, or the like; or an oral liquid preparation such as an oral solution or an oral mixture. Suspension, syrup, and the like.
  • the pharmaceutical preparation may further contain a suitable filler, binder, disintegrant, lubricant, and the like.
  • the pharmaceutical preparation When used for parenteral administration, the pharmaceutical preparation can be prepared as an injection, including an injection, a sterile powder for injection, and a concentrated solution for injection.
  • the pharmaceutical composition When formulated as an injection, the pharmaceutical composition can be produced by a conventional method in the existing pharmaceutical field.
  • an additional agent may be added to the pharmaceutical preparation, and a suitable additional agent may be added depending on the nature of the drug.
  • the pharmaceutical preparation When used for rectal administration, can be formulated into a suppository or the like.
  • the pharmaceutical preparation For pulmonary administration, the pharmaceutical preparation can be formulated as an inhalant or a spray.
  • the Form IV of the compound of Formula (I) of the present invention is present in a pharmaceutical composition or medicament in a therapeutically and/or prophylactically effective amount.
  • the Form IV of the compound of Formula (I) of the present invention is present in a pharmaceutical composition or drug in unit dosage form.
  • a compound of formula (I) according to the invention for the manufacture of a medicament for the treatment of a disease or condition associated with a protein kinase.
  • the present application also relates to the use of the IV crystal form of the compound of the formula (I) of the present invention for the preparation of a medicament for use in a medicament for the treatment of a disease associated with protein kinases.
  • the present application relates to a method of inhibiting a protein kinase-associated disease comprising administering to a subject in need thereof a therapeutically and/or prophylactically effective amount of an IV crystalline form of a compound of the formula (I) according to the invention, Or a pharmaceutical composition of the invention.
  • the disease is cancer, preferably a lung cancer, breast cancer, epidermal squamous cell carcinoma or gastric cancer.
  • the IV crystal form of the compound of the formula (I) prepared by the present invention has good solubility and high purity, and the crystal form is not changed by XRPD under high temperature, high humidity and light conditions, and the crystal form is stable.
  • the invention has good IV; the IV crystal form of the compound of the formula (I) obtained by the technical scheme of the invention can meet the medicinal requirements for production transportation and storage, the production process is stable, reproducible and controllable, and can be adapted to industrial production.
  • Figure 1 is an XRPD pattern of the crystalline form of Compound IV of formula (I).
  • Figure 2 is a DSC chart of the crystalline form of Compound IV of formula (I).
  • the compound of the formula (I) (dimaleate) is prepared by the method of the patent application WO2014008794A1 (publication date 2014.01.16).

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Abstract

本发明涉及一种酪氨酸激酶抑制剂的二马来酸盐的晶型及其制备方法。具体而言，本发明涉及一种表皮生长因子受体(EGFR)抑制剂的二马来酸盐的Ⅳ晶型及其制备方法。该Ⅳ晶型具备良好的化学稳定性和晶型稳定性，可更好地用于临床治疗。

Description

一种酪氨酸激酶抑制剂的二马来酸盐的晶型及其制备方法 技术领域
本发明涉及酪氨酸激酶抑制剂的二马来酸盐的晶型及其制备方法。
背景技术
研究表明，超过50％的原癌基因和癌基因产物都具有酪氨酸激酶活性，它们的异常表达将导致肿瘤发生。酪氨酸激酶抑制剂从2001年开始上市，已成为异军突起的一类新型抗癌药。
表皮生长因子受体(EGFR)是受体酪氨酸激酶家族的一员，表皮生长因子受体通路在肿瘤发生、发展过程中起非常重要的作用，目前已成为肿瘤治疗领域最主要的研究和开发靶点之一。现已经上市的此类药物有埃罗替尼(erlotinib)、吉非替尼(gefitinib)和拉帕替尼(lapatinb,Tykerb，GW572016)。
WO2011029265A1(公开日2011.03.17)公开一种表皮生长因子受体(EGFR)抑制剂，其化学名为(R,E)-N-(4-(3-氯-4-(吡啶-2-基甲氧基)苯基氨基)-3-氰基-7-乙氧基喹啉-6-基)-3-(1-甲基吡咯烷基-2-基)丙烯酰胺，该药物分子具有明显的药代、药效优势，结构如式(II)所示：
Figure PCTCN2018098950-appb-000001
WO2014008794A1(公开日2014.01.16)公开式(II)所示化合物的二马来酸盐的I晶型，该盐的结构如式(I)所示：
Figure PCTCN2018098950-appb-000002
作为药用活性成分的晶型结构往往影响到该药物的化学和物理稳定性，结晶条件及储存条件的不同有可能导致化合物的晶体结构的变化，有时还会伴随着产生其他形态的晶型。一般来说，无定形的药物产品没有规则的晶体结构，往往具有其它缺陷，比如产物稳定性较差，过滤较难，易结块，流动性差等。因此，在I晶型的基础上我们又发现了Ⅳ晶型。
发明内容
本发明要解决的技术问题是提供一种(R,E)-N-(4-(3-氯-4-(吡啶-2-基甲氧基)苯基氨基)-3-氰基-7-乙氧基喹啉-6-基)-3-(1-甲基吡咯烷基-2-基)丙烯酰胺二马来酸盐(如式(I)所示)的Ⅳ晶型及其制备方法，该晶型具备良好的稳定性。
本发明的技术方案如下：
本发明提供一种式(I)所示化合物的Ⅳ晶型，其特征在于：使用Cu-Kα辐射，得到以衍射角2θ角度表示的X-射线粉末衍射图谱，其在6.2、6.4、9.0、10.3、11.4、18.1、19.1、20.8、22.0、23.6和25.1处有特征峰，误差范围可以是±0.3、±0.2或±0.1，
Figure PCTCN2018098950-appb-000003
优选的，Ⅳ晶型在6.2、6.4、9.0、10.3、11.4、12.5、18.1、19.1、20.8、22.0、23.6、24.3、25.1、25.7、26.9、27.7处有特征峰，误差范围可以是±0.3、±0.2或±0.1。
更优选的，Ⅳ晶型在6.21、6.45、9.02、9.84、10.26、11.41、12.50、16.16、16.66、18.10、19.14、20.76、22.03、22.60、23.58、24.27、25.14、25.71、26.92、27.69、29.41和31.56处有特征峰，误差范围可以是±0.3、±0.2或±0.1。
本发明还提供一种制备Ⅳ晶型的方法，其特征在于，所述方法选自：
(1)将式(I)所示化合物溶解于良溶剂中，加入反溶剂，析晶，过滤，干燥后即得目标Ⅳ晶型；所述良溶剂选自醇类溶剂，所述醇类溶剂选自甲醇、乙醇或异丙 醇，所述反溶剂选自醚类溶剂，所述醚类溶剂选自1,4-二氧六环；所述析晶的方法选自室温析晶、冷却析晶、挥发溶剂析晶或加入晶种诱导析晶；
(2)将式(I)所示化合物加入溶剂中，打浆，过滤，干燥后即得目标Ⅳ晶型；所述溶剂选自醇类与醚类的混合溶剂，所述醇类溶剂优选甲醇、乙醇或异丙醇，所述醚类溶剂优选1,4-二氧六环。
本发明还涉及Ⅳ晶型的药物组合物，所述药物组合物由Ⅳ晶型与药学上可接受的载体、稀释剂或赋形剂组成。
本发明还涉及Ⅳ晶型、Ⅳ晶型的药物组合物在制备治疗和/或预防与蛋白质激酶有关的疾病或病症的药物中的用途，所述蛋白质激酶选自EGFR受体酪氨酸激酶或HER-2受体酪氨酸激酶，所述疾病或病症选自癌症，所述癌症优选肺癌、乳腺癌、表皮鳞癌或胃癌。
通过X-射线粉末衍射图谱(XRPD)、差示扫描量热分析(DSC)对所得到式(I)所示化合物的Ⅳ晶型进行结构测定、晶型研究。
晶型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中溶解后加入反溶剂析晶，结晶完成后，经过滤干燥，即可得到所需要的结晶。
本发明析晶的方法有室温析晶、冷却析晶、挥发溶剂析晶、加入晶种诱导析晶等，所述冷却的温度选自40℃以下，优选-10℃至40℃，所述析晶过程中还可以搅拌。
本发明晶型制备方法中所用的起始原料可以是任意形式的式(I)所示化合物，具体形式包括但不限于：无定型、任意晶型等。
发明详述
在本申请的说明书和权利要求书中，除非另有说明，否则本文中使用的科学和技术名词具有本领域技术人员所通常理解的含义。然而，为了更好地理解本发明，下面提供了部分相关术语的定义和解释。另外，当本申请所提供的术语的定义和解释与本领域技术人员所通常理解的含义不一致时，以本申请所提供的术语的定义和解释为准。
本发明所述“卤素或卤素原子”是指氟原子、氯原子、溴原子、碘原子等。
本发明所述“C 1-6烷基”表示直链或支链的含有1-6个碳原子的烷基，具体实例包括但不限于：甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔 丁基、正戊基、异戊基、2-甲基丁基、新戊基、1-乙基丙基、正己基、异己基、3-甲基戊基、2-甲基戊基、1-甲基戊基、3,3-二甲基丁基、2,2-二甲基丁基、1,1-二甲基丁基、1,2-二甲基丁基、1,3-二甲基丁基、2,3-二甲基丁基、2-乙基丁基、1,2-二甲基丙基等。
本发明所述的“醇类溶剂”是指一个或多个“羟基”取代“C 1-6烷基”上的一个或多个氢原子所衍生的基团，所述“C 1-6烷基”如前文所定义，具体实例包括但不限于：甲醇、乙醇、异丙醇、正丙醇、正丁醇、异戊醇或三氟乙醇。
本发明所述的“醚类溶剂”是指含有醚键-O-且碳原子数为1至10个的链状化合物或环状化合物，具体实例包括但不限于：四氢呋喃、乙醚、丙二醇甲醚、甲基叔丁基醚或1,4-二氧六环。
本发明所述的“反溶剂”是指对分子(或溶质)的溶解能力低、差或不溶；通过将良溶剂与反溶剂结合使用，从而降低待结晶物在溶剂中的溶解性；由于反溶剂与良溶剂结合，降低了分子(或溶质)的溶解性，从而使分子(或溶质)析出形成固相，然后从液相中过滤出固体，再分离两种溶剂，即可得到目标的结晶物。
本发明所述的“X-射线粉末衍射图谱或XRPD”是指根据布拉格公式2d sinθ＝nλ(式中，λ为X射线的波长，
Figure PCTCN2018098950-appb-000004
衍射的级数n为任何正整数，一般取一级衍射峰，n＝1)，当X射线以掠角θ(入射角的余角，又称为布拉格角)入射到晶体或部分晶体样品的某一具有d点阵平面间距的原子面上时，就能满足布拉格方程，从而测得了这组X射线粉末衍射图。
本发明所述的“差示扫描量热分析或DSC”是指在样品升温或恒温过程中，测量样品与参考物之间的温度差、热流差，以表征所有与热效应有关的物理变化和化学变化，得到样品的相变信息。
本发明所述的“2θ或2θ角度”是指衍射角，θ为布拉格角，单位为°或度，2θ的误差范围为±0.1～±0.5，优选±0.1～±0.3，更优选±0.2。
本发明所述的“晶面间距或晶面间距(d值)”是指空间点阵选择3个不相平行的连结相邻两个点阵点的单位矢量a，b，c，它们将点阵划分成并置的平行六面体单位，称为晶面间距。空间点阵按照确定的平行六面体单位连线划分，获得一套直线网格，称为空间格子或晶格。点阵和晶格是分别用几何的点和线反映晶体结构的周期性，不同的晶面，其面间距(即相邻的两个平行晶面之间的距离)各不相同；单位为
Figure PCTCN2018098950-appb-000005
或埃。
本发明还涉及，包括式(I)所示的化合物的Ⅳ晶型，以及任选的一种或多种药用载体和/或稀释剂的药物组合物。所述药物组合物可以制成药学上可接受的任一剂型。例如，本发明的式(I)所示的化合物的Ⅳ晶型或药物制剂可以配制为片剂、胶囊剂、丸剂、颗粒剂、溶液剂、混悬剂、糖浆剂、注射剂(包括注射液、注射用无菌粉末与注射用浓溶液)、栓剂、吸入剂或喷雾剂。
此外，本发明所述药物组合物还可以以任何合适的给药方式，例如口服、肠胃外、直肠、经肺或局部给药等方式施用于需要这种治疗的患者或受试者。当用于口服给药时，所述药物组合物可制成口服制剂，例如口服固体制剂，如片剂、胶囊剂、丸剂、颗粒剂等；或，口服液体制剂，如口服溶液剂、口服混悬剂、糖浆剂等。当制成口服制剂时，所述药物制剂还可包含适宜的填充剂、粘合剂、崩解剂、润滑剂等。当用于肠胃外给药时，所述药物制剂可制成注射剂，包括注射液、注射用无菌粉末与注射用浓溶液。当制成注射剂时，所述药物组合物可采用现有制药领域中的常规方法来进行生产。当配制注射剂时，所述药物制剂中可以不加入附加剂，也可根据药物的性质加入适宜的附加剂。当用于直肠给药时，所述药物制剂可制成栓剂等。用于经肺给药时，所述药物制剂可制成吸入剂或喷雾剂等。在某些优选的实施方案中，本发明的式(I)所示的化合物的Ⅳ晶型以治疗和/或预防有效量存在于药物组合物或药物中。在某些优选的实施方案中，本发明式(I)所示的化合物的Ⅳ晶型以单位剂量的形式存在于药物组合物或药物中。
本发明式(I)化合物、其Ⅳ晶型可用于制备治疗与蛋白质激酶有关的疾病或病症的药物中的用途。因此，本申请还涉及，本发明式(I)化合物的Ⅳ晶型用于制备药物的用途，所述药物用于治疗与蛋白质激酶有关的疾病的药物中的用途。此外，本申请还涉及，一种抑制与蛋白质激酶有关的疾病的方法，其包括给有此需要的受试者施用治疗和/或预防有效量的本发明式(I)化合物的Ⅳ晶型，或者本发明的药物组合物。
在某些优选的实施方案中，所述疾病为癌症，所述癌症优选肺癌、乳腺癌、表皮鳞癌或胃癌。
发明的有益效果
与现有技术相比，本发明的技术方案具有以下优点：
经研究表明，本发明制备的式(I)所示化合物的Ⅳ晶型溶解性良好、纯度较 高，在高温、高湿、光照的条件下晶型经XRPD检测均未发生改变、晶型稳定性良好；本发明技术方案得到的式(I)所示化合物的Ⅳ晶型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为式(I)所示化合物Ⅳ晶型的XRPD图谱。
图2为式(I)所示化合物Ⅳ晶型的DSC图谱。
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、差示扫描量热仪(Differential Scanning Calorimeter,DSC)
仪器型号：Mettler Toledo DSC 3 +STAR e System
吹扫气：氮气
升温速率：10.0℃/min
温度范围：25-350
2、X-射线衍射谱(X-ray Powder Diffraction,XRPD)
仪器型号：Bruker D8Discover A25X-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：10-48°
电压：40KV，电流：40mA
式(II)所示化合物(游离态)参照专利申请WO2011029265A1(公开日2011.03.17)中的方法制备；
式(I)所示化合物(二马来酸盐)参照专利申请WO2014008794A1(公开日2014.01.16)中的方法制备。
实施例1、Ⅳ晶型的制备
取(R,E)-N-(4-(3-氯-4-(吡啶-2-基甲氧基)苯基氨基)-3-氰基-7-乙氧基喹啉-6-基)-3-(1-甲基吡咯烷基-2-基)丙烯酰胺二马来酸盐(0.5g)加入到反应瓶中，加入甲醇 (5mL)搅拌使溶解，所得溶液体系在搅拌下缓慢加入1,4-二氧六环，直至有大量混浊出现，持续搅拌5h后收集滤饼，真空干燥，得到产物，产率为91％。该结晶样品的X-射线粉末衍射谱图(XRPD图谱)见图1、DSC谱图见图2，在约127.7℃有尖锐熔融吸热峰，将此晶型定义为Ⅳ晶型，其2θ特征峰位置如下表所示：
表1、Ⅳ晶型特征峰
Figure PCTCN2018098950-appb-000006
Figure PCTCN2018098950-appb-000007
实施例2、Ⅳ晶型的制备
取(R,E)-N-(4-(3-氯-4-(吡啶-2-基甲氧基)苯基氨基)-3-氰基-7-乙氧基喹啉-6-基)-3-(1-甲基吡咯烷基-2-基)丙烯酰胺二马来酸盐(20mg)加入到反应瓶中，加入甲醇和1,4-二氧六环的混合溶剂(v/v＝1:1，200μL)，加热至50℃，打浆搅拌72h，收集滤饼，真空干燥，得到产物，产率为93％，该产物经X-射线粉末衍射检测确定为Ⅳ晶型。

Claims (7)

  1. 式(I)所示化合物的Ⅳ晶型，其特征在于：使用Cu-Kα辐射，得到以衍射角2θ角度表示的X-射线粉末衍射图谱，其在6.2、6.4、9.0、10.3、11.4、18.1、19.1、20.8、22.0、23.6和25.1处有特征峰，
    Figure PCTCN2018098950-appb-100001
  2. 如权利要求1所述的Ⅳ晶型，其特征在于，使用Cu-Kα辐射，得到以衍射角2θ角度表示的X-射线粉末衍射图谱，其在6.2、6.4、9.0、10.3、11.4、12.5、18.1、19.1、20.8、22.0、23.6、24.3、25.1、25.7、26.9和27.7处有特征峰。
  3. 如权利要求1所述的Ⅳ晶型，其特征在于，使用Cu-Kα辐射，得到以衍射角2θ角度表示的X-射线粉末衍射图谱，其在6.21、6.45、9.02、9.84、10.26、11.41、12.50、15.62、16.16、16.66、17.62、18.10、19.14、20.76、21.39、22.03、22.60、23.58、24.27、25.14、25.71、26.92、27.69、29.41和31.56处有特征峰。
  4. 根据权利要求1-3中任一项所述的Ⅳ晶型，其中所述2θ角误差范围为±0.20。
  5. 一种制备如权利要求1-4中任一项所述Ⅳ晶型的方法，其特征在于，所述方法选自：
    (1)将式(I)所示化合物溶解于良溶剂中，加入反溶剂，析晶，过滤，干燥后即得目标Ⅳ晶型；所述良溶剂选自醇类溶剂，所述醇类溶剂选自甲醇、乙醇或异丙醇，所述反溶剂选自醚类溶剂，所述醚类溶剂选自1,4-二氧六环；所述析晶的方法选自室温析晶、冷却析晶、挥发溶剂析晶或加入晶种诱导析晶；
    (2)将式(I)所示化合物加入溶剂中，打浆，过滤，干燥后即得目标Ⅳ晶型；所述溶剂选自醇类与醚类的混合溶剂，所述醇类溶剂优选甲醇、乙醇或异丙醇，所述醚类溶剂优选1,4-二氧六环。
  6. 一种药物组合物，所述药物组合物由权利要求1-4中任一项所述的Ⅳ晶型与药学上可接受的载体、稀释剂或赋形剂组成。
  7. 权利要求1-4任一项所述的Ⅳ晶型、权利要求5所述的药物组合物在制备治疗和/或预防与蛋白质激酶有关的疾病或病症的药物中的用途，所述蛋白质激酶选自EGFR受体酪氨酸激酶或HER-2受体酪氨酸激酶，所述疾病或病症选自癌症，所述癌症优选肺癌、乳腺癌、表皮鳞癌或胃癌。
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